JP2774417B2 - Branched-chain saccharide complex having peptide skeleton and fine particle carrier - Google Patents
Branched-chain saccharide complex having peptide skeleton and fine particle carrierInfo
- Publication number
- JP2774417B2 JP2774417B2 JP4232879A JP23287992A JP2774417B2 JP 2774417 B2 JP2774417 B2 JP 2774417B2 JP 4232879 A JP4232879 A JP 4232879A JP 23287992 A JP23287992 A JP 23287992A JP 2774417 B2 JP2774417 B2 JP 2774417B2
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
【０００１】[0001]
【産業上の利用分野】本発明は、ペプチド骨格を有する
新規な物質である分枝鎖型糖複合体及び該複合体を原材
料として使用した微粒子キャリヤーに関する。この微粒
子キャリヤーは優れた臓器指向性を有する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a branched saccharide complex which is a novel substance having a peptide skeleton and a fine particle carrier using the conjugate as a raw material. This fine particle carrier has excellent organ directivity.
【０００２】[0002]
【従来の技術】生体に投与された薬物を必要な組織に必
要な時に必要な量だけ送達し、有効な薬物治療を行なう
ドラッグデリバリーシステムの１つの手段として、リポ
ソームやリピッドマイクロスフェアーなどの微粒子キャ
リヤーを利用することは一般にすでに公知である。しか
しながら、これら微粒子キャリヤーが血管内に投与され
た場合には、肝臓、ひ臓等に代表される細網内皮系に捕
捉され易く、従って薬物放出をコントロールする徐放性
製剤や標的組織への薬物送達を目指すターゲティング型
製剤への利用においてはなお問題があることもよく知ら
れているところである。2. Description of the Related Art As one means of a drug delivery system for delivering a drug administered to a living body to a required tissue in a required amount at a required time and performing an effective drug treatment, fine particles such as liposomes and lipid microspheres are used. The use of carriers is generally already known. However, when these fine particle carriers are administered intravascularly, they are easily trapped by the reticuloendothelial system represented by the liver, spleen, etc., and therefore, sustained-release preparations for controlling drug release and drug delivery to target tissues. It is also well known that there is still a problem in the application to targeting-type preparations aiming at.
【０００３】従来からリポソームの微小循環性の改善、
すなわちリポソームを末梢毛細血管に循環しやすくする
ための工夫については種々の試みがなされてきた。例え
ば、下記文献１）〜９）に示されるごとくである。[0003] Conventionally, the microcirculation of liposomes has been improved,
That is, various attempts have been made to make the liposome easier to circulate in the peripheral capillaries. For example, as shown in the following documents 1) to 9).
【０００４】 １） Biochem.Pharmacol.,32,609(1983) ２） Biochim.Biophys.Acta.,839,1(1985) ３） J.Pharmacol.Exp.Therap.,226,539(1983) ４） Biochim.Biophys.Acta.,981,27(1989) ５） 「第９回生体膜と薬物の相互作用シンポジウム講
演集」p.193(東京1986） ６） Chem.Pharm.Bull.,36,4187(1988) ７） Chem.Lett.,pp.1781(1988) ８） J.Appl.Biochem.,121-125(1982) ９） 「脳神経」39(8):783-788(1987) 文献１）及び２）にはリポソームにそれぞれコレステロ
ールおよび相転移温度の高い脂質を添加することが記載
されており、また文献３）にはリポソームのサイズを小
さくすることにより微小循環性を増加した例が示されて
いる。文献４）には細胞膜由来の糖脂質であるガングリ
オシドＧＭ1 を、また文献５）にはヒト赤血球由来の糖
蛋白質であるグリコホリンを、更に文献６）には血清蛋
白質であるフェツイン由来の糖蛋白質をそれぞれリポソ
ーム膜内に再構成したことが記載されており、４）及び
５）では微小循環性を改善したと述べられている。文献
７）にはプルランやアミロペクチン等の多糖体にコレス
テロール残基と共にシアル酸を結合してリポソーム膜成
分として使用したことが述べられている。文献８）及び
９）にはリポソーム膜にスルファチドを挿入してそれぞ
れ血液脳関門の通過及びヒトGlioma細胞への取込みに成
功したことが述べられている。1) Biochem. Pharmacol., 32,609 (1983) 2) Biochim. Biophys. Acta., 839, 1 (1985) 3) J. Pharmacol. Exp. Therap., 226, 539 (1983) 4) Biochim. Biophys. Acta., 981, 27 (1989) 5) "The 9th Symposium on Interaction between Biomembranes and Drugs" p.193 (Tokyo 1986) 6) Chem. Pharm. Bull., 36, 4187 (1988) 7) Chem. Lett., Pp. 1781 (1988) 8) J. Appl. Biochem., 121-125 (1982) 9) "Cranial nerve" 39 (8): 783-788 (1987) References 1) and 2) It is described that cholesterol and a lipid having a high phase transition temperature are added to each liposome, and Reference 3) shows an example in which microcirculation is increased by reducing the size of the liposome. Ganglioside GM 1 in the literature 4) derived glycolipid cell membrane, also glycophorin is a glycoprotein derived from human erythrocytes in the literature 5), a further glycoprotein derived fetuin, a serum protein in the literature 6) Each is described to be reconstituted in the liposome membrane, and it is stated in 4) and 5) that the microcirculation was improved. Reference 7) states that sialic acid was bound to a polysaccharide such as pullulan or amylopectin together with a cholesterol residue and used as a liposome membrane component. References 8) and 9) state that sulfatide was inserted into the liposome membrane and succeeded in crossing the blood brain barrier and incorporation into human Glioma cells, respectively.
【０００５】他方、臓器には固有の蛋白レクチンの存在
することが知られており、この蛋白は糖との結合サイト
を有し、しかも結合する糖の種類は臓器毎に異なること
から、糖を末端に持つリガンドに対するレセプターとし
て機能することが期待される。即ち、薬物運搬技術にお
いて特定の臓器の認識のための手がかりとなることが期
待される。[0005] On the other hand, it is known that organs have a specific protein lectin. This protein has a site for binding to sugar, and the type of sugar to be bound varies from organ to organ. It is expected to function as a receptor for the ligand at the end. In other words, it is expected that the drug delivery technique will be a key for recognition of a specific organ.
【０００６】レセプターとこれに対する糖を末端に持つ
リガンドとの関係については例えば下記文献10）〜12）
があり、また技術的な応用の例としては例えば下記文献
13）〜14）がある。The relationship between a receptor and a ligand having a sugar at the end thereof is described in, for example, the following references 10) to 12).
There are also examples of technical applications
13) to 14).
【０００７】 10） Biochemistry,23,4255-4261(1981) 11） 1989 Carbohydrate recognition in cellular ju
nction. Wiley,Chichester (Ciba Foundation Symposium 145)
p.80-95 12） Carbohydrate Research,198,235-246(1990) 13） 特開昭57-181095 14） 特開平2-288891 10）〜12）ではペプチドを骨格としてこれに糖を末端に
クラスター化した合成リガンドを用意し、これとレセプ
ターとの親和性から所謂クラスター効果の存在を認めて
いる。13）では合成リガンド、すなわち糖ペプチドに薬
物を結合し、薬物の選択的な運搬を意図する技術が示さ
れている。14）も同様な技術を開示しているが、特に糖
をトリス基に結合することによって糖密度を高める点に
特徴がある。[0007] 10) Biochemistry, 23, 4255-4261 (1981) 11) 1989 Carbohydrate recognition in cellular ju
nction. Wiley, Chichester (Ciba Foundation Symposium 145)
p.80-95 12) Carbohydrate Research, 198, 235-246 (1990) 13) JP-A-57-181095 14) JP-A-2-88891 10) to 12) in which a peptide was used as a skeleton and a sugar was clustered at the terminal. A synthetic ligand is prepared, and the affinity of the ligand with the receptor has confirmed the existence of a so-called cluster effect. 13) discloses a technique for binding a drug to a synthetic ligand, that is, a glycopeptide, and intending to selectively deliver the drug. 14) discloses a similar technique, but is characterized in that the sugar density is increased by binding the sugar to a tris group.
【０００８】[0008]
【発明が解決しようとする課題】本発明の目的は、微小
循環性が改善され、臓器指向性において顕著に優れた微
粒子キャリヤーを提供することにある。SUMMARY OF THE INVENTION An object of the present invention is to provide a fine particle carrier which has improved microcirculation and is remarkably excellent in organ directivity.
【０００９】[0009]
【課題を解決するための手段】本発明者は、上記課題を
解決すべく鋭意研究の結果、糖を末端にクラスター化し
た合成リガンドを微粒子キャリヤーに被覆し、これを薬
物運搬のための担体として使用すると顕著な臓器指向性
の示されることを見出し、換言すれば、合成リガンドを
微粒子キャリヤーに被覆するためには合成リガンドに適
切な化学修飾を加えることが必要であり、具体的にはペ
プチド骨格を有する分枝鎖型糖脂質複合体新規物質を得
て、かつこれを被覆した微粒子キャリヤーはこれを被覆
しない微粒子キャリヤーそれ自体とは異なり、優れた臓
器指向性を示すことを見出し、本発明を完成するに至っ
た。Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have coated a fine particle carrier with a synthetic ligand in which a sugar is clustered at the terminal, and used this as a carrier for drug delivery. It has been found that when used, it exhibits remarkable organ tropism, in other words, in order to coat the synthetic ligand on the fine particle carrier, it is necessary to add an appropriate chemical modification to the synthetic ligand, and specifically, a peptide skeleton. It has been found that a branched carrier having a branched-chain glycolipid complex having the above and a fine particle carrier coated with the same exhibit excellent organ directivity, unlike the fine particle carrier itself not coated with the same, and the present invention It was completed.
【００１０】以下、本発明を詳細に説明する。Hereinafter, the present invention will be described in detail.
【００１１】本発明の物質は下記（Ｉ）によって示され
るペプチド骨格を有する分枝鎖型糖複合体である。The substance of the present invention is a branched saccharide complex having a peptide skeleton represented by the following (I).
【００１２】 （Ｘ1 ，…，Ｘn+1 ）（ＡＡ）n Ｙ （Ｉ） 式（Ｉ）においてはｎは０，１，２のいずれかの整数を
表す。(X 1 ,..., X n + 1 ) (AA) n Y (I) In the formula (I), n represents an integer of 0, 1, or 2.
【００１３】（ＡＡ）n は、ｎが０のときは単結合であ
り、ｎが１のときはアミノ酸残基であり、ｎが２のとき
はジペプチド残基であるが、本発明においてはこれらを
総称してペプチド骨格と呼ぶことにする。(AA) n is a single bond when n is 0, is an amino acid residue when n is 1, and is a dipeptide residue when n is 2; Are collectively referred to as a peptide backbone.
【００１４】これを化学構造式をもって具体的に示せ
ば、以下のごとくである。This is specifically shown by the chemical structural formula as follows.
【００１５】まず、ｎが０のときは１個の単結合を示
す。First, when n is 0, it indicates one single bond.
【００１６】ｎが１のときは下記式（II）、（III)、
（IV）のいずれかを示す。（II）はグルタミン酸、（II
I)はアスパラギン酸、（IV）はセリンにそれぞれ由来す
るアミノ酸残基である。When n is 1, the following formulas (II), (III),
(IV). (II) is glutamic acid, (II
I) is an amino acid residue derived from aspartic acid, and (IV) is an amino acid residue derived from serine.
【００１７】[0017]
【化３】 また、ｎが２のときは下記式（Ｖ）〜（XIV)のいずれか
を示す。いずれも２個のアミノ酸が以下のごとく結合し
たジペプチド残基である。Embedded image When n is 2, it represents any of the following formulas (V) to (XIV). Each is a dipeptide residue in which two amino acids are linked as follows.
【００１８】[0018]
【化４】 ジペプチド残基について付言すると、（Ｖ）及び（VI）
は２個のグルタミン酸に由来し、（Ｖ）はα−アミノ基
とγ−カルボキシル基との酸アミド結合により、（VI）
はα−アミノ基とα−カルボキシル基との酸アミド結合
によりそれぞれ構成される；（VII)及び（VIII) は２個
のアスパラギン酸に由来し、（VII)はα−アミノ基とβ
−カルボキシル基との酸アミド結合により、（VIII) は
α−アミノ基とα−カルボキシル基との酸アミド結合に
よりそれぞれ構成される；（IX）はグルタミン酸とセリ
ンに由来し、また（Ｘ）はアスパラギン酸とセリンに由
来し、それぞれグルタミン酸およびアスパラギン酸のα
−アミノ基とセリンのα−カルボキシル基との酸アミド
結合により構成される；（XI）及び（XII)はアスパラギ
ン酸とグルタミン酸に由来し、（XI）はアスパラギン酸
のα−アミノ基とグルタミン酸のα−カルボキシル基と
の、また（XII)は同じくグルタミン酸のγ−カルボキシ
ル基とのそれぞれ酸アミド結合により構成される；（XI
II) 及び及び（XIV)はグルタミン酸とアスパラギン酸に
由来し、（XIII) はグルタミン酸のα−アミノ基とアス
パラギン酸のα−カルボキシル基との、また（XIV)は同
じくアスパラギン酸のβ−カルボキシル基とのそれぞれ
酸アミド結合により構成される。Embedded image In addition to the dipeptide residues, (V) and (VI)
Is derived from two glutamic acids, (V) is formed by an acid amide bond between an α-amino group and a γ-carboxyl group, and (VI)
Are each constituted by an acid amide bond between an α-amino group and an α-carboxyl group; (VII) and (VIII) are derived from two aspartic acids, and (VII) is an α-amino group and β
(VIII) is constituted by an acid amide bond between an α-amino group and an α-carboxyl group, respectively; (IX) is derived from glutamic acid and serine, and (X) is formed by an acid amide bond with a carboxyl group. Derived from aspartic acid and serine, the α of glutamic acid and aspartic acid respectively
(XI) and (XII) are derived from aspartic acid and glutamic acid, and (XI) is derived from the α-amino group of aspartic acid and glutamic acid. (XII) is also constituted by an acid amide bond with the γ-carboxyl group of glutamic acid, respectively (XI
(II) and (XIV) are derived from glutamic acid and aspartic acid, (XIII) is the α-amino group of glutamic acid and α-carboxyl group of aspartic acid, and (XIV) is the β-carboxyl group of aspartic acid. And an acid amide bond.
【００１９】これらの残基（ＡＡ）n の中で、（II）、
（IV）、（Ｖ）及び（IX）はこれらへの糖鎖の導入が容
易である点で特に好ましいペプチド骨格である。Among these residues (AA) n , (II)
(IV), (V) and (IX) are particularly preferable peptide skeletons because sugar chains can be easily introduced into them.
【００２０】式（Ｉ）中のＸ1 ，…，Ｘn+1 及びＹはペ
プチド骨格（ＡＡ）n に結合する結合基を表しており、
式（Ｉ）における（Ｘ1 ，…，Ｘn+1 ）の部分は結合基
の個数がｎの数に応じて定まり、その結合基は（ ）内
に示されるものであることを意味している。なお、（
）内に示される結合基の中の少なくとも１つは下記に
定義されるような−Ｒ基または−ＮＨＲ2 基でなければ
ならず、−ＮＨＲ2 基である場合にはそのＲ2 は下記の
式（XV）又は式（XVI)のいずれかでなければならない。X 1 ,..., X n + 1 and Y in the formula (I) represent a bonding group bonded to the peptide skeleton (AA) n ,
The part (X 1 ,..., X n + 1 ) in the formula (I) means that the number of bonding groups is determined according to the number n, and the bonding groups are those shown in parentheses. I have. Note that (
) At least one of the coupling groups represented in must be -R group or -NHR 2 groups as defined below, in the case of -NHR 2 groups that R 2 is the following It must be either formula (XV) or formula (XVI).
【００２１】詳述すれば、ｎが０のときは式（Ｉ）は１
個の結合基Ｘ1 が単結合を介して結合基Ｙに結合してい
ることを示しており、この場合にＸ1 は−ＮＨＲ2 基で
ある。More specifically, when n is 0, equation (I) becomes 1
This indicates that each of the bonding groups X 1 is bonded to the bonding group Y via a single bond, in which case X 1 is a —NHR 2 group.
【００２２】ｎが１又は２のときの（ＡＡ）n は結合手
としてカルボニル基、オキシド基、アミド基を持ってい
るが、式（Ｉ）中の結合基Ｘ1 ，…，Ｘn+1 は（ＡＡ）
n 中のカルボニル基又はオキシド基にのみ結合し、ただ
しカルボニル基に結合するときは−ＯＲ1 基又は−ＮＨ
Ｒ2 基であり、またオキシド基に結合するときは−Ｒ基
でなければならない。ここで、Ｒ1 は水素原子、アルカ
リ金属、炭素数１〜３のアルキル基、ベンジル基を表
し、Ｒ2 は水素原子又は下記の式（XV）又は式（XVI)を
表し、Ｒはアセチル基で保護された又は保護されていな
いグリコシル基を表している。(AA) when n is 1 or 2, n has a carbonyl group, an oxide group, or an amide group as a bond, but the bond groups X 1 ,..., X n + 1 in the formula (I) Is (AA)
only bound to a carbonyl group or oxide groups in the n, provided that -OR 1 group or -NH when bound to a carbonyl group
A group R 2, also when bound to oxide groups must be -R group. Here, R 1 represents a hydrogen atom, an alkali metal, an alkyl group having 1 to 3 carbon atoms, or a benzyl group; R 2 represents a hydrogen atom or the following formula (XV) or (XVI); Represents a protected or unprotected glycosyl group.
【００２３】 （ＣＨ2 ）a ＯＲ （XV） （ＣＨ2 ＣＨ2 Ｏ）b Ｒ （XVI) 式（XV）においてａは１〜10の整数、好ましくは１〜６
の整数、そして式（XVI)においてｂは１〜８の整数、好
ましくは１〜４の整数を表している。また、グリコシル
基の例としてはＤ−マンノシル、Ｄ−ガラクトシル、Ｎ
−アセチル−Ｄ−ガラクトサミニル、Ｌ−フコシル、ラ
クトシル、Ｄ−リボシル等を挙げることができるが、こ
れらに限定されるものではない。(CH 2 ) a OR (XV) (CH 2 CH 2 O) b R (XVI) In the formula (XV), a is an integer of 1 to 10, preferably 1 to 6
In the formula (XVI), b represents an integer of 1 to 8, preferably 1 to 4. Examples of glycosyl groups include D-mannosyl, D-galactosyl, N
-Acetyl-D-galactosaminyl, L-fucosyl, lactosyl, D-ribosyl and the like, but are not limited thereto.
【００２４】他方、結合基Ｙは（ＡＡ）n 中のアミド基
にのみ結合し、水素原子、ベンジルオキシカルボニル
基、ｔ−ブトキシカルボニル基又は直鎖若しくは分枝鎖
のアルキルカルボニル基（アルキル鎖中にエーテル結合
および／または酸アミド結合を含んでもよい）を表して
いる。直鎖のアルキルカルボニル基としては例えばパル
ミトイル基を、アルキル鎖中にエーテル結合を含む直鎖
のアルキルカルボキニル基としては例えば下記式（XVI
I) を、分枝鎖のアルキルカルボキニル基としては例え
ば下記式（XVIII)を、アルキル鎖中にエーテル結合を含
む分枝鎖のアルキルカルボキニル基としては例えば下記
式（XIX)を、同じくアルキル鎖中にエーテル結合および
酸アミド結合を含む分枝鎖のアルキルカルボキニル基と
して下記式（XX）を、それぞれ、挙げることができる。On the other hand, the bonding group Y is bonded only to the amide group in (AA) n and is a hydrogen atom, a benzyloxycarbonyl group, a t-butoxycarbonyl group or a linear or branched alkylcarbonyl group (in the alkyl chain). May contain an ether bond and / or an acid amide bond). As a straight-chain alkylcarbonyl group, for example, a palmitoyl group, and as a straight-chain alkylcarbokinyl group containing an ether bond in the alkyl chain, for example, a compound represented by the following formula (XVI
I) is represented by the following formula (XVIII) as a branched alkylcarbokinyl group, and the following formula (XIX) as a branched alkylcarbokinyl group containing an ether bond in the alkyl chain. The following formula (XX) can be exemplified as a branched alkylcarboxynyl group containing an ether bond and an acid amide bond in the chain.
【００２５】[0025]
【化５】 本発明物質の製造は、後記実施例によって知られるごと
く目標物質の化学構造式に応じて適宜に合成工程をアレ
ンジして行なえばよいが、一般的な例を示せば次のごと
くである。Embedded image The production of the substance of the present invention may be carried out by appropriately arranging the synthesis steps according to the chemical structural formula of the target substance, as will be known from the examples described later. A general example is as follows.
【００２６】前記式（Ｉ）において（AA）n がアミノ酸
残基の場合は、まず、本発明に係るアミノ酸のアミノ基
を保護しておいて該アミノ酸の遊離カルボン酸にヒドロ
キシサクシンイミドと脱水縮合剤の存在下で結合基Ｘの
糖鎖アミンを反応させる。なお、糖鎖アミンの糖の水酸
基は予めアセチル基で保護して使用する。次に、例えば
還元してアミノ基の保護基を除去し、その結果生成する
遊離アミンにヒドロキシサクシンイミドと脱水縮合剤の
存在下で結合基Ｙに対応する脂質カルボン酸を反応させ
る。In the above formula (I), when (AA) n is an amino acid residue, the amino group of the amino acid according to the present invention is first protected, and the free carboxylic acid of the amino acid is dehydrated with hydroxysuccinimide. The sugar chain amine of the linking group X is reacted in the presence of the agent. In addition, the hydroxyl group of the sugar of the sugar chain amine is used by being protected with an acetyl group in advance. Next, the protecting group of the amino group is removed, for example, by reduction, and the resulting free amine is reacted with hydroxysuccinimide and a lipid carboxylic acid corresponding to the linking group Y in the presence of a dehydrating condensing agent.
【００２７】前記式（Ｉ）において（AA）n がジペプチ
ド残基の場合は、前記遊離アミンに、アミノ基の保護さ
れた遊離カルボキシル基を１個持つ別の本発明に係るア
ミノ酸を反応させ、その後に還元してアミノ基の保護基
を除去し、その結果生成する遊離アミンに前記と同様に
して結合基Ｙに対応する所定の脂質カルボン酸を反応さ
せる。又は、本発明に係るジペプチドのアミノ基を保護
しておいて該ジペプチドの遊離カルボキシル基にヒドロ
キシサクシンイミドと脱水縮合剤の存在下で結合基Ｘに
対応する糖鎖アミンを反応させ、その後に還元してアミ
ノ基の保護基を除去し、その結果生成する遊離アミンに
前記と同様にして結合基Ｙに対応する脂質カルボン酸を
反応させてもよい。In the above formula (I), when (AA) n is a dipeptide residue, the free amine is reacted with another amino acid according to the present invention having one free carboxyl group protected by an amino group, Thereafter, reduction is performed to remove the amino-protecting group, and the resulting free amine is reacted with a predetermined lipid carboxylic acid corresponding to the linking group Y in the same manner as described above. Alternatively, the amino group of the dipeptide according to the present invention is protected, and the free carboxyl group of the dipeptide is reacted with a sugar chain amine corresponding to the bonding group X in the presence of hydroxysuccinimide and a dehydrating condensing agent, and then reduced. Then, the protecting group of the amino group may be removed, and the resulting free amine may be reacted with the lipid carboxylic acid corresponding to the linking group Y in the same manner as described above.
【００２８】いずれの場合も、最後に必要に応じてメタ
ノール中でナトリウムメチラートを反応せしめて糖の水
酸基からアセチル基を除去すればよい。In any case, the acetyl group may be removed from the hydroxyl group of the sugar by reacting sodium methylate in methanol as needed.
【００２９】糖鎖アミンは、ヒドロキシアルキルハライ
ド又はヒドロキシポリオキシエチレンハライドを出発物
質としてそのヒドロキシ基をグリコシル化し、他方ナト
リウムアジドを反応せしめてハライドをアジドに換え、
最後に還元して用意することができる。The sugar chain amine is glycosylated at its hydroxy group starting from a hydroxyalkyl halide or hydroxypolyoxyethylene halide, while reacting sodium azide to convert the halide into an azide.
Finally, it can be prepared by reduction.
【００３０】このようにして製造される本発明物質はＲ
F 値、［α］D 値、ＮＭＲ値、ＩＲ値等の物性値を適宜
に組合せて同定することができる。The substance of the present invention thus produced is represented by R
It can be identified by appropriately combining physical property values such as F value, [α] D value, NMR value and IR value.
【００３１】本発明の微粒子キャリヤーは前記式（Ｉ）
によって示される新規物質の、ペプチド骨格を有する分
枝鎖型糖複合体を配合して得られる微粒子キャリヤーで
あって、該物質の特定の性質を専ら利用する物である。The fine particle carrier of the present invention has the above formula (I)
A fine particle carrier obtained by blending a branched saccharide complex having a peptide skeleton of the novel substance represented by the formula (1), which exclusively utilizes a specific property of the substance.
【００３２】本発明微粒子キャリヤーは具体的にはリポ
ソーム、リピッドマイクロスフェアー、ミセル、エマル
ジョンを挙げることができる。これらキャリヤーの調製
はそれぞれ従来公知の方法に従って行えばよく、基本的
には本発明物質を両親媒性物質である他の膜成分と共に
溶媒に溶解または分散して混合する。Specific examples of the fine particle carrier of the present invention include liposomes, lipid microspheres, micelles and emulsions. Each of these carriers may be prepared according to a conventionally known method. Basically, the substance of the present invention is dissolved or dispersed in a solvent together with another membrane component which is an amphiphilic substance and mixed.
【００３３】例えばリポソームの場合には、ホスファジ
ルコリン、スフィンゴミエリン、ホスファチジルエタノ
ールアミン等のリン脂質やジアルキル型合成界面活性剤
等の膜成分物質と本発明物質とを予め混合し、これを公
知の方法(Ann.Rev.Biophys.Bioeng.,9,467(1980))に従
いリポソームの水分散液を調製する。かかるリポソーム
は膜安定化剤としてコレステロール等のステロール類、
ジアルキルリン酸、ステアリルアミン等の荷電物質およ
びトコフェロール等の酸化防止剤を含んでいてもよい。For example, in the case of a liposome, a phospholipid such as phosphadylcholine, sphingomyelin, phosphatidylethanolamine or a membrane component material such as a dialkyl type synthetic surfactant is mixed in advance with the substance of the present invention, and this is mixed with a known substance. A liposome aqueous dispersion is prepared according to the method (Ann. Rev. Biophys. Bioeng., 9, 467 (1980)). Such liposomes are sterols such as cholesterol as membrane stabilizers,
It may contain charged substances such as dialkyl phosphoric acid and stearylamine and antioxidants such as tocopherol.
【００３４】リピッドマイクロフェアーの場合には、ホ
スファチジルコリンと本発明物質とを予め混合し、これ
に大豆油を加えて公知のリピッドマイクロスフェアーの
調製方法に従い処理することにより目的のリピッドマイ
クロスフェアーを得ることができる。In the case of lipid microspheres, phosphatidylcholine and the substance of the present invention are mixed in advance, soybean oil is added thereto, and the mixture is treated according to a known method for preparing lipid microspheres, whereby the desired lipid microspheres are obtained. Obtainable.
【００３５】ミセルの場合には、ポリオキシソルビタン
脂肪酸エステル、脂肪酸ナトリウム、ポリオキシエチレ
ン硬化ヒマシ油等の界面活性剤と本発明物質とを予め混
合し、公知のミセルの調製方法に従い処理することによ
り目的のミセルを製造することができる。In the case of micelles, a surfactant such as polyoxysorbitan fatty acid ester, sodium fatty acid, polyoxyethylene hydrogenated castor oil and the like are mixed in advance with the substance of the present invention, and the mixture is treated according to a known method for preparing micelles. The desired micelle can be manufactured.
【００３６】エマルジョンの場合には、ポリオキシソル
ビタン脂肪酸エステル、脂肪酸ナトリウム、ポリオキシ
エチレン硬化ヒマシ油等の界面活性剤と本発明物質とを
予め混合し、これに大豆油等の油脂を加えて公知のエマ
ルジョンの調製方法に従い処理することにより目的のエ
マルジョンを製造することができる。In the case of an emulsion, a surfactant such as polyoxysorbitan fatty acid ester, fatty acid sodium, polyoxyethylene hydrogenated castor oil and the like are mixed in advance with the substance of the present invention, and a fat or oil such as soybean oil is added thereto. The desired emulsion can be produced by treating according to the method for preparing an emulsion described above.
【００３７】上記のようにして製造される微粒子キャリ
ヤーにおいて本発明物質が全脂質膜成分に対して占める
割合は約1/40モル比以上、好ましくは1/20モル比以上と
するのが望ましい。In the fine particle carrier produced as described above, the ratio of the substance of the present invention to the total lipid membrane component is preferably about 1/40 mol ratio or more, more preferably 1/20 mol ratio or more.
【００３８】かかる微粒子キャリヤーが保持しうる薬物
には特に制限はなく、水溶性薬物でも脂溶性薬物でもよ
く、例えばシトシンアラビノシド、ダウノルビシン、メ
トトレキセートに代表される制癌剤、ペニシリンＧに代
表される抗生物質、インシュリン、インターフェロン、
組織プラスミノーゲンアクチベータに代表される生理活
性物質などを挙げることができる。There is no particular limitation on the drug that the fine particle carrier can hold, and it may be a water-soluble drug or a fat-soluble drug. For example, an anticancer drug represented by cytosine arabinoside, daunorubicin, methotrexate, and an antibiotic represented by penicillin G Substance, insulin, interferon,
Bioactive substances typified by tissue plasminogen activator can be mentioned.
【００３９】[0039]
【作用】後記実験例によって示される如く、全部又は一
部の構成成分として本発明物質を配合して調製される微
粒子キャリヤーは微小循環性が改善され、臓器指向性が
優れたものとなる。すなわち、本発明物質を配合した本
発明微粒子キャリヤーは標的細胞に良好に取込まれる性
質があり、従って優れた薬物運搬担体としての作用を有
する。As shown in the experimental examples described below, the fine particle carrier prepared by incorporating the substance of the present invention as a whole or a part of the component has improved microcirculation and excellent organ directivity. That is, the fine particle carrier of the present invention containing the substance of the present invention has a property of being taken up well by target cells, and thus has an excellent action as a drug carrier.
【００４０】[0040]
【実施例】以下、実施例により本発明を更に具体的に説
明する。EXAMPLES The present invention will be described more specifically with reference to the following examples.
【００４１】なお、実施例中の略記として、ｐ−ＴｓＯ
Ｈはｐ−トルエンスルホン酸を、ＮＥｔ3 はトリエチル
アミンを、Ｂｏｃはブトキシカルボニルを、ＨＯ−Ｓｕ
はヒドロキシコハク酸イミドを、Ｐａｌはパルミトイル
を、Ｂｎはベンジルを、ＤＣＣはジシクロヘキシルカル
ボジイミドを、そしてＴＦＡはトリフルオロ酢酸を表
す。Incidentally, as an abbreviation in the examples, p-TsO
H is p-toluenesulfonic acid, NEt 3 is triethylamine, Boc is butoxycarbonyl, HO-Su
Represents hydroxysuccinimide, Pal represents palmitoyl, Bn represents benzyl, DCC represents dicyclohexylcarbodiimide, and TFA represents trifluoroacetic acid.
【００４２】実施例１（アセチルガラクトサミン系誘導
体の合成） 本実施例における反応式を図１ａ乃至図１ｃに示す。Example 1 (Synthesis of Acetylgalactosamine Derivative) The reaction formula in this example is shown in FIGS. 1a to 1c.
【００４３】なお、本実施例において、旋光度はすべて
Perkin-Elmer Model 241 MC polarimeter を使用し、23
℃で測定した。シリカゲルカルムクロマトグラフィー
は、半井Silica gel 60 を、そしてＴＬＣプレートはSi
lica Gel F254 (Merck, Darmstadt)を使用した。ＩＲス
ペクトルは270-30 Hitachi IR Spectrometerにて測定
し、 1Ｈ−NMR はJNM-GSX270を、そして質量分析はHita
chi M-80A を使用して測定した。In this embodiment, the optical rotation is all
Using a Perkin-Elmer Model 241 MC polarimeter, 23
Measured in ° C. Silica gel column chromatography was performed on a Hanoi Silica gel 60, and the TLC plate was
lica Gel F 254 (Merck, Darmstadt) was used. IR spectra were measured with a 270-30 Hitachi IR Spectrometer, 1 H-NMR was JNM-GSX270, and mass spectrometry was Hitachi
Measured using chi M-80A.
【００４４】(a) 化合物102 及び103 の合成 ガラクトサミン塩酸塩101 （Σ社）30ｇをＭｅＯＨ 560
ml及びＮＥｔ3 38mlの混合溶媒に溶解し、室温にてＡｃ
2 Ｏ 250mlを滴下した。室温にて一晩反応後、溶媒を減
圧留去した。ついで、ピリジン 300ml及びＡｃ2 Ｏ 100
mlを加え、室温にて一晩攪拌した。再び溶媒を減圧留去
後、残渣を酢酸エチル溶液とし、水洗をし、さらに濃縮
をした。 (A) Synthesis of Compounds 102 and 103 30 g of galactosamine hydrochloride 101 (company) was added to MeOH 560
dissolved in a mixed solvent of 38 ml of NEt 3 and 38 ml of NEt 3.
250 ml of 2 O was added dropwise. After reaction at room temperature overnight, the solvent was distilled off under reduced pressure. Then, 300 ml of pyridine and Ac 2 O 100
ml was added and stirred at room temperature overnight. After the solvent was again distilled off under reduced pressure, the residue was made into an ethyl acetate solution, washed with water, and further concentrated.
【００４５】析出した結晶を濾取して、β−アセテート
体102 を5.76ｇ得た。ＲF ＝0.40（ＣＨＣｌ3 −ＭｅＯ
Ｈ 20：１）。The precipitated crystals were collected by filtration to obtain 5.76 g of β-acetate compound 102. R F = 0.40 (CHCl 3 -MeO
H 20: 1).
【００４６】さらに濃縮をして析出したα−アセテート
体103 を濾取して 19.33ｇ得ることができた。ＲF ＝0.
43（ＣＨＣｌ3 −ＭｅＯＨ 20：１）。The α-acetate body 103 precipitated after further concentration was collected by filtration to obtain 19.33 g. R F = 0.
43 (CHCl 3 -MeOH 20: 1 ).
【００４７】また、母液はシリカゲルカラムクロマトグ
ラフィー（50：１ ＣＨＣｌ3 −ＭｅＯＨ）にて精製し
てα−アセテート体を更に 2.4ｇ得た。The mother liquor was purified by silica gel column chromatography (50: 1 CHCl 3 -MeOH) to obtain 2.4 g of α-acetate.
【００４８】β−アセテート体102 ［α］D +7.0°(C=0.2,CHCl 3 ）。 Β-acetate body 102 [α] D + 7.0 ° (C = 0.2, CHCl 3 ).
【００４９】NMR： 1H ，δ（CDCl3 ) 5.69(d,1H,J=8.8
Hz)，5.38(bd,1H,J=3.2Hz) ，5.36(d,1H,J=9.6Hz)，5.0
8(dd,1H,J=3.4,11.2Hz)，4.46(dt,1H,J=9.6,11.2Hz)，
4.18(dd,1H,J=5.96,11.5Hz) ，4.11(dd,1H,J=5.96,11.5
Hz) ，4.02(bt,1H,J=6.42Hz)。NMR: 1 H, δ (CDCl 3 ) 5.69 (d, 1 H, J = 8.8
Hz), 5.38 (bd, 1H, J = 3.2 Hz), 5.36 (d, 1H, J = 9.6 Hz), 5.0
8 (dd, 1H, J = 3.4,11.2Hz), 4.46 (dt, 1H, J = 9.6,11.2Hz),
4.18 (dd, 1H, J = 5.96,11.5Hz), 4.11 (dd, 1H, J = 5.96,11.5
Hz), 4.02 (bt, 1H, J = 6.42Hz).
【００５０】α−アセテート体103 ［α］D +87.70℃（C=0.2,CHCl3 ）。 Α-acetate 103 [α] D + 87.70 ° C. (C = 0.2, CHCl 3 ).
【００５１】NMR： 1H ，δ（CDCl3 ) 6.22(d,1H,J=3.6
6Hz) ，5.43(bd,1H,J=3.2Hz) ，5.39(d,1H,J=9.5Hz)，
5.23(dd,1H,J=3.2,11.5Hz)，4.73(ddd,1H,J=11.5,9.5,
3.66Hz)，4.24(bt,1H,J=6.6Hz) ，4.12(dd,J=6.84,11.2
Hz)，4.07(dd,1H,J=6.6,11.2Hz)。NMR: 1 H, δ (CDCl 3 ) 6.22 (d, 1 H, J = 3.6
6 Hz), 5.43 (bd, 1H, J = 3.2Hz), 5.39 (d, 1H, J = 9.5Hz),
5.23 (dd, 1H, J = 3.2,11.5Hz), 4.73 (ddd, 1H, J = 11.5,9.5,
3.66Hz), 4.24 (bt, 1H, J = 6.6Hz), 4.12 (dd, J = 6.84,11.2.
Hz), 4.07 (dd, 1H, J = 6.6, 11.2Hz).
【００５２】(b) オキサゾリン化合物104 の合成 1) β−アセテート体102 を 3.768ｇ、 1,2−dichloro
etane 49mlに溶解し、室温にてTMSOTf（トリメチルシリ
ルトリフレート） 1.87ml を滴下した。同温度にて 2.5
時間反応後、ＮＥｔ3 を２倍当量加えたあと溶媒を留去
してオキサゾリン104 を定量的に得た。ＲF ＝0.56（Ｃ
ＨＣｌ3 −ＭｅＯＨ 20：１）。 (B) Synthesis of oxazoline compound 104 1) 3.768 g of β-acetate compound 102, 1,2-dichloro
The solution was dissolved in 49 ml of etane, and 1.87 ml of TMSOTf (trimethylsilyl triflate) was added dropwise at room temperature. 2.5 at the same temperature
After the reaction for 2 hours, 2 equivalents of NEt 3 were added and the solvent was distilled off to obtain oxazoline 104 quantitatively. R F = 0.56 (C
HCl 3 -MeOH 20: 1).
【００５３】2) α−アセテート体103 を7.97ｇ、 1,2
−dichloroethane 100mlに溶解し、室温にてTMSOTf 3.8
9ml を滴下した。同温度にて一晩、ついで50℃にて 9.5
時間反応後、ＮＥｔ3 を２倍当量加えたあと溶媒を留去
した。シリカゲルカラムクロマトグラフィー（2000：
５：20 ＣＨＣｌ3 −ＭｅＯＨ−ＮＥｔ3 ）にて精製し
て同じくオキサゾリン104 を 5.4ｇ得た。2) 7.97 g of α-acetate body 103
-Dissolve in 100ml of dichloroethane and at room temperature TMSOTf 3.8
9 ml was added dropwise. Overnight at the same temperature, then 9.5 at 50 ° C
After the reaction for 2 hours, 2 equivalents of NEt 3 were added, and then the solvent was distilled off. Silica gel column chromatography (2000:
5:20 CHCl 3 -MeOH-NEt 3 ) to obtain 5.4 g of oxazoline 104 in the same manner.
【００５４】［α］D +101.2°(C=0.5, CHCl3 ）。[Α] D + 101.2 ° (C = 0.5, CHCl 3 ).
【００５５】NMR： 1H ，δ（CDCl3 ) 6.00(d,1H,J=6.8
Hz)，5.47(t,1H,J=3.0Hz)，4.91(dd,1H,J=3.4, 7.6H
z)，4.25(dt,1H,J=2.7, 6.8Hz)，4.20(dd,1H,J=6.84, 1
1.2Hz)，4.11(dd,1H,J=5.8, 11.2Hz），4.00(bt,1H,J=
6.4Hz) 。NMR: 1 H, δ (CDCl 3 ) 6.00 (d, 1 H, J = 6.8
Hz), 5.47 (t, 1H, J = 3.0Hz), 4.91 (dd, 1H, J = 3.4, 7.6H
z), 4.25 (dt, 1H, J = 2.7, 6.8 Hz), 4.20 (dd, 1H, J = 6.84, 1
1.2Hz), 4.11 (dd, 1H, J = 5.8, 11.2Hz), 4.00 (bt, 1H, J =
6.4Hz).
【００５６】(c) グリコシド体105 の合成 前項(b) の1)で得られたオキサゾリン3.16ｇおよび 6−
chlorohexanol 2.2mlを 1,2−dichloroethane 30ml に
溶解し、M.S.4A(Molecular Sieves 4A) 存在下、50℃に
てTMSOTf 1.9mlを滴下した。室温にて一晩攪拌して反応
させたあと、シリカゲルカラムクロマトグラフィー（Ｐ
ｈＣＨ3 −ＡｃＯＥｔ １：１）にて精製してクロルグ
リコシド体を4.01ｇ得た。ＲF ＝0.34（ＣＨＣｌ3 −Ｍ
ｅＯＨ20：１）。 (C) Synthesis of Glycoside 105 3.16 g of the oxazoline obtained in 1) of item (b) above and 6-
2.2 ml of chlorohexanol was dissolved in 30 ml of 1,2-dichloroethane, and 1.9 ml of TMSOTf was added dropwise at 50 ° C. in the presence of MS4A (Molecular Sieves 4A). After stirring overnight at room temperature to react, silica gel column chromatography (P
Purification with hCH 3 -AcOEt 1: 1) gave 4.01 g of a chloroglycoside. R F = 0.34 (CHCl 3 -M
MeOH 20: 1).
【００５７】［α］D -14.9°(C=0.95,CHCl3 ）。[Α] D -14.9 ° (C = 0.95, CHCl 3 ).
【００５８】NMR： 1H ，δ（CDCl3 ) 5.33(m,1H)，5.0
5(dd,1H,J=3.4, 11.2Hz) ，4.55(d,1H,J=8.5Hz)，3.55
(t,2H,J=6.8Hz)，2.14，2.02，1.95，1.92。NMR: 1 H, δ (CDCl 3 ) 5.33 (m, 1H), 5.0
5 (dd, 1H, J = 3.4, 11.2Hz), 4.55 (d, 1H, J = 8.5Hz), 3.55
(t, 2H, J = 6.8Hz), 2.14, 2.02, 1.95, 1.92.
【００５９】ついで、前記クロルグリコシド体をＤＭＦ
溶液とし、ＮａＮ3 を２倍当量加え、50℃にて一晩攪拌
した。酢酸エチルを加え、水洗を４度したあと、溶媒を
留去してグリコシド体105 を3.44ｇ得た。ＲF 値はクロ
ルグリコシト体と同一（ＣＨＣｌ3 −ＭｅＯＨ 20：
１）であった。Next, the chloroglycoside was converted to DMF.
The mixture was made into a solution, NaN 3 was added in an amount of 2 equivalents, and the mixture was stirred at 50 ° C. overnight. Ethyl acetate was added, and the mixture was washed four times with water. The solvent was distilled off to obtain 3.44 g of glycoside 105. R F values are the same and chloride glycolate citrate body (CHCl 3 -MeOH 20:
1).
【００６０】［α］D -15.8°(C=0.97,CHCl3 ）。[Α] D -15.8 ° (C = 0.97, CHCl 3 ).
【００６１】NMR： 1H ，δ（CDCl3 ) 5.33(m,1H)，5.0
5(dd,1H,J=3.4, 11.2Hz) ，4.54(d,1H,J=8.3Hz)，4.16
(dd,1H,J=6.6, 11.0Hz) ，4.11(dd,1H,J=6.6, 11.0Hz)
，4.07(dd,1H,J=8.31, 11.2Hz)，4.00(dt,1H,J=0.98,
6.4Hz) ，3.85(dt,1H,J=6.1,9.8Hz)，3.51(dt,1H,J=6.
4, 9.5Hz)，2.14，2.02，1.65，1.92。NMR: 1 H, δ (CDCl 3 ) 5.33 (m, 1H), 5.0
5 (dd, 1H, J = 3.4, 11.2Hz), 4.54 (d, 1H, J = 8.3Hz), 4.16
(dd, 1H, J = 6.6, 11.0Hz), 4.11 (dd, 1H, J = 6.6, 11.0Hz)
, 4.07 (dd, 1H, J = 8.31, 11.2Hz), 4.00 (dt, 1H, J = 0.98,
6.4Hz), 3.85 (dt, 1H, J = 6.1,9.8Hz), 3.51 (dt, 1H, J = 6.
4, 9.5 Hz), 2.14, 2.02, 1.65, 1.92.
【００６２】(d) アミン体106 の合成 アジト体105 を1.90ｇ及びＴｓＯＨ・Ｈ2 Ｏ 836mgをＥ
ｔＯＨ 20ml に溶解し、Lindlar 触媒（N.E.CHEMCAT)
2.0ｇを加え、１時間水添した。 (D) Synthesis of Amine Form 106 1.90 g of azide form 105 and 836 mg of TsOH · H 2 O were added to E
Dissolve in 20 ml of tOH and use Lindlar catalyst (NECHEMCAT)
2.0 g was added and hydrogenated for 1 hour.
【００６３】触媒を濾去後、溶媒を留去してアミン体10
6 を得た。After removing the catalyst by filtration, the solvent was distilled off and the amine compound 10 was removed.
I got 6.
【００６４】(e) 化合物107 の合成 Carbobenzoxy-L-glutamic acid 1.45 ｇ、 HOSu 1.38ｇ
及びDCC 2.30ｇをＣＨ3 ＣＮに溶解し、室温で30分間攪
拌した。析出したウレアを濾去後、溶媒を留去して活性
エステル体を2.80ｇ得た。このうちの460mg とアミン体
106 (2mmol相当）をＣＨ3 ＣＮ中で混合し、ＮＥｔ3 0.
7ml を加え、室温で 0.5時間反応させた。 (E) Synthesis of Compound 107 1.45 g of Carbobenzoxy-L-glutamic acid, 1.38 g of HOSu
And 2.30 g of DCC were dissolved in CH 3 CN and stirred at room temperature for 30 minutes. After removing the precipitated urea by filtration, the solvent was distilled off to obtain 2.80 g of an active ester compound. 460mg of these and amines
106 (equivalent to 2 mmol) were mixed in CH 3 CN, and NEt 30 .
7 ml was added and reacted at room temperature for 0.5 hour.
【００６５】ＣＨ3 ＣＮを留去後、ＣＨＣｌ3 溶液と
し、水洗した。次に、ＡｃＯＥｔを加え、析出した寒天
様沈殿物を濾取し、シリカゲルカラムクロマトグラフィ
ーにかけ精製した。ＲF 0.59（ＣＨＣｌ3 −ＭｅＯＨ
10：１）。After CH 3 CN was distilled off, the solution was made CHCl 3 solution and washed with water. Next, AcOEt was added, and the precipitated agar-like precipitate was collected by filtration and purified by silica gel column chromatography. R F 0.59 (CHCl 3 -MeOH
10: 1).
【００６６】［α］D -11.5°(C=0.75,CHCl3 ）。[Α] D -11.5 ° (C = 0.75, CHCl 3 ).
【００６７】NMR： 1H ，δ（CDCl3 ) 7.35(m,5H)，5.3
3(m,2H)，4.55(d,1H,J=8.31Hz) ，4.15(dd,2H) ，4.11
(dd,2H) ，4.00(bt,2H,J=6.6Hz) ，3.84(dt,2H,J=5.7,
6.2Hz)，3.50(dt,2H,J=6.6, 6.4Hz)，2.13，2.02，1.9
4，1.91。NMR: 1 H, δ (CDCl 3 ) 7.35 (m, 5H), 5.3
3 (m, 2H), 4.55 (d, 1H, J = 8.31Hz), 4.15 (dd, 2H), 4.11
(dd, 2H), 4.00 (bt, 2H, J = 6.6Hz), 3.84 (dt, 2H, J = 5.7,
6.2Hz), 3.50 (dt, 2H, J = 6.6, 6.4Hz), 2.13, 2.02, 1.9
4, 1.91.
【００６８】ついで、脱ベンジル化してｐ−トルエンス
ルホン酸塩107 を得た。Then, debenzylation was performed to obtain p-toluenesulfonic acid salt 107.
【００６９】(f) 化合物113 の合成 L-Glutamic acid α，γ-di-benzyl ester p-toluenesu
lfonate およびt-Butoxycarbonyl-L-glutamic acid α
-benzyl ester を常法により縮合したあと、脱ベンジル
化してトリカルボン酸113 を得た。 (F) Synthesis of Compound 113 L-Glutamic acid α, γ-di-benzyl ester p-toluenesu
lfonate and t-Butoxycarbonyl-L-glutamic acid α
-Benzyl ester was condensed by a conventional method and debenzylated to obtain tricarboxylic acid 113.
【００７０】NMR： 1H ，δ（CD3 OD) 4.41(m,1H)，4.1
0(m,1H)，1.40(s,9H)。NMR: 1 H, δ (CD 3 OD) 4.41 (m, 1 H), 4.1
0 (m, 1H), 1.40 (s, 9H).
【００７１】(g) 化合物115 の合成 トリカルボン酸113 およびアミン体106 を常法により縮
合後、シリカゲルカラムクロマトグラフィー（20：１
ＣＨＣｌ3 −ＭｅＯＨ）にかけて精製して化合物114 を
得た。ＲF ＝0.93（ＣＨＣｌ3 −ＭｅＯＨ 10：１）。 (G) Synthesis of Compound 115 Condensation of tricarboxylic acid 113 and amine 106 by a conventional method, followed by silica gel column chromatography (20: 1)
(CHCl 3 -MeOH) to give compound 114. R F = 0.93 (CHCl 3 -MeOH 10: 1).
【００７２】［α］D -6.90°(C=1.13,CHCl3 ）。[Α] D -6.90 ° (C = 1.13, CHCl 3 ).
【００７３】NMR： 1H δ（CD3 OD) 5.32(m,3H)， 5.06
(dd×2)，4.56(d×3,3H,J=8.5Hzほか），4.25(m,1H)，
2.14，2.02，1.95，1.93，1.44(s,9H)。NMR: 1 H δ (CD 3 OD) 5.32 (m, 3H), 5.06
(dd × 2), 4.56 (d × 3, 3H, J = 8.5Hz etc.), 4.25 (m, 1H),
2.14, 2.02, 1.95, 1.93, 1.44 (s, 9H).
【００７４】ついで、脱アセチル化して化合物115 を得
た。ＲF 0.68（ＣＨＣｌ3 −ＭｅＯＨ−Ｈ2 Ｏ 10：1
0：３）。Then, compound 115 was obtained by deacetylation. R F 0.68 (CHCl 3 -MeOH-H 2 O 10: 1
0: 3).
【００７５】NMR： 1H ，δ（DMSO) 4.23(d,1H,J=8.3H
z)，1.81(s,9H)，1.38(s,9H)。NMR: 1 H, δ (DMSO) 4.23 (d, 1 H, J = 8.3 H
z), 1.81 (s, 9H), 1.38 (s, 9H).
【００７６】(h) 化合物116 の合成 化合物114 を脱Ｂｏｃ後、パルミチン酸活性エステルと
反応させ、プレパラチブ薄層クロマトグラフィー（10：
１ ＣＨＣｌ3 −ＭｅＯＨ）にて精製して縮合体を得
た。ＲF ＝0.56（ＣＨＣｌ3 −ＭｅＯＨ 10：１）。 (H) Synthesis of Compound 116 After removing Compound 114 from Boc, the compound was reacted with an active ester of palmitic acid, and was subjected to preparative thin layer chromatography (10:
1CHCl 3 -MeOH) to obtain a condensate. R F = 0.56 (CHCl 3 -MeOH 10: 1).
【００７７】［α］D -5.3° (C=0.3,CHCl3 ）。[Α] D -5.3 ° (C = 0.3, CHCl 3 ).
【００７８】NMR： 1H ，δ（CD3 OD) 5.33(m,3H)，5.0
7(dd,3H,J=2.9, 11.2Hzほか），4.55(d,3H,J=8.3Hz)，
4.28(m,2H)，4.16(dd,3H,J=6.8, 11.0Hz) ，4.11(dd,3
H,J=6.4, 11.2Hz) ，4.07(m,3H)，4.01(bt,3H,J=6.6Hz)
，2.14，2.02，1.94，1.93，0.90(t,3H,J=7.5Hz)。NMR: 1 H, δ (CD 3 OD) 5.33 (m, 3H), 5.0
7 (dd, 3H, J = 2.9, 11.2Hz etc.), 4.55 (d, 3H, J = 8.3Hz),
4.28 (m, 2H), 4.16 (dd, 3H, J = 6.8,11.0Hz), 4.11 (dd, 3
H, J = 6.4, 11.2Hz), 4.07 (m, 3H), 4.01 (bt, 3H, J = 6.6Hz)
, 2.14, 2.02, 1.94, 1.93, 0.90 (t, 3H, J = 7.5Hz).
【００７９】この縮合体を脱アセチル化して化合物116
を得た。ＲF ＝0.81（ＣＨＣｌ3 −ＭｅＯＨ−Ｈ2 Ｏ
10：10：３）。The condensate is deacetylated to give compound 116
I got R F = 0.81 (CHCl 3 -MeOH -H 2 O
10: 10: 3).
【００８０】NMR： 1H ，δ (DMSO) 4.22(d,3H,J=8.6H
z) ，1.79(s,9H)，0.87(t,9H)。NMR: 1 H, δ (DMSO) 4.22 (d, 3H, J = 8.6H
z), 1.79 (s, 9H), 0.87 (t, 9H).
【００８１】実施例２（ガラクトース系誘導体の合成） 本実施例における反応式を図２ａ乃至図２ｑに示す。Example 2 (Synthesis of Galactose Derivative) The reaction formulas in this example are shown in FIGS. 2a to 2q.
【００８２】なお、本実施例における旋光度、シリカゲ
ルカラムクロマトグラフィー、ＴＬＣプレート、ＩＲス
ペクトル、 1Ｈ−ＮＭＲ及び質量分析に関する使用機
器、測定条件などは実施例１におけると同じである。The optical rotation, silica gel column chromatography, TLC plate, IR spectrum, equipment used for 1 H-NMR and mass spectrometry, measurement conditions, and the like in this example are the same as those in Example 1.
【００８３】(a) 化合物203 の合成 β-D-Galactose pentaacetate 201 を 100ｇ及び 2-bro
moethanol 38.4ｇを乾燥塩化メチレン 900mlに溶かし、
氷冷下ＢＦ3 ・Ｅｔ2 Ｏ 260mlを滴下した。室温で２時
間半攪拌後、重曹水にあけ、水洗を２度したあと溶媒を
留去した。イソプロピルエーテルにて結晶化してグリコ
シド体を63ｇ（収率54％）得た。ＲF ＝0.49（ＰｈＣＨ
3 −ＡｃＯＥｔ ２：１）。 (A) Synthesis of Compound 203 100 g of β-D-Galactose pentaacetate 201
Dissolve 38.4 g of moethanol in 900 ml of dry methylene chloride,
260 ml of BF 3 .Et 2 O was added dropwise under ice cooling. After stirring at room temperature for 2.5 hours, the mixture was poured into aqueous sodium bicarbonate, washed twice with water, and then the solvent was distilled off. Crystallization with isopropyl ether gave 63 g of a glycoside (54% yield). R F = 0.49 (PhCH
3- AcOEt 2: 1).
【００８４】ブロモエチルグリコシド体60ｇをN,N-ジメ
チルホルムアミド 200mlに溶かし、ＮａＮ3 32ｇを加
え、室温にて一晩攪拌した。ついで、80℃で２時間攪拌
後、酢酸エチル200ml 加えたあと固形物を濾去した。N,
N-ジメチルホルムアミドを留去後残渣を酢酸エチル溶液
とし、水洗を４度してアジドエチルグリコシド体202 を
定量的に得た。ＲF ＝0.4 （ＰｈＣＨ3 −ＡｃＯＥｔ
２：１）。60 g of the bromoethyl glycoside was dissolved in 200 ml of N, N-dimethylformamide, 32 g of NaN 3 was added, and the mixture was stirred at room temperature overnight. Then, after stirring at 80 ° C. for 2 hours, 200 ml of ethyl acetate was added, and the solid matter was removed by filtration. N,
After the N-dimethylformamide was distilled off, the residue was converted to an ethyl acetate solution, and washed four times with water to quantitatively obtain an azidoethyl glycoside 202. R F = 0.4 (PhCH 3 -AcOEt
2: 1).
【００８５】アシド体4.17ｇとｐ−ＴｓＯＨ・Ｈ2 Ｏ
2.28ｇのエタノール溶液をリンドラー触媒 4.0ｇの存在
下水添(45psi,1.5h)して、アミン体203 をえた。ＲF ＝
0.18（ＣＨＣｌ3 −ＭｅＯＨ 20：１）。4.17 g of the acid compound and p-TsOH.H 2 O
2.28 g of the ethanol solution was hydrogenated (45 psi, 1.5 h) in the presence of 4.0 g of Lindlar's catalyst to give the amine 203. R F =
0.18 (CHCl 3 -MeOH 20: 1 ).
【００８６】(b) 化合物206 の合成 L-Glutamyl-L-glutamic acid 440mg及びＮＥｔ3 0.52ml
のメタノール（８ml）溶液にN-(benzyloxycarbonyloxy)
succinimide 440mg の乾燥塩化メチレン溶液を加え、室
温にて３時間攪拌した。溶媒を留去後、残渣をアセトニ
トリル溶液とし、これに化合物203 の2.82ｇ（５mmol）
のアセトニトリル（30ml）溶液、DCC 1.07ｇ、ＮＥｔ3
1.0ml 及びＨＯＳｕ 575mgを加え、室温にて一晩攪拌し
た。酢酸1.0mlを加えたあと溶媒を酢酸エチルに替え、
水洗したのち、溶媒を留去してオイルを得た。シリカゲ
ルカラムクロマトグラフィー（50：１ ＣＨＣｌ3 −Ｍ
ｅＯＨ）にかけて化合物206 を 269mg（収率11％）得
た。 (B) Synthesis of Compound 206 L-Glutamyl-L-glutamic acid 440 mg and NEt 3 0.52 ml
N- (benzyloxycarbonyloxy) in methanol (8 ml) solution
A solution of 440 mg of succinimide in dry methylene chloride was added and stirred at room temperature for 3 hours. After the solvent was distilled off, the residue was converted to an acetonitrile solution, and 2.82 g (5 mmol) of compound 203 was added thereto.
In acetonitrile (30 ml), DCC 1.07 g, NEt 3
1.0 ml and HOSu (575 mg) were added, and the mixture was stirred at room temperature overnight. After adding 1.0 ml of acetic acid, the solvent was changed to ethyl acetate,
After washing with water, the solvent was distilled off to obtain an oil. Silica gel column chromatography (50: 1 CHCl 3 -M
MeOH) to give 269 mg (yield 11%) of compound 206.
【００８７】［α］D -8.6°(C=1.0, CHCl3 ）。[Α] D -8.6 ° (C = 1.0, CHCl 3 ).
【００８８】NMR： 1H ，δ（CDCl3 ) 7.76，7.12，6.5
6，6.41，6.25，7.35(5H)，5.39(m,3H)，2.16，2.15×2
，2.09，2.07，2.06，2.048 ，2.046 ，2.043 ，1.9
9，1.989 ，1.986 。NMR: 1 H, δ (CDCl 3 ) 7.76, 7.12, 6.5
6, 6.41, 6.25, 7.35 (5H), 5.39 (m, 3H), 2.16, 2.15 × 2
, 2.09, 2.07, 2.06, 2.048, 2.046, 2.043, 1.9
9, 1.989, 1.986.
【００８９】(c) 化合物207 の合成 化合物206 を64mg、10％Pd／C 60mg及びp-TsOH 20mg の
エタノール（３ml）溶液を一晩水添(45psi) してアミン
体を定量的に得た。 (C) Synthesis of Compound 207 A solution of 64 mg of Compound 206, 60 mg of 10% Pd / C and 20 mg of p-TsOH in ethanol (3 ml) was hydrogenated (45 psi) overnight to give an amine compound quantitatively. .
【００９０】このアミン体のテトラヒドロフラン（２m
l）溶液に3-(4-hydroxyphenyl)-propionic acid N-hydr
oxysuccinimide ester 26mg及びＮＥｔ3 0.023ml を加
え、室温にて一晩攪拌した。濃縮し、水洗後、シリカゲ
ルカラムクロマトグラフィー（15：１ ＣＨＣｌ3 −Ｍ
ｅＯＨ）にかけてアミド体を57mg得た。ＲF ＝0.48（Ｃ
ＨＣｌ3 −ＭｅＯＨ 10：１）。The amine tetrahydrofuran (2 m
l) 3- (4-hydroxyphenyl) -propionic acid N-hydr
26 mg of oxysuccinimide ester and 0.023 ml of NEt 3 were added, and the mixture was stirred at room temperature overnight. After concentrating and washing with water, silica gel column chromatography (15: 1 CHCl 3 -M
OH) to give 57 mg of the amide. R F = 0.48 (C
HCl 3 -MeOH 10: 1).
【００９１】ついで、常法により脱アセチル化して化合
物207 を得た。ＲF ＝0.31（ＣＨＣｌ3 −ＭｅＯＨ−Ｈ
2 Ｏ 10：10：３）。Then, the compound was deacetylated by a conventional method to obtain a compound 207. R F = 0.31 (CHCl 3 -MeOH-H
2 O 10: 10: 3).
【００９２】［α］D -10.9°(C=0.34, MeOH)。[Α] D -10.9 ° (C = 0.34, MeOH).
【００９３】NMR： 1H ，δ（CD3 OD) 7.02(d,2H)，6.7
0(d,2H)，4.30(m,1H)，4.25(m,1H)，4.26(d,1H,J=7.6H
z)，4.25(d,1H,J=7.3Hz)，4.24(d,1H,J=7.6Hz)。NMR: 1 H, δ (CD 3 OD) 7.02 (d, 2H), 6.7
0 (d, 2H), 4.30 (m, 1H), 4.25 (m, 1H), 4.26 (d, 1H, J = 7.6H
z), 4.25 (d, 1H, J = 7.3 Hz), 4.24 (d, 1H, J = 7.6 Hz).
【００９４】(d) 化合物209 の合成 化合物208 のジ−活性エステル体（-OSu体）0.9mmol と
アミン体203(1.85mmol) をテトラヒドロフラン中、ＮＥ
ｔ3 存在下、室温で一晩反応させた。溶媒を酢酸エチル
に替え、重曹水で洗浄後シリカゲルカラムクロマトグラ
フィー（20：１ＣＨＣｌ3 −ＭｅＯＨ）にかけて化合物
209 を843mg 得た。収率91％。ＲF ＝0.61（ＣＨＣｌ3
−ＭｅＯＨ 10：１）。 (D) Synthesis of Compound 209 0.9 mmol of a di-active ester form (-OSu form) of compound 208 and an amine form 203 (1.85 mmol) were added to NE in tetrahydrofuran.
t 3 presence was reacted at room temperature overnight. The solvent was changed to ethyl acetate, washed with aqueous sodium bicarbonate, and then subjected to silica gel column chromatography (20: 1 CHCl 3 -MeOH) to give the compound.
843 mg of 209 was obtained. Yield 91%. R F = 0.61 (CHCl 3
-MeOH 10: 1).
【００９５】［α］D +0.21°(C=0.94,CDCl3 ）。[Α] D + 0.21 ° (C = 0.94, CDCl 3 ).
【００９６】NMR： 1H ，δ（CDCl3 ) 7.35(5H)，6.9
6，6.25，6.05，4.50(d,2H,J=7.6Hz)。NMR: 1 H, δ (CDCl 3 ) 7.35 (5H), 6.9
6, 6.25, 6.05, 4.50 (d, 2H, J = 7.6Hz).
【００９７】(e) 化合物210 の合成 化合物209 (515mg,0.5mmol) をエタノール（６ml）溶液
とし、10％Pd／C 及びp-TsOH存在下水添(45psi,3.5h)し
てアミン体とした後、溶媒をテトラヒドロフランに替え
た。これに3-(4-hydroxyphenyl)-propionic acid N-hyd
roxysuccinimide ester 0.8mmol を加え、ＮＥｔ3 ２mm
ol存在下室温で一晩攪拌反応させた。ついで溶媒を酢酸
エチルに替え、水洗したのちシリカゲルカラムクロマト
グラフィー（30：１ ＣＨＣｌ3 −ＭｅＯＨ）にかけて
380mgのオクタアセテート体を得た。収率73％。 (E) Synthesis of Compound 210 Compound 209 (515 mg, 0.5 mmol) was dissolved in ethanol (6 ml) and hydrogenated (45 psi, 3.5 h) in the presence of 10% Pd / C and p-TsOH to give an amine compound. Thereafter, the solvent was changed to tetrahydrofuran. 3- (4-hydroxyphenyl) -propionic acid N-hyd
Add 0.8 mmol of roxysuccinimide ester and add 2 mm of NEt 3
The reaction was stirred overnight at room temperature in the presence of ol. Then, the solvent was changed to ethyl acetate, washed with water, and then subjected to silica gel column chromatography (30: 1 CHCl 3 -MeOH).
380 mg of octaacetate was obtained. 73% yield.
【００９８】このオクタアセテート体 300mgをＮａＯＭ
ｅで処理して化合物210 を 183mg得た。ＲF ＝0.59（Ｃ
ＨＣｌ3 −ＭｅＯＨ−Ｈ2 Ｏ 10：10：３）。300 mg of this octaacetate compound was added to NaOM
e to give 183 mg of compound 210. R F = 0.59 (C
HCl 3 -MeOH-H 2 O 10 : 10: 3).
【００９９】［α］D -12.6°(C=0.66, MeOH)。[Α] D -12.6 ° (C = 0.66, MeOH).
【０１００】NMR： 1H ，δ(MeOH) 7.03(d,2H) ，6.70
(d,2H)，4.25(d,1H,J=7.6Hz)，4.24(d,1H,J=7.6Hz)。NMR: 1 H, δ (MeOH) 7.03 (d, 2H), 6.70
(d, 2H), 4.25 (d, 1H, J = 7.6 Hz), 4.24 (d, 1H, J = 7.6 Hz).
【０１０１】(f) 化合物212 の合成 化合物209 と同様にして、化合物208 のＤ体（化合物21
1)を得（収率98％）、ついで水添してアミン体のトシレ
ート塩である化合物212 を得た。 (F) Synthesis of Compound 212 Similarly to Compound 209, D-form of Compound 208 (Compound 21)
1) was obtained (98% yield) and then hydrogenated to obtain a compound 212 which was a tosylate salt of an amine compound.
【０１０２】(g) 化合物214 の合成 1.69ｇの化合物213 をDCC/HOSu法により2.82ｇの化合物
203 と縮合し、シリカゲルカラムクロマトグラフィー
（50：１ ＣＨＣｌ3 −ＭｅＯＨ）で精製するとベンジ
ルエステル体が2.775 ｇ得られた。収率78％。ＲF ＝0.
52（ＣＨＣｌ3 −ＭｅＯＨ 40：１）。 (G) Synthesis of Compound 214 1.69 g of Compound 213 was converted to 2.82 g of Compound 214 by the DCC / HOSu method.
The residue was purified by silica gel column chromatography (50: 1 CHCl 3 -MeOH) to obtain 2.775 g of a benzyl ester. 78% yield. R F = 0.
52 (CHCl 3 -MeOH 40: 1 ).
【０１０３】［α］D +2.4°(C=1.65,CH3 COCH3 ）。[Α] D + 2.4 ° (C = 1.65, CH 3 COCH 3 ).
【０１０４】NMR： 1H ，δ（CDCl3 ) 7.37(5H)，6.46
(1H)，4.49(d,1H,J=7.8Hz)，1.44(s,9H)。NMR: 1 H, δ (CDCl 3 ) 7.37 (5H), 6.46
(1H), 4.49 (d, 1H, J = 7.8 Hz), 1.44 (s, 9H).
【０１０５】ついで、このベンジルエステル体を水添
（10％Pd/C,EtOH,45psi,2h) して化合物214 を定量的に
得た。ＲF ＝0.34（ＣＨＣｌ3 −ＭｅＯＨ 10：１）。Then, the benzyl ester was hydrogenated (10% Pd / C, EtOH, 45 psi, 2 h) to give Compound 214 quantitatively. R F = 0.34 (CHCl 3 -MeOH 10: 1).
【０１０６】(h) 化合物215 の合成 1.07ｇの化合物212 と 620mgの化合物214 とをDCC/HOSu
法で縮合してシリカゲルカラムクロマトグラフィー（5
0：１ ＣＨＣｌ3 −ＭｅＯＨ）で精製すると化合物215
が 867mg得られた。収率58％。ＲF ＝0.54（ＣＨＣｌ
3 −ＭｅＯＨ 10：１）。 (H) Synthesis of compound 215 1.07 g of compound 212 and 620 mg of compound 214 were combined with DCC / HOSu
Column chromatography (5)
0: 1 CHCl 3 -MeOH) to give compound 215
867 mg were obtained. Yield 58%. R F = 0.54 (CHCl
3- MeOH 10: 1).
【０１０７】［α］D +2.8°(C=1.22,CH2 Cl2 ）。[Α] D + 2.8 ° (C = 1.22, CH 2 Cl 2 ).
【０１０８】NMR： 1H ，δ（CDCl3 ) 7.72，7.45，7.3
1，6.32，5.55，4.55(d,1H,J=8.1Hz)，4.51(d,1H,J=7.8
Hz)，1.43(s,9H)。NMR: 1 H, δ (CDCl 3 ) 7.72, 7.45, 7.3
1, 6.32, 5.55, 4.55 (d, 1H, J = 8.1 Hz), 4.51 (d, 1H, J = 7.8
Hz), 1.43 (s, 9H).
【０１０９】(i) 化合物216 の合成 化合物215 を 150mg、ＮａＯＭｅで処理して化合物216
を定量的に得た。ＲF ＝0.41（ＣＨＣｌ3 −ＭｅＯＨ−
Ｈ2 Ｏ 10：10：３）。 (I) Synthesis of Compound 216 150 mg of Compound 215 was treated with NaOMe to give Compound 216.
Was quantitatively obtained. R F = 0.41 (CHCl 3 -MeOH-
H 2 O 10: 10: 3 ).
【０１１０】［α］D +5.9°(C=0.17, MeOH)。[Α] D + 5.9 ° (C = 0.17, MeOH).
【０１１１】NMR： 1H ，δ（CD3 OD) 4.30および4.26
(m,1H)，4.26(d,1H,J=7.6Hz)，4.255(d,1H,J=7.1Hz) 。NMR: 1 H, δ (CD 3 OD) 4.30 and 4.26
(m, 1H), 4.26 (d, 1H, J = 7.6 Hz), 4.255 (d, 1H, J = 7.1 Hz).
【０１１２】(j) 化合物217 の合成 化合物215 (200mg) をトリフルオロ酢酸２mlに溶解し、
室温で１時間攪拌した。トリフルオロ酢酸を留去後、残
渣をアセトニトリル溶液とし、これに3-(4-hydroxyphen
yl)-propionic acid N-hydroxysuccinimide ester 46mg
及びＮＥｔ3 0.14mlを加え、室温で２時間攪拌した。溶
媒をクロロホルムに置換後、シリカゲルカラムクロマト
グラフィー（30：１ ＣＨＣｌ3 −ＭｅＯＨ）にかけて
アミド体200mgを得た（収率97％）。ＲF 0.68（ＣＨＣ
ｌ3 −ＭｅＯＨ 10：１）。 (J) Synthesis of Compound 217 Compound 215 (200 mg) was dissolved in 2 ml of trifluoroacetic acid,
Stirred at room temperature for 1 hour. After distilling off trifluoroacetic acid, the residue was converted to an acetonitrile solution, to which 3- (4-hydroxyphene) was added.
yl) -propionic acid N-hydroxysuccinimide ester 46mg
And 0.14 ml of NEt 3 were added, and the mixture was stirred at room temperature for 2 hours. After replacing the solvent with chloroform, the residue was subjected to silica gel column chromatography (30: 1 CHCl 3 -MeOH) to obtain 200 mg of the amide (97% yield). R F 0.68 (CHC
l 3 -MeOH 10: 1).
【０１１３】ついでＮａＯＭｅ処理をして化合物217 を
得た。ＲF ＝0.36（ＣＨＣｌ3 −ＭｅＯＨ−Ｈ2 Ｏ 1
0：10：３）。Then, NaOMe treatment was carried out to obtain Compound 217. R F = 0.36 (CHCl 3 -MeOH -H 2 O 1
0: 10: 3).
【０１１４】［α］D +1.1°(C=0.64, MeOH)。[Α] D + 1.1 ° (C = 0.64, MeOH).
【０１１５】NMR： 1H ，δ（CD3 OD) 7.04および6.70
(d,2H)，4.30×2(m,2H) ，4.254(d,1H,J=7.6Hz) ， 4.2
49×2(d,2H,J=7.3Hz) 。NMR: 1 H, δ (CD 3 OD) 7.04 and 6.70
(d, 2H), 4.30 × 2 (m, 2H), 4.254 (d, 1H, J = 7.6Hz), 4.2
49 × 2 (d, 2H, J = 7.3 Hz).
【０１１６】(k) 化合物218 の合成 化合物215 を前項(i) におけると同様にして処理して
（ただし、3-(4-hydroxyphenyl)-propionic acid N-hyd
roxysuccinimide ester に替え、palmitic acidN-hydro
xysuccinimide esterを用いた。）化合物218 を得た
（収率96％）。ＲF ＝0.74（ＣＨＣｌ3 −ＭｅＯＨ−Ｈ
2 Ｏ 10：10：３），ＲF ＝0.10（ＣＨＣｌ3 −ＭｅＯ
Ｈ−Ｈ2 Ｏ 65：30：4)。 (K) Synthesis of Compound 218 Compound 215 was treated in the same manner as in (i) above (provided that 3- (4-hydroxyphenyl) -propionic acid N-hyd
Replace palmitic acid N-hydro with roxysuccinimide ester
xysuccinimide ester was used. ) Compound 218 was obtained (96% yield). R F = 0.74 (CHCl 3 -MeOH -H
2 O 10: 10: 3), R F = 0.10 (CHCl 3 -MeO
H-H 2 O 65: 30 : 4).
【０１１７】［α］D -4.34°(C=0.99,CHCl3 ）。[Α] D -4.34 ° (C = 0.99, CHCl 3 ).
【０１１８】NMR： 1H ，δ（CDCl3 ) 7.80，7.41×2
，6.62，6.37，5.39(m,3H)， 5.16(dd×3, 3H)，5.03
(dd ×3, 3H)，4.70(m,1H)，5.56, 4.51, 4.51(d,1H,J=
8.1Hz)，3.95(m,3H)。NMR: 1 H, δ (CDCl 3 ) 7.80, 7.41 × 2
, 6.62, 6.37, 5.39 (m, 3H), 5.16 (dd × 3, 3H), 5.03
(dd × 3, 3H), 4.70 (m, 1H), 5.56, 4.51, 4.51 (d, 1H, J =
8.1Hz), 3.95 (m, 3H).
【０１１９】(l) 化合物220 の合成 化合物219 を、化合物213 の場合（前出(g) 項）と全く
同様に処理して化合物220 を得た。ＲF 値は化合物213
と同じであった。収率86％。 (L) Synthesis of Compound 220 Compound 220 was obtained by treating Compound 219 in the same manner as Compound 213 (item (g) above). R F value is Compound 213
Was the same as 86% yield.
【０１２０】なお、ベンジルエステル体の測定値は次の
通りであった。The measured values of the benzyl ester compound were as follows.
【０１２１】［α］D +3.1°(C=0.91,CH3 COCH3 ）。[Α] D + 3.1 ° (C = 0.91, CH 3 COCH 3 ).
【０１２２】NMR： 1H ，δ（CDCl3 ) 7.35(m,5H)，6.4
9(1H)，5.49(d,1H,J=7.8Hz)，2.15，2.06，2.04，1.9
8，1.43(s,9H)。NMR: 1 H, δ (CDCl 3 ) 7.35 (m, 5H), 6.4
9 (1H), 5.49 (d, 1H, J = 7.8Hz), 2.15, 2.06, 2.04, 1.9
8, 1.43 (s, 9H).
【０１２３】(m) 化合物221 の合成 化合物212 と化合物220 とから、化合物215 の合成（前
出(h) 項）と同じようにして、化合物221 を得た（収率
60％）。(M ) Synthesis of compound 221 Compound 221 was obtained from compound 212 and compound 220 in the same manner as in the synthesis of compound 215 (section (h)).
60%).
【０１２４】［α］D -2.2°(C=0.94,CH2 Cl2 ）。[Α] D -2.2 ° (C = 0.94, CH 2 Cl 2 ).
【０１２５】NMR： 1H ，δ（CDCl3 ) 7.42，7.26，7.1
8，6.88，5.59，4.53(d×3, 3H,J=7.8Hz)。NMR: 1 H, δ (CDCl 3 ) 7.42, 7.26, 7.1
8, 6.88, 5.59, 4.53 (d × 3, 3H, J = 7.8Hz).
【０１２６】(n) 化合物222 の合成 化合物221 を、化合物217 の合成（前出(j) 項）におけ
ると同様に処理してアセチル体化合物222 を得た（収率
98％）。 (N) Synthesis of Compound 222 Compound 221 was treated in the same manner as in the synthesis of compound 217 (Section (j) above) to give acetylated compound 222 (yield).
98%).
【０１２７】その測定値は次の通りであった。The measured values were as follows.
【０１２８】［α］D +2.6°(C=0.98,CHCl3 ）。[Α] D + 2.6 ° (C = 0.98, CHCl 3 ).
【０１２９】NMR： 1H ，δ（CDCl3 ) 7.08 and 6.82
(d,2H) ，7.05，6.98，6.68，6.60，6.42，5.40(m,3
H)， 2×4.53(d,2H,J=8.1Hz)，4.51(d,1H,J=7.8Hz)。NMR: 1 H, δ (CDCl 3 ) 7.08 and 6.82
(d, 2H), 7.05, 6.98, 6.68, 6.60, 6.42, 5.40 (m, 3
H), 2 × 4.53 (d, 2H, J = 8.1 Hz), 4.51 (d, 1H, J = 7.8 Hz).
【０１３０】また、化合物222 の測定値は、次の通りで
あった。The measured values of the compound 222 were as follows.
【０１３１】［α］D +10.6°(C=0.5, MeOH）。[Α] D + 10.6 ° (C = 0.5, MeOH).
【０１３２】NMR： 1H ，δ（CD3 OD) 7.04 and 6.70
(d,2H,J=8.6Hz) ，4.28(m,2H)，4.252(d,1H,J=7.8Hz)
，4.249(d,1H,J=7.1Hz) ，4.245(d,1H,J=7.3Hz) 。NMR: 1 H, δ (CD 3 OD) 7.04 and 6.70
(d, 2H, J = 8.6Hz), 4.28 (m, 2H), 4.252 (d, 1H, J = 7.8Hz)
, 4.249 (d, 1H, J = 7.1 Hz), 4.245 (d, 1H, J = 7.3 Hz).
【０１３３】(o) 化合物223 の合成 化合物221 を、化合物215 からの化合物218 の合成（前
出(k) 項）におけると同様の処理に付してアセチル体化
合物223 を得た（収率85％）。 (O) Synthesis of Compound 223 Compound 221 was subjected to the same treatment as in the synthesis of compound 218 from compound 215 (section (k) above) to give acetylated compound 223 (yield: 85). %).
【０１３４】その測定値は次の通りであった。The measured values were as follows.
【０１３５】［α］D -5.5°(C=1.01,CHCl3 ）。[Α] D -5.5 ° (C = 1.01, CHCl 3 ).
【０１３６】NMR： 1H ，δ（CDCl3 ) 7.70，7.22，7.0
1，6.94，6.64，4.54(d,1H,J=7.8Hz)，4.53(d,1H,J=8.1
Hz)，4.52(d,1H,J=7.8Hz)。NMR: 1 H, δ (CDCl 3 ) 7.70, 7.22, 7.0
1, 6.94, 6.64, 4.54 (d, 1H, J = 7.8 Hz), 4.53 (d, 1H, J = 8.1
Hz), 4.52 (d, 1H, J = 7.8Hz).
【０１３７】また化合物223 の測定値は次の通りであっ
た。The measured values of the compound 223 were as follows.
【０１３８】［α］D +3.1°(C=0.49,CHCl3 - MeOH-H2
O=10:10:3)。[Α] D + 3.1 ° (C = 0.49, CHCl 3 -MeOH-H 2
O = 10: 10: 3).
【０１３９】NMR： 1H ，δ（DMSO-D6) 7.9-7.7(4H)，
4.1(3H) ，0.86(t,3H)。NMR: 1 H, δ (DMSO-D6) 7.9-7.7 (4H),
4.1 (3H), 0.86 (t, 3H).
【０１４０】(p) 化合物224 の合成 化合物212 （１mmol) に、アセトニトリル８ml及びトル
エン８mlの混合溶媒中、palmitic acid N-hydroxysucci
nimide ester 1.2mmol及びＮＥｔ3 ３mmolを室温で一晩
作用させてオクタアセテート体を1.058 ｇ得た。収率93
％。シリカゲルカラムクロマトグラフィー（40：１ Ｃ
ＨＣｌ3 −ＭｅＯＨ）にかけて精製。ＲF ＝0.47（ＣＨ
Ｃｌ3 −ＭｅＯＨ 20：１）。 (P) Synthesis of Compound 224 Compound 212 (1 mmol) was added to palmitic acid N-hydroxysucci in a mixed solvent of 8 ml of acetonitrile and 8 ml of toluene.
1.2 mmol of nimide ester and 3 mmol of NEt 3 were allowed to act overnight at room temperature to obtain 1.058 g of an octaacetate compound. Yield 93
%. Silica gel column chromatography (40: 1 C
HCl 3 -MeOH). R F = 0.47 (CH
Cl 3 -MeOH 20: 1).
【０１４１】ついで、ＮａＯＭｅ処理することにより化
合物224 を定量的に得た。ＲF ＝0.15（ＣＨＣｌ3 −Ｍ
ｅＯＨ−Ｈ2 Ｏ 65：30：４）。Then, the compound 224 was quantitatively obtained by NaOMe treatment. R F = 0.15 (CHCl 3 -M
eOH-H 2 O 65: 30 : 4).
【０１４２】NMR： 1H ，δ(C5 H5 N) 4.79 and 4.78
(d,1H,J=7.6Hz)，0.87(t,3H)。NMR: 1 H, δ (C 5 H 5 N) 4.79 and 4.78
(d, 1H, J = 7.6Hz), 0.87 (t, 3H).
【０１４３】(q) 化合物228 の合成（図２ｆ） 1) 化合物225 の合成 β−Ｄ−ガラクトースペンタアセテート化合物201 、5.
254 ｇ及び２−［２−（２−アジドエトキシ）エトキ
シ］エタノール3.066 ｇを塩化メチレン50mlに溶かし、
氷冷下撹拌した。ここに三フッ化硼素ジエチルエーテル
錯体6.62mlを塩化メチレン10mlに溶かして10分間で滴下
した。室温で14時間撹拌した後、氷水にあけ、有機層を
分離した。３回水洗した後（水層は中性となった）、飽
和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を
減圧下留去した。残渣をシリカゲルカラムクロマトグラ
フィーで精製し（溶出溶媒：ｎ−ヘキサン−酢酸エチル
１：１）、目的物を無色油状物として2.62ｇ得た。 (Q) Synthesis of compound 228 (FIG. 2f) 1) Synthesis of compound 225 β-D-galactose pentaacetate compound 201, 5.
254 g and 3.066 g of 2- [2- (2-azidoethoxy) ethoxy] ethanol were dissolved in 50 ml of methylene chloride.
The mixture was stirred under ice cooling. Here, 6.62 ml of boron trifluoride-diethyl ether complex was dissolved in 10 ml of methylene chloride and added dropwise over 10 minutes. After stirring at room temperature for 14 hours, the mixture was poured into ice water and the organic layer was separated. After washing three times with water (the aqueous layer became neutral), it was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 1: 1) to obtain 2.62 g of the desired product as a colorless oil.
【０１４４】 1H-NMR(δ, CDCl3 ) ：1.99(s,3H)，2.05
(s,3H)，2.06(s,3H)，2.15(s,3H)，3.40(t,2H,J=5.0H
z)，3.64-3.69(m,8H) ，3.73-3.78(m,1H) ，3.90-3.93
(m,1H)，3.94-3.98(m,1H) ，4.12(dd,1H,J=6.8Hz,11.2H
z)，4.18(dd,1H,J=6.3Hz,11.2Hz)，4.57(d,1H,J=8.1H
z)，5.02(dd,1H,J=3.4Hz,10.5Hz)，5.21(dd,1H,J=8.1H
z,10.5Hz)，5.39(dd,1H,J=1.0Hz,3.4Hz) 。 1 H-NMR (δ, CDCl 3 ): 1.99 (s, 3H), 2.05
(s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 3.40 (t, 2H, J = 5.0H
z), 3.64-3.69 (m, 8H), 3.73-3.78 (m, 1H), 3.90-3.93
(m, 1H), 3.94-3.98 (m, 1H), 4.12 (dd, 1H, J = 6.8Hz, 11.2H
z), 4.18 (dd, 1H, J = 6.3Hz, 11.2Hz), 4.57 (d, 1H, J = 8.1H
z), 5.02 (dd, 1H, J = 3.4Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.1H
z, 10.5Hz), 5.39 (dd, 1H, J = 1.0Hz, 3.4Hz).
【０１４５】［α］D 20= -8.1゜(c=1.03 ，CHCl3 ) 。[Α] D 20 = −8.1 ゜ (c = 1.03, CHCl 3 ).
【０１４６】２）化合物226 の合成 化合物225 、0.928 ｇに酢酸エチル70mlを加えて溶かし
た。ここにｐ−トルエンスルホン酸１水和物0.350 ｇ及
びリンドラー触媒0.506 ｇを加え、50ｐｓｉで４時間接
触還元した。さらにリンドラー触媒0.509 ｇを加え、50
ｐｓｉで６時間接触還元した。触媒を濾去し、目的物を
淡褐色油状物として1.001 ｇ得た。これ以上の精製はせ
ずに、以下の反応に用いた。2) Synthesis of compound 226 To 0.928 g of compound 225, 70 ml of ethyl acetate was added and dissolved. 0.350 g of p-toluenesulfonic acid monohydrate and 0.506 g of Lindlar catalyst were added thereto, and the mixture was catalytically reduced at 50 psi for 4 hours. Add 0.509 g of Lindlar's catalyst and add 50
Catalytic reduction was performed at psi for 6 hours. The catalyst was removed by filtration to obtain 1.001 g of the desired product as a pale brown oil. It was used for the following reaction without further purification.
【０１４７】３）化合物227 の合成 化合物226 、1.001 ｇに塩化メチレン20mlを加え、ここ
にトリエチルアミン214 μｌを加えて均一溶液とし、氷
冷下撹拌した。ここに（Ｎ−パルミトイルオキシ）スク
シンイミド0.815 ｇを塩化メチレン６mlに溶かして加
え、室温まで昇温させながら３日間撹拌した。減圧下溶
媒を留去し、残渣をシリカゲルクロマトグラフィーで精
製して（溶出溶媒：ｎ−ヘキサン−酢酸エチル １：
１）、目的物を0.38ｇ得た。3) Synthesis of compound 227 To 1.001 g of compound 226, 20 ml of methylene chloride was added, and 214 μl of triethylamine was added thereto to form a homogeneous solution, which was stirred under ice cooling. 0.815 g of (N-palmitoyloxy) succinimide dissolved in 6 ml of methylene chloride was added thereto, and the mixture was stirred for 3 days while warming to room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: n-hexane-ethyl acetate 1:
1) 0.38 g of the desired product was obtained.
【０１４８】 1H-NMR(δ, CDCl3 ) ：0.87(t,3H,J=7.0H
z)，1.16-1.32(m,24H)，1.59-1.65(m,2H) ，1.99(s,3
H)，2.05(s,3H) 2.06(s,3H) ，2.15(s,3H)，2.18(t,2H,
J=7.6Hz)，3.44-3.48(m,2H) ，3.55(t,2H,J=5.3Hz)，3.
59-3.67(m,6H) ，3.72-3.76(m,1H) ，3.90-3.93(m,1H)
，3.97-4.00(m,1H) ，4.13(dd,1H,J=6.8Hz,11.2Hz)，
4.18(dd,1H,J=6.3Hz,11.2Hz)，4.55(d,1H,J=7.8Hz)，5.
02(dd,1H,J=3.3Hz,10.3Hz)，5.21(dd,1H,J=7.8Hz,10.3H
z)，5.39(dd,1H,J=0.5Hz,3.3Hz) ，6.04(bs,1H) 。 1 H-NMR (δ, CDCl 3 ): 0.87 (t, 3H, J = 7.0H
z), 1.16-1.32 (m, 24H), 1.59-1.65 (m, 2H), 1.99 (s, 3
H), 2.05 (s, 3H) 2.06 (s, 3H), 2.15 (s, 3H), 2.18 (t, 2H,
J = 7.6Hz), 3.44-3.48 (m, 2H), 3.55 (t, 2H, J = 5.3Hz), 3.
59-3.67 (m, 6H), 3.72-3.76 (m, 1H), 3.90-3.93 (m, 1H)
, 3.97-4.00 (m, 1H), 4.13 (dd, 1H, J = 6.8Hz, 11.2Hz),
4.18 (dd, 1H, J = 6.3Hz, 11.2Hz), 4.55 (d, 1H, J = 7.8Hz), 5.
02 (dd, 1H, J = 3.3Hz, 10.3Hz), 5.21 (dd, 1H, J = 7.8Hz, 10.3H
z), 5.39 (dd, 1H, J = 0.5 Hz, 3.3 Hz), 6.04 (bs, 1H).
【０１４９】［α］D 23=-7.1 ゜(c=1.02 ，CHCl3 ) 。[Α] D 23 = −7.1 c (c = 1.02, CHCl 3 ).
【０１５０】４）化合物228 の合成 化合物227 、1.42ｇにメタノール20mlを加えて、氷冷下
撹拌した。ここに28％ナトリウムメトキシドメタノール
溶液を６滴加えてｐＨ＝12とし、室温で12.5時間撹拌し
た。ここに「ダウエックス50Ｘ−８」イオン交換樹脂
（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒を減圧
下留去し、残渣を「セファデックスＬＨ−20」で精製し
（溶出溶媒：クロロホルム−メタノール １：１）、目
的化合物を1.11ｇ得た。4) Synthesis of compound 228 To 1.42 g of compound 227, 20 ml of methanol was added, and the mixture was stirred under ice cooling. To this was added 6 drops of a 28% sodium methoxide methanol solution to adjust the pH to 12, followed by stirring at room temperature for 12.5 hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 1: 1) to obtain 1.11 g of the desired compound.
【０１５１】 1H-NMR(δ, pyridine-d5 -D2 O)：0.87
(t,3H,J=7.0Hz)，1.23-1.38(m,24H)，1.80(quintet,2H,
J=7.6Hz)，2.40(t,1H,J=7.6Hz)，3.55-3.57(m,2H) ，3.
58-3.60(m,6H) ，3.63-3.71(m,6H) ，3.89(dt,1H,J=5.3
Hz,10.6Hz)，4.02-4.05(m,1H)，4.13(dd,1H,J=3.4Hz,9.
5Hz) ，4.25(dt,1H,J=5.3Hz,10.6Hz)，4.41-4.44(m,3H)
，4.54(bd,1H) ，4.78(d,1H,J=7.6Hz)，8.54(bt,1H)
。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.87
(t, 3H, J = 7.0Hz), 1.23-1.38 (m, 24H), 1.80 (quintet, 2H,
J = 7.6Hz), 2.40 (t, 1H, J = 7.6Hz), 3.55-3.57 (m, 2H), 3.
58-3.60 (m, 6H), 3.63-3.71 (m, 6H), 3.89 (dt, 1H, J = 5.3
Hz, 10.6Hz), 4.02-4.05 (m, 1H), 4.13 (dd, 1H, J = 3.4Hz, 9.
5Hz), 4.25 (dt, 1H, J = 5.3Hz, 10.6Hz), 4.41-4.44 (m, 3H)
, 4.54 (bd, 1H), 4.78 (d, 1H, J = 7.6 Hz), 8.54 (bt, 1H)
.
【０１５２】［α］D 25=-1.7 ゜(c=1.00 ，CHCl3 -MeO
H 1:1)。[Α] D 25 = −1.7 ゜ (c = 1.00, CHCl 3 -MeO
H 1: 1).
【０１５３】FAB-MS:[M+H]+ ;m/z=550。FAB-MS: [M + H] + ; m / z = 550.
【０１５４】(r) 化合物230 の合成（図２ｇ） １）化合物229 の合成 β−ガラクトースペンタアセテート（化合物201 ）1.14
1 ｇ及びＮ−パルミトイルエタノールアミン1.137 ｇを
塩化メチレン15mlに溶かし、氷冷下撹拌した。ここに三
フッ化硼素ジエチルエーテル錯体1.44mlを加えた。室温
で21時間撹拌した後、氷水にあけ、有機層を分離した。
４回水洗した後（水層は中性となった）、飽和食塩水で
洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去
した。残渣をシリカゲルカラムクロマトグラフィーで精
製し（溶出溶媒：トルエン−酢酸エチル ３：２）、目
的物を1.43ｇ得た。 (R) Synthesis of Compound 230 (FIG. 2g) 1) Synthesis of Compound 229 β-galactose pentaacetate (Compound 201) 1.14
1 g and N-palmitoylethanolamine (1.137 g) were dissolved in methylene chloride (15 ml) and stirred under ice-cooling. To this, 1.44 ml of boron trifluoride diethyl ether complex was added. After stirring at room temperature for 21 hours, the mixture was poured into ice water and the organic layer was separated.
After washing four times with water (the aqueous layer became neutral), it was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene-ethyl acetate 3: 2) to give 1.43 g of the desired product.
【０１５５】 1H-NMR(δ, CDCl3 ) ：0.88(t,3H,J=7.0H
z)，1.18-1.33(m,24H)，1.59-1.65(m,2H) ，1.99(s,3
H)，2.05(s,3H)，2.07(s,3H)，2.16(s,3H)，2.16(m,1
H)，3.39-3.45(m,1H) ，3.48-3.54(m,1H) ，3.66-3.70
(m,1H) ，3.85-3.89(m,1H) ，3.90-3.93(m,1H) ，4.14
(dd,1H,J=5.6Hz,10.4Hz)，4.18(dd,1H,J=5.9Hz,10.4H
z)，4.47(d,1H,J=7.9Hz)，5.02(dd,1H,J=5.6Hz,10.4H
z)，5.19(dd,1H,J=7.9Hz,10.5Hz)，5.40(dd,1H,J=1.0H
z) ，6.04(bt,1H) 。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 3H, J = 7.0H
z), 1.18-1.33 (m, 24H), 1.59-1.65 (m, 2H), 1.99 (s, 3
H), 2.05 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 2.16 (m, 1
H), 3.39-3.45 (m, 1H), 3.48-3.54 (m, 1H), 3.66-3.70
(m, 1H), 3.85-3.89 (m, 1H), 3.90-3.93 (m, 1H), 4.14
(dd, 1H, J = 5.6Hz, 10.4Hz), 4.18 (dd, 1H, J = 5.9Hz, 10.4H
z), 4.47 (d, 1H, J = 7.9Hz), 5.02 (dd, 1H, J = 5.6Hz, 10.4H
z), 5.19 (dd, 1H, J = 7.9Hz, 10.5Hz), 5.40 (dd, 1H, J = 1.0H
z), 6.04 (bt, 1H).
【０１５６】［α］D 23=+0.1 ゜(c=1.01 ，CHCl3 -MeO
H 1:1)。[Α] D 23 = + 0.1 c (c = 1.01, CHCl 3 -MeO
H 1: 1).
【０１５７】２）化合物230 の合成 化合物229 、1.10ｇにメタノール15mlを加えて溶かし、
氷冷下撹拌した。ここに28％ナトリウムメトキシドメタ
ノール溶液を６滴加えてｐＨ＝13とし、室温で30分間撹
拌した。沈殿が生じたため、ベンゼン10mlを加え、さら
に室温で7.5 時間撹拌した。ここにクロロホルムを加え
て沈殿を溶かし、「ダウエックス50Ｘ−８」イオン交換
樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒を
減圧下留去し、残渣を塩化メチレン−ｎ−ヘキサンから
再沈殿させて、目的化合物を0.72ｇ得た。2) Synthesis of Compound 230 To 1.10 g of Compound 229, 15 ml of methanol was added and dissolved.
The mixture was stirred under ice cooling. To this was added 6 drops of a 28% sodium methoxide methanol solution to adjust the pH to 13, followed by stirring at room temperature for 30 minutes. Since precipitation occurred, 10 ml of benzene was added, and the mixture was further stirred at room temperature for 7.5 hours. Chloroform was added thereto to dissolve the precipitate, neutralized by adding "Dowex 50X-8" ion exchange resin (H type), and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was reprecipitated from methylene chloride-n-hexane to obtain 0.72 g of the desired compound.
【０１５８】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,3H,J=7.0Hz)，1.18-1.33(m,24H)，1.78(quintet,2H,
J=7.6Hz)，2.40(t,1H,J=7.6Hz)，3.71-3.82(m,1H) ，3.
97-4.01(m,1H) ，4.03(bt,1H) ，4.13(dd,1H,J=3.3Hz,
9.6Hz) ，4.20-4.25(m,1H) ，4.37(dd,1H,J=5.5Hz,11.1
Hz)，4.41(dd,1H,J=6.7Hz,11.1Hz)，4.43(bt,1H) ，4.5
0(d,1H,J=3.3Hz)，4.77(d,1H,J=7.8Hz)，8.61(bt,1H)
。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88
(t, 3H, J = 7.0Hz), 1.18-1.33 (m, 24H), 1.78 (quintet, 2H,
J = 7.6Hz), 2.40 (t, 1H, J = 7.6Hz), 3.71-3.82 (m, 1H), 3.
97-4.01 (m, 1H), 4.03 (bt, 1H), 4.13 (dd, 1H, J = 3.3Hz,
9.6Hz), 4.20-4.25 (m, 1H), 4.37 (dd, 1H, J = 5.5Hz, 11.1)
Hz), 4.41 (dd, 1H, J = 6.7Hz, 11.1Hz), 4.43 (bt, 1H), 4.5
0 (d, 1H, J = 3.3Hz), 4.77 (d, 1H, J = 7.8Hz), 8.61 (bt, 1H)
.
【０１５９】［α］D 25=+2.6 ゜(c=1.01 ，CHCl3 -MeO
H- H2 O 10:10:3)。[Α] D 25 = + 2.6 ゜ (c = 1.01, CHCl 3 -MeO
H- H 2 O 10: 10: 3).
【０１６０】FAB-MS:[M+H]+ ;m/z=462。FAB-MS: [M + H] + ; m / z = 462.
【０１６１】(s) 化合物235 の合成（図２ｈ） １）化合物231 の合成 β−Ｄ−ガラクトースペンタアセテート5.030 ｇ及び２
−（２−クロロエトキシ）エタノール2.179 ｇ塩化メチ
レン50mlに溶かし、氷冷下撹拌した。ここに三フッ化硼
素ジエチルエーテル錯体6.34mlを塩化メチレン10mlに溶
かして10分間で滴下した。室温で11時間撹拌した後、氷
水にあけ、有機層を分離した。３回水洗した後（水層は
中性となった）、飽和食塩水で洗い、硫酸マグネシウム
上乾燥させ、溶媒を減圧下留去した。残渣をシリカゲル
カラムクロマトグラフィーで精製し（溶出溶媒：ｎ−ヘ
キサン−酢酸エチル ３：２）、目的物を無償油状物と
して3.81ｇ得た。 (S) Synthesis of Compound 235 (FIG. 2h) 1) Synthesis of Compound 231 5.030 g of β-D-galactose pentaacetate and 2
-(2-Chloroethoxy) ethanol was dissolved in 2.179 g of methylene chloride in 50 ml and stirred under ice cooling. Here, 6.34 ml of boron trifluoride-diethyl ether complex was dissolved in 10 ml of methylene chloride and added dropwise over 10 minutes. After stirring at room temperature for 11 hours, the mixture was poured into ice water and the organic layer was separated. After washing three times with water (the aqueous layer became neutral), it was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 3: 2) to obtain 3.81 g of the desired product as a free oil.
【０１６２】 1H-NMR(δ, CDCl3 ) ：1.99(s,3H)，2.05
(s,3H)，2.07(s,3H)，2.15(s,3H)，3.61-3.63(m,2H) ，
3.67-3.70(m,2H) ，3.73-3.79(m,3H) ，3.90-3.93(m,1
H) ，3.95-3.99(m,1H) ，4.13(dd,1H,J=6.8Hz,11.2H
z)，4.18(dd,1H,J=6.6Hz,11.2Hz)，4.58(d,1H,J=8.0H
z)，5.02(dd,1H,J=3.4Hz,10.5Hz)，5.22(dd,1H,J=8.0H
z,10.5Hz)，5.39(dd,1H,J=1.0Hz,3.4Hz) ，。 1 H-NMR (δ, CDCl 3 ): 1.99 (s, 3H), 2.05
(s, 3H), 2.07 (s, 3H), 2.15 (s, 3H), 3.61-3.63 (m, 2H),
3.67-3.70 (m, 2H), 3.73-3.79 (m, 3H), 3.90-3.93 (m, 1
H), 3.95-3.99 (m, 1H), 4.13 (dd, 1H, J = 6.8Hz, 11.2H
z), 4.18 (dd, 1H, J = 6.6Hz, 11.2Hz), 4.58 (d, 1H, J = 8.0H
z), 5.02 (dd, 1H, J = 3.4Hz, 10.5Hz), 5.22 (dd, 1H, J = 8.0H
z, 10.5Hz), 5.39 (dd, 1H, J = 1.0Hz, 3.4Hz) ,.
【０１６３】［α］D 20=-10.6゜(c=1.03 ，CHCl3 ) 。[Α] D 20 = -10.6 ゜ (c = 1.03, CHCl 3 ).
【０１６４】２）化合物232 の合成 化合物231 、3.619 ｇをＮ，Ｎ−ジメチルホルムアミド
50mlに溶かし、アジ化ナトリウム1.035 ｇを加え、窒素
雰囲気下60℃で16時間撹拌した。酢酸エチル約150ml を
加え、沈殿を濾去し、溶媒を減圧下留去した。ｌ残渣を
酢酸エチルに溶かし、水洗し、硫酸マグネシウム上乾燥
させ、溶媒を減圧下留去した。残渣をシリカゲルカラム
クロマトグラフィーで精製し（溶出溶媒：ｎ−ヘキサン
−酢酸エチル ２：３）、目的物を無色油状物として3.
479 ｇ得た。2) Synthesis of compound 232 3.619 g of compound 231, N, N-dimethylformamide
The mixture was dissolved in 50 ml, 1.035 g of sodium azide was added, and the mixture was stirred at 60 ° C. for 16 hours under a nitrogen atmosphere. About 150 ml of ethyl acetate was added, the precipitate was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate 2: 3) to give the desired product as a colorless oil.
479 g were obtained.
【０１６５】 1H-NMR(δ, CDCl3 ) ：1.99(s,3H)，2.05
(s,3H)，2.07(s,3H)，2.15(s,3H)，3.33-3.42(m,2H) ，
3.65-3.68(m,4H) ，3.75-3.79(m,1H) ，3.90-3.93(m,1
H) ，3.97(dt,1H,J=4.0Hz,7.2Hz) ，4.13(dd,1H,J=6.8H
z,11.2Hz)，4.18(dd,1H,J=6.3Hz,11.2Hz)，4.59(d,1H,J
=7.8Hz)，5.03(dd,1H,J=3.4Hz,10.5Hz)，5.22(dd,1H,J=
7.8Hz,10.5Hz)，5.39(dd,1H,J=1.0Hz,3.4Hz) 。 1 H-NMR (δ, CDCl 3 ): 1.99 (s, 3H), 2.05
(s, 3H), 2.07 (s, 3H), 2.15 (s, 3H), 3.33-3.42 (m, 2H),
3.65-3.68 (m, 4H), 3.75-3.79 (m, 1H), 3.90-3.93 (m, 1
H), 3.97 (dt, 1H, J = 4.0Hz, 7.2Hz), 4.13 (dd, 1H, J = 6.8H
z, 11.2Hz), 4.18 (dd, 1H, J = 6.3Hz, 11.2Hz), 4.59 (d, 1H, J
= 7.8Hz), 5.03 (dd, 1H, J = 3.4Hz, 10.5Hz), 5.22 (dd, 1H, J =
7.8Hz, 10.5Hz), 5.39 (dd, 1H, J = 1.0Hz, 3.4Hz).
【０１６６】［α］D 27=-11.5゜(c=1.00 ，CHCl3 ) 。[Α] D 27 = -11.5 ゜ (c = 1.00, CHCl 3 ).
【０１６７】３）化合物233 の合成 化合物232 、0.961 ｇに酢酸エチル90mlを加えて溶かし
た。ここにｐ−トルエンスルホン酸１水和物0.363 ｇ及
びリンドラー触媒0.483 ｇを加え、50ｐｓｉで３時間接
触還元した。さらにリンドラー触媒0.480 ｇを加え、50
ｐｓｉで5.5 時間接触還元した。触媒を濾去し、目的物
を淡褐色油状物として0.083 ｇ得た。これ以上の精製は
せずに、以下の反応に用いた。3) Synthesis of compound 233 90 ml of ethyl acetate was added to 0.961 g of compound 232 and dissolved. 0.363 g of p-toluenesulfonic acid monohydrate and 0.483 g of a Lindlar catalyst were added thereto, and the mixture was catalytically reduced at 50 psi for 3 hours. Further, 0.480 g of Lindlar catalyst was added, and 50
Catalytic reduction at psi for 5.5 hours. The catalyst was removed by filtration to obtain 0.083 g of the desired product as a pale brown oil. It was used for the following reaction without further purification.
【０１６８】４）化合物1103の合成 ２−（ｎ−ヘキサデシル）オクタデカン酸0.965 ｇに塩
化チオニル４mlを加え、３時間加熱還流させた。塩化チ
オニルを減圧下留去した。残渣にベンゼンを加えて溶か
し、減圧下留去した（２回）。これ以上の精製はせず
に、以下の反応に用いた。4) Synthesis of Compound 1103 To 0.965 g of 2- (n-hexadecyl) octadecanoic acid was added 4 ml of thionyl chloride, and the mixture was refluxed for 3 hours. Thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue to dissolve it, and evaporated under reduced pressure (twice). It was used for the following reaction without further purification.
【０１６９】５）化合物234 の合成 化合物233 、0.887 ｇに塩化メチレン10ml及びトリエチ
ルアミン465 μｌを加えて溶かし、ここに上記反応で得
た化合物1103全量を塩化メチレン５mlに溶かして加え、
室温に昇温させつつ12時間撹拌した。塩化メチレンで希
釈し、水及び飽和食塩水で洗い、硫酸マグネシウム上乾
燥させ、溶媒を減圧下留去した。残渣をシリカゲルカラ
ムクロマトグラフィーで精製し（溶出溶媒：ｎ−ヘキサ
ン−酢酸エチル １：１）、目的物を無色油状物として
0.935 ｇ得た。5) Synthesis of Compound 234 To 0.887 g of Compound 233, 10 mL of methylene chloride and 465 μL of triethylamine were added and dissolved, and the entire amount of Compound 1103 obtained by the above reaction was dissolved in 5 mL of methylene chloride and added.
The mixture was stirred for 12 hours while warming to room temperature. The mixture was diluted with methylene chloride, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate 1: 1) to give the desired product as a colorless oil.
0.935 g was obtained.
【０１７０】 1H-NMR(δ, CDCl3 ) ：0.88(t,6H,J=7.0H
z)，1.21-1.34(m,56H)，1.35-1.44(m,2H) ，1.53-1.63
(m,2H) ，2.04-2.08(m,1H) ，1.99(s,3H)，2.05(s,3
H)，2.06(s,3H)，2.15(s,3H)，3.36-3.43(m,1H) ，3.48
-3.54(m,3H) ，3.60(bt,2H) ，3.70(dt,1H,J=5.3Hz,10.
6Hz)，3.90-3.93(m,1H) ，3.98(dt,1H,J=4.2Hz,10.6H
z)，4.13(dd,1H,J=7.0Hz,11.2Hz)，4.19(Gal C6-H,dd,1
H,J=6.3Hz,11.2Hz) ，4.53(d,1H,J=8.0Hz)，5.04(dd,1
H,J=3.3Hz,10.5Hz)，5.22(dd,1H,J=8.0Hz,10.5Hz)，5.4
0(dd,1H,J=0.7Hz,3.3Hz) ，5.97(t,1H,J=5.2Hz)。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 6H, J = 7.0H
z), 1.21-1.34 (m, 56H), 1.35-1.44 (m, 2H), 1.53-1.63
(m, 2H), 2.04-2.08 (m, 1H), 1.99 (s, 3H), 2.05 (s, 3
H), 2.06 (s, 3H), 2.15 (s, 3H), 3.36 to 3.43 (m, 1H), 3.48
-3.54 (m, 3H), 3.60 (bt, 2H), 3.70 (dt, 1H, J = 5.3Hz, 10.
6Hz), 3.90-3.93 (m, 1H), 3.98 (dt, 1H, J = 4.2Hz, 10.6H
z), 4.13 (dd, 1H, J = 7.0Hz, 11.2Hz), 4.19 (Gal C6-H, dd, 1
H, J = 6.3Hz, 11.2Hz), 4.53 (d, 1H, J = 8.0Hz), 5.04 (dd, 1
H, J = 3.3Hz, 10.5Hz), 5.22 (dd, 1H, J = 8.0Hz, 10.5Hz), 5.4
0 (dd, 1H, J = 0.7Hz, 3.3Hz), 5.97 (t, 1H, J = 5.2Hz).
【０１７１】［α］D 26=-10.0゜(c=1.01 ，CHCl3 ) 。[Α] D 26 = -10.0 ゜ (c = 1.01, CHCl 3 ).
【０１７２】６）化合物235 の合成 化合物234 、0.865 ｇにメタノール7.5ml 及びベンゼン
15mlを加えて溶かした。ここに28％ナトリウムメトキシ
ドメタノール溶液を５滴加えてｐＨ＝11とし、室温で75
分間撹拌した。ここに「ダウエックス50Ｘ−８」イオン
交換樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶
媒を減圧下留去し、残渣を「セファデックスＬＨ−20」
で精製し（溶出溶媒：クロロホルム−メタノール １：
１）、目的化合物を0.672 ｇ得た。6) Synthesis of compound 235 To 0.865 g of compound 234 was added 7.5 ml of methanol and benzene.
15 ml was added and dissolved. 5 drops of a 28% sodium methoxide methanol solution are added thereto to adjust the pH to 11, and
Stirred for minutes. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was separated using "Sephadex LH-20".
(Elution solvent: chloroform-methanol 1:
1), 0.672 g of the target compound was obtained.
【０１７３】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,6H,J=6.8Hz)，1.20-1.38(m,52H)，1.42-1.60(m,6H)
，1.90-1.98(m,2H) ，2.51-2.57(m,1H) ，3.68-3.78
(m,6H) ，3.92(dt,1H,J=5.3Hz,10.8Hz)，4.01-4.04(m,1
H) ，4.13(dd,1H,J=3.4Hz,9.5Hz)，4.24(dt,1H,J=4.8H
z,10.8Hz)，4.39-4.43(m,3H) ，4.53(bd,1H) ，4.78(d,
1H,J=7.8Hz,) ，8.76(bt,1H) 。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88
(t, 6H, J = 6.8Hz), 1.20-1.38 (m, 52H), 1.42-1.60 (m, 6H)
, 1.90-1.98 (m, 2H), 2.51-2.57 (m, 1H), 3.68-3.78
(m, 6H), 3.92 (dt, 1H, J = 5.3Hz, 10.8Hz), 4.01-4.04 (m, 1
H), 4.13 (dd, 1H, J = 3.4Hz, 9.5Hz), 4.24 (dt, 1H, J = 4.8H
z, 10.8Hz), 4.39-4.43 (m, 3H), 4.53 (bd, 1H), 4.78 (d,
1H, J = 7.8Hz,), 8.76 (bt, 1H).
【０１７４】［α］D 28= -1.9゜(c=0.99 ，CHCl3 -MeO
H 1:1)。[Α] D 28 = -1.9 ゜ (c = 0.99, CHCl 3 -MeO
H 1: 1).
【０１７５】FAB-MS:[M+H]+ ;m/z=758。FAB-MS: [M + H] + ; m / z = 758.
【０１７６】(t) 化合物237 の合成（図２ｉ） １）化合物236 の合成 化合物233 、0.757 ｇに塩化メチレン10mlを加えて氷冷
下撹拌した。ここにトリエチルアミン174 μｌを加え、
氷冷下撹拌した。ここに（Ｎ−パルミトイルオキシ）ス
クシンイミド0.882 ｇを塩化メチレン５mlに溶かして加
え、室温まで昇温させながら21時間撹拌した。減圧下溶
媒を留去し、残渣をシリカゲルクロマトグラフィーで精
製して（溶出溶媒：ｎ−ヘキサン−酢酸エチル １：
３）、目的物を0.70ｇ得た。 (T) Synthesis of Compound 237 (FIG. 2I) 1) Synthesis of Compound 236 To 0.757 g of Compound 233, 10 mL of methylene chloride was added, and the mixture was stirred under ice cooling. To this, add 174 μl of triethylamine,
The mixture was stirred under ice cooling. 0.882 g of (N-palmitoyloxy) succinimide dissolved in 5 ml of methylene chloride was added thereto, and the mixture was stirred for 21 hours while warming to room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: n-hexane-ethyl acetate 1:
3), 0.70 g of the desired product was obtained.
【０１７７】 1H-NMR(δ, CDCl3 ) ：0.88(t,3H,J=7.0H
z)，1.22-1.33(m,24H)，1.61-1.67(m,2H) ，2.00(s,3
H)，2.05(s,3H)，2.06(s,3H)，2.15(s,3H)，2.11(t,2H,
J=7.6Hz)，3.34-3.40(m,1H) ，3.47-3.57(m,3H) ，3.58
-3.65(m,4H) ，3.68-3.72(m,1H) ，3.90-3.93(m,1H) ，
3.96-4.00(m,1H) ，4.13(dd,1H,J=7.1Hz,11.3Hz)，4.19
(dd,1H,J=6.5Hz,11.3Hz)，4.52(d,1H,J=7.8Hz)，5.04(d
d,1H,J=3.4Hz,10.5Hz)，5.22(dd,1H,J=7.8Hz,10.5Hz)，
5.39(dd,1H,J=1.0Hz,3.4Hz) ，6.06(bs,1H) 。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 3H, J = 7.0H
z), 1.22-1.33 (m, 24H), 1.61-1.67 (m, 2H), 2.00 (s, 3
H), 2.05 (s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 2.11 (t, 2H,
J = 7.6Hz), 3.34-3.40 (m, 1H), 3.47-3.57 (m, 3H), 3.58
-3.65 (m, 4H), 3.68-3.72 (m, 1H), 3.90-3.93 (m, 1H),
3.96-4.00 (m, 1H), 4.13 (dd, 1H, J = 7.1Hz, 11.3Hz), 4.19
(dd, 1H, J = 6.5Hz, 11.3Hz), 4.52 (d, 1H, J = 7.8Hz), 5.04 (d
d, 1H, J = 3.4Hz, 10.5Hz), 5.22 (dd, 1H, J = 7.8Hz, 10.5Hz),
5.39 (dd, 1H, J = 1.0Hz, 3.4Hz), 6.06 (bs, 1H).
【０１７８】［α］D 27=-14.9゜(c=1.00 ，CHCl3 ) 。[Α] D 27 = -14.9 ゜ (c = 1.00, CHCl 3 ).
【０１７９】２）化合物237 の合成 化合物236 、1.42ｇにメタノール20mlを加えて溶かし、
氷冷下撹拌した。ここに28％ナトリウムメトキシドメタ
ノール溶液を６滴加えてｐＨ＝12とし、室温で12.5時間
撹拌した。ここに「ダウエックス50Ｘ−８」イオン交換
樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒を
減圧下留去し、残渣を「セファデックスＬＨ−20」で精
製し（溶出溶媒：クロロホルム−メタノール １：
１）、目的化合物を1.11ｇ得た。2) Synthesis of Compound 237 To 1.42 g of Compound 236, 20 ml of methanol was added and dissolved.
The mixture was stirred under ice cooling. To this was added 6 drops of a 28% sodium methoxide methanol solution to adjust the pH to 12, followed by stirring at room temperature for 12.5 hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified with "Sephadex LH-20" (elution solvent: chloroform-methanol 1:
1) 1.11 g of the target compound was obtained.
【０１８０】 1H-NMR(δ, pyridine-d5 -D2 O)：0.87
(t,3H,J=7.0Hz)，1.21-1.36(m,24H)，1.79(quintet,2H,
J=7.6Hz)，2.41(t,1H,J=7.6Hz)，3.59-3.71(m,6H) ，3.
88(dt,1H,J=5.3Hz,10.8Hz)，4.00-4.03(m,1H) ，4.11(d
d,1H,J=3.4Hz,9.5Hz) ，4.20(dt,1H,J=4.6Hz,10.8Hz)，
4.39-4.42(m,3H) ，4.52(bd,1H) ，4.77(d,1H,J=7.6H
z,) ，8.54(bs,1H) 。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.87
(t, 3H, J = 7.0Hz), 1.21-1.36 (m, 24H), 1.79 (quintet, 2H,
J = 7.6Hz), 2.41 (t, 1H, J = 7.6Hz), 3.59-3.71 (m, 6H), 3.
88 (dt, 1H, J = 5.3Hz, 10.8Hz), 4.00-4.03 (m, 1H), 4.11 (d
d, 1H, J = 3.4Hz, 9.5Hz), 4.20 (dt, 1H, J = 4.6Hz, 10.8Hz),
4.39-4.42 (m, 3H), 4.52 (bd, 1H), 4.77 (d, 1H, J = 7.6H
z,), 8.54 (bs, 1H).
【０１８１】［α］D 27=-2.9 ゜(c=1.01 ，CHCl3 -MeO
H 1:1)。[Α] D 27 = −2.9 ゜ (c = 1.01, CHCl 3 -MeO
H 1: 1).
【０１８２】FAB-MS:[M+H]+ ;m/z=506。FAB-MS: [M + H] + ; m / z = 506.
【０１８３】(u) 化合物239 の合成（図２ｊ） １）化合物238 の合成 化合物226 、 0.429ｇに塩化メチレン10mlを加えて溶か
し、氷冷下攪拌した。ここにトリエチルアミン 193μｌ
を加えた。さらにクロロギ酸コレステリル 0.325ｇを加
え、室温まで昇温させながら２日半攪拌した。塩化メチ
レンで希釈し、水及び飽和食塩水で洗浄し、硫酸マグネ
シウム上乾燥させた。減圧下溶媒を留去し、残渣をシリ
カゲルクロマトグラフィーで精製して（溶出溶媒：ｎ−
ヘキサン−酢酸エチル１：２）、目的物を 0.536ｇを得
た。 (U) Synthesis of Compound 239 (FIG. 2j) 1) Synthesis of Compound 238 To 0.429 g of Compound 226, 10 ml of methylene chloride was added and dissolved, followed by stirring under ice-cooling. 193μl of triethylamine here
Was added. Further, 0.325 g of cholesteryl chloroformate was added, and the mixture was stirred for 2.5 days while being heated to room temperature. The mixture was diluted with methylene chloride, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: n-
Hexane-ethyl acetate 1: 2) to obtain 0.536 g of the desired product.
【０１８４】 1H=NMR(δ, CDCl3 ) ：0.67(s,3H)，0.86
(d,3H,J=2.0Hz)，0.86(d,3H,J=6.5Hz)，0.87(d,3H,J=7.
Hz) ，0.91(d,3H,J=6.5Hz)，0.91-2.38(m,31H)，3.34-
3.39(m,2H) ，3.55(t,2H,J=5.3Hz)，3.58-3.69(m,6H)
，3.75(ddd,1H,J=4.3Hz,6.8Hz,11.0Hz) ，3.90-3.92
(m,1H) ，3.97(dt,1H,J=4.3Hz,11.0Hz)，4.13(dd,1H,J=
7.0Hz,11.2Hz)，4.18(dd,1H,J=6.6Hz,11.2Hz)，4.50(b
s,1H) ，4.56(d,1H,J=8.0Hz)，5.02(dd,1H,J=3.4Hz,10.
4Hz)，5.10(bs,1H) ，5.21(dd,1H,J=8.0Hz,10.4Hz)，5.
37-5.38(m,1H) ，5.39(dd,1H,J=0.7Hz,3.4Hz) 。 1 H = NMR (δ, CDCl 3 ): 0.67 (s, 3H), 0.86
(d, 3H, J = 2.0Hz), 0.86 (d, 3H, J = 6.5Hz), 0.87 (d, 3H, J = 7.
Hz), 0.91 (d, 3H, J = 6.5Hz), 0.91-2.38 (m, 31H), 3.34-
3.39 (m, 2H), 3.55 (t, 2H, J = 5.3Hz), 3.58-3.69 (m, 6H)
, 3.75 (ddd, 1H, J = 4.3Hz, 6.8Hz, 11.0Hz), 3.90-3.92
(m, 1H), 3.97 (dt, 1H, J = 4.3Hz, 11.0Hz), 4.13 (dd, 1H, J =
7.0Hz, 11.2Hz), 4.18 (dd, 1H, J = 6.6Hz, 11.2Hz), 4.50 (b
s, 1H), 4.56 (d, 1H, J = 8.0Hz), 5.02 (dd, 1H, J = 3.4Hz, 10.
4Hz), 5.10 (bs, 1H), 5.21 (dd, 1H, J = 8.0Hz, 10.4Hz), 5.
37-5.38 (m, 1H), 5.39 (dd, 1H, J = 0.7Hz, 3.4Hz).
【０１８５】［α］D 27=-17.4゜(c=1.01,CHCl3 ）。[Α] D 27 = -17.4 ° (c = 1.01, CHCl 3 ).
【０１８６】２）化合物239 の合成 化合物238 、 0.470ｇにメタノール５ml及びベンゼン10
mlを加えて溶かした。ここに28％ナトリウムメトキシド
メタノール溶液を７滴加えてｐＨ＝11とし、室温で 1.5
時間攪拌した。ここに「ダウエックス50Ｘ−８」イオン
交換樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶
媒を減圧下留去し、残渣を「セファデックスＬＨ−20」
で精製し（溶出溶媒：クロロホルム−メタノール２：
１）、目的化合物を 0.297ｇ得た。2) Synthesis of compound 239 Compound 238 (0.470 g) was added to methanol (5 ml) and benzene (10).
ml was added to dissolve. To this, 7 drops of a 28% sodium methoxide methanol solution was added to adjust the pH to 11, and the solution was added at room temperature for 1.5 hours.
Stirred for hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was separated using "Sephadex LH-20".
(Elution solvent: chloroform-methanol 2:
1), 0.297 g of the target compound was obtained.
【０１８７】 1H=NMR(δ, pyridine-d5 -D2 O)：0.67
(s,3H)，0.86(d,3H,J=2.0Hz)，0.90(d,3H,J=6.6Hz)，0.
91(d,3H,J=6.8Hz)，0.98(d,3H,J=6.3Hz)，0.86-2.06(m,
29H)，2.43(bt,1H) ，2.55-2.60(m,1H) ，3.58-3.67(m,
8H) ，3.72(t,2H,J=5.2Hz)，3.91(dt,1H,J=5.2Hz,10.4H
z)，4.03(bt,1H) ，4.13(dd,1H,J=3.3Hz,9.5Hz) ，4.25
(dt,1H,J=5.2Hz,10.4Hz)，4.39-4.43(m,3H) ，4.52(d,1
H,J=3.3Hz)，4.77(d,1H,J=7.8Hz)，4.78-4.85(m,1H) ，
5.38-5.39(m,1H) ，7.87(t,1H,J=5.2Hz)。 1 H = NMR (δ, pyridine-d 5 -D 2 O): 0.67
(s, 3H), 0.86 (d, 3H, J = 2.0Hz), 0.90 (d, 3H, J = 6.6Hz), 0.
91 (d, 3H, J = 6.8Hz), 0.98 (d, 3H, J = 6.3Hz), 0.86-2.06 (m,
29H), 2.43 (bt, 1H), 2.55-2.60 (m, 1H), 3.58-3.67 (m,
8H), 3.72 (t, 2H, J = 5.2Hz), 3.91 (dt, 1H, J = 5.2Hz, 10.4H
z), 4.03 (bt, 1H), 4.13 (dd, 1H, J = 3.3Hz, 9.5Hz), 4.25
(dt, 1H, J = 5.2Hz, 10.4Hz), 4.39-4.43 (m, 3H), 4.52 (d, 1
H, J = 3.3Hz), 4.77 (d, 1H, J = 7.8Hz), 4.78-4.85 (m, 1H),
5.38-5.39 (m, 1H), 7.87 (t, 1H, J = 5.2Hz).
【０１８８】［α］D 28=-14.3゜(c=1.01,CHCl3 -MeOH
1 ： 1）。[Α] D 28 = -14.3 ゜ (c = 1.01, CHCl 3 -MeOH
1: 1).
【０１８９】FAB-MS：[M+H] + ；m/z=724 。FAB-MS: [M + H] + ; m / z = 724.
【０１９０】(v) 化合物243 の合成（図２ｋ） １）化合物240 の合成 Ｊ．Ｏｒｇ，Ｃｈｅｍ．，56，4326(1991)に記載の方法
で合成した２−｛２−［２−（２−アジドエキトキ）エ
トキシ］エトキシ｝エタノール 1,980ｇ及びβ−Ｄ−ガ
ラクト−スペンタアセート 3.525ｇを塩化メチレン50ml
に溶かし、氷冷下攪拌した。ここに三フッ化硼素ジエチ
ルエーテル錯体4.44mlを滴下した。室温で17.5時間攪拌
した後、氷水にあけ、有機層を分離した。飽和食塩水で
５回洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下
留去した。残渣をシリカゲルカラムクロマトグラフィー
で精製し（溶出溶媒：ｎ−ヘキサン−酢酸エチル１：
５）、目的物を無色油状物として 1.238ｇ得た。 (V) Synthesis of Compound 243 (FIG. 2k) 1) Synthesis of Compound 240 Org, Chem. 56 , 4326 (1991), 1,980 g of 2- {2- [2- (2-azidoethoxy) ethoxy] ethoxy} ethanol and 3.525 g of β-D-galacto-spentaacetate in 50 ml of methylene chloride.
And stirred under ice-cooling. To this, 4.44 ml of boron trifluoride diethyl ether complex was added dropwise. After stirring at room temperature for 17.5 hours, the mixture was poured into ice water and the organic layer was separated. The extract was washed 5 times with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 1:
5), 1.238 g of the desired product was obtained as a colorless oil.
【０１９１】 1H-MNR(δ, CDCl3 ) ：1.99(s,3H)，2.05
(s,3H)，2.06(s,3H)，2.15(s,3H)，3.40(t,2H,J=5.0H
z)，3.62-3.69(m,12H)，3.75(ddd,1H,J=3.7Hz,7.4Hz,1
1.1Hz)，3.90-3.93(m,1H) ，3.94-9.98(dt,1H,J=4.3Hz,
11.1Hz) ，4.13(dd,1H,J=6.8Hz,11.2Hz)，4.18(dd,1H,J
=6.6Hz,11.2Hz)，4.57(d,1H,J=8.1Hz)，5.02(dd,1H,J=
3.4Hz,10.5Hz)，5.21(dd,1H,J=8.1Hz,10.5Hz)，5.39(d
d,1H,J=1.0Hz,3.4Hz) 。 1 H-MNR (δ, CDCl 3 ): 1.99 (s, 3H), 2.05
(s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 3.40 (t, 2H, J = 5.0H
z), 3.62-3.69 (m, 12H), 3.75 (ddd, 1H, J = 3.7Hz, 7.4Hz, 1
1.1Hz), 3.90-3.93 (m, 1H), 3.94-9.98 (dt, 1H, J = 4.3Hz,
11.1Hz), 4.13 (dd, 1H, J = 6.8Hz, 11.2Hz), 4.18 (dd, 1H, J
= 6.6Hz, 11.2Hz), 4.57 (d, 1H, J = 8.1Hz), 5.02 (dd, 1H, J =
3.4Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.39 (d
d, 1H, J = 1.0Hz, 3.4Hz).
【０１９２】［α］D 23=-5.4 ゜(c=1.02, CHCl 3 ）。[Α] D 23 = −5.4 ゜ (c = 1.02, CHCl 3 ).
【０１９３】２）化合物241 の合成 化合物240 、1.129 ｇに酢酸エチル120ml を加えて溶か
した。ここにｐ−トルエンスルホン酸１水和物 0.391ｇ
及びリンドラー触媒 0.570ｇを加え、50ｐｓｉで 5.5時
間触媒還元した。さらにリンドラー触媒 0.564ｇを加
え、50ｐｓｉで５時間触媒還元した。触媒を濾去し、目
的物を淡褐色油状物として 1.172ｇ得た。これ以上の精
製はせず、以下の反応に用いた。2) Synthesis of compound 241 To 1.129 g of compound 240, 120 ml of ethyl acetate was added and dissolved. Here, p-toluenesulfonic acid monohydrate 0.391 g
And 0.570 g of Lindlar's catalyst were added, and the catalyst was reduced at 50 psi for 5.5 hours. Further, 0.564 g of Lindlar's catalyst was added, and the catalyst was reduced at 50 psi for 5 hours. The catalyst was removed by filtration to give 1.172 g of the desired product as a pale brown oil. It was used for the following reaction without further purification.
【０１９４】３）化合物1103の合成 ２−（ｎ−ヘキサデシル）オクタデカン酸 0.525ｇに塩
化チオニル２mlを加え、６時間熱還流させた。塩化チオ
ニルを減圧下留去した。残渣にベンゼンを加えて溶か
し、減圧下濾去した（３回）。これ以上の精製はせず
に、以下の反応に用いた。3) Synthesis of Compound 1103 To 0.525 g of 2- (n-hexadecyl) octadecanoic acid was added 2 ml of thionyl chloride, and the mixture was refluxed for 6 hours. Thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue to dissolve and filtered off under reduced pressure (three times). It was used for the following reaction without further purification.
【０１９５】４）化合物242 の合成 化合物241 、0.618 ｇに塩化メチレン10mlを加えて溶か
し、氷冷下攪拌した。ここにトリエチルアミン 268μｌ
を加え、さらに上記反応で得た化合物1103全量を塩化メ
チレン４mlに溶かして加え、室温に昇温させつつ14時間
攪拌した。塩化メチレンで希釈し、水及び飽和食塩水で
洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去
した。残渣をシリカゲルカラムクロマトグラフィーで精
製し（溶出溶媒：ｎ−ヘキサン−酢酸エチル２：３）、
目的物を 0.550ｇ得た。4) Synthesis of Compound 242 To 0.618 g of Compound 241, 10 ml of methylene chloride was added and dissolved, followed by stirring under ice-cooling. Here 268μl of triethylamine
Was added, and the whole amount of the compound 1103 obtained in the above reaction was dissolved in 4 ml of methylene chloride, and the mixture was stirred for 14 hours while warming to room temperature. The mixture was diluted with methylene chloride, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 2: 3),
0.550 g of the desired product was obtained.
【０１９６】 1H-NMR(δ, CDCl3 ) ：0.88(t,6H,J=7.0H
z)，1.19-1.33(m,56H)，1.35-1.42(m,2H) ，1.53-1.62
(m,2H) ，1.97-2.03(m,1H) ，1.99(s,3H)，2.05(s,3
H)，2.06(s,3H)，2.15(s,3H)，3.45-3.48(m,1H) ，3.48
-3.54(t,2H,J=5.0Hz) ，3.61-3.68(m,10H)，3.75(ddd,1
H,J=3.7Hz,7.3Hz,11.0Hz) ，3.90-3.94(m,1H) ，3.96(d
t,1H,J=4.4Hz) ，4.13(dd,1H,J=7.1Hz,11.2Hz)，4.17(d
d,1H,J=6.6Hz,11.2Hz)，4.56(d,1H,J=8.1Hz)，5.02(dd,
1H,J=3.5Hz,10.5Hz)，5.21(dd,1H,J=8.1Hz,10.5Hz)，5.
39(dd,1H,J=1.0Hz，3.5Hz)，5.96(t,1H,J=5.6Hz)。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 6H, J = 7.0H
z), 1.19-1.33 (m, 56H), 1.35-1.42 (m, 2H), 1.53-1.62
(m, 2H), 1.97-2.03 (m, 1H), 1.99 (s, 3H), 2.05 (s, 3
H), 2.06 (s, 3H), 2.15 (s, 3H), 3.45 to 3.48 (m, 1H), 3.48
-3.54 (t, 2H, J = 5.0Hz), 3.61-3.68 (m, 10H), 3.75 (ddd, 1
H, J = 3.7Hz, 7.3Hz, 11.0Hz), 3.90-3.94 (m, 1H), 3.96 (d
t, 1H, J = 4.4Hz), 4.13 (dd, 1H, J = 7.1Hz, 11.2Hz), 4.17 (d
d, 1H, J = 6.6Hz, 11.2Hz), 4.56 (d, 1H, J = 8.1Hz), 5.02 (dd,
1H, J = 3.5Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.
39 (dd, 1H, J = 1.0 Hz, 3.5 Hz), 5.96 (t, 1H, J = 5.6 Hz).
【０１９７】［α］D 23=-2.5 ゜(c=1.00,CHCl3 -MeOH
1:1)。[Α] D 23 = −2.5 ゜ (c = 1.00, CHCl 3 -MeOH
1: 1).
【０１９８】５）化合物243 の合成 化合物242 、0.518 ｇにメタノール５ml及びベンゼン10
mlを加えて溶かした。ここに28％ナトリウムメトキシド
メタノール溶液を６滴加えてｐＨ＝10とし、室温で19時
間攪拌した。ここに「ダウエックス50Ｘ−８」イオン交
換樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒
を減圧下留去し、残渣を「セファデックスＬＨ−20」で
精製し（溶出溶媒：クロロホルム−メタノール１：
１）、目的化合物を 0.403ｇ得た。5) Synthesis of compound 243 Compound 242 (0.518 g) was added to methanol (5 ml) and benzene (10).
ml was added to dissolve. To this was added 6 drops of a 28% sodium methoxide methanol solution to adjust the pH to 10, followed by stirring at room temperature for 19 hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 1:
1), 0.403 g of the target compound was obtained.
【０１９９】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,6H,J=7.0Hz)，1.02-1.39(m,52H)，1.44-1.62(m,6H)
，1.92-2.00(m,2H) ，2.51-2.57(m,1H) ，3.63-3.77
(m,14H)，3.93(dt,1H,J=5.3Hz,10.7Hz)，4.02-4.05(m,1
H) ，4.14(dd,1H,J=3.4Hz,9.5Hz)，4.26(dt,1H,J=4.9H
z,10.7Hz)，4.40-4.44(m,3H) ，4.54(bd,1H) ，4.78(d,
1H,J1 , 2 =7.6Hz) ， 8.776(bt,1H) 。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88
(t, 6H, J = 7.0Hz), 1.02-1.39 (m, 52H), 1.44-1.62 (m, 6H)
, 1.92-2.00 (m, 2H), 2.51-2.57 (m, 1H), 3.63-3.77
(m, 14H), 3.93 (dt, 1H, J = 5.3Hz, 10.7Hz), 4.02-4.05 (m, 1
H), 4.14 (dd, 1H, J = 3.4Hz, 9.5Hz), 4.26 (dt, 1H, J = 4.9H
z, 10.7Hz), 4.40-4.44 (m, 3H), 4.54 (bd, 1H), 4.78 (d,
1H, J 1, 2 = 7.6Hz ), 8.776 (bt, 1H).
【０２００】［α］D 28=-3.6 ゜(c=1.00, CHCl 3 -MeO
H 1:1)。[Α] D 28 = -3.6 ゜ (c = 1.00, CHCl 3 -MeO
H 1: 1).
【０２０１】FAB-MS：［M+H]+ ；m/z=846 。FAB-MS: [M + H] + ; m / z = 846.
【０２０２】(w) 化合物245 の合成（図２ｌ） １）化合物244 の合成 化合物241 、 0.545ｇに塩化メチレン10mlを加えて氷冷
下攪拌した。ここにトリエチルアミン 109μｌを加え、
氷冷下攪拌した。ここに（Ｎ−パルモトイルオキシ）ス
クシンイミド 0.554ｇを塩化メチレン４mlに溶かして加
え、室温まで昇温させながら14.5時間攪拌した。減圧下
溶媒を留去し、残渣をシリカゲルクロマトグラフィーで
精製して（溶出溶媒：塩化メチレン−メタノール50：
１）、目的物を0.39ｇ得た。 (W) Synthesis of Compound 245 (FIG. 2L ) 1) Synthesis of Compound 244 To 0.545 g of Compound 241 was added 10 mL of methylene chloride, followed by stirring under ice-cooling. To this add 109 μl of triethylamine,
The mixture was stirred under ice cooling. 0.554 g of (N-palmotoyloxy) succinimide dissolved in 4 ml of methylene chloride was added thereto, and the mixture was stirred for 14.5 hours while being heated to room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methylene chloride-methanol 50:50).
1) 0.39 g of the desired product was obtained.
【０２０３】 1H-MNR(δ, CDCl3 ）：0.88(t,3H,J=7.0H
z)，1.21-1.32(m,24H)，1.59-1.65(m,2H) ，1.99(s,3
H)，2.05(s,3H)，2.06(s,3H)，2.15(s,3H)，2.17(t,2H,
J=7.6Hz)，3.44-3.47(m,1H) ，3.56(t,2H,J=5.1Hz)，3.
60-3.68(m,10H)，3.75(ddd,1H,J ＝4.3Hz,6.7Hz,11.0H
z) ，3.90-3.93(m,1H) ，3.97(dt,1H,J=4.3Hz,11.0H
z)，4.13(dd,1H,J=7.1Hz,11.2Hz)，4.18(dd,1H,J=6.6H
z,11.2Hz)，4.57(d,1H,J=8.1Hz)，5.02(dd,1H,J=3.4Hz,
10.5Hz)，5.21(dd,1H,J=8.1Hz,10.5Hz)，5.39(dd,1H,J=
1.0Hz,3.4Hz) ，6.5(bs,1H)。 1 H-MNR (δ, CDCl 3 ): 0.88 (t, 3H, J = 7.0H
z), 1.21-1.32 (m, 24H), 1.59-1.65 (m, 2H), 1.99 (s, 3
H), 2.05 (s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 2.17 (t, 2H,
J = 7.6Hz), 3.44-3.47 (m, 1H), 3.56 (t, 2H, J = 5.1Hz), 3.
60-3.68 (m, 10H), 3.75 (ddd, 1H, J = 4.3Hz, 6.7Hz, 11.0H
z), 3.90-3.93 (m, 1H), 3.97 (dt, 1H, J = 4.3Hz, 11.0H
z), 4.13 (dd, 1H, J = 7.1Hz, 11.2Hz), 4.18 (dd, 1H, J = 6.6H
z, 11.2Hz), 4.57 (d, 1H, J = 8.1Hz), 5.02 (dd, 1H, J = 3.4Hz,
10.5Hz), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.39 (dd, 1H, J =
1.0Hz, 3.4Hz), 6.5 (bs, 1H).
【０２０４】［α］D 24=-1.9 ゜(c=0.99, CHCl 3 -MeO
H 1:1)。[Α] D 24 = −1.9 ゜ (c = 0.99, CHCl 3 -MeO
H 1: 1).
【０２０５】２）化合物245 の合成 化合物244 、0.359 ｇにベンゼン６ml及びメタノール３
mlを加えて溶かし、氷冷下攪拌した。ここに28％ナトリ
ウムメトキシドメタノール溶液を８滴加えてｐＨ＝11と
し、室温で11.5時間攪拌した。ここに「ダエエックス50
Ｘ−８」イオン交換樹脂（Ｈ型）を加えて中和し、樹脂
を濾去した。溶媒を減圧下留去し、残渣を「セファデッ
クスＬＨ−20」で精製し（溶出溶媒：クロロフォルム−
メタノール１：１）、目的化合物を無色粉末として 0.2
50ｇ得た。2) Synthesis of compound 245 Compound (244) (0.359 g) was added to benzene (6 ml) and methanol (3).
The mixture was added and dissolved, and stirred under ice cooling. Eight drops of a 28% sodium methoxide methanol solution were added thereto to adjust the pH to 11, and the mixture was stirred at room temperature for 11.5 hours. Here, "DAEX 50
X-8 "ion exchange resin (H type) was added for neutralization, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-
Methanol 1: 1).
50 g were obtained.
【０２０６】 1H-NMR(δ, pyridine-d5 -D2 O)：0.87
(t,3H,J=7.0Hz)，1.19-1.38(m,24H)，1.81(quintet,2H,
J=7.6Hz)，2.42(t,1H,J=7.6Hz)，3.59-3.73(m,14H)，3.
91(dt,1H,J=5.3Hz,10.5Hz)，4.02-4.04(m,1H) ，4.13(d
d,1H,J=3.4Hz,9.5Hz) ，4.24(dt,1H,J=4.7Hz,10.5Hz)，
4.40-4.44(m,3H) ，4.53(bd,1H) ，4.77(d,1H,J=7.6H
z)，8.62(bt,1H) 。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.87
(t, 3H, J = 7.0Hz), 1.19-1.38 (m, 24H), 1.81 (quintet, 2H,
J = 7.6Hz), 2.42 (t, 1H, J = 7.6Hz), 3.59-3.73 (m, 14H), 3.
91 (dt, 1H, J = 5.3Hz, 10.5Hz), 4.02-4.04 (m, 1H), 4.13 (d
d, 1H, J = 3.4Hz, 9.5Hz), 4.24 (dt, 1H, J = 4.7Hz, 10.5Hz),
4.40-4.44 (m, 3H), 4.53 (bd, 1H), 4.77 (d, 1H, J = 7.6H
z), 8.62 (bt, 1H).
【０２０７】［α］D 26=-2.3 ゜(c=0.99, CHCl 3 -MeO
H 1:1)。[Α] D 26 = −2.3 ゜ (c = 0.99, CHCl 3 -MeO
H 1: 1).
【０２０８】FAB-MS：[M+H] + ；m/z=594 。FAB-MS: [M + H] + ; m / z = 594.
【０２０９】(x) 化合物247 の合成（図２ｍ） １）化合物246 の合成 化合物226 、 0.634ｇに塩化メチレン10ml及びテトラヒ
ドロフラン５mlを加えて溶かし、ここにアラキジン酸0.
395 ｇ及びＮ−ヒドロキシスクシンイミド 0.157ｇを加
え、氷冷下攪拌した。ここに、４−ジメチルアミノピリ
ジン 0.119ｇ及びＮ，Ｎ′−ジシクロヘキシカルボジイ
ミド 0.261ｇを加え、室温で34時間攪拌した。不溶物を
濾去し、溶媒を減圧下留去した。酢酸エチルを加え、不
溶物を濾去した。10％クエン酸及び10％炭酸ナトリウム
で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留
去した。残渣をシリカゲルカラムクロマトグラフィーで
精製し（溶出溶媒：酢酸エチル）、目的物を無色非晶質
として 0.365ｇ得た。 (X) Synthesis of Compound 247 (FIG. 2m) 1) Synthesis of Compound 246 To 0.634 g of compound 226, 10 ml of methylene chloride and 5 ml of tetrahydrofuran were added and dissolved.
395 g and 0.157 g of N-hydroxysuccinimide were added, and the mixture was stirred under ice cooling. 0.119 g of 4-dimethylaminopyridine and 0.261 g of N, N'-dicyclohexcarbodiimide were added thereto, and the mixture was stirred at room temperature for 34 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate was added, and the insolubles were removed by filtration. The extract was washed with 10% citric acid and 10% sodium carbonate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 0.365 g of the desired product as a colorless amorphous.
【０２１０】 1H-NMR(δ, CDCl3 ) ：0.88(t,3H,J=7.0H
z)，1.17-1.33(m,32H)，1.62(br quintet)，1.99(s,3
H)，2.05(s,3H)，2.06(s,3H)，2.15(s,3H)，2.18(t,2H,
J=7.7Hz)，3.42-3.49(m,2H) ，3.55(t,2H,J=5.1Hz)，3.
59-3.67(m,6H) ，3.74(ddd,1H,J=4.6Hz,6.3Hz,10.9Hz)
，3.91(br t, 1H)，3.98(dt,1H,J=4.3Hz,10.9Hz)，4.1
3(dd,1H,J=6.8Hz,11.2Hz)，4.18(dd,1H,J=6.3Hz,11.2H
z)，4.55(d,1H,J=8.1Hz)，5.02(dd,1H,J=3.4Hz,10.5H
z)，5.21(dd,1H,J=8.1Hz,10.5Hz)，5.39(dd,1H,J=0.7H
z,3.4Hz) ，6.03(br t,1H) 。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 3H, J = 7.0H
z), 1.17-1.33 (m, 32H), 1.62 (br quintet), 1.99 (s, 3
H), 2.05 (s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 2.18 (t, 2H,
J = 7.7Hz), 3.42-3.49 (m, 2H), 3.55 (t, 2H, J = 5.1Hz), 3.
59-3.67 (m, 6H), 3.74 (ddd, 1H, J = 4.6Hz, 6.3Hz, 10.9Hz)
, 3.91 (brt, 1H), 3.98 (dt, 1H, J = 4.3Hz, 10.9Hz), 4.1
3 (dd, 1H, J = 6.8Hz, 11.2Hz), 4.18 (dd, 1H, J = 6.3Hz, 11.2H
z), 4.55 (d, 1H, J = 8.1Hz), 5.02 (dd, 1H, J = 3.4Hz, 10.5H
z), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.39 (dd, 1H, J = 0.7H
z, 3.4Hz), 6.03 (br t, 1H).
【０２１１】［α］D 27=-7.3 ゜(c=1.00, CHCl 3 ）。[Α] D 27 = -7.3 ゜ (c = 1.00, CHCl 3 ).
【０２１２】２）化合物247 の合成 化合物246 、 0.334ｇにメタノール10mlを加えて溶かし
た。ここに28％ナトリウムメトキシドメタノール溶液を
５滴加えてｐＨ＝１０とし、室温で15.5時間攪拌した。
ここに「ダウエックス50Ｘ−８」イオン交換樹脂（Ｈ
型）を加えて中和し、樹脂を濾去した。溶媒を減圧下留
去し、残渣を「セファデックスＬＨ−20」で精製し（溶
出溶媒：クロロホルム−メタノール１：１）、目的化合
物を無色粉末として 0.238ｇ得た。2) Synthesis of Compound 247 To 0.334 g of Compound 246, 10 mL of methanol was added and dissolved. Five drops of a 28% sodium methoxide methanol solution were added thereto to adjust the pH to 10, and the mixture was stirred at room temperature for 15.5 hours.
Here, "DOWEX 50X-8" ion exchange resin (H
) Was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 1: 1) to obtain 0.238 g of the target compound as a colorless powder.
【０２１３】 1H-NMR(δ, pyridine-d5 ,D2 O)：0.87(3
H,t,J=7.0Hz)，1.22-1.38(m,32H),1.81(quintet,2H,J=
7.5Hz),2.42(t,2H,J=7.5Hz)，3.56-3.62(m,4H) ，3.64-
3.72(m,6H) ，3.91(dt,1H,J=5.3Hz,10.6Hz)，4.04(dt,1
H,J=0.9Hz,6.0Hz) ，4.14(dd,1H,J=3.4Hz,9.5Hz) ，4.2
5(dt,1H,J=4.9Hz,10.9Hz)，4.42(d,sH,J=6.0Hz)，4.44
(dd,1H,J=7.6Hz,9.5Hz) ，4.55(brd,1H)，4.79(d,1H,J=
7.7Hz)，8.57(brt,1H)。 1 H-NMR (δ, pyridine-d 5 , D 2 O): 0.87 (3
H, t, J = 7.0Hz), 1.22-1.38 (m, 32H), 1.81 (quintet, 2H, J =
7.5Hz), 2.42 (t, 2H, J = 7.5Hz), 3.56-3.62 (m, 4H), 3.64-
3.72 (m, 6H), 3.91 (dt, 1H, J = 5.3Hz, 10.6Hz), 4.04 (dt, 1H
H, J = 0.9Hz, 6.0Hz), 4.14 (dd, 1H, J = 3.4Hz, 9.5Hz), 4.2
5 (dt, 1H, J = 4.9Hz, 10.9Hz), 4.42 (d, sH, J = 6.0Hz), 4.44
(dd, 1H, J = 7.6Hz, 9.5Hz), 4.55 (brd, 1H), 4.79 (d, 1H, J =
7.7 Hz), 8.57 (brt, 1H).
【０２１４】［α］D 26＝-1.8゜(c=1.22,CHCl3 -MeOH
1:1)。[Α] D 26 = -1.8 ゜ (c = 1.22, CHCl 3 -MeOH
1: 1).
【０２１５】FAB-MS： [M+H]+ ；m/z=606 。FAB-MS: [M + H] + ; m / z = 606.
【０２１６】(y) 化合物249 の合成（図２ｎ） 1) メリシン酸クロリドの合成 メリシン酸 0.634ｇに塩化チオニル３mlを加え、80℃で
5.5時間攪拌した。塩化チオニルを減圧下留去し、残渣
にベンゼンを加えて溶かし、ベンゼンを減圧下留去した
（２回）。このまま以下の反応に用いた。 (Y) Synthesis of Compound 249 (FIG. 2n) 1) Synthesis of Melic Acid Chloride To 0.634 g of meric acid, 3 ml of thionyl chloride was added, and the mixture was heated at 80 ° C.
Stir for 5.5 hours. Thionyl chloride was distilled off under reduced pressure, benzene was added to the residue to dissolve it, and benzene was distilled off under reduced pressure (twice). This was used for the following reaction as it was.
【０２１７】２）化合物248 の合成 化合物226 、 0.715ｇに塩化メチレン５mlを加えて溶か
し、氷冷下攪拌した。ここに、トリエチルアミン 381μ
ｌを加え、さらに1)で得たメリシン酸クロリド全量を塩
化メチレン５mlに溶かして加え、室温に昇温させつつ３
日間攪拌した。水を加えて不溶物を濾去し、有機層を分
離した。10％クエン酸及び10％炭酸ナトリウムで洗い、
硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。
残渣をシリカゲルカラムクロマトグラフィーで精製し
（溶出溶媒：酢酸エチル）、目的物を無色粉末として
0.669ｇ得た。2) Synthesis of compound 248 To 0.715 g of compound 226, 5 ml of methylene chloride was added and dissolved, followed by stirring under ice-cooling. Here, triethylamine 381μ
Then, the whole amount of melisic acid chloride obtained in 1) was dissolved in 5 ml of methylene chloride and added.
Stirred for days. Water was added, insolubles were removed by filtration, and the organic layer was separated. Wash with 10% citric acid and 10% sodium carbonate,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate), and the target substance is obtained as a colorless powder.
0.669 g was obtained.
【０２１８】 1H-NMR(δ, CDCl3 ) ：0.88(t,3H,J=7.0H
z)，1.17-1.32(m,52H)，1.62(br quintet)，1.99(s,3
H)，2.05(s,3H)，2.06(s,3H)，2.15(s,3H)，2.18(t,2H,
J=7.7Hz)，3.42-3.49(m,2H) ，3.55(t,2H,J=5.1Hz)，3.
59-3.67(m,6H) ，3.74(ddd,1H,J=4.5Hz,6.3Hz,10.8Hz)
，3.91(br t,1H) ，3.98(dt,1H,J=4.3Hz,10.8Hz)，4.1
3(dd,1H,J=7.1Hz,11.2Hz)，4.18(dd,1H,J=6.3Hz,11.2H
z)，4.55(d,1H,J=8.1Hz)，5.02(dd,1H,J=3.4Hz,10.5H
z)，5.21(dd,1H,J=8.1Hz,10.5Hz)，5.39(dd,1H,J=0.7H
z,3.4Hz) ，6.05(br t,1H) 。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 3H, J = 7.0H
z), 1.17-1.32 (m, 52H), 1.62 (br quintet), 1.99 (s, 3
H), 2.05 (s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 2.18 (t, 2H,
J = 7.7Hz), 3.42-3.49 (m, 2H), 3.55 (t, 2H, J = 5.1Hz), 3.
59-3.67 (m, 6H), 3.74 (ddd, 1H, J = 4.5Hz, 6.3Hz, 10.8Hz)
, 3.91 (br t, 1H), 3.98 (dt, 1H, J = 4.3Hz, 10.8Hz), 4.1
3 (dd, 1H, J = 7.1Hz, 11.2Hz), 4.18 (dd, 1H, J = 6.3Hz, 11.2H
z), 4.55 (d, 1H, J = 8.1Hz), 5.02 (dd, 1H, J = 3.4Hz, 10.5H
z), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.39 (dd, 1H, J = 0.7H
z, 3.4Hz), 6.05 (br t, 1H).
【０２１９】［α］D 26=-5.8 ゜(c=1.03, CHCl 3 ) 。[Α] D 26 = -5.8 ゜ (c = 1.03, CHCl 3 ).
【０２２０】２）化合物249 の合成 化合物248 、 0.639ｇにベンゼン10ml及びメタノール５
mlを加えて溶かした。ここに28％ナトリウムメトキシド
メタノール溶液を５滴加えてｐＨ＝10とし、室温で２時
間攪拌した。ここに「ダウエックス50Ｘ−８」イオン交
換樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒
を減圧下留去し、残渣を「セファデックスＬＨ−20」で
精製し（溶出溶媒：クロロホルム−メタノール３：
１）、目的化合物を無色粉末として 0.483ｇ得た。2) Synthesis of Compound 249 Compound 248 (0.639 g) was added to benzene (10 ml) and methanol (5).
ml was added to dissolve. Five drops of a 28% sodium methoxide methanol solution were added thereto to adjust the pH to 10, and the mixture was stirred at room temperature for 2 hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 3:
1), 0.483 g of the target compound was obtained as a colorless powder.
【０２２１】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88(3
H,t,J=7.0Hz)，1.21-1.38(m,52H)，1.81(quintet,2H,J=
7.6z) ，2.42(t,2H,J=7.6Hz)，3.56-3.62(m,4H) ，3.64
-3.72(m,6H) ，3.91(dt,1H,J=5.3Hz,10.6Hz)，4.04(dt,
1H,J=0.7Hz,6.1Hz) ，4.13(dd,1H,J=3.4Hz,9.5Hz) ，4.
25(dt 1H,J=4.9Hz,10.7Hz)，4.41(d,2H,J=6.1Hz)，4.43
(dd,1H,J=7.8Hz,9.5Hz) ，4.54(brd,1H)，4.78(d,1H,J=
7.8Hz)，8.57(brt,1H)。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88 (3
H, t, J = 7.0Hz), 1.21-1.38 (m, 52H), 1.81 (quintet, 2H, J =
7.6z), 2.42 (t, 2H, J = 7.6Hz), 3.56-3.62 (m, 4H), 3.64
-3.72 (m, 6H), 3.91 (dt, 1H, J = 5.3Hz, 10.6Hz), 4.04 (dt,
1H, J = 0.7Hz, 6.1Hz), 4.13 (dd, 1H, J = 3.4Hz, 9.5Hz), 4.
25 (dt 1H, J = 4.9Hz, 10.7Hz), 4.41 (d, 2H, J = 6.1Hz), 4.43
(dd, 1H, J = 7.8Hz, 9.5Hz), 4.54 (brd, 1H), 4.78 (d, 1H, J =
7.8Hz), 8.57 (brt, 1H).
【０２２２】［α］D 26＝-1.8゜(c=1.01,CHCl3 -MeOH
3:1)。[Α] D 26 = -1.8 ゜ (c = 1.01, CHCl 3 -MeOH
3: 1).
【０２２３】FAB-MS： [M+H]+ ；m/z=746 。FAB-MS: [M + H] + ; m / z = 746.
【０２２４】(z) 化合物251 の合成（図２ｏ） １）化合物ＨＨＨの合成 水素化ナトリウム1.55ｇ（60％分散液）をｎ−ヘキサン
で洗い、Ｎ，Ｎ−ジメチルホルムアミド40mlに懸濁さ
せ、氷冷下攪拌した。ここにマロン酸ジベンジルエステ
ル4.47mlをＮ，Ｎ−ジメチルホルムアミド10mlに溶かし
て滴下し、室温で30分間攪拌した。再び氷冷してｎ−オ
クチルブロミド7.29mlを加え、60℃で18時間攪拌した。
溶媒を減圧下濾去した。残渣に酢酸エチルと水を加え、
有機層を分離した。飽和食塩水で洗い、硫酸マグネシウ
ム上乾燥させ、溶媒を減圧下留去した。残渣をシリカゲ
ルカラムクロマトグラフィーで精製し（溶出溶媒：ｎ−
ヘキサン−酢酸エチル20：１）、目的物を無色油状物と
して 7.227ｇ得た。 (Z) Synthesis of Compound 251 (FIG. 2o) 1) Synthesis of Compound HHH 1.55 g (60% dispersion) of sodium hydride was washed with n-hexane and suspended in 40 ml of N, N-dimethylformamide. The mixture was stirred under ice cooling. To this, 4.47 ml of malonic acid dibenzyl ester was dissolved in 10 ml of N, N-dimethylformamide and added dropwise, followed by stirring at room temperature for 30 minutes. After cooling again with ice, 7.29 ml of n-octyl bromide was added, and the mixture was stirred at 60 ° C for 18 hours.
The solvent was removed by filtration under reduced pressure. Ethyl acetate and water were added to the residue,
The organic layer was separated. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: n-
Hexane-ethyl acetate 20: 1) to give 7.227 g of the desired product as a colorless oil.
【０２２５】 1H-NMR(δ, CDCl3 ) ：0.87(t,6H,J=7.1H
z)，1.02-1.09(m,4H) ，1.15-1.30(m,20H)，1.86-1.89
(m,4H) ，5.10(s,4H)，5.10(s,4H)，7.25-7.32(m,10
H)。 1 H-NMR (δ, CDCl 3 ): 0.87 (t, 6H, J = 7.1H)
z), 1.02-1.09 (m, 4H), 1.15-1.30 (m, 20H), 1.86-1.89
(m, 4H), 5.10 (s, 4H), 5.10 (s, 4H), 7.25 to 7.32 (m, 10
H).
【０２２６】２）化合物ＪＪＪの合成 化合物ＨＨＨ 6.967ｇに酢酸エチル70mlを加えて溶か
し、10％Pd-C 0.105ｇ（乾物）を加え、11.5時間常圧接
触還元した。触媒を濾去し、溶媒を減圧下留去した。化
合物ＩＩＩを無色粉末として得た。これをアルゴン雰囲
気下 140℃で 2.5時間加熱した。放冷して化合物ＪＪＪ
を無色結晶として 3.824ｇ得た。2) Synthesis of Compound JJJ 70 ml of ethyl acetate was added to and dissolved in 6.967 g of the compound HHH, and 0.105 g (dry matter) of 10% Pd-C was added thereto, followed by catalytic reduction under normal pressure for 11.5 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. Compound III was obtained as a colorless powder. This was heated at 140 ° C. for 2.5 hours under an argon atmosphere. Allow to cool and compound JJJ
Was obtained as colorless crystals, 3.824 g.
【０２２７】化合物ＩＩＩ： 1H-NMR(δ, CDCl3 ) ：0.
87(t,6H,J=7.1Hz)，1.20-1.32(m,24H)，1.94-1.97(m,4
H) 。Compound III : 1 H-NMR (δ, CDCl 3 ): 0.
87 (t, 6H, J = 7.1Hz), 1.20-1.32 (m, 24H), 1.94-1.97 (m, 4
H).
【０２２８】化合物ＪＪＪ： 1H-NMR(δ, CDCl3 ) ：0.
88(t,6H,J=7.0Hz)，1.21-1.34(m,24H)，1.43-1.51(m,2
H) ，1.58-1.64(m,2H) ，2.33-2.38(m,1H) 。Compound JJJ : 1 H-NMR (δ, CDCl 3 ): 0.
88 (t, 6H, J = 7.0Hz), 1.21-1.34 (m, 24H), 1.43-1.51 (m, 2
H), 1.58-1.64 (m, 2H), 2.33-2.38 (m, 1H).
【０２２９】３）化合物ＫＫＫの合成 化合物ＪＪＪ 0.336ｇに塩化チオニル 1.5mlを加え、80
℃で 2.5時間加熱した。塩化チオニルを減圧下留去し
た。残渣にベンゼンを加えて溶かし、減圧下留去した
（３回）。これ以上の精製はせずに、以下の反応に用い
た。3) Synthesis of Compound KKK 1.5 ml of thionyl chloride was added to 0.336 g of Compound JJJ , and
Heated at C for 2.5 hours. Thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue to dissolve it and distilled off under reduced pressure (three times). It was used for the following reaction without further purification.
【０２３０】４）化合物250 の合成 化合物226 、 0.442ｇに塩化メチレン５mlを加えて溶か
し、氷冷下攪拌した。ここにトリエチルアミン 259μｌ
を加え、さらに上記反応で得た化合物ＫＫＫ全量を塩化
メチレン５mlを溶かして加え、室温に昇温させつつ12時
間攪拌した。クロロホルムで希釈し、水及び飽和食塩水
で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留
去した。残渣をシリカゲルクロマトグラフィーで精製し
（溶出溶媒：ｎ−ヘキサン−酢酸エチル１：２）、目的
物を無色非晶質として 0.357ｇ得た。4) Synthesis of Compound 250 To 0.442 g of Compound 226, 5 ml of methylene chloride was added and dissolved, followed by stirring under ice-cooling. 259μl of triethylamine
Was added, and the whole amount of the compound KKK obtained in the above reaction was dissolved in 5 ml of methylene chloride, and the mixture was stirred for 12 hours while warming to room temperature. The mixture was diluted with chloroform, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: n-hexane-ethyl acetate 1: 2) to obtain 0.357 g of the desired product as a colorless amorphous.
【０２３１】 1H-NMR(δ, CDCl3 ) ：0.88 (t,6H,J=7.0
Hz),1.17-1.32(m,24H)，1.36-1.43(m,2H) ，1.53-1.62
(m,2H) ，1.97-2.03(m,1H) ，1.99(s,3H)，2.05(s,3
H)，2.06(s,3H)，2.15(s,3H)，3.46-3.49(m,2H) ，3.54
(t,2H,J=5.0Hz)，3.58-3.69(m,6H) ，3.74(ddd,1H,J=4.
0Hz,6.7Hz,10.7Hz) ，3.91(brt,1H)，3.98(dt,1H,J=4.4
Hz,10.7Hz)，4.13(dd,1H,J=7.0Hz,11.3Hz)，4.18(dd,1
H,J=6.6Hz,11.3Hz)，4.55(d,1H,J=8.0Hz)，5.02(dd,1H,
J=3.4Hz,10.5Hz)，5.21(dd,1H,J=8.0Hz,10.5Hz)，5.39
(dd,1H,J=1.0Hz) ，5.96(t,1H,J=5.5Hz)。 1 H-NMR (δ, CDCl 3 ): 0.88 (t, 6H, J = 7.0
Hz), 1.17-1.32 (m, 24H), 1.36-1.43 (m, 2H), 1.53-1.62
(m, 2H), 1.97-2.03 (m, 1H), 1.99 (s, 3H), 2.05 (s, 3
H), 2.06 (s, 3H), 2.15 (s, 3H), 3.46-3.49 (m, 2H), 3.54
(t, 2H, J = 5.0Hz), 3.58-3.69 (m, 6H), 3.74 (ddd, 1H, J = 4.
0Hz, 6.7Hz, 10.7Hz), 3.91 (brt, 1H), 3.98 (dt, 1H, J = 4.4
Hz, 10.7 Hz), 4.13 (dd, 1H, J = 7.0 Hz, 11.3 Hz), 4.18 (dd, 1
H, J = 6.6Hz, 11.3Hz), 4.55 (d, 1H, J = 8.0Hz), 5.02 (dd, 1H,
J = 3.4Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.0Hz, 10.5Hz), 5.39
(dd, 1H, J = 1.0Hz), 5.96 (t, 1H, J = 5.5Hz).
【０２３２】［α］D 25=-5.6 ゜(c=0.98, CHCl 3 ) 。[Α] D 25 = -5.6 ゜ (c = 0.98, CHCl 3 ).
【０２３３】５）化合物251 の合成 化合物250 、 0.325ｇにメタノール10ml及びベンゼン５
mlを加えて溶かした。ここに28％ナトリウムメトキシド
メタノール溶液を４滴加えてｐＨ＝11とし、室温で14時
間攪拌した。ここに「ダウエックス50Ｘ−８」イオン交
換樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒
を減圧下留去し、残渣を「セファデックスＬＨ−20」で
精製し（溶出溶媒：クロロホルム−メタノール１：
１）、目的化合物を無色非晶質として 0.235ｇ得た。5) Synthesis of Compound 251 Compound 250 (0.325 g) was added to methanol (10 ml) and benzene (5).
ml was added to dissolve. To this was added 4 drops of a 28% sodium methoxide methanol solution to adjust the pH to 11, followed by stirring at room temperature for 14 hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 1:
1), 0.235 g of the target compound was obtained as a colorless amorphous.
【０２３４】 1H-NMR(δ, pyridine-d5 -D2 O)：0.85
(t,6H,J=7.0Hz)，1.16-1.38(m,20H)，1.40-1.58(m,6H)
，1.89-1.98(m,2H) ，2.49-2.55(m,1H) ，3.60-3.65
(m,4H) ，3.69-3.77(m,6H) ，3.93(dt,1H,J=5.3Hz,10.7
Hz)，405(brt,1H) ，4.15(dd,1H,J=3.4Hz) ，4.27(dt,1
H,J=5.0Hz,10.7Hz)，4.42(d,2H,J=6.1Hz)，4.44(dd,1H,
J=7.6Hz,9.5Hz) ，4.55(br d,1H) ，4.79(d,1H,J=7.6H
z)，8.75(brt,1H)。 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.85
(t, 6H, J = 7.0Hz), 1.16-1.38 (m, 20H), 1.40-1.58 (m, 6H)
, 1.89-1.98 (m, 2H), 2.49-2.55 (m, 1H), 3.60-3.65
(m, 4H), 3.69-3.77 (m, 6H), 3.93 (dt, 1H, J = 5.3Hz, 10.7
Hz), 405 (brt, 1H), 4.15 (dd, 1H, J = 3.4 Hz), 4.27 (dt, 1
H, J = 5.0Hz, 10.7Hz), 4.42 (d, 2H, J = 6.1Hz), 4.44 (dd, 1H,
J = 7.6Hz, 9.5Hz), 4.55 (br d, 1H), 4.79 (d, 1H, J = 7.6H
z), 8.75 (brt, 1H).
【０２３５】［α］D 25=-2.0 ゜(c=0.98, CHCl 3 -MeO
H 1:1 ）。[Α] D 25 = −2.0 ゜ (c = 0.98, CHCl 3 -MeO
H 1: 1).
【０２３６】FAB-MS： [M+H]+ ；m/z=578 。FAB-MS: [M + H] + ; m / z = 578.
【０２３７】(a′) 化合物253 の合成（図２ｐ） １） 化合物202 の合成 ２′−ブロモエチル−２，３，４，６−テトラ−Ｏ−ア
セチル−β−Ｄ−ガラクトピラノシド（60ｇ）(J.Dahme
n et al., Carbohydrate Research, 114(1983)328-330
の方法によって合成した）をＤＭＦ(200ml) に溶解し、
ナトリウムアジド（32ｇ）を加え、80℃で２時間攪拌し
た。溶液を室温まで冷却し、酢酸エチル（200ml)を加
え、濾過した。溶媒を減圧下留去し、残渣を酢酸エチル
(1000ml)に溶解し、４回水洗した。有機層を無水硫酸ナ
トリウムで乾燥した。溶液を濾過し、残渣をジイソプロ
ピルエーテルより結晶化し、目的物を得た。（44ｇ、80
％）。 (A ′) Synthesis of compound 253 (FIG. 2p) 1) Synthesis of compound 202 2′-bromoethyl-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (60 g) ) (J. Dahme
n et al., Carbohydrate Research, 114 (1983) 328-330
Was dissolved in DMF (200 ml),
Sodium azide (32 g) was added, and the mixture was stirred at 80 ° C for 2 hours. The solution was cooled to room temperature, ethyl acetate (200ml) was added and filtered. The solvent was distilled off under reduced pressure, and the residue was ethyl acetate.
(1000 ml) and washed four times with water. The organic layer was dried with anhydrous sodium sulfate. The solution was filtered, and the residue was crystallized from diisopropyl ether to obtain the desired product. (44g, 80
%).
【０２３８】m.p.66.5-657.5℃。M.p. 66.5-657.5 ° C.
【０２３９】［α］D 24=-33.6゜(c 1.1, CHCl3 ）。[Α] D 24 = -33.6 ゜ (c 1.1, CHCl 3 ).
【０２４０】 1H-NMR(CDCl3 , δ) ；1.990,2.005,2.07
0,2.160(4s,3H ×4)，3.29-3.33(m,1H) ，3.49-3.54(m,
1H) ，3.67-3.72(m,1H) ，3.929(dt,1H)，4.03-4.07(m,
1H)，4.133(dd,1H,J=6.8Hz,11.2Hz) ，4.191(dd,1H,J=
6.6Hz)，4.565(d,1H,J=7.8Hz) ，5.030(dd,1H,J=3.4H
z)，5.247(dd,1H,J=10.2Hz) ，5.402(dd,1H,J=1.0Hz)。 1 H-NMR (CDCl 3 , δ); 1.990,2.005,2.07
0,2.160 (4s, 3H × 4), 3.29-3.33 (m, 1H), 3.49-3.54 (m,
1H), 3.67-3.72 (m, 1H), 3.929 (dt, 1H), 4.03-4.07 (m,
1H), 4.133 (dd, 1H, J = 6.8Hz, 11.2Hz), 4.191 (dd, 1H, J =
6.6Hz), 4.565 (d, 1H, J = 7.8Hz), 5.030 (dd, 1H, J = 3.4H)
z), 5.247 (dd, 1H, J = 10.2 Hz), 5.402 (dd, 1H, J = 1.0 Hz).
【０２４１】２）化合物252 の合成 化合物202(0.931 ｇ）及びパラトルエンスルホン酸１水
和物(0.350ｇ) のエタノール（50ml）溶液にリンドラー
触媒(0.5ｇ）を加え、50ｐｓｉの水素雰囲気下５時間攪
拌した。触媒を濾過し、減圧下溶媒を留去した。(1.200
ｇ）。残渣からその650mg を取り、塩化メチレン(80ml)
及びヘキサン（40ml）に溶解し、２−パルミチルステア
リン酸(0.662ｇ）、Ｎ−ヒドロキシコハク酸イミド(0.1
50ｇ）、トリエチルアミン(0.181ml）及びジシクロヘキ
シルカルボジイミド(0.268ｇ）を加え、一晩攪拌した。
溶液を減圧下濃縮し、残渣に酢酸エチルを加え不溶物を
濾去した。濾液を濃縮し、シリカゲルカラムクロマトグ
ラフィーにて分離し（ヘキサン：酢酸エチル＝２：1.5
）、目的物を得た(0.429ｇ、50.7％）。2) Synthesis of compound 252 To a solution of compound 202 (0.931 g) and paratoluenesulfonic acid monohydrate (0.350 g) in ethanol (50 ml) was added a Lindlar catalyst (0.5 g), and the mixture was added under a 50 psi hydrogen atmosphere. Stirred for hours. The catalyst was filtered and the solvent was distilled off under reduced pressure. (1.200
g). Take 650 mg of the residue, methylene chloride (80 ml)
And hexane (40 ml) and dissolved in 2-palmitylstearic acid (0.662 g), N-hydroxysuccinimide (0.1
50 g), triethylamine (0.181 ml) and dicyclohexylcarbodiimide (0.268 g) were added, and the mixture was stirred overnight.
The solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate = 2: 1.5).
) To give the desired product (0.429 g, 50.7%).
【０２４２】［α］D 22＝+0.3゜(c 1.01,クロロホル
ム）。[Α] D 22 = + 0.3 ゜ (c 1.01, chloroform).
【０２４３】 1H-NMR(CDCl3 , δ）；0.880(t,6H) ，1.
18-1.32(m,56H)，1.35-1.43(m,4H)，1.54-1.61(m,2H)
，1.987 ，2.050 ，2.057 ，2.151(4s,12H) ，3.45-3.
66(m,H)，3.67-3.74(m,1H) ，3.897(dt,1H)，3.93-3.99
(m,1H) ，4.131(dd,1H,J=7.1，11.2Hz) ，4.179(dd,1H,
J=6.3,11.2Hz) ，4.548(d,1H,J=7.8Hz) ，5.023(dd,1H,
J=10.5,3.4Hz），5.213(dd,1H,J=7.8 ，10.5Hz) ，5.39
3(dd,1H,J=3.4,1.0Hz)，5.955(brt,1H) 。[0243] 1 H-NMR (CDCl 3, δ); 0.880 (t, 6H), 1.
18-1.32 (m, 56H), 1.35-1.43 (m, 4H), 1.54-1.61 (m, 2H)
, 1.987, 2.050, 2.057, 2.151 (4s, 12H), 3.45-3.
66 (m, H), 3.67-3.74 (m, 1H), 3.897 (dt, 1H), 3.93-3.99
(m, 1H), 4.131 (dd, 1H, J = 7.1,11.2Hz), 4.179 (dd, 1H,
J = 6.3,11.2Hz), 4.548 (d, 1H, J = 7.8Hz), 5.023 (dd, 1H,
J = 10.5,3.4Hz), 5.213 (dd, 1H, J = 7.8,10.5Hz), 5.39
3 (dd, 1H, J = 3.4,1.0Hz), 5.955 (brt, 1H).
【０２４４】３）化合物253 の合成 化合物252(463mg ）をベンゼン（９ml）及びメタノール
（１ml）に溶解し、５Ｍ／１のナトリウムメチラートメ
タノール溶液を８滴加え、一晩攪拌した。溶液にＨ型強
酸性イオン交換樹脂「Ｄｏｗｅｘ 50ｗ×８」を加えて
中和した。溶液を濾過し、減圧下濃縮し、残渣を「セフ
ァデックスＬＨ−20」（クロロホルム：メタノール＝
９：１、22mmφ×45cm）にて精製し、目的化合物を得た
(341mg、91％）。3) Synthesis of compound 253 Compound 252 (463 mg) was dissolved in benzene (9 ml) and methanol (1 ml), and 8 drops of a 5 M / 1 methanol solution of sodium methylate were added, followed by stirring overnight. The solution was neutralized by adding H-type strongly acidic ion exchange resin “Dowex 50w × 8”. The solution was filtered, concentrated under reduced pressure, and the residue was purified with "Sephadex LH-20" (chloroform: methanol =
9: 1, 22 mmφ × 45 cm) to obtain the desired compound
(341 mg, 91%).
【０２４５】［α］D 21=+1.5 ゜(c 1.06,クロロフォル
ム：メタノール＝９：１）。[Α] D 21 = + 1.5 ゜ (c 1.06, chloroform: methanol = 9: 1).
【０２４６】 1H-NMR(pyridine-d5 -D2 O,δ) ；0.88
(t,6H,J=7.0Hz)，.1.19-1.24(m,52H)，1.36-1.55(m,6H)
，1.84-1.92(m,2H) ，2.46-2.53(m,1H) ，3.69-3.76
(m,1H)，3.79-3.85(m,1H) ，3.94-4.00(m,2H) ，4.04(d
d,J=3.4Hz,9.5Hz)，4.17-4.21(m,1H) ，4.28-4.36(m,3
H) ，4.43(dd,1H,J=3.4Hz，0.9Hz)，4.71(d,1H,J=7.6H
z)，8.63(bt,1H) 。 1 H-NMR (pyridine-d 5 -D 2 O, δ); 0.88
(t, 6H, J = 7.0Hz) ,. 1.19-1.24 (m, 52H), 1.36-1.55 (m, 6H)
, 1.84-1.92 (m, 2H), 2.46-2.53 (m, 1H), 3.69-3.76
(m, 1H), 3.79-3.85 (m, 1H), 3.94-4.00 (m, 2H), 4.04 (d
d, J = 3.4Hz, 9.5Hz), 4.17-4.21 (m, 1H), 4.28-4.36 (m, 3
H), 4.43 (dd, 1H, J = 3.4Hz, 0.9Hz), 4.71 (d, 1H, J = 7.6H
z), 8.63 (bt, 1H).
【０２４７】(b′) 化合物256 の合成（図２ｑ） １）化合物254 の合成 ガラクトースパーアセテート（10.0ｇ，25.62mmol ）及
びモノクロトリエチレングリコール(5.616ｇ，33.3mmo
l，1.3 ｅｑ）の塩化メチレン(150ml）溶液にボロント
リフルオライドエーテル錯体（12.6ml，4.0 ｅｑ）の塩
化メチレン（30ml）溶液を氷冷下加え、一晩室温にて攪
拌した。得られた溶液を氷水に加え、クロロフォルム(1
50ml）に加えて抽出した。有機槽を２回水洗し、無水硫
酸ナトリウムにて乾燥した。溶媒を減圧下留去し、残渣
を1000mlのシリカゲルカラムクロマトグラフィーにて分
離し（ヘキサン：酢酸エチル＝２：１−１：１）、目的
物を得た（6.51ｇ、50.9％）。 (B ') Synthesis of Compound 256 (FIG. 2q) 1) Synthesis of Compound 254 Galactose peracetate (10.0 g, 25.62 mmol) and monochlorotriethylene glycol (5.616 g, 33.3 mmol)
1,1.3 eq) in methylene chloride (150 ml) was added with a solution of boron trifluoride ether complex (12.6 ml, 4.0 eq) in methylene chloride (30 ml) under ice-cooling, and the mixture was stirred overnight at room temperature. The resulting solution was added to ice water, and chloroform (1
50 ml) and extracted. The organic bath was washed twice with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by 1000 ml of silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) to obtain the desired product (6.51 g, 50.9%).
【０２４８】［α］D 20=-0.4 ゜(c 1.098、クロロフォ
ルム）。[Α] D 20 = −0.4 ゜ (c 1.098, chloroform).
【０２４９】 1H-NMR(CDCl3 , δ) ；1.986 ，2.051 ，
2.063 ，2.152(4s,3H ×4)，3.63-3.78(m,11H)，3.95-
3.98(m,1H) ，3.917(brt,1H) ，4.131(dd,1H,J=6.8Hz,1
1.2Hz) ，4.178(dd,1H,J=6.6Hz)，4.576(d,1H,J=8.1Hz)
，5.023(dd,1H,J=3.4Hz)，5.212(dd,1H,J=10.5Hz) ，
5.390(brd,1H) 。 1 H-NMR (CDCl 3 , δ); 1.986, 2.051,
2.063, 2.152 (4s, 3H × 4), 3.63-3.78 (m, 11H), 3.95
3.98 (m, 1H), 3.917 (brt, 1H), 4.131 (dd, 1H, J = 6.8Hz, 1
1.2Hz), 4.178 (dd, 1H, J = 6.6Hz), 4.576 (d, 1H, J = 8.1Hz)
, 5.023 (dd, 1H, J = 3.4 Hz), 5.212 (dd, 1H, J = 10.5 Hz),
5.390 (brd, 1H).
【０２５０】２）化合物225 の合成 化合物254(3.445 ｇ，12.91mmol)及びナトリウムアジド
（1.26ｇ，19.4mmol，1.5 ｅｑ）にＤＭＦ（50ml）を加
え、60℃にて17時間加熱攪拌した。得られた溶液に水
（100ml)を加え、酢酸エチルで抽出した。有機層を水洗
し、無水硫酸ナトリウムにて乾燥した。溶媒を減圧下留
去し、残渣を 500mlのシリカゲルカラムクロマトグラフ
ィーにて分離し（ヘキサン：酢酸エチル＝２：1.5 −
１：１）目的物を得た（5.30ｇ、81.2％）。2) Synthesis of compound 225 DMF (50 ml) was added to compound 254 (3.445 g, 12.91 mmol) and sodium azide (1.26 g, 19.4 mmol, 1.5 eq), and the mixture was heated with stirring at 60 ° C. for 17 hours. Water (100 ml) was added to the obtained solution, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by 500 ml silica gel column chromatography (hexane: ethyl acetate = 2: 1.5 −
1: 1) The desired product was obtained (5.30 g, 81.2%).
【０２５１】［α］D 17=-3.2 ゜(c 1.04 、CHCl3 ) 。[Α] D 17 = −3.2 c (c 1.04, CHCl 3 ).
【０２５２】 1H-NMR(CDCl3 , δ) ；1.984 ，2.048 ，
2.060 ，2.148(4s,3H ×4)，3.398(t,2H,J=5.0Hz) ，3.
63-3.69(m,8H) ，3.73-3.78(m,1H) ，3.95-3.98(m,1H)
，3.910(brt,1H) ，4.131(dd,1H,J=6.8Hz,11.2Hz) ，
4.176(dd,1H,J=6.3Hz)，4.571(d,1H,J=7.8Hz) ，5.023
(dd,1H,J=3.4Hz)，5.210(dd,1H,J=10.5Hz) ，5.387(dd,
1H,J=1.0Hz)。 1 H-NMR (CDCl 3 , δ); 1.984, 2.048,
2.060, 2.148 (4s, 3H × 4), 3.398 (t, 2H, J = 5.0Hz), 3.
63-3.69 (m, 8H), 3.73-3.78 (m, 1H), 3.95-3.98 (m, 1H)
, 3.910 (brt, 1H), 4.131 (dd, 1H, J = 6.8Hz, 11.2Hz),
4.176 (dd, 1H, J = 6.3Hz), 4.571 (d, 1H, J = 7.8Hz), 5.023
(dd, 1H, J = 3.4Hz), 5.210 (dd, 1H, J = 10.5Hz), 5.387 (dd,
1H, J = 1.0Hz).
【０２５３】３）化合物225 (0.417ｇ）及びパラトルス
ルホン酸１水和物(0.190ｇ）にメタノール（20ml）及び
酢酸エチル（40ml）を加えて溶解した。溶液にリンドラ
ー触媒(0.2ｇ）を加え、50ｐｓｉの水素雰囲気下で８時
間攪拌した。触媒を濾去し、減圧下溶媒を留去した。残
渣を塩化メチレン（20ml）及びヘキサン（10ml）に溶解
し、２−パルミチルステアリン酸(0.662ｇ) 、Ｎ−ヒド
ロキシコハク酸（0.150ｇ）、トリエチルアミン(0.181m
l）及びジシクロヘキシルカルボジイミド(0.268ｇ）を
加え、一晩攪拌した。溶液を減圧下濃縮し、残渣に酢酸
エチルを加え、不溶物を濾去した。濾液を濃縮し、シリ
カゲルカラムクロマトグラフィーにて分離し（ヘキサ
ン：酢酸エチル＝２：１）、目的物を得た(0.504ｇ、5
7.1％）。3) Compound 225 (0.417 g) and paratolusulfonic acid monohydrate (0.190 g) were dissolved by adding methanol (20 ml) and ethyl acetate (40 ml). A Lindlar catalyst (0.2 g) was added to the solution, and the mixture was stirred under a hydrogen atmosphere at 50 psi for 8 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (20 ml) and hexane (10 ml), and 2-palmitylstearic acid (0.662 g), N-hydroxysuccinic acid (0.150 g), and triethylamine (0.181 m
l) and dicyclohexylcarbodiimide (0.268 g) were added and stirred overnight. The solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (0.504 g, 5
7.1%).
【０２５４】［α］D 18=-0.4 ゜(c 1.04 ，クロロフォ
ルム）。[Α] D 18 = −0.4 ゜ (c 1.04, chloroform).
【０２５５】 1H-NMR(CDCl3 , δ) ；0.88(t,6H,J=7.0H
z)，1.18-1.26(m,56H)，1.34-1.43(m,2H) ，1.52-1.62
(m,2H) ，1.99(bs,4H) ，2.05(s,3H)，2.06(s,3H)，2.1
5(s,3H)，3.46-3.49(m,2H) ，3.54(t,2H,J=5.0Hz)，3.5
9-3.67(m,6H) ，3.74(ddd,1H,J=3.6Hz,7.2Hz,10.8Hz)
，3.90-3.93(m,1H) ，3.98(dt,1H,J=4.4Hz) ，4.13(d
d,1H,J=6.8Hz,11.2Hz)，4.18(dd,1H,J=6.6Hz,11.2Hz)，
4.55(d,1H,J=7.9Hz)，5.02(dd,1H,J=3.4Hz,10.5Hz)，5.
21(dd,1H,J=7.9Hz,10.5Hz)，5.39(dd,1H,J=3.4Hz,1.0H
z) ，5.92(t,1H,J=5.6Hz)。[0255] 1 H-NMR (CDCl 3, δ); 0.88 (t, 6H, J = 7.0H
z), 1.18-1.26 (m, 56H), 1.34-1.43 (m, 2H), 1.52-1.62
(m, 2H), 1.99 (bs, 4H), 2.05 (s, 3H), 2.06 (s, 3H), 2.1
5 (s, 3H), 3.46-3.49 (m, 2H), 3.54 (t, 2H, J = 5.0Hz), 3.5
9-3.67 (m, 6H), 3.74 (ddd, 1H, J = 3.6Hz, 7.2Hz, 10.8Hz)
, 3.90-3.93 (m, 1H), 3.98 (dt, 1H, J = 4.4Hz), 4.13 (d
d, 1H, J = 6.8Hz, 11.2Hz), 4.18 (dd, 1H, J = 6.6Hz, 11.2Hz),
4.55 (d, 1H, J = 7.9Hz), 5.02 (dd, 1H, J = 3.4Hz, 10.5Hz), 5.
21 (dd, 1H, J = 7.9Hz, 10.5Hz), 5.39 (dd, 1H, J = 3.4Hz, 1.0H
z), 5.92 (t, 1H, J = 5.6Hz).
【０２５６】４）化合物256 の合成 化合物225(341mg ）をベンゼン（10ml）に溶解し、５Ｍ
／１のナトリウムメチラートメタノール溶液を８滴加
え、一晩攪拌した。溶液に強酸性イオン交換樹脂「Ｄｏ
ｗｅｘ 50ｗ×８」のＨ型を加えて中和した。溶液を濾
過し、減圧下濃縮し、残渣を「セファデックスＬＨ−2
0」（クロロフォルム：メタノール＝９：１、22mmφ×4
5cm）にて精製し、目的化合物を得た(252mg、90％）。4) Synthesis of Compound 256 Compound 225 (341 mg) was dissolved in benzene (10 ml) and 5M
Eight drops of a methanol solution of sodium methylate / 1 were added, and the mixture was stirred overnight. Add strongly acidic ion exchange resin "Do
Wex 50w × 8 ”form H was added for neutralization. The solution was filtered, concentrated under reduced pressure, and the residue was treated with Sephadex LH-2.
0 "(chloroform: methanol = 9: 1, 22mmφ × 4
5 cm) to give the desired compound (252 mg, 90%).
【０２５７】［α］D 20=-1.1 ゜(c 1.12,クロロフォル
ム：メタノール＝９：１）。[Α] D 20 = -1.1 ゜ (c 1.12, chloroform: methanol = 9: 1).
【０２５８】 1H-NMR(pyridine-d5 -D2 O,δ) ；0.88
(t,6H,J=7.0Hz)，1.21-1.39(m,52H)，1.43-1.62(m,6H)
，1.91-1.99(m,6H) ，2.51-2.57(m,1H) ，3.61-3.66(4
H,m) ，3.70-3.78(6H,m) ，3.93(dt,1H,J=5.3Hz,10.7H
z)，4.02-4.04(m,1H) ，4.13(dd,J=3.3Hz,9.4Hz)，4.26
(dt,1H,J=10.7Hz,4.8Hz)，4.40-4.44(m,3H) ，4.54(bd,
1H) ，4.78(d,1H,J=7.8Hz)，8.76(bt,1H) 。 1 H-NMR (pyridine-d 5 -D 2 O, δ); 0.88
(t, 6H, J = 7.0Hz), 1.21-1.39 (m, 52H), 1.43-1.62 (m, 6H)
, 1.91-1.99 (m, 6H), 2.51-2.57 (m, 1H), 3.61-3.66 (4
H, m), 3.70-3.78 (6H, m), 3.93 (dt, 1H, J = 5.3Hz, 10.7H
z), 4.02-4.04 (m, 1H), 4.13 (dd, J = 3.3Hz, 9.4Hz), 4.26
(dt, 1H, J = 10.7Hz, 4.8Hz), 4.40-4.44 (m, 3H), 4.54 (bd,
1H), 4.78 (d, 1H, J = 7.8 Hz), 8.76 (bt, 1H).
【０２５９】実施例３（マンノース系誘導体の合成） 本実施例における反応式を図３ａ乃至図３ｋに示す。Example 3 (Synthesis of Mannose Derivative) The reaction formulas in this example are shown in FIGS. 3a to 3k.
【０２６０】本実施例における旋光度は全て25℃での測
定値である。The optical rotations in this example are all measured values at 25 ° C.
【０２６１】(a) Benzyloxycarbonylanomoethyl 2,3,4,
6-tetra-O-acetyl- α-and- β-D-man-nopyranoside (3
05α及び 305β）の合成 減圧下 150℃で２時間乾燥した粉末「ＭＳ４Ａ」(Molec
ular Sieves ４Ａ、2.00ｇ）、塩化亜鉛（0.88ｇ，6.4m
mol)及びアルコール体304 （1.25ｇ，6.4mmol)を塩化メ
チレン(20ml)中室温で１時間攪拌した。混合物に、ブロ
ム体303 （1.32ｇ，3.2mmol)と「ＭＳ４Ａ」（1.00ｇ）
を塩化メチレン(30ml)中室温で１時間攪拌した混合物を
滴下し、室温で４日間攪拌した。 (A) Benzyloxycarbonylanomoethyl 2,3,4,
6-tetra-O-acetyl- α-and- β-D-man-nopyranoside (3
05α and 305β) Powder “MS4A” (Molec ) dried at 150 ° C. for 2 hours under reduced pressure
ular Sieves 4A, 2.00g), zinc chloride (0.88g, 6.4m)
mol) and the alcohol derivative 304 (1.25 g, 6.4 mmol) were stirred in methylene chloride (20 ml) at room temperature for 1 hour. To the mixture, bromide 303 (1.32 g, 3.2 mmol) and “MS4A” (1.00 g)
Was stirred at room temperature for 1 hour in methylene chloride (30 ml), and the mixture was stirred at room temperature for 4 days.
【０２６２】その後不溶物をセライト濾過し、濾液を５
％ＮａＨＣＯ3 水、ついで水で洗浄、乾燥後溶媒を減圧
下留去した。残渣をシリカゲル（80ｇ）を用いるカラム
クロマトグラフィー（クロロホルム）にて分離し、α−
グリコシド体305 α（0.99ｇ，59％）およびβ−グリコ
シド体 305β（20mg，１％）をそれぞれ無色油状物質と
して得た。Thereafter, the insolubles were filtered through celite, and the filtrate was filtered.
% NaHCO 3 , then washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (chloroform) using silica gel (80 g).
Glycoside 305α (0.99 g, 59%) and β-glycoside 305β (20 mg, 1%) were obtained as colorless oils, respectively.
【０２６３】化合物 305α ［α］D +31.1°(c 1.02,CHCl3 ）。 Compound 305α [α] D + 31.1 ° (c 1.02, CHCl 3 ).
【０２６４】 1H-NMR （CDCl3 ) δ：2.00，2.04，2.0
9，2.16(each 3H, each s），3.37-3.45(1H,m) ，3.45-
3.52(1H,m) ，3.56-3.62(1H,m) ，3.76-3.82(1H,m) ，
3.96(1H,ddd, J5,4 =10.02Hz,J5,6 =5.62Hz, J 5,6′=
2.44Hz)，4.08(1H,dd,J 6,6′=12.21Hz,J 5,6′=2.44H
z)，4.26(1H,dd,J 6,6′=12.21Hz,J6,5 =5.62Hz)，4.82
(1H,d, J1,2 =1.47Hz)，5.12(2H,s)，5.25(1H,dd,J2,3
=3.42Hz, J2,1 =1.47Hz)，5.26(1H,t, J4,3 =10.02Hz,J
4,5 =10.02Hz) ，5.31(1H,dd,J3,4 =10.02Hz,J3,2 =3.4
2Hz)，7.3-7.4(5H,m) 。 1 H-NMR (CDCl 3 ) δ: 2.00, 2.04, 2.0
9, 2.16 (each 3H, each s), 3.37-3.45 (1H, m), 3.45
3.52 (1H, m), 3.56-3.62 (1H, m), 3.76-3.82 (1H, m),
3.96 (1H, ddd, J 5,4 = 10.02Hz, J 5,6 = 5.62Hz, J 5,6 ′ =
2.44Hz), 4.08 (1H, dd, J 6,6 '= 12.21Hz, J 5,6 ' = 2.44H
z), 4.26 (1H, dd, J 6,6 '= 12.21 Hz, J 6,5 = 5.62 Hz), 4.82
(1H, d, J 1,2 = 1.47Hz), 5.12 (2H, s), 5.25 (1H, dd, J 2,3
= 3.42Hz, J 2,1 = 1.47Hz), 5.26 (1H, t, J 4,3 = 10.02Hz, J
4,5 = 10.02Hz), 5.31 (1H, dd, J 3,4 = 10.02Hz, J 3,2 = 3.4
2Hz), 7.3-7.4 (5H, m).
【０２６５】化合物 305β ［α］D -19.7°(c 0.89,CHCl3 ）。 Compound 305β [α] D -19.7 ° (c 0.89, CHCl 3 ).
【０２６６】 1H-NMR （CDCl3 ) δ：2.00，2.05，2.0
7，2.18(each 3H, each s) ，3.3-3.4(1H,m) ，3.4-3.5
(1H,m) ，3.64(1H,ddd, J5,4 =10.01Hz,J5,6 =5.86Hz,
J 5,6′=2.44Hz)，3.67-3.73(1H,m) ，3.88-3.94(1H,m)
，4.15(1H,dd,J 6,6′=12.21Hz,J 5,6′=2.44Hz)，4.2
7(1H,dd,J 6,6′=2.21Hz,J 6,5 =5.86Hz)，4.63(1H,
s)，5.03(1H,dd,J3,4 =10.10Hz,J3,2 =3.18Hz)，5.11(2
H,s)，5.24(1H,t, J4,3 =10.01Hz,J4,5 =10.01Hz) ，5.
47(1H,d, J2,3 =3.18Hz)，7.3-7.4(5H,m) 。 1 H-NMR (CDCl 3 ) δ: 2.00, 2.05, 2.0
7, 2.18 (each 3H, each s), 3.3-3.4 (1H, m), 3.4-3.5
(1H, m), 3.64 (1H, ddd, J 5,4 = 10.01Hz, J 5,6 = 5.86Hz,
J 5,6 '= 2.44Hz), 3.67-3.73 (1H, m), 3.88-3.94 (1H, m)
, 4.15 (1H, dd, J 6,6 ′ = 12.21 Hz, J 5,6 ′ = 2.44 Hz), 4.2
7 (1H, dd, J 6,6 ′ = 2.21Hz, J 6,5 = 5.86Hz), 4.63 (1H,
s), 5.03 (1H, dd, J 3,4 = 10.10Hz, J 3,2 = 3.18Hz), 5.11 (2
H, s), 5.24 (1H, t, J 4,3 = 10.01Hz, J 4,5 = 10.01Hz), 5.
47 (1H, d, J2, 3 = 3.18 Hz), 7.3-7.4 (5H, m).
【０２６７】(b) 2-Benzyloxycarbonyl-2-palmitoylami
noethyl-2,3,4,6-tetra-0-acetyl- α-and- β-D-manno
pyranoside(307α及び 307β）の合成 減圧下 150℃で３時間乾燥した粉末「ＭＳ４Ａ」（2.00
ｇ）、塩化亜鉛（0.81ｇ，5.9mmol)及びアルコール体30
6 （2.57ｇ，5.9mmol)を塩化メチレン(20ml)中室温で２
時間攪拌した混合物に、ブロム体303 （1.22ｇ，3.0mmo
l)と「ＭＳ４Ａ」（1.00ｇ）を塩化メチレン(20ml)中室
温で４時間攪拌した混合物を滴下し、室温で７日間攪拌
した。 (B) 2-Benzyloxycarbonyl-2-palmitoylami
noethyl-2,3,4,6-tetra-0-acetyl- α-and- β-D-manno
Synthesis of pyranoside (307α and 307β) Powder “MS4A” (2.00
g), zinc chloride (0.81 g, 5.9 mmol) and alcohol 30
6 (2.57 g, 5.9 mmol) in methylene chloride (20 ml) at room temperature
Add the bromide 303 (1.22 g, 3.0 mmo)
A mixture of l) and "MS4A" (1.00 g) in methylene chloride (20 ml) at room temperature for 4 hours was added dropwise, and the mixture was stirred at room temperature for 7 days.
【０２６８】その後不溶物をセライト濾過し、濾液を５
％ＮａＨＣＯ3 水、ついで水で洗浄、乾燥後溶媒を減圧
下留去した。残渣をシリカゲル（30ｇ）を用いるカラム
クロマトグラフィー（ヘキサン−酢酸エチル３：１）に
て分離し、α−グリコシド体307α（1.32ｇ，58％）お
よびβ−グリコシド体 307β（54mg，２％）をそれぞれ
無色油状物質として得た。Thereafter, the insolubles were filtered through celite, and the filtrate was filtered.
% NaHCO 3 , then washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (hexane-ethyl acetate 3: 1) using silica gel (30 g) to give α-glycoside 307α (1.32 g, 58%) and β-glycoside 307β (54 mg, 2%). Each was obtained as a colorless oil.
【０２６９】化合物 307α ［α］D +33.2°(c 1.10,CHCl3 ）。 Compound 307α [α] D + 33.2 ° (c 1.10, CHCl 3 ).
【０２７０】 1H-NMR （CDCl3 ) δ：0.88(3H,t,J=7.33
Hz) ，1.2-1.4(24H,m)，1.60-1.68(2H,m) ，2.00，2.0
5，2.10，2.15(each 3H,each s)，2.28(2H,t,J=7.57Hz)
，3.86(1H,ddd, J5,4 =10.02Hz,J5,6 5.62Hz,J 5,6′=
2.45Hz)，3.95(1H,dd,J=10.50Hz,J=2.69Hz)，4.02(1H,d
d,J=10.50Hz,J=3.18Hz)，4.14(1H,dd,J 6,6′=12.21Hz,
J 5,6′=2.45Hz)，4.19(1H,dd,J 6,6′=12.21Hz,J6,5 =
5.62Hz)，4.69(1H,d, J1,2 =1.47Hz)，4.85(1H,ddd,J=
7.82Hz,J=3.18Hz,J=2.69Hz) ，5.14(1H,dd,J2,3 =3.18H
z, J2,1 =1.47Hz)，5.20 and 5.26(2H,ABq,J=12.21Hz)
，5.21(1H,t, J4,3 =10.02Hz,J4,5 =10.02Hz) ，5.22
(1H,dd,J3,4 =10.02Hz,J3,2 =3.18Hz)，6.47(1H,d,J=7.
82Hz) ，7.3-7.4(5H,m) 。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.33)
Hz), 1.2-1.4 (24H, m), 1.60-1.68 (2H, m), 2.00, 2.0
5, 2.10, 2.15 (each 3H, each s), 2.28 (2H, t, J = 7.57Hz)
, 3.86 (1H, ddd, J 5,4 = 10.02Hz, J 5,6 5.62Hz, J 5,6 ′ =
2.45Hz), 3.95 (1H, dd, J = 10.50Hz, J = 2.69Hz), 4.02 (1H, d
d, J = 10.50Hz, J = 3.18Hz), 4.14 (1H, dd, J 6,6 '= 12.21Hz,
J 5,6 '= 2.45Hz), 4.19 (1H, dd, J 6,6 ' = 12.21Hz, J 6,5 =
5.62Hz), 4.69 (1H, d, J 1,2 = 1.47Hz), 4.85 (1H, ddd, J =
7.82Hz, J = 3.18Hz, J = 2.69Hz), 5.14 (1H, dd, J 2,3 = 3.18H
z, J 2,1 = 1.47Hz), 5.20 and 5.26 (2H, ABq, J = 12.21Hz)
, 5.21 (1H, t, J 4,3 = 10.02Hz, J 4,5 = 10.02Hz), 5.22
(1H, dd, J 3,4 = 10.02Hz, J 3,2 = 3.18Hz), 6.47 (1H, d, J = 7.
82Hz), 7.3-7.4 (5H, m).
【０２７１】化合物 307β ［α］D -10.2°(c 0.50,CHCl3 ）。 Compound 307β [α] D -10.2 ° (c 0.50, CHCl 3 ).
【０２７２】 1H-NMR （CDCl3 ) δ：0.88(3H,t,J=7.08
Hz) ，1.2-1.4(24H,m)，1.60-1.68(2H,m) ，2.01，2.0
2，2.06，2.07(each 3H,each s)，2.26(2H,t,J=7.58Hz)
，3.59(1H,ddd, J5,4 =10.02Hz,J5,6 =5.62Hz,
J 5,6′=2.69Hz)，3.80(1H,dd,J=9.77Hz,J=3.42Hz) ，
4.13(1H,dd,J 6,6′=12.21Hz,J 5,6′=2.69Hz)，4.27(1
H,dd,J6,6′=12.21Hz,J6,5 5.62Hz) ，4.37(1H,dd,J=9.
77Hz,J=2.93Hz) ，4.60(1H,d,J=1.22Hz) ，4.84(1H,dd
d,J=8.06Hz,J=3.42Hz,J=2.93Hz) ，5.02(1H,dd,J3,4 =1
0.02Hz,J3,2 =3.42Hz)，5.16 and 5.22(2H,ABq,J=12.46
Hz) ，5.25(1H,t, J4,3 =10.02Hz,J4,5 =10.02Hz) ，5.
44(1H,d, J2,3 =3.42Hz, J2,1 =1.22Hz)，6.34(1H,d,J=
8.06Hz) ，7.3-7.4(5H,m) 。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08
Hz), 1.2-1.4 (24H, m), 1.60-1.68 (2H, m), 2.01, 2.0
2, 2.06, 2.07 (each 3H, each s), 2.26 (2H, t, J = 7.58Hz)
, 3.59 (1H, ddd, J 5,4 = 10.02Hz, J 5,6 = 5.62Hz,
J 5,6 '= 2.69Hz), 3.80 (1H, dd, J = 9.77Hz, J = 3.42Hz),
4.13 (1H, dd, J 6,6 '= 12.21Hz, J 5,6 ' = 2.69Hz), 4.27 (1
H, dd, J 6,6 '= 12.21Hz, J 6,5 5.62Hz), 4.37 (1H, dd, J = 9.
77Hz, J = 2.93Hz), 4.60 (1H, d, J = 1.22Hz), 4.84 (1H, dd
d, J = 8.06Hz, J = 3.42Hz, J = 2.93Hz), 5.02 (1H, dd, J 3,4 = 1
0.02Hz, J 3,2 = 3.42Hz), 5.16 and 5.22 (2H, ABq, J = 12.46
Hz), 5.25 (1H, t, J 4,3 = 10.02Hz, J 4,5 = 10.02Hz), 5.
44 (1H, d, J 2,3 = 3.42Hz, J 2,1 = 1.22Hz), 6.34 (1H, d, J =
8.06Hz), 7.3-7.4 (5H, m).
【０２７３】(c) 2-Aminoethyl-3,3,4,6-tetra-O-acety
l-α-D-mannopyranoside p-toluene-sulfonate (308)の
合成 化合物 305α（3.70ｇ，7.0mmol)とトシル酸１水和物
（1.33ｇ，7.0mmol)をメタノール（80ml）に溶解し、10
％Ｐｄ−Ｃ（0.70ｇ）を加え室温、40psi で６時間接触
還元を行った。 (C) 2-Aminoethyl-3,3,4,6-tetra-O-acety
l-α-D-mannopyranoside p-toluene-sulfonate (308)
Synthetic compound 305α (3.70 g, 7.0 mmol) and tosylic acid monohydrate (1.33 g, 7.0 mmol) were dissolved in methanol (80 ml),
% Pd-C (0.70 g) was added, and catalytic reduction was carried out at room temperature and 40 psi for 6 hours.
【０２７４】触媒を濾去後、濾液を減圧下濃縮して目的
物308(4.00ｇ，quant)を無色泡状物質として得た。After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the desired product 308 (4.00 g, quant) as a colorless foam.
【０２７５】(d) 2-Palmitoylaminoethyl-2,3,4,6-tetr
a-O-acetyl- α-D-mannopyranoside (310)の合成 アミン体308(564mg ，1.00mmol) と活性エステル体309
(385mg ，1.09mmol) を塩化メチレン（50ml）に溶解
し、ＤＭＡＰ（ジメチルアミノピリジン，224mg ，2.00
mmol) を加え、室温で20時間攪拌して反応させた。 (D) 2-Palmitoylaminoethyl-2,3,4,6-tetr
aO-acetyl-α-D-mannopyranoside (310) Synthetic amine 308 (564 mg, 1.00 mmol) and active ester 309
(385 mg, 1.09 mmol) in methylene chloride (50 ml) was dissolved in DMAP (dimethylaminopyridine, 224 mg, 2.00 mmol).
mmol), and reacted by stirring at room temperature for 20 hours.
【０２７６】反応液を水、10％クエン酸水、水で順次洗
浄、乾燥後溶媒を減圧下留去した。残渣をシリカゲル
（30ｇ）を用いるカラムクロマトグラフィー（クロロホ
ルム−アセトン50：１）で精製し、目的化合物310 を無
色粉末として得た(535mg，85％）。The reaction solution was washed sequentially with water, 10% aqueous citric acid and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-acetone 50: 1) using silica gel (30 g) to obtain the desired compound 310 as a colorless powder (535 mg, 85%).
【０２７７】［α］D ＋26.5°(c 0.98,CHCl3 ) 。[Α] D + 26.5 ° (c 0.98, CHCl 3 ).
【０２７８】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.64(2H,m)，2.01，2.05，2.1
0，2.16(each 3H,each s)，2.21(2H,t,J=7.32Hz) ，3.3
8-3.46(1H,m) ，3.52-3.62(2H,m) ，3.76-3.82(1H,m)
，3.97(1H,ddd, J5,4 =10.01Hz,J5,6 =5.86Hz,
J 5,6′=2.44Hz)，4.12(1H,dd,J 6,6′ =12.21Hz, J
5,6′ =2.44Hz) ，4.26(1H,dd,J 6,6′=12.21Hz， J
6,5 =5.86Hz),4.82(1H,s) ，5.26(1H,d,J2,3 =3.42H
z)，5.26(1H,t, J4,3 =10.01Hz,J4,5 =10.01Hz) ，5.33
(1H,dd,J3,4 =10.01Hz,J3,2 =3.42Hz)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.64 (2H, m), 2.01, 2.05, 2.1
0, 2.16 (each 3H, each s), 2.21 (2H, t, J = 7.32Hz), 3.3
8-3.46 (1H, m), 3.52-3.62 (2H, m), 3.76-3.82 (1H, m)
, 3.97 (1H, ddd, J 5,4 = 10.01Hz, J 5,6 = 5.86Hz,
J 5,6 ′ = 2.44Hz), 4.12 (1H, dd, J 6,6 ′ = 12.21Hz, J
5,6 '= 2.44Hz), 4.26 (1H, dd, J 6,6 ' = 12.21Hz, J
6,5 = 5.86Hz), 4.82 (1H, s), 5.26 (1H, d, J 2,3 = 3.42H
z), 5.26 (1H, t, J 4,3 = 10.01Hz, J 4,5 = 10.01Hz), 5.33
(1H, dd, J 3,4 = 10.01Hz, J 3,2 = 3.42Hz).
【０２７９】(e) 2-Palmitoylaminoethyl α-D-mannopy
ranoside (311)の合成 化合物310 (307mg，0.49mmol) をメタノール（５ml）に
溶解し、28％ＭｅＮａｉｎ ＭｅＯＨ（20μl)を加え室
温で６時間攪拌した。 (E) 2-Palmitoylaminoethyl α-D-mannopy
A synthetic compound 310 (307 mg, 0.49 mmol) of ranoside (311) was dissolved in methanol (5 ml), 28% MeOH (20 μl) was added, and the mixture was stirred at room temperature for 6 hours.
【０２８０】反応液に「アンバーライトＩＲＣ−50」を
加えて中和後、溶媒を減圧下留去した。析出した粉末を
エーテルで洗浄し目的化合物311 を無色粉末として得た
(215mg，96％）。After neutralization by adding "Amberlite IRC-50" to the reaction solution, the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain the desired compound 311 as a colorless powder.
(215 mg, 96%).
【０２８１】［α］D ＋36.3°(c 0.96,MeOH) 。[Α] D + 36.3 ° (c 0.96, MeOH).
【０２８２】 1H-NMR(CD3 OD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.60(2H,m)，2.19(2H,t,J=7.57H
z) ，4.74(1H,s)。 1 H-NMR (CD 3 OD) δ: 0.90 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.60 (2H, m), 2.19 (2H, t, J = 7.57H
z), 4.74 (1H, s).
【０２８３】(f) 化合物 313Ｌの合成 アミン体308(4.19ｇ，7.4mmol)と活性エステル体 312Ｌ
（3.23ｇ，7.4mmol)を塩化メチレン（80ml）に溶解し、
ＤＭＡＰ（1.00ｇ，8.1mmol)を加え室温で３日間攪拌し
た。 (F) Synthesis of Compound 313L Amine 308 (4.19 g, 7.4 mmol) and active ester 312 L
(3.23 g, 7.4 mmol) dissolved in methylene chloride (80 ml),
DMAP (1.00 g, 8.1 mmol) was added, and the mixture was stirred at room temperature for 3 days.
【０２８４】反応液を塩化メチレンで希釈後、水、10％
クエン酸水、水で順次洗浄、乾燥後溶媒を減圧下留去し
た。残渣をシリカゲル(100ｇ）を用いるカラムクロマト
グラフィー（クロロホルム→クロロホルム−アセトン5
0：１）で精製し、目的化合物313Ｌを無色泡状物質とし
て得た（4.43ｇ，84％）。After diluting the reaction solution with methylene chloride, 10%
After washing with citric acid water and water sequentially and drying, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g) (chloroform → chloroform-acetone 5).
0: 1) to give the desired compound 313L as a colorless foam (4.43 g, 84%).
【０２８５】［α］D ＋21.6°(c 0.92,CHCl3 ) 。[Α] D + 21.6 ° (c 0.92, CHCl 3 ).
【０２８６】 1H-NMR(CDCl3 ) δ：1.43(9H,s)，1.90-
2.00(1H,m) ，1.99，2.04，2.10，2.15(each 3H,each
s)，2.42-2.52(1H,m) ，2.54-2.62(1H,m) ，3.48-3.58
(3H,m)，3.76-3.82(1H,m) ，4.02(1H,ddd)，4.09(1H,d
d) ，4.15-4.23(1H,m) ，4.83(1H,d)，5.13(2H,s)，5.2
5(1H,dd) ，5.27(1H,t)，5.34(1H,dd) ，6.81(1H,br
s)，7.3-7.4(5H,m) 。 1 H-NMR (CDCl 3 ) δ: 1.43 (9H, s), 1.90-
2.00 (1H, m), 1.99, 2.04, 2.10, 2.15 (each 3H, each
s), 2.42-2.52 (1H, m), 2.54-2.62 (1H, m), 3.48-3.58
(3H, m), 3.76-3.82 (1H, m), 4.02 (1H, ddd), 4.09 (1H, d
d), 4.15-4.23 (1H, m), 4.83 (1H, d), 5.13 (2H, s), 5.2
5 (1H, dd), 5.27 (1H, t), 5.34 (1H, dd), 6.81 (1H, br
s), 7.3-7.4 (5H, m).
【０２８７】(g) 化合物 313Ｄの合成 化合物 313Ｌの合成（前項(f))に準じて化合物 313Ｄを
合成した（6.38ｇ，90％）。 (G) Synthesis of Compound 313D Compound 313D was synthesized (6.38 g, 90%) according to the synthesis of compound 313L (previous section (f)).
【０２８８】［α］D ＋24.7°(c 0.86,CHCl3 ) 。[Α] D + 24.7 ° (c 0.86, CHCl 3 ).
【０２８９】 1H-NMR(CDCl3 ) δ：1.43(9H,s)，1.86-
1.96(1H,m) ，1.99，2.03，2.10，2.15(each 3H,each
s)，2.12-2.22(1H,m) ，2.40-2.50(1H,m) ，2.52-2.62
(1H,m)，3.40-3.48(1H,m) ，3.50-3.60(2H,m) ，3.74-
3.80(1H,m) ，4.00(1H,ddd, J5,4 =10.02Hz,J5,6 =5.62
Hz, J 5,6′=2.44Hz)，4.11(1H,dd,J 6,6′ =12.21Hz,
J 5,6′=2.44Hz)，4.12-4.20(1H,m) ，4.28(1H,dd,J
6,6′=12.21Hz,J6,5 =5.62Hz)，4.83(1H,d, J1,2 =0.9
8Hz)，5.13(2H,s)，5.27(1H,dd,J2,3 =3.42Hz, J2,1 =
0.98Hz)，5.27(1H,t, J4,3 =J4,5 =10.02Hz) ，5.32(1
H,dd,J3,4 =10.02Hz,J3,2 =3.42Hz)，7.3-7.4(5H,m) 。[0289]1H-NMR (CDClThree) δ: 1.43 (9H, s), 1.86
1.96 (1H, m), 1.99, 2.03, 2.10, 2.15 (each 3H, each
s), 2.12-2.22 (1H, m), 2.40-2.50 (1H, m), 2.52-2.62
(1H, m), 3.40-3.48 (1H, m), 3.50-3.60 (2H, m), 3.74-
3.80 (1H, m), 4.00 (1H, ddd, J5,4= 10.02Hz, J5,6= 5.62
Hz, J5,6′ = 2.44Hz), 4.11 (1H, dd, J6,6′ = 12.21Hz,
J 5,6'= 2.44Hz), 4.12-4.20 (1H, m), 4.28 (1H, dd, J
6,6'= 12.21Hz, J6,5= 5.62Hz), 4.83 (1H, d, J1,2= 0.9
8Hz), 5.13 (2H, s), 5.27 (1H, dd, J2,3= 3.42Hz, J2,1=
0.98Hz), 5.27 (1H, t, J4,3= J4,5= 10.02Hz), 5.32 (1
H, dd, J3,4= 10.02Hz, J3,2= 3.42Hz), 7.3-7.4 (5H, m).
【０２９０】(h) 化合物 314Ｌの合成 ベンジルエステル体 313Ｌ（4.43ｇ，6.2mmol)をエタノ
ール(100ml) に溶解し、10％Ｐｄ−Ｃ（1.00ｇ）を加
え、室温、40psi で３時間接触還元を行った。 (H) Synthesis of Compound 314 L Benzyl ester 313 L (4.43 g, 6.2 mmol) was dissolved in ethanol (100 ml), 10% Pd—C (1.00 g) was added, and catalytic reduction was performed at room temperature and 40 psi for 3 hours. Was done.
【０２９１】触媒を濾過後、濾液を減圧下濃縮して目的
化合物 314Ｌを無色泡状物質として得た（3.84ｇ，quan
t)。After filtering the catalyst, the filtrate was concentrated under reduced pressure to obtain 314 L of the desired compound as a colorless foam (3.84 g, quan).
t).
【０２９２】(i) 化合物 314Ｄの合成 化合物 313Ｄを出発原料として、化合物 314Ｌの合成
（前項(h))に準じて化合物 314Ｄ(quant) を得た。 (I) Synthesis of Compound 314D Using Compound 313D as a starting material, Compound 314D (quant) was obtained according to the synthesis of Compound 314L ((h) in the preceding section).
【０２９３】(j) 化合物 315Ｌの合成 カルボン酸 314Ｌ（1.94ｇ，3.14mmol) を塩化メチレン
（70ml）に溶解し、ＨＯＳｕ(361mg，3.31mmol) とＤＣ
Ｃ(648mg，3.14mmol) を加え、室温で20時間攪拌して反
応させた。反応液にアミン体308 （1.77ｇ，3.14mmol)
とＤＭＡＰ（0.77ｇ，6.30mmol) を加え、室温で４日間
攪拌を続けた。 (J) Synthesis of Compound 315 L 314 L (1.94 g, 3.14 mmol) of carboxylic acid was dissolved in methylene chloride (70 ml), and HOSu (361 mg, 3.31 mmol) and DC
C (648 mg, 3.14 mmol) was added, and the mixture was stirred and reacted at room temperature for 20 hours. Amine compound 308 (1.77 g, 3.14 mmol) was added to the reaction mixture.
And DMAP (0.77 g, 6.30 mmol) were added, and stirring was continued at room temperature for 4 days.
【０２９４】この反応混合物を塩化メチレンで稀釈後、
水、10％クエン酸水、水、５％ＮａＨＣＯ3 水、水で順
次洗浄、乾燥後溶媒を減圧下留去した。残渣をシリカゲ
ル(100ｇ）を用いるカラムクロマトグラフィー（クロロ
ホルム→クロロホルム：メタノール 100：１）で精製し
て目的化合物 315Ｌを無色泡状物質として得た（2.06
ｇ，66％）。After diluting the reaction mixture with methylene chloride,
After washing sequentially with water, 10% aqueous citric acid, water, 5% aqueous NaHCO 3 and water, and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (100 g) (chloroform → chloroform: methanol 100: 1) to obtain 315 L of the desired compound as a colorless foam (2.06).
g, 66%).
【０２９５】［α］D ＋34.5°(c 0.76,CHCl3 ) 。[Α] D + 34.5 ° (c 0.76, CHCl 3 ).
【０２９６】 1H-NMR(CDCl3 ) δ：1.43(9H,s)，1.99(3
H,s)，1.99(3H,s)，2.06(6H,s)，2.10(3H,s)，2.11(3H,
s)，2.15(6H,s)，4.85(2H,s)。 1 H-NMR (CDCl 3 ) δ: 1.43 (9H, s), 1.99 (3
H, s), 1.99 (3H, s), 2.06 (6H, s), 2.10 (3H, s), 2.11 (3H, s)
s), 2.15 (6H, s), 4.85 (2H, s).
【０２９７】(k) 化合物 315Ｄの合成 化合物 314Ｄ(3.0ｇ) を出発原料として、化合物315 Ｌ
の合成に準じて化合物315Ｄを得た（2.33ｇ，49％）。 (K) Synthesis of Compound 315D Starting from Compound 314D (3.0 g), Compound 315L was prepared.
Compound 315D was obtained according to the synthesis of (2.33 g, 49%).
【０２９８】［α］D ＋26.4°(c 1.01,CHCl3 ) 。[Α] D + 26.4 ° (c 1.01, CHCl 3 ).
【０２９９】 1H-NMR(CDCl3 ) δ：1.43(9H,s)，1.99(3
H,s)，2.00(3H,s)，2.05(3H,s)，2.10(6H,s)，2.15(3H,
s)，4.85(2H,d,J=1.47Hz) 。 1 H-NMR (CDCl 3 ) δ: 1.43 (9H, s), 1.99 (3
H, s), 2.00 (3H, s), 2.05 (3H, s), 2.10 (6H, s), 2.15 (3H, s
s), 4.85 (2H, d, J = 1.47 Hz).
【０３００】(l) 化合物 316Ｌの合成 Ｂｏｃ体 315Ｌ（2.81ｇ，2.83mmol) に氷冷下ＴＦＡ
（30ml) を加え、同温にて１時間半攪拌して反応させ
た。 (L) Synthesis of compound 316L Boc form TFA was added to 315L (2.81g, 2.83mmol) under ice-cooling.
(30 ml) was added, and the mixture was stirred at the same temperature for 1.5 hours to react.
【０３０１】反応液を減圧下濃縮し、目的物 316Ｌを無
色油状物質として得た。The reaction solution was concentrated under reduced pressure to obtain 316 L of the desired product as a colorless oily substance.
【０３０２】(m) 化合物 316Ｄの合成 化合物 315Ｄを出発原料として、化合物316 Ｌの合成
（前項(l))に準じて化合物 316Ｄを得た。 (M) Synthesis of Compound 316D Starting from Compound 315D, Compound 316D was obtained according to the synthesis of Compound 316L ((1) above).
【０３０３】(n) 化合物 317Ｌの合成 アミン体 316Ｌ(642mg，0.64mmol) と活性エステル体30
9 (225mg，0.64mmol)を塩化メチレン(30ml)に溶解し、
ＴＥＡを加えて中和した。室温で20時間攪拌して反応さ
せた。 (N) Synthetic amine 316L (642 mg, 0.64 mmol) of compound 317 L and active ester 30
9 Dissolve (225 mg, 0.64 mmol) in methylene chloride (30 ml),
Neutralized by adding TEA. The reaction was carried out by stirring at room temperature for 20 hours.
【０３０４】この反応液を塩化メチレンで希釈し、水、
10％クエン酸水、水、５％ＮａＨＣＯ3 水、水で順次洗
浄、乾燥後溶媒を減圧下留去した。残渣をシリカゲル
（50ｇ）を用いるカラムクロマトグラフィー（クロロホ
ルム→クロロホルム−メタノール50：１）で精製して目
的化合物 317Ｌを得た(339mg，47％）。The reaction solution was diluted with methylene chloride, and
After washing with 10% aqueous citric acid, water, 5% aqueous NaHCO 3 and water sequentially and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (50 g) (chloroform → chloroform-methanol 50: 1) to obtain 317 L of the desired compound (339 mg, 47%).
【０３０５】［α］D ＋29.3°(c 0.99,CHCl3 ) 。[Α] D + 29.3 ° (c 0.99, CHCl 3 ).
【０３０６】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.6-1.7(2H,m) ，1.99(6H,s)，
2.05(3H,s)，2.06(3H,s)，2.11(3H,s)，2.15(6H,s)，2.
21(2H,t,J=7.57Hz) ，2.32-2.40(1H,m) ，2.40-2.48(1
H,m) ，4.84(1H,d,J=1.47Hz) ，4.86(1H,d,J=1.23Hz)
。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.6-1.7 (2H, m), 1.99 (6H, s),
2.05 (3H, s), 2.06 (3H, s), 2.11 (3H, s), 2.15 (6H, s), 2.
21 (2H, t, J = 7.57Hz), 2.32-2.40 (1H, m), 2.40-2.48 (1
H, m), 4.84 (1H, d, J = 1.47Hz), 4.86 (1H, d, J = 1.23Hz)
.
【０３０７】(o) 化合物 317Ｄの合成 化合物 316Ｄを出発原料として、化合物 317Ｌの合成
（前項(n))に準じて化合物 317Ｄを得た（21％）。 (O) Synthesis of Compound 317D Using Compound 316D as a starting material, Compound 317D was obtained (21%) according to the synthesis of Compound 317L ((n) above).
【０３０８】［α］D ＋29.4°(c 0.99,CHCl3 ) 。[Α] D + 29.4 ° (c 0.99, CHCl 3 ).
【０３０９】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.6-1.7(2H,m) ，1.99(6H,s)，
2.05(3H,s)，2.06(3H,s)，2.11(6H,s)，2.15(3H,s)，2.
15(3H,s)，2.22(2H,t,J=7.09Hz) ，2.32-2.40(1H,m) ，
2.40-2.48(1H,m) ，4.86(1H,s)，4.88(1H,s)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.6-1.7 (2H, m), 1.99 (6H, s),
2.05 (3H, s), 2.06 (3H, s), 2.11 (6H, s), 2.15 (3H, s), 2.
15 (3H, s) 、 2.22 (2H, t, J = 7.09Hz) 、 2.32-2.40 (1H, m) 、
2.40-2.48 (1H, m), 4.86 (1H, s), 4.88 (1H, s).
【０３１０】(p) 化合物 318Ｌの合成 化合物 317Ｌ(272mg，0.27mmol) をメタノール（４ml）
に溶解し、28％ＭｅＯＮａ ｉｎ ＭｅＯＨ（20μl)を
加え、室温で３時間攪拌して反応させた。 (P) Synthesis of Compound 318 L Compound 317 L (272 mg, 0.27 mmol) was added to methanol (4 ml).
, 28% MeOH in MeOH (20 μl) was added, and the mixture was stirred and reacted at room temperature for 3 hours.
【０３１１】反応液に「アンバーライトＩＲＣ−50」を
加えて中和後、溶媒を減圧下留去した。析出した粉末を
エーテルで洗浄して目的化合物 318Ｌを無色粉末として
得た(172mg，90％）。[0311] After neutralization by adding "Amberlite IRC-50" to the reaction solution, the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain 318 L of the desired compound as a colorless powder (172 mg, 90%).
【０３１２】［α］D ＋36.1°(c 0.99,MeOH) 。[Α] D + 36.1 ° (c 0.99, MeOH).
【０３１３】 1H-NMR(CD3 OD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.61(2H,m)，1.86-1.95(1H,m)
，2.03-2.10(1H,m) ，2.25(2H,t,J=7.82Hz) ，2.29(2
H,t,J=7.58Hz) ，4.76(2H,s)。 1 H-NMR (CD 3 OD) δ: 0.90 (3H, t, J = 7.08H)
z), 1.2-1.4 (24H, m), 1.61 (2H, m), 1.86-1.95 (1H, m)
, 2.03-2.10 (1H, m), 2.25 (2H, t, J = 7.82Hz), 2.29 (2H
H, t, J = 7.58Hz), 4.76 (2H, s).
【０３１４】(q) 化合物 318Ｄの合成 化合物 317Ｄ（83mg）を出発原料として、化合物 318Ｌ
の合成（前項(p))に準じて化合物 318Ｄを得た（53mg，
92％）。 (Q) Synthesis of Compound 318D Starting from Compound 317D (83 mg), Compound 318L
Compound 318D was obtained according to the synthesis of the above (53 mg,
92%).
【０３１５】［α］D ＋40.8°(c 0.98,MeOH) 。[Α] D + 40.8 ° (c 0.98, MeOH).
【０３１６】 1H-NMR(CD3 OD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.62(2H,m)，1.86-1.95(1H,m)
，2.02-2.10(1H,m) ，2.22-2.31(4H,m) ，4.30(1H,dd,
J=8.55Hz,J=5.62Hz) ，4.75(1H,d,J=1.71Hz) ，4.76(1
H,d,J=1.47Hz) 。 1 H-NMR (CD 3 OD) δ: 0.90 (3H, t, J = 7.08H)
z), 1.2-1.4 (24H, m), 1.62 (2H, m), 1.86-1.95 (1H, m)
, 2.02-2.10 (1H, m), 2.22-2.31 (4H, m), 4.30 (1H, dd,
J = 8.55Hz, J = 5.62Hz), 4.75 (1H, d, J = 1.71Hz), 4.76 (1
H, d, J = 1.47Hz).
【０３１７】(r) 合成 319Ｌの合成 カルボン酸 314Ｌ(496mg，0.80mmol) を塩化メチレン
（20ml）に溶解し、ＨＯＳｕ（92mg，0.80mmol) とＤＣ
Ｃ(165mg，0.80mmolを加え、室温で20時間攪拌した。つ
いで、アミン体 316Ｌ(800mg，0.80mmol) とＤＭＡＰ(5
30mg，4.33mol)を加え、室温で24時間攪拌して反応させ
た。 (R) Synthesis 319 L of synthetic carboxylic acid (314 L, 496 mg, 0.80 mmol) was dissolved in methylene chloride (20 ml), and HOSu (92 mg, 0.80 mmol) and DC
C (165 mg, 0.80 mmol) was added and the mixture was stirred at room temperature for 20 hours. Then, 316 L of the amine compound (800 mg, 0.80 mmol) and DMAP (5
30 mg, 4.33 mol), and the mixture was stirred and reacted at room temperature for 24 hours.
【０３１８】反応液を塩化メチレンで希釈し、水、10％
クエン酸水、水５％ＮａＨＣＯ3 水、水で順次洗浄、乾
燥後溶媒を減圧下留去した。残渣をシリカゲル（40ｇ）
を用いるカラムクロマトグラフィー（クロロホルム→ク
ロロホルム−メタノール50：１）で精製して目的化合物
319Ｌを得た(495mg，41％）。The reaction solution was diluted with methylene chloride, and water, 10%
After washing with citric acid water, water 5% NaHCO 3 water and water in that order and drying, the solvent was distilled off under reduced pressure. Residue is silica gel (40 g)
Purification by column chromatography using chloroform (chloroform → chloroform-methanol 50: 1)
319 L were obtained (495 mg, 41%).
【０３１９】［α］D ＋32.3°(c 1.00,CHCl3 ) 。[Α] D + 32.3 ° (c 1.00, CHCl 3 ).
【０３２０】 1H-NMR(CDCl3 ) δ：1.43(9H,s)，1.99(3
H,s)，2.00(3H,s)，2.05(3H,s)，2.06(3H,s)，2.10(3H,
s)，2.11(6H,s)，2.15(6H,s)，2.16(3H,s)，4.85(3H,d,
J=1.71Hz) 。 1 H-NMR (CDCl 3 ) δ: 1.43 (9H, s), 1.99 (3
H, s), 2.00 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.10 (3H, s
s), 2.11 (6H, s), 2.15 (6H, s), 2.16 (3H, s), 4.85 (3H, d,
J = 1.71Hz).
【０３２１】(s) 化合物 319Ｄの合成 化合物 314Ｄ(430mg) を出発原料として、化合物 319Ｌ
の合成（前項(r))に準じて化合物 319Ｄを得た(384mg，
27％）。 (S) Synthesis of Compound 319D Starting from Compound 314D (430 mg), Compound 319L
Compound 319D was obtained according to the synthesis of the above ((r)) (384 mg,
27%).
【０３２２】［α］D ＋36.6°(c 1.08,CHCl3 ) 。[Α] D + 36.6 ° (c 1.08, CHCl 3 ).
【０３２３】 1H-NMR(CDCl3 ) δ：1.43(9H,s)，1.98(3
H,s)，1.99(3H,s)，2.04(3H,s)，2.05(3H,s)，2.06(3H,
s)，2.10(9H,s)，2.15(9H,s)，4.85(2H,s)，4.89(1H,
s)。 1 H-NMR (CDCl 3 ) δ: 1.43 (9H, s), 1.98 (3
H, s), 1.99 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 2.06 (3H,
s), 2.10 (9H, s), 2.15 (9H, s), 4.85 (2H, s), 4.89 (1H,
s).
【０３２４】(t) 化合物 320Ｌの合成 Ｂｏｃ体 319Ｌ(415mg，0.28mmol) に氷冷下ＴＦＡ（５
ml）を加え、同温度で１時間攪拌して反応させた。反応
液を減圧下濃縮し、残渣に塩化メチレン（10ml）を加
え、さらにに活性エステル体309 （98mg，0.28mmol) と
ＤＭＡＰ(169mg，1.38mmol）を加えて室温で16時間攪拌
して反応させた。 (T) Synthetic Boc form of compound 320 L 319 L (415 mg, 0.28 mmol) was added to TFA (5
ml), and the mixture was stirred at the same temperature for 1 hour to react. The reaction solution was concentrated under reduced pressure, methylene chloride (10 ml) was added to the residue, and the activated ester 309 (98 mg, 0.28 mmol) and DMAP (169 mg, 1.38 mmol) were further added, and the mixture was stirred and reacted at room temperature for 16 hours. Was.
【０３２５】この反応液を塩化メチレンで希釈し、水、
10％クエン酸水、水、５％ＮａＨＣＯ3 水、水で順次洗
浄、乾燥後溶媒を減圧下留去した。残渣をシリカゲル
（30ｇ）を用いるカラムクロマトグラフィー（クロロホ
ルム→クロロホルム−メタノール50：１）で精製し、目
的化合物 320Ｌを得た(331mg，73％）。The reaction solution was diluted with methylene chloride, and
After washing with 10% aqueous citric acid, water, 5% aqueous NaHCO 3 and water sequentially and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform → chloroform-methanol 50: 1) using silica gel (30 g) to obtain 320 L of the desired compound (331 mg, 73%).
【０３２６】［α］D ＋32.5°(c 1.06,CHCl3 ) 。[Α] D + 32.5 ° (c 1.06, CHCl 3 ).
【０３２７】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.98(3H,s)，1.99(3H,s)，2.00
(3H,s)，2.05(3H,s)，2.06(3H,s)，2.10(3H,s)，2.11(6
H,s)，2.15(6H,s)，2.16(3H,s)，4.83(1H,s)，4.85(2H,
s)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.98 (3H, s), 1.99 (3H, s), 2.00
(3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 2.11 (6
H, s), 2.15 (6H, s), 2.16 (3H, s), 4.83 (1H, s), 4.85 (2H,
s).
【０３２８】(u) 化合物 220Ｄの合成 化合物 319Ｄ(250mg) を出発原料として、化合物320 Ｌ
の合成（前項(t))に準じて化合物 320Ｄを得た(102mg，
37％）。 (U) Synthesis of compound 220D Starting from compound 319D (250 mg), compound 320 L
Compound 320D was obtained according to the synthesis of the above ((t) above) (102 mg,
37%).
【０３２９】［α］D ＋38.1°(c 0.93,CHCl3 ) 。[Α] D + 38.1 ° (c 0.93, CHCl 3 ).
【０３３０】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.55-1.65(2H,m) ，1.98(3H,
s)，1.99(3H,s)，2.04(6H,s)，2.06(3H,s)，2.11(9H,
s)，2.15(9H,s)，4.83(1H,d,J=0.73Hz) ，4.87(1H,s)，
4.88(1H,s)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.55-1.65 (2H, m), 1.98 (3H, m
s), 1.99 (3H, s), 2.04 (6H, s), 2.06 (3H, s), 2.11 (9H,
s), 2.15 (9H, s), 4.83 (1H, d, J = 0.73Hz), 4.87 (1H, s),
4.88 (1H, s).
【０３３１】(v) 化合物 321Ｌの合成 化合物 320Ｌ(273mg，0.17mmol）をメタノール（４ml）
に溶解し、28％ＭｅＯＮａ ｉｎ ＭｅＯＨ（20μl)を
加え、室温で４時間攪拌して反応させた。 (V) Synthesis of Compound 321 L Compound 320 L (273 mg, 0.17 mmol) was added to methanol (4 ml).
, 28% MeOH in MeOH (20 μl) was added, and the mixture was stirred and reacted at room temperature for 4 hours.
【０３３２】反応液に「アンバーライトＩＲＣ−50」を
加えて中和後、溶媒を減圧下留去した。析出した粉末を
エーテルで洗浄して目的物 321Ｌを無色粉末として得た
(154mg，82％）。The reaction solution was neutralized by adding “Amberlite IRC-50”, and the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain 321 L of the desired product as a colorless powder.
(154 mg, 82%).
【０３３３】［α］D ＋36.1°(c 0.71,MeOH）。[Α] D + 36.1 ° (c 0.71, MeOH).
【０３３４】 1H-NMR(CD3 OD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.61(2H,m)，1.89(2H,m)，2.08
(2H,m)，2.26(2H,t,J=7.33Hz) ，2.30(2H,t,J=7.57Hz)
，2.35(2H,t,J=7.33Hz) ，4.77-4.78(3H,m) 。 1 H-NMR (CD 3 OD) δ: 0.90 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.61 (2H, m), 1.89 (2H, m), 2.08
(2H, m), 2.26 (2H, t, J = 7.33Hz), 2.30 (2H, t, J = 7.57Hz)
, 2.35 (2H, t, J = 7.33 Hz), 4.77-4.78 (3H, m).
【０３３５】(w) 化合物 321Ｄの合成 化合物 320Ｄ（90mg）を出発原料として、化合物 321Ｌ
の合成（前項(v))に準じて化合物 321Ｄを得た（56mg，
90％）。 (W) Synthesis of compound 321D Starting from compound 320D (90 mg), compound 321L
Compound 321D was obtained according to the synthesis (56 mg,
90%).
【０３３６】［α］D ＋37.9°(c 0.92,MeOH）。[Α] D + 37.9 ° (c 0.92, MeOH).
【０３３７】 1H-NMR(CD3 OD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.61(2H,m)，1.85-1.96(2H,m)
，2.03-2.14(2H,m) ，2.24-2.38(6H,m) ，4.76(1H,d,J
=1.71Hz) ，4.77(2H,d,J=1.22Hz) 。 1 H-NMR (CD 3 OD) δ: 0.90 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.61 (2H, m), 1.85-1.96 (2H, m)
, 2.03-2.14 (2H, m), 2.24-2.38 (6H, m), 4.76 (1H, d, J
= 1.71Hz), 4.77 (2H, d, J = 1.22Hz).
【０３３８】(x) 化合物 322の合成 ベンジルエステル体 307α（6.44ｇ，8.4mmol)をエタノ
ール(130ml）に溶解し、10％Ｐｄ−Ｃ（0.32ｇ）を加
え、室温、40psi で３時間半接触還元を行った。 (X) Synthesis of Compound 322 Benzyl ester 307α (6.44 g, 8.4 mmol) was dissolved in ethanol (130 ml), 10% Pd—C (0.32 g) was added, and the mixture was contacted at room temperature and 40 psi for 3 半 hours. Reduction was performed.
【０３３９】触媒を濾過後、濾液を減圧下濃縮し、目的
物322 を無色泡状物質として得た（5.65ｇ，quant)。After filtering the catalyst, the filtrate was concentrated under reduced pressure to obtain the desired product 322 as a colorless foam (5.65 g, quant).
【０３４０】(y) 化合物323 の合成 カルボン酸322 (693mg，1.03mmol) を塩化メチレン（20
ml）に溶解し、ＨＯＳｕ(119mg，1.03mmol) とＤＣＣ(2
13mg，1.03mmol) を加え室温で19時間攪拌した。つい
で、アミン体308 (580mg，1.03mmol) とＤＭＡＰ(252m
g，2.06mmol) を加え、室温で２日間攪拌して反応させ
た。 (Y) Synthesis of Compound 323 The carboxylic acid 322 (693 mg, 1.03 mmol) was added to methylene chloride (20
HOSu (119 mg, 1.03 mmol) and DCC (2
13 mg, 1.03 mmol) and stirred at room temperature for 19 hours. Then, the amine compound 308 (580 mg, 1.03 mmol) and DMAP (252 mM
g, 2.06 mmol), and reacted by stirring at room temperature for 2 days.
【０３４１】反応液を塩化メチレンで希釈し、水、10％
クエン酸水、水、５％ＮａＨＣＯ3 水、水で順次洗浄、
乾燥後溶媒を減圧下留去した。残渣をシリカゲル（50
ｇ）を用いるカラムクロマトグラフィー（トルエン−酢
酸エチル２：３）で精製し、目的化合物323 を無色泡状
物質として得た(771mg，71％）。The reaction solution was diluted with methylene chloride, and water, 10%
Wash sequentially with citric acid water, water, 5% NaHCO 3 water and water,
After drying, the solvent was distilled off under reduced pressure. The residue was silica gel (50
Purification by column chromatography (toluene-ethyl acetate 2: 3) using g) gave the target compound 323 as a colorless foam (771 mg, 71%).
【０３４２】［α］D ＋41.2°(c 1.05,CHCl3 ) 。[Α] D + 41.2 ° (c 1.05, CHCl 3 ).
【０３４３】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.63(2H,m)，1.98(3H,s)，2.00
(3H,s)，2.04(3H,s)，2.06(3H,s)，2.10(3H,s)，2.11(3
H,s)，2.15(3H,s)，2.26(2H,t,J=7.08Hz) ，4.86(1H,d,
J=1.47Hz) ，4.90(1H,d,J=0.98Hz) 。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.63 (2H, m), 1.98 (3H, s), 2.00
(3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 2.11 (3
H, s), 2.15 (3H, s), 2.26 (2H, t, J = 7.08Hz), 4.86 (1H, d,
J = 1.47Hz), 4.90 (1H, d, J = 0.98Hz).
【０３４４】(z) 化合物324 の合成 化合物323 (369mg，0.35mmol) をメタール（５ml）に溶
解し、28％ＭｅＯＮａｉｎ ＭｅＯＨ（20μl)を加え、
室温で４時間攪拌して反応させた。 (Z) Synthesis of Compound 324 Compound 323 (369 mg, 0.35 mmol) was dissolved in methal (5 ml), and 28% MeOH in MeOH (20 μl) was added.
The reaction was carried out by stirring at room temperature for 4 hours.
【０３４５】反応液に「アンバーライトＩＲＣ−50」を
加えて中和後、溶媒を減圧下留去した。析出した粉末を
エーテルで洗浄し、目的物324 を無色粉末として得た(2
27mg，91％）。The reaction solution was neutralized by adding “Amberlite IRC-50”, and the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain the desired product 324 as a colorless powder (2
27 mg, 91%).
【０３４６】［α］D ＋45.1°(c 0.98,MeOH) 。[Α] D + 45.1 ° (c 0.98, MeOH).
【０３４７】 1H-NMR(CD3 CD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.61(2H,m)，2.27(2H,t,J=7.33H
z) ，4.78(2H,s)。(a′) 化合物325 の合成 カルボン酸322 (539mg，0.80mmol) を塩化メチレン（20
ml）に溶解し、ＨＯＳｕ（92mg，0.80mmol）とＤＣＣ(1
65mg，0.80mmol) を加え、室温で20時間攪拌した。つい
で、アミン体 316Ｌ(800mg，0.80mmol) とＤＭＡＰ(530
mg，4.33mmol)を加え、室温で２日間攪拌して反応させ
た。 1 H-NMR (CD 3 CD) δ: 0.90 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.61 (2H, m), 2.27 (2H, t, J = 7.33H
z), 4.78 (2H, s). (a ') Synthetic carboxylic acid 322 (539 mg, 0.80 mmol ) of compound 325
HOSu (92 mg, 0.80 mmol) and DCC (1 ml).
(65 mg, 0.80 mmol) and stirred at room temperature for 20 hours. Then, the amine compound 316L (800 mg, 0.80 mmol) and DMAP (530 mg)
mg, 4.33 mmol), and reacted by stirring at room temperature for 2 days.
【０３４８】反応液を塩化メチレンで希釈し、水、10％
クエン酸水、水、５％ＮａＨＣＯ3 水、水で順次洗浄、
乾燥後溶媒を減圧下留去した。残渣をシリカゲル（40
ｇ）を用いるカラムクロマトグラフィー（クロロホルム
→クロロホルム−メタノール 100：１）で精製し、目的
化合物325 を無色泡状物質として得た(715mg，58％）。The reaction solution was diluted with methylene chloride, and added with water, 10%
Wash sequentially with citric acid water, water, 5% NaHCO 3 water and water,
After drying, the solvent was distilled off under reduced pressure. Residue is silica gel (40
Purification by column chromatography (chloroform → chloroform-methanol 100: 1) using g) gave the desired compound 325 as a colorless foam (715 mg, 58%).
【０３４９】［α］D ＋30.8°(c 1.00,CHCl3 ) 。[Α] D + 30.8 ° (c 1.00, CHCl 3 ).
【０３５０】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.98(3H,s)，1.99(3H,s)，2.04
(3H,s)，2.05(3H,s)，2.05(3H,s)，2.11(9H,s)，2.14(3
H,s)，2.15(3H,s)，2.32(2H,t,J=7.82Hz) ，2.44(2H,
m)，4.83(1H,d,J=0.98Hz) ，4.83(1H,d,J=1.47Hz) ，4.
88(1H,d,J=1.23Hz) 。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.98 (3H, s), 1.99 (3H, s), 2.04
(3H, s), 2.05 (3H, s), 2.05 (3H, s), 2.11 (9H, s), 2.14 (3
H, s), 2.15 (3H, s), 2.32 (2H, t, J = 7.82Hz), 2.44 (2H,
m), 4.83 (1H, d, J = 0.98Hz), 4.83 (1H, d, J = 1.47Hz), 4.
88 (1H, d, J = 1.23Hz).
【０３５１】(b′) 化合物326 の合成 化合物325 (183mg，0.12mmol) をメタノール（５ml）と
水(0.5ml) の混合溶媒に溶解し、ＴＥＡ（50μl)を加
え、室温で２日間攪拌して反応させた。 (B ′) Synthesis of Compound 326 Compound 325 (183 mg, 0.12 mmol) was dissolved in a mixed solvent of methanol (5 ml) and water (0.5 ml), TEA (50 μl) was added, and the mixture was stirred at room temperature for 2 days. And reacted.
【０３５２】反応液に「アンバーライトＩＲＣ−50」を
加えて中和後、溶媒を減圧下留去した。析出した粉末を
エーテルで洗浄して目的物326 を無色粉末として得た(1
22mg，99％）。The reaction solution was neutralized by adding “Amberlite IRC-50”, and the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain the desired product 326 as a colorless powder (1
22 mg, 99%).
【０３５３】［α］D ＋36.5°(c 0.98,MeOH) 。[Α] D + 36.5 ° (c 0.98, MeOH).
【０３５４】 1H-NMR(CD3 CD) δ：0.90(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.62(2H,m)，1.88-1.98(1H,m)
，2.06-2.18(1H,m) ，2.27-2.36(4H,m) ，4.77(2H,d,J
=1.47Hz) 。 1 H-NMR (CD 3 CD) δ: 0.90 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.62 (2H, m), 1.88-1.98 (1H, m)
, 2.06-2.18 (1H, m), 2.27-2.36 (4H, m), 4.77 (2H, d, J
= 1.47Hz).
【０３５５】(c′) 化合物329 の合成 カルボン酸328 (405mg，0.50mmol）を塩化メチレン（10
ml) に溶解し、ＨＯＳｕ（63mg，0.55mmol) とＤＣＣ(1
13mg，0.55mmol) を加え、室温で19時間攪拌した。つい
でアミン体308 (280mg，0.50mmol) とＤＭＡＰ(122mg，
1.00mmol) を加え、室温で20時間攪拌して反応させた。 (C ′) Synthesis of Compound 329 Carboxylic acid 328 (405 mg, 0.50 mmol) was treated with methylene chloride (10%).
HOSu (63 mg, 0.55 mmol) and DCC (1 ml).
13 mg, 0.55 mmol) and stirred at room temperature for 19 hours. Next, the amine compound 308 (280 mg, 0.50 mmol) and DMAP (122 mg,
(1.00 mmol), and the mixture was stirred and reacted at room temperature for 20 hours.
【０３５６】反応液を塩化メチレンで希釈し、水、10％
クエン酸水、水、５％ＮａＨＣＯ3 水、水で順次洗浄、
乾燥後溶媒を減圧下留去した。残渣をシリカゲル（60
ｇ）を用いるカラムクロマトグラフィー（クロロホルム
→クロロホルム−メタノール 100：１）で精製した。再
度、シリカゲル（60ｇ）を用いるカラムクラモトグラフ
ィー（アセトニトリル−ジイソプロピルエーテル３：
２）で精製して目的化合物329 を得た(186mg，32％）。The reaction solution was diluted with methylene chloride, and water, 10%
Wash sequentially with citric acid water, water, 5% NaHCO 3 water and water,
After drying, the solvent was distilled off under reduced pressure. The residue was purified on silica gel (60
Purified by column chromatography (chloroform → chloroform-methanol 100: 1) using g). Again, column chromatography using silica gel (60 g) (acetonitrile-diisopropyl ether 3:
Purification in 2) gave the desired compound 329 (186 mg, 32%).
【０３５７】［α］D ＋12.7°(c 1.01,CHCl3 ) 。[Α] D + 12.7 ° (c 1.01, CHCl 3 ).
【０３５８】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=7.08H
z) ，1.2-1.4(24H,m)，1.89(3H,s)，1.99(3H,s)，2.02
(3H,s)，2.04(3H,s)，2.06(3H,s)，2.10(3H,s)，2.14(3
H,s)，2.15(6H,s)，2.26(2H,t,J=6.84Hz) ，2.59(1H,d
d,J3e,3a =12.94Hz,J3e,4=4.64Hz)，3.84(3H,s)，4.84
(1H,d,J=1.47Hz) 。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.08H
z), 1.2-1.4 (24H, m), 1.89 (3H, s), 1.99 (3H, s), 2.02
(3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 2.14 (3
H, s), 2.15 (6H, s), 2.26 (2H, t, J = 6.84Hz), 2.59 (1H, d
d, J 3e, 3a = 12.94Hz, J 3e, 4 = 4.64Hz), 3.84 (3H, s), 4.84
(1H, d, J = 1.47Hz).
【０３５９】(d′) 化合物330 の合成 化合物329 (170mg，0.14mmol) をメタノール（４ml）と
水（１ml）の混合溶媒に溶解し、ＴＥＡ（50μl)を加
え、室温で２日間攪拌した。保護基が完全には除去され
ないため、 0.1Ｎ水酸化ナトリウム水（５ml）を追加し
さらに室温で３日間攪拌を続けて反応させた。 (D ′) Synthesis of Compound 330 Compound 329 (170 mg, 0.14 mmol) was dissolved in a mixed solvent of methanol (4 ml) and water (1 ml), TEA (50 μl) was added, and the mixture was stirred at room temperature for 2 days. Since the protecting group was not completely removed, 0.1N aqueous sodium hydroxide (5 ml) was added, and the mixture was further reacted at room temperature with stirring for 3 days.
【０３６０】反応液に「アンバーライトＩＲＣ−50」を
加えて中和後、溶媒を減圧留去した。析出した粉末をエ
ーテルで洗浄し目的物330 を無色粉末として得た（88m
g，73％）。After the reaction solution was neutralized by adding “Amberlite IRC-50”, the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain the desired product 330 as a colorless powder (88 m
g, 73%).
【０３６１】(e′) 化合物331 の合成（図３ｆ） α−セチル−ステアリン酸(335mg) に塩化チオニル (３
ml) を加え、２時間加熱還流した。過剰の塩化チオニル
を留去し、ベンゼンを加え、溶媒を留去した。この操作
を３回繰り返したのち、残渣を塩化メチレン (３ml) に
溶解した。この溶液をマンノース誘導体308(0.6mmol 相
当) およびトリエチルアミン(0.18ml)の塩化メチレン(1
5ml)溶液に氷冷下滴下した後、室温にて終夜撹拌した。
反応液を水及び半飽和食塩水にて洗浄し、硫酸マグネシ
ウムにて乾燥した。溶媒を留去し、残渣をシリカゲルク
ロマトグラフィー（シリカゲル 40 ｇ、トルエン：酢酸
エチルエステル＝88：12）にて精製してアミド体(464m
g) を得た。 (E ′) Synthesis of Compound 331 (FIG. 3f) α-Cetyl-stearic acid (335 mg) was added to thionyl chloride (3
ml), and the mixture was heated under reflux for 2 hours. Excess thionyl chloride was distilled off, benzene was added, and the solvent was distilled off. After repeating this operation three times, the residue was dissolved in methylene chloride (3 ml). This solution was treated with mannose derivative 308 (equivalent to 0.6 mmol) and triethylamine (0.18 ml) in methylene chloride (1
(5 ml) was added dropwise to the solution under ice cooling, followed by stirring at room temperature overnight.
The reaction solution was washed with water and half-saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (silica gel 40 g, toluene: ethyl acetate = 88: 12) to give the amide compound (464m
g) was obtained.
【０３６２】［α］D 27+16.5 ゜(c 1.2，クロロホル
ム) 。[Α] D 27 +16.5 ゜ (c 1.2, chloroform).
【０３６３】IR(KBr) ：3450，3360，1755，1640，1550
cm-1。IR (KBr): 3450, 3360, 1755, 1640, 1550
cm -1 .
【０３６４】 1H-NMR(CDCl3 ) ：0.88(3H,t,J=7Hz)，1.
22-1.25(56H,m)，2.01(3H,s)，2.05(3H,s)，2.10(3H,
s)，2.16(3H,s)，3.97(1H,ddd,J=2,5.5,8Hz)，4.10(1H,
dd,J=2.5,12Hz)，4.28(1H,dd,J=5.5,12Hz)，4.81(1H,d,
J=1.5Hz)，5.26(1H,dd,J=1.5,3.5Hz) ，5.27(1H,dd,J=
8,10Hz)，5.32(1H,dd,J=3.5,10Hz)，5.85(1H,t,J=6H
z)。 1 H-NMR (CDCl 3 ): 0.88 (3H, t, J = 7 Hz), 1.
22-1.25 (56H, m), 2.01 (3H, s), 2.05 (3H, s), 2.10 (3H,
s), 2.16 (3H, s), 3.97 (1H, ddd, J = 2,5.5,8Hz), 4.10 (1H,
dd, J = 2.5,12Hz), 4.28 (1H, dd, J = 5.5,12Hz), 4.81 (1H, d,
J = 1.5Hz), 5.26 (1H, dd, J = 1.5,3.5Hz), 5.27 (1H, dd, J =
8,10Hz), 5.32 (1H, dd, J = 3.5,10Hz), 5.85 (1H, t, J = 6H
z).
【０３６５】Ｒf =0.24 （トルエン：酢酸エチルエステ
ル＝４：１）。R f = 0.24 (toluene: ethyl acetate = 4: 1).
【０３６６】上記で得たアミド体（360mg)のメタノール
(30ml)溶液にナトリウムメトキシド（28％メタノール溶
液80μｌ）を加え、室温にて終夜撹拌した。塩化メチレ
ンを加えて析出した粉末を溶解した後「アンバーリスト
15Ｅ」を液性が中性になるまで加えた後樹脂を濾去し、
濾液を濃縮し、残渣を「セファデックスＬＨ−20」（メ
タノール：クロロホルム＝１：１）にて精製し、目的化
合物331(256mg)を得た。The amide (360 mg) obtained above in methanol
(30 ml) solution was added with sodium methoxide (80 μl of 28% methanol solution) and stirred at room temperature overnight. After dissolving the precipitated powder by adding methylene chloride,
15E "until the solution becomes neutral, and then the resin is filtered off.
The filtrate was concentrated, and the residue was purified with "Sephadex LH-20" (methanol: chloroform = 1: 1) to obtain the desired compound 331 (256 mg).
【０３６７】［α］D 28+22.2 ゜(c 1.2，クロロホル
ム：メタノール=1:1 )。[Α] D 28 +22.2 ゜ (c 1.2, chloroform: methanol = 1: 1).
【０３６８】IR(KBr) ：3440，3430，1650，1545cm-1。IR (KBr): 3440, 3430, 1650, 1545 cm -1 .
【０３６９】 1H-NMR(CD3 OD) ：0.89(3H,t,J=7Hz)，1.
27(56H,m) ，1.4(2H,m) ，1.55(2H,m)，2.15(1H,m)。 1 H-NMR (CD 3 OD): 0.89 (3H, t, J = 7 Hz), 1.
27 (56H, m), 1.4 (2H, m), 1.55 (2H, m), 2.15 (1H, m).
【０３７０】Ｒf =0.51 （クロロホルム：メタノール＝
９：１）。R f = 0.51 (chloroform: methanol =
9: 1).
【０３７１】(f′) 化合物331 の合成（図３ｇ） １）化合物327 の合成 α−Ｄ−マンノースペンタアセテート（化合物302 ）
（3.90ｇ）と２−［２−（２−クロロエトキシ）エトキ
シ］エタノール（3.37ｇ）を塩化メチレン(200ml）に溶
解し、ＢＦ3 ・Ｅｔ2 Ｏ（5.68ｇ）を加え、室温で５日
間攪拌した。反応液を塩化メチレンで希釈し、水、５％
ＮａＨＣＯ3 水及び水で順次洗浄し、乾燥後溶媒を減圧
下留去した。残渣をシリカゲル(200ｇ）を用いるカラム
クロマトグラフィー（クロロホルム）で精製し、α−グ
リコシド化合物327 （4.13ｇ）を無色油状物として得
た。 (F ′) Synthesis of Compound 331 (FIG. 3G) 1) Synthesis of Compound 327 α-D-mannose pentaacetate (Compound 302)
(3.90 g) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (3.37 g) were dissolved in methylene chloride (200 ml), and BF 3 .Et 2 O (5.68 g) was added. Stirred. Dilute the reaction solution with methylene chloride, water, 5%
The extract was washed successively with aqueous NaHCO 3 and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (200 g) to obtain α-glycoside compound 327 (4.13 g) as a colorless oil.
【０３７２】［α］D +38.7 °(c 1.51,CHCl3 ) 。[Α] D + 38.7 ° (c 1.51, CHCl 3 ).
【０３７３】 1H-NMR(CDCl3 ) δ：2.04(3H,s)，2.05(3
H,s)，2.10(3H,s)，2.16(3H,s)，3.63-3.70(9H,m) ，3.
75-3.85(3H,m) ，4.07(1H,ddd,J=2.4Hz,5.1Hz,10.0Hz)
，4.11(1H,dd,J=2.4Hz,12.2Hz)，4.29(1H,dd,J=4.9Hz,
12.2Hz)，4.88(1H,d,J=1.5Hz)，5.27(1H,dd,J=1.5Hz,3.
4Hz) ，5.29(1H,t,J=10.0Hz) ，5.36(1H,dd,J=3.4Hz,1
0.0Hz)。 1 H-NMR (CDCl 3 ) δ: 2.04 (3H, s), 2.05 (3
H, s), 2.10 (3H, s), 2.16 (3H, s), 3.63-3.70 (9H, m), 3.
75-3.85 (3H, m), 4.07 (1H, ddd, J = 2.4Hz, 5.1Hz, 10.0Hz)
, 4.11 (1H, dd, J = 2.4Hz, 12.2Hz), 4.29 (1H, dd, J = 4.9Hz,
12.2Hz), 4.88 (1H, d, J = 1.5Hz), 5.27 (1H, dd, J = 1.5Hz, 3.
4Hz), 5.29 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz, 1
0.0Hz).
【０３７４】２）化合物328 の合成 クロル体化合物327(3.68ｇ）をＤＭＦ(50ml)に溶解し、
アジ化ナトリウム(0.72 ｇ) を加え、60℃で24時間撹拌
した。反応液を酢酸エチルで希釈し、水洗し、乾燥後溶
媒を減圧下留去した。残渣をシリカゲル(150ｇ) を用い
るカラムクロマトグラフィー（クロロホルム−アセトン
10：１）で精製し、アジド体化合物328(3.05ｇ) を無色
油状物として得た。2) Synthesis of Compound 328 The chlorinated compound 327 (3.68 g) was dissolved in DMF (50 ml).
Sodium azide (0.72 g) was added, and the mixture was stirred at 60 ° C for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (150 g) (chloroform-acetone).
Purification by 10: 1) gave the azide compound 328 (3.05 g) as a colorless oil.
【０３７５】［α］D +35.6 °(c 2.54,CHCl3 ) 。[Α] D + 35.6 ° (c 2.54, CHCl 3 ).
【０３７６】 1H-NMR(CDCl3 ) δ：1.99(3H,s)，2.04(3
H,s)，2.11(3H,s)，2.16(3H,s)，3.40(2H,t,J=5.1Hz)，
3.62-3.86(10H,m)，4.06(1H,ddd,J=2.4Hz,4.9Hz,10.0H
z) ，4.10(1H,dd,J=2.4Hz,12.2Hz)，4.29(1H,dd,J=4.9H
z,12.2Hz)，4.88(1H,d,J=1.5Hz)，5.27(1H,dd,J=1.5Hz,
3.4Hz) ，5.29(1H,t,J=10.0Hz) ，5.36(1H,dd,J=3.4Hz,
10.0Hz)。 1 H-NMR (CDCl 3 ) δ: 1.99 (3H, s), 2.04 (3
H, s), 2.11 (3H, s), 2.16 (3H, s), 3.40 (2H, t, J = 5.1Hz),
3.62-3.86 (10H, m), 4.06 (1H, ddd, J = 2.4Hz, 4.9Hz, 10.0H
z), 4.10 (1H, dd, J = 2.4Hz, 12.2Hz), 4.29 (1H, dd, J = 4.9H
z, 12.2Hz), 4.88 (1H, d, J = 1.5Hz), 5.27 (1H, dd, J = 1.5Hz,
3.4Hz), 5.29 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz,
10.0Hz).
【０３７７】３）化合物329 の合成 アジド体化合物328(386mg ）とｐ−トルエンスルホン酸
(145mg）をエタノール（20ml）に溶解し、リンドラー触
媒(770mg）を加え、室温50ｐｓｉで 7.5時間接触還元を
行った。触媒を濾去後、濾液を減圧下濃縮し、アミン体
化合物329 を得た。3) Synthesis of compound 329 Azide compound 328 (386 mg) and p-toluenesulfonic acid
(145 mg) was dissolved in ethanol (20 ml), a Lindlar catalyst (770 mg) was added, and catalytic reduction was carried out at room temperature at 50 psi for 7.5 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain an amine compound 329.
【０３７８】４）化合物330 の合成 ２−（１−ヘキサデシル）オクタデカン酸(153mg）をヘ
キサン（15ml）と塩化メチレン（20ml）の混合溶媒に溶
解し、Ｎ−ヒドロキシスクシンイミド（35mg）とＮ，
Ｎ′−ジンクロヘキシルカルボジイミド（62mg）を加
え、室温で24時間攪拌した。反応混合物にアセトニトリ
ル（15ml）に溶解したアミン体化合物329(235mg ）を加
え、ついでトルエチルアミン（67mg）を加えた後、室温
で23時間攪拌した。不溶物を濾去し、濾液をクロロホル
ムで希釈し、水洗し、乾燥後溶媒を減圧下留去した。残
渣をシリカゲル（60ｇ）を用いるカラムクロマトグラフ
ィー（クロロホルム−メタノール 150：１）で精製し
た。再度、シリカゲル（60ｇ）を用いるカラムクロマト
グラフィー（ヘキサン−酢酸エチル５：４）で精製し、
目的化合物(130mg）を無色油状物として得た。4) Synthesis of Compound 330 2- (1-hexadecyl) octadecanoic acid (153 mg) was dissolved in a mixed solvent of hexane (15 ml) and methylene chloride (20 ml), and N-hydroxysuccinimide (35 mg) and N,
N'-Zinclohexylcarbodiimide (62 mg) was added, and the mixture was stirred at room temperature for 24 hours. Amine compound 329 (235 mg) dissolved in acetonitrile (15 ml) was added to the reaction mixture, and then toluethylamine (67 mg) was added, followed by stirring at room temperature for 23 hours. The insoluble material was removed by filtration, the filtrate was diluted with chloroform, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (60 g) (chloroform-methanol 150: 1). Purify again by column chromatography (hexane-ethyl acetate 5: 4) using silica gel (60 g),
The desired compound (130 mg) was obtained as a colorless oil.
【０３７９】［α］D +18.2 °(c 1.02,CHCl3 ) 。[Α] D + 18.2 ° (c 1.02, CHCl 3 ).
【０３８０】 1H-NMR(CDCl3 ) δ；0.88(6H,t,J=6.8H
z)，1.20-1.33(56H,m)，1.34-1.43(2H,m) ，1.53-1.62
(2H,m) ，2.00(3H,s)，2.04(3H,s)，2.11(3H,s)，2.16
(3H,s)，3.47(2H,q)，3.55(2H,t)，3.60-3.73(7H,m) ，
3.80-3.85(1H,m) ，4.07(1H,ddd,J=2.4Hz,4.9Hz,10.0H
z) ，4.12(1H,dd,J=2.4Hz,12.2Hz)，4.29(1H,dd,J=4.9H
z)，4.89(1H,d,J=1.7Hz)，5.27(1H,dd,J=1.7Hz,3.4Hz)
，5.30(1H,t,J=10.0Hz) ，5.36(1H,dd,J=3.4Hz,10.0H
z)，6.00(1H,m)。[0380] 1 H-NMR (CDCl 3) δ; 0.88 (6H, t, J = 6.8H
z), 1.20-1.33 (56H, m), 1.34-1.43 (2H, m), 1.53-1.62
(2H, m), 2.00 (3H, s), 2.04 (3H, s), 2.11 (3H, s), 2.16
(3H, s), 3.47 (2H, q), 3.55 (2H, t), 3.60-3.73 (7H, m),
3.80-3.85 (1H, m), 4.07 (1H, ddd, J = 2.4Hz, 4.9Hz, 10.0H
z), 4.12 (1H, dd, J = 2.4Hz, 12.2Hz), 4.29 (1H, dd, J = 4.9H
z), 4.89 (1H, d, J = 1.7Hz), 5.27 (1H, dd, J = 1.7Hz, 3.4Hz)
, 5.30 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz, 10.0H
z), 6.00 (1H, m).
【０３８１】５）化合物331 の合成 化合物330(123mg ）をメタノール（10ml）に溶解し、28
％ＮａＯＭＥ ｉｎＭｅＯＨ（20μｌ）を加え、室温で
４時間攪拌した。反応液に「アンバーライトＩＲＣ−5
0」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し
た。残渣にクロロホルムを加え、不溶物を濾去後濾液を
減圧下濃縮乾固し、残渣を氷冷下ヘキサンで洗浄して目
的化合物231(101mg ）を無色粉末として得た。5) Synthesis of Compound 331 Compound 330 (123 mg) was dissolved in methanol (10 ml), and 28
% NaOME in MeOH (20 μl) was added and stirred at room temperature for 4 hours. Add “Amberlite IRC-5” to the reaction mixture.
"0" was added, the insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. Chloroform was added to the residue, the insolubles were removed by filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with hexane under ice-cooling to obtain the desired compound 231 (101 mg) as a colorless powder.
【０３８２】［α］D +19.5 °(c 0.59,CHCl3 ) 。[Α] D + 19.5 ° (c 0.59, CHCl 3 ).
【０３８３】 1H-NMR(CDCl3 ) δ：0.88(6H,t,J=6.8H
z)，1.20-1.33(56H,m)，1.34-1.44(2H,m) ，1.52-1.61
(2H,m) ，2.00(1H,m)，3.42-3.96(18H,m)，4.89(1H,
s(，6.10(1H,m)。 1 H-NMR (CDCl 3 ) δ: 0.88 (6H, t, J = 6.8H
z), 1.20-1.33 (56H, m), 1.34-1.44 (2H, m), 1.52-1.61
(2H, m), 2.00 (1H, m), 3.42-3.96 (18H, m), 4.89 (1H, m
s (, 6.10 (1H, m).
【０３８４】(g′) 化合物333 の合成（図３ｈ） １）化合物332 の合成 アミン体化合物329(210mg ）とパルミチン酸Ｎ−ヒドロ
キシスクシンイミドエステル(113mg）を塩化メチレン
（20ml）に溶解し、トリエチルアミン（65mg）を加え、
室温で４時間攪拌した。反応液を塩化メチレンで希釈
し、水、10％クエン酸水及び水で順次洗浄し、乾燥後溶
媒を減圧下留去した。残渣をシリカゲル（50ｇ）を用い
るカラムクロマトグラフィー（クロロホルム−メタノー
ル 100：１）で精製し、目的化合物332(194mg ）を得
た。 (G ′) Synthesis of compound 333 (FIG. 3h) 1) Synthesis of compound 332 Amine compound 329 (210 mg) and palmitic acid N-hydroxysuccinimide ester (113 mg) were dissolved in methylene chloride (20 ml), and triethylamine (65mg)
Stirred at room temperature for 4 hours. The reaction solution was diluted with methylene chloride, washed sequentially with water, 10% aqueous citric acid and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 100: 1) using silica gel (50 g) to obtain the desired compound 332 (194 mg).
【０３８５】［α］D +23.7 °(c 1.07,CHCl3 ) 。[Α] D + 23.7 ° (c 1.07, CHCl 3 ).
【０３８６】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=6.8H
z)，1.23-1.33(24H,m)，1.63(2H,m)，2.00(3H,s)，2.04
(3H,s)，2.11(3H,s)，2.16(3H,s)，2.17(2H,t,J=7.8H
z)，3.45(2H,q)，3.56(2H,t)，3.60-3.73(7H,m) ，3.80
-3.85(1H,m) ，4.07(1H,ddd,J=2.4Hz,4.9Hz,10.0Hz) ，
4.11(1H,dd,J=2.4Hz,12.2Hz)，4.28(1H,dd,J=4.9Hz,12.
2Hz)，4.89(1H,d,J=1.5Hz)，5.27(1H,dd,J=1.5Hz,3.4H
z) ，5.30(1H,t,J=10.0Hz)，5.36(1H,dd,J=3.4Hz,10.0H
z)，6.06(1H,m)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 6.8H
z), 1.23-1.33 (24H, m), 1.63 (2H, m), 2.00 (3H, s), 2.04
(3H, s), 2.11 (3H, s), 2.16 (3H, s), 2.17 (2H, t, J = 7.8H
z), 3.45 (2H, q), 3.56 (2H, t), 3.60-3.73 (7H, m), 3.80
-3.85 (1H, m), 4.07 (1H, ddd, J = 2.4Hz, 4.9Hz, 10.0Hz),
4.11 (1H, dd, J = 2.4Hz, 12.2Hz), 4.28 (1H, dd, J = 4.9Hz, 12.
2Hz), 4.89 (1H, d, J = 1.5Hz), 5.27 (1H, dd, J = 1.5Hz, 3.4H
z), 5.30 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz, 10.0H
z), 6.06 (1H, m).
【０３８７】２）化合物333 の合成 化合物332(185mg ）をメタノール（５ml）に溶解し、28
％ＮａＯＭｅ ｉｎＭｅＯＨ（20μｌ）を加え、室温で
４時間攪拌した。反応液に「アンバーライトＩＲＣ−5
0」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し
た。残渣にクロロホルムを加え、不溶物を濾去後濾液を
減圧下濃縮乾固し、残渣をエーテルで洗浄して目的化合
物333(128mg ）を無色粉末として得た。2) Synthesis of compound 333 Compound 332 (185 mg) was dissolved in methanol (5 ml), and
% NaOMe in MeOH (20 μl) was added and stirred at room temperature for 4 hours. Add “Amberlite IRC-5” to the reaction mixture.
"0" was added, and the insoluble material was removed by filtration. Chloroform was added to the residue, the insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with ether to obtain the desired compound 333 (128 mg) as a colorless powder.
【０３８８】［α］D +28.2 °(c 1.02,CHCl3 ) 。[Α] D + 28.2 ° (c 1.02, CHCl 3 ).
【０３８９】 1H-NMR(CDCl3 ) δ：0.88(3H,t,J=6.6H
z)，1.20-1.34(24H,m)，1.62(2H,m)，2.18(2H,t,J=7.6H
z)，3.42-3.93(18H,m)，4.88(1H,s)，6.31(1H,m)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 6.6H
z), 1.20-1.34 (24H, m), 1.62 (2H, m), 2.18 (2H, t, J = 7.6H
z), 3.42-3.93 (18H, m), 4.88 (1H, s), 6.31 (1H, m).
【０３９０】(h′) 化合物339 の合成（図３ｉ） １）化合物336 の合成 減圧下 150℃で１時間乾燥した粉末「モレキュラーシー
ブ４Ａ」（20.0ｇ）、塩化亜鉛（12.1ｇ）および６−ベ
ンジルオキシカルボニルアミノ−１−ヘキサノール（3
0.0ｇ）を塩化メチレン(100ml）中室温で２時間攪拌し
た。一方、ブロム体化合物303 （24.5ｇ）と「モレキュ
ラーシーブ４Ａ」（15.0ｇ）を塩化メチレン(400ml）中
室温で２時間攪拌後、上記反応混合液に滴下した。室温
で10日間攪拌後不溶物をセライト濾去し、濾液を５％Ｎ
ａＨＣＯ3 水、ついで水で洗浄し、乾燥後溶媒を減圧下
留去した。残渣をシリカゲル(800ｇ）を用いるカラムク
ロマトグラフィー（クロロホルム）で分離し、α−グリ
コシド体化合物336(9.3 ｇ）を無色油状物質として得
た。 (H ′) Synthesis of Compound 339 (FIG. 3I) 1) Synthesis of Compound 336 Powder “Molecular Sieve 4A” (20.0 g), zinc chloride (12.1 g) and 6- Benzyloxycarbonylamino-1-hexanol (3
0.0g) was stirred in methylene chloride (100ml) at room temperature for 2 hours. On the other hand, bromo compound 303 (24.5 g) and "molecular sieve 4A" (15.0 g) were stirred in methylene chloride (400 ml) at room temperature for 2 hours, and then added dropwise to the above reaction mixture. After stirring at room temperature for 10 days, insolubles were removed by filtration through Celite, and the filtrate was filtered with 5%
The extract was washed with aHCO 3 water and then with water, dried, and the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (chloroform) using silica gel (800 g) to give α-glycoside compound 336 (9.3 g) as a colorless oil.
【０３９１】［α］D +34.0 °(c 1.27,CHCl3 ) 。[Α] D + 34.0 ° (c 1.27, CHCl 3 ).
【０３９２】 1H-NMR(CDCl3 ) δ：1.32-1.40(2H,m) ，
1.49-1.55(2H,m) ，1.56-1.64(2H,m) ，1.99，2.04，2.
10，2.15(each 3H,each s)，3.15-3.25(2H,m) ，3.40-
3.47(1H,m) ，3.64-3.70(1H,m) ，3.97(1H,ddd,J=10.01
Hz,5.37Hz,2.44Hz)，4.11(1H,dd,J=12.21Hz,2.44Hz)，
4.28(1H,dd,J=12.21Hz,5.37Hz)，4.79(1H,d,J=1.47H
z)，4.82(1H,br,NH)，5.09(2H,s)，5.22(1H,dd,J=3.42H
z,1.47Hz) ，5.27(1H,t,J=10.01Hz)，5.34(1H,dd,J=10.
01Hz,3.42Hz)，7.3-7.4(5H,m) 。 1 H-NMR (CDCl 3 ) δ: 1.32-1.40 (2H, m),
1.49-1.55 (2H, m), 1.56-1.64 (2H, m), 1.99, 2.04, 2.
10, 2.15 (each 3H, each s), 3.15-3.25 (2H, m), 3.40-
3.47 (1H, m), 3.64-3.70 (1H, m), 3.97 (1H, ddd, J = 10.01
Hz, 5.37Hz, 2.44Hz), 4.11 (1H, dd, J = 12.21Hz, 2.44Hz),
4.28 (1H, dd, J = 12.21Hz, 5.37Hz), 4.79 (1H, d, J = 1.47H
z), 4.82 (1H, br, NH), 5.09 (2H, s), 5.22 (1H, dd, J = 3.42H
z, 1.47Hz), 5.27 (1H, t, J = 10.01Hz), 5.34 (1H, dd, J = 10.
01Hz, 3.42Hz), 7.3-7.4 (5H, m).
【０３９３】２）化合物337 の合成 化合物336 （3.03ｇ）とｐ−トルエンスルホン酸１水和
物（0.66ｇ）をメタノール（40ml）に溶解し、10％Ｐｄ
−Ｃ（0.20ｇ）を加え室温50ｐｓｉで３時間接触還元を
行った。触媒を濾去後、濾液を減圧下濃縮して目的物
（2.10ｇ）を得た。2) Synthesis of compound 337 Compound 336 (3.03 g) and p-toluenesulfonic acid monohydrate (0.66 g) were dissolved in methanol (40 ml), and 10% Pd
-C (0.20 g) was added and catalytic reduction was performed at room temperature and 50 psi for 3 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the desired product (2.10 g).
【０３９４】３）化合物338 の合成 Ｎ−ｔ−ブトキシカルボニル−Ｌ−グルタミン酸（58m
g）をアセトニトリル（10ml）に溶解し、Ｎ−ヒドロイ
シスクシンイミド（60mg）とＮ，Ｎ′−ジシクロヘキシ
ルカルボイミド(107mg）を加え、室温で３時間撹拌し
た。反応液にアミン体化合物337(321mg)とトリエチルア
ミン(105mg) を加え、室温で16時間攪拌を続けた。不溶
物を濾去し、濾液を酢酸エチルで希釈後、水、10％クエ
ン酸水、水、５％ＮａＣＯ3 水及び水で順次洗浄し、乾
燥後溶媒を減圧下留去した。残渣をシリカゲル（40ｇ）
を用いるカラムクロマトグラフィー（クロロホルム→ク
ロロホルム：メタノール 100 ：１）で精製し、目的化
合物(218mg）を無色泡状物質として得た。3) Synthesis of compound 338 Nt-butoxycarbonyl-L-glutamic acid (58m
g) was dissolved in acetonitrile (10 ml), N-hydroisuccinimide (60 mg) and N, N'-dicyclohexylcarbimide (107 mg) were added, and the mixture was stirred at room temperature for 3 hours. Amine compound 337 (321 mg) and triethylamine (105 mg) were added to the reaction solution, and stirring was continued at room temperature for 16 hours. The insoluble material was removed by filtration, and the filtrate was diluted with ethyl acetate, washed successively with water, 10% aqueous citric acid, water, 5% aqueous NaCO 3 and water, dried, and the solvent was distilled off under reduced pressure. Residue is silica gel (40 g)
The residue was purified by column chromatography using chloroform (chloroform → chloroform: methanol 100: 1) to obtain the desired compound (218 mg) as a colorless foam.
【０３９５】［α］D +34.0 °(c 0.90,CHCl3 ) 。[Α] D + 34.0 ° (c 0.90, CHCl 3 ).
【０３９６】 1H-NMR(CDCl3 ) δ：1.44(9H,s)，2.00(6
H,s)，2.05(6H,s)，2.16(6H,s)，4.80(2H,s)。 1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 2.00 (6
H, s), 2.05 (6H, s), 2.16 (6H, s), 4.80 (2H, s).
【０３９７】４）化合物339 の合成 化合物338 （43mg）をメタノール（３ml）に溶解し、28
％ナトリウムメトキシドメタノール溶液（20μｌ）を加
え、室温で 1.5時間攪拌した。反応液「アンバーライト
ＩＲＣ−50」を加えて中和後、溶媒を減圧下留去した。
析出した粉末をエーテルで洗浄し目的化合物（24mg）を
無色粉末として得た。4) Synthesis of compound 339 Compound 338 (43 mg) was dissolved in methanol (3 ml), and
% Sodium methoxide methanol solution (20 μl) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was neutralized by adding “Amberlite IRC-50”, and the solvent was distilled off under reduced pressure.
The precipitated powder was washed with ether to obtain the desired compound (24 mg) as a colorless powder.
【０３９８】 1H-NMR(CD3 OD) δ：1.44(9H,s)，4.72(2
H,d,J=1.47Hz) 。 1 H-NMR (CD 3 OD) δ: 1.44 (9H, s), 4.72 (2
H, d, J = 1.47Hz).
【０３９９】(i′) 化合物341 の合成（図３ｊ） １）化合物340 の合成 Ｎα−ｔ−ブトキシカルボニル−γ−グルタミルグルタ
ミン酸（化合物840 ）（61mg）をアセトニトリル（10m
l）に溶解し、Ｎ−ヒドロキシスクシンイミド（61mg）
とＮ，Ｎ′−ジシクロヘキシルカルボジイミド(110mg）
を加え、室温で１時間攪拌した。ついで、アミン体化合
物337(330mg ）とトリエチルアミン(108mg）を加え、室
温で 1.5時間攪拌した。不溶物を濾去し、濾液を酢酸エ
チルで希釈し、水、10％クエン酸水、水、５％ＮａＨＣ
Ｏ3 水及び水で順次洗浄し、乾燥後溶媒を減圧下留去し
た。残渣をシリカゲル（50ｇ）を用いるカラムクロマト
グラフィー（クロロホルム→クロロホルム−メタノール
50：１）で精製し、目的化合物(220mg）を得た。 (I ′) Synthesis of Compound 341 (FIG. 3j) 1) Synthesis of Compound 340 Nα-t-butoxycarbonyl-γ-glutamylglutamic acid (Compound 840) (61 mg) was treated with acetonitrile (10 m
l) and dissolved in N-hydroxysuccinimide (61 mg)
And N, N'-dicyclohexylcarbodiimide (110 mg)
Was added and stirred at room temperature for 1 hour. Then, the amine compound 337 (330 mg) and triethylamine (108 mg) were added, and the mixture was stirred at room temperature for 1.5 hours. The insoluble material was removed by filtration, and the filtrate was diluted with ethyl acetate. Water, 10% aqueous citric acid, water, 5% NaHC
The organic layer was washed successively with O 3 water and water, dried and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (50 g) (chloroform → chloroform-methanol).
Purification by 50: 1) gave the target compound (220 mg).
【０４００】［α］D +35.4 °(c 0.92,CHCl3 ) 。[Α] D + 35.4 ° (c 0.92, CHCl 3 ).
【０４０１】 1H-NMR(CDCl3 ) δ：1.44(9H,s)，1.99(6
H,s)，2.00(6H,s)，2.05(3H,s)，2.11(9H,s)，2.16(9H,
s)，4.80(3H,d,J=1.47Hz) 。 1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 1.99 (6
H, s), 2.00 (6H, s), 2.05 (3H, s), 2.11 (9H, s), 2.16 (9H, s
s), 4.80 (3H, d, J = 1.47 Hz).
【０４０２】２）化合物341 の合成 化合物340 （95mg）をメタノール（３ml）に溶解し、28
％ナトリウムメトキシドメタノール溶液（20μｌ）を加
え、室温で５時間攪拌した。反応液に「アンバーライト
ＩＲＣ−50」を加えて中和後、溶媒を減圧下留去した。
析出した粉末エーテルで洗浄し、目的化合物（54mg）を
無色粉末として得た。2) Synthesis of Compound 341 Compound 340 (95 mg) was dissolved in methanol (3 ml), and 28
% Sodium methoxide methanol solution (20 μl) was added, and the mixture was stirred at room temperature for 5 hours. After neutralization by adding “Amberlite IRC-50” to the reaction solution, the solvent was distilled off under reduced pressure.
The precipitate was washed with ether powder to obtain the desired compound (54 mg) as a colorless powder.
【０４０３】 1H-NMR(CDCl3 ) δ：1.45(9H,s)，4.73(3
H,s)。 1 H-NMR (CDCl 3 ) δ: 1.45 (9H, s), 4.73 (3
H, s).
【０４０４】(j′) 化合物335 の合成（図３ｋ） １）化合物334 の合成 トリカルボン酸体化合物840(80mg) をアセトニトリル(1
0ml)に溶解し、ＨＯＳｕ(81mg)とＤＣＣ(144mg) を加
え、室温で３時間撹拌した。反応混合物にアミン体化合
物329(495mg)とトリエチルアミン(154mg) を加え、室温
で５時間撹拌した。不溶物を濾去し、濾液をクロロホル
ムで希釈し、水洗し、乾燥後溶媒を減圧下留去した。残
渣をシリカゲル(50 ｇ) を用いるカラムクロマトグラフ
ィー（クロロホルム−メタノール 20：１）で精製し、
目的化合物334(307mg)を無色油状物として得た。 (J ′) Synthesis of Compound 335 (FIG. 3k) 1) Synthesis of Compound 334 Tricarboxylic acid compound 840 (80 mg) was obtained by acetonitrile (1
0mL), HOSu (81mg) and DCC (144mg) were added, and the mixture was stirred at room temperature for 3 hours. Amine compound 329 (495 mg) and triethylamine (154 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. The insoluble material was removed by filtration, the filtrate was diluted with chloroform, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 20: 1) using silica gel (50 g).
The target compound 334 (307 mg) was obtained as a colorless oil.
【０４０５】２）化合物335 の合成 化合物334(73mg) をメタノール（３ml）に溶解し、28％
ＮａＯＭｅ ｉｎ ＭｅＯＨ(20 μｌ) を加え、室温で
２時間撹拌した。反応液に「アンバーライトＩＲＣ−5
0」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し、
残渣をエーテルで洗浄して目的化合物335 を無色粉末と
して得た。2) Synthesis of compound 335 Compound 334 (73 mg) was dissolved in methanol (3 ml), and 28%
NaOMein in MeOH (20 μl) was added and stirred at room temperature for 2 hours. Add “Amberlite IRC-5” to the reaction mixture.
0 '' was added, the insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure.
The residue was washed with ether to obtain the target compound 335 as a colorless powder.
【０４０６】 1H-NMR(CD3 OD) δ：1.44(9H,s)，1.82-
1.96(2H,m) ，1.96-2.12(2H,m) ，2.31(2H,t,J=7.6H
z)，2.35(2H,t,J=7.6Hz)。 1 H-NMR (CD 3 OD) δ: 1.44 (9H, s), 1.82-
1.96 (2H, m), 1.96-2.12 (2H, m), 2.31 (2H, t, J = 7.6H
z), 2.35 (2H, t, J = 7.6Hz).
【０４０７】実施例４（アセチルガラクトサミン系誘導
体の合成） 本実施例における反応式を図４ａ乃至図４ｂに示す。Example 4 (Synthesis of Acetylgalactosamine Derivative) The reaction formula in this example is shown in FIGS. 4a to 4b.
【０４０８】本実施例における旋光度は全て25℃での測
定値である。The optical rotations in this example are all measured values at 25 ° C.
【０４０９】(a) 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-
(2,2,2-trichloroethoxycarbonylamino)-D-galactopyra
nose (403) の合成 ガラクトサミン401(5.00ｇ，23.2mmol) を水（70ml) に
溶解し、氷冷攪拌下、ＮａＨＣＯ3 （5.00ｇ，59.5mmo
l) とtrichloroethoxycarbonyl chloride (7.35ｇ，34.
7mmol) を加え、ついで室温にて２日間攪拌した。析出
した結晶を濾取し、氷水で洗浄した。濾液と洗液を合わ
せて減圧下濃縮し、析出した結晶を濾取し、氷水で洗浄
した。得られた結晶（6.45ｇ）をピリジン（26ml）に溶
解し、無水酢酸（20ml）を加え、室温で１夜攪拌して反
応させた。[0409](a) 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-
(2,2,2-trichloroethoxycarbonylamino) -D-galactopyra
Synthesis of nose (403) Galactosamine 401 (5.00 g, 23.2 mmol) in water (70 ml)
After dissolving and stirring under ice-cooling, NaHCO3 (5.00 g, 59.5 mmol)
l) and trichloroethoxycarbonyl chloride (7.35g, 34.
7 mmol), and the mixture was stirred at room temperature for 2 days. Precipitation
The crystals formed were collected by filtration and washed with ice water. Combine the filtrate and washings
And concentrate under reduced pressure.The precipitated crystals are collected by filtration and washed with ice water.
did. Dissolve the obtained crystals (6.45 g) in pyridine (26 ml).
Then, acetic anhydride (20 ml) was added, and the mixture was stirred at room temperature overnight, and then stirred.
I responded.
【０４１０】反応液を酢酸エチルで希釈し、水、クエン
酸水、水、ＮａＨＣＯ3 水、水で順次洗浄、乾燥後溶媒
を減圧下留去した。残渣をシリカゲル(250ｇ）を用いる
カラムクロマトグラフィー（ヘキサン−酢酸エチル３：
１）で精製し、目的化合物403 を無色油状物として得た
（9.27ｇ，76％）。The reaction solution was diluted with ethyl acetate, washed sequentially with water, aqueous citric acid, water, aqueous NaHCO 3 and water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (250 g) (hexane-ethyl acetate 3:
Purification in 1) gave the target compound 403 as a colorless oil (9.27 g, 76%).
【０４１１】(b) 3,4,6-Tri-O-acetyl -2-deoxy-2-(2,
2,2-trichloroethoxycarbonylamino)- α-D-galactopyr
anosyl bromide (404) の合成 化合物403 (8.72 ｇ，16.7mmol) を25％ＨＢｒ−ＡｃＯ
Ｈ（21ml) に溶解し、室温で19時間攪拌して反応させ
た。[0411](b) 3,4,6-Tri-O-acetyl-2-deoxy-2- (2,
2,2-trichloroethoxycarbonylamino)-α-D-galactopyr
Synthesis of anosyl bromide (404) Compound 403 (8.72 g, 16.7 mmol) was added to 25% HBr-AcO
H (21 ml) and stirred at room temperature for 19 hours to react.
Was.
【０４１２】反応液を酢酸エチルで希釈し、水で３回、
ＮａＨＣＯ3 水で２回洗浄し、乾燥後溶媒を減圧下留去
し、目的化合物404 を黒褐色泡状物として得た（7.99
ｇ，88％）。この物は精製することなく次の反応に用い
た。The reaction solution was diluted with ethyl acetate and three times with water.
After washing twice with aqueous NaHCO 3 and drying, the solvent was distilled off under reduced pressure to obtain the target compound 404 as a black-brown foam (7.99).
g, 88%). This product was used for the next reaction without purification.
【０４１３】 1H-NMR(CDCl3 ) δ：2.02(3H,s)，2.07(3
H,s)，2.18(3H,s)，4.12(1H,dd,J5,6 =6.35Hz, J 6,6′
=11.48Hz) ，4.21(1H,dd,J 5,6′=6.35Hz, J 6,6′=11.
48Hz) ，4.37(1H,ddd, J1,2 =3.67Hz, J2,NH=9.53Hz, J
2,3 =11.24Hz) ，4.48(1H,t,J5,6 =J 5,6′=6.35Hz)，
4.67(1H,d,J=11.97Hz)，4.83(1H,d,J=11.97Hz)，5.16(1
H,d, J2,NH=9.53Hz)，5.28(1H,dd,J3,4 =3.18Hz, J2,3
=11.24Hz) ，5.49(1H,d, J3,4 =3.18Hz)，6.62(1H,d, J
1,2 =3.67Hz)。 1 H-NMR (CDCl 3 ) δ: 2.02 (3H, s), 2.07 (3
H, s), 2.18 (3H, s), 4.12 (1H, dd, J 5,6 = 6.35Hz, J 6,6 '
= 11.48Hz), 4.21 (1H, dd, J 5,6 '= 6.35Hz, J 6,6 ' = 11.
48Hz), 4.37 (1H, ddd, J 1,2 = 3.67Hz, J 2, NH = 9.53Hz, J
2,3 = 11.24Hz), 4.48 (1H, t, J 5,6 = J 5,6 '= 6.35Hz),
4.67 (1H, d, J = 11.97Hz), 4.83 (1H, d, J = 11.97Hz), 5.16 (1
H, d, J 2, NH = 9.53Hz), 5.28 (1H, dd, J 3,4 = 3.18Hz, J 2,3
= 11.24Hz), 5.49 (1H, d, J 3,4 = 3.18Hz), 6.62 (1H, d, J
1,2 = 3.67Hz).
【０４１４】(c) 6-Chlorohexyl 3,4,6-tri-O-acetyl-2
-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-α-D
-galactopyranoside (406)の合成 ブロム体404(3.75ｇ，6.9mol) とアルコール体405(1.88
ｇ，13.8mmol) を塩化メチレン(100ml) に溶解し、臭化
亜鉛（3.11ｇ，13.8mmol）を加え、室温で２日間攪拌し
て反応させた。 (C) 6-Chlorohexyl 3,4,6-tri-O-acetyl-2
-deoxy-2- (2,2,2-trichloroethoxycarbonylamino) -α-D
-galactopyranoside (406) synthesized bromide 404 (3.75 g, 6.9 mol) and alcohol 405 (1.88
g, 13.8 mmol) was dissolved in methylene chloride (100 ml), zinc bromide (3.11 g, 13.8 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 days.
【０４１５】反応混合物を塩化メチレンで希釈し、水、
５％ＮａＨＣＯ3 水、水で洗浄、乾燥後溶媒を減圧下留
去した。残渣をシリカゲル(150ｇ）を用いるカラムクロ
マトグラフィー（ヘキサン−酢酸エチル５：１）にて精
製し、目的化合物406 を無色油状物質として得た（2.90
ｇ，70％）。The reaction mixture was diluted with methylene chloride and water,
After washing with 5% aqueous NaHCO 3 and water and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane-ethyl acetate 5: 1) using silica gel (150 g) to obtain the desired compound 406 as a colorless oil (2.90).
g, 70%).
【０４１６】［α］D ＋74.0°(c 1.11,CHCl3 ) 。[Α] D + 74.0 ° (c 1.11, CHCl 3 ).
【０４１７】 1H-NMR(CDCl3 ) δ：1.36-1.43(2H,m) ，
1.46-1.52(2H,m) ，1.60-1.68(2H,m) ，1.77-1.83(2H,
m) ，1.98(3H,s)，2.05(3H,s)，2.17(3H,s)，3.45-3.50
(1H,m) ，3.55(2H,t,J=6.59Hz) ，3.69-3.74(1H,m) ，
4.08-4.13(2H,m) ，4.17(1H,t,J5,6 = 5,6 ′=6.59H
z)，4.29-(1H,ddd,J1,2 =3.42Hz, J2,NH=10.02Hz,J2,3
=11.24Hz) ，4.65(1H,d,J=11.97Hz)，4.82(1H,d,J=11.9
7Hz)，4.92(1H,d, J1,2 =3.42Hz)，5.10(1H,d, J2,NH=1
0.02Hz) ，5.16(1H,dd,J3,4 =3.18Hz, J2,3 =11.24Hz)
，5.40(1H,d, J3,4 =3.18Hz)。 1 H-NMR (CDCl 3 ) δ: 1.36-1.43 (2H, m),
1.46-1.52 (2H, m), 1.60-1.68 (2H, m), 1.77-1.83 (2H, m
m), 1.98 (3H, s), 2.05 (3H, s), 2.17 (3H, s), 3.45-3.50
(1H, m), 3.55 (2H, t, J = 6.59Hz), 3.69-3.74 (1H, m),
4.08-4.13 (2H, m), 4.17 (1H, t, J 5,6 = 5,6 '= 6.59H
z), 4.29- (1H, ddd, J 1,2 = 3.42Hz, J 2, NH = 10.02Hz, J 2,3
= 11.24Hz), 4.65 (1H, d, J = 11.97Hz), 4.82 (1H, d, J = 11.9
7Hz), 4.92 (1H, d, J 1,2 = 3.42Hz), 5.10 (1H, d, J 2, NH = 1
0.02Hz), 5.16 (1H, dd, J 3,4 = 3.18Hz, J 2,3 = 11.24Hz)
, 5.40 (1H, d, J 3 , 4 = 3.18 Hz).
【０４１８】(d) 6-Cholorohexyl 3,4,6-tri-O-acetyl-
2-deoxy-2-acetamido-α-D-galactopyranoside (407)の
合成 化合物406(1.95ｇ，3.25mmol) と無水酢酸（４ml）を酢
酸（20ml）溶解し、亜鉛末（2.00ｇ）を少しずつ加え、
その後室温で４時間半攪拌を続けた。 (D) 6-Cholorohexyl 3,4,6-tri-O-acetyl-
2-deoxy-2-acetamido-α-D-galactopyranoside (407)
Synthetic compound 406 (1.95 g, 3.25 mmol) and acetic anhydride (4 ml) were dissolved in acetic acid (20 ml), and zinc dust (2.00 g) was added little by little.
Thereafter, stirring was continued at room temperature for 4.5 hours.
【０４１９】不溶物をセライト濾過し、濾液を減圧濃縮
した。残渣を酢酸エチルと水に分配し、有機層を水、Ｎ
ａＨＣＯ3 水および水で洗浄、乾燥後溶媒を減圧下留去
した。残渣をシリカゲル（60ｇ）を用いるカラムクロマ
トグラフィー（クロロホルム）にて精製し、目的化合物
407 無色油状物質として得た（1.42ｇ，94％）。The insolubles were filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was separated from water, N
After washing with aHCO 3 water and water and drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (60 g) to obtain the target compound.
407 obtained as a colorless oil (1.42 g, 94%).
【０４２０】［α］D ＋82.8°(c 1.04,CHCl3 ) 。[Α] D + 82.8 ° (c 1.04, CHCl 3 ).
【０４２１】 1H-NMR(CDCl3 ) δ：1.36-1.42(2H,m) ，
1.46-1.54(2H,m) ，1.60-1.67(2H,m) ，1.77-1.83(2H,
m) ，1.97(3H,s)，2.00(3H,s)，2.05(3H,s),2.17(3H,s)
，3.42-3.47(1H,m) ，3.56(2H,t,J=6.59Hz) ，3.66-3.
72(1H,m) ，4.06-4.17(3H,m)，4.58(1H,ddd, J1,2 =3.6
7Hz, J2,NH=9.77Hz, J2,3 =11.24Hz) ，4.88(1H,d, J
1,2 =3.67Hz)，5.16(1H,dd,J3,4 =3.18Hz ， J2,3 =11.
24Hz) ，5.37(1H,d, J3,4 =3.18Hz)，5.54(1H,d, J2,NH
=9.77Hz)。 1 H-NMR (CDCl 3 ) δ: 1.36-1.42 (2H, m),
1.46-1.54 (2H, m), 1.60-1.67 (2H, m), 1.77-1.83 (2H, m
m), 1.97 (3H, s), 2.00 (3H, s), 2.05 (3H, s), 2.17 (3H, s)
, 3.42-3.47 (1H, m), 3.56 (2H, t, J = 6.59Hz), 3.66-3.
72 (1H, m), 4.06-4.17 (3H, m), 4.58 (1H, ddd, J 1,2 = 3.6
7Hz, J 2, NH = 9.77Hz, J 2,3 = 11.24Hz), 4.88 (1H, d, J
1,2 = 3.67Hz), 5.16 (1H, dd, J 3,4 = 3.18Hz, J 2,3 = 11.
24Hz), 5.37 (1H, d, J 3,4 = 3.18Hz), 5.54 (1H, d, J 2, NH
= 9.77Hz).
【０４２２】(e) 6-Azidohexyl 3,4,6-tri-O-acetyl-2-
deoxy-2-acetamido-α-D-galactopyranoside (408)の合
成 化合物407(1.41ｇ，3.03mmol) をＤＭＦ（25ml) に溶解
し、アジ化ナトリウム（0.29ｇ，4.46mmol) を加え、浴
温50〜60℃で18時間攪拌して反応させた。 (E) 6-Azidohexyl 3,4,6-tri-O-acetyl-2-
Deoxy-2-acetamido-α-D-galactopyranoside (408)
Forming compound 407 (1.41 g, 3.03 mmol) was dissolved in DMF (25 ml), sodium azide (0.29 g, 4.46 mmol) was added, and the reaction was stirred 18 hours at a bath temperature of 50-60 ° C..
【０４２３】反応混合物を酢酸エチルで希釈し、水洗、
乾燥後溶媒を減圧下留去した。残渣をシリカゲル（60
ｇ）を用いるカラムクロマトグラフィー（クロロホル
ム）にて精製し、目的化合物408 を無色油状物質として
得た（1.40ｇ，98％）。The reaction mixture was diluted with ethyl acetate, washed with water,
After drying, the solvent was distilled off under reduced pressure. The residue was purified on silica gel (60
Purification by column chromatography (chloroform) using g) gave the target compound 408 as a colorless oil (1.40 g, 98%).
【０４２４】［α］D ＋84.9°(c 1.72,CHCl3 ) 。[Α] D + 84.9 ° (c 1.72, CHCl 3 ).
【０４２５】 1H-NMR(CDCl3 ) δ：1.36-1.46(4H,m) ，
1.58-1.66(4H,m) ，1.97(3H,s)，2.00(3H,s)，2.05(3H,
s)，2.17(3H,s)，3.30(2H,t,J=6.84Hz) ，3.42-3.47(1
H,m)，3.68-3.72(1H,m) ，4.06-4.18(3H,m) ，4.57(1H,
ddd, J1,2 =3.67Hz, J2,NH=9.77Hz, J2,3 =11.24Hz) ，
4.87(1H,d, J1,2 =3.67Hz)，5.16(1H,dd,J3,4 =3.18Hz,
J2,3 =11.24Hz) ，5.37(1H,d, J3,4 =3.18Hz)，5.86(1
H,d, J2,NH=9.77Hz)。 1 H-NMR (CDCl 3 ) δ: 1.36-1.46 (4H, m),
1.58-1.66 (4H, m), 1.97 (3H, s), 2.00 (3H, s), 2.05 (3H,
s), 2.17 (3H, s), 3.30 (2H, t, J = 6.84 Hz), 3.42-3.47 (1
H, m), 3.68-3.72 (1H, m), 4.06-4.18 (3H, m), 4.57 (1H,
ddd, J 1,2 = 3.67Hz, J 2, NH = 9.77Hz, J 2,3 = 11.24Hz),
4.87 (1H, d, J 1,2 = 3.67Hz), 5.16 (1H, dd, J 3,4 = 3.18Hz,
J 2,3 = 11.24 Hz), 5.37 (1H, d, J 3,4 = 3.18 Hz), 5.86 (1
H, d, J 2, NH = 9.77Hz).
【０４２６】(f) 6-Aminohexyl 3,4,6-tri-O-acetyl-2-
deoxy-2-acetamido-α-D-galactopyranoside p-toluens
ulfonate (409)の合成 化合物408 (820mg，1.74mmol) とトシル酸１水和物(330
mg，1.74mmol) をエタノール（30ml) に溶解し、リンド
ラー触媒(430mg) を加え、室温、50psi で１時間半接触
還元を行った。 (F) 6-Aminohexyl 3,4,6-tri-O-acetyl-2-
deoxy-2-acetamido-α-D-galactopyranoside p-toluens
Sulfonate (409) synthesized compound 408 (820 mg, 1.74 mmol) and tosylic acid monohydrate (330
mg, 1.74 mmol) was dissolved in ethanol (30 ml), a Lindlar catalyst (430 mg) was added, and the mixture was subjected to catalytic reduction at room temperature and 50 psi for 1.5 hours.
【０４２７】触媒を濾過後、濾過を減圧下濃縮し、目的
化合物409 を無色泡状物質として得た（1.00ｇ，93
％）。After filtering the catalyst, the filtrate was concentrated under reduced pressure to obtain the target compound 409 as a colorless foam (1.00 g, 93%).
%).
【０４２８】(g) 化合物411 の合成 カルボン酸410(64mg，0.17mmol) をアセトニトリル（10
ml）に溶解し、ＨＯ−Ｓｕ（65mg，0.56mmol) とＤＣＣ
(116mg，0.56mmol) を加え、室温で１時間半攪拌した。
ついで、アミン体409 (347mg，0.56mmol) とトリエチル
アミン(114mg，1.12mmol) を加え、室温で18時間攪拌し
て反応させた。 (G) Synthesis of Compound 411 A carboxylic acid 410 (64 mg, 0.17 mmol) was added to acetonitrile (10
HO-Su (65 mg, 0.56 mmol) and DCC
(116 mg, 0.56 mmol) was added and the mixture was stirred at room temperature for 1.5 hours.
Then, amine 409 (347 mg, 0.56 mmol) and triethylamine (114 mg, 1.12 mmol) were added, and the mixture was stirred and reacted at room temperature for 18 hours.
【０４２９】反応液を酢酸エチルで希釈し、水、10％ク
エン酸水、水、５％ＮａＨＣＯ3 水、水で順次洗浄、乾
燥後、溶媒を減圧下留去した。残渣をシリカゲル（50
ｇ）を用いるカラムクロマトグラフィー（クロロホルム
−メタノール25：１）で精製し、目的化合物411 を無色
泡状物質として得た(217mg，77％）。The reaction mixture was diluted with ethyl acetate, washed successively with water, 10% aqueous citric acid, water, 5% aqueous NaHCO 3 and water, dried, and the solvent was distilled off under reduced pressure. The residue was silica gel (50
Purification by column chromatography (chloroform-methanol 25: 1) using g) gave the desired compound 411 as a colorless foam (217 mg, 77%).
【０４３０】［α］D ＋73.7°(c 0.98,CHCl3 ) 。[Α] D + 73.7 ° (c 0.98, CHCl 3 ).
【０４３１】 1H-NMR(CDCl3 ) δ：1.45(9H)，1.95(18
H,s) ，2.03(9H,s)，2.14(9H,s)。 1 H-NMR (CDCl 3 ) δ: 1.45 (9H), 1.95 (18
H, s), 2.03 (9H, s), 2.14 (9H, s).
【０４３２】(h) 化合物412 の合成 化合物411(78mg，0.047mmol)をメタノール（４ml）に溶
解し、28％ ＭｅＯＮａ ｉｎ ＭｅＯＨ（20μl)を加
え、室温で20時間攪拌して反応させた。 (H) Synthesis of Compound 412 Compound 411 (78 mg, 0.047 mmol) was dissolved in methanol (4 ml), 28% MeOH in MeOH (20 μl) was added, and the mixture was stirred and reacted at room temperature for 20 hours.
【０４３３】反応液に水を加えて析出結晶を溶解し、
「アンバーライトＩＲＣ−50」を加えて中和後、溶媒を
減圧下留去した。析出した粉末をエーテルで洗浄して目
的化合物412 を無色粉末として得た（47mg，78％）。Water was added to the reaction solution to dissolve the precipitated crystals,
After adding “Amberlite IRC-50” for neutralization, the solvent was distilled off under reduced pressure. The precipitated powder was washed with ether to obtain the target compound 412 as a colorless powder (47 mg, 78%).
【０４３４】［α］D ＋63.9°(c 1.02, H2 O)。[Α] D + 63.9 ° (c 1.02, H 2 O).
【０４３５】実施例５（フコース系及びフコースガラク
トース混合系誘導体の合成） 本実施例における反応式を図５ａ乃至図５ｎに示す。Example 5 (Synthesis of fucose-based and fucose-galactose mixed-based derivatives) The reaction formulas in this example are shown in FIGS. 5a to 5n.
【０４３６】また、本実施例において使用した測定機器
及び実験条件は次の通りであった。The measuring instruments and experimental conditions used in this example were as follows.
【０４３７】（測定機器） NMR ：Varian VXR-500S (Cosy and J spectral) IR ：Shimadzu FTIR-4300 MS ：JEOL JMS HX-110/HX-110 旋光計：PERKIN-ELMER 241 Polarimeter （実験条件） TLC ：MERCK Kieselgel 60 F254 (Art.5729) Column：Nacalai Tesque Silicagel 60 (230〜400mesh) Merck silica gel 60 (230〜400mesh) YMC YMC・GEL SIL-60-350/250 乾燥 ：無水硫酸マグネシウムを使用、モレキュラーシ
ーブス(4A.AW-300) は粉末を 150度で12時間以上減圧乾
燥したものを使用 溶媒 ：特級をモレキュラーシーブスで乾燥して使用(a) 化合物501aの合成 Fischer 法により得られた化合物をアセチル化した2-br
omethyl 2,3,4-tri-acetyl- α-L-fucopyranoside 512
(14.46ｇ）のＤＭＦ(120ml) 溶液に、ＮａＮ3 （7.09
ｇ）を加え、室温で19時間攪拌して反応させた。(Measurement equipment) NMR: Varian VXR-500S (Cosy and J spectral) IR: Shimadzu FTIR-4300 MS: JEOL JMS HX-110 / HX-110 Polarimeter: PERKIN-ELMER 241 Polarimeter (Experimental conditions) TLC: MERCK Kieselgel 60 F 254 (Art.5729) Column: Nacalai Tesque Silicagel 60 (230-400mesh) Merck silica gel 60 (230-400mesh) YMC YMC / GEL SIL-60-350 / 250 Dry: Use anhydrous magnesium sulfate, molecular For sieves (4A.AW-300), use powder obtained by drying powder under reduced pressure at 150 ° C for 12 hours or more. Solvent: Use a special grade by drying it with molecular sieves. (A) Synthesis of compound 501a Compound obtained by Fischer method is acetylated 2-br
omethyl 2,3,4-tri-acetyl- α-L-fucopyranoside 512
(14.46 g) in DMF (120 ml) was added to NaN 3 (7.09 g).
g) was added, and the mixture was stirred and reacted at room temperature for 19 hours.
【０４３８】ＡｃＯＥｔと水を加え分液後有機層を乾燥
し、シリカゲルカラムクロマトグラフィー（ＣＨＣ
ｌ3 ）で精製し、化合物513 を 12.54ｇ（収率96％）取
得した。[0438] AcOEt and water were added, and the mixture was separated. The organic layer was dried, and subjected to silica gel column chromatography (CHC
Purification by l 3), the compound 513 12.54 g (96% yield) was obtained.
【０４３９】ＲF 0.51 (Toluene-AcOEt 2:1)。R F 0.51 (Toluene-AcOEt 2: 1).
【０４４０】［α］D 20− 135°(c 1.17 CHCl3 ）。[Α] D 20 -135 ° (c 1.17 CHCl 3 ).
【０４４１】1H-NMR(CDCl3 ) ：δppm,J in Hz 1.16(d,3H,J=6.6)，1.99，2.09，2.17(s) ，3.28，3.4
7，3.62， 3.87(m,1H×4)，4.19(q,1H,J=6.6)，5.12(d,
1H)，5.14(dd,1H,J=3.9，10.5) ，5.32(dd,1H,J=1.2,3.
4) ，5.38(dd,1H,J=3.4,10.5)。1H-NMR (CDCl 3 ): δppm, J in Hz 1.16 (d, 3H, J = 6.6), 1.99, 2.09, 2.17 (s), 3.28, 3.4
7, 3.62, 3.87 (m, 1H × 4), 4.19 (q, 1H, J = 6.6), 5.12 (d,
1H), 5.14 (dd, 1H, J = 3.9, 10.5), 5.32 (dd, 1H, J = 1.2, 3.
4), 5.38 (dd, 1H, J = 3.4,10.5).
【０４４２】IR(Neat)：cm-1 2120，1750，1228。IR (Neat): cm -1 2120, 1750, 1228.
【０４４３】化合物513(4.50ｇ）のＥｔＯＨ（70ml）溶
液に、ｐ−ＴｓＯＨ・Ｈ2 Ｏ（2.37ｇ）とリンドラー触
媒（5.00ｇ）を加えＰａｒｒで２時間反応後、更にリン
ドラー触媒（1.00ｇ）を追加し、２時間反応させた。To a solution of compound 513 (4.50 g) in EtOH (70 ml) was added p-TsOH.H 2 O (2.37 g) and a Lindlar catalyst (5.00 g), and the mixture was reacted with Parr for 2 hours. ) Was added, and the mixture was reacted for 2 hours.
【０４４４】触媒を濾過後、減圧下溶媒を留去して化合
物501aを5.84ｇ（収率92.3％）取得した。After filtering the catalyst, the solvent was distilled off under reduced pressure to obtain 5.84 g of compound 501a (yield 92.3%).
【０４４５】(b) 化合物502aの合成 化合物501a(300mg) のＣＨ2 Ｃｌ2 （10ml) 溶液に、Ｎ
Ｅｔ3 （72mg）、Palmitoyl chloride(180mg) を加え、
室温で 1.5時間攪拌して反応させた。 (B) Synthesis of Compound 502a A solution of compound 501a (300 mg) in CH 2 Cl 2 (10 ml) was added with N
Add Et 3 (72mg) and Palmitoyl chloride (180mg)
The reaction was stirred at room temperature for 1.5 hours.
【０４４６】反応液を水洗し、乾燥後減圧下溶媒を留去
し、シリカゲルカラムクロマトグラフィー (Merck CHCl
3 ) で精製し化合物502aを 194mg（収率57％）取得し
た。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (Merck CHCl
Purification was performed in 3 ) to obtain 194 mg of compound 502a (57% yield).
【０４４７】ＲF 0.30 (Toluene-MeOH 10:1)。R F 0.30 (Toluene-MeOH 10: 1).
【０４４８】［α］D 21−88.4°(c 1.01 CHCl3 ）。[Α] D 21 -88.4 ° (c 1.01 CHCl 3 ).
【０４４９】m.p.67.5〜68.5℃。M.p. 67.5-68.5 ° C.
【０４５０】1H-NMR(CDCl3 ) ：δppm,J in Hz 0.88(t,3H,J=6.6)，1.15(d,3H,J=6.6)，2.01，2.08，
2.18(s,3H×3)，4.13(q,1H,J=6.6)，5.30(d,1H,J=3.
4)。1H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.6), 1.15 (d, 3H, J = 6.6), 2.01, 2.08,
2.18 (s, 3H × 3), 4.13 (q, 1H, J = 6.6), 5.30 (d, 1H, J = 3.
Four).
【０４５１】IR(KBr) ：cm-1 1747，1639，1373，1251，1232，1074。IR (KBr): cm -1 1747, 1639, 1373, 1251, 1232, 1074.
【０４５２】(c) 化合物502a′の合成 化合物502a(173.4mg) のＭｅＯＨ（３ml）溶液に、28％
ＮａＯＭｅ ｉｎＭｅＯＨ (10μｌ）を加え、室温で
1.5時間攪拌して反応させた。 (C) Synthesis of Compound 502a ′ To a solution of compound 502a (173.4 mg) in MeOH (3 ml) was added 28%
Add NaOMe in MeOH (10 μl) and at room temperature
The mixture was reacted by stirring for 1.5 hours.
【０４５３】反応液から減圧下溶媒を留去し、ゲル濾過
（ＬＨ−20，ＣＨＣｌ3 −ＭｅＯＨ１：１）で精製して
化合物502a′を120.0mg （収率88.8％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl 3 -MeOH 1: 1) to obtain 120.0 mg of compound 502a ′ (yield: 88.8%).
【０４５４】ＲF 0.28 (CHCl3 -MeOH 10:1) 。R F 0.28 (CHCl 3 -MeOH 10: 1).
【０４５５】［α］D 27 -76.7°(c 0.49,CHCl3 -MeOH-
H2 O 10:10:3)。[Α] D 27 -76.7 ° (c 0.49, CHCl 3 -MeOH-
H 2 O 10: 10: 3 ).
【０４５６】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)，1.24(d,3H,J=6.8)，4.80(d,1H,J=2.
7)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.24 (d, 3H, J = 6.8), 4.80 (d, 1H, J = 2.
7).
【０４５７】IR(KBr) ：cm-1 1645，1076，1034。IR (KBr): cm −1 1645, 1076, 1034.
【０４５８】(d) 化合物504aL 及び504aD の合成 化合物501a（4.29ｇ）及びＮＥｔ3 （1.03ｇ）のＣＨ2
Ｃｌ2 (20ml)の溶液に、Boc-L-Glutamic acid 503 （1.
00ｇ）のＣＨ2 Ｃｌ2 (50ml)溶液にHO-Su(1.02ｇ）とＤ
ＣＣ（1.83ｇ）を加え室温で 2.7時間攪拌後の濾液を加
え、室温で３時間攪拌して反応させた。 (D) Synthesis of Compounds 504aL and 504aD CH 2 of Compound 501a (4.29 g) and NEt 3 (1.03 g)
To a solution of Cl 2 (20 ml) was added Boc-L-Glutamic acid 503 (1.
HO-Su (1.02 g) and D in a solution of CH 2 Cl 2 (50 ml)
CC (1.83 g) was added, and the filtrate after stirring at room temperature for 2.7 hours was added, followed by stirring at room temperature for 3 hours to cause a reaction.
【０４５９】反応液を水洗し、乾燥後減圧下溶媒を留去
し、シリカゲルカラムクロマトグラフィー（ナカライ，
ＣＨＣｌ3 −ＭｅＯＨ 100：１）で精製し、化合物504a
L を2.84ｇ（収率80％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Nacalai, Japan).
Purification with CHCl 3 -MeOH 100: 1) gave compound 504a.
2.84 g (yield 80%) of L was obtained.
【０４６０】ＲF 0.72 (CHCl3 -MeOH 10:1) 。R F 0.72 (CHCl 3 -MeOH 10: 1).
【０４６１】［α］D 23-106°(c 0.98,CHCl3 ）。[Α] D 23 -106 ° (c 0.98, CHCl 3 ).
【０４６２】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.14， 1.15(d,3H×2,J=6.4)，1.43(s,9H)，1.99，2.0
0，2.09，2.10， 2.17(s,3H×6)，5.05，5.06(d,1H,J=
3.8)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.14, 1.15 (d, 3H × 2, J = 6.4), 1.43 (s, 9H), 1.99, 2.0
0, 2.09, 2.10, 2.17 (s, 3H × 6), 5.05, 5.06 (d, 1H, J =
3.8).
【０４６３】IR(KBr) ：cm-1 1747，1674，1528，1372，1252，1230，1067。IR (KBr): cm -1 1747, 1674, 1528, 1372, 1252, 1230, 1067.
【０４６４】Ｚ−Ｄ−Ｇｌｕｔａｍｉｃ ａｃｉｄ 503
（1.14ｇ）を用いた以外は上記と同様にして化合物504a
D を3.04ｇ（収率82％）取得した。[0464] ZD-Glutamic acid 503
Compound 504a was prepared in the same manner as above except that (1.14 g) was used.
3.04 g (yield 82%) of D was obtained.
【０４６５】ＲF 0.74 (CHCl3 -MeOH 10:1) 。R F 0.74 (CHCl 3 -MeOH 10: 1).
【０４６６】［α］D 26-116°(c 1.01,CHCl3 ）。[Α] D 26 -116 ° (c 1.01, CHCl 3 ).
【０４６７】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.13(d,3H×2,J=6.4)，1.98，1.99，2.07，2.16， 2.17
(s,3H×6)，5.27， 5.30(d,1H×2,J=2.4)，5.30(s,2
H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.13 (d, 3H × 2, J = 6.4), 1.98, 1.99, 2.07, 2.16, 2.17
(s, 3H × 6), 5.27, 5.30 (d, 1H × 2, J = 2.4), 5.30 (s, 2
H).
【０４６８】IR(KBr) ：cm-1 1747，1660，1373，1255，1231，1067。IR (KBr): cm -1 1747, 1660, 1373, 1255, 1231, 1067.
【０４６９】(e) 化合物509aL 及び509aD の合成 化合物504aL(300.0mg)にＴＦＡ(1.5ml) を加え、室温で
１時間攪拌後、減圧下ＴＦＡを留去し、ＣＨ2 Ｃｌ
2 （３ml）、ＮＥｔ3 (700μｌ）及びＰａｌ−ＯＳｕ(1
33mg) を加え、室温で３時間攪拌して反応させた。 (E) Synthesis of Compounds 509aL and 509aD TFA (1.5 ml) was added to Compound 504aL (300.0 mg), and the mixture was stirred at room temperature for 1 hour, and TFA was distilled off under reduced pressure to give CH 2 Cl 2
2 (3 ml), NEt 3 (700 μl) and Pal-OSu (1
33 mg) was added and the mixture was stirred and reacted at room temperature for 3 hours.
【０４７０】反応液を水洗後乾燥した後減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 100：１）で精製して化合物
509aL を290.3mg （収率83.6％）取得した。After the reaction solution was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Merc).
k, purified by CHCl 3 -MeOH 100: 1)
290.3 mg (yield 83.6%) of 509aL was obtained.
【０４７１】ＲF 0.70 (CHCl3 -MeOH 10:1) 。R F 0.70 (CHCl 3 -MeOH 10: 1).
【０４７２】［α］D 24-103°(c 1.00,CHCl3 ）。[Α] D 24 -103 ° (c 1.00, CHCl 3 ).
【０４７３】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.14，1.15(d,3H,J=6.6)，1.99，2.
09， 2.17(s,3H×6)，5.28， 5.29(d,1H×2,J=3.4)，6.
99(d,1H,J=6.8)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.14, 1.15 (d, 3H, J = 6.6), 1.99, 2.
09, 2.17 (s, 3H × 6), 5.28, 5.29 (d, 1H × 2, J = 3.4), 6.
99 (d, 1H, J = 6.8).
【０４７４】IR(KBr) ：cm-1 1749，1641，1373，1250，1231，1069。IR (KBr): cm -1 1749, 1641, 1373, 1250, 1231, 1069.
【０４７５】化合物504aD(2.230 ｇ）のＥｔＯＨ(50ml)
溶液にｐ−ＴｓＯＨ・Ｈ2 Ｏ(0.465ｇ）と10％ Ｐｄ／
Ｃ (223mg)を加え、Ｐａｒｒで１時間接触還元を行なっ
た。触媒を濾去して脱保護体 2.323ｇ（収率 100％）を
取得した。その一部(400.0mg) のＣＨ2 Ｃｌ2 （３ml）
溶液にＮＥｔ3 (52mg)、続いてＰａｌ−ＯＳｕ(164mg)
を加え、室温で３時間攪拌して反応させた。Compound 504aD (2.230 g) in EtOH (50 ml)
Add p-TsOH.H 2 O (0.465 g) and 10% Pd /
C (223 mg) was added, and the mixture was subjected to catalytic reduction with Parr for 1 hour. The catalyst was removed by filtration to obtain 2.323 g (100% yield) of the deprotected product. Part (400.0 mg) of CH 2 Cl 2 (3 ml)
NEt 3 (52 mg) was added to the solution, followed by Pal-OSu (164 mg).
Was added and stirred at room temperature for 3 hours to react.
【０４７６】反応液を水洗し、乾燥後減圧下溶媒を留去
し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製し、化合物
509aDを346.8mg （収率81.0％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure.
k, purified by CHCl 3 -MeOH 50: 1) to give the compound
346.8 mg (81.0% yield) of 509aD was obtained.
【０４７７】ＲF 0.66 (CHCl3 -MeOH 10:1) 。R F 0.66 (CHCl 3 -MeOH 10: 1).
【０４７８】［α］D 25-103°(c 1.01,CHCl3 ）。[Α] D 25 -103 ° (c 1.01, CHCl 3 ).
【０４７９】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.139 ，1.145(d,3H×2,J=6.6)，1.
98，2.00，2.08，2.10，2.17(s,3H×6)，5.28， 5.30
(d,1H×2,J=3.4)，6.87(d,1H,J=7.1)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.139, 1.145 (d, 3H × 2, J = 6.6), 1.
98, 2.00, 2.08, 2.10, 2.17 (s, 3H × 6), 5.28, 5.30
(d, 1H × 2, J = 3.4), 6.87 (d, 1H, J = 7.1).
【０４８０】IR(KBr) ：cm-1 1749，1639，1373，1250，1229，1069。IR (KBr): cm -1 1749, 1639, 1373, 1250, 1229, 1069.
【０４８１】(f) 化合物509a′L 及び509a′D の合成 化合物509aL(254.7mg)のＭｅＯＨ（６ml）溶液に、28％
ＮａＯＭｅ ｉｎＭｅＯＨ (20μｌ）を加え、室温で
２時間攪拌して反応させた。 (F) Synthesis of Compounds 509a'L and 509a'D To a solution of compound 509aL (254.7 mg) in MeOH (6 ml) was added 28%
NaOMe in MeOH (20 μl) was added, and the mixture was reacted by stirring at room temperature for 2 hours.
【０４８２】反応液から減圧下溶媒を留去し、ゲル濾過
（ＬＨ−20，ＣＨＣｌ3 −ＭｅＯＨ１：１）で精製し、
化合物509a′L を165.7mg （収率86.5％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl 3 -MeOH 1: 1).
165.7 mg (yield 86.5%) of compound 509a'L was obtained.
【０４８３】ＲF 0.62 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.62 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０４８４】［α］D 27 -85.5°(c 1.01,CHCl3 -MeOH-
H2 O 10:10:3)。[Α] D 27 -85.5 ° (c 1.01, CHCl 3 -MeOH-
H 2 O 10: 10: 3 ).
【０４８５】 1H-NMR(CDCl3 ：CD3 OD=1:1）：δ ppm，
J in Hz 0.89(t,3H,J=6.8)， 1.25(d,3H×2,J=6.6)，4.80， 4.8
2(d,1H×2,J=2.7)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3H × 2, J = 6.6), 4.80, 4.8
2 (d, 1H × 2, J = 2.7).
【０４８６】IR(KBr) ：cm-1 3400，1637，1559，1082。IR (KBr): cm -1 3400, 1637, 1559, 1082.
【０４８７】同様にして、化合物509aD(305.9mg)から化
合物509a′D を222.7mg （収率96.9％）取得した。Similarly, 222.7 mg (yield 96.9%) of compound 509a'D was obtained from compound 509aD (305.9 mg).
【０４８８】ＲF 0.59 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.59 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０４８９】［α］D 25 -74.5°(c 1.01,CHCl3 -MeOH
1:1)。[Α] D 25 -74.5 ° (c 1.01, CHCl 3 -MeOH
1: 1).
【０４９０】 1H-NMR(CDCl3 ：CD3 OD=1:1）：δ ppm，
J in Hz 0.89(t,3H,J=6.8)， 1.25(d,3H×2,J=6.6)，4.80， 4.8
2(d,1H×2,J=2.4)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3H × 2, J = 6.6), 4.80, 4.8
2 (d, 1H × 2, J = 2.4).
【０４９１】IR(KBr) ：cm-1 3389，1639，1545，1076。IR (KBr): cm -1 3389, 1639, 1545, 1076.
【０４９２】(g) 化合物506aL 及び506aD の合成 化合物 505′Ｂｏｃ−（γ−ｂｅｎｚｙｌ）−ｓｕｃｃ
ｉｎｙｌ Ｌ−ｇｌｕｔａｍａｔｅ（Ｂｏｃ−Ｌ−Ｇｌ
ｕ（ＯＢｚｌ）−ＯＳｕ）(473mg) のＣＨ2 Ｃｌ2 (10m
l)溶液にＮＥｔ3 (120mg) 、続いて化合物501a(500.0m
g) を加え、室温で３時間攪拌して反応させた。 (G) Synthetic Compound of Compounds 506aL and 506aD 505′Boc- (γ-benzyl) -succ
inyl L-glutamate (Boc-L-Gl
u (OBzl) -OSu) (473 mg) in CH 2 Cl 2 (10 m
l) NEt 3 (120mg) was added to the solution, followed by compound 501a (500.0m
g) was added and the mixture was stirred and reacted at room temperature for 3 hours.
【０４９３】反応液を水洗し、乾燥後減圧下溶媒を留去
し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 ）で精製して化合物506aL を522.8mg
（収率81.0％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure.
k, CHCl 3 ) to give 522.8 mg of compound 506aL
(81.0% yield).
【０４９４】ＲF 0.20 (Toluene-MeOH 10:1)。R F 0.20 (Toluene-MeOH 10: 1).
【０４９５】［α］D 18 -76.8°(c 0.94,CHCl3 ) 。[Α] D 18 -76.8 ° (c 0.94, CHCl 3 ).
【０４９６】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.14(d,3H,J=6.6)，1.43(s,9H)，1.99，2.10， 2.17(s,
3H×3)，5.14(s,2H)，5.35(d,1H,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.14 (d, 3H, J = 6.6), 1.43 (s, 9H), 1.99, 2.10, 2.17 (s,
3H × 3), 5.14 (s, 2H), 5.35 (d, 1H, J = 3.2).
【０４９７】IR(KBr) ：cm-1 1747，1678，1369，1248，1229，1167，1067，1053。IR (KBr): cm -1 1747, 1678, 1369, 1248, 1229, 1167, 1067, 1053.
【０４９８】化合物501a(1.362ｇ）及びＮＥｔ3 (327m
g) のＣＨ2 Ｃｌ2 (10ml)の溶液に、化合物505 Ｂｏｃ
−γ−ｂｅｎｚｙｌ Ｄ−Ｇｌｕｔａｍａｔｅ（Ｂｏｃ
−Ｄ−Ｇｌｕ（ＯＢｚｌ）−ＯＨ）（1.00ｇ）のＣＨ2
Ｃｌ2 (10ml)溶液にＨＯ−Ｓｕ375mgとＤＣＣ 673mgを
加え、室温で２時間攪拌後の濾液を加え、室温で４時間
攪拌して反応させた。Compound 501a (1.362 g) and NEt 3 (327 m
g) in CH 2 Cl 2 (10 ml) was added to Compound 505 Boc.
-Γ-benzyl D-Glutamate (Boc
-D-Glu CH 2 of (OBzl) -OH) (1.00g)
HO-Su (375 mg) and DCC (673 mg) were added to a Cl 2 (10 ml) solution, and the filtrate after stirring at room temperature for 2 hours was added, followed by stirring at room temperature for 4 hours to react.
【０４９９】反応液を水洗し、乾燥後減圧下溶媒を留去
し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 ）で精製し、化合物506aD を 1.403ｇ
（収率79.8％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure.
k, CHCl 3 ) to give 1.403 g of compound 506aD
(79.8% yield).
【０５００】ＲF 0.21 (Toluene-MeOH 10:1)。R F 0.21 (Toluene-MeOH 10: 1).
【０５０１】［α］D 20 -77.7°(c 0.74,CHCl3 ) 。[Α] D 20 -77.7 ° (c 0.74, CHCl 3 ).
【０５０２】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.14(d,3H,J=6.4)，1.43(s,9H)，1.99，2.08， 2.17(s,
3H×3)，5.13(s,2H)，5.30(d,1H,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.14 (d, 3H, J = 6.4), 1.43 (s, 9H), 1.99, 2.08, 2.17 (s,
3H × 3), 5.13 (s, 2H), 5.30 (d, 1H, J = 3.4).
【０５０３】IR(KBr) ：cm-1 1747，1678，1369，1250，1231，1167，1067，1053。IR (KBr): cm -1 1747, 1678, 1369, 1250, 1231, 1167, 1067, 1053.
【０５０４】(h) 化合物507aL 及び507aD の合成 化合物506aL (1.875ｇ）のＥｔＯＨ(50ml)溶液に、10％
Ｐｄ／Ｃ 187mgを加え、Ｐａｒｒで２時間接触還元し
た。 (H) Synthesis of Compounds 507aL and 507aD 10% was added to a solution of Compound 506aL (1.875 g) in EtOH (50 ml).
187 mg of Pd / C was added, and the mixture was catalytically reduced with Parr for 2 hours.
【０５０５】触媒を濾去後減圧下溶媒を留去して化合物
507aL を 1.675ｇ（収率 100％）取得した。After the catalyst was removed by filtration, the solvent was distilled off under reduced pressure to give the compound
1.675 g (100% yield) of 507aL was obtained.
【０５０６】化合物506aD (0.900ｇ）を用いた以外は上
記と同様にして化合物507aD を775.0mg （収率99.9％）
取得した。Compound 507aD was 775.0 mg (yield 99.9%) in the same manner as above except that compound 506aD (0.900 g) was used.
I got it.
【０５０７】(i) 化合物510aLL、510aDD及び510aDLの合
成 化合物504aL(250.0mg)にＴＦＡ(1.5ml) を加え、室温で
１時間攪拌後減圧下ＴＦＡを留去し、ＣＨ2 Ｃｌ2 （２
ml）及びＮＥｔ3 (316μｌ）を加えた溶液に、化合物50
7aL(160.0mg)にＣＨ2 Ｃｌ2 （５ml）、ＨＯ−Ｓｕ（36
mg）及びＤＣＣ(64.5mg)を加え、室温で 2.5時間攪拌し
た後濾過して得られた濾液を加え、室温で３時間攪拌し
て反応させた。 (I) Compound of Compounds 510aLL, 510aDD and 510aDL
To the compound 504aL (250.0 mg) was added TFA (1.5 ml), and the mixture was stirred at room temperature for 1 hour, and then TFA was distilled off under reduced pressure to give CH 2 Cl 2 (20.0 mg).
ml) and NEt 3 (316 μl) were added to the solution.
7Al (160.0 mg) in CH 2 Cl 2 (5ml), HO-Su (36
mg) and DCC (64.5 mg), and the mixture was stirred at room temperature for 2.5 hours, and then the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 3 hours.
【０５０８】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
510aLLを319.8mg （収率85.0％）取得した。The reaction mixture was washed with water and dried, and then the solvent was distilled off under reduced pressure.
k, CHCl 3 -MeOH 50: 1)
319.8 mg (yield: 85.0%) of 510aLL was obtained.
【０５０９】ＲF 0.62 (CHCl3 -MeOH 10:1) 。R F 0.62 (CHCl 3 -MeOH 10: 1).
【０５１０】［α］D 23-107°(c 1.02,CHCl3 ) 。[Α] D 23 -107 ° (c 1.02, CHCl 3 ).
【０５１１】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.10，1.12， 1.12(d,3H×3,J=6.6)，1.43(s,9H)，1.9
8，1.99，2.06，2.08，2.14， 2.15(s,3H×9)，5.24，
5.27， 5.28(d,1H×3,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.10, 1.12, 1.12 (d, 3H × 3, J = 6.6), 1.43 (s, 9H), 1.9
8, 1.99, 2.06, 2.08, 2.14, 2.15 (s, 3H × 9), 5.24,
5.27, 5.28 (d, 1H × 3, J = 3.2).
【０５１２】IR(KBr) ：cm-1 1749，1654，1371，1250，1231，1069。IR (KBr): cm -1 1749, 1654, 1371, 1250, 1231, 1069.
【０５１３】化合物504aD （2.23ｇ）のＥｔＯＨ(50ml)
溶液にｐ−ＴｓＯＨ・Ｈ2 Ｏ(0.465ｇ）及び10％ Ｐｄ
／Ｃ(223mg) を加え、Ｐａｒｒで１時間接触還元し、触
媒を濾去後減圧下で溶媒を留去して脱ベンジルオキシカ
ルボニル体を 2.323ｇ（収率100％）得、その一部(422.
0mg) を分取し、これとＮＥｔ3 (54mg)のＣＨ2 Ｃｌ2
（５ml）溶液に、化合物507aD(250.7mg)にＣＨ2 Ｃｌ2
（８ml）、ＨＯ−Ｓｕ(56mg)とＤＣＣ(101mg) を加え、
室温で２時間攪拌した後濾過して得られた濾液を加え、
室温で２時間攪拌して反応させた。Compound 504aD (2.23 g) in EtOH (50 ml)
Add p-TsOH.H 2 O (0.465 g) and 10% Pd
/ C (223 mg), and the mixture was catalytically reduced with Parr for 1 hour, and the catalyst was removed by filtration. The solvent was distilled off under reduced pressure to obtain 2.323 g of debenzyloxycarbonyl compound (100% yield). 422.
0 mg), and this was mixed with CH 2 Cl 2 of NEt 3 (54 mg).
(5 ml) solution, compound 507aD (250.7 mg) was added to CH 2 Cl 2
(8 ml), HO-Su (56 mg) and DCC (101 mg) were added.
After stirring at room temperature for 2 hours, the filtrate obtained by filtration was added,
The reaction was carried out by stirring at room temperature for 2 hours.
【０５１４】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製し、化合物
510aDDを451.3mg （収率76.5％）取得した。The reaction mixture was washed with water and dried, and then the solvent was distilled off under reduced pressure.
k, purified by CHCl 3 -MeOH 50: 1) to give the compound
451.3 mg (76.5% yield) of 510aDD was obtained.
【０５１５】ＲF 0.71 (CHCl3 -MeOH 10:1) 。R F 0.71 (CHCl 3 -MeOH 10: 1).
【０５１６】［α］D 26-111°(c 0.80,CHCl3 ) 。[Α] D 26 -111 ° (c 0.80, CHCl 3 ).
【０５１７】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.12， 1.14(d,3H×3,J=6.4)，1.42(s,9H)，1.98，2.0
8，2.09， 2.16(s,3H×9)，5.27， 5.28(d,1H×3,J=3.
4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.12, 1.14 (d, 3H × 3, J = 6.4), 1.42 (s, 9H), 1.98, 2.0
8, 2.09, 2.16 (s, 3H × 9), 5.27, 5.28 (d, 1H × 3, J = 3.
Four).
【０５１８】IR(KBr) ：cm-1 1747，1657，1371，1250，1231，1069。IR (KBr): cm -1 1747, 1657, 1371, 1250, 1231, 1069.
【０５１９】上記化合物510aDDの合成の中で、化合物50
7aD の代わりに化合物507aL(250mg)を用いた以外は同様
に行なって化合物510aDLを452.7mg （収率77.0％）取得
した。In the synthesis of Compound 510aDD, Compound 50
Compound 510aDL (452.7 mg, yield 77.0%) was obtained in the same manner except that Compound 507aL (250 mg) was used instead of 7aD.
【０５２０】ＲF 0.57 (CHCl3 -MeOH 10:1) 。R F 0.57 (CHCl 3 -MeOH 10: 1).
【０５２１】［α］D 26-102°(c 1.00,CHCl3 ) 。[Α] D 26 -102 ° (c 1.00, CHCl 3 ).
【０５２２】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.12， 1.13(d,3H×3,J=6.6)，1.43(s,9H)，1.98，1.9
9，2.00，2.08，2.16， 2.17(s,3H×9)，5.27，5.28，
5.29(d,1H×3,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.12, 1.13 (d, 3H × 3, J = 6.6), 1.43 (s, 9H), 1.98, 1.9
9, 2.00, 2.08, 2.16, 2.17 (s, 3H × 9), 5.27, 5.28,
5.29 (d, 1H × 3, J = 3.2).
【０５２３】IR(KBr) ：cm-1 1749，1655，1373，1250，1231，1067。IR (KBr): cm -1 1749, 1655, 1373, 1250, 1231, 1067.
【０５２４】(j) 化合物511aLL、511aDD及び511aDLの合
成 化合物510aLL(208.2mg) にＴＦＡ(81.5ml)を加え、室温
で１時間攪拌後減圧下ＴＦＡを留去した後ＣＨ2 Ｃｌ2
（２ml）、ＮＥｔ3 (300μｌ）及びＰａｌ−ＯＳｕ(62m
g)を加え、室温で３時間攪拌して反応させた。 (J) Compound 511aLL, 511aDD and 511aDL
Forming compound 510aLL the (208.2mg) in TFA (81.5ml) was added, CH 2 Cl 2 was distilled off 1 hour after stirring under reduced pressure TFA at room temperature
(2 ml), NEt 3 (300 μl) and Pal-OSu (62 ml)
g) was added thereto, and the mixture was stirred and reacted at room temperature for 3 hours.
【０５２５】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
511aLLを193.6mg （収率84.2％）取得した。The reaction mixture was washed with water and dried, and then the solvent was distilled off under reduced pressure.
k, CHCl 3 -MeOH 50: 1)
193.6 mg (yield 84.2%) of 511aLL was obtained.
【０５２６】ＲF 0.59 (CHCl3 -MeOH 10:1) 。R F 0.59 (CHCl 3 -MeOH 10: 1).
【０５２７】［α］D 25-111°(c 1.01,CHCl3 ) 。[Α] D 25 -111 ° (c 1.01, CHCl 3 ).
【０５２８】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.5)，1.11，1.13， 1.14(d,3H×3,J=6.
6)，1.98，1.99，2.01，2.07，2.09，2.15， 2.16(s,3H
×9)，5.24， 5.29(d,1H×3,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.5), 1.11, 1.13, 1.14 (d, 3H × 3, J = 6.
6), 1.98, 1.99, 2.01, 2.07, 2.09, 2.15, 2.16 (s, 3H
× 9), 5.24, 5.29 (d, 1H × 3, J = 3.2).
【０５２９】IR(KBr) ：cm-1 1749，1641，1373，1250，1229，1067。IR (KBr): cm -1 1749, 1641, 1373, 1250, 1229, 1067.
【０５３０】化合物510aDD(201.8mg) を用いて上記と同
様に行い、シリカゲルカラムクロマトグラフィー（Ｍｅ
ｒｃｋ，ＣＨＣｌ3 −ＭｅＯＨ 75：１）で精製して化
合物511aDDを153.4mg （収率68.8％）取得した。The same procedure as above was carried out using Compound 510aDD (201.8 mg), followed by silica gel column chromatography (Me
rck, CHCl 3 -MeOH 75: 1) to obtain 153.4 mg (yield 68.8%) of compound 511aDD.
【０５３１】ＲF 0.75 (CHCl3 -MeOH 10:1) 。R F 0.75 (CHCl 3 -MeOH 10: 1).
【０５３２】［α］D 24-116°(c 0.81,CHCl3 ) 。[Α] D 24 -116 ° (c 0.81, CHCl 3 ).
【０５３３】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.12，1.13，1.14(d,J=6.6) ，1.9
8，1.99，2.08，2.09，2.10， 2.16(s,3H×9)，5.26，
5.28(d,1H×3,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.12, 1.13, 1.14 (d, J = 6.6), 1.9
8, 1.99, 2.08, 2.09, 2.10, 2.16 (s, 3H × 9), 5.26,
5.28 (d, 1H × 3, J = 3.4).
【０５３４】IR(KBr) ：cm-1 1747，1637，1373，1250，1230，1070。IR (KBr): cm -1 1747, 1637, 1373, 1250, 1230, 1070.
【０５３５】化合物510aDL(202.6mg) を用いて上記と同
様に行い、シリカゲルカラムクロマトグラフィー（Ｍｅ
ｒｃｋ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化
合物511aDLを176.3mg （収率78.8％）取得した。Compound 510aDL (202.6 mg) was used in the same manner as described above, and silica gel column chromatography (Me
rck, CHCl 3 -MeOH 50: 1) to obtain 176.3 mg (yield 78.8%) of compound 511aDL.
【０５３６】ＲF 0.69 (CHCl3 -MeOH 10:1) 。R F 0.69 (CHCl 3 -MeOH 10: 1).
【０５３７】［α］D 26-101°(c 1.00,CHCl3 ) 。[Α] D 26 -101 ° (c 1.00, CHCl 3 ).
【０５３８】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.12， 1.15(d,3H×3,J=6.8)，1.9
8，1.99，2.00，2.07，2.08，2.16， 2.17(s,3H×9)，
5.26，5.28， 5.30(d,1H×3,J=3.5)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.12, 1.15 (d, 3H × 3, J = 6.8), 1.9
8, 1.99, 2.00, 2.07, 2.08, 2.16, 2.17 (s, 3H × 9),
5.26, 5.28, 5.30 (d, 1H × 3, J = 3.5).
【０５３９】IR(KBr) ：cm-1 1747，1641，1373，1250，1229，1070。IR (KBr): cm -1 1747, 1641, 1373, 1250, 1229, 1070.
【０５４０】(k) 化合物511a′LL、511a′DD及び511a′
DLの合成 化合物510aLL(168.2mg) のＭｅＯＨ（３ml）溶液に、28
％ ＮａＯＭｅ ｉｎＭｅＯＨ（10μｌ）を加え、室温
で２時間攪拌して反応させた。 (K) Compounds 511a′LL, 511a′DD and 511a ′
To a solution of 510aLL (168.2 mg) in DL MeOH (3 ml) was added 28
% NaOMe in MeOH (10 μl) was added, and the mixture was stirred and reacted at room temperature for 2 hours.
【０５４１】反応液から減圧下溶媒を留去し、ゲル濾過
（ＬＨ−20，ＣＨＣｌ3 −ＭｅＯＨ１：１）で精製して
化合物511a′LLを114.0mg （収率91.5％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl 3 -MeOH 1: 1) to obtain 114.0 mg (yield 91.5%) of compound 511a'LL.
【０５４２】ＲF 0.54 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.54 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０５４３】［α］D 26 -88.3°(c 1.00,CHCl3 -MeOH
-H2 O 10:10:3)。[Α] D 26 -88.3 ° (c 1.00, CHCl 3 -MeOH
-H 2 O 10: 10: 3 ).
【０５４４】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)， 1.25(d,3H×3,J=6.6)，4.81，4.8
2， 4.83(1H×3)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3H × 3, J = 6.6), 4.81,4.8
2, 4.83 (1H × 3).
【０５４５】IR(KBr) ：cm-1 3449，1637，1076。[0545] IR (KBr): cm -1 3449,1637,1076 .
【０５４６】化合物510aDD(141.6mg) のＭｅＯＨ（６m
l）溶液に、28％ ＮａＯＭｅ ｉｎＭｅＯＨ（20μ
ｌ）を加え、室温で 3.5時間攪拌して反応させた。Compound 510aDD (141.6mg) in MeOH (6m
l) Add 28% NaOMe in MeOH (20μ
l) was added, and the mixture was reacted by stirring at room temperature for 3.5 hours.
【０５４７】反応液から減圧下溶媒を留去し、白色粉末
として化合物511a′DDを104.5mg （収率99.6％）取得し
た。The solvent was distilled off from the reaction solution under reduced pressure to obtain 104.5 mg (yield: 99.6%) of compound 511a'DD as a white powder.
【０５４８】ＲF 0.47 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.47 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０５４９】［α］D 27 -80.0°(c 0.99,CHCl3 -MeOH
-H2 O 10:10:3)。[Α] D 27 -80.0 ° (c 0.99, CHCl 3 -MeOH
-H 2 O 10: 10: 3 ).
【０５５０】 1H-NMR (C5 D5 N)：δ ppm，J in Hz 0.87(t,3H,J=6.6)，1.48-1.53(m,3H×3)，5.25，5.26，
5.27(d,1H×3,J=3.7)。 1 H-NMR (C 5 D 5 N): δ ppm, J in Hz 0.87 (t, 3H, J = 6.6), 1.48-1.53 (m, 3H × 3), 5.25, 5.26,
5.27 (d, 1H × 3, J = 3.7).
【０５５１】IR(KBr) ：cm-1 3450，1639，1076。[0551] IR (KBr): cm -1 3450,1639,1076 .
【０５５２】化合物510aDL(167.3mg) のＭｅＯＨ(7.5m
l) 溶液に、28％ ＮａＯＭｅ ｉｎＭｅＯＨ（20μ
ｌ）を加え、室温で 3.5時間攪拌して反応させた。Compound 510aDL (167.3mg) in MeOH (7.5m
l) Add 28% NaOMe in MeOH (20μ
l) was added, and the mixture was reacted by stirring at room temperature for 3.5 hours.
【０５５３】反応液から減圧下溶媒を留去し、白色粉末
として化合物511a′DLを122.8mg （収率99.0％）取得し
た。The solvent was distilled off from the reaction solution under reduced pressure to obtain 122.8 mg (yield 99.0%) of compound 511a'DL as a white powder.
【０５５４】ＲF 0.47 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.47 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０５５５】［α］D 27 -78.8°(c 1.00,CHCl3 -MeOH
-H2 O 10:10:3)。[Α] D 27 -78.8 ° (c 1.00, CHCl 3 -MeOH
-H 2 O 10: 10: 3 ).
【０５５６】 1H-NMR (C5 D5 N)：δ ppm，J in Hz 0.87(t,3H,J=6.8)，1.48-1.53(m,3H×3)，5.24， 5.27
(d,1H×3,J=3.7)。 1 H-NMR (C 5 D 5 N): δ ppm, J in Hz 0.87 (t, 3H, J = 6.8), 1.48-1.53 (m, 3H × 3), 5.24, 5.27
(d, 1H × 3, J = 3.7).
【０５５７】IR(KBr) ：cm-1 3443，1639，1076。IR (KBr): cm -1 3443, 1639, 1076.
【０５５８】(l) 化合物501bの合成 化合物514 β−Ｄ−Ｇａｌａｃｔｏｓｅ ｐｅｎｔａａ
ｃｅｔａｔｅ(20.00ｇ）のＣＨ2 Ｃｌ2 (100ml) 溶液に
２−（ｂｅｎｚｙｌｏｘｙｃａｒｂｏｎｙｌ）ｅｔｈｙ
ｌ ａｌｃｏｈｏｌ（15ｇ）とＢＦ3 ・Ｅｔ2 Ｏ(39.8m
l)を加え、室温で21時間攪拌して反応させた。 (L) Synthetic Compound 514 β-D-Galactose pentaa of Compound 501b
2- (benzyloxycarbonyl) ethyl was added to CH 2 Cl 2 (100 ml) solution of acetate (20.00 g).
l alcohol and (15g) BF 3 · Et 2 O (39.8m
l) was added and the mixture was stirred and reacted at room temperature for 21 hours.
【０５５９】反応液を炭酸水素ナトリウム水で中和後分
液し、有機層を乾燥後減圧下に溶媒を留去し、シリカゲ
ルカラムクロマトグラフィー（ナカライ，ＣＨＣｌ3 ）
で精製して化合物515 を18.164ｇ（収率67.5％）取得し
た。The reaction mixture was neutralized with aqueous sodium hydrogen carbonate and separated, and the organic layer was dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Nacalai, CHCl 3 ).
To obtain 18.164 g (yield 67.5%) of compound 515.
【０５６０】ＲF 0.29 (Toluene-MeOH 10:1)。R F 0.29 (Toluene-MeOH 10: 1).
【０５６１】［α］D 23 -1.57°(c 1.02,CHCl3 ) 。[Α] D 23 -1.57 ° (c 1.02, CHCl 3 ).
【０５６２】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.99，2.00，2.03， 2.15(s,3H×4)，3.34-3.48(m,2H)
，3.66-3.72(m,1H) ，3.89(t,2H,J=6.6)，4.14(dd,2H)
，4.45(d,1H,J=8.1)，5.00(dd,1H,J=3.4, 10.5)，5.10
(s,2H)，5.18(dd,1H) ，5.39(d,1H,J=3.4)，7.36(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.99, 2.00, 2.03, 2.15 (s, 3H × 4), 3.34-3.48 (m, 2H)
, 3.66-3.72 (m, 1H), 3.89 (t, 2H, J = 6.6), 4.14 (dd, 2H)
, 4.45 (d, 1H, J = 8.1), 5.00 (dd, 1H, J = 3.4, 10.5), 5.10
(s, 2H), 5.18 (dd, 1H), 5.39 (d, 1H, J = 3.4), 7.36 (5H).
【０５６３】IR(KBr) ：cm-1 1747，1720，1525，1371，1232，1060。IR (KBr): cm -1 1747, 1720, 1525, 1371, 1232, 1060.
【０５６４】化合物515 （8.50ｇ）のＥｔＯＨ(150ml)
溶液に、ｐ−ＴｓＯＨ・Ｈ2 Ｏ(3.079ｇ）及び10％ Ｐ
ｄ／Ｃ (850mg)を加えＰａｒｒで４時間接触還元した。Compound 515 (8.50 g) in EtOH (150 ml)
Add p-TsOH.H 2 O (3.079 g) and 10% P
d / C (850 mg) was added and the mixture was catalytically reduced with Parr for 4 hours.
【０５６５】反応液から触媒を濾去後、減圧下で溶媒を
留去して化合物501bを 9.217ｇ（収率 100％）取得し
た。After removing the catalyst from the reaction solution by filtration, the solvent was distilled off under reduced pressure to obtain 9.217 g of compound 501b (yield: 100%).
【０５６６】(m) 化合物504bL 及び504bD の合成 化合物501b（2.39ｇ）及びＮＥｔ3 (0.515ｇ）のＣＨ2
Ｃｌ2 (10ml)の溶液に、化合物503 Ｂｏｃ−Ｌ−Ｇｌｕ
ｔａｍｉｃ ａｃｉｄ（0.50ｇ）のＣＨ2 Ｃｌ2 (25ml)
の溶液にＨＯ−Ｓｕ（0.51ｇ）とＤＣＣ（0.92ｇ）を加
え、室温で２時間攪拌した後濾過して得られた濾液を加
え、室温で２時間攪拌して反応させた。(M) Synthesis of Compounds 504bL and 504bD CH 2 of Compound 501b (2.39 g) and NEt 3 (0.515 g)
Compound 503 Boc-L-Glu was added to a solution of Cl 2 (10 ml).
CH 2 Cl 2 (25 ml) of tamic acid (0.50 g)
HO-Su (0.51 g) and DCC (0.92 g) were added to the above solution, and the mixture was stirred at room temperature for 2 hours, and then the filtrate obtained by filtration was added.
【０５６７】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ＹＭＣ，
ＣＨＣｌ3 −ＭｅＯＨ 100：１）で精製して化合物504b
L を1.262ｇ（収率62.8％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC,
Purification with CHCl 3 -MeOH 100: 1) gives compound 504b.
1.262 g (yield 62.8%) of L was obtained.
【０５６８】ＲF 0.64 (CHCl3 -MeOH 10:1) 。R F 0.64 (CHCl 3 -MeOH 10: 1).
【０５６９】［α］D 25 -0.71°(c 0.99,CHCl3 ) 。[Α] D 25 -0.71 ° (c 0.99, CHCl 3 ).
【０５７０】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.44(s,9H)，1.99，2.05，2.08，2.09， 2.16(s,3H×
8)，4.50， 4.51(d,1H×2,J=8.0)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.44 (s, 9H), 1.99, 2.05, 2.08, 2.09, 2.16 (s, 3H ×
8), 4.50, 4.51 (d, 1H × 2, J = 8.0).
【０５７１】IR(KBr) ：cm-1 1753，1670，1360，1230，1076，1059。IR (KBr): cm -1 1753, 1670, 1360, 1230, 1076, 1059.
【０５７２】化合物501b（2.95ｇ）及びＮＥｔ3 （0.64
ｇ）のＣＨ2 Ｃｌ2 (10ml)の溶液に、化合物503 Ｚ−Ｄ
−Ｇｌｕｔａｍｉｃ ａｃｉｄ（0.70ｇ）のＣＨ2 Ｃｌ
2 (20ml)の溶液にＨＯ−Ｓｕ（0.63ｇ）とＤＣＣ（1.13
ｇ）を加え、室温で２時間攪拌した後濾過して得られた
濾液を加え、室温で３時間攪拌して反応させた。Compound 501b (2.95 g) and NEt 3 (0.64 g)
g) in CH 2 Cl 2 (10 ml) was added to compound 503 ZD.
-Glutamic CH 2 Cl the acid (0.70 g)
2 (20 ml) in a solution of HO-Su (0.63 g) and DCC (1.13 g).
g) was added thereto, and the mixture was stirred at room temperature for 2 hours, and then a filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 3 hours.
【０５７３】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ＹＭＣ，
ＣＨＣｌ3 −ＭｅＯＨ 75：１）で精製して化合物504b
D を1.781ｇ（収率69.6％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC,
Purification with CHCl 3 -MeOH 75: 1) gives compound 504b.
1.781 g (yield 69.6%) of D was obtained.
【０５７４】ＲF 0.77 (CHCl3 -MeOH 10:1) 。R F 0.77 (CHCl 3 -MeOH 10: 1).
【０５７５】［α］D 26 -5.73°(c 0.82,CHCl3 ) 。[Α] D 26 -5.73 ° (c 0.82, CHCl 3 ).
【０５７６】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.99，2.05，2.06，2.07，2.15， 2.16(s,3H×8)， 4.4
5(d,1H×2,J=7.8)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.99, 2.05, 2.06, 2.07, 2.15, 2.16 (s, 3H × 8), 4.4
5 (d, 1H × 2, J = 7.8).
【０５７７】IR(KBr) ：cm-1 1751，1668，1371，1231，1078，1059。IR (KBr): cm -1 1751, 1668, 1371, 1231, 1078, 1059.
【０５７８】(n) 化合物506bL 及び506bD の合成 化合物505 Ｂｏｃ−（γ−ｂｅｎｚｙｌ）−ｓｕｃｃｉ
ｎｙｌ Ｌ−ｇｌｕｔａｍａｔｅ（Ｂｏｃ−Ｌ−Ｇｌｕ
（ＯＢｚｌ）−ＯＳｕ）（1.70ｇ）のＣＨ2 Ｃｌ2 (40m
l)溶液にＮＥｔ3 (431mg) 、続いて化合物501b（2.00
ｇ）を加え、室温で２時間攪拌して反応させた。 (N) Synthesis of Compounds 506bL and 506bD Compound 505 Boc- (γ-benzyl) -succi
nyl L-glutamate (Boc-L-Glu
(OBzl) -OSu) CH 2 Cl 2 (40m of (1.70 g)
l) NEt 3 (431 mg) was added to the solution, followed by compound 501b (2.00 mg).
g) was added thereto, and the mixture was stirred and reacted at room temperature for 2 hours.
【０５７９】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 ）で精製して化合物506bL を 1.901ｇ
（収率75.4％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure.
k, CHCl 3 ) to give 1.901 g of compound 506bL
(75.4% yield).
【０５８０】ＲF 0.31 (Toluene-MeOH 10:1)。R F 0.31 (Toluene-MeOH 10: 1).
【０５８１】［α］D 27 +1.10°(c 0.82,CHCl3 ) 。[Α] D 27 + 1.10 ° (c 0.82, CHCl 3 ).
【０５８２】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.43(s,9H)，1.99，2.05，2.08， 2.15(s,3H×4)，4.49
(d,1H,J=7.8)，5.13(s,2H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.43 (s, 9H), 1.99, 2.05, 2.08, 2.15 (s, 3H × 4), 4.49
(d, 1H, J = 7.8), 5.13 (s, 2H).
【０５８３】IR(KBr) ：cm-1 1753，1674，1369，1225，1171，1076，1065。IR (KBr): cm -1 1753, 1674, 1369, 1225, 1171, 1076, 1065.
【０５８４】化合物501b(1.678ｇ）及びＮＥｔ3 (362m
g) のＣＨ2 Ｃｌ2 (10ml)の溶液に、化合物505 Ｂｏｃ
−γ−ｂｅｎｚｙｌ Ｄ−Ｇｌｕｔａｍａｔｅ（Ｂｏｃ
−Ｄ−Ｇｌｕ（ＯＢｚｌ）−ＯＨ）（1.14ｇ）のＣＨ2
Ｃｌ2 (10ml)溶液にＨＯ−Ｓｕ(428mg) 及びＤＣＣ(767
mg) を加え室温で２時間攪拌した後濾過して得られた濾
液を加え、室温で３時間攪拌して反応させた。Compound 501b (1.678 g) and NEt 3 (362 m
g) in CH 2 Cl 2 (10 ml) was added to Compound 505 Boc.
-Γ-benzyl D-Glutamate (Boc
CH 2 of -D-Glu (OBzl) -OH) (1.14 g)
Cl 2 (10 ml) was added HO-Su (428mg) and DCC (767
mg) was added and the mixture was stirred at room temperature for 2 hours, and the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 3 hours.
【０５８５】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、シリカゲルカラムクロマトグラフイー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 ）で精製し、化合物506bD を 1.555ｇ
（収率73.5％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Merc).
k, CHCl 3 ) to give 1.555 g of Compound 506bD.
(73.5% yield).
【０５８６】ＲF 0.31 (Toluene-MeOH 10:1)。R F 0.31 (Toluene-MeOH 10: 1).
【０５８７】［α］D 27 -3.75°(c 1.04,CHCl3 ) 。[Α] D 27 -3.75 ° (c 1.04, CHCl 3 ).
【０５８８】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.44(s,9H)，1.99，2.05，2.06， 2.16(s,3H×4)，4.50
(d,1H,J=8.1)，5.13(s,2H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.44 (s, 9H), 1.99, 2.05, 2.06, 2.16 (s, 3H × 4), 4.50
(d, 1H, J = 8.1), 5.13 (s, 2H).
【０５８９】IR(KBr) ：cm-1 1753，1676，1369，1225，1171，1078，1055。IR (KBr): cm -1 1753, 1676, 1369, 1225, 1171, 1078, 1055.
【０５９０】(o) 化合物507bL の合成 化合物506bL (1.403ｇ）のＥｔＯＨ(50ml)溶液に、10％
Ｐｄ／Ｃ 140mgを加え、Ｐａｒｒで１時間接触還元し
た。 (O) Synthesis of Compound 507bL To a solution of compound 506bL (1.403g) in EtOH (50ml) was added 10%
140 mg of Pd / C was added, and the mixture was catalytically reduced with Parr for 1 hour.
【０５９１】触媒を濾去後、減圧下で溶媒を留去し、化
合物507bL を 1.096ｇ（収率89.5％）取得した。After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 1.096 g (yield: 89.5%) of compound 507bL.
【０５９２】(p) 化合物508ab の合成 化合物501b (300mg)及びＮＥｔ3 (64.7mg)のＣＨ2 Ｃｌ
2 （２ml）の溶液に、化合物507a (300mg)のＣＨ2 Ｃｌ
2 （８ml）の溶液にＨＯ−Ｓｕ（67.5mg）とＤＣＣ (13
2mg)を加え、室温で２時間攪拌した後濾過して得られた
濾液を加え、室温で３時間攪拌して反応させた。 (P) Synthesis of Compound 508ab CH 2 Cl of compound 501b (300 mg) and NEt 3 (64.7 mg)
2 (2 ml) in a solution of compound 507a (300 mg) in CH 2 Cl
2 (8 ml) solution to HO-Su (67.5mg) and DCC (13
2 mg) was added, and the mixture was stirred at room temperature for 2 hours, and then the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 3 hours.
【０５９３】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ＹＭＣ，
ＣＨＣｌ3 −ＭｅＯＨ 150：１）で精製し、化合物508a
b を392.9mg （収率78.7％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC,
Purification with CHCl 3 -MeOH 150: 1) gave compound 508a.
392.9 mg (yield 78.7%) of b was obtained.
【０５９４】ＲF 0.70 (CHCl3 -MeOH 10:1) 。R F 0.70 (CHCl 3 -MeOH 10: 1).
【０５９５】［α］D 27 -53.4°(c 0.79,CHCl3 ) 。[Α] D 27 -53.4 ° (c 0.79, CHCl 3 ).
【０５９６】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.14(d,3H,J=6.4)，1.43(s,9H)，1.99，2.00，2.05，2.
09，2.10， 2.17(s,3H×7)，4.50(d,1H,J=8.1)，5.28(d
d,1H,J=1.0, 3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.14 (d, 3H, J = 6.4), 1.43 (s, 9H), 1.99, 2.00, 2.05, 2.
09, 2.10, 2.17 (s, 3H × 7), 4.50 (d, 1H, J = 8.1), 5.28 (d
d, 1H, J = 1.0, 3.4).
【０５９７】IR(KBr) ：cm-1 1740，1371，1231，1067。IR (KBr): cm -1 1740, 1371, 1231, 1067.
【０５９８】(q) 化合物509ab の合成 化合物508ab(227.7mg)にＴＦＡ（２ml）を加え室温で２
時間攪拌後、減圧下ＴＦＡを留去し、ＣＨ2 Ｃｌ2 （３
ml）、ＮＥｔ3 (300μｌ）及びＰａｌ−ＯＳｕ(94.6mg)
を加え室温で３時間攪拌して反応させた。 (Q) Synthesis of Compound 509ab To Compound 508ab (227.7 mg) was added TFA (2 ml), and the mixture was added at room temperature.
After stirring for an hour, TFA was distilled off under reduced pressure, and CH 2 Cl 2 (3
ml), NEt 3 (300 μl) and Pal-OSu (94.6 mg)
Was added and stirred at room temperature for 3 hours to react.
【０５９９】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、ＣＨ2 Ｃｌ2 (10ml)、ＨＯ−Ｓｕ(97mg)とＤＣＣ
(190mg) を加え、室温で３時間攪拌して反応させた。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. CH 2 Cl 2 (10 ml), HO-Su (97 mg) and DCC
(190 mg) was added, and the mixture was stirred and reacted at room temperature for 3 hours.
【０６００】この反応液を水洗し、乾燥後減圧下で溶媒
を留去し、シリカゲルカラムクロマトグラフィー（ＹＭ
Ｃ，ＣＨＣｌ3 −ＭｅＯＨ 100：１）で精製し、化合物
509ab を201.4mg （収率77.1％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure.
C, CHCl 3 -MeOH 100: 1)
201.4 mg (yield 77.1%) of 509ab was obtained.
【０６０１】ＲF 0.84 (CHCl3 -MeOH 10:1) 。R F 0.84 (CHCl 3 -MeOH 10: 1).
【０６０２】［α］D 28 -49.2°(c 0.71,CHCl3 ) 。[Α] D 28 -49.2 ° (c 0.71, CHCl 3 ).
【０６０３】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.14(d,3H,J=6.6)，1.99，2.00，2.
05，2.09， 2.16(s,3H×7)，4.53(d,1H,J=7.8)，5.28(d
d,1H,J=1.0, 3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.14 (d, 3H, J = 6.6), 1.99, 2.00, 2.
05, 2.09, 2.16 (s, 3H × 7), 4.53 (d, 1H, J = 7.8), 5.28 (d
d, 1H, J = 1.0, 3.4).
【０６０４】IR(KBr) ：cm-1 1751，1639，1371，1227，1072，1060。IR (KBr): cm -1 1751, 1639, 1371, 1227, 1072, 1060.
【０６０５】(r) 化合物509a′ b′の合成 化合物509ab(170.0mg)のＭｅＯＨ（３ml）溶液に、28％
ＮａＯＭｅ ｉｎＭｅＯＨ（20μｌ）を加え、室温で
１時間攪拌して反応させた。 (R) Synthesis of compound 509a ′ b ′ 28% was added to a solution of compound 509ab (170.0 mg) in MeOH (3 ml).
NaOMe in MeOH (20 μl) was added, and the mixture was stirred and reacted at room temperature for 1 hour.
【０６０６】反応液から減圧下で溶媒を留去し、ゲル濾
過（ＬＨ−20，ＣＨＣｌ3 −ＭｅＯＨ １：１）で精製
して白色粉末として化合物509a′ b′を118.7mg （収率
96.2％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, CHCl 3 -MeOH 1: 1) to obtain 118.7 mg of the compound 509a'b 'as a white powder (yield).
96.2%).
【０６０７】ＲF 0.64 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.64 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０６０８】［α］D 24 -40.6°(c 1.00,CHCl3 -MeOH
1:1)。[Α] D 24 -40.6 ° (c 1.00, CHCl 3 -MeOH
1: 1).
【０６０９】 1H-NMR(CDCl3 -CD3 OD 1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=7.0)，1.25(d,3H,J=6.6)，4.25(d,1H,J=7.
8)，4.80(d,1H,J=2.9)。 1 H-NMR (CDCl 3 -CD 3 OD 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 7.0), 1.25 (d, 3H, J = 6.6), 4.25 (d, 1H, J = 7.
8), 4.80 (d, 1H, J = 2.9).
【０６１０】IR(KBr) ：cm-1 3400，1637，1074。[0610] IR (KBr): cm -1 3400,1637,1074 .
【０６１１】(s) 化合物510c、510d及び510eの合成 化合物504bL(441.7mg)にＴＦＡ（２ml）を加え室温で１
時間攪拌後、減圧下でＴＦＡを留去した後の残渣のＣＨ
2 Ｃｌ2 （２ml）及びＮＥｔ3 (500μｌ）の溶液に、化
合物507aL(250mg)のＣＨ2 Ｃｌ2 （８ml）溶液にＨＯ−
Ｓｕ(56mg)及びＤＣＣ(101mg) を加え室温で 1.5時間攪
拌した後濾過して得られた濾液を加え、室温で17間攪拌
して反応させた。 (S) Synthesis of Compounds 510c, 510d and 510e To compound 504bL (441.7 mg) was added TFA (2 ml), and the mixture was added at room temperature for 1 hour.
After stirring for an hour, the residue CH 2 was distilled off under reduced pressure.
Compound 507aL (250 mg) in CH 2 Cl 2 (8 ml) was added to a solution of 2 Cl 2 (2 ml) and NEt 3 (500 μl) in HO-
Su (56 mg) and DCC (101 mg) were added, the mixture was stirred at room temperature for 1.5 hours, and the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 17 hours.
【０６１２】反応液を水洗し、乾燥後減圧下で溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ＹＭＣ，
ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物510c
を549.8mg （収率86.0％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC,
Purification with CHCl 3 -MeOH 50: 1) gives compound 510c
Was obtained in an amount of 549.8 mg (86.0% yield).
【０６１３】ＲF 0.60 (CHCl3 -MeOH 10:1) 。R F 0.60 (CHCl 3 -MeOH 10: 1).
【０６１４】［α］D 28 -39.2°(c 1.20,CHCl3 ) 。[Α] D 28 -39.2 ° (c 1.20, CHCl 3 ).
【０６１５】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.11(d,3H,J=6.6)，1.42(s,9H)，1.98，1.99，2.05，2.
06， 2.08(s,3H×11) ，4.50， 4.51(d,1H×2,J=7.8)，
5.34(d,1H,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.11 (d, 3H, J = 6.6), 1.42 (s, 9H), 1.98, 1.99, 2.05, 2.
06, 2.08 (s, 3H × 11), 4.50, 4.51 (d, 1H × 2, J = 7.8),
5.34 (d, 1H, J = 3.4).
【０６１６】IR(KBr) ：cm-1 1750，1657，1371，1230，1061。IR (KBr): cm -1 1750, 1657, 1371, 1230, 1061.
【０６１７】化合物508ab(377.0mg)にＴＦＡ（４ml）を
加え、室温で２時間攪拌後、減圧下でＴＦＡを留去した
後の残渣のＣＨ2 Ｃｌ2 （２ml）及びＮＥｔ3 (500μ
ｌ）の溶液に、化合物507bL(250.0mg)のＣＨ2 Ｃｌ
2 （８ml）溶液にＨＯ−Ｓｕ(51mg)及びＤＣＣ(100mg)
を加え、室温で３時間攪拌した後濾過して得られた濾液
を加え、室温で３間攪拌して反応させた。To compound 508ab (377.0 mg) was added TFA (4 ml), and the mixture was stirred at room temperature for 2 hours, and the TFA was distilled off under reduced pressure. The residue was CH 2 Cl 2 (2 ml) and NEt 3 (500 μm).
l) in a solution of compound 507bL (250.0 mg) in CH 2 Cl
HO-Su (51 mg) and DCC (100 mg) were added to 2 (8 ml) solution.
Was added, and the mixture was stirred at room temperature for 3 hours, and then the filtrate obtained by filtration was added. The mixture was stirred and reacted at room temperature for 3 hours.
【０６１８】反応液を水洗し、乾燥後、減圧下で溶媒を
留去し、シリカゲルカラムクロマトグラフィー（ＹＭ
Ｃ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
510dを470.5mg （収率81.2％）取得した。The reaction mixture was washed with water and dried, and then the solvent was distilled off under reduced pressure.
C, purified with CHCl 3 -MeOH 50: 1)
470.5 mg (81.2% yield) of 510d was obtained.
【０６１９】ＲF 0.63 (CHCl3 -MeOH 10:1) 。R F 0.63 (CHCl 3 -MeOH 10: 1).
【０６２０】［α］D 28 -37.4°(c 1.03,CHCl3 ) 。[Α] D 28 -37.4 ° (c 1.03, CHCl 3 ).
【０６２１】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.13(d,3H,J=6.6)，1.42(s,9H)，1.98，1.99，2.05，2.
06，2.07，2.08，2.15，2.16(s,3H×11) ，4.51， 4.53
(d,1H×2,J=8.0)，5.28(d,1H,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.13 (d, 3H, J = 6.6), 1.42 (s, 9H), 1.98, 1.99, 2.05, 2.
06, 2.07, 2.08, 2.15, 2.16 (s, 3H × 11), 4.51, 4.53
(d, 1H × 2, J = 8.0), 5.28 (d, 1H, J = 3.4).
【０６２２】IR(KBr) ：cm-1 1749，1655，1371，1229，1061。IR (KBr): cm -1 1749, 1655, 1371, 1229, 1061.
【０６２３】化合物508ab(306.4mg)にＴＦＡ（３ml）を
加え、室温で２時間攪拌後、減圧下ＴＦＡを留去した残
渣のＣＨ2 Ｃｌ2 （３ml）及びＮＥｔ3 (300μｌ) の溶
液に、化合物507aL(184.2mg)のＣＨ2 Ｃｌ2 （８ml）溶
液にＨＯ−Ｓｕ(41.4mg)及びＤＣＣ(81mg)を加え、室温
で３時間攪拌した後濾過して得られた濾液を加え、室温
で４時間攪拌して反応させた。[0623] TFA and (3 ml) was added to the compound 508ab (306.4mg), after stirring for 2 hours at room temperature, to a solution of of CH 2 Cl 2 the residue was evaporated under reduced pressure TFA (3 ml) and NEt 3 (300 [mu] l), compound 507aL the CH 2 Cl 2 (8ml) was added HO-Su of (184.2mg) (41.4mg) and DCC (81 mg) was added, the filtrate obtained by filtration after stirring for 3 hours at room temperature was added, at room temperature The reaction was carried out by stirring for 4 hours.
【０６２４】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ナカラ
イ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
510eを319.1mg （収率70.6％）取得した。The reaction mixture was washed with water, dried, evaporated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (Nacalai, CHCl 3 -MeOH 50: 1) to give the compound.
319.1 mg (yield 70.6%) of 510e was obtained.
【０６２５】ＲF 0.78 (CHCl3 -MeOH 10:1) 。R F 0.78 (CHCl 3 -MeOH 10: 1).
【０６２６】［α］D 28 -71.3°(c 0.77,CHCl3 ) 。[Α] D 28 -71.3 ° (c 0.77, CHCl 3 ).
【０６２７】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.12， 1.14(d,3H×2,J=6.6)，1.43(s,9H)，1.99，2.0
0，2.05，2.07，2.08，2.09， 2.16(s,3H×10) ，4.52
(d,1H,J=8.1)，5.26， 5.29(d,1H×2,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.12, 1.14 (d, 3H × 2, J = 6.6), 1.43 (s, 9H), 1.99, 2.0
0, 2.05, 2.07, 2.08, 2.09, 2.16 (s, 3H × 10), 4.52
(d, 1H, J = 8.1), 5.26, 5.29 (d, 1H × 2, J = 3.4).
【０６２８】IR(KBr) ：cm-1 1749，1657，1371，1229，1061。IR (KBr): cm -1 1749, 1657, 1371, 1229, 1061.
【０６２９】(t) 化合物511c、511d及び511eの合成 化合物510c(250.0mg) にＴＦＡ（３ml）を加え室温で１
時間攪拌後、減圧下ＴＦＡを留去し、残渣にＣＨ2 Ｃｌ
2 （２ml）、ＮＥｔ3 (300μｌ）及びＰａｌ−ＯＳｕ
（67.6mg）を加え室温で５時間攪拌して反応させた。 (T) Synthesis of Compounds 511c, 511d and 511e To compound 510c (250.0 mg) was added TFA (3 ml), and the mixture was added at room temperature for 1 hour.
After stirring for an hour, TFA was distilled off under reduced pressure, and CH 2 Cl
2 (2 ml), NEt 3 (300 μl) and Pal-OSu
(67.6 mg) was added and the mixture was stirred and reacted at room temperature for 5 hours.
【０６３０】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
511cを204.6mg （収率74.7％）取得した。The reaction solution was washed with water and dried, and then the solvent was distilled off under reduced pressure.
k, CHCl 3 -MeOH 50: 1)
204.6 mg (yield 74.7%) of 511c was obtained.
【０６３１】ＲF 0.77 (CHCl3 -MeOH 10:1) 。R F 0.77 (CHCl 3 -MeOH 10: 1).
【０６３２】［α］D 28 -40.5°(c 0.97,CHCl3 ) 。[Α] D 28 -40.5 ° (c 0.97, CHCl 3 ).
【０６３３】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.11(d,3H,J=6.6)，1.98，1.99，2.
02，2.05，2.06，2.08，2.15， 2.16(s,3H×11) ， 4.5
2(d,1H×2,J=7.8)，5.25(d,1H,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.11 (d, 3H, J = 6.6), 1.98, 1.99, 2.
02, 2.05, 2.06, 2.08, 2.15, 2.16 (s, 3H × 11), 4.5
2 (d, 1H × 2, J = 7.8), 5.25 (d, 1H, J = 3.2).
【０６３４】IR(KBr) ：cm-1 1751，1639，1371，1229，1068。IR (KBr): cm -1 1751, 1639, 1371, 1229, 1068.
【０６３５】化合物510d(202.5mg) にＴＦＡ(1.5ml) を
加え室温で 1.5時間攪拌後、減圧下ＴＦＡを留去し、残
渣にＣＨ2 Ｃｌ2 （３ml）、ＮＥｔ3 (500μｌ）及びＰ
ａｌ−ＯＳｕ(54mg)を加え、室温で４時間攪拌して反応
させた。To compound 510d (202.5 mg) was added TFA (1.5 ml), and the mixture was stirred at room temperature for 1.5 hours. TFA was distilled off under reduced pressure, and CH 2 Cl 2 (3 ml), NEt 3 (500 μl) and P
Al-OSu (54 mg) was added and reacted at room temperature with stirring for 4 hours.
【０６３６】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトクラフィー（ナカラ
イ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
511dを188.4mg （収率84.9％）取得した。The reaction mixture was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Nacalai, CHCl 3 -MeOH 50: 1) to give the compound.
188.4 mg (yield 84.9%) of 511d was obtained.
【０６３７】ＲF 0.90 (CHCl3 -MeOH 10:1) 。R F 0.90 (CHCl 3 -MeOH 10: 1).
【０６３８】［α］D 25 -37.5°(c 0.77,CHCl3 ) 。[Α] D 25 -37.5 ° (c 0.77, CHCl 3 ).
【０６３９】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.13(d,3H,J=6.6)，1.99，2.05，2.
07，2.09， 2.16(s,3H×11) ，4.51，4.52(d,1AH×2,J=
7.8)，5.28(d,1H,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.13 (d, 3H, J = 6.6), 1.99, 2.05, 2.
07, 2.09, 2.16 (s, 3H × 11), 4.51, 4.52 (d, 1AH × 2, J =
7.8), 5.28 (d, 1H, J = 3.2).
【０６４０】IR(KBr) ：cm-1 1751，1641，1371，1230，1061。IR (KBr): cm -1 1751, 1641, 1371, 1230, 1061.
【０６４１】化合部510e(198.9mg) にＴＦＡ(1.5ml) を
加え室温で１時間攪拌後、減圧下ＴＦＡを留去し、残渣
にＣＨ2 Ｃｌ2 （２ml）、ＮＥｔ3 (400μｌ）及びＰａ
ｌ−ＯＳｕ(56mg)を加え、室温で３時間攪拌して反応さ
せた。To the compound (510e, 198.9 mg) was added TFA (1.5 ml), and the mixture was stirred at room temperature for 1 hour. TFA was distilled off under reduced pressure, and CH 2 Cl 2 (2 ml), NEt 3 (400 μl) and Pa
l-OSu (56 mg) was added, and the mixture was stirred and reacted at room temperature for 3 hours.
【０６４２】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ナカラ
イ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
511eを177.6mg （収率81.2％）取得した。The reaction mixture was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Nacalai, CHCl 3 -MeOH 50: 1) to give the compound.
177.6 mg (yield 81.2%) of 511e was obtained.
【０６４３】ＲF 0.74 (CHCl3 -MeOH 10:1) 。R F 0.74 (CHCl 3 -MeOH 10: 1).
【０６４４】［α］D 27 -77.5°(c 1.00,CHCl3 ) 。[Α] D 27 -77.5 ° (c 1.00, CHCl 3 ).
【０６４５】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.12， 1.14(d,3H×2,J=6.6)，1.9
9，2.00，2.05，2.06，2.07，2.09，2.15， 2.16(s,3H
×10) ，4.53(d,1H,J=8.1)，5.25， 5.29(d,1H×2,J=3.
4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.12, 1.14 (d, 3H × 2, J = 6.6), 1.9
9, 2.00, 2.05, 2.06, 2.07, 2.09, 2.15, 2.16 (s, 3H
× 10), 4.53 (d, 1H, J = 8.1), 5.25, 5.29 (d, 1H × 2, J = 3.
Four).
【０６４６】IR(KBr) ：cm-1 1751，1643，1371，1229，1069。IR (KBr): cm -1 1751, 1643, 1371, 1229, 1069.
【０６４７】(u) 化合物511c′、511d′及び511e′の合
成 化合物511c (195.2mg)のＭｅＯＨ（３ml）及びＣＨＣｌ
3 （２ml）の混合溶媒溶液に、28％ ＮａＯＭｅ ｉｎ
ＭｅＯＨ（20μｌ）を加え、室温で 1.5時間攪拌して
反応させた。 (U) Compound 511c ′, 511d ′ and 511e ′
MeOH adult compound 511c (195.2mg) (3ml) and CHCl
3 (2 ml) in a mixed solvent solution, 28% NaOMe in
MeOH (20 μl) was added, and the mixture was stirred and reacted at room temperature for 1.5 hours.
【０６４８】反応液から減圧下溶媒を留去し、白色粉末
として化合物511c′を137.3mg （収率99.5％）取得し
た。The solvent was distilled off from the reaction solution under reduced pressure to obtain 137.3 mg (yield 99.5%) of compound 511c 'as a white powder.
【０６４９】ＲF 0.25 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.25 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０６５０】［α］D 27 -29.4°(c 1.01,CHCl3 -MeOH
-H2 O 10:10:3)。[Α] D 27 -29.4 ° (c 1.01, CHCl 3 -MeOH
-H 2 O 10: 10: 3 ).
【０６５１】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)，1.25(d,3H,J=6.6)，4.26， 4.27(d,
1H×2,J=7.8)，4.28(1H)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3H, J = 6.6), 4.26,4.27 (d,
1H × 2, J = 7.8), 4.28 (1H).
【０６５２】IR(KBr) ：cm-1 3431，1637，1074。IR (KBr): cm - 13431, 1637, 1074.
【０６５３】上記合成反応を化合物511cの代わりに化合
物511d (178.3mg)を用いて同様に行い、白色粉末として
化合物511d′を116.9mg （収率92.8％）取得した。The above synthesis reaction was carried out similarly using compound 511d (178.3 mg) instead of compound 511c, to obtain 116.9 mg (yield 92.8%) of compound 511d ′ as a white powder.
【０６５４】ＲF 0.47 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.47 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０６５５】［α］D 26 -27.0°(c 0.99,CHCl3 -MeOH
-H2 O 10:10:3)。[Α] D 26 -27.0 ° (c 0.99, CHCl 3 -MeOH
-H 2 O 10: 10: 3 ).
【０６５６】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)，1.25(d,3H,J=6.6)，4.26， 4.28(d,
1H×2,J=7.6)，4.81(d,1H,J=2.0) 。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3H, J = 6.6), 4.26,4.28 (d,
1H × 2, J = 7.6), 4.81 (d, 1H, J = 2.0).
【０６５７】IR(KBr) ：cm-1 3435，1636，1076。[0657] IR (KBr): cm -1 3435,1636,1076 .
【０６５８】前記合成反応を化合物511cの代わりに化合
物511e (169.4mg)を用いて同様に行い、白色粉末として
化合物511e′を119.5mg （収率97.5％）取得した。The above synthesis reaction was carried out similarly using compound 511e (169.4 mg) instead of compound 511c, to obtain 119.5 mg of compound 511e ′ (yield 97.5%) as a white powder.
【０６５９】ＲF 0.64 (CHCl3 -MeOH -H2 O 10:5:1) 。R F 0.64 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０６６０】［α］D 26 -57.8°(c 1.00,CHCl3 -MeOH
-H2 O 10:10:3)。[Α] D 26 -57.8 ° (c 1.00, CHCl 3 -MeOH
-H 2 O 10: 10: 3 ).
【０６６１】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)， 1.23(d,3H×2,J=6.6)，4.26(d,1H,
J=7.6)，4.81， 4.82(d,1H×2,J=1.5)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.23 (d, 3H × 2, J = 6.6), 4.26 (d, 1H,
J = 7.6), 4.81, 4.82 (d, 1H × 2, J = 1.5).
【０６６２】IR(KBr) ：cm-1 3450，1639，1076。[0662] IR (KBr): cm -1 3450,1639,1076 .
【０６６３】(v) 化合物517a及び517bの合成 化合物501a(1.362ｇ）及びＮＥｔ3 (327mg) のＣＨ2 Ｃ
ｌ2 (10ml)溶液に、化合物516 Ｂｏｃ−α−ｂｅｎｚｙ
ｌ Ｄ−Ｇｌｕｔａｍａｔｅ（1.00ｇ）のＣＨ2 Ｃｌ2
(10ml)溶液にＨＯ−Ｓｕ (375mg)及びＤＣＣ (673mg)を
加え、室温で２時間攪拌下後濾過して得られた濾液を加
え、室温で３時間攪拌して反応させた。 (V) Synthesis of Compounds 517a and 517b CH 2 C of compound 501a (1.362 g) and NEt 3 (327 mg)
Compound 516 Boc-α-benzyl was added to l 2 (10 ml) solution.
l D-Glutamate (1.00 g) CH 2 Cl 2
(10 ml), HO-Su (375 mg) and DCC (673 mg) were added to the solution, and the mixture was stirred at room temperature for 2 hours, and then filtered.
【０６６４】反応液を水洗し、乾燥後減圧下溶媒を留去
し、シリカゲルカラムクロマトグラフィー（ナカライ，
ＣＨＣｌ3 −ＭｅＯＨ 100：１）で精製して化合物517a
を 1.157ｇ（収率59.8％）取得した。The reaction mixture was washed with water, dried, and the solvent was distilled off under reduced pressure.
Purification with CHCl 3 -MeOH 100: 1) gives compound 517a.
1.157 g (59.8% yield) was obtained.
【０６６５】ＲF 0.58 (CHCl3 -MeOH 25:1) 。R F 0.58 (CHCl 3 -MeOH 25: 1).
【０６６６】［α］D 25 -75.2°(c 0.90,CHCl3 ) 。[Α] D 25 -75.2 ° (c 0.90, CHCl 3 ).
【０６６７】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.12(d,3H,J=6.6)，1.43(s,9H)，1.99，2.06， 2.17(s,
3H×3)，5.29(dd,1H,J=1.0,3.4) ，7.36(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.12 (d, 3H, J = 6.6), 1.43 (s, 9H), 1.99, 2.06, 2.17 (s,
3H × 3), 5.29 (dd, 1H, J = 1.0, 3.4), 7.36 (5H).
【０６６８】IR(KBr) ：cm-1 1749，1716，1660，1371，1254，1229，1166，1065，10
53。IR (KBr): cm -1 1749, 1716, 1660, 1371, 1254, 1229, 1166, 1065, 10
53.
【０６６９】化合物501aの代りに化合物501b(1.518ｇ）
を用いた以外上記と同様に行い、化合物517bを 1.252ｇ
（収率59.4％）取得した。Compound 501b (1.518 g) instead of compound 501a
Compound 517b was obtained in the same manner as above except that
(59.4% yield).
【０６７０】ＲF 0.51 (CHCl3 -MeOH 25:1) 。R F 0.51 (CHCl 3 -MeOH 25: 1).
【０６７１】［α］D 26 +1.20°(c 1.00,CHCl3 ) 。[Α] D 26 + 1.20 ° (c 1.00, CHCl 3 ).
【０６７２】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.43(s,9H)，1.99，2.04，2.05， 2.16(s,3H×4)，4.48
(dd,1H,J=8.1) ，7.36(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.43 (s, 9H), 1.99, 2.04, 2.05, 2.16 (s, 3H × 4), 4.48
(dd, 1H, J = 8.1), 7.36 (5H).
【０６７３】IR(KBr) ：cm-1 1753，1715，1664，1369，1227，1169，1076，1057。IR (KBr): cm -1 1753, 1715, 1664, 1369, 1227, 1169, 1076, 1057.
【０６７４】(w) 化合物518a及び518bの合成 化合物517a(522.0mg) にＴＦＡ（４ml）を加え、室温で
１時間攪拌後、減圧下ＴＦＡを留去した残渣のＣＨ2 Ｃ
ｌ2 （５ml）及びＮＥｔ3 (700μｌ）の混合溶媒溶液
に、化合物507aL(450.0mg)のＣＨ2 Ｃｌ2 (15ml)溶液に
ＨＯ−Ｓｕ(101mg) 及びＤＣＣ(198mg) を加え、室温で
２時間攪拌した後濾過して得られた濾液を加え、室温で
３時間攪拌して反応させた。 (W) Synthesis of Compounds 518a and 518b TFA (4 ml) was added to Compound 517a (522.0 mg), and the mixture was stirred at room temperature for 1 hour, and CH 2 C of the residue obtained by removing TFA under reduced pressure was added.
HO-Su (101 mg) and DCC (198 mg) were added to a solution of compound 507aL (450.0 mg) in CH 2 Cl 2 (15 ml) to a mixed solvent solution of l 2 (5 ml) and NEt 3 (700 μl). After stirring for an hour, the filtrate obtained by filtration was added, and the mixture was stirred and reacted at room temperature for 3 hours.
【０６７５】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ナカラ
イ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
518aを794.9mg （収率90.6％）取得した。The reaction mixture was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Nacalai, CHCl 3 -MeOH 50: 1) to give the compound.
794.9 mg (yield 90.6%) of 518a was obtained.
【０６７６】ＲF 0.74 (CHCl3 -MeOH 10:1) 。R F 0.74 (CHCl 3 -MeOH 10: 1).
【０６７７】［α］D 27 -77.9°(c 0.99,CHCl3 ) 。[Α] D 27 -77.9 ° (c 0.99, CHCl 3 ).
【０６７８】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.11， 1.14(d,3H×2,J=6.6)，1.44(s,9H)，1.99，2.0
5，2.08， 2.16(s,3H×6)，5.27， 5.29(d,1H×2,J=3.
4)，7.36(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.11, 1.14 (d, 3H × 2, J = 6.6), 1.44 (s, 9H), 1.99, 2.0
5, 2.08, 2.16 (s, 3H × 6), 5.27, 5.29 (d, 1H × 2, J = 3.
4), 7.36 (5H).
【０６７９】IR(KBr) ：cm-1 1747，1653，1371，1231，1166，1067。IR (KBr): cm -1 1747, 1653, 1371, 1231, 1166, 1067.
【０６８０】化合物517b(1.084ｇ）にＴＦＡ（６ml）を
加え室温で１時間攪拌後、減圧下ＴＦＡを留去した残渣
のＣＨ2 Ｃｌ2 (15ml)及びＮＥｔ3 （１ml）の混合溶媒
溶液に、化合物507aL(858.0mg)のＣＨ2 Ｃｌ2 (20ml)溶
液にＨＯ−Ｓｕ(193mg) 及びＤＣＣ（377mg)を加え、室
温で２時間攪拌した後濾過して得られた濾液を加え、室
温で時間攪拌して反応させた。TFA (6 ml) was added to compound 517b (1.084 g), and the mixture was stirred at room temperature for 1 hour. TFA was distilled off under reduced pressure, and the residue was added to a mixed solvent solution of CH 2 Cl 2 (15 ml) and NEt 3 (1 ml). To a solution of compound 507aL (858.0 mg) in CH 2 Cl 2 (20 ml) were added HO-Su (193 mg) and DCC (377 mg), the mixture was stirred at room temperature for 2 hours, and the filtrate obtained by filtration was added. The mixture was stirred for an hour to react.
【０６８１】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ナカラ
イ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
518bを1.437ｇ（収率81.6％）取得した。The reaction mixture was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Nacalai, CHCl 3 -MeOH 50: 1) to give the compound.
1.437 g (81.6% yield) of 518b was obtained.
【０６８２】ＲF 0.34 (CHCl3 -MeOH 25:1) 。R F 0.34 (CHCl 3 -MeOH 25: 1).
【０６８３】［α］D 27 -34.4°(c 0.99,CHCl3 ) 。[Α] D 27 -34.4 ° (c 0.99, CHCl 3 ).
【０６８４】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 1.13(d,3H,J=6.6)，1.44(s,9H)，1.96，1.99，2.04，2.
05，2.07，2.15， 2.16(s,3H×7)，4.48(d,1H,J=8.1)，
5.33(d,1H,J=3.4)，7.37(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 1.13 (d, 3H, J = 6.6), 1.44 (s, 9H), 1.96, 1.99, 2.04, 2.
05, 2.07, 2.15, 2.16 (s, 3H × 7), 4.48 (d, 1H, J = 8.1),
5.33 (d, 1H, J = 3.4), 7.37 (5H).
【０６８５】IR(KBr) ：cm-1 1749，1670，1371，1229，1169，1063。IR (KBr): cm -1 1749, 1670, 1371, 1229, 1169, 1063.
【０６８６】(x) 化合物519a及び519bの合成 化合物518a(466.9mg) にＴＦＡ（４ml）を加え、室温で
1.5時間攪拌後、減圧下ＴＦＡを留去した後の残渣にＣ
Ｈ2 Ｃｌ2 （６ml）、ＮＥｔ3 (600μｌ）及びＰａｌ−
ＯＳｕ(165mg) を加え、室温で 2.5時間攪拌して反応さ
せた。 (X) Synthesis of Compounds 519a and 519b To compound 518a (466.9 mg) was added TFA (4 ml), and the mixture was added at room temperature.
After stirring for 1.5 hours, TFA was distilled off under reduced pressure.
H 2 Cl 2 (6 ml), NEt 3 (600 μl) and Pal-
OSu (165 mg) was added, and the mixture was stirred and reacted at room temperature for 2.5 hours.
【０６８７】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ナカラ
イ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
519aを364.1mg（収率69.3％）取得した。The reaction mixture was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Nacalai, CHCl 3 -MeOH 50: 1) to give the compound.
364.1 mg (69.3% yield) of 519a was obtained.
【０６８８】ＲF 0.38 (CHCl3 -MeOH 25:1) 。R F 0.38 (CHCl 3 -MeOH 25: 1).
【０６８９】［α］D 24 -83.3°(c 1.00,CHCl3 ) 。[Α] D 24 -83.3 ° (c 1.00, CHCl 3 ).
【０６９０】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.12， 1.13(d,3H×2,J=6.8)，1.9
6，1.99，2.05，2.06， 2.16(s,3H×6)，5.27， 5.28
(d,1H×2,J=3.4)，7.36(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.12, 1.13 (d, 3H × 2, J = 6.8), 1.9
6, 1.99, 2.05, 2.06, 2.16 (s, 3H x 6), 5.27, 5.28
(d, 1H × 2, J = 3.4), 7.36 (5H).
【０６９１】IR(KBr) ：cm-1 1749，1639，1371，1229，1069。IR (KBr): cm -1 1749, 1639, 1371, 1229, 1069.
【０６９２】化合物518b(1.004ｇ）にＴＦＡ（７ml）を
加え、室温で 1.5時間攪拌後、減圧下ＴＦＡを留去した
後の残渣にＣＨ2 Ｃｌ2 (10ml)、ＮＥｔ3 (1,2ml) 及び
Ｐａｌ−ＯＳｕ(330mg) を加え、室温で16時間攪拌して
反応させた。To compound 518b (1.004 g) was added TFA (7 ml), and the mixture was stirred at room temperature for 1.5 hours, and after removing TFA under reduced pressure, CH 2 Cl 2 (10 ml) and NEt 3 (1.2 ml) were added to the residue. And Pal-OSu (330 mg) were added, and the mixture was stirred and reacted at room temperature for 16 hours.
【０６９３】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ＹＭＣ，
ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物519b
を966.2mg （収率85.9％）取得した。The reaction mixture was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC,
Purification with CHCl 3 -MeOH 50: 1) gave compound 519b.
Was obtained in an amount of 966.2 mg (85.9% yield).
【０６９４】ＲF 0.59 (CHCl3 -MeOH 20:1) 。R F 0.59 (CHCl 3 -MeOH 20: 1).
【０６９５】［α］D 28 -36.3°(c 1.01,CHCl3 ) 。[Α] D 28 -36.3 ° (c 1.01, CHCl 3 ).
【０６９６】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.13(d,3H,J=6.6)，1.96，1.99，2.
03，2.04，2.05，2.14，2.16(s,3H×7)，4.48(d,1H,J=
8.1)，5.29(d,1H,J=3.4)，7.36(5H)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.13 (d, 3H, J = 6.6), 1.96, 1.99, 2.
03, 2.04, 2.05, 2.14, 2.16 (s, 3H × 7), 4.48 (d, 1H, J =
8.1), 5.29 (d, 1H, J = 3.4), 7.36 (5H).
【０６９７】IR(KBr) ：cm-1 1751，1637，1371，1227，1169，1065。IR (KBr): cm -1 1751, 1637, 1371, 1227, 1169, 1065.
【０６９８】(y) 化合物520a及び520bの合成 化合物519a(363.8mg) のＥｔＯＨ(50ml)及びＴＨＦ（４
ml）の混合溶媒溶液に10％ Ｐｄ／Ｃ36mgを加えＰａｒ
ｒで１時間接触還元した後触媒を濾別し、濾液から減圧
下溶媒を留去して脱ベンジル体を337.1mg （収率 100
％）取得した。 (Y) Synthesis of Compounds 520a and 520b Compound 519a (363.8 mg) of EtOH (50 ml) and THF (4
Par) was added to the mixed solvent solution of
After 1 hour of catalytic reduction with r, the catalyst was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give 337.1 mg of the debenzylated product (yield 100
%) Acquired.
【０６９９】この化合物のＭｅＯＨ(10ml)溶液に、氷冷
下トリメチルシリルジアゾメタンの10％ヘキサン溶液
（４ml）を加え、20分間攪拌して反応させた。To a solution of this compound in MeOH (10 ml) was added a 10% hexane solution of trimethylsilyldiazomethane (4 ml) under ice-cooling, and the mixture was stirred and reacted for 20 minutes.
【０７００】反応液から減圧下溶媒を留去し、シリカゲ
ルカラムクロマトグラフィー（ＹＭＣ，ＣＨＣｌ3 −Ｍ
ｅＯＨ 50：１）で精製して化合物520aを302.4mg （収
率88.6％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and silica gel column chromatography (YMC, CHCl 3 -M
Purification with MeOH 50: 1) gave 302.4 mg (yield 88.6%) of compound 520a.
【０７０１】ＲF 0.35 (CHCl3 -MeOH 25:1) 。R F 0.35 (CHCl 3 -MeOH 25: 1).
【０７０２】［α］D 26 -83.4°(c 1.00,CHCl3 ) 。[Α] D 26 -83.4 ° (c 1.00, CHCl 3 ).
【０７０３】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.13， 1.14(d,3H×2,J=6.6)，1.9
8，1.99，2.05，2.06， 2.16(s,3H×6)，3.76(s,3H)，
5.28(d,1H×2,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.13, 1.14 (d, 3H × 2, J = 6.6), 1.9
8, 1.99, 2.05, 2.06, 2.16 (s, 3H x 6), 3.76 (s, 3H),
5.28 (d, 1H × 2, J = 3.4).
【０７０４】IR(KBr) ：cm-1 1749，1647，1373，1229，1067。IR (KBr): cm -1 1749, 1647, 1373, 1229, 1067.
【０７０５】化合物519b(937.9mg) のＥｔＯＨ(100ml)
及びＴＨＦ(10ml)の混合溶媒溶液に10％ Ｐｄ／Ｃ(94m
g)を加えＰａｒｒで１時間接触還元した後触媒を濾去
後、濾液から減圧下溶媒を留去して脱ベンジル体を873.
1mg （収率 100％）取得した。Compound 519b (937.9 mg) in EtOH (100 ml)
And 10% Pd / C (94m3) in a mixed solvent solution of
g) was added thereto, and the mixture was subjected to catalytic reduction with Parr for 1 hour. After removing the catalyst by filtration, the solvent was distilled off from the filtrate under reduced pressure to obtain 873.
1 mg (100% yield) was obtained.
【０７０６】この化合物の一部(420.8mg) のＭｅＯＨ
（６ml）溶液に、氷冷下10％ ＴＭＳ−ＣＨ2 Ｎ2 ｉ
ｎ Ｈｅｘａｎｅ(3.5ml) を加え、20分間攪拌して反応
させた。A portion of this compound (420.8 mg) in MeOH
(6 ml) was added, under ice-cooling 10% TMS-CH 2 N 2 i
n Hexane (3.5 ml) was added, and the mixture was stirred and reacted for 20 minutes.
【０７０７】反応液から減圧下溶媒を留去し、シリカゲ
ルカラムクロマトグラフィー（ＹＭＣ，ＣＨＣｌ3 −Ｍ
ｅＯＨ 75：１）で精製して化合物520bを373.5mg （収
率87.7％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was subjected to silica gel column chromatography (YMC, CHCl 3 -M
Purification with MeOH 75: 1) afforded 373.5 mg of compound 520b (87.7% yield).
【０７０８】ＲF 0.34 (CHCl3 -MeOH 25:1) 。R F 0.34 (CHCl 3 -MeOH 25: 1).
【０７０９】［α］D 26 -38.2°(c 0.99,CHCl3 ) 。[Α] D 26 -38.2 ° (c 0.99, CHCl 3 ).
【０７１０】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.14(d,3H,J=6.6)，1.98，1.99，2.
05，2.06， 2.16(s,3H×7)，3.75(s,3H)，4.49(d,1H,J=
7.8)，5.28(d,1H,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.14 (d, 3H, J = 6.6), 1.98, 1.99, 2.
05, 2.06, 2.16 (s, 3H × 7), 3.75 (s, 3H), 4.49 (d, 1H, J =
7.8), 5.28 (d, 1H, J = 3.4).
【０７１１】IR(KBr) ：cm-1 1751，1647，1371，1229，1070。IR (KBr): cm -1 1751, 1647, 1371, 1229, 1070.
【０７１２】(z) 化合物521a及び521bの合成 化合物519a(240.8mg) のＥｔＯＨ(33ml)及びＴＨＦ(2.6
ml) の混合溶媒溶液に10％ Ｐｄ／Ｃ(24mg)を加えＰａ
ｒｒで１時間接触還元した後触媒を濾別し、濾液から減
圧下溶媒を留去し、取得した残渣のＣＨ2 Ｃｌ2 （５m
l）溶液に、ＨＯ−Ｓｕ(24,7mg)及びＤＣＣ(48.3mg)を
加え、室温で２時間攪拌後、 2.0Ｍ ＮＨ3 ｉｎ Ｍ
ｅＯＨ(0.5ml) を加え室温で２時間攪拌して反応させ
た。 (Z) Synthesis of Compounds 521a and 521b Compound 519a (240.8 mg) of EtOH (33 ml) and THF (2.6
10% Pd / C (24 mg) to the mixed solvent solution of
After catalytic reduction for 1 hour at rr, the catalyst was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was CH 2 Cl 2 (5 m 2 ).
l) HO-Su (24,7 mg) and DCC (48.3 mg) were added to the solution, and the mixture was stirred at room temperature for 2 hours, and then 2.0 M NH 3 in M was added.
MeOH (0.5 ml) was added, and the mixture was stirred and reacted at room temperature for 2 hours.
【０７１３】反応液を水洗し、乾燥後、減圧下に溶媒を
留去し、シリカゲルカラムクロマトグラフィー（ＹＭ
Ｃ，ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物
521aを171.8mg （収率77.0％）取得した。The reaction mixture was washed with water, dried, and then the solvent was distilled off under reduced pressure.
C, purified with CHCl 3 -MeOH 50: 1)
171.8 mg (77.0% yield) of 521a was obtained.
【０７１４】ＲF 0.60 (CHCl3 -MeOH 10:1) 。R F 0.60 (CHCl 3 -MeOH 10: 1).
【０７１５】［α］D 27 -93.4°(c 1.00,CHCl3 ) 。[Α] D 27 -93.4 ° (c 1.00, CHCl 3 ).
【０７１６】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.88(t,3H,J=6.8)，1.14， 1.15(d,3H×2,J=6.6)，1.9
9，2.07，2.16， 2.17(s,3H×6)，5.26， 5.29(d,1H×
2,J=3.2)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.88 (t, 3H, J = 6.8), 1.14, 1.15 (d, 3H × 2, J = 6.6), 1.9
9, 2.07, 2.16, 2.17 (s, 3H × 6), 5.26, 5.29 (d, 1H ×
2, J = 3.2).
【０７１７】IR(KBr) ：cm-1 1749，1641，1371，1248，1229，1069。IR (KBr): cm -1 1749, 1641, 1371, 1248, 1229, 1069.
【０７１８】化合物519b(937.9mg) のＥｔＯＨ(100ml)
及びＴＨＦ(10ml)の混合溶媒溶液に、10％ Ｐｄ／Ｃ(9
4mg)を加えＰａｒｒで１時間接触還元した後触媒を濾別
し、濾液から減圧下溶媒を留去し脱ベンジル体を873.1m
g （収率 100％）取得した。Compound 519b (937.9 mg) in EtOH (100 ml)
And 10% Pd / C (9 mL) in a mixed solvent solution of
4 mg), and the mixture was subjected to catalytic reduction with Parr for 1 hour, and the catalyst was separated by filtration.
g (100% yield).
【０７１９】この化合物の一部(452.3mg) のＣＨ2 Ｃｌ
2 （５ml）溶液に、ＨＯ−Ｓｕ(146.3mg) 及びＤＣＣ(9
3.0mg)を加え、室温で２時間攪拌後、 2.0Ｍ ＮＨ3
ｉｎＭｅＯＨ（１ml）を加え、室温で17時間撹拌して反
応させた。A part (452.3 mg) of this compound was CH 2 Cl
In 2 (5 ml) solution, HO-Su (146.3mg) and DCC (9
3.0 mg) was added thereto, followed by stirring for 2 hours at room temperature, 2.0 M NH 3
InMeOH (1 ml) was added, and the mixture was stirred at room temperature for 17 hours to react.
【０７２０】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（ＹＭＣ，
ＣＨＣｌ3 −ＭｅＯＨ 50：１）で精製して化合物521b
を335.2mg （収率74.1％）取得した。The reaction mixture was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (YMC,
The compound 521b was purified by CHCl 3 -MeOH 50: 1).
Was obtained in an amount of 335.2 mg (74.1% yield).
【０７２１】ＲF 0.56 (CHCl3 -MeOH 10:1) 。R F 0.56 (CHCl 3 -MeOH 10: 1).
【０７２２】［α］D 26 -45.2°(c 1.00,CHCl3 ) 。[Α] D 26 -45.2 ° (c 1.00, CHCl 3 ).
【０７２３】 1H-NMR(CDCl3 ）：δ ppm，J in Hz 0.89(t,3H,J=6.8)，1.15(d,3H,J=6.6)，1.99，2.05，2.
06，2.07，2.16， 2.17(s,3H×7)，4.49(d,1H,J=7.8)，
5.26(d,1H,J=3.4)。 1 H-NMR (CDCl 3 ): δ ppm, J in Hz 0.89 (t, 3H, J = 6.8), 1.15 (d, 3H, J = 6.6), 1.99, 2.05, 2.
06, 2.07, 2.16, 2.17 (s, 3H × 7), 4.49 (d, 1H, J = 7.8),
5.26 (d, 1H, J = 3.4).
【０７２４】IR(KBr) ：cm-1 1751，1643，1371，1229，1070。IR (KBr): cm -1 1751, 1643, 1371, 1229, 1070.
【０７２５】(a′) 化合物521a′及び521b′の合成 化合物521a(169.3mg) のＭｅＯＨ（３ml）溶液に28％
ＮａＯＭｅ ｉｎ ＭｅＯＨ（10μl)を加え、室温で１
時間撹拌して反応させた。 (A ′) Synthesis of Compounds 521a ′ and 521b ′ 28% of a solution of Compound 521a (169.3 mg) in MeOH (3 ml) was added.
Add NaOMe in MeOH (10 μl) and add 1 at room temperature.
The mixture was stirred for an hour to react.
【０７２６】減圧下溶媒を留去し、白色粉末として化合
物521a′を118.3mg(収率89.6％）取得した。The solvent was distilled off under reduced pressure to obtain 118.3 mg (yield: 89.6%) of compound 521a 'as a white powder.
【０７２７】ＲF 0.64 (CHCl3 -MeOH- H2 O 10:5:1) 。R F 0.64 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０７２８】［α］D 27−70.6°(c 0.51,CHCl3 -MeOH-
H2 O 10:10:3)。[Α] D 27 -70.6 ° (c 0.51, CHCl 3 -MeOH-
H 2 O 10: 10: 3 ).
【０７２９】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)， 1.25(d,3H×2,J=6.6)，4.81，4.82
(d,1H,J=3.4)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.25 (d, 3H × 2, J = 6.6), 4.81,4.82
(d, 1H, J = 3.4).
【０７３０】IR(KBr) ：cm-1 3398，1639，1076。IR (KBr): cm - 13398, 1639, 1076.
【０７３１】化合物521b(308.1mg) のＭｅＯＨ（７ml）
溶液に28％ ＮａＯＭｅ ｉｎ ＭｅＯＨ（10μl)を加
え、室温で１．５時間撹拌して反応させた。Compound 521b (308.1 mg) in MeOH (7 ml)
To the solution was added 28% NaOMe in MeOH (10 μl), and the mixture was stirred and reacted at room temperature for 1.5 hours.
【０７３２】反応液から減圧下溶媒を留去し、白色粉末
として化合物521b′を232.2mg(収率99.8％）取得した。The solvent was distilled off from the reaction solution under reduced pressure to obtain 232.2 mg (yield 99.8%) of compound 521b 'as a white powder.
【０７３３】ＲF 0.61 (CHCl3 -MeOH- H2 O 10:5:1) 。R F 0.61 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０７３４】［α］D 27−32.9°(c 0.556, CHCl3 -MeO
H- H2 O 10:10:3)。[Α] D 27 -32.9 ° (c 0.556, CHCl 3 -MeO
H- H 2 O 10: 10: 3).
【０７３５】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.6)，1.24(d,3H,J=6.6)，4.26(d,1H,J=7.
6)，4.81(d,1H,J=2.9)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.6), 1.24 (d, 3H, J = 6.6), 4.26 (d, 1H, J = 7.
6), 4.81 (d, 1H, J = 2.9).
【０７３６】IR(KBr) ：cm-1 3400，1661，1637，1070。IR (KBr): cm -1 3400,1661,1637,1070.
【０７３７】(b′) 化合物520a′及び520b′の合成 化合物520a(298.0mg) のＭｅＯＨ（５ml）溶液に28％
ＮａＯＭｅ ｉｎ ＭｅＯＨ（20μl)を加え、室温で１
時間撹拌して反応させた。 (B ') Synthesis of Compounds 520a' and 520b '28% of a solution of Compound 520a (298.0 mg) in MeOH (5 mL) was added.
Add NaOMe in MeOH (20 μl) and add 1 at room temperature.
The mixture was stirred for an hour to react.
【０７３８】反応液から減圧下溶媒を留去し、シリカゲ
ルカラムクロマトグラフィー（ＹＭＣ，ＣＨＣｌ3 −Ｍ
ｅＯＨ ５：１）で精製して白色粉末として化合物520
a′を137.6mg(収率59.6％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was subjected to silica gel column chromatography (YMC, CHCl 3 -M
Purified with MeOH 5: 1) to give compound 520 as a white powder.
a ′ was obtained in an amount of 137.6 mg (yield 59.6%).
【０７３９】ＲF 0.86 (CHCl3 -MeOH 2:1)。R F 0.86 (CHCl 3 -MeOH 2: 1).
【０７４０】［α］D 28−71.3°(c 1.01,MeOH) 。[Α] D 28 -71.3 ° (c 1.01, MeOH).
【０７４１】 1H-NMR(CD3 OD) ：δ ppm，J in Hz 0.90(t,3H,J=6.8)，1.20， 1.21(d,3H×2,J=6.6)，4.7
6， 4.78(d,1H×2,J=2.2)。 1 H-NMR (CD 3 OD): δ ppm, J in Hz 0.90 (t, 3H, J = 6.8), 1.20, 1.21 (d, 3H × 2, J = 6.6), 4.7
6, 4.78 (d, 1H × 2, J = 2.2).
【０７４２】IR(KBr) ：cm-1 3400，1643，1078。[0742] IR (KBr): cm -1 3400,1643,1078 .
【０７４３】化合物520b(348.2mg) のＭｅＯＨ（７ml）
溶液に、28％ ＮａＯＭｅ ｉｎＭｅＯＨ（10μl)を加
え、室温で２時間撹拌して反応させた。Compound 520b (348.2 mg) in MeOH (7 ml)
To the solution was added 28% NaOMe in MeOH (10 μl), and the mixture was stirred and reacted at room temperature for 2 hours.
【０７４４】反応液から減圧下溶媒を留去し、シリカゲ
ルカラムクロマトグラフィ−（ＹＭＣ，ＣＨＣｌ3 −Ｍ
ｅＯＨ 25：10）で精製して白色粉末として化合物520
b′を187.5mg(収率71.0％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was subjected to silica gel column chromatography (YMC, CHCl 3 -M
Compound 520 as a white powder after purification with MeOH 25:10).
187.5 mg (yield 71.0%) of b 'was obtained.
【０７４５】ＲF 0.70 (CHCl3 -MeOH 2:1)。R F 0.70 (CHCl 3 -MeOH 2: 1).
【０７４６】［α］D 27−30.7°(c 0.505, CHCl3 -MeO
H- H2 O 10:10:3)。[Α] D 27 −30.7 ° (c 0.505, CHCl 3 -MeO
H- H 2 O 10: 10: 3).
【０７４７】 1H-NMR(CD3 OD) ：δ ppm，J in Hz 0.90(t,3H,J=6.8)，1.21(d,3H,J=6.6)，3.67(s,3H)，4.
24(d,1H,J=7.3)。 1 H-NMR (CD 3 OD): δ ppm, J in Hz 0.90 (t, 3H, J = 6.8), 1.21 (d, 3H, J = 6.6), 3.67 (s, 3H), 4.
24 (d, 1H, J = 7.3).
【０７４８】IR(KBr) ：cm-1 3422，1637，1074。IR (KBr): cm - 13422, 1637, 1074.
【０７４９】(c′) 化合物522a′及び522b′の合成 化合物520a′(104.0mg) のＭｅＯＨ（３ml）溶液に 0.1
Ｎ ＮａＯＨ（1.15ml）を加え、室温で24時間撹拌して
反応させた。 (C ′) Synthesis of Compounds 522a ′ and 522b ′ A solution of Compound 520a ′ (104.0 mg) in MeOH (3 ml) was added at 0.1%.
N NaOH (1.15 ml) was added, and the mixture was stirred and reacted at room temperature for 24 hours.
【０７５０】反応液から減圧下溶媒を留去し、ゲル濾過
（ＬＨ−20，ＭｅＯＨ）で精製し、白色粉末として化合
物522a′を98.2mg（収率93.6％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, MeOH) to obtain 98.2 mg (yield 93.6%) of compound 522a 'as a white powder.
【０７５１】ＲF 0.49 (CHCl3 -MeOH- H2 O 10:5:1) 。R F 0.49 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０７５２】［α］D 27−68.5°(c 1.05,CHCl3 -MeOH-
H2 O 10:10:3)。[Α] D 27 -68.5 ° (c 1.05, CHCl 3 -MeOH-
H 2 O 10: 10: 3 ).
【０７５３】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.88(t,3H,J=6.8)，1.24(d,3H,J=6.6)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.88 (t, 3H, J = 6.8), 1.24 (d, 3H, J = 6.6).
【０７５４】IR(KBr) ：cm-1 3400，1639，1558，1078，1038。[0754] IR (KBr): cm -1 3400,1639,1558,1078,1038 .
【０７５５】化合物520b′(138,8mg) のＭｅＯＨ（３m
l）溶液に、 0.1Ｎ ＮａＯＨ(1.504ml) を加え、室温
で68時間撹拌して反応させた。Compound 520b '(138,8 mg) in MeOH (3m
l) 0.1N NaOH (1.504 ml) was added to the solution, and the mixture was reacted by stirring at room temperature for 68 hours.
【０７５６】反応液から減圧下溶媒を留去し、ゲル濾過
（ＬＨ−20，ＭｅＯＨ）で精製し、白色粉末としとて化
合物522b′を135.1mg(収率96.5％）取得した。The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by gel filtration (LH-20, MeOH) to obtain 135.1 mg (yield 96.5%) of compound 522b 'as a white powder.
【０７５７】ＲF 0.39 (CHCl3 -MeOH- H2 O 10:5:1) 。R F 0.39 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０７５８】［α］D 27−28.2°(c 1.02,CHCl3 -MeOH-
H2 O 10:10:3)。[Α] D 27 -28.2 ° (c 1.02, CHCl 3 -MeOH-
H 2 O 10: 10: 3 ).
【０７５９】 1H-NMR(CDCl3 ：CD3 OD=1:1) ：δ ppm，
J in Hz 0.89(t,3H,J=6.8)，1.24(d,3H,J=6.6)。 1 H-NMR (CDCl 3 : CD 3 OD = 1: 1): δ ppm,
J in Hz 0.89 (t, 3H, J = 6.8), 1.24 (d, 3H, J = 6.6).
【０７６０】IR(KBr) ：cm-1 3400，1637，1560，1076，1041。[0760] IR (KBr): cm -1 3400,1637,1560,1076,1041 .
【０７６１】(d′) 化合物523 の合成（図５ｊ） ２−セチル−ステアリン酸(304mg) に塩化チオニル (３
ml) を加え、３時間加熱還流した。過剰の塩化チオニル
を留去し、ベンゼンを加え、溶媒を留去した。この操作
を３回繰り返したのち、残渣を塩化メチレン (３ml) に
溶解した。この溶液をフコース誘導体501 ａ(276mg) お
よびトリエチルアミン(0.18ml)の塩化メチレン(15ml)溶
液に氷冷下滴下した後、室温にて終夜撹拌した。反応液
を水及び半飽和食塩水にて洗浄し、硫酸マグネシウムに
て乾燥した。溶媒を留去し、残渣をシリカゲルカラムク
ロマトグラフィー（シリカゲル 50 ｇ、クロロホルム）
にて精製してアミド体(450mg）を得た。 (D ′) Synthesis of Compound 523 (FIG. 5j) 2-cetyl-stearic acid (304 mg) was added to thionyl chloride (3
ml), and the mixture was heated under reflux for 3 hours. Excess thionyl chloride was distilled off, benzene was added, and the solvent was distilled off. After repeating this operation three times, the residue was dissolved in methylene chloride (3 ml). This solution was added dropwise to a solution of fucose derivative 501a (276 mg) and triethylamine (0.18 ml) in methylene chloride (15 ml) under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was washed with water and half-saturated saline, and dried over magnesium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (silica gel 50 g, chloroform).
To give an amide form (450 mg).
【０７６２】［α］D 27-60.3 ゜(c 1.0，クロロホル
ム) 。[Α] D 27 -60.3 ゜ (c 1.0, chloroform).
【０７６３】IR(KBr) ：3450，3300，1750，1640，1550
cm-1。[0763] IR (KBr): 3450, 3300, 1750, 1640, 1550
cm -1 .
【０７６４】 1H-NMR(CD3 OD) ：0.88(3H,t,J=7Hz)，1.
14(3H,d,J=6.5Hz)，2.00(3H,s)，2.07(3H,s)，2.17(3H,
s)，4.13(1H,q,J=6.5Hz)，5.04(1H,d,J=4Hz)，5.16(1H,
dd,J=4,11Hz)，5.29(1H,brd,J=3Hz)，5.36(1H,dd,J=3,1
1Hz)，5.81(1H,t,J=5Hz)。 1 H-NMR (CD 3 OD): 0.88 (3H, t, J = 7 Hz), 1.
14 (3H, d, J = 6.5Hz), 2.00 (3H, s), 2.07 (3H, s), 2.17 (3H,
s), 4.13 (1H, q, J = 6.5 Hz), 5.04 (1H, d, J = 4 Hz), 5.16 (1H,
dd, J = 4,11Hz), 5.29 (1H, brd, J = 3Hz), 5.36 (1H, dd, J = 3,1
1Hz), 5.81 (1H, t, J = 5Hz).
【０７６５】m/z(FAB)846 。M / z (FAB) 846.
【０７６６】Ｒf =0.53 （クロロホルム：メタノール＝
99:1）。R f = 0.53 (chloroform: methanol =
99: 1).
【０７６７】上記で得たアミド体(235mg) のメタノール
(30ml)溶液にナトリウムメトキシド（28％メタノール溶
液55μｌ）を加え、室温にて６時間撹拌した。「アンバ
ーリスト15Ｅ」を液性が中性になるまで加えた後樹脂を
濾去し、濾液を濃縮し、残渣を「セファデックスＬＨ−
20」（メタノール：クロロホルム =１：１）にて精製
し、目的化合物523(183mg)を得た。The amide (235 mg) obtained above in methanol
(30 ml) solution was added with sodium methoxide (55 μl of 28% methanol solution), and the mixture was stirred at room temperature for 6 hours. After adding “Amberlyst 15E” until the solution becomes neutral, the resin is removed by filtration, the filtrate is concentrated, and the residue is separated with “Sephadex LH-
20 "(methanol: chloroform = 1: 1) to obtain the desired compound 523 (183 mg).
【０７６８】［α］D 26-44.6 ゜(c 1.0，クロロホル
ム：メタノール=1:1) 。[Α] D 26 -44.6 ゜ (c 1.0, chloroform: methanol = 1: 1).
【０７６９】IR(KBr) ：3450，3300，1640，1550cm-1。IR (KBr): 3450, 3300, 1640, 1550 cm -1 .
【０７７０】 1H-NMR(CD3 OD) ：0.89(3H,t,J=7Hz)，1.
22(3H,d,J=6.5Hz)，1.4 (2H,m)，1.55(2H,m)，3.93(1H,
q,J=6.5Hz)。 1 H-NMR (CD 3 OD): 0.89 (3H, t, J = 7 Hz), 1.
22 (3H, d, J = 6.5Hz), 1.4 (2H, m), 1.55 (2H, m), 3.93 (1H,
q, J = 6.5Hz).
【０７７１】Ｒf =0.45 （クロロホルム：メタノール=9
3:7 ）。R f = 0.45 (chloroform: methanol = 9
3: 7).
【０７７２】(e′) 化合物529 の合成（図５ｋ） １）化合物524 の合成 Ｌ−フコーステトラアセテート（化合物523 ）（10.16
ｇ）と２−［２−（２−クロロエトキシ）エトキシ］エ
タノール(10.31ｇ）を塩化メチレン(300ml）に溶解し、
ＢＦ3 ・Ｅｔ2 Ｏ(17.36ｇ）を加え、室温で25時間攪拌
した。反応液を塩化メチレンで希釈し、水、５％ＮａＨ
ＣＯ3 水及び水で順次洗浄し、乾燥後溶媒を減圧下留去
した。残渣をピリジン（26ml）に溶解し、無水酢酸（20
ml）を加え、室温で15時間攪拌した。反応混合物を酢酸
エチルで希釈し、水、５％ＮａＨＣＯ3 水、水、10％ク
エン酸水及び水で順次洗浄し、乾燥後溶媒を減圧下留去
した。残渣シリカゲル(250ｇ）を用いるカラムクロマト
グラフィー（クロロホルム）で精製し、α−グリコシド
体化合物524 （4.40ｇ，33％）とβ−グリコシド体化合
物525 （1.79ｇ）を無色油状物として得た。 (E ′) Synthesis of Compound 529 (FIG. 5k) 1) Synthesis of Compound 524 L-Fucosetetraacetate (Compound 523) (10.16
g) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (10.31 g) were dissolved in methylene chloride (300 ml).
BF 3 .Et 2 O (17.36 g) was added, and the mixture was stirred at room temperature for 25 hours. Dilute the reaction with methylene chloride and add water, 5% NaH
After washing with CO 3 water and water successively and drying, the solvent was distilled off under reduced pressure. The residue was dissolved in pyridine (26 ml) and acetic anhydride (20
ml) and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with water, 5% aqueous NaHCO 3 , water, 10% aqueous citric acid and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (250 g) to obtain α-glycoside compound 524 (4.40 g, 33%) and β-glycoside compound 525 (1.79 g) as colorless oils.
【０７７３】α−グリコシド体化合物524 ：［α］D -1
12.3°(c 0.96,CHCl3 ) 。The α-glycoside compound 524: [α] D -1
12.3 ° (c 0.96, CHCl 3 ).
【０７７４】 1H-NMR(CDCl3 ) δ：1.14(3H,d,J=6.6H
z)，1.99(3H,s)，2.08(3H,s)，2.17(3H,s)，3.62-3.84
(12H,m)，4.23(1H,q,J=6.6Hz)，5.11(1H,d,J=3.7Hz)，
5.12(1H,dd,J=3.7Hz,10.0Hz)，5.30(1H,d,J=3.4Hz)，5.
37(1H,dd,J=3.4Hz,10.0Hz)。 1 H-NMR (CDCl 3 ) δ: 1.14 (3H, d, J = 6.6H
z), 1.99 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 3.62-3.84
(12H, m), 4.23 (1H, q, J = 6.6Hz), 5.11 (1H, d, J = 3.7Hz),
5.12 (1H, dd, J = 3.7Hz, 10.0Hz), 5.30 (1H, d, J = 3.4Hz), 5.
37 (1H, dd, J = 3.4Hz, 10.0Hz).
【０７７５】２）化合物526 の合成 クロル体化合物524 （3.56ｇ）をＤＭＦ（50ml）に溶解
し、アジ化ナトリウム（1.05ｇ）を加え、70℃で２日間
攪拌した。反応液を酢酸エチルで希釈し、水洗し、乾燥
後溶媒を減圧下留去した。残渣をシリカゲル(100ｇ）を
用いるカラムクロマトグラフィー（クロロホルム）で精
製し、アジド体化合物526 （2.98ｇ）を無色油状物とし
て得た。2) Synthesis of Compound 526 The chlorinated compound 524 (3.56 g) was dissolved in DMF (50 ml), sodium azide (1.05 g) was added, and the mixture was stirred at 70 ° C. for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform) using silica gel (100 g) to give the azide compound 526 (2.98 g) as a colorless oil.
【０７７６】［α］D -113.7°(c 0.96,CHCl3 ) 。[Α] D -113.7 ° (c 0.96, CHCl 3 ).
【０７７７】 1H-NMR(CDCl3 ) δ：1.14(3H,d,J=6.6H
z)，1.99(3H,s)，2.07(3H,s)，2.16(3H,s)，3.40(2H,t,
J=5.0Hz)，3.62-3.70(9H,m) ，3.78-3.84(1H,m) ，4.23
(1H,dq,J=1.2Hz,6.6Hz) ，5.10(1H,d,J=3.7Hz)，5.12(1
H,dd,J=3.7Hz,10.3Hz)，5.30(1H,dd,J=1.2Hz,3.4Hz) ，
5.37(1H,dd,J=3.4Hz,10.3Hz)。 1 H-NMR (CDCl 3 ) δ: 1.14 (3H, d, J = 6.6H
z), 1.99 (3H, s), 2.07 (3H, s), 2.16 (3H, s), 3.40 (2H, t,
J = 5.0Hz) 、 3.62-3.70 (9H, m) 、 3.78-3.84 (1H, m) 、 4.23
(1H, dq, J = 1.2Hz, 6.6Hz), 5.10 (1H, d, J = 3.7Hz), 5.12 (1
H, dd, J = 3.7Hz, 10.3Hz), 5.30 (1H, dd, J = 1.2Hz, 3.4Hz),
5.37 (1H, dd, J = 3.4Hz, 10.3Hz).
【０７７８】３）化合物527 の合成 アジド体化合物526 （2.21ｇ）とｐ−トルエンスルホン
酸（0.94ｇ）をエタノール(100ml) に溶解し、リンドラ
ー触媒（4.40ｇ）を加え、室温50ｐｓｉで７時間接触還
元を行った。触媒を濾去後、濾液を減圧下濃縮し、アミ
ン体化合物527（2.84ｇ）を無色油状物質として得た。3) Synthesis of Compound 527 Azide compound 526 (2.21 g) and p-toluenesulfonic acid (0.94 g) were dissolved in ethanol (100 ml), and a Lindlar catalyst (4.40 g) was added. Catalytic reduction was performed. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain an amine compound 527 (2.84 g) as a colorless oily substance.
【０７７９】４）化合物528 の合成 アミン体化合物527(240mg ）とパルチミン酸Ｎ−ヒドロ
キシスクシンイミドエステル(143mg）を塩化メチレン
（20ml）に溶解し、トリエチルアミン（82mg）を加え、
室温で３時間攪拌した。反応液を塩化メチレンで希釈
し、水、10％クエン酸水及び水で順次洗浄し、乾燥後溶
媒を減圧下留去した。残渣をシリガゲル（50ｇ）を用い
るカラムクロマトグラフィー（クロロホルム−メタノー
ル 100：１）で精製し、目的化合物(241mg）を得た。4) Synthesis of Compound 528 The amine compound 527 (240 mg) and palmitic acid N-hydroxysuccinimide ester (143 mg) were dissolved in methylene chloride (20 ml), and triethylamine (82 mg) was added.
Stir at room temperature for 3 hours. The reaction solution was diluted with methylene chloride, washed sequentially with water, 10% aqueous citric acid and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 100: 1) using silica gel (50 g) to obtain the desired compound (241 mg).
【０７８０】［α］D -65.0 °(c 1.01,CHCl3 ) 。[Α] D -65.0 ° (c 1.01, CHCl 3 ).
【０７８１】1H-NMR(CDCl3 ) δ：0.88(3H,t,J=6.8H
z)，1.14(3H,d,J=6.6Hz)，1.20-1.34(24H,m)，1.63(2H,
m)，1.99(3H,s)，2.07(3H,s)，2.17(3H,s)，2.18(2H,
m)，3.46(2H,m)，3.56(2H,m)，3.58-3.68(7H,m) ，3.80
(1H,m)，4.23(1H,dq,J=1.2Hz,6.6Hz) ，5.12(1H,dd,J=
3.7Hz,10.3Hz)，5.13(1H,d,J=3.7Hz)，5.29(1H,dd,J=1.
2Hz,3.4Hz) ，5.37(1H,dd,J=3.4Hz,0.3Hz) ，6.10(1H,
m)。1H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 6.8H
z), 1.14 (3H, d, J = 6.6 Hz), 1.20-1.34 (24H, m), 1.63 (2H,
m), 1.99 (3H, s), 2.07 (3H, s), 2.17 (3H, s), 2.18 (2H,
m), 3.46 (2H, m), 3.56 (2H, m), 3.58-3.68 (7H, m), 3.80
(1H, m), 4.23 (1H, dq, J = 1.2Hz, 6.6Hz), 5.12 (1H, dd, J =
3.7Hz, 10.3Hz), 5.13 (1H, d, J = 3.7Hz), 5.29 (1H, dd, J = 1.
2Hz, 3.4Hz), 5.37 (1H, dd, J = 3.4Hz, 0.3Hz), 6.10 (1H,
m).
【０７８２】５）化合物529 の合成 化合物528(208mg ）をメタノール（５ml）に溶解し、28
％ＮａＯＭｅ ｉｎＭｅＯＨ（20μｌ）を加え、室温で
2.5時間攪拌した。反応液に「アンバーライトＩＲＣ−
50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し
た。残渣にクロロホルムを加え、不溶物を濾去後濾液を
減圧下濃縮乾固し、残渣をエーテルで洗浄して目的化合
物529(151mg ）を無色粉末として得た。5) Synthesis of Compound 529 Compound 528 (208 mg) was dissolved in methanol (5 ml), and
% NaOMe in MeOH (20 μl) and add at room temperature
Stirred for 2.5 hours. Add “Amberlite IRC-
50 "was added, the insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. Chloroform was added to the residue, the insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with ether to obtain the desired compound 529 (151 mg) as a colorless powder.
【０７８３】［α］D -55.2 °（c 0.56, CHCl3 ) 。[Α] D -55.2 ° (c 0.56, CHCl 3 ).
【０７８４】 1H-NMR (CDCl 3 ) δ：0.88(3H,t,J=6.8H
z)，1.20-1.34(24H,m)，1.30(3H,d,J=6.6Hz)，1.62(2H,
m)，2.18(2H,m)，3.40-3.72(11H,m)，3.74-3.84(3H,m)
，3.90-3.94(1H,m) ，4.04(1H,q,J=3.3Hz)，4.92(1H,
d,J=3.4Hz)，6.43(1H,m)。 1 H-NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 6.8H
z), 1.20-1.34 (24H, m), 1.30 (3H, d, J = 6.6Hz), 1.62 (2H,
m), 2.18 (2H, m), 3.40-3.72 (11H, m), 3.74-3.84 (3H, m)
, 3.90-3.94 (1H, m), 4.04 (1H, q, J = 3.3Hz), 4.92 (1H, m
d, J = 3.4Hz), 6.43 (1H, m).
【０７８５】(f′) 化合物531 の合成（図５ｌ） １）化合物530 の合成 ２−（１−ヘキサデシル）オクタデカン酸(153mg）をヘ
キサン（15ml）と塩化メチレン（20ml）の混合溶液に溶
解し、Ｎ−ヒドロキシスクシンイミド（35mg）とＮ，
Ｎ′−ジシクロヘキシルカルボジイミド（62mg）を加
え、室温で24時間攪拌した。反応混合物にアセトニトリ
ル（15ml）を溶解したアミン体化合物527(214mg ）を加
え、ついでトリエチルアミン（67mg）を加えた後、室温
で24時間攪拌した。不溶物を濾去し、濾液をクロロホル
ムで希釈し、水洗し、乾燥後溶媒を減圧下留去した。残
渣をシリカゲル（60ｇ）を用いるカラムクロマトグラフ
ィー（クロロホルム−メタノール 150：１）で精製し
た。再度、シリカゲル（60ｇ）を用いるカラムクロマト
グラフィー（ヘキサン−酢酸エチル２：１）で精製し、
目的化合物530(165mg ）を無色油状物として得た。 (F ′) Synthesis of Compound 531 (FIG. 5L) 1) Synthesis of Compound 530 2- (1-hexadecyl) octadecanoic acid (153 mg) was dissolved in a mixed solution of hexane (15 ml) and methylene chloride (20 ml). , N-hydroxysuccinimide (35 mg) and N,
N'-Dicyclohexylcarbodiimide (62 mg) was added, and the mixture was stirred at room temperature for 24 hours. Amine compound 527 (214 mg) in which acetonitrile (15 ml) was dissolved was added to the reaction mixture, and then triethylamine (67 mg) was added, followed by stirring at room temperature for 24 hours. The insoluble material was removed by filtration, the filtrate was diluted with chloroform, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (60 g) (chloroform-methanol 150: 1). Again, it was purified by column chromatography (hexane-ethyl acetate 2: 1) using silica gel (60 g).
The desired compound 530 (165 mg) was obtained as a colorless oil.
【０７８６】［α］D -51.4 °（c 0.84, CHCl3 ) 。[Α] D -51.4 ° (c 0.84, CHCl 3 ).
【０７８７】 1H-NMR (CDCl 3 ) δ：0.88(6H,t,J=6.8H
z)，1.14(3H,d,J=6.4Hz)，1.20-1.33(56H,m)，1.34-1.4
3(2H,m) ，1.56-1.62(2H,m) ，1.99(3H,s)，2.07(3H,
s)，2.17(3H,s)，3.47(2H,m)，3.54(2H,m)，3.58-3.70
(7H,m) ，3.76-3.83(1H,m) ，4.22(1H,dq,J=1.2Hz，6.4
Hz)，5.12(1H,dd,J=3.7Hz,10.0Hz)，5.13(1H,d,J=3.7H
z),5.29(1H,dd,J=1.2Hz,3.4Hz)，5.37(1H,dd,J=3.4Hz,1
0.0Hz)，6.02(1H,m)。 1 H-NMR (CDCl 3 ) δ: 0.88 (6H, t, J = 6.8H
z), 1.14 (3H, d, J = 6.4Hz), 1.20-1.33 (56H, m), 1.34-1.4
3 (2H, m), 1.56-1.62 (2H, m), 1.99 (3H, s), 2.07 (3H,
s), 2.17 (3H, s), 3.47 (2H, m), 3.54 (2H, m), 3.58-3.70
(7H, m), 3.76-3.83 (1H, m), 4.22 (1H, dq, J = 1.2Hz, 6.4
Hz), 5.12 (1H, dd, J = 3.7Hz, 10.0Hz), 5.13 (1H, d, J = 3.7H
z), 5.29 (1H, dd, J = 1.2Hz, 3.4Hz), 5.37 (1H, dd, J = 3.4Hz, 1
0.0Hz), 6.02 (1H, m).
【０７８８】２）化合物531 の合成 化合物530(138mg ）をメタノール（10ml）に溶解し、28
％ＮａＯＭｅ ｉｎＭｅＯＨ（20μｌ）を加え、室温で
2.5時間攪拌した。反応液に「アンバーライトＩＲＣ−
50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し
た。残渣にクロロホルムに加え、不溶物を濾去後濾液を
減圧下濃縮乾固し、残渣をエーテルで洗浄して目的化合
物(101mg）を無色粉末として得た。2) Synthesis of Compound 531 Compound 530 (138 mg) was dissolved in methanol (10 ml), and
% NaOMe in MeOH (20 μl) and add at room temperature
Stirred for 2.5 hours. Add “Amberlite IRC-
50 "was added, the insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was added to chloroform, the insolubles were removed by filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with ether to obtain the desired compound (101 mg) as a colorless powder.
【０７８９】［α］D -36.7 ゜(c 0.69, CHCl 3 ) 。[Α] D -36.7 ゜ (c 0.69, CHCl 3 ).
【０７９０】 1H-NMR(CDCl3 ) δ：0.88(6H,t,J=6.8H
z)，1.20-1.30(56H,m)，1.30(3H,d,J=6.8Hz)，1.34-1.4
3(2H,m) ，3.37-3.72(11H,m)，3.74-3.85(3H,m) ，3.88
-3.94(1H,m) ，4.03(1H,q,J=6.8Hz)，4.92(1H,d,J=3.4H
z)，6.37(1H,m)。 1 H-NMR (CDCl 3 ) δ: 0.88 (6H, t, J = 6.8H
z), 1.20-1.30 (56H, m), 1.30 (3H, d, J = 6.8Hz), 1.34-1.4
3 (2H, m), 3.37-3.72 (11H, m), 3.74-3.85 (3H, m), 3.88
-3.94 (1H, m), 4.03 (1H, q, J = 6.8Hz), 4.92 (1H, d, J = 3.4H
z), 6.37 (1H, m).
【０７９１】(g′) 化合物540 の合成（図５ｍ） １）化合物535 の合成 化合物534(340mg ）、Ｚｎ（ＯＴｆ）2 (318mg）及び６
−クロロヘキサノール(151mg）をアセトニトリル（15m
l）に溶解し、氷冷攪拌下ＴＭＳＣｌ（95mg）を加え
た。同温で 1.5時間攪拌後、反応混合物を酢酸エチルで
希釈し、水、５％ＮａＨＣＯ3 水及び水で順次洗浄し、
乾燥後溶媒を減圧下留去した。残渣をシリカゲル（25
ｇ）を用いるカラムクロマトグラフィー（クロロホルム
−ヘキサン２：１）で精製し、目的化合物(319mg）を無
色油状物として得た。 (G ′) Synthesis of Compound 540 (FIG. 5m) 1) Synthesis of Compound 535 Compound 534 (340 mg), Zn (OTf) 2 (318 mg) and 6
-Chlorohexanol (151 mg) in acetonitrile (15 m
l) and TMSCl (95 mg) was added under ice-cooling and stirring. After stirring at the same temperature for 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed sequentially with water, 5% aqueous NaHCO 3 and water,
After drying, the solvent was distilled off under reduced pressure. Residue is silica gel (25
Purification by column chromatography (chloroform-hexane 2: 1) using g) gave the target compound (319 mg) as a colorless oil.
【０７９２】［α］D -42.4 °(c 0.88,CHCl3 ) 。[Α] D -42.4 ° (c 0.88, CHCl 3 ).
【０７９３】 1H-NMR(CDCl3 ) δ：1.11(3H,d,J=6.6H
z)，1.32-1.40(2H,m) ，1.40-1.48(2H,m) ，1.56-1.68
(2H,m) ，1.76(2H,m)，3.43(1H,m)，3.51(2H,t,J=6.6H
z)，3.60(1H,m)，3.66(1H,d,J=2.9Hz)，3.86(1H,q,J=6.
6Hz)，3.93(1H,dd,J=2.9Hz,10.0Hz)，4.02(1H,dd,J=3.7
Hz,10.0Hz)，4.65(1H,d,J=11.7Hz) ，4.67(1H,d,J=12.0
Hz) ，4.74(1H,d,J=11.7Hz) ，4.78(1H,d,J=3.7Hz)，4.
81(1H,d,J=12.1Hz) ，4.88(1H,d,J=11.7Hz) ，4.98(1H,
d,J=11.7Hz) ，7.24-7.41(15H,m)。 1 H-NMR (CDCl 3 ) δ: 1.11 (3H, d, J = 6.6H
z), 1.32-1.40 (2H, m), 1.40-1.48 (2H, m), 1.56-1.68
(2H, m), 1.76 (2H, m), 3.43 (1H, m), 3.51 (2H, t, J = 6.6H
z), 3.60 (1H, m), 3.66 (1H, d, J = 2.9Hz), 3.86 (1H, q, J = 6.
6Hz), 3.93 (1H, dd, J = 2.9Hz, 10.0Hz), 4.02 (1H, dd, J = 3.7
Hz, 10.0Hz), 4.65 (1H, d, J = 11.7Hz), 4.67 (1H, d, J = 12.0)
Hz), 4.74 (1H, d, J = 11.7Hz), 4.78 (1H, d, J = 3.7Hz), 4.
81 (1H, d, J = 12.1Hz), 4.88 (1H, d, J = 11.7Hz), 4.98 (1H,
d, J = 11.7Hz), 7.24-7.41 (15H, m).
【０７９４】２）化合物537 の合成 クロル体化合物535 （1.03ｇ）をＤＭＦ（15ml）に溶解
し、アジ化ナトリウム（0.24ｇ）を加え、60℃で６日間
攪拌した。反応液を酢酸エチルで希釈し、水洗し、乾燥
後溶媒を減圧下留去した。残渣をシリカゲル(100ｇ）を
用いるカラムクロマトグラフィー（ヘキサン−酢酸エチ
ル15：１）で精製し、アジト体化合物537 （0.94ｇ）を
無色油状物として得た。2) Synthesis of Compound 537 The chlorinated compound 535 (1.03 g) was dissolved in DMF (15 ml), sodium azide (0.24 g) was added, and the mixture was stirred at 60 ° C. for 6 days. The reaction solution was diluted with ethyl acetate, washed with water, dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane-ethyl acetate 15: 1) using silica gel (100 g) to give an azido compound 537 (0.94 g) as a colorless oil.
【０７９５】［α］D -39.4 °(c 1.08,CHCl3 ) 。[Α] D -39.4 ° (c 1.08, CHCl 3 ).
【０７９６】 1H-NMR(CDCl3 ) δ：1.10(3H,d,J=6.6H
z)，1.34-1.42(4H,m) ，1.54-1.68(4H,m) ，3.24(2H,t,
J=7.0Hz)，3.40-3.46(1H,m) ，3.58-3.64(1H,m) ，3.66
(1H,d,J=2.9Hz)，3.86(1H,q,J=3.3Hz)，3.93(1H,dd,J=
2.9Hz,10.0Hz)，4.03(1H,dd,J=3.7Hz,10.0Hz)，4.66(1
H,d,J=11.5Hz) ，4.67(1H,d,J=12.0Hz) ，4.74(1H,d,J=
12.0Hz) ，4.78(1H,d,J=3.7Hz)，4.81(1H,d,J=12.0Hz)
，4.87(1H,d,J=12.0Hz) ，4.98(1H,d,J=11.5Hz) ，7.2
4-7.41(15H,m)。 1 H-NMR (CDCl 3 ) δ: 1.10 (3H, d, J = 6.6H
z), 1.34-1.42 (4H, m), 1.54-1.68 (4H, m), 3.24 (2H, t,
J = 7.0Hz), 3.40-3.46 (1H, m), 3.58-3.64 (1H, m), 3.66
(1H, d, J = 2.9Hz), 3.86 (1H, q, J = 3.3Hz), 3.93 (1H, dd, J =
2.9Hz, 10.0Hz), 4.03 (1H, dd, J = 3.7Hz, 10.0Hz), 4.66 (1
H, d, J = 11.5Hz), 4.67 (1H, d, J = 12.0Hz), 4.74 (1H, d, J =
12.0Hz), 4.78 (1H, d, J = 3.7Hz), 4.81 (1H, d, J = 12.0Hz)
, 4.87 (1H, d, J = 12.0 Hz), 4.98 (1H, d, J = 11.5 Hz), 7.2
4-7.41 (15H, m).
【０７９７】３）化合物538 の合成 アジト体化合物537 （0.90ｇ）とｐ−トルエンスルホン
酸（0.31ｇ）をエタノール（30ml）に溶解し、リンドラ
ー触媒（1.80ｇ）を加え、室温50ｐｓｉで５時間接触還
元を行った。触媒を濾去後、濾液減圧下濃縮し、アミン
体化合物538 （1.12ｇ）を無色泡状物質として得た。3) Synthesis of Compound 538 Azido compound 537 (0.90 g) and p-toluenesulfonic acid (0.31 g) were dissolved in ethanol (30 ml), a Lindlar catalyst (1.80 g) was added, and the mixture was stirred at room temperature at 50 psi for 5 hours. Catalytic reduction was performed. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the amine compound 538 (1.12 g) as a colorless foam.
【０７９８】４）化合物539 の合成 Ｎ−ｔ−２ブトキシカルボニル−Ｌ−グルタミン酸（74
mg）をアセトニトリル（20ml）に溶解し、Ｎ−ヒドロキ
シスクシンイミド（76mg）とＮ，Ｎ′−ジシクロヘキシ
ルカルボジイミド(136mg）を加え、室温で４時間攪拌し
た。反応混合物にアミン体化合物538(466mg ）とトリエ
チルアミン(134mg）を加え、室温で２時間攪拌した。析
出晶を濾過し、シリカゲル（60ｇ）を用いるカラムクロ
マトグラフィー（クロロホルム−メタノール 100：１）
で精製し、目的化合物(288mg）を無色粉末として得た。4) Synthesis of compound 539 Nt-2 butoxycarbonyl-L-glutamic acid (74
mg) was dissolved in acetonitrile (20 ml), N-hydroxysuccinimide (76 mg) and N, N'-dicyclohexylcarbodiimide (136 mg) were added, and the mixture was stirred at room temperature for 4 hours. Amine compound 538 (466 mg) and triethylamine (134 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals are filtered and column chromatography using silica gel (60 g) (chloroform-methanol 100: 1)
The title compound (288 mg) was obtained as a colorless powder.
【０７９９】［α］D -34.0 °(c 1.45,CHCl3 ) 。[Α] D -34.0 ° (c 1.45, CHCl 3 ).
【０８００】 1H-NMR(CDCl3 ) δ：1.10(6H,d,J=6.6H
z)，1.28-1.37(8H,m) ，1.43(9H,m)，1.45-1.52(4H,m)
，1.55-1.62(4H,m) ，1.85-1.95(1H,m) ，2.02-2.10(1
H,m) ，2.21-2.39(2H,m) ，3.16-3.29(4H,m) ，3.38-3.
46(2H,m) ，3.54-3.61(2H,m) ，3.66(2H,d,J=2.9Hz)，
3.86(2H,q,J=6.6Hz)，3.90-3.96(2H,m) ，4.00-4.05(2
H,m) ，4.65(2H,d,J=11.7Hz) ，4.67(2H,d,J=12.0Hz)
，4.74(2H,d,J=11.7Hz) ，4.77(1H,d,J=3.4Hz)，4.78
(1H,d,J=3.4Hz)，4.81(2H,d,J=12.0Hz) ，4.87(1H,d,J=
11.7Hz) ，4.88(1H,d,J=11.7Hz) ，4.98(2H,d,J=11.7H
z) ，7.24-7.41(30H,m)。 1 H-NMR (CDCl 3 ) δ: 1.10 (6H, d, J = 6.6H
z), 1.28-1.37 (8H, m), 1.43 (9H, m), 1.45-1.52 (4H, m)
, 1.55-1.62 (4H, m), 1.85-1.95 (1H, m), 2.02-2.10 (1
H, m), 2.21-2.39 (2H, m), 3.16-3.29 (4H, m), 3.38-3.
46 (2H, m), 3.54-3.61 (2H, m), 3.66 (2H, d, J = 2.9Hz),
3.86 (2H, q, J = 6.6Hz), 3.90-3.96 (2H, m), 4.00-4.05 (2
H, m), 4.65 (2H, d, J = 11.7Hz), 4.67 (2H, d, J = 12.0Hz)
, 4.74 (2H, d, J = 11.7Hz), 4.77 (1H, d, J = 3.4Hz), 4.78
(1H, d, J = 3.4Hz), 4.81 (2H, d, J = 12.0Hz), 4.87 (1H, d, J =
11.7Hz), 4.88 (1H, d, J = 11.7Hz), 4.98 (2H, d, J = 11.7H)
z), 7.24-7.41 (30H, m).
【０８０１】５）化合物540 の合成 ベンジルエーテル体化合物539(230mg ）を酢酸エチル
（20ml）とテトラヒドロフラン（20ml）の混合溶媒に溶
解し、10％Ｐｄ−Ｃ(460mg）を加え、室温60ｐｓｉで３
日間接触還元を行った。触媒を濾去後、濾液を減圧下濃
縮し、残渣をエーテルで洗浄して目的化合物(113mg）を
無色粉末として得た。5) Synthesis of compound 540 The benzyl ether compound 539 (230 mg) was dissolved in a mixed solvent of ethyl acetate (20 ml) and tetrahydrofuran (20 ml), and 10% Pd-C (460 mg) was added.
The catalytic reduction was performed for one day. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was washed with ether to obtain the desired compound (113 mg) as a colorless powder.
【０８０２】［α］D -80.9 ゜(c 0.78,MeOH) 。[Α] D -80.9 ゜ (c 0.78, MeOH).
【０８０３】 1H-NMR(CD3 OD) δ：1.21(6H,d,J=6.6H
z)，1.34-1.44(8H,m) ，1.44(9H,s)，1.47-1.57(4H,m)
，1.57-1.68(4H,m) ，1.80-1.88(1H,m) ，1.95-2.04(1
H,m) ，2.25(2H,m)，3.94(2H,q,J=6.6Hz),4.73(2H,d,J=
2.7Hz) 。 1 H-NMR (CD 3 OD) δ: 1.21 (6H, d, J = 6.6H
z), 1.34-1.44 (8H, m), 1.44 (9H, s), 1.47-1.57 (4H, m)
, 1.57-1.68 (4H, m), 1.80-1.88 (1H, m), 1.95-2.04 (1
H, m), 2.25 (2H, m), 3.94 (2H, q, J = 6.6Hz), 4.73 (2H, d, J =
2.7Hz).
【０８０４】(h′) 化合物533 の合成（図５ｍ） １）化合物532 の合成 ｔ−Ｂｏｃ−Ｌ−グルタミン酸(74mg)をアセトニトリル
(20ml)に溶解し、ＨＯＳｕ(76mg)とＤＣＣ(136mg) を加
え、室温で18時間撹拌した。反応混合物にアミン体化合
物527 (392mg) とトリエチルアミン(134mg) を加え、室
温で24時間撹拌した。不溶物を濾去し、濾液をクロロホ
ルムで希釈し、水、５％ＮａＨＣＯ3 水、水、10％クエ
ン酸水及び水で順次洗浄し、乾燥後溶媒を減圧下留去し
た。残渣をシリカゲル(50 ｇ) を用いるカラムクロマト
グラフィー（クロロホルム−メタノール50：１）で精製
し、目的化合物532(207mg)を無色泡状物として得た。 (H ′) Synthesis of Compound 533 (FIG. 5m) 1) Synthesis of Compound 532 t-Boc-L-glutamic acid (74 mg) was acetonitrile
(20 ml), HOSu (76 mg) and DCC (136 mg) were added, and the mixture was stirred at room temperature for 18 hours. Amine compound 527 (392 mg) and triethylamine (134 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The insoluble material was removed by filtration, the filtrate was diluted with chloroform, washed sequentially with water, 5% aqueous NaHCO 3 , water, 10% aqueous citric acid and water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol 50: 1) using silica gel (50 g) to obtain the desired compound 532 (207 mg) as a colorless foam.
【０８０５】２）化合物533 の合成 化合物532(180mg)をメタノール（３ml）に溶解し、28％
ＮａＯＭｅ ｉｎ ＭｅＯＨ(20 μｌ) を加え、室温で
４時間撹拌した。反応液に「アンバーライトＩＲＣ−5
0」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し、
目的化合物533(114mg)を無色泡状物として得た。2) Synthesis of Compound 533 Compound 532 (180 mg) was dissolved in methanol (3 ml), and 28%
NaOMein in MeOH (20 μl) was added and the mixture was stirred at room temperature for 4 hours. Add “Amberlite IRC-5” to the reaction mixture.
0 '' was added, the insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure.
The target compound 533 (114 mg) was obtained as a colorless foam.
【０８０６】［α］D -67.2 ゜(c 0.62,MeOH) 。[Α] D -67.2 @ (c 0.62, MeOH).
【０８０７】 1H-NMR(CD3 OD) δ：1.21(6H,d,J=6.6H
z)，1.44(9H,s)，1.82-1.92(1H,m) ，1.98-2.06(1H,m)
，2.29(2H,m)，4.00(2H,q,J=6.6Hz)。 1 H-NMR (CD 3 OD) δ: 1.21 (6H, d, J = 6.6H
z), 1.44 (9H, s), 1.82-1.92 (1H, m), 1.98-2.06 (1H, m)
, 2.29 (2H, m), 4.00 (2H, q, J = 6.6 Hz).
【０８０８】実施例６（アセチルガラクトサミン系誘導
体の合成） 本実施例における反応式を図６に示す。Example 6 (Synthesis of Acetylgalactosamine Derivative) The reaction formula in this example is shown in FIG.
【０８０９】(a) 化合物607 の合成 化合物114(129.9mg)にＴＦＡ（２ml）を加え、室温で１
時間撹拌後、減圧下ＴＦＡを留去した後の残渣にＣＨ2
Ｃｌ2 （２ml）及びＮＥｔ3 (200μl)を加えた溶液に、
化合物606(43mg) にＣＨ2 Ｃｌ2 （５ml）、ＨＯ−Ｓｕ
（12mg）及びＤＣＣ（21mg）を加え、室温で１時間撹拌
した後濾過した濾液を加え、室温で24時間撹拌して反応
させた。 (A) Synthesis of Compound 607 To Compound 114 (129.9 mg) was added TFA (2 ml), and the mixture was added at room temperature for 1 hour.
After stirring for an hour, CH 2 was added to the residue after distilling off TFA under reduced pressure.
To a solution containing Cl 2 (2 ml) and NEt 3 (200 μl),
Compound 606 (43mg) CH 2 Cl 2 (5ml), HO-Su
(12 mg) and DCC (21 mg) were added, and the mixture was stirred at room temperature for 1 hour, and the filtrate was added. The mixture was stirred and reacted at room temperature for 24 hours.
【０８１０】反応液を水洗し、乾燥後、減圧下溶媒を留
去し、シリカゲルカラムクロマトグラフィー（Ｍｅｒｃ
ｋ，ＣＨＣｌ3 −ＭｅＯＨ 20：１）で精製して化合物
607を36.7mg（収率23.4％）取得した。The reaction mixture was washed with water and dried, and then the solvent was distilled off under reduced pressure.
k, purified by CHCl 3 -MeOH 20: 1)
36.7 mg (yield 23.4%) of 607 was obtained.
【０８１１】ＲF 0.53 (CHCl3 -MeOH 10:1) 。R F 0.53 (CHCl 3 -MeOH 10: 1).
【０８１２】［α］D 22−16.8°(c 0.98,MeOH) 。[Α] D 22 -16.8 ° (c 0.98, MeOH).
【０８１３】 1H-NMR(CD3 OD) ：δ ppm，J in Hz 0.90(t,3H)， 1.92(s,3H×3)，1.95，2.02， 2.14(s,3H
×9)，3.55-3.76(m,12H)，4.05(s,2H)， 4.56(d,1H×3,
J=8.5)，5.07(dd,1H×3,J=3.5,11.2) ， 5.33(d,1H×3,
J=3.5)。 1 H-NMR (CD 3 OD): δ ppm, J in Hz 0.90 (t, 3H), 1.92 (s, 3H × 3), 1.95, 2.02, 2.14 (s, 3H
× 9), 3.55-3.76 (m, 12H), 4.05 (s, 2H), 4.56 (d, 1H × 3,
J = 8.5), 5.07 (dd, 1H × 3, J = 3.5,11.2), 5.33 (d, 1H × 3,
J = 3.5).
【０８１４】(b) 化合物608 の合成 化合物607 （36.0mg) のＭｅＯＨ（３ml）溶液に、28％
ＮａＯＭｅ ｉｎＭｅＯＨ（５μl)を加え、室温で23
時間撹拌して反応させた。 (B) Synthesis of Compound 608 28% of a solution of Compound 607 (36.0 mg) in MeOH (3 mL) was added.
Add NaOMe in MeOH (5 μl) and add 23
The mixture was stirred for an hour to react.
【０８１５】反応液から減圧下溶媒を留去し、ＭｅＯＨ
で洗浄し、化合物608 を21.6mg（収率74.0％）取得し
た。The solvent was distilled off from the reaction solution under reduced pressure, and MeOH was removed.
Then, 21.6 mg (yield: 74.0%) of compound 608 was obtained.
【０８１６】ＲF 0.34 (CHCl3 -MeOH- H2 O 10:5:1) 。R F 0.34 (CHCl 3 -MeOH-H 2 O 10: 5: 1).
【０８１７】［α］D 25− 4.0°(c 0.177, CHCl3 -MeO
H- H2 O 10:10:3)。[Α] D 25 −4.0 ° (c 0.177, CHCl 3 -MeO
H- H 2 O 10: 10: 3).
【０８１８】 1H-NMR(CDCl3 ：CD3 OD： D2 O=3:6:1)：
δ ppm，J in Hz 0.89(t,3H)， 2.01(s,3H×3)。 1 H-NMR (CDCl 3 : CD 3 OD: D 2 O = 3: 6: 1):
δ ppm, J in Hz 0.89 (t, 3H), 2.01 (s, 3H × 3).
【０８１９】実施例７（ラクトース系誘導体の合成） 本実施例における反応式を図７ａ乃至図７ｄに示す。Example 7 (Synthesis of Lactose Derivative) The reaction formulas in this example are shown in FIGS. 7A to 7D.
【０８２０】また、本実施例における旋光度は全て25℃
で測定した値である。Also, in this example, the optical rotation was 25 ° C.
It is the value measured in.
【０８２１】(a) 化合物702 の合成 アルゴン雰囲気下、β−アセチル体701 (15.04ｇ）、６
−ブロモヘキサノール（4.82ｇ）及び「モレキュラーシ
ーブス４Ａ」（25ｇ、減圧下 150℃にて終夜乾燥）の
１，２−ジクロルエタン(200ml) 溶液に室温にてトリフ
ルオロメタンスルホン酸トリメチルシリル(5.1ml) を滴
下し、20分間撹拌して反応させた。 (A) Synthesis of Compound 702 Under an argon atmosphere, β-acetyl compound 701 (15.04 g), 6
To a solution of -bromohexanol (4.82 g) and "molecular sieves 4A" (25 g, dried under reduced pressure at 150 ° C overnight) in 1,2-dichloroethane (200 ml) was added dropwise trimethylsilyl trifluoromethanesulfonate (5.1 ml) at room temperature. And stirred for 20 minutes to react.
【０８２２】反応液からモレキュラーシーブスを濾去
し、濾液を希重曹水−氷にあけてクロロホルム抽出し
た。抽出液を重曹水、水、飽和食塩水で洗浄後、乾燥し
た。溶媒を留去後、残渣をシリカゲルカラムクロマトグ
ラフィー（ヘキサン−酢酸エチル７：３−６：４）にて
精製してβ−グリコシド体化合物702 を3.12ｇ（収率18
％）得た。[0822] The molecular sieves were removed by filtration from the reaction solution, and the filtrate was poured into dilute aqueous sodium bicarbonate-ice and extracted with chloroform. The extract was washed with an aqueous solution of sodium bicarbonate, water, and saturated saline, and then dried. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-ethyl acetate 7: 3-6: 4) to obtain 3.12 g of β-glycoside compound 702 (yield 18).
%)Obtained.
【０８２３】ＲF 0.59（ベンゼン−酢酸エチル 1:1)。R F 0.59 (benzene-ethyl acetate 1: 1).
【０８２４】［α］D ＋ 3.9°(c 1.0，クロロホル
ム）。[Α] D + 3.9 ° (c 1.0, chloroform).
【０８２５】 1H-NMR(CDCl3 ) δ (ppm)in 500MHz ：1.
969(d,3H) ，2.039(s,3H) ，2.063(s,3H) ，2.124(s,3
H) ，2.155(s,3H) ，2.047(s,6H) ，4.45(d,1H)，4.48
(d,1H)，4.88(dd,1H) ，4.95(dd,1H) ，5.11(dd,1H) ，
5.20(t,1H)，5.35(dd,1H) 。[0825] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 1.
969 (d, 3H), 2.039 (s, 3H), 2.063 (s, 3H), 2.124 (s, 3
H), 2.155 (s, 3H), 2.047 (s, 6H), 4.45 (d, 1H), 4.48
(d, 1H), 4.88 (dd, 1H), 4.95 (dd, 1H), 5.11 (dd, 1H),
5.20 (t, 1H), 5.35 (dd, 1H).
【０８２６】IR(KBr) ：1753，1236cm-1。IR (KBr): 1753, 1236 cm -1 .
【０８２７】MS(FAB)(m/z)：799(MH+)。MS (FAB) (m / z): 799 (MH +).
【０８２８】(b) 化合物703 の合成 β−グリコシド体化合物702 （3.84ｇ）のジメチルホル
ムアミド（25ml）溶液にアジ化ナトリウム（0.78ｇ）を
加え、室温にて３日間、さらに50℃にて２時間加熱撹拌
して反応させた。 (B) Synthesis of Compound 703 Sodium azide (0.78 g) was added to a solution of β-glycoside compound 702 (3.84 g) in dimethylformamide (25 ml), and the mixture was added at room temperature for 3 days and at 50 ° C. for 2 days. The mixture was reacted by heating and stirring for an hour.
【０８２９】反応液を水にあけて酢酸エチルにて抽出
し、抽出液を水、飽和食塩水で洗浄後、乾燥した。溶媒
を留去して、アジド体化合物703 を3.61ｇ（収率99％）
得た。[0827] The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried. The solvent was distilled off, and 3.61 g of azide compound 703 (99% yield) was obtained.
Obtained.
【０８３０】ＲF 0.59（ベンゼン−酢酸エチル 1:1)。R F 0.59 (benzene-ethyl acetate 1: 1).
【０８３１】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz ：
1.966(s,3H) ，2.035(s,3H) ，2.062(s,3H) ，2.120(s,
3H) ，2.152(s,3H) ，2.046(s,6H) ，4.45(d,1H)，4.48
(d,1H)，4.88(dd,1H) ，4.96(dd,1H) ，5.11(dd,1H) ，
5.19(t,1H)，5.35(brd,1H)。 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz:
1.966 (s, 3H), 2.035 (s, 3H), 2.062 (s, 3H), 2.120 (s,
3H), 2.152 (s, 3H), 2.046 (s, 6H), 4.45 (d, 1H), 4.48
(d, 1H), 4.88 (dd, 1H), 4.96 (dd, 1H), 5.11 (dd, 1H),
5.19 (t, 1H), 5.35 (brd, 1H).
【０８３２】IR(KBr) ：1757cm-1。IR (KBr): 1757 cm -1 .
【０８３３】MS(FAB)(m/z)：762(MH+ ) 。MS (FAB) (m / z): 762 (MH + ).
【０８３４】(c) 化合物704 の合成 アジド体化合物703 （3.60ｇ）及びトルエンスルホン酸
（0.45ｇ）のエタノール（55ml）溶液にリンドラー触媒
（1.51ｇ）を加え、水素加圧下(50psi) ２時間振とう撹
拌して反応させた。 (C) Synthesis of Compound 704 A Lindlar catalyst (1.51 g) was added to a solution of azide compound 703 (3.60 g) and toluenesulfonic acid (0.45 g) in ethanol (55 ml), and the mixture was pressurized with hydrogen (50 psi) for 2 hours. The reaction was carried out with shaking and stirring.
【０８３５】反応液から触媒をセライトにて濾去し、濾
液を濃縮してアミノ体化合物704 の粗生成物を4.16ｇ得
た。The catalyst was removed from the reaction solution by filtration with Celite, and the filtrate was concentrated to obtain 4.16 g of a crude product of amino compound 704.
【０８３６】(d) 化合物706 の合成 氷冷下、前項(c) で得たアミノ体化合物704 （1.39ｇ）
及び化合物705 の（Ｌ）−Ｂｏｃ−Ｇｌｕ（ＯＢｚｌ）
−ＯＳｕ（0.82ｇ）のジメチルホルムアミド（15ml）溶
液にトリエチルアミン(0.26ml)を加え、そのまま20分
間、さらに室温にて40分間撹拌して反応させた。 (D) Synthesis of compound 706 The amino compound 704 (1.39 g) obtained in the above (c) under ice-cooling
And (L) -Boc-Glu (OBzl) of compound 705
Triethylamine (0.26 ml) was added to a solution of -OSu (0.82 g) in dimethylformamide (15 ml), and the mixture was allowed to react with stirring for 20 minutes and further at room temperature for 40 minutes.
【０８３７】反応液を酢酸エチルにて抽出し、抽出液を
水、飽和食塩水で洗浄後、乾燥した。溶媒を留去後、残
渣をシリカゲルカラムクロマトグラフィー（トルエン−
酢酸エチル ７：３−６：４）にて精製してベンジル体
化合物706 を1.32ｇ（収率82％）得た。[0837] The reaction solution was extracted with ethyl acetate, and the extract was washed with water and saturated saline and dried. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (toluene-
Purification with ethyl acetate 7: 3-6: 4) gave 1.32 g (yield 82%) of benzyl compound 706.
【０８３８】ＲF 0.27（ベンゼン−酢酸エチル 1:1)。R F 0.27 (benzene-ethyl acetate 1: 1).
【０８３９】［α］D −11.1°(c 1.0，クロロホル
ム）。[Α] D -11.1 ° (c 1.0, chloroform).
【０８４０】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
40(s,9H)，1.965(s,3H) ，2.031(s,3H) ，2.044(s,6H)
，2.059(s,3H) ，2.117(s,3H) ，2.151(s,3H) ，2.43
(dt,1H) ，2.55(dt,1H) ，4.44(d,1H)，4.49(d,1H)，4.
48-4.52(m,1H) ，4.88(dd,1H)，4.96(dd,1H) ，5.11(d
d,1H) ，5.13(s,2H)，5.19(t,1H)，5.35(dd,1H) 。 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz: 1.
40 (s, 9H), 1.965 (s, 3H), 2.031 (s, 3H), 2.044 (s, 6H)
, 2.059 (s, 3H), 2.117 (s, 3H), 2.151 (s, 3H), 2.43
(dt, 1H), 2.55 (dt, 1H), 4.44 (d, 1H), 4.49 (d, 1H), 4.
48-4.52 (m, 1H), 4.88 (dd, 1H), 4.96 (dd, 1H), 5.11 (d
d, 1H), 5.13 (s, 2H), 5.19 (t, 1H), 5.35 (dd, 1H).
【０８４１】IR(KBr) ：3400，1753，1670，1520cm-1。IR (KBr): 3400, 1753, 1670, 1520 cm -1 .
【０８４２】MS(FAB)(m/z)： 1055(MH+ ) 。MS (FAB) (m / z): 1055 (MH + ).
【０８４３】(e) 化合物708 の合成 氷冷下、前出項(c) で得たアミノ体化合物704 （2.78
ｇ）、化合物707 の（Ｌ）−Ｂｏｃ−Ｇｌｕｔａｍｉｃ
ａｃｉｄ(390mg) 及びＮ−ヒドロキシスクシンイミド
(436mg) のジメチルホルムアミド（30ml）溶液にトリエ
チルアミン（0.53ml）を加え、次いでＮ，Ｎ′−ジシク
ロヘキシルカルボジイミド(782mg) のジメチルホルムア
ミド（５ml）溶液を滴下した。そのまま氷冷下で20分
間、室温にて17時間撹拌して反応させた。 (E) Synthesis of Compound 708 The amino compound 704 (2.78) obtained in the above item (c) was synthesized under ice-cooling.
g) Compound (707) of (L) -Boc-Glutamic
acid (390 mg) and N-hydroxysuccinimide
(436 mg) in dimethylformamide (30 ml) was added with triethylamine (0.53 ml), and then a solution of N, N'-dicyclohexylcarbodiimide (782 mg) in dimethylformamide (5 ml) was added dropwise. The reaction was stirred for 20 minutes under ice-cooling and for 17 hours at room temperature.
【０８４４】反応液から不溶物を濾去し、濾液を半飽和
食塩水にあけて、酢酸エチルにて抽出し、抽出液を水、
飽和食塩水で洗浄後、乾燥した。溶媒を留去後、残渣を
アセトニトリルに溶解後不溶物を濾去した。濾液を濃縮
し、残渣をシリカゲルカラムクロマトグラフィー（酢酸
エチルートルエン ７：３−95：５）にて精製しＢｏｃ
体化合物708 を1.55ｇ（収率60％）得た。[0844] The insoluble material was removed by filtration from the reaction solution, and the filtrate was poured into half-saturated saline and extracted with ethyl acetate.
After washing with a saturated saline solution, it was dried. After evaporating the solvent, the residue was dissolved in acetonitrile and the insolubles were removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-toluene 7: 3-95: 5) to give Boc
1.55 g (yield 60%) of isomer compound 708 was obtained.
【０８４５】ＲF 0.33（クロロホルム−メタノール 9
5:5) 。R F 0.33 (chloroform-methanol 9
5: 5).
【０８４６】［α］D −11.0°(c 0.99 ，クロロホル
ム）。[Α] D -11.0 ° (c 0.99, chloroform).
【０８４７】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
43(s,9H)，1.966(s,6H) ，2.036(s,6H) ，2.046(s,12
H)，2.061(s,6H) ，2.121(s,6H) ，2.152(s,6H) ，4.44
6(d,1H) ，4.450(d,1H) ，4.48(d,1H)，4.49(d,1H)，4.
88(dd,2H) ，4.958(dd,1H)，4.96(dd,1H) ，5.11(dd,2
H) ，5.19(t,2H)，5.35(brd,2H)，5.7(brs,1H) ，6.1(b
rs,1H) ，6.5(brs,1H) 。[0847] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 1.
43 (s, 9H), 1.966 (s, 6H), 2.036 (s, 6H), 2.046 (s, 12
H), 2.061 (s, 6H), 2.121 (s, 6H), 2.152 (s, 6H), 4.44
6 (d, 1H), 4.450 (d, 1H), 4.48 (d, 1H), 4.49 (d, 1H), 4.
88 (dd, 2H), 4.958 (dd, 1H), 4.96 (dd, 1H), 5.11 (dd, 2
H), 5.19 (t, 2H), 5.35 (brd, 2H), 5.7 (brs, 1H), 6.1 (b
rs, 1H), 6.5 (brs, 1H).
【０８４８】IR(KBr) ：3400，1755，1670，1540cm-1。IR (KBr): 3400, 1755, 1670, 1540 cm -1 .
【０８４９】MS(FAB)(m/z)： 1682(MH+ ) 。MS (FAB) (m / z): 1682 (MH + ).
【０８５０】(f) 化合物709 の合成 ｉ） Ｂｏｃ体化合物708 （0.53ｇ）にトリフルオロ酢
酸（５ml）を加え室温下１時間撹拌した。トリフルオロ
酢酸を留去し、得られたアミノ体のジメチルホルムアミ
ド溶液に、液性が弱塩基性になるまでトリエチルアミン
を加えた。 (F) Synthesis of Compound 709 i) Trifluoroacetic acid (5 ml) was added to Boc compound 708 (0.53 g), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and triethylamine was added to a solution of the obtained amino compound in dimethylformamide until the solution became weakly basic.
【０８５１】ii） ベンジル体化合物706(320mg)のエタ
ノール（10ml）溶液に10％パラジウムカーボン(289mg)
を加え、水素加圧下(50psi) １時間振とう撹拌した。触
媒を濾去後、溶媒を留去し、残渣(308mg) のジメチルホ
ルムアミド（15ml）溶液にｉ）で得たアミノ体のジメチ
ルホルムアミド溶液及びＮ−ヒドロキシスクシンイミド
（43mg）を加えた。次いで、氷冷下Ｎ，Ｎ′−ジシクロ
ヘキシルカルボジイミド（77mg）のジメチルホルムアミ
ド溶液を滴下し、室温にて20時間撹拌し反応させた。Ii) 10% palladium carbon (289 mg) was added to a solution of the benzyl compound 706 (320 mg) in ethanol (10 ml).
Was added, and the mixture was shaken and stirred under hydrogen pressure (50 psi) for 1 hour. After removing the catalyst by filtration, the solvent was distilled off, and to the solution of the residue (308 mg) in dimethylformamide (15 ml) were added a solution of the amino compound obtained in i) in dimethylformamide and N-hydroxysuccinimide (43 mg). Then, a solution of N, N'-dicyclohexylcarbodiimide (77 mg) in dimethylformamide was added dropwise under ice cooling, and the mixture was stirred and reacted at room temperature for 20 hours.
【０８５２】反応液から不溶物を濾去し、濾液を食塩水
にあけて、酢酸エチルにて抽出し、抽出液を水、飽和食
塩水で洗浄後、乾燥した。溶媒を留去後、残渣にアセト
ニトリルを加え、不溶物を濾去した。濾液を濃縮し、残
渣をシリカゲルカラムクロマトグラフィー（クロロホル
ム−メタノール 99：１−98：２）にて精製してＢｏｃ
体化合物709 を 530mg（収率70％）得た。[0832] The insolubles were removed from the reaction solution by filtration, the filtrate was poured into saline, extracted with ethyl acetate, and the extract was washed with water and saturated saline, and then dried. After the solvent was distilled off, acetonitrile was added to the residue, and the insoluble matter was removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform-methanol 99: 1-98: 2) to give Boc
530 mg (70% yield) of the isomer compound 709 were obtained.
【０８５３】ＲF 0.38（クロロホルム−メタノール 9
5:5) 。[0853] R F 0.38 (chloroform-methanol 9
5: 5).
【０８５４】［α］D −11.0°(c 1.00 ，クロロホル
ム）。[Α] D -11.0 ° (c 1.00, chloroform).
【０８５５】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
42(s,9H)，1.97(s,9H)，2.03(s,9H)，2.05(s,18H) ，2.
06(s,9H)，2.12(s,9H)，2.15(s,9H)，4.87(t,3H)，4.96
(dd,3H) ，5.11(dd,3H) ，5.19(t,3H)，5.35(brd,3H)，
5.59(brd,1H)，6.75(brs,1H)，6.89(brs,1H)，7.09(br
d,1H)，7.40(brs,1H)。[0855] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 1.
42 (s, 9H), 1.97 (s, 9H), 2.03 (s, 9H), 2.05 (s, 18H), 2.
06 (s, 9H), 2.12 (s, 9H), 2.15 (s, 9H), 4.87 (t, 3H), 4.96
(dd, 3H), 5.11 (dd, 3H), 5.19 (t, 3H), 5.35 (brd, 3H),
5.59 (brd, 1H), 6.75 (brs, 1H), 6.89 (brs, 1H), 7.09 (br
d, 1H), 7.40 (brs, 1H).
【０８５６】IR(KBr) ：3480，1755，1650，1540，1520
cm-1。[0856] IR (KBr): 3480, 1755, 1650, 1540, 1520
cm -1 .
【０８５７】MS(FAB)(m/z)： 2350(MH+ ) 。MS (FAB) (m / z): 2350 (MH + ).
【０８５８】(g) 化合物710 の合成 Ｂｏｃ体化合物709 （52mg）のメタノール溶液にナトリ
ウムメトキシド（20μl ｉｎ 28％メタノール溶液）を
加えて、氷冷下１時間撹拌して反応させた。 (G) Synthesis of Compound 710 Sodium methoxide (20 μl in 28% methanol solution) was added to a methanol solution of Boc compound 709 (52 mg), and the mixture was stirred and reacted under ice cooling for 1 hour.
【０８５９】反応液に「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を
液性が中性になるまで加えた後、反応液より析出し、浮
遊している粉末をデカンテーションして取り出し、溶媒
を留去して、ラクトース誘導体である化合物710 を26mg
（収率77％）得た。After adding “Amberlyst 15E” to the reaction solution until the solution becomes neutral, the powder precipitated from the reaction solution, the suspended powder was removed by decantation, the solvent was distilled off, and the lactose derivative was removed. 26mg of compound 710
(77% yield).
【０８６０】ＲF 0.62（酢酸エチル−ピリジン−酢酸−
水 5:5:1:3)。R F 0.62 (ethyl acetate-pyridine-acetic acid-
Water 5: 5: 1: 3).
【０８６１】［α］D − 7.2°(c 0.5，メタノール−水
1:1)。[Α] D −7.2 ° (c 0.5, methanol-water
1: 1).
【０８６２】 1H-NMR(CD3 OD+D2 O)δ (ppm) in 500MH
z：1.45(s,9H)，4.31(d,3H)，4.38(d,3H)。[0862] 1 H-NMR (CD 3 OD + D 2 O) δ (ppm) in 500MH
z: 1.45 (s, 9H), 4.31 (d, 3H), 4.38 (d, 3H).
【０８６３】IR(KBr) ：3400，1650，1560，1540cm-1。IR (KBr): 3400, 1650, 1560, 1540 cm -1 .
【０８６４】MS(FAB)(m/z)： 1668 (MH+Na+ ) 。MS (FAB) (m / z): 1668 (MH + Na + ).
【０８６５】(h) 化合物711 の合成 Ｂｏｃ体化合物709(200mg)にトリフルオロ酢酸（４ml）
を加え、室温下１時間撹拌した。トリフルオロ酢酸を留
去し、残渣のジメチルホルムアミド溶液に液性が弱塩基
性になるまでトリエチルアミンを加えた。この溶液にＮ
−パルミトイルオキシサクシンイミド（33mg）のトルエ
ン（２ml）溶液を加え室温にて７時間撹拌して反応させ
た。 (H) Synthesis of Compound 711 Boc derivative Compound 709 (200 mg) was added to trifluoroacetic acid (4 ml).
Was added and stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and triethylamine was added to a solution of the residue in dimethylformamide until the solution became weakly basic. N
-A solution of palmitoyloxysuccinimide (33 mg) in toluene (2 ml) was added, and the mixture was stirred and reacted at room temperature for 7 hours.
【０８６６】反応液から目的物を酢酸エチルにて抽出
し、抽出液を水、飽和食塩水で洗浄後、乾燥した。溶媒
を留去後、残渣をシリカゲルカラムクロマトグラフィー
（クロロホルム−メタノール 50：１）にて精製しパル
ミトイル体 化合物711 を235mg(quant)得た。[0866] The target substance was extracted from the reaction solution with ethyl acetate, and the extract was washed with water and saturated saline and dried. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol 50: 1) to obtain 235 mg (quant) of palmitoyl compound 711.
【０８６７】ＲF 0.26（クロロホルム−メタノール 9
5:5) 。[0867] R F 0.26 (chloroform-methanol 9
5: 5).
【０８６８】［α］D −10.7°(c 1.0，クロロホル
ム）。[Α] D -10.7 ° (c 1.0, chloroform).
【０８６９】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：0.
88(t,3H)，1.965(s,9H) ，2.032(s,6H) ，2.038(s,3H)
，2.046(s,9H) ，2.060(s,9H) ，2.119(s,6H) ，2.123
(s,3H) ，2.152(s,9H) ，4.869(t,1H) ，4.872(t,1H)
，4.875(t,1H) ，4.962(dd,1H)，4.964(d,2H) ，5.11
(dd,3H) ，5.19(t,3H)，5.35(brd,3H)。[0869] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 0.
88 (t, 3H), 1.965 (s, 9H), 2.032 (s, 6H), 2.038 (s, 3H)
, 2.046 (s, 9H), 2.060 (s, 9H), 2.119 (s, 6H), 2.123
(s, 3H), 2.152 (s, 9H), 4.869 (t, 1H), 4.872 (t, 1H)
, 4.875 (t, 1H), 4.962 (dd, 1H), 4.964 (d, 2H), 5.11
(dd, 3H), 5.19 (t, 3H), 5.35 (brd, 3H).
【０８７０】IR(KBr) ：3430，1755，1640，1540cm-1。IR (KBr): 3430, 1755, 1640, 1540 cm -1 .
【０８７１】MS(FAB)(m/z)： 2668(MH+ ) 。MS (FAB) (m / z): 2668 (MH + ).
【０８７２】(i) 化合物712 の合成 パルミトイル体化合物711(214mg)をメタノール（５ml）
−テトラヒドロフラン(1.5ml) の混合液に溶解し、氷冷
下ナトリウムメトキシド（50μl 、28％ メタノール溶
液）を滴下し、そのまま氷冷下で４時間、さらに室温に
て 1.5時間撹拌して反応させた。 (I) Synthesis of Compound 712 Palmitoyl derivative Compound 711 (214 mg) was added to methanol (5 ml).
-Tetrahydrofuran (1.5 ml), sodium methoxide (50 μl, 28% methanol solution) was added dropwise under ice-cooling, and the mixture was allowed to react under ice-cooling for 4 hours and further at room temperature for 1.5 hours. Was.
【０８７３】反応液に氷冷下、水、塩化メチレンを加え
て析出した粉末を溶解し、これに液性が中性になるまで
「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を加えた。加えた樹脂を
濾去し、濾液を濃縮した。残渣にアセトニトリルを加え
て析出したラクトース誘導体（化合物712)を103mg(収率
69％）得た。[0873] Water and methylene chloride were added to the reaction solution under ice cooling to dissolve the precipitated powder, and "Amberlyst 15E" was added to the solution until the solution became neutral. The added resin was removed by filtration, and the filtrate was concentrated. 103 mg of lactose derivative (compound 712) precipitated by adding acetonitrile to the residue (yield
69%).
【０８７４】ＲF 0.76（酢酸エチル−ピリジン−酢酸−
水 5:5:1:3)。R F 0.76 (ethyl acetate-pyridine-acetic acid-
Water 5: 5: 1: 3).
【０８７５】［α］D − 4.6°(c 0.35 ，ジメチルスル
ホキシド）。[Α] D −4.6 ° (c 0.35, dimethyl sulfoxide).
【０８７６】 1H-NMR(DMSO) δ (ppm) in 500MHz：0.86
(t,3H)，4.17(d,3H)，4.20(d,3H)，7.74(brt,1H)，7.78
(brt,1H)，7.84(brt,1H)，7.86(brd,1H)，7.90(brd,1
H)。[0876] 1 H-NMR (DMSO) δ (ppm) in 500MHz: 0.86
(t, 3H), 4.17 (d, 3H), 4.20 (d, 3H), 7.74 (brt, 1H), 7.78
(brt, 1H), 7.84 (brt, 1H), 7.86 (brd, 1H), 7.90 (brd, 1
H).
【０８７７】IR(KBr) ：3400，1700，1640，1540cm-1。IR (KBr): 3400, 1700, 1640, 1540 cm -1 .
【０８７８】MS(FAB)(m/z)： 1786(MH+ ) 。MS (FAB) (m / z): 1786 (MH + ).
【０８７９】(j) 化合物714 の合成（図７ｃ） １）化合物713 の合成 β−ラクトースオクタアセテート化合物701(1.36ｇ,2mm
ol) 、トリエチレングリコールモノｎ−オクタデシルエ
ーテル(1.21 ｇ,3mmol) 及び塩化メチレン28mlの混合物
を氷冷し、３弗化ホウ素エーテル(1.42 ｇ,10mmol)を滴
下し、次いで室温で１晩反応した。反応液を10％重曹水
中に注加し、有機層をシリカゲルカラムクロマトグラフ
ィー（酢酸エチル−塩化メチレン、１：１）により精製
して化合物713(0.87ｇ,43 ％) を得た。 (J) Synthesis of Compound 714 (FIG. 7c) 1) Synthesis of Compound 713 β-Lactose Octaacetate Compound 701 (1.36 g, 2 mm
ol), a mixture of triethylene glycol mono n-octadecyl ether (1.21 g, 3 mmol) and methylene chloride (28 ml) was cooled on ice, boron trifluoride etherate (1.42 g, 10 mmol) was added dropwise, and the mixture was reacted at room temperature overnight. . The reaction solution was poured into 10% aqueous sodium bicarbonate, and the organic layer was purified by silica gel column chromatography (ethyl acetate-methylene chloride, 1: 1) to obtain Compound 713 (0.87 g, 43%).
【０８８０】元素分析値は、 C50 H84 O21としての計算
値：C,58.77 ；H,8.29に対し実測値：C,58.53 ；H,8.3
1。The elemental analysis values were calculated as C 50 H 84 O 21 : C, 58.77; H, 8.29, found: C, 58.53; H, 8.3
1.
【０８８１】［α］D 11.2゜(c 1.0, CHCl3 ) 。[Α] D 11.2 ゜ (c 1.0, CHCl 3 ).
【０８８２】 1H-NMR(500 MHz,CDCl3 ) ：δ=0.88(3H,
t,7.0Hz) ，1.25(30H,s) ，1.56(2H,m)，1.96，2.03，
2.041 ，2.043 ，2.06，2.12，2.15(each 3H) ，3.44(2
H,t,7.OHz)，3.62，3.71，3.91(10H,1H,1H,respectvel
y,m) ，〜3.6(1H) ，3.79(1H,t,9.5Hz)，3.87(1H,ddd,
7.3Hz,6.3Hz,1.0Hz)，4.08(1H,dd,11.2Hz,7.3Hz)，4.09
(1H,dd,12.0OHz,5.6Hz) ，4.13(1H,dd,11.2Hz,6.3Hz)，
4.48(2H,d,8.0Hz and dd,12.0Hz,2.0Hz)，4.56(1H,d,8.
0Hz)，4.89(1H,dd,9.5Hz,8.0Hz) ，4.95(1H,dd,10.4Hz,
3.4Hz)，5.11(1H,dd,10.4Hz,8.0Hz)，5.19(1H,t,9.5H
z)，5.34(1H,dd,3.4Hz,1.0Hz) 。 1 H-NMR (500 MHz, CDCl 3 ): δ = 0.88 (3H,
t, 7.0Hz), 1.25 (30H, s), 1.56 (2H, m), 1.96, 2.03,
2.041, 2.043, 2.06, 2.12, 2.15 (each 3H), 3.44 (2
H, t, 7.OHz), 3.62, 3.71, 3.91 (10H, 1H, 1H, respectvel
y, m), ~ 3.6 (1H), 3.79 (1H, t, 9.5Hz), 3.87 (1H, ddd,
7.3Hz, 6.3Hz, 1.0Hz), 4.08 (1H, dd, 11.2Hz, 7.3Hz), 4.09
(1H, dd, 12.0OHz, 5.6Hz), 4.13 (1H, dd, 11.2Hz, 6.3Hz),
4.48 (2H, d, 8.0Hz and dd, 12.0Hz, 2.0Hz), 4.56 (1H, d, 8.
0Hz), 4.89 (1H, dd, 9.5Hz, 8.0Hz), 4.95 (1H, dd, 10.4Hz,
3.4Hz), 5.11 (1H, dd, 10.4Hz, 8.0Hz), 5.19 (1H, t, 9.5H
z), 5.34 (1H, dd, 3.4Hz, 1.0Hz).
【０８８３】２）化合物714 の合成 化合物713(0.6 ｇ,0.587mmol) 、28％ナトリウムメチラ
ート0.2ml 及びメタノール18mlの混合物を室温で４時間
撹拌し、中和後溶媒を留去し、残固体を塩化メチレン−
メタノールで再結晶して化合物714(0.37ｇ,87 ％) を得
た。2) Synthesis of compound 714 A mixture of compound 713 (0.6 g, 0.587 mmol), 28% sodium methylate 0.2 ml and methanol 18 ml was stirred at room temperature for 4 hours. After neutralization, the solvent was distilled off. With methylene chloride
Recrystallization from methanol gave compound 714 (0.37 g, 87%).
【０８８４】m.p.：159-160 ℃。M.p .: 159-160 ° C.
【０８８５】元素分析値は、 C36 H70 O14としての計算
値：C ，59.48 ；H ，9.71に対し実測値：C ，58.81 ；
H ，9.51。The elemental analysis values were calculated as C 36 H 70 O 14 : C, 59.48; H, 9.71, actual values: C, 58.81;
H, 9.51.
【０８８６】［α］D -4.1゜(c 1.0, CHCl3 -CH3 OH、
1:1)。[Α] D -4.1 ゜ (c 1.0, CHCl 3 —CH 3 OH,
1: 1).
【０８８７】 1H-NMR(500 MHz,CDCl3 -CD3 OD、9:1)：
δ=0.87(3H,t,7.0Hz) ，1.28(30H,s)，1.57(2H,m)，3.1
〜4.0(26H,m)，4.33(1H,d,7.5Hz)，4.39(1H,d,8.0H
z)。 1 H-NMR (500 MHz, CDCl 3 -CD 3 OD, 9: 1):
δ = 0.87 (3H, t, 7.0Hz), 1.28 (30H, s), 1.57 (2H, m), 3.1
~ 4.0 (26H, m), 4.33 (1H, d, 7.5Hz), 4.39 (1H, d, 8.0H
z).
【０８８８】(k) 化合物718 の合成（図７ｄ） １）化合物715 の合成 β−Ｄ−ラクト−スオクタアセテート（化合物701 ）6.
99ｇ及び２−［２−（２−アジドエトキシ）エトキシ］
エタノール2.35ｇを塩化メチレン40mlに溶かし、氷冷下
撹拌した。ここに三フッ化硼素ジエチルエーテル錯体5.
1ml を塩化メチレン15mlに溶かして15分間で滴下した。
室温で15時間撹拌した後、氷水にあけ、有機層を分離し
た。３回水洗した後（水層は中性となった）、飽和食塩
水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下
留去した。残渣をシリカゲルカラムクロマトグラフィー
で精製し（溶出溶媒：ｎ−ヘキサン−酢酸エチル １：
２）、目的物を無色油状物として2.87ｇ得た。 (K) Synthesis of Compound 718 (FIG. 7d) 1) Synthesis of Compound 715 β-D-lactosoctoacetate (Compound 701) 6.
99 g and 2- [2- (2-azidoethoxy) ethoxy]
2.35 g of ethanol was dissolved in 40 ml of methylene chloride and stirred under ice cooling. Here boron trifluoride diethyl ether complex 5.
1 ml was dissolved in 15 ml of methylene chloride and added dropwise over 15 minutes.
After stirring at room temperature for 15 hours, the mixture was poured into ice water and the organic layer was separated. After washing three times with water (the aqueous layer became neutral), it was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 1:
2), 2.87 g of the desired product was obtained as a colorless oil.
【０８８９】 1H-NMR(δ, CDCl3 ) ：1.97(s,3H)，2.04
(s,9H)，2.06(s,3H)，2.12(s,3H)，2.15(s,3H)，3.40
(t,2H,J=5.0Hz)，3.58-3.75(m,10H)，3.79(t,1H,J=9.4H
z)，3.85-3.88(m,1H) ，3.89-3.93(m,1H) ，4.06-4.15
(m,2H) ，4.47-4.50(m,2H) ，4.57(d,1H,J=8.0Hz)，4.9
0(dd,1H,J=8.0Hz, 9.5Hz)，4.95(dd,1H,J=3.5Hz,10.3H
z)，5.11(dd,1H,J=8.0Hz,10.3Hz)，5.20(t,1H,J=9.4H
z)，5.35(bd,1H,J=3.5Hz) 。 1 H-NMR (δ, CDCl 3 ): 1.97 (s, 3H), 2.04
(s, 9H), 2.06 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.40
(t, 2H, J = 5.0Hz), 3.58-3.75 (m, 10H), 3.79 (t, 1H, J = 9.4H
z), 3.85-3.88 (m, 1H), 3.89-3.93 (m, 1H), 4.06-4.15
(m, 2H), 4.47-4.50 (m, 2H), 4.57 (d, 1H, J = 8.0Hz), 4.9
0 (dd, 1H, J = 8.0Hz, 9.5Hz), 4.95 (dd, 1H, J = 3.5Hz, 10.3H
z), 5.11 (dd, 1H, J = 8.0Hz, 10.3Hz), 5.20 (t, 1H, J = 9.4H
z), 5.35 (bd, 1H, J = 3.5Hz).
【０８９０】［α］D 24= -9.8゜(c=1.03 ，CHCl3 ) 。[Α] D 24 = −9.8 ゜ (c = 1.03, CHCl 3 ).
【０８９１】２）化合物716 の合成 化合物715 、2.69ｇに酢酸エチル150ml を加えて溶かし
た。ここにｐ−トルエンスルホン酸１水和物0.65ｇ及び
リンドラー触媒1.32ｇを加え、50ｐｓｉで4.5時間接触
還元した。さらにリンドラー触媒1.31ｇを加え、50ｐｓ
ｉで2.5 時間接触還元した。触媒を濾去し、目的物を淡
褐色油状物として3.11ｇ得た。これ以上の精製はせず
に、以下の反応を用いた。2) Synthesis of compound 716 To 2.69 g of compound 715, 150 ml of ethyl acetate was added and dissolved. 0.65 g of p-toluenesulfonic acid monohydrate and 1.32 g of Lindlar catalyst were added thereto, and the mixture was catalytically reduced at 50 psi for 4.5 hours. Add 1.31g of Lindlar catalyst and add 50ps
i for 2.5 hours. The catalyst was removed by filtration to obtain 3.11 g of the desired product as a pale brown oil. The following reaction was used without further purification.
【０８９２】４）化合物717 の合成 化合物716 、1.51ｇに塩化メチレン20ml及びトリエチル
アミン220 μｌを加えて溶かし、ここに上記反応で得た
化合物1103全量を塩化メチレン５mlに溶かして加え、さ
らに19.5時間撹拌した。塩化メチレンで希釈し、10％ク
エン酸、水及び飽和食塩水で洗い、硫酸マグネシウム上
乾燥させ、溶媒を減圧下留去した。残渣をシリカゲルカ
ラムクロマトグラフィーで精製し（溶出溶媒：ｎ−ヘキ
サン−酢酸エチル １：２）、目的物を無色油状物とし
て1.62ｇ得た。4) Synthesis of Compound 717 To 1.51 g of Compound 716, 20 mL of methylene chloride and 220 μL of triethylamine were added and dissolved, and the entire amount of Compound 1103 obtained by the above reaction was dissolved in 5 mL of methylene chloride, and the mixture was further stirred for 19.5 hours. did. The mixture was diluted with methylene chloride, washed with 10% citric acid, water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate 1: 2) to give 1.62 g of the desired product as a colorless oil.
【０８９３】 1H-NMR(δ, CDCl3 ) ：0.88(t,6H,J=7.0H
z)，1.19-1.43(m,58H)，1.54-1.61(m,2H) ，1.97(s,3
H)，1.97-2.11(m,1H) ，2.04(s,3H)，2.05(s,6H)，2.06
(s,3H)，2.12(s,3H)，2.15(s,3H)，3.44-3.73(m,12H)，
3.79(t,1H,J=9.4Hz)) ，3.86-3.89(m,1H) ，3.91-3.95
(m,1H) ，4.06-4.15(m,3H) ，4.48-4.51(m,2H) ，4.55
(d,1H,J=8.0Hz)，4.90(dd,1H,J=8.0Hz, 9.4Hz)，4.96(d
d,1H,J=3.4Hz,10.5Hz)，5.11(dd,1H,J=8.1Hz,10.5Hz)，
5.20(t,1H,J=9.4Hz)，5.34(dd,1H,J=0.9Hz,3.4Hz)， 5.
95(t,1H,J=5.5Hz) 。[0893] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z), 1.19-1.43 (m, 58H), 1.54-1.61 (m, 2H), 1.97 (s, 3
H), 1.97-2.11 (m, 1H), 2.04 (s, 3H), 2.05 (s, 6H), 2.06
(s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.44-3.73 (m, 12H),
3.79 (t, 1H, J = 9.4Hz)), 3.86-3.89 (m, 1H), 3.91-3.95
(m, 1H), 4.06-4.15 (m, 3H), 4.48-4.51 (m, 2H), 4.55
(d, 1H, J = 8.0Hz), 4.90 (dd, 1H, J = 8.0Hz, 9.4Hz), 4.96 (d
d, 1H, J = 3.4Hz, 10.5Hz), 5.11 (dd, 1H, J = 8.1Hz, 10.5Hz),
5.20 (t, 1H, J = 9.4Hz), 5.34 (dd, 1H, J = 0.9Hz, 3.4Hz), 5.
95 (t, 1H, J = 5.5 Hz).
【０８９４】［α］D 24=-6.6 ゜(c=1.05 ，CHCl3 ) 。[Α] D 24 = −6.6 c (c = 1.05, CHCl 3 ).
【０８９５】５）化合物718 の合成 化合物717 、0.79ｇにメタノール５ml及びベンゼン10ml
を加えて溶かし、氷冷下撹拌した。ここに28％ナトリウ
ムメトキシドメタノール溶液を５滴加えてｐＨ＝12と
し、室温で３時間撹拌した。ここに「ダウエックス50Ｘ
−８」イオン交換樹脂（Ｈ型）を加えて中和し、樹脂を
濾去した。溶媒を減圧下留去し、残渣を「セファデック
スＬＨ−20」で精製し（溶出溶媒：クロロホルム−メタ
ノール ２：１）、目的化合物を0.60ｇ得た。5) Synthesis of Compound 718 Compound (717) (0.79 g) was added to methanol (5 ml) and benzene (10 ml).
Was added and dissolved, and the mixture was stirred under ice cooling. Five drops of a 28% sodium methoxide methanol solution were added thereto to adjust the pH to 12, and the mixture was stirred at room temperature for 3 hours. Here, "Dowex 50X
-8 "Ion exchange resin (H type) was added for neutralization, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 2: 1) to obtain 0.60 g of the desired compound.
【０８９６】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,6H,J=6.8Hz)，1.20-1.61(m,58H)，1.90-2.00(m,2H)
，2.50-2.58(m,1H) ，3.59-3.82(m,11H)，3.84-3.91
(m,2H) ，3.99(bt,1H) ，4.10-4.14(m,2H) ，4.18-4.26
(m,3H) ，4.34(dd,1H,J=5.0Hz,11.0Hz)，4.40-4.50(m,5
H) ，4.77(d,1H,J=7.5Hz)，5.06(d,1H,J=8.0Hz)，8.82
(bt,1H) 。[0896] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.88
(t, 6H, J = 6.8Hz), 1.20-1.61 (m, 58H), 1.90-2.00 (m, 2H)
, 2.50-2.58 (m, 1H), 3.59-3.82 (m, 11H), 3.84-3.91
(m, 2H), 3.99 (bt, 1H), 4.10-4.14 (m, 2H), 4.18-4.26
(m, 3H), 4.34 (dd, 1H, J = 5.0Hz, 11.0Hz), 4.40-4.50 (m, 5
H), 4.77 (d, 1H, J = 7.5 Hz), 5.06 (d, 1H, J = 8.0 Hz), 8.82
(bt, 1H).
【０８９７】［α］D 22= -3.0゜(c=1.01 ，CHCl3 -MeO
H 2:1)。[Α] D 22 = −3.0 ゜ (c = 1.01, CHCl 3 -MeO
H 2: 1).
【０８９８】FAB-MS:[M+H]+ ;m/z=964。FAB-MS: [M + H] + ; m / z = 964.
【０８９９】実施例８（アセチルガラクトサミン系誘導
体の合成） 本実施例における反応式を図８ａ乃至図８ｋに示す。Example 8 (Synthesis of Acetylgalactosamine Derivative) The reaction formulas in this example are shown in FIGS. 8A to 8K.
【０９００】また、旋光度は特に指示のない限り全て25
℃での測定値である。[0900] All optical rotations are 25 unless otherwise specified.
It is a measured value in ° C.
【０９０１】(a) 化合物816 の合成 室温でα−アセチル体化合物813(10.0ｇ）の１，２−ジ
クロロエタン(100ml)溶液にトリフルオロメタンスルホ
ン酸トリメチルシリル(5.5ml) を加え、50〜55℃にて
5.5時間加熱撹拌して反応させた。反応液に氷冷下トリ
エチルアミン(7.9ml) を加え、溶媒を留去し、残渣をシ
リカゲルカラムクロマトグラフィー（クロロホルム−メ
タノール−トリエチルアミン 99:0.5:0.5) にて精製し
た。 (A) Synthesis of Compound 816 To a solution of α-acetyl compound 813 (10.0 g) in 1,2-dichloroethane (100 ml) at room temperature was added trimethylsilyl trifluoromethanesulfonate (5.5 ml), and the mixture was heated to 50 to 55 ° C. hand
The mixture was reacted by heating and stirring for 5.5 hours. Triethylamine (7.9 ml) was added to the reaction mixture under ice cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform-methanol-triethylamine 99: 0.5: 0.5).
【０９０２】得られたオキサゾリン誘導体（8.12ｇ）及
び「モレキュラーシーブス４Ａ」（10ｇ）の１，２−ジ
クロロエタン(100ml) 溶液に、室温下、トリフルオロメ
タンスルホン酸トリメチルシリル(5.2ml) を加え、つい
で２−［２−（２−クロルエトキシ）エトキシ］エタノ
ール(7.2ml) を加え、16時間撹拌して反応させた。To a solution of the obtained oxazoline derivative (8.12 g) and “Molecular Sieves 4A” (10 g) in 1,2-dichloroethane (100 ml) at room temperature was added trimethylsilyl trifluoromethanesulfonate (5.2 ml). -[2- (2-Chloroethoxy) ethoxy] ethanol (7.2 ml) was added, and the mixture was stirred and reacted for 16 hours.
【０９０３】反応液にトリエチルアミン(7.9ml) を加え
た後、水にあけ、塩化メチレンにて抽出し、抽出液を
水、食塩水で順次洗浄後、乾燥した。溶媒を留去後、残
渣(17.04ｇ）をシリカゲルカラムクロマトグラフィー
（トルエン−酢酸エチル ３：７→クロロホルム−メタ
ノール 97：３）にて精製しグリコシド体 化合物816
を8.53ｇ（収率67％）を得た。[0993] After adding triethylamine (7.9 ml) to the reaction solution, the mixture was poured into water, extracted with methylene chloride, and the extract was washed with water and brine in that order and dried. After evaporating the solvent, the residue (17.04 g) was purified by silica gel column chromatography (toluene-ethyl acetate 3: 7 → chloroform-methanol 97: 3) to give glycoside compound 816.
8.53 g (67% yield).
【０９０４】ＲF 0.35（クロロホルム−メタノール 9
5:5) 。R F 0.35 (chloroform-methanol 9
5: 5).
【０９０５】［α］D −29.6°(c 1.13 ，クロロホル
ム）。[Α] D -29.6 ° (c 1.13, chloroform).
【０９０６】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
99(s,6H)，2.05(s,3H)，2.16(s,3H)，4.10(dd,1H) ，4.
80(d,1H)，5.02(dd,1H) ，5.3(brd,1H) ，6.21(d,1H)。 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz: 1.
99 (s, 6H), 2.05 (s, 3H), 2.16 (s, 3H), 4.10 (dd, 1H), 4.
80 (d, 1H), 5.02 (dd, 1H), 5.3 (brd, 1H), 6.21 (d, 1H).
【０９０７】IR(neat)：3300，1740，1670，1560cm-1。IR (neat): 3300, 1740, 1670, 1560 cm -1 .
【０９０８】(b) 化合物817 の合成 グリコシド体化合物816 （8.53ｇ）のジメチルホルムア
ミド（50ml）溶液にアジ化ナトリウム(5.6ｇ）を加え、
60℃にて15時間加熱撹拌して反応させた。 (B) Synthesis of Compound 817 Glycoside derivative To a solution of compound 816 (8.53 g) in dimethylformamide (50 ml) was added sodium azide (5.6 g).
The mixture was reacted by heating and stirring at 60 ° C. for 15 hours.
【０９０９】反応液を水にあけ、酢酸エチルで抽出し、
抽出液を水、飽和食塩水で洗浄後、乾燥した。溶媒を留
去してアジト体化合物817 を8.22ｇ（収率96％）得た。[0909] The reaction solution was poured into water and extracted with ethyl acetate.
The extract was washed with water and saturated saline and then dried. The solvent was distilled off to obtain 8.22 g (96% yield) of an azido compound 817.
【０９１０】ＲF 0.35（クロロホルム−メタノール 9
5:5) 。R F 0.35 (chloroform-methanol 9
5: 5).
【０９１１】［α］D −33.4°(c 1.73 ，クロロホル
ム）。[Α] D -33.4 ° (c 1.73, chloroform).
【０９１２】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：1.
94(s,3H)，1.95(s,3H)，2.03(s,3H)，2.14(s,3H)，4.65
(d,1H)，5.06(dd,1H) ，5.33(brd,1H)。 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 1.
94 (s, 3H), 1.95 (s, 3H), 2.03 (s, 3H), 2.14 (s, 3H), 4.65
(d, 1H), 5.06 (dd, 1H), 5.33 (brd, 1H).
【０９１３】IR(KBr) ：3300，1740，1670，1550cm-1。IR (KBr): 3300, 1740, 1670, 1550 cm -1 .
【０９１４】(c) 化合物819 の合成 ｉ） アジド体化合物817 （8.22ｇ）のエタノール（80
ml) 溶液にトルエンスルホン酸（3.25ｇ，17.1mmol) お
よびリンドラー触媒（４ｇ）を加え、水素加圧下(50ps
i) １時間振とう撹拌した。リンドラー触媒（３ｇ）を
追加し、更に１時間振とう撹拌した後、触媒をセライト
にて濾去し、溶媒を留去してアミノ体化合物818 を10.5
ｇ得た。 (C) Synthesis of Compound 819 i) Azide Compound 817 (8.22 g) in ethanol (80
Toluenesulfonic acid (3.25 g, 17.1 mmol) and Lindlar catalyst (4 g) were added to the solution, and the mixture was added under hydrogen pressure (50 ps).
i) Shake and stir for 1 hour. After adding a Lindlar catalyst (3 g) and shaking and stirring for an additional hour, the catalyst was removed by filtration through Celite, and the solvent was distilled off to give the amino compound 818 in 10.5.
g was obtained.
【０９１５】ii） 上で得たアミノ体化合物818 の一部
（3.05ｇ）のアセトニトリル（20ml）溶液にトリエチル
アミン(1.5ml) を加え、これを化合物805 Ｂｏｃ−Ｇｌ
ｕ（ＯＢｚｌ）ＯＳｕ（2.15ｇ）のアセトニトリル（60
ml）溶液に滴下し、室温にて14時間撹拌して反応させ
た。Ii) To a solution of a part (3.05 g) of the amino compound 818 obtained above in acetonitrile (20 ml) was added triethylamine (1.5 ml), and this was added to the compound 805 Boc-Gl.
u (OBzl) OSu (2.15 g) in acetonitrile (60
ml), and the mixture was stirred and reacted at room temperature for 14 hours.
【０９１６】反応液から溶媒を留去し、残渣を塩化メチ
レンに溶解し水、食塩水にて洗浄後、乾燥した。溶媒を
留去後、残渣（3.76ｇ）をシリカゲルカラムクロマトグ
ラフィー（クロロホルム：メタノール 99：１−98：
２）にて精製してベンジル体化合物819 を3.29ｇ（収率
88％）を得た。[0916] The solvent was distilled off from the reaction solution, and the residue was dissolved in methylene chloride, washed with water and brine, and dried. After the solvent was distilled off, the residue (3.76 g) was subjected to silica gel column chromatography (chloroform: methanol 99: 1-98:
Purified in 2), 3.29 g of benzyl compound 819 (yield)
88%).
【０９１７】ＲF 0.40（クロロホルム−メタノール 9
5:5) 。R F 0.40 (chloroform-methanol 9
5: 5).
【０９１８】［α］D −12.3°(c 1.0，CHCl3 ）。[Α] D -12.3 ° (c 1.0, CHCl 3 ).
【０９１９】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
43(s,9H)，1.93(s,3H)，1.94(s,3H)，2.02(s,3H)，2.13
(s,3H)，4.65(d,1H)，5.08(dd,1H) ，5.13(s,2H)，5.33
(brd,1H)，7.2-7.4(m,5H) 。 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz: 1.
43 (s, 9H), 1.93 (s, 3H), 1.94 (s, 3H), 2.02 (s, 3H), 2.13
(s, 3H), 4.65 (d, 1H), 5.08 (dd, 1H), 5.13 (s, 2H), 5.33
(brd, 1H), 7.2-7.4 (m, 5H).
【０９２０】IR (CHCl3 ) ：3400，1740，1670，1520cm
-1。[0920] IR (CHCl 3): 3400,1740,1670,1520cm
-1 .
【０９２１】(d) 化合物820 の合成 化合物807 のＢｏｃ−Ｇｌｕ（1.33ｇ）及びＮ−ヒドロ
キシスクシンイミド（1.37ｇ）の塩化メチレン（80ml）
溶液に、室温にてＮ，Ｎ′−ジシクロヘキシルカルボジ
イミド（2.45ｇ）の塩化メチレン（40ml）溶液を加え１
時間撹拌して反応させた。先に得たアミノ体化合物818
（7.37ｇ）の塩化メチレン（20ml）溶液にトリエチルア
ミン(3.5ml) を加え、これを上記の反応混合物に滴下し
た。室温で14時間撹拌して反応させた。 (D) Synthesis of Compound 820 Compound 807 Boc-Glu (1.33 g) and N-hydroxysuccinimide (1.37 g) in methylene chloride (80 ml)
To the solution was added a solution of N, N'-dicyclohexylcarbodiimide (2.45 g) in methylene chloride (40 ml) at room temperature.
The mixture was stirred for an hour to react. Amino compound 818 obtained earlier
To a solution of (7.37 g) in methylene chloride (20 ml) was added triethylamine (3.5 ml), which was added dropwise to the above reaction mixture. The reaction was carried out by stirring at room temperature for 14 hours.
【０９２２】反応液を水にあけて塩化メチレンにて抽出
し、抽出液を水、飽和食塩水で洗浄後、乾燥した。溶媒
を留去後、残渣（6.93ｇ）をシリカゲルカラムクロマト
グラフィー（クロロホルム：メタノール 97：３−95：
５）にて精製してジアミド体化合物820 を4.43ｇ（収率
68％）得た。[0922] The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and saturated saline, and then dried. After the solvent was distilled off, the residue (6.93 g) was subjected to silica gel column chromatography (chloroform: methanol 97: 3-95:
Purified in 5), 4.43 g of diamide compound 820 (yield)
68%).
【０９２３】ＲF 0.59（クロロホルム−メタノール 9:
1)。R F 0.59 (chloroform-methanol 9:
1).
【０９２４】［α］D −16.3°(c 1.0，メタノール）。[Α] D -16.3 ° (c 1.0, methanol).
【０９２５】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
44(s,9H)，1.93(s,6H)，1.95(s,6H)，2.03(s,6H)，2.14
(s,6H)，4.64(d,1H)，4.65(d,1H)，5.07(dd,1H) ，5.08
(dd,1H) ，5.33(brd,2H)。 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz: 1.
44 (s, 9H), 1.93 (s, 6H), 1.95 (s, 6H), 2.03 (s, 6H), 2.14
(s, 6H), 4.64 (d, 1H), 4.65 (d, 1H), 5.07 (dd, 1H), 5.08
(dd, 1H), 5.33 (brd, 2H).
【０９２６】IR(KBr) ：3400，1750，1650，1245cm-1。IR (KBr): 3400, 1750, 1650, 1245 cm -1 .
【０９２７】(e) 化合物821 の合成 ｉ） ベンジル体化合物819 （1.27ｇ）のエタノール
（60ml）溶液に10％パラジウムカーボン(200mg) を加
え、室温にて水素加圧下(50psi)1.5時間振とう撹拌し
た。触媒を濾去し、濾液を濃縮し得られた残渣（1.22g)
およびＮ−ヒドロキシスクシンイミド(219mg) の塩化メ
チレン（85ml）溶液にＮ，Ｎ′−ジシクロホキシルカル
ボジイミド(394mg) を加え、１時間撹拌した。 (E) Synthesis of Compound 821 i) To a solution of benzyl compound 819 (1.27 g) in ethanol (60 ml) was added 10% palladium carbon (200 mg), and the mixture was shaken at room temperature under hydrogen pressure (50 psi) for 1.5 hours. Stirred. The catalyst was removed by filtration, and the filtrate was concentrated to give a residue (1.22 g).
N, N'-dicyclooxylcarbodiimide (394 mg) was added to a methylene chloride (85 ml) solution of N-hydroxysuccinimide (219 mg) and N-hydroxysuccinimide (219 mg), and the mixture was stirred for 1 hour.
【０９２８】ii） ジアミド体化合物820 (1.7ｇ）にト
リフロロ酢酸（15ml）を加え、室温にて１時間撹拌し
た。トリフロロ酢酸を留去し、得られた残渣の塩化メチ
レン（40ml）溶液に、液性が弱塩基性になるまでトリエ
チルアミンを加えた。Ii) Trifluoroacetic acid (15 ml) was added to the diamide derivative 820 (1.7 g), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and triethylamine was added to a solution of the obtained residue in methylene chloride (40 ml) until the solution became weakly basic.
【０９２９】この溶液を、上記ｉ）の反応混合物に滴下
した。室温で終夜撹拌して反応させた。This solution was added dropwise to the reaction mixture of the above i). The reaction was stirred overnight at room temperature.
【０９３０】反応液を水にあけ、塩化メチレンにて抽出
し、抽出液を水、食塩水で洗浄後、乾燥した。溶媒を留
去後、残渣にアセトニトリルを加え、不溶物を濾去し、
濾液を濃縮し、残渣(3.4ｇ）をシリカゲルカラムクロマ
トグラフィー（クロロホルム：メタノール 93：７−9
2：８）にて精製してトリアミド体化合物821 を1.44ｇ
（収率68％）得た。[0930] The reaction solution was poured into water and extracted with methylene chloride. The extract was washed with water and brine, and dried. After evaporating the solvent, acetonitrile was added to the residue, and the insoluble material was removed by filtration.
The filtrate was concentrated, and the residue (3.4 g) was subjected to silica gel column chromatography (chloroform: methanol 93: 7-9).
2: 8) Purified by 1.44g of triamide compound 821
(68% yield).
【０９３１】ＲF 0.41（クロロホルム−メタノール 9:
1)。R F 0.41 (chloroform-methanol 9:
1).
【０９３２】［α］D −16.6°(c 1.22 ，メタノー
ル）。[Α] D −16.6 ° (c 1.22, methanol).
【０９３３】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：1.
44(s,9H)，1.94(s,9H)，1.95(s,9H)，2.03(s,9H)，2.15
(s,9H)，4.64(d,1H)，4.65(d,2H)，5.08(m,3H)，5.34(b
rd,3H)。 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz: 1.
44 (s, 9H), 1.94 (s, 9H), 1.95 (s, 9H), 2.03 (s, 9H), 2.15
(s, 9H), 4.64 (d, 1H), 4.65 (d, 2H), 5.08 (m, 3H), 5.34 (b
rd, 3H).
【０９３４】IR(KBr) ：3400，1750，1660，1550cm-1。IR (KBr): 3400, 1750, 1660, 1550 cm -1 .
【０９３５】(f) 化合物822 の合成 トリアミド体化合物821 （30mg）のメタノール（１ml）
溶液にナトリウムメトキシド（６μl 、28％メタノール
溶液）を加え、室温にて３時間撹拌して反応させた。 (F) Synthesis of Compound 822 Triamide Compound 821 (30 mg) in methanol (1 ml)
Sodium methoxide (6 μl, 28% methanol solution) was added to the solution, and the mixture was stirred and reacted at room temperature for 3 hours.
【０９３６】反応液に「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を
加え、液性をほぼ中性とし、加えた樹脂を濾去後、濾液
を濃縮し、Ｂｏｃ体化合物822 を14mg（収率59％）得
た。[0936] "Amberlyst 15E" was added to the reaction solution to make the solution almost neutral, and the added resin was removed by filtration. The filtrate was concentrated to obtain 14 mg of Boc compound 822 (yield 59%).
【０９３７】ＲF 0.37（酢酸エチル−ピリジン−酢酸−
水 5:5:1:3)。R F 0.37 (ethyl acetate-pyridine-acetic acid-
Water 5: 5: 1: 3).
【０９３８】［α］D − 7.3°(c 0.78 ，メタノー
ル）。[Α] D −7.3 ° (c 0.78, methanol).
【０９３９】 1H-NMR(CD3 OD＋CDCl3 ) δ (ppm) in 50
0MHz：1.44(s,9H)，1.99(s,9H)，4.4-4.45(m,3H)。 1 H-NMR (CD 3 OD + CDCl 3 ) δ (ppm) in 50
0 MHz: 1.44 (s, 9H), 1.99 (s, 9H), 4.4-4.45 (m, 3H).
【０９４０】IR(KBr) ：3450，1650，1560，1120，1070
cm-1。[0940] IR (KBr): 3450, 1650, 1560, 1120, 1070
cm -1 .
【０９４１】(g) 化合物823 の合成 トリアミド体化合物821(176mg)にトリフルオロ酢酸（４
ml）を加え、室温にて１時間撹拌した。シリフルオロ酢
酸を留去し、残渣の塩化メチレン（６ml）溶液にトリエ
チルアミンを加えて、液性を弱塩基性としてた。この溶
液にＮ−パルミトイルオキシスクシンイミド（43mg）の
トルエン（４ml）溶液を加え、室温にて18時間撹拌して
反応させた。 (G) Synthesis of Compound 823 Triamide derivative Compound 821 (176 mg) was added to trifluoroacetic acid (4
ml) and stirred at room temperature for 1 hour. The silyfluoroacetic acid was distilled off, and triethylamine was added to a solution of the residue in methylene chloride (6 ml) to make the solution weakly basic. To this solution was added a solution of N-palmitoyloxysuccinimide (43 mg) in toluene (4 ml), and the mixture was stirred and reacted at room temperature for 18 hours.
【０９４２】反応液を食塩水にあけて、塩化メチレンに
て抽出し、抽出液を水、食塩水で洗浄後、乾燥した。溶
媒を留去後、残渣(185mg) をシリカゲルカラムクロマト
グラフィー（クロロホルム：メタノール 95：５−93：
７）にて精製し、パルミトイル体化合物823 を132mg(収
率70％）得た。[0942] The reaction solution was poured into saline and extracted with methylene chloride. The extract was washed with water and saline and dried. After the solvent was distilled off, the residue (185 mg) was subjected to silica gel column chromatography (chloroform: methanol 95: 5-93:
Purification was performed in 7) to obtain 132 mg (yield: 70%) of palmitoyl compound 823.
【０９４３】ＲF 0.38（クロロホルム−メタノール 9:
1)。[0931] R F 0.38 (chloroform-methanol 9:
1).
【０９４４】［α］D −18.3°(c 0.9，メタノール）。[Α] D -18.3 ° (c 0.9, methanol).
【０９４５】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(t,3H)，1.93(s,3H)，1.94(s,6H)，1.95(s,9H)，2.03
(s,9H)，2.14(s,9H)，4.64(d,1H)，4.65(d,2H)，5.06(d
d,2H) ，5.07(dd,1H) ，5.34(brd,3H)。[1045] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 0.
90 (t, 3H), 1.93 (s, 3H), 1.94 (s, 6H), 1.95 (s, 9H), 2.03
(s, 9H), 2.14 (s, 9H), 4.64 (d, 1H), 4.65 (d, 2H), 5.06 (d
d, 2H), 5.07 (dd, 1H), 5.34 (brd, 3H).
【０９４６】IR(KBr) ：3480，1750，1650，1245cm-1。IR (KBr): 3480, 1750, 1650, 1245 cm -1 .
【０９４７】(h) 化合物824 の合成 パルミトイル体化合物823 （19mg) のメタノール（１m
l）溶液にナトリウムメトキシド（３μl 、28％メタノ
ール溶液）を加え、氷冷下２時間撹拌した。 (H) Synthesis of Compound 824 Palmitoyl Form Compound 823 (19 mg) of methanol (1 m
l) To the solution was added sodium methoxide (3 µl, 28% methanol solution), and the mixture was stirred for 2 hours under ice cooling.
【０９４８】析出した粉末を濾取して、ＧａｌＮＡｃ誘
導体化合物824 を10mg（収率65％）得た。The precipitated powder was collected by filtration to obtain 10 mg (yield: 65%) of GalNAc derivative compound 824.
【０９４９】ＲF 0.14（クロロホルム−メタノール−水
10:6:1) 。R F 0.14 (chloroform-methanol-water
10: 6: 1).
【０９５０】［α］D − 3.7°(c 0.54 ，クロロホルム
−メタノール−水 10:10:3)。[Α] D −3.7 ° (c 0.54, chloroform-methanol-water 10: 10: 3).
【０９５１】 1H-NMR(CD3 OD＋CDCl3 ) δ (ppm) in 50
0MHz：0.89(t,3H)，2.01(s,9H)，4.456(d,1H) ，4.463
(d,1H) ，4.47(d,1H)。[0951] 1 H-NMR (CD 3 OD + CDCl 3) δ (ppm) in 50
0MHz: 0.89 (t, 3H), 2.01 (s, 9H), 4.456 (d, 1H), 4.463
(d, 1H), 4.47 (d, 1H).
【０９５２】IR(KBr) ：3440，3300，1640，1550cm-1。IR (KBr): 3440, 3300, 1640, 1550 cm -1 .
【０９５３】(i) 化合物826 の合成 ｉ） カルボン酸化合物825 （55mg）およびＮ−ヒドロ
キシスクシンイミド（14mg）のアセトニトリル（４ml）
溶液にＮ，Ｎ′−ジシクロヘキシルカルボジイミド（25
mg）を加え室温にて 1.5時間撹拌した。 (I) Synthesis of compound 826 i) Carboxylic acid compound 825 (55 mg) and N-hydroxysuccinimide (14 mg) in acetonitrile (4 ml)
N, N'-dicyclohexylcarbodiimide (25
mg) and stirred at room temperature for 1.5 hours.
【０９５４】ii） トリアミド体化合物821(176mg)にト
リフルオロ酢酸（４ml）を加え、室温にて１時間撹拌し
た。トリフルオロ酢酸を留去し、残渣のアセトニトリル
溶液にトリエチルアミンを加えて液性を弱塩基性とし
た。この溶液をｉ）の反応液に滴下し、室温にて18時間
撹拌して反応させた。Ii) Triamide Compound 821 (176 mg) was added with trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 1 hour. The trifluoroacetic acid was distilled off, and triethylamine was added to an acetonitrile solution of the residue to make the liquid weakly basic. This solution was added dropwise to the reaction solution of i), and the mixture was reacted by stirring at room temperature for 18 hours.
【０９５５】反応液を濃縮し、残渣を塩化メチレンに溶
解し、水、食塩水で洗浄後、乾燥した。溶媒を留去後、
残渣(195mg) をシリカゲルカラムクロマトグラフィー
（クロロホルム−メタノール 95：５−93：７）にて精
製し、アミド体化合物826 を138mg(収率66％）得た。[0955] The reaction solution was concentrated, the residue was dissolved in methylene chloride, washed with water and brine, and dried. After distilling off the solvent,
The residue (195 mg) was purified by silica gel column chromatography (chloroform-methanol 95: 5-93: 7) to obtain 138 mg (66% yield) of amide compound 826.
【０９５６】ＲF 0.53（クロロホルム−メタノール 9:
1)。[0956] R F 0.53 (chloroform-methanol 9:
1).
【０９５７】［α］D −13.8°(c 0.91 ，メタノー
ル）。[Α] D -13.8 ° (c 0.91, methanol).
【０９５８】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(t,3H)，1.94(s,9H)，1.95(s,9H)，2.03(s,9H)，2.15
(s,9H ），4.55(s,2H)，4.648(d,1H) ，4.653(d,1H) ，
4.657(d,1H) ，5.07(m,3H)，5.34(brd,3H)。[0958] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 0.
90 (t, 3H), 1.94 (s, 9H), 1.95 (s, 9H), 2.03 (s, 9H), 2.15
(s, 9H), 4.55 (s, 2H), 4.648 (d, 1H), 4.653 (d, 1H),
4.657 (d, 1H), 5.07 (m, 3H), 5.34 (brd, 3H).
【０９５９】IR(KBr) ：3480，1750，1660cm-1。[0959] IR (KBr): 3480, 1750, 1660 cm -1 .
【０９６０】(j) 化合物827 の合成 アミド体化合物826(136mg)のメタノール（３ml）溶液に
ナトリウムメトキシド（12μl 、28％メタノール溶液）
を加え、氷冷下２時間撹拌して反応させた。 (J) Synthetic amide of compound 827 To a solution of compound 826 (136 mg) in methanol (3 ml) was added sodium methoxide (12 μl, 28% methanol solution).
Was added and stirred for 2 hours under ice cooling to cause a reaction.
【０９６１】反応後に「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を
加え、液性をほぼ中和とし、加えた樹脂を濾去後、濾液
を濃縮し、ＧａｌＮＡｃ誘導体化合物827 を80mg（収率
65％）得た。[0961] After the reaction, "Amberlyst 15E" was added to substantially neutralize the liquidity, and the added resin was removed by filtration. The filtrate was concentrated to obtain 80 mg of the GalNAc derivative compound 827 (yield).
65%).
【０９６２】ＲF 0.21（クロロホルム−メタノール−水
10:6:1) 。R F 0.21 (chloroform-methanol-water
10: 6: 1).
【０９６３】［α］D − 6.5°(c 1.3，メタノール）。[Α] D −6.5 ° (c 1.3, methanol).
【０９６４】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(t,3H)，1.99(s,9H)，4.44-4.46(m,3H) 。[0964] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 0.
90 (t, 3H), 1.99 (s, 9H), 4.44-4.46 (m, 3H).
【０９６５】IR(KBr) ：3440，1650，1555cm-1。IR (KBr): 3440, 1650, 1555 cm -1 .
【０９６６】(k) 化合物829 の合成 ｉ） カルボン酸化合物828 （47mg）及びＮ−ヒドロキ
シスクシンイミド（12mg）の塩化メチレン（４ml）溶液
にＮ，Ｎ′−ジシクロヘキシルカルボジイミド（21mg）
を加え室温にて１時間撹拌した。 (K) Synthesis of Compound 829 i) N, N'-Dicyclohexylcarbodiimide (21 mg) was added to a solution of carboxylic acid compound 828 (47 mg) and N-hydroxysuccinimide (12 mg) in methylene chloride (4 ml).
Was added and stirred at room temperature for 1 hour.
【０９６７】ii） トリアミド体化合物821(100mg)にト
リフルオロ酢酸（３ml）を加え、室温にて１時間撹拌し
た。トリフルオロ酢酸を留去し、残渣の塩化メチレン溶
液にトリエチルアミンを加えて、液性を弱塩基性とし
た。この溶液をｉ）の反応液に滴下し、室温にて18時間
撹拌し反応させた。Ii) Triamide (3 mg) was added to the compound 821 (100 mg), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and triethylamine was added to a methylene chloride solution of the residue to make the solution weakly basic. This solution was added dropwise to the reaction solution of i), and the mixture was stirred and reacted at room temperature for 18 hours.
【０９６８】反応液を水にあけ、塩化メチレンで抽出
し、抽出液を水、食塩水で洗浄後、乾燥した。溶媒を留
去後、残渣(195mg) をシリカゲルカラムクロマトグラフ
ィー（クロロホルム−メタノール 95：５−93：７）に
て精製してアミド体化合物829を89mg（収率71％）得
た。[0968] The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and brine, and dried. After evaporating the solvent, the residue (195 mg) was purified by silica gel column chromatography (chloroform-methanol 95: 5-93: 7) to obtain 89 mg of an amide compound 829 (yield 71%).
【０９６９】ＲF 0.52（クロロホルム−メタノール 9:
1)。R F 0.52 (chloroform-methanol 9:
1).
【０９７０】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(s,6H)，1.934(s,3H) ，1.937(s,6H) ，1.95(s,9H)，
2.03(s,9H)，2.15(s,9H)，4.63-4.67(m,3H) ，5.05-5.1
2(m,3H) ，5.34(brd,3H)。 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 0.
90 (s, 6H), 1.934 (s, 3H), 1.937 (s, 6H), 1.95 (s, 9H),
2.03 (s, 9H), 2.15 (s, 9H), 4.63-4.67 (m, 3H), 5.05-5.1
2 (m, 3H), 5.34 (brd, 3H).
【０９７１】IR(KBr) ：3450，1750，1660，1550cm-1。IR (KBr): 3450, 1750, 1660, 1550 cm -1 .
【０９７２】(l) 化合物830 の合成 アミド体化合物829 （87mg）のメタノール（４ml）溶液
にナトリウムメトキシド（８μl 、28％メタノール溶
液）を加え、室温下 1.5時間撹拌して反応させた。 (L) Synthesis of Compound 830 Amide Compound 829 (87 mg) was added to a methanol (4 ml) solution of sodium methoxide (8 μl, 28% methanol solution), and reacted by stirring at room temperature for 1.5 hours.
【０９７３】反応液を遠心分離に付し、得られた不溶物
にメタノールを加えて再び遠心分離に付し、ＧａｌＮＡ
ｃ誘導体化合物830 を49mg（収率67％）得た。[0973] The reaction solution was centrifuged, methanol was added to the obtained insoluble matter, and the mixture was centrifuged again.
49 mg (yield 67%) of c derivative compound 830 was obtained.
【０９７４】ＲF 0.37（クロロホルム−メタノール−水
10:6:1) 。R F 0.37 (chloroform-methanol-water
10: 6: 1).
【０９７５】 1H-NMR(CD3 OD＋CDCl3 ) δ (ppm) in 50
0MHz：0.89(s,6H)，2.01(brs,9H)，4.45-4.50(m,3H) 。 1 H-NMR (CD 3 OD + CDCl 3 ) δ (ppm) in 50
0 MHz: 0.89 (s, 6H), 2.01 (brs, 9H), 4.45 to 4.50 (m, 3H).
【０９７６】IR(KBr) ：3400，3300，1650，1560cm-1。IR (KBr): 3400, 3300, 1650, 1560 cm -1 .
【０９７７】(m) 化合物832 の合成 ｉ） カルボン酸化合物831 （64mg）及びＮ−ヒドロキ
シスクシンイミド（９mg）の塩化メチレン（４ml）溶液
にＮ，Ｎ′−ジシクロヘキシルカルボジイミド（16mg）
を加え、室温にて１時間撹拌した。(M) Synthesis of Compound 832 i) N, N′-Dicyclohexylcarbodiimide (16 mg) was added to a solution of carboxylic acid compound 831 (64 mg) and N-hydroxysuccinimide (9 mg) in methylene chloride (4 ml).
Was added and stirred at room temperature for 1 hour.
【０９７８】ii） トリアミド体化合物821(120mg)にト
リフルオロ酢酸（３ml）を加え、室温にて１時間撹拌し
た。トリフルオロ酢酸を留去し、残渣の塩化メチレン溶
液にトリエチルアミンを加えて液性を弱塩基性とした。
この溶液をｉ）の反応液に滴下し、室温にて18時間撹拌
して反応させた。Ii) Triamide compound 821 (120 mg) was added with trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and triethylamine was added to a methylene chloride solution of the residue to make the solution weakly basic.
This solution was added dropwise to the reaction solution of i), and the mixture was reacted by stirring at room temperature for 18 hours.
【０９７９】反応液を水にあけ、塩化メチレンで抽出
し、抽出液を水、食塩水で洗浄後、乾燥した。溶媒を留
去後、残渣(200mg) をシリカゲルカラムクロマトグラフ
ィー（クロロホルム−メタノール 95：５−93：７）に
て精製して粗生成物（96mg）を得た。これをさらにＬＨ
−20（メタノール）にて精製し、アミド体化合物832 を
71mg（収率48％）得た。[0979] The reaction solution was poured into water and extracted with methylene chloride. The extract was washed with water and brine, and dried. After evaporating the solvent, the residue (200 mg) was purified by silica gel column chromatography (chloroform-methanol 95: 5-93: 7) to obtain a crude product (96 mg). This is further LH
-20 (methanol) to give the amide compound 832
71 mg (48% yield) were obtained.
【０９８０】ＲF 0.42（クロロホルム−メタノール 9:
1)。R F 0.42 (chloroform-methanol 9:
1).
【０９８１】［α］D −12.9°(c 0.86 ，メタノー
ル）。[Α] D -12.9 ° (c 0.86, methanol).
【０９８２】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(t,6H)，1.934(s,9H) ，1.953(s,9H) ，2.03(s,9H)，
2.15(s,9H)，4.65-4.66(m,3H) ，5.05-5.1(m,3H)，5.34
(brd,3H)。[0982] 1 H-NMR (CD 3 OD ) δ (ppm) in 500MHz: 0.
90 (t, 6H), 1.934 (s, 9H), 1.953 (s, 9H), 2.03 (s, 9H),
2.15 (s, 9H), 4.65-4.66 (m, 3H), 5.05-5.1 (m, 3H), 5.34
(brd, 3H).
【０９８３】IR(KBr) ：3465，1750，1660，1550cm-1。IR (KBr): 3465, 1750, 1660, 1550 cm -1 .
【０９８４】(n) 化合物833 の合成 アミド体化合物832 （69mg）のメタノール（３ml）溶液
にナトリウムメトキシド（６μl 、28％メタノール溶
液）を加え、室温下３時間撹拌して反応させた。 (N) Synthesis of Compound 833 A sodium methoxide (6 μl, 28% methanol solution) was added to a solution of compound 832 (69 mg) in methanol (3 ml), and the mixture was stirred and reacted at room temperature for 3 hours.
【０９８５】反応液を遠心分離に付し、得られた不溶物
にメタノールを加えて再び遠心分離に付し、ＧａｌＮＡ
ｃ誘導体化合物833 を42mg（収率73％）得た。[0985] The reaction solution was centrifuged, methanol was added to the obtained insoluble matter, and the mixture was centrifuged again.
42 mg (73% yield) of the c derivative compound 833 were obtained.
【０９８６】ＲF 0.35（クロロホルム−メタノール−水
10:6:1) 。R F 0.35 (chloroform-methanol-water
10: 6: 1).
【０９８７】［α］D − 2.6°(c 0.58 ，クロロホルム
−メタノール−水 10:10:3)。[Α] D −2.6 ° (c 0.58, chloroform-methanol-water 10: 10: 3).
【０９８８】 1H-NMR(CD3 OD＋CDCl3 ) δ (ppm) in 50
0MHz：0.89(t,3H)，2.02(s,9H)，4.4-4.5(m,3H) 。 1 H-NMR (CD 3 OD + CDCl 3 ) δ (ppm) in 50
0MHz: 0.89 (t, 3H), 2.02 (s, 9H), 4.4-4.5 (m, 3H).
【０９８９】IR(KBr) ：3400，3300，1650，1550cm-1。IR (KBr): 3400, 3300, 1650, 1550 cm -1 .
【０９９０】(o) 化合物834 の合成 ジアミド体化合物820 （80mg）のメタノール（３ml）溶
液にナトリウムメトキシド（13μl 、28％メタノール溶
液）を加え、室温にて４時間撹拌して反応させた。 (O) Synthesis of Compound 834 To a solution of compound 820 (80 mg) in methanol (3 ml) was added sodium methoxide (13 μl, 28% methanol solution), and the mixture was stirred and reacted at room temperature for 4 hours.
【０９９１】反応液に「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を
加え、液性をほぼ中性とし、加えた樹脂を濾去後、濾液
を濃縮し、Ｂｏｃ体化合物834 を34mg（収率56％）得
た。[0991] "Amberlyst 15E" was added to the reaction solution to make the solution almost neutral, the added resin was removed by filtration, and the filtrate was concentrated to obtain 34 mg of Boc compound 834 (yield: 56%).
【０９９２】ＲF 0.60（酢酸エチル−ピリジン−酢酸−
水 5:5:1:3)。R F 0.60 (ethyl acetate-pyridine-acetic acid-
Water 5: 5: 1: 3).
【０９９３】［α］D − 8.2°(c 0.5，メタノール）。[Α] D -8.2 ° (c 0.5, methanol).
【０９９４】 1H-NMR(CD3 OD＋CDCl3 ) δ (ppm) in 50
0MHz：1.44(s,9H)，2.04(s,6H)，4.51(d,2H)。[0994] 1 H-NMR (CD 3 OD + CDCl 3) δ (ppm) in 50
0 MHz: 1.44 (s, 9H), 2.04 (s, 6H), 4.51 (d, 2H).
【０９９５】IR(KBr) ：3430，1650，1560cm-1。[0995] IR (KBr): 3430, 1650, 1560 cm- 1 .
【０９９６】(p) 化合物835 の合成 ジアミド体化合物820 （51mg）にトリフルオロ酢酸（２
ml）を加え、室温にて１時間撹拌した。トリフルオロ酢
酸を留去し、残渣の塩化メチレン（４ml）溶液にトリエ
チルアミンを加えて、液性を弱塩基性とした。この溶液
にＮ−パルミトイルオキシスクシンイミド（27mg）のト
ルエン（２ml）溶液を加え、室温にて18時間撹拌して反
応させた。 (P) Synthesis of Compound 835 Diamide derivative Compound 820 (51 mg) was added to trifluoroacetic acid (2 mg).
ml) and stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and triethylamine was added to a solution of the residue in methylene chloride (4 ml) to make the solution weakly basic. To this solution was added a solution of N-palmitoyloxysuccinimide (27 mg) in toluene (2 ml), and the mixture was stirred and reacted at room temperature for 18 hours.
【０９９７】反応液を食塩水にあけ、塩化メチレンにて
抽出し、抽出液を水、食塩水で洗浄後、乾燥した。溶媒
を留去後、残渣（70mg）をシリカゲルカラムクロマトグ
ラフィー（クロロホルム：メタノール 94：６−93：
７）にて精製してパルミトイル体化合物835 を41mg（収
率71％）得た。[0997] The reaction solution was poured into saline and extracted with methylene chloride. The extract was washed with water and saline and dried. After the solvent was distilled off, the residue (70 mg) was subjected to silica gel column chromatography (chloroform: methanol 94: 6-93:
Purification was performed in 7) to obtain 41 mg (yield 71%) of palmitoyl compound 835.
【０９９８】ＲF 0.45（クロロホルム−メタノール 9:
1)。R F 0.45 (chloroform-methanol 9:
1).
【０９９９】［α］D −16.8°(c 0.81 ，メタノー
ル）。[Α] D -16.8 ° (c 0.81, methanol).
【１０００】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(t,3H)，1.933(s,3H) ，1.937(s,3H) ，1.953(s,6H)
，2.03(s,6H)，2.14(s,6H)，4.645(d,1H) ，4.654(d,1
H) ，5.08(dd,1H) ，5.09(dd,1H) ，5.34(d,2H)。[1000] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 0.
90 (t, 3H), 1.933 (s, 3H), 1.937 (s, 3H), 1.953 (s, 6H)
, 2.03 (s, 6H), 2.14 (s, 6H), 4.645 (d, 1H), 4.654 (d, 1
H), 5.08 (dd, 1H), 5.09 (dd, 1H), 5.34 (d, 2H).
【１００１】IR(KBr) ：3450，1750，1660，1560cm-1。[1001] IR (KBr): 3450, 1750, 1660, 1560 cm- 1 .
【１００２】(q) 化合物836 の合成 パルミトイル体化合物835 （38mg）のメタノール（３m
l）溶液にナトリウムメトキシド（６μl 、28％メタノ
ール溶液）を加え、室温にて４時間撹拌した。 (Q) Synthesis of compound 836 Palmitoyl form compound 835 (38 mg) in methanol (3 m
l) To the solution was added sodium methoxide (6 µl, 28% methanol solution), and the mixture was stirred at room temperature for 4 hours.
【１００３】析出した粉末を濾取して、ＧａｌＮＡｃ誘
導体化合物836 を27mg（収率90％）得た。The precipitated powder was collected by filtration to obtain 27 mg (90% yield) of GalNAc derivative compound 836.
【１００４】ＲF 0.69（クロロホルム−メタノール−水
10:6:1) 。[1004] R F 0.69 (chloroform-methanol-water
10: 6: 1).
【１００５】［α］D − 9.4°(c 0.5，クロロホルム−
メタノール 1:1)。[1005] [α] D -9.4 ° (c 0.5, chloroform-
Methanol 1: 1).
【１００６】 1H-NMR(CD3 OD＋CDCl3 ) δ (ppm) in 50
0MHz：0.90(t,3H)，1.995(s,3H) ，1.996(s,3H) ，4.44
(d,1H)，4.45(d,1H)。[1006] 1 H-NMR (CD 3 OD + CDCl 3 ) δ (ppm) in 50
0MHz: 0.90 (t, 3H), 1.995 (s, 3H), 1.996 (s, 3H), 4.44
(d, 1H), 4.45 (d, 1H).
【１００７】IR(KBr) ：3440，3300，1640，1560cm-1。[1007] IR (KBr): 3440, 3300, 1640, 1560 cm- 1 .
【１００８】(r) 化合物837 の合成 室温下、α−アセチル体化合物813 (2.0ｇ）の１，２−
ジクロロエタン（30ml）溶液トリフルオロメタンスルホ
ン酸トリメチルシリル（1.05ml）を加え、50〜55℃にて
5.5時間加熱して反応させた。反応液に氷冷下トリエチ
ルアミン(1.4ml) を加え、溶媒を留去し、残渣をシリカ
ゲルカラムクロマトグラフィー（クロロホルム−メタノ
ール−トリエチルアミン 99:0.5:0.5) にて精製した。
得られたオキサゾリン誘導体（1.68ｇ）及び「モレキュ
ラーシーブス４Ａ」（２ｇ）の１，２−ジクロロエタン
（40ml）溶液に、室温下、トリフルオロメタンスルホン
酸トリメチルシリル（1.05ml）を加え、ついで２−ブロ
モエタノール（0.73ml）を加えて、16時間撹拌して反応
させた。 (R) Synthesis of Compound 837 At room temperature, α-acetylated Compound 813 (2.0 g) was prepared from 1,2-
Dichloroethane (30 ml) solution Trimethylsilyl trifluoromethanesulfonate (1.05 ml) was added, and the mixture was heated at 50 to 55 ° C.
The mixture was reacted by heating for 5.5 hours. Triethylamine (1.4 ml) was added to the reaction mixture under ice cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform-methanol-triethylamine 99: 0.5: 0.5).
To a solution of the obtained oxazoline derivative (1.68 g) and "molecular sieves 4A" (2 g) in 1,2-dichloroethane (40 ml) at room temperature was added trimethylsilyl trifluoromethanesulfonate (1.05 ml), followed by 2-bromoethanol. (0.73 ml) was added, and the mixture was stirred and reacted for 16 hours.
【１００９】反応液にトリエチルアミン(1.4ml) を加え
た後、水にあけ、塩化メチレンにて抽出し、抽出液を
水、食塩水で洗浄後、乾燥した。溶媒を留去後、残渣
（1.77ｇ）にトルエン−酢酸エチルの混合液（１：１）
を加え、析出した粉末を濾取し、グリコシド体化合物83
7 を1.04ｇ（収率45％）得た。After adding triethylamine (1.4 ml) to the reaction mixture, the mixture was poured into water and extracted with methylene chloride. The extract was washed with water and brine, and dried. After evaporating the solvent, a mixed solution of toluene-ethyl acetate (1: 1) was added to the residue (1.77 g).
Was added, and the precipitated powder was collected by filtration.
1.04 g (yield 45%) of 7 was obtained.
【１０１０】ＲF 0.37（クロロホルム−メタノール 9
6:4) 。[1010] R F 0.37 (chloroform-methanol 9
6: 4).
【１０１１】［α］D −13.1°(c 1.10 ，クロロホル
ム）。[Α] D -13.1 ° (c 1.10, chloroform).
【１０１２】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：1.
938(s,3H) ，1.951(s,3H) ，2.027(s,3H) ，2.144(s,3
H) ，4.64(d,1H)，5.08(dd,1H) ，5.34(brd,1H)。[1012] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 1.
938 (s, 3H), 1.951 (s, 3H), 2.027 (s, 3H), 2.144 (s, 3
H), 4.64 (d, 1H), 5.08 (dd, 1H), 5.34 (brd, 1H).
【１０１３】IR(KBr) ：3450，1755，1745，1650cm-1。[1013] IR (KBr): 3450, 1755, 1745, 1650 cm- 1 .
【１０１４】(s) 化合物838 の合成 グリコシド体化合物837(910mg)のジメチルホルムアミド
（５ml）溶液にアジ化ナトリウム(650mg) を加え、室温
にて14時間、さらに50℃にて２時間加熱撹拌して反応さ
せた。 (S) Synthetic Glycoside of Compound 838 To a solution of compound 837 (910 mg) in dimethylformamide (5 ml) was added sodium azide (650 mg), and the mixture was heated with stirring at room temperature for 14 hours and further at 50 ° C. for 2 hours. And reacted.
【１０１５】反応液を水にあけ、酢酸エチルで抽出し、
抽出液を水、飽和食塩水で洗浄後、乾燥した。溶媒を留
去してアジド体化合物838 を783mg(収率94％）得た。[1015] The reaction solution was poured into water and extracted with ethyl acetate.
The extract was washed with water and saturated saline and then dried. The solvent was distilled off to obtain 783 mg (yield 94%) of azide compound 838.
【１０１６】ＲF 0.37（クロロホルム−メタノール 9
6:4) 。[1016] R F 0.37 (chloroform-methanol 9
6: 4).
【１０１７】［α］D −34.9°(c 1.06 ，クロロホル
ム）。[Α] D −34.9 ° (c 1.06, chloroform).
【１０１８】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：1.
992(s,3H) ，1.948(s,3H) ，2.025(s,3H) ，2.144(s,3
H) ，4.65(d,1H)，5.07(dd,1H) ，5.34(brd,1H)。[1018] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 1.
992 (s, 3H), 1.948 (s, 3H), 2.025 (s, 3H), 2.144 (s, 3
H), 4.65 (d, 1H), 5.07 (dd, 1H), 5.34 (brd, 1H).
【１０１９】IR(KBr) ：3400，2110，1750，1740，1650
cm-1。[1019] IR (KBr): 3400, 2110, 1750, 1740, 1650
cm -1 .
【１０２０】(t) 化合物841 の合成 ｉ） アジド体化合物838(202mg)のエタノール（10ml）
溶液にトルエンスルホン酸(100mg) 及びリンドラー触媒
(100mg) を加え、水素加圧下(50psi) １時間振とう撹拌
した。リンドラー触媒(100mg) を追加した後、更に１時
間振とう撹拌した。触媒をセライトにて濾去し、溶媒を
留去した。得られたアミノ体化合物839 のアセトニトリ
ル（２ml）溶液にトリエチルアミン（0.14ml）を加え
た。 (T) Synthesis of Compound 841 i) Azide Compound 838 (202 mg) in ethanol (10 ml)
Toluenesulfonic acid (100mg) and Lindlar catalyst in solution
(100 mg), and the mixture was shaken and stirred under hydrogen pressure (50 psi) for 1 hour. After the addition of the Lindlar catalyst (100 mg), the mixture was shaken and stirred for an additional hour. The catalyst was removed by filtration through Celite, and the solvent was distilled off. Triethylamine (0.14 ml) was added to a solution of the obtained amino compound 839 in acetonitrile (2 ml).
【１０２１】ii） 化合物840 Ｂｏｃ−Ｇｌｕ（Ｇｌ
ｕ）ＯＨ（55mg）及びＮ−ヒドロキシサクシンイミド
（61mg）のアセトニトリル（５ml）溶液にＮ，Ｎ′−ジ
シクロヘキシルカルボジイミド(108mg) を加え室温にて
２時間撹拌した。析出した不溶物を濾去し、濾液にｉ）
で得たアミノ体化合物839 のアセトニトリル溶液を加
え、室温にて29時間撹拌して反応させた。Ii) Compound 840 Boc-Glu (Gl
u) To a solution of OH (55 mg) and N-hydroxysuccinimide (61 mg) in acetonitrile (5 ml) was added N, N'-dicyclohexylcarbodiimide (108 mg), and the mixture was stirred at room temperature for 2 hours. The precipitated insoluble material was removed by filtration, and the filtrate was treated with i).
An acetonitrile solution of the amino compound 839 obtained in the above was added, and the mixture was stirred and reacted at room temperature for 29 hours.
【１０２２】反応液を濃縮し、塩化メチレンに溶解し、
水、食塩水で洗浄後、乾燥した。溶媒を留去後、残渣(2
24mg) をシリカゲルカラムクロマトグラフィー（クロロ
ホルム−メタノール 95：５−93：７）にて精製してト
リアミド体化合物841 を133mg(収率59％）得た。The reaction mixture was concentrated and dissolved in methylene chloride.
After washing with water and saline, it was dried. After evaporating the solvent, the residue (2
24mg) was purified by silica gel column chromatography (chloroform-methanol 95: 5-93: 7) to obtain 133 mg (yield 59%) of a triamide compound 841.
【１０２３】ＲF 0.50（クロロホルム−メタノール 9:
1)。[1023] R F 0.50 (chloroform - methanol 9:
1).
【１０２４】［α］D −19.3°(c 1.1，メタノール）。[Α] D -19.3 ° (c 1.1, methanol).
【１０２５】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：1.
45(s,9H)，1.94(s,3H)，1.95(s,15H) ，2.03(s,9H)，2.
14(s,9H)，4.5-4.6(m,3H) ，5.0-5.1(m,3H) ，5.3(m,3
H) 。[1025] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 1.
45 (s, 9H), 1.94 (s, 3H), 1.95 (s, 15H), 2.03 (s, 9H), 2.
14 (s, 9H), 4.5-4.6 (m, 3H), 5.0-5.1 (m, 3H), 5.3 (m, 3
H).
【１０２６】IR(KBr) ：3320，1750，1660cm-1。[1026] IR (KBr): 3320, 1750, 1660 cm- 1 .
【１０２７】(u) 化合物842 の合成 トリアミド体化合物841 （36mg）のメタノール（２ml）
溶液にナトリウムメトキシド（５μl 、28％メタノール
溶液）を加え、氷冷下２時間、室温にてさらに４時間撹
拌して反応させた。 (U) Synthesis of compound 842 Triamide form compound 841 (36 mg) in methanol (2 ml)
Sodium methoxide (5 μl, 28% methanol solution) was added to the solution, and the mixture was stirred for 2 hours under ice-cooling, and further stirred at room temperature for 4 hours to react.
【１０２８】反応液に「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を
加え、液性をほぼ中性とし、加えた樹脂を濾去後、濾液
を濃縮してＢｏｃ体化合物842 を24mg（収率87％）得
た。[1028] "Amberlyst 15E" was added to the reaction solution to make the solution almost neutral. After the added resin was removed by filtration, the filtrate was concentrated to obtain 24 mg of Boc compound 842 (yield 87%).
【１０２９】ＲF 0.46（酢酸エチル−ピリジン−酢酸−
水 5:5:1:3)。R F 0.46 (ethyl acetate-pyridine-acetic acid-
Water 5: 5: 1: 3).
【１０３０】［α］D 22− 4.1°(c 1.41 ，メタノール
−水 1:1)。[Α] D 22 −4.1 ° (c 1.41, methanol-water 1: 1).
【１０３１】 1H-NMR (D2 O)δ (ppm) in 500MHz：1.44
(s,9H)，2.04(s,3H)，2.05(s,6H)，4.46(d,1H)，4.47
(d,2H)。[1030] 1 H-NMR (D 2 O) δ (ppm) in 500 MHz: 1.44
(s, 9H), 2.04 (s, 3H), 2.05 (s, 6H), 4.46 (d, 1H), 4.47
(d, 2H).
【１０３２】IR(KBr) ：3430，1650，1560，1540cm-1。[1032] IR (KBr): 3430, 1650, 1560, 1540 cm- 1 .
【１０３３】(v) 化合物843 の合成 ｉ） カルボン酸体化合物825 （33mg）及びＮ−ヒドロ
キシスクシンイミド（９mg）のアセトニトリル（３ml）
溶液にＮ，Ｎ′−ジシクロヘキシルカルジイミド（16m
g）を加え室温にて３時間撹拌した。 (V) Synthesis of compound 843 i) Carboxylic acid compound 825 (33 mg) and N-hydroxysuccinimide (9 mg) in acetonitrile (3 ml)
N, N'-dicyclohexyl carbimide (16m
g) was added and the mixture was stirred at room temperature for 3 hours.
【１０３４】ii） トリアミド体化合物841 （90mg）に
トリフルオロ酢酸（２ml）を加え、室温にて１時間撹拌
した。トリフルオロ酢酸を留去し、残渣のアセトニトリ
ル溶液にトリエチルアミンを加えて、液性を弱塩基性と
した。この溶液をｉ）の反応液に滴下し、室温にて18時
間撹拌して反応させた。Ii) Triamide compound 841 (90 mg) was added with trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The trifluoroacetic acid was distilled off, and triethylamine was added to a solution of the residue in acetonitrile to make the solution weakly basic. This solution was added dropwise to the reaction solution of i), and the mixture was reacted by stirring at room temperature for 18 hours.
【１０３５】反応液を濃縮し、残渣を塩化メチレンに溶
解し、水、食塩水で洗浄後、乾燥した。溶媒を留去後、
残渣(111mg) をシリカゲルクロマトグラフィー（クロロ
ホルム−メタノール 95：５−92：８）にて精製してア
ミド体化合物843 を93mg（収率84％）得た。[1035] The reaction solution was concentrated, the residue was dissolved in methylene chloride, washed with water and brine, and dried. After distilling off the solvent,
The residue (111 mg) was purified by silica gel chromatography (chloroform-methanol 95: 5-92: 8) to give 93 mg (yield 84%) of amide compound 843.
【１０３６】ＲF 0.45（クロロホルム−メタノール 9:
1)。[1036] R F 0.45 (chloroform-methanol 9:
1).
【１０３７】［α］D −15.3°(c 1.05 ，メタノー
ル）。[Α] D -15.3 ° (c 1.05, methanol).
【１０３８】 1H-NMR(CD3 OD) δ (ppm) in 500MHz：0.
90(t,3H)，1.936(s,3H) ，1.945(s,3H) ，1.950(s,3H)
，1.953(s,6H) ，1.958(s,3H) ，2.028(s,9H) ，2.144
(s,9H) ，4.6(m,3H) ，5.02-5.08(m,3H) ，5.33(brd,3
H)。[1038] 1 H-NMR (CD 3 OD) δ (ppm) in 500 MHz: 0.
90 (t, 3H), 1.936 (s, 3H), 1.945 (s, 3H), 1.950 (s, 3H)
, 1.953 (s, 6H), 1.958 (s, 3H), 2.028 (s, 9H), 2.144
(s, 9H), 4.6 (m, 3H), 5.02-5.08 (m, 3H), 5.33 (brd, 3
H).
【１０３９】IR(KBr) ：3300，1750，1660，1550cm-1。[1039] IR (KBr): 3300, 1750, 1660, 1550 cm- 1 .
【１０４０】(w) 化合物844 の合成 アミド体化合物843 （91mg）のメタノール（３ml）溶液
にナトリウムメトキシド（10μl 、28％メタノール溶
液）を加え、氷冷下４時間撹拌して反応させた。 (W) Synthesis of Compound 844 A sodium methoxide (10 μl, 28% methanol solution) was added to a solution of compound 843 (91 mg) in methanol (3 ml), and the mixture was stirred and reacted for 4 hours under ice cooling.
【１０４１】反応液に「Ａｍｂｅｒｌｙｓｔ 15Ｅ」を
加え、液性をほぼ中性とし、加えた樹脂を濾去後、濾液
を濃縮し、粗精製物（72mg）を得た。メタノールを加
え、不溶物を濾取してＧａｌＮＡｃ誘導体化合物844 を
52mg（収率72％）得た。[1041] "Amberlyst 15E" was added to the reaction solution to make the solution almost neutral, the added resin was removed by filtration, and the filtrate was concentrated to obtain a crude product (72 mg). Methanol was added, and the insoluble material was collected by filtration to obtain the GalNAc derivative compound 844.
52 mg (72% yield) were obtained.
【１０４２】ＲF 0.16（クロロホルム−メタノール−水
10:6:1) 。[1042] R F 0.16 (chloroform-methanol-water
10: 6: 1).
【１０４３】 1H-NMR(CD3 OD＋CDCl3 ＋ D2 O)δ (ppm)
in 500MHz：0.89(s,3H)，2.015(s,3H) ，2.022(s,3H)
，2.029(s,3H) 。[1043] 1 H-NMR (CD 3 OD + CDCl 3 + D 2 O) δ (ppm)
in 500MHz: 0.89 (s, 3H), 2.015 (s, 3H), 2.022 (s, 3H)
, 2.029 (s, 3H).
【１０４４】IR(KBr) ：3430，3300，1640，1560cm-1。[1044] IR (KBr): 3430, 3300, 1640, 1560 cm- 1 .
【１０４５】(x) 化合物846 の合成 水素化ナトリウム(580mg、60％ ｄｉｓｐｅｒｓｉｏｎ
ｉｎ ｍｉｎｅｒａｌ ｏｉｌ）をヘキサンにて洗浄
後テトラヒドロフラン（50ml）に懸濁し、室温にて化合
物845 の２−［２−（２−オクタデシルオキシエトキ
シ）エトキシ］エタノール（4.86ｇ）のテトラヒドロフ
ラン（15ml）溶液を滴下した。反応混合物を60℃にて１
時間加熱撹拌した後、氷冷下ブロモ酢酸エチル(1.9ml)
のテトラヒドロフラン（３ml）溶液を加えて、室温に放
置し、18時間撹拌して反応させた。 (X) Synthesis of Compound 846 Sodium hydride (580 mg, 60% dispersion)
After washing with hexane, the suspension was suspended in tetrahydrofuran (50 ml), and a solution of compound 845 in 2- (2- (2-octadecyloxyethoxy) ethoxy] ethanol (4.86 g) in tetrahydrofuran (15 ml) was added at room temperature. It was dropped. The reaction mixture is heated at 60 ° C for 1
After stirring under heating for an hour, ethyl bromoacetate (1.9 ml) under ice cooling
Was added thereto, and the mixture was allowed to stand at room temperature and reacted by stirring for 18 hours.
【１０４６】反応液を水にあけ、酢酸エチルにて抽出
し、抽出液を水、飽和食塩水で洗浄後、乾燥した。溶媒
を留去後、残渣（6.15ｇ）をシリカゲルカラムクロマト
グラフィー（ヘキサン−酢酸エチル 4:1)にて精製して
エステル体化合物846 を4.66ｇ（収率85％）得た。[1045] The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried. After evaporating the solvent, the residue (6.15 g) was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 4.66 g of the ester compound 846 (yield: 85%).
【１０４７】ＲF 0.49（ヘキサン−酢酸エチル 1:1)。R F 0.49 (hexane-ethyl acetate 1: 1).
【１０４８】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：0.
88(t,3H)，1.29(t,3H)，3.44(t,2H)，4.15(s,2H)，4.21
(q,2H)。[1048] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 0.
88 (t, 3H), 1.29 (t, 3H), 3.44 (t, 2H), 4.15 (s, 2H), 4.21
(q, 2H).
【１０４９】IR (CHCl3 ) ：1750cm-1。IR (CHCl 3 ): 1750 cm -1 .
【１０５０】(y) 化合物825 の合成 エステル体化合物846(4.6 ｇ）をメタノール（10ml）お
よびテトラヒドロフラン（５ml）の混合溶媒に溶解し、
苛性カリ（1.09ｇ）の水溶液（15ml）を滴下後、室温に
て 2.5時間撹拌して反応させた。 (Y) Synthetic ester of Compound 825 Compound (846 g) was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (5 ml).
An aqueous solution (15 ml) of caustic potash (1.09 g) was added dropwise, and the mixture was stirred and reacted at room temperature for 2.5 hours.
【１０５１】反応液を食塩水にあけ、塩化メチレンにて
抽出した後、水層をクエン酸酸性とし、塩化メチレンに
て抽出した。抽出液を水、飽和食塩水で洗浄後、乾燥し
た。溶媒を留去してカルボン酸化合物825 を3.63ｇ（収
率89％）得た。[1051] The reaction solution was poured into saline and extracted with methylene chloride. The aqueous layer was made acidic with citric acid and extracted with methylene chloride. The extract was washed with water and saturated saline and then dried. The solvent was distilled off to obtain carboxylic acid compound 825 (3.63 g, yield 89%).
【１０５２】ＲF 0.54（ブタノール−酢酸−水 4:1:
1)。[1052] R F 0.54 (butanol-acetic acid-water 4: 1:
1).
【１０５３】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：0.
88(t,3H)，3.47(t,2H)，3.6-3.8(m,12H)，4.15(s,2H)。[1053] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 0.
88 (t, 3H), 3.47 (t, 2H), 3.6-3.8 (m, 12H), 4.15 (s, 2H).
【１０５４】IR(KBr) ：3500，1730，1700cm-1。IR (KBr): 3500, 1730, 1700 cm -1 .
【１０５５】(z) 化合物847 の合成 化合物815 の２−［２−（２−クロロエトキシ）エトキ
シ］エタノール(8.4mg，50mmol）のジメチルホルムアミ
ド（20ml）溶液にアジ化ナトリウム（24.3ｇ，0.37mol)
を加え、50℃にて３日間撹拌して反応させた。 (Z) Synthesis of Compound 847 To a solution of compound 815 in 2- [2- (2-chloroethoxy) ethoxy] ethanol (8.4 mg, 50 mmol) in dimethylformamide (20 ml) was added sodium azide (24.3 g, 0.37 mol). )
Was added and stirred at 50 ° C. for 3 days to cause a reaction.
【１０５６】「ＨＰ−20」(150ml、水）にて精製し、２
−［２−（２−アジドエトキシ）エトキシ］エタノール
（化合物847)を3.28ｇ（収率37％）得た。[1056] Purification was performed using "HP-20" (150 ml, water).
3.28 g (37% yield) of-[2- (2-azidoethoxy) ethoxy] ethanol (compound 847) was obtained.
【１０５７】ＲF 0.58（酢酸エチル）。R F 0.58 (ethyl acetate).
【１０５８】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：3.
41(t,2H)，3.62-3.63(m,2H) ，3.68-3.70(m,6H) ，3.73
-3.76(m,2H) 。[1058] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 3.
41 (t, 2H), 3.62-3.63 (m, 2H), 3.68-3.70 (m, 6H), 3.73
-3.76 (m, 2H).
【１０５９】IR(neat)：3450，2100cm-1。IR (neat): 3450, 2100 cm -1 .
【１０６０】(a′) 化合物848 の合成 ｉ） あらかじめヘキサンにて洗浄した水素化ナトリウ
ム(900mg，60％ ｄｉｓｐｅｒｓｉｏｎ ｉｎ ｍｉｎ
ｅｒａｌ ｏｉｌ）をジメチルホルムアミド（10ml）に
懸濁し、氷冷下アジド体化合物847(3.28ｇ）のジメチル
ホルムアミド（10ml）溶液を滴下後、室温に戻して１時
間撹拌した。 (A ′) Synthesis of Compound 848 i) Sodium hydride (900 mg, 60% dispersion in min) previously washed with hexane
eral oil) was suspended in dimethylformamide (10 ml), and a solution of the azide compound 847 (3.28 g) in dimethylformamide (10 ml) was added dropwise under ice-cooling, and the mixture was returned to room temperature and stirred for 1 hour.
【１０６１】ii） Ｂｕ4 ＮＯＨ（30ml、ｉｎ １Ｍ
メタノール）にクロル酢酸（2.82ｇ）を加えた後、溶媒
を留去し、さらにトルエンを加え、溶媒を留去した。残
渣をジメチルホルムアミド（17ml）に溶解し、ｉ）の反
応混合物に滴下し、終夜撹拌して反応させた。反応混合
物に臭化ベンジル(5.3ml) を加え更に５日間撹拌して反
応させた。Ii) Bu 4 NOH (30 ml, in 1M)
After adding chloroacetic acid (2.82 g) to methanol), the solvent was distilled off. Toluene was further added, and the solvent was distilled off. The residue was dissolved in dimethylformamide (17 ml), added dropwise to the reaction mixture of i), and reacted by stirring overnight. Benzyl bromide (5.3 ml) was added to the reaction mixture, and the mixture was further stirred for 5 days to react.
【１０６２】反応液を食塩水にあけ、酢酸エチルにて抽
出し、抽出液を水、飽和食塩水で洗浄後、乾燥した。溶
媒を留去後、残渣(8.5ｇ）をシリカゲルカラムクロマト
グラフィー（ヘキサン−酢酸エチル 9:1−酢酸エチル）
にて精製してベンジル体化合物848 を1.60ｇ（収率39
％）得た。The reaction mixture was poured into saline and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried. After evaporating the solvent, the residue (8.5 g) was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1-ethyl acetate).
1.60 g (yield 39) of the benzyl compound 848
%)Obtained.
【１０６３】ＲF 0.46（ヘキサン−酢酸エチル 1:1)。R F 0.46 (hexane-ethyl acetate 1: 1).
【１０６４】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：3.
37(t,2H)，3.66(m,6H)，3.71-3.74(m,2H) ，4.21(s,2
H)，5.20(s,2H)。[1064] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 3.
37 (t, 2H), 3.66 (m, 6H), 3.71-3.74 (m, 2H), 4.21 (s, 2
H), 5.20 (s, 2H).
【１０６５】IR(KBr) ：1755，2100cm-1。IR (KBr): 1755, 2100 cm -1 .
【１０６６】(b′) 化合物850 の合成 ｉ） ベンジル体化合物848(150mg)のエタノール（８m
l）溶液にトルエンスルホン酸(106mg) 及びリンドラー
触媒（75mg）を加え、水素加圧下(50psi) １時間、振と
う撹拌した。触媒をセライトにて濾去し、溶媒を留去
し、得られたアミノ体化合物849 の塩化メチレン（４m
l）溶媒にトリエチルアミン（0.13ml）を加えた。 (B ′) Synthesis of compound 850 i) Benzyl compound 848 (150 mg) in ethanol (8 m
l) Toluenesulfonic acid (106 mg) and Lindlar's catalyst (75 mg) were added to the solution, and the mixture was stirred with shaking under hydrogen pressure (50 psi) for 1 hour. The catalyst was removed by filtration through Celite, the solvent was distilled off, and methylene chloride (4m) of the obtained amino compound 849 was obtained.
l) Triethylamine (0.13 ml) was added to the solvent.
【１０６７】ii） ジセチル酢酸(234mg) およびＮ−ヒ
ドロキシスクシンイミド（58mg）の塩化メチレン（10m
l）溶液に、室温にてＮ，Ｎ′−ジシクロヘキシルカル
ボジイミド(104mg) を加え、１時間撹拌した。これに
ｉ）で得られたアミノ体化合物849の塩化メチレン溶液
を滴下し、室温で14時間撹拌して反応させた。Ii) Dicetyl acetic acid (234 mg) and N-hydroxysuccinimide (58 mg) in methylene chloride (10 m
l) N, N'-Dicyclohexylcarbodiimide (104 mg) was added to the solution at room temperature, and the mixture was stirred for 1 hour. A methylene chloride solution of the amino compound 849 obtained in i) was added dropwise thereto, and the mixture was stirred and reacted at room temperature for 14 hours.
【１０６８】反応液を水にあけ、塩化メチレンにて抽出
し、抽出液を水、食塩水で洗浄後、乾燥した。溶媒を留
去後、残渣にアセトニトリルを加え、可溶部(137mg) を
シリカゲルカラムクロマトグラフィー（クロロホルム−
トルエン 9:1)にて精製してアミド体化合物850 を 125
mg（収率34％）得た。The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and brine, and dried. After the solvent was distilled off, acetonitrile was added to the residue, and the soluble portion (137 mg) was subjected to silica gel column chromatography (chloroform-
Purify with toluene 9: 1) and convert amide compound 850 to 125
mg (34% yield).
【１０６９】ＲF 0.35（ヘキサン−酢酸エチル 6:4)。R F 0.35 (hexane-ethyl acetate 6: 4).
【１０７０】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：0.
88(t,6H)，1.99(sestet,1H) ，3.4-3.8(m,12H)，4.20
(s,2H)，5.19(s,2H)，6.00(t,1H)，7.2(m,5H) 。[1070] 1 H-NMR (CDCl 3) δ (ppm) in 500MHz: 0.
88 (t, 6H), 1.99 (sestet, 1H), 3.4-3.8 (m, 12H), 4.20
(s, 2H), 5.19 (s, 2H), 6.00 (t, 1H), 7.2 (m, 5H).
【１０７１】IR(KBr) ：3450，3300，1750，1645，163
0，1573，1550cm-1。[1071] IR (KBr): 3450, 3300, 1750, 1645, 163
0,1573,1550cm -1 .
【１０７２】(c′) 化合物831 の合成 ｉ） アミド体化合物850 （50mg）のトルエン（10ml）
及び酢酸エチル（10ml）の混合溶媒溶液に10％パラジウ
ムカーボン（10mg）を加え、室温にて水素加圧下(50ps
i)1.5時間振とう撹拌して反応させた。 (C ′) Synthesis of Compound 831 i) Amide Compound 850 (50 mg) in toluene (10 ml)
10% palladium carbon (10 mg) was added to a mixed solvent solution of ethyl acetate and ethyl acetate (10 ml), and hydrogen pressure was applied at room temperature (50 ps).
i) The reaction was carried out with shaking and stirring for 1.5 hours.
【１０７３】反応液から溶媒を留去し、カルボン酸化合
物831 を44mg(quant) 得た。The solvent was distilled off from the reaction solution to obtain 44 mg (quant) of carboxylic acid compound 831.
【１０７４】ＲF 0.80（クロロホルム−メタノール 4:
1)。R F 0.80 (chloroform-methanol 4:
1).
【１０７５】 1H-NMR(CDCl3 ) δ (ppm) in 500MHz：0.
88(t,6H)，3.4-3.8(m,12H)，4.17(s,2H)，6.25(t,1H)。[1075] 1 H-NMR (CDCl 3 ) δ (ppm) in 500 MHz: 0.
88 (t, 6H), 3.4-3.8 (m, 12H), 4.17 (s, 2H), 6.25 (t, 1H).
【１０７６】IR（クロロホルム）：3690，3620，3030，
1740，1660cm-1。[1076] IR (chloroform): 3690, 3620, 3030,
1740, 1660cm -1 .
【１０７７】(d′) 化合物851 の合成（図８ｊ） アミノ体のパラトルエンスルホン酸塩818(167mg)の塩化
メチレン(10ml)溶液にＮ−パルミトイルオキシスクシン
イミド(115mg) のトルエン（５ml）溶液にトリエチルア
ミン（90μｌ）を加えたもの加え、終夜撹拌した。反応
液を水及び半飽和食塩水にて洗浄し、硫酸マグネシクム
にて乾燥した。溶媒を留去し、残渣をシリカゲルカラム
クロマトグラフィーにて精製し、パルミトイル体(181m
g) を得た。 (D ′) Synthesis of Compound 851 (FIG. 8j) N-palmitoyloxysuccinimide (115 mg) in toluene (5 ml) was added to a methylene chloride (10 ml) solution of the para-toluenesulfonic acid salt 818 (167 mg) of the amino compound. Triethylamine (90 μl) was added, and the mixture was stirred overnight. The reaction solution was washed with water and a half-saturated saline solution, and dried with magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain a palmitoyl compound (181 m
g) was obtained.
【１０７８】［α］D 23-20.6 ゜(c 1.2, クロロホル
ム) 。[Α] D 23 -20.6 ゜ (c 1.2, chloroform).
【１０７９】IR(KBr) ：3700，3600，2980，2435，152
0，1480，1420cm-1。[1079] IR (KBr): 3700, 3600, 2980, 2435, 152
0, 1480, 1420 cm -1 .
【１０８０】 1H-NMR(CD3 OD) ：0.90(3H,t,J=7Hz)，1.
93(3H,s)，1.95(3H,s)，2.02(3H,s)，2.14(3H,s)，4.46
(1H,d,J=4.6Hz)，5.06(1H,dd,J=3.5,11.5Hz)，5.33(1H,
brs)。[1080] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 1.
93 (3H, s), 1.95 (3H, s), 2.02 (3H, s), 2.14 (3H, s), 4.46
(1H, d, J = 4.6Hz), 5.06 (1H, dd, J = 3.5,11.5Hz), 5.33 (1H,
brs).
【１０８１】Ｒf =0.4( クロロホルム：メタノール=93:
7)。[1081] R f = 0.4 (chloroform: methanol = 93:
7).
【１０８２】上記で得たパルミトイル体(141mg) のメタ
ノール(15ml)溶液にナトリウムメトキシド(28 ％メタノ
ール溶液40μｌ) を加え、室温にて5.5 時間撹拌した。
陽イオン交換樹脂「アンバーリスト15Ｅ」（ローム・ア
ンド・ハース社製）を液性が中性になるまで加えた後樹
脂を濾去して、濾液を濃縮し、目的化合物851(104mg,90
％) を得た。To a solution of the palmitoyl compound (141 mg) obtained above in methanol (15 ml) was added sodium methoxide (40 μl of a 28% methanol solution), and the mixture was stirred at room temperature for 5.5 hours.
After adding a cation exchange resin “Amberlyst 15E” (manufactured by Rohm and Haas Co.) until the solution becomes neutral, the resin was filtered off, the filtrate was concentrated, and the target compound 851 (104 mg, 90 mg) was added.
%).
【１０８３】［α］D 26+43.9 ゜(c 1.0，メタノール)
。[108] [α] D 26 +43.9 ゜ (c 1.0, methanol)
.
【１０８４】IR(KBr) ：3340，3330，1640，1560，1470
-1cm。[1084] IR (KBr): 3340, 3330, 1640, 1560, 1470
-1 cm.
【１０８５】 1H-NMR(CD3 OD) ：0.90(3H,t,J=7Hz)，1.
98(3H,s)，2.19(2Ht,J=7Hz,)，3.83(1H,d,J=3Hz)，3.90
(1H,t,J=8.5Hz)，4.44(1H,d,J=8.5Hz)。[1085] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 1.
98 (3H, s), 2.19 (2Ht, J = 7Hz,), 3.83 (1H, d, J = 3Hz), 3.90
(1H, t, J = 8.5Hz), 4.44 (1H, d, J = 8.5Hz).
【１０８６】Ｒf =0.26(クロロホルム：メタノール= 9:
1)。[1086] R f = 0.26 (chloroform: methanol = 9:
1).
【１０８７】(e′) 化合物852 の合成（図８ｊ） カルボン酸828(180mg)およびＮ−ヒドロキシスクシンイ
ミド(41mg)の塩化メチレン溶液(10ml)にＮ，Ｎ′−ジシ
クロヘキシルカルボジイミド(74mg)を加え、室温にて１
時間撹拌した。この溶液にアミノ体のパラトルエンスル
ホン酸塩818(190mg)およびトリエチルアミン(90 μｌ)
の塩化メチレン（５ml）溶液を加え、室温にて終夜撹拌
した。不溶物を濾去した後、濾液を水及び半飽和食塩水
にて洗浄し、硫酸マグネシウムにて乾燥した。溶媒を留
去し、残渣をシリカゲルカラムクロマトグラフィー（シ
リカゲル 40 ｇ、クロロホルム：メタノール =98：２）
にて精製してアミド体(310mg，77％) を得た。 (E ′) Synthesis of Compound 852 (FIG. 8j) To a solution of carboxylic acid 828 (180 mg) and N-hydroxysuccinimide (41 mg) in methylene chloride (10 ml) was added N, N′-dicyclohexylcarbodiimide (74 mg). 1 at room temperature
Stirred for hours. To this solution was added the amino-form paratoluenesulfonate 818 (190 mg) and triethylamine (90 μl).
Was added and the mixture was stirred overnight at room temperature. After filtering off insolubles, the filtrate was washed with water and half-saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (silica gel 40 g, chloroform: methanol = 98: 2).
To give an amide (310 mg, 77%).
【１０８８】IR(KBr) ：3700，3600，1745，1710，151
0，1480，1420cm-1。[1088] IR (KBr): 3700, 3600, 1745, 1710, 151
0, 1480, 1420 cm -1 .
【１０８９】 1H-NMR(CD3 OD) ：0.90(3H,t,J=7Hz)，1.
93(3H,s)，1.95(3H,s)，2.03(3H,s)，2.14(3H,s)，4.65
(1H,d,J=8.5Hz)，5.07(1H,dd,J=3.5,11.5Hz)，5.33(1H,
d,J=3.5Hz)。[1089] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 1.
93 (3H, s), 1.95 (3H, s), 2.03 (3H, s), 2.14 (3H, s), 4.65
(1H, d, J = 8.5Hz), 5.07 (1H, dd, J = 3.5,11.5Hz), 5.33 (1H,
d, J = 3.5Hz).
【１０９０】Ｒf =0.6（クロロホルム：メタノール=93:
7 ）。[1090] Rf = 0.6 (chloroform: methanol = 93:
7).
【１０９１】上記で得たアミド体(270mg) のメタノール
(20ml)溶液にナトリウムメトキシド（28％メタノール溶
液55μｌ）を加え、室温にて5.5 時間撹拌した。「アン
バーリスト15Ｅ」を液性が中性になるまで加えた後樹脂
を濾去して、濾液を濃縮し、目的化合物852(215mg)を得
た。[1091] Methanol of the amide (270 mg) obtained above
Sodium methoxide (55 μl of a 28% methanol solution) was added to the (20 ml) solution, and the mixture was stirred at room temperature for 5.5 hours. After adding “Amberlyst 15E” until the solution became neutral, the resin was removed by filtration and the filtrate was concentrated to obtain the target compound 852 (215 mg).
【１０９２】［α］D 26+43.9 ゜(c 1.0，メタノール)
。[1092] [α] D 26 +43.9 ゜ (c 1.0, methanol)
.
【１０９３】IR(KBr) ：3340，3330，1655，1555，1470
cm-1。[1093] IR (KBr): 3340, 3330, 1655, 1555, 1470
cm -1 .
【１０９４】 1H-NMR(CD3 OD) ：0.90(3H,t,J=7Hz)，2.
00(3H,s)，3.84(1H,d,J=3Hz)，4.45(1H,dJ=8.3H)。[1094] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 2.
00 (3H, s), 3.84 (1H, d, J = 3Hz), 4.45 (1H, dJ = 8.3H).
【１０９５】Ｒf =0.37 （クロロホルム：メタノール=
9:1）。[1095] R f = 0.37 (chloroform: methanol =
9: 1).
【１０９６】(f′) 化合物853 の合成（図８ｊ） アミノ体のパラトルエンスルホン酸塩818(60mg) のジオ
キサン (４ml) 溶液にジ−ｔｅｒｔ−ブチルジカーボネ
ート(50mg)およびトリエチルアミン（８滴）を加え、室
温にて終夜撹拌した。反応液を水及び半飽和食塩水にて
洗浄し、硫酸マグネシウムにて乾燥した。溶媒を留去
し、残渣をシリカゲルカラムクロマトグラフィー（シリ
カゲル 10ｇ、クロロホルム：メタノール＝97：３）に
て精製しＢｏｃ体（43mg) を得た。 (F ′) Synthesis of Compound 853 (FIG. 8j) Di-tert-butyl dicarbonate (50 mg) and triethylamine (8 drops) were added to a dioxane (4 ml) solution of amino toluene paratoluenesulfonate 818 (60 mg). Was added and stirred at room temperature overnight. The reaction solution was washed with water and half-saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (silica gel 10 g, chloroform: methanol = 97: 3) to obtain a Boc form (43 mg).
【１０９７】［α］D 27-20.3 ゜(c 2.86，クロロホル
ム) 。[Α] D 27 -20.3 ゜ (c 2.86, chloroform).
【１０９８】IR(KBr) ：3450，3350，2400，1745，171
0，1690，1520cm-1。[1098] IR (KBr): 3450, 3350, 2400, 1745, 171
0, 1690, 1520 cm -1 .
【１０９９】 1H-NMR(CD3 OD) ：1.44(9H,s)，1.93(3H,
s)，1.95(3H,s)，2.03(3H,s)，2.14(3H,s)，4.66，4.67
(1H,d,J=8.5Hz)，5.06，5.07(1H,dd,J=3.5,11.5Hz)，5.
33(1H,brd,J=3.5Hz)。[1099] 1 H-NMR (CD 3 OD ): 1.44 (9H, s), 1.93 (3H,
s), 1.95 (3H, s), 2.03 (3H, s), 2.14 (3H, s), 4.66, 4.67
(1H, d, J = 8.5Hz), 5.06, 5.07 (1H, dd, J = 3.5,11.5Hz), 5.
33 (1H, brd, J = 3.5 Hz).
【１１００】Ｒf =0.32 （クロロホルム：メタノール＝
35：５）。[1100] R f = 0.32 (chloroform: methanol =
35: 5).
【１１０１】上記で得たＢｏｃ体(40mg)のメタノール(1
0ml)溶液にナトリウムメトキシド（28％メタノール溶液
10μｌ）を加え、室温ににて２時間撹拌した。「アンバ
ーリスト15Ｅ」を液性が中性になるまで加えた後樹脂を
濾去して、濾液を濃縮し、目的化合物853 (32mg)を得
た。The Boc form (40 mg) obtained above in methanol (1
Sodium methoxide (28% methanol solution)
10 μl) and stirred at room temperature for 2 hours. After adding “Amberlyst 15E” until the solution became neutral, the resin was removed by filtration and the filtrate was concentrated to obtain the desired compound 853 (32 mg).
【１１０２】［α］D 26-4.2゜(c 0.55，メタノール)
。[1102] [α] D 26 -4.2 ゜ (c 0.55, methanol)
.
【１１０３】IR(KBr) ：3400，1690，1650，1550cm-1。[1103] IR (KBr): 3400, 1690, 1650, 1550 cm -1 .
【１１０４】 1H-NMR(CD3 OD) ：1.43(9H,s)，1.99(3H,
s)，3.83(1H,d,J=3Hz)，3.92(1H,dd,J=8.5,11Hz)，4.45
(1H,d,J=8.5Hz)。[1104] 1 H-NMR (CD 3 OD): 1.43 (9H, s), 1.99 (3H,
s) 、 3.83 (1H, d, J = 3Hz) 、 3.92 (1H, dd, J = 8.5,11Hz) 、 4.45
(1H, d, J = 8.5Hz).
【１１０５】Ｒf =0.68 （クロロホルム：メタノール=
4:1）。[1105] R f = 0.68 (chloroform: methanol =
4: 1).
【１１０６】(g′) 化合物854 の合成（図８ｊ） アミノ体のパラトルエンスルホン酸塩818(240mg)の塩化
メチレン (８ml) 溶液にトリエチルアミン(0.1ml) を加
えた後、氷冷下コレステリルクロロフォルメイト(174m
g) を加え、室温に戻して終夜撹拌した。反応液を水及
び半飽和食塩水にて洗浄し、硫酸マグネシウムにて乾燥
した。溶媒を留去し、残渣をシリカゲルカラムクロマト
グラフィー（シリカゲル 20ｇ、酢酸エチルエステル）
にて精製してカルバメイト体（256mg ，90％）を得た。 (G ′) Synthesis of Compound 854 (FIG. 8j) Triethylamine (0.1 ml) was added to a methylene chloride (8 ml) solution of the para-toluenesulfonic acid salt 818 (240 mg) of the amino compound, and then cholesterylchloroform was added under ice cooling. Formate (174m
g) was added, and the mixture was returned to room temperature and stirred overnight. The reaction solution was washed with water and half-saturated saline, and dried over magnesium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (silica gel 20 g, ethyl acetate).
To give a carbamate form (256 mg, 90%).
【１１０７】［α］D 27-31.1 ゜(c 1.0，クロロホル
ム) 。[Α] D 27 -31.1 ゜ (c 1.0, chloroform).
【１１０８】IR(KBr) ：3340，1750，1720，1540cm-1。[1108] IR (KBr): 3340, 1750, 1720, 1540 cm- 1 .
【１１０９】 1H-NMR(CD3 OD) ：0.71(3H,s)，0.86(3H,
d,J=6.5Hz)，0.87(3H,d,J=6.5Hz)，0.94(3H,d,J=6.5H
z)，1.03(3H,s)，1.92(3H,s)，1.94(3H,s)，2.02(3H,
s)，2.13(3H,s)，4.08(1H,dd,J=8.5,11Hz)，4.36(1H,
m)，4.65(1H,d,J=8.5Hz)，5.06(1H,J=3,11Hz) ，5.32(1
H,d,J=3Hz)，5.38(1H,m)。[1109] 1 H-NMR (CD 3 OD): 0.71 (3H, s), 0.86 (3H,
d, J = 6.5Hz), 0.87 (3H, d, J = 6.5Hz), 0.94 (3H, d, J = 6.5H
z), 1.03 (3H, s), 1.92 (3H, s), 1.94 (3H, s), 2.02 (3H, s)
s), 2.13 (3H, s), 4.08 (1H, dd, J = 8.5,11Hz), 4.36 (1H,
m), 4.65 (1H, d, J = 8.5 Hz), 5.06 (1H, J = 3, 11 Hz), 5.32 (1
H, d, J = 3Hz), 5.38 (1H, m).
【１１１０】Ｒf =0.53 （クロロホルム：メタノール=9
5:5 ）。[1110] R f = 0.53 (chloroform: methanol = 9
5: 5).
【１１１１】上記で得たカルバメート体(240mg) のメタ
ノール(20ml)溶液にナトリウムメトキシド（28％メタノ
ール溶液20μｌ）を加え、室温にて２時間撹拌した。
「アンバーリスト15Ｅ」を液性が中性になるまで加えた
後樹脂を濾去し、濾液を濃縮し、残渣を「セファデック
スＬＨ−20」（メタノール：クロロホルム１：１）にて
精製し、目的化合物854(199mg)を得た。To a solution of the carbamate derivative (240 mg) obtained above in methanol (20 ml) was added sodium methoxide (20 μl of a 28% methanol solution), and the mixture was stirred at room temperature for 2 hours.
After adding “Amberlyst 15E” until the solution becomes neutral, the resin is removed by filtration, the filtrate is concentrated, and the residue is purified with “Sephadex LH-20” (methanol: chloroform 1: 1). The target compound 854 (199 mg) was obtained.
【１１１２】［α］D 26-19.8 ゜(c 1.34，クロロホル
ム：メタノール=1:1) 。[Α] D 26 −19.8 c (c 1.34, chloroform: methanol = 1: 1).
【１１１３】IR(KBr) ：3340，1716，1655，1650，1550
cm-1。[1113] IR (KBr): 3340, 1716, 1655, 1650, 1550
cm -1 .
【１１１４】 1H-NMR(CD3 OD) ：0.72(3H,s)，0.85(3H,
d,J=6.5Hz)，0.88(3H,d,J=6.5Hz)，0.94(3H,d,J=6.5H
z)，1.04(3H,s)，1.99(3H,s)，3.83(1H,d,J=3Hz)，3.93
(1H,dd,J=9,10.5Hz)，3.83(1H,m)，4.52(1H,d,J=9Hz)，
5.38(1H,m)。[1114] 1 H-NMR (CD 3 OD ): 0.72 (3H, s), 0.85 (3H,
d, J = 6.5Hz), 0.88 (3H, d, J = 6.5Hz), 0.94 (3H, d, J = 6.5H)
z), 1.04 (3H, s), 1.99 (3H, s), 3.83 (1H, d, J = 3Hz), 3.93
(1H, dd, J = 9,10.5Hz), 3.83 (1H, m), 4.52 (1H, d, J = 9Hz),
5.38 (1H, m).
【１１１５】Ｒf =0.38 （クロロホルム：メタノール=
9:1）。[1115] R f = 0.38 (chloroform: methanol =
9: 1).
【１１１６】(h′) 化合物852 の合成（図８ｋ） １）化合物1103の合成 ２−（ｎ−ヘキサデシル）オクタデカン酸 0.291ｇに塩
化チオニル２mlを加え、６時間加熱還流した。塩化チオ
ニルを減圧下留去した。残渣にベンゼンを加えて溶か
し、減圧下濾去した。（２回）。これ以上の精製はせず
に、以下の反応に用いた。 (H ′) Synthesis of Compound 852 (FIG. 8k) 1) Synthesis of Compound 1103 To 0.291 g of 2- (n-hexadecyl) octadecanoic acid was added 2 ml of thionyl chloride, and the mixture was heated under reflux for 6 hours. Thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue to dissolve it, and filtered off under reduced pressure. (Twice). It was used for the following reaction without further purification.
【１１１７】２）化合物851 の合成 化合物818 、 0.278ｇに塩化メチレン５mlを加えて溶か
し、氷冷下攪拌した。ここにトリエチルアミン 139μｌ
を加え、さらに上記反応で得た化合物1103全量を塩化メ
チレン５mlに溶かして加え、室温に昇温させつつ３日間
攪拌した。塩化メチレンで希釈し、水及び飽和食塩水で
洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去
した。残渣をシリカゲルカラムクロマトグラフィーで精
製し（溶出溶媒：塩化メチレン−メタノール70：１）、
目的物を無色非晶質として 0.318ｇ得た。2) Synthesis of Compound 851 To 0.278 g of Compound 818, 5 ml of methylene chloride was added and dissolved, followed by stirring under ice-cooling. 139μl of triethylamine here
Was added, and the whole amount of the compound obtained in the above reaction was dissolved in 5 ml of methylene chloride, and the mixture was stirred for 3 days while warming to room temperature. The mixture was diluted with methylene chloride, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride-methanol 70: 1),
0.318 g of the desired product was obtained as a colorless amorphous.
【１１１８】 1H-NMR で２種のconformer の約１：１の
混合物となっており、以下のＮＭＲの水素数は、各々の
conformer の水素１つを１Ｈとして数えて示してある。In 1 H-NMR, a mixture of two conformers of about 1: 1 was obtained. The number of hydrogen atoms in the following NMR was as follows.
One hydrogen of the conformer is shown counted as 1H.
【１１１９】 1H-NMR(δ, CD3 OD) ：0.90(t,12H,J=7.0
Hz) ，1.20-1.42(m,116H) ，1.51-1.59(m,4H) ，1.93
(s,3H)，1.94(2,3H)，1.95(s,6H)，2.03(s,3H)，2.14
(s,3H)，2.15-2.21(m,2H) ，3.34-3.41(m,4H) ，3.36
(t,2H,J=5.6Hz)，3.57-5.76(m,10H)，3.90-3.96(m,2H)
，4.02(brt,2H)，4.07-4.19(m,6H) ，4.64(d,1H,J=8.5
Hz)，4.65(d,1H,J=8.5Hz)，5.05(dd,1H,J=9.5Hz,3.4Hz)
，5.08(dd,1H,J=9.4Hz,3.3Hz) ，5.33(brd,1H),5.34(b
rd,1H) 。[1119] 1 H-NMR (δ, CD 3 OD): 0.90 (t, 12H, J = 7.0
Hz), 1.20-1.42 (m, 116H), 1.51-1.59 (m, 4H), 1.93
(s, 3H), 1.94 (2, 3H), 1.95 (s, 6H), 2.03 (s, 3H), 2.14
(s, 3H), 2.15-2.21 (m, 2H), 3.34-3.41 (m, 4H), 3.36
(t, 2H, J = 5.6Hz), 3.57-5.76 (m, 10H), 3.90-3.96 (m, 2H)
, 4.02 (brt, 2H), 4.07-4.19 (m, 6H), 4.64 (d, 1H, J = 8.5
Hz), 4.65 (d, 1H, J = 8.5Hz), 5.05 (dd, 1H, J = 9.5Hz, 3.4Hz)
, 5.08 (dd, 1H, J = 9.4Hz, 3.3Hz), 5.33 (brd, 1H), 5.34 (b
rd, 1H).
【１１２０】［α］D 26=-12.2゜(c=1.00,CHCl3 -MeOH
1:1 ）。[1120] [α] D 26 = -12.2 ゜ (c = 1.00, CHCl 3 -MeOH
1: 1).
【１１２１】３）化合物852 （GalNAc-t-pas) の合成 化合物851 、 0.300ｇにベンゼン４ml及びメタノール２
mlを加えて溶かし、氷冷下攪拌した。ここに28％ナトリ
ウムメトキシドメタノール溶液を３滴加えてｐＨ＝12と
し、室温で12時間攪拌した。ここに「ダウエックス50Ｘ
−８」イオン交換樹脂（Ｈ型）を加えて中和し、樹脂を
濾去した。溶媒を減圧下留去し、残渣を「セファデック
スＬＨ−20」で精製し（溶出溶媒：クロロホルム−メタ
ノール１：１）、目的化合物を無色粉末として 0.147ｇ
得た。[1121] 3) Synthesis of compound 852 (GalNAc-t-pas) Compound 851 was added to 0.300 g of benzene 4 ml and methanol 2
The mixture was added and dissolved, and stirred under ice cooling. To this was added 3 drops of a 28% sodium methoxide methanol solution to adjust the pH to 12, and the mixture was stirred at room temperature for 12 hours. Here, "Dowex 50X
-8 "Ion exchange resin (H type) was added for neutralization, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: chloroform-methanol 1: 1), and 0.147 g of the target compound was obtained as a colorless powder.
Obtained.
【１１２２】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,3H,J=7.0Hz)，1.19-1.41(m,52H)，1.43-1.62(m,6H)
，1.92-2.00(m,2H) ，2.13(s,3H)，2.52-2.59(m,1H)
，3.63-3.80(m,10H)，3.91(dt,1H,J=5.4Hz) ，3.99-4.
01(br t,1H)，4.19(dt,1H,H=4.6Hz,11.0Hz)，4.33(dd,1
H,J=3.2Hz,10.6Hz)，4.37-4.42(m,3H) ，4.49(dm1H,J=
3.2Hz)，4.82(dd,1H,J=8.4Hz,10.6Hz)，5.05(d,1H,J=8.
4Hz)，8.84(br t,1H) 。[1122] 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88
(t, 3H, J = 7.0Hz), 1.19-1.41 (m, 52H), 1.43-1.62 (m, 6H)
, 1.92-2.00 (m, 2H), 2.13 (s, 3H), 2.52-2.59 (m, 1H)
, 3.63-3.80 (m, 10H), 3.91 (dt, 1H, J = 5.4Hz), 3.99-4.
01 (br t, 1H), 4.19 (dt, 1H, H = 4.6Hz, 11.0Hz), 4.33 (dd, 1H
H, J = 3.2Hz, 10.6Hz), 4.37-4.42 (m, 3H), 4.49 (dm1H, J =
3.2Hz), 4.82 (dd, 1H, J = 8.4Hz, 10.6Hz), 5.05 (d, 1H, J = 8.
4Hz), 8.84 (br t, 1H).
【１１２３】［α］D 25=-5.9 ゜(c=0.99, CHCl 3 -MeO
H 1:1)。[1123] [α] D 25 = -5.9 ゜ (c = 0.99, CHCl 3 -MeO
H 1: 1).
【１１２４】FAB-MS： [M+H]+ ；m/z=843 。[1124] FAB-MS: [M + H] + ; m / z = 843.
【１１２５】実施例９ Ｌ−α−ジパルミトイルホスファチジリコリン60μmol
、コレステロール60μmol 、ジセチルリン酸６μmol
及び実施例６で得られた化合物（化合物608)６μmol を
クロロホルムおよびメタノールの混液（容積比２：１）
に溶かした。次に、窒素ガス気流中で有機溶媒を除去し
て遠沈管のガラス壁にリピッドフィルムを生成させた。Example 9 L-α-dipalmitoyl phosphatidylcholine 60 μmol
, Cholesterol 60μmol, dicetyl phosphate 6μmol
And 6 μmol of the compound obtained in Example 6 (compound 608) in a mixture of chloroform and methanol (volume ratio 2: 1)
Melted into. Next, the organic solvent was removed in a stream of nitrogen gas to form a lipid film on the glass wall of the centrifuge tube.
【１１２６】ここに予め約45℃に加温した１mMイヌリン
のリン酸緩衝化生理食塩水(pH7.4、以下ＰＢＳと略すこ
とがある）６mlを加えて振蘯し、更に軽く超音波処理し
てリピソームの懸濁液を調製した。これを45〜60℃に加
温し、次いで0.08μm の孔径を有するポリカーボネート
製メンブランフィルターに通過させ、粒径約0.08μmの
リポソームの懸濁液を調製した。[1126] To this is added 6 ml of 1 mM inulin phosphate-buffered saline (pH 7.4, sometimes abbreviated as PBS hereinafter) preliminarily heated to about 45 ° C., shaken, and further sonicated lightly. To prepare a suspension of liposomes. This was heated to 45 to 60 ° C., and then passed through a polycarbonate membrane filter having a pore size of 0.08 μm to prepare a suspension of liposomes having a particle size of about 0.08 μm.
【１１２７】次にこれを超遠心分離し（105 ×ｇ，１時
間，３回）、上澄液を除去することによりリポソームに
保持されなかったイヌリンを除去し、ＰＢＳを加えて、
全量4.9mlのリポソーム懸濁液を得た。Next, this was ultracentrifuged (10 5 × g, 1 hour, 3 times), the supernatant was removed to remove inulin not retained in the liposome, and PBS was added.
A total of 4.9 ml of the liposome suspension was obtained.
【１１２８】実施例10 Ｌ−α−ジパルミトイルホスファチジルコリン70μmol
、コレステロール70μmol 、ジセチルリン酸７μmol
及び実施例８で得られた化合物（化合物827)７μmol を
クロロホルムおよびメタノールの混液（容積比２：１）
に溶かした。次に、窒素ガス気流中で有機溶媒を除去し
て遠沈管のガラス壁にリピッドフィルムを生成させた。Example 10 L-α-Dipalmitoyl phosphatidylcholine 70 μmol
, Cholesterol 70μmol, dicetyl phosphate 7μmol
And a mixture of chloroform and methanol (2: 1 by volume) with 7 μmol of the compound obtained in Example 8 (compound 827).
Melted into. Next, the organic solvent was removed in a stream of nitrogen gas to form a lipid film on the glass wall of the centrifuge tube.
【１１２９】ここに予め約45℃に加温した１mMイヌリン
のリン酸緩衝化生理食塩水(pH7.4)７mlを加えて振蘯
し、更に軽く超音波処理してリポソームの懸濁液を調製
した。これを45〜60℃に加温し、次いで0.08μm の孔径
を有するポリカーボネート製メンブランフィルターに通
過させ、粒径約0.08μm のリポソームの懸濁液を調製す
る。[1129] 7 ml of 1 mM inulin phosphate-buffered saline (pH 7.4) preliminarily heated to about 45 ° C is added, shaken, and further sonicated slightly to prepare a liposome suspension. did. This is heated to 45 to 60 ° C. and then passed through a polycarbonate membrane filter having a pore size of 0.08 μm to prepare a suspension of liposomes having a particle size of about 0.08 μm.
【１１３０】次にこれを超遠心分離し（104 ×ｇ，１時
間，３回）、上澄液を除去することによりリポソームに
保持されなかったイヌリンを除去してＰＢＳを加え、全
量 5.8mlのリポソーム懸濁液を得た。Next, this was ultracentrifuged (10 4 × g, 1 hour, 3 times), the supernatant was removed to remove inulin not retained in the liposome, and PBS was added. Was obtained.
【１１３１】実施例11 実施例10において、実施例８で得られた化合物（化合物
827)７μmol の代わりに実施例８で得られた他の化合物
（化合物824)７μmol を使用した以外は実施例10におけ
ると同様に処理して、全量６mlのリポソーム懸濁液を得
た。Example 11 In Example 10, the compound obtained in Example 8 (compound
827) The same procedure as in Example 10 was repeated, except that 7 μmol of the other compound (compound 824) obtained in Example 8 was used instead of 7 μmol, to give a liposome suspension in a total amount of 6 ml.
【１１３２】実施例12 実施例10において、実施例８で得られた化合物（化合物
827)７μmol の代わりに実施例８で得られた他の化合物
（化合物830)７μmol を使用した以外は実施例10におけ
ると同様に処理して、全量６mlのリポソーム懸濁液を得
た。Example 12 In Example 10, the compound obtained in Example 8 (compound
827) In the same manner as in Example 10 except that 7 μmol of the other compound (compound 830) obtained in Example 8 was used instead of 7 μmol, a liposome suspension having a total amount of 6 ml was obtained.
【１１３３】実施例13 実施例10において、実施例８で得られた化合物（化合物
827)７μmol の代わりに実施例８で得られた他の化合物
（化合物833)７μmol を使用した以外は実施例10におけ
ると同様に処理して、全量６mlのリポソーム懸濁液を得
た。Example 13 In Example 10, the compound obtained in Example 8 (compound
827) The same procedure as in Example 10 was repeated, except that 7 μmol of the other compound (compound 833) obtained in Example 8 was used instead of 7 μmol, to give a liposome suspension in a total amount of 6 ml.
【１１３４】実施例14 大豆油500mg 、卵黄レシチン60mg及びグリセリン 125mg
を秤取し、注射用蒸留水５ml中に加えてホモジナイザー
を用いて粗乳化を行なった。これに実施例８で得られた
化合物（化合物833) 9.8mgを添加し、更に超音波処理し
て乳化を行い、目的のリピッドマイクロフェアー５mlを
得た。Example 14 500 mg of soybean oil, 60 mg of egg yolk lecithin and 125 mg of glycerin
Was weighed, added to 5 ml of distilled water for injection, and coarsely emulsified using a homogenizer. To this, 9.8 mg of the compound (compound 833) obtained in Example 8 was added, and the mixture was further ultrasonically emulsified to obtain 5 ml of the target lipid microsphere.
【１１３５】試験例１ イ．試料 実施例12及び実施例13において、１mMイヌリンの代わり
に 3Ｈ−イヌリン 140μＣｉを含有する１mMイヌリンを
使用した以外は実施例12及び実施例13におけると同様に
処理して、全量 4.9ml及び６mlのリポソーム懸濁液を得
た。これらをそれぞれ検体試料１及び２として引用す
る。なお、Ｌ−α−ジパルミトイルホスファチジルコリ
ンのコリン基をマーカーとして酸素法により１ml当りの
リン脂質を定量し、いずれの検体試料も10.0μmol を含
有するように調製した。Test Example 1 a. Samples The same procedures as in Examples 12 and 13 except that 1 mM inulin containing 140 μCi of 3 H-inulin were used in place of 1 mM inulin, and the total volume was 4.9 ml and 6 ml. Was obtained. These are referred to as sample samples 1 and 2, respectively. The amount of phospholipid per ml was determined by the oxygen method using the choline group of L-α-dipalmitoylphosphatidylcholine as a marker, and each sample was prepared so as to contain 10.0 μmol.
【１１３６】また、実施例９において、化合物608 を配
合せずかつ１mMイヌリンの代わりに3Ｈ−イヌリン 140
μＣｉを含有する１mMイヌリンを使用した以外は実施例
９におけると同様に処理して、全量６mlのリポソーム懸
濁液を得た。これを対照試料１（コントロールリポソー
ム）として引用する。なお、Ｌ−α−ジパルミトイルホ
スファチジルコリンのコリン基をマーカーとして酵素法
により１ml当りのリン脂質を定量し、10.0μmol を含有
するように調製した。[1136] Further, in Example 9, instead of 3 H- inulin 140 without and 1mM inulin was blended compound 608
The same procedure as in Example 9 was carried out except that 1 mM inulin containing μCi was used to obtain a liposome suspension in a total volume of 6 ml. This is referred to as control sample 1 (control liposome). The phospholipid per ml was quantified by enzymatic method using the choline group of L-α-dipalmitoylphosphatidylcholine as a marker, and was prepared to contain 10.0 μmol.
【１１３７】ロ．試験方法 用意した３種の試料をそれぞれＳＤ系雄性ラット（体重
200〜250 ｇ）の後肢静脈より体重 100ｇ当たりＬ−α
−ジパルミトイルホスファチジルコリン及びコレステロ
ールの合計として５μmol を注入した。[1137] b. Test method Each of the three prepared samples was subjected to SD male rats (body weight).
200-250 g) L-α per 100 g body weight from hind limb vein
5 μmol of dipalmitoylphosphatidylcholine and cholesterol were injected in total.
【１１３８】投与後15分、30分、１時間、２時間、４時
間及び６時間目に頸静脈より血液を約 0.2ml採血し、遠
心後血漿約 100μｌをろ紙に採り、乾燥後燃焼装置にて
燃焼し、液体シンチレーション法によりその放射活性を
求めた。また、６時間後にラットを屠殺し、肝臓を約 4
00mg採り、乾燥後燃焼装置にて燃焼し、液体シンチレー
ション法によりその放射活性を求め、肝臓１ｇあたりの
イヌリン濃度を求めた。At 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after administration, about 0.2 ml of blood was collected from the jugular vein, and after centrifugation, about 100 μl of plasma was collected on a filter paper, dried, and then burned. It was burned and its radioactivity was determined by the liquid scintillation method. After 6 hours, the rats were sacrificed and the liver was
After taking 100 mg, drying and burning in a combustion device, the radioactivity was determined by a liquid scintillation method, and the inulin concentration per 1 g of liver was determined.
【１１３９】ハ．結果 結果を図９ａ及び図９ｂに示す。[1139] c. Results The results are shown in FIGS. 9a and 9b.
【１１４０】図９ａは血中濃度の経時的変化を表すグラ
フであり、図中の□、●及び△の各線はそれぞれ対照試
料、検体試料１及び検体試料２における結果を示す。図
９ｂは対照試料、検体試料１及び検体試料２におけるラ
ット一匹あたりの肝臓への集積度（組織１ｇ中の投与量
に対する％×肝臓重量）の結果を示す。[1140] Fig. 9a is a graph showing the time-dependent change in blood concentration. In the figure, the lines □, ● and △ show the results for the control sample, sample sample 1 and sample sample 2, respectively. FIG. 9b shows the results of the degree of accumulation in the liver per rat in the control sample, sample sample 1 and sample sample 2 (% of the dose in 1 g of tissue × liver weight).
【１１４１】両図より、本発明リポソームが、コントロ
ールリポソームに比較して血中から速やかに消失し、肝
臓に移行していることが判明した。From both figures, it was found that the liposome of the present invention disappeared more rapidly from the blood than the control liposome and was transferred to the liver.
【１１４２】試験例２ イ．試料 実施例11において、１mMイヌリンの代わりに 3Ｈ−イヌ
リン 140μＣｉを含有する１mMイヌリンを使用した以外
は実施例11におけると同様に処理して、全量６mlのリポ
ソーム懸濁液を得た。これを検体試料として引用する。
なお、Ｌ−α−ジパルミトイルホスファチジルコリンの
コリン基をマーカーとして酵素法により１ml当りのリン
脂質を定量し、10.0μmol を含有するように調製した。Test Example 2 a. Sample A liposome suspension having a total volume of 6 ml was obtained in the same manner as in Example 11, except that 1 mM inulin containing 140 μCi of 3 H-inulin was used instead of 1 mM inulin. This is referred to as a specimen sample.
The phospholipid per ml was quantified by enzymatic method using the choline group of L-α-dipalmitoylphosphatidylcholine as a marker, and was prepared to contain 10.0 μmol.
【１１４３】なお、試験例１で用意した対照試料をその
まま本試験例における対照試料として使用した。The control sample prepared in Test Example 1 was used as it was in this Test Example.
【１１４４】ロ．試験方法 コラゲネース還流法によってラットより調製した肝実質
細胞と各試料とをそれぞれ37℃で１時間及び４℃で２時
間インキュベートし、その後にオイルチューブ遠心法に
より反応液中の遊離リポソームと肝実質細胞に結合した
結合リポソームとを分離した。[1144] b. Test Method Hepatocytes prepared from rats by the collagenase perfusion method and each sample were incubated at 37 ° C. for 1 hour and at 4 ° C. for 2 hours, respectively, and then free liposomes and hepatocytes in the reaction solution were subjected to oil tube centrifugation. And the bound liposome bound to.
【１１４５】沈殿によって得られた結合リポソームをア
ルカリ液に溶かし、トルエンシンチレータを加え、液体
シンチレーションカウンターにより 3Ｈ−イヌリン取込
量を測定した。The bound liposome obtained by precipitation was dissolved in an alkaline solution, toluene scintillator was added, and the amount of 3 H-inulin uptake was measured by a liquid scintillation counter.
【１１４６】ハ．結果 結果を図９ｃに示す。[1146] C. Results The results are shown in FIG. 9c.
【１１４７】この図は対照試料及び検体試料における取
込量を細胞106 個当たりの取込脂質量(nmol)をもって示
した棒グラフであり、図中のクロスハッチングおよびハ
ッチングの各カラムは37℃での取込量及び４℃での取込
量（細胞付着量）を示し、白抜きのカラムは37℃での取
込量４℃の取込量との差、すなわち細胞内取込量を示
す。対照試料での細胞内取込量を 100とすると検体試料
でのそれは 388であり、約４倍に増大する。従って、実
施例７で得られた化合物（化合物824)を用いて調製する
本発明リポソームは肝実質細胞への薬物送達のキャリヤ
ーとして有用であることが知られる。This figure is a bar graph showing the uptake amount in the control sample and the test sample as the uptake lipid amount (nmol) per 10 6 cells. The cross-hatched and hatched columns in the figure were at 37 ° C. And the uptake amount at 4 ° C. (the amount of adhered cells). The white column shows the difference between the uptake amount at 37 ° C. and the uptake amount at 4 ° C., that is, the uptake amount in cells. . Assuming that the amount of intracellular uptake in the control sample is 100, that in the test sample is 388, which is about a four-fold increase. Therefore, it is known that the liposome of the present invention prepared using the compound (compound 824) obtained in Example 7 is useful as a carrier for drug delivery to hepatocytes.
【１１４８】実施例15（グルコース誘導体の合成） 本実施例における反応式を図10ａ乃至図10ｂに示す。Example 15 (Synthesis of Glucose Derivative) The reaction formula in this example is shown in FIGS. 10A and 10B.
【１１４９】(a) 化合物1105の合成（図10ａ） １）化合物1101の合成 β−Ｄ−グルコースペンタアセテート6.16ｇ及び２−
［２−（２−アジドエトキシ）エトキシ］エタノール6.
59ｇを塩化メチレン50mlに溶かし、氷冷下撹拌した。こ
こに三フッ化硼素ジエチルエーテル錯体8.7ml を塩化メ
チエン10mlに溶かして５分間で滴下した。室温で19時間
撹拌した後、氷水にあけ、有機層を分離した。４回水洗
いした後（水層は中性となった）、飽和食塩水で洗い、
硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。
残渣をシリカゲルカラムクロマトグラフィーで精製し
（溶出溶媒：ｎ−ヘキサン−酢酸エチル ２：１）、目
的物を無色油状物として2.27g を得た。 (A) Synthesis of Compound 1105 (FIG. 10a) 1) Synthesis of Compound 1101 6.16 g of β-D-glucose pentaacetate and 2-
[2- (2-azidoethoxy) ethoxy] ethanol 6.
59 g was dissolved in 50 ml of methylene chloride and stirred under ice cooling. 8.7 ml of boron trifluoride-diethyl ether complex was dissolved in 10 ml of methene chloride and added dropwise over 5 minutes. After stirring at room temperature for 19 hours, the mixture was poured into ice water and the organic layer was separated. After washing with water four times (the aqueous layer became neutral), wash with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 2: 1) to obtain 2.27 g of the desired product as a colorless oil.
【１１５０】 1H-NMR(δ, CDCl3 ) ：2.01(s,3H)，2.03
(s,3H)，2.05(s,3H)，2.09(s,3H)，3.41(t,2H,J=5.0H
z)，3.63-3.78(m,10H)，3.93-3.97(m,1H) ，4.14(dd,1
H,J=2.0Hz,12.5Hz)，4.26(dd,1H,5.0Hz,12.5Hz)，4.62
(d,1H,J=7.9Hz)，5.00(dd,1H,J=7.9Hz,9.8Hz) ，5.09
(t,J=9.8Hz) ，5.21(t,1H,J=9.8Hz)。[1150] 1 H-NMR (δ, CDCl 3 ): 2.01 (s, 3H), 2.03
(s, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 3.41 (t, 2H, J = 5.0H
z), 3.63-3.78 (m, 10H), 3.93-3.97 (m, 1H), 4.14 (dd, 1
H, J = 2.0Hz, 12.5Hz), 4.26 (dd, 1H, 5.0Hz, 12.5Hz), 4.62
(d, 1H, J = 7.9Hz), 5.00 (dd, 1H, J = 7.9Hz, 9.8Hz), 5.09
(t, J = 9.8Hz), 5.21 (t, 1H, J = 9.8Hz).
【１１５１】［α］D 20=-12.1゜(c=1.01 ，CHCl3 ) 。[Α] D 20 = -12.1 ゜ (c = 1.01, CHCl 3 ).
【１１５２】２）化合物1102の合成 化合物1101、2.11ｇに酢酸エチル150ml を加えて溶かし
た。ここにｐ−トルエンスルホン酸１水和物0.79ｇ及び
リンドラー触媒1.04ｇを加え、50ｐｓｉで6.5時間接触
還元した。さらにリンドラー触媒1.04ｇを加え、50ｐｓ
ｉで３時間接触還元した。触媒を濾去し、目的物を淡褐
色油状物として2.49ｇ得た。これ以上の精製はせずに、
以下の反応に用いた。2) Synthesis of compound 1102 To 110 g of compound 1101, 2.11 g of ethyl acetate was added and dissolved. 0.79 g of p-toluenesulfonic acid monohydrate and 1.04 g of Lindlar catalyst were added thereto, and the mixture was subjected to catalytic reduction at 50 psi for 6.5 hours. Add 1.04g of Lindlar catalyst and add 50ps
Catalytic reduction with i for 3 hours. The catalyst was removed by filtration to give 2.49 g of the desired product as a pale brown oil. Without further purification
The following reaction was used.
【１１５３】３）化合物1103の合成 ２−（ｎ−ヘキサデシル）オクタデカン酸0.91ｇに塩化
チオニル５mlを加え、６時間加熱還流させた。塩化チオ
ニルを減圧下留去した。残渣にベンゼンを加えて溶か
し、減圧下留去した（２回）。これ以上の精製はせず
に、以下の反応に用いた。3) Synthesis of Compound 1103 To 0.91 g of 2- (n-hexadecyl) octadecanoic acid was added 5 ml of thionyl chloride, and the mixture was refluxed for 6 hours. Thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue to dissolve it, and evaporated under reduced pressure (twice). It was used for the following reaction without further purification.
【１１５４】４）化合物1104の合成 化合物1102、0.90ｇに塩化メチレン30ml及びトリエチル
アミン190 μｌを加えて溶かし、ここに上記反応で得た
化合物1103全量を塩化メチレン５mlに溶かして加え、さ
らに２時間撹拌し、さらに室温で30分間撹拌した。塩化
メチレンで希釈し、１Ｎ塩酸、水及び飽和食塩水で洗
い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去し
た。残渣をシリカゲルカラムクロマトグラフィーで精製
し（溶出溶媒：ｎ−ヘキサン−酢酸エチル １：１）、
目的物を無色油状物として0.67ｇ得た。4) Synthesis of Compound 1104 To 0.90 g of Compound 1102, 30 mL of methylene chloride and 190 μL of triethylamine were added and dissolved. The entire amount of Compound 1103 obtained by the above reaction was dissolved in 5 mL of methylene chloride, and the mixture was further stirred for 2 hours. And further stirred at room temperature for 30 minutes. The mixture was diluted with methylene chloride, washed with 1N hydrochloric acid, water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 1: 1),
0.67 g of the desired product was obtained as a colorless oil.
【１１５５】 1H-NMR(δ, CDCl3 ) ：0.88(t,6H,J=7.0H
z)，1.22-1.43(m,58H)，1.56-1.62(bs,2H)，1.97-2.02
(m,1H) ，2.01(s,3H)，2.03(s,3H)，2.05(s,3H)，2.09
(s,3H)，3.44-3.76(m,12H)，3.95-3.98(m,1H) ，4.10-
4.16(m,2H) ，4.26(dd,1H,J=4.8Hz,12.3Hz)，4.60(d,1
H,J=8.1Hz)，5.00(dd,1H,J=8.1Hz,9.5Hz) ，5.09(t,1H,
J=9.5Hz)，5.21(t,1H,J=9.5Hz)，5.99(t,1H,J=5.6Hz)。[1155] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z), 1.22-1.43 (m, 58H), 1.56-1.62 (bs, 2H), 1.97-2.02
(m, 1H), 2.01 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 2.09
(s, 3H), 3.44-3.76 (m, 12H), 3.95-3.98 (m, 1H), 4.10-
4.16 (m, 2H), 4.26 (dd, 1H, J = 4.8Hz, 12.3Hz), 4.60 (d, 1H
H, J = 8.1Hz), 5.00 (dd, 1H, J = 8.1Hz, 9.5Hz), 5.09 (t, 1H,
J = 9.5Hz), 5.21 (t, 1H, J = 9.5Hz), 5.99 (t, 1H, J = 5.6Hz).
【１１５６】［α］D 21= -8.3゜(c=1.02 ，CHCl3 ) 。[Α] D 21 = −8.3 ゜ (c = 1.02, CHCl 3 ).
【１１５７】５）化合物1105の合成 化合物1104、0.62ｇにメタノール６ml及びベンゼン12ml
を加えて溶かし、氷冷下撹拌した。ここに28％ナトリウ
ムメトキシドメタノール溶液を５滴加えてｐＨ＝12と
し、室温で５時間撹拌した。ここに「ダウエックス50Ｘ
−８」イオン交換樹脂（Ｈ型）を加えて中和し、樹脂を
濾去した。溶媒を減圧下留去し、残渣を「セファデック
スＬＨ−２０」で精製し（溶出溶媒：塩化メチレン−メ
タノール１：１）、目的化合物を0.46ｇ得た。5) Synthesis of Compound 1105 Compound 1104 (0.62 g) was mixed with methanol (6 ml) and benzene (12 ml).
Was added and dissolved, and the mixture was stirred under ice cooling. Five drops of a 28% sodium methoxide methanol solution were added thereto to adjust the pH to 12, and the mixture was stirred at room temperature for 5 hours. Here, "Dowex 50X
-8 "Ion exchange resin (H type) was added for neutralization, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: methylene chloride-methanol 1: 1) to obtain 0.46 g of the desired compound.
【１１５８】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,6H,J=6.8Hz)，1.22-1.60(m,58H)，1.92-1.99(m,2H)
，2.51-2.58(m,1H) ，3.59-3.67(m,4H) ，3.68-3.78
(m,6H) ，3.90-3.95(m,2H) ，4.00(t,1H,J=7.8Hz)，4.1
5-4.27(m,3H) ，4.32(dd,1H,J=5.5Hz,11.7Hz)，4.51(d,
1H,J=11.7Hz) ，4.85(d,1H,J=7.8Hz)，8.78(t,1H,J=5.0
Hz)。[1158] 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88
(t, 6H, J = 6.8Hz), 1.22-1.60 (m, 58H), 1.92-1.99 (m, 2H)
, 2.51-2.58 (m, 1H), 3.59-3.67 (m, 4H), 3.68-3.78
(m, 6H), 3.90-3.95 (m, 2H), 4.00 (t, 1H, J = 7.8Hz), 4.1
5-4.27 (m, 3H), 4.32 (dd, 1H, J = 5.5Hz, 11.7Hz), 4.51 (d,
1H, J = 11.7Hz), 4.85 (d, 1H, J = 7.8Hz), 8.78 (t, 1H, J = 5.0
Hz).
【１１５９】［α］D 21= -7.1゜c=1.02，CHCl3 ) 。[Α] D 21 = −7.1 ゜ c = 1.02, CHCl 3 ).
【１１６０】FAB-MS:[M+H] + ;m/z=802。[1160] FAB-MS: [M + H] + ; m / z = 802.
【１１６１】(b) 化合物1107の合成（図10ｂ） １）化合物1106の合成 β−Ｄ−グルコースペンタアセテート1.44ｇ及びトリエ
チレングリコールモノオクタデシルエーテル1.93ｇを塩
化メチレン10mlに溶かし、氷冷下撹拌した。ここに三フ
ッ化硼素ジエチルエーテル錯体2.0ml を滴下した。室温
で14時間撹拌した後、氷水にあけ、有機層を分離した。
４回水洗した後（水層は中性となった）、飽和食塩水で
洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去
した。残渣にピリジン20mlを加えて溶かし、無水酢酸1.
74mlを加えて室温で４日間撹拌した。氷水にあけ、酢酸
エチルで希釈して有機層を分離した。２Ｎ塩酸（５
回）、水及び飽和食塩水で洗い、硫酸マグネシウム上乾
燥させ、溶媒を減圧下留去した。残渣をシリカゲルカラ
ムクロマトグラフィーで精製し（溶出溶媒：ｎ−ヘキサ
ン−酢酸エチル ２：１）、目的物を無色油状物として
0.77ｇ得た。 (B) Synthesis of Compound 1107 (FIG. 10b) 1) Synthesis of Compound 1106 1.44 g of β-D-glucose pentaacetate and 1.93 g of triethylene glycol monooctadecyl ether were dissolved in 10 ml of methylene chloride and stirred under ice-cooling. . 2.0 ml of boron trifluoride-diethyl ether complex was added dropwise thereto. After stirring at room temperature for 14 hours, the mixture was poured into ice water and the organic layer was separated.
After washing four times with water (the aqueous layer became neutral), it was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 20 ml of pyridine was added to the residue to dissolve, and acetic anhydride 1.
74 ml was added and the mixture was stirred at room temperature for 4 days. The mixture was poured into ice water, diluted with ethyl acetate, and the organic layer was separated. 2N hydrochloric acid (5
Times), washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 2: 1) to give the desired product as a colorless oil.
0.77 g was obtained.
【１１６２】 1H-NMR(δ, CDCl3 ) ：0.88(t,3H,J=7.0H
z)，1.18-1.33(m,30H)，1.54-1.60(m,2H) ，2.00(s,3
H)，2.02(s,3H)，2.05(s,3H)，2.09(s,3H)，3.44(t,2H,
J=6.8Hz)，3.57-3.77(m,12H)，3.92-3.96(m,1H) ，4.14
(dd,1H,J=2.8Hz,12.0Hz)，4.26(dd,1H,J=4.8Hz,12.0H
z)，4.61(d,1H,J=8.0Hz)，4.99(dd,1H,J=8.0Hz,9.8Hz)
，5.08(t,1H,J=9.8Hz)，5.20(t,1H,J=9.8Hz)。[1162] 1 H-NMR (δ, CDCl 3): 0.88 (t, 3H, J = 7.0H
z), 1.18-1.33 (m, 30H), 1.54-1.60 (m, 2H), 2.00 (s, 3
H), 2.02 (s, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 3.44 (t, 2H,
J = 6.8Hz), 3.57-3.77 (m, 12H), 3.92-3.96 (m, 1H), 4.14
(dd, 1H, J = 2.8Hz, 12.0Hz), 4.26 (dd, 1H, J = 4.8Hz, 12.0H
z), 4.61 (d, 1H, J = 8.0Hz), 4.99 (dd, 1H, J = 8.0Hz, 9.8Hz)
, 5.08 (t, 1H, J = 9.8 Hz), 5.20 (t, 1H, J = 9.8 Hz).
【１１６３】［α］D 26=-10.7゜(c=1.02 ，CHCl3 ) 。[Α] D 26 = -10.7 ゜ (c = 1.02, CHCl 3 ).
【１１６４】２）化合物1107の合成 化合物1106、0.20ｇにメタノール５mlを加えて溶かし、
氷冷下撹拌した。ここに28％ナトリウムメトキシドメタ
ノール溶液を２滴加えてｐＨ＝12とし、室温で５時間撹
拌した。ここに「ダウエックス50Ｘ−８」イオン交換樹
脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶媒を減
圧下留去し、残渣を「セファデックスＬＨ−20」で精製
し（溶出溶媒：メタノール）、目的化合物を0.13ｇ得
た。2) Synthesis of Compound 1107 To 0.20 g of Compound 1106, 5 ml of methanol was added and dissolved.
The mixture was stirred under ice cooling. Two drops of a 28% sodium methoxide methanol solution were added thereto to adjust the pH to 12, and the mixture was stirred at room temperature for 5 hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by "Sephadex LH-20" (elution solvent: methanol) to obtain 0.13 g of the desired compound.
【１１６５】 1H-NMR(δ, pyridine-d5 -D2 O)：0.88
(t,3H,J=6.8Hz)，1.22-1.38(m,30H)，1.58-1.64(m,2H)
，3.45(t,2H,J=6.5Hz)，3.59-3.76(m,10H)，3.90-3.95
(m,2H)，4.02(t,1H,J=8.3Hz)，4.18-4.28(m,3H) ，4.34
(dd,1H,J=5.5Hz,12.0Hz)，4.53(dd,1H,J=2.5Hz,12.0H
z)，4.85(d,1H,J=8.0Hz)。[1165] 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.88
(t, 3H, J = 6.8Hz), 1.22-1.38 (m, 30H), 1.58-1.64 (m, 2H)
, 3.45 (t, 2H, J = 6.5 Hz), 3.59-3.76 (m, 10H), 3.90-3.95
(m, 2H), 4.02 (t, 1H, J = 8.3Hz), 4.18-4.28 (m, 3H), 4.34
(dd, 1H, J = 5.5Hz, 12.0Hz), 4.53 (dd, 1H, J = 2.5Hz, 12.0H
z), 4.85 (d, 1H, J = 8.0Hz).
【１１６６】［α］D 26=-10.5゜(c=1.04 ，MeOH) 。[Α] D 26 = -10.5 ゜ (c = 1.04, MeOH).
【１１６７】FAB-MS:[M+H] + ;m/z=565。FAB-MS: [M + H] + ; m / z = 565.
【１１６８】実施例16（リボース誘導体の合成）(a) 化合物1205の合成（図11） １）化合物1202の合成 β−Ｄ−リボ−ステトラアセテート（化合物1201）4.29
9 ｇ及び２−［２−（２−アジドエトキシ）エトキシ］
エタノール1.183 ｇを塩化メチレン40mlに溶かし、氷冷
下撹拌した。ここに三フッ化硼素ジエチルエーテル錯体
3.32mlを塩化メチレン6ml に溶かして滴下した。室温で
１時間撹拌した後、氷水にあけ、有機層を分離した。６
回水洗した後（水層は中性となった）、飽和食塩水で洗
い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去し
た。残渣をシリカゲルカラムクロマトグラフィーで精製
し（溶出溶媒：ｎ−ヘキサン−酢酸エチル １：１）、
目的物を無色油状物として1.967 ｇ得た。Example 16 (Synthesis of ribose derivative) (a) Synthesis of compound 1205 (FIG. 11) 1) Synthesis of compound 1202 β-D-ribo-tetraacetate (Compound 1201) 4.29
9 g and 2- [2- (2-azidoethoxy) ethoxy]
1.183 g of ethanol was dissolved in 40 ml of methylene chloride and stirred under ice cooling. Here is the boron trifluoride diethyl ether complex
3.32 ml was dissolved in 6 ml of methylene chloride and added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into ice water and the organic layer was separated. 6
After washing with water (the aqueous layer became neutral), the mixture was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate 1: 1),
1.967 g of the desired product was obtained as a colorless oil.
【１１６９】 1H-NMR(δ, CDCl3 ) ：2.06(s,3H)，2.09
(s,3H)，2.11(s,3H)，3.40(t,2H,J=5.0Hz)，3.64-3.69
(m,9H) ，3.85(ddd,1H,J=3.1Hz,5.1Hz,10.3Hz) ，4.14
(dd,1H,J=6.0Hz,11.4Hz)，4.28-4.32(m,1H) ，4.34(dd,
1H,J=3.8Hz,11.4Hz)，5.06(s,1H)，5.28(d,1H,J=4.8H
z)，5.35(dd,1H,J=4.8Hz,7.0Hz) 。[1169] 1 H-NMR (δ, CDCl 3): 2.06 (s, 3H), 2.09
(s, 3H), 2.11 (s, 3H), 3.40 (t, 2H, J = 5.0Hz), 3.64-3.69
(m, 9H), 3.85 (ddd, 1H, J = 3.1Hz, 5.1Hz, 10.3Hz), 4.14
(dd, 1H, J = 6.0Hz, 11.4Hz), 4.28-4.32 (m, 1H), 4.34 (dd,
1H, J = 3.8Hz, 11.4Hz), 5.06 (s, 1H), 5.28 (d, 1H, J = 4.8H
z), 5.35 (dd, 1H, J = 4.8Hz, 7.0Hz).
【１１７０】［α］D 20=-14.5゜(c=1.04 ，CHCl3 ) 。[Α] D 20 = -14.5 ゜ (c = 1.04, CHCl 3 ).
【１１７１】２）化合物1203の合成 化合物1202、1.844 ｇに酢酸エチル100ml を加えて溶か
した。ここにｐ−トルエンスルホン酸１水和物0.809 ｇ
及びリンドラー触媒0.944 ｇを加え、50ｐｓｉで４時間
接触還元した。さらにリンドラー触媒0.855 ｇを加え、
50ｐｓｉで３時間接触還元した。触媒を濾去し、目的物
を淡褐色油状物として2.422 ｇ得た。これ以上の精製は
せずに、以下の反応に用いた。2) Synthesis of compound 1203 [0177] Ethyl acetate (100 ml) was added to 1.844 g of compound 1202 and dissolved. Here, 0.809 g of p-toluenesulfonic acid monohydrate
And 0.944 g of Lindlar's catalyst, and the mixture was catalytically reduced at 50 psi for 4 hours. Further, 0.855 g of Lindlar's catalyst was added,
Catalytic reduction was performed at 50 psi for 3 hours. The catalyst was removed by filtration to obtain 2.422 g of the desired product as a pale brown oil. It was used for the following reaction without further purification.
【１１７２】３）化合物1103の合成 ２−（ｎ−ヘキサデシル）オクタデカン酸1.024 ｇに塩
化チオニル５mlを加え、2.5 時間加熱還流させた。塩化
チオニルを減圧下留去した。残渣にベンゼンを加えて溶
かし、減圧下留去した（３回）。これ以上の精製はせず
に、以下の反応に用いた。3) Synthesis of compound 1103 To 1.024 g of 2- (n-hexadecyl) octadecanoic acid was added 5 ml of thionyl chloride, and the mixture was refluxed for 2.5 hours. Thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue to dissolve it and distilled off under reduced pressure (three times). It was used for the following reaction without further purification.
【１１７３】４）化合物1204の合成 化合物1203に塩化メチレン20ml及びトリエチルアミン23
6 μｌを加えて溶かし、氷冷下撹拌した。ここにトリエ
チルアミン283 μｌを加え、さらに上記反応で得た化合
物1103全量を塩化メチレン５mlに溶かして加え、室温に
昇温させつつ17時間撹拌した。塩化メチレンで希釈し、
水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥さ
せ、溶媒を減圧下留去した。残渣をシリカゲルカラムク
ロマトグラフィーで精製し（溶出溶媒：ｎ−ヘキサン−
酢酸エチル ３：２）、目的物を0.910 ｇ得た。4) Synthesis of compound 1204 Compound 1203 was added to methylene chloride (20 ml) and triethylamine (23).
6 μl was added to dissolve and stirred under ice cooling. To this, 283 μl of triethylamine was added, and the entire amount of the compound 1103 obtained in the above reaction was dissolved in 5 ml of methylene chloride, and the mixture was stirred for 17 hours while warming to room temperature. Diluted with methylene chloride,
The extract was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: n-hexane-
Ethyl acetate 3: 2) to obtain 0.910 g of the desired product.
【１１７４】 1H-NMR(δ, CDCl3 ) ：0.88(t,6H,J=7.0H
z)，1.21-1.34(m,56H)，1.35-1.44(m,2H) ，1.56-1.63
(m,2H) ，1.96-2.02(m,1H) ，2.06(s,3H)，2.09(s,3
H)，2.11(s,3H)，3.45-3.48(m,2H) ，3.54(t,2H,J=5.0H
z)，3.59-3.66(m,7H) ，3.84-3.88(m,1H) ，4.15(dd,1
H,J=5.3Hz,10.9Hz)，4.29-4.32(m,1H) ，4.33(dd,1H,J=
4.0Hz,10.9Hz)，5.06(s,1H)，5.28(d,1H ，J=5.0Hz)，
5.35(dd,1H,J=5.0Hz,6.7Hz)，6.01(t,1H,J=5.6Hz)。[1174] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z), 1.21-1.34 (m, 56H), 1.35-1.44 (m, 2H), 1.56-1.63
(m, 2H), 1.96-2.02 (m, 1H), 2.06 (s, 3H), 2.09 (s, 3
H), 2.11 (s, 3H), 3.45-3.48 (m, 2H), 3.54 (t, 2H, J = 5.0H
z), 3.59-3.66 (m, 7H), 3.84-3.88 (m, 1H), 4.15 (dd, 1
H, J = 5.3Hz, 10.9Hz), 4.29-4.32 (m, 1H), 4.33 (dd, 1H, J =
4.0Hz, 10.9Hz), 5.06 (s, 1H), 5.28 (d, 1H, J = 5.0Hz),
5.35 (dd, 1H, J = 5.0Hz, 6.7Hz), 6.01 (t, 1H, J = 5.6Hz).
【１１７５】［α］D 20=-6.9 ゜(c=1.03, CHCl 3 ) 。[Α] D 20 = −6.9 ゜ (c = 1.03, CHCl 3 ).
【１１７６】５）化合物1205の合成 化合物1204、 0.477ｇにメタノール３ml及びベンゼン６
mlを加えて溶かした。ここに28％ナトリウムメトキシド
メタノール溶液を６滴加えてｐＨ＝12とし、室温で 1.5
時間攪拌した。ここに「ダウエックス50Ｘ−８」イオン
交換樹脂（Ｈ型）を加えて中和し、樹脂を濾去した。溶
媒を減圧下留去し、残渣を「セファデックスＬＨ−20」
で精製し（溶出溶媒：クロロホルム−メタノール１：
１）、目的物を0.389 ｇ得た。5) Synthesis of compound 1205 To 0.477 g of compound 1204, 3 ml of methanol and 6 parts of benzene were added.
ml was added to dissolve. 6 drops of a 28% sodium methoxide methanol solution are added thereto to adjust the pH to 12, and the
Stirred for hours. A "Dowex 50X-8" ion exchange resin (H type) was added to neutralize the mixture, and the resin was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was separated using "Sephadex LH-20".
(Elution solvent: chloroform-methanol 1:
1) 0.389 g of the desired product was obtained.
【１１７７】 1H-NMR(δ, pyridine-d5 -D2 O)：0.89
(t,6H,J=7.0Hz)，1.20-1.39(m,52H)，1.44-1.62(m,6H)
，1.92-2.01(m,2H) ，2.55-2.60(m,1H) ，3.65-3.78
(m,7H) ，4.09(ddd,1H,J=3.3Hz,6.0Hz,10.8Hz) ，4.14
(dd,1H,J=5.3Hz,11.8Hz)，4.27(dd,1H,J=3.3Hz,11.8Hz)
4.55(d,1H,J=4.9Hz) ，4.72-4.75(m,1H) ，4.84-4.86
(m,1H) ，5.48(s,1H)，8.84(bt,1H) 。[1177] 1 H-NMR (δ, pyridine-d 5 -D 2 O): 0.89
(t, 6H, J = 7.0Hz), 1.20-1.39 (m, 52H), 1.44-1.62 (m, 6H)
, 1.92-2.01 (m, 2H), 2.55-2.60 (m, 1H), 3.65-3.78
(m, 7H), 4.09 (ddd, 1H, J = 3.3Hz, 6.0Hz, 10.8Hz), 4.14
(dd, 1H, J = 5.3Hz, 11.8Hz) 、 4.27 (dd, 1H, J = 3.3Hz, 11.8Hz)
4.55 (d, 1H, J = 4.9Hz), 4.72-4.75 (m, 1H), 4.84-4.86
(m, 1H), 5.48 (s, 1H), 8.84 (bt, 1H).
【１１７８】［α］D 20=-13.3゜(c=1.00,CHCl3 -MeOH
1 ：1 ) 。[Α] D 20 = -13.3 ゜ (c = 1.00, CHCl 3 -MeOH
1: 1).
【１１７９】FAB-MS:[M+H]+ ；m/z=772 。[1179] FAB-MS: [M + H] + ; m / z = 772.
【１１８０】[1180]
【発明の効果】本発明により、微小循環性が改善され、
臓器指向性が顕著に優れた薬物送達系が提供されるとこ
ろとなった。According to the present invention, microcirculation is improved,
A drug delivery system with remarkably excellent organ directivity has been provided.
図１ａ乃至図１ｃ、図２ａ乃至図２ｑ、図３ａ乃至図３
ｋ、図４ａ乃至図４ｂ、図５ａ乃至図５n、図６、図７
ａ乃至図７ｄ及び図８ａ乃至図８ｋは、それぞれ実施例
１，２，３，４，５，６，７及び８における反応式を示
す。図９ａ及び図９ｂは試験例１における試験結果を、
そして図９ｃは試験例２における試験結果を表す。図10
ａ乃至図10ｂ及び図11は、それぞれ、実施例15及び16に
おける反応式を示す。1a to 1c, 2a to 2q, 3a to 3
k, FIGS. 4a to 4b, FIGS. 5a to 5n, FIGS. 6, 7
7a to 7d and 8a to 8k show the reaction formulas in Examples 1, 2, 3, 4, 5, 6, 7 and 8, respectively. 9a and 9b show the test results in Test Example 1,
FIG. 9C shows the test result in Test Example 2. FIG.
a to 10b and FIG. 11 show the reaction formulas in Examples 15 and 16, respectively.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ｃ０７Ｋ 9/00 Ｃ０７Ｋ 9/00 (72)発明者 渡辺 宏 千葉県松戸市新松戸７−131 セブンピ ア301 (72)発明者 田中 勲 茨城県つくば市二の宮２−５−16 (72)発明者 佐々木 淳 茨城県つくば市春日４−19−13 エーザ イ紫山寮307 (72)発明者 村橋 直一 茨城県北相馬郡守谷町松前台７−２−４ (72)発明者 青野 勝利 奈良県奈良市学園朝日元町２−529−４ エクセルハイツＢ−308 (72)発明者 森川 安理 静岡県富士市鮫島390−６ 田子ノ浦ベ イピア２−305 (58)調査した分野(Int.Cl.6，ＤＢ名) C07H 15/04 A61K 9/00 A61K 9/127 A61K 47/26 C07K 9/00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＷＰＩＤＳ（ＳＴＮ)──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. 6 Identification symbol FI C07K 9/00 C07K 9/00 (72) Inventor Hiroshi Watanabe 7-131 Shinpito 301, Shinmatsudo, Matsudo-shi, Chiba 301 (72) Inventor Tanaka Isao 2-5-16 Ninomiya, Tsukuba City, Ibaraki Prefecture (72) Inventor Atsushi Sasaki 4-19-13 Kasuga, Tsukuba City, Ibaraki Prefecture 7-2-4 (72) Inventor Katsutoshi Aono 2-529-4 Asamotomotocho, Nara City, Nara Prefecture Excel Heights B-308 (72) Inventor Yuri Morikawa 390-6 Samejima, Fuji City, Shizuoka Prefecture Tagonoura Baypia 2 -305 (58) Fields investigated (Int. Cl. 6 , DB name) C07H 15/04 A61K 9/00 A61K 9/127 A61K 47/26 C07K 9/00 CA (STN) REGISTRY (STN) WPIDS (STN)
Claims (9)
チド骨格を有する分枝鎖型糖複合体。 （Ｘ1，…，Ｘn+1）（ＡＡ）nＹ （Ｉ） 式（Ｉ）中、ｎは０，１及び２のいずれかの整数を表
し、 （ＡＡ）nは、ｎ＝０のときは１個の単結合を表し、 ｎ＝１のときは下記式（II）、（III)及び（IV）のいず
れかのアミノ酸残基を表し、そして 【化１】 ｎ＝２のときは下記式（Ｖ）〜（XIV)のいずれかのジペ
プチド残基を表す。 【化２】 式（Ｉ）中、Ｘ1，…，及びＸn+1は、それぞれ、（Ａ
Ａ）n中のカルボニル基に結合している−ＯＲ1基及び−
ＮＨＲ2基のいずれかを又は（ＡＡ）n中のオキシ基に結
合している−Ｒ基を表し、ここでＲ1は水素原子、アル
カリ金属、炭素数１〜３のアルキル基、及びベンジル基
のいずれかを表し、Ｒ2は水素原子、下記式（XV）及び
下記式（XVI)のいずれかを表し、そしてＲはアセチル基
で保護された又は保護されていないグリコシル基を表
す。 （ＣＨ2）aＯＲ （XV） （ＣＨ2ＣＨ2Ｏ）bＲ （XVI) 式（XV）においてａは１〜10の整数を、そして式（XVI)
においてｂは１〜８の整数を表す。式（Ｉ）中、
（Ｘ1，…，Ｘn+1）は、ｎの数に応じて結合基の個数が
定まり、その結合基は（ ）内に示されるものであるこ
とを意味する。なお、その結合基の中の少なくとも１つ
は−Ｒ基又は−ＮＨＲ2基であり、−ＮＨＲ2基である場
合にはそのＲ2は上記の式（XV）及び式（XVI)のいずれ
かである。式（Ｉ）中、Ｙは（ＡＡ）n中のアミノ基に
結合している水素原子、ベンジルオキシカルボニル基又
はｔ−ブトキシカルボニル基を表す。1. A branched sugar conjugate having a peptide skeleton represented by the following general formula (I). (X 1 ,..., X n + 1 ) (AA) n Y (I) In the formula (I), n represents any integer of 0, 1, and 2, and (AA) n represents the value of n = 0 Represents one single bond, n = 1 represents an amino acid residue of any of the following formulas (II), (III) and (IV); When n = 2, it represents any of the dipeptide residues of the following formulas (V) to (XIV). Embedded image In the formula (I), X 1 ,..., And X n + 1 each represent (A
A) -OR 1 group and-bonded to the carbonyl group in n
Represents an —R group bonded to any of the NHR 2 groups or to the oxy group in (AA) n , wherein R 1 is a hydrogen atom, an alkali metal, an alkyl group having 1 to 3 carbon atoms, and a benzyl group Wherein R 2 represents a hydrogen atom, one of the following formulas (XV) and (XVI), and R represents a glycosyl group protected or unprotected by an acetyl group. (CH 2 ) a OR (XV) (CH 2 CH 2 O) b R (XVI) In the formula (XV), a is an integer of 1 to 10, and the formula (XVI)
In the above, b represents an integer of 1 to 8. In the formula (I),
(X 1 ,..., X n + 1 ) means that the number of bonding groups is determined according to the number n, and the bonding groups are those shown in parentheses. In addition, at least one of the bonding groups is a —R group or a —NHR 2 group. When the bonding group is a —NHR 2 group, the R 2 is one of the above formulas (XV) and (XVI). It is. In the formula (I), Y represents a hydrogen atom, a benzyloxycarbonyl group or a t-butoxycarbonyl group bonded to an amino group in (AA) n .
チド骨格を有する分枝鎖型糖複合体。 （Ｘ1，…，Ｘn+1）（ＡＡ）nＹ （Ｉ） 式（Ｉ）中、ｎは０，１及び２のいずれかの整数を表
し、 （ＡＡ）nは、ｎ＝０のときは１個の単結合を表し、 ｎ＝１のときは下記式（II）、（III)及び（IV）のいず
れかのアミノ酸残基を表し、そして 【化３】 ｎ＝２のときは下記式（Ｖ）〜（XIV)のいずれかのジペ
プチド残基を表す。 【化４】 式（Ｉ）中、Ｘ1，…，及びＸn+1は、それぞれ、（Ａ
Ａ）n中のカルボニル基に結合している−ＯＲ1基及び−
ＮＨＲ2基のいずれかを又は（ＡＡ）n中のオキシ基に結
合している−Ｒ基を表し、ここでＲ1は水素原子、アル
カリ金属、炭素数１〜３のアルキル基、及びベンジル基
のいずれかを表し、Ｒ2は水素原子、下記式（XV）及び
下記式（XVI)のいずれかを表し、そしてＲはアセチル基
で保護された又は保護されていないグリコシル基を表
す。 （ＣＨ2）aＯＲ （XV） （ＣＨ2ＣＨ2Ｏ）bＲ （XVI) 式（XV）においてａは１〜10の整数を、そして式（XVI)
においてｂは１〜８の整数を表す。式（Ｉ）中、
（Ｘ1，…，Ｘn+1）は、ｎの数に応じて結合基の個数が
定まり、その結合基は（ ）内に示されるものであるこ
とを意味する。なお、その結合基の中の少なくとも１つ
は−Ｒ基又は−ＮＨＲ2基であり、−ＮＨＲ2基である場
合にはそのＲ2は上記の式（XV）及び式（XVI)のいずれ
かである。式（Ｉ）中、Ｙは（ＡＡ）n中のアミノ基に
結合している直鎖又は分枝鎖のアルキルカルボニル基
（アルキル鎖中にエーテル結合及び／又は酸アミド結合
を含んでもよい）を表す。2. A branched sugar conjugate having a peptide skeleton represented by the following general formula (I). (X 1 ,..., X n + 1 ) (AA) n Y (I) In the formula (I), n represents any integer of 0, 1, and 2, and (AA) n represents the value of n = 0 Represents one single bond; n = 1 represents an amino acid residue of any of the following formulas (II), (III) and (IV); When n = 2, it represents any of the dipeptide residues of the following formulas (V) to (XIV). Embedded image In the formula (I), X 1 ,..., And X n + 1 each represent (A
A) -OR 1 group and-bonded to the carbonyl group in n
Represents an —R group bonded to any of the NHR 2 groups or to the oxy group in (AA) n , wherein R 1 is a hydrogen atom, an alkali metal, an alkyl group having 1 to 3 carbon atoms, and a benzyl group; Wherein R 2 represents a hydrogen atom, one of the following formulas (XV) and (XVI), and R represents a glycosyl group protected or unprotected by an acetyl group. (CH 2 ) a OR (XV) (CH 2 CH 2 O) b R (XVI) In the formula (XV), a is an integer of 1 to 10, and the formula (XVI)
In the above, b represents an integer of 1 to 8. In the formula (I),
(X 1 ,..., X n + 1 ) means that the number of bonding groups is determined according to the number n, and the bonding groups are those shown in parentheses. In addition, at least one of the bonding groups is a —R group or a —NHR 2 group. When the bonding group is a —NHR 2 group, the R 2 is one of the above formulas (XV) and (XVI). It is. In the formula (I), Y represents a linear or branched alkylcarbonyl group (which may contain an ether bond and / or an acid amide bond in the alkyl chain) bonded to the amino group in (AA) n. Represent.
ル、Ｎ−アセチル−Ｄ−ガラクトサミニル、Ｄ−リボシ
ル、Ｌ−フコシル及びラクトシルのいずれかである請求
項１に記載のペプチド骨格を有する分枝鎖型糖複合体。3. The branched chain having a peptide skeleton according to claim 1, wherein R is any one of D-mannosyl, D-galactosyl, N-acetyl-D-galactosaminyl, D-ribosyl, L-fucosyl and lactosyl. Type sugar complex.
ル、Ｎ−アセチル−Ｄ−ガラクトサミニル、Ｄ−リボシ
ル、Ｌ−フコシル及びラクトシルのいずれかである請求
項２に記載のペプチド骨格を有する分枝鎖型糖複合体。4. The branched chain having a peptide skeleton according to claim 2, wherein R is any one of D-mannosyl, D-galactosyl, N-acetyl-D-galactosaminyl, D-ribosyl, L-fucosyl and lactosyl. Type sugar complex.
４に記載のペプチド骨格を有する分枝鎖型糖複合体。5. The branched saccharide conjugate having a peptide skeleton according to claim 2, wherein Y is a palmitoyl group.
化合物残基である請求項２又は４に記載のペプチド骨格
を有する分枝鎖型糖複合体。6. The branched sugar conjugate having a peptide skeleton according to claim 2, wherein Y is a compound residue having two alkyl groups in the molecule.
５又は６に記載のペプチド骨格を有する分枝鎖型糖複合
体。7. The method according to claim 2, wherein a is an integer of 1 to 6.
7. A branched saccharide complex having the peptide skeleton according to 5 or 6.
５、６又は７に記載のペプチド骨格を有する分枝鎖型糖
複合体。8. The method according to claim 2, wherein b is an integer of 1 to 4.
8. A branched saccharide complex having the peptide skeleton according to 5, 6, or 7.
のペプチド骨格を有する分枝鎖型糖複合体を構成成分と
して含有する微粒子キャリヤー。9. A fine particle carrier comprising the branched saccharide complex having a peptide skeleton according to claim 2, 4, 5, 6, 7, or 8 as a constituent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4232879A JP2774417B2 (en) | 1991-08-07 | 1992-08-07 | Branched-chain saccharide complex having peptide skeleton and fine particle carrier |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3-222214 | 1991-08-07 | ||
| JP22221491 | 1991-08-07 | ||
| JP4232879A JP2774417B2 (en) | 1991-08-07 | 1992-08-07 | Branched-chain saccharide complex having peptide skeleton and fine particle carrier |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05202085A JPH05202085A (en) | 1993-08-10 |
| JP2774417B2 true JP2774417B2 (en) | 1998-07-09 |
Family
ID=26524753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4232879A Expired - Lifetime JP2774417B2 (en) | 1991-08-07 | 1992-08-07 | Branched-chain saccharide complex having peptide skeleton and fine particle carrier |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2774417B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6811996B1 (en) | 1998-10-30 | 2004-11-02 | Daiichi Pharmaceutical Co., Ltd. | DDS compounds and method for assaying the same |
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|---|---|---|---|---|
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| FR2764304B1 (en) * | 1997-06-06 | 1999-07-16 | Rhone Poulenc Rorer Sa | NEW CLASS OF CATIONIC NUCLEIC ACID TRANSFECTANTS |
| JP4070966B2 (en) | 2001-06-28 | 2008-04-02 | 株式会社カネボウ化粧品 | Novel galactosylceramide analogues and applications |
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| US7799565B2 (en) | 2004-06-07 | 2010-09-21 | Protiva Biotherapeutics, Inc. | Lipid encapsulated interfering RNA |
| DE102005014424A1 (en) * | 2005-03-24 | 2006-10-12 | Beiersdorf Ag | New surfactants and new emulsifiers based on disaccharides |
| WO2008081686A1 (en) * | 2006-12-28 | 2008-07-10 | Konica Minolta Holdings, Inc. | Cholesterol derivative, liposome, method for forming liposome and contrast agent for x-ray |
| WO2009127060A1 (en) | 2008-04-15 | 2009-10-22 | Protiva Biotherapeutics, Inc. | Novel lipid formulations for nucleic acid delivery |
| US9018187B2 (en) | 2009-07-01 | 2015-04-28 | Protiva Biotherapeutics, Inc. | Cationic lipids and methods for the delivery of therapeutic agents |
| US8569256B2 (en) | 2009-07-01 | 2013-10-29 | Protiva Biotherapeutics, Inc. | Cationic lipids and methods for the delivery of therapeutic agents |
| CA2767127A1 (en) | 2009-07-01 | 2011-01-06 | Protiva Biotherapeutics, Inc. | Novel lipid formulations for delivery of therapeutic agents to solid tumors |
| WO2012000104A1 (en) | 2010-06-30 | 2012-01-05 | Protiva Biotherapeutics, Inc. | Non-liposomal systems for nucleic acid delivery |
| IT201700123886A1 (en) * | 2017-10-31 | 2019-05-01 | Univ Degli Studi Di Modena E Reggio Emilia | NEW MOLECULES FUNCTIONALISING FOR THE TARGETING OF LIPID VECTORS |
| TW202214301A (en) * | 2020-06-16 | 2022-04-16 | 大陸商上海拓界生物醫藥科技有限公司 | Carbohydrate molecular cluster and preparation method and medical use thereof |
| WO2023002452A1 (en) * | 2021-07-23 | 2023-01-26 | Janssen Pharmaceuticals, Inc. | Process for preparation of targeting ligands |
-
1992
- 1992-08-07 JP JP4232879A patent/JP2774417B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6811996B1 (en) | 1998-10-30 | 2004-11-02 | Daiichi Pharmaceutical Co., Ltd. | DDS compounds and method for assaying the same |
| US7041818B2 (en) | 1998-10-30 | 2006-05-09 | Daiichi Pharmaceutical Co., Ltd. | DDS compound and method for measurement thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05202085A (en) | 1993-08-10 |
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