JPH07309889A - New 16-membered cyclic macrolide derivative and its new production - Google Patents
New 16-membered cyclic macrolide derivative and its new productionInfo
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- JPH07309889A JPH07309889A JP6105096A JP10509694A JPH07309889A JP H07309889 A JPH07309889 A JP H07309889A JP 6105096 A JP6105096 A JP 6105096A JP 10509694 A JP10509694 A JP 10509694A JP H07309889 A JPH07309889 A JP H07309889A
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Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明はグラム陽性菌に有効な新
規16員環マクロリド誘導体とそれらの新規製造法に関
する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel 16-membered ring macrolide derivatives effective against Gram-positive bacteria and a novel method for producing them.
【0002】[0002]
【従来の技術】臨床における有用性を向上させることを
目的として、現在各国のグループが積極的に16員環マ
クロリド抗生物質の誘導体研究を行なっている。それら
の内のある種の誘導体は、特定の水酸基をアシル化する
ことによりin vitroの抗菌活性及び/或いは体内動態を
改善しようとして合成されたものである。しかしながら
最近の誘導体研究の主流は、16員環ラクトンへの置換
されたアミノ基の導入(ジャーナル・オブ・アンチビオ
チックス, 44(4), 448(1991))、又は特定の水酸基のデ
オキシ化(ジャーナル・オブ・アンチビオチックス, 45
(1), 144(1992))或いは薬物動態上意味のある水酸基の
アルキル化に集中してきた。2. Description of the Related Art At present, groups in various countries are actively conducting derivative research on 16-membered macrolide antibiotics for the purpose of improving their clinical utility. Certain of these derivatives were synthesized in an attempt to improve in vitro antibacterial activity and / or pharmacokinetics by acylating a specific hydroxyl group. However, the mainstream of recent research on derivatives has been the introduction of substituted amino groups into 16-membered ring lactones (Journal of Antibiotics, 44 (4), 448 (1991)), or deoxylation of specific hydroxyl groups ( Journal of Antibiotics, 45
(1), 144 (1992)) or the alkylation of hydroxyl groups, which has a pharmacokinetic significance.
【0003】本発明者らは、エリスロマイシンの構成糖
の一つであるL-クラジノースの化学構造を発想の基礎に
誘導体研究を重ね、ラクトン環の9位がsp3炭素であり
中性糖部分である3"位の水酸基がメチル化されている1
6員環マクロリド誘導体(4"位は遊離の水酸基であって
もアシル化された水酸基であってもよい)を、グリコシ
ル化反応を経由することによって調製し、それらが優れ
た抗菌活性を有することを明らかにし特許出願した(特
願平5-169418)。一方で、9位がsp2炭素であり3"位の
水酸基がメチル化されている16員環マクロリド誘導体
の合成及び抗菌活性については、本発明者らの出願(特
願平5-3545)に先立ち既に竜田らによる報告がある(ケ
ミストリー・レターズ, 769(1977))。The inventors of the present invention conducted derivative research based on the idea of the chemical structure of L-cladinose, which is one of the constituent sugars of erythromycin, and found that the 9-position of the lactone ring was the sp 3 carbon and the neutral sugar moiety. The hydroxyl group at the 3 "position is methylated 1
A 6-membered ring macrolide derivative (the 4 "position may be a free hydroxyl group or an acylated hydroxyl group) is prepared by way of a glycosylation reaction, and they have excellent antibacterial activity. On the other hand, regarding the synthesis and antibacterial activity of the 16-membered ring macrolide derivative in which the 9-position is sp 2 carbon and the hydroxyl group at the 3 "-position is methylated, There is already a report by Tatsuta et al. Prior to the application by the present inventors (Japanese Patent Application No. 5-3545) (Chemistry Letters, 769 (1977)).
【0004】ところで、ラクトン環の9位がsp3炭素で
あり中性糖である3"位の水酸基がメチル化された16員
環マクロリド誘導体は大別すると2種に分類でき、その
一方はラクトン環の3位水酸基がアシル化されているタ
イプであり、他方は同3位水酸基が遊離なタイプであ
る。このうち前者のタイプの誘導体に関しては、グリコ
シル化反応を経由せず純合成化学的に効率良く製造する
方法を見いだし、本発明者らが既に特許出願(特願平5-
300686)した。By the way, 16-membered macrolide derivatives in which the 9-position of the lactone ring is sp 3 carbon and the hydroxyl group at the 3 "-position, which is a neutral sugar, is methylated can be roughly classified into two types, one of which is a lactone. The hydroxyl group at the 3-position of the ring is acylated, and the other is the type at which the 3-position hydroxyl group is free.Of these, the former type of derivative does not undergo glycosylation and is purely chemically synthesized. After finding a method for efficient production, the present inventors have already applied for a patent (Japanese Patent Application No. 5-
300686).
【0005】一方、ラクトン環の3位の水酸基がアシル
化された16員環マクロリド誘導体を微生物変換等の生
化学的手法を用いて変換することにより、その3位の水
酸基に結合しているアシル基を除去することは知られて
いる(ジャーナル・オブ・ファーメンテーション・テク
ノロジー, 57(6), 519 (1979)、特開平6-16691)。その
応用として、ラクトン環の3位がアシル化されており、
同9位が遊離の水酸基であり、中性糖部分である3"位の
水酸基がメチル化された16員環マクロリド誘導体の3
位の水酸基に結合したアシル基を生化学的手法により選
択的に除去する技術は、本発明者らが既に確立した(特
願平5ー169418)。On the other hand, a 16-membered ring macrolide derivative in which the hydroxyl group at the 3-position of the lactone ring is acylated is converted by a biochemical technique such as microbial conversion, whereby the acyl bonded to the hydroxyl group at the 3-position. It is known to remove a group (Journal of Fermentation Technology, 57 (6), 519 (1979), JP-A-6-16691). As its application, the 3-position of the lactone ring is acylated,
The 9-position is a free hydroxyl group, and the 3'-position of the neutral sugar moiety is methylated.
The present inventors have already established a technique for selectively removing the acyl group bonded to the hydroxyl group at the position by a biochemical method (Japanese Patent Application No. 5-169418).
【0006】ここで、16員環マクロリド誘導体のラク
トン環の3位の水酸基に関する保護基について触れる。
スピラマイシン類及びタイロシン類においてはラクトン
環の3位水酸基を不斉炭素を有するアセタール系置換基
で保護された誘導体が報告されている。しかしながら、
スピラマイシン類以外のプラテノリド骨格(ロイコマイ
シンのラクトン環)を有する合成中間体において、ラク
トン環の3位の水酸基が不斉炭素を有するアセタール系
の置換基で修飾された化合物は知られていない。Here, a protecting group for the hydroxyl group at the 3-position of the lactone ring of the 16-membered macrolide derivative will be mentioned.
In spiramycins and tylosins, derivatives in which the 3-position hydroxyl group of the lactone ring is protected by an acetal-based substituent having an asymmetric carbon have been reported. However,
Among synthetic intermediates having a platenolide skeleton (lactone ring of leucomycin) other than spiramycins, a compound in which the hydroxyl group at the 3-position of the lactone ring is modified with an acetal-based substituent having an asymmetric carbon is not known.
【0007】[0007]
【発明が解決しようとする課題】第一に、副作用及び薬
物相互作用が少ない16員環マクロリドでありながら1
4員環ニューマクロリドに匹敵する抗菌活性を有する優
れた誘導体の発見が期待されている。一方、ラクトン環
の3位水酸基が遊離であり、中性糖部分である3"位の水
酸基がメチル化されている16員環マクロリド誘導体
を、グリコシル化反応を経由することなく純合成化学的
に調製する方法については、9位の構造の如何にかかわ
らず現在までのところ全く報告されていない。そこで、
第二にラクトン環の3位が遊離の水酸基である当該化合
物を、グリコシル化反応を経由することなく可能な限り
短工程で純合成化学的に調製する方法の発明が期待され
ている。First, although it is a 16-membered ring macrolide with few side effects and drug interactions,
It is expected to find an excellent derivative having an antibacterial activity comparable to that of a 4-membered ring macrolide. On the other hand, a 16-membered macrolide derivative in which the hydroxyl group at the 3-position of the lactone ring is free and the hydroxyl group at the 3 "-position, which is a neutral sugar moiety, is methylated is chemically synthesized purely without going through a glycosylation reaction. No method of preparation has been reported so far regardless of the structure of the 9-position.
Secondly, an invention of a method for preparing the compound in which the 3-position of the lactone ring is a free hydroxyl group by pure synthetic chemistry in the shortest possible step without passing through a glycosylation reaction is expected.
【0008】[0008]
【課題を解決するための手段】本発明者らは上記の期待
に応えるべく合成化学的研究を重ね、ラクトン環の3位
及び9位がいずれも遊離の水酸基であり、中性糖部分で
ある4"位の水酸基がアシル化されている天然のロイコマ
イシン類(例えばロイコマイシンA5)を出発原料とし
て用いて、ラクトン環の3位の水酸基が不斉炭素を有す
るアセタール系の置換基で保護されており、3"位の水酸
基がメチルチオメチル化された合成中間体を経由し、ラ
クトン環の3位水酸基が遊離であり中性糖部分である3"
位の3級水酸基がメチル化されたロイコマイシン類誘導
体を、グリコシル化反応を経由することなく純合成化学
的に製造することに成功した。しかも本発明製造法を用
いて調製したある種の誘導体は、14員環ニューマクロ
リド同様、臨床上重要なグラム陽性菌等の発育を著しく
強く阻止することを見い出し、本発明を完成した。Means for Solving the Problems The inventors of the present invention have conducted synthetic chemical research to meet the above-mentioned expectations, and the 3- and 9-positions of the lactone ring are both free hydroxyl groups and neutral sugar moieties. Using natural leucomycins in which the hydroxyl group at the 4 "position is acylated (for example, leucomycin A 5 ) as a starting material, the hydroxyl group at the 3 position of the lactone ring is protected by an acetal-based substituent having an asymmetric carbon atom. The 3 "hydroxyl group of the lactone ring is free and is a neutral sugar moiety via a synthetic intermediate in which the 3" hydroxyl group is methylthiomethylated.
We succeeded in producing a leucomycin derivative in which the tertiary hydroxyl group at the position was methylated by pure synthetic chemistry without passing through a glycosylation reaction. Moreover, it was found that certain derivatives prepared by using the production method of the present invention, like the 14-membered ring macrolide, remarkably strongly inhibit the growth of clinically important Gram-positive bacteria and the like, and completed the present invention.
【0009】第一の本発明の要旨とするところは、新規
化合物としての次の式(I)The gist of the first aspect of the present invention resides in the following formula (I) as a novel compound.
【化5】 [Chemical 5]
【0010】[式中、R1は水素原子又は水酸基を修飾
(或いは保護)する置換基であり、R2は水素原子又は水
酸基を修飾(或いは保護)する置換基であり、R3は炭素
数1〜4の直鎖又は分枝鎖のアルキル基]で表される化
合物、又はその薬学的に許容し得る塩に関するものであ
る。[In the formula, R 1 is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, R 2 is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, and R 3 is a number of carbon atoms. 1 to 4 straight chain or branched chain alkyl group] or a pharmaceutically acceptable salt thereof.
【0011】第二の本発明の要旨とするところは、次の
式(II)The gist of the second invention is that the following formula (II)
【化6】 [Chemical 6]
【0012】[式中、R3は炭素数1〜4の直鎖又は分枝
鎖のアルキル基]で表される天然に存在する16員環マ
クロリド抗生物質、又はその塩を出発原料として用い
て、次の式(III)A naturally-occurring 16-membered macrolide antibiotic represented by the formula: wherein R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, or a salt thereof is used as a starting material. , The following formula (III)
【化7】 [Chemical 7]
【0013】[式中、R3は炭素数1〜4の直鎖又は分枝
鎖のアルキル基であり、R4は水酸基を修飾(或いは保
護)する置換基であり、R5は水酸基を修飾(或いは保
護)する置換基であり、R6は水素原子又は水酸基を保護
する置換基]で表される3"位水酸基のメチルチオメチル
エーテル合成中間体、又はその塩を経由し、次の式
(I)[In the formula, R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, R 4 is a substituent for modifying (or protecting) a hydroxyl group, and R 5 is a modifying group for a hydroxyl group. (Or is a substituent that protects), R 6 is a substituent that protects a hydrogen atom or a hydroxyl group], and the compound of the following formula (3) I)
【化8】 [Chemical 8]
【0014】[式中、R1は水素原子又は水酸基を修飾
(或いは保護)する置換基であり、R2は水素原子又は水
酸基を修飾(或いは保護)する置換基であり、R3は炭素
数1〜4の直鎖又は分枝鎖のアルキル基]で表される化
合物、又はその塩を純合成化学的に調製することのでき
る新規製造法に関するものである。本発明による一般式
(I)で表される化合物は、工程図1に示す方法により
以下の様に製造される。[In the formula, R 1 is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, R 2 is a substituent for modifying (or protecting) a hydrogen atom or a hydroxyl group, and R 3 is a number of carbon atoms. 1 to 4 straight chain or branched chain alkyl group] or a salt thereof, can be prepared by pure synthetic chemistry. The compound represented by the general formula (I) according to the present invention is produced as follows by the method shown in Process Diagram 1.
【0015】[0015]
【化9】 [Chemical 9]
【0016】[0016]
【化10】 [Chemical 10]
【0017】16員環マクロリド誘導体において中性糖
部分である3"位の水酸基に選択的にメチル基を導入した
化合物が、抗菌剤としていかに有望であるかについては
先願(特願平5-169418)において記述した。一方16員
環マクロリド化合物、特にロイコマイシン類に関して
は、特別な合成中間体を経由することなく水酸基を直接
アルキル化しようとすると、困難な問題を生ずることが
知られている(特願平5-206731)。本願は、ラクトン環
の3位及び9位の水酸基が遊離であり、中性糖部分であ
る4"位の水酸基がアシル化された化合物に関して、中性
糖部分である3"位の3級水酸基に対し間接的にメチル基
を導入する合成法について記述されており、本発明製造
法等により調製した新規誘導体の著しく優れた抗菌活性
についても記載されている。Regarding the promising antibacterial agent, a compound in which a methyl group is selectively introduced into a hydroxyl group at the 3 "position of a neutral sugar moiety in a 16-membered ring macrolide derivative is a prior application (Japanese Patent Application No. 169418). On the other hand, for 16-membered ring macrolide compounds, especially leucomycins, it is known that direct alkylation of the hydroxyl group without going through a special synthetic intermediate causes a difficult problem. (Japanese Patent Application No. 5-206731). The present application relates to a compound in which the hydroxyl groups at the 3- and 9-positions of the lactone ring are free and the hydroxyl group at the 4 "-position, which is a neutral sugar moiety, is acylated. The synthetic method in which a methyl group is indirectly introduced to the tertiary hydroxyl group at the 3 "position is described, and the remarkably excellent antibacterial activity of the novel derivative prepared by the production method of the present invention is also described.
【0018】合成法を述べるに先立ち、16員環マクロ
リド誘導体における中性糖部分である3"位の水酸基への
メチル基の導入について述べる。当該水酸基に対し、ヨ
ウ化メチルを用い直接的にメチル基を導入する方法(特
願平5-206731)に関しては、本発明者らが既に特許出願
した。そこでは、中性糖部分である4"位の水酸基が既に
アルキル化されている化合物を反応基質として当該メチ
ル化を実施した。一方、本願における製造工程において
は、4"位の水酸基に結合したアシル基は除去及び再導入
する必要がないことから製造工程の全段階において同一
のアシル基が結合したままである。ところで、糖質化学
においては、隣接したシスの水酸基の一方がアシル化さ
れており(例えば4"位)他方が遊離である(例えば3"
位)状況下に、当該遊離水酸基を直接的にメチル化しよ
うとすると種々の副反応が誘起される。しかるに、本発
明製造法においても、3"位の3級水酸基へのメチル基の
導入はメチルチオメチルエーテル合成中間体を経由する
製造法を選択した。Prior to describing the synthetic method, the introduction of a methyl group into the hydroxyl group at the 3 "position, which is the neutral sugar moiety in the 16-membered macrolide derivative, will be described. Regarding the method of introducing a group (Japanese Patent Application No. 5-206731), the present inventors have already applied for a patent, in which a compound in which the hydroxyl group at the 4 "-position of the neutral sugar moiety has already been alkylated is reacted. The methylation was performed as a substrate. On the other hand, in the production process of the present application, it is not necessary to remove and reintroduce the acyl group bonded to the 4 "-position hydroxyl group, so that the same acyl group remains bonded in all stages of the production process. In chemistry, one of the adjacent cis hydroxyl groups is acylated (eg 4 "position) and the other is free (eg 3").
Position), various side reactions are induced when the free hydroxyl group is directly methylated. However, also in the production method of the present invention, the production method of introducing a methyl group into the tertiary hydroxyl group at the 3 "-position was selected via a methylthiomethyl ether synthetic intermediate.
【0019】またメチルチオメチルエーテル合成中間体
を経由する水酸基へのメチル基の本導入法は、必ずしも
18位のアルデヒド基を保護する必要もないことから、
本発明製造法におけるラクトン環の3位水酸基の保護
は、試薬が安価であり、かつ脱保護条件の穏和な不斉炭
素を有するアセタール系の置換基により達成している。
なお、工程図1においては、その製造法の一例としてラ
クトン環の9位がsp3炭素である天然の16員環マクロ
リド抗生物質を出発原料として用いているが、9位がカ
ルボニル基である化合物を出発原料として用いた場合
も、同様の方法論によって間接的に3"位の3級水酸基に
効率良くメチル基を導入することが可能である。Further, in the present method for introducing a methyl group into a hydroxyl group via a methylthiomethyl ether synthetic intermediate, it is not always necessary to protect the aldehyde group at the 18-position.
The protection of the 3-position hydroxyl group of the lactone ring in the production method of the present invention is achieved by an acetal-based substituent having a mild asymmetric carbon which is inexpensive as a reagent and which is a deprotection condition.
In the process diagram 1, as an example of the production method, a natural 16-membered macrolide antibiotic in which the 9-position of the lactone ring is sp 3 carbon is used as a starting material, but a compound in which the 9-position is a carbonyl group is used. Even when is used as a starting material, it is possible to indirectly introduce a methyl group into the tertiary hydroxyl group at the 3 "position efficiently by the same methodology.
【0020】第一に、式(II)で表された化合物の遊離
水酸基のうち、3"位以外の三つの水酸基、即ち3位、9
位及び2'位の水酸基に同一の又は異なる置換基を導入し
て、式(V)で表される化合物を得る。始めに式(II)
(式中、R3は炭素数1〜4の直鎖又は分枝鎖のアルキル
基である)で表される化合物のマイカミノース(アミノ
糖)部分である2'位の水酸基をアセチル基により保護
し、式(IV)(式中、R3は炭素数1〜4の直鎖又は分枝
鎖のアルキル基である)で表される化合物を得る。例え
ば、ロイコマイシンA5(ジャーナル・オブ・アンチビ
オチックス, 21(4), 272(1968))(式(II)において、
R3がノルマルプロピル基である化合物)を無水アセトニ
トリル中無水酢酸と反応させて化合物(1)(ジャーナ
ル・オブ・メディシナルケミストリー, 20(5), 732(197
7))(式(IV)において、R3がノルマルプロピル基であ
る化合物)を定量的に得た。First, among the free hydroxyl groups of the compound represented by the formula (II), three hydroxyl groups other than the 3 "position, that is, the 3 and 9 positions
The same or different substituents are introduced into the hydroxyl groups at the 2'-position and 2'-position to obtain the compound represented by the formula (V). Introduction formula (II)
(Wherein R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms), the 2'-position hydroxyl group of the mycaminose (amino sugar) moiety of the compound is protected by an acetyl group. To obtain a compound represented by the formula (IV) (wherein R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms). For example, leucomycin A 5 (Journal of Antibiotics, 21 (4), 272 (1968)) (in formula (II),
Compound (1) (where R 3 is a normal propyl group) is reacted with acetic anhydride in anhydrous acetonitrile (Journal of Medicinal Chemistry, 20 (5), 732 (197)
7)) (a compound in which R 3 is a normal propyl group in the formula (IV)) was quantitatively obtained.
【0021】次いで式(IV)で表される化合物の、ラク
トン環3位及び9位の水酸基に置換基を導入して、式
(V)(式中、R3は炭素数1〜4の直鎖又は分枝鎖のア
ルキル基であり、R4は水酸基を修飾(或いは保護)する
置換基であり、R5は水酸基を修飾(或いは保護)する置
換基である)で表される化合物を得る。例えば、化合物
(1)を無水塩化メチレン中ピリジニウム p-トルエン
スルホナート(PPTS)の存在下にエチルビニルエーテル
と反応させて、化合物(2)(式(V)において、R3が
ノルマルプロピル基であり、R4が1-エトキシエチル基で
あり、R5が1-エトキシエチル基である化合物)を収率良
く得た。Next, a substituent is introduced into the hydroxyl groups at the 3- and 9-positions of the lactone ring of the compound represented by the formula (IV) to give a compound of the formula (V) (wherein R 3 is a straight chain having 1 to 4 carbon atoms). A chain or branched alkyl group, R 4 is a substituent that modifies (or protects) a hydroxyl group, and R 5 is a substituent that modifies (or protects) a hydroxyl group. . For example, compound (1) is reacted with ethyl vinyl ether in anhydrous methylene chloride in the presence of pyridinium p-toluenesulfonate (PPTS) to give compound (2) (in formula (V), R 3 is a normal propyl group). , R 4 is a 1-ethoxyethyl group, and R 5 is a 1-ethoxyethyl group) in good yield.
【0022】なお、当該工程において用いることのでき
る置換基の種類及び置換基を導入する際の反応条件はこ
こに記述したものに限定されることなく、水酸基の保護
基として用いられている一般の置換基(Theodora W. Gr
eene; Peter G. M. Wuts. Protective Groups in Organ
ic Synthesis, 2nd ed., Wiley: New York, 1991)はも
とより、当該基質に関して脱保護することが困難な置換
基に関しても、それらの種類とそれらを導入する反応条
件の全てを包含するものである。なかでも、脱保護条件
が穏和であるという観点から、不斉炭素を有するアセタ
ール系の置換基、例えば1-エトキシエチル基、テトラヒ
ドロフラニル基、テトラヒドロピラニル基等がとりわけ
優れている。The types of substituents that can be used in the step and the reaction conditions for introducing the substituents are not limited to those described here, and the general protective groups used for hydroxyl groups can be used. Substituent (Theodora W. Gr
eene; Peter GM Wuts. Protective Groups in Organ
ic Synthesis , 2nd ed., Wiley: New York, 1991), as well as the substituents that are difficult to deprotect with respect to the substrate, and include all of their types and reaction conditions for introducing them. . Of these, acetal-based substituents having an asymmetric carbon atom, such as a 1-ethoxyethyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group, are particularly excellent from the viewpoint of mild deprotection conditions.
【0023】ところで不斉炭素を有するアセタール系の
保護基、例えば1-エトキシエチル基等をラクトン環の3
位及び9位の水酸基に導入すると、当該置換基の導入さ
れている間は、誘導体は四種類のジアステレオ異性体の
混合物として存在する。しかしながらこれらの異性体は
分離してもしなくともよい。又、当該置換基をラクトン
環の3位水酸基の修飾基としてとらえている場合も、こ
れらの異性体は分離してもしなくともよい。By the way, an acetal-based protecting group having an asymmetric carbon, such as a 1-ethoxyethyl group, is attached to the lactone ring.
When introduced at the hydroxyl groups at the 9- and 9-positions, the derivative exists as a mixture of four diastereoisomers while the substituent is introduced. However, these isomers may or may not be separated. Also, when the substituent is regarded as a modifying group for the 3-position hydroxyl group of the lactone ring, these isomers may or may not be separated.
【0024】一方、ラクトン環9位の水酸基に関わる置
換基、即ちR5は、必ずしもR4と同一である必要はない。
具体的には、9位と2'位の水酸基に同一の置換基、例え
ばアセチル基を導入した後、ラクトン環の3位の水酸基
に不斉炭素を有するアセタール系の置換基、例えば1-エ
トキシエチル基を導入して、式(V)で表される化合物
を得ることも可能である(実施例5参照)。On the other hand, the substituent relating to the hydroxyl group at the 9-position of the lactone ring, that is, R 5 does not necessarily have to be the same as R 4 .
Specifically, the same substituent, for example, an acetyl group, is introduced into the 9-position and 2'-position hydroxyl groups, and then an acetal-based substituent having an asymmetric carbon atom in the 3-position hydroxyl group of the lactone ring, such as 1-ethoxy. It is also possible to introduce an ethyl group to obtain a compound represented by the formula (V) (see Example 5).
【0025】さらに工程図1には示していないものの、
式(II)で表される化合物の3位、9位、及び2'位の3
つの遊離水酸基に対して同一のアセタール系の置換基、
例えば1-エトキシエチル基を導入して、メチルチオメチ
ル化の反応基質に供することも可能である。Further, although not shown in the process drawing 1,
The 3-, 9-, and 2'-positions of the compound represented by formula (II)
The same acetal-based substituent for the two free hydroxyl groups,
For example, it is possible to introduce a 1-ethoxyethyl group and use it as a reaction substrate for methylthiomethylation.
【0026】第二に鍵化合物であるメチルチオメチルエ
ーテル合成中間体を調製し、2'位のアセチル基を脱保護
する。ところで、メチルチオメチルエーテルの合成法に
関する諸事項は、既に先願(特願平5-300686)において
詳述したゆえ省略する。まず当社研究グループの方法
(ジャーナル・オブ・アンチビオチックス, 33(1), 61
(1980))に従い、式(V)で表される化合物の3"位の水
酸基をメチルチオメチル化し、副生成物を与えることな
く、式(VI)(式中、R3は炭素数1〜4の直鎖又は分枝
鎖のアルキル基であり、R4は水酸基を修飾(或いは保
護)する置換基であり、R5は水酸基を修飾(或いは保
護)する置換基である)で表される化合物を合成する。
例えば化合物(2)にジメチルスルホキシド(DMSO)と
無水酢酸を反応させて、化合物(3)(式(VI)におい
てR3がノルマルプロピル基であり、R4が1-エトキシエチ
ル基であり、R5が1-エトキシエチル基である化合物)を
合成した。水酸基へのメチルチオメチル基の導入法に関
しては多くの既知の方法(TheodoraW. Greene; Peter
G. M. Wuts., Protective Groups in Organic Synthesi
s, 2nd ed., Wiley: New York, 1991)があるので、本
発明製造法はメチルチオメチル基の導入法を限定するも
のではなく、当該導入法に関する全ての既知の方法を包
含する。Secondly, a key compound, a methylthiomethyl ether synthetic intermediate, is prepared and the 2'-position acetyl group is deprotected. Incidentally, various matters relating to the method for synthesizing methyl thiomethyl ether will be omitted because they have already been described in detail in the prior application (Japanese Patent Application No. 5-300686). First, our research group method (Journal of Antibiotics, 33 (1), 61
(1980)), the 3 "-position hydroxyl group of the compound represented by the formula (V) is methylthiomethylated to give a by-product, and the formula (VI) (in the formula, R 3 has 1 to 4 carbon atoms). Is a linear or branched alkyl group, R 4 is a substituent that modifies (or protects) a hydroxyl group, and R 5 is a substituent that modifies (or protects) a hydroxyl group) To synthesize.
For example, by reacting compound (2) with dimethyl sulfoxide (DMSO) and acetic anhydride, compound (3) (in formula (VI), R 3 is a normal propyl group, R 4 is a 1-ethoxyethyl group, R A compound in which 5 is a 1-ethoxyethyl group was synthesized. There are many known methods (Theodora W. Greene; Peter) for introducing a methylthiomethyl group into a hydroxyl group.
GM Wuts., Protective Groups in Organic Synthesi
s , 2nd ed., Wiley: New York, 1991), the production method of the present invention does not limit the method of introducing a methylthiomethyl group, and includes all known methods relating to the method of introduction.
【0027】次いで、式(VI)で表される化合物の2'位
の水酸基に結合していたアセチル基を脱保護し、式(VI
I)(式中、R3は炭素数1〜4の直鎖又は分枝鎖のアル
キル基であり、R4は水酸基を修飾(或いは保護)する置
換基であり、R5は水酸基を修飾(或いは保護)する置換
基である)で表される鍵化合物、即ちメチルチオメチル
エーテル合成中間体を定量的に得る。例えば化合物
(3)をメタノール中で反応することにより化合物
(4)(式(VII)において、R3がノルマルプロピル基
であり、R4が1-エトキシエチル基であり、R5が1-エトキ
シエチル基である化合物)を得た。Next, the acetyl group bonded to the 2'-position hydroxyl group of the compound represented by the formula (VI) is deprotected to give the compound represented by the formula (VI
I) (in the formula, R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, R 4 is a substituent for modifying (or protecting) a hydroxyl group, and R 5 is a modifying group for a hydroxyl group ( Alternatively, a key compound represented by (which is a protecting group), that is, a methylthiomethyl ether synthetic intermediate is quantitatively obtained. For example, by reacting compound (3) in methanol, compound (4) (in formula (VII), R 3 is a normal propyl group, R 4 is a 1-ethoxyethyl group, and R 5 is 1-ethoxy. A compound which is an ethyl group) was obtained.
【0028】第三に、式(VII)で表される鍵中間体の
中性糖部分である3"位の3級水酸基に導入されたメチル
チオメチル基を選択的に還元して、3"位の3級水酸基が
メチル化された16員環マクロリド誘導体を効率的に合
成する。メチルチオメチル化された水酸基を接触還元す
ることによりメトキシ基へ導く方法論並びに、当該方法
を16員環マクロリド誘導体合成へ応用することの諸問
題等に関しては、既に先願(特願平5-300686)において
詳述したゆえ省略する。さらには、当該選択的還元反応
における金属触媒に関する活性の制御などについても同
様に省略する。Thirdly, the methylthiomethyl group introduced into the tertiary hydroxyl group at the 3 "position, which is the neutral sugar moiety of the key intermediate represented by the formula (VII), is selectively reduced to give the 3" position. The 16-membered ring macrolide derivative in which the tertiary hydroxyl group is methylated is efficiently synthesized. Regarding the methodology for leading a methoxy group by catalytically reducing a methylthiomethylated hydroxyl group and various problems in applying the method to the synthesis of a 16-membered macrolide derivative, there is already a prior application (Japanese Patent Application No. 5-300686). Since it has been described in detail in Section 3, it is omitted. Further, the control of the activity of the metal catalyst in the selective reduction reaction will be omitted as well.
【0029】本発明者らは、適度に活性をコントロール
したラネーニッケルを用いて、式(VII)で表される化
合物の二重結合及び遊離のアルデヒド基が還元を受ける
ことなく、メチルチオメチル化された3"位の3級水酸基
をメトキシ基に化学変換し、式(VIII)(式中、R3は炭
素数1〜4の直鎖又は分枝鎖のアルキル基であり、R4は
水酸基を修飾(或いは保護)する置換基であり、R5は水
酸基を修飾(或いは保護)する置換基である)で表され
る化合物を選択的に合成する実質的な調製法を見い出し
た。The inventors of the present invention used methyl Raney nickel whose activity was appropriately controlled to methylthiomethylate the double bond and the free aldehyde group of the compound represented by the formula (VII) without undergoing reduction. By chemically converting the tertiary hydroxyl group at the 3 "position into a methoxy group, formula (VIII) (in the formula, R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, and R 4 is a modified hydroxyl group. We have found a substantial preparation method for selectively synthesizing a compound represented by (or protecting) a substituent and R 5 is a substituent that modifies (or protects) a hydroxyl group.
【0030】次いで式(VIII)で表される化合物を単離
した後、或いは単離することなく、必要に応じて当該化
合物のラクトン環の3位及び/又は9位水酸基に導入さ
れている置換基を、その置換基に相応しい条件(Theodo
ra W. Greene; Peter G. M.Wuts., Protective Groups
in Organic Synthesis, 2nd ed., Wiley: New York,199
1)を用いて脱保護し、式(I)(式中、R1は水素原子又
は水酸基を修飾(或いは保護)する置換基であり、R2は
水素原子又は水酸基を修飾(或いは保護)する置換基で
あり、R3は炭素数1〜4の直鎖又は分枝鎖のアルキル
基)で表される化合物を収率良く得る。Then, after the compound represented by the formula (VIII) is isolated or without isolation, a substituent introduced at the 3-position and / or the 9-position hydroxyl group of the lactone ring of the compound, if necessary. A group under suitable conditions (Theodo
ra W. Greene; Peter GMWuts., Protective Groups
in Organic Synthesis , 2nd ed., Wiley: New York, 199
1) is used for deprotection, and formula (I) (in the formula, R 1 is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, and R 2 modifies (or protects) a hydrogen atom or a hydroxyl group. A compound represented by a substituent, R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms) can be obtained in good yield.
【0031】例えば、化合物(4)をエタノール中、適
度に活性をコントールしたラネーニッケルとともに室温
で短時間撹拌することにより、選択的に化合物(5)
(式(VIII)中、R3がノルマルプロピル基であり、R4が
1-エトキシエチル基であり、R5が1-エトキシエチル基で
ある化合物)を得た。これを単離することなく5%酢酸
水溶液:アセトニトリル(3:1)の混合溶媒で反応さ
せることにより、化合物(6)(式(I)において、R1
が水素原子であり、R2が水素原子であり、R3がノルマル
プロピル基である化合物)を得た。以上の如く製造した
式(I)で表される化合物のうちのある種の誘導体は、
それ自身で14員環ニューマクロリド同様臨床上重要な
グラム陽性菌等の発育を著しく強く阻止する。ところで
当該選択的還元反応は、R5がアセタール系以外の置換
基、例えば化合物(10)の如くアセチル基等のアシル
基で修飾(或いは保護)されていた場合にも問題なく進
行する(実施例9、10参照)。For example, the compound (4) is selectively stirred in ethanol with Raney nickel whose activity is moderately controlled at room temperature for a short period of time to selectively produce the compound (5).
(In the formula (VIII), R 3 is a normal propyl group and R 4 is
A compound which is a 1-ethoxyethyl group and R 5 is a 1-ethoxyethyl group) was obtained. By reacting this with a mixed solvent of 5% aqueous acetic acid: acetonitrile (3: 1) without isolation, compound (6) (in the formula (I), R 1
Is a hydrogen atom, R 2 is a hydrogen atom, and R 3 is a normal propyl group). Certain derivatives of the compound represented by the formula (I) produced as described above are:
By itself, like the 14-membered ring macrolide, it markedly strongly inhibits the development of clinically important Gram-positive bacteria and the like. By the way, the selective reduction reaction proceeds without problems even when R 5 is modified (or protected) with a substituent other than acetal, for example, an acyl group such as an acetyl group like the compound (10) (Examples) 9, 10).
【0032】工程図1においては、式(VII)で表され
る化合物より式(I)で表される化合物を合成する際
は、始めに中性糖部分である3"位のメチルチオメチルエ
ーテルをメトキシ基に還元した後に、ラクトン環の3位
及び/又は9位水酸基に結合している置換基を脱保護し
た。一方、あらかじめ3位及び/又は9位を脱保護した
後に3"位の還元を行なった場合も、式(I)で表される
化合物を製造することが可能である。In the process diagram 1, when synthesizing the compound represented by the formula (I) from the compound represented by the formula (VII), first, methylthiomethyl ether at the 3 "-position, which is a neutral sugar moiety, is added. After reduction to the methoxy group, the substituents bonded to the 3- and / or 9-position hydroxyl groups of the lactone ring were deprotected. On the other hand, the 3- and / or 9-position was previously deprotected and then the 3 "-position was reduced. The compound represented by the formula (I) can also be produced by carrying out
【0033】さらに工程図1には示していないものの、
式(II)で表される化合物の3位、9位、2'位の3つの
遊離水酸基に対して同一の保護基、例えばアセタール系
の置換基を導入した後に中性糖である3"位の水酸基をメ
チルチオメチル化した際も、3つの水酸基に導入された
置換基を脱保護した後に選択的に3"位をメトキシ基変換
することが可能であり、さらにその際、脱保護を最終工
程として行ってもよい。Further, although not shown in the process drawing 1,
The 3'-position which is a neutral sugar after introducing the same protecting group, for example, an acetal-based substituent to the three free hydroxyl groups at the 3-position, 9-position and 2'-position of the compound represented by the formula (II) It is possible to selectively convert the 3 "-position to a methoxy group after deprotecting the substituents introduced into the three hydroxyl groups when methylthiomethylating the hydroxyl groups of. You may go as.
【0034】ところで式(I)で表される化合物、又は
その塩に対しては、希薄な酸の存在下に9位又は2'位の
水酸基を選択的にアシル化する公知の方法(発酵と工
業, 37(12), 1171(1979))又は希薄な酸の存在下に9位
の水酸基を11位又は13位へアリル転位させる公知の方法
(ケミカル・アンド・ファーマシューチカル・ブレタ
ン, 18(8), 1501(1970)、明治製菓研究年報, 12, 85(19
72)、ジャーナル・オブ・アンチビオチックス, 35(11),
1521(1982))或いは9位の水酸基を選択的に酸化する
公知の方法(ジャーナル・オブ・アンチビオチックス,
24(8), 526(1971))等を実施して、本発明を基軸とした
新規有用物質を造出することが可能である。次に本発明
を実施例によって詳細に記述する。By the way, for the compound represented by the formula (I) or a salt thereof, a known method for selectively acylating the 9-position or 2'-position hydroxyl group in the presence of a dilute acid (fermentation and Kogyo, 37 (12), 1171 (1979)) or a known method for allylic rearrangement of the 9-position hydroxyl group to the 11- or 13-position in the presence of a dilute acid (Chemical and Pharmaceutical Bretan, 18 (8)). , 1501 (1970), Annual Report of Meiji Seika, 12 , 85 (19
72), Journal of Antibiotics, 35 (11),
1521 (1982)) or a known method for selectively oxidizing the hydroxyl group at the 9-position (Journal of Antibiotics,
24 (8), 526 (1971)), etc., and a novel useful substance based on the present invention can be produced. The present invention will now be described in detail by way of examples.
【0035】なお、本願に記述する実施例においては、
その製造法をR3がノルマルプロピル基、即ち中性糖であ
る4"位の水酸基に結合するアシル側鎖がノルマルブチリ
ル基の場合を例にとり述べたが、本発明製造法は、その
適用範囲が当該アシル側鎖にのみ限定されるわけではな
く、他のいかなる天然型のアシル側鎖を有する化合物の
場合においてもまた、実施することが可能である。In the embodiment described in the present application,
The production method has been described by taking as an example the case where R 3 is a normal propyl group, that is, the case where the acyl side chain bonded to the hydroxyl group at the 4 ″ position which is a neutral sugar is a normal butyryl group. The scope is not limited only to the acyl side chain concerned, it can also be carried out in the case of compounds with any other naturally occurring acyl side chain.
【0036】ところで本願実施例13においては、化合
物(6)より1工程で化合物(13)を製造している
が、同(13)は、化合物(12)を調製した際に用い
た製造法等によってもまた容易に合成することが可能で
ある。By the way, in Example 13 of the present application, the compound (13) was produced from the compound (6) in one step. However, the production method (13) used when the compound (12) was prepared was used. Can also be easily synthesized.
【0037】[0037]
実施例1化合物(2)(式(V)において、R3がノルマルプロピ
ル基で表され、R4が1-エトキシエチル基で表され、R5が
1-エトキシエチル基で表される化合物)の製造法 化合物(1)(式(IV)において、R3がノルマルプロピ
ル基で表される化合物)(ジャーナル・オブ・メディシ
ナルケミストリー, 20(5), 732(1977)) 1.20gを塩化メ
チレン 36 mlとエチルビニルエーテル 1.3 mlの混合溶
液に溶解した後、PPTS 488 mgを加え、30℃で16時間
反応させた。反応液を飽和炭酸水素ナトリウム水溶液 1
50 mlに徐々に加え、塩化メチレン 150 mlで抽出した。
塩化メチレン層を5%硫酸水素カリウム水溶液 150 ml、
飽和炭酸水素ナトリウム水溶液 150 ml及び飽和塩化ナ
トリウム水溶液 150 mlで順次洗浄した。塩化メチレン
層を無水硫酸ナトリウムを用いて乾燥した後、減圧濃縮
して得られた残さ 1.70 gをシリカゲルカラムクロマト
グラフィー(120 g:ヘキサン−酢酸エチル(1:1)→(2:
3))で精製して、化合物(2) 740 mgを得た。 化合物(2)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C49H83NO17 (3) マススペクトル (SIMS) : m/z 958 (M+H)+ (4) 比旋光度 : [α]D 13 -90°(c1.0, CHCl3) (5) 融点 : 明瞭な融点を示さず、72〜75℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 3.87(m, 3-H),2.88(br d, 4-H), 3.38(s, 4-
OCH3), 3.43(s, 4-OCH3), 4.15(br d, 5-H), 3.90(dd,
9-H), 4.01(dd, 9-H), 6.13(dd, 11-H), 6.17(dd, 11-
H), 6.19(dd, 11-H), 6.03(br dd, 12-H), 6.04(br dd,
12-H), 5.15(m, 15-H), 5.23(m,15-H), 9.76(s, 18-
H), 9.77(s, 18-H), 9.87(s, 18-H), 4.82(q, 3-OCH(OC
H2CH3)CH3), 4.87(q, 3-OCH(OCH2CH3)CH3), 4.67(d, 1'
-H), 4.99(dd, 2'-H)), 2.05(s, 2'-OCOCH3), 2.39(s,
3'-N(CH3)2), 2.41(s, 3'-N(CH3)2), 5.06(br d, 1"-
H), 1.84(br dd, 2"-Hax), 2.00(d, 2"-Heq), 1.12(s,
3"-CH3), 4.62(d, 4"-H), 4.37(dq, 5"-H), 1.69(tq,
4"-OCOCH2CH2 CH3), 0.97(t, 4"-OCOCH2CH2CH3 )Example 1 Compound (2) (in the formula (V), R 3 is normal propene
Represented by a R group, R 4 represents a 1-ethoxyethyl group, and R 5 represents
Compound (1) (compound represented by formula (IV) in which R 3 represents a normal propyl group) (Journal of Medicinal Chemistry, 20 (5) , 732 (1977)) 1.20 g was dissolved in a mixed solution of 36 ml of methylene chloride and 1.3 ml of ethyl vinyl ether, 488 mg of PPTS was added, and the mixture was reacted at 30 ° C. for 16 hours. The reaction solution was saturated aqueous sodium hydrogen carbonate solution 1
The mixture was gradually added to 50 ml and extracted with 150 ml of methylene chloride.
The methylene chloride layer was added with 5% potassium hydrogen sulfate aqueous solution 150 ml,
The extract was washed successively with 150 ml of saturated aqueous sodium hydrogen carbonate solution and 150 ml of saturated aqueous sodium chloride solution. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.70 g of the residue, which was subjected to silica gel column chromatography (120 g: hexane-ethyl acetate (1: 1) → (2:
Purification by 3)) yielded 740 mg of compound (2). Physicochemical properties of compound (2) (1) Color and shape: colorless solid (2) Molecular formula: C 49 H 83 NO 17 (3) Mass spectrum (SIMS): m / z 958 (M + H) + (4) Specific rotation: [α] D 13 -90 ° (c1.0, CHCl 3 ) (5) Melting point: Melting at 72-75 ℃ without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 3.87 (m, 3-H), 2.88 (br d, 4-H), 3.38 (s, 4-
OCH 3 ), 3.43 (s, 4-OCH 3 ), 4.15 (br d, 5-H), 3.90 (dd,
9-H), 4.01 (dd, 9-H), 6.13 (dd, 11-H), 6.17 (dd, 11-
H), 6.19 (dd, 11-H), 6.03 (br dd, 12-H), 6.04 (br dd,
12-H), 5.15 (m, 15-H), 5.23 (m, 15-H), 9.76 (s, 18-
H), 9.77 (s, 18-H), 9.87 (s, 18-H), 4.82 (q, 3-OC H (OC
H 2 CH 3 ) CH 3 ), 4.87 (q, 3-OC H (OCH 2 CH 3 ) CH 3 ), 4.67 (d, 1 '
-H), 4.99 (dd, 2'-H)), 2.05 (s, 2'-OCOCH 3 ), 2.39 (s,
3'-N (CH 3) 2 ), 2.41 (s, 3'-N (CH 3) 2), 5.06 (br d, 1 "-
H), 1.84 (br dd, 2 "-Hax), 2.00 (d, 2" -Heq), 1.12 (s,
3 "-CH 3 ), 4.62 (d, 4" -H), 4.37 (dq, 5 "-H), 1.69 (tq,
4 "-OCOCH 2 C H 2 CH 3 ), 0.97 (t, 4" -OCOCH 2 CH 2 C H 3 )
【0038】実施例2化合物(3)(式(VI)において、R3がノルマルプロピ
ル基で表され、R4が1-エトキシエチル基で表され、R5が
1-エトキシエチル基で表される化合物)の製造法 化合物(2) 575 mgをDMSO 17 mlと無水酢酸 1.7 mlの
混合溶液に溶解した後、30℃で24時間反応させた。
反応液をトルエン 500 mlに徐々に加え、水 500 mlで3
回洗浄した。トルエン層を無水硫酸ナトリウムで乾燥後
これを濾過し、濾液を減圧濃縮して得られた残さ 750 m
gをシリカゲルカラムクロマトグラフィー(65 g:ヘキサ
ン−酢酸エチル(1:1))で精製して、化合物(3) 325
mgを得た。また、この時化合物(2) 135 mgを回収し
た。 化合物(3)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C51H87NO17S (3) マススペクトル (SIMS) : m/z 1018 (M+H)
+ (4) 比旋光度 : [α]D 13 -100°(c1.0, CHC
l3) (5) 融点 : 明瞭な融点を示さず、59〜61℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 3.86(m, 3-H),2.90(br d, 4-H), 3.38(s, 4-
OCH3), 3.44(s, 4-OCH3), 4.18(br d, 5-H), 3.90(dd,
9-H), 4.01(dd, 9-H), 6.14(dd, 11-H), 6.19(dd, 11-
H), 6.03(br dd, 12-H), 6.04(br dd, 12-H), 5.14(m,
15-H), 5.20(m, 15-H), 9.76(s, 18-H), 9.78(s, 18-
H), 9.88(s, 18-H), 4.94(dd, 2'-H), 3.17(t, 4'-H),
2.03(s, 2'-OCOCH3), 2.42(s, 3'-N(CH3)2), 4.83(br
d, 1"-H), 2.26(br d, 2"-Heq), 1.18(s, 3"-CH3), 1.0
5(br d, 6"-H), 4.51(d, 3"-OCH 2SCH3), 2.20(s, 3"-OC
H2SCH3 ),1.69(tq, 4"-OCOCH2CH2 CH3), 0.97(t, 4"-OCOC
H2CH2CH3 )Example 2 Compound (3) (in formula (VI), R 3 is normal propene
Represented by a R group, R 4 represents a 1-ethoxyethyl group, and R 5 represents
Method for producing 1-ethoxyethyl group) Compound (2) (575 mg) was dissolved in a mixed solution of DMSO (17 ml) and acetic anhydride (1.7 ml), and the mixture was reacted at 30 ° C for 24 hours.
The reaction solution was gradually added to 500 ml of toluene and the mixture was mixed with 500 ml of water to 3
Washed twice. The toluene layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue of 750 m.
g was purified by silica gel column chromatography (65 g: hexane-ethyl acetate (1: 1)) to give compound (3) 325.
to obtain mg. At this time, 135 mg of compound (2) was recovered. Physicochemical properties of compound (3) (1) Color and shape: colorless solid (2) Molecular formula: C 51 H 87 NO 17 S (3) Mass spectrum (SIMS): m / z 1018 (M + H)
+ (4) Specific rotation: [α] D 13 -100 ° (c1.0, CHC
l 3 ) (5) Melting point: Melting at 59 to 61 ° C. without showing clear melting point (6) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ
(ppm): 3.86 (m, 3-H), 2.90 (br d, 4-H), 3.38 (s, 4-
OCH 3 ), 3.44 (s, 4-OCH 3 ), 4.18 (br d, 5-H), 3.90 (dd,
9-H), 4.01 (dd, 9-H), 6.14 (dd, 11-H), 6.19 (dd, 11-
H), 6.03 (br dd, 12-H), 6.04 (br dd, 12-H), 5.14 (m,
15-H), 5.20 (m, 15-H), 9.76 (s, 18-H), 9.78 (s, 18-
H), 9.88 (s, 18-H), 4.94 (dd, 2'-H), 3.17 (t, 4'-H),
2.03 (s, 2'-OCOCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 4.83 (br
d, 1 "-H), 2.26 (br d, 2" -Heq), 1.18 (s, 3 "-CH 3 ), 1.0
5 (br d, 6 "-H), 4.51 (d, 3" -OC H 2 SCH 3 ), 2.20 (s, 3 "-OC
H 2 SC H 3 ), 1.69 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.97 (t, 4" -OCOC
H 2 CH 2 C H 3 )
【0039】実施例3化合物(4)(式(VII)において、R3がノルマルプロ
ピル基で表され、R4が1-エトキシエチル基で表され、R5
が1-エトキシエチル基で表される化合物)の製造法 化合物(3) 37 mgをメタノール 1.2 mlに溶解した
後、 30℃で16時間反応させた。反応液を減圧濃縮
し、得られた残さ 36 mgを分離用TLC(展開系:ヘキサン
−酢酸エチル(1:1))で精製し、化合物(4) 27 mgを
得た。 化合物(4)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C49H85NO16S (3) マススペクトル (EIMS) : m/z 975 (M)+ (4) 比旋光度 : [α]D 17 -118°(c1.0, CH3O
H) (5) 融点 : 明瞭な融点を示さず、63〜66℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.82(dd, 2-H), 3.48(s, 4-OCH3), 3.54(s,
4-OCH3), 1.86(m, 8-H), 3.95(dd, 9-H), 4.05(dd, 9-
H), 6.18(dd, 11-H), 6.19(dd, 11-H), 5.16(m, 15-H),
5.24(m, 15-H), 9.76(s, 18-H), 9.77(s, 18-H), 9.88
(s, 18-H), 0.99(d, 19-H3), 4.80(q, 3-OCH(OCH2CH3)C
H3), 2.54(s, 3'-N(CH3)2), 1.71(dd, 2"-Hax), 1.19
(s, 3"-CH3), 4.65(d, 4"-H), 1.07(d, 6"-H), 4.52(d,
3"-OCH 2SCH3), 4.65(d, 3"-OCH 2SCH3),2.18(s, 3"-OCH
2SCH3 ), 2.21(s, 3"-OCH2SCH3 ), 2.37(m, 4"-OCOCH2 CH2
CH3), 1.69(tq, 4"-OCOCH2CH2 CH3), 0.97(t, 4"-OCOCH2
CH2CH3 )Example 3 Compound (4) (in the formula (VII), R 3 is normal
Represented by a pill group, R 4 represents a 1-ethoxyethyl group, R 5
( Compound represented by 1-ethoxyethyl group ) 37 mg of compound (3) was dissolved in 1.2 ml of methanol and reacted at 30 ° C. for 16 hours. The reaction liquid was concentrated under reduced pressure, and 36 mg of the obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (1: 1)) to obtain 27 mg of compound (4). Physicochemical properties of compound (4) (1) Color and shape: colorless solid (2) Molecular formula: C 49 H 85 NO 16 S (3) Mass spectrum (EIMS): m / z 975 (M) + (4) ratio Optical rotation: [α] D 17 -118 ° (c1.0, CH 3 O
H) (5) Melting point: Melting at 63 to 66 ° C. without showing clear melting point (6) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ
(ppm): 2.82 (dd, 2-H), 3.48 (s, 4-OCH 3 ), 3.54 (s,
4-OCH 3 ), 1.86 (m, 8-H), 3.95 (dd, 9-H), 4.05 (dd, 9-
H), 6.18 (dd, 11-H), 6.19 (dd, 11-H), 5.16 (m, 15-H),
5.24 (m, 15-H), 9.76 (s, 18-H), 9.77 (s, 18-H), 9.88
(s, 18-H), 0.99 (d, 19-H 3 ), 4.80 (q, 3-OC H (OCH 2 CH 3 ) C
H 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 1.71 (dd, 2 "-Hax), 1.19
(s, 3 "-CH 3 ), 4.65 (d, 4" -H), 1.07 (d, 6 "-H), 4.52 (d,
3 "-OC H 2 SCH 3 ), 4.65 (d, 3" -OC H 2 SCH 3 ), 2.18 (s, 3 "-OCH
2 SC H 3 ), 2.21 (s, 3 "-OCH 2 SC H 3 ), 2.37 (m, 4" -OCOC H 2 CH 2
CH 3 ), 1.69 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.97 (t, 4" -OCOCH 2
CH 2 C H 3 )
【0040】実施例4化合物(6)(式(I)において、R1が水素原子で表さ
れ、R2が水素原子で表され、R3がノルマルプロピル基で
表される化合物)の製造法 始めにラネーニッケルの活性をコントロールした。即ち
ラネーニッケル 1.3 mlを各 2.0 mlの水で2回洗浄した
後、発熱を抑えつつ各 2.0 mlのアセトンで3回洗浄し
活性を適度に調整した。次いで各 2.0 mlのエタノール
で2回洗浄し反応に用いることにした。化合物(4) 5
0 mgをエタノール 1.3 mlに溶解した後、活性をコント
ロールした上記ラネーニッケルを 1.3 mlのエタノール
と共に上記溶液に加えた。これを室温で20分間激しく
撹拌した後、不溶物を濾過し、1%(v/v)の濃アンモニア
水を含むエタノール各 5.0 mlで2回洗浄した。濾液と
洗液を合わせ、減圧濃縮して得られた粗化合物(5)
(式(VIII)において、R3がノルマルプロピル基で表さ
れ、R4が1-エトキシエチル基で表され、R5が1-エトキシ
エチル基で表される化合物) 57 mgを5%酢酸水溶液 3.
8 mlとアセトニトリル1.3 mlの混合溶液に溶解した後、
室温で16時間反応させた。反応液を減圧濃縮して得ら
れた残さをクロロホルム 10 mlに溶解した後、飽和炭酸
水素ナトリウム水溶液 10 mlで2回及び飽和塩化ナトリ
ウム水溶液 10 mlで順次洗浄した。クロロホルム層を無
水硫酸ナトリウムで乾燥後これを濾過し、濾液を減圧濃
縮して得られた残さ 33 mgを分離用TLC(展開系:トルエ
ン−アセトン(1:1))で精製し、化合物(6) 8.0 mgを
得た。 化合物(6)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C40H67NO14 (3) マススペクトル (FDMS) : m/z 786 (M+H)+ (4) 比旋光度 : [α]D 15 -76°(c0.9, CH3OH) (5) 融点 : 明瞭な融点を示さず、100〜104℃で
熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.22(br d, 2-H), 2.70(dd, 2-H), 3.79(br
d, 3-H), 3.10(br d, 4-H), 3.54(s, 4-OCH3), 4.11(br
d, 5-H), 1.60(br dt, 7-H), 1.91(m, 8-H), 4.10(dd,
9-H), 5.69(dd, 10-H), 6.26(dd, 11-H), 6.04(br dd,
12-H), 5.61(ddd, 13-H), 2.12(dt, 14-H), 5.29(ddq,
15-H), 1.31(d, 16-H3), 2.34(br dd, 17-H), 2.87(br
dd, 17-H),9.80(s, 18-H), 0.99(d, 19-H3), 4.59(d,
1'-H), 3.23(dd, 2'-H), 3.46(t, 4'-H), 3.28(dq, 5'-
H), 1.20(d, 6'-H3), 2.58(s, 3'-N(CH3)2), 4.94(d,
1"-H), 1.67(dd, 2"-Hax), 2.29(d, 2"-Heq), 1.11(s,
3"-CH3), 4.72(d, 4"-H), 4.54(dq, 5"-H), 1.08(d, 6"
-H3), 3.26(s, 3"-OCH3), 2.39(m, 4"-OCOCH2 CH2CH3),
1.69(tq, 4"-OCOCH2CH2 CH3), 0.96(t, 4"-OCOCH2CH2C
H3 )Example 4 Compound (6) (in the formula (I), R 1 represents a hydrogen atom)
R 2 is a hydrogen atom and R 3 is a normal propyl group.
(Compound represented) The activity of Raney nickel was controlled at the beginning. That is, 1.3 ml of Raney nickel was washed twice with 2.0 ml of water each time, and then washed with 2.0 ml of acetone three times while suppressing the heat generation to appropriately adjust the activity. Then, it was washed twice with 2.0 ml of ethanol each and used for the reaction. Compound (4) 5
After dissolving 0 mg in 1.3 ml of ethanol, the Raney nickel whose activity was controlled was added to the above solution together with 1.3 ml of ethanol. This was vigorously stirred at room temperature for 20 minutes, the insoluble material was filtered off, and washed twice with 5.0 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The crude compound (5) obtained by combining the filtrate and the washing solution and concentrating under reduced pressure
(A compound represented by the formula (VIII) in which R 3 is a normal propyl group, R 4 is a 1-ethoxyethyl group, and R 5 is a 1-ethoxyethyl group) 57 mg of a 5% acetic acid aqueous solution 3.
After dissolving in a mixed solution of 8 ml and 1.3 ml of acetonitrile,
The reaction was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 10 ml of chloroform, and then the mixture was washed twice with 10 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 10 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 33 mg of the residue, which was purified by preparative TLC (developing system: toluene-acetone (1: 1)) to give the compound (6 ) 8.0 mg was obtained. Physicochemical properties of compound (6) (1) Color and shape: colorless solid (2) Molecular formula: C 40 H 67 NO 14 (3) Mass spectrum (FDMS): m / z 786 (M + H) + (4) Specific rotation: [α] D 15 -76 ° (c0.9, CH 3 OH) (5) Melting point: Melting at 100-104 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.22 (br d, 2-H), 2.70 (dd, 2-H), 3.79 (br
d, 3-H), 3.10 (br d, 4-H), 3.54 (s, 4-OCH 3 ), 4.11 (br
d, 5-H), 1.60 (br dt, 7-H), 1.91 (m, 8-H), 4.10 (dd,
9-H), 5.69 (dd, 10-H), 6.26 (dd, 11-H), 6.04 (br dd,
12-H), 5.61 (ddd, 13-H), 2.12 (dt, 14-H), 5.29 (ddq,
15-H), 1.31 (d, 16-H 3 ), 2.34 (br dd, 17-H), 2.87 (br
dd, 17-H), 9.80 (s, 18-H), 0.99 (d, 19-H 3 ), 4.59 (d,
1'-H), 3.23 (dd, 2'-H), 3.46 (t, 4'-H), 3.28 (dq, 5'-
H), 1.20 (d, 6' -H 3), 2.58 (s, 3'-N (CH 3) 2), 4.94 (d,
1 "-H), 1.67 (dd, 2" -Hax), 2.29 (d, 2 "-Heq), 1.11 (s,
3 "-CH 3 ), 4.72 (d, 4" -H), 4.54 (dq, 5 "-H), 1.08 (d, 6"
-H 3 ), 3.26 (s, 3 "-OCH 3 ), 2.39 (m, 4" -OCOC H 2 CH 2 CH 3 ),
1.69 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.96 (t, 4" -OCOCH 2 CH 2 C
H 3 )
【0041】実施例5化合物(8)(式(V)において、R3がノルマルプロピ
ル基で表され、R4が1-エトキシエチル基で表され、R5が
アセチル基で表される化合物)の製造法 化合物(7)(式(V)において、R3がノルマルプロピル
基で表され、R4が水素原子で表され、R5がアセチル基で
表される化合物)(ジャーナル・オブ・メディシナルケ
ミストリー, 20(5), 732(1977))2.10 gを塩化メチレン
63 mlとエチルビニルエーテル 1.2 mlの混合溶液に溶
解した後、PPTS 923 mgを加え、30℃で16時間反応さ
せた。反応液を飽和炭酸水素ナトリウム水溶液 250 ml
に徐々に加え、塩化メチレン 250 mlで抽出した。塩化
メチレン層を5%硫酸水素カリウム水溶液 250 ml、飽和
炭酸水素ナトリウム水溶液 250 ml及び飽和塩化ナトリ
ウム水溶液 250 mlで順次洗浄した。塩化メチレン層を
減圧濃縮して得られた残さ 2.20gをシリカゲルカラムク
ロマトグラフィー(200 g:ヘキサン−酢酸エチル(2:
3))で精製して、化合物(8) 1.20 gを得た。 化合物(8)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C47H77NO17 (3) マススペクトル (FDMS) : m/z 928 (M+H)+ (4) 比旋光度 : [α]D 19 -90°(c1.0, CHCl3) (5) 融点 : 明瞭な融点を示さず、80〜85℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 3.88(m, 3-H),2.87(br d, 4-H), 3.36(s, 4-
OCH3), 3.43(s, 4-OCH3), 4.18(br d, 5-H), 1.43(br d
t, 7-H), 1.92(m, 8-H), 5.23(dd, 9-H), 5.55(dd, 10-
H), 5.58(dd, 10-H), 6.23(dd, 11-H), 6.34(dd, 11-
H), 6.02(br dd, 12-H), 5.65(ddd, 13-H),5.69(ddd, 1
3-H), 2.13(br dt, 14-H), 5.15(ddq, 15-H), 1.29(d,
16-H3), 9.77(br s, 18-H), 9.88(s, 18-H), 0.99(d, 1
9-H3), 1.01(d, 19-H3), 4.83(q, 3-OCH(OCH2CH3)CH3),
4.89(q, 3-OCH(OCH2CH3)CH3), 3.50(dq, 3-OCH(OCH 2CH
3)CH3), 3.60(dq, 3-OCH(OCH 2CH3)CH3), 1.16(t, 3-OCH
(OCH2CH3 )CH3), 1.23(t, 3-OCH(OCH2CH3 )CH3), 1.27(d,
3-OCH(OCH2CH3)CH3 ), 1.28(d, 3-OCH(OCH2CH3)CH3 ),4.
66(d, 1'-H), 4.99(dd, 2'-H)), 3.28(t, 4'-H), 1.24
(d, 6'-H3), 2.02, 2.04, 2.05, 2.07(4×s, 9-OCOCH3,
2'-OCOCH3), 2.39(s, 3'-N(CH3)2), 2.41(s, 3'-N(C
H3)2), 5.06(d, 1"-H), 1.84(dd, 2"-Hax), 2.01(dd,
2"-Heq), 1.12(s, 3"-CH3), 4.62(d, 4"-H), 1.13(d,
6"-H3), 1.69(tq, 4"-OCOCH2CH2 CH3), 0.97(t, 4"-OCOC
H2CH2CH3 )Example 5 Compound (8) (in the formula (V), R 3 is normal propene
Represented by a R group, R 4 represents a 1-ethoxyethyl group, and R 5 represents
Method for producing compound represented by acetyl group) Compound (7) (in formula (V), R 3 is represented by normal propyl group, R 4 is represented by hydrogen atom, and R 5 is represented by acetyl group. Compound) (Journal of Medicinal Chemistry, 20 (5), 732 (1977)) 2.10 g methylene chloride
After dissolving in a mixed solution of 63 ml and 1.2 ml of ethyl vinyl ether, 923 mg of PPTS was added and reacted at 30 ° C. for 16 hours. 250 ml of saturated aqueous sodium hydrogen carbonate solution
The mixture was gradually added to and extracted with 250 ml of methylene chloride. The methylene chloride layer was washed successively with 250 ml of 5% aqueous potassium hydrogen sulfate solution, 250 ml of saturated aqueous sodium hydrogen carbonate solution and 250 ml of saturated aqueous sodium chloride solution. The methylene chloride layer was concentrated under reduced pressure, and 2.20 g of the residue obtained was subjected to silica gel column chromatography (200 g: hexane-ethyl acetate (2:
Purification by 3)) yielded 1.20 g of compound (8). Physicochemical properties of compound (8) (1) Color and shape: colorless solid (2) Molecular formula: C 47 H 77 NO 17 (3) Mass spectrum (FDMS): m / z 928 (M + H) + (4) Specific rotation: [α] D 19 -90 ° (c1.0, CHCl 3 ) (5) Melting point: Melting at 80-85 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 3.88 (m, 3-H), 2.87 (br d, 4-H), 3.36 (s, 4-
OCH 3 ), 3.43 (s, 4-OCH 3 ), 4.18 (br d, 5-H), 1.43 (br d
t, 7-H), 1.92 (m, 8-H), 5.23 (dd, 9-H), 5.55 (dd, 10-
H), 5.58 (dd, 10-H), 6.23 (dd, 11-H), 6.34 (dd, 11-
H), 6.02 (br dd, 12-H), 5.65 (ddd, 13-H), 5.69 (ddd, 1
3-H), 2.13 (br dt, 14-H), 5.15 (ddq, 15-H), 1.29 (d,
16-H 3 ), 9.77 (br s, 18-H), 9.88 (s, 18-H), 0.99 (d, 1
9-H 3 ), 1.01 (d, 19-H 3 ), 4.83 (q, 3-OC H (OCH 2 CH 3 ) CH 3 ),
4.89 (q, 3-OC H (OCH 2 CH 3 ) CH 3 ), 3.50 (dq, 3-OCH (OC H 2 CH
3 ) CH 3 ), 3.60 (dq, 3-OCH (OC H 2 CH 3 ) CH 3 ), 1.16 (t, 3-OCH
(OCH 2 C H 3 ) CH 3 ), 1.23 (t, 3-OCH (OCH 2 C H 3 ) CH 3 ), 1.27 (d,
3-OCH (OCH 2 CH 3 ) C H 3 ), 1.28 (d, 3-OCH (OCH 2 CH 3 ) C H 3 ), 4.
66 (d, 1'-H), 4.99 (dd, 2'-H)), 3.28 (t, 4'-H), 1.24
(d, 6'-H 3 ), 2.02, 2.04, 2.05, 2.07 (4 × s, 9-OCOCH 3 ,
2'-OCOCH 3 ), 2.39 (s, 3'-N (CH 3 ) 2 ), 2.41 (s, 3'-N (C
H 3 ) 2 ), 5.06 (d, 1 "-H), 1.84 (dd, 2" -Hax), 2.01 (dd,
2 "-Heq), 1.12 (s, 3" -CH 3 ), 4.62 (d, 4 "-H), 1.13 (d,
6 "-H 3 ), 1.69 (tq, 4" -OCOCH 2 C H 2 CH 3 ), 0.97 (t, 4 "-OCOC
H 2 CH 2 C H 3 )
【0042】実施例6化合物(9H)(式(VI)において、R3がノルマルプロ
ピル基で表され、R4が1-エトキシエチル基で表され、R5
がアセチル基で表される化合物のうち後述した展開系に
おけるTLCにおいてRf値の大きい方の異性体)及び化合
物(9L)(式(VI)において、R3がノルマルプロピル
基で表され、R4が1-エトキシエチル基で表され、R5がア
セチル基で表される化合物のうち同Rf値の小さい方の異
性体)の製造法 化合物(8) 200 mgをDMSO 6.0 mlと無水酢酸 0.60 ml
の混合溶液に溶解した後、30℃で40時間反応させた。
反応液をトルエン 50 mlに徐々に加え、水 50mlで3回
洗浄した。トルエン層を無水硫酸ナトリウムで乾燥後こ
れを濾過し、濾液を減圧濃縮した。得られた残さ 215 m
gを分離用TLC(展開系:ヘキサン−酢酸エチル(1:1))で
精製して、化合物(9H) 32 mg及び化合物(9L) 2
9 mgを得た。 化合物(9H)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C49H81NO17S (3) マススペクトル (SIMS) : m/z 988 (M+H)+ (4) TLCにおけるRf値 : 0.58(ヘキサン:酢酸
エチル(1:1)) (5) 比旋光度 : [α]D 15 -102°(c1.0, CHC
l3) (6) 融点 : 明瞭な融点を示さず、68〜73℃で熔
融 (7) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 3.87(m, 3-H),2.88(br d, 4-H), 3.44(s, 4-
OCH3), 4.20(br d, 5-H), 1.44(br dt, 7-H), 1.90(m,
8-H), 5.23(dd, 9-H), 5.58(dd, 10-H), 6.34(dd, 11-
H), 6.02(br dd, 12-H), 5.65(ddd, 13-H), 2.13(dt, 1
4-H), 5.15(ddq, 15-H), 1.29(d, 16-H3),9.88(br s, 1
8-H), 1.00(d, 19-H3), 4.84(q, 3-OCH(OCH2CH3)CH3),
3.50(dq, 3-OCH(OCH 2CH3)CH3), 3.60(dq, 3-OCH(OCH 2CH
3)CH3), 1.23(t, 3-OCH(OCH2CH3 )CH 3), 1.28(d, 3-OCH
(OCH2CH3)CH3 ), 4.65(d, 1'-H), 4.93(dd, 2'-H)), 2.7
1(t,3'-H), 3.16(t, 4'-H), 3.29(dq, 5'-H), 1.19(d,
6'-H3), 2.02, 2.03(2×s, 9-OCOCH3, 2'-OCOCH3), 2.4
1(s, 3'-N(CH3)2), 4.81(d, 1"-H), 1.68(dd, 2"-Hax),
2.25(d, 2"-Heq), 1.17(s, 3"-CH3), 4.55(dq, 5"-H),
1.04(d, 6"-H3), 4.51(d, 3"-OCH 2SCH3), 4.63, 4.64
(2×d, 4"-H, 3"-OCH 2SCH3), 2.19(s, 3"-OCH2SCH3 ),
2.37(m, 4"-OCOCH2 CH2CH3), 1.69(tq, 4"-OCOCH2CH2 C
H3), 0.97(t, 4"-OCOCH2CH2CH3 ) 化合物(9L)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C49H81NO17S (3) マススペクトル (SIMS) : m/z 988 (M+H)+ (4) TLCにおけるRf値 : 0.50(ヘキサン:酢酸
エチル(1:1)) (5) 比旋光度 : [α]D 14 -92°(c1.0, CHCl3) (6) 融点 : 明瞭な融点を示さず、70〜74℃で熔
融 (7) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 1.84(m, 8-H),5.56(dd, 10-H), 6.24(dd, 11
-H), 6.01(br dd, 12-H), 5.69(ddd, 13-H), 2.13(dt,
14-H), 1.28(d, 16-H3), 2.89(br dd, 17-H), 9.76(s,
18-H), 0.99(d, 19-H3), 4.90(q, 3-OCH(OCH2CH3)CH3),
3.48(dq, 3-OCH(OCH 2CH3)CH3), 3.62(dq,3-OCH(OCH 2CH
3)CH3), 1.15(t, 3-OCH(OCH2CH3 )CH3), 1.27(d, 3-OCH
(OCH2CH3)CH3 ), 4.54(d, 1'-H), 4.95(dd, 2'-H), 2.74
(t, 3'-H), 3.17(t, 4'-H), 1.19(d, 6'-H3), 2.03, 2.
05(2×s, 9-OCOCH3, 2'-OCOCH3), 2.41(s, 3'-N(C
H3)2), 4.82(d, 1"-H), 1.68(dd, 2"-Hax), 2.24(dd,
2"-Heq), 1.17(s, 3"-CH3), 4.56(dq, 5"-H), 1.04(d,
6"-H3), 4.51(d, 3"-OCH 2SCH3), 4.63, 4.64(2×d, 4"-
H, 3"-OCH 2SCH3), 2.20(s, 3"-OCH2SCH3 ), 2.37(m, 4"-
OCOCH2 CH2CH3), 1.69(tq, 4"-OCOCH2CH2 CH3), 0.97(t,
4"-OCOCH2CH2CH3 )Example 6Compound (9H) (in formula (VI), R 3 is normal
Represented by a pill group, R 4 represents a 1-ethoxyethyl group, R 5
Among the compounds represented by acetyl group,
Isomer with higher Rf value in TLC in
(9L) (in formula (VI), R 3 is normal propyl
Group, R 4 is represented by a 1-ethoxyethyl group, and R 5 is represented by
Of the compounds represented by the cetyl group, different compounds with the same Rf value
Sexual body) manufacturing method Compound (8) 200 mg was added to DMSO 6.0 ml and acetic anhydride 0.60 ml.
After being dissolved in the mixed solution of, the reaction was carried out at 30 ° C. for 40 hours.
The reaction solution was gradually added to 50 ml of toluene, and 50 ml of water was added 3 times.
Washed. After drying the toluene layer with anhydrous sodium sulfate,
It was filtered and the filtrate was concentrated under reduced pressure. Residue obtained 215 m
g with TLC for separation (developing system: hexane-ethyl acetate (1: 1))
32 mg of compound (9H) and compound (9L) 2 after purification
9 mg was obtained. Physicochemical properties of compound (9H) (1) Color and shape: Colorless solid (2) Molecular formula: C49H81NO17S (3) Mass spectrum (SIMS): m / z 988 (M + H)+ (4) Rf value in TLC: 0.58 (hexane: acetic acid
Ethyl (1: 1)) (5) Specific rotation: [α]D 15 -102 ° (c1.0, CHC
l3) (6) Melting point: Melting at 68-73 ° C without showing clear melting point.
Melt (7)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 3.87 (m, 3-H), 2.88 (br d, 4-H), 3.44 (s, 4-
OCH3), 4.20 (br d, 5-H), 1.44 (br dt, 7-H), 1.90 (m,
8-H), 5.23 (dd, 9-H), 5.58 (dd, 10-H), 6.34 (dd, 11-
H), 6.02 (br dd, 12-H), 5.65 (ddd, 13-H), 2.13 (dt, 1
4-H), 5.15 (ddq, 15-H), 1.29 (d, 16-H3), 9.88 (br s, 1
8-H), 1.00 (d, 19-H3), 4.84 (q, 3-OCH(OCH2CH3) CH3),
3.50 (dq, 3-OCH (OCH 2CH3) CH3), 3.60 (dq, 3-OCH (OCH 2CH
3) CH3), 1.23 (t, 3-OCH (OCH2CH 3 ) CH 3), 1.28 (d, 3-OCH
(OCH2CH3) CH 3 ), 4.65 (d, 1'-H), 4.93 (dd, 2'-H)), 2.7
1 (t, 3'-H), 3.16 (t, 4'-H), 3.29 (dq, 5'-H), 1.19 (d,
6'-H3), 2.02, 2.03 (2 × s, 9-OCOCH3, 2'-OCOCH3), 2.4
1 (s, 3'-N (CH3)2), 4.81 (d, 1 "-H), 1.68 (dd, 2" -Hax),
2.25 (d, 2 "-Heq), 1.17 (s, 3" -CH3), 4.55 (dq, 5 "-H),
1.04 (d, 6 "-H3), 4.51 (d, 3 "-OCH 2SCH3), 4.63, 4.64
(2 × d, 4 "-H, 3" -OCH 2SCH3), 2.19 (s, 3 "-OCH2SCH 3 ),
2.37 (m, 4 "-OCOCH 2 CH2CH3), 1.69 (tq, 4 "-OCOCH2CH 2 C
H3), 0.97 (t, 4 "-OCOCH2CH2CH 3 ) Physicochemical properties of compound (9L) (1) Color and shape: Colorless solid (2) Molecular formula: C49H81NO17S (3) Mass spectrum (SIMS): m / z 988 (M + H)+ (4) Rf value in TLC: 0.50 (hexane: acetic acid
Ethyl (1: 1)) (5) Specific rotation: [α]D 14 -92 ° (c1.0, CHCl3) (6) Melting point: Melting at 70-74 ℃ without showing clear melting point.
Melt (7)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 1.84 (m, 8-H), 5.56 (dd, 10-H), 6.24 (dd, 11
-H), 6.01 (br dd, 12-H), 5.69 (ddd, 13-H), 2.13 (dt,
14-H), 1.28 (d, 16-H3), 2.89 (br dd, 17-H), 9.76 (s,
18-H), 0.99 (d, 19-H3), 4.90 (q, 3-OCH(OCH2CH3) CH3),
3.48 (dq, 3-OCH (OCH 2CH3) CH3), 3.62 (dq, 3-OCH (OCH 2CH
3) CH3), 1.15 (t, 3-OCH (OCH2CH 3 ) CH3), 1.27 (d, 3-OCH
(OCH2CH3) CH 3 ), 4.54 (d, 1'-H), 4.95 (dd, 2'-H), 2.74
(t, 3'-H), 3.17 (t, 4'-H), 1.19 (d, 6'-H3), 2.03, 2.
05 (2 × s, 9-OCOCH3, 2'-OCOCH3), 2.41 (s, 3'-N (C
H3)2), 4.82 (d, 1 "-H), 1.68 (dd, 2" -Hax), 2.24 (dd,
2 "-Heq), 1.17 (s, 3" -CH3), 4.56 (dq, 5 "-H), 1.04 (d,
6 "-H3), 4.51 (d, 3 "-OCH 2SCH3), 4.63, 4.64 (2 × d, 4 "-
H, 3 "-OCH 2SCH3), 2.20 (s, 3 "-OCH2SCH 3 ), 2.37 (m, 4 "-
OCOCH 2 CH2CH3), 1.69 (tq, 4 "-OCOCH2CH 2 CH3), 0.97 (t,
4 "-OCOCH2CH2CH 3 )
【0043】実施例7化合物(10H)(式(VII)において、R3がノルマル
プロピル基で表され、R4が1-エトキシエチル基で表さ
れ、R5がアセチル基で表される化合物のうち化合物(9
H)より誘導される異性体)の製造法 化合物(9H) 19 mgをメタノール 1.9 mlに溶解した
後、 30℃で16時間反応させた。反応液を減圧濃縮
し、得られた残さ 18 mgを分離用TLC(展開系:ヘキサン
−酢酸エチル(1:2))で精製し、化合物(10H) 14 m
gを得た。 化合物(10H)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C47H79NO16S (3) マススペクトル (SIMS) : m/z 946 (M+H)+ (4) TLCにおけるRf値 : 0.33(クロロホルム:
メタノール(30:1)) (5) 比旋光度 : [α]D 16 -90°(c1.0, CH3OH) (6) 融点 : 明瞭な融点を示さず、72〜75℃で熔
融 (7) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.69(dd, 2-H), 3.93(m, 3-H), 2.95(br d,
4-H), 3.55(s, 4-OCH3), 4.07(br d, 5-H), 1.48(br d
t, 7-H), 1.93(m, 8-H), 5.26(dd, 9-H), 5.59(dd, 10-
H), 6.33(dd, 11-H), 6.03(br dd, 12-H), 5.66(ddd, 1
3-H), 2.15(dt, 14-H), 5.16(ddq, 15-H), 1.28(d, 16-
H3), 2.73(br dd 17-H), 9.89(br s, 18-H), 1.00(d, 1
9-H3), 4.82(q, 3-OCH(OCH2CH3)CH3), 3.50(dq, 3-OCH
(OCH 2CH3)CH3), 3.60(dq, 3-OCH(OCH 2CH3)CH3), 1.23
(t, 3-OCH(OCH2CH3 )CH3), 1.29(d, 3-OCH(OCH2CH3)C
H3 ), 2.03(s,9-OCOCH3), 4.56(d, 1'-H), 3.36(dd, 2'-
H)), 2.47(t, 3'-H), 1.21(d, 6'-H3), 2.53(s, 3'-N(C
H3)2), 4.88(d, 1"-H), 1.71(dd, 2"-Hax), 2.27(d, 2"
-Heq), 1.19(s, 3"-CH3), 4.58(dq, 5"-H), 1.06(d, 6"
-H3), 4.52(d, 3"-OCH 2SCH3),4.64, 4.65(2×d, 4"-H,
3"-OCH 2SCH3), 2.19(s, 3"-OCH2SCH3 ), 2.37(m, 4"-OCO
CH2 CH2CH3), 1.69(tq, 4"-OCOCH2CH2 CH3), 0.97(t, 4"-
OCOCH2CH2CH3 )Example 7 Compound (10H) (in the formula (VII), R 3 is normal
It is represented by a propyl group, and R 4 is represented by a 1-ethoxyethyl group.
Of the compounds represented by R 5 as an acetyl group (9
Method for producing isomer derived from H) 19 mg of compound (9H) was dissolved in 1.9 ml of methanol and then reacted at 30 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue (18 mg) was purified by preparative TLC (developing system: hexane-ethyl acetate (1: 2)) to give compound (10H) 14 m
got g. Physicochemical properties of compound (10H) (1) Color and shape: colorless solid (2) Molecular formula: C 47 H 79 NO 16 S (3) Mass spectrum (SIMS): m / z 946 (M + H) + (4 ) Rf value in TLC: 0.33 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] D 16 -90 ° (c1.0, CH 3 OH) (6) Melting point: Melting at 72 to 75 ° C without showing a clear melting point ( 7) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.69 (dd, 2-H), 3.93 (m, 3-H), 2.95 (br d,
4-H), 3.55 (s, 4-OCH 3 ), 4.07 (br d, 5-H), 1.48 (br d
t, 7-H), 1.93 (m, 8-H), 5.26 (dd, 9-H), 5.59 (dd, 10-
H), 6.33 (dd, 11-H), 6.03 (br dd, 12-H), 5.66 (ddd, 1
3-H), 2.15 (dt, 14-H), 5.16 (ddq, 15-H), 1.28 (d, 16-
H 3 ), 2.73 (br dd 17-H), 9.89 (br s, 18-H), 1.00 (d, 1
9-H 3 ), 4.82 (q, 3-OC H (OCH 2 CH 3 ) CH 3 ), 3.50 (dq, 3-OCH
(OC H 2 CH 3 ) CH 3 ), 3.60 (dq, 3-OCH (OC H 2 CH 3 ) CH 3 ), 1.23
(t, 3-OCH (OCH 2 C H 3 ) CH 3 ), 1.29 (d, 3-OCH (OCH 2 CH 3 ) C
H 3 ), 2.03 (s, 9-OCOCH 3 ), 4.56 (d, 1'-H), 3.36 (dd, 2'-
H)), 2.47 (t, 3'-H), 1.21 (d, 6'-H 3 ), 2.53 (s, 3'-N (C
H 3 ) 2 ), 4.88 (d, 1 "-H), 1.71 (dd, 2" -Hax), 2.27 (d, 2 "
-Heq), 1.19 (s, 3 "-CH 3 ), 4.58 (dq, 5" -H), 1.06 (d, 6 "
-H 3 ), 4.52 (d, 3 "-OC H 2 SCH 3 ), 4.64, 4.65 (2 × d, 4" -H,
3 "-OC H 2 SCH 3 ), 2.19 (s, 3" -OCH 2 SC H 3 ), 2.37 (m, 4 "-OCO
C H 2 CH 2 CH 3 ), 1.69 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.97 (t, 4"-
OCOCH 2 CH 2 C H 3 )
【0044】実施例8化合物(10L)(式(VII)において、R3がノルマル
プロピル基で表され、R4が1-エトキシエチル基で表さ
れ、R5がアセチル基で表される化合物のうち化合物(9
L)より誘導される異性体)の製造法 化合物(9L) 20 mgをメタノール 2.0 mlに溶解した
後、 30℃で16時間反応させた。反応液を減圧濃縮
し、得られた残さ 19 mgを分離用TLC(展開系:ヘキサン
−酢酸エチル(1:2))で精製し、化合物(10L) 15 m
gを得た。 化合物(10L)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C47H79NO16S (3) マススペクトル (SIMS) : m/z 946 (M+H)+ (4) TLCにおけるRf値 : 0.24(クロロホルム:
メタノール(30:1)) (5) 比旋光度 : [α]D 16 -77°(c0.5, CH3OH) (6) 融点 : 明瞭な融点を示さず、70〜72℃で熔
融 (7) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.83(dd, 2-H), 3.47(s, 4-OCH3), 1.86(m,
8-H), 5.29(dd, 9-H), 5.55(dd, 10-H), 6.21(dd,11-
H), 6.02(br dd, 12-H), 5.66(ddd, 13-H), 2.13(dt, 1
4-H), 5.25(ddq, 15-H), 1.28(d, 16-H3), 2.98(br dd,
17-H), 9.77(s, 18-H), 0.98(d, 19-H3), 4.92(q, 3-O
CH(OCH2CH3)CH3), 3.49(dq, 3-OCH(OCH 2CH3)CH3), 3.59
(dq, 3-OCH(OCH 2CH3)CH3), 1.16(t, 3-OCH(OCH2CH3 )C
H3), 1.29(d, 3-OCH(OCH2CH3)CH3 ), 2.04(s, 9-OCOC
H3), 4.42(d, 1'-H), 3.25(t, 4'-H), 1.24(d, 6'-H3),
2.53(s, 3'-N(CH3)2), 4.87(d, 1"-H), 1.70(dd, 2"-H
ax), 2.26(d, 2"-Heq), 1.19(s, 3"-CH3), 4.60(dq, 5"
-H), 1.06(d, 6"-H3), 4.52(d, 3"-OCH 2SCH3), 4.65,
4.66(2×d, 4"-H, 3"-OCH 2SCH3), 2.20(s, 3"-OCH2SC
H3 ), 2.37(m, 4"-OCOCH2 CH2CH3),1.69(tq, 4"-OCOCH2CH
2 CH3), 0.97(t, 4"-OCOCH2CH2CH3 )Example 8 Compound (10 L) (in the formula (VII), R 3 is normal
It is represented by a propyl group, and R 4 is represented by a 1-ethoxyethyl group.
Of the compounds represented by R 5 as an acetyl group (9
Method for producing isomer derived from L) 20 mg of the compound (9L) was dissolved in 2.0 ml of methanol, and then reacted at 30 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue (19 mg) was purified by preparative TLC (developing system: hexane-ethyl acetate (1: 2)) to give compound (10 L) 15 m
got g. Physicochemical properties of compound (10 L) (1) Color and shape: Colorless solid (2) Molecular formula: C 47 H 79 NO 16 S (3) Mass spectrum (SIMS): m / z 946 (M + H) + (4) ) Rf value in TLC: 0.24 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] D 16 -77 ° (c0.5, CH 3 OH) (6) Melting point: Melting at 70-72 ° C without showing clear melting point ( 7) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.83 (dd, 2-H), 3.47 (s, 4-OCH 3 ), 1.86 (m,
8-H), 5.29 (dd, 9-H), 5.55 (dd, 10-H), 6.21 (dd, 11-
H), 6.02 (br dd, 12-H), 5.66 (ddd, 13-H), 2.13 (dt, 1
4-H), 5.25 (ddq, 15-H), 1.28 (d, 16-H 3 ), 2.98 (br dd,
17-H), 9.77 (s, 18-H), 0.98 (d, 19-H 3 ), 4.92 (q, 3-O
C H (OCH 2 CH 3 ) CH 3 ), 3.49 (dq, 3-OCH (OC H 2 CH 3 ) CH 3 ), 3.59
(dq, 3-OCH (OC H 2 CH 3 ) CH 3 ), 1.16 (t, 3-OCH (OCH 2 C H 3 ) C
H 3 ), 1.29 (d, 3-OCH (OCH 2 CH 3 ) C H 3 ), 2.04 (s, 9-OCOC
H 3 ), 4.42 (d, 1'-H), 3.25 (t, 4'-H), 1.24 (d, 6'-H 3 ),
2.53 (s, 3'-N (CH 3 ) 2 ), 4.87 (d, 1 "-H), 1.70 (dd, 2" -H
ax), 2.26 (d, 2 "-Heq), 1.19 (s, 3" -CH 3 ), 4.60 (dq, 5 "
-H), 1.06 (d, 6 "-H 3 ), 4.52 (d, 3" -OC H 2 SCH 3 ), 4.65,
4.66 (2 × d, 4 "-H, 3" -OC H 2 SCH 3 ), 2.20 (s, 3 "-OCH 2 SC
H 3 ), 2.37 (m, 4 "-OCOC H 2 CH 2 CH 3 ), 1.69 (tq, 4" -OCOCH 2 C H
2 CH 3 ), 0.97 (t, 4 "-OCOCH 2 CH 2 C H 3 )
【0045】実施例9化合物(11H)(式(VIII)において、R3がノルマル
プロピル基で表され、R4が1-エトキシエチル基で表さ
れ、R5がアセチル基で表される化合物のうち化合物(1
0H)より誘導される異性体)の製造法 化合物(10H) 34 mgをエタノール 0.90 mlに溶解し
た後、ラネーニッケル0.90 mlを実施例4と同様の方法
で活性をコントロールし、 0.90 mlのエタノールと共に
上記溶液に加えた。これを室温で40分間激しく撹拌し
た後、不溶物を濾過し、1%(v/v)の濃アンモニア水を含
むエタノール各 4.0 mlで2回洗浄した。濾液と洗液を
合わせ、減圧濃縮して得られた残さ 31 mgを分離用TLC
(展開系:トルエン−アセトン(2:1))で精製し、化合物
(11H) 3.3 mgを得た。 化合物(11H)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C46H77NO16 (3) マススペクトル (SIMS) : m/z 900 (M+
H)+ (4) TLCにおけるRf値 : 0.17(クロロホルム:
メタノール(30:1)) (5) 比旋光度 : [α]D 17 -73°(c0.3, CH3OH) (6) 融点 : 明瞭な融点を示さず、74〜77℃で熔
融 (7) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.71(dd, 2-H), 3.92(m, 3-H), 2.97(br d,
4-H), 3.56(s, 4-OCH3), 4.10(br d, 5-H), 1.50(br d
t, 7-H), 1.93(m, 8-H), 5.26(dd, 9-H), 5.59(dd, 10-
H), 6.33(dd, 11-H), 6.03(br dd, 12-H), 5.65(ddd, 1
3-H), 2.15(dt, 14-H), 5.15(ddq, 15-H), 1.29(d, 16-
H3), 2.72(br dd 17-H), 9.90(br s, 18-H), 1.00(d, 1
9-H3), 4.83(q, 3-OCH(OCH2CH3)CH3), 3.50(dq, 3-OCH
(OCH 2CH3)CH3), 3.59(dq, 3-OCH(OCH 2CH3)CH3), 1.23
(t, 3-OCH(OCH2CH3 )CH3), 1.28(d, 3-OCH(OCH2CH3)C
H3 ), 2.02(s,9-OCOCH3), 4.57(d, 1'-H), 2.47(t, 3'-
H), 2.53(s, 3'-N(CH3)2), 4.89(d, 1"-H), 1.64(dd,
2"-Hax), 2.27(d, 2"-Heq), 1.09(s, 3"-CH3), 4.71(d,
4"-H),1.06(d, 6"-H3), 3.25(s, 3"-OCH3), 2.38(m,
4"-OCOCH2 CH2CH3), 1.68(tq, 4"-OCOCH2CH2 CH3), 0.95
(t, 4"-OCOCH2CH2CH3 )Example 9 Compound (11H) (in the formula (VIII), R 3 is normal
It is represented by a propyl group, and R 4 is represented by a 1-ethoxyethyl group.
And R 5 is a compound (1
Method for producing isomer derived from 0H) 34 mg of compound (10H) was dissolved in 0.90 ml of ethanol, and then 0.90 ml of Raney nickel was controlled for activity in the same manner as in Example 4, and 0.90 ml of ethanol was added to control the activity. Added to the solution. This was vigorously stirred at room temperature for 40 minutes, then the insoluble matter was filtered off, and washed twice with 4.0 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The filtrate and washings were combined and concentrated under reduced pressure.
The product was purified with (developing system: toluene-acetone (2: 1)) to obtain 3.3 mg of compound (11H). Physicochemical properties of compound (11H) (1) Color and shape: colorless solid (2) Molecular formula: C 46 H 77 NO 16 (3) Mass spectrum (SIMS): m / z 900 (M +
H) + (4) Rf value in TLC: 0.17 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] D 17 -73 ° (c0.3, CH 3 OH) (6) Melting point: Melting at 74-77 ° C without showing clear melting point ( 7) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.71 (dd, 2-H), 3.92 (m, 3-H), 2.97 (br d,
4-H), 3.56 (s, 4-OCH 3 ), 4.10 (br d, 5-H), 1.50 (br d
t, 7-H), 1.93 (m, 8-H), 5.26 (dd, 9-H), 5.59 (dd, 10-
H), 6.33 (dd, 11-H), 6.03 (br dd, 12-H), 5.65 (ddd, 1
3-H), 2.15 (dt, 14-H), 5.15 (ddq, 15-H), 1.29 (d, 16-
H 3 ), 2.72 (br dd 17-H), 9.90 (br s, 18-H), 1.00 (d, 1
9-H 3 ), 4.83 (q, 3-OC H (OCH 2 CH 3 ) CH 3 ), 3.50 (dq, 3-OCH
(OC H 2 CH 3 ) CH 3 ), 3.59 (dq, 3-OCH (OC H 2 CH 3 ) CH 3 ), 1.23
(t, 3-OCH (OCH 2 C H 3 ) CH 3 ), 1.28 (d, 3-OCH (OCH 2 CH 3 ) C
H 3 ), 2.02 (s, 9-OCOCH 3 ), 4.57 (d, 1'-H), 2.47 (t, 3'-
H), 2.53 (s, 3'-N (CH 3 ) 2 ), 4.89 (d, 1 "-H), 1.64 (dd,
2 "-Hax), 2.27 (d, 2" -Heq), 1.09 (s, 3 "-CH 3 ), 4.71 (d,
4 "-H), 1.06 (d, 6" -H 3 ), 3.25 (s, 3 "-OCH 3 ), 2.38 (m,
4 "-OCOC H 2 CH 2 CH 3 ), 1.68 (tq, 4" -OCOCH 2 C H 2 CH 3 ), 0.95
(t, 4 "-OCOCH 2 CH 2 C H 3 )
【0046】実施例10化合物(11L)(式(VIII)において、R3がノルマル
プロピル基で表され、R4が1-エトキシエチル基で表さ
れ、R5がアセチル基で表される化合物のうち化合物(1
0L)より誘導される異性体)の製造法 化合物(10L) 18 mgをエタノール 0.40 mlに溶解し
た後、ラネーニッケル0.50 mlを実施例4と同様の方法
で活性をコントロールし、 0.50 mlのエタノールと共に
上記溶液に加えた。これを室温で40分間激しく撹拌し
た後、不溶物を濾過し、1%(v/v)の濃アンモニア水を含
むエタノール各 2.0 mlで2回洗浄した。濾液と洗液を
合わせ、減圧濃縮して得られた残さ 16 mgを分離用TLC
(展開系:トルエン−アセトン(2:1))で精製し、化合物
(11L) 1.7 mgを得た。 化合物(11L)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C46H77NO16 (3) マススペクトル (SIMS) : m/z 900 (M+
H)+ (4) TLCにおけるRf値 : 0.10(クロロホルム:
メタノール(30:1)) (5) 比旋光度 : [α]D 20 -100°(c0.2, CH3O
H) (6) 融点 : 明瞭な融点を示さず、69〜72℃で熔
融 (7) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.83(dd, 2-H), 3.48(s, 4-OCH3), 1.85(m,
8-H), 5.28(dd, 9-H), 5.55(dd, 10-H), 6.22(dd,11-
H), 6.02(br dd, 12-H), 5.67(ddd, 13-H), 2.14(dt, 1
4-H), 5.24(ddq, 15-H), 2.98(br dd, 17-H), 9.78(br
s, 18-H), 0.99(d, 19-H3), 4.92(q, 3-OCH(OCH2CH3)CH
3), 3.49(dq, 3-OCH(OCH 2CH3)CH3), 3.60(dq, 3-OCH(OC
H 2CH3)CH3),1.16(t, 3-OCH(OCH2CH3 )CH3), 1.28(d, 3-O
CH(OCH2CH3)CH3 ), 2.04(s, 9-OCOCH3), 4.44(d, 1'-H),
2.54(s, 3'-N(CH3)2), 4.89(d, 1"-H), 1.63(dd, 2"-H
ax),2.27(d, 2"-Heq), 1.09(s, 3"-CH3), 4.70(d, 4"-
H), 1.06(d, 6"-H3), 3.26(s,3"-OCH3), 2.38(m, 4"-OC
OCH2 CH2CH3), 1.69(tq, 4"-OCOCH2CH2 CH3), 0.96(t,4"-
OCOCH2CH2CH3 )Example 10 Compound (11 L) (in the formula (VIII), R 3 is normal
It is represented by a propyl group, and R 4 is represented by a 1-ethoxyethyl group.
And R 5 is a compound (1
Method for producing isomer) derived from 0 L) 18 mg of compound (10 L) was dissolved in 0.40 ml of ethanol, and then 0.50 ml of Raney nickel was controlled for activity in the same manner as in Example 4, and 0.50 ml of ethanol was added together with the above. Added to the solution. This was vigorously stirred at room temperature for 40 minutes, the insoluble matter was filtered off, and washed twice with 2.0 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The filtrate and washings were combined and concentrated under reduced pressure to obtain 16 mg of the residue, which was separated by TLC for separation.
The product was purified with (developing system: toluene-acetone (2: 1)) to obtain 1.7 mg of the compound (11 L). Physicochemical properties of compound (11L) (1) Color and shape: colorless solid (2) Molecular formula: C 46 H 77 NO 16 (3) Mass spectrum (SIMS): m / z 900 (M +)
H) + (4) Rf value in TLC: 0.10 (chloroform:
Methanol (30: 1)) (5) Specific rotation: [α] D 20 -100 ° (c0.2, CH 3 O
H) (6) Melting point: Melting at 69 to 72 ° C without showing clear melting point (7) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.83 (dd, 2-H), 3.48 (s, 4-OCH 3 ), 1.85 (m,
8-H), 5.28 (dd, 9-H), 5.55 (dd, 10-H), 6.22 (dd, 11-
H), 6.02 (br dd, 12-H), 5.67 (ddd, 13-H), 2.14 (dt, 1
4-H), 5.24 (ddq, 15-H), 2.98 (br dd, 17-H), 9.78 (br
s, 18-H), 0.99 (d, 19-H 3 ), 4.92 (q, 3-OC H (OCH 2 CH 3 ) CH
3 ), 3.49 (dq, 3-OCH (OC H 2 CH 3 ) CH 3 ), 3.60 (dq, 3-OCH (OC
H 2 CH 3 ) CH 3 ), 1.16 (t, 3-OCH (OCH 2 C H 3 ) CH 3 ), 1.28 (d, 3-O
CH (OCH 2 CH 3 ) C H 3 ), 2.04 (s, 9-OCOCH 3 ), 4.44 (d, 1'-H),
2.54 (s, 3'-N (CH 3 ) 2 ), 4.89 (d, 1 "-H), 1.63 (dd, 2" -H
ax), 2.27 (d, 2 "-Heq), 1.09 (s, 3" -CH 3 ), 4.70 (d, 4 "-
H), 1.06 (d, 6 "-H 3 ), 3.26 (s, 3" -OCH 3 ), 2.38 (m, 4 "-OC
OC H 2 CH 2 CH 3 ), 1.69 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.96 (t, 4"-
OCOCH 2 CH 2 C H 3 )
【0047】実施例11化合物(12)(式(I)において、R1が水素原子で表
され、R2がアセチル基で表され、R3がノルマルプロピル
基で表される化合物)の製造法 化合物(11H) 4.0 mgを5%酢酸水溶液 3.0 mlとア
セトニトリル 1.0 mlの混合溶液に溶解した後、室温で
16時間反応させた。反応液を減圧濃縮して得られた残
さをクロロホルム 10 mlに溶解した後、飽和炭酸水素ナ
トリウム水溶液 10 mlで3回および飽和塩化ナトリウム
水溶液 10 mlで順次洗浄した。クロロホルム層を無水硫
酸ナトリウムで乾燥後これを濾過し、濾液を減圧濃縮し
て得られた残さ 4.5 mgを分離用TLC(展開系:クロロホ
ルム−メタノール(10:1))で精製し、化合物(12)
3.0 mgを得た。 化合物(12)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C42H69NO15 (3) マススペクトル (EIMS) : m/z 828 (M+H)+ (4) 比旋光度 : [α]D 17 -75°(c0.6, CH3OH) (5) 融点 : 明瞭な融点を示さず、102〜105℃で
熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.22(br d, 2-H), 2.71(dd, 2-H), 3.79(br
d, 3-H), 3.09(br d, 4-H), 3.54(s, 4-OCH3), 4.14(br
d, 5-H), 1.62(br dt, 7-H), 1.99(m, 8-H), 5.17(dd,
9-H), 5.60(dd, 10-H), 6.40(dd, 11-H), 6.03(br dd,
12-H), 5.65(ddd, 13-H), 2.12(dt, 14-H), 2.50(br d
t, 14-H), 5.29(ddq, 15-H), 1.30(d, 16-H3), 2.46(br
dd, 17-H),2.82(br dd, 17-H), 9.80(s, 18-H), 0.98
(d, 19-H3), 2.00(s, 9-OCOCH3), 4.57(d, 1'-H), 3.20
(dd, 2'-H), 2.42(t, 3'-H), 3.45(t, 4'-H), 3.27(dq,
5'-H), 1.20(d, 6'-H3), 2.57(s, 3'-N(CH3)2), 4.93
(d, 1"-H), 1.67(dd, 2"-Hax),2.30(d, 2"-Heq), 1.10
(s, 3"-CH3), 4.72(d, 4"-H), 4.54(dq, 5"-H), 1.08
(d, 6"-H3), 3.26(s, 3"-OCH3), 2.39(m, 4"-OCOCH2 CH2
CH3), 1.68(tq, 4"-OCOCH2CH2 CH3), 0.96(t, 4"-OCOCH2
CH2CH3 )Example 11 Compound (12) (in formula (I), R 1 represents a hydrogen atom)
R 2 is represented by an acetyl group and R 3 is normal propyl
It was dissolved preparation compounds of represented by group compound) to (11H) 4.0 mg in a mixed solution of 5% acetic acid aqueous solution 3.0 ml and acetonitrile 1.0 ml, was reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 10 ml of chloroform, and then the mixture was washed 3 times with 10 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 10 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4.5 mg of the residue, which was purified by preparative TLC (developing system: chloroform-methanol (10: 1)) to give the compound (12 )
3.0 mg was obtained. Physicochemical properties of compound (12) (1) Color and shape: colorless solid (2) Molecular formula: C 42 H 69 NO 15 (3) Mass spectrum (EIMS): m / z 828 (M + H) + (4) Specific rotation: [α] D 17 -75 ° (c0.6, CH 3 OH) (5) Melting point: Melting at 102-105 ° C without showing a clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.22 (br d, 2-H), 2.71 (dd, 2-H), 3.79 (br
d, 3-H), 3.09 (br d, 4-H), 3.54 (s, 4-OCH 3 ), 4.14 (br
d, 5-H), 1.62 (br dt, 7-H), 1.99 (m, 8-H), 5.17 (dd,
9-H), 5.60 (dd, 10-H), 6.40 (dd, 11-H), 6.03 (br dd,
12-H), 5.65 (ddd, 13-H), 2.12 (dt, 14-H), 2.50 (br d
t, 14-H), 5.29 (ddq, 15-H), 1.30 (d, 16-H 3 ), 2.46 (br
dd, 17-H), 2.82 (br dd, 17-H), 9.80 (s, 18-H), 0.98
(d, 19-H 3 ), 2.00 (s, 9-OCOCH 3 ), 4.57 (d, 1'-H), 3.20
(dd, 2'-H), 2.42 (t, 3'-H), 3.45 (t, 4'-H), 3.27 (dq,
5'-H), 1.20 (d , 6'-H 3), 2.57 (s, 3'-N (CH 3) 2), 4.93
(d, 1 "-H), 1.67 (dd, 2" -Hax), 2.30 (d, 2 "-Heq), 1.10
(s, 3 "-CH 3 ), 4.72 (d, 4" -H), 4.54 (dq, 5 "-H), 1.08
(d, 6 "-H 3 ), 3.26 (s, 3" -OCH 3 ), 2.39 (m, 4 "-OCOC H 2 CH 2
CH 3 ), 1.68 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.96 (t, 4" -OCOCH 2
CH 2 C H 3 )
【0048】実施例12化合物(12)(式(I)において、R1が水素原子で表
され、R2がアセチル基で表され、R3がノルマルプロピル
基で表される化合物)の製造法 化合物(11L) 1.6 mgを5%酢酸水溶液 1.2 mlとア
セトニトリル 0.30 mlの混合溶液に溶解した後、室温で
16時間反応させた。反応液を減圧濃縮して得られた残
さをクロロホルム 5.0 mlに溶解した後、飽和炭酸水素
ナトリウム水溶液 5.0 mlで3回および飽和塩化ナトリ
ウム水溶液 5.0 mlで順次洗浄した。クロロホルム層を
無水硫酸ナトリウムで乾燥後これを濾過し、濾液を減圧
濃縮して化合物(12) 1.2mgを得た。Example 12 Compound (12) (in the formula (I), R 1 represents a hydrogen atom.
R 2 is represented by an acetyl group and R 3 is normal propyl
Method for producing compound represented by group ) 1.6 mg of the compound (11 L) was dissolved in a mixed solution of 1.2 ml of 5% acetic acid aqueous solution and 0.30 ml of acetonitrile, and then reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue obtained was dissolved in 5.0 ml of chloroform, and the mixture was washed 3 times with 5.0 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 5.0 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.2 mg of compound (12).
【0049】実施例13化合物(13)(式(I)において、R1が水素原子で表
され、R2がプロピオニル基で表され、R3がノルマルプロ
ピル基で表される化合物)の製造法 化合物(6) 10 mgに無水トルエン 0.50 mlを加えて溶
解し、無水ピリジン 4.4μl及び塩化プロピオニル 4.8
μlを順次加えた後、室温で20分間撹拌した。反応混
合物に酢酸エチル 10 ml及びトリエチルアミン 4.1μl
を加え抽出し、酢酸エチル層を水 10 mlで2回洗浄した
後、無水硫酸ナトリウムで乾燥後これを濾過した。濾液
を減圧濃縮して得られた残さ 10 mgを分離用TLC(展開
系:クロロホルム−メタノール−28%アンモニア水溶液
(10:1:0.1))で精製し、化合物(13) 4.0 mgを得
た。 化合物(13)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C43H71NO15 (3) マススペクトル (FDMS) : m/z 841 (M)+ (4) 比旋光度 : [α]D 19 -73°(c0.3, CH3O
H) (5) 融点 : 明瞭な融点を示さず、99〜103℃で
熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.22(br d, 2-H), 2.70(dd, 2-H), 3.79(br
d, 3-H), 3.09(br d, 4-H), 3.54(s, 4-OCH3), 4.14(br
d, 5-H), 1.62(br dt, 7-H), 2.00(m, 8-H), 5.18(dd,
9-H), 5.61(dd, 10-H), 6.40(dd, 11-H), 6.03(br dd,
12-H), 5.65(ddd, 13-H), 2.12(dt, 14-H), 2.51(br d
t, 14-H), 5.29(ddq, 15-H), 1.30(d, 16-H3), 2.47(br
dd, 17-H),2.82(br dd, 17-H), 9.80(s, 18-H), 0.98
(d, 19-H3), 2.39(q, 9-OCOCH2 CH3),1.09(t, 9-OCOCH2C
H3 ), 4.57(d, 1'-H), 3.21(dd, 2'-H), 3.45(t, 4'-H),
3.28(dq, 5'-H), 1.20(d, 6'-H3), 2.57(s, 3'-N(CH3)
2), 4.93(d, 1"-H), 1.67(dd, 2"-Hax), 2.28(d, 2"-He
q), 1.09(s, 3"-CH3), 4.72(d, 4"-H), 4.54(dq, 5"-
H), 1.07(d, 6"-H3), 3.26(s, 3"-OCH3), 2.39(m, 4"-O
COCH2 CH2CH3), 1.69(tq,4"-OCOCH2CH2 CH3), 0.96(t, 4"
-OCOCH2CH2CH3 )Example 13 Compound (13) (in the formula (I), R 1 represents a hydrogen atom.
R 2 is represented by a propionyl group and R 3 is a normal propionyl group.
Method for producing compound represented by pill group) 0.50 ml of anhydrous toluene was added to 10 mg of compound (6) and dissolved, 4.4 μl of anhydrous pyridine and propionyl chloride 4.8
After sequentially adding μl, the mixture was stirred at room temperature for 20 minutes. 10 ml of ethyl acetate and 4.1 μl of triethylamine were added to the reaction mixture.
After extraction with ethyl acetate, the ethyl acetate layer was washed twice with 10 ml of water, dried over anhydrous sodium sulfate, and filtered. 10 mg of the residue obtained by concentrating the filtrate under reduced pressure was used for separation TLC (developing system: chloroform-methanol-28% aqueous ammonia solution).
(10: 1: 0.1)) to obtain 4.0 mg of compound (13). Physicochemical properties of compound (13) (1) Color and shape: Colorless solid (2) Molecular formula: C 43 H 71 NO 15 (3) Mass spectrum (FDMS): m / z 841 (M) + (4) Specific rotation Degree: [α] D 19 -73 ° (c0.3, CH 3 O
H) (5) Melting point: Melting at 99 to 103 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.22 (br d, 2-H), 2.70 (dd, 2-H), 3.79 (br
d, 3-H), 3.09 (br d, 4-H), 3.54 (s, 4-OCH 3 ), 4.14 (br
d, 5-H), 1.62 (br dt, 7-H), 2.00 (m, 8-H), 5.18 (dd,
9-H), 5.61 (dd, 10-H), 6.40 (dd, 11-H), 6.03 (br dd,
12-H), 5.65 (ddd, 13-H), 2.12 (dt, 14-H), 2.51 (br d
t, 14-H), 5.29 (ddq, 15-H), 1.30 (d, 16-H 3 ), 2.47 (br
dd, 17-H), 2.82 (br dd, 17-H), 9.80 (s, 18-H), 0.98
(d, 19-H 3 ), 2.39 (q, 9-OCOC H 2 CH 3 ), 1.09 (t, 9-OCOCH 2 C
H 3 ), 4.57 (d, 1'-H), 3.21 (dd, 2'-H), 3.45 (t, 4'-H),
3.28 (dq, 5'-H) , 1.20 (d, 6'-H 3), 2.57 (s, 3'-N (CH 3)
2 ), 4.93 (d, 1 "-H), 1.67 (dd, 2" -Hax), 2.28 (d, 2 "-He
q), 1.09 (s, 3 "-CH 3 ), 4.72 (d, 4" -H), 4.54 (dq, 5 "-
H), 1.07 (d, 6 "-H 3 ), 3.26 (s, 3" -OCH 3 ), 2.39 (m, 4 "-O
COC H 2 CH 2 CH 3 ), 1.69 (tq, 4 "-OCOCH 2 C H 2 CH 3 ), 0.96 (t, 4"
-OCOCH 2 CH 2 C H 3 )
【0050】[0050]
【発明の効果】第一の本発明の効果とするところは、最
強の抗菌活性を有する新規16員環マクロリド誘導体の
造出にある。即ち本発明で得られる一般式(I)で表さ
れる化合物のうちのある種の誘導体は、臨床上重要なグ
ラム陽性菌等に対して、極めて優れた抗菌活性を有して
いる。具体的に、一般式(I)で表される化合物のうち
3位及び9位が遊離の水酸基であり、4"位の水酸基がノ
ルマルブチリル化された化合物(6)(式(I)におい
てR1が水素原子であり、R2が水素原子であり、R3がノル
マルプロピル基である化合物)、ロキタマイシン(RK
M)(ジャーナル・オブ・アンチビオチックス, 34(8),
1001(1981))及びクラリスロマイシン(CAM)の同時測
定による抗菌力を表1に示す。ロイコマイシンA5より
化学誘導した化合物(6)は、市販されている16員環
マクロリド抗生物質の中で最も優れた抗菌力を有するRK
Mと比較して、顕著に優れたin vitroの抗菌活性を有し
ている。さらに本化合物は、先に本発明者らがロイコマ
イシン類誘導体において最も抗菌活性の優れた化合物の
一つであるとして特許出願(特願平5ー169418)した3"-O
-メチルロイコマイシンA7(式(I)においてR1が水素
原子であり、R2が水素原子であり、R3がエチル基である
化合物)と比較しても全般に抗菌活性が改善されてお
り、その極だつ抗菌力は、現在ニューマクロリド抗生物
質の中でも最も優れた抗菌活性を有するCAMに完全に匹
敵した。CAMと同等の抗菌活性を有する16員環マクロ
リド誘導体は、世界中でも殆ど知られていない。The first effect of the present invention is to create a novel 16-membered ring macrolide derivative having the strongest antibacterial activity. That is, certain derivatives of the compounds represented by the general formula (I) obtained in the present invention have extremely excellent antibacterial activity against clinically important Gram-positive bacteria and the like. Specifically, in the compound represented by the general formula (I), the 3- and 9-positions are free hydroxyl groups, and the 4 "-position hydroxyl group is compound (6) (in the formula (I)) R 1 is a hydrogen atom, R 2 is a hydrogen atom, and R 3 is a normal propyl group), rokitamycin (RK
M) (Journal of Antibiotics, 34 (8),
1001 (1981)) and antibacterial activity by simultaneous measurement of clarithromycin (CAM) are shown in Table 1. Compound (6), which is chemically derived from leucomycin A 5, has the best antibacterial activity among the commercially available 16-membered macrolide antibiotics RK.
It has remarkably excellent in vitro antibacterial activity as compared with M. Furthermore, this compound was previously filed by the present inventors as one of the compounds having the most excellent antibacterial activity among the leucomycin derivatives, and the patent application (Japanese Patent Application No. 5-169418) 3 "-O
The antibacterial activity was generally improved even when compared with -methylleucomycin A 7 (a compound in which R 1 is a hydrogen atom, R 2 is a hydrogen atom and R 3 is an ethyl group in the formula (I)). However, its extreme antibacterial activity was completely comparable to that of CAM, which currently has the best antibacterial activity among new macrolide antibiotics. A 16-membered ring macrolide derivative having an antibacterial activity equivalent to that of CAM is hardly known in the world.
【0051】一方化合物(6)のラクトン環9位の水酸
基がアセチル化されている化合物(12)及び同プロピ
オニル化されている化合物(13)の抗菌活性は、化合
物(6)と比較してわずかに或いは若干劣るものの、そ
れ自体優れた抗菌力を有していた。On the other hand, the antibacterial activity of the compound (12) in which the hydroxyl group at the 9-position of the lactone ring of the compound (6) is acetylated and the compound (13) in which the propionylation thereof is smaller than that of the compound (6). Although it was slightly inferior, it had excellent antibacterial activity.
【0052】[0052]
【表1】 [Table 1]
【0053】第二の本発明の効果とするところは、ラク
トン環の3位が遊離の水酸基である本発明化合物、即ち
一般式(I)で表される化合物のうちR1が水素原子であ
る化合物又はそれに準じる化合物を、一般式(II)で表
される天然に存在する公知の16員環マクロリド抗生物
質を出発原料として、3"-メチルチオメチルエーテル合
成中間体を経由することにより、グリコシル化反応並び
に3, 18ーヘミアセタール-18-O-シリル合成中間体を用い
ることなく、6工程ないしはそれ以下の工程数で調製す
る新規製造法を提供する事にある。本発明製造法を用い
ることにより、ラクトン環の3位が遊離の水酸基であり
中性糖部分である3"位の水酸基がメチル化された16員
環マクロリド誘導体を、純合成化学的手法により初めて
調製することが可能となった。The second effect of the present invention is that the compound of the present invention in which the 3-position of the lactone ring is a free hydroxyl group, that is, in the compound represented by the general formula (I), R 1 is a hydrogen atom. Glycosylation of a compound or a compound equivalent thereto by using a naturally occurring known 16-membered macrolide antibiotic represented by the general formula (II) as a starting material and passing through a 3 "-methylthiomethyl ether synthetic intermediate It is intended to provide a novel production method which can be prepared by 6 steps or less steps without using a reaction and a 3, 18-hemiacetal-18-O-silyl synthetic intermediate. A 16-membered macrolide derivative in which the 3-position hydroxyl group of the lactone ring, which is a free hydroxyl group and the neutral sugar moiety is methylated, can be prepared for the first time by a pure synthetic chemical method. It was
【0054】第三の本発明の効果とするところは、スピ
ラマイシン類を除くラクトン環の9位がsp3炭素である
ロイコマイシン類の誘導体研究におけるラクトン環3位
の水酸基の効率的な保護基を提供することにある。天然
より得られる化合物を出発原料として化学反応により優
れた誘導体を製造する際には、一般に特定の官能基、例
えばアミノ基或いは水酸基等を保護する必要のある場合
が少なくない。16員環マクロリド化合物の合成化学的
誘導体研究において、ラクトン環の3位水酸基の保護基
として不斉炭素を有するアセタール系の置換基を応用し
た例はタイロシン類、スピラマイシン類に限られてい
た。なぜなら、当該保護基を酸触媒存在下ラクトン環3
位の水酸基へ導入する時に、ラクトン環の9位が遊離の
水酸基である化合物ではアリル位の水酸基(9位)の存
在により分子の異性化が誘起してしまうため、それらの
保護基としての応用性が制限されていたからである。本
発明者らは不斉炭素を有するアセタール系の保護基、特
に1-エトキシエチル基が、ラクトン環の9位が遊離の水
酸基である16員環マクロリド化合物におけるラクトン
環3位の水酸基に対し保護基としての特性を充分に備え
ていることを実証した。The third effect of the present invention is to provide an efficient protecting group for the hydroxyl group at the 3-position of the lactone ring in the study of derivatives of leucomycins in which the 9-position of the lactone ring excluding spiramycin is sp 3 carbon. To provide. When producing an excellent derivative by a chemical reaction using a compound obtained from nature as a starting material, it is often necessary to protect a specific functional group such as an amino group or a hydroxyl group. In the study of synthetic chemical derivatives of 16-membered macrolide compounds, the examples in which an acetal substituent having an asymmetric carbon atom was applied as a protective group for the 3-position hydroxyl group of the lactone ring were limited to tylosins and spiramycins. The reason is that the protecting group is attached to the lactone ring 3 in the presence of an acid catalyst.
When a compound having a free hydroxyl group at the 9-position of the lactone ring is introduced into the hydroxyl group at the 2-position, isomerization of the molecule is induced by the presence of the hydroxyl group at the allylic position (9-position). This is because the sex was limited. The present inventors protected an acetal-based protecting group having an asymmetric carbon, especially a 1-ethoxyethyl group, against a hydroxyl group at the 3-position of the lactone ring in a 16-membered macrolide compound in which the 9-position of the lactone ring was a free hydroxyl group. It has been proved that it has sufficient characteristics as a base.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 原 修 神奈川県横浜市港北区師岡町760番地 明 治製菓株式会社薬品総合研究所内 (72)発明者 柴原 聖至 神奈川県横浜市港北区師岡町760番地 明 治製菓株式会社薬品総合研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Osamu Hara 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Seiji Shibahara 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Address Meiji Seika Co., Ltd. Pharmaceutical Research Institute
Claims (8)
する置換基であり、R2は水素原子又は水酸基を修飾(或
いは保護)する置換基であり、R3は炭素数1〜4の直鎖
又は分枝鎖のアルキル基]で表される化合物、又はその
薬学的に許容し得る塩。1. The following formula (I): [In the formula, R 1 modifies (or protects) a hydrogen atom or a hydroxyl group.
A substituent represented by R 2 , R 2 is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, and R 3 is a compound represented by a linear or branched alkyl group having 1 to 4 carbon atoms, Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がノルマルプ
ロピル基で表される化合物、又はその薬学的に許容し得
る塩。2. A compound represented by the formula (I) according to claim 1, wherein R 1 is a hydrogen atom, R 2 is a hydrogen atom and R 3 is a normal propyl group, or a pharmaceutically acceptable compound thereof. Acceptable salt.
原子で表され、R2がアセチル基で表され、R3がノルマル
プロピル基で表される化合物、又はその薬学的に許容し
得る塩。3. A compound represented by the formula (I) according to claim 1, wherein R 1 is a hydrogen atom, R 2 is an acetyl group, and R 3 is a normal propyl group, or a pharmaceutically acceptable compound thereof. Acceptable salt.
原子で表され、R2がプロピオニル基で表され、R3がノル
マルプロピル基で表される化合物、又はその薬学的に許
容し得る塩。4. A compound represented by formula (I) according to claim 1, wherein R 1 is a hydrogen atom, R 2 is a propionyl group and R 3 is a normal propyl group, or a pharmaceutically acceptable compound thereof. Acceptable salt.
トキシエチル基で表され、R2がアセチル基で表され、R3
がノルマルプロピル基で表される化合物のうちTLCにお
いてより低極性の物質、又はその薬学的に許容し得る
塩。5. In the formula (I) of claim 1, R 1 is a 1-ethoxyethyl group, R 2 is an acetyl group, and R 3 is
Of the compounds represented by normal propyl group, a less polar substance in TLC, or a pharmaceutically acceptable salt thereof.
トキシエチル基で表され、R2がアセチル基で表され、R3
がノルマルプロピル基で表される化合物のうちTLCにお
いてより高極性の物質、又はその薬学的に許容し得る
塩。6. In the formula (I) of claim 1, R 1 is represented by a 1-ethoxyethyl group, R 2 is represented by an acetyl group, and R 3
A compound having a higher polarity in TLC among compounds represented by normal propyl group, or a pharmaceutically acceptable salt thereof.
基]で表される天然に存在する16員環マクロリド抗生
物質、又はその塩を出発原料として用いて、次の式(II
I) 【化3】 [式中、R3は炭素数1〜4の直鎖又は分枝鎖のアルキル
基であり、R4は水酸基を修飾(或いは保護)する置換基
であり、R5は水酸基を修飾(或いは保護)する置換基で
あり、R6は水素原子又は水酸基を保護する置換基]で表
される化合物、又はその塩を経由し、次の式(I) 【化4】 [式中、R1は水素原子又は水酸基を修飾(或いは保護)
する置換基であり、R2は水素原子又は水酸基を修飾(或
いは保護)する置換基であり、R3は炭素数1〜4の直鎖
又は分枝鎖のアルキル基]で表される化合物、又はその
塩を得るための新規効率的製造法。7. The following formula (II): [Wherein R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms], which is a naturally-occurring 16-membered macrolide antibiotic, or a salt thereof, as a starting material. Formula (II
I) [Chemical 3] [In the formula, R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, R 4 is a substituent that modifies (or protects) the hydroxyl group, and R 5 modifies (or protects) the hydroxyl group. And a substituent represented by the formula (I), wherein R 6 is a substituent which protects a hydrogen atom or a hydroxyl group, or a salt thereof. [In the formula, R 1 modifies (or protects) a hydrogen atom or a hydroxyl group.
A substituent represented by R 2 , R 2 is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, and R 3 is a compound represented by a linear or branched alkyl group having 1 to 4 carbon atoms, Or a new efficient production method for obtaining a salt thereof.
において、ラクトン環の9位水酸基にD-フォロサミンが
β-グリコシド結合している化合物、即ちスピラマイシ
ン類以外のロイコマイシン類誘導体(タイロシン類は除
く)のラクトン環の3位水酸基の保護基として、不斉炭
素を有するアセタール系置換基、例えば1-エトキシエチ
ル基、テトラヒドロフラニル基或いはテトラヒドロピラ
ニル基等を用いる方法。8. A compound having a β-glycosidic bond of D-folosamine to the 9-position hydroxyl group of the lactone ring in the chemical synthesis of a 16-membered macrolide derivative, that is, a leucomycin derivative other than spiramycin (tylosin (Excluding) a protecting group for the 3-hydroxyl group of the lactone ring, which is an acetal-based substituent having an asymmetric carbon atom, such as a 1-ethoxyethyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6105096A JPH07309889A (en) | 1994-05-19 | 1994-05-19 | New 16-membered cyclic macrolide derivative and its new production |
CA002127578A CA2127578A1 (en) | 1993-07-08 | 1994-07-07 | 16-membered macrolide derivatives and process for producing the same |
EP94110679A EP0633266B1 (en) | 1993-07-08 | 1994-07-08 | 16-Membered macrolide derivatives and process for producing the same |
AT94110679T ATE165604T1 (en) | 1993-07-08 | 1994-07-08 | 16-MEMBER MACROLIDE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
ES94110679T ES2115816T3 (en) | 1993-07-08 | 1994-07-08 | 16-LINK MACROLID DERIVATIVES AND THEIR PREPARATION PROCEDURE. |
CN94115983A CN1046534C (en) | 1993-07-08 | 1994-07-08 | 16-membered macrolide derivatives and process for producing the same |
US08/271,996 US5602106A (en) | 1993-07-08 | 1994-07-08 | 16-membered macrolide derivatives |
DE69409874T DE69409874T2 (en) | 1993-07-08 | 1994-07-08 | 16-link macrolide derivatives and process for their preparation |
KR1019940016581A KR100360568B1 (en) | 1993-07-08 | 1994-07-08 | 16-membered ring macrolide derivative and method for manufacturing the same |
CN98116380A CN1093134C (en) | 1993-07-08 | 1998-07-23 | 16-membered marcrolide derivatives and process for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6105096A JPH07309889A (en) | 1994-05-19 | 1994-05-19 | New 16-membered cyclic macrolide derivative and its new production |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH07309889A true JPH07309889A (en) | 1995-11-28 |
Family
ID=14398380
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6105096A Pending JPH07309889A (en) | 1993-07-08 | 1994-05-19 | New 16-membered cyclic macrolide derivative and its new production |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH07309889A (en) |
-
1994
- 1994-05-19 JP JP6105096A patent/JPH07309889A/en active Pending
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