JPH10251280A - Lipid compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtrain a novel lipid that is an inositol phosphate in which a saccharide hydroxyl group is substituted with 2-[2-(levulinoyloxy)-ethyl]benzoyl group and the hydroxyl group of the phosphoric acid is protected with fluorenylmethyl group and is useful as a medicine. SOLUTION: The saccharide hydroxyl group in an inositol phosphate as phosphatidylinositol polyphosphate is substituted with 2-[levulinoyloxy]ethyl]benzoyl (Lev) and the hydroxyl group of the phosphoric acid is protected with a fluorenylmethyl group to give novel lipid. This novel lipid is used for synthesis of an unsaturated phosphatidyl inositol polyphosphate which can be used as a medicine that can be dosed to human and animals, for example, agonist or antagonist. This compound is prepared by substituting the saccharide hydroxyl group of inositol with 2-[2-(levulinoyloxoy)-ethyl]benzoyl group and other sites are protected by protective phosphorylation with fluoromethyl N,N-diisoprolylphosphoroamidite.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【発明の属する技術分野】本発明は、脂質類化合物、特
にイノシトールリン脂質類、即ちホスファチジルイノシ
トールポリリン酸（ポリホスホイノシチド）類化合物の
新規な製造方法、および最終化合物に至る途中の新規な
中間化合物およびその製造方法に関するものである。The present invention relates to a novel process for producing lipid compounds, particularly inositol phospholipids, that is, phosphatidylinositol polyphosphate (polyphosphoinositide) compounds, and a novel intermediate on the way to the final compound. The present invention relates to a compound and a method for producing the compound.

【０００２】[0002]

【従来の技術】生体のイノシトールリン脂質代謝の主要
経路は、細胞膜の微量成分であるホスファチジルイノシ
トール−４，５−ビスホスフェート（ＰＩ−４，５−Ｐ
₂、ＰＩＰ₂）がホスホリパーゼＣ（ＰＬＣ）で分解を受
け、イノシトール−三リン酸（ＩＰ₃）とジアシルグリ
セロール（ＤＡＧ）が生成される行程であり、これらセ
カンドメッセンジャーは、それぞれ細胞内のＣａ²⁺濃度
の上昇、プロティンキナーゼＣ（ＰＫＣ）の活性化をひ
きおこし、ホルモン作用のみならず、細胞増殖・分化や
癌化の情報伝達において主要な役割を果たす。またＰＩ
Ｐ₂自身がα−アクチニンやビンキュリン、Ｈ１ヒスト
ンなどと結合して様々な生理作用を有することも明らか
にされてきた。2. Description of the Related Art The main pathway of inositol phospholipid metabolism in living organisms is phosphatidylinositol-4,5-bisphosphate (PI-4,5-P) which is a minor component of cell membrane.
₂ , PIP ₂ ) is degraded by phospholipase C (PLC) to produce inositol-triphosphate (IP ₃ ) and diacylglycerol (DAG). These second messengers are caused by intracellular Ca ^{2. +} Increases concentration and activates protein kinase C (PKC), and plays a major role not only in hormonal action but also in signaling of cell proliferation / differentiation and canceration. Also PI
P ₂ itself α- actinin or vinculin, have also been demonstrated to have binding to a variety of physiological actions and the like H1 histone.

【０００３】ポリホスホイノシチドの代謝では、ホスフ
ァチジルイノシトール（ＰＩ）からＰＩ−４−キナーゼ
によってホスファチジルイノシトール−４−モノホスフ
ェート（ＰＩ−４−Ｐ）が生成し、さらにＰＩＰキナー
ゼによってＰＩ−４，５−Ｐ₂（ＰＩＰ₂）が生成する行
程が主要経路であるが、最近、ＰＩからＰＩ−３キナー
ゼによりＰＩ−３−Ｐが、ＰＩ−４−ＰからＰＩ−３キ
ナーゼによりＰＩ−３，４−Ｐ₂が、そしてＰＩ−４，
５−Ｐ₂からＰＩ−３キナーゼによりＰＩ−３，４，５
−トリホスフェート（Ｐ₃）が生成する経路等が発見さ
れてきた。これらＰＩ−３−Ｐ、ＰＩ−３，４−Ｐ₂、
ＰＩ−３，４，５−Ｐ₃等のリン脂質の生理作用は明ら
かではないが、細胞増殖時や癌において増加していると
いう（蛋白質、核酸、酵素、３６（３）、２６３、１９
９１）。In the metabolism of polyphosphoinositides, phosphatidylinositol 4-monophosphate (PI-4-P) is produced from phosphatidylinositol (PI) by PI-4-kinase, and PI-4,5 is produced by PIP kinase. The main pathway is the process of -P ₂ (PIP ₂ ) generation, but recently PI-3-P by PI-3 kinase from PI, and PI-3,4 by PI-3 kinase from PI-4-P. -P ₂ is and PI-4,,
5-P ₂ PI-3,4,5 by the PI-3-kinase from
- triphosphate (P ₃₎ route or the like to produce have been discovered. These PI-3-P, PI-3,4-P ₂ ,
Although the physiological action of phospholipids, such as PI-3,4,5-P ₃ is not clear, that has increased during cell growth and cancer (protein, nucleic acid, enzyme, 36 (3), 263,19
91).

【０００４】ところが、これらリン脂質類化合物はごく
微量しか生体内にはなく、またこれらの化合物を生合成
するＰＩ−キナーゼ類、特にＰＩ−３キナーゼなどはcr
udeなものが微量しかなく、生合成させることも困難な
現状において、化学的にこれらリン脂質類を全合成し、
量的に確保しその機能を明らかにすることが強く要求さ
れている。[0004] However, only a very small amount of these phospholipid compounds are present in living organisms, and PI-kinases for biosynthesizing these compounds, especially PI-3 kinase, etc.
Under the current situation where there is only a trace amount of ude and biosynthesis is difficult, these phospholipids are totally synthesized chemically,
It is strongly required to secure the quantity and clarify its function.

【０００５】そこで本発明者らはイノシトールを出発原
料として、イノシトールリン脂質類化合物を全合成する
ことを企て、鋭意研究を進め、その結果特開平５−２７
１２５６特許出願を出願した。ついで研究を進め、本発
明の下記の合成中間体3から1位をリン酸化後3,4,5位を
リン酸エステルとするPIP₃の合成法につき報文を報告し
た（Synthesis of 1D distearoyl phosphatidyl-myo-in
ositol 3,4,5-tris(dihydrogen phosphate), Yutaka Wa
tanabe, Masaya Tomioka and Shoichiro Ozaki, Tetrah
edron,51(33), 8969-8976(1995)）。The inventors of the present invention have sought to synthesize inositol phospholipid compounds entirely using inositol as a starting material, and have conducted intensive studies.
A 1256 patent application has been filed. Subsequently, the research was advanced, and a report was made on a method for synthesizing PIP ₃ from the following synthetic intermediate 3 of the present invention, in which the first position is phosphorylated and the _third , fourth and fifth positions are phosphate esters (Synthesis of 1D distearoyl phosphatidyl) -myo-in
ositol 3,4,5-tris (dihydrogen phosphate), Yutaka Wa
tanabe, Masaya Tomioka and Shoichiro Ozaki, Tetrah
edron, 51 (33), 8969-8976 (1995)).

【０００６】[0006]

【発明が解決しようとする課題】本発明者らのこれら研
究において、所望の低級、高級の飽和型の脂肪酸からな
るリン脂質類化合物は合成しうることが明らかとなった
が、不飽和型のリン脂質類化合物の合成は、イノシトー
ルの糖水酸基やリン酸残基の保護基を種々組み合わせて
遂行しようとしても困難で、目的とする化合物を取得す
るには至らなかった。In these studies of the present inventors, it has been found that phospholipid compounds composed of desired lower and higher saturated fatty acids can be synthesized. It has been difficult to synthesize phospholipid compounds using various combinations of protecting groups for sugar hydroxyl groups and phosphate residues of inositol, and it has not been possible to obtain the desired compounds.

【０００７】[0007]

【課題を解決するための手段】そこで、本発明者らは鋭
意研究を続け、不飽和脂肪酸を有するホスファチジルイ
ノシトールの合成に有用なリン酸残基の保護基をかたっ
ぱしから広く検討し、９−フルオレニルメチル基を利用
することに思いあたった。そしてこのフルオレニルメチ
ル基をリン酸残基の保護基として採用することにより、
所望の不飽和型イノシトールリン脂質類化合物の合成に
成功し、本発明を完成した。The inventors of the present invention have conducted intensive studies and have conducted extensive studies on protecting groups for phosphate residues useful for the synthesis of phosphatidylinositol having an unsaturated fatty acid. I came up with the idea of using an oleenylmethyl group. And by adopting this fluorenylmethyl group as a protecting group for a phosphate residue,
The synthesis of the desired unsaturated inositol phospholipid compound was successful, and the present invention was completed.

【０００８】[0008]

【発明の実施の形態】本発明によれば、イノシトールを
出発原料として３、６位を proximately assisted clea
vable ２−［２−（レブリノイルオキシ）エチル］ベン
ゾイル（ＰＡＣ_Lev）基で保護し、４、５位水酸基をテ
トラゾール存在下Difluorenylmethy N,N-disopropylpho
sphoramiditeによりリン酸化し、１、２−ジオールに導
き、ついでこの１位水酸基をホスファイトとピリジニウ
ムトリブロミド（ＰｙＨＢｒ₃）による位置選択的リン
酸化により１−リン酸エステル２８を得た。ＮａＩによ
り１位リン酸保護基の除去後、塩基を作用させ４、５位
リン酸保護基を除去し、引き続きヒドラジンを作用させ
ることにより３、６位ＰＡＣレブリニル基を除去する。
生成するヒドロキシエチル体を、ピリジン溶媒中、加熱
処理することによりグリセロエステル部を損なうことな
くＰＡＣ基の除去ができ、目的の不飽和脂肪酸を有する
リン脂質の合成に到達した。DETAILED DESCRIPTION OF THE INVENTION According to the present invention, starting from inositol, positions 3 and 6 are proximately assisted clea
vable Protected with 2- [2- (levulinoyloxy) ethyl] benzoyl (PAC _Lev ) group and hydroxyl groups at the 4- and 5-positions in the presence of tetrazole Difluorenylmethy N, N-disopropylpho
Phosphorylation with sphoramidite led to 1,2-diol, and then the 1-hydroxyl group was regioselectively phosphorylated with phosphite and pyridinium tribromide (PyHBr ₃ ) to give 1-phosphate ester 28. After removing the 1-position phosphate protecting group with NaI, a base is actuated to remove the 4- and 5-position phosphate protecting groups, followed by hydrazine to remove the PAC levulinyl group at the 3- and 6-positions.
By subjecting the resulting hydroxyethyl compound to heat treatment in a pyridine solvent, the PAC group could be removed without damaging the glyceroester moiety, and the synthesis of the target phospholipid having unsaturated fatty acids was achieved.

【０００９】ホスファチジルイノシトール 3,4,5-三リ
ン酸（PIP₃）の合成を図１に従って行った。まず、光学
的に純粋な、あるいはラセミ体の１から４に誘導した。
このトリオールをアミダイト法によりリン酸ジ9-フルオ
レニルメチルエステル５に誘導した。ついで５を1,2-ジ
オールにし、順次トリエチルシリル化し、本発明ではこ
れまで殆ど実用的に使われたことのない9-フルオレニル
メチル基をリン酸保護基として利用することを検討し
た。その結果、これまでの既知法と異なり、不飽和脂肪
酸を有するホスファチジルイノシトール類の合成も可能
となった。グリセロール部の脂肪酸としては炭素数２の
酢酸から炭素数３０までの飽和、不飽和のカルボン酸類
が利用できる。たとえば、パルミチン酸、ステアリン
酸、オレイン酸、リノール酸、リノレン酸、アラキドン
酸などの天然の脂肪酸や、他の天然にはない脂肪酸など
である。The synthesis of phosphatidylinositol 3,4,5-triphosphate (PIP ₃ ) was carried out according to FIG. First, it was derived from optically pure or racemic 1-4.
This triol was converted into phosphoric acid di-9-fluorenyl methyl ester 5 by the amidite method. Then, 5 was converted to 1,2-diol and then sequentially triethylsilylated. In the present invention, the use of a 9-fluorenylmethyl group, which has hardly been practically used, as a phosphate protecting group was examined. As a result, unlike the known methods, phosphatidylinositols having unsaturated fatty acids can be synthesized. As the fatty acid in the glycerol part, saturated or unsaturated carboxylic acids having 2 carbon atoms up to 30 carbon atoms can be used. For example, natural fatty acids such as palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and other non-naturally occurring fatty acids.

【００１０】図２に示すメントキシ酢酸を用いても、化
合物15に誘導後、これをシリカゲルクロマトグラフィー
により光学分割できる。これから、化合物４に誘導し、
図１に従ってPIP₃ の合成ができる。一方、グリセリル
ホスファイトをピリジニウムトリブロミドの存在下18に
作用させ、１位をリン酸化後20a あるいは20b とし、脱
シリル化に続くリン酸化により10 あるいは22b を得
た。これより図１と同様の脱保護の工程を行い、PIP₃
の合成ができる。なお、20b の場合には、11 から12 へ
の工程は不要である。[0010] Even when menthoxyacetic acid shown in FIG. 2 is used, it can be optically resolved by silica gel chromatography after derivation to compound 15. From this, it is induced to compound 4,
PIP ₃ can be synthesized according to FIG. On the other hand, glyceryl phosphite was allowed to act on 18 in the presence of pyridinium tribromide, and phosphorylation at position 1 was changed to 20a or 20b, and phosphorylation following desilylation yielded 10 or 22b. The same deprotection step as FIG. 1 than this, PIP ₃
Can be synthesized. In the case of 20b, the steps from 11 to 12 are unnecessary.

【００１１】ホスファチジルイノシトール 4,5-二リン
酸（PIP₂）の合成法を図３に示す。ここでは、新しいリ
ン酸の保護基に加え、最近開発した水酸基の保護基（Pr
oximately Assisted and Chemoselectivity Cleavable
Protecting Groups for Alcohols, 2-[2-(Arylmethylox
y)ethylbenzoic Esters: Yutaka Watanabe, MasanoriIs
himaru, and Shoichiro Ozaki, Chem. Lett., 1994(1
1), 2163-2166)の類縁体であるPACLev 基（2-[2-(レブ
リノイルオキシ)エチル]ベンゾイル基）を活用した。こ
の基の導入に必要なカルボン酸38 の合成法は図５に示
すように、市販の34から４工程で、容易に得られた。こ
の保護基により、図４に示すように、酒石酸誘導体32を
アシル化剤とする速度論的分割（ラセミ体の一方の光学
異性体＝エナンチオマーとより早く反応し、一方の生成
物を優先して得る光学分割の方法）により化合物27の光
学活性体（98％ee）が効率良く得られた。化合物27
は、汎用される23にPAC基を導入後、ケタール交換、リ
ン酸化、及び加水分解により得られる。その後、リン酸
化により28を得、順次脱保護を行いPIP₂を得た。FIG. 3 shows a method for synthesizing phosphatidylinositol 4,5-diphosphate (PIP ₂ ). Here, in addition to the new phosphoric acid protecting group, the recently developed hydroxyl protecting group (Pr
oximately Assisted and Chemoselectivity Cleavable
Protecting Groups for Alcohols, 2- [2- (Arylmethylox
y) ethylbenzoic Esters: Yutaka Watanabe, MasanoriIs
himaru, and Shoichiro Ozaki, Chem. Lett., 1994 (1
A PACLev group (2- [2- (levulinoyloxy) ethyl] benzoyl group) which is an analog of 1), 2163-2166) was utilized. As shown in FIG. 5, the method for synthesizing the carboxylic acid 38 required for the introduction of this group was easily obtained in four steps from 34 commercially available. By this protecting group, as shown in FIG. 4, kinetic resolution using the tartaric acid derivative 32 as an acylating agent (one of the racemates reacts more quickly with the enantiomer and preferentially reacts with one of the products. The optically active form of compound 27 (98% ee) was efficiently obtained by the obtained optical resolution method). Compound 27
Can be obtained by introducing a PAC group into commonly used 23, followed by ketal exchange, phosphorylation, and hydrolysis. Then, to obtain a 28 by phosphorylation to give the PIP ₂ performs sequential deprotection.

【００１２】PIP₃ の場合と同じように、6に相当する27
から1位をシリル化後2位を保護してから1位をリン酸化
するルートでもPIP₂ が得られる。図１から４の中で、
化合物14,15,16,26,27,28,29,30,31は本発明で新規に合
成された化合物である。As in the case of PIP ₃ , 27 corresponding to 6
PIP ₂ can also be obtained by a route that silylates position 1 after, protects position 2 and then phosphorylates position 1. In Figures 1 to 4,
Compounds 14, 15, 16, 26, 27, 28, 29, 30, 31 are compounds newly synthesized in the present invention.

【００１３】[0013]

【実施例】以下詳細に実施例をもって本発明を説明する
が、本発明はこれらに限定されるものではない。EXAMPLES The present invention will be described in detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

【００１４】実施例１ ［化合物５の合成］窒素雰囲気下、1,2-O-Cyclohexylid
ene-6-O-levulinoyl-myo-inositol (4, 3.0 g, 8.4 mmo
l)をdry CHCl₃(80 ml)に溶解させ、0 ℃に冷やしておき
di-9-fluorenylmethyl N,N-Diisopropylphosphoroamidi
te (18.3 g, 35.1 mmol)、Tetrazole (2.5 g, 35.7 mmo
l)を加え、室温で2時間攪拌した。その後、-72℃に冷や
しmCPBA (6.5 g, 37.7 mmol)を加え、室温で1時間攪拌
した。10% Na₂SO₃を加え室温で1時間攪拌しAcOEtで抽出
した後に有機層を順次、sat.NaHCO₃、sat.NaCl で洗浄
しNa₂SO₄で乾燥させた。濾過、濃縮後、フラッシュカラ
ムクロマトグラフィー(AcOEt/CHCl₃=1/2)により1,2-O-C
yclohexylidene 3,4,5-tri-O-(bis-9-fluorenylmethyl
phosphoryl) 6-O-levulinoyl-myo- inositol (５, 12.
5 g, 90%)で得た。Example 1 [Synthesis of Compound 5] 1,2- O- Cyclohexylid in a nitrogen atmosphere
ene-6- O -levulinoyl- myo -inositol (4, 3.0 g, 8.4 mmo
l) in dry CHCl ₃ (80 ml) and cool to 0 ° C.
di-9-fluorenylmethyl N, N -Diisopropylphosphoroamidi
te (18.3 g, 35.1 mmol), Tetrazole (2.5 g, 35.7 mmo)
l) was added and the mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was cooled to -72 ° C, mCPBA (6.5 g, 37.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After adding 10% Na ₂ SO ₃ and stirring at room temperature for 1 hour and extracting with AcOEt, the organic layer was washed successively with sat. NaHCO ₃ and sat. NaCl and dried over Na ₂ SO ₄ . After filtration and concentration, by flash column chromatography _{(AcOEt / CHCl 3 = 1/} 2) 1,2- O -C
yclohexylidene 3,4,5-tri- O- (bis-9-fluorenylmethyl
phosphoryl) 6- O -levulinoyl- myo -inositol (5, 12.
5 g, 90%).

【００１５】¹H NMR (CDCl₃, 270 MHz) δ=1.20-1.73(1
0H, complex, Cyclohexylidene H),2.01(3H, s, -CH₃),
2.39-2.64(4H, complex, -OC(O)CH₂CH₂C(O)-), 3.94-
4.39(22H, complex, Ins-H₁, H₂, H₃, H₅, -OCH₂CH-*
6), 4.90(1H, q, J _4-3=J _4-5=J _{H -P}=7.6 Hz, Ins-H₄), 5.
26(1H, t, J _6-1=J _6-5=6.4 Hz, Ins-H₆), 7.01-7.67(48
H, complex, Aromatic H)³¹ P NMR(CDCl₃, 109 MHz) d=-0.98(1P), -0.55(1P), -
0.10(1P) ¹ H NMR (CDCl ₃ , 270 MHz) δ = 1.20-1.73 (1
0H, complex, Cyclohexylidene H), 2.01 (3H, s, -CH ₃ ),
2.39-2.64 (4H, complex, -OC (O) CH ₂ CH ₂ C (O)-), 3.94-
4.39 (22H, complex, Ins-H ₁ , H ₂ , H ₃ , H ₅ , -OCH ₂ CH- *
6), 4.90 (1H, q, J _4-3 = J _4-5 = J _{H -P} = 7.6 Hz, Ins-H ₄ ), 5.
26 (1H, t, J _6-1 = J _6-5 = 6.4 Hz, Ins-H ₆ ), 7.01-7.67 (48
H, complex, Aromatic H) ³¹ P NMR (CDCl ₃ , 109 MHz) d = -0.98 (1P), -0.55 (1P),-
0.10 (1P)

【００１６】実施例２ ［化合物6の合成］1,2-O-Cyclohexylidene 3,4,5-tri-O
-(bis-9-fluorenylmethyl phosphoryl) 6-O-levulinoyl
-myo-inositol (5, 12.5 mg, 7.5 mmol)をdry CHCl₃(12
0 ml)に溶解させ、-5℃に冷やしCH₃OH (1.27 g, 37.2 m
mol)、TFA (21.5 g, 292.1 mmol)を加え、-5〜0℃で8時
間攪拌した。これをAcOEtで抽出し、有機層を順次H₂O、
sat.NaHCO₃、sat.NaClで洗浄しNa₂SO₄で乾燥させた。濾
過、濃縮後、フラシュカラムクロマトグラフィー(AcOEt
/CHCl₃=4/1)により3,4,5-Tri-O-(bis-9-fluorenylmethy
l phosphoryl) 6-O-levulinoyl-myo-inositol (6, 10.3
g, 87%)を得た。Example 2 [Synthesis of Compound 6] 1,2- O- Cyclohexylidene 3,4,5-tri- O
-(bis-9-fluorenylmethyl phosphoryl) 6- O -levulinoyl
- myo -inositol (5, 12.5 mg , 7.5 mmol) and dry CHCl ₃ (12
0 ml), cooled to -5 ° C and cooled with CH ₃ OH (1.27 g, 37.2 m
mol) and TFA (21.5 g, 292.1 mmol) were added, and the mixture was stirred at -5 to 0 ° C for 8 hours. This was extracted with AcOEt, and the organic layer was sequentially extracted with H ₂ O,
Washed with sat.NaHCO ₃ , sat.NaCl and dried over Na ₂ SO ₄ . After filtration and concentration, flash column chromatography (AcOEt
/ CHCl ₃ = 4/1) to 3,4,5-Tri- O- (bis-9-fluorenylmethy
l phosphoryl) 6- O -levulinoyl- myo -inositol (6, 10.3
g, 87%).

【００１７】¹H NMR (CDCl₃, 270 MHz) δ=2.07(3H, s,
-CH₃), 2.13-2.73(4H, complex, -OC(O)CH₂CH₂C(O)-),
2.83(1H, br, -OH), 3.03(1H, br, -OH), 3.22(1H, b
r, Ins-H₁), 3.75(1H, ddd, J _3-2=2.7 Hz, J _3-4=7.0 H
z, J _H-P=6.4 Hz, Ins-H₃), 3.82(1H, br, Ins-H₂), 3.
83-4.36(19H, complex, Ins-H₅, -OCH₂CH-*6), 4.75(1
H, q, J _4-3=J _4-5=J _H-P=7.0 Hz, Ins-H₄), 5.24(1H, t,
J _6-1=J _6-5=9.8 Hz, Ins-H₆), 6.91-7.72(48H, complex,
Aromatic H)³¹ P NMR (CDCl₃, 109 MHz) δ=-1.75(1P), -0.66(1P),
-0.49(1P) ¹ H NMR (CDCl ₃ , 270 MHz) δ = 2.07 (3H, s,
-CH ₃ ), 2.13-2.73 (4H, complex, -OC (O) CH ₂ CH ₂ C (O)-),
2.83 (1H, br, -OH), 3.03 (1H, br, -OH), 3.22 (1H, b
r, Ins-H ₁ ), 3.75 (1H, ddd, J _3-2 = 2.7 Hz, J _3-4 = 7.0 H
z, J _HP = 6.4 Hz, Ins-H ₃ ), 3.82 (1H, br, Ins-H ₂ ), 3.
83-4.36 (19H, complex, Ins-H ₅ , -OCH ₂ CH- * 6), 4.75 (1
H, q, J _4-3 = J _4-5 = J _HP = 7.0 Hz, Ins-H ₄ ), 5.24 (1H, t,
J _6-1 = J _6-5 = 9.8 Hz, Ins-H ₆ ), 6.91-7.72 (48H, complex,
Aromatic H) ³¹ P NMR (CDCl ₃ , 109 MHz) δ = -1.75 (1P), -0.66 (1P),
-0.49 (1P)

【００１８】実施例３ ［化合物7の合成］窒素雰囲気下、Benzene共沸した3,4,
5-Tri-O-(bis-9-fluorenylmethyl phosphoryl)-6-O-lev
ulinoyl-myo-inositol (6, 9.8 g, 6.2 mmol)をdry CHC
l₃ (100 ml)に溶解させ-42℃に冷やし2,6-t-Butyl-4-me
thylpyridine (3.2 g, 15.6 mmol)、Triethylsilyl tri
fluoromethylsulfonate (2.45 g, 9.3 mmol)を加え-20
℃で2時間攪拌した。これにMethanolを加え室温で30分
攪拌し、この溶液をAcOEtで抽出し有機層を順次、H₂O、
sat.KHSO₄、H₂O、sat.NaHCO₃、sat.NaClで洗浄しNa₂SO₄
で乾燥させた。濾過、濃縮後、フラシュカラムクロマト
グラフイー(Acetone/CHCl₃=1/10→1/3)により1-O-Triet
hylsilyl 3,4,5-tri-O-(bis-9-fluorenylmethylphospho
ryl) 6-O-levulinoyl-myo-inositol (７、7.1 g, 68
%)、原料 (2.1 g, 22%)で得た。Example 3 [Synthesis of Compound 7] 3,4,
5-Tri- O- (bis-9-fluorenylmethyl phosphoryl) -6- O -lev
ulinoyl- myo -inositol (6, 9.8 g, 6.2 mmol) in dry CHC
Dissolve in l ₃ (100 ml) and cool to -42 ° C, 2,6- t- Butyl-4-me
thylpyridine (3.2 g, 15.6 mmol), Triethylsilyl tri
Add fluoromethylsulfonate (2.45 g, 9.3 mmol) and add -20
Stirred at C for 2 hours. Methanol was added to this, and the mixture was stirred at room temperature for 30 minutes. This solution was extracted with AcOEt, and the organic layer was successively extracted with H ₂ O,
Wash with sat.KHSO ₄ , H ₂ O, sat.NaHCO ₃ , sat.NaCl and Na ₂ SO ₄
And dried. After filtration and concentration, 1- O- Triet by flash column chromatography (Acetone / CHCl ₃ = 1/10 → 1/3)
hylsilyl 3,4,5-tri- O- (bis-9-fluorenylmethylphospho
ryl) 6- O -levulinoyl- myo -inositol (7, 7.1 g, 68
%) As a raw material (2.1 g, 22%).

【００１９】¹H NMR (CDCl₃, 270 MHz) δ=0.58(6H, q,
JCH₂CH₃=7.9 Hz, -Si(CH₂ CH₃)₃),0.91(9H, t, JCH₂CH₃
=7.9 Hz, -Si(CH ₂CH₃ )₃), 1.98(3H, s, Levulinyl-C
H₃),2.25-2.62(4H, complex, -OC(O)CH₂CH₂ C(O)-), 3.
60(1H, J _1-2=2.7 Hz, J _1-6=9.8 Hz, Ins-H₁), 3.87-4.3
8(21H, complex, Ins-H₂, H₃, H₅, -OCH₂CH-*6), 4.97
(1H, q, J _4-3=J _4-5=J _H-P=9.8 Hz, Ins-H₄), 5.38(1H,
t, J _6-1=J _6-5=9.8 Hz, Ins-H₆), 6.91-7.72(48H, compl
ex, Aromatic H)³¹ P NMR(CDCl₃, 109 MHz) δ=-1.71(1P), -1.29(1P), -
1.15(1P) ¹ H NMR (CDCl ₃ , 270 MHz) δ = 0.58 (6H, q,
J CH ₂ CH ₃ = 7.9 Hz, -Si ( CH ₂ CH ₃ ) ₃ ), 0.91 (9H, t, J CH ₂ CH ₃
= 7.9 Hz, -Si (CH ₂ CH ₃ ) ₃ ), 1.98 (3H, s, Levulinyl-C
H ₃ ), 2.25-2.62 (4H, complex, -OC (O) CH ₂ CH ₂ C (O)-), 3.
60 (1H, J _1-2 = 2.7 Hz, J _1-6 = 9.8 Hz, Ins-H ₁ ), 3.87-4.3
8 (21H, complex, Ins-H ₂ , H ₃ , H ₅ , -OCH ₂ CH- * 6), 4.97
(1H, q, J _4-3 = J _4-5 = J _HP = 9.8 Hz, Ins-H ₄ ), 5.38 (1H,
t, J _6-1 = J _6-5 = 9.8 Hz, Ins-H ₆ ), 6.91-7.72 (48H, compl
ex, Aromatic H) ³¹ P NMR (CDCl ₃ , 109 MHz) δ = -1.71 (1P), -1.29 (1P),-
1.15 (1P)

【００２０】実施例４ ［化合物8の合成］窒素雰囲気下、1-O-Triethylsilyl-
3,4,5-tri-O-(bis-9-fluorenylmethyl phosphoryl)-6-O
-levulinoyl-myo-inositol (7, 7.0 g, 4.1 mmol)をdry
CHCl₃ (70ml)に溶解させ0℃に冷やしピリジン (3.2 g,
4.95 mmol)、Chloroacetic anhydride (4.2 g, 24.6 m
mol)、DMAP (100.3 mg, 0.8 mmol)を加え室温で30分攪
拌した。この溶液をAcOEtで抽出し有機層を順次、H₂O、
sat.KHSO₄、H₂O、sat.NaHCO₃、sat.NaClで洗浄しMgSO₄
で乾燥させた。濾過、濃縮後、2-O-Chloroacetyl-1-O-t
riethylsilyl-3,4,5-tri-O-(bis-9-fluorenylmethyl ph
osphoryl)-6-O-levulinoyl-myo-inositol (8, 6.8 g, 9
3%)で得た。Example 4 [Synthesis of Compound 8] 1- O- Triethylsilyl-
3,4,5-tri- O- (bis-9-fluorenylmethyl phosphoryl) -6- O
-levulinoyl- myo -inositol (7, 7.0 g, 4.1 mmol) in dry
Dissolve in CHCl ₃ (70 ml), cool to 0 ° C, and add pyridine (3.2 g,
4.95 mmol), Chloroacetic anhydride (4.2 g, 24.6 m
mol) and DMAP (100.3 mg, 0.8 mmol), and the mixture was stirred at room temperature for 30 minutes. This solution was extracted with AcOEt, and the organic layer was sequentially extracted with H ₂ O,
Wash with sat.KHSO ₄ , H ₂ O, sat.NaHCO ₃ , sat.NaCl and MgSO ₄
And dried. After filtration and concentration, 2- O- Chloroacetyl-1- O- t
riethylsilyl-3,4,5-tri- O- (bis-9-fluorenylmethyl ph
osphoryl) -6- O -levulinoyl- myo -inositol (8, 6.8 g, 9
3%).

【００２１】¹H NMR (CDCl₃, 270 MHz) δ=0.62(6H, q,
JCH₂CH₃=8.2 Hz, -Si(CH₂ CH₃)₃),0.92(9H, t, JCH₂CH₃
=8.2 Hz, -Si(CH ₂CH₃ )₃), 2.20(3H, s, -CH₃), 2.60(2
H,t, J _CH2CH2=6.1 Hz, -OC(O)CH₂ CH₂C(O)-), 2.87(2H,
t, J _CH2CH2=6.1 Hz, -OC(O)CH ₂CH₂ C(O)-), 3.69(1H, d
d, J _1-2=2.3 Hz, J _1-6=9.8 Hz, Ins-H₁), 3.77-4.41(22
H, complex, Ins-H₃, H₅, -OCH₂CH-*6, -CH₂Cl), 4.76
(1H, q, J _4-3=J _4-5=J _{H -P}=9.8 Hz, Ins-H₄), 5.29(1H,
t, J _6-1=J _6-5=9.8 Hz, Ins-H₆), 5.74(1H, t, J _2-1=J
_2-3=2.3 Hz, Ins-H₂), 7.00-7.65(48H, complex, Aroma
tic H)³¹ P NMR(CDCl₃, 109 MHz) δ=-0.10(1P), -0.08(1P), -
0.03(1P) ¹ H NMR (CDCl ₃ , 270 MHz) δ = 0.62 (6H, q,
J CH ₂ CH ₃ = 8.2 Hz, -Si ( CH ₂ CH ₃ ) ₃ ), 0.92 (9H, t, J CH ₂ CH ₃
= 8.2 Hz, -Si (CH ₂ CH ₃ ) ₃ ), 2.20 (3H, s, -CH ₃ ), 2.60 (2
H, t, J _CH2CH2 = 6.1 Hz, -OC (O) CH ₂ CH ₂ C (O)-), 2.87 (2H,
t, J _CH2CH2 = 6.1 Hz, -OC (O) CH ₂ CH ₂ C (O)-), 3.69 (1H, d
d, J _1-2 = 2.3 Hz, J _1-6 = 9.8 Hz, Ins-H ₁ ), 3.77-4.41 (22
H, complex, Ins-H ₃ , H ₅ , -OCH ₂ CH- * 6, -CH ₂ Cl), 4.76
(1H, q, J _4-3 = J _4-5 = J _{H -P} = 9.8 Hz, Ins-H ₄ ), 5.29 (1H,
t, J _6-1 = J _6-5 = 9.8 Hz, Ins-H ₆ ), 5.74 (1H, t, J _2-1 = J
_2-3 = 2.3 Hz, Ins-H ₂ ), 7.00-7.65 (48H, complex, Aroma
tic H) ³¹ P NMR (CDCl ₃ , 109 MHz) δ = -0.10 (1P), -0.08 (1P),-
0.03 (1P)

【００２２】実施例５ ［化合物9の合成］2-O-Chloroacetyl-1-O-triethylsily
l-3,4,5-tri-O-(bis-9-fluorenylmethylphosphoryl)-6-
O-levulinoyl-myo-inositol (8, 5.3 g, 3.0 mmol)をdr
y CHCl₃(15 ml)に溶解させ0℃に冷やし80％ 酢酸(30 m
l)、TsOH・H₂O (2.9 g, 15.0 mmol)を加え室温で7時間
攪拌した。この溶液を再び0℃に冷やし、AcOEtで抽出し
有機層をH₂O、sat.NaHCO₃で、sat.NaClで洗浄しMgSO₄で
乾燥させた。濾過、濃縮後、フラシュカラムクロマトグ
ラフィ−(Acetone/CHCl₃=1/5)により2-O-Chloroacetyl-
3,4,5-tri-O-(bis-9-fluorenylmethyl phosphoryl)-6-O
-levulinoyl-myo-inositol (9, 4.3 g, 88%)で得た。Example 5 [Synthesis of Compound 9] 2- O- Chloroacetyl-1- O- triethylsily
l-3,4,5-tri- O- (bis-9-fluorenylmethylphosphoryl) -6-
O- levulinoyl- myo- inositol (8, 5.3 g, 3.0 mmol)
y Dissolve in CHCl ₃ (15 ml), cool to 0 ° C, and add 80% acetic acid (30 m
l), TsOH.H ₂ O (2.9 g, 15.0 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The solution was cooled again to 0 ° C., extracted with AcOEt, and the organic layer was washed with H ₂ O, sat. NaHCO ₃ , sat. NaCl, and dried over MgSO ₄ . After filtration and concentration, flash column chromatography (Acetone / CHCl ₃ = 1/5) gave 2- O- Chloroacetyl-
3,4,5-tri- O- (bis-9-fluorenylmethyl phosphoryl) -6- O
-levulinoyl- myo -inositol (9, 4.3 g, 88%).

【００２３】¹H NMR (CDCl₃, 270 MHz) δ=2.09(3H, s,
-CH₃), 2.18-2.78(4H, complex, -OC(O)CH₂CH₂C(O)-),
3.56(1H, J _1-2=2.4 Hz, J _1-6=9.8 Hz, Ins-H₁), 3.64
(1H,br, -OH, disappear after D₂O-treatment), 3.79-
4.41(22H, complex, Ins-H₃,H₅, -OCH₂CH-*6, -CH₂Cl),
4.75(1H, q, J _4-3=J _4-5=J _H-P=9.8 Hz, Ins-H₄), 5.28
(1H, t, J _6-1=J _6-5=9.8 Hz, Ins-H₆), 5.61(1H, t, J
_2-1=J _2-3=2.4 Hz, Ins-H₂), 6.99-7.72(48H, complex,
Aromatic H)¹³ C NMR (CDCl₃, 68 MHz) δ=28.07 (-OC(O)CH₂ CH₂C(O)
-), 29.62(-CH₃), 38.25 (-OC(O)CH ₂CH₂ C(O)-), 40.68
(-CH₂Cl), 47.42-47.75 (6C, complex, -OCH ₂CH-), 67.
94 (Ins-H₆), 68.87 (d, J _C-P=5.5 Hz, -OCH₂ CH-), 69.
26-69.63 (5C,complex, -OCH₂ CH), 72.39 (Ins-C₂), 7
2.55 (Ins-C₁), 73.28 (Ins-C₃), 75.17(m,Ins-C₄), 7
6.08 (Ins-C₅), 119.70-119.90 (12C, Aromatic-C₅), 1
24.67 (29%), 124.90(354%), 124.94 (36%), 125.02 (4
1%), 125.08(76%), 125.19(68%)&125.34(32%) (12C, Ar
omatic-C₂), 126.75 (36%), 126.85 (87%), 126.96 (10
0%), 127.01 (76%), 127.13 (32%), 127.56 (85%), 12
7.57 (88%), 127.66 (51%),127.74 (94%) & 127.95 (4
%) (24C, Aromatic-C₃, C₄), 141.03 (39%), 141.07
(60%), 141.12 (47%), 141.14 (50%), 141.16 (66%), 1
41.19 (46%), 141.27(38%), 141.31 (37%) & 141.35 (3
3%) (12C, Aromatic-C₆), 142.60 (38%), 142.68 (37
%), 142.73 (42%), 142.76 (42%), 142.83 (91%), 142.
86 (50%), 142.88 (46%), 142.96 (33%), 143.10 (39%)
& 143.22 (41%) (12C, Aromatic-C₁),166.34 (-OC(O)
CH₂Cl), 172.35 (Levulinyl -OC(O)-), 208.18 ( -C(O)
-)³¹ P NMR(CDCl₃, 109 MHz) δ=-0.90(1P), -0.51(1P), -
0.21(1P) ¹ H NMR (CDCl ₃ , 270 MHz) δ = 2.09 (3H, s,
-CH ₃ ), 2.18-2.78 (4H, complex, -OC (O) CH ₂ CH ₂ C (O)-),
3.56 (1H, J _1-2 = 2.4 Hz, J _1-6 = 9.8 Hz, Ins-H ₁ ), 3.64
(1H, br, -OH, disappear after D ₂ O-treatment), 3.79-
4.41 (22H, complex, Ins-H ₃ , H ₅ , -OCH ₂ CH- * 6, -CH ₂ Cl),
4.75 (1H, q, J _4-3 = J _4-5 = J _HP = 9.8 Hz, Ins-H ₄ ), 5.28
(1H, t, J _6-1 = J _6-5 = 9.8 Hz, Ins-H ₆ ), 5.61 (1H, t, J
_2-1 = J _2-3 = 2.4 Hz, Ins-H ₂ ), 6.99-7.72 (48H, complex,
Aromatic H) ¹³ C NMR (CDCl ₃ , 68 MHz) δ = 28.07 (-OC (O) CH ₂ CH ₂ C (O)
-), 29.62 (-CH ₃ ), 38.25 (-OC (O) CH ₂ CH ₂ C (O)-), 40.68
(-CH ₂ Cl), 47.42-47.75 (6C, complex, -OCH ₂ CH- ), 67.
94 (Ins-H ₆ ), 68.87 (d, J _CP = 5.5 Hz, -O CH ₂ CH-), 69.
26-69.63 (5C, complex, -O CH ₂ CH), 72.39 (Ins-C ₂ ), 7
2.55 (Ins-C ₁ ), 73.28 (Ins-C ₃ ), 75.17 (m, Ins-C ₄ ), 7
6.08 (Ins-C ₅ ), 119.70-119.90 (12C, Aromatic-C ₅ ), 1
24.67 (29%), 124.90 (354%), 124.94 (36%), 125.02 (4
1%), 125.08 (76%), 125.19 (68%) & 125.34 (32%) (12C, Ar
omatic-C ₂ ), 126.75 (36%), 126.85 (87%), 126.96 (10
0%), 127.01 (76%), 127.13 (32%), 127.56 (85%), 12
7.57 (88%), 127.66 (51%), 127.74 (94%) & 127.95 (4
%) (24C, Aromatic-C ₃ , C ₄ ), 141.03 (39%), 141.07
(60%), 141.12 (47%), 141.14 (50%), 141.16 (66%), 1
41.19 (46%), 141.27 (38%), 141.31 (37%) & 141.35 (3
3%) (12C, Aromatic-C ₆ ), 142.60 (38%), 142.68 (37
%), 142.73 (42%), 142.76 (42%), 142.83 (91%), 142.
86 (50%), 142.88 (46%), 142.96 (33%), 143.10 (39%)
& 143.22 (41%) (12C, Aromatic-C ₁ ), 166.34 (-O C (O)
CH ₂ Cl), 172.35 (Levulinyl -OC (O)-), 208.18 (-C (O)
-) ³¹ P NMR (CDCl ₃ , 109 MHz) δ = -0.90 (1P), -0.51 (1P),-
0.21 (1P)

【００２４】実施例６ ［化合物10の合成］窒素雰囲気下、2-O-Chloroacetyl-
3,4,5-tri-O-(bis-9-fluorenylmethyl phosphoryl)-6-O
-levulinoyl-myo-inositol (9, 704.8 mg, 0.42 mmol)
をdry CHCl₃(8.0 ml)に溶解させN,N-Diisopropyl cyano
ethyl a,b-Di-O-Oleoylgleceryl phosphoroamidite (52
3.5 mg, 0.64 mmol)、Tetrazole (51.2 mg, 0.73 mmol)
を加え室温で3時間攪拌した。この溶液を-72℃に冷や
し、mCPBA (41.2 mg, 0.24 mmol)を加え室温で1時間攪
拌した。この溶液をAcOEtで抽出し有機層を10% Na₂SO₃,
H₂O、sat.NaHCO₃、sat.NaClで洗浄しMgSO₄で乾燥させ
た。濾過、濃縮後、フラシュカラムクロマトグラフィ−
(AcOEt/CHCl₃=1/4→Acetone/CHCl₃=1/4)により1-O-(a,b
-Di-O-Oleoylgleceryl cyanoethyl phosphoryl) 2-O-ch
loroacetyl-3,4,5-tri-O-(bis-9-fluorenylmethyl phos
phoryl)-6-O-levulinoyl-myo-inositol (10,905.8 mg,
89%)で得た。Example 6 [Synthesis of compound 10] 2- O- Chloroacetyl-
3,4,5-tri- O- (bis-9-fluorenylmethyl phosphoryl) -6- O
-levulinoyl- myo -inositol (9, 704.8 mg, 0.42 mmol)
Was dissolved in dry CHCl ₃ (8.0 ml) and N, N-Diisopropyl cyano
ethyl a, b-Di- O -Oleoylgleceryl phosphoroamidite (52
3.5 mg, 0.64 mmol), Tetrazole (51.2 mg, 0.73 mmol)
Was added and stirred at room temperature for 3 hours. The solution was cooled to -72 ° C, mCPBA (41.2 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solution was extracted with AcOEt and the organic layer was 10% Na ₂ SO ₃ ,
Washed with H ₂ O, sat. NaHCO ₃ , sat. NaCl and dried over MgSO ₄ . After filtration and concentration, flash column chromatography
(AcOEt / CHCl ₃ = 1/4 → Acetone / CHCl ₃ = 1/4) yields 1- O- (a, b
-Di- O -Oleoylgleceryl cyanoethyl phosphoryl) 2- O -ch
loroacetyl-3,4,5-tri- O- (bis-9-fluorenylmethyl phos
phoryl) -6- O -levulinoyl- myo -inositol (10,905.8 mg,
89%).

【００２５】¹H NMR (CDCl₃, 270 MHz) δ=0.89(6H, t,
J=6.56 Hz, Oleoyl-CH₃), 1.22(40H, br, Oleoyl-CH
₂-), 1.50(4H, br, Oleoyl-OC(O)CH ₂CH₂ -), 1.95(8H, b
r, Allylic H), 1.98&1.99(3H, s*2, Levulinyl -CH₃),
2.15-2.91(10H, complex, -C(O)CH₂-, Levulinyl -CH₂
-, OCH ₂CH₂ CN), 3.68-4.34(26H, complex, Ins-H₃,
H₅, Glyceryl Hα, Hγ,-OCH₂CH-*6, -OCH₂ CH₂CN), 4.4
6(1H, m, Ins-H₁), 4.70(1H, m, Ins-H₄), 5.20-5.39
(6H, complex, Ins-H₆, Glyseryl Hβ, Vinylic H),5.9
6&6.00(1H, t*2, J _2-3=J _2-1=2.3 Hz, Ins-H₂), 6.96-7.
73(48H, complex, Aromatic H)¹³ C NMR (CDCl₃, 68 MHz) δ=14.05(2C, -CH ₂CH₃ ), 19.
28&19.35(-OCH ₂CH₂ CN), 22.48&22.59(2C, -CH₂ CH₃), 2
7.25(2C, Allylic C), 27.76(-OC(O)CH₂ CH₂C(O)-), 28.
92-29.74(16C, complex, Oleoyl-CH₂-), 31.70, 31.83&
32.05(-C(O)CH₃ ), 32.45&32.52(2C, -CH₂ CH₂CH₃), 33.8
2&34.02(2C, -OC(O)CH₂ -), 36.89&37.04(-OC(O)CH ₂CH₂ C
(O)-), 40.37(-C(O)CH₂ Cl), 47.52, 47.67&47.74(6C, -
OCH ₂CH-),61.52&61.61(d*2, J _C-P=9.2 Hz, -OCH₂ CH₂C
N), 62.47, 62.58, 62.87&62.94(d*4, J _C-P=5.5 Hz, Gl
yceryl-Cα), 66.34&66.63(br*2, Glyceryl-Cγ), 69.2
5(d,J _C-P=7.3 Hz, Glyceryl-Cβ), 69.54-69.65(7C, co
mplex, Ins-C₆, -OCH₂ CH-*6), 71.06(Ins-C₂), 72.41(I
ns-C₃), 72.72(Ins-C₁), 74.50(m,Ins-C₄), 75.39(Ins-
C₅), 116.36&116.43(-CN), 119.74(38%), 119.87(49%),
120.1(12%)&120.14(12%)(12C, Aromatic-C₅), 124.82
(21%), 124.90(10%), 125.06(45%), 125.17(32%)&125.3
1(27%)(12C, Aromatic-C₂), 126.76(21%), 126.82(36
%), 126.91(21%),127.04(77%), 127.11(24%), 127.21(5
%), 127.59(46%), 127.73(49%)&127.77(44%)(24C, Arom
atic-C₃, C₄), 129.63 (10%), 129.76(3%), 129.89(12
%), 129.98(5%), 130.11(4%), 130.18(4%), 130.33(5%)
& 130.44(3%)(4C, Vinylic-C), 141.12(42%), 141.19(2
3%)&141.34(26%)(12C, Aromatic-C₆), 142.60(17%), 14
2.67(25%), 142.76(25%), 142.84(19%), 142.97(19%),
143.13(18%)(12C, Aromatic-C₁), 166.14&166.28(Chlo
roacetyl-OC(O)-), 171.88&171.92 (Levulinyl -OC(O)
-), 172.76&173.10 (2C, Oleoyl-OC(O)-), 205.84, 20
5.89&206.28 ( -C(O)-)³¹P NMR(CDCl₃, 109 MHz) δ=-1.85(41%), -1.74(36%), -1.49(95%) -1.09(96%)&-
1.06(100%) ¹ H NMR (CDCl ₃ , 270 MHz) δ = 0.89 (6H, t,
J = 6.56 Hz, Oleoyl-CH ₃ ), 1.22 (40H, br, Oleoyl-CH
_2- ), 1.50 (4H, br, Oleoyl-OC (O) CH ₂ CH _2- ), 1.95 (8H, b
r, Allylic H), 1.98 & 1.99 (3H, s * 2, Levulinyl -CH ₃ ),
2.15-2.91 (10H, complex, -C (O) CH _2- , Levulinyl -CH ₂
-, OCH ₂ CH ₂ CN), 3.68-4.34 (26H, complex, Ins-H ₃ ,
H ₅ , Glyceryl Hα, Hγ, -OCH ₂ CH- * 6, -O CH ₂ CH ₂ CN), 4.4
6 (1H, m, Ins-H ₁ ), 4.70 (1H, m, Ins-H ₄ ), 5.20-5.39
(6H, complex, Ins-H ₆ , Glyseryl Hβ, Vinylic H), 5.9
6 & 6.00 (1H, t * 2, J _2-3 = J _2-1 = 2.3 Hz, Ins-H ₂ ), 6.96-7.
73 (48H, complex, Aromatic H) ¹³ C NMR (CDCl ₃ , 68 MHz) δ = 14.05 (2C, -CH ₂ CH ₃ ), 19.
28 & 19.35 (-OCH ₂ CH ₂ CN), 22.48 & 22.59 (2C, -CH ₂ CH ₃ ), 2
7.25 (2C, Allylic C), 27.76 (-OC (O) CH ₂ CH ₂ C (O)-), 28.
92-29.74 (16C, complex, Oleoyl-CH _2- ), 31.70, 31.83 &
32.05 (-C (O) CH ₃ ), 32.45 & 32.52 (2C, -CH ₂ CH ₂ CH ₃ ), 33.8
2 & 34.02 (2C, -OC (O) CH _2- ), 36.89 & 37.04 (-OC (O) CH ₂ CH ₂ C
(O) -), 40.37 ( -C (O) CH 2 Cl), 47.52, 47.67 & 47.74 (6C, -
OCH ₂ CH- ), 61.52 & 61.61 (d * 2, J _CP = 9.2 Hz, -O CH ₂ CH ₂ C
N), 62.47, 62.58, 62.87 & 62.94 (d * 4, J _CP = 5.5 Hz, Gl
yceryl-Cα), 66.34 & 66.63 (br * 2, Glyceryl-Cγ), 69.2
5 (d, J _CP = 7.3 Hz, Glyceryl-Cβ), 69.54-69.65 (7C, co
mplex, Ins-C ₆ , -O CH ₂ CH- * 6), 71.06 (Ins-C ₂ ), 72.41 (I
ns-C ₃ ), 72.72 (Ins-C ₁ ), 74.50 (m, Ins-C ₄ ), 75.39 (Ins-C ₄ )
C ₅ ), 116.36 & 116.43 (-CN), 119.74 (38%), 119.87 (49%),
120.1 (12%) & 120.14 ( 12%) (12C, Aromatic-C 5), 124.82
(21%), 124.90 (10%), 125.06 (45%), 125.17 (32%) & 125.3
1 (27%) (12C, Aromatic-C 2), 126.76 (21%), 126.82 (36
%), 126.91 (21%), 127.04 (77%), 127.11 (24%), 127.21 (5
%), 127.59 (46%), 127.73 (49%) & 127.77 (44%) (24C, Arom
atic-C ₃ , C ₄ ), 129.63 (10%), 129.76 (3%), 129.89 (12
%), 129.98 (5%), 130.11 (4%), 130.18 (4%), 130.33 (5%)
& 130.44 (3%) (4C, Vinylic-C), 141.12 (42%), 141.19 (2
3%) & 141.34 (26%) (12C, Aromatic-C ₆ ), 142.60 (17%), 14
2.67 (25%), 142.76 (25%), 142.84 (19%), 142.97 (19%),
143.13 (18%) (12C, Aromatic-C ₁ ), 166.14 & 166.28 (Chlo
roacetyl-OC (O)-), 171.88 & 171.92 (Levulinyl -OC (O)
-), 172.76 & 173.10 (2C, Oleoyl-OC (O)-), 205.84, 20
5.89 & 206.28 (-C (O)-) ³¹ P NMR (CDCl ₃ , 109 MHz) δ = -1.85 (41%), -1.74 (36%), -1.49 (95%) -1.09 (96%) &-
1.06 (100%)

【００２６】実施例７ ［化合物11の合成］窒素雰囲気下、Benzene共沸した1-O
-(a,b-Di-O-oleoylglyceryl cyanoethyl phosphoryl)-2
-O-chloroacetyl 3,4,5-tri-O-(bis-9-fluorenylmethyl
phosphoryl) 6-O-levulinoyl-myo-inositol (10, 724.
3 mg, 0.30 mmol)をdry CH₃CN (8.0ml) に溶解させ、0
℃に冷やしておいてTriethyl amine (914.9 mg, 9.04 m
mol)を加えて室温で20時間攪拌する。溶媒留去を行い残
査をHexeneによって洗浄し1-O-(a,b-Di-O-oleoylglycer
yl phosphoryl) 2-O-chloroacetyl-3,4,5-tri-O-phosph
oryl-6-O-levulinoyl-myo-inositol (11, 420.2 mg, 8
3%) で得た。Example 7 [Synthesis of Compound 11] Benzene azeotrope 1- O under nitrogen atmosphere
-(a, b-Di- O -oleoylglyceryl cyanoethyl phosphoryl) -2
- O -chloroacetyl 3,4,5-tri- O - (bis-9-fluorenylmethyl
phosphoryl) 6- O -levulinoyl- myo -inositol (10, 724.
3 mg, 0.30 mmol) in dry CH ₃ CN (8.0 ml)
Chill to Triethylamine (914.9 mg, 9.04 m
mol) and stirred at room temperature for 20 hours. The solvent is distilled off and the residue is washed with Hexene, and 1- O- (a, b-Di- O- oleoylglycer
yl phosphoryl) 2- O- chloroacetyl-3,4,5-tri- O- phosph
oryl-6- O -levulinoyl- myo -inositol (11, 420.2 mg, 8
3%).

【００２７】¹H NMR (270 MHz, 47.3 mg, CDCl₃/CD₃OD=
10/1)) δ=0.90(6H, br, Oleoyl-CH₃), 1.31(76H, br,
Oleoyl-CH₂-*20, N(CH ₂CH₃ )₃*4), 1.59(4H, br, Oleoyl
-OC(O)CH ₂CH₂ -), 2.01(8H, br, Allylic H), 2.17(3H,
s, Levulinyl-CH₃), 2.30&2.33(4H, t*2, J=5.4 Hz, Ol
eoyl-C(O)CH₂-), 2.68~2.95(4H, complex, Levulinyl-C
H₂-), 3.16(24H, br, N(CH₂ CH₃)₃), 3.97(3H, br, Gly
ceryl Hα, Hγ*2), 4.16(1H, br, Glyceryl Hα), 4.3
1-4.49(5H, complex, Ins-H₁, H₃, H₅), 4.60(1H, q, J
_4-3=J _4-5=J _H-P=9.8 Hz, Ins-H₄), 5.23(1H,br, Glycery
l Hβ), 5.30-5.42(5H, complex, Ins-H₆, Vinylic H*
4), 5.91(1H, br, Ins-H₂)³¹ P NMR(109 MHz, 47.3 mg, CDCl₃/CD₃OD=10/1+NEt₃, p
H=ca.9 ) d=-0.80(1P), 0.64(1P), 0.99(1P), 3.04(1P) ¹ H NMR (270 MHz, 47.3 mg, CDCl ₃ / CD ₃ OD =
10/1)) δ = 0.90 (6H, br, Oleoyl-CH ₃ ), 1.31 (76H, br,
Oleoyl-CH _2- * 20, N (CH ₂ CH ₃ ) ₃ * 4), 1.59 (4H, br, Oleoyl
-OC (O) CH ₂ CH _2- ), 2.01 (8H, br, Allylic H), 2.17 (3H,
s, Levulinyl-CH ₃ ), 2.30 & 2.33 (4H, t * 2, J = 5.4 Hz, Ol
eoyl-C (O) CH _2- ), 2.68 ~ 2.95 (4H, complex, Levulinyl-C
H _2- ), 3.16 (24H, br, N ( CH ₂ CH ₃ ) ₃ ), 3.97 (3H, br, Gly
ceryl Hα, Hγ * 2), 4.16 (1H, br, Glyceryl Hα), 4.3
1-4.49 (5H, complex, Ins- H 1, H 3, H 5), 4.60 (1H, q, J
_4-3 = J _4-5 = J _HP = 9.8 Hz, Ins-H ₄ ), 5.23 (1H, br, Glycery
l Hβ), 5.30-5.42 (5H, complex, Ins-H ₆ , Vinylic H *
4), 5.91 (1H, br, Ins-H ₂ ) ³¹ P NMR (109 MHz, 47.3 mg, CDCl ₃ / CD ₃ OD = 10/1 + NEt ₃ , p
H = ca.9) d = -0.80 (1P), 0.64 (1P), 0.99 (1P), 3.04 (1P)

【００２８】実施例８ ［化合物12の合成］窒素雰囲気下、Benzene共沸をした1
-O-(a,b-Di-O-oleoylglyceryl phosphoryl) 2-O-chloro
acetyl 3,4,5-tri-O-phosphoryl 6-O-levulinoyl-myo-i
nositol (11, 382.5 mg, 0.23 mmol)をdry CHCl₃に溶解
し0℃に冷やしておきHDTCのEtOH溶液(4.5 mmol)を加え
て、室温で4時間攪拌した。この溶液を0℃に冷やしsat.
KHSO₄を加えquenchし酸性であるのを確認後CHCl₃で逆抽
出した。有機層をNa₂SO₄で乾燥させ、濾過、濃縮後、少
量のCHCl₃で溶解させCH₃CNを加えることにより沈殿し、
1-O-(a,b-Di-O-Oleoylglyceryl phosphoryl)-3,4,5-tri
-O-phosphoryl-6-O-levulinoyl-myo -inositol (12, 16
8.2 mg, 46%)を得た。³¹ P NMR(109 MHz, 115.6 mg, CDCl₃/CD₃OD=10/1, pH=c
a.7 ) d=0.89(1P), 1.48(1P), 2.27(1P), 2.52(1P)Example 8 [Synthesis of Compound 12] Benzene azeotrope was prepared in a nitrogen atmosphere.
- O - (a, b- Di- O -oleoylglyceryl phosphoryl) 2- O -chloro
acetyl 3,4,5-tri- O -phosphoryl 6- O -levulinoyl- myo -i
Nositol (11, 382.5 mg, 0.23 mmol) was dissolved in dry CHCl ₃ , cooled to 0 ° C., and an EtOH solution of HDTC (4.5 mmol) was added, followed by stirring at room temperature for 4 hours. This solution was cooled to 0 ° C and sat.
After KHSO ₄ was added and quenched to confirm that it was acidic, back extraction was performed with CHCl ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated, dissolved in a small amount of CHCl ₃ and precipitated by adding CH ₃ CN,
1- O- (a, b-Di- O -Oleoylglyceryl phosphoryl) -3,4,5-tri
- O -phosphoryl-6- O -levulinoyl- myo -inositol (12, 16
8.2 mg, 46%). ³¹ P NMR (109 MHz, 115.6 mg, CDCl ₃ / CD ₃ OD = 10/1, pH = c
a.7) d = 0.89 (1P), 1.48 (1P), 2.27 (1P), 2.52 (1P)

【００２９】実施例９ ［PIP3 の合成］1-O-(1,2-Di-O-Oleoylgleceryl phosph
oryl)-3,4,5-tri-O-phosphoryl-6-O-levulinoyl-myo- i
nositol (128.2 mg, 0.09 mmol)をPy/CH₃CO₂H=4/1(3.0
ml)に溶解させ0 ℃に冷やしておきHydrazine hydrate
(38.7 mg, 0.77 mmol)を加え室温で3時間攪拌した。溶
媒留去後、CHCl₃を加えて、この溶液を0 ℃に冷やしsa
t.KHSO₄を加え酸性であるのを確認後CHCl₃で逆抽出し
た。有機層をNa₂SO₄で乾燥させ、濾過、濃縮後、少量の
CHCl₃で溶解させCH₃CNを加えることにより沈殿を誘起
し、1-O-(1,2-Di-O-oleoylglyceryl phosphoryl)-3,4,5
-tri-O-phosphoryl-myo-inositol (94.5 mg, 78%)を得
た。R f=0.4(CHCl₃/Acetone/CH₃OH/CH₃COOH/H₂O=25/12/13/7/
10)Example 9 [Synthesis of PIP3] 1- O- (1,2-Di- O- Oleoylgleceryl phosph
oryl) -3,4,5-tri- O -phosphoryl-6- O -levulinoyl- myo -i
nositol (128.2 mg, 0.09 mmol) in Py / CH ₃ CO ₂ H = 4/1 (3.0
solution) and cooled to 0 ° C.
(38.7 mg, 0.77 mmol) was added and the mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, CHCl ₃ was added and the solution was cooled to 0 ° C.
t. KHSO ₄ was added to confirm acidity, and then back-extracted with CHCl ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated,
Dissolve in CHCl ₃ and induce precipitation by adding CH ₃ CN, 1- O- (1,2-Di- O- oleoylglyceryl phosphoryl) -3,4,5
-tri- O- phosphoryl- myo- inositol (94.5 mg, 78%) was obtained. R f = 0.4 (CHCl ₃ / Acetone / CH ₃ OH / CH ₃ COOH / H ₂ O = 25/12/13/7 /
Ten)

【００３０】実施例１０ ［化合物24 の合成］窒素雰囲気下、1,2:4,5-dicyclohe
xylidene-myo-inositol (23, 2.15 g , 6.32 mmol )
、PACLev-OH (4.00 g, 15.1 mmol, 2.4 eq.) 、DCC
(4.06 g, 19.7 mmol, 3.0 eq.) を無水塩化メチレン 1
5 mlに溶解する。反応系を0℃に冷却しDMAP (310.0 mg,
2.54 mmol, 0.4 eq) を加え、一晩攪拌する。反応終了
後、ジエチルエーテルを加え、飽和硫酸水素カリウム、
飽和炭酸水素ナトリウム、飽和食塩水で洗浄する。有機
層を無水硫酸ナトリウムで乾燥し、濾過、濃縮後、残査
を得た。その残査を、フラッシュカラムクロマトグラフ
ィー (AcOEt/Hex.=1/1)により単離し 目的物1,2:4,5-O-
dicyclohexylidene-3,6-O- {2-[2-(levulinoyloxy)ethy
l]benzoyl}-myo-inositol (24, 5.26 g, 95%)を得た。R f 0.7 (AcOEt/Hex.=2/1)Example 10 [Synthesis of Compound 24] Under a nitrogen atmosphere, 1,2: 4,5-dicyclohe
xylidene- myo- inositol (23, 2.15 g, 6.32 mmol)
, PACLev-OH (4.00 g, 15.1 mmol, 2.4 eq.), DCC
(4.06 g, 19.7 mmol, 3.0 eq.) In anhydrous methylene chloride 1
Dissolve in 5 ml. The reaction was cooled to 0 ° C and DMAP (310.0 mg,
2.54 mmol, 0.4 eq) and stir overnight. After completion of the reaction, diethyl ether was added, and saturated potassium hydrogen sulfate was added.
Wash with saturated sodium bicarbonate and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was isolated by flash column chromatography (AcOEt / Hex. = 1/1) to obtain the target compound 1,2: 4,5- O-
dicyclohexylidene-3,6- O- (2- [2- (levulinoyloxy) ethy
l] benzoyl} - myo -inositol was obtained (24, 5.26 g, 95% ). R f 0.7 (AcOEt / Hex. = 2/1)

【００３１】¹H-NMR (270 MHz, CDCl₃) δ= 1.30-1.96
(20H, complex, cyclohexylidene*2), 2.17(3H, s, C
H₃), 2.18(3H, s, CH₃), 2.556 & 2.559(4H, t*2, J=7.
02 Hz,OC(O)CH₂ CH₂-), 2.71 & 2.73(4H, t, J=7.02 Hz,
OC(O)CH2CH2- ), 3.32(4H, complex, Ar-CH₂ CH₂), 3.7
2(1H, dd, J ₅₆ =10.99, J ₅₄=9.46 Hz, Ins-H₅), 4.37(6
H, complex, CH₂O-*2, Ins-H_1,4), 4.79(1H, t, J ₂₁=J
₂₃=4.43 Hz, Ins-H₂), 5.42 (1H, dd, J ₃₄ =10.37, J ₃₂
=4.43 Hz, Ins-H₃), 5.59 (1H, dd, J ₆₅ =10.99,J ₆₁=6.
87 Hz, Ins-H₆), 7.23-7.38[4H, complex, (Aromatic H
_3,5)*2], 7.47(1H, td, J=6.72, 1.42 Hz, Aromatic
H₄), 7.51(1H, td, J=6.72, 1.42 Hz, Aromatic H₄),
7.98(1H, dd, J=6.72, 1.42 Hz, Aromatic H₆), 8.03(1
H, dd, J=6.72, 1.42 Hz, Aromatic H6'),¹³C-NMR (CDC
l₃, 100.5 MHz) δ =23.55, 23.61, 23.65, 23.84, 24.
82, 24.84(6C, cyclohexylidene C_{3,3',4,4',5,5'}), 2
7.87[2C, s, OC(O)CH₂ *2], 29.74, 29.76(2C, CH₃ *
2), 33.67, 33.78(2C, PhCH₂ *2), 35.00, 36.20, 36.2
6, 37.42(4C, cyclohexylidene C_2,2',6,6'), 37.82, 3
7.85[2C, OC(O)CH ₂CH₂ *2], 65.30, 65.35(2C, CH₂O *
2), 71.64(C₃), 75.08(C₁), 75.23(C₂), 75.50(C₆), 7
6.32(C₅), 79.29(C₄), 111.58, 113.96(2C, cyclohexyl
idene C_1,1'), 126.96,127.05(2C, Aromatic C_5,5'), 1
29.93, 130.26(2C, Aromatic C_1,1'), 131.30,131.72(2
C, Aromatic C_6,6'), 132.14, 132.21(2C, Aromatic C
_3,3'), 132.36,132.61(2C, Aromatic C_4,4'), 139.51,
139.82(2C, Aromatic C_2,2'), 166.50,167.16[2C, OC
(O) * 2], 172.77[2C, OC(O) * 2 in Levulinyl], 206.
63, 206.72[2C, C(O) * 2] IR (cm^-1, neat ) 1720, 1160, 1124, 1085, 754 cm^-1 FAB-MAS (positive, m-nitrobenzyl alcohol) m/z 833
[M(C₄₆H₅₆O₁₄)+1], 735 [M-cyclohexylid- ene+1], 471
[M-(cyclohexylidene*2+PAC_Lev)+1] ¹ H-NMR (270 MHz, CDCl ₃ ) δ = 1.30-1.96
(20H, complex, cyclohexylidene * 2), 2.17 (3H, s, C
H ₃ ), 2.18 (3H, s, CH ₃ ), 2.556 & 2.559 (4H, t * 2, J = 7.
02 Hz, OC (O) C H ₂ CH _2- ), 2.71 & 2.73 (4H, t, J = 7.02 Hz,
OC (O) CH2C H2 -) , 3.32 (4H, complex, Ar-C H 2 CH 2), 3.7
2 (1H, dd, J ₅₆ = 10.99, J ₅₄ = 9.46 Hz, Ins-H ₅ ), 4.37 (6
H, complex, CH ₂ O- * 2, Ins-H _1,4 ), 4.79 (1H, t, J ₂₁ = J
₂₃ = 4.43 Hz, Ins-H ₂ ), 5.42 (1H, dd, J ₃₄ = 10.37, J ₃₂
= 4.43 Hz, Ins-H ₃ ), 5.59 (1H, dd, J ₆₅ = 10.99, J ₆₁ = 6.
87 Hz, Ins-H ₆ ), 7.23-7.38 [4H, complex, (Aromatic H
_3,5 ) * 2], 7.47 (1H, td, J = 6.72, 1.42 Hz, Aromatic
H ₄ ), 7.51 (1H, td, J = 6.72, 1.42 Hz, Aromatic H ₄ ),
7.98 (1H, dd, J = 6.72, 1.42 Hz, Aromatic H ₆ ), 8.03 (1
H, dd, J = 6.72, 1.42 Hz, Aromatic H6 '), ¹³ C-NMR (CDC
l ₃ , 100.5 MHz) δ = 23.55, 23.61, 23.65, 23.84, 24.
82, 24.84 (6C, cyclohexylidene C _{3,3 ', 4,4', 5,5 '} ), 2
7.87 [2C, s, OC (O) C H ₂ * 2], 29.74, 29.76 (2C, CH ₃ *
2), 33.67, 33.78 (2C, Ph C H ₂ * 2), 35.00, 36.20, 36.2
6, 37.42 (4C, cyclohexylidene C _{2,2 ', 6,6} '), 37.82, 3
7.85 [2C, OC (O) CH ₂ C H ₂ * 2], 65.30, 65.35 (2C, CH ₂ O *
2), 71.64 (C ₃ ), 75.08 (C ₁ ), 75.23 (C ₂ ), 75.50 (C ₆ ), 7
6.32 (C ₅ ), 79.29 (C ₄ ), 111.58, 113.96 (2C, cyclohexyl
idene C _{1,1 '} ), 126.96,127.05 (2C, Aromatic C _5,5' ), 1
29.93, 130.26 (2C, Aromatic C _{1,1 '} ), 131.30,131.72 (2
C, Aromatic C _{6,6 '} ), 132.14, 132.21 (2C, Aromatic C
_{3,3 '} ), 132.36,132.61 (2C, Aromatic C _4,4' ), 139.51,
139.82 (2C, Aromatic C _{2,2 '} ), 166.50,167.16 [2C, OC
(O) * 2], 172.77 [2C, OC (O) * 2 in Levulinyl], 206.
63, 206.72 [2C, C (O) * 2] IR (cm ^-1 , neat) 1720, 1160, 1124, 1085, 754 cm ^-1 FAB-MAS (positive, m- nitrobenzyl alcohol) m / z 833
[M (C ₄₆ H ₅₆ O ₁₄ ) +1], 735 [M-cyclohexylidene-1], 471
[M- (cyclohexylidene * 2 + PAC _Lev ) +1]

【００３２】実施例１１ ［化合物25の合成］1,2:4,5-dicyclohexylidene-3,6-{2
-[2-(levulinoyloxy) ethyl] benzoate}-myo-inositol
(24, 936.8 mg, 1.12 mmol)を塩化メチレン 15 mlに溶
解する。反応系を0 ℃に冷却し、TFA(860 ml, 10.1 mmo
l, 10 eq.)を加え、室温で14時間攪拌する。その後、飽
和炭酸水素ナトリウムで quenchする。酢酸エチルを加
え飽和炭酸水素ナトリウム、飽和食塩水で洗浄する。有
機層を無水硫酸ナトリウムで乾燥し、濾過、濃縮後、残
査を得た。その残査を、フラッシュカラムクロマトグラ
フィー (AcOEt/Hex.=3/2)により単離し目的物1,2-O-cyc
lohexylidene-3,6-di-O-{2-[2-(levulinoyloxy)ethyl]b
enzoate}-myo-inositol (25, 654.3 mg, 77%)、3,6-{2-
[2-(levulinoyloxy) ethyl] benzoate}-myo-inositol
(115.7 mg, 12%)を得た。Example 11 [Synthesis of Compound 25] 1,2: 4,5-dicyclohexylidene-3,6- {2
- [2- (levulinoyloxy) ethyl] benzoate} - myo -inositol
(24, 936.8 mg, 1.12 mmol) is dissolved in 15 ml of methylene chloride. The reaction was cooled to 0 ° C and TFA (860 ml, 10.1 mmo
l, 10 eq.) and stir at room temperature for 14 hours. Then quench with saturated sodium bicarbonate. Ethyl acetate is added, and the mixture is washed with saturated sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was isolated by flash column chromatography (AcOEt / Hex. = 3/2) to give the desired product 1,2- O- cyc
lohexylidene-3,6-di- O- {2- [2- (levulinoyloxy) ethyl] b
enzoate} - myo -inositol (25, 654.3 mg, 77%), 3,6- {2-
[2- (levulinoyloxy) ethyl] benzoate } - myo -inositol
(115.7 mg, 12%).

【００３３】Rf 0.4 (AcOEt/Hex.=3/1)¹ H-NMR (270 MHz, CDCl3) δ= 1.30-1.96(10H, comple
x, cyclohexylidene),2.17(3H, s, CH₃), 2.18(3H, s,
CH₃), 2.53(2H, t, J=6.41 Hz, OC(O)CH₂ CH₂-), 2.53(2
H, complex, OC(O)CH₂ CH₂-), 2.71(2H, t, J=6.41 Hz,
OC(O)CH₂CH₂ -),2.71(2H, complex, OC(O)CH₂CH₂ - ), 3.
20-3.48[4H, complex, (Ar-CH₂ CH₂O-)*2], 3.62(1H, t,
J ₅₄=J ₅₆=9.92 Hz, Ins-H₅ ), 4.21(1H, t, J ₄₃=J ₄₅=9.
92 Hz,Ins-H₄ ), 4.27-4.49(4H, complex, CH₂O- *2),
4.36(1H, dd, J ₁₆=7.78, J ₁₂=4.28 Hz, Ins-H₁), 4.67
(1H, t, J ₂₁=J ₂₃=4.28 Hz, Ins-H₂), 5.32(1H, dd, J ₃₄
=9.92, J ₃₂=4.28 Hz, Ins-H₃), 5.47 (1H, dd, J ₆₅ =9.
92, J ₆₁=7.78 Hz, Ins-H₆), 7.29(2H, td, J=7.63, 1.2
2 Hz, Aromatic H_3,5), 7.35(2H, td, J=7.63,1.22 Hz,
Aromatic H_3',5'), 7.45(1H, td, J=7.63, 1.22 Hz, A
romatic H₄), 7.48(1H, td, J=7.63, 1.22 Hz, Aromati
c H_4'), 7.96(1H, dd, J=7.63, 1.22 Hz, Aromatic
H₆), 8.01(1H, dd, J=7.63, 1.22 Hz, Aromatic H_6')¹³ C-NMR (CDCl3, 67.9 MHz) δ =23.66, 23.79, 24.80
(3C, cyclohexylideneC_3,4,5), 27.81, 27.85[2C, OC
(O)CH₂ * 2], 29.74, 29.76(2C, CH₃ *2), 33.67(2C,
s, PhCH₂ *2), 35.09, 37.54(2C, cyclohexylidene C
_2,6), 37.78, 37.82[2C, OC(O)CH ₂CH₂ *2], 64.92, 65.
16(2C, CH₂O *2), 70.82(C₆), 72.12(C₁), 72.34(C₂),
73.32(C₃), 76.11(C₅), 76.28(C₄), 111.21(cyclohexyl
idene C₁), 126.67, 126.79(2C, Aromatic C_5,5'), 12
9.82, 130.05(2C, Aromatic C_1,1'), 130.94, 131.41(2
C, Aromatic C_6,6'), 131.73, 131.91(2C, Aromatic C
_3,3'), 131.98, 132.25(2C, Aromatic C_4,4'), 138.85,
139.05(2C, Aromatic C_2,2'), 167.11, 167.21[2C, OC
(O) * 2], 172.74, 172.78[2C, OC(O) in Levulinyl *
2],207.30, 207.49[2C, C(O) *2] IR (cm^-1, neat ) 3487, 2937, 1720, 1259, 1160, 109
0 cm^-1 元素分析 Calcd for C₄0H₄₈O₁₄ (mol wt 752.6); C, 63.82; H, 6.43 found ; C, 63.88; H, 6.54[0033]Rf 0.4 (AcOEt / Hex. = 3/1)¹ H-NMR (270 MHz, CDCl3) δ = 1.30-1.96 (10H, comple
x, cyclohexylidene), 2.17 (3H, s, CH_Three), 2.18 (3H, s,
CH_Three), 2.53 (2H, t,J= 6.41 Hz, OC (O) CH ₂ CH_Two-), 2.53 (2
H, complex, OC (O) CH ₂ CH_Two-), 2.71 (2H, t,J= 6.41 Hz,
OC (O) CH_TwoCH ₂ -), 2.71 (2H, complex, OC (O) CH_TwoCH ₂ -), 3.
20-3.48 [4H, complex, (Ar-CH ₂ CH_TwoO-) * 2], 3.62 (1H, t,
 J ₅₄=J ₅₆= 9.92 Hz, Ins-H_Five ), 4.21 (1H, t,J ₄₃=J ₄₅= 9.
92 Hz, Ins-H_Four ), 4.27-4.49 (4H, complex, CH_TwoO- * 2),
4.36 (1H, dd,J ₁₆= 7.78,J ₁₂= 4.28 Hz, Ins-H₁), 4.67
(1H, t,J _{twenty one}=J _{twenty three}= 4.28 Hz, Ins-H_Two), 5.32 (1H, dd,J ₃₄
= 9.92,J ₃₂= 4.28 Hz, Ins-H_Three), 5.47 (1H, dd,J ₆₅ = 9.
92,J ₆₁= 7.78 Hz, Ins-H₆), 7.29 (2H, td,J= 7.63, 1.2
2 Hz, Aromatic H_3,5), 7.35 (2H, td,J= 7.63,1.22 Hz,
 Aromatic H_{3 ', 5'}), 7.45 (1H, td,J= 7.63, 1.22 Hz, A
romatic H_Four), 7.48 (1H, td,J= 7.63, 1.22 Hz, Aromati
c H_Four'), 7.96 (1H, dd,J= 7.63, 1.22 Hz, Aromatic
H₆), 8.01 (1H, dd,J= 7.63, 1.22 Hz, Aromatic H_{6 '})¹³ C-NMR (CDCl3, 67.9 MHz) δ = 23.66, 23.79, 24.80
(3C, cyclohexylideneC_3,4,5), 27.81, 27.85 [2C, OC
(O)CH_Two * 2], 29.74, 29.76 (2C, CH_Three * 2), 33.67 (2C,
s, PhCH_Two * 2), 35.09, 37.54 (2C, cyclohexylidene C
_2,6), 37.78, 37.82 [2C, OC (O) CH ₂ CH_Two * 2], 64.92, 65.
16 (2C, CH_TwoO * 2), 70.82 (C₆), 72.12 (C₁), 72.34 (C_Two),
73.32 (C_Three), 76.11 (C_Five), 76.28 (C_Four), 111.21 (cyclohexyl
idene C₁), 126.67, 126.79 (2C, Aromatic C_{5,5 '}), 12
9.82, 130.05 (2C, Aromatic C_{1,1 '}), 130.94, 131.41 (2
C, Aromatic C_{6,6 '}), 131.73, 131.91 (2C, Aromatic C
_{3,3 '}), 131.98, 132.25 (2C, Aromatic C_{4,4 '}), 138.85,
 139.05 (2C, Aromatic C_{2,2 '}), 167.11, 167.21 [2C, OC
(O) * 2], 172.74, 172.78 [2C, OC (O) in Levulinyl *
2], 207.30, 207.49 [2C, C (O) * 2] IR (cm^-1, neat) 3487, 2937, 1720, 1259, 1160, 109
0 cm^-1 Elemental analysis Calcd for C_Four0H₄₈O₁₄ (mol wt 752.6); C, 63.82; H, 6.43 found; C, 63.88; H, 6.54

【００３４】実施例１２ ［化合物26の合成］窒素雰囲気下、 1,2-O-cyclohexyli
dene-3,6-di-O- {2-[2-(levulinoyloxy)ethyl]benzoat
e}-myo-inositol (25, 2.1 g, 2.79 mmol)とdi-9-fluo
renylmethyl N,N-diisopropylphosphoroamidite (3.5
g, 6.71 mmol, 2.4 eq.)をクロロホルム50 mlに溶解
し、 室温で攪伴しながら 1H-Tetrazole (596.1 mg,
9.56 mmol, 3.0 eq.)を加える。1.5 時間攪拌後、- 72
℃に冷却し mCPBA (1.65 g, 9.56mmol, 3.3 eq.) を加
え室 温にもどし1.5 時間攪拌する。10% Na₂SO₃で quen
chし、酢酸エチルを抽出溶媒として、飽和炭酸水素ナト
リウム、 飽和食塩水で洗浄する。有機層を無水硫酸ナ
トリウムで乾燥し、濾過、濃縮、残査を得た。フラッシ
ュカラムクロマトグラフィー(AcoEt/Hex=3/2)で単離
し、目的物 1,2-O-cyclohexylidene-3,6-di-O-{2-[2-(l
evulinoyloxy)ethyl]-benzoate}- 4,5-bis-O-(difluore
nylmethyloxyphosphate)-myo-inositol (26, 4.20 g, 9
3%)を得た。Example 12 [Synthesis of Compound 26] 1,2- O- cyclohexyli under nitrogen atmosphere
dene-3,6-di- O- {2- [2- (levulinoyloxy) ethyl] benzoat
e} - myo -inositol (25, 2.1 g, 2.79 mmol) and di-9-fluo
renylmethyl N, N -diisopropylphosphoroamidite (3.5
g, 6.71 mmol, 2.4 eq.) in 50 ml of chloroform, and 1H- Tetrazole (596.1 mg,
9.56 mmol, 3.0 eq.). After stirring for 1.5 hours, -72
Cool to ℃, add mCPBA (1.65 g, 9.56 mmol, 3.3 eq.), Return to room temperature and stir for 1.5 hours. Quen with 10% Na ₂ SO ₃
and wash with saturated sodium bicarbonate and brine using ethyl acetate as the extraction solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and a residue was obtained. It was isolated by flash column chromatography (AcoEt / Hex = 3/2), and the target product was 1,2- O- cyclohexylidene-3,6-di- O- {2- [2- (l
evulinoyloxy) ethyl] -benzoate}-4,5-bis- O- (difluore
nylmethyloxyphosphate) - myo -inositol (26, 4.20 g, 9
3%).

【００３５】Rf 0.4 (AcOEt/Hex.=3/2)¹ H-NMR (270 MHz,CDCl₃) δ = 1.38-1.96(10H, comple
x, cyclohexylidene),2.10 & 2.12(3H, s*2, CH₃), 2.3
7 & 2.40[4H, t*2, J=6.7 Hz, OC(O)CH₂ CH₂-],2.58 &
2.60[4H, t*2, J=6.7 Hz, OC(O)CH₂CH₂ -], 3.10-3.43[6
H, complex, Ar-CH₂ CH₂O- & OCH₂CH in Fm), 3.62-4.57
(10H, complex, OCH₂ CH*4 & OCH₂CH*2 in Fm), 4.30(4
H, complex, Ar-CH₂CH₂ O-), 4.40(1H, dd, J ₁₆=6.9, J
₁₂=4.9 Hz,Ins-H₁), 4.68(1H, t, J ₂₁=J ₂₃=4.9 Hz, Ins
-H₂), 4.77(1H, q, J=8.7 Hz, Ins-H₅), 5.26(1H, q, J
=8.7 Hz, Ins-H₄), 5.66(1H, dd, J ₃₄ =8.7, J ₃₂=4.9 H
z,Ins-H₃), 5.77(1H, dd, J ₆₅ =8.7, J ₆₁=6.9 Hz, Ins-
H₆), 6.94-7.48(30H, complex, Aromatic H_3,4,5 in PA
C & Aromatic H_2-4,9-11 in Fm), 7.52, 7.54, 7.58 &
7.61(8H, d*4, J=7.8 Hz, Aromatic H_5,8 in Fm), 8.1
7(2H, d, J=7.8 Hz,Aromatic H₆ in PAC)¹³ C-NMR(100.5 MHz, CDCl₃), δ = 23.54, 23.83, 24.8
7(3C, cyclohexylidene C_3,4,5), 27.74[2C, C(O)CH₂],
29.66 & 29.70(2C, CH₃), 33.67, 33.87(2C,ArCH₂), 3
4.67 & 36.85(2C, cyclohexylidene C_2,6), 37.75[2C,
OC(O)CH ₂CH₂],46.04 & 47.13(2C, d*2, J=9.7 Hz, OCH₂
CH in Fm), 47.37, 47.47(2C, d*2,J=7.4 Hz, OCH ₂CH
in Fm), 64.64, 64.73(2C, ArCH ₂CH₂), 69.26, 69.3
4, 69.49 & 69.56(2C, d*4, J=6.4 Hz, OCH₂ in Fm),
69.70(Ins. C₃), 72.73(Ins.C₂), 72.84(Ins. C₆),
75.27(Ins. C₁), 76.02 & 76.32(d*2, J=6.5 Hz, Ins.C
₄), 77.19(m, Ins. C₅), 111.87(cyclohexylidene C₁),
119.58(37%), 119.63(47%) & 119.68 (8C, Aromatic C
_5,8 in Fm), 124.80, 124.85, 124.89, 125.01, 125.0
5, 125.16, 125.25 & 125.30 (8C, Aromatic C_2,11 in
Fm), 12.73(45%), 126.76(100%), 126.81(97%), 126.
91(67%), 127.45(60%), 127.47(57%) &127.58(67%) (18
C, Aromatic C₅ in PAC &Aromatic C_3,4,9,10 in Fm),
128.36& 128.67(2C, Aromatic C₁ in PAC ), 131.61(2
1%), 131.91(48%) & 132.07(29%) (4C, Aromatic C_3,6
in PAC ), 132.47, 132.57(2C, Aromatic C₄ in PAC
), 140.37(2C, Aromatic C₂ in PAC ), 140.82, 140.8
6, 140.94, 141.04, 141.06, 141.09, 141.13 & 141.28
(8C, Aromatic C_6,7 in Fm ), 142.42, 142.48, 142.6
1, 142.68, 142.96, 142.99, 143.03 & 143.09(8C, Aro
matic C_1,12 in Fm ), 165.25, 165.84[2C, OC(O) in
PAC], 172.34 & 172.36[2C, OC(O) in Levulinoyl], 20
6.37 & 206.44[2C, OC(O) in Levulinoyl] 31P-NMR(109.4 MHz, CDCl₃), d = 0.28, 0.33 元素分析 Calcd for C₉₆H₉₀O₂₀P₂ (mol wt 1625.7); C, 70.93; H, 5.76 found ; C, 70.56; H, 5.60 R f 0.4 (AcOEt / Hex. = 3/2) ¹ H-NMR (270 MHz, CDCl ₃ ) δ = 1.38-1.96 (10H, comple
x, cyclohexylidene), 2.10 & 2.12 (3H, s * 2, CH ₃ ), 2.3
7 & 2.40 [4H, t * 2, J = 6.7 Hz, OC (O) C H ₂ CH _2- ], 2.58 &
2.60 [4H, t * 2, J = 6.7 Hz, OC (O) CH ₂ C H _2- ], 3.10-3.43 [6
H, complex, Ar-C H ₂ CH ₂ O- & OCH ₂ C H in Fm), 3.62-4.57
(10H, complex, OC H ₂ CH * 4 & OCH ₂ C H * 2 in Fm), 4.30 (4
H, complex, Ar-CH ₂ C H ₂ O-), 4.40 (1H, dd, J ₁₆ = 6.9, J
₁₂ = 4.9 Hz, Ins-H ₁ ), 4.68 (1H, t, J ₂₁ = J ₂₃ = 4.9 Hz, Ins
-H ₂ ), 4.77 (1H, q, J = 8.7 Hz, Ins-H ₅ ), 5.26 (1H, q, J
= 8.7 Hz, Ins-H ₄ ), 5.66 (1H, dd, J ₃₄ = 8.7, J ₃₂ = 4.9 H
z, Ins-H ₃ ), 5.77 (1H, dd, J ₆₅ = 8.7, J ₆₁ = 6.9 Hz, Ins-
H ₆ ), 6.94-7.48 (30H, complex, Aromatic H _3,4,5 in PA
C & Aromatic H _2-4,9-11 in Fm), 7.52, 7.54, 7.58 &
7.61 (8H, d * 4, J = 7.8 Hz, Aromatic H _5,8 in Fm), 8.1
7 (2H, d, J = 7.8 Hz, Aromatic H ₆ in PAC) ¹³ C-NMR (100.5 MHz, CDCl ₃ ), δ = 23.54, 23.83, 24.8
7 (3C, cyclohexylidene C _3,4,5 ), 27.74 [2C, C (O) CH ₂ ],
29.66 & 29.70 (2C, CH ₃ ), 33.67, 33.87 (2C, Ar C H ₂ ), 3
4.67 & 36.85 (2C, cyclohexylidene C _2,6 ), 37.75 [2C,
OC (O) CH ₂ C H ₂ ], 46.04 & 47.13 (2C, d * 2, J = 9.7 Hz, OCH ₂
C H in Fm), 47.37, 47.47 (2C, d * 2, J = 7.4 Hz, OCH ₂ C H
in Fm), 64.64, 64.73 (2C, ArCH ₂ C H ₂ ), 69.26, 69.3
4, 69.49 & 69.56 (2C, d * 4, J = 6.4 Hz, O C H ₂ in Fm),
_{69.70 (Ins. C 3),} 72.73 (Ins.C 2), 72.84 (Ins. C 6),
75.27 (Ins.C ₁ ), 76.02 & 76.32 (d * 2, J = 6.5 Hz, Ins.C
₄ ), 77.19 (m, Ins.C ₅ ), 111.87 (cyclohexylidene C ₁ ),
119.58 (37%), 119.63 (47%) & 119.68 (8C, Aromatic C
_5,8 in Fm), 124.80, 124.85, 124.89, 125.01, 125.0
5, 125.16, 125.25 & 125.30 ( 8C, Aromatic C 2,11 in
Fm), 12.73 (45%), 126.76 (100%), 126.81 (97%), 126.
91 (67%), 127.45 (60%), 127.47 (57%) & 127.58 (67%) (18
C, Aromatic C ₅ in PAC & Aromatic C _3,4,9,10 in Fm),
128.36 & 128.67 (2C, Aromatic C ₁ in PAC), 131.61 (2
1%), 131.91 (48%) & 132.07 (29%) (4C, Aromatic C _3,6
in PAC), 132.47, 132.57 (2C, Aromatic C ₄ in PAC
), 140.37 (2C, Aromatic C ₂ in PAC), 140.82, 140.8
6, 140.94, 141.04, 141.06, 141.09, 141.13 & 141.28
(8C, Aromatic C _6,7 in Fm), 142.42, 142.48, 142.6
1, 142.68, 142.96, 142.99, 143.03 & 143.09 (8C, Aro
matic C _1,12 in Fm), 165.25, 165.84 [2C, OC (O) in
PAC], 172.34 & 172.36 [2C, OC (O) in Levulinoyl], 20
6.37 & 206.44 [2C, OC (O) in Levulinoyl] 31P-NMR (109.4 MHz, CDCl ₃ ), d = 0.28, 0.33 Elemental analysis Calcd for C ₉₆ H ₉₀ O ₂₀ P ₂ (mol wt 1625.7); C, 70.93 ; H, 5.76 found; C, 70.56; H, 5.60

【００３６】実施例１３ ［化合物27の合成］1,2-O-cyclohexylidene-3,6-di-O-
{2-[2-(levulinoyloxy)- ethyl]benzoate}-4,5-bis-O-
(difluorenyl- methyloxyphosphate)-myo-inositol (2
6, 1.05 g, 0.646 mmol)を 80 % 酢酸 20 ml に溶解し
２時間還流する。その後、酢酸エチルを抽出溶媒とし
て、水、sat. NaHCO₃ 、 sat. NaClで洗浄する。有機層
を無水硫酸ナトリウムで乾燥し、濾過、濃縮、残査を得
た。フラッシュカラムクロマトグラフィー(AcoEt/Et2O=
1/3)で単離し、目的物3,6-di-O-{2-[2-(levulinoyloxy)
ethyl]benzoate}-4,5-bis-O-(difluorenylmethyloxy- p
hosphate)-myo- inositol (27, 783.8 mg, 79%)を得
た。R f 0.4 (AcOEt/Hex.=2/1)Example 13 [Synthesis of Compound 27] 1,2- O- cyclohexylidene-3,6-di- O-
{2- [2- (levulinoyloxy) -ethyl] benzoate} -4,5-bis- O-
(difluorenyl- methyloxyphosphate) - myo -inositol ( 2
6, 1.05 g, 0.646 mmol) in 20 ml of 80% acetic acid and reflux for 2 hours. Thereafter, the mixture is washed with water, sat. NaHCO ₃ and sat. NaCl using ethyl acetate as an extraction solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and a residue was obtained. Flash column chromatography (AcoEt / Et2O =
1/3) and the desired product 3,6-di- O- {2- [2- (levulinoyloxy)
ethyl] benzoate} -4,5-bis- O- (difluorenylmethyloxy- p
hosphate) - myo - inositol (27 , obtained a 783.8 mg, 79%). R f 0.4 (AcOEt / Hex. = 2/1)

【００３７】¹H-NMR (400 MHz, CDCl₃) δ = 2.09(6H,
s, CH₃), 2.32[4H, complex, OC(O)CH₂ CH₂-], 2.54[4
H, complex, OC(O)CH₂CH₂ -], 3.06-3.46[6H, complex,
Ar-CH₂ CH₂O- & OCH₂CH *2 in Fm), 3.57-3.97(9H, comp
lex, Ins. H₁, OCH₂ CH*3 & OCH₂CH*2 in Fm), 4.18-4.2
7(2H, complex, OCH₂ CH in Fm), 4.28-4.40(4H, compl
ex, Ar-CH₂CH₂ O-), 4.42(1H, br, Ins-H₂), 4.91(1H,
brq, J=9.8 Hz, Ins-H₅), 5.35(2H, complex, Ins-
H_3,4), 5.88(1H, t, J=9.8 Hz, Ins-H₆), 6.88-7.53(34
H, complex, Aromatic H_3,4,5 in PAC & Aromatic H in
Fm), 7.57-7.62(4H,complex, Aromatic H_5,8 in Fm),
8.24 & 8.27(2H, dd*2, J=7.1, 1.5 Hz, Aromatic H₆
in PAC)¹³ C-NMR(67.9 MHz, CDCl₃), δ =27.64 & 27.70[2C, C
(O)CH₂ in Levulinoyl], 29.67(2C, CH₃ in Levulinoy
l), 33.66 & 33.82(2C, ArCH₂ in PAC), 37.69 &37.74
[2C, OC(O)CH ₂CH₂ in Levulinoyl], 46.76 & 46.88(2C,
d*2, J=8.4 Hz,OCH ₂CH in Fm), 47.27(2C, d, J=8.4
Hz, OCH ₂CH in Fm), 64.30 & 64.46(2C, ArCH ₂CH₂ in
PAC), 69.16 & 69.24(2C, d*2, J=6.0 Hz, OCH₂ in F
m), 69.52(2C, d, J=6.0 Hz, OCH₂ in Fm), 70.05(In
s. C₂), 70.25(Ins. C₁), 72.15(Ins. C₃), 72.94(I
ns. C₆), 76.66 & 76.74(d*2, J=5.5 Hz, Ins. C₄), 7
7.47(m, Ins. C₅), 119.58(52%) & 119.68(78%) (8C, A
romatic C_5,8 in Fm), 124.72, 124.78, 124.99, 125.
00, 125.12, 125.20, 125.23 & 125.35(8C, AromaticC
_2,11 in Fm), 12.66(36%), 126.78(100%), 126.91(34
%), 127.42(57%), 127.56(56%) & 127.59(58%)(18C, Ar
omatic C₅ in PAC & Aromatic C_3,4,9,10 in Fm), 12
8.48 & 128.89(2C, Aromatic C₁ in PAC ), 131.82, 13
1.99, 132.03 & 132.11(4C, Aromatic C_3,6 in PAC ),
132.43 & 132.61(2C, Aromatic C₄ in PAC ), 140.20
& 140.24(2C, Aromatic C₂ in PAC ), 140.71(24%), 14
0.75(31%),140.82(28%), 140.85(31%), 141.00(58%) &
141.07(33%)(8C, Aromatic C_6,7 in Fm ), 142.31(51
%), 142.43(29%), 142.52(30%), 1442.96(46%), 143.01
(34%)& 143.05(32%)(8C, Aromatic C_1,12 in Fm ), 16
5.83 & 166.42[2C, OC(O) inPAC], 172.52 & 172.55[2
C, OC(O) in Levulinoyl], 206.96 & 207.14[2C, OC(O)
in Levulinoyl]³¹ P-NMR(109.4 MHz, CDCl₃), δ = 0.79, 0.89 元素分析 Calcd for C₉₀H₈₂O₂₀P₂ (mol wt 1545.6); C, 69.94; H, 5.35 found ; C, 69.54; H, 5.43 ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 2.09 (6H,
s, CH ₃ ), 2.32 [4H, complex, OC (O) C H ₂ CH _2- ], 2.54 [4
H, complex, OC (O) CH ₂ C H _2- ], 3.06-3.46 [6H, complex,
Ar-C H ₂ CH ₂ O- & OCH ₂ C H * 2 in Fm), 3.57-3.97 (9H, comp
_{lex, Ins. H 1, OC} H 2 CH * 3 & OCH 2 C H * 2 in Fm), 4.18-4.2
7 (2H, complex, OC H ₂ CH in Fm), 4.28-4.40 (4H, compl
ex, Ar-CH ₂ C H ₂ O-), 4.42 (1H, br, Ins-H ₂ ), 4.91 (1H,
brq, J = 9.8 Hz, Ins-H ₅ ), 5.35 (2H, complex, Ins-H
H _3,4 ), 5.88 (1H, t, J = 9.8 Hz, Ins-H ₆ ), 6.88-7.53 (34
H, complex, Aromatic H _3,4,5 in PAC & Aromatic H in
Fm), 7.57-7.62 (4H, complex, Aromatic H _5,8 in Fm),
8.24 & 8.27 (2H, dd * 2, J = 7.1, 1.5 Hz, Aromatic H ₆
in PAC) ¹³ C-NMR (67.9 MHz, CDCl ₃ ), δ = 27.64 & 27.70 [2C, C
(O) CH ₂ in Levulinoyl], 29.67 (2C, CH ₃ in Levulinoy
l), 33.66 & 33.82 (2C, Ar C H ₂ in PAC), 37.69 & 37.74
[2C, OC (O) CH ₂ C H ₂ in Levulinoyl], 46.76 & 46.88 (2C,
d * 2, J = 8.4 Hz, OCH ₂ C H in Fm), 47.27 (2C, d, J = 8.4
Hz, OCH ₂ C H in Fm), 64.30 & 64.46 (2C, ArCH ₂ C H ₂ in
PAC), 69.16 & 69.24 (2C, d * 2, J = 6.0 Hz, O C H ₂ in F
m), 69.52 (2C, d , J = 6.0 Hz, O C H 2 in Fm), 70.05 (In
s.C ₂ ), 70.25 (Ins.C ₁ ), 72.15 (Ins.C ₃ ), 72.94 (I
ns.C ₆ ), 76.66 & 76.74 (d * 2, J = 5.5 Hz, Ins.C ₄ ), 7
7.47 (m, Ins.C ₅ ), 119.58 (52%) & 119.68 (78%) (8C, A
romatic C _5,8 in Fm), 124.72, 124.78, 124.99, 125.
00, 125.12, 125.20, 125.23 & 125.35 (8C, AromaticC
_2,11 in Fm), 12.66 (36%), 126.78 (100%), 126.91 (34
%), 127.42 (57%), 127.56 (56%) & 127.59 (58%) (18C, Ar
omatic C ₅ in PAC & Aromatic C _3,4,9,10 in Fm), 12
8.48 & 128.89 (2C, Aromatic C ₁ in PAC), 131.82, 13
1.99, 132.03 & 132.11 (4C, Aromatic C _3,6 in PAC),
132.43 & 132.61 (2C, Aromatic C ₄ in PAC), 140.20
& 140.24 (2C, Aromatic C ₂ in PAC), 140.71 (24%), 14
0.75 (31%), 140.82 (28%), 140.85 (31%), 141.00 (58%) &
141.07 (33%) (8C, Aromatic C _6,7 in Fm), 142.31 (51
%), 142.43 (29%), 142.52 (30%), 1442.96 (46%), 143.01
(34%) & 143.05 (32%) (8C, Aromatic C _1,12 in Fm), 16
5.83 & 166.42 [2C, OC (O) inPAC], 172.52 & 172.55 [2
C, OC (O) in Levulinoyl], 206.96 & 207.14 [2C, OC (O)
in Levulinoyl] ³¹ P-NMR (109.4 MHz, CDCl ₃ ), δ = 0.79, 0.89 Elemental analysis Calcd for C ₉₀ H ₈₂ O ₂₀ P ₂ (mol wt 1545.6); C, 69.94; H, 5.35 found; C, 69.54 ; H, 5.43

【００３８】実施例１４ ［化合物28の合成］1,2-Dioleoyl glycerol (1.72 mg,
2.77 mmol, 5.0 eq.) を 窒素雰囲気下、無水クロロホ
ルム 10 ml に溶解し攪拌する。これに N,N-diisopropy
l-O-dimethyloxy phosphroamidite (530 ml, 3.34 mmo
l, 6.0 eq.) と 1H-Tetrazole (355.4 mg, 5.07 mmol,
9.0 eq.) を加え 30分間攪拌する。反応終了後ジエチル
エーテルで抽出し、飽和炭酸水素ナトリウム、飽和食塩
水で洗う。有機層を無水硫酸ナトリウムで乾燥、濾過、
濃縮し、ホスファイトを得た。ひきつづき、ホスファイ
トと3,6-di-O-{2-[2-(levulinoyloxy)ethyl]benzoate}
-4,5-bis-O-(difluorenylmethyloxyphosphate)-myo-ino
sitol (27, 867.9 mg, 0.562 mmol, 1.0 eq.)を窒素雰
囲気下、無水クロロホルム 20 ml に溶解し、2,6-Lutid
ine (490 ml, 4.21 mmol, 7.5 eq.)を加える。さらに、
-72 ℃で PyHBr3 (1060.0 mg, 3.31 mmol, 6.0 eq.) を
加え、0℃で 30分間攪拌する。その後、水を加え１時間
攪拌しquench. し、酢酸エチルを加え、飽和硫酸水素カ
リウム、飽和炭酸水素ナトリウム、飽和食塩水で洗い、
有機層を無水硫酸ナトリウムで乾燥、濾過、濃縮する。
フラッシュカラムクロマトグラフィ−(AcOEt/Hex.=1/
1：Rf値0.3)で精製し、目的物1-O-(1,2-Dioleoylglycer
yl methyl phospholyl)-3,6-di-O-{2-[2-(levulinoylox
y)ethyl]benzoate}-4,5-bis-O-(difluorenylmethyloxyp
hosphate)-myo-inositol (28, 1131.0 mg, 90%) を得
た。Example 14 [Synthesis of Compound 28] 1,2-Dioleoyl glycerol (1.72 mg,
Dissolve 2.77 mmol, 5.0 eq.) In 10 ml of anhydrous chloroform under a nitrogen atmosphere and stir. N, N- diisopropy
l- O -dimethyloxy phosphroamidite (530 ml, 3.34 mmo
l, 6.0 eq.) and 1 H- Tetrazole (355.4 mg, 5.07 mmol,
9.0 eq.) And stir for 30 minutes. After completion of the reaction, the reaction solution is extracted with diethyl ether and washed with saturated sodium hydrogen carbonate and saturated saline. The organic layer is dried over anhydrous sodium sulfate, filtered,
Concentration gave a phosphite. The phosphite and 3,6-di- O- {2- [2- (levulinoyloxy) ethyl] benzoate}
-4,5-bis- O - (difluorenylmethyloxyphosphate) - myo -ino
sitol (27, 867.9 mg, 0.562 mmol, 1.0 eq.) was dissolved in 20 ml of anhydrous chloroform under a nitrogen atmosphere, and 2,6-Lutid
Add ine (490 ml, 4.21 mmol, 7.5 eq.). further,
PyHBr3 (1060.0 mg, 3.31 mmol, 6.0 eq.) Is added at -72 ° C, and the mixture is stirred at 0 ° C for 30 minutes. After that, add water, stir for 1 hour, quench, add ethyl acetate, wash with saturated potassium hydrogen sulfate, saturated sodium hydrogen carbonate and saturated saline,
The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated.
Flash column chromatography (AcOEt / Hex. = 1 /
1: Purification by Rf value 0.3), the target product 1- O- (1,2-Dioleoylglycer)
yl methyl phospholyl) -3,6-di- O- {2- [2- (levulinoylox
y) ethyl] benzoate} -4,5-bis- O- (difluorenylmethyloxyp
hosphate) - myo -inositol (28, to obtain a 1131.0 mg, 90%).

【００３９】Rf 0.4 (AcOEt/Hex.=3/2)¹ H-NMR (400 MHz, CDCl₃) δ = 0.88(6H, t, J=6.8 Hz,
CH₃ in Oleoyl), 1.25(40H, br, CH₂ in Oleoyl), 1.5
4(4H, br, b-CH₂ in Oleoyl), 2.00(8H, br ,Allylic H
in Oleoyl), 2.08(6H, s, CH₃ in Levulinoyl), 2.21-
2.34[8H, complex, a-CH₂ in Oleoyl & OC(O)CH₂ in L
evulinoyl], 2.53[4H, t, J=6.8 Hz, OC(O)CH₂CH₂ in
Levulinoyl], 3.08-3.38(6H, complex, ArCH₂ in PAC &
OCH₂CH*2 in Fm), 3.29, 3.31, 3.667, 3.674(3H, d*
4, J=11.2 Hz each, OCH₃), 3.43-4.39(14H, complex,
CH₂ O in PAC, OCH₂ CH*4 & OCH₂CH*2 in Fm), 3.80-4.20
(2H, complex, Hγ in Glyceryl), 4.02-4.38(2H, comp
lex, Hα in Glyceryl), 4.47 & 4.63(1H, br*2, Ins.
H₂), 4.60-4.75(1H, br, Ins. H₁), 4.97 & 5.14-5.27
(1H, br, Hβ in Glyceryl), 5.35(7H, br, Ins. H_3,4
& HC=CH), 6.09 & 6.10(1H, t*2, J=11.2 Hz, Ins.
H₆), 6.82-7.59(38H, complex, Aromatic H_3,4,5in PAC
& Aromatic H in Fm), 8.25(2H, complex, Aromatic H
₆ in PAC)¹³ C-NMR(100.5 MHz, CDCl₃), δ =14.10(2C, CH₃ in
Oleoyl), 22.66(2C, CH₂CH₃ in Oleoyl), 24.70[2C, O
C(O)CH₂CH₃], 27.13 & 27.17[2C, C(O)CH₂ inLevulinoy
l], 27.64 & 27.73(2C, Allylic C), 29.09-29.65(18C,
complex, CH₂in Oleoyl & CH₃ in Levulinoyl), 31.8
5(2C, CH₂CH₂CH₃ in Oleoyl), 32.54[2C, C(O)CH₂ in O
leoyl], 33.68, 33.88 & 33.97(2C, br, ArCH₂ in PA
C), 37.77[2C, OC(O)CH ₂CH₂ in Levulinoyl], 46.84 &
47.00(2C, d*2, J=9.2 Hz, OCH ₂CH in Fm), 47.39(2C,
d, J=9.2 Hz, OCH ₂CH in Fm), 61.32 & 61.80(1C, C
αin Glyceryl), 64.41, 64.47, 64.54 & 64.58(2C, Ar
CH ₂CH₂ in PAC), 65.51 &65.80(1C, complex, Cγ in G
lyceryl), 68.76, 69.00, 69.09 & 69.15(2C, complex,
Ins. C₃ & Cγ in Glyceryl), 69.30 & 69.60(4C, d*
2, J=5.6 Hz, OCH₂in Fm), 70.50(Ins. C₂), 71.13
(m, Ins. C₆), 75.80-76.26(3C, complex, Ins. H1,4,
5), 119.64(18%) & 119.73(28%)(8C, Aromatic C_5,8 in
Fm), 124.74(8%), 124.89(8%), 125.04(br, 10%), 12
5.22(15%), 125.33(9%) & 125.47(7%)(8C, Aromatic
C₂, 11 in Fm), 126.74(13%), 126.85(32%), 126.92
(17%), 127.03(11%), 127.45(15%), 127.50(19%), 127.
65(br, 16%) & 127.72(11%)(18C, Aromatic C₅ in PAC
&Aromatic C_3,4,9,10 in Fm), 128.42 & 128.47(2C, A
romatic C₁ in PAC ), 129.69(9%), 129.97(10%), 130.
16(4%), 130.23(4%), 130.39(4%), 130.45(4%) & 130.5
4(3%)(4C, Vinyl C), 131.93(3%), 132.11(10%), 132.3
7(4%), 132.48(4%) & 132.72(4C, Aromatic C_3,4,6 in
PAC ), 140.42(3%), 140.56(2%), 140.76(6%), 140.85
(11%), 140.91(11%), 141.09(14%) & 141.20(7%)(9C, A
romatic C₂ in PAC & Aromatic C₆, 7 in Fm ), 142.3
0, 142.46, 142.52, 142.67, 142.96, 143.01, 143.10
& 143.18(8C, Aromatic C_1,12 in Fm ), 165.23(4%),
165.31(2%), 165.58(4%) & 165.71(3%)[2C, OC(O) in P
AC], 172.36(7%), 172.46(5%), 172.53(5%), 172.73(3
%), 173.10(2%), 173.17(2%) & 173.46(2%)[4C, OC(O)
in Oleoyl & OC(O) in Levulinoyl], 206.53, 206.58,
206.76& 206.89[2C, OC(O) in Levulinoyl]³¹ P-NMR(109.4 MHz, CDCl₃), δ = -0.76(74%), -0.71
(64%), 0.52(100%), 0.42(32%), 0.47(35%), 1.05(21
%), 1.19(35%) 元素分析 Calcd for C₁₃₀H₁₅₅O₂₇P₃ (mol wt 1545.6); C, 69.63; H, 69.63 C₁₃₀H₁₅₅O₂₇P₃・2H₂O(mol wt 1563.6); C, 68.53; H, 7.03 found ; C, 68.55; H, 7.15 R f 0.4 (AcOEt / Hex. = 3/2) ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 0.88 (6H, t, J = 6.8 Hz,
CH ₃ in Oleoyl), 1.25 (40H, br, CH ₂ in Oleoyl), 1.5
4 (4H, br, b-CH ₂ in Oleoyl), 2.00 (8H, br, Allylic H
in Oleoyl), 2.08 (6H, s, CH ₃ in Levulinoyl), 2.21-
2.34 [8H, complex, a-CH ₂ in Oleoyl & OC (O) C H ₂ in L
evulinoyl], 2.53 [4H, t, J = 6.8 Hz, OC (O) CH ₂ C H ₂ in
Levulinoyl], 3.08-3.38 (6H, complex, ArC H ₂ in PAC &
OCH ₂ C H * 2 in Fm), 3.29, 3.31, 3.667, 3.674 (3H, d *
4, J = 11.2 Hz each, OCH ₃ ), 3.43-4.39 (14H, complex,
C H ₂ O in PAC, OC H ₂ CH * 4 & OCH ₂ C H * 2 in Fm), 3.80-4.20
(2H, complex, Hγ in Glyceryl), 4.02-4.38 (2H, comp
lex, Hα in Glyceryl), 4.47 & 4.63 (1H, br * 2, Ins.
H ₂ ), 4.60-4.75 (1H, br, Ins.H ₁ ), 4.97 & 5.14-5.27
(1H, br, Hβ in Glyceryl), 5.35 (7H, br, Ins.H _3,4
& H C = C H ), 6.09 & 6.10 (1H, t * 2, J = 11.2 Hz, Ins.
H ₆ ), 6.82-7.59 (38H, complex, Aromatic H _3,4,5 in PAC
& Aromatic H in Fm), 8.25 (2H, complex, Aromatic H
₆ in PAC) ¹³ C-NMR (100.5 MHz, CDCl ₃ ), δ = 14.10 (2C, CH ₃ in
Oleoyl), 22.66 (2C, C H ₂ CH ₃ in Oleoyl), 24.70 [2C, O
C (O) CH ₂ CH ₃ ], 27.13 & 27.17 [2C, C (O) CH ₂ inLevulinoy
l], 27.64 & 27.73 (2C, Allylic C), 29.09-29.65 (18C,
complex, CH ₂ in Oleoyl & CH ₃ in Levulinoyl), 31.8
5 (2C, C H ₂ CH ₂ CH ₃ in Oleoyl), 32.54 [2C, C (O) C H ₂ in O
leoyl], 33.68, 33.88 & 33.97 (2C, br, Ar C H ₂ in PA
C), 37.77 [2C, OC (O) CH ₂ C H ₂ in Levulinoyl], 46.84 &
47.00 (2C, d * 2, J = 9.2 Hz, OCH ₂ C H in Fm), 47.39 (2C,
d, J = 9.2 Hz, OCH ₂ C H in Fm), 61.32 & 61.80 (1C, C
αin Glyceryl), 64.41, 64.47, 64.54 & 64.58 (2C, Ar
CH ₂ C H ₂ in PAC), 65.51 & 65.80 (1C, complex, Cγ in G
lyceryl), 68.76, 69.00, 69.09 & 69.15 (2C, complex,
Ins.C ₃ & Cγ in Glyceryl), 69.30 & 69.60 (4C, d *
2, J = 5.6 Hz, O C H ₂ in Fm), 70.50 (Ins.C ₂ ), 71.13
(m, Ins.C ₆ ), 75.80-76.26 (3C, complex, Ins.H1,4,
5), 119.64 (18%) & 119.73 (28%) (8C, Aromatic C _5,8 in
Fm), 124.74 (8%), 124.89 (8%), 125.04 (br, 10%), 12
5.22 (15%), 125.33 (9%) & 125.47 (7%) (8C, Aromatic
C ₂ , 11 in Fm), 126.74 (13%), 126.85 (32%), 126.92
(17%), 127.03 (11%), 127.45 (15%), 127.50 (19%), 127.
65 (br, 16%) & 127.72 (11%) (18C, Aromatic C ₅ in PAC
& Aromatic C _3,4,9,10 in Fm), 128.42 & 128.47 (2C, A
romatic C ₁ in PAC), 129.69 (9%), 129.97 (10%), 130.
16 (4%), 130.23 (4%), 130.39 (4%), 130.45 (4%) & 130.5
4 (3%) (4C, Vinyl C), 131.93 (3%), 132.11 (10%), 132.3
7 (4%), 132.48 ( 4%) & 132.72 (4C, Aromatic C 3,4,6 in
PAC), 140.42 (3%), 140.56 (2%), 140.76 (6%), 140.85
(11%), 140.91 (11%), 141.09 (14%) & 141.20 (7%) (9C, A
romatic C ₂ in PAC & Aromatic C ₆ , 7 in Fm), 142.3
0, 142.46, 142.52, 142.67, 142.96, 143.01, 143.10
& 143.18 (8C, Aromatic C _1,12 in Fm), 165.23 (4%),
165.31 (2%), 165.58 (4%) & 165.71 (3%) [2C, OC (O) in P
AC], 172.36 (7%), 172.46 (5%), 172.53 (5%), 172.73 (3
%), 173.10 (2%), 173.17 (2%) & 173.46 (2%) [4C, OC (O)
in Oleoyl & OC (O) in Levulinoyl], 206.53, 206.58,
206.76 & 206.89 [2C, OC (O) in Levulinoyl] ³¹ P-NMR (109.4 MHz, CDCl ₃ ), δ = -0.76 (74%), -0.71
(64%), 0.52 (100%), 0.42 (32%), 0.47 (35%), 1.05 (21
%), 1.19 (35%) Elemental analysis Calcd for C ₁₃₀ H ₁₅₅ O ₂₇ P ₃ (mol wt 1545.6); C, 69.63; H, 69.63 C ₁₃₀ H ₁₅₅ O ₂₇ P ₃・ 2H ₂ O (mol wt 1563.6) ; C, 68.53; H, 7.03 found; C, 68.55; H, 7.15

【００４０】実施例１５ ［化合物29の合成］窒素雰囲気下、1-O-(1,2-Dioleoylg
lyceryl methyl phospholyl)-3,6-di-O-{2-[2-(levulin
oyloxy) ethyl]benzoate}-4,5 -bis-O-(difluorenylmet
hyloxy- phosphate)-myo-inositol (28, 573.5 mg, 0.2
56 mmol) を特級アセトンに溶解する。ヨウ化ナトリウ
ム (191.5 mg, 1.28 mmol, 5.0 eq.) を加え、4.5時間
還流する。その後、フラッシュカラムクロマトグラフィ
ー (AcOEt/Hex.=4/1→CHCl3/MeOH/Acetone=4/2/1) で精
製し目的物 1-O-(1,2-Dioleoylglyceryl-phospholyl)-
3,6-di- O-{2-[2-(levulinoyloxy)ethyl]- benzoate}-
4,5-bis-O- (difluorenylmethyloxyphosphate)-myo-ino
sitol (29, 483.6 mg, 84%) を得た。Example 15 [Synthesis of Compound 29] 1- O- (1,2-Dioleoylg) under a nitrogen atmosphere
lyceryl methyl phospholyl) -3,6-di- O- {2- [2- (levulin
oyloxy) ethyl] benzoate} -4,5-bis- O- (difluorenylmet
hyloxy- phosphate) - myo -inositol (28 , 573.5 mg, 0.2
(56 mmol) is dissolved in special grade acetone. Add sodium iodide (191.5 mg, 1.28 mmol, 5.0 eq.) And reflux for 4.5 hours. After that, it was purified by flash column chromatography (AcOEt / Hex. = 4/1 → CHCl3 / MeOH / Acetone = 4/2/1) and the target product 1- O- (1,2-Dioleoylglyceryl-phospholyl)-
3,6-di- O- {2- [2- (levulinoyloxy) ethyl] -benzoate}-
4,5-bis- O - (difluorenylmethyloxyphosphate) - myo -ino
sitol (29, 483.6 mg, 84%) was obtained.

【００４１】Rf 0.5 (CHCl3/Acetone/MeOH=3/2/1)¹ H-NMR (270 MHz, CDCl₃) δ = 0.88(6H, t, J=6.6 Hz,
CH₃ in Oleoyl), 1.26(40H, br, CH₂ in Oleoyl), 1.5
3(4H, br, b-CH₂ in Oleoyl), 2.04(14H, br ,Allylic
H in Oleoyl & CH₃ in Levulinoyl), 2.18(4H, br, a-C
H₂ in Oleoyl), 2.31[4H, br, OC(O)CH₂ in Levulinoy
l], 2.55[4H, complex, OC(O)CH₂CH₂ in Levulinoyl],
2.84-4.40(25H, complex, Ins. H₁, Hα, γ' in Glyc
eryl,OCH₂ CH*2 in Fm, ArCH₂ CH₂ in PAC & OCH₂CH*2 i
n Fm), 4.80(1H, br, Ins. H₂), 4.96(1H, br, Ins.
H₅), 5.36(7H, br, Ins. H_3,4, Hβ in Glyceryl & HC=
CH), 5.90(1H, brt, J=5.8 Hz, Ins. H₆), 6.81-7.60(3
8H, complex, Aromatic H_3,4,5 in PAC & Aromatic H i
n Fm), 8.20 & 8.38(2H, complex, Aromatic H₆ in PA
C)³¹ P-NMR(109.4 MHz, CDCl₃), δ = -1.16(1P, s), -0.2
5(1P, br), 3.55(1P,br) R f 0.5 (CHCl 3 / Acetone / MeOH = 3/2/1) ¹ H-NMR (270 MHz, CDCl ₃ ) δ = 0.88 (6H, t, J = 6.6 Hz,
CH ₃ in Oleoyl), 1.26 (40H, br, CH ₂ in Oleoyl), 1.5
3 (4H, br, b-CH ₂ in Oleoyl), 2.04 (14H, br, Allylic
H in Oleoyl & CH ₃ in Levulinoyl), 2.18 (4H, br, aC
H ₂ in Oleoyl), 2.31 [4H, br, OC (O) C H ₂ in Levulinoy
l], 2.55 [4H, complex, OC (O) CH ₂ C H ₂ in Levulinoyl],
2.84-4.40 (25H, complex, Ins.H ₁ , Hα, γ 'in Glyc
eryl, OC H ₂ C H * 2 in Fm, ArC H ₂ C H ₂ in PAC & OCH ₂ C H * 2 i
n Fm), 4.80 (1H, br, Ins.H ₂ ), 4.96 (1H, br, Ins.
H ₅ ), 5.36 (7H, br, Ins.H _3,4 , Hβ in Glyceryl & H C =
C H ), 5.90 (1H, brt, J = 5.8 Hz, Ins.H ₆ ), 6.81-7.60 (3
8H, complex, Aromatic H _3,4,5 in PAC & Aromatic H i
n Fm), 8.20 & 8.38 (2H, complex, Aromatic H ₆ in PA
C) ³¹ P-NMR (109.4 MHz, CDCl ₃ ), δ = -1.16 (1P, s), -0.2
5 (1P, br), 3.55 (1P, br)

【００４２】実施例１６ ［化合物30の合成］1-O-(1,2-Dioleoylglyceryl-phosph
olyl)-3,6-di-O-{2- [2-(levulinoyloxy)ethyl]benzoat
e}-4,5-bis-O-(difluorenylmethyloxyphosphate)-myo-i
nositol (29, 481.0 mg, 0.214 mmol) をプロピオニト
リルで共沸し水を除き、プロピオニトリル 2.5 ml 、ア
セトニトリル 7.5 ml 、トリエチルアミン (4 ml, 28.7
mmol, 130 eq.) を加える。室温で一晩攪拌した後、7
時間還流する。溶媒留去した後、ヘキサンに溶けるもの
を除き精製する。この時、３位のPAC基が２位に転移し
た1-O-(1,2-Dioleoylglyceryl phosphoryl)-3,6-di-O-
{2-[2-(levulinoyloxy)ethyl] benzoate}-myo-inositol
4,5-bis-phosphate (30) (30, 321.3 mg, 86%)を得
た。Example 16 [Synthesis of Compound 30] 1- O- (1,2-Dioleoylglyceryl-phosph)
olyl) -3,6-di- O- {2- [2- (levulinoyloxy) ethyl] benzoat
e} -4,5-bis- O - ( difluorenylmethyloxyphosphate) - myo -i
Nositol (29, 481.0 mg, 0.214 mmol) was azeotropically distilled with propionitrile to remove water, and propionitrile 2.5 ml, acetonitrile 7.5 ml, triethylamine (4 ml, 28.7
mmol, 130 eq.). After stirring overnight at room temperature, 7
Reflux for hours. After distilling off the solvent, the residue is purified except that it dissolves in hexane. At this time, the 1- O- (1,2-Dioleoylglyceryl phosphoryl) -3,6-di- O- in which the PAC group at the 3-position has been transferred to the 2-position
{2- [2- (levulinoyloxy) ethyl ] benzoate} - myo -inositol
4,5-bis-phosphate (30) (30, 321.3 mg, 86%) was obtained.

【００４３】Rf 0.4 (CHCl3/Acetone/MeOH/AcOH/H2O=4
0/15/13/12/8)¹ H-NMR (270 MHz, NEt₃ salt, 20.0 mg in 2.5 ml CDCl
₃ & 0.3 ml CD₃OD & 1drop D₂O, pH ca. 7) δ = 0.88
(6H, t, J=5.4 Hz, CH₃ in Oleoyl), 1.12(18H,t, J=7.
3 Hz, NCH₂CH₃ ), 1.26(40H, br, CH₂ in Oleoyl), 1.5
3(4H, br, b-CH2 in Oleoyl), 1.98(8H, br , Allylic
H in Oleoyl), 2.16 & 2.17(6H, s*2, CH₃ in Levulino
yl), 2.19(4H, complex, α-CH₂ in Oleoyl), 2.52[4H,
t, J=6.4 Hz, OC(O)CH₂ in Levulinoyl], 2.73[4H, b
rt, J=6.4 Hz, OC(O)CH₂CH₂ inLevulinoyl], 2.91(12H,
q, J=7.3 Hz, NCH₂ ), 3.15-3.38(4H, complex, 29ArC
H₂ in PAC), 3.60-3.91(3H, complex, Hα,γ,γ' in
Glyceryl), 4.07(1H, brdd, Ins. H₃), 4.11(1H, brt,
J=10.7 Hz, Hα' in Glyceryl), 4.34(4H, complex, CH
₂ O in PAC), 4.40-4.62(3H, complex, Ins. H_1,4,5),
5.01(1H, br, Hβin Glyceryl), 5.35(4H, br, HC=CH),
5.74(1H, t, J=9.3 Hz, Ins. H₆), 5.98(1H, br, Ins.
H₂), 7.25(1H, d, J=7.3 Hz, Aromatic H₃), 7.32(2H,
complex,Aromatic H_3',5), 7.41(2H, t, J=7.3 Hz, Ar
omatic H_4,5'), 7.49(1H, t, J=7.3 Hz, Aromatic
H_4'), 8.06 & 8.27(2H, d*2, J=7.3 Hz, Aromatic H
_6,6') ³¹ P-NMR (109.4 MHz, NEt₃ salt, 20.0 mg in 2.5 ml C
DCl₃ & 0.3 ml CD₃OD& 1drop D₂O, pH ca. 9) δ =0.08
(1P, s), 0.8.4(1P, br), 6.96(1P, br) R f 0.4 (CHCl 3 / Acetone / MeOH / AcOH / H 2 O = 4
0/15/13/12/8) ¹ H-NMR (270 MHz, NEt ₃ salt, 20.0 mg in 2.5 ml CDCl
₃ & 0.3 ml CD ₃ OD & 1 drop D ₂ O, pH ca. 7) δ = 0.88
(6H, t, J = 5.4 Hz, CH ₃ in Oleoyl), 1.12 (18H, t, J = 7.
3 Hz, NCH ₂ CH ₃ ), 1.26 (40H, br, CH ₂ in Oleoyl), 1.5
3 (4H, br, b-CH2 in Oleoyl), 1.98 (8H, br, Allylic
H in Oleoyl), 2.16 & 2.17 (6H, s * 2, CH ₃ in Levulino
yl), 2.19 (4H, complex, α-CH ₂ in Oleoyl), 2.52 [4H,
t, J = 6.4 Hz, OC (O) C H ₂ in Levulinoyl], 2.73 [4H, b
rt, J = 6.4 Hz, OC (O) CH ₂ C H ₂ inLevulinoyl], 2.91 (12H,
q, J = 7.3 Hz, NC H ₂ ), 3.15-3.38 (4H, complex, 29ArC
H ₂ in PAC), 3.60-3.91 (3H, complex, Hα, γ, γ 'in
Glyceryl), 4.07 (1H, brdd, Ins.H ₃ ), 4.11 (1H, brt,
J = 10.7 Hz, Hα 'in Glyceryl), 4.34 (4H, complex, C H
₂ O in PAC), 4.40-4.62 (3H, complex, Ins.H _1,4,5 ),
5.01 (1H, br, Hβin Glyceryl), 5.35 (4H, br, H C = C H ),
5.74 (1H, t, J = 9.3 Hz, Ins.H ₆ ), 5.98 (1H, br, Ins.
H ₂ ), 7.25 (1H, d, J = 7.3 Hz, Aromatic H ₃ ), 7.32 (2H,
complex, Aromatic H _{3 ', 5} ), 7.41 (2H, t, J = 7.3 Hz, Ar
omatic H _{4,5 '} ), 7.49 (1H, t, J = 7.3 Hz, Aromatic
H _{4 '} ), 8.06 & 8.27 (2H, d * 2, J = 7.3 Hz, Aromatic H
_{6,6 ')} ³¹ P-NMR (109.4 MHz, NEt ₃ salt, 20.0 mg in 2.5 ml C
DCl ₃ & 0.3 ml CD ₃ OD & 1 drop D ₂ O, pH ca. 9) δ = 0.08
(1P, s), 0.8.4 (1P, br), 6.96 (1P, br)

【００４４】実施例１７ ［化合物31の合成］1-O-(1,2-Dioleoylglyceryl phosph
oryl)-3,6-di-O-{2- [2-(levulinoyloxy)ethyl]benzoat
e}-myo- inositol 4,5-bis-phosphate (30, 144.3 mg,
0.083 mmol) をピリジン/酢酸＝4/1 溶媒 3 ml に溶解
し、反応系を０ ℃に冷却しヒドラジン・1水和物 (28 m
l, 0.58 mmol, 6 eq.) を加える。室温で３時間攪拌し
た後、溶媒を留去する。クロロホルム/メタノール＝2/1
溶媒に溶解し0.5N 塩酸で洗浄し、有機層を無水硫酸ナ
トリウムで乾燥し、ろ過、濃縮後、残査を得た。この残
査をエーテルに溶けるものを除き、精製し、目的物 1-O
-(1,2-Dioleoylglycerylphosphoryl)-3,6-di-O-[2-(2-h
ydroxyethyl)benzoate]- myo-inositol 4,5- bis-phosp
hate (31, 118.1 mg, 88%) を得た。Example 17 [Synthesis of Compound 31] 1- O- (1,2-Dioleoylglyceryl phosph)
oryl) -3,6-di- O- {2- [2- (levulinoyloxy) ethyl] benzoat
e} -myo -inositol 4,5-bis-phosphate (30, 144.3 mg,
0.083 mmol) was dissolved in 3 ml of pyridine / acetic acid = 4/1 solvent, the reaction system was cooled to 0 ° C, and hydrazine monohydrate (28 m
l, 0.58 mmol, 6 eq.). After stirring at room temperature for 3 hours, the solvent is distilled off. Chloroform / methanol = 2/1
After dissolving in a solvent and washing with 0.5N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. This residue was purified except that it was soluble in ether, and the target compound 1- O
-(1,2-Dioleoylglycerylphosphoryl) -3,6-di- O- [2- (2-h
ydroxyethyl) benzoate] - myo -inositol 4,5- bis-phosp
hate (31, 118.1 mg, 88%) was obtained.

【００４５】Rf 0.3 (CHCl₃/Acetone/MeOH/AcOH/H2O=4
0/15/13/12/8)¹ H-NMR (270 MHz, NEt₃ salt, 20.1 mg in 2.5 ml CDCl
₃ & 0.3 ml CD₃OD & 1drop D₂O, pH ca. 7) δ = 0.88
(6H, t, J=6.8 Hz, CH₃ in Oleoyl), 1.26(67H,br, CH₂
in Oleoyl & NCH₂CH₃ ), 1.55(4H, br, b-CH₂ in Oleoy
l), 1.99(8H, br , Allylic H in Oleoyl), 2.23(4H, b
r, a-CH₂ in Oleoyl), 2.90-3.37(22H,br, ArCH₂ in PA
C & NCH₂ ), 3.63-4.26(9H, br, Ins. H₃, CH₂ OH in PAC
& Hα,γ in Glyceryl), 4.40-4.58(3H, complex, In
s. H_1,4,5), 5.03(1H, br, Hβ in Glyceryl), 5.36(4
H, br, HC=CH), 5.74(1H, brt, J=10.6 Hz, Ins. H₆),
6.07(1H, br, Ins. H₂), 7.28-7.46(6H, complex, Arom
atic H_3,4,5), 7.82(1H, brd, J=6.8 Hz, Aromatic
H₆), 8.10(1H, brd, J=6.8 Hz, Aromatic H_6')³¹ P-NMR (109.4 MHz, NEt₃ salt, 20.1 mg in 2.5 ml C
DCl₃ & 0.3 ml CD₃OD& 1drop D₂O, pH ca. 8) δ = -0.
13, 0.31, 7.04 R f 0.3 (CHCl ₃ / Acetone / MeOH / AcOH / H2O = 4
0/15/13/12/8) ¹ H-NMR (270 MHz, NEt ₃ salt, 20.1 mg in 2.5 ml CDCl
₃ & 0.3 ml CD ₃ OD & 1 drop D ₂ O, pH ca. 7) δ = 0.88
(6H, t, J = 6.8 Hz, CH ₃ in Oleoyl), 1.26 (67H, br, CH ₂
in Oleoyl & NCH ₂ CH ₃ ), 1.55 (4H, br, b-CH ₂ in Oleoy
l), 1.99 (8H, br, Allylic H in Oleoyl), 2.23 (4H, b
r, a-CH ₂ in Oleoyl), 2.90-3.37 (22H, br, ArC H ₂ in PA
C & NC H ₂ ), 3.63-4.26 (9H, br, Ins.H ₃ , C H ₂ OH in PAC
& Hα, γ in Glyceryl), 4.40-4.58 (3H, complex, In
_{s.H 1,4,5} ), 5.03 (1H, br, Hβ in Glyceryl), 5.36 (4
H, br, H C = C H ), 5.74 (1H, brt, J = 10.6 Hz, Ins.H ₆ ),
6.07 (1H, br, Ins.H ₂ ), 7.28-7.46 (6H, complex, Arom
atic H _3,4,5 ), 7.82 (1H, brd, J = 6.8 Hz, Aromatic
H ₆ ), 8.10 (1H, brd, J = 6.8 Hz, Aromatic H _{6 '} ) ³¹ P-NMR (109.4 MHz, NEt ₃ salt, 20.1 mg in 2.5 ml C
DCl ₃ & 0.3 ml CD ₃ OD & 1 drop D ₂ O, pH ca. 8) δ = -0.
13, 0.31, 7.04

【００４６】実施例１８ ［PIP₂の合成］1-O-(1,2-Dioleoylglyceryl phosphory
l)-3,6-di-O-[2-(2-hydroxyethyl)- benzoate]-myo-ino
sitol 4,5- bis-phosphate (31, 86.8 mg, 0.053 mmol)
を念入りにピリジン共沸し、完全に水を除く。その後、
無水塩化メチレン 3 ml に溶解し、反応系を０℃ に冷
却する。t-BuOK (45.3 mg, 0.404 mmol, 7.0 eq.) を加
え、室温に戻し4.5時間攪拌する。クロロホルム/メタノ
ール＝2/1 を抽出溶媒とし飽和硫酸水素カリウムで洗浄
する。有機層を無水硫酸ナトリウムで乾燥し、ろ過、濃
縮後、残査を得た。この残査をエーテルに溶けるものを
除き、精製し、目的物 1-O-(1,2-Dioleoylglyceryl pho
sphoryl)-myo-inositol 4,5- bis-phosphate (32, 22.
2 mg, ) を得た。Example 18 [Synthesis of PIP ₂ ] 1- O- (1,2-Dioleoylglyceryl phosphory)
l) -3,6-di- O - [ 2- (2-hydroxyethyl) - benzoate] - myo -ino
sitol 4,5-bis-phosphate (31, 86.8 mg, 0.053 mmol)
Carefully evaporate pyridine to completely remove water. afterwards,
Dissolve in 3 ml of anhydrous methylene chloride and cool the reaction to 0 ° C. Add t- BuOK (45.3 mg, 0.404 mmol, 7.0 eq.), return to room temperature and stir for 4.5 hours. Wash with saturated potassium hydrogen sulfate using chloroform / methanol = 2/1 as an extraction solvent. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified except that it was soluble in ether, and purified to give the desired product 1- O- (1,2-Dioleoylglyceryl phopho.
sphoryl) - myo -inositol 4,5- bis- phosphate (32, 22.
2 mg,).

【００４７】Rf 0.2 (CHCl₃/Acetone/MeOH/AcOH/H2O=4
0/15/13/12/8)¹ H-NMR (400 MHz, NEt₃ salt, 22.2 mg in 2.5 ml CDCl
3 & 0.3 ml CD3OD & 1drop D2O, pH ca. 7 ) δ = 0.88
(6H, t, J=7.7 Hz, CH₃ in Oleoyl), (67H, br, CH₂ in
Oleoyl & NCH2CH3), 1.59(4H, br, β-CH ₂ in Oleoy
l), 1.98(8H, br, Allylic H in Oleoyl), 2.15(4H, b
r, α-CH₂ in Oleoyl), 4.39(1H, br, H α,γ in Glyce
ryl), 5.36(5H, br, Hβ in Glyceryl & HC=CH), Ins.H
s unclear(3.0-4.35)¹³ C-NMR (100.4 MHz, NEt₃ salt, 22.2 mg in 0.5 ml C
DCl₃ & 50 ml CD₃OD &1drop D₂O, pH ca. 7 ) δ = 8.3
8(9C, NCH ₂CH₃), 13.98(2C, CH₂ in Oleoyl),24.75(2C,
β-CH in Oleoyl), 27.11 & 27.71(2C, Allylic C), 2
9.10-29.60(16C, CH₂ in Oleoyl), 31.81 & 32.51(2C,
CH₂CH₂CH₃ in Oleoyl), 33.97(2C, α-CH₂ in Oleoyl),
64.80(2C, br, Cα,γ in Glyceryl), 68.50(2C, br,
Ins. C_2,6), 70.00-71.50(2C, br, Ins. C₃ & Cβ in G
lyceryl), 127.20, 127.67, 129.90 & 130.35(4C, Viny
l C), 174.05[2C, OC(O) in Oleoyl], Ins. C_1,4,5 car
bons were hidden by CDCl₃.³¹ P-NMR (109.4 MHz, NEt₃ salt, 53.5 mg in 2.5 ml C
DCl₃ & 0.3 ml CD₃OD& 1drop D₂O, pH ca. 7 ) δ = 2.
04(1P, m), 4.12(1P, m), 5.30(1P, m)[0047]Rf 0.2 (CHCl_Three/ Acetone / MeOH / AcOH / H2O = 4
0/15/13/12/8)¹ H-NMR (400 MHz, NEt_Three salt, 22.2 mg in 2.5 ml CDCl
3 & 0.3 ml CD3OD & 1drop D2O, pH ca. 7) δ = 0.88
(6H, t,J= 7.7 Hz, CH_Three in Oleoyl), (67H, br, CH_Two in
 Oleoyl & NCH2CH3), 1.59 (4H, br, β-CH _Two in Oleoy
l), 1.98 (8H, br, Allylic H in Oleoyl), 2.15 (4H, b
r, α-CH_Two in Oleoyl), 4.39 (1H, br, H α, γ in Glyce
ryl), 5.36 (5H, br, Hβ in Glyceryl &HC = CH), Ins.H
s unclear (3.0-4.35)¹³ C-NMR (100.4 MHz, NEt_Three salt, 22.2 mg in 0.5 ml C
DCl_Three & 50 ml CD_ThreeOD & 1drop D_TwoO, pH ca. 7) δ = 8.3
8 (9C, NCH ₂ CH_Three), 13.98 (2C, CH_Two in Oleoyl), 24.75 (2C,
 β-CH in Oleoyl), 27.11 & 27.71 (2C, Allylic C), 2
9.10-29.60 (16C, CH_Two in Oleoyl), 31.81 & 32.51 (2C,
CH_TwoCH_TwoCH_Three in Oleoyl), 33.97 (2C, α-CH_Two in Oleoyl),
 64.80 (2C, br, Cα, γ in Glyceryl), 68.50 (2C, br,
Ins. C_2,6), 70.00-71.50 (2C, br, Ins.C_Three & Cβ in G
lyceryl), 127.20, 127.67, 129.90 & 130.35 (4C, Viny
l C), 174.05 [2C, OC (O) in Oleoyl], Ins. C_1,4,5 car
bons were hidden by CDCl_Three.³¹ P-NMR (109.4 MHz, NEt_Three salt, 53.5 mg in 2.5 ml C
DCl_Three & 0.3 ml CD_ThreeOD & 1drop D_TwoO, pH ca. 7) δ = 2.
04 (1P, m), 4.12 (1P, m), 5.30 (1P, m)

【００４８】[0048]

【発明の効果】本発明の到達により、従来天然の資源を
大量に採取・収集し、数多くの行程を経て、抽出・単離
していた天然型の不飽和型リン脂質類のＰＩＰやＰＩＰ
₂やＰＩＰ₃などを、化学合成的に全合成し、手にするこ
とができるようになった。本発明が化学合成操作による
不飽和型リン脂質類の製造に関するものであることか
ら、天然には知られていない、ＰＩＰやＰＩＰ₂やＰＩ
Ｐ₃などのアナローグを自在に合成・取得することがで
きる。また天然には微量しか存在しないＰＩ−３−Ｐや
ＰＩ−３，４−Ｐ₂などの不飽和型リン脂質類も製造す
ることができる。天然での存在が知られていない新規合
成の不飽和型リン脂質は、ヒトや動物に投与しうる薬剤
（アゴニスト、アンタゴニスト）として用いることがで
きる。またＰＩＰやＰＩＰ₂やＰＩＰ₃などの抗体を製造
する抗原としても用いることができ、ＰＩＰやＰＩＰ₂
やＰＩＰ₃などに由来・関連するする疾患の診断方法の
開発、診断薬の創製に道を開く。本発明により上記の様
々なアゴニスト、アンタゴニストを創製・提供すること
によって、ＰＩＰやＰＩＰ₂やＰＩＰ₃などの不飽和型リ
ン脂質類の生体内での未知の役割を解明するtoolとし
て、これら化合物は大いに役立ち、新たな医学生物学的
知見を人類が取得することに寄与しよう。According to the present invention, PIPs and PIPs of natural unsaturated phospholipids which have been collected and collected in a large amount in the past and which have been extracted and isolated through a number of steps have been obtained.
₂ and PIP ₃ can now be synthesized and obtained by chemical synthesis. Since the present invention relates to the production of unsaturated phospholipids by a chemical synthesis operation, PIP, PIP ₂ and PI which are not known in nature are known.
P ₃ can freely be synthesized and obtained the analogs such. The naturally can be also produced unsaturated phospholipids such as PI-3-P and PI-3,4-P ₂ there is only trace amounts. Newly synthesized unsaturated phospholipids whose existence in nature is not known can be used as drugs (agonists and antagonists) that can be administered to humans and animals. Further, it can be used as an antigen for producing an antibody such as PIP, PIP ₂ or PIP ₃ , and PIP or PIP ₂
Development of diagnostic methods for diseases derived from-related, such as in or PIP _3, opening the way to the creation of a diagnostic agent. By creating and providing the above-mentioned various agonists and antagonists according to the present invention, as a tool for elucidating the unknown role of unsaturated phospholipids such as PIP, PIP ₂ and PIP ₃ in vivo, these compounds are It will be of great help and help humanity acquire new medical and biological knowledge.

【図面の簡単な説明】[Brief description of the drawings]

【図１】ＰＩＰ_３の合成ルートを表した図である。1 is a diagram showing the synthesis route of PIP _3.

【図２】メントキシ酢酸誘導体による光学分割法を表し
た図である。FIG. 2 is a diagram illustrating an optical resolution method using a menthoxyacetic acid derivative.

【図３】ＰＩＰ_２の合成ルートを表した図である。3 is a diagram showing the synthesis route of PIP _2.

【図４】酒石酸を用いるイノシトール誘導体の光学分割
法を表した図である。FIG. 4 is a diagram showing an optical resolution method of an inositol derivative using tartaric acid.

【図５】安息香酸誘導体３８の合成ルートを表した図で
あるFIG. 5 is a diagram showing a synthesis route of a benzoic acid derivative 38.

Claims (3)

【特許請求の範囲】[Claims] 【請求項１】 リン酸保護基としてのフルオレニルメチ
ル基を用いることを特徴とする、不飽和型ホスファチジ
ルイノシトールポリリン酸類化合物の製造方法。1. A method for producing an unsaturated phosphatidylinositol polyphosphate compound, comprising using a fluorenylmethyl group as a phosphate protecting group. 【請求項２】 イノシトールリン酸化合物の糖水酸基が
２−［２−（レブリノイルオキシ）エチル］ベンゾイル
（Ｌｅｖ）基で置換され、リン酸の水酸基がフルオレニ
ルメチル基で保護された新規な化合物。2. A novel inositol phosphate compound in which the sugar hydroxyl group is substituted by a 2- [2- (levulinoyloxy) ethyl] benzoyl (Lev) group and the hydroxyl group of phosphoric acid is protected by a fluorenylmethyl group. Compound. 【請求項３】 イノシトールリン酸化合物がホスファチ
ジルイノシトールポリリン酸類化合物である請求項２の
新規な化合物。3. The novel compound according to claim 2, wherein the inositol phosphate compound is a phosphatidylinositol polyphosphate compound.