JPH0791219B2 - New prostaglandin type I - Google Patents
New prostaglandin type IInfo
- Publication number
- JPH0791219B2 JPH0791219B2 JP63332219A JP33221988A JPH0791219B2 JP H0791219 B2 JPH0791219 B2 JP H0791219B2 JP 63332219 A JP63332219 A JP 63332219A JP 33221988 A JP33221988 A JP 33221988A JP H0791219 B2 JPH0791219 B2 JP H0791219B2
- Authority
- JP
- Japan
- Prior art keywords
- bicyclo
- tetrahydropyranyloxy
- octenyl
- ene
- oct
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、新規なプロスタグランジンI類(以下、PGI
類と云う)に関する。TECHNICAL FIELD The present invention relates to novel prostaglandins I (hereinafter referred to as PGI).
Related to).
従来技術 PGI2に強い血小板凝集抑制作用および血圧下降作用を有
することは知られているが、同時に脈拍数増加、顔面紅
潮、腹痛などの副作用のあることも知られている(S.M.
M.Karimら著PG.Med.,9,307(1982))。Prior art PGI2 is known to have a strong platelet aggregation inhibitory action and blood pressure lowering action, but at the same time, it is also known to have side effects such as increased pulse rate, hot flushes and abdominal pain (SM
M. Karim et al., PG. Med., 9, 307 (1982)).
一方、特開昭61−78734号公報では多環式芳香族トリカ
ルボニル金属(VI−B)化合物がα,β−不飽和カルボ
ニル化合物の還元用触媒として有用であることが伸べら
れ、その実施例7に{3(E)−(4′−メトキシカル
ボニルブチリデン)−6(S)−(3′−オキソ−トラ
ンス−1′−オクテニル)−7(R)−テトラヒドロピ
ラニルオキシ−(1S,5S)−シス−ビシクロ[3.3.0]オ
クタン}を還元して{3(E)−(4′−メトキシカル
ボニルブチリデン)−6(R)−(3′−オキソオクチ
ル)−7−(R)−テトラヒドロピラニルオキシ−(1
S,5S)−シス−ビシクロ[3.3.0]オクタン}を得る方
法が示されている。さらに、特開昭61−37740号公報の
実施例7にも同じ化合物が記載されている。On the other hand, in JP-A-61-78734, polycyclic aromatic tricarbonyl metal (VI-B) compounds have been found to be useful as catalysts for reducing α, β-unsaturated carbonyl compounds, and examples thereof are shown. 7 to {3 (E)-(4'-methoxycarbonylbutylidene) -6 (S)-(3'-oxo-trans-1'-octenyl) -7 (R) -tetrahydropyranyloxy- (1S, 5S) -cis-bicyclo [3.3.0] octane} is reduced to {3 (E)-(4′-methoxycarbonylbutylidene) -6 (R)-(3′-oxooctyl) -7- (R ) -Tetrahydropyranyloxy- (1
A method of obtaining (S, 5S) -cis-bicyclo [3.3.0] octane} is shown. Further, the same compound is described in Example 7 of JP-A No. 61-37740.
しかしながらいずれの先行技術にも本発明一般式〔I〕
および〔II〕で示される化合物については開示がなく、
しかも前述化合物の有用性について全く開示していな
い。However, the general formula [I]
There is no disclosure about the compound represented by [II],
Moreover, it does not disclose the usefulness of the above compounds.
発明が解決しようとする課題 本願発明は血圧下降剤としての有用性が期待される新規
PGI類を提供することを目的とする。DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention is expected to be useful as a blood pressure lowering agent.
The purpose is to provide PGIs.
課題を解決するための手段 本願発明は一般式〔I〕または〔II〕: [式中、R1は水素原子またはアルキル基およびR2、R2′
はそれぞれ独立して水素原子またはハロゲン原子を示す
(但し、R2およびR2′の少なくとも一方はハロゲン原子
を示す)]で表わされるプロスタグランジンI類または
その塩に関する。Means for Solving the Problems The present invention has the general formula [I] or [II]: [In the formula, R1 represents a hydrogen atom or an alkyl group and R2 and R2 '.
Each independently represent a hydrogen atom or a halogen atom (provided that at least one of R2 and R2 'represents a halogen atom)].
本発明一般式〔I〕で示されるPGI類は15−ケト−16−
置換−9(O)−メタノ−△6(9α)−PGI1類であ
り、一般式〔II〕で示されるPGI類は15−ケト16−置換
−9(O)−メタノ−PGI2類である。The PGIs represented by the general formula [I] of the present invention are 15-keto-16-
The substituted -9 (O) -methano-Δ6 (9α) -PGI1s, and the PGIs represented by the general formula [II] are 15-keto 16-substituted-9 (O) -methano-PGI2s.
本発明の特徴的部分は、分子骨格中にビシクロ環を有す
ることである。さらに、この置換基の存在は、PGI類の
血圧効果作用に寄与し、PGI類が有する脈拍数増加等の
他の薬理的、生理的作用を軽減する上で有遥と考えられ
る。A characteristic part of the present invention is to have a bicyclo ring in the molecular skeleton. Furthermore, the presence of this substituent is considered to be promising in contributing to the blood pressure effect of PGIs and reducing other pharmacological and physiological effects of PGIs such as increase in pulse rate.
R2およびR2′で示される基としては、水素原子またはフ
ッ素、塩素等のハロゲン原子である。好ましくはその一
方または両方がハロゲン、特にフッ素原子である。The group represented by R2 and R2 'is a hydrogen atom or a halogen atom such as fluorine or chlorine. Preferably one or both are halogen, especially a fluorine atom.
R1は水素原子またはアルキル基である。アルキル基とし
ては、例えばメチル、エチル、n−プロピル、イソプロ
ピル、n−ブチル、t−ブチル等である。R1が水素原子
のときは、適当なアルカリと塩を形成してもよく、特に
本発明を医薬として用いるときは生理学的に許容し得る
塩、例えばアルリ金属、アルカリ土類金属、アンモニ
ア、アルキルアミン、アルカノールアミン、アルキルア
ルカノールアミン等から導びかれる塩が例示される。R1 is a hydrogen atom or an alkyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like. When R1 is a hydrogen atom, it may form a salt with a suitable alkali, and particularly when the present invention is used as a medicine, a physiologically acceptable salt such as ally metal, alkaline earth metal, ammonia or alkylamine. Examples thereof include salts derived from alkanolamines, alkylalkanolamines and the like.
本発明は一般式〔I〕で示されるPGI1類を合成する方法
としては例えば合成チャート[I]に示すごとく、市販
の6−(トリアルキルシロキシメチル)−3−ホルミル
−7−テトラヒドロピラニルオキシ−ビシクロ[3.3.
0]オクト−2−エン(アルデヒド体(1))を原料と
し、これに(3−カルボキシプロピル)トリフェニルホ
スフィンブロミドとカリウムt−ブトキシドから調製し
たイリドを反応させ、さらにジアゾメタンと反応させ
て、エステル体(2)を得、パラジウム炭素を用いて還
元して、4−カルボメトキシブチル体(3)を得、これ
をn−ブチルアンモニウムフロリド等を用いて、脱シリ
ル化してアルコール体(4)を得る。これをコリンズ酸
化してアルデヒド体(5)を得、このアルデヒド体
(5)に所望の置換基を有するジメチル(2−オキソ−
3−置換−ヘプチル)ホスホネートと水素化ナトリウム
から調製したアニオンを反応させてω鎖を導入し、15−
ケト−体(6)を得る。次いで保護基であるテトラヒド
ロピラニル基を酸を用いて外して、目的とする化合物
[I]のエステル体(7)を得る。常法により加水分解
することにより、カルボン酸型の目的化合物を得ること
ができる。ω鎖導入に用いられるホスホネートとして3
位の置換基がフッ素原子である例を実施例1に示すが、
前述のごとくこの置換基は塩素原子、メチル基、エチル
基、フェニル基、ベンジル基、水酸基、メトキシ基、エ
トキシ基であってよい。The present invention provides a method for synthesizing the PGI1s represented by the general formula [I], for example, as shown in the synthesis chart [I], commercially available 6- (trialkylsiloxymethyl) -3-formyl-7-tetrahydropyranyloxy. -Bicyclo [3.3.
0] Oct-2-ene (aldehyde derivative (1)) was used as a starting material, and this was reacted with (3-carboxypropyl) triphenylphosphine bromide and ylide prepared from potassium t-butoxide, and further reacted with diazomethane, The ester form (2) is obtained and reduced with palladium on carbon to obtain the 4-carbomethoxybutyl form (3), which is desilylated with n-butylammonium fluoride or the like to give the alcohol form (4 ) Get. This is Collins-oxidized to obtain an aldehyde derivative (5), and the aldehyde derivative (5) has dimethyl (2-oxo-) having a desired substituent.
3-substituted-heptyl) phosphonate is reacted with an anion prepared from sodium hydride to introduce the ω chain,
A keto body (6) is obtained. Next, the tetrahydropyranyl group, which is a protecting group, is removed with an acid to obtain the ester compound (7) of the target compound [I]. The desired compound of carboxylic acid type can be obtained by hydrolysis according to a conventional method. 3 as phosphonate used for introducing ω chain
An example in which the substituent at the position is a fluorine atom is shown in Example 1,
As mentioned above, this substituent may be a chlorine atom, a methyl group, an ethyl group, a phenyl group, a benzyl group, a hydroxyl group, a methoxy group or an ethoxy group.
一般式〔II〕で示されるPGI2類は、合成チャートIIIに
示すごとく、市販の6−(トリアルキルシロキシメチ
ル)−3−ホルミル−7−テトラヒドロピラニルオキシ
−ビシクロ[3.3.0]オクト−2−エン(アルデヒド体
(1))を原料とし、これに(3−カルボキシプロピ
ル)トリフェニルホスフィンブロミドとカリウムt−ブ
トキシドから調製したイリドを反応させ、さらにジアゾ
メタンと反応させて、エステル体(2)を得、これをn
−ブチルアンモニウムフロリド等を用いて、脱シリル化
してアルコール体(4′)を得る。これをコリンズ酸化
してアルデヒド体(5′)を得、このアルデヒド体にPG
I1類と同様にして、ω鎖を導入した化合物(10)のカル
ボニル基を水素化ホウ素ナトリウムで還元し、15−ヒド
ロキシ化合物(11)を得、これをトリカルボニルクロム
安息香酸メチル錯体(例えば特開昭61−37740号公報)
を用いて還元し(この場合環内二重結合と共役するα鎖
の二重結合は還元されて環とα鎖とが二重結合で結合し
た構造をとる)、これをアルカリにより加水分解して遊
離酸(13)を得、さらにジョーンズ酸化してケトン(1
4)を得、これをそのまゝ酸によりテトラヒドロピラニ
ル基を除去することにより、目的とする[II]のエステ
ル体(15)が得られる。上で得られた化合物のカルボニ
ル基に隣接する炭素上の置換基はこの場合、フッ素原子
であるが、他の置換基であってもよい。As shown in Synthesis Chart III, PGI2's represented by the general formula [II] are commercially available 6- (trialkylsiloxymethyl) -3-formyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2. -Ene (aldehyde body (1)) was used as a raw material, and this was reacted with (3-carboxypropyl) triphenylphosphine bromide and an ylide prepared from potassium t-butoxide, and further reacted with diazomethane to give an ester body (2). And get this n
-Desilylation using butylammonium fluoride or the like to give the alcohol compound (4 '). This is Collins-oxidized to obtain an aldehyde (5 ').
In the same manner as I1s, the carbonyl group of the compound (10) having the ω chain introduced is reduced with sodium borohydride to obtain a 15-hydroxy compound (11), which is a tricarbonylchromiumbenzoic acid methyl complex (for example, a special compound). (Kaisho 61-37740)
(In this case, the double bond of the α chain conjugated with the endocyclic double bond is reduced to form a structure in which the ring and the α chain are bound by a double bond), and this is hydrolyzed with alkali. To obtain the free acid (13), which is further oxidized by Jones to give ketone (1
4) is obtained, and the tetrahydropyranyl group is removed from the resulting product by using malic acid to obtain the desired ester form (15) of [II]. The substituent on the carbon adjacent to the carbonyl group of the compound obtained above is in this case a fluorine atom, but it may be another substituent.
本発明PGI類は、異性体および異性体混合物も包含す
る。これらの異性体の例は11位の水酸基と15位のカルボ
ニル基間のケト−ヘミアセタール互変異性体、あるいは
光学異性体、幾何異性体等が例示される。The PGIs of the present invention also include isomers and isomer mixtures. Examples of these isomers include keto-hemiacetal tautomers between the 11-position hydroxyl group and the 15-position carbonyl group, or optical isomers and geometric isomers.
以下、本発明を実施例にもとづいて説明する。Hereinafter, the present invention will be described based on Examples.
実施例においては、化合物を示すため最終目的化合物以
外はIUPAC命名法に準じて命名し、ビシクロ環の炭素番
号は各々の以下の通りである。In the examples, compounds other than the final target compound are named according to the IUPAC nomenclature, and the carbon number of the bicyclo ring is as follows.
実施例1 16(RS)−フルオロ−15−ケト−9(O)−メタノ−△
6(9α)−PGI1メチルエステルの合成: 1−1 (1S,5S,6S,7R)−6−(t−ブチルジメチルシ
ロキシメチル)−3−[4−カルボメトキシ−1(EZ)
−ブテニル]−7−テトラヒドロピラニルオキシ−ビシ
クロ[3.3.0]オクト−2−エン(2)の合成: 市販の(1S,5S,6S,7R)−6−(t−ブチルジメチルシ
ロキシメチル)−3−ホルミル−7−テトラヒドロピラ
ニルオキシ−ビシクロ[3.3.0]オクト−2−エン(1.0
0g)(1)をTHF中、(3−カルボキシプロピル)トリ
フェニルホスフィンプロミドとカリウムt−ブトキシド
から調製したイリドと反応させた。常法の処理により粗
カルボン酸を得た。これをジアゾメタンのエーテル溶液
と反応させた。常法の処理により得た粗生成物をカラム
クロマトグラフィー(ヘキサン/酢酸エチル10:1)で精
製し、無色油状物として(1S,5S,6S,7R)−6−(t−
ブチルジメチルシロキシメチル)−3−[4−カルボメ
トキシ−1(EZ)−ブテニル]−7−テトラヒドロピラ
ニルオキシ−ビシクロ[3.3.0]オクト−2−エン
(2)を得た。収量0.85g(67%)。 Example 1 16 (RS) -Fluoro-15-keto-9 (O) -methano-Δ
Synthesis of 6 (9α) -PGI1 methyl ester: 1-1 (1S, 5S, 6S, 7R) -6- (t-butyldimethylsiloxymethyl) -3- [4-carbomethoxy-1 (EZ)
Synthesis of -butenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (2): commercially available (1S, 5S, 6S, 7R) -6- (t-butyldimethylsiloxymethyl) -3-Formyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (1.0
0g) (1) was reacted in THF with an ylide prepared from (3-carboxypropyl) triphenylphosphine bromide and potassium t-butoxide. Crude carboxylic acid was obtained by a conventional treatment. This was reacted with a solution of diazomethane in ether. The crude product obtained by the conventional treatment was purified by column chromatography (hexane / ethyl acetate 10: 1) to give (1S, 5S, 6S, 7R) -6- (t-
Butyldimethylsiloxymethyl) -3- [4-carbomethoxy-1 (EZ) -butenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (2) was obtained. Yield 0.85g (67%).
1H NMR(CDCl3)δ0.05(6H,s)、0.90(9H,s)、1.05
〜1.95(10H,m)、2.10〜3.13(7H,m)、3.27〜4.22(5
H,m)、3.63(3H,s)、4.45〜4.69(1H,m)、5.05〜5.6
5(2H,m)、5.97(0.67H,d,J=12Hz)、6.22(0.33H,d,
J=16Hz)。1H NMR (CDCl3) δ0.05 (6H, s), 0.90 (9H, s), 1.05
~ 1.95 (10H, m), 2.10 ~ 3.13 (7H, m), 3.27 ~ 4.22 (5
H, m), 3.63 (3H, s), 4.45 ~ 4.69 (1H, m), 5.05 ~ 5.6
5 (2H, m), 5.97 (0.67H, d, J = 12Hz), 6.22 (0.33H, d,
J = 16Hz).
1−2 (1S,5S,6S,7R)−6−(t−ブチルジメチルシ
ロキシメチル)−3−[4−カルボメトキシブチル)−
7−テトラヒドロピラニルオキシ−ビシクロ[3.3.0]
オクト−2−エン(3)の合成: (1S,5S,6S,7R)−6−(t−ブチルジメチルシロキシ
メチル)−3−[4−カルボメトキシ−1(EZ)−ブテ
ニル]−7−テトラヒドロピラニルオキシ−ビシクロ
[3.3.0]オクト−2−エン(2)(0.214g)メタノー
ルに溶解し、10%パラジウム炭素(0.050g)を加え、水
素雰囲気下、室温で45分間撹拌した。反応液を濾過し、
濾液を減圧濃縮した。得られた粗生成物を硝酸銀処理し
たシリカゲル(10wt.%)を用いてカラムクロマトグラ
フィー(ヘキサン/酢酸エチル40:1〜30:1)し、無色油
状物として(1S,5S,6S,7R)−6−(t−ブチルジメチ
ルシロキシメチル)−3−[4−カルボメトキシブチ
ル)−7−テトラヒドロピラニルオキシ−ビシクロ[3.
3.0]オクト−2−エン(3)を得た。収量0.151g(70
%)。1-2 (1S, 5S, 6S, 7R) -6- (t-butyldimethylsiloxymethyl) -3- [4-carbomethoxybutyl)-
7-Tetrahydropyranyloxy-bicyclo [3.3.0]
Synthesis of Oct-2-ene (3): (1S, 5S, 6S, 7R) -6- (t-Butyldimethylsiloxymethyl) -3- [4-carbomethoxy-1 (EZ) -butenyl] -7- Tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (2) (0.214 g) was dissolved in methanol, 10% palladium carbon (0.050 g) was added, and the mixture was stirred at room temperature for 45 minutes under a hydrogen atmosphere. The reaction solution is filtered,
The filtrate was concentrated under reduced pressure. The obtained crude product was subjected to column chromatography (hexane / ethyl acetate 40: 1 to 30: 1) using silica gel treated with silver nitrate (10 wt.%) To give a colorless oil (1S, 5S, 6S, 7R). -6- (t-Butyldimethylsiloxymethyl) -3- [4-carbomethoxybutyl) -7-tetrahydropyranyloxy-bicyclo [3.
3.0] Oct-2-ene (3) was obtained. Yield 0.151g (70
%).
1H NMR(CDCl3)δ0.05(6H,s)、0.97−−3.03(21H,
m)、3.23〜4.15(5H,m)、3.62(3H,s)、4.45〜4.69
(1H,m)、5.10〜5.33(1H,m)。1H NMR (CDCl3) δ0.05 (6H, s), 0.97−−3.03 (21H,
m), 3.23-4.15 (5H, m), 3.62 (3H, s), 4.45-4.69
(1H, m), 5.10 to 5.33 (1H, m).
1−3 (1S,5S,6S,7R)−3−(4−カルボメトキシブ
チル)−6−ヒドロキシメチル−7−テトラヒドロピラ
ニルオキシ−ビシクロ[3.3.0]オクト−2−エン
(4)の合成: (1S,5S,6S,7R)−6−(t−ブチルジメチルシロキシ
メチル)−3−(4−カルボメトキシブチル)−7−テ
トラヒドロピラニルオキシ−ビシクロ[3.3.0]オウト
−2−エン(3)(0.294g)をTHFに溶解し、n−ブチ
ルアンモニウムフロリドのTHF溶液(1.1M,2.2mL)を加
え、室温で18時間撹拌した。常法の処理により得た粗生
成物をカラムクロマトグラフィー(ヘキサン/酢酸エチ
ル1:1)で精製し、無色油状物として(1S,5S,6S,7R)−
3−(4−カルボメトキシブチル)−6−ヒドロキシメ
チル−7−テトラヒドロピラニルオキシ−ビシクロ[3.
3.0]オクト−2−エン(4)を得た。収量0.228g(定
量的)。Of 1-3 (1S, 5S, 6S, 7R) -3- (4-carbomethoxybutyl) -6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (4) Synthesis: (1S, 5S, 6S, 7R) -6- (t-Butyldimethylsiloxymethyl) -3- (4-carbomethoxybutyl) -7-tetrahydropyranyloxy-bicyclo [3.3.0] out-2- Ene (3) (0.294 g) was dissolved in THF, a THF solution of n-butylammonium fluoride (1.1 M, 2.2 mL) was added, and the mixture was stirred at room temperature for 18 hours. The crude product obtained by the conventional treatment was purified by column chromatography (hexane / ethyl acetate 1: 1) to give a colorless oil (1S, 5S, 6S, 7R)-
3- (4-carbomethoxybutyl) -6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.
3.0] Oct-2-ene (4) was obtained. Yield 0.228g (quantitative).
1H NMR(CDCl3)δ0.76〜3.13(22H,m)、3.27〜4.13
(5H,m)、3.63(3H,s)、4.46〜4.77(1H,m)、5.02〜
5.42(1H,m)。1H NMR (CDCl3) δ 0.76 to 3.13 (22H, m), 3.27 to 4.13
(5H, m), 3.63 (3H, s), 4.46 ~ 4.77 (1H, m), 5.02 ~
5.42 (1H, m).
1−4 (1S,5S,6S,7R)−3−(4−カルボメトキシブ
チル)−6−[4(RS)−フルオロ−3−オキソ(E)
−1−オクテニル]−7−テトラヒドロピラニルオキシ
−ビシクロ[3.3.0]オクト−2−エン(6)の合成: (1S,5S,6S,7R)−3−(4−カルボメトキシブチル)
−6−ヒドロキシメチル−7−テトラヒドロピラニルオ
キシ−ビシクロ[3.3.0]オクト−2−エン(4)(0.1
25g)をDMSOに溶解し、トリエチルアミン(0.93mL)お
よび三酸化イオウ・ピリジン錯体(0.504g)のDMSO溶液
を加え、室温で1.5時間撹拌した。常法の処理により粗
アルデヒド体(5)を得た。これをTHFに溶解し、ジメ
チル(2−オキソ−3−フルオロヘプチル)ホスホネー
ト(0.341g)と水素化ナトリウムから調製したアニオン
と50℃で反応させた。3時間攪拌し酢酸を加えて中和し
た。常法の処理により得た粗生成物をカラムクロマトグ
ラフィー(ヘキサン/酢酸エチル7:1)で精製し、(1S,
5S,6S,7R)−3−(4−カルボメトキシブチル)−6−
[4(RS)−フルオロ−3−オキソ(E)−1−オクテ
ニル]−7−テトラヒドロピラニルオキシ−ビシクロ
[3.3.0]オクト−2−エン(6)を得た。収量0.088g
(56%)。1-4 (1S, 5S, 6S, 7R) -3- (4-Carbomethoxybutyl) -6- [4 (RS) -fluoro-3-oxo (E)
Synthesis of -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (6): (1S, 5S, 6S, 7R) -3- (4-carbomethoxybutyl)
-6-Hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (4) (0.1
25 g) was dissolved in DMSO, a DMSO solution of triethylamine (0.93 mL) and sulfur trioxide / pyridine complex (0.504 g) was added, and the mixture was stirred at room temperature for 1.5 hours. The crude aldehyde compound (5) was obtained by the conventional treatment. This was dissolved in THF and reacted at 50 ° C. with dimethyl (2-oxo-3-fluoroheptyl) phosphonate (0.341 g) and an anion prepared from sodium hydride. The mixture was stirred for 3 hours and acetic acid was added for neutralization. The crude product obtained by a conventional method was purified by column chromatography (hexane / ethyl acetate 7: 1), and the (1S,
5S, 6S, 7R) -3- (4-Carbomethoxybutyl) -6-
[4 (RS) -Fluoro-3-oxo (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (6) was obtained. Yield 0.088g
(56%).
1H NMR(CDCl3)δ0.75〜1.06(3H,m)、1.05〜3.14(2
7H,m)、3.26〜4.13(3H,m)、3.63(3H,s)、4.38〜4.
71(1.5H,m)、5.01〜5.43(1.5H,m)、6.26〜6.68(1
H,m)、6.80〜7.26(1H,m)。1H NMR (CDCl3) δ 0.75 to 1.06 (3H, m), 1.05 to 3.14 (2
7H, m), 3.26 to 4.13 (3H, m), 3.63 (3H, s), 4.38 to 4.
71 (1.5H, m), 5.01 ~ 5.43 (1.5H, m), 6.26 ~ 6.68 (1
H, m), 6.80 to 7.26 (1H, m).
1−5 16(RS)−フルオロ−15−ケト−9(O)−メタ
ノ−△6(9α)−PGI1メチルエステル(7)の合成: (1S,5S,6S,7R)−3−(4−カルボメトキシブチル)
−6−[4(RS)−フルオロ−3−オキソ(E)−1−
オクテニル]−7−テトラヒドロピラニルオキシ−ビシ
クロ[3.3.0]オクト−2−エン(6)(0.088g)を酢
酸、水、およびTHFの4:2:1混合溶媒に溶解し、45℃で3
時間撹拌した。反応液を減圧濃縮し、得られた粗精製物
をカラムクロマトグラフィー(ヘキサン/酢酸エチル3:
1)で精製し、無色油状物として16(RS)−フルオロ−1
5−ケト−9(O)−メタノ−△6(9α)−PGI1メチ
ルエステル(7)を得た。Synthesis of 1-5 16 (RS) -fluoro-15-keto-9 (O ) -methano-Δ6 (9α) -PGI1 methyl ester (7): (1S, 5S, 6S, 7R) -3- (4 -Carbomethoxybutyl)
-6- [4 (RS) -Fluoro-3-oxo (E) -1-
Octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (6) (0.088g) was dissolved in a 4: 2: 1 mixed solvent of acetic acid, water, and THF at 45 ° C. Three
Stir for hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (hexane / ethyl acetate 3:
Purified in 1), 16 (RS) -fluoro-1 as colorless oil
5-Keto-9 (O) -methano-Δ6 (9α) -PGI1 methyl ester (7) was obtained.
収量0.069g(96%)。Yield 0.069g (96%).
1H NMR(CDCl3)δ0.72〜1.04(3H,m)、1.04〜3.18(2
2H,m)、3.62(3H,s)、3.70〜4.12(1H,m)、4.43〜4.
63(0.5H,m)、4.98〜5.23(0.5H,m)、6.53(1H,dd,J
=16Hz,J=3Hz)、6.98(1H,dd,J=16Hz,J=9Hz)。1H NMR (CDCl3) δ 0.72 to 1.04 (3H, m), 1.04 to 3.18 (2
2H, m), 3.62 (3H, s), 3.70 to 4.12 (1H, m), 4.43 to 4.
63 (0.5H, m), 4.98 to 5.23 (0.5H, m), 6.53 (1H, dd, J
= 16Hz, J = 3Hz), 6.98 (1H, dd, J = 16Hz, J = 9Hz).
実施例2 16,16−ジフルオロ−15−ケト−9(O)−メタノ−△
6(9α)−PGI1メチルエステルの合成: 2−1 (1S,5S,6S,7R)−3−(4−カルボメトキシブ
チル)−6−[4(RS)−フルオロ−3−オキソ(E)
−1−オクテニル]−7−テトラヒドロピラニルオキシ
−ビシクロ[3.3.0]オクト−2−エン(8)の合成: (1S,5S,6S,7R)−3−(4−カルボメトキシブチル)
−6−ヒドロキシメチル−7−テトラヒドロピラニルオ
キシ−ビシクロ[3.3.0]オクト−2−エン(4)(0.1
08g)をDMSOに溶解し、トリエチルアミン(0.90mL)お
よび三酸化イオウ・ピリジン錯体(0.488g)のDMSO溶液
を加え、室温で30分撹拌した。常法の処理により粗アル
デヒド体(5)を得た。これをTHFに溶解し、ジメチル
(2−オキソ−3,3−ジフルオロヘプチル)ホスホネー
ト(0.435g)と水素化ナトリウムから調製したアニオン
と反応させた。48時間加熱還流し、酢酸を加えて中和し
た。常法の処理により得た粗生成物をカラムクロマトグ
ラフィー(ヘキサン/酢酸エチル7:1)で精製し、無色
油状物として(1S,5S,6S,7R)−3−(4−カルボメト
キシブチル)−6−[4,4−ジフルオロ−3−オキソ−
(E)−1−オクテニル]−7−テトラヒドロピラニル
オキシ−ビシクロ[3.3.0]オクト−2−エン(8)を
得た。Example 2 16,16-Difluoro-15-keto-9 (O) -methano-Δ
Synthesis of 6 (9α) -PGI1 methyl ester: 2-1 (1S, 5S, 6S, 7R) -3- (4-carbomethoxybutyl) -6- [4 (RS ) -fluoro-3-oxo (E)
Synthesis of -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (8): (1S, 5S, 6S, 7R) -3- (4-carbomethoxybutyl)
-6-Hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (4) (0.1
08 g) was dissolved in DMSO, triethylamine (0.90 mL) and a sulfur trioxide-pyridine complex (0.488 g) in DMSO were added, and the mixture was stirred at room temperature for 30 minutes. The crude aldehyde compound (5) was obtained by the conventional treatment. This was dissolved in THF and reacted with dimethyl (2-oxo-3,3-difluoroheptyl) phosphonate (0.435g) and an anion prepared from sodium hydride. The mixture was heated under reflux for 48 hours and neutralized by adding acetic acid. The crude product obtained by conventional treatment was purified by column chromatography (hexane / ethyl acetate 7: 1) to give (1S, 5S, 6S, 7R) -3- (4-carbomethoxybutyl) as a colorless oil. -6- [4,4-difluoro-3-oxo-
(E) -1-Octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (8) was obtained.
収量0.091g(64%)。Yield 0.091g (64%).
1H NMR(CDCl3)δ0.76〜1.05(3H,m)、1.05〜3.17(2
7H,m)、3.25〜4.15(3H,m)、3.63(3H,s)、4.35〜4.
75(1H,m)、5.09〜5.37(1H,m)、6.56(1H,dd,J=15H
z,J=6Hz)、6.86〜7.37(1H,m)。1H NMR (CDCl3) δ 0.76 to 1.05 (3H, m), 1.05 to 3.17 (2
7H, m), 3.25 ~ 4.15 (3H, m), 3.63 (3H, s), 4.35 ~ 4.
75 (1H, m), 5.09 to 5.37 (1H, m), 6.56 (1H, dd, J = 15H
z, J = 6Hz), 6.86-7.37 (1H, m).
2−2 16,16−ジフルオロ−15−ケト−9(O)−メタ
ノ−△6(9α)−PGI1メチルエステル(9)の合成。Synthesis of 2-2 16,16-difluoro-15-keto-9 (O ) -methano-Δ6 (9α) -PGI1 methyl ester (9).
(1S,5S,6S,7R)−3−(4−カルボメトキシブチル)
−6−[4,4−ジフルオロ−3−オキソ−(E)−1−
オクテニル]−7−テトラヒドロピラニルオキシ−ビシ
クロ[3.3.0]オクト−2−エン(8)(0.091g)を酢
酸、水、およびTHFの4:2:1混合溶媒に溶解し、45℃で3
時間撹拌した。反応液を減圧濃縮し、得られた粗生成物
をカラムクロマトグラフィー(ヘキサン/酢酸エチル2:
1)で精製し、無色油状物として16,16−ジフルオロ−15
−ケト−9(O)−メタノ−△6(9α)−PGI1メチル
エステル(9)を得た。収量0.060g(80%)。(1S, 5S, 6S, 7R) -3- (4-carbomethoxybutyl)
-6- [4,4-Difluoro-3-oxo- (E) -1-
Octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (8) (0.091g) was dissolved in a 4: 2: 1 mixed solvent of acetic acid, water, and THF at 45 ° C. Three
Stir for hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (hexane / ethyl acetate 2:
Purified in 1), 16,16-difluoro-15 as colorless oil
-Keto-9 (O) -methano- [Delta] 6 (9 [alpha])-PGI1 methyl ester (9) was obtained. Yield 0.060g (80%).
1H NMR(CDCl3)δ0.76〜1.05(3H,m)、1.05〜3.21(2
2H,m)、3.62(3H,s)、3.73〜4.17(1H,m)、5.09〜5.
43(1H,m)、6.56(1H,d,J=15Hz)、7.12(1H,dd,J=1
5Hz,J=7.5Hz)。1H NMR (CDCl3) δ 0.76 to 1.05 (3H, m), 1.05 to 3.21 (2
2H, m), 3.62 (3H, s), 3.73 to 4.17 (1H, m), 5.09 to 5.
43 (1H, m), 6.56 (1H, d, J = 15Hz), 7.12 (1H, dd, J = 1)
5Hz, J = 7.5Hz).
実施例3 16(RS)−フルオロ−15−ケト−9(O)−メタノ−PG
I2の合成: 3−1 (1S,5S,6S,7R)−3−[4−カルボメトキシ−
1(EZ)−ブテニル]−6−ヒドロキシメチル−7−テ
トラヒドロピラニルオキシ−ビシクロ[3.3.0]オクト
−2−エン(4′)の合成: (1S,5S,6S,7R)−6−(t−ブチルジメチルシロキシ
メチル)−3−[4−カルボメトキシ−1(EZ)−ブテ
ニル]−7−テトラヒドロピラニルオキシ−ビシクロ
[3.3.0]オクト−2−エン(2)(0.85g)をTHFに溶
解し、テトラn−ブチルアンモニウムフロリドのTHF溶
液(1.1M,6.43mL)を加え、室温で18時間撹拌した。常
法の処理により得た粗生成物をカラムクロマトグラフィ
ー(ヘキサン/酢酸エチル1:1)で精製し、無色油状物
として(1S,5S,6S,7R)−3−[4−カルボメトキシ−
1(EZ)−ブテニル]−6−ヒドロキシメチル−7−テ
トラヒドロピラニルオキシ−ビシクロ[3.3.0]オクト
−2−エン(4′)を得た。収量0.59g(96%)。Example 3 16 (RS) -Fluoro-15-keto-9 (O) -methano-PG
Synthesis of I2: 3-1 (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-
Synthesis of 1 (EZ) -butenyl] -6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (4 '): (1S, 5S, 6S, 7R) -6- (T-Butyldimethylsiloxymethyl) -3- [4-carbomethoxy-1 (EZ) -butenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (2) (0.85g) Was dissolved in THF, a THF solution of tetra-n-butylammonium fluoride (1.1M, 6.43 mL) was added, and the mixture was stirred at room temperature for 18 hours. The crude product obtained by conventional treatment was purified by column chromatography (hexane / ethyl acetate 1: 1) to give (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-
1 (EZ) -butenyl] -6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (4 ') was obtained. Yield 0.59g (96%).
1H NMR(CDCl3)δ1.18〜1.93(10H,m)、2.16〜3.28
(8H,m)、3.42〜4.07(5H,m)、3.63(3H,s)、4.55〜
4.64(0.5H,m)、4.66〜4.77(0.5H,m)、5.33(0.67H,
dt,J=7.5Hz,J=12.5Hz),5.42〜5.67(1.33H,m)、5.9
9(0.67H,d,J=12.5Hz)、6.26(0.33H,d,J=15.5H
z)。1H NMR (CDCl3) δ1.18 to 1.93 (10H, m), 2.16 to 3.28
(8H, m), 3.42 ~ 4.07 (5H, m), 3.63 (3H, s), 4.55 ~
4.64 (0.5H, m), 4.66 ~ 4.77 (0.5H, m), 5.33 (0.67H,
dt, J = 7.5Hz, J = 12.5Hz), 5.42 to 5.67 (1.33H, m), 5.9
9 (0.67H, d, J = 12.5Hz), 6.26 (0.33H, d, J = 15.5H)
z).
3−2 (1S,5S,6S,7R)−3−[4−カルボメトキシ−
1(EZ)−ブテニル]−6−[4−(RS)−フルオロ−
3−オキソ−(E)−1オクテニル]−7−テトラヒド
ロピラニルオキシ−ビシクロ[3.3.0]オクト−2−エ
ン(10)の合成: (1S,5S,6S,7R)−3−[4−カルボメトキシ−1(E
Z)−ブテニル]−6−ヒドロキシメチル−7−テトラ
ヒドロピラニルオキシ−ビシクロ[3.3.0]オクト−2
−エン(4′)(0.240g)を塩化メチレン中、0℃でコ
リンズ酸化した。反応液に硫酸水素ナトリウムを加え、
濾過した。濾液を減圧濃縮して得た粗アルデヒド
(5′)をTHFに溶解し、ジメチル(2−オキソ−3−
フルオロヘプチル)ホスホネート(0.61g)と水素化ナ
トリウムから調製したアニオンと50℃で反応させ、5時
間撹拌し酢酸を加えて中和した。常法の処理により得た
粗生成物をカラムクロマトグラフィー(ヘキサン/酢酸
エチル6:1)で精製し、淡黄色油状物として(1S,5S,6S,
7R)−3−[4−カルボメトキシ−1(EZ)−ブテニ
ル]−6−[4−(RS)−フルオロ−3−オキソ−
(E)−1オクテニル]−7−テトラヒドロピラニルオ
キシ−ビシクロ[3.3.0]オクト−2−エン(10)を得
た。3-2 (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-
1 (EZ) -butenyl] -6- [4- (RS) -fluoro-
Synthesis of 3-oxo- (E) -1 octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (10): (1S, 5S, 6S, 7R) -3- [4 -Carbomethoxy-1 (E
Z) -Butenyl] -6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2
The ene (4 ') (0.240g) was Collins oxidised at 0 ° C in methylene chloride. Sodium hydrogen sulfate was added to the reaction solution,
Filtered. The crude aldehyde (5 ') obtained by concentrating the filtrate under reduced pressure was dissolved in THF, and dimethyl (2-oxo-3-
Fluoroheptyl) phosphonate (0.61 g) was reacted with an anion prepared from sodium hydride at 50 ° C., stirred for 5 hours, and acetic acid was added to neutralize. The crude product obtained by a conventional method was purified by column chromatography (hexane / ethyl acetate 6: 1) to give a pale yellow oil (1S, 5S, 6S,
7R) -3- [4-Carbomethoxy-1 (EZ) -butenyl] -6- [4- (RS) -fluoro-3-oxo-
(E) -1 octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (10) was obtained.
収量0.250g(85%)。Yield 0.250g (85%).
1H NMR(CDCl3)δ0.70〜1.07(3H,m)、1.06〜2.14(1
5H,m)、2.15〜4.16(11H,m)、3.66(3H,s)、4.43〜
4.72(1.5H,m)、4.96〜5.71(2.5H,m)、5.95(0.67H,
d,J=11Hz)、6.24(0.33H,d,J=16Hz)、6.36〜6.73
(1H,m)、6.83〜7.23(1H,m)。1H NMR (CDCl3) δ 0.70 to 1.07 (3H, m), 1.06 to 2.14 (1
5H, m), 2.15 ~ 4.16 (11H, m), 3.66 (3H, s), 4.43 ~
4.72 (1.5H, m), 4.96 to 5.71 (2.5H, m), 5.95 (0.67H,
d, J = 11Hz), 6.24 (0.33H, d, J = 16Hz), 6.36 to 6.73
(1H, m), 6.83 to 7.23 (1H, m).
3−3 (1S,5S,6S,7R)−3−[4−カルボメトキシ−
1(EZ)−ブテニル]−6−[4−(RS)−フルオロ−
3(RS)−ヒドロキシ−(E)−1オクテニル]−7−
テトラヒドロピラニルオキシ−ビシクロ[3.3.0]オク
ト−2−エン(11)の合成: (1S,5S,6S,7R)−3−[4−カルボメトキシ−1(E
Z)−ブテニル]−6−[4−(RS)−フルオロ−3−
オキソ−(E)−1オクテニル]−7−テトラヒドロピ
ラニルオキシ−ビシクロ[3.3.0]オクト−2−エン(1
0)(0.088g)をメタノールに溶解し、0℃で水素化ホ
ウ素ナトリウム(0.008g)を加え30分攪拌した。常法の
処理により無色油状物として(1S,5S,6S,7R)−3−
[4−カルボメトキシ−1(EZ)−ブテニル]−6−
[4−(RS)−フルオロ−3(RS)−ヒドロキシ−
(E)−1オクテニル]−7−テトラヒドロピラニルオ
キシ−ビシクロ[3.3.0]オクト−2−エン(11)を得
た。収量0.089g(定量的)。3-3 (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-
1 (EZ) -butenyl] -6- [4- (RS) -fluoro-
3 (RS) -hydroxy- (E) -1 octenyl] -7-
Synthesis of tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (11): (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-1 (E
Z) -Butenyl] -6- [4- (RS) -fluoro-3-
Oxo- (E) -1 octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (1
0) (0.088g) was dissolved in methanol, sodium borohydride (0.008g) was added at 0 ° C, and the mixture was stirred for 30 minutes. (1S, 5S, 6S, 7R) -3- as colorless oil by conventional treatment
[4-carbomethoxy-1 (EZ) -butenyl] -6-
[4- (RS) -Fluoro-3 (RS) -hydroxy-
(E) -1 octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (11) was obtained. Yield 0.089g (quantitative).
1H NMR(CDCl3)δ0.67〜1.03(3H,m)、1.03〜3.19(2
4H,m)、3.22〜4.34(4.5H,m)、3.62(3H,s)、4.40〜
4.74(1.5H,m)、5.07〜6.32(5H,m)。1H NMR (CDCl3) δ 0.67 to 1.03 (3H, m), 1.03 to 3.19 (2
4H, m), 3.22-4.34 (4.5H, m), 3.62 (3H, s), 4.40-
4.74 (1.5H, m), 5.07 to 6.32 (5H, m).
3−4 (1S,2S,3R,5S)−(E)−7−(4−カルボメ
トキシブチリデン)−2−[4−(RS)−フルオロ−3
(RS)−ヒドロキシ−(E)−1−オクテニル]−3−
テトラヒドロピラニルオキシ−ビシクロ[3.3.0]オク
タン(12)の合成: オートクレーブ中に、(1S,5S,6S,7R)−3−[4−カ
ルボメトキシ−1(EZ)−ブテニル]−6−[4−(R
S)−フルオロ−3(RS)−ヒドロキシ−(E)−1オ
クテニル]−7−テトラヒドロピラニルオキシ−ビシク
ロ[3.3.0]オクト−2−エン(11)(0.089g)を加え
アセトンに溶解し、トリカルボニクロム・安息香酸メチ
ル錯体(0.011g)を加え脱気した。水素加圧下(70kg/c
m2)、120℃で15時間攪拌した。反応液を減圧濃縮し、
得られた粗生成物をカラムクロマトグラフィー(ヘキサ
ン/酢酸エチル2:1)で精製し、無色油状物として(1S,
2S,3R,5S)−(E)−7−(4−カルボメトキシブチリ
デン)−2−[4−(RS)−フルオロ−3(RS)−ヒド
ロキシ−(E)−1−オクテニル]−3−テトラヒドロ
ピラニルオキシ−ビシクロ[3.3.0]オクタン(12)を
得た。3-4 (1S, 2S, 3R, 5S)-(E) -7- (4-carbomethoxybutylidene) -2- [4- (RS) -fluoro-3
(RS) -Hydroxy- (E) -1-octenyl] -3-
Synthesis of tetrahydropyranyloxy-bicyclo [3.3.0] octane (12): (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-1 (EZ) -butenyl] -6-in an autoclave. [4- (R
S) -Fluoro-3 (RS) -hydroxy- (E) -1 octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (11) (0.089g) was added and dissolved in acetone. Then, tricarbonichrome / methyl benzoate complex (0.011 g) was added and degassed. Under hydrogen pressure (70kg / c
m2) and stirred at 120 ° C. for 15 hours. The reaction solution is concentrated under reduced pressure,
The resulting crude product was purified by column chromatography (hexane / ethyl acetate 2: 1) to give a colorless oil (1S,
2S, 3R, 5S)-(E) -7- (4-Carbomethoxybutylidene) -2- [4- (RS) -fluoro-3 (RS) -hydroxy- (E) -1-octenyl] -3 -Tetrahydropyranyloxy-bicyclo [3.3.0] octane (12) was obtained.
収量0.078g(87%)。Yield 0.078g (87%).
1H NMR(CDCl3)δ0.70〜1.04(3H,m)、1.04〜2.67(2
8H,m)、3.21〜4.32(4.5H,m)、4.36〜4.75(1.5H,
m)、4.99〜5.30(1H,m)、5.30〜5.92(2H,m)。1H NMR (CDCl3) δ 0.70 to 1.04 (3H, m), 1.04 to 2.67 (2
8H, m), 3.21-4.32 (4.5H, m), 4.36-4.75 (1.5H,
m), 4.99 to 5.30 (1H, m), 5.30 to 5.92 (2H, m).
3−5 (1S,2S,3R,5S)−(E)−7−(4−カルボメ
トキシブチリデン)−2−[4−(RS)−フルオロ−3
(RS)−ヒドロキシ−(E)−1−オクテニル]−3−
テトラヒドロピラニルオキシ−ビシクロ[3.3.0]オク
タン(13)の合成: (1S,2S,3R,5S)−(E)−7−(4−カルボメトキシ
ブチリデン)−2−[4−(RS)−フルオロ−3(RS)
−ヒドロキシ−(E)−1−オクテニル]−3−テトラ
ヒドロピラニルオキシ−ビシクロ[3.3.0]オクタン(1
2)(0.129g)をメタノールに溶解し、1N水酸化ナトリ
ウム水溶液(2mL)を加え、室温で6時間攪拌した。常
法の処理により無色油状物として(1S,2S,3R,5S)−
(E)−7−(4−カルボメトキシブチリデン)−2−
[4−(RS)−フルオロ−3(RS)−ヒドロキシ−
(E)−1−オクテニル]−3−テトラヒドロピラニル
オキシ−ビシクロ[3.3.0]オクタン(13)を得た。3-5 (1S, 2S, 3R, 5S)-(E) -7- (4-carbomethoxybutylidene) -2- [4- (RS) -fluoro-3
(RS) -Hydroxy- (E) -1-octenyl] -3-
Synthesis of tetrahydropyranyloxy-bicyclo [3.3.0] octane (13): (1S, 2S, 3R, 5S)-(E) -7- (4-carbomethoxybutylidene) -2- [4- (RS ) -Fluoro-3 (RS)
-Hydroxy- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (1
2) (0.129 g) was dissolved in methanol, 1N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 6 hr. As a colorless oil by conventional treatment (1S, 2S, 3R, 5S)-
(E) -7- (4-Carbomethoxybutylidene) -2-
[4- (RS) -Fluoro-3 (RS) -hydroxy-
(E) -1-Octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (13) was obtained.
収量0.140g(定量的)。1 H NMR(CDCl3)δ0.70〜1.05(3H,m)、1.05〜2.70(2
7H,m)、3.26〜6.06(10H,m)。Yield 0.140 g (quantitative). 1 H NMR (CDCl 3 ) δ 0.70 to 1.05 (3H, m), 1.05 to 2.70 (2
7H, m), 3.26 to 6.06 (10H, m).
3−6 (1S,2S,3R,5S)−(E)−7−(4−カルボキ
シブチリデン)−2−[4(RS)−フルオロ−3−オキ
ソ−(E)−1−オクテニル]−3−テトラヒドロピラ
ニルオキシ−ビシクロ[3.3.0]オクタン(14)の合
成: (1S,2S,3R,5S)−(E)−7−(4−カルボキシブチ
リデン)−2−[4(RS)−フルオロ−3(RS)−ヒド
ロキシ−(E)−1−オクテニル]−3−テトラヒドロ
ピラニルオキシ−ビシクロ[3.3.0]オクタン(13)
(0.10g)を−15〜−20℃でジョーンズ酸化した。30分
攪拌後、イソプロピルアルコールを加え、常法により処
理した。得られた粗生成物を酸処理したシリカゲル(マ
リンクロット社,CC−4)を用いたカラムクロマトグラ
フィー(ヘキサン/酢酸エチル6:1〜5:1)で精製し無色
油状物として、(1S,2S,3R,5S)−(E)−7−(4−
カルボキシブチリデン)−2−[4(RS)−フルオロ−
3−オキソ−(E)−1−オクテニル]−3−テトラヒ
ドロピラニルオキシ−ビシクロ[3.3.0]オクタン(1
4)を得た。3-6 (1S, 2S, 3R, 5S)-(E) -7- (4-Carboxybutylidene) -2- [4 (RS) -fluoro-3-oxo- (E) -1-octenyl]- Synthesis of 3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (14): (1S, 2S, 3R, 5S)-(E) -7- (4-Carboxybutylidene) -2- [4 (RS ) -Fluoro-3 (RS) -hydroxy- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (13)
(0.10 g) was Jones-oxidized at -15 to -20 ° C. After stirring for 30 minutes, isopropyl alcohol was added and the mixture was treated by a conventional method. The obtained crude product was purified by column chromatography (hexane / ethyl acetate 6: 1 to 5: 1) using acid-treated silica gel (Malinklot Co., CC-4) to give a colorless oil (1S, 2S, 3R, 5S)-(E) -7- (4-
Carboxybutylidene) -2- [4 (RS) -fluoro-
3-oxo- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (1
4) got.
収量0.106g(76%)。1 H NMR(CDCl3)δ0.75〜1.04(3H,m)、1.04〜2.78(2
7H,m)、3.23〜4.14(3H,m)、4.37〜4.73(1.5H,m)、
5.02〜5.36(1.5H,m)、6.32〜6.67(1H,m)、6.73〜7.
23(1H,m)。Yield 0.106g (76%). 1 H NMR (CDCl 3 ) δ 0.75 to 1.04 (3H, m), 1.04 to 2.78 (2
7H, m), 3.23-4.14 (3H, m), 4.37-4.73 (1.5H, m),
5.02 to 5.36 (1.5H, m), 6.32 to 6.67 (1H, m), 6.73 to 7.
23 (1H, m).
3−7 16(RS)−フルオロ−15−ケト−9(O)−メタ
ノPGI2(15)の合成: (1S,2S,3R,5S)−(E)−7−(4−カルボキシブチ
リデン)−2−[4(RS)−フルオロ−3−オキソ−
(E)−1−オクテニル]−3−テトラヒドロピラニル
オキシ−ビシクロ[3.3.0]オクタン(14)(0.106g)
を酢酸、水、およびTHFの4:2:1混合溶媒に溶解し、45℃
で3.5時間攪拌した。反応液を減圧濃縮し、得られた粗
生成物をシリカゲル(マリンクロット社,CC−4)を用
いたカラムクロマトグラフィー(ヘキサン/酢酸エチル
6:1〜2:1)で精製し、無色油状物として16(RS)−フル
オロ−15−ケト−9(O)−メタノPGI2(15)を得た。
収量0.047g(52%)。1 H NMR(CDCl3)δ0.74〜1.04(3H,m)、1.04〜2.80(2
1H,m)、3.67〜4.07(1H,m)、4.43〜4.65(0.5H,m)、
4.99〜5.37(1.5H,m)、4.00〜5.60(2H,brs)、6.51
(1H,dd,J=17Hz、J=4Hz)、6.94(1H,dd,J=17Hz,J
=7Hz)。Synthesis of 3-7 16 (RS) -fluoro-15-keto-9 (O) -methano-PGI 2 (15): (1S, 2S, 3R, 5S)-(E) -7- (4-carboxybutylidene ) -2- [4 (RS) -Fluoro-3-oxo-
(E) -1-Octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (14) (0.106g)
Was dissolved in a 4: 2: 1 mixed solvent of acetic acid, water, and THF, and the temperature was 45 ° C.
And stirred for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (hexane / ethyl acetate) using silica gel (Marincklot Co., CC-4).
Purification by 6: 1 to 2: 1) gave 16 (RS) -fluoro-15-keto-9 (O) -methano PGI 2 (15) as a colorless oil.
Yield 0.047g (52%). 1 H NMR (CDCl 3 ) δ 0.74 to 1.04 (3H, m), 1.04 to 2.80 (2
1H, m), 3.67 to 4.07 (1H, m), 4.43 to 4.65 (0.5H, m),
4.99 ~ 5.37 (1.5H, m), 4.00 ~ 5.60 (2H, brs), 6.51
(1H, dd, J = 17Hz, J = 4Hz), 6.94 (1H, dd, J = 17Hz, J
= 7Hz).
実施例4 16,16−ジフルオロ−15−ケト−9(O)−メタノPGI2
の合成: 4−1 (1S,5S,6S,7R)−3−[4−カルボメトキシ−
1(EZ)−ブテニル]−6−[4,4−ジフルオロ−3−
オキソ−(E)−1−オクテニル]−7−テトラヒドロ
ピラニルオキシ−ビシクロ[3.3.0]オクト−2−エン
(16)の合成: (1S,5S,6S,7R)−3−[4−カルボメトキシ−1(E
Z)−ブテニル]−6−ヒドロキシメチル−7−テトラ
ヒドロピラニルオキシ−ビシクロ[3.3.0]オクト−2
−エン(41)(0.333g)を塩化メチレン中、0℃でコリ
ンズ酸化した。30分後反応液に硫酸水素ナトリウムを加
え、濾過した。濾液を減圧濃縮し、粗アルデヒド
(5′)を得た。粗アルデヒド(5′)をTHFに溶解
し、ジメチル(2−オキソ−3,3−ジフルオロヘプチ
ル)ホスホネート(0.970g)と水素化ナトリウムから調
製したアニオンと70℃で反応させた。17時間攪拌した
後、酢酸を加えて中和した。常法の処理により得た粗生
成物をカラムクロマトグラフィー(ヘキサン/酢酸エチ
ル6:1)で精製し、無色油状物として(1S,5S,6S,7R)−
3−[4−カルボメトキシ−1(EZ)−ブテニル]−6
−[4,4−ジフルオロ−3−オキソ−(E)−1−オク
テニル]−7−テトラヒドロピラニルオキシ−ビシクロ
[3.3.0]オクト−2−エン(16)を得た。収量0.196g
(43%)。1 H NMR(CDCl3)δ0.73〜1.06(3H,m)、1.04〜2.90(2
3H,m)、2.90〜4.17(3H,m)、3.63(3H,s)、4.33〜4.
71(1H,m)、5.10〜5.66(2H,m)、5.94(0.67H,d,J=1
2Hz)、6.22(0.33H,d,J=16.5Hz)、6.57(1H,dd,J=1
5Hz,J=6Hz)、6.86〜7.33(1H,m)。Example 4 16,16-Difluoro-15-keto-9 (O) -methano PGI 2
Synthesis of 4-1 (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-
1 (EZ) -butenyl] -6- [4,4-difluoro-3-
Synthesis of oxo- (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (16): (1S, 5S, 6S, 7R) -3- [4- Carbomethoxy-1 (E
Z) -Butenyl] -6-hydroxymethyl-7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2
The ene (41) (0.333g) was Collins oxidised at 0 ° C in methylene chloride. After 30 minutes, sodium hydrogensulfate was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a crude aldehyde (5 '). The crude aldehyde (5 ') was dissolved in THF and reacted at 70 ° C with an anion prepared from dimethyl (2-oxo-3,3-difluoroheptyl) phosphonate (0.970g) and sodium hydride. After stirring for 17 hours, acetic acid was added to neutralize. The crude product obtained by a conventional method was purified by column chromatography (hexane / ethyl acetate 6: 1) to obtain a colorless oily substance (1S, 5S, 6S, 7R)-
3- [4-carbomethoxy-1 (EZ) -butenyl] -6
-[4,4-Difluoro-3-oxo- (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (16) was obtained. Yield 0.196g
(43%). 1 H NMR (CDCl 3 ) δ 0.73 to 1.06 (3H, m), 1.04 to 2.90 (2
3H, m), 2.90-4.17 (3H, m), 3.63 (3H, s), 4.33-4.
71 (1H, m), 5.10 to 5.66 (2H, m), 5.94 (0.67H, d, J = 1)
2Hz), 6.22 (0.33H, d, J = 16.5Hz), 6.57 (1H, dd, J = 1)
5Hz, J = 6Hz), 6.86-7.33 (1H, m).
4−2 (1S,5S,6S,7R)−3−[4−カルボメトキシ−
1(EZ)−ブテニル]−6−[4,4−ジフルオロ−3(R
S)−ヒドロキシ−(E)−1−オクテニル]−7−テ
トラヒドロピラニルオキシ−ビシクロ[3.3.0]オクト
−2−エン(17)の合成: (1S,5S,6S,7R)−3−[4−カルボメトキシ−1(E
Z)−ブテニル]−6−[4,4−ジフルオロ−3−オキソ
−(E)−1−オクテニル]−7−テトラヒドロピラニ
ルオキシ−ビシクロ[3.3.0]オクト−2−エン(16)
(0.196g)をメタノールに溶解し、0℃で水素化ホウ素
ナトリウム(0.015g)を加え30分攪拌した。常法の処理
により無色油状物として(1S,5S,6S,7R)−3−[4−
カルボメトキシ−1(EZ)−ブテニル]−6−[4,4−
ジフルオロ−3−(RS)−ヒドロキシ−(E)−1−オ
クテニル]−7−テトラヒドロピラニルオキシ−ビシク
ロ[3.3.0]オクト−2−エン(17)を得た。収量0.184
g(93%)。1 H NMR(CDCl3)δ0.70〜1.03(3H,m)、1.03〜2.72(2
4H,m)、2.85〜3.23(1H,m)、3.23〜3.96(2H,m)、3.
63(3H,s)、3.96〜4.35(1H,m)、4.46〜4.68(1H,
m)、5.05〜6.35(5H,m)。4-2 (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-
1 (EZ) -butenyl] -6- [4,4-difluoro-3 (R
Synthesis of (S) -hydroxy- (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (17): (1S, 5S, 6S, 7R) -3- [4-carbomethoxy-1 (E
Z) -Butenyl] -6- [4,4-difluoro-3-oxo- (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (16)
(0.196 g) was dissolved in methanol, sodium borohydride (0.015 g) was added at 0 ° C, and the mixture was stirred for 30 minutes. (1S, 5S, 6S, 7R) -3- [4-
Carbomethoxy-1 (EZ) -butenyl] -6- [4,4-
Difluoro-3- (RS) -hydroxy- (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] oct-2-ene (17) was obtained. Yield 0.184
g (93%). 1 H NMR (CDCl 3 ) δ 0.70 to 1.03 (3H, m), 1.03 to 2.72 (2
4H, m), 2.85 to 3.23 (1H, m), 3.23 to 3.96 (2H, m), 3.
63 (3H, s), 3.96 to 4.35 (1H, m), 4.46 to 4.68 (1H, m
m), 5.05 to 6.35 (5H, m).
4−3 (1S,2S,3R,5S)−(E)−7−(4−カルボメ
トキシブチリデン)−2−[4,4−ジフルオロ−3(R
S)−ヒドロキシ−(E)−1−オクテニル]−3テト
ラヒドロピラニルオキシ−ビシクロ[3.3.0]オクタン
(18)の合成: オートクレーブ中に、(1S,5S,6S,7R)−3−[4−カ
ルボメトキシ−1(EZ)−ブテニル]−6−[4,4−ジ
フルオロ−3(RS)−ヒドロキシ−(E)−1−オクテ
ニル]−7−テトラヒドロピラニルオキシ−ビシクロ
[3.3.0]オクト−2−エン(17)(0.184g)を加えア
セトンに溶解し、トリカルボニルクロム・安息香酸メチ
ル錯体(0.021g)を加え脱気した。水素加圧(70kg/c
m2)、120℃で15時間攪拌した。反応液を減圧濃縮し、
得られた粗精製物をカラムクロマトグラフィー(ヘキサ
ン/酢酸エチル7:2〜3:1)で精製し、無色油状物として
(1S,2S,3R,5S)−(E)−7−(4−カルボメトキシ
ブチリデン)−2−[4,4−ジフルオロ−3(RS)−ヒ
ドロキシ−(E)−1−オクテニル]−3−テトラヒド
ロピラニルオキシ−ビシクロ[3.3.0]オクタン(18)
を得た。4-3 (1S, 2S, 3R, 5S)-(E) -7- (4-carbomethoxybutylidene) -2- [4,4-difluoro-3 (R
Synthesis of S) -Hydroxy- (E) -1-octenyl] -3 tetrahydropyranyloxy-bicyclo [3.3.0] octane (18): (1S, 5S, 6S, 7R) -3- [in the autoclave. 4-Carbomethoxy-1 (EZ) -butenyl] -6- [4,4-difluoro-3 (RS) -hydroxy- (E) -1-octenyl] -7-tetrahydropyranyloxy-bicyclo [3.3.0] ] Oct-2-ene (17) (0.184 g) was added and dissolved in acetone, and tricarbonylchromium / benzoic acid methyl complex (0.021 g) was added and degassed. Hydrogen pressurization (70kg / c
m 2 ), and stirred at 120 ° C. for 15 hours. The reaction solution is concentrated under reduced pressure,
The crude product thus obtained was purified by column chromatography (hexane / ethyl acetate 7: 2 to 3: 1) to give (1S, 2S, 3R, 5S)-(E) -7- (4- Carbomethoxybutylidene) -2- [4,4-difluoro-3 (RS) -hydroxy- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (18)
Got
収量0.175g(95%)。1 H NMR(CDCl3)δ0.75〜1.05(3H,m),1.05〜2.63(28
H,m),3.23〜4.00(3H,m)、3.62(3H,s)、4.00〜4.40
(1H,m)、4.48〜4.66(1H,m)、5.03〜5.32(1H,m)、
5.33〜6.05(2H,m)。Yield 0.175g (95%). 1 H NMR (CDCl 3 ) δ 0.75 to 1.05 (3H, m), 1.05 to 2.63 (28
H, m), 3.23 ~ 4.00 (3H, m), 3.62 (3H, s), 4.00 ~ 4.40
(1H, m), 4.48 ~ 4.66 (1H, m), 5.03 ~ 5.32 (1H, m),
5.33 to 6.05 (2H, m).
4−4 (1S,2S,3R,5S)−(E)−7−(4−カルボキ
シブチリデン)−2−[4,4−ジフルオロ−3(RS)−
ヒドロキシ−(E)−1−オクテニル]−3−テトラヒ
ドロピラニルオキシ−ビシクロ[3.3.0]オクタン(1
9)の合成: (1S,2S,3R,5S)−(E)−7−(4−カルボメトキシ
ブチリデン)−2−[4,4−ジフルオロ−3(RS)−ヒ
ドロキシ−(E)−1−オクテニル]−3−テトラヒド
ロピラニルオキシ−ビシクロ[3.3.0]オクタン(18)
(0.175g)をメタノールに溶解し、1N水酸化ナトリウム
水溶液を加え、原料が消失するまで攪拌した。常法の処
理により粗生成物として(1S,2S,3R,5S)−(E)−7
−(4−カルボキシブチリデン)−2−[4,4−ジフル
オロ−3(RS)−ヒドロキシ−(E)−1−オクテニ
ル]−3−テトラヒドロピラニルオキシ−ビシクロ[3.
3.0]オクタン(19)を得た。収量0.172g(定量的)。1 H NMR(CDCl3)δ0.70〜1.03(3H,m)、1.03〜2.73(2
7H,m)、3.22〜4.39(4H,m)、4.40〜4.72(1H,m)、4.
98〜5.35(1H,m)、5.35〜6.03(2H,m)、3.22〜6.13
(2H,brs)。4-4 (1S, 2S, 3R, 5S)-(E) -7- (4-Carboxybutylidene) -2- [4,4-difluoro-3 (RS)-
Hydroxy- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (1
Synthesis of 9): (1S, 2S, 3R, 5S)-(E) -7- (4-Carbomethoxybutylidene) -2- [4,4-difluoro-3 (RS) -hydroxy- (E)- 1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (18)
(0.175 g) was dissolved in methanol, 1N aqueous sodium hydroxide solution was added, and the mixture was stirred until the raw materials disappeared. As a crude product, (1S, 2S, 3R, 5S)-(E) -7 was obtained by a conventional treatment.
-(4-Carboxybutylidene) -2- [4,4-difluoro-3 (RS) -hydroxy- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.
3.0] Octane (19) is obtained. Yield 0.172 g (quantitative). 1 H NMR (CDCl 3 ) δ 0.70 to 1.03 (3H, m), 1.03 to 2.73 (2
7H, m), 3.22 to 4.39 (4H, m), 4.40 to 4.72 (1H, m), 4.
98-5.35 (1H, m), 5.35-6.03 (2H, m), 3.22-6.13
(2H, brs).
4−5 (1S,2S,3R,5S)−(E)−7−(4−カルボキ
シブチリデン)−2−[4,4−ジフルオロ−3−オキソ
−(E)−1−オクテニル]−3−テトラヒドロピラニ
ルオキシ−ビシクロ[3.3.0]オクタン(20)の合成: (1S,2S,3R,5S)−(E)−7−(4−カルボキシブチ
リデン)−2−[4,4−ジフルオロ−3(RS)−ヒドロ
キシ−(E)−1−オクテニル]−3−テトラヒドロピ
ラニルオキシ−ビシクロ[3.3.0]オクタン(19)(0.1
72g)を室温でコリンズ酸化した。30分攪拌後、反応液
に硫酸水素ナトリウムを加え、濾過した。濾液を濃縮し
て得られた粗生成物を酸処理したシリカゲル(マリンク
ロット社,CC−4)を用いたカラムクロマトグラフィー
(ヘキサン/酢酸エチル20:1〜10:1)で精製し(1S,2S,
3R,5S)−(E)−7−(4−カルボキシブチリデン)
−2−[4,4−ジフルオロ−3−オキソ−(E)−1オ
クテニル]−3−テトラヒドロピラニルオキシ−ビシク
ロ[3.3.0]オクタン(20)を得た。4-5 (1S, 2S, 3R, 5S)-(E) -7- (4-Carboxybutylidene) -2- [4,4-difluoro-3-oxo- (E) -1-octenyl] -3 -Synthesis of tetrahydropyranyloxy-bicyclo [3.3.0] octane (20): (1S, 2S, 3R, 5S)-(E) -7- (4-Carboxybutylidene) -2- [4,4- Difluoro-3 (RS) -hydroxy- (E) -1-octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (19) (0.1
72 g) was Collins oxidized at room temperature. After stirring for 30 minutes, sodium hydrogen sulfate was added to the reaction solution, and the mixture was filtered. The crude product obtained by concentrating the filtrate was purified by column chromatography (hexane / ethyl acetate 20: 1 to 10: 1) using acid-treated silica gel (Malinklot Co., CC-4) (1S, 2S,
3R, 5S)-(E) -7- (4-Carboxybutylidene)
2- [4,4-Difluoro-3-oxo- (E) -1 octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (20) was obtained.
収量0.050g(30%)。1 H NMR(CDCl3)δ0.66〜1.03(3H,m)、1.03〜2.75(2
7H,m)、3.24〜4.08(3H,m)、4.36〜4.68(1H,m)、5.
07〜5.36(1H,m)、6.52(1H,dd,J=15Hz,J=6Hz)、6.
83〜7.30(1H,m)、7.20〜8.20(1H,brs)。Yield 0.050g (30%). 1 H NMR (CDCl 3 ) δ 0.66 to 1.03 (3H, m), 1.03 to 2.75 (2
7H, m), 3.24 to 4.08 (3H, m), 4.36 to 4.68 (1H, m), 5.
07 to 5.36 (1H, m), 6.52 (1H, dd, J = 15Hz, J = 6Hz), 6.
83 to 7.30 (1H, m), 7.20 to 8.20 (1H, brs).
4−6 16,16−ジフルオロ−15−ケト−9(O)−メタ
ノPGI2(21)の合成: (1S,2S,3R,5S)−(E)−7−(4−カルボキシブチ
リデン)−2−[4,4−ジフルオロ−3−オキソ−
(E)−1オクテニル]−3−テトラヒドロピラニルオ
キシ−ビシクロ[3.3.0]オクタン(20)(0.050g)を
酢酸、水、およびTHFの4:2:1混合溶媒に溶解し、45℃で
3.5時間攪拌した。反応液を減圧濃縮し、得られた粗生
成物をシリカゲル(マリンクロット社、CC−4)を用い
たカラムクロマトグラフィー(ヘキサン/酢酸エチル4:
1)で精製し、無色油状物として16,16−ジフルオロ−15
−ケト−9(O)−メタノPGI2(21)を得た。Synthesis of 4-6 16,16-difluoro-15-keto-9 (O) -methano-PGI 2 (21): (1S, 2S, 3R, 5S)-(E) -7- (4-carboxybutylidene) -2- [4,4-difluoro-3-oxo-
(E) -1 octenyl] -3-tetrahydropyranyloxy-bicyclo [3.3.0] octane (20) (0.050 g) was dissolved in a 4: 2: 1 mixed solvent of acetic acid, water, and THF, and the mixture was mixed at 45 ° C. so
Stir for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (hexane / ethyl acetate 4: 4 on silica gel (Malinklot, CC-4)).
Purified in 1), 16,16-difluoro-15 as colorless oil
- to obtain a methanol PGI 2 (21) - keto -9 (O).
収量0.033g(80%)。1 H NMR(CDCl3)δ0.70〜1.05(3H,m)、1.05〜2.90(2
1H,m)、3.65〜4.20(1H,m)、5.05〜5.40(1H,m)、4.
80〜5.95(2H,brs)、6.53(1H,d,J=16Hz)、7.07(1
H,dd,J=16Hz,J=7.5Hz)。Yield 0.033g (80%). 1 H NMR (CDCl 3 ) δ 0.70 to 1.05 (3H, m), 1.05 to 2.90 (2
1H, m), 3.65 to 4.20 (1H, m), 5.05 to 5.40 (1H, m), 4.
80 to 5.95 (2H, brs), 6.53 (1H, d, J = 16Hz), 7.07 (1
H, dd, J = 16Hz, J = 7.5Hz).
発明の効果 本発明は、新規なプロスタグランジンI類、即ち、15−
ケト−(16−置換)−9(O)−メタノ−△6(9α)
−PGI1類および、15−ケト−(16−置換)−9(0)−
メタノ−PGI2類を提供する。これらの化合物は、血圧下
降剤としての有用性が期待される。 EFFECTS OF THE INVENTION The present invention provides a novel prostaglandin type I, namely 15-
Keto- (16-substituted) -9 (O) -methano-Δ6 (9α)
-PGI 1 and 15-keto- (16-substituted) -9 (0)-
Provide methano-PGI 2 class. These compounds are expected to be useful as blood pressure lowering agents.
Claims (2)
はそれぞれ独立して水素原子またはハロゲン原子を示す
(但し、R2およびR2′の少なくとも一方はハロゲン原子
を示す)]で表わされるプロスタグランジンI類または
その塩。1. A general formula [I] or [II]: [In the formula, R1 represents a hydrogen atom or an alkyl group and R2 and R2 '.
Each independently represent a hydrogen atom or a halogen atom (provided that at least one of R2 and R2 'represents a halogen atom)].
子である第1項記載のプロスタグランジンI類。2. A prostaglandin I according to claim 1, wherein one or both of R2 and R2 'is a fluorine atom.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63332219A JPH0791219B2 (en) | 1988-12-27 | 1988-12-27 | New prostaglandin type I |
CA002016300A CA2016300C (en) | 1988-12-27 | 1990-05-08 | Prostaglandin i analogue |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63332219A JPH0791219B2 (en) | 1988-12-27 | 1988-12-27 | New prostaglandin type I |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH02178252A JPH02178252A (en) | 1990-07-11 |
JPH0791219B2 true JPH0791219B2 (en) | 1995-10-04 |
Family
ID=18252506
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63332219A Expired - Fee Related JPH0791219B2 (en) | 1988-12-27 | 1988-12-27 | New prostaglandin type I |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0791219B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0431571A3 (en) * | 1989-12-05 | 1992-01-02 | Sagami Chemical Research Center | Cis-bicyclo(4.3.0)non-2-ene derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6042348A (en) * | 1983-08-19 | 1985-03-06 | Sagami Chem Res Center | (3-oxo-1-alkenyl)-cis-bicyclo(3.3.0)octene derivative |
-
1988
- 1988-12-27 JP JP63332219A patent/JPH0791219B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH02178252A (en) | 1990-07-11 |
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