JPH0575755B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing isocarbacyclines and raw materials thereof. More specifically, the new 9-
The present invention relates to a method for producing isocarbacyclines via silylated carbacyclines using (benzoyloxysilylmethyl) prostaglandin F ₂ as a key substance. <Technical background> Carbacyclin is a prostaglandin (sometimes abbreviated as PG), which is a physiologically active substance in vivo.
I ₂ (PGI ₂ ) is a prostaglandin I ₂ analog in which the oxygen atoms at the 6 and 9-positions are substituted with methylene groups, and is a natural prostaglandin I ₂ that has an enol ether partial structure in the molecule. Comparatively, it is chemically stable, making it a useful compound as a pharmaceutical agent such as an antithrombotic agent. In recent years, isocarbacyclin, a type of double-bond isomer of carbacyclin, i.e., 9(O)-methano-△ ^{6(9〓 )} -prostaglandin I class ₁ , has been shown to have the strongest platelet aggregation potential among its congeners. It was discovered that it exhibits an inhibitory effect, and its application as a pharmaceutical was expected [Ikegami et al., Tetrahedron Letters]
Letters), 33 , 3493 and 3497 (1983) and JP-A-59-137445 and 59-210044]. Conventionally, several methods for producing such 9(O)-methanol △ _{6 (9} 〓 ₎ -prostaglandin I ₁ (isocarbacycline) have been known, and an overview of the method and the key synthetic intermediate used, To summarize and report, (1) Ikegami et al., Tetrahedron letters, 24 , 3493 (1983) and Chemistry letters.
(2) Ikegami et al., Tetrahedron Letters, 24 , 3497 (1983): (3) Ikegami et al., Journal of the Chemical・
J.Chem.Soc., Chemical Communica
tions), 1984 , 1602: (4) Shibasaki et al., Tetrahedron Letters, 25 5087 (1984): Chemistry Letters,
579 (1984): [C] [C] (5) Shibasaki et al., Tetrahedron Letters, 25 1067 (1984) and JP-A-60-94934: [C] (6) Kojima et al., Chemical・And Pharmaceutical Bulletin (Chem.Pharm.Bull.),
32, 2866 (1984): [KA] (7) Kojima et al., JP-A-60-28943: [KA] (8) Sakauchi et al., Collection of abstracts from the 106th Annual Meeting of the Pharmaceutical Society of Japan.
p379 (1986): [Ka] (9) Hani et al., Abstracts of the 106th Annual Meeting of the Pharmaceutical Society of Japan
p379 (1986): [Ka] (10) Okamura et al., Abstracts of the 106th Annual Meeting of the Pharmaceutical Society of Japan
p380 (1986): There are 10 methods of [C]. Among these 10 methods, method (1) and method (5) are
PGE ₂ is used as a starting material, which is led through several steps to a key intermediate, and then through several more steps to obtain the target product, isocarbacycline, so it cannot be described as an industrial production method. In addition, both method (2) and method (3) require a multi-step process from expensive Corey lactone to obtain the corresponding starting materials and key intermediates, and the total yield is not high, and The problem is that it is not an industrially advantageous method. Methods (6) and (7) yield the final product only in the dl form, and are therefore out of the question as production methods intended for pharmaceutical production. In method (4), the starting material is not only easily obtained from optically active (R)-4-hydroxy-2-cyclopentenone by the method of the present inventors (Japanese Unexamined Patent Publication No. 1986-57
-155116), the derivation of the key intermediate from the starting material is also a method that can be produced industrially without any problems. However, there are many difficulties in the process from key intermediates to final isocarbacyclines, such as the use of organic mercury compounds, loss of regiospecificity, and contamination of non-separable by-products. However, there is a major drawback in that the total yield is low and it is difficult to implement a practical or industrial production method. In addition, although method (8) is most advantageous in deriving isocarbacycline from a key intermediate and has high practicality, it has the disadvantage that the number of steps for producing the key intermediate from the starting material is relatively long. Method (9) has the drawback that carbacycline is produced as a by-product during the production of the product isocarbacycline. Although method (10) can produce isocarbacycline from the starting materials in the shortest number of steps, the yield is low and it cannot be said to be an industrially satisfactory method. Recently, the present inventors reported (Chemical Society of Japan No.
53 Autumn Annual Meeting Abstracts p. 499 (1986)) is a method that uses a (methylthio)thiocarbonyloxysilylmethyl derivative as a key intermediate, as shown below. There are difficulties in selectively producing isocarbacyclines, and the development of an industrially advantageous production method for isocarbacyclines remains an unresolved problem. <Object of the invention> The object of the present invention is to develop a new key intermediate that enables the industrial production of isocarbacyclines;
Our goal is to provide an efficient manufacturing method that goes through this process. (In principle, the naming of compounds in this specification is based on the prostaglandin nomenclature). <Structure and effects of the invention> The present inventors focused on the above-mentioned points, and produced (9)(O)-methano△ ^{6(9〓 )} -prostaglandin I class ₁ (isocarbacyclines) which met the above objectives. ) The present invention was achieved as a result of intensive research to find a new practical manufacturing method. That is, in the present invention, the following formula [ ] [In the formula, R ¹ , R ² , and R ³ are the same or different and represent a C ₁ to C ₇ alkyl group or an aryl group, and R ⁴ is a C ₁ to C 7 alkyl group or an aryl group. represents an alkyl of ₆ ,
R ⁵ and R ⁶ are the same or different, and tri (C ₁ to _{C 7} )
represents a hydrocarbon silyl group, R ⁷ represents a hydrogen atom, R ⁸ represents a linear or branched C ₃ to _{C 9} alkyl group, R ⁹ represents a hydrogen atom,
n represents 0 or 1. ] The compound represented by, its enantiomer, or any proportion thereof (hereinafter, the expression "represented compound" is also synonymous with "the represented compound, its enantiomer, or any proportion thereof" is provided as _a key intermediate to achieve the above object. ¹ , R ² and R ³ are the same or different and represent a C ₁ to C ₇ hydrocarbon group,
For example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl, benzyl,
Examples include tolyl group, especially methyl, t-
Butyl and phenyl groups are preferred. Among others
Most preferably, the combination of R ¹ , R ² , and R ³ in the R ¹ R ² R ³ Si group is a dimethylphenylsilyl group. In the above formula [], R ⁴ represents a C ₁ to C ₅ alkyl group, and examples of the C ₁ to C ₆ alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, and hexyl group. Examples include. Reference examples for R ⁴ include C ₃ to C ₆ alkenyl groups, specific examples of which include 2-propenyl, 2-butenyl, 2-butenyl, and 2-propenyl.
-hexenyl, phenyl groups, etc.
R ⁴ is preferably a methyl or ethyl group. In addition, in the above formula [], R ⁵ and R ⁶ are the same or different and represent a tri(C ₁ to C ₇ ) hydrocarbon silyl group, but as another reference example, a group that forms an acetal bond with the oxygen atom of a hydroxyl group is Can be mentioned. As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tri(C ₁ -C ₄ )alkylsilyl group such as t-butyldimethylsilyl group, diphenyl(C 1 -C ₄ )alkylsilyl group such as t-butyldiphenylsilyl group, Preferred examples include a _C4 ) alkylsilyl group, a di( _C1 - _C4 )alkylphenyl group such as a dimethylphenyl group, and a tribenzylsilyl group. Among them, tri(C ₁ -C ₄ )alkylsilyl, diphenyl(C ₁ -C ₄ )alkylsilyl, phenyldi(C ₁
~ _C4 ) Alkylsilyl group is preferred, and t-butyldimethylsilyl group and trimethylsilyl group are particularly preferred. Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, a methoxymethyl group,
1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2-
methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-
Mention may be made of the 3-oxa-2-oxobicyclo[3.1.0]hex-4-yl group. 2-tetrahydropyranyl, 2-tetrahydrofuranyl,
1-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, 6,6-
Particularly preferred is dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl. Among them, 2-tetrahydropyranyl is particularly preferred. It is to be understood that these silyl groups and groups forming acetal bonds are hydroxyl protecting groups. These protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to provide free hydroxyl groups useful as pharmaceuticals. Therefore, a hydroxyl protecting group having such properties can be used in place of a silyl group or a group forming an acetal bond. Further, in the above formula [], R ⁷ represents a hydrogen atom, but other reference examples include a methyl group or a vinyl group. Furthermore, in the above formula [], R ⁸ represents a linear or branched C ₃ to C ₉ alkyl group. In addition, R ⁸
As another reference example, C ₃ interrupted by an oxygen atom
~ _C9 alkyl group, alkenyl group or alkynyl group optionally interrupted by an oxygen atom; substituted or unsubstituted phenyl group, phenoxy group, or _C3 - _C10 cycloalkyl group; or _C1 - _C6 alkoxy group, an optionally substituted phenyl group,
It represents a linear or branched C1 _{- C5} alkyl group substituted with an optionally substituted phenoxy or an optionally substituted _C3 - _C10 cycloalkyl group. Straight-chain or branched _C3 - _C9 alkyl groups for ^R8 include propyl, butyl, pentyl,
hexyl, heptyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-methylpentyl, 2
-methylhexyl, 2,2-dimethylhexyl, and the like. butyl, pentyl,
Preferred are hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, and 2-methylpentyl. Specific examples of the alkyl group interrupted by an oxygen atom, which are reference examples for ^R8 , include 2-methoxyethyl and 2-ethoxyethyl.
Furthermore, the linear or branched _C3 - _C9 alkenyl group which may be interrupted by an oxygen atom includes, for example, 1-butylvinyl, 2-propylaryl,
2-pentenyl, 4-pentenyl, 2-methyl-
3-pentenyl, 4-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl groups, etc. preferable. Straight-chain or branched _C3 - _C9 alkynyl groups optionally interrupted by oxygen atoms include, for example,
2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl, 1-methyl-
3-pentynyl group is preferred. Substituted phenyl group, substituted phenoxy group, or
Examples of the substituent of the C ₃ to _{C 10} substituted cycloalkyl group include a halogen atom, a protected hydrogen group (e.g., a silyloxy group, a C ₁ to _{C 6} alkoxy group, etc.), a trifluoromethyl group, a C ₁ to C ₄ Examples include alkyl groups. Examples of the C ₃ to _{C 10} cycloalkyl group include:
Examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and cyclodecyl groups. Cyclopentyl and cyclohexyl groups are preferred. Straight chain or branched chain substituted with a C ₁ to C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃ to C ₁₀ cycloalkyl group In the chain _C1 - _C5 alkyl groups, _C1 - _C6 alkoxy groups include, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, t
-butoxy, hexyloxy groups, etc. The substituents of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted C ₃ to _{C 10} cycloalkyl group and the C ₃ to _{C 10} cycloalkyl group include the above-mentioned examples. The same thing can be mentioned. Straight chain or branched chain _C1 - _C5 alkyl groups include, for example,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl groups and the like can be mentioned. It costs R ⁸
Examples include butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl,
Preferred examples include 2-methylbutyl, 2-methylpentyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, cyclopentylmethyl, and cyclohexylmethyl groups. Note that the substituent may be bonded to any position thereof. Furthermore, in the above formula [], R ⁹ represents a hydrogen atom. In addition, substituents can be mentioned as other reference examples of R ⁹ , and such substituents include the same substituents as those listed for the substituted phenyl group of R ⁸ above, and the substitution positions are the ortho position, Both the meta and para positions can be mentioned. Among these, a trifluoromethyl group and a chlorine atom are preferred. R ⁹ is preferably a hydrogen atom, p-chloro group, or m-trifluoromethyl group, and particularly preferably m-trifluoromethyl group. Further, in the above formula [], n represents 0 or 1, and n is particularly preferably 0. In addition, in the compound represented by the above formula [], the carbon atoms to which substituents are bonded on the cyclopentane ring and in the side chain have stereoisomers due to the asymmetric environment. It includes both stereoisomers, and may be a mixture of these stereoisomers in any proportion. Furthermore, the compound represented by the formula refers to all of these stereoisomers and a mixture of these isomers in any proportion, but the most preferred are compounds having the stereostructure represented by the formula. Preferred specific examples of the 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin _F2 represented by the above formula [] provided by the present invention are shown below. ] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸
and n are the same as defined above. Regarding ^the 5,6 ^- dehydro-9-deoxy- ^9- (hydroxysilylmethyl) prostaglandin _F2 represented by It becomes like this. still,
(02), (05) to (14) are reference examples. (01) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)
PGF ₂ 〓 (02) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
15-Methyl PGF ₂ 〓 (03) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
16,16-dimethyl PGF ₂ 〓 (04) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
17,20-dimethyl PGF ₂ 〓 (05) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
18,19,20-trinor-17-ethoxyPGF ₂ 〓 (06) 5,6,17,18-tetradehydro-9-deoxy-9-(hydroxydimethylphenylsilylmethyl) PGF ₂ 〓 (07) 5, 6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
17-Methyl-19,20-dinol-18-(1-propynyl)PGF ₂ 〓 (08) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
17-Methyl-20-isopropylidene PGF ₂ 〓 (09) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
17,18,19,20-tetranol-16-phenoxy
PGF ₂ 〓 (10) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
17,18,19,20-tetranor-16-m-chlorophenoxy PGF ₂ 〓 (11) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
16,17,18,19,20-pentanol-15-cyclohexyl PGF ₂ 〓 (12) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
16,17,18,19,20-pentanol-15-cyclopentyl PGF ₂ 〓 (13) 5,6-dehydro-9-deoxy-9-
(Hydroxydimethylphenylsilylmethyl)-
17,18,19,20-tetranor-16-cyclohexyl PGF ₂ 〓 (14) 5,6-dehydro-9,15-bisdeoxy-16-hydroxy-9-(hydroxydimethylphenylsilylmethyl)-16-methyl PGF ₂ 〓 (15) 5,6-dehydro-9,15-bisdeoxy-16-hydroxy-9-(hydroxydimethylphenylsilylmethyl) PGF ₂ 〓 (16) Hydroxydimethylphenylsilyl of (01) to (15) Compound (17) in which the methyl group is substituted with a hydroxytrimethylsilylmethyl group The hydroxydimethylphenylsilylmethyl group of (01) to (15) is substituted with hydroxydimethyl-t
- Compound (18) substituted with a butylsilylmethyl group Compound (19) (01) in which the hydroxydimethylphenylsilylmethyl group of (01) to (15) is substituted with a hydroxydi-t-butylphenylsilylmethyl group ) to (15) in which the hydroxydimethylphenylsilylmethyl group is substituted with a hydroxydiphenylmethylsilylmethyl group Examples of compounds that take into account the definitions of R ⁴ , R ⁵ , and R ⁶ are as follows: Become. Furthermore, (21), (23),
(24) and (27) are reference examples. (20) 11,15 (or 16)-bis-t-butyldimethylsilyl ether of (01) to (19) (21) 11,15 (or 16)-bis-tetrahydropyranyl ether of (01) to (19) (22) 11,15 (or 16)-bis-t-butyldiphenylsilyl ether of (01) to (19) (23) 11-t-butyldimethylsilyl-15 (or 16)-tetrahydropyranyl ether (24) 11-tetrahydropyranyl-15 (or 16)-t-butyldimethylsilyl ether (25) of (01) to (19) methyl ester of (01) to (24) (26) ) Ethyl ester of (01) to (24) (27) Allyl ester of (01) to (24) (28) t-butyl ester of (01) to (24) (29) Hexyl ester Specific examples of compounds represented by the above formula [] are:
An example of the benzoylated compound of the compound represented by the above formula [] is (30). Note that (31) and (32) are reference examples. (30) (01) to (29) are 9α-benzoyl derivatives (31) (01) to (29) are 9α-(m-trifluoromethylbenzoyl) derivatives (32) (01) to (29) are 9α- (p-Chlorobenzoyl) derivatives The 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ of the present invention represented by the above formula [] is easily available. ,6-dehydro-9-deoxy-
It is produced through the following steps using 9-formyl prostaglandin F ₂ (formula []) as a starting material, leading to silylated carbacyclines which can be derived into isocarbacyclines. [Chemical Formula] That is, as a first step, the production method of the present invention comprises the following formula [] [Chemical Formula] [wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and n are the same as defined above] It is. ] 5,6-dehydro-9-deoxy- represented by
9-Formyl prostaglandin F ₂ 〓 has the following formula [] (R ¹ R ² R ³ Si) _q (L) _2-q CuLi ... [] [In the formula, R ¹ , R ² , and R ³ are Same as above definition, L is cyano group, phenylthio group, 1-
It represents a pentynyl group or an iodine atom, and q represents 1 or 2. ] The silyl copper lithium compound reaction (silyl addition reaction) represented by the following formula [] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above. ] 5,6-dehydro-9-deoxy- represented by
9-(Hydroxysilylmethyl) prostaglandin F ₂ is obtained, and as a second step, the above formula []
5,6-dehydro-9-deoxy- represented by
9-(Hydroxysilylmethyl) prostaglandin F ₂ 〓 in the presence of a basic substance is prepared by the following formula [] [Chemical formula] [In the formula, R ⁹ is the same as defined above. ] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , ^R7 , ^R8 ,
R ⁹ and n are the same as defined above. ] 5,6-dehydro-9-deoxy- represented by
This is a manufacturing method for obtaining 9-(benzoyloxysilylmethyl) prostaglandin F ₂ . Furthermore, in the present invention, as a third step, the 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ 〓 represented by the above formula [] is added in the presence of a solvent. By irradiating the bottom with light (photocyclization reaction),
The following formula [] [Chemical formula] [where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above, and ~ represents that the steric configuration of the double bond is E, Z, or a mixture of E and Z in any proportion. ] Silylated carbacyclines represented by these are produced. Each step will be explained in detail below. (1) Silyl addition reaction; 5,6-dehydro-
9-deoxy-9-formyl prostaglandin
The F ₂ 〓 class is the method of Ikegami et al. (Ikegami et al., Chemistry Letters, 1069).
(1984)), 5,6-dehydro-9
-deoxy-9-methylene prostaglandin
It is easily produced by combining the hydroboration monoxidation reaction and oxidation reaction using E ₂ as a starting material. The 5,6-dehydro-9
-deoxy-9-methylene prostaglandin
One of the E class ₂ is a known compound, and the method of G, L, Bundy et al.
-135957), 4130720, and 4166187]. That is, 5,6-dehydro-9 is produced by methylenation of the carbonyl group at the 9-position of 5,6-dehydroprostaglandin E ₂ .
-deoxy-9-methylene prostaglandin
E It is possible to manufacture type ₂ . In the above formula [], R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above, and the above formula []
5,6-dehydro-9-deoxy- represented by
9-(benzoyloxysilylmethyl) prostaglandin F ₂ The groups exemplified in the group are similarly preferred, and 5,6-dehydro-9-deoxy-9-formyl prostaglandin represented by the above formula [] Specific examples of F ₂ 〓 are also 5,6-dehydro-9-deoxy-9- represented by the above formula
Preferred examples include derivatives corresponding to the compounds exemplified as (benzoyloxysilylmethyl) prostaglandin F ₂ . In the silyl addition reaction of the method of the present invention, 5,6-dehydro-9-deoxy-9-formyl prostaglandin F ₂ represented by the formula [] is reacted with silyl copper lithium represented by the formula [] in an organic medium. This is achieved by reacting with a compound. In the above formula [], R ¹ , R ² , and R ³ are the same or different and represent a C ₁ to _{C 7} hydrocarbon group, such as methyl, ethyl, propyl, butyl, t-butyl, phenyl, benzyl, tolyl group. are mentioned,
Particularly preferred are methyl, t-butyl, and phenyl groups. For example, the most preferable example of the silyl copper lithium compound is bis(dimethylphenyl) copper lithium. The amount of these silyl copper lithium compounds used is expressed by the formula []
0.8 to 1 mole of 5,6-dehydro-9-deoxy-9-formyl prostaglandin _F2
The amount is 5 times by mole, preferably 0.9 to 3 times by mole. The organic medium for the smooth progress of the reaction is a medium that is inert to the silyl copper lithium compound, such as ethers such as ethyl ether, tetrahydrofuran, dioxane, hydrocarbons such as pentane, hexane, or any of these. Mixtures are used, preferably tetrahydrofuran. The reaction temperature is -100°C to 0°C, preferably -78°C to -40°C, and the reaction time is usually about 5 minutes to 30 minutes. After the reaction, the reaction solution is treated in a conventional manner. That is, the reaction solution is mixed with saturated ammonium chloride water or saturated ammonium sulfate water, and then extracted using an organic solvent that is sparingly soluble in water, such as hexane, pentane, petroleum ether, ethyl ether, or ethyl acetate. The mixture is washed with brine or the like if necessary, dried with a desiccant such as anhydrous magnesium sulfate, anhydrous sodium sulfate, or anhydrous calcium chloride, and then the organic medium is removed under reduced pressure to obtain a crude product. The crude product can be purified, if desired, by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, or the like. Thus, the following formula [] [where R ¹ , R ² , R ³ .R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above. ] 5,6-dehydro-9-deoxy- represented by
9-(Hydroxysilylmethyl) prostaglandin _F2 is produced. (2) Benzoylation reaction; The second stage benzoylation reaction is performed using 5,6-dehydro-9, which is represented by the formula [] obtained in the first stage.
-deoxy-9-(hydroxysilylmethyl) prostaglandin F ₂ 〓 is reacted with an acid halide or acid anhydride of benzoic acids represented by the above formula [] in the presence of a basic substance. . In the above formula [], R ⁹ represents a hydrogen atom or a substituent, and such substituents preferably include the same substituents as those listed for the substituted phenyl group of R ⁸ above, such as a fluorine atom,
Examples include halogen atoms such as chlorine atom and bromine atom, methoxy group, ethoxy group, methyl group, ethyl group, t-butyl group, and trifluoromethyl group, with chlorine atom and trifluoromethyl group being particularly preferred. The substitution positions of such substituents include the ortho position, the meta position, and the rose position, but the most preferred combinations are p-chloro group and m-trifluoromethyl group. The benzoic acids represented by the above formula [] are subjected to the reaction as acid halides or acid anhydrides. Preferred examples of the acid halide include acid chlorides and acid bromides. The amount of these acid halides or acid anhydrides used is 5,6-dehydro-9 represented by the formula []
-Deoxy-9-(hydroxysilylmethyl)prostaglandin F ₂ The amount is 0.8 to 10 moles, preferably 0.9 to 5 moles, particularly preferably 1.0 to 3 moles. The reaction is carried out in the presence of a basic substance. Such basic substances include:
Examples include aromatic bases such as pyridine, 4-(dimethylamino)pyridine, and imidazole, aliphatic bases such as triethylamine and tributylamine, and inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate. The amount of the basic substance used is 0.8 to 10 times the mole of the acid halide or acid anhydride used.
Preferably 0.9 to 5 times the mole, particularly preferably 1.0 to 5 times the mole
It is 3 times the mole. In order for the reaction to proceed smoothly, it is preferable to carry out the reaction in an organic medium. Such organic media include inert organic media normally used in such esterification reactions, such as ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, aliphatic hydrocarbons such as pentane and hexane, benzene, toluene, etc. aromatic hydrocarbons, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, acetonitrile, or any mixture thereof, preferably tetrahydrofuran, methylene chloride, acetonitrile, etc. are used. Reaction temperature is -100℃~
The reaction is carried out at 100°C, preferably -78°C to 50°C, more preferably 0°C to 30°C, and the reaction time varies depending on the reaction temperature, but for example, at 20°C, about 1 hour to 1 day is sufficient. After the reaction, the reaction solution is post-treated by a conventional method. That is, the reaction solution is added with a saturated ammonium chloride aqueous solution to terminate the reaction, and then extracted using a commonly used organic solvent that is sparingly soluble in water, such as hexane, pentane, ethyl ether, or ethyl acetate. The organic mixture is washed with an aqueous potassium hydrogen sulfate solution, an aqueous sodium hydrogen carbonate solution, and an aqueous sodium chloride solution as necessary, and after drying over anhydrous sodium sulfate and anhydrous magnesium sulfate, the organic medium is distilled off under reduced pressure to obtain a crude product. . The crude product can be produced by purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc., if desired. Thus, the following formula [] [where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ and n are the same as defined above. ] 5,6-dehydro-9-deoxy- represented by
9-(benzoyloxysilylmethyl) prostaglandin F ₂ is produced. (3) Photocyclization reaction: The photocyclization reaction in the third step is performed on the 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin represented by the formula [] obtained in the second step. A silylated carbacycline represented by the above formula [] can be produced by irradiating F ₂ 〓 in a solvent in the coexistence of N-methylcarbazole. Such photocyclization reaction is carried out by the method reported by Matsuura et al. (J.Amer.Chem.Soc., 108,
3115 (1986)). The N-methylcarbazole used is 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin represented by the formula []
0.1 to 10 moles per mole of F ₂ 〓, preferably
It is carried out using an amount of 0.5 to 5 moles, particularly preferably 0.8 to 3 moles. 1,2,4,5-tetramethoxybenzene, 1,5-dimethoxynaphthalene, and 1-(dimethylamino)naphthalene can also be used instead of N-methylcarbazole.
As the solvent used, alcohols such as tetrahydrofuran, isopropanol, and propanol are used in the coexistence of water. Water content is 10
It is carried out using around %. Light irradiation is carried out by a conventional method, for example, using a 100W high-pressure mercury lamp as a light source and a Pyrex filter. When such a photocyclization reaction is carried out in the presence of magnesium perchlorate, an acceleration effect is observed. The magnesium perchlorate used is the formula []
It is preferable to use the same amount as the compound represented by. The post-treatment after the reaction is suitably carried out in the same manner as the post-treatment of the second stage benzoylation reaction,
The following formula [] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above, and ~ represents that the steric configuration of the double bond is E, Z, or a mixture of E and Z in any proportion. ] Silylated carbacyclines represented by these are produced. Specific examples of the silylated carbacyclines represented by the formula [] obtained in this way include 5, represented by the formula [] as a starting material for the method of the present invention.
Products corresponding to the compounds specifically exemplified as 6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ can be directly exemplified. Thus, by the method of the present invention, a novel key intermediate, 5,6-dehydro-9-
Deoxy-9-(benzoyloxysilylmethyl)
Silicated carbacyclines represented by the formula [], which are industrially advantageously produced via prostaglandin F ₂ It is possible to derive isocarbacyclines useful as pharmaceuticals through desilyl isomerization and deprotection reactions, according to the 53rd Autumn Annual Conference Abstracts p. 499 (1986). Therefore, the present invention and the above-mentioned reference examples are also reproduced as follows. 1 The following formula [] [In the formula, R ¹ , R ² , and R ³ are the same or different and represent a C ₁ to C 7 hydrocarbon group, and R ⁴ is a C ₁ to _{C 7} hydrocarbon group.
Represents a C ₆ alkyl group or a C ₃ to _{C 6} alkenyl group, R ⁵ and R ⁶ are the same or different and form an acetal bond with the tri(C ₁ to _{C 7} ) hydrocarbon silyl group or the oxygen atom of the hydroxyl group. group, R ⁷ represents a hydrogen atom, methyl group, or vinyl group, and R ⁸ represents a straight or branched chain C ₃ to _{C 9} which may be interrupted by an oxygen atom.
an alkyl group, an alkenyl group, or an alkynyl group; a substituted or unsubstituted phenyl group, a phenoxy group, or a _C3 - _C10 cycloalkyl group; or a _C1 - _C6 alkoxy group, an optionally substituted phenyl group, optionally substituted phenoxy group or optionally substituted
represents a straight chain or branched C ₁ to C ₅ alkyl group substituted with a C ₃ to C ₁₀ cycloalkyl group, R ⁹ represents a hydrogen atom or a substituent,
n represents 0 or 1. ] 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 2. The compound according to item 1, wherein the combination of R ¹ , R ² and R ³ is dimethylphenyl. 3. The compound according to item 1, wherein ^R4 is a _C1 - _C4 alkyl group. 4. The compound according to item 1, wherein R ⁷ is a hydrogen atom or a methyl group. 5. The compound according to item 1, wherein ^R8 is a linear or branched C3 _{- C9} alkyl group or a _C3 - _C10 cycloalkyl group. 6 R ⁸ is n-butyl group, n-pentyl group, n-
2. The compound according to item 1, which is a hexyl group, 2-hexyl group, 2-methylhexyl group, cyclopentyl group, or cyclohexyl group. 7 ^R9 is a hydrogen atom, p-chloro group, or m-
2. The compound according to item 1, which is a trifluoromethyl group. 8 The first in which R ⁹ is m-trifluoromethyl group
Compounds described in Section. 9. The compound according to item 1, wherein n is 0. 10. The compound according to item 1, which has a three-dimensional structure represented by formula []. 11 The following formula [] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above. ] 5,6-dehydro-9-deoxy-9-(hydroxysilylmethyl), which is a compound represented by, its enantiomer, or a mixture of any proportion thereof
Prostaglandin F ₂ 〓 is prepared by the following formula in the presence of a basic substance: [In the formula, R ⁹ is the same as defined above]. ] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ and n are the same as defined above. ] A method for producing 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 12 The 5,6-dehydro-9-deoxy-9-
(Hydroxysilylmethyl) prostaglandin F ₂ is represented by the following formula [] [In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and n are the same as defined above]. ] The compound represented by the following formula [] ( ^{R 1} _R ² R ³ Si) _q (L) _2-q CuLi ... [] [In the formula, R ¹ , R ² and R ³ are the same as defined above, and L is a cyano group, phenylthio group, 1-
It represents a pentynyl group or an iodine atom, and q represents 1 or 2. ] The 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin _F2 according to claim 11, which is obtained by reacting a silyl copper lithium compound represented by 〓Production method of class. 13 The following formula [] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ and n are the same as defined above. 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ , which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion, in the presence of a solvent. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above, and ~ represents that the steric configuration of the double bond is E, Z, or a mixture of E and Z in any proportion. ] A method for producing a silylated carbacycline, which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 14 The solvent is hydrous tetrahydrofuran.
The manufacturing method described in Section 13. 15 No. 13, where the solvent is hydrous isopropanol
Manufacturing method described in section. 16 The production method according to any one of the above items 13 to 15, which comprises irradiating light in the coexistence of N-methylcarbazole. 17. The production method according to any one of the above items 13 to 16, which comprises irradiating light in the coexistence of magnesium perchlorate. Hereinafter, the present invention will be explained in more detail with reference to Examples. In the examples, the symbol Z is Si(CH ₃ ) ₂ -t-
C ₄ H ₉ represents a t-butyldimethylsilyl group. Example 1 [Chemical formula] A solution of bis(dimethylphenylsilyl)copper lithium in tetrahydrofuran (0.27M, 1.20ml, 0314mmol) was added to a solution of aldehyde 1~ (159.0mg, 0.262mmol) in tetrahydrofuran (15.0ml) at -78°C.
and stirred for 30 minutes. A saturated aqueous ammonium chloride solution (10 ml) was added to the reaction solution to terminate the reaction, and the resulting mixture was extracted with ether (10 ml x 3).
did. Wash the ether layer with saturated saline (25 ml),
The separated ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. This was subjected to column chromatography (6 g of silica gel, solvent used: hexane: ethyl acetate = 15:1) to obtain the target product, silyl alcohol 2~ (165.0 mg,
0.222 mmol, 84.7%) was obtained as a colorless oil (diastereomixture). TLC (hexane: ethyl acetate = 5:1);
Rf0.31, IR (CHCl ₃ ); 3400, 1740, 1250, 830 cm ^-1 , ¹ H-NMR (CDCl ₃ , 270 MHz) δ; −0.02, 0.01, 0.03 (s each, 12, OSi
(CH ₃ ) ₂ × 2) 0.36, 0.37 (s each, 6,
SiCH ₃ ×2), 0.85, 0.87 (s each, 21,
OSiC( _CH3 ) ₃ ×2,( _CH3 ),1.1−1.7(m,
10, CH ₂ × 5), 1.73 (tt, 2, J = 7.3, 7.3
Hz, CH ₂ CH ₂ C(O)), 1.93 (dt, 1, J=
7.1, 7.3Hz, CH), 2.0−2.3(m, 6, CH ₂
×2, CH×2), 2.38 (t,2, J=7.4
Hz, CH ₂ C(O)), 3.66 (s, 3, OCH ₃ ), 3.9
−4.1 (m, 3, CHO×3), 5.29 (dd, 1,
J = 8.4, 15.7Hz, vinyl), 5.40 (dd, 1,
J = 5.4, 15.3Hz, vinyl), 7.3-7.6 (m,
5, phenyl), ^13C -NMR (CDCl ₃ , 22.5MHz) δ; 13.9, 18.1, 18.3, 18.4, 22.6, 24.5, 25.0, 26.0, 32.0, 33.1, 37.5, 38.8, 42.0, 48.7, 51.2, 57.4, 64.6, 73.2, 79.4, 79.5, 80.7, 127.9, 129.1, 131.2, 134, 1, 135.2, 138.1, 173.4, MS (m/e); 743 (M+1), 135. Example 2 [C] In Example 1 The obtained silyl alcohol 2~(62.3
4-dimethylaminopyridine (25.0 mg, 0.084 mmol) in acetonitrile (3.0 ml) at 18°C.
mg, 0.21 mmol) and m-trifluoromethylbenzoic acid chloride (0.03 ml, 0.18 mmol),
The resulting reaction mixture was stirred at 18°C for 15 hours. After the reaction, it was poured into a saturated aqueous ammonium chloride solution (3 ml), and the resulting mixture was extracted with ether (3 ml
3) I did. The collected ether layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the remaining crude product was subjected to column chromatography (5 g of silica gel, solvent used: hexane: ethyl acetate = 20:1) to obtain the target silyl benzoate. 3～(69.3mg,
0.076 mmol, 90.1%) was obtained as a colorless oil (diastereomixture). TLC (hexane: ethyl acetate = 5:1);
Rf0.33, IR (CHCl ₃ ); 1710, 1610, 1320, 1250, 1150, 830 cm ^-1 , ¹ H-NMR (CDCl ₃ , 270 MHz) δ; −0.04, −0.03, 0.00, (s each, 12,
OSiCH ₃ × 4), 0.40, 0.41 (s each, 6, SiCH ₃ × 2), 0.85, 0.86 (s each, 21, OSiC (CH ₃ ) ₂ × 2,
CH ₃ ), 1.1−1.6 (m, 10, CH ₂ ×5), 1.74 (tt, 2, J = 7.3, 7.3Hz, CH ₂ CHC
(O)), 1.8-2.3 (m, 7, CH ₂ × 2, CH × 3), 2.40 (t, 2, J = 7.6Hz, CH ₂ C(O)), 2.4-2.5 (m, 1, Allyl CH), 3.69 (s, 3, OCH ₃ ), 3.76 (dd, 1, J=7.3, 15.5Hz, CHO), 3.9-4.0 (m, 1, allyl CHO), 5.20 (s, 1, vinyl) , 5.22 (d, 1, J = 2.0Hz), vinyl), 5.65 (d, 1, J = 2.3Hz, CH(Si)O), 7.3−8.4 (m, 9, phenyl), ¹³ C-NMR ( CDCl ₃ , 22.5MHz) δ; −4.6, −4.4, −4.1, −3.9, −3.7, 13.9 18.1, 18.3, 18.5, 18.6, 22.6, 24.5, 25.0, 26.0, 32.0, 33.1, 36.9, 38.7, 39.5, 46.2, 51.2, 55.7, 70.7, 73.1, 78.2, 79.8, 80.0, 126.6 (q, J _CF = 4.1Hz,
CF ₃ ), 127.9, 128.3, 129.0, 129.5, 129.9, 130.6, 132.0 132.76, 134.2, 135.8, 136.24, 164.9, 173.47, MS (m/e); Example 3 Silyl obtained in Example 2 Benzoate 3~
(14.0 mg, 15.3 μmol), magnesium perchlorate (3.4 mg, 15.3 μmol), and N-methylcarbazole (3.0 mg, 16.6 μmol) in 10 ml of hydrous tetrahydrofuran (tetrahydrofuran:water = 10:1.8 ml). It was placed in a tube and irradiated with light for 16 hours at 18°C using a 500W high-pressure mercury lamp. The reaction solution was poured into a saturated aqueous sodium carbonate solution (5 ml), and the reaction mixture was extracted with ether (3 ml x 3). The collected ether layer was concentrated under reduced pressure, and the residue was subjected to column chromatography (1.5 g of silica gel, solvent used: hexane:ethyl acetate = 100:1) to obtain the target product, silylated carbacycline 4~ (8.3 mg,
11.4 μmol1, 74.7%) as a colorless oily substance (E, Z
obtained as a mixture of bodies). TLC (hexane: ethyl acetate = 5:1);
Rf0.46, IR (CHCl ₃ ); 1740, 1360, 1250, 1100, 830 cm ^-1 , ¹ H-NMR (CDCl ₃ , 500 MHz) δ; 0.00, 0.02, 0.03, (s, each, 12,
OSICH ₃ × 4), 0.24, 0.25, 0.26, 0.28,
(s, each, 6, SiCH ₃ × 2), 0.7−1.0 (m, 21, OSiC (CH ₃ ) ₃ × 2,
CH ₃ ), 1.0−1.7 (m, 12, CH ₂ ×6), 1.7−2.0 (m, 5, CH ₃ ×3, CH ₂ ), 2.0−2.3 (m, 5, allyl CH ₂ ×2, allyl CH), 3.5-3.7 (m, 1, CHO), 3.66, 3.67 (s each 3, OCH ₃ ), 4.02 (br, 1, CHO), 4.92, 5.09 (br each, 1, vinyl), 5.3-5.5 (m, 2, vinyl), 7.3−7.5 (m, 5, phenyl), ^13C -NMR (CDCl ₃ , 22.5MHz) δ; −4.6, −4.5, −4.4, −4.1, −3.9, −3.4, 14.1，18.1，18.3，22.6，25.1，25.4，26.0，29.2，31.8，33.6，33.9，38.7，39.4，39.7，43.5，43.7，44.5，45.0，46.0，51.4，56.1，73.3，78.2，119. 2,119.7, 127.7, 128.9, 129.0, 130.9, 133.8, 134.0, 134.3, 134.4, 138.3, 138.4, 143.1, 144.3, 174.1, MS (m/e); 726 (M ⁺ ), High resolution MS; C ₄₂ H ₇₄ O ₄ Si Calculated value for ₃ (M ⁺ ): 726,4895, measured value: 726,4906.

Claims (1)

[Claims] 1 The following formula [] [In the formula, R ¹ , R ² , and R ³ are the same or different and represent a C ₁ to C ₇ alkyl group or an aryl group, and R ⁴ is a C ₁ ~represents a _C6 alkyl group,
R ⁵ and R ⁶ are the same or different, and tri (C ₁ to _{C 7} )
represents a hydrocarbon silyl group, R ⁷ represents a hydrogen atom, R ⁸ represents a linear or branched C ₃ to _{C 9} alkyl group, R ⁹ represents a hydrogen atom,
n represents 0 or 1. 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 2 The following formula [] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
and n are the same as defined above. ] 5,6-dehydro-9-deoxy-9-(hydroxysilylmethyl), which is a compound represented by, its enantiomer, or a mixture thereof in any proportion
Prostaglandin F ₂ 〓 is prepared by the following formula in the presence of a basic substance: [In the formula, R ⁹ is the same as defined above]. ] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ and n are the same as defined above. ] A method for producing 5,6-dehydro-9-deoxy-9-(benzoyloxysilylmethyl) prostaglandin F ₂ which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion.