JP2713333B2 - Isocarbacyclines and process for producing the same - Google Patents

Description

The present invention relates to isocarbacyclines and a method for producing the same. More specifically, the present invention relates to novel 15-deoxy-16-hydroxyisocarbacyclines and a method for producing the same. <Prior art> Carbacycline is a bioactive substance, prostaglandin (sometimes abbreviated as PG) I ₂ (PGI ₂ )
A prostaglandin I ₂ analog in which the 6,9-position oxygen atom is substituted with a methylene group, which is chemically more stable than natural prostaglandin I ₂ having a partial structure of an enol ether in the molecule. Because of its existence, it is a compound useful as a pharmaceutical such as an antithrombotic agent. Recently, carbacyclin double bond isomers which is one type isocarbacyclin, i.e., 9 (O) - methanol - △ 6 (9α) - prostaglandin I ₁ such that the strongest inhibiting platelet aggregation Among the homologues It has been found to exhibit an effect and is expected to be applied as a drug [Ikegami et al., Tetrahebron Letters, 33, 3493 and 3497 (198
3) and JP-A-59-137445 and JP-A-59-210044]. Heretofore, several methods for producing 9 (O) -methano- △ 6 (9α) -prostaglandin I ₁ (isocarbacycline) have been known, and an outline of the method is as follows. It is. (1) Ikegami et al., Tetrahed Letters
ron Letters), 24,3493 (1983) and Chemistry
Chemistry Letters, 1984, 1069: (2) Ikegami et al., Tetrahed Letters
ron Letters), 24, 3497 (1983): (3) Ikegami et al., Journal of the Chemical Society, Chemical Communication (J. Che
m.Soc., Chemical Communications), 1984 , 1602: (4) Shibasaki et al., Tetrahed Letters
ron Letters), 25, 5087 (1984): (5) Shibasaki et al., Tetrahed Letters
ron Letters), 25 , 1067 (1984): (6) Kojima et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull), 32 , 2866 (19)
84): (7) Kojima et al., JP-A-60-28943: Of these seven methods, method (1) and method (5)
Difficult is the PGE ₂ starting material, guided through several steps to the key intermediate, say that industrial production method in that obtaining the isocarbacyclin of the object further via several steps. Both methods (2) and (3) require multiple steps from expensive corey lactones to obtain the corresponding starting materials and key intermediates, the overall yield is not high, and industrial There is a drawback that it is not an advantageous method. Method (6)
And the method (7) is a method out of the question as a production method intended for commercialization because the final product can be obtained only in dl form. Finally, the method (4) is not only easy to obtain from optically active (R) -4-hydroxy-2-cyclopentenone (JP-A-57-155116), but also provides a key intermediate from its starting material. Is a method that can be produced industrially without any problem. However, in the process from the key intermediate to the final isocarbacyclines, the overall yield is low due to the use of organic mercury compounds and various difficulties such as the loss of regiospecificity, resulting in practical and industrial production. The major drawback is that it cannot be a law. <Problems to be Solved by the Invention> The inventors of the present invention focused on the above-mentioned points, and as a result of intensive studies to find a new method for producing 9 (O) methanoprostacyclins, as a result, 4,4-bisarylsulfonyl iso- The inventors have found that the intended isocarbacyclines can be produced industrially advantageously by reacting a carbacycline with a reducing agent, and have reached the present invention. <Means for Solving the Problems> In the present invention, the following formula [I] 1. The following formula [I] Or an enantiomer thereof, or a mixture thereof in any proportion. Reacting 4,4-bis (arylsulfonyl) isocarbacycline with a reducing agent,
The following formula [II] characterized by being subjected to a deprotection reaction and / or a hydrolysis reaction as required. The present invention provides a method for producing 9 (O) -methanoprostacyclin, which is a compound represented by the formula: In this case, the skeleton of the raw material [I] is completely retained. The present invention is also an isocarbacycline represented by the above formula [II]. The compound of the above formula [I] used as a raw material in the present invention
4,4-bis (arylsulfonyl) isocarbacyclines can be synthesized by two different routes (chart 1, route A, route B). Starting materials (a) in Route A are described, for example, in Shibasaki et al., Tetrahedron.
It is produced in the same manner as in the method described in Tetrahedron Letters 25 , 5087 (1984), and the starting material (b) in Route B can be synthesized from the intermediate at the time of (a) synthesis (Chart 2). In the above formula [I], R ¹ represents a C ₁ -C ₄ alkyl group. Examples of R ¹ include a methyl group, an ethyl group, a propyl group, and a butyl group, and a methyl group and a 2-propenyl group are preferred. In the above formula [I], R ² and R ³ are the same or different and represent a tri (C ₁ -C ⁷ ) hydrocarbon silyl group. Tri (C ₁ -C ₇ ) hydrocarbon silyl groups include, for example,
Tri (C ₁ -C ₄ ) alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group and diphenyl (C ₁ -C ₄ ) such as t-butyldiphenylsilyl group Preferred examples include an alkylsilyl group, a di (C ₁ -C ₄ ) alkylphenyl group such as a dimethylphenyl group, and a tribenzylsilyl group. A tri (C ₁ -C ₄ ) alkylsilyl group, a diphenyl (C ₁ -C ₄ ) alkylsilyl group, and a phenyldi (C ₁ -C ₄ ) alkylsilyl group are preferable. Among them, a t-butyldimethylsilyl group and a trimethylsilyl group are preferable. Particularly preferred. It should be understood that these silyl groups are hydroxyl protecting groups. These protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to give free hydroxyl groups useful as medicaments. Therefore, a hydroxyl-protecting group having such properties can be used instead of a silyl group. In the above formula [I], R ⁴ represents a hydrogen atom or a methyl group. In the above formula [I], R ⁵ is a linear or branched C ₃ to
It represents an alkyl group or a cycloalkyl group of C ₅ -C ₆ of C _9. A straight or branched C ₃ -C ₉ alkyl group is 2-
Methoxyethyl group, 2-ethoxyethyl group, propyl group,
Butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-methylpentyl, 2-methylhexyl, 2,2-dimethylhexyl And the like. Butyl, ventil, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-
A methylpentyl group is preferred. Examples of the cycloalkyl group C ₅ -C _6, a cyclopentyl group, a cyclohexyl group are preferable. In the compound represented by the above formula [I], the bicyclo [3.3.0] octane ring itself and its bicyclo [3.3.0]
The carbon attached to the substituent attached to the octane ring
The carbon atom at the 11-position, 12-position or 15-position has stereoisomers due to an asymmetric environment.In the present invention, any of these stereoisomers is included, and any of these stereoisomers may be used. Even a mixture of stereoisomers is acceptable. The compound represented by the formula represents all of these stereoisomers and a mixture of these isomers in an arbitrary ratio, and a compound having a steric structure represented by the formula is most preferred. . In the method of the present invention, 4,4-bis (arylsulfonyl) isocarbacycline represented by the above formula [I] is reacted with a reducing agent, and if necessary, subjected to a deprotection reaction and / or a hydrolysis reaction. This leads to the desired 9 (O) -methanoprostacyclins represented by the formula [II]. This reaction is achieved by reacting the above formula [I] with an alkali metal amalgam. This reaction is basically performed according to the method of Trost et al., Tetrahedron Lett., 3477 (1676). That is, as the alkali metal amalgam used in the above production method, sodium amalgam is suitably used, and one having a sodium content of 1 to 20%, preferably 2 to 10% is suitably used. The amount of sodium used is 5-500 moles, preferably 50-500 moles, as sodium relative to 1 mole of the 5-arylsulfonylisocarbacycline represented by the above formula [I]. The reaction temperature is in the range of -78 ° C to 100 ° C, preferably -40 ° C to 30 ° C, and the reaction time varies depending on the reaction temperature.
At ℃, it is sufficient to react for about 4 hours. This reaction is carried out in the presence of 1 to 10 molar times disodium phosphate. Such a reaction is performed in an organic medium. Such organic media include hexane, benzene, toluene, ether,
Tetrahydrofuran, dimethoxyethane, dioxane,
N, N-dimethylformamide, methanol, ethanol and the like are used, and methanol is preferably used. The amount used may be any amount that allows the reaction to proceed smoothly, and is usually performed using 1.0 to 100 volumes, preferably 5.0 to 50 volumes, based on the volume of the reactants. The treatment of the reaction solution thus obtained may be post-treated according to a method usually performed. For example, an organic mixture obtained by adding a water-insoluble organic solvent such as hexane, pentane, petroleum ether, ethyl ether, and ethyl acetate is washed with a saline solution as necessary, and dried over anhydrous magnesium sulfate and anhydrous sodium sulfate. After drying with a desiccant such as anhydrous calcium chloride, 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, or liquid chromatography. In the method of the present invention, the product obtained here is further subjected to a deprotection reaction and a hydrolysis reaction, if necessary, to finally obtain the compound represented by the above formula [II], its enantiomer or any of them. , Isocarbacyclines are produced. Specific examples when R ¹¹ is a C ₁ -C ₄ alkyl group are the same as those exemplified for R ¹ in the above formula [I]. Specific examples when R ²¹ and R ³¹ are tri (C ₁ -C ₇ ) hydrocarbon silyl groups are the same as those exemplified for R ² and R ³ in the above formula [I]. The removal of the protecting group for the hydroxyl group can be carried out, for example, in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, aqueous hydrogen fluoride or pyridine-hydrogen fluoride in the above-mentioned reaction solvent at the same temperature and at the same temperature. Implemented for hours. Thus, by using the arylsulfonyl isocarbacycline represented by the above formula [I] as a starting material, the isocarbacycline represented by the above formula [II] of the present invention can be obtained by the method of the present invention. Hereinafter, the present invention will be described in more detail with reference to Examples.
The present invention is not limited to this. Incidentally, -OZ in Examples ^-OSi-t Bime ₂ represents (t-butyl-dimethylsilyl group), -OY represents -OSiMe ₃ a (trimethylsilyloxy group). <Example> Reference example 1 62 mg (0.071 mmol) of 4,4-bis (phenylsulfonyl) isocarbacycline methyl ester-11,15 (t-butyldimethylsilyl) ether in anhydrous methanol (1.5%)
Under a nitrogen stream, 41 mg (0.
29 mmol) and cooled to -30 ° C. 600 mg of sodium amalgam (6% inHg) was added thereto, and the mixture was stirred for 2 hours. Further, 200 mg of sodium amalgam was added and stirred for 3 hours. Terminate the reaction with aqueous ammonium chloride,
Extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 50: 1 → 10: 1) to give isocarbacycline methyl ester-11,15-bis (t
-Butyl, dimethylsilyl) ether 36 mg (86%) was obtained. This sample was separately synthesized and TLC and spectrum data agreed. NMR (δ ppm, CDCl ₃ ): 0.9 (s + m, 21H), 1.2-2.5 (m, 22H) 3.0 (m, 1H), 3.7 (s, 3H), 3.7-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n = hexane: ethyl acetate = 4: 1) Reference Example 2 A solution of isocarbacycline methyl ester-11.15-bis (t-butyldimethylsilyl) ether (35 mg, 0.06 mmol) obtained in Reference Example 1 in dry THF (3 ml) was added at 0 ° C. with tetrabutylammonium fluorite (1 M in). TH
F) 400 µ (0.4 mmol) was added, and after 30 minutes, the mixture was stirred at room temperature for 14 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → 1: 2) to obtain 18 mg (85%) of isocarbacycline methyl ester. The HPLC, TLC, and spectrum data of this product agreed with those of a separately synthesized sample. NMR (δ ppm, CDCl ₃ ): 0.9 (m, 3H), 1.2 to 2.5 (m, 24H) 3.0 (m, 1H), 3.7 (s, 3H) 3.7 to 4.1 (m, 2H), 5.3 (m, 1H) 5.55 (m, 2H) TLC: Rf = 0.5 (n = hexane: ethyl acetate = 1: 4) HPLC: (Zorbax-SIL 2.5% ethanol / hexane 1.3 ml /
Min) Holding time 24 minutes Reference example 3 45 mg (0.05 mm) of 17 ( S ), 20-dimethyl-4,4-bis (phenylsulfonyl) isocarbacycline methyl ester-11,15 bis (t-butyldimethylsilyl) ether
ol) in anhydrous methanol (1.5 ml) was added with 28 mg (0.2 mmol) of anhydrous disodium phosphate under a stream of nitrogen and cooled to -30 ° C. Here is sodium amalgam (6% in Hg)
600 mg was added and stirred for 6 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 50: 1 → 10: 1) to give 17 (s), 20-
Dimethyl isocarbacycline methyl ester-11,15
-Bis (t-butyldimethylsilyl) ether 24 mg (79
%). This sample was separately synthesized and TLC and spectrum data agreed. NMR (δ ppm, CDCl ₃ ): 0.9 (s + m, 21H), 1.0-2.5 (m, 26H) 3.0 (m, 1H), 3.7 (s, 3H), 3.7-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n = hexane: ethyl acetate = 4: 1) 15-deoxy-16-methyl-16-vidroxy-4,4-
Bis (phenylerphonyl) isocarbacycline methyl ester-11-t-butyldimethylsilyl ether-
To a solution of 34 mg (0.04 mmlo) of 16-trimethylsilyl ether in anhydrous methanol (1 ml) was added 24 mg (0.17 mmol) of anhydrous disodium phosphate under a nitrogen stream, and the mixture was cooled to -30 ° C. 400 mg of sodium amalgam (6% in Hg) was added thereto, and the mixture was stirred for 7 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel chromatography (n-hexane: ethyl acetate = 50: 1 → 10: 1) to give 15-deoxy-16-methyl-16-hydroxyisocarbacycline methyl ester-11-t-butyldimethyl. Silyl ether-16-trimethylsilyl ether 17mg
(75%). The TLC and spectrum data of this product were identical to those of a separately synthesized sample. NMR (δ ppm, CDCl ₃ ): 0.9 (s + m, 12H), 1.1 (s, 3H), 1.2 to 2.5 (m, 22H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8 to 4.0 (m , 1H) 5.3 (m, 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n = hexane: ethyl acetate = 4: 1) Reference Example 4 16,17,18,19,20-Pentanol-15-cyclopentyl-
Disodium phosphate anhydrous disodium phosphate in a solution of 51 mg (0.059 mmol) of 4,4-bis (phenylsulfonyl) isocarbacycline methyl ester-11,15-bis (t-butyldimethylsilyl) ether in anhydrous methanol (1.5 ml) under a nitrogen stream 36m
g (0.25 mmol) was added and cooled to -30 ° C. 600 mg of sodium amalgam (6% in Hg) was added thereto, and the mixture was stirred for 5 hours. Terminate the reaction with aqueous ammonium chloride,
Extracted with ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The crude product was subjected to silica gel column chromatography (n-
Hexane: ethyl acetate = 50: 1 → 10: 1) to give 16,17,1
There was obtained 25 mg (72%) of 8,19,20-pentanor-15-cyclopentylisocarbacycline methyl ester-11,15 bis (t-butyldimethylsilyl) ether. The TLC and spectrum data of this product were identical to those of a separately synthesized sample. MMR (δ ppm, CDCl ₃ ): 0.9 (s, 18H), 1.0 to 2.5 (m, 23H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m , 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n = hexane: ethyl acetate = 4: 1) The disilyl form obtained in Examples and Reference Examples 3 and 4 was removed in the same manner as in Reference Example 2. Protected. The NMR spectrum is described below. (Δppm, CDCl ₃ ) 0.9 (m, 3H), 1.0-2.5 (m, 28H), 0.3 (m, 1H), 3.7 (s, 3H) 3.0-4.1 (m, 2H), 5.3 (m, 1H) 5.55 (m, 2H) 0.9 (m, 3H), 1.1 (s, 3H), 1.2 to 2.5 (m, 24H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8 to 4.0 (m, 1H), 5.3 (m, 1H), 5.55 (m, 1H) 1.0 to 2.5 (m, 25H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 1H)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07F 7/18 C07F 7/18 A

Claims (1)

(57) [Claims] The following formula [II] Wherein R ¹¹ represents a hydrogen atom or a C ₁ -C ₄ alkyl group; R ²¹ and R ³¹ are the same or different and represent a hydrogen atom or a tri (C ₁ -C ₇ ) hydrocarbon silyl group; ⁴ represents a hydrogen atom or a methyl group, and R ⁵ is a linear or branched C ₃
It represents an alkyl group or a cycloalkyl group of C ₅ -C ₆ of -C _9, n represents 1. ] The isocarbacycline represented by these. 2. R ²¹ and R ³¹ are the same or different and each represents a hydrogen atom or t-
The isocarbacycline according to claim 1, which is a butyldimethylsilyl group. 3. 2. The isocarbacycline according to claim 1, wherein R ²¹ and R ³¹ are both hydrogen atoms. 4. ^{4. The} method according to claim 1, wherein R ⁴ is a methyl group.
The isocarbacycline according to any one of the above items. 5. Isocarbacyclin acids according to any one of R ⁵ is claims the first term of a n- butyl group fourth term. 6. The following formula [I] [Wherein, R ¹ represents a C ₁ -C ₄ alkyl group, R ² and R ³ are the same or different and represent a tri (C ₁ -C ₇ ) hydrocarbon silyl group, and R ⁴ represents a hydrogen atom or methyl R ⁵ represents a linear or branched C ₃ -C ₉ alkyl group or a C ₅ -C ₆ cycloalkyl group; n represents 1; and Ar represents a phenyl group. Wherein the compound represented by the formula (I), an enantiomer thereof, or a mixture thereof in any proportion is reacted with a reducing agent, and if necessary, subjected to a deprotection reaction and / or a hydrolysis reaction. Wherein R ¹¹ represents a hydrogen atom or a C ₁ -C ₄ alkyl group; R ²¹ and R ³¹ are the same or different and represent a hydrogen atom or a tri (C ₁ -C ₇ ) hydrocarbon silyl group; ⁴ , R ⁵ and n are the same as defined above. ] A method for producing an isocarbacycline which is a compound represented by the formula (I), an enantiomer thereof, or a mixture thereof in any ratio. 7. The method for producing isocarbacyclines according to claim 6, wherein an alkali metal amalgam is used as the reducing agent. 8. The method for producing isocarbacycline according to claim 7, wherein the alkali metal amalgam is sodium amalgam. 9. 9. The method according to claim 6, wherein R ¹ is a methyl group.
Item 14. The method for producing isocarbacyclines according to any one of the above items. 10. 10. The method for producing isocarbacyclines according to claim 6, wherein R ⁴ is a methyl group, and R ⁵ is an n-butyl group.