SU1751173A1 - Method of (1r,4s)-4-acylhydroxy-1-hydroxycyclopent-2-enъs synthesis - Google Patents

Abstract

Use: a method for producing (1R, 45} -4-acyloxy-1-hydroxycyclopent-2-ene, which can serve as a starting material for the synthesis of prostaglandin derivatives used in medicine. Invention: (1R, 45) - 4-acyloxy-1-gmdroxycyclopent-2-ene is obtained by acylation of cis-1.4-dihydroxycyclopent-2-ene with carboxylic acid vinyl ester in the presence of porcine pancreatase. The reaction is carried out in the presence of an anhydrous organic solvent or anhydrous base, or in the presence of mixtures thereof. The desired product is obtained from in The output of 60% with a very high enantiomeric excess. 1 Cp f-crystals. (C

Description

The invention relates to a method for producing (1R, 4P) -4-acyloxy-1-hydroxycyclic • lopent-2-enes of the general formula g O in which Ri is lower alkyl.

This type of derivative is the starting material for the synthesis of optically active prostaglandins and their derivatives, which can be used to prevent and treat cardiovascular diseases. for diagnosis in obstetrics, for the prevention and treatment of gastric and intestinal ulcers in human medicine, as well as for the synchronization of childbirth and hunting in animal husbandry.

Enzyme-catalyzed transesterification of cis-1,4-dihydroxycyclopent-2ene with esters of carboxylic acids, in particular 2,2,2-trichloroacetate, in an anhydrous organic solvent in the presence of a base and lipase at 0-80 ° C, although it will lead to the formation of the target compound with a high enantiomeric excess (~ 95%), but with a yield below 50%.

The purpose of the invention is to accelerate the process and increase the yield of the target product while maintaining high stereoselectivity of the reaction.

The goal is achieved in that the meso-compound cis-1,4-dihydroxycyclo

1751173 A1 pent-2-ene reacts with vinyl esters of carboxylic acids of the general formula where Ri is lower alkyl in an anhydrous organic solvent such as diethyl ether 1,4-dioxane, tetrahydrofuran or toluene, preferably tetrahydrofuran, in the presence of a base such as pyridine. triethylamine, 4-M, I-dimethylaminopyridine or imidazole, preferably triethylamine, with or without the addition of a base ^: and in the presence of crude pancreas lipase; The basics of a pig in the form of a preparation of pa n creatine are preferably without an organic solvent in the presence of a base of the above type at 25 ° C.

In this case, (1R, 45) -4-acyloxy-1-hydroxycyclopent-2-enes of the formula (1) are obtained with satisfactory chemical yields (~ 60%) with a very high enantiomeric excess (i.e., 99%). At the same time, the choice of reaction conditions, the reaction of obtaining the target product becomes technically simpler.

EXAMPLE 1. To a solution of 1.0 g (10 mmol) of cis-1,4-dihydroxycyclopent-2-ene (II), 6.02 g (70 mmol) of vinyl acetate and 0.71 g (7, 0 mmol) of absolute triethylamine in 25 ml of absolute tetrahydrofuran at 25 ° C. Add 5 g of crude pig pancreatase in the form of a pancreatin preparation and stir 2.5 hours at 25 ° C. Then the suspension is filtered and the filter residue washed with ethyl acetate. The solvents are evaporated in vacuo. The residue was purified by flash chromatography. 0.921 g (65%) of (1R, 4S) -4acetoxy-1-hydroxycyclopent-2-ene (I) is obtained. colorless crystals, mp 46-48 ° C.

1 H-NMR spectrum (dmd. CDCI3): 1.58 (dt, 1H, L5 & 4Hz, H ⁵ ); 1.86 (s, 1N. OH); 1.99 (s. ZN, OAc): 2.74 (dt, 1H, L5i8Hz, N ^5p V 4.65 (m, 1 Η, H '*); 5.42 (m 1H, H ^4ci ); 5.88 and 6.03 [br. D (each), 2H, ZbHz, HC-CH].

- [a] ² ° D - 65.1 ° (s 1.00, CHCI3). Enantiomeric excess. > 99% [ ¹⁹ F-RMP spectrum of (+) - Mosher esters]. In addition, 0.588 g (32%) of cis-1,4-diacetoxycyclopent-2-ene is obtained.

Example 2. To a solution of 0.8 g (8 mmol) of cis-1,4-dihydroxycyclopent-2-ene (II), 6.32 g (55 mmol) of vinyl butyrate and 0.58 g (5.7 mmol) of absolute triethylamine in 25 ml absolute tetrahydrofuran at 25 ° C add 4 g of crude porcine pancreatase in the form of a pancreatin preparation and mix 2.5 hours at 25 ° C. Then the suspension is filtered and the filter residue washed with ethyl acetate. The solvents are evaporated in vacuo. The residue was purified by flash chromatography. Obtain 0.747 g (55%) (1R. 4S) -4-6yTanoyloxy-1-hydroxycyclopent -2-ene (I), b.p. 140 ° C / 15 Pa (Kugelrohr).

1 H-NMR spectrum (gem.d., CDCh): 0.84 (t.ZN, LHz, CHz); 1.36-1.81 (m.s.N. H ⁵ * + CH ₂ ): 2.04 (s. 1H, OH); 2.74 (dt, 1H, L5 & 8Hz, 4 ^): 4.64 (m. 1H, H ^{f, <} ); 5.44 (m, 1 H, H ⁴ *); 5.85 and 6.02 [br.s.d (each), 2H, 6Hz, HC-CH].

[a] ² ° 56.7 ° (c 1.00, CHC1z).

Enantiomeric excess of 93% [ ¹⁹ F-RMP spectrum (+} - Mosher esters].

In addition, 0.613 g (32%) of cis

1.4-dibutanoyloxycyclopent-2-ene.

Example Z. To a mixture of 1.0 g (10 mmol) of cis-1,4-dihydroxycyclopent-2-ene (II), 13.0 g (350 mmol) of vinyl acetate and 0.71 g (7.0 mmol) of triethylamine, 5 g of crude are added at 25 ° C. pig pancreases in the form of a pancreatin preparation and stirred for 2.5 hours at 25 ° C. After processing similar to that described in example 1., 0.807 g (57%) of (1R, 4B) -4-acetoxy-1-hydroxycyclopen-2ene (I) is obtained.

[a] ² ° o64.4 ° (s1.00, CHC1z). Enantiomeric excess> 99% [ ¹⁹ F-RMP spectrum of (+) Mosher esters].

In addition, 0.745 g (40%) of cis

1.4-diacetoxycyclopent-2-ene.

Examples To a solution of 1.0 g (10 mmol) of cis-1,4-dihydroxycyclopent-2-ene (II) and 6.02 g (70 mmol) of vinyl acetate in 25 ml of absolute tetrahydrofuran at 25 ° C. was added 5 g of crude porcine pancrease in the form of a pancreatin preparation and stirred for 2.5 hours at 25 ° C. After processing similar to that described in Example 1, 0.849 g (60%) of (1R, 45) -4-acetoxy-1-hydroxycyclopent-2-ene (I) is obtained. · []] ²⁰ d -64.6 ° (c 1.00, CHC1z).

Enantiomeric excess> 99% [ ¹⁹ FNMR spectrum of (+) - Mosher esters].

In addition, 0.563 g (31%) of cis

1,4-diacetoxycyclopent-2-ene.

Claims (2)

Claim 1. A process for preparing (1R, 45) -4-acyloxy-1-hydroxycyclopentyl-2-enes of general formula _Mo II О where Ri is lower alkyl, including the reaction of cis-1,4-dihydroxycyclopent-2-ene with an ester of carboxylic acid in the presence of pig pancrease, characterized in that, in order to accelerate the process and increase the yield of the target product while maintaining high stereoselectivity of the reaction , as the 5 carboxylic acid ester, a vinyl ester of the general formula is used Ri is COOCH = CH ₂ , where Ri is lower alkyl. 2. The method according to claim 1, with the fact that the process is carried out in the presence of an anhydrous organic solvent, or an anhydrous base, or a mixture thereof.