CS239696B1 - A method of separating the 15S-and 15R-isomers of 4- [4- (substituted X-phenoxy) -3-hydroxy-1-butenyl] hexahydro-5-hydroxy-2H-cyclopenta [b] furan-2-one - Google Patents

Abstract

The method of separating 15S- and 15R-isomers of 4-/4-/substituted X-phenoxy/-3-hydroxy- -1-butenyl/hexahydro-5-hydroxy-2H-cyclopenta [b] furan-2-ones of the general formula I and their racemic mixtures consists in dissolving the crude mixture of 15S- and 15R-enols of the general formula I at a temperature of 20 to 60 °C in an organic solvent to a solution with a concentration of 5 to 40 X by weight, then adding aliphatic alcohol with stirring until the first permanent turbidity is formed, optionally adding 0.1 to 5% by weight of the 15S-isomer to the starting mixture and then cooling the mixture to a temperature of 0 to -30 C and the separated crystals of the 15S-isomer of the general formula I are filtered off with suction and dried. Compounds of general formula I are important intermediates in the production of prostaglandin analogues.

Description

The present invention relates to a process for separating 15S and 15R (prostaglandin labeling) isomers of 4- (4-) substituted X-phenoxy) -3-hydroxy-1-buteayl] hexahydro-5-hydroxy-2H-cyclopenta-fbj furan-2-ones of the general formula 1 and racemic mixtures thereof, wherein R is phenyl or biphenyl, X is hydrogen, chloro or trifluoromethyl, A is hydrogen or hydroxyl and B is hydroxyl or hydrogen, wherein when A is hydroxyl, B is hydrogen; 15S-isomer (or, if A is hydrogen, B is hydroxyl) (corresponds to the 15R-isomer-prostaglandin designation).

Compounds of formula I wherein A is hydroxyl and B is hydrogen are important intermediates in the production of prostaglandin analogues, which have found widespread clinical use in obstetrics and gynecology (X = H, Sulproston) and veterinary medicine (X = 3-C1, Cloprostenol; X = 3-CF3, Fluprostenol (in cattle and mare-syn heat) (Chem. Eng. News 1982, Aug. 16, p. 30 /.

To date, the 15S-enols of formula (X) have been prepared by stereospecific reduction of the corresponding ketoderivates of formula (II) and its racemic mixtures, wherein R and X are as defined above using special, inexpensive industrial reagents and complex reaction conditions / low temperature. inert atmosphere (see JS Bindra and R. Bindra in Prostaglandin Syntesis, Academic Press, New York 1977 and references cited therein).

The second method used in industrial practice is based on non-specific reduction of the ketone of formula II with conventional reducing agents, whereupon the obtained mixture of 15S and 15H-enols of formula I is separated by various separation techniques, most often by column chromatography or high pressure liquid chromatography. . Certificate No 229075 /.

These methods of separation of the above isomers have a number of disadvantages, especially when introduced on a technological scale: a / limited throughput and require qualified personnel, b / considerable consumption of relatively expensive sorbent materials, c / high consumption of pure solvents, d / laborious product isolation.

From this is evident both technological and economic disadvantage of these methods of separation of enols.

These known processes are followed in a positive way by the process according to the invention, which brings new simple separations of the 15S and 15R-isomers of the general formula (I), thus eliminating the drawbacks of the hitherto used processes.

The process of the invention utilizes fractional crystallization from a mixture of appropriately selected organic solvents and programmed cooling rates to separate the isomers of the enols of Formula I. The process is carried out by starting from a crude mixture of 15S- and 15R-enols of the general formula I obtained by reduction of the ketoderivative II according to known procedures (cf. No. 223404) to prepare a solution containing 5 to 40% of this mixture at a temperature of 20 to 60 ° C. Aliphatic ketones containing 3 to 6 carbon atoms are preferably used as the solvent, such as acetone, butanone, diethyl ketone, esters of organic acids having 2 to 6 carbon atoms such as ethyl formate or methyl acetate, chlorinated hydrocarbons having 1 to 2 carbon atoms and 2 to 6 carbon atoms. 4 chlorine atoms, benzene and its alkyl homologs.

To the solution thus prepared is added with stirring such amounts of a C 1 -C 4 aliphatic alcohol, preferably methanol or ethanol, until the first permanent haze is formed, followed by a gradual programmed cooling of the mixture (cooling rate 0.1 to 0.5 ° C / min) to 0 to -30 ° C.

For a better crystallization, it is advantageous to add 0.1 to 5% by weight of the crystalline 15S-isomer to the starting mixture after the first turbidity is formed. After 1 to 10 hours, the precipitated S-isomer crystals of formula (I) are aspirated and determined by high pressure liquid chromatography to determine their isomeric purity.

From the concentrated mother liquors, the S-isomer enriched further product is obtained in the same manner and the residue then contains predominantly the undesired R-isomer of formula (I), which is converted into the enone of formula (XI) by known procedure no. evaluates.

The advantage of this method is that it is simple to implement and does not require expensive equipment, while solvent and energy consumption is low. This process makes it possible to obtain large amounts of the desired 15S-isomer of formula (I) easily and is therefore economically advantageous.

The invention and its effects are illustrated in more detail by the following examples, which are illustrative only and in no way limit the scope of the invention.

Example 1

A mixture of 9.5 g of the enol / comprising according to HPLC 40% of the 15S-isomer / the general formula I wherein RsCgH-CGH, X = 3-C1 / was dissolved at 50 C ^In 40 ml of acetone, and then gradually at this temperature 80 mL of ethanol was added and the solution was slowly cooled (gradient of 0.3 ° C / min) to -20 ° C. After 4 hours of cooling at this temperature, the precipitated crystals were aspirated, yielding 3.21 g (72%) of the 15S-isomer with a purity of 87% (as determined by HPLC). After evaporation of about 40 ml of solvents from the mother liquors and after the above treatment, 5 g of enriched material was obtained which contained 65% of the 15S-isomer.

Example 2

A mixture of 9.4 g of an enol mixture (containing 48.5% of the 15S-isomer) of formula (I) wherein R = C ₈ H ₆ G ₆ H 2, X = 3-F 3C was dissolved in 52 mL of methyl acetate at 60 ° C and then added 155 ml of ethanol, after turbidity formation, 0.1 g of 15S-isomer was added and the solution was cooled to -5 ° C as in Example 1. After analogous work-up, 3.1 g (68%) of the 15S-isomer with an isomeric purity of 91 was obtained. 54.

Example 3

A mixture of 7.3 g of enols (containing 51% of the 15S-isomer) of formula (I) wherein R = Ο Η Η Η Η, Η, byla was dissolved in 280 ml of chloroform at 50 ° C. After addition of 300 ml of methanol, it was cooled to -20 ° C and treated as in Example 1. 2.6 g (71%) were obtained.

The 15S-isomer of formula (1) (wherein R and X are as defined above, with a purity of 93% (determined by high pressure liquid chromatography).

Claims (2)

A process for the resolution of the 15S- and 15R-isomers of the 4- (4-) substituted X-phenoxy / -3-hydroxy-1-butenyl / hexahydro-5-hydroxy-2H-yl-penta-b-furan-2-ones of formula I and their racemic mixtures wherein R is phenyl or biphenyl, X is hydrogen, chloro or trifluoromethyl, A is hydrogen or hydroxyl, B is hydroxyl or hydrogen, and when A is hydroxyl, B is hydrogen corresponding to The 15S-isomer, or when A is hydrogen, then B is a hydroxyl group corresponding to the 15R-isomer, characterized in that the crude mixture of 15S- and 15R-enols of formula I is dissolved in an organic solvent at 20 to 60 ° C. to a solution having a concentration of 5 to 40% by weight, followed by the addition, with stirring, of an aliphatic alcohol containing 1 to 4 carbon atoms, preferably methanol and ethanol, until a first permanent haze is formed, optionally 0.1 to 5% by weight, 5S-isomer to the starting mixture and the mixture is then It is cooled at a rate of 0.1 to 0.5 ° C per minute to a temperature of 0 to -30 ° C and the precipitated 15S-isomer crystals of formula I are suctioned off and dried. 2. A process according to claim 1, wherein the organic solvent is aliphatic ketones having 3 to 6 carbon atoms, organic acid esters having 2 to 6 carbon atoms, esters of organic acids having 2 to 6 carbon atoms, such as ethyl formate or acetate methyl, chlorinated hydrocarbons containing 1 or 2 carbon atoms and 2 to 4 chlorine atoms, such as chloroform or 1,2-dichloroethane or benzene and its alkyl homologues containing 1 or 2 carbon atoms in the alkyl chain.