CS223404B1 - Process for the preparation of intermediates for the preparation of prostadienic acid derivatives - Google Patents

Abstract

The subject of the invention is a method for producing an important intermediate for the preparation of biologically active prostadienoic acid derivatives, such as the "enol" of the general formula II « o |CH=CH-CH-CH OH {ID where R is a residue, where X is halogen and n is an integer from 0 to 3, Ri is a group —CO—R2, where R2 is phenyl substituted by phenyl, or phenylcarbamoyl. Prostaglandin derivatives are among the substances that are already commercially produced and are of considerable importance in veterinary medicine. The poison

Description

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of an important intermediate for the preparation of biologically active derivatives of prostadienoic acid, such as an "enol" of formula

CH = CH-CH-CH

OH {ID wherein R is a residue wherein X is halogen and n is an integer from 0 to 3, R1 is a group —CO — R2 wherein R2 is phenyl substituted with phenyl, or phenylcarbamoyl.

Prostaglandin derivatives are among the substances which are already commercially produced and are of great importance in veterinary medicine. One of the most technologically promising ways is the Corey synthesis developed in 1969 [E. J. Corey, Ann N.Y. Acad. Sci., 180, 24 (1971 j), consisting of introducing both side chains of prostaglandin to the Corey lactone in the two subsequent Wittig reactions It is known that the Horner Emmons modification of the Wittig reaction is predominantly used to introduce the ω-chain into the molecule. (J. Bindra, R. Bindra, Prostaglandin Synthesis p. 201, Academic Press Inc. 1977 j. The resulting substance, the so-called "enone" of the general formula I

O

Λ

CH-CH-C-CH 2 R

Thus, R 1 (I) where R and R 1 are as defined above, therefore, has a keto group on the future 15th ato 223404 mu carbon of the prostadienoic acid derivative.

The main problem of further synthesis lies in the reduction of the ketone group to the alcohol group. Reduction is conveniently performed with sodium borohydride, zinc borohydride [EJ Corey et al., J. Am. Chem. Soc., 90, 3247 (1968) and F. Kienzle et al., J. Org. Chem., 38, 3440 (1973)], for the F _2a derivative. Meerwin Ponndorf reduction [J. Bowler, Κ. B. Mallion, Sianth. Comm., 4, 211 (1974)]. However, the stereospecific reduction of "enone" with special hydrides, described by Corey for F _2a derivatives, became the most significant. [EJ Corey et al., J. Am. Chem. Soc., 94, 8646 (1972)]. The reduction takes place at temperatures around 153.2 K and the stereospecificity is up to 90% in favor of the S epimer. However, this method is of limited use for substances of the 16-phenoxy-17,18,19,20-tetranor type PGF _2k , which form a very important group of prostadienoic acid derivatives i and are already commercially produced (Fluprostenol, Cloprostenolj). At higher temperatures (173.2 K), the reduction is no longer selective and is therefore not economically advantageous due to the high prices of special hydrides (e.g., Selectride, ie diisobutyl lithium borohydride).

The above-mentioned drawbacks are overcome by the process according to the invention, which consists in reducing the "enone" of the formula I

O

Λ

C31 < ch = ch-c-c h ^ r

a) wherein R is a radical wherein X is halogen and an integer of 0 to 3, R 1 is a group -CO-R 2, where R 2 is phenyl substituted with phenyl, or phenylcarbamoyl, to an "enol" of formula II a modification of the Meerwin Ponndorf reduction in a mixture of aromatic hydrocarbons (preferably benzene, toluene) with isopropyl alcohol with catalysis of one to ten moles, preferably one to two moles, of trialkoxyaluminate (alkoxy is C2 to C4) at 293, It is also advantageous to continuously remove the resulting ketone by rectification.

This reaction is not stereospecific in terms of the reduction of the keto group of the "enone", but unlike hydride reduction, it is absolutely selective in terms of possible reduction of the lactone ring. It is easily feasible on a technological scale using conventional apparatus and raw materials. It avoids the use of expensive specialty hydrides and is also simpler by treating the reaction mixture (it is not necessary to remove boron compounds, etc.). At the same time, the total cooking time will be significantly reduced, about twice.

Exemplary embodiment

7.2 g of the "enone" of the above general formula I, wherein R is m-chlorophenoxy and R 1 is p-phenylbenzoyl, were dissolved in a mixture of 150 ml of benzene and 150 ml of isopropyl alcohol. After addition of 7.1 g of isopropylaluminate, the reaction mixture was boiled and the resulting acetone was separated by rectification. After one hour, the reaction was complete and the solvents were evaporated in vacuo. The residue was dissolved in chloroform (200 ml) and the inorganics were shaken with 0.5 N hydrochloric acid. The organic layer was neutralized with sodium hydrogen carbonate solution and after drying over magnesium sulfate, the solvents were evaporated in vacuo. 7.0 g of "enol" of the above formula (II) were obtained, i.e. 97% yield. The identity of the product was confirmed by thin layer chromatography, the RF value on silica gel eluting with 3% methanol in chloroform was 0.47, and by mass spectrometry, elemental composition:

H, 5.23; Cl, 6.19. Found: C, 69.1; H, 5.31; Cl, 6.11.

Claims (1)

A process for the preparation of intermediates for the preparation of prostadienoic acid derivatives, such as "enols" of formula II O AND OH wherein R is a residue wherein X is halogen and n is an integer of 0 to 3, R 1 is a group -CO-R 2 wherein R 2 is phenyl substituted with phenyl, or phenylcarbamoyl, characterized in that the "enones" of formula I O AND C 3 Z <CH = CH-C-CH 2 (I) wherein R and R 1 are as defined above, are treated with a trialkoxy aluminum wherein the alkoxy group contains 2 to 4 carbon atoms in a mixture of an aromatic solvent such as benzene and a low boiling aliphatic alcohol such as isopropanol, in a molar ratio of 1: 1, at temperatures of 293.2 to 423.2 K, preferably at the boiling point of the reaction mixture from which the resulting ketone is optionally removed by rectification.