CS258295B1 - Process for preparing 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing 2-(tetrahydrofurfuryl)-3-(1-naphthyl)propionic acid of formula I, which is an intermediate in the production of drugs, especially substances with cerebral vasodilating activity. The method for preparing the substance of formula I according to the solution consists in thermal decarboxylation of crystalline 1-(tetrahydro-2-furyl)-3-(11-naphthyl)propane-2,2-dicarboxylic acid by gradual heating to 140 to 160 °C. The obtained practically pure mixture of racemates A and B of acid I is either used for further work as such or is further purified by converting it into an aqueous solution of the potassium salt, releasing the acid back using dilute mineral acid, extracting with ether and crystallization of the residue, which leads to an almost pure and crystalline racemate B of acid of formula I. Purification can also be carried out by neutralizing the crude acid of formula I with a suspension of calcium hydroxide in water, suctioning off the insoluble calcium salt of acid of formula I, washing with water and releasing the free acid of formula I back by acidification with dilute hydrochloric acid.

Description

The present invention relates to a process for the preparation of 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid

O θ— ^ch 2 <(° y ~ ^ch 2 ^z

CHCOOH

The compound of formula (I) is an intermediate in the manufacture of medicaments, particularly substances with vasodilating, spasmolytic and locally anesthetic activity. Representative of this class of drugs is the naphthyrdrofuryl, i.e. 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid 2-diethylaminoethyl ester, used in the form of hydrogen oxalate as a cerebral vasodilator in gerontology, particularly gerontopsychiatry.

The preparation of the compound of formula I in the form of a stereoisomeric mixture was described by thermal decarboxylation of the crude, oleic acid 1- (tetrahydro-2-furyl) -3- (1-naphthyl) propane-2,2-dicarboxylic acid of formula II

(Mjjojan A. L., Baladajan C. E.: Armjan. Chim. Journal 22, 8ΊΊ, 1969). The preparation of the compound of formula I (also in the form of a stereoisomeric mixture) by saponification and decarboxylation of diethyl ester of formula II by boiling with a 1-fold excess of potassium hydroxide in benzyl alcohol (Szarvasi E. et al .: Bull. Soc. Chim. Fr. 181; Belg. Pat. 613,547). The acid of the formula I obtained by these processes can be used for further processing only after purification by very difficult distillation. Mp 212-214 ° C / 133 Pa.

This temperature is very close to the decomposition temperature of the acid of the formula I which occurs at 220 to 230 ° C. In view of the preparation of larger quantities of the acid of formula (I) in this manner, the process seems technologically difficult. Finally, one homogeneous racemate of the acid of formula I (referred to as racemate B) was obtained in crystalline form (mp 90 ° C) by separation of a stereoisomeric mixture of 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid 2-diethylaminoethyl esters by preparative HPLC. or by fractional crystallization of salts (oxalate, nitrate, citrate or methanesulfonate) followed by saponification of the predominant racemate B with aqueous methanolic sodium hydroxide solution (European Pat. Appl. 69 013).

This latter method is of no significance in terms of preparative. A disadvantage of the first two processes is therefore, in addition to the necessity of distillation of the product, also the necessity of distillation of the starting ester of formula II and finally the distillation of the substances obtained from the thus obtained acid of formula I. All these distillations are very technologically demanding for the relatively large molecule of the series and require high temperatures and high vacuum.

It has now been found that if a crystalline acid of formula (Ii) not previously described in the literature is used as a starting material, the stereoisomeric mixture of acids of formula (I) is obtained by thermal decarboxylation such that distillation is not required for further processing. The preparation of the crystalline acid of formula (II) is described in the example and is the subject of U.S. Pat. A.O. 258 294.

In addition, the acid of the formula I thus obtained provides, by simple operations, other substances (methyl ester, 2-diethylaminoethyl ester), which also need not be distilled. Another important fact is that the acid of formula I is so. pure that by simple purification by transfer to an aqueous potassium salt solution and acid release upon prolonged standing, yields almost pure racemate B (m.p. 84-87 ° C). Accordingly, the present invention provides thermal decarboxylation of the crystalline acid of formula II and a process for purifying the resulting acid of formula I which leads to crystallization of racemate B of this acid.

The following example is merely illustrative of the scope of the invention and is not intended to fully describe the scope of the invention.

Example

Crystalline 1- (tetrahydro-2-furyl) -3- (1-naphthyl) propane-2,2-dicarboxylic acid (60.4 g) was heated at 140 ° C for 1 h and at 160 ° for 1 h. C. Decarboxylation is manifested by leakage of carbon dioxide and is terminated at 160 ° C. The waxy residue (50.2 g, 96%) is a very pure mixture of both racemates of the desired acid of formula I, which, according to high pressure liquid chromatography, contains 38% of racemates A and 62 as well as racemates Β. In this form, it is useful for further processing, ie, for example, transformation into the methyl ester or the 2-diethylaminoethyl ester.

For further purification, 12.0 g of this stereoisomeric mixture of acids of formula I are dissolved in 450 ml of toluene, from this solution the acid of formula I is extracted three times with 100 ml of a 10% aqueous potassium carbonate solution, the combined aqueous solutions are acidified with 60 ml of 6M- HCl (final pH 1) and the product was extracted with chloroform. After evaporation of the solvent, the residue obtained crystallizes after prolonged standing at -10 ° C. The mixture of crystals and oil is stirred in a mixture of benzene and hexane and filtered off with suction. Crystallization from said mixture yields crystalline racemate B of the acid of formula I, m.p. Mp 84-87 ° C. According to HPLC, it contains 10% of racemates A and 90% of racemates B.

Neutralization of the stereoisomeric mixture of acids of formula I with a suspension of calcium hydroxide in water precipitates a solid calcium salt of the acid of formula I which is practically insoluble in water and melts at 190-220 ° C with decomposition. Decomposition of the aspirated and water-washed calcium salt with dilute hydrochloric acid and extraction with chloroform yields a further purified stereoisomeric mixture of acids of formula I.

The crystalline 1- (tetrahydro-2-furyl) -3- (1-naphthyl) propane-2,2-dicarboxylic acid (II), which has not been previously described in the literature, is obtained, for example, by the following procedure:

A mixture of 22.0 g of 1- (tetrahydro-2-furyl) -3- (1-naphthyl) propane-2,2-dicarboxylic acid diethyl ester (Szarvasi E., Neuvy L.: Bull. Soc. Chim. Fr. 1962, 1343 (Belg. Pat. 613 547), 80 ml of ethanol, 40 g of 85% potassium hydroxide and 40 ml of water are stirred and refluxed for 3 hours. The ethanol is evaporated, the residue is diluted with 120 ml of water and the solution is washed with ether. It is then neutralized to pH 1 with 5M-HCl, filtered with charcoal and the filtrate acidified with pH 5 with 1M-HCl. The semi-solid product is isolated by extraction with 50 ml of benzene and the solvent is evaporated off under reduced pressure. 11.7 g (63%) of crude crystalline acid of formula II are obtained, which after recrystallization from acetone / hexane melts at 142-143 ° C.

Claims (3)

SUBJECT OF THE INVENTION 1. A process for preparing 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid of formula I <^ _ ^CH2 / ' CHCOOH (i) by thermal decarboxylation of an acid of formula II 1- (tetrahydro-2-furyl) -3- (1-naphthyl) propane-2,2-dicarboxylic acid ^2-ch / C COOH CH _{2 of} ^Z 2 cooh (II) characterized in that the crystalline acid of formula II is used as the starting material and the decarboxylation is carried out successively at one hour intervals by heating to 140 ° C and then 160 ° C, and further purify. 2. The process of claim 1 wherein the primary product is dissolved in toluene, the acid of formula I is extracted with an aqueous potassium carbonate solution, the aqueous solution is acidified, the purified acid of formula I is extracted with chloroform and the chloroform evaporated. at -10 ° C and then from a mixture of benzene and hexane to the crystalline racemate B and to the oily mixture of racemates A and B. 3. The process of claim 1 wherein the primary product is neutralized with a suspension of calcium hydroxide in water, the precipitated insoluble calcium salt of the acid of formula I is filtered off with suction and washed with water, then decomposed with dilute hydrochloric acid and recovered purified acid of formula I.