SK40097A3 - A process for the quantitative synthesis of 3-(l-pyroglutamyl)-l- -thiazolidine-4-carboxylic acid and derivatives thereof - Google Patents

Abstract

3-(L-Pyroglutamyl)-L-thiazolidine-4-carboxylic acid and the derivatives thereof are prepared in quantitative yields by a condensation process between L-pyroglutamic acid or substitution products thereof in the presence of an aliphatic or aromatic hydrocarbon solvent, or of chlorinated solvents in the presence of dicyclohexylcarbodiimide or similar condensing agents, or by condensation of L-pyroglutamic acid reactive derivatives with thiazolidine-4-carboxylic acid derivatives. The hydrolysis of the protective groups of thiazolidine-4-carboxylic acid is carried out by phase transfer catalysts in quantitative yields.

Description

Process for the preparation of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid and its derivatives

Technical field

The present invention relates to a process for the preparation of L-pyroglutamic acid or derivatives thereof.

BACKGROUND OF THE INVENTION

Italian patent no. No. 1,202,426 discloses 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid having immunostimulatory, antitoxic, anti-inflammatory, antioxidant and aging retarding properties and is prepared from a reactive ester of L-pyroglutamic acid or its chloride and from L-thiazolidine-4-carboxylic acid.

In particular, the reactive esters of L-glutamic acid with pentachlorophenol, pentafluorophenol, 2,4,5-trichlorophenol, N-hydrosuccinimide, N-hydroxyphthalimide, which react with L-thiazolidine-4-carboxylic acid in aprotic solvents, are used in the process. the presence of tertiary bases, or L-pyroglutamic acid chloride, which reacts with L-thiazolidine-4-carboxylic acid in an alkaline medium.

Italian patent no. No. 1,230,706 described 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid derivatives having the same pharmacological effects and prepared by similar procedures from L-pyroglutamyl-thiazolidine-4-carboxylic acid reactive esters or amides and alcohols or amines.

In practice, these processes have some drawbacks, namely: difficult processes with extremely low overall yields, the use of highly toxic to humans and the environment, such as halogenated phenols, the use of L-pyroglutamyl chloride, which is difficult to prepare and difficult to handle, as well as poor stability of the reactive esters of L-pyroglutamic acid with N-hydroxysuccinimide and N-hydroxyphthalimide.

Italian patent no. No. 1,239,029 discloses a process wherein the above-mentioned problems have been partially solved by a simpler process, without the use of particularly toxic substances, demanding and / or unstable intermediates, and with higher yields. Such a process has shown the surprising stability of ethylthiazolidine-4-carboxylate to yield substantially higher yields than other simple esters such as methyl and isopropyl esters.

It has now been found that the process can be further improved to obtain almost quantitative yields of the desired products, by condensing ethylthiazolidine-4-carboxylate or a derivative thereof with an L-pyroglutamic acid derivative in apolar aprotic solvents and finally hydrolyzing the ethyl ester under phase transfer conditions.

SUMMARY OF THE INVENTION

Therefore, the invention provides a process for the preparation of a compound of formula III,

wherein R 6 is H, C 1 -C 6 alkyl, -Cycycloalkyl, C 1 -C 6 cycloalkylalkyl, aryl and substituted aryl, C 2 -C 5 alkoxycarbonyl, C 2 -C 6 alkylcarbonyl, arylcarbonyl and aralkylcarbonyl, C 6 -C 6 garalkoxycarbonyl, substituted aralkoxycarbonyl, includes:

a) reaction of a compound of formula I,

(I) wherein R ¹ is as defined above and X is OH, Cl or OR ² , wherein R ² is an activating group, with a compound of formula II,

wherein H is C 3 -C 8trialkylsilyl, in apolar aprotic solvents;

b) basic hydrolysis of the ethyl ester obtained in step a) under phase transfer conditions.

The apolar aprotic solvents are particularly selected from n-pentane, n-hexane, n-heptane, n-octane, isooctane, nonane, decane, petroleum ether, ligroin, toluene, xylene, cumene, dichloromethane, chloroform, dichloroethane and mixtures thereof. When a compound of formula I wherein X = OH is used, the reaction with the compound of formula II is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide.

The ethyl ester obtained in step a) is transformed into the corresponding acid, in quantitative yield, under conditions of moderate hydrolysis by phase transfer catalysts in a basic medium.

Catalysts such as tetrabutylammonium halide or hydrogen sulphate or tetrafluoroborate, tetraethylammonium halide or hydrogen sulphate or tetrafluoroborate are used in this step; cetypyridinium halide, methyltributyl halide, Adogen 464, trimethylacetyl ammonium p-toluenesulfonate, tetrabutylphosphonium halide, tetrafenylphosphonium halide, triphenylmethylphosphonium halide, butylpyridinium halide.

Under these conditions, significantly lower yields are obtained using thiazolidine-4-carboxylic acid derivatives esterified with methanol, propanol or isopropanol. The following examples are used to illustrate the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

16.78 g of ethyl L-thiazolidine-4-carboxylate hydrochloride (0.084 mol) are suspended in 160 ml of toluene, 7.06 g of sodium bicarbonate (0.085 mol) are added, heated to reflux with stirring for 5 hours, water is azeotropically removed . The mixture is cooled to 0-5 ° C, 12 g of L-pyroglutamic acid (0.093 moles) are added, then a solution of 19.2 g of dicyclohexylcarbodiimide in 20 ml of toluene is added dropwise. After 1 hour at 0 ° C the temperature is raised to 20-25 ° C for an additional 12 hours, then the dicyclohexylurea is filtered off.

The filtered solution is made up to 20 ml with water, 0.64 g of tetrabutylammonium hydrogen sulphate (0.0042 moles) is added, cooled to 0-5 ° C, then a solution of 3.36 g of sodium hydroxide (0.084 moles) in 20 ml of water is added. After stirring for 30 minutes, the aqueous phase is separated, acidified to pH 1 with hydrochloric acid, after 2 hours the solution is filtered, washed with water and dried to give 19.5 g (96%) of the acid.

3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid, m.p. 193 to 194 ’C.

Example 2

Operating as in Example 1, toluene is replaced with dichloromethane to give 19.2 g (95%) of 3- (Lpyroglutamyl) -L-thiazolidine-4-carboxylic acid, m.p. 193 to 194 ’C.

Example 3

Operating as in Example 1, toluene is replaced with N-hexane to give 19.1 g (94%) of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid, m.p. 193 to 194 ’C.

Example 4 g of LNt-butoxycarbonylpyroglutamic acid and 16.1 g of ethyl L-thiazolidine-4-carboxylate are dissolved in 150 ml of dichloromethane, cooled to 0.5 ° C, then 21 g of dicyclohexylcarbodiimide (0.105 moles) are added and stirred 15 hours at the indicated temperature.

The dicyclohexylurea is filtered off, then the filtrate is made up with 50 ml of water, 0.75 g of tetrabutylammonium hydrogen sulfate (0.005 mol). The mixture is cooled to 0-5 ° C, then a solution of 6.6 g of potassium hydroxide (0.1 mol) in 30 ml of water is added to the mixture, stirred at this temperature for 30 minutes, then the two phases are separated. The aqueous phase is acidified to pH 1 with concentrated hydrochloric acid. The precipitated solid is filtered off, washed with water and dried. 21.3 g of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid are obtained, m.p. 193-194 ° C, yield 88%.

The following table shows the results obtained using L-thiazolidine-4-carboxylic acid esters; this patent application is an ethyl ester which reacted under the same conditions as those described in the above examples.

table

• ester Example yield Example yield methyl 1 53 2 33 n-propyl 1 48 2 41 i-propyl 1 61 2 54

Claims (9)

PATENT CLAIMS A process for producing a compound of formula III, wherein R ¹ is H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 cycloalkylalkyl, aryl and substituted aryl, C 2 -C 6 alkoxycarbonyl, C 8 -C 6 aralkoxycarbonyl, arylcarbonyl and aralkylcarbonyl, substituted aralkoxycarbonyl, that includes: a) reaction of a compound of formula I, Wherein R is as defined above and X is OH, Cl or OR, wherein R is an activating group, with a compound of Formula II, (II) COOCjHg q wherein R is H, C1-C6trialkylsilyl, in apolar aprotic solvents; b) basic hydrolysis of the ethyl ester obtained in step a) under phase transfer conditions. Method according to claim 1, characterized by Ί in that the apolar aprotic solvents are selected from n-pentane, n-hexane, n-heptane, n-octane, isooctane, nonane, decane, petroleum ether, ligroin, toluene, xylene, cumene, dichloromethane, chloroform, dichloroethane and mixtures thereof . The method of claim 1, wherein X is OH and step a) is carried out in the presence of a condensing agent selected from dicyclohexylcarbodiimide and diisopropylcarbodiimide. The process of claim 1, wherein the phase transfer catalysts are selected from tetrabutylammonium halide or hydrogen sulphate or tetrafluoroborate, tetraethylammonium halide or hydrogen sulphate or tetrafluoroborate; cetylpyridinium halide, methyltributyl halide, Adogen 464, trimethylcetylammonium p-toluenesulfonate, tetrabutylphosphonium halide, tetrafenylphosphonium halide, triphenylmethylphosphonium halide, butylpyridinium halide. The process of claim 1, wherein R 6 is selected from hydrogen and C 2 -C 3 alkoxycarbonyl. The process of claim 1 wherein the compound of formula I is L-pyroglutamic acid. A process according to claim 1 wherein the compound of formula I is L-N-t-butoxycarbonylpyroglutamic acid. Process according to any one of the preceding claims for the preparation of 3- (L-pyroglutamyl) -L-thiazolidine-4-carboxylic acid. The process according to claim 8, wherein the compound of formula I wherein R ¹ is hydrogen and X is OH is reacted with a compound of formula II wherein R is hydrogen.