WO2009065797A1

WO2009065797A1 - Process for obtaining mixtures of 4-carboxy-1,3-thiazolidinium carboxylate and n-acyl-1,3-thiazolidin-4-carboxylic acid

Info

Publication number: WO2009065797A1
Application number: PCT/EP2008/065652
Authority: WO
Inventors: Ramon Canela Garayoa; Merce Balcells Fluvia; Jorge Eras Joli; Javier Maria Hijos Bitrian; Montserrat Llovera Arcas
Original assignee: Universitat De Lleida; Axeb Biotech, S. L.
Priority date: 2007-11-23
Filing date: 2008-11-17
Publication date: 2009-05-28
Also published as: ES2326060A1; ES2326060B1; ES2345430B1; ES2345430A1

Abstract

The present invention relates to a process for obtaining in a single synthesis stage mixtures of 4-carboxy-1,3-thiazolidium carboxylate and N-acyl-1, 3-thiazolidin-4- carboxylic acids from 1,3-thiazolidin-4-carboxylic acids and derivatives of carboxylic acids, which has the following advantages: use of environmentally friendly solvents, lower energy consumption, lower consumption of acylating reagents, which allows the corresponding mixtures to be obtained with suitable characteristics and specifications, ease of recovery from the reaction medium and high yields.

Description

PROCESS FOR OBTAINING MIXTURES OF 4-CARBOXY-l , 3- THIAZOLIDINIUM CARBOXYLATE AND N-ACYL-1, 3-THIAZOLIDIN-4-

CARBOXYLIC ACID

FIELD OF THE INVENTION

The present invention relates to the field of the derivatives of 1, 3-thiazolidines . In particular, the present invention relates to a process for obtaining in a single synthesis stage mixtures of 4-carboxy-l, 3- thiazolidium carboxylate and N-acyl-1, 3-thiazolidin-4- carboxylic acids from 1, 3-thiazolidin-4-carboxylic acids and derivatives of carboxylic acids.

The process of the present invention is carried out with certain characteristics, such as the use of environmentally friendly solvents, lower energy consumption, lower consumption of acylating reagents, which allows the corresponding mixtures to be obtained with suitable characteristics and specifications, ease of recovery from the reaction medium and high yields, for use in various industrial applications, such as the formulation and manufacturing of agrochemical and defensive products for plant health or the making of antioxidant supplements for the animal feed industry.

BACKGROUND OF THE INVENTION

Mixtures of 4-carboxy-l, 3-thiazolidium carboxylate and N-acyl-1 , 3-thiazolidin-4-carboxylic acid have been shown to be a very useful type of compounds as a prodrug.

By means of chemical or metabolic conversion they release cysteine, which is the precursor in the biosynthesis of glutathion. Another use of interest lies in the functionality of the thiol group, which shows specific properties for scavenging free radicals.

In general, said mixtures show very useful protective biological properties against a broad spectrum of toxic substances and stress situations of the biotic or abiotic type.

To date, said mixtures have been obtained by means of chemical methods based on the following process: a) preparation of N-acyl-1, 3-thiazolidin-4-carboxylic acids using 1, 3-thiazolidin-4-carboxylic acids and an excess of acid anhydride in aqueous medium; b) removal by vacuum distillation of the water, excess of anhydride used and the carboxylic acid formed; c) recrystallisation of the acylthiazolidine formed in order to achieve a final purification; d) preparation of 1, 3-thiazolidine carboxylates by means of the corresponding reaction between carboxylic acid and 1, 3-thiazolidines; e) mixture of the acylthiazolidine and the 1,3- thiazolidine carboxylate thereby obtained;

(For greater detail, see "Action of formaldehyde on L-cysteine" Ratner, S. and Clarke, H. T., J. Am. Chem. Soc. 59, 200 (1937), "Subsequent studies on the effect of aldehydes on cysteine and cystine" W. C. Hess and M. X. Sullivan J. Biol. Chem., Oct 1937; 121: 323 - 329).

Removal of the water, excess acid anhydride and carboxylic acid formed in the reaction for obtaining acylthiazolidines nevertheless requires high temperatures and the application of vacuum, in addition to involving a process of low atomic yield, due to the use of an excess of one of the two reagents, in this case the acid anhydride. Finally, preparation of the two products to be mixed by using parallel processes involves a greater demand on reactor time and processing time. There are several publications concerning the preparation of N-acyl-1, 3-thiazolidin-4-carboxylic acids and carboxylates of 4-carboxy-l, 3-thiazolidines, from which the most significant are those already cited above. None of them, however, or the patents found, disclose the process disclosed in the present invention. Accordingly, patent US3537838 describes a process for obtaining by condensation of cysteine and homocysteine with aldehydes and derivatives thereof. Patent FR1559851 claims a process of synthesis based on acylation of the corresponding esters or esterification of the acylated acids of thizolidincarboxylic. US patent 2002/0082427 claims an energy-cheap process for obtaining thiazolidincarboxylic acid and its salts from hexamethylentetraamine and cysteamine in alcohol medium and using ammonium in the reaction. However, none of them overcome all the disadvantages noted above (use of excess reagents, the need in the last step to remove the water and excess of reagents used by vacuum distillation, and the need to carry out two reactions in parallel) , and additionally the present invention further allows a mixture to be obtained in a single synthesis stage which, in suitable proportions, magnifies one or more positive effects or boosts the collateral effects of the aforesaid substances in relation to their properties for eliminating or preventing oxidation reactions when compared with the pure products. In particular, said mixtures act in a positive synergic way by amplifying the improved detoxification of xenobiotics with electrophylic centres, the elimination of free radicals and maintenance of the reduced state in certain biological states due to their redox buffer effect .

BRIEF DESCRIPTION OF THE INVENTION The present inventors have developed a process for obtaining mixtures of 4-carboxy-l, 3-thiazolidine carboxylate and N-acyl-1, 3-thiazolidin-4-carboxylic acid starting from 1, 3-thiazolidin-4-carboxylic acids and derivatives of carboxylic acids in a single synthesis stage .

Surprisingly, the present inventors have observed that the use of derivatives of carboxylic acid in a suitable proportion achieves a number of advantages in relation to what has been described in the prior art:

1. A mixture of the two compounds in solid form is obtained and can be used directly without the need for employing any subsequent purification.

2. It avoids the need to concentrate the solution to dryness.

3. It avoids the loss of a large quantity of acylating reagent in carrying out the reaction.

4. The energy consumption is much lower compared to methods that choose a process of synthesis in parallel and subsequent removal of the water, excess of acid anhydride and carboxylic acid.

5. The end product, a mixture of 4-carboxyl-l, 3- thiazolidine carboxylate and N-acyl-1, 3-thiazolidin—4- carboxylic acid, presents mass spectrums, optical rotation and chromatographic profile indicating that it has a suitable purity for use on an industrial scale.

6. By using molar proportions from 0.5 to 1 of 1,3- thiazolidin-4-carboxylic acid in relation to the derivative of carboxylic acid, and preferably from 0.8 to 1, temperatures between 2O⁰C and 12O⁰C, preferably between 40 and 85⁰C, and suitable reaction times, usually between 2 and 6 h, a mixture of the aforesaid two products can be obtained that magnifies one or more positive effects or boosts the collateral effects of the aforesaid substances in relation to their properties for eliminating or preventing oxidation reactions compared to when they are used individually.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the chromatogram corresponding to the obtained material, with the presence of two chromatographic peaks corresponding to the two products, whose mass spectrum is shown in figures 2 and 3. Figure 2 shows the mass spectrum of the 4-carboxy- 1, 3-thiazolidine acetate.

Figure 3 shows the mass spectrum of the N-acetyl- 1, 3-thiazolidin-4-carboxylic acid.

Figure 4 shows the IR spectrum of the mixture obtained corresponding to the two products of Figures 2 and 3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for obtaining mixtures of 4-carboxy-l, 3-thiazolidium carboxylate and N-acyl-1, 3-thiazolidin-4-carboxylic acid comprising a single synthesis stage of: - mixing, at a suitable temperature, a 1,3- thiazolidin-4-carboxylic acid of synthetic origin and a derivative of carboxylic acid selected from acid anhydride, acyl halide and activated acid, optionally in the presence of a polar solvent.

As usual in this type of synthesis processes, it will be obvious to a skilled person in the art to carry out one or more stages of isolating the product obtained, such as filtering the solid obtained, washing the product, subsequent drying to remove the solvent, etc., together with the characterisation of the product.

The heating for the mixing can be carried out by conventional methods or by using microwaves.

In the present invention, "1, 3-thiazolidin-4- carboxylic acid" is taken to mean any substance with a structure of the type shown in the figure below:

with X and Y being independently equal to H, an alkyl radical or an aryl radical. Preferably the alkyl radical is a straight chain of 2 to 5 atoms of carbon, and the aryl radical is phenyl.

"Derivative of carboxylic acid" is taken to mean any acylation agent that enables the reaction between the nitrogen of the thiazolidine ring and the acyl group. Said derivatives include the acid anhydrides, in particular acetic anhydride.

"N-acyl-1, 3-thiazolidin-4-carboxylic acid" is taken to mean any substance with a ring of 1,3- thiazolidine with the nitrogen linked to an acyl group (RCO or ArCO) and a carboxyl group in the carbon 4 of the ring, in particular N-acetyl-1, 3-thiazolidin-4-carboxylic acid.

with X and Y being independently equal to H, an alkyl radical or an aryl radical, and Z equal to an alkyl radical or an aryl radical. Preferably the alkyl radical is a straight chain of 2 to 5 atoms of carbon, and the aryl radical is phenyl.

"4-carboxy-l , 3-thiazolidinium carboxylate" is taken to mean any salt between a 1, 3-thiazolidin-4- carboxylic acid and a carboxylic acid (RCOOH or ArCOOH) , in particular 4-carboxy-l, 3-thiazolidinium acetate.

"Polar solvent" is taken to mean any polar substance with a structure of the XCH(OH)Y type, with X and Y being independently equal to H, an alkyl or aryl group, in particular ethanol, methanol or mostanol, preferably, ethanol. In a preferred embodiment, the solvent of the reaction is the acid derivative of the 5 reaction itself, without the need to add any polar solvent to the medium. In this case the stirring is carried out in an orbital system and not by means of magnetic stirring or internal mechanical stirring.

10 In a preferred embodiment of the present invention the process is carried out at a temperature varying between 2O⁰C and 12O⁰C, preferably between 4O⁰C and 85⁰C.

In a preferred embodiment of the present 15 invention, the acid derivative is acetic anhydride and the solvent is ethanol.

In another preferred embodiment, the mixture obtained is made up of N-acetyl-1, 3-thiazolidin-4- 20 carboxylic acid and 4-carboxy-l, 3-thiazolidinium acetate.

There follows, by way of non-restrictive illustration, some examples of embodiment of the present invention . 25

EXAMPLES

Example 1

The process was carried out in a stirred tank reactor of

30 25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (2.3 g) ,

2 mL of acetic anhydride and 2 mL of ethanol were introduced therein. The system was stirred at 200 rpm for

24 h at 22⁰C. 1, 3-thiazolidin-4-carboxylic acid (1.7 g) was then added to a pH of 5.5-6. The solid was recovered

35 by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 2.8 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l, 3-thiazolidinium acetate were recovered.

5 Example 2

The process was carried out in a reactor of 25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (2.3 g) and 2 mL of acetic anhydride were introduced therein. The system was stirred by orbital stirring at 200 rpm for 24 h at

10 22⁰C. 1 , 3-thiazolidin-4-carboxylic acid (1.7 g) was then added to a pH of 5.5-6. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 2.0 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and

15 4-carboxy-l, 3-thiazolidinium acetate were recovered.

Example 3

The process was carried out in a stirred tank reactor of 25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (2.3 g) ,

20 2 mL of acetic anhydride and 2 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. 1, 3-thiazolidin-4- carboxylic acid (1.2 g) was then added to a pH of 5.5-6. The solid was recovered by vacuum filtering and washed

25 with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 3.0 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

30 Example 4

The process was carried out in a stirred tank reactor of 25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (2.7 g) , 1 mL of acetic anhydride and 3 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 35 1 h at 22⁰C and 4 h at reflux. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 2.1 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l , 3-thiazolidinium acetate were recovered.

Example 5

The process was carried out in a stirred tank reactor of

25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (1.4 g) ,

1 mL of acetic anhydride and 3 mL of ethanol were introduced therein. The system was stirred at 200 rpm for

1 h at 22⁰C and 4 h at reflux. 1, 3-thiazolidin-4- carboxylic acid (1.3 g) was then added to a pH of 5.5-6. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 2.2 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 6 The process was carried out in a stirred tank reactor of 25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (2.3 g) ,

2 mL of acetic anhydride and 2 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. 1, 3-thiazolidin-4- carboxylic acid (1.3 g) was then added to a pH of 5.5-6. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 3.1 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 7

The process was carried out in a stirred tank reactor of

25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (2.8 g) , 1 mL of acetic anhydride and 3 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 24 h at 22⁰C. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum- drying the solid in a desiccator, 2.4 g of a mixture of N- 5 acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy- 1, 3-thiazolidinium acetate were recovered.

Example 8

The process was carried out in a stirred tank reactor of

10 25 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (1.4 g) , 1 mL of acetic anhydride and 3 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. 1, 3-thiazolidin-4- carboxylic acid (1.4 g) was then added. The solid was

15 recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 2.3 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

20

Example 9

The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (11.1 g) , 4 mL of acetic anhydride and 12 mL of ethanol were

25 introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. The ethanol was then removed by distillation. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 10.0 g of a

30 mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l, 3-thiazolidinium acetate were recovered.

Example 10

The process was carried out in a stirred tank reactor of 35 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (11.0 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 8 h at reflux. The ethanol was then removed by distillation. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum- drying the solid in a desiccator, 8.5 g of a mixture of N- acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy- 1, 3-thiazolidinium acetate were recovered.

Example 11

The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (11.0 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 16 h at reflux. The ethanol was then removed by distillation. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum- drying the solid in a desiccator, 8.6 g of a mixture of N- acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy- 1, 3-thiazolidinium acetate were recovered.

Example 12 The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (10.3 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 16 h at reflux. The solid was recovered by vacuum filtering. Finally, and after vacuum-drying the solid in a desiccator, 6.1 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 13 The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (10,2 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 24 h at reflux. The solid was recovered by vacuum filtering. Finally, and after vacuum-drying the solid in a desiccator, 5.6 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 14

The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (11.1 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 2 h. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 10.5 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l, 3-thiazolidinium acetate were recovered.

Example 15

The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (10.8 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. 1 ml of hexane was then added. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 6.0 g of a mixture of N-acetyl- 1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 16 The process was carried out in a stirred tank reactor of 50 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (10.3 g) , 4 mL of acetic anhydride and 12 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then left for 24 h in a refrigerator. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 5.5 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l , 3-thiazolidinium acetate were recovered.

Example 17

The process was carried out in a stirred tank reactor of 100 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (22.3 g) , 8 mL of acetic anhydride and 24 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 2 h. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 20.4 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l , 3-thiazolidinium acetate were recovered.

Example 18 The process was carried out in a stirred tank reactor of 500 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (110.3 g) , 40 mL of acetic anhydride and 120 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 2 h. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 107.5 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l , 3-thiazolidinium acetate were recovered. Example 19

The process was carried out in a stirred tank reactor of 500 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (223.5 g) , 80 mL of acetic anhydride and 240 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 2 h. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 220.1 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l, 3-thiazolidinium acetate were recovered.

Example 20

The process was carried out in a stirred tank reactor of 1000 ml capacity. 1, 3-thiazolidin-4-carboxylic acid

(331.09 g) , 120 mL of acetic anhydride and 360 mL of methanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 4 h. The solid was recovered by vacuum filtering and washed with cold methanol. Finally, and after vacuum-drying the solid in a desiccator, 305.3 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 21

The process was carried out in a stirred tank reactor of 1000 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (330.02 g) , 120 mL of acetic anhydride and 360 mL of mostanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 4 h. The solid was recovered by vacuum filtering and washed with cold mostanol. Finally, and after vacuum-drying the solid in a desiccator, 412.2 g of a mixture of N-acetyl-1, 3- thiazolidin-4-carboxylic acid and 4-carboxy-l, 3- thiazolidinium acetate were recovered.

Example 22

The process was carried out in a stirred tank reactor of 2000 ml capacity. 1, 3-thiazolidin-4-carboxylic acid (661.3 g) , 240 mL of acetic anhydride and 720 mL of ethanol were introduced therein. The system was stirred at 200 rpm for 1 h at 22⁰C and 4 h at reflux. It was then cooled with a water-ice bath for 4 h. The solid was recovered by vacuum filtering and washed with cold ethanol. Finally, and after vacuum-drying the solid in a desiccator, 663.4 g of a mixture of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4-carboxy-l, 3-thiazolidinium acetate were recovered.

Said resulting mixture is a white powder with [α]_D ²° (HCl IM) = -109° and has a chromatogram and mass spectrums like those shown in the figures.

Claims

C L A I M S

1. Process for obtaining mixtures of 4-carboxy- 5 1, 3-thiazolidium carboxylate and N-acyl-1, 3-thiazolidin-4- carboxylic acid, characterised in that it comprises a single synthesis stage of: mixing, at a suitable temperature, a 1,3- thiazolidin-4-carboxylic acid of synthetic origin and a 10 derivative of carboxylic acid selected from acid anhydride, acyl halide and activated acid, optionally in the presence of a polar solvent, wherein the molar proportion of 1, 3-thiazolidin-4- carboxylic acid in relation to the derivative of 15 carboxylic acid is from 0.5 to 1.

2. Process according to claim 1, characterised in that the polar solvent used is ethanol, methanol or mostanol .

3. Process according to claim 2, characterised in 20 that the polar solvent used is ethanol.

4. Process according to any of the preceding claims, characterised in that the molar proportion of 1,3- thiazolidin-4-carboxylic acid in relation to the derivative of carboxylic acid is from 0.8 to 1.

25 5. Process according to any of the preceding claims, characterised in that said process is carried out at a temperature between 20 and 12O⁰C.

6. Process according to claim 5, characterised in that said process is carried out at a temperature between

30 40 and 85⁰C.

7. Process according to any of the preceding claims characterised in that the acid derivative used is acetic anhydride.

8. Process according to any of the preceding 35 claims, characterised in that 1, 3-thiazolidin-4-carboxylic acid is used with X = Y being H, as 1, 3-thiazolidin-4- carboxylic acid.

9. Process according to any of the preceding claims characterised in that the mixture obtained is made up of N-acetyl-1, 3-thiazolidin-4-carboxylic acid and 4- carboxy-1 , 3-thiazolidinium acetate, where X, Y = H, ZCO =

CH₃CO and ZCOO^" = CH₃COO^".