HU203108B - Process for producing levamisol - Google Patents

Abstract

The present invention relates to a novel process for the preparation of anthelmintic Levamisol. According to the present invention, a racemic compound (I), (II) or (ΠΙ) is resolved and the resulting compound (-) - (1) is reacted with thionyl chloride, obtained or obtained by resolution (+) (II). Compound (I) is converted to the compound of formula (+) - (IU) by reaction with thionyl chloride and the resulting compound of formula (-) - (V) is reacted with the compound of formula (I) to (IU) by partial hydrolysis and ring closure. in a solvent with an aqueous base. EN 203 108 B Scope of the description: 6 pages, 1 drawing -1-

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of the known left-rotating 6-phenyl-2,3,5,6-tetrahydroimidazo [2,1-b] thiazole enantiomer (Levamisol) from optically active intermediates. The compound of the present invention can be used as a wormicide.

A common method for the preparation of Levamisol for use as a worm in human medicine is that the final product is prepared by resolving Tetramisol for veterinary use. Tetramisol and Levamisol are represented by the formula (V), in which the star is a

Designates a 6-position asymmetric carbon atom.

It is known that, in principle, the resolution of the first racemic phase product in the preparation of optically active end products can lead to the most economical technology. However, the application of this principle is limited by the possibility of resolution of racemic intermediates. Therefore, in practice it is expedient to develop this technology during synthesis starting from the first economically resolvable racemic intermediate. However, since the antipode of the optically active final product is not usually used alone, the unfavorable antipode of the resolvable intermediate is resolved after racemization, if possible.

For the preparation of the racemic intermediates used in the process of the present invention, reference is made to the following patents (Roman numerals in parentheses after the number of patents refer to which reaction steps are described in that description):

No. 233,481 Federal Publications Bulletin [(-) -> (ΙΙ) -> (ΙΙΙ) _; (I) ->(H); (II) ->(III)];

No. 679,696 U.S. Patent No. 4,677,684 ((ffl) -> (IV) -XV);

No. 325,356 (III) -KV) and

No. 027,030 Federal Government Gazette [(V) Resolution].

In practice, the resolution of racemic bases with predominantly optically active acids, so-called. resolving agents In the process, with the enantiomers of the racemic base, the resolving agent forms diastereomers with different properties. The next step in the separation is the fractional crystallization of diastereomers. One enantiomer is separated from the solvent while the other enantiomer remains in solution so that they can be isolated by filtration. The crystalline salt is liberated and recovered from one of the crystalline salts and the other from the mother liquor.

The laws of resolution are unknown. It is not possible to predict in advance which resolving agents, solvent (s) and concentrations can be separated into their enantiomers by a particular racemic base. The systematic testing of the resolving agents used (e.g., tartaric acid, tartaric acid derivatives, camphorsulfonic acids, N-acyl amino acids, etc.) and solvents would require almost unpredictable experimental work.

Optionally, it is known that racemic 6-phenyl-2,3,5,6-tetrahydro-imidazo [2,3-b] thia7.ol, i.e., Tetramisol, with dibenzoyl-d-tartaric acid (furthermore camphor-10-sulfonic acid and N-acyl glutamic acids) in alcohol, water and water / dichloroethane (furthermore camphorsulfonic acid in chloroform and N-acyl amino acids in water). It is not even legal that once the possible derivatives of the phenyl substituted imidazothiazole 2 compound are prepared, they can all be resolved with dibenzoyl d-tartaric acid, since it is not possible to provide a solvent and conditions which allow the resulting diastereomers to be separated by crystallization.

In view of the above, the resolution of each racemic intermediate during the Levamisol synthesis was investigated, since the optically active enantiomers were not known; furthermore, we investigated the potential of the Levamisol syntheses derived from the corresponding enantiomers to maintain optical activity, as well as the racemization of the enantiomers which could not be converted to Levamisol following the synthetic route and leading to the equally valuable Tetramisol.

We have now surprisingly found that N- (2-hydroxyethyl) -N- (2-hydroxy-2-phenylethyl) amine (compound of formula I), N- (2-chloroethyl) ) -N- (2-Chloro-2-phenylethyl) -amine (Compound (Π)) and 3- (2-hydroxy-2-phenylethyl) -2-iminothiazolidine (Formula III) Compound] racemic intermediates can be separated into their enantiomers with dibenzoyl d -boroic acid. Compounds of formula (I), (II) and (III) are bases of chemically different properties - compound of formula (I) is an amino alcohol, compound of formula (II) is a substituted amine, and compound of formula (III) is a substituted thiazole derivative, so it is surprising to see the possibility of resolution with the resolving agent itself or with the same resolving agent. The enantiomers obtained by resolution of the compounds of formula (II) and (III) are new, so far not mentioned in the literature, and the enantiomers of the compound of formula (I) have not yet been prepared by resolution. That is, the compounds (+) - (11), (+) - (111) and (-) - (IV) involved in the process of the invention are novel.

In the remainder of this specification, racemic compounds are referred to only with the corresponding Roman numeral or their enantiomers, indicated by a rotational (+) or (-) sign before the Roman numeral.

According to the invention, (I) -boh (-) (I), (-) - (I) (+) - (II), (+) - (II) (+) ) - (ni) or (+) - (ni) and (-) - fiV) -c and from this Levamisol is prepared. Any of the above intermediates can be synthesized to Levamisole by retaining optical activity because it is converted to (+) - (11) by thionyl chloride chlorination of (-) - (I) to form (+) - (ΙΠ) by partial hydrolysis and thiourea ring closure, from which it can also be prepared by chlorination with thionyl chloride (-) - (1 V) to provide the optically active final product ((-) - (V)) by alkaline ring closure.

However, the utilization of the antipodes of the above enantiomers does not require racemization, since (+) - (1) and (-) - (11) can be converted to (-) - (III) intermediate by analogy with the foregoing. we can also win. The ring closure of (-) - (III) sulfuric acid yields the equally valuable Tetramisol. (This process is provided outside the scope of the invention only as a teaching of the economics of the process of the invention to be described later.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of the 6-phenyl-2,3,5,6-tetrahydroimidazo [2,1-b] thiazole enantiomer (Levamisol).

In the description of the process according to the invention, operations or products which, although not within the scope of the invention, are indicated in square brackets

They play an important role in the economics of the process (to which we will return to the advantages of the process of the invention). Of course, these operations are optional. According to the present invention, (a) the racemic N- (2-hydroxyethyl) -N- (2-hydroxy-2-phenylethyl) amine of formula ban in aqueous alcohol is preferably 0.1 to 1, preferably In the presence of 0.4-0.6 molar equivalents of hydrochloric acid, 0.11, preferably 0.4-0.6 molar, more preferably 0.48-0.52 molar equivalent of dibenzoyl-d-tartaric acid of the formula (VI), and from the resulting enantiomers reacting the left-rotating enantiomer (i.e., (-) - (I)) with thionyl chloride in a solvent to give (+) - (ip) (+) - N- (2-chloroethyl) -N- ( 2-Chloro-2-phenylethyl) amine is converted to (+) - ()) (+) - 3- (2-hydroxy-2-phenylethyl) -2-iminothiazolidine by partial hydrolysis and thiourea which is then reacted with thionyl chloride in a solvent and the resulting (-) - (IV) (-) - 3- (2-chloro-2-phenylethyl) -2-iminothiazolidine in a solvent is treated with an aqueous base, and (i) thionyl chloride in the solvent of the right-handed enantiomer of (+) - (1) (-) (Π) to give (-) - N- (2-chloroetha) -N- (2-chloro-2-phenylethyl) amine (-) (Π) by hydrolysis and thiourea ring closure (-) ( (-) - 3- (2-hydroxy-2-phenylethyl) -2-iminothiazolidine, which is treated with concentrated sulfuric acid, or (b) the racemic compound (ID) is water and a in a mixture of water-immiscible solvent with 0.1 to 1, preferably 0.4 to 0.6, more preferably 0.48 to 0.52 molar equivalents of dibenzoyl-d-tartaric acid, followed by the addition of (+) - (11) (+) - N- (2-Chloroethyl) -N- (2-chloro-2-phenylethyl) amine by partial hydrolysis and thiourea ring closure of (+) - (ΙΠ) (+) - 3- ( 2-hydroxy-2-phenylethyl) -2-iminothiazolidine, which is then reacted with thionyl chloride in a solvent, followed by (-) - 3- (2-chloro-2-) - (IV). phenylethyl) -2-iminothiazolidine in a solvent is reacted with an aqueous base and [(ii) the (-) - N- ( 2-Chloroethyl) -N- (2-fluoro-2-phenylethyl) amine by hydrolysis and thiourea ring closure to (-) - (111) (-) - 3- (2-hydroxy-2-phenylethyl) ) -2-iminothiazolidine and the latter compound is treated with concentrated sulfuric acid; or (c) the racemic compound of formula (III) in an alcoholic solution is 0.5 to 15, preferably 0.9 to 1.1 molar equivalents of dibenzoyl-d-. (+) - (UD) (+) - 3- (2-hydroxy-2-phenylethyl) -2-iminothiazolidine is reacted with thionyl chloride in a solvent, followed by ) - (-) - 3- (2-chloro-2-phenylethyl) -2-iminothiazolidine (IV) is reacted with an aqueous base in a solvent [and (iii) the (-) - (Hp) -3- (2-hydroxy-2-phenylethyl) 2-iminothiazolidine is treated with concentrated sulfuric acid].

In accordance with the present invention, it is convenient to resolve (±) - (D) in 0.7-0.52 molar equivalents of dibenzoyl-d-tartaric acid (VD) in about 7 volumes of 50% aqueous ethyl alcohol. In the presence of -0.6 molar equivalents of hydrochloric acid, so that the (+) - (1) salt of (+) - (D (VD1) crystallized, which was isolated. 1) The enantiomer is liberated with alkali and extracted with chloroform. The (+) - (!) Enantiomer is the intermediate (±) (V).] After evaporation from the mother liquor of the salt, the residue is decomposed with alkali and the (-) - (D) , which is an intermediate of (-) - (V).

The (±) - (Π) hydrochloride is dissolved in about 6 volumes of water at 50 ° C and a solution of approximately 0.5 molar equivalent of dibenzoyl d-tartaric acid in about 5 volumes of chloroform is added. The biphasic solvent precipitates the (+) - (II) - (VD) salt, from which the (+) - (Π) enantiomer is liberated as described above. The (+) - (Π) enantiomer may also be prepared by dissolving the (-) - (D) enantiomer in dichloroethane and chlorinating with thionyl chloride in the presence of dimethylformamide, followed by precipitation of the (+) - (Π) enantiomer. The hydrochloric acid is filtered off and the aqueous portion is separated from the mother liquor of the (+) - (11) - (VI) salt and the residue is the salt of (-) - (s) hydrochloride which is an intermediate of (+) - (V). The (-) - (ΙΓ) enantiomer may also be prepared by chlorinating the (+) - (D) enantiomer in an analogous manner to that described above.]

A solution of (±) - (III) in about 5 volumes of methyl alcohol is reacted with a solution of 0.5 to 1.5, preferably 0.9 to 1.1 molar equivalents of reagent (VI) in about 2.5 volumes of methyl alcohol. The (+) - (HD- (yD salt) crystalline precipitates out of the salt. The (+) - (ÜD) enantiomer, which is an intermediate of () - (V), water and dichloroethane and hydrochloric acid is added to the separated aqueous phase. by alkalization and filtration of the precipitated base.

The (+) - (IID) enantiomer may also be prepared by partially hydrolyzing the hydrochloride of the (+) - (11) enantiomer in water with sodium hydroxide and adjusting the pH to 2.5-3 with thiourea for 4 hours. The pH is then adjusted to 1 (also with hydrochloric acid), refluxed for a further 4 hours and then allowed to stand, after removal of some of the water, to precipitate the (+) - (III) -hydrochloride salt of the enantiomer.

. [The mother liquor of the (+) - (1H) - (VD) salt obtained during the hydrolysis is evaporated and water and ammonium hydroxide are added to the residue to precipitate the base (-) - (µD), which is an intermediate of (+) (V). The hydrochloride salt of the -) - (ΠΙ) enantiomer may also be prepared starting from the hydrochloride salt of the (-) - (11) enantiomer as described above.]

The hydrochloride salt of the (+) - (III) enantiomer is chlorinated with thionyl chloride in chloroform in the presence of dimethylformamide and the reaction mixture is partially concentrated. The (-) - (IV) hydrochloride salt, which is an intermediate of (-) - (V), precipitates.

(-) - (IV) Hydrochloride is suspended in chloroform, aqueous potassium carbonate is added and refluxed for one hour. The chloroform portion is then separated, hydrochloric alcohol is added and evaporated. The residue was dissolved in hot 12.5% aqueous sodium chloride solution, clarified on charcoal and crystallized. The precipitated material is approximately the hydrochloride of the racemic compound (V). Yield: 14.3%. After filtration of the material, the mother liquor is basified to a pH of about 10 and extracted with chloroform. The solution was dried over sodium sulfate, ethyl acetate (HCl) was added and evaporated. The residue was 64.7% based on (-) - (IV) hydrochloride (Levamisol). [The hydrogen chloride of the (-) (III) enantiomer was added under cooling to concentrated sulfuric acid, stirred for 1 hour at 15 ° C, and ice, dichloroethane and alkali were added while maintaining the pH at 9. The two phases are separated, the aqueous phase is extracted with dichloroethane, and the organic phase is separated.

The reaction mixture was combined and dried, hydrochloric alcohol was added and the mixture was evaporated; the remaining (±) - (V) (Tetramisol)].

Among the advantages of the process according to the invention are the following:

(1) Compared to the known processes (in which Tetramisol, i.e., the compound of formula (±) - V) is resolved), the material loss is significantly lower; because it is well known that the earlier the stage of the synthesis is the resolution, the smaller the loss;

(2) Performing the resolution step early in the synthesis not only reduces the loss but also allows the use of cheaper starting materials, thus making the process economically more economical.

(3) Advantages of the process according to the invention include the significantly higher levamisole yields than the known processes and, in addition to the above advantages, the obtaining of tetramizole or, in addition to the levamisole, a useful material other than levamisole.

The economics of the process of the invention are illustrated below by comparative values for the steps in which anterior yield was found:

(a) yields according to the invention:

(29.6% out-of-scope procedure)

43.2% 68.5%, (-) - aiI) -► (±> (V) (±) - (ΙΙΙ) ζ ^ ^ (+) - (111) -► (-) - (IV) - ► (-) - (V)

733% 84.8% 973%

59.6%

(b) a combination of the process according to United States Patent 3,679,969 and the resolution of the resulting racemic product according to US Patent 2,027,030:

59.0% 94.0% 69.0% (±) - (ΠΙ) -► (±) - (IV) -► (+) - (V) -► (-) - (V)

38.3%

38.3%

c) Combining the process of U.S. Patent 3,325,356 with the resolution of the resulting racemic product according to US Patent 2,027,030.

81.9% 69.0% (± - (ΙΠ) -► (±) - (V) -► (-) - (V)

--J

56.5%

It can be seen that the total yield of the above process step b) is more than 50% higher than that of the comparative process step of the process according to the invention and that tetramisol is also produced; Comparison of process c) does not represent such a large excess, but it can be stated that the yield of the process according to the invention is at least equal to the known process, and furthermore, the production of tetramisole as a by-product provides additional economics.

The first steps of the process, i.e. (-) - (1) —► (+) - (II) -> (+) - (ΙΠ), cannot be included because (±) - (I) -> (±) - (II) -> (±) - (ΙΠ)

No. 233,481, U.S. Patent No. 233,481, discloses no yield data.

The following examples illustrate the process of the invention.

Example 1

18.0 g (0.1 mol) of (±) - (I) are dissolved in 130 ml of 50% aqueous ethanol by the addition of 4.3 ml (0.05 mol) of conc. Dibenzoyl-d-tartaric acid (05 mol). A solution is formed from which crystallization begins by scraping. After standing for 2 hours, the mixture is decanted and the resulting diastereomeric salt is washed with 2 x 5 ml of 50% aqueous ethanol. Product weight: 23.3 g (83%).

To the diastereomeric salt (23.3 g) was added 10% sodium hydroxide solution (50 ml) and the resulting solution was extracted with chloroform (30 ml) and the combined extracts were dried. The weight of the (+) - (I) enantiomer was 3.0 g (33.3%). [α] = + 50 ° (c = 1, CHCl 3).]

The mother liquor of the diastereomeric salt was basified with 20 ml of 10% w / w sodium hydroxide, extracted with 3 x 30 ml of chloroform and evaporated after drying. The weight of the remaining (-) - (I) enantiomer was 8.2 g (91.0%). [α] D = -40 '(c = 1, CHCl ₃ ).

Example 2

Dissolve 5.0 g (0.0196 mole) of (±) - (II) hydrochloride in 30 ml of 50 ° C water and 4.3 g (0.0115 mole) of dibenzoyl d-tartaric acid in 20 ml of chloroform. Add a 40 ° C solution. The resulting mixture begins to crystallize, which is complete after standing at room temperature for 2 hours. The acid dibenzoyl-d-tartrate of the (+) - (11) enantiomer precipitates, which is filtered off and washed with 2 x 3 ml of chloroform. Product weight: 5.8 g (90%); 124-126 ° C;

[?] D = -94 '(c = 1, methanol).

The salt (5.8 g) was suspended in water (30 ml) and treated with 5% sodium hydroxide solution (20 ml) and extracted with dichloroethane (3 x 20 ml). The combined solutions were dried over sodium sulfate and evaporated. The remaining (+) - (11) enantiomer weighed 1.84 g (86%). [α] D = + 40 '(c = 1, dichloroethane).

[The aqueous phase of the mother liquor of the diastereomeric salt is separated and evaporated. The residue is the hydrochloride salt of the (-) - (II) enantiomer. Weight: 1.6 g (64.0%); m.p. 149-151 'C. [a] 5,8 = +42 '(c = 1, methanol).]

Example 3

33.5 g (0.15 mol) of (±) - (ΠΙ) base are dissolved in 250 ml of methyl alcohol and 56.6 g (0.15 mol) of dibenzoyl-d-tartaric acid dissolved in 180 ml of methyl alcohol are added in two portions. Crystallization is facilitated by inoculation and the mixture is allowed to stand for 2 hours. The precipitated diastereomeric salt was lysed with 3 x 10 mL of methyl alcohol.

EN 203 108 Β suk and dried. Weight: 44.7 g (almost quantitative yield).

The diastereomeric salt (44.7 g) was suspended in ethyl alcohol (200 ml) and hydrochloric acid (20% w / w) was added under reflux until a solution was formed. After cooling, crystallization begins, and the (+) -? - hydrochloride which is liberated after one day is decanted off and washed with 2 x 10 ml of acetone. Weight: 9.6 g (49.2%). [Α] ί? = + ό0 · (ο = 1, νίζ).

The alcoholic mother liquor is ca. Concentrated to 50 ml; for scraping, further precipitation begins. The mixture was kept at a temperature below 10 ° C for 10 hours, then (+) - (111) hydrochloride was decanted and washed with 2 x 10 ml acetone to give 4.6 g (23.5%) of [α] = +60 '(c = 1, water).

(+) - (III) hydrochloride was obtained in a total yield of 72.7%.

[To the mother liquor of the diastereomeric salt is added 30 ml of 20% hydrochloric acid in ethyl alcohol, concentrated and worked up with 100 ml of dichloroethane. After standing overnight, the precipitated (-) - (HI) hydrochloride is filtered off and washed with 2 x 10 ml of acetone. Product weight: 8.4 g (43.2%).

[a] g> = -39 '(c = 1, water).]

Reference Example 1

30.0 g (0.166 mole) of (+) - (1) enantiomer ([a] □ = +27 ', C = 1, CHC1 ₃₎ were dissolved in 85 ml of bulge-dichloroethane, 0.15 ml of dimethylformamide was added and 27 ml of thionyl chloride are added dropwise to the solution under stirring at 40 ° C over a period of 30 minutes. The reaction mixture was then stirred for two hours at 45 ° C while crystallization started. After cooling with ice-water for 30 minutes, the (-) - (II) hydrochloride precipitated is washed off, washed with dichloroethane (2 x 10 ml) and dried. weight:

18.6 g (44.0%); [a] g> = -30 '(c = 1, water).

Reference Example 2

18.5 g (0.073 mol) of (-) - (II) hydrochloride [a] d = -30 ', (c = 1, water) are added to 102 ml of water followed by 12 ml of 25% w / w aqueous sodium -hydroxide (pH-5.5) is added. The resulting mixture was refluxed for 1.5 hours, then cooled to 20 ° C and the pH adjusted to 2.5-3 with 25% w / w aqueous sodium hydroxide. The solution is then clarified with charcoal, 5.6 g of thiourea is added and the mixture is refluxed for 4 hours. Concentrated hydrochloric acid is adjusted to pH 1 and the solution is refluxed for an additional 4 hours while 75 ml of water are distilled off. The residue which opalescent is cooled and then separated into two phases. After standing overnight at a temperature below 20 ° C, the precipitated crystals are lysed. The resulting () (TII) -hydrochloride was washed with 5 mL of saturated aqueous NaCl and 20 mL of acetone. Product weight: 2.2 g (13.5%). [a] '= + 17.5' (c = 2, water).

Example 4

5.2 g (0.02 mol) of (+) - (III) -hydrochloride ([a] d = +47 ', c = 1, water) are suspended in 100 ml of chloroform and stirred at 20 ° C. Thionyl chloride (6.0 mL, 9.7 g, 0.08 mol) was added. The mixture was then refluxed for one hour and then cooled to 20 ° C. The precipitated material was decanted, washed with chloroform (2 x 5 ml) and dried. The weight of (-) - (IV) hydrochloride obtained was 4.8 g (84.8%). [a] "= -36 '(c = 1, water).

Example J.

4.1 g (0.015 mol) of (-) - (IV) -hydrochloride ([a] d = -29 * c = 1 in 157 ml of chloroform) and 8.7 g (0.063 mol) of potassium carbonate are added. The mixture was refluxed for 1 hour, cooled to 20 ° C, the two phases were separated and the aqueous portion was extracted with 30 ml of chloroform. The combined chloroform solutions were dried over sodium sulfate (3 ml, 25%). hydrochloric acid (3.5 g, 97.2%), [α] d = -75 '(c = 1, water).

The material (3.5 g) was dissolved in water (16 ml), sodium chloride (2.0 g) was added, the solution clarified with charcoal, the filtrate was cooled and, after standing overnight, the precipitate, approximately (±) - (V), was filtered. [Mass: 0.5 g (14.3%); [a] g> = -5 '(c = 1, water).]

The mother liquor was basified to pH ~ 10 with 40% sodium hydroxide solution and the resulting oil was extracted with chloroform (3 x 10 mL). The combined chloroform solutions were dried over sodium sulfate, 2 mL of 25% HCl alcohol was added and evaporated. The resulting (-) - N-hydrochloride weighed 22 g (64.7%); mp: 213 'C; [a] "= -116 '(c = 1, water); enantiomer content: 94.6%.

Reference Example 3

52 g (0.02 mol) of (-) - (III) -hydrochloride ([a] d = -60, c = 1, water) in 5.0 ml of concentrated sulfuric acid under stirring at 10 ° C for 15 minutes. and then stirred for an additional hour at 15 ° C while hydrochloric acid was developing. Then 10 g of ice and 30 ml of dichloroethane are added and the mixture is adjusted to pH 9 with 40% sodium hydroxide at 40-45 ° C. The two phases are separated and the aqueous phase is extracted with 5 ml of dichloroethane. The combined dichloroethane solution was dried over sodium sulfate, then 5 mL of 25% HCl alcohol was added and evaporated. The weight of (±) - (V) obtained was 3.3 g (68.5%). [a] d = 0 * (c = 1, water).

Claims (5)

1. Procedure for Reversible 6-Phenyl- 2, For the preparation of 3,5,6-tetrahydroimidazo [2,1b] thiazole (Levamisol), characterized in that (a) the racemic N- (2-hydroxyethyl) -N- (2-hydroxy) 2-phenylethyl) amine in aqueous alcohol 0.1-1, preferably 0, In the presence of 4-0.6 molar equivalents of hydrochloric acid, 0.1 to 1 molar, preferably 0.4-0.6 molar equivalent, more preferably 0.48-0.52 molar equivalent of dibenzoyl d-boyoic acid (VD), followed by resolution of the resulting enantiomers. reacting the left-rotating enantiomer (i.e., (-) - (D)) with thionyl chloride in a solvent to give (+) - (11) (+) - N- (2-chloroethyl) -N- (2-) chloro-2-phenylethylamine by partial hydrolysis and cyclization with thiourea (+) - (+) - 3- (25) HU 203 108 Β -hydroxy-2-phenylethyl) -2-iminothiazolidine, which is then reacted with thionyl chloride in a solvent to give (-) - 3- (2-chloro-2-phenyl) (-) - (IV). -ethyl) -2-iminothiazolidine in a solvent by reaction with an aqueous base, (b) 0.1-1, preferably 0.4-0.6, more preferably 0, in a mixture of the racemic compound II with water and a water immiscible solvent. , 48-0.52 molar equivalent of dibenzoyl-d-tartaric acid, followed by (+) - N- (2-chloroethyl) -N- (2-chloro-2) (+) - (11) enantiomer. -phenylethyl) amine is converted to (+) - (ΠΙ) (+) - 3- (2-hydroxy-2-phenylethyl) -2-iminothiazolidine by partial hydrolysis and thiourea, which is then treated with thionyl in a solvent. chloride and the resulting (-) - (IV) (-) - 3- (2-chloro-2-phenylethyl) -2-iminothiazolidine in a solvent is reacted with an aqueous base, (C) resolving the racemic compound of formula (III) in an alcoholic solution with 0.5 to 1.5, preferably 0.9 to 1.1 molar equivalents of dibenzoyl-d-tartaric acid, followed by (+) - (ΠΙ) (+) - 3- (2-hydroxy-2-phenylethyl) -210-iminothiazolidine is reacted with thionyl chloride in a solvent to give (-) - (IV) - (3-) - (2-) chloro-2-phenylethyl) -2-iminothiazolidine is reacted with an aqueous base in a solvent.