RU2213724C1 - Method for separation of racemic 3-(2-methoxyphenoxy)-1,2- propanediol and 3-(2-methylphenoxy)-1,2-propanediol for enantiomers - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to method for separation of racemic 3-(2-methoxyphenoxy)-1,2-propanediol and 3-(2- methylphenoxy)-1,2-propanediol for enantiomers that can be used in pharmaceutical industry in preparing non-racemic medicinal preparations. Racemic diol is enriched a little with one of enantiomers in suitable solvent at temperature 40-60 C to obtain concentrated solution and stirred with graduate cooling to 10-40 C to provide its supersaturation. Then crystalline primer of the same enantiomer is added that is added for enrichment, kept at crystallization point in the range 5- 33 C for 30-60 min, solid precipitate of scalenohedral diol is filtered off that shows the same configuration as a sample of added prime. Then racemic compound is added to mother liquor enriched with the second enantiomer being racemic compound is taken in the amount compensating the separated precipitate, heated to complete dissolution at 40-60 C and then cooled to 10-40 C. Then crystalline primer of enantiomer prevailing in solution is added, kept at stirring at crystallization point in the range 5-33 C, precipitated enriched with the second enantiomer is separated followed repeating indicated process some times. As a rule, benzene, carbon tetrachloride or its mixture with methylene chloride in the ratio 1:1, 40% ethanol aqueous solution and water are used a solvent. Method provides preparing the known drugs in non-racemic form from inexpensive racemic substrates. EFFECT: improved separating method. 2 cl, 1 tbl, 7 ex

Description

 The invention relates to the chemistry of organic compounds, and in particular to a method for the separation of the individual enantiomers of racemic 3- (2-methoxyphenoxy) -1,2-propanediol (I), the international non-proprietary name guaifenesin (guaiphenesin), and 3- (2-methylphenoxy) - 1,2-propanediol (II), the international nonproprietary name of mephenesin (mephenesin). The invention can be used in the pharmaceutical industry in the production of non-racemic (scalemic, enantiopure) drugs.

 Currently, these compounds are registered as substances of drugs in racemic form.

Гвайфенезин применяется как мышечный релаксант и отхаркивающее средство, мефенезин используется как релаксант скелетных мышц. Зарегистрированными лекарственными средствами являются и простейшие производные рацемических диолов (I) и (II), а именно, их 1-карбаматы, так же являющиеся релаксантами скелетных мышц и спазмолитиками. Химическую структуру (I) и (II) можно модифицировать и в другие физиологически активные производные с хиральным С₃-фрагментом, например (Бредихина З.А., Савельев Д. В., Бредихин А.А. // Ж. орган, химии. 2002. Т. 38. 2. С. 233-239) через циклические сульфиты в 1-алкиламино-3-арилокси-2-пропанолы, многие из которых являются хиральными лекарственными средствами класса бета-адреноблокаторов.

Guaifenesin is used as a muscle relaxant and expectorant; mefenesin is used as a skeletal muscle relaxant. Registered medicines are also the simplest derivatives of racemic diols (I) and (II), namely, their 1-carbamates, which are also skeletal muscle relaxants and antispasmodics. The chemical structure (I) and (II) can also be modified into other physiologically active derivatives with a chiral C ₃ fragment, for example (Bredikhina Z.A., Savelyev D.V., Bredikhin A.A. // J. Organ, Chemistry 2002. T. 38. 2. S. 233-239) via cyclic sulfites to 1-alkylamino-3-aryloxy-2-propanols, many of which are chiral drugs of the beta-blocker class.

 Racemic drugs (PMs) are a mixture of equal amounts of opposite enantiomers of constitutionally identical compounds. In a chirally polarized environment of a living organism, enantiomers exhibit different physiological activity. While one of the enantiomers has useful target activity for a given drug (such an enantiomer is called an eutomer), its antipode (called a distomer) may turn out to be physiologically neutral, act as a synergist or antagonist of the eutomer, have a completely different spectrum of physiological activity, have a different, often greater than the eutomer, toxicity, teratogenicity, etc. In particular, for metocarbamol, guaifenesin 1-carbamate, it is shown that the (+) - (R) -isomer exhibits greater physiological activity than the racemic or (-) - (S) -methocarbamol (Souri E., Sharifzadeh M., Farsam H., Gharavi N. // J. Pharm. Pharmacol., 1999. Vol. 51. N 7. P. 853-855 )

 It has now been firmly established that always (except when drugs are rapidly racemized during storage or in physiological environments of a living organism), scalemic (enriched in one of the enantiomers or enantiopure) drug substances have significant therapeutic advantages over racemic (Lehmann P.A. II Trends Pharmacol. Sci., 1986. Vol. 7, N 7. P. 281-285). The differences in the physiological action of enantiomers are the greater, the higher the physiological activity (less physiological dose) of a given drug (Pfeiffer S. C. // Science, 1956. N 124. P. 29-41). Today's drugs are highly active, therefore, the main trend in modern medical chemistry and the pharmaceutical industry is the replacement, where appropriate, of racemic substances with scalemic substances (Deutsch DH // Chemtech. 1991. Vol. 21. N 3. P. 157-159; Stinson SC // Chem. Eng. News. 1998. Vol. 76. N 38. P. 83; Aboul-Enein HY Impact of Stereochemistry on Drug Development and Use. NY: Wiley, 1997. 736 pp.). In this regard, the problem of obtaining scalemic aryloxypropanediols, which are substances of drugs, is in demand.

 Three general methods are known for preparing scalemic compounds. Firstly, it is the chemical transformation of the starting enantiopure compounds by conventional methods. Secondly, this is a modification of the prochiral starting compounds by enantioselective synthesis methods. Thirdly, this is the separation into individual enantiomers of racemic target (or specially prepared intermediates) substances. All existing laboratory and industrial methods for producing scalemic compounds belong to one of these categories or are a combination of them (Crosby J. // Tetrahedron. 1991. Vol. 47. N 27. P. 4789-4846; Sheldon RA Chirotechnology: Industrial Synthesis of Optically Active Compounds. NY: M. Deccer, 1993. 416 pp.).

Этот способ достаточно прост и хорошо воспроизводится, однако для реализации он нуждается в наличии дорогостоящего энантиочистого глицидола.With respect to the preparation of scalemic 3-aryloxypropanediols, the addition of ArOH phenols to scalemic glycidol, regioselectively proceeding in the presence of catalysts such as Ti (OAlk) ₄ (Klunder JM, Co. SY, Sharpless KB. // J. Org Chem. 1986. Vol. 51. N 19. P. 3710-3712), Alk ₃ N (Chen J., Shum W. // Tetrahedron Lett. 1995. Vol. 36. N. 14. P. 2379-2380 ; Bredikhina Z.A., Savelyev D.V., Bredikhin A.A. // ZhORKh. 2002.V. 38. Issue 2.P. 233-239) or CsF (Kitaori K., Furukawa Y., Yoshimoto H., Otera J. // Tetrahedron, 1999. Vol. 55. N 50. P. 14381-14390), and leading to scalemic 3-aryloxy-propane-1,2-diols:

This method is quite simple and well reproduced, however, for implementation it needs the presence of expensive enantiopure glycidol.

 An example of the second approach is a method for producing enantiopure 3-aryloxy-propan-1,2-diols by asymmetric Charpless dihydroxylation of phenyl allyl ethers (Wang Z.-M., Zhang X.-L., Sharpless KB // Tetrahedron Lett. 1993. Vol. 34, 2267-2270; Kolb HC, VanNieuwenhze MS, Sharpless KB // Chem. Rev. 1994. Vol. 94. N 8. P.2483-2547).

На схеме AD-mix-α - торговое название смеси, содержащей хиральный лиганд (DHQ)₂PHAL, К₃Fе(СN)₆, K₂CO₃, K₂OsO₄•2H₂O; здесь (DHQ)₂PHAL:

Для проведения этого процесса используются экологически вредные производные тяжелого металла осмия и дорогостоящие энантиочистые катализаторы. Кроме того, полученные этим способом аналоги (I) и (II) имеют невысокий энантиомерный избыток (в пределах 60%).

In the AD-mix-α scheme, the trade name of a mixture containing a chiral ligand (DHQ) ₂ PHAL, K ₃ Fe (CN) ₆ , K ₂ CO ₃ , K ₂ OsO ₄ • 2H ₂ O; here (DHQ) ₂ PHAL:

To carry out this process, environmentally harmful derivatives of the heavy metal osmium and expensive enantiopure catalysts are used. In addition, analogues (I) and (II) obtained by this method have a low enantiomeric excess (within 60%).

 As an example of the third approach, we describe the described multistage method for producing diols (I) and (II) with moderate enantiomeric purity by kinetic separation of racemic 3-aryloxy-1,2-propanediols using the transesterification process catalyzed by biological enzymes of lipases (Theil F., Weidner J ., Ballschuh S., Kunath A., Schick H. // J. Org. Chem. 1994. Vol. 59. N 2. P. 388-393) (prototype).

 In the first stage, rac-1,2-diols with the help of lipases are regioselectively acylated with vinyl acetate at the primary hydroxy group without manifesting enantioselectivity. The subsequent stage of lipase-catalyzed acylation of the secondary hydroxy group proceeds with satisfactory enantioselectivity (for R = OMe, ee = 87%; R = Me, ee = 80%). Monoacetate is separated from diacetate by flash chromatography and then, after successive removal of the acyl groups, the desired (S) - and (R) -diols are isolated.

Недостатком этого способа является то, что результаты использования биоэнзимов сильно зависят от условий проведения процесса и от характера заместителей в ароматическом кольце. Метод нуждается в значительном ассортименте вспомогательных реактивов, при разработке используется хроматография, процесс трудно масштабируется.

The disadvantage of this method is that the results of the use of bioenzymes strongly depend on the process conditions and on the nature of the substituents in the aromatic ring. The method needs a significant assortment of auxiliary reagents; chromatography is used in the development; the process is difficult to scale.

 It is known to produce some chiral compounds in a non-racemic form by resolving the racemic substance into fractions enriched with the opposite enantiomers by crystallization by the involvement method. The use of selective crystallization ("preferential crystallization") or the resolution separation method (optical by resolution) for optical cleavage of racemic compounds is described in the literature (Jacques J., Collet A., Wilen SH "Enantiomers, Racemates, and Resolutions", Krieger Publishing Co. Malabar, FL., 1994. P. 217-368; Collet A., Brienne MJ., Jacques J. // Chem. Rev. 1980. Vol. 80. N 3. P. 215-230).

 As a rule, racemic substances crystallize in the form of racemic compounds, racemic conglomerates and racemic solid solutions. Only substances exhibiting the property of spontaneous separation into enantiomers during crystallization, that is, forming racemic conglomerates, can be separated by selective crystallization. Selective crystallization is achieved by introducing a small amount of the seed of the pure enantiomer into a supersaturated solution of a racemic or slightly enriched in the same enantiomer substance. In this way, for example, separation of D, L-threonine (Amiard G. // Bull. Soc. Chim. France. 1956. P. 447), D, L-valine hydrochloride (US Patent 3 182 079, 1965; Chem. Abstr. 1965, Vol. 63, 5740 pp.), Salts of racemic glutamic acid (French Patent 1,389,840, 1965; Chem. Abstr. 1965, Vol. 63, 5740f). The separation of (R; S) -bromosuccinic acid is described (Shiraiwa T., Ohkubo M., Miyazaki H., Kubo M., Nishigawa H., Tsujimoto T., Kurokawa N. // Bull. Chem. Soc. Jpn. 1998. Vol. 71. N 3. P. 735-739), separation of the salt of racemic phenylethylamine with itaconic acid (Bocskey Z., Kassai C., Simon K., Fogassy E., Kozma D. // J. Chem. Soc., Perkin Trans. 2. 1996. P. 1511-1515), separation of diethylamine salt and racemic naproxen (Eur. Patent 298 395; Chem. Abstr. 1989, Vol. 111, 7085a).

 We first discovered that racemic diols (I) and (II) crystallize as racemic conglomerates without any prior conversion to other chemical derivatives, for example salts, as in most known cases, and we propose a method for their separation into individual enantiomers according to selective crystallization scheme. Previously, the property of spontaneous cleavage during crystallization for compounds (I) and (II) was not known, and non-racemic compounds (I) and (II) were not obtained in this way. In addition, it was not obvious that the use of this property would result in non-racemic compounds (I) and (II).

 The purpose of the invention is the creation of a method that allows to obtain well-known drugs - guaifenesin and mefenesin in a non-racemic form from cheap racemic substrates by their separation during crystallization by the involvement method.

This goal is achieved in that the racemic diol is slightly enriched with one of the enantiomers in a suitable solvent at a temperature of 40-60 ^o C to obtain a concentrated solution and stirred, gradually cooling to 10-40 ^o C, achieving its supersaturation, after which the crystal seed is introduced with the same enantiomer that is added for enriching, kept under stirring at a temperature of crystallization in the range 5-33 ^o C for 30-60 minutes, then the solid precipitate was filtered off scalemic diol, having the same configuration walkie-talkie, as the sample seeding. The racemic compound is added to the mother liquor enriched with the second enantiomer in an amount that compensates for the separated precipitate, heated to complete dissolution at 40-60 ^° C, then cooled to 10-40 ^° C, the crystalline seed is introduced into the enantiomer prevailing in the solution, and kept under stirring at crystallization temperature in the range 5-33 ^o C, the precipitate is isolated, enriched in the second enantiomer, followed by repeating the above process several times, carefully analyzing the optical purity and amount of selected wasp ka.

 Separation into enantiomers was carried out for compounds (I) and (II) in benzene, aqueous ethanol, water, carbon tetrachloride, or a mixture thereof with methylene chloride (1: 1). The inventive method for the separation of diols (I) and (II) is illustrated by the following examples.

EXAMPLE 1
4.56 g of (R, S) -guaifenesin (I) (mp. 76-78 ^o C) and 0.50 g of (S) -guaifenesin (mp. 97 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +9.4 (s 1.0, MeOH), op = 99.5%) is dissolved in 135 ml of benzene at 50 ^° C and cooled with stirring to 30 ^° C, then finely ground seed (S) -guaifenesin (0.02 g) is added with the same optical purity and the solution was stirred at 60.degree ^. C. for 60 minutes. After filtration and drying, 0.90 g of (S) -guaifenesin with [α] was collected $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +6.5 (s 2.0, MeOH), op = 69.1%. To the filtrate remaining after separation of the precipitate, add 0.90 g of (R, S) -guaifenesin, dissolve it at 50 ^° C, cool the solution to 30 ^° C, seed the crushed (R) -guaifenesin (0.02 g), op> 99% and mix the solution at 29 ^{° C. for} 60 minutes 0.80 g of (R) -guaifenesin with [α] are separated $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -7.2 (s 1.6, MeOH), op = 76.6%. In the same way, the cycle is repeated several times, adding the missing amount of racemic diol each time. After the 2nd cycle, 0.8 g of (S) -guaifenesin with op = 64.5% and 0.70 g of (R) -guaifenesin with op = 66.7% were isolated. After the 3rd cycle, 0.70 g of (S) -guaifenesin with op = 60.4% and 0.65 g of (R) -guaifenesin with op = 61.2% were isolated.

An increase in the enantiomeric purity of the thus obtained scalemic (R) - and (S) -guaifenesin is possible by additional recrystallization from organic or mixed solvents. For example, 0.8 g of (S) -guaifenesin (op = 69.1%) is dissolved in 3.5 ml of 40% (by volume) aqueous ethanol at 50 ^° C. After cooling the solution to 10 ^° C and seeding with (S) -guaifenesin (0.008 g ) the mixture is stirred at 5 ^{° C. for} 5 hours. After filtration and drying, (5) -guaifenesin is collected: yield 0.45 g, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +8.9 (s 0.5, MeOH), op = 94.3% {cf. for (R) -guaifenesin [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -9.4 (c 1.0, MeOH), op = 99.4% [Kitaori K., Furukawa Y., Yoshimoto H., Otera J. // Tetrahedron, 1999. Vol. 55. N 50. P. 14381-14390]}.

EXAMPLE 2
5.00 g of (R, S) -guaifenesin (I) and 0.20 g of (R) -guaifenesin are dissolved in 20 ml of 40% aqueous ethanol at 40 ^° C and cooled with stirring to 10 ^° C, then finely ground seed of (R) -guaifenesin is introduced (0.05 g, op> 99%) and the solution is stirred for 60 minutes at 5 ^° C. After filtration and drying, 0.45 g of (R) -guaifenesin with [α] is collected $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -8.5 (s 1.0, MeOH), op = 89.1%. 0.45 g of (R, S) -guaifenesin is added to the filtrate remaining after separation of the precipitate, it is dissolved at 40 ^° C, the solution is cooled to 10 ^° C, and the ground (S) -guaifenesin (0.05 g) is seeded, op> 99% and mix the solution at 5 ^{° C. for} 60 minutes. 0.41 g of (S) -guaifenesin with [α] is isolated. $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +8.4 (s 0.8, MeOH), op = 88.5%. The cycle is repeated several times.

EXAMPLE 3
2.55 g of (R, S) -guaifenesin (I) and 0.25 g of (R) -guaifenesin (op = 90.0%) are dissolved in 20 ml of water at 60 ^° C and cooled with stirring to 30 ^° C, then finely ground seed (R ) -guaifenesin (0.02 g, op> 99%) and the solution is stirred for 60 minutes at 20 ^° C. After filtration and drying, 0.44 g of (R) -guaifenesin with [α] is collected $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -8.6 (s 1.0, MeOH), op = 90.5%. 0.44 g of (R, S) -guaifenesin is added to the filtrate remaining after separation of the precipitate, it is dissolved at 60 ^° C, the solution is cooled to 30 ^° C, and the ground (S) -guaifenesin (0.02 g) is seeded, op> 99% and mix the solution at 20 ^{° C. for} 60 minutes. 0.41 g of (S) -guaifenesin with [α] is isolated. $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +7.8 (s 0.8, MeOH), op = 82.1%. The cycle is repeated several times.

EXAMPLE 4
0.4 g of (R, S) -mephenesin (II) (mp. 70-71 ^o C) and 0.04 g of (S) -mephenesin (mp. 90-92 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -19.3 (c 0.9, hexane-isopropyl alcohol 4: 1), op = 99.5%) is dissolved in 15 ml of benzene at 50 ^° C and cooled with stirring to 30 ^° C, then finely ground (S) -mephenesin is added with the same optical purity (0.004 g) and for 60 minutes the solution is stirred at 30 ^o C. Then 0.09 g of (S) -mephenesin with [α] is filtered off. $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -17.1 (s 2.0, s 0.9, hexane-isopropyl alcohol 4: 1), op = 86.0% {cf. [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -19.3 (c 0.9, hexane-isopropyl alcohol 4: 1), op> 99% [Theil F., Weidner J., Ballschuh S., Kunath A., Schick H. // J. Org. Chem. 1994. Vol. 59. N 2. P. 388-393]}. 0.09 g of (R, S) -mephenesin is added to the filtrate remaining after separation of the precipitate, the solid additive is dissolved at 50 ^° C, cooled to 30 ^° C, and the ground (R) -mephenesin (0.004 g) is seeded, op> 99% and mix the solution at 30 ^{° C. for} 60 minutes. 0.08 g of (R) -mephenesin with [α] is filtered off. $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ +15.5 (c 0.5, hexane-isopropyl alcohol 4: 1), op = 78.0% {cf. [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ +19.8 (c 0.9, hexane-isopropyl alcohol 4: 1), op> 99% [Theil F., Weidner J., Ballschuh S. Kunath A., Schick H. // J. Org. Chem. 1994. Vol. 59. N 2. P. 388-393]}. The cycle is repeated several times.

EXAMPLE 5
2.00 g of (R, S) -mephenesin (II) and 0.20 g of (R) -mephenesin are dissolved in 24 ml of 40% (by volume) aqueous ethanol at 40 ^° C and cooled with stirring to 10 ^° C, then finely seeds are introduced ( R) -mephenesin (0.01 g), op> 99%, and the solution is stirred at +5 ^° C for 60 minutes. Then 0.50 g of (R) -mefenesin with [α] is filtered off. $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ +16.3 (c 1.15, hexane-isopropyl alcohol 4: 1), op = 81.8%. 0.50 g of (R, S) -mephenesin is added to the filtrate remaining after separation of the precipitate, the solid component is dissolved at 40 ^° C, cooled to 10 ^° C, and the ground (S) -mephenesin (0.01 g) is seeded, op> 99% and mix the solution at +5 ^o With 60 minutes 0.31 g of (S) -mephenesin with [α] is filtered off. $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -17.1 (c 0.49, hexane-isopropyl alcohol 4: 1), op = 85.5%.

EXAMPLE 6
4.50 g of (R, S) -mephenesin (II) and 0.50 g of (R) -mefenesin are dissolved in 165 ml of water at 60 ^° C and cooled with stirring to 40 ^° C, then finely ground seed of (R) -mephenesin (0.025 g ), op> 99%, cool the solution to 33 ^o C (7 min) and stir the solution for 60 minutes at this temperature. Then 0.86 g of (R) - mefenesin with [α] is filtered off. $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ +17.1 (c 1.15, hexane-isopropyl alcohol 4: 1), op = 87.7% (operation 1 in the table). 0.86 g of (R, S) -mephenesin is added to the filtrate remaining after separation of the precipitate, the solid component is dissolved at 60 ^° C, cooled to 40 ^° C, and the ground (S) -mephenesin (0.025 g) is seeded, op> 99% , cool the solution to 33 ^o C and mix the solution at this temperature for 40 minutes 0.82 g of (S) -mephenesin with [α] is filtered off. $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -16.8 (from 1.10, hexane-isopropyl alcohol 4: 1), op = 86.1% (operation 2 in the table). In the same way, the cycle is repeated several times, adding the missing amount of racemic diol each time. Details are described in the table under steps 3-6.

An increase in the enantiomeric purity of the thus obtained scalemic (R) - and (S) -mephenesin is possible by additional recrystallization from organic or mixed solvents. For example, 0.47 g of (R) -mephenesin (op 81.8%) is dissolved in 7.0 ml of 40% aqueous ethanol at 50 ^° С, then cooled to 20 ^° С, and seed (0.004 g) of (R) -mephenesin (ор> 99%), cooled to 8 ^{° C.} , stirred for 30 minutes, 0.21 g of (R) -mephenesin [α] filtered $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ +18.6 (s 1.0, hexane-isopropyl alcohol 4: 1), op = 95.4%
EXAMPLE 7

0.53 g of (R, S) -guaifenesin (I) and 0.06 g of (S) -guaifenesin are dissolved in 14 ml of a mixture of carbon tetrachloride and methylene chloride 1: 1 at 40 ^o C and cooled with stirring to 25 ^o C, then finely seed (S) -guaifenesin (0.002 g) op = 99.5%) and the solution is stirred for 30 minutes at 20 ^° C. After filtration and drying, 0.08 g of (S) -guaifenesin with [α] is collected $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +7.7 (s 1.0, MeOH), op = 82.3%.

Claims (2)

1. The method of separation of racemic 3- (2-methoxyphenoxy) - or 3- (2methylphenoxy) -1,2-propanediols into enantiomers, namely, that the racemic diol is slightly enriched with one of the enantiomers in a suitable solvent at 40-60 ^{° C.} obtaining a concentrated solution and mix, gradually cooling to 10-40 ^o C, achieving its supersaturation, after which the crystal is seeded with the same enantiomer, which was added for enrichment, kept under stirring at a crystallization temperature in the range of 5-33 ^o C for 30- 60 min, filter A solid precipitate of a scalemic diol is formed having the same configuration as the seed sample, then the racemic compound in an amount compensating the separated precipitate is added to the mother liquor enriched with the second enantiomer, heated to complete dissolution at 40-60 ^° C, then cooled to 10-40 ^o C, seeded with crystalline contribute predominant enantiomer in solution, kept under stirring at a temperature of crystallization in the range 5-33 ^o C, the precipitate is isolated, enriched in the second enantiomer with subsequent repeating the above process several times.  2. The method according to p. 1, characterized in that the solvent used is benzene, carbon tetrachloride or a mixture thereof with methylene chloride 1: 1, a 40% aqueous solution of ethanol, water.

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