RU2396247C2 - Method of separating 1-carbamoyloxy-2-hydroxy-3-(2-methoxyphenoxy)propane into enantiomers - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry of organic compounds, namely, to method of division into separate enantiomers of racemic 1-carbamoyloxy-2-hydroxy-3-(2-methoxyphenoxy)propane

and lies in the following: at 50-55°C saturated water solution of racemic 1-carbamoyloxy-2-hydroxy-3-(2-methoxyphenoxy)propane, enriched with one of enentiomers, is prepared, mixed with gradual cooling to room temperature, achieving its supersaturation, after that crystalline seeding of the same enantiomer, which is added for enrichment, is introduced, kept while mixing and thermostating until maximal value of enantiomer excess of mother liquor is reached, scalemic 1-carbamoyloxy-2-hydroxy-3-(2-methoxyphenoxy)propane, possessing the same configuration as the sample of introduced seeding, is filtered; racemic compound is added into mother liquor, enriched with the second enantiomer, in amount that compensates separated sediment, heated to complete dissolution at 50-55°C, after that cooled to room temperature ensuring supersaturation, crystalline seeding of prevailing in solution enantiomer is introduced, kept while mixing and thermostating, sediment, enriched with the second enantiomer is separated with further repetition of said process for several times, with thorough analysis of enantiomer purity of target compound.

EFFECT: ensuring possibility to obtain enantiomers of methocarbamole (1-carbamoyloxy-2-hydroxy-3-(2-methoxyphenoxy)propane) of high optic purity from racemic mixture.

1 cl, 3 ex, 2 tbl

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 1-carbamoyloxy-2-hydroxy-3- (2-methoxyphenoxy) propane. The invention can be used in the pharmaceutical industry for the production of non-racemic drugs.

The test compound of formula (1) is registered as a drug substance metocarbamol (international name "Methocarbamol") in racemic form and is mainly used as a skeletal muscle relaxant and antispasmodic for diseases and injuries of the musculoskeletal system [Negwer M., Scharnow H.- G. Organic-Chemical Drugs and Their Synonyms. Eighth Edition; Wiley-VCH: Weinheim, 2001, 2900; The Merck Index. 14 ^th ed., Ed. MJ O'Neil, Merck and Co., Inc., Whitehouse Station, NJ, USA; 2006, 5980].

Recent studies have shown that two-thirds of muscle relaxant prescriptions for people with back pain are metocarbamol (along with cyclobenzaprine and carisoprodol) [Luo X., Pietrobon R., Curtis L.H., Hey L.A. Spine 2004, 29, E531-537]. Currently, methocarbamol is used as a racemate, although experiments in mice have shown that the activity of the racemic and pure (R) -1 enantiomers are different, while the (R) -isomer exhibits greater physiological activity than the racemic or (S) -metocarbamol [Souri E., Sharifzadeh M., Farsam N., Gharavi NJ Pharm. Pharmacol 1999, 51, 853-855]. Since the enantiomers of metocarbamol have different biological activity, it is advisable to use individual enantiomers separately. In addition, bearing in mind the general tendency to replace racemic drugs with their enantiopure analogues [Murakami N. From racemates to single enantiomers - chiral synthetic drugs over the last 20 years. Top Curr. Chem. 2007, 269, 273-299], the urgent task of replacing the racemic substance of metocarbamol with an individual (R) enantiomer.

Three general methods for producing non-racemic compounds are known: transformation of the starting enantiopure compounds, enantioselective synthesis, separation of racemic 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, 47, N 27, 4789-4846; Sheldon R.A. Chirotechnology: Industrial Synthesis of Optically Active Compounds. N.Y .: M. Deccer, 1993, 416 pp.]. The resolution of racemic substances into enantiomers by resolution (entrainment) seems to be the most efficient way to separate racemic mixtures [a) Collet A., Jacques J., Brienne M.J. Chem. Rev., 1980, 80, 215-230; b) Jacques J., Collet A., Wilen S.H. Enantiomers, Racemates, and Resolutions, Krieger Publishing Co. Malabar, FL., 1994, 217-368; c) Coquerel G. Preferential crystallization. Top Curr. Chem. 2007, 269, 1-51]. A necessary prerequisite for the separation of the racemic substance into enantiomers by the involvement method is its crystallization from solution in the form of a racemic conglomerate, i.e. a mechanical mixture of individual crystals, each of which is formed by molecules of one enantiomer. By the involvement method, for example, the separation of D, L-threonine [Amiard G. Bull. Soc. Chim. France, 1956, 447], hydrochloride D, L-valine [U.S. Patent 3182079, 1965; Chem. Abstr. 1965, 63, 5740c], salts of racemic glutamic acid [French Patent 1389840, 1965; Chem. Abstr. 1965, 63, 5740f]. The separation of (R, S) -bromosuccinic acid is described [Shiraiwa T., Ohkubo M., Miyazaki H., Kubo M., Nishigawa H., Tsujimoto T., Kurokawa H. Bull. Chem. Soc. Jpn. 1998, 71, 735-739], separation of the racemic phenylethylamine salt with itaconic acid [Bocskey Z., Kassai C., Simon K., Fogassy E., Kozma D.J. Chem. Soc., Perkin Trans. 2. 1996, 1511-1515], separation of diethylamine salt and racemic naproxen [Eur. Patent 298395; Chem. Abstr. 1989, 111, 7085a]. The authors of the application filed previously described the separation of racemic propranolol hydrofluoride [Bredikhin A.A., Bredikhina Z.A., Dieva S.A., Sinyashin O.G. RF patent №2245868, 2005], separation of drugs guaifenesin and mefenesin [Bredikhin A.A., Bredikhina Z.A., Lazarev S.N., Sinyashin O.G. RF patent No. 2213724, 2003].

For the drug methocarbamol (1), a racemate synthesis scheme is described in the literature [Baizer M.M., Clark J.R., Swidinsky J.J. Org. Chem. 1957, 22, 1595-1599] and both enantiomers of methocarbamol (1) [Bredikhin A.A., Bredikhina Z.A., Zakharychev D.V., Pashagin A.V. Tetrahedron: Asymmetry. 2007, 18, 1239-1244]. Racemic guaifenesin (2) is used as the starting compound in the synthesis of the racemate, which, when heated with diethyl carbonate, leads to the formation of cyclic carbonate (3) with the subsequent conversion of the latter to methocarbamol (1) by reaction with ammonia. To obtain enantiopure derivatives (1), the method of spontaneous separation into enantiomers during the crystallization of racemic guaifenesin developed by A. Bredikhin et al. [a) Bredikhin A.A., Bredikhina Z.A., Lazarev S.N., Sinyashin O.G. RF patent No. 2213724, 2003; b) Bredikhina Z.A., Novikova V.G., Zakharychev D.V., Bredikhin A.A. Tetrahedron: Asymmetry, 2006, 17, 3015-3020]. For the enantiopure (S) - and (R) -2 obtained in this way, the entire chain of transformations is repeated with each enantiomer separately, giving respectively (R) - and (S) -l (Scheme 1) [Bredikhin A.A., Bredikhina ZA , Zakharychev DV, Pashagin AV Tetrahedron: Asymmetry. 2007, 18, 1239-1244].

It should be noted that the method with the process of separation of the starting material clearly loses in comparison with the separation of the final product, since enantiopure raw materials are more expensive than racemic and losses are inevitable at two stages of synthesis. Therefore, it is economically feasible, if possible, to carry out the process of separation of the final product obtained in racemic form.

In the work of Bredikhin et al. [Bredikhin A.A., Bredikhina Z.A., Zakharychev D.V., Pashagin A.V. Tetrahedron: Asymmetry. 2007, 18, 1239-1244] for the first time it was shown that metocarbamol crystallizes from solution in the form of a racemic conglomerate, which makes it possible to divide it into enantiomers by the involvement method. Previously, methods based on the phenomenon of spontaneous separation of enantiomers during crystallization for methocarbamol have not been developed, while its ability to crystallize as a conglomerate is a necessary but not sufficient condition for the successful implementation of the preparative separation method. So, in the works of J. Kokurel it is shown that about half of conglomerate-forming compounds demonstrate poor separation efficiency [Coquerel G. Top. Curr. Chem., 2007, 269, 1-51; Dufour F., Perez G., Coquerel G. Bull. Chem. Soc. Jpn. 2004, 77, 79-86].

We are the first to propose a method for the separation of methocarbamol into individual enantiomers by the involvement method. Previously, the non-racemic compound (1) was not obtained in this way. In addition, it was not obvious that the use of the spontaneous separation property would result in a non-racemic compound (1) with high efficiency.

The objective of the invention is the creation of a method that allows you to get the well-known drug metocarbamol in non-racemic form from the racemate by its separation during crystallization by the involvement method.

The technical result - the possibility of obtaining enantiomers of metocarbamol of high optical purity by separation of racemic metocarbamol by the involvement method.

The technical result is achieved in that a saturated aqueous solution of racemic methocarbamol (1), enriched in one of the enantiomers, is prepared at a temperature of 50-55 ° C. The resulting solution was stirred, gradually cooled to room temperature, achieving its supersaturation, and crystalline seed was introduced with the same enantiomer, which was added for enrichment. The solution is kept under stirring and thermostating until the maximum enantiomeric excess of the other enantiomer in the mother liquor is reached. Then the scalemic (enantiophenic) metocarbamol is filtered off, having the same configuration as the seed sample. After separation of the precipitate into the mother liquor, enriched with the opposite enantiomer prevailing in the separated solid precipitate, solid racemic metocarbamol is added in an amount equal to the weight of the precipitate separated in the first stage, and heated to 50-55 ° C. Having reached the complete dissolution of the introduced solid, the solution is cooled, again achieving supersaturation, and the crystal is seeded with the enantiomer prevailing in the solution. The solution is stirred, cooled and the precipitate of the second enantiomer is separated. The described cycle is repeated several times, carefully analyzing the enantiomeric purity and amount of solution and precipitate.

Determination of enantiomeric purity of non-racemic metocarbamol

In the crystallization process, at certain time intervals, an aliquot (10 μl) of the mother liquor filtered through a membrane filter (Millex ^R ) is taken and mixed with 1 ml of water. A portion of 20 μl of the solution was analyzed by HPLC on a Shimadzu LC-20AD chromatograph with a UV spectrophotometric detector at a wavelength of 275 nm. Chiralcel OD-RH steel packing columns (0.46 cm × 15 cm) from Daicel, Inc. are used. Elution is carried out in isocratic mode (eluent: iso-propanol-water, 1: 3) with thermostating (T = 40 ° C). The flow rate of the eluent is 0.4 ml / min; t _R (S) = 9.2 min, t _R (R) = 10.8 min To analyze the solid precipitate, ~ 1 mg of the substance is dissolved in 10 ml of hot water and a portion of 20 μl is analyzed by HPLC. Enantiomeric excess, it is calculated by the formula ee = (RS / R + S) × l00%, where R and S are the content of the corresponding enantiomer in the mixture.

Racemic 1-carbamoyloxy-2-hydroxy-3- (2-methoxyphenoxy) propane [(R, S) -methocarbamol] was used by Sigma-Aldrich. The enantiomers of (R) -methocarbamol and (S) -methocarbamol (its 99%) were obtained according to the method described in [Bredikhin A.A., Bredikhina Z.A., Zakharychev D.V., Pashagin A.V. Tetrahedron: Asymmetry. 2007, 18, 1239-1244].

The inventive method for the separation of racemic methocarbamol into enantiomers is illustrated by the following examples.

EXAMPLE 1

10 g of (R, S) -methocarbamol (1) enriched in (R) -enantiomer are dissolved in 320 ml of water at 50-55 ° С and cooled with stirring to 28 ° С (its substances in solution are 9.2%, solution concentration 3.0 % by weight), then finely ground seeds of (R) -metocarbamol (0.025 g) are added. The solution is cooled to 25.5 ° C, thermostatted and stirred at this temperature, and after 80 minutes from the time of seeding, 2.89 g of (R) -metocarbamol, 60% of it, are filtered off. Its mother liquor is 12.6% (with a predominance of the S-enantiomer). 2.89 g of (R, S) -methocarbamol is added to the filtrate remaining after separation of the precipitate, dissolved at 50-55 ° С, cooled to 28 ° С, and the ground (S) -metocarbamol (0.025 g) is seeded. The solution is cooled to 25.5 ° C, thermostated and stirred at this temperature, and after 70 minutes from the time of seeding, 3.36 g of (S) -methocarbamol, 46%; its mother liquor 7.4% (with a predominance of the R-enantiomer).

EXAMPLE 2

2.76 g of (R, S) -methocarbamol (1) enriched in (R) -enantiomer is dissolved in 115 ml of water at 50-55 ° С, the solution is cooled with stirring to 29 ° С (its solution is 13.4%, concentration 2.3%) and add finely ground seed of (R) -methocarbamol (0.014 g). The solution is cooled to 27.5 ° C, thermostatted and stirred at this temperature, and after 45 minutes from the time of seeding, 0.90 g of (R) -metocarbamol is filtered off, its 72%; its mother liquor 15.6% (S) (operation No. 1 in table 1). 0.90 g of (R, S) -methocarbamol is added to the filtrate remaining after separation of the precipitate, the solid component is dissolved at 50-55 ° С, cooled to 29 ° С, and the ground (S) -metocarbamol (0.014 g) is seeded. Then the solution is cooled to 27 ° C, thermostated and stirred at this temperature, and after 50 minutes from the time of seeding, 0.96 g of (S) -metocarbamol is filtered off, its 50%; its mother liquor 11.5% (R) (operation No. 2 in table 1). In the same way, the cycle is repeated several times, adding the missing amount of racemic metocarbamol each time. Details are described in table 1 for operations No. 3-6.

EXAMPLE 3

8.17 g of (R, S) -methocarbamol (1) enriched in (R) -enantiomer is dissolved in 355 ml of water at 50-55 ° C and cooled with stirring to 29 ° C (its solution is 10.9%, concentration 2.25%), then a finely ground seed of (R) -metocarbamol (0.020 g) is added. The solution is cooled to 27 ° C, thermostated and stirred at this temperature, and after 85 minutes from the moment of seedling, 2.20 g of (R) -metocarbamol is filtered off, its 75.5%; its mother liquor 13.0% (S). Operation No. 1 in table 2.

To the filtrate remaining after separation of the precipitate, add 2.20 g of (R, S) -methocarbamol and dissolve at 50-55 ° С, the solution is cooled to 29 ° С, and the ground (S) -methocarbamol (0.020 g) is seeded. Then the solution is cooled to 27 ° C, thermostated and stirred at this temperature, and after 65 minutes from the moment of seeding, 1.97 g of (S) -metocarbamol is filtered off, its 72%; its mother liquor 8.4% (R) (operation No. 2 in table 2). In the same way, the cycle is repeated several times, adding the missing amount of racemic metocarbamol each time. Details are described in table 2 for operations No. 3-4.

Purification of (R) and (S) -methocarbamol

An increase in the enantiomeric purity of the thus obtained non-racemic samples of (R) and (S) -methocarbamol is possible by additional recrystallization from a suitable solvent, for example ethyl acetate. (R) -methocarbamol (2.20 g, its 75.5%) is dissolved in 28 ml of ethyl acetate at the boil and cooled to 13-15 ° С, 1.83 g of crystals are obtained (yield 83%, 87.9% of it). The resulting precipitate is dissolved by boiling in 35 ml of ethyl acetate and cooled to 13-15 ° C. 1.58 g of crystals are filtered off (yield 87%, 96.5%). The resulting precipitate was again recrystallized from 20 ml of ethyl acetate. Obtain 1.46 g of enantiopure (R) -1: So pl. ° C; her 99.8%; [α] _D ²⁰ = -0.8 (s 1.0, MeOH); lit .: [α] _D ²² = -0.8 (s 1, MeOH) [Demian I. Chirality 1993, 5, 238-240].

By analogy, by recrystallization of the scalemic samples of (S) -metocarbamol, enanti-pure (S) -1 was obtained. For example, 3.82 g of scalemic (S) -methocarbamol (obtained by combining the samples with its 76.7% 1.95 g and 72% 1.77 g) is dissolved by boiling in ethyl acetate (45 ml) and cooled to 13-15 ° C. 3.0 g of colorless crystals are filtered off (yield 80%, 75.5%). After two subsequent recrystallizations, 2.16 g of enantiopure (S) -1 are obtained: mp. 113-114 ° C; its 99.5%. [α] _D ²⁰ = + 0.8 (s 1.1, MeOH); lit .: [α] _D ²² = + 0.5 (s 1, MeOH)) [Demian I. Chirality 1993, 5, 238-240].

The mother liquors obtained after recrystallization are evaporated to the volumes necessary for repeated recrystallization and combined with solutions similar in optical purity obtained from other experiments for carrying out enlarged recrystallizations.

Claims (1)

The method of separation into enantiomers of racemic 1-carbamoyloxy-2-hydroxy-3- (2-methoxyphenoxy) propane, which consists in the fact that:
a saturated aqueous solution of racemic 1-carbamoyloxy-2-hydroxy-3- (2-methoxyphenoxy) propane enriched in one of the enantiomers is prepared at 50-55 ° C, stirred, gradually cooling to room temperature, achieving its supersaturation;
crystalline seed of the same enantiomer is added, which is added for enrichment, kept under stirring and thermostating until the maximum value of the enantiomeric excess of the mother liquor is reached, the scalemic 1-carbamoyloxy-2-hydroxy-3- (2-methoxyphenoxy) propane having the same configuration is filtered off as the sample of the introduced seed;
add to the mother liquor enriched with the second enantiomer, the racemic compound in an amount that compensates for the separated precipitate is heated to complete dissolution at 50-55 ° C, then cooled to room temperature, achieving supersaturation;
they add crystalline seed to the enantiomer prevailing in the solution, stand with stirring and thermostating, and the precipitate enriched in the second enantiomer is separated, followed by repeating this process several times.