RU2245868C2 - Method of separating racemic 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol into enantiomers - Google Patents

Abstract

FIELD: special methods in organic synthesis.

SUBSTANCE: known drug: racemic 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol, briefly called propranolol, is converted into propranolol hydrofluoride, which is dissolved in ethanol at 55-70^оС to form concentrated solution. The latter is gradually cooled to 20-26^оС, after which is added seed of one of enantiomers, solution is stirred for 30-60 min, filtered non-racemic propranolol hydrofluoride enantiomer having the same configuration as the seed previously added. Racemic compound is added to mother liquor in amount compensating separated precipitate, mother liquor is heated at 55-70^оС to entirely dissolve added material and seed of the other enantiomer is added. Subsequent crystallization gives precipitate rich in the other enantiomer and process is several times repeated. Enantiomer purity is then raised by recrystallization. Non-racemic propranolol salts are finally converted into free propranolol enantiomers. Method of invention can be used in pharmaceutical practice.

EFFECT: enabled involvement method-assisted preparation of non-racemic propranolol.

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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- (isopropylamino) -3- (1-naphthyloxy) -2-propanol (1). The invention can be used in the pharmaceutical industry for the production of non-racemic drugs.

The named compound is registered as a substance of the drug propranolol in racemic form. Propranolol, 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol (1),

As a means of regulating cardiovascular activity in humans, it has been known for about half a century (M.D. Mashkovsky. Medicines. Part I.I. M .: Medicine, 1978, P.269; JWBlack, AFCrowther, RGShanks, LH Smith, ACDomhurst, Lancet., 1964, 1, 1080). Currently, propranolol (Merck Index, 12, 8025) by itself and mainly in the form of propranolol hydrochloride (2), under various trade names, is universally used as a non-selective β-blocker with a wide spectrum of action [a) B.G. Main, β-Adrenergic Receptors in Comprehensive Medicinal Chemistry Eds. C. Hansch, P. G. Sammer, J.B. Taylor; Pergamon, Oxford, 1990, 3, 187. b) S.V. Yuzhakov, Chem. - forms. Zh., 1995. 29, 3]. Being the oldest in its class and having a simple chemical structure, propranolol is deeply and variedly studied. It was shown that the different enantiomers of propranolol differ in physiological activity (R. Howe, R. G. Schanks, Nature, 1966, 210, 1336). Subsequently, it turned out that in the case of propranolol, the (S) -isomer acts as the eutomer (the enantiomer causing the desired effect on cardiovascular activity), while the distomer, the (R) -isomer, stimulates the smooth muscles of the uterus and, therefore, is responsible for side effects (A. Barren, VACullum, Brit. J. Pharmacol., 1968, 34, 43). The main trend in modern medical chemistry and the pharmaceutical industry is the replacement, where appropriate, of racemic substances with non-racemic substances (Deutsch DH // Chemtech. 1991. Vol.21. N 3. P.157-159; Stmson SC // Chem. Eng. News . 1998. Vol. 76. N 38. P.83; Aboul-Enem HY Impact of Stereochemistry on Drug Development and Use. NY: Wiley, 1997. 736 pp.). Therefore, in relation to propranolol as a β-blocker, the task of replacing the racemic substance with an individual (S) -enantiomer is relevant. There is also evidence of biological activity for (R) -propranolol: it is a selective adenosine antagonist ((US Patent 5116867, 1992), can be used against sexually transmitted bacteria (US Patent 4988736, 1991; Chem. Abstr. 1991, Vol. 114, 199664v), can be used in contraceptive compositions (US Patent 4795761, 1989; EP Patent 238218, 1988; Chem. Ahstr. 1988, Vol.108, 44055z), its metabolites have antioxidant activity (US Patent 5854287, 1998; Chem. Abstr. 1999, Vol.130, 61083d) Thus, the enantiomers of propranolol have different biological activity, and therefore, to achieve specific Performan expedient use of the individual enantiomers individually.

Three general methods are known for preparing non-racemic compounds.

Firstly, this is a chemical or biochemical transformation of the starting compounds used in an enantiopure form. 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. II Tetrahedron. 1991. Vol.47. N 27. P.4789-4846; Sheldon RA Chirotechnology: Industrial Synthesis of Optically Active Compounds. NY: M. Deccer, 1993. 416 pp.).

Starting from the work (R. Howe, R. G. Schanks, Nature, 1966, 210, 1336), to date, many methods have been described for the preparation of propranolol in enantiopure form. In most cases, the proposed methods are laboratory developments, the scaling of which for industrial production is problematic. Several methods for the separation of racemic propranolol are known. Thus, the biochemical separation of d, l-propranolol is described, for example, using lipase enzymes (esterases) or esterase-producing microorganisms (Jpn. Patent 6394992, 1988; Chem. Abstr. 1989, Vol. 110, 93558. Jpn. Patent 621511, 1987). In addition, biochemical separation methods are often used at the stage preceding the formation of propranolol. For example, the synthesis of enantiopure propranolol is known according to the scheme (H.S.Bevinakatti, A.A. Banerji, J. Org. Chem., 1991, 56, No. 18, 5372-5375). A key step in this synthesis is the enantioselective hydrolysis of propanediol acetate, catalyzed by pancreatic lipases, Pseudomonas cepacia or Candida cylmdracea lipases.

The advantages of the mentioned enzymes include accessibility and relative cheapness, and the disadvantages, and this disadvantage is common to any biocatalysts, are high sensitivity to the conditions of the experiment.

The best known method is the separation of racemates through the formation of auxiliary diastereomers. The mixture of diastereomeric compounds is obtained by treating the racemic substrate with an enantiopure reagent, the so-called cleavage agent. Under certain conditions, either one of the diastereomers or a mixture enriched in one of the diastereomers can be isolated from the resulting mixture of diastereomers under certain conditions. Accordingly, the mother liquor is enriched with the opposite diastereomer. For example, (±) -propranolol forms diastereomeric monoesters with anhydride (R, R) -O, O-diacetyl tartaric acid, which are separated by crystallization or chromatography, then hydrolyzed to form (R) - and (S) -propranolol of satisfactory optical purity ( Ger. Patent 3330005, 1985; Chem. Abstr. 1985, Vol. 103, 178036z). Similarly, separation is performed with dibenzoyl tartaric acid (DDR Patent 247486; Chem, Abstr. 1990, Vol. 112, 55280). An increase in the enantiomeric purity of the resulting propranolol is achieved by recrystallization of its hydrochloride salt. The disadvantage of this method is the need to use auxiliary enantiopure substances, namely derivatives of tartaric acid, which increases the cost of the separation process.

In contrast, methods based on the phenomenon of spontaneous separation of enantiomers during crystallization for propranolol derivatives are not known.

It was found for the first time that racemic propranolol in the form of its salt with HF (3) crystallizes as a racemic conglomerate, and a method for the separation of propranolol into individual enantiomers according to the scheme of selective crystallization of a supersaturated solution of propranolol salt with HF is proposed.

Crystallization of a racemic substance in the form of a conglomerate, i.e. a mechanical mixture of individual crystals, each of which is formed by molecules of the same enantiomer, is a necessary prerequisite for the separation of racemic substances into enantiomers by resolution (entrainment), which is apparently the most effective of the existing methods for the separation of racemic mixtures [a) A.Collet, J. Jacques, M.J. Bnemie, Chem. Rev., 1980, 80, 215-230; b) J. Jacques. A.Collet, S.H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publishing Co. Malabar, FL., 1994. P.217-368]. In this way, for example, the separation of D, L-threonine (Amiard G. II Bull. Soc. Chim. France. 1956. P.447), hydrochloride D, L-valine (US Patent 3182079, 1965; Chem. Abstr. 1965 Vol.63, 5740c), salts of racemic glutamic acid (French Patent 1389840, 1965; Chem. Abstr. 1965. Vol.63, 5740f). The separation of (R, S) -bromosuccinic acid is described (Shiraiwa T., Ohkubo M., Miyazaki H., Kuho M., Nishigawa H., Tsujimoto T., Kurokawa H. // Bull. Chern. Soc. Jpn. 1998. Vol. 71. N 3. P.735-739), separation of the racemic phenylethylamine salt with itaconic acid (Bocskey Z., Kassai C., Simon K., Fogassy E., Kozma D. // J. Chem. Soc., Perkm Trans. 2. 1996. P.1511-1515), separation of diethylamine salt and racemic naproxen (Eur. Patent 298395; Chem. Abstr. 1989, Vol. 111, 7085a).

Previously, the property of spontaneous cleavage during crystallization for the compound (3) was not known, and in this way the non-racemic compound (3) and, accordingly, the non-racemic compound (1) were not obtained. In addition, it was not obvious that the use of this property would result in non-racemic compounds (1) and (3).

The purpose of the invention is the creation of a method that allows you to get the well-known drug propranolol in non-racemic form from cheap racemic substrates by their separation during crystallization by the involvement method.

This goal is achieved in that the racemic propranolol base (1) is reacted with hydrofluoric acid in propranolol hydrofluoride (3) and a concentrated solution of racemic propranolol hydrofluoride in ethanol is prepared at a temperature of 55-70 ° C. The resulting solution is stirred, gradually cooled to 20-26 ° C, achieving its supersaturation and subsequent crystallization by seeding the desired enantiomer. At this temperature, the solution is stirred for 30-60 minutes, then non-racemic propranolol hydrofluoride is filtered off having the same configuration as the seed sample. After separation of the precipitate, solid racemic propranolol hydrofluoride in an amount compensating the separated precipitate is added to the mother liquor enriched with the second enantiomer, and complete dissolution is achieved with stirring at about 55-70 ° C. The solution is gradually cooled to 20-26 ° C, again achieving supersaturation, and the crystal is seeded with the enantiomer predominant in the solution. The solution is stirred at this temperature for 30-60 minutes, the precipitate enriched in the second enantiomer is separated, followed by repeating this process several times and further purifying the recovered enantiomers by recrystallization. From the obtained salts of the non-racemic propranolol hydrofluoride, the non-racemic propranolol base is obtained by neutralization with alkali.

The inventive method for the separation of propranolol is illustrated by the following examples.

Obtaining hydrofluoride (R, S) -propranolol (3).

EXAMPLE 1

13.4 g (0.052 mol) of the racemic propranolol base (1) are dissolved in 95 ml of isopropanol with heating at about 45-50 ° C. 3.0 g of commercial hydrofluoric acid (~ 35%) was added to the resulting solution. The solution was incubated for about a day at room temperature, the precipitate formed was filtered off, washed with isopropanol and dried. 12.3 g of propranolol salt are isolated, yield 85.5%, 1.4 g of salt are additionally isolated by evaporation of the mother liquor (3). Total yield 13.7 g (95%). Mp 151.9-155.5 ° C (decomp.) (Determined by differential scanning calorimetry). Mass spectrum, m / z: 259 (M), C ₁₆ H ₂₁ NO ₂ . Calculated: 259.1572. Found: 259.157; 244 (M-15), C ₁₅ H ₁₈ NO ₂ . Calculated: 244.1338. Found: 244.134. ¹ H NMR spectrum (250 MHz, CD ₃ OH, δ, ppm): 1.37 and 1.39 (two d, 6H, CH ₃ , J 6.5 Hz), 3.19-3.51 (m, 3H, CH ₂ , CH) ; 4.17-4.27 (m, 2H, CH ₂ ), 4.33-4.45 (m, 1H, CH), 6.92-8.29 (m, 7H, naphthyl). IR spectrum (KBr): 3331, 3194 (OH, NH), 2981, 2863, 2706, 2540, 2311 (NH ⁺ ) 1628, 1580, 1510 (Ar).

Separation of hydrofluoride (R, S) -propranolol into enantiomers.

EXAMPLE 2

+19.8 (с 1.0, этанол) и в течение 30 минут перемешивают раствор при этой температуре. После фильтрования, и высушивания собирают 0.32 г гидрофторида (R)-пропранолола с

+6.5 (с 0.69, этанол). К фильтрату, оставшемуся после отделения осадка, добавляют 0.31 г гидрофторида (R,S)-пропранолола, растворяют его при 55-70°С, охлаждают раствор до 22.5°С около 30 мин, вносят затравку гидрофторида (S)-пропранолола (0.01 г),

-19.8 (с 0.89, этанол) и перемешивают раствор при температуре около 22.5°С 30 минут. Отделяют 0.23 г гидрофторида (S)-пропранолола с

-8.0 (с 0.74, этанол). Затем добавляют недостающее количество рацемического гидрофторида пропранолола (0.22 г) и аналогично проводят кристаллизацию внесением затравки (R)-пропранолола гидрофторида с

+17.8 (с 0,94, этанол), перемешивая при температуре 25.5°С 45 минут. Выделяют 0.14 г гидрофторида (R)-пропранолола с

+8.0 (с 0.54, этанол). К маточному раствору вновь добавляют недостающее количество рацемата проводят кристаллизацию внесением 0.01 г затравки с

-15.7 (с 0.54, этанол) и перемешивают при 24.5°С 60 минут. Выделяют 0.080 г гидрофторида (S)-пропранолола с

-8.0 (с 0.55, этанол).1.00 g of (R, S) propranolol hydrofluoride (3) is dissolved in 7.5 ml of rectified ethanol (~ 96%) at 55-70 ° С and cooled with stirring to 20 ° С for about 30 minutes, then the hydrofluoride (R) is seeded. propranolol (0.01 g) s

+19.8 (c 1.0, ethanol) and the solution is stirred for 30 minutes at this temperature. After filtration and drying, 0.32 g of (R) -propranolol hydrofluoride c

+6.5 (s 0.69, ethanol). 0.31 g of (R, S) -propranolol hydrofluoride is added to the filtrate remaining after separation of the precipitate, it is dissolved at 55-70 ° С, the solution is cooled to 22.5 ° С for about 30 minutes, the (S) -propranolol hydrofluoride is introduced (0.01 g ),

-19.8 (s 0.89, ethanol) and mix the solution at a temperature of about 22.5 ° C for 30 minutes. 0.23 g of (S) -propranolol hydrofluoride c

-8.0 (c 0.74, ethanol). The missing amount of racemic propranolol hydrofluoride (0.22 g) is then added and crystallization is likewise carried out by seeding with (R) -propranolol hydrofluoride with

+17.8 (c 0.94, ethanol), stirring at a temperature of 25.5 ° C for 45 minutes. 0.14 g of (R) -propranolol hydrofluoride c

+8.0 (c 0.54, ethanol). To the mother liquor again add the missing amount of the racemate, crystallization is carried out by adding 0.01 g of seed with

-15.7 (c 0.54, ethanol) and stirred at 24.5 ° C for 60 minutes. 0.080 g of (S) -propranolol hydrofluoride c is isolated

-8.0 (c 0.55, ethanol).

EXAMPLE 3

+20.0 (с 0.70, этанол) и в течение 45 минут перемешивают раствор, поддерживая температуру около 25°С. После фильтрования, и высушивания собирают 0.60 г гидрофторида (R)-пропранолола с

+8.0 (с 0.78, этанол). К фильтрату, оставшемуся после отделения осадка добавляют 0.56 г гидрофторида (R,S)-пропранолола, растворяют его при 55-70°С, охлаждают раствор до 25°С около 30 мин, вносят затравку гидрофторида (S)-пропранолола (0.04 г),

-19.5 (с 0.89, этанол) и перемешивают раствор при температуре около 25°С 60 минут. Отделяют 0.56 г гидрофторида (S)-пропранолола с

-9.0 (с 0.75, этанол). Таким же образом цикл повторяют несколько раз, добавляя каждый раз недостающее количество рацемического гидрофторида пропранолола. После 2-го цикла выделено 0.42 г гидрофторида (R)-пропранолола с

+9.6 (с 0.76, этанол) и 0.40 г гидрофторида (S)-пропранолола с

-9.1 (с 0.77, этанол). После 3-го цикла выделено 0.45 г гидрофторида (R)-пропранолола с

+8.0 (с 0.78, этанол) и 0.58 г гидрофторида (S)-пропранолола с

-8.2 (с 0.78, этанол). Цикл повторяют необходимое число раз, контролируя объем и оптическую чистоту кристаллизующихся осадков.4.00 g of (R, S) -propranolol hydrofluoride (3) is dissolved in 32 ml of rectified ethanol at 55-70 ° C and cooled with stirring to 25 ° C for about 30 minutes, then the (R) -propranolol hydrofluoride (0.04 g) is seeded. ) from

+20.0 (c 0.70, ethanol) and stir the solution for 45 minutes, maintaining the temperature at about 25 ° C. After filtration and drying, 0.60 g of (R) -propranolol hydrofluoride c

+8.0 (c 0.78, ethanol). 0.56 g of (R, S) -propranolol hydrofluoride is added to the filtrate remaining after separation of the precipitate, it is dissolved at 55-70 ° С, the solution is cooled to 25 ° С for about 30 min, the (S) -propranolol hydrofluoride is seeded (0.04 g) ,

-19.5 (c 0.89, ethanol) and mix the solution at a temperature of about 25 ° C for 60 minutes. 0.56 g of (S) -propranolol hydrofluoride c

-9.0 (c 0.75, ethanol). In the same way, the cycle is repeated several times, each time adding the missing amount of racemic propranolol hydrofluoride. After the 2nd cycle, 0.42 g of (R) -propranolol hydrofluoride with

+9.6 (s 0.76, ethanol) and 0.40 g of (S) -propranolol hydrofluoride with

-9.1 (c 0.77, ethanol). After the 3rd cycle, 0.45 g of (R) -propranolol hydrofluoride with

+8.0 (s 0.78, ethanol) and 0.58 g of hydrofluoride (S) -propranolol s

-8.2 (c 0.78, ethanol). The cycle is repeated as many times as necessary, controlling the volume and optical purity of crystallizing precipitates.

Purification of hydrofluorides of (R) and (S) -propranolol.

An increase in the enantiomeric purity of the thus obtained non-racemic hydrofluorides of (R) and (S) -propranolol is possible by additional recrystallization from ethanol.

EXAMPLE 4

-8.0 (с 0.78, этанол)) растворяют в 27.5 мл этанола-ректификата при перемешивании и нагревании около 60°С. Раствор охлаждают до 25.5°С и перемешивают при этой температуре 60 мин. После фильтрования и высушивания собирают гидрофторид (S)-пропранолола: выход 2.48 г,

-13.0 (с 0.56, этанол). Полученный осадок вновь растворяют в 20 мл этанола при нагревании около 60°С, охлаждают и перемешивают при 25.5°С около 60 мин и получают 1.66 г гидрофторида (S)-пропранолола

-15.9 (с 0.62, этанол). Полученный осадок растворяют в 13.8 мл этанола при нагревании около 60°С, охлаждают и перемешивают при 25.5°С около 60 мин и получают 1.29 г гидрофторида (S)-пропранолола

-17.6 (с 0.88, этанол). Далее его еще раз аналогично перекристаллизовывают из 10.7 мл этанола и получают 0.80 г гидрофторида (S)-пропранолола

-19.5 (с 0.89, этанол). Маточные растворы, полученные после перекристализаций, упаривают до нужной для повторных перекристаллизации объемов и объединяют с аналогичными по оптической чистоте растворами, полученными из других опытов для проведения укрупненных перекристаллизаций.3.65 g of (S) -propranolol hydrofluoride

-8.0 (c 0.78, ethanol)) is dissolved in 27.5 ml of rectified ethanol with stirring and heating at about 60 ° C. The solution is cooled to 25.5 ° C and stirred at this temperature for 60 minutes. After filtering and drying, (S) -propranolol hydrofluoride is collected: yield 2.48 g,

-13.0 (s 0.56, ethanol). The resulting precipitate was redissolved in 20 ml of ethanol with heating at about 60 ° C, cooled and stirred at 25.5 ° C for about 60 minutes to obtain 1.66 g of (S) -propranolol hydrofluoride

-15.9 (s 0.62, ethanol). The resulting precipitate was dissolved in 13.8 ml of ethanol with heating at about 60 ° C, cooled and stirred at 25.5 ° C for about 60 minutes to obtain 1.29 g of (S) -propranolol hydrofluoride

-17.6 (s 0.88, ethanol). Then it is again recrystallized in a similar manner from 10.7 ml of ethanol to obtain 0.80 g of (S) -propranolol hydrofluoride

-19.5 (s 0.89, ethanol). 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.

EXAMPLE 5

+15.9 (с 1.0, этанол) растворяют в 8.1 мл этанола при нагревании около 60°С. Раствор охлаждают и оставляют на ночь при комнатной температуре. После фильтрования и высушивания собирают 0.647 г гидрофторида (R)-пропранолола,

+17.8 (с 0.96, этанол). Полученный осадок растворяют в 6.0 мл этанола при нагревании около 60°С, охлаждают и оставляют на ночь при комнатной температуре. Отфильтровывают 0.373 г гидрофторида (R)-пропранолола

+19.8 (с 0.92, этанол). Проведя еще одну перекристаллизацию из этанола, получают 0.162 г гидрофторида (S)-пропранолола

+20.9 (с 0.92, этанол). Т.пл. 166.9-172.4°С (с разл.) (определена методом дифференциальной сканирующей калориметрии).0.874 g of hydrofluoride (R) -propranolol s

+15.9 (c 1.0, ethanol) is dissolved in 8.1 ml of ethanol with heating at about 60 ° C. The solution was cooled and left overnight at room temperature. After filtration and drying, 0.647 g of (R) -propranolol hydrofluoride is collected,

+17.8 (c 0.96, ethanol). The resulting precipitate was dissolved in 6.0 ml of ethanol with heating at about 60 ° C, cooled and left overnight at room temperature. 0.373 g of (R) -propranolol hydrofluoride is filtered off

+19.8 (s 0.92, ethanol). After another recrystallization from ethanol, 0.162 g of (S) -propranolol hydrofluoride are obtained.

+20.9 (s 0.92, ethanol). Mp 166.9-172.4 ° C (decomp.) (Determined by differential scanning calorimetry).

(S) -Propranolol base.

EXAMPLE 6

-19.5 (с 0.89, этанол)) растворяют в 6.5 мл теплой воды. К полученному раствору добавляют 1.5 мл 10% раствора NaOH. Смесь экстрагируют хлористым метиленом (общий объем около 120 мл), экстракт промывают водой, сушат над подходящим осушителем, например, MgSО₄. После удаления растворителя получают 0.85 г (91.2%) (S)-пропранолола-основания (т.пл. 73-74°С).1.0 g of (S) -propranolol hydrofluoride (

-19.5 (c 0.89, ethanol)) dissolved in 6.5 ml of warm water. To the resulting solution was added 1.5 ml of a 10% NaOH solution. The mixture is extracted with methylene chloride (total volume of about 120 ml), the extract is washed with water, dried over a suitable desiccant, for example, MgSO ₄ . After removal of the solvent, 0.85 g (91.2%) of (S) -propranolol base (mp. 73-74 ° C.) is obtained.

Determination of enantiomeric purity of non-racemic propranolol hydrofluoride.

Determination of enantiomeric purity of non-racemic propranolol hydrofluoride is carried out by comparing the optical rotation angle of a propranolol hydrochloride sample obtained from hydrofluoride with literature data for propranolol hydrochloride.

EXAMPLE 7

-19.5 (с 0.89, этанол) получают, как описано в примере 6, 0.85 г пропранолола, растворяют его в 4.25 мл изо-пропилового спирта при слабом нагревании и добавляют 0.49 г 35% соляной кислоты. На следующий день осадок отфильтровывают, промывают эфиром и получают 0.90 г гидрохлорида (S)-пропранолола с

-25.8 (с 0.50, ЕtOН), т.пл. 197-199°С. (лит.

-25.5 (с 1.05, этанол), т.пл. 194-196°С [Н.S.Bevmakatti, A.A.Banerji, J. Org. Chem., 1991, 56, 5372]; лит.

=-25.0±1 (с 1.0, этанол) er. S:R≥99:1 (данные ВЭЖХ), [Fluka catalogue for laboratory chemicals, 2001/2002, 1223]. Следовательно, образец гидрофторида пропранолола с

-19.5 (с 0.89, этанол) содержит (S)-энантиомера ≥99%.From 1.00 g of (S) -propranolol hydrofluoride with

-19.5 (c 0.89, ethanol), as described in Example 6, 0.85 g of propranolol are obtained, dissolved in 4.25 ml of isopropyl alcohol with gentle heating, and 0.49 g of 35% hydrochloric acid is added. The next day, the precipitate was filtered off, washed with ether, and 0.90 g of (S) -propranolol hydrochloride was obtained with

-25.8 (s 0.50, EtOH), so pl. 197-199 ° C. (lit.

-25.5 (from 1.05, ethanol), mp 194-196 ° C [H.S. Bevmakatti, AABanerji, J. Org. Chem., 1991, 56, 5372]; lit.

= -25.0 ± 1 (s 1.0, ethanol) er. S: R≥99: 1 (HPLC data), [Fluka catalog for laboratory chemicals, 2001/2002, 1223]. Therefore, a sample of propranolol hydrofluoride with

-19.5 (c 0.89, ethanol) contains (S) -enantiomers ≥99%.

Claims (1)

A method for resolving the enantiomers of racemic 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol, wherein the racemic 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol (propranolol base ) by reaction with hydrofluoric acid, they are transferred to propranolol hydrofluoride, a concentrated solution of it in ethanol rectified is prepared at a temperature of 55-70 ° С and stirring, then the solution is gradually cooled to a temperature of about 20-26 ° С, achieving its supersaturation, after which crystalline enantiose seed, withstand pr and at this temperature and stirring for 30-60 minutes, a solid precipitate of non-racemic propranolol hydrofluoride having the same configuration as the seed sample is filtered off, then racemic propranolol hydrofluoride 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 55-70 ° C and stirring, then cooled to 20-26 ° C, again add the crystal seed to the enantiomer prevailing in the solution, mix at the same time perature of 30-60 minutes, the precipitate is isolated, enriched in the second enantiomer, followed by repeating the above process several times and further purified by recrystallization isolated enantiomers, and for subsequent transfer into isolated enantiomers of propranolol, propranolol base hydrofluoride neutralized with alkali, for example NaOH.