KR100408122B1 - Manufacturing method of β-adrenergic antagonists having the characteristic of optical stereoisomers - Google Patents

Abstract

The present invention relates to a method for preparing a beta adrenergic antagonist having the properties of optical stereoisomers, by treating aryl alcohol of general formula (2) with a strong base and adding epichlorohydrin to obtain an epoxy compound of general formula (3) , By adding amines of formula (4) to the epoxy compound of formula (3) and stirring under a certain temperature to improve the production yield and obtain a high purity beta adrenergic antagonist, characterized in that the properties of the optical stereoisomer It relates to a method for producing a beta adrenergic antagonist of the general formula (1) having a.

Description

Manufacturing method of beta-adrenergic antagonists having the characteristic of optical stereoisomers

The present invention relates to a method for preparing a beta adrenergic antagonist having the properties of optical stereoisomers, and more specifically, to treating aryl alcohol of general formula (2) with a strong base and adding epichlorohydrin to general formula (3) After the epoxy compound is obtained, the amines of the general formula (4) are added to the epoxy compound of the general formula (3) and stirred under a constant temperature to improve the production yield and obtain a high purity beta adrenergic antagonist. A method for producing a beta adrenergic antagonist of the general formula (1) having the properties of optical stereoisomers. <Formula 2> ArOH <Formula 3> RH _{2 In} General Formulas (1) to (4), Ar is a substituted phenyl group represented by General Formula (5) and Formulas (1) to (7), and R is iso It is a propyl group or t-butyl group. Wherein R ₂ is hydrogen or an acetyl group, R ₃ is hydrogen, butaneamido, carbamoylmethyl, cyclopropylmethoxyethyl, methoxycarbonylethyl, methoxyethyl, 2-hydroxyethyl, 2-hydroxy Rockcarbonylmethyl or isopropoxyethoxymethyl. <Formula 2> <Formula 3> <Formula 4> <Formula 5> <Formula 6> <Formula 7> In particular, in general formula (1), when Ar is formula 1 or 2, R is an isopropyl group, and when Ar is general formula 3-7, R is a t-butyl group. Generally, the beta adrenergic antagonist is an adrenaline of the heart. Mechanisms such as inhibiting endogenous catecholamines in the nerve area, central effects of reducing sympathetic ejection output in the peripheral area, and inhibiting renin activity have been introduced. The effects of beta adrenergic antagonists in the treatment of angina are known to have an effect on reducing the oxygen demand of the heart, which reduces the rate of heart rate, blood pressure and myocardial contraction.

These beta adrenergic antagonists have optical stereoisomers as the absent carbon is present at position 2. The efficacy of these compounds is known to vary significantly depending on the optical stereoisomer. It is known that (S) -optical stereoisomers have an effect while (R) -optical stereoisomers are very weak. For example, metoprolol is a complex of optical stereoisomers and is called a racemic body. The optical stereoisomers of metoprolol have very different effects in physiological systems: the (S) -optical stereoisomers exhibit activity while the (R) -optical stereoisomers have no or less activity. In practice, (S) -enantiomers have been reported to exhibit about 33 times the effect of (R) -enantiomers in the heart (Nathansson, et al., J. Pharmacol. Exp. Ther., 245, 1, 94 -101, 1988).

Metoprolol is eliminated through hepatic metabolism mainly by oxidative deamination and O-dialkylation and fatty hydroxylation (Chiu, et al., J. Chromatogr. B., 696,69-74

, 1997; Borg, et al., Acta Pharmacol. Toxicol., 36, 125-135, 1075; Johnsson, e

t al., Clin. Pharmacokinet., 1, 4, 233-263, 1976). Since metoprolol has various metabolites in the body, it is important to determine their major metabolites and enantiomers in measuring their pharmacokinetic aspects (Murthy, et al., Biochem.

Pharmacol., 40, 1637-1644, 1990; Li, et al., J. Chromatogr. B., 668, 1, 67-75,

1995).

Therefore, the selective preparation of optical stereoisomers of these beta adrenergic antagonists is of great importance for enhancing drug efficacy and pharmacokinetic studies of these compounds. Selective synthesis of optical stereoisomers of such beta adrenergic antagonists has already been reported. For example, asymmetric synthesis of metoprolol (Gurjar, et al., Heterocycles, 48,1471-6, 1988), fluorinated metoprolol synthesis method (Iseki, et al., Bioorganic medicinalchem. Letters, 7, 1273-4, 1997 ) And so on.

On the other hand, as a method for producing another beta adrenergic antagonist, using a microorganism of U.S. Patent No. 4,956,284, the 3- (2-methoxyethyl) phenyl allyl ether is converted to 4- (2-methoxyethyl) phenyl glycidyl ether. A method for synthesizing (S) -metoprolol through selective epoxylation has been proposed, and is also separate from (S) -5-hydroxymethyl-3-isopropyloxazolidin-2-one of US Pat. No. 5,034,535. Obtained by reacting ((S) -5-hydroxymethyl-3-isopropyloxazolidin-2-one) with 4- (2-methoxyethyl) phenol (4- [2-methoxyethyl] phenol) A method for synthesizing (S) -metoprolol via intermediates has been proposed.

However, among the various conventional methods for synthesizing beta adrenergic antagonists as described above, there are asymmetric synthesis methods of metoprolol and fluoromethoproteol synthesis methods, but these methods require five or more experiments, and the overall yield and enantiometric yield are relatively high. There is a low disadvantage.

In addition, using microorganisms of U.S. Patent No. 4,956,284, (S) through stereoselective epoxylation of 4- (2-methoxyethyl) phenyl allyl ether to 4- (2-methoxyethyl) phenyl glycidyl ether -Method for synthesizing metoprolol and the intermediate obtained by reacting (S) -5-hydroxymethyl-3-isopropyloxazolidin-2-one with 4- (2-methoxyethyl) phenol of US Pat. No. 5,034,535. The method of synthesizing (S) -methoprolol through has caused a rise in manufacturing cost due to a complicated manufacturing process, which has not been commercialized until now.

Accordingly, the object of the present invention is to solve the problems of the conventional method of synthesizing beta adrenergic antagonist, which is difficult to commercialize due to its low yield and purity, as well as its complicated manufacturing process, as described above. Aryl alcohol was treated with a strong base, epichlorohydrin was added to obtain an epoxy compound of the general formula (3), and then amines of the general formula (4) were added to the epoxy compound of the general formula (3), followed by stirring at a constant temperature. It is to provide a method for producing a beta adrenergic antagonist of the general formula (1) having the properties of the optical stereoisomer, characterized in that to improve the production yield and obtain a high purity beta adrenergic antagonist.

In order to achieve the above object, a method for preparing a beta adrenergic antagonist having the properties of the optical stereoisomer of the present invention is a 3-aryloxy-2-hydroxy-1-alkylaminopropane derivative (General Formula 1) used as a beta adrenergic antagonist. The optical stereoisomer of 3-aryloxy-2-hydroxy-1-alkylaminopropane) can be selectively prepared, and the aryl alcohol of the formula (2) is treated with a strong base in a solvent as described in Scheme 1 below. And condensation with (S)-or (R) -epichlorohydrin to yield (R)-or (S) -3- [4- (substituted) aryloxy] -1,2-epoxypropane of formula (3). The amines of the general formula (4) were added to (R)-or (S) -3- [4- (substituted) aryloxy] -1,2-epoxypropane of general formula (3), and the mixture was stirred under a constant temperature. Optical stereoisomerization of (R)-or (S) -3-aryloxy-2-hydroxy-1-alkylaminopropane derivatives (formula 1) Jilche and selective production of the optical stereoisomers of acceptable acid addition salts with pharmaceutically. In the above scheme, Ar and R are as described above.

The present invention provides a method for the selective synthesis of optical stereoisomers which are (S)-or (R) -enantiomers of the compounds of the beta adrenergic antagonist Formula 1 and their metabolites as shown in Scheme 2 in a simple but high yield. To present.

Example 1 Preparation of 3- [4- (2-methoxyethyl) phenoxy] -1,2-epoxypropane 0.5 g of 4- (2-methoxyethyl) phenol was dissolved in 5 ml of methanol, and 0.14 g of sodium hydroxide. Was added and stirred at room temperature for 20 minutes. 0.26 ml of (R) -epichlorohydrin was added to the reaction mixture, which was stirred at room temperature for 12 hours, followed by 20 ml of distilled water, and the mixture was extracted three times with 20 ml of chloroform. After filtration it was evaporated in vacuo. The residue was purified by column chromatography on silica gel using chloroform: methanol (20: 1, v / v) as eluent, and the pure fractions were collected and the eluent was evaporated to give a pale brown liquid 3- [4- (2 0.36 g (51.5%) of -methoxyethyl) phenoxy] -1,2-epoxy] propane was obtained.

¹ H-NMR (CDCl ₃ ): δ 2.74 (4H, m), 3.35 (3H, s), 3.56 (2H, t, J = 7.2 Hz), 3.90 (3H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz)

Example 2 Preparation of (S) -Metoprolol 0.2 g of 3- [4- (2-methoxyethyl) phenoxy] -1,2-epoxypropane obtained in Example 1 was added with 5 ml of methanol and 2 ml of isopropylamine. The mixture was stirred at 60-65 ° C. for 20 minutes, then the solvent was dried and the residue was dried in vacuo to give (S) -1- [4- (2-methoxyethyl) phenoxy] -3- [ 0.25 g (98%) of (1-methylethyl) amino] -2-propanol were obtained.

Melting point: 39-40 ⁰ C; ee = 97.2%,

[α] _D ²⁶ = -8.70 (c, 10.0, CHCl ₃ )

IR (KBr): 3270, 3100 cm ^-1

¹ H-NMR (CDCl ₃ ): δ 1.08 (6H, d, J = 6.3 Hz), 2.80 (5H, m), 3.35 (3H, s), 3.56 (2H, t, J = 7.2 Hz), 3.99 ( 3H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz)

MS m / z (rel. Intensity): 267 (M +, 30), 252 (41), 223 (100), 107 (45)

Anal. Calcd. for C ₁₅ H ₂₅ NO ₃ : C 67.38, H 9.42, N 5.24

Found C 68.11, H 9.98, N 5.11.

Example 3 Preparation of (R) -Methoprolol 3- [4- (2-methoxyethyl) phenoxyl obtained using (S) -epichlorohydrin instead of (R) -epichlorohydrin in Example 1 ] 0.2 g of 1,2-epoxypropane and 5 ml of methanol and 2 ml of isopropylamine were stirred at 60-65 ° C. for 20 minutes, and then the solvent was dried and the residue was dried in vacuo to give a white powder of (R). 0.25 g (94.4%) of -1- [4- (2-methoxyethyl) phenoxy] -3-[(1-methylethyl) amino] -2-propanol were obtained.

Melting point: 39-40 ⁰ C; ee = 94.4%,

[α] _D ²⁶ = +8.70 (c, 10.0, CHCl ₃ )

IR (KBr): 3270, 3100 cm ^-1

¹ H-NMR (CDCl ₃ ): δ 1.08 (6H, d, J = 6.3 Hz), 2.80 (5H, m), 3.35 (3H, s), 3.56 (2H, t, J = 7.2 Hz), 3.99 ( 3H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz)

MS m / z (rel. Intensity): 267 (M +, 30), 252 (41), 223 (100), 107 (45)

Anal. Calcd. for C ₁₅ H ₂₅ NO ₃ : C 67.38, H 9.42, N 5.24

Found C 68.11, H 9.98, N 5.11.

Example 4 Preparation of (S) -O-Dimethylmetoprolol

0.5 g of 4- (2-hydroxyethyl) phenol was dissolved in 5 ml of methanol, 0.145 g of sodium hydroxide was added, followed by stirring at room temperature for 20 minutes. 0.28 ml of (R) -epichlorohydrin was added to the reaction mixture, stirred at 60-65 ° C. for 45 minutes, followed by 20 ml of distilled water. The reaction mixture was extracted three times with 20 ml of chloroform, and then dried by adding sodium sulfate to the obtained organic layer. , Filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using hexanes: ethyl acetate (2: 1, v / v) as eluent. The pure fractions were combined and the eluent was evaporated to yield 0.32 g (47.2%) of 2- [4- (2,3-epoxy) propoxyphenyl] ethanol as white powder.

¹ H-NMR (CDCl ₃ ) δ 2.74 (4H, m), 3.90 (5H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz).

A mixture of 2- [4- (2,3-epoxy) propoxyphenyl] ethanol, 5 ml of methanol, and 2 ml of isopropylamine obtained above was stirred at 60-65 DEG C for 20 minutes, then the solvent was dried and the residue was dried in vacuo. This gave 0.12 g (94%) of (S) -2- [4- (2-hydroxy-3-isopropylamino) propoxyphenyl] ethanol as a white powder.

Melting point: 91-93 ⁰ C; ee = 93.5%,

[α] _D ²⁵ = -7.80 (c, 10.0, CHCl ₃ )

IR (KBr): 3400, 2950 cm ^-1

¹ H-NMR (CDCl ₃ ): δ 1.08 (6H, d, J = 6.3 Hz), 2.80 (5H, m), 3.99 (5H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 ( 2H, d, J = 9.0 Hz)

MS m / z (rel. Intensity): 253 (M +, 19), 209 (15), 107 (100) Anal. Calcd. for C ₁₄ H ₂₃ NO ₃ : C 66.37, H 9.15, N 5.53 Found C 66.51, H 9.60, N 5.33.

Example 5 Preparation of (R) -O-Dimethylmetoprolol 0.5 g of 4- (2-hydroxyethyl) phenol was dissolved in 5 ml of methanol, 0.145 g of sodium hydroxide was added, followed by stirring at room temperature for 20 minutes. 0.28 ml of (S) -epiclohydrin was added to the reaction mixture, stirred at 60-65 ° C. for 45 minutes, followed by 20 ml of distilled water. The reaction mixture was extracted three times with 20 ml of chloroform, and then dried by adding sodium sulfate to the obtained organic layer. , Filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using hexane: ethyl acetate (2: 1, v / v) as eluent to collect pure fractions and eluent to evaporate the white powder of 2- [4- (2, 0.32 g (47.2%) of 3-epoxy) propoxyphenyl] ethanol was obtained.

1 H-NMR (CDCl ₃ ): δ 2.74 (4H, m), 3.90 (5H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz).

The resulting mixture of 2- [4- (2,3-epoxy) propoxyphenyl] ethanol, 5 ml of methanol, and 2 ml of isopropylamine was stirred at 60-65 ° C. for 20 minutes, and then the solvent was dried and the residue was dried in vacuo. 0.12 g (93.6%) of (R) -2- [4- (2-hydroxy-3-isopropylamino) propoxyphenyl] ethanol of white powder was obtained.

Melting point: 91-93 ⁰ C; ee = 93.5%,

[α] _D ²⁵ = +7.80 (c, 10.0, CHCl ₃ )

IR (KBr): 3400, 2950 cm ^-1

¹ H-NMR (CDCl ₃ ): δ 1.08 (6H, d, J = 6.3 Hz), 2.80 (5H, m), 3.99 (5H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 ( 2H, d, J = 9.0 Hz)

MS m / z (rel. Intensity): 253 (M +, 19), 209 (15), 107 (100) Anal. Calcd. for C ₁₄ H ₂₃ NO ₃ : C 66.37, H 9.15, N 5.53 Found C 66.51, H 9.60, N 5.33.

Example 6 Preparation of Potassium (S) -4- (2-hydroxy-3-isopropylamino) propoxyphenyl acetate 1.03 g of methyl-4-hydroxyphenyl acetate and 0.245 g of sodium hydroxide were added to 5 ml of methanol. Stir at room temperature for 20 minutes. 0.485 ml of (R) -epichlorohydrin was added to the reaction solution, and the mixture was refluxed for 90 minutes. The reaction mixture was evaporated in vacuo, the residue was diluted with 20 ml of distilled water, extracted 20 times with 20 ml of chloroform, and then dried over sodium sulfate to the obtained organic layer, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using chloroform: methanol (20: 1, v / v) as eluent to collect pure fractions and eluent to evaporate the liquid methyl-4- (2,3-epoxy). 0.64 g (46.5%) of propoxyphenyl acetate was obtained.

¹ H-NMR (CDCl ₃ ): δ 2.78 (2H, m), 3.59 (2H, s), 3.64 (3H, s), 4.02 (3H, m), 6.85 (2H, d, J = 9.0 Hz), 7.14 (2H, doublet, J = 9.0 Hz).

A mixed solution of 0.64 g of methyl 4- (2,3-epoxy) propoxyphenyl acetate, 5 ml of methanol, and 1.5 ml of isopropylamine was stirred at 60-65 ° C. for 20 minutes, and then the solvent was dried and the residue was diluted with dichloromethane: methanol (20 : 1, v / v) was purified by column chromatography on silica gel using eluent to dissolve 0.7 g (86.5%) of methyl 4- (2-hydroxy-3-isopropylamino) propoxyphenyl acetate as a yellow liquid. Obtained.

¹ H-NMR (CDCl ₃ ): δ 1.19 (6H, d, J = 6.3 Hz), 2.94 (3H, m), 3.56 (2H, s), 3.68 (3H, s), 4.06 (3H, m), 6.87 (2H, doublet, J = 9.0 Hz), 7.18 (2H, doublet, J = 9.0 Hz).

0.7 g of methyl 4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate (3c) was added to methanol: distilled water (1: 1, v / v), and 0.138 g of potassium hydroxide was added thereto for 2 hours. Stirred. The reaction solution was filtered, and the filtrate was dried in vacuo and purified by column chromatography on silica gel using methanol: distilled water (10: 1, 5: 1, 100: 0, v / v) as eluent to obtain white powder of potassium. 0.64 g (85.4%) of (S) -4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate was obtained.

Melting point: 182-184 ⁰ C; ee = 91.1%

[α] _D ²³ = -13.3 (c, 2.0, CH ₃ OH: H ₂ O = 1: 1)

IR (KBr): 3400, 3210, 1550 cm ^-1

¹ H-NMR (CD ₃ OD): δ 1.05 (6H, d, J = 6.3 Hz), 2.75 (3H, m), 3.36 (2H, s), 4.00 (3H, m), 6.87 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz)

MS m / z (rel. Intensity): 267 (M +, 15), 223 (100), 107 (98) Anal. Calcd. for C ₁₄ H ₂₀ NO ₄ K: C 55.06, H 6.60, N 4.59 Found C 55.84, H 6.60, N 4.59.

Example 7 Preparation of Potassium (R) -4- (2-hydroxy-3-isopropylamino) propoxyphenyl acetate In the same manner as in Example 6, (S) -Epi instead of (R) -Epichlorohydrin Prepared using chlorohydrin.

Melting point: 182-184 ⁰ C; ee = 91.1%

[α] _D ²³ = +13.3 (c, 2.0, CH ₃ OH: H ₂ O = 1: 1)

IR (KBr): 3400, 3210, 1550 cm ^-1

¹ H-NMR (CD ₃ OD): δ 1.05 (6H, d, J = 6.3 Hz), 2.75 (3H, m), 3.36 (2H, s), 4.00 (3H, m), 6.07 (2H, d, J = 9.0Hz), 7.18 (2H, d, J = 9.0Hz)

MS m / z (rel. Intensity): 267 (M +, 15), 223 (100), 107 (98) Anal. Calcd. for C ₁₄ H ₂₀ NO ₄ K: C 55.06, H 6.60, N 4.59 Found C 55.84, H 6.60, N 4.59. Example 8 Preparation of (S) -1- [4- (carbamoylmethyl) phenoxy] -2,3-epoxypropane

0.5 g of 4-hydroxyphenylacetamide was dissolved in 5 ml of methanol, 0.14 g of sodium hydroxide was added, followed by stirring at room temperature for 20 minutes. 0.26 ml of (R) -epichlorohydrin was added to the reaction mixture, which was stirred at room temperature for 12 hours, followed by 20 ml of distilled water. The mixture was extracted three times with 20 ml of chloroform, and then dried by adding sodium sulfate to the obtained organic layer. Then vacuum evaporated. The residue was purified by column chromatography on silica gel using chloroform: methanol (20: 1, v / v) as eluent, and then pure fractions were collected and the eluent was evaporated to afford (S) -1- [4. 0.6 g (87.8%) of-(carbamoylmethyl) phenoxy] -2,3-epoxypropane were obtained.

Melting point: 167-169 ⁰ C; ee = 99.1%

[α] _D ²¹ = +10.9 (c, 0.5, CH ₃ OH)

¹ H-NMR (DMSO-d6): δ 2.69 (1 H, m), 2.83 (1 H, dt), 3.29 (1 H, s), 3.33 (1 H, m) 3.80 (1 H, ddd), 4.29 (1 H, ddd), 6.82 (1H, brs), 6.89 (2H, d), 7.17 (2H, d), 7.39 (1H, brs)

Example 9 Preparation of (S) -Athenolol 0.2 g of (S) -1- [4- (carbamoylmethyl) phenoxy] -2,3-epoxypropane obtained in Example 8 was dissolved in 5 ml of methanol and isopropylamine. After 2 ml of the mixture was stirred at 60-65 ° C. for 20 minutes, the solvent was dried and the residue was dried in vacuo to yield 0.25 g (97%) of (S) -atenolol as a white powder.

Melting Point: 153-154 ⁰ C

[a] _D ²¹ = -17.3 (c, 1.0, 1N HCl)

¹ H-NMR (DMSO-d6): δ 0.99 (6H, d), 2.60-2.75 (2H, m), 3.28 (2H, s), 3.30-3.40 (1H, m), 3.77-3.96 (3H, m ), 6.80 (1H, brs), 6.86 (2H, d), 7.17 (2H, d), 7.37 (1H, brs)

Example 10 Preparation of (S) -4- (2,3-epoxypropoxy) indole 0.5 g of 4-hydroxyindole was dissolved in 5 ml of methanol, 0.14 g of sodium hydroxide was added, followed by stirring at room temperature for 20 minutes. 0.26 ml of (R) -epichlorohydrin was added to the reaction mixture, which was stirred at room temperature for 12 hours, followed by 20 ml of distilled water. The mixture was extracted three times with 20 ml of chloroform, and then dried by adding sodium sulfate to the obtained organic layer. Then vacuum evaporated. The residue was purified by column chromatography on silica gel using chloroform: methanol (20: 1, v / v) as eluent, and then pure fractions were collected and the eluent was evaporated to give a colorless liquid (S) -4- (2). 0.67 g (94.1%) of, 3-epoxypropoxy) indole was obtained.

[α] _D ²⁴ = +28.2 (c, 0.5, CH ₃ OH)

¹ H-NMR (CDCl ₃ ): δ 2.66 (1 H, dd), 2.77 (1 H, t), 3.27-3.33 (1 H, m), 3.94 (1 H, dd),

4.22 (1H, dd), 6.38 (1H, d), 6.55-6.57 (1H, m), 6.84-7.00 (3H, m), 8.20 (1H, brs) Example 11 Preparation of (S) -pindolol After mixing 0.2 g of (S) -4- (2,3-epoxypropoxy) indole obtained in Example 10 with a mixture of 5 ml of methanol and 2 ml of isopropylamine for 20 minutes at 60-65 ° C, the solvent was dried and the residue was left. The water was dried in vacuo to yield 0.26 g (99%) of (S) -pindolol as a white powder.

Melting Point: 171-173 ⁰ C

[α] _D ²⁴ = -4.5 (c, 0.5, CH ₃ OH)

¹ H-NMR (CDCl ₃ ): δ 1.08 (6H, d), 2.57 (2H, brs), 2.78-2.95 (3H, m), 4.08-4.15 (3H, m), 6.50 (1H, dd), 6.63 (1H, d), 6.98-7.10 (3H, m), 8.52 (1H, brs)

Experimental Example: Measurement of Optical Purity In order to measure the optical purity of the general formula 1 enantiomer, it was dissolved in 0.1 mg / ml of methanol and analyzed by high-performance liquid chromatography using a chiral column. Entry No. Chiralcel OD (4.6 × 250 mm, 5 μm) column for separating enantiomers of 1 and 2, n-hexane: ethanol: 2-propanol: diethylamine (88: 6: 6: 0.25, v as mobile phase / v) was used. Entry No. Sumychiral OA (4.6 × 250 mm, 5 μm) column, n-hexane: dichloromethane: trifluoroacetic acid (24: 60: 2, v / v) was used as a mobile phase to separate the enantiomer of 3. It was. The flow rate was 1.0 ml / min, the detector was UV 276 nm, and the optical purity was calculated by obtaining the respective peak areas. Table 1 below shows the specific optical rotations and optical purity of Examples 2, 3, 4, 5, 6, and 7.

entry No compound [α] _D ^{1 」} % ee ^{2 」} S R S R One Product of Examples 2 and 3 -8.70 +8.70 99.8 97.2 2 Product of Examples 4 and 5 -7.80 +7.80 96.8 96.8 3 Product of Examples 6 and 7 -13.30 +13.30 91.1 91.1

Note 1: [α] _D ²⁶ of entry No. 1, [α] _D ²⁵ of entry No. 2, and [α] _D ²³ of entry No. 3 are average values of three measurements.

2: Optical purity (% ee) is the value measured by HPLC.

As apparent from the above description, according to the method for producing a beta adrenergic antagonist having the properties of the optical stereoisomer of the present invention, aryl alcohol is treated with a strong base and epichlorohydrin is added to obtain an epoxy compound. By adding amines to the compound and stirring under a certain temperature, it provides useful effects such as high production yield and high purity of the product, and high quality beta adrenergic antagonist with a simple manufacturing process.

Claims (5)

Treating the aryl alcohol of the formula (2) with a strong base and adding epichlorohydrin to obtain an epoxy chemical of the general formula (3), and then add amines of the general formula (4) to the epoxy compound of the general formula (3) Method of producing a beta adrenergic antagonist of the general formula (1) having the properties of the optical stereoisomer, characterized by improving the production yield and obtaining a high purity beta adrenergic antagonist by stirring under a constant temperature. <Formula 1> <Formula 2> ArOH <Formula 3> <Formula 4> RNH ₂ In the general formulas (1) to (4), Ar is a substituted phenyl group represented by general formula (5) and general formula (1) to general formula (7), and R is isopropyl group or t-butyl group to be. <Formula 5> Wherein R ₂ is hydrogen or an acetyl group, R ₃ is hydrogen, butaneamido, carbamoylmethyl, cyclopropylmethoxyethyl, methoxycarbonylethyl, methoxyethyl, 2-hydroxyethyl, 2-hydroxy Rockcarbonylmethyl or isopropoxyoxymethyl. <Formula 1> <Formula 2> <Formula 3> <Formula 4> <Formula 5> <Formula 6> <Formula 7> In particular, when Ar is general formula (1) or (1), R is an isopropyl group, and when Ar is general formula 3-7, R is a t-butyl group. The method for producing a beta adrenergic antagonist of the general formula (1) according to claim 1, wherein the solvent is an aprotic, characterized by using sodium amide, sodium hydride or potassium hydride as a strong base. . The beta adrenergic antagonist of the general formula (1) according to claim 1, wherein the strong base uses potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide or potassium t-butoxide. Method of preparation. The method for producing a beta adrenergic antagonist of the general formula (1) according to claim 1, wherein the optical stereoisomer has a purity of 96% or more. The method of claim 1, wherein the beta adrenergic antagonist produced is bunolol, carteolol, metipranolol, nadolol, nadolo-1, fenbutolol penbutolol, pindolol, timolol, timolol, meto-prolol, bisprolol, bisprolol, esmolol, acebutolol, atenolol, aroti Norolol, propranolol, betasolol, labetolol, oxprenolol, carve-dilol, celiprolol, cetamolol , Cycloprolol, cicloprolo-l, bucindolol, adaprolol, adaprolol, mepindolol, mepandolol, epinolol, esprolol, landiolol, and nabivolol (nebivolol), ridazolol (ridazolol), sotalol (sotalol), talinolol, tertatolol (tert- Method for producing a beta adrenergic antagonist of the general formula (1) having the properties of optical stereoisomers, characterized in that any one of atolol), thienoxolol (tilisoxo) or tilisolol (tilisolol).