Asymmetrical synthetic method of R-/S-acebutolol

A technology of acebutolol and a synthesis method is applied in the field of asymmetric synthesis of optically pure cardiovascular and cerebrovascular drugs R- or S-acebutolol, and can solve the problems of long reaction steps, high production cost, expensive raw materials and the like, Achieve the effect of few reaction steps, low production cost and expensive raw materials

Inactive Publication Date: 2011-11-16
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to pr...

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  • Asymmetrical synthetic method of R-/S-acebutolol

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Embodiment 1

[0044] Synthesis of R-acebutolol

[0045] (1) Synthesis of N-(4-methoxyphenyl)-butanamide

[0046] In a 250ml reaction vessel, dissolve 5.0g of p-aminoanisole in 30ml of toluene, add 15ml of n-butyric acid, heat to 140°C, and stop the reaction after reflux for 6 hours. The excess solvent and n-butyric acid were distilled off while hot, cooled to room temperature, the solid obtained was washed with petroleum ether, and recrystallized in a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of ethyl acetate and petroleum ether of 1:1. 6.28 g of white crystals were obtained, which was determined to be N-(4-methoxyphenyl)-butyramide by nuclear magnetic resonance (400 MHz nuclear magnetic analyzer from Bruker, Switzerland), yield: 80%.

[0047] Mp.86-87°C.

[0048] 1 H NMR (400MHz, CDCl 3 ): δ=1.02(t, J=7.36Hz, 3H, CH 2 CH 3 ), 1.77 (m, 2H, CH 2 CH 2 ), 2.33(t, J=7.36Hz, 2H, CH 2 CH 2 ), 3.79 (s, 3H, OCH 3 ), 6.86 (d, J=8.92Hz, 2H, C 6 h 4 ), 7.05(s,...

Embodiment 2

[0064] Synthesis of R-acebutolol

[0065] (1) Synthesis of N-(4-methoxyphenyl)-butanamide

[0066] In a 250ml reaction vessel, dissolve 10.0g of p-aminoanisole in 60ml of toluene, add 30ml of n-butyric acid, heat to 150°C for reflux reaction, and stop the reaction after 8 hours. The excess solvent and n-butyric acid were distilled off while hot, cooled to room temperature, the solid obtained was washed with petroleum ether, and recrystallized in a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of ethyl acetate and petroleum ether of 1:1. 13.5 g of white crystals were obtained, which was determined to be N-(4-methoxyphenyl)-butyramide by nuclear magnetic resonance (400 MHz nuclear magnetic analyzer from Bruker, Switzerland), with a yield of 86%.

[0067] Mp.87-88°C.

[0068] 1 H NMR (400MHz, CDCl 3 ): δ=1.02(t, J=7.36Hz, 3H, CH 2 CH 3 ), 1.77 (m, 2H, CH 2 CH 2 ), 2.33(t, J=7.36Hz, 2H, CH 2 CH 2 ), 3.79 (s, 3H, OCH 3 ), 6.86 (d, J=8.92Hz, 2H, C...

Embodiment 3

[0083] Synthesis of R-acebutolol

[0084] (1) Synthesis of N-(4-methoxyphenyl)-butanamide

[0085] In a 250 ml reaction vessel, dissolve 5.0 g of p-aminoanisole in 50 ml of toluene, add 18 ml of n-butyric acid, heat to 130° C., and stop the reaction after reflux for 9 hours. The excess solvent and n-butyric acid were distilled off while hot, cooled to room temperature, the solid obtained was washed with petroleum ether, and recrystallized in a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of ethyl acetate and petroleum ether of 1:1. 6.24 g of white crystals were obtained, which was determined to be N-(4-methoxyphenyl)-butyramide by nuclear magnetic resonance (400 MHz nuclear magnetic analyzer from Bruker, Switzerland), yield: 80%.

[0086] Mp.86-87°C.

[0087] 1 H NMR (400MHz, CDCl 3 ): δ=1.02(t, J=7.36Hz, 3H, CH 2 CH 3 ), 1.77 (m, 2H, CH 2 CH 2 ), 2.33(t, J=7.36Hz, 2H, CH 2 CH 2 ), 3.79 (s, 3H, OCH 3 ), 6.86 (d, J=8.92Hz, 2H, C 6 h 4 ), 7...

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Abstract

The invention relates to an asymmetrical synthetic method of R-/S-acebutolol. The method comprises the following steps of: making a p-aminoanisole solution react with ethyl acetic acid to obtain N-(4-methoxyphenyl)-butyrylamide; mixing a solution of the N-(4-methoxyphenyl)-butyrylamide with Lewis acid, dropwise adding an acylation reagent to obtain a 5-butyramide-2-hydroxyacetophenone solid product, and dissolving the solid product in an inorganic alkali solution; and dropwise adding R-/S-epoxy chloropropane in the presence of a phase transfer catalyst to obtain R-/S-5-butyramide-2-(2,3-glycidoxy)-acetophenone, and making the R-/S-5-butyramide-2-(2,3-glycidoxy)-acetophenone react with isopropylamine in the presence of water to obtain R-/S-acebutolol with high optical purity. According to the method, a small number of steps are performed, the yield of each step is over 74 percent, the total yield is over 48 percent, and proved by OD-H chiral column HPLC (High Performance Liquid Chromatography) analysis, the e.e. value of a product is up to 94 percent in maximum.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to an asymmetric synthesis method of optically pure cardiovascular and cerebrovascular drug R- or S-acebutolol. Background technique [0002] Acebutolol (Ac) is a beta-adrenergic blocker used to treat high blood pressure, irregular heartbeat, or angina. The drug was approved by the US FDA in 1999, and like many other beta-blocker drugs, at present, the drug is still administered in a mixed manner. However, it has been reported in many literatures that the β-receptor blocking activity of acebutolol mainly comes from its S-configuration enantiomer and its metabolite S-form diacetolol (Dc). As we all know, drug administration with a single enantiomer is the current trend of drug development in the world, and there are great differences in pharmacodynamics and pharmacokinetics between different enantiomers of the same drug. Therefore, it is of great significance to synthesize optica...

Claims

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Application Information

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IPC IPC(8): C07C233/33C07C231/18
Inventor 王乃兴汤新亮
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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