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Preparation method of clobazam

A technology of chlorobazam and malonyl chloride, applied in the field of preparation of chlorobazam, can solve problems such as unfavorable industrialized production, high operational risk and the like

Inactive Publication Date: 2017-07-14
SHIJIAZHUANG BOCE BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Phosphorus pentachloride is used in this method, the cyclization requires strong acid conditions, the operation is dangerous, and it is not conducive to industrial production

Method used

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  • Preparation method of clobazam

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Embodiment

[0023] A preparation method of clobazam, comprising the following steps:

[0024] (1) Synthesis of N-phenyl-5-chloro-1,2-phenylenediamine

[0025] In the high-pressure hydrogenation kettle, the compound 5-chloro-2-nitro- N - Phenylaniline (20 g, 80.43 mmol), Raney-nickel (0.6 g), ethanol (80 mL) and dichloromethane (20 mL). After addition, under 1 bar hydrogen pressure, stir the reaction at room temperature for 1.5 h, stop the reaction, cool and stir in an ice-water bath, a solid precipitates, filter with suction, wash the filter cake with 30 mL of water and 30 mL of petroleum ether successively, and dry in vacuo to obtain a white solid N- Phenyl-5-chloro-1,2-phenylenediamine (15.83 g), mp. 102.5-104.8°C. MS-ESI(m / z): 219.1[M+H] + , 241.1[M+Na] + , 217.0[M-H] - . 1 H-NMR (500MHz, DMSO- d 6 ), δ (ppm): 4.91 (s, 2H, -NH 2 ), 6.70~6.82(m, 5H, Ar-H), 6.95(s, 1H, -NH-), 7.15~7.21(m, 3H, Ar-H),

[0026] (2) 8-Chloro-1-phenyl-1,5-benzodiazepine-2,4(1 H , 3 H )-Diketone Sy...

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Abstract

The invention discloses a preparation method of clobazam, and belongs to the field of organic synthesis. The method comprises the following steps: (1) adding 2-nitro-5-chlorodiphenylamine into a lower alcohol and water mixed solvent, adding a Pd-C catalyst, and introducing hydrogen to synthesize N-phenyl-5-chloro-1,2-phenylenediamine; (2) adding the N-phenyl-5-chloro-1,2-phenylenediamine obtained in step (1) into a THF solvent, and adding malonyl chloride in batches to obtain 1-phenyl-8-chloro-1,2,4,5-tetrahydro-1,5-benzodiazepine-2,4-dione; and (3) reacting the 1-phenyl-8-chloro-1,2,4,5-tetrahydro-1,5-benzodiazepine-2,4-dione obtained in step 2 with halomethane or dimethyl sulfate to obtain the target product clobazam. The preparation method is a simple and highly-efficient clobazam synthesis method.

Description

technical field [0001] The invention relates to a preparation method of clobazam, which belongs to the field of organic synthesis. Background technique [0002] Clobazam (Clobazam), chemical name: 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3 H )-diketone, a benzodiazepine compound developed by Lundbeck Company in Denmark. The product name is Onfi, which was approved by the U.S. Food and Drug Administration (FDA) on October 21, 2011. The main indications are the treatment of anxiety and refractory epilepsy, and the treatment of complex seizures and Ringo syndrome (Lennox-Gaslaut) works even better. The chemical structural formula of clobazam is: [0003] [0004] In the prior art, 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3 H )-dione synthetic method: with 5-chloro-2-nitro- N -Phenylaniline as the starting material, after hydrogenation and reduction, N-phenyl-5-chloro-1,2-phenylenediamine is obtained. The intermediate N-phenyl-5-chloro-1,2-phenylenedia...

Claims

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Application Information

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IPC IPC(8): C07D243/12
CPCC07D243/12
Inventor 方瑜杜玉民
Owner SHIJIAZHUANG BOCE BIO TECH
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