Synthesis method of compound 1-(2-halogenophenyl)-3-methyl-butanone-1

A synthesis method and halophenyl technology are applied in the field of organic chemical synthesis, which can solve the problems of not meeting the requirements of green chemistry, inability to apply, and many side reactions, and achieve the effects of low cost, few side reactions and high product quality.

Inactive Publication Date: 2013-02-27
NORTHWEST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Above these methods have all used organic solvent, wherein some methods also need to use conditions such as catalyst, low temperature; In addition, some methods have many side reactions,...

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1, the synthesis of 1-(2-chlorophenyl)-3-methyl-butanone-1

[0021] (1) Synthesis of 2-chloro-N-methoxy-N-methylbenzamide

[0022] In a round bottom flask, add 2-chlorobenzoic acid (15.65g, 0.1 mol), N-methoxymethylamine (18.3g, 0.3 mol), anhydrous toluene (200ml), cool to about 0°C in an ice bath, Add the toluene solution of phosphorus trichloride (phosphorus trichloride 6.878g, 0.05 mol, toluene 100 ml) dropwise, stir for 30 minutes, then warm up to room temperature, react for 2 hours, then heat up to about 60°C, continue to react for 30 minutes ; After the reaction, add saturated NaHCO to the reaction mixture 3 The solution was quenched, extracted with ethyl acetate (3 × 200 mL), the organic phases were combined, MgSO 4 Dry, filter, concentrate, and purify by column chromatography to obtain 2-chloro-N-methoxy-N-methylbenzamide. 19.5 g, yield 97.7%.

[0023] 1 HNMR (400 MHz, CDCl 3 ): δ (ppm): 7.42~7.28 (m, 4H), 3.47 (s, 3H), 3.39 (s, 3H).

[0024] (...

Embodiment 2

[0028] Embodiment two, the synthesis of 1-(2-fluorophenyl)-3-methyl-butanone-1

[0029] (1) Synthesis of 2-fluoro-N-methoxy-N-methylbenzamide

[0030] In a round bottom flask, add 2-fluorobenzoic acid (163.6g, 1mol), N-methoxymethylamine (183g, 3mol), anhydrous toluene (600ml), cool to about 0°C in an ice bath; Add the toluene solution of phosphorus trichloride dropwise (phosphorus trichloride 0.5mol, toluene 100 ml), react for 30 minutes, then raise the temperature to room temperature and react for 2 hours, then raise the temperature to 60 ｏ C for 30 minutes; after the reaction, add saturated NaHCO 3 The solution was quenched, extracted with ethyl acetate (3 x 5 mL), the organic phases were combined, MgSO 4 Dry, filter, concentrate, and purify by column chromatography to give 2-fluoro-N-methoxy-N-methylbenzamide 。 211.48g, yield 98.9%.

[0031] 1 HNMR (400 MHz, CDCl 3 ): δ (ppm): 7.45~7.39 (m, 2H), 7.38~7.19 (m, 1H), 7.18~7.08 (m, 1H), 3.53 (S, 3H), 3.35 (S, 3H); 13 CN...

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Abstract

The invention provides a preparation method of a key intermediate compound 1-(2-halogeno)-2-methyl-butanone-1 for the synthesis of an oral antidiabetic medicament Repaglinide, belonging to the field of organic chemical synthesis. The preparation method comprises the following steps: under the action of phosphorus trichloride, preparing 2-halogenobenzoic acid and N-methoxy methylamine used as raw materials into 2-halogeno-N-methoxy-N-methyl benzamide in anhydrous methylbenzene used as solvent; and then, further reacting with magnesium isobutyl bromide under the protection of nitrogen gas for 2-3 hours, separating, and purifying to obtain the target compound 1-(2-halogenophenyl)-3-methyl-butanone-1. The preparation method provided by the invention has the advantages of accessible raw materials, simple process, short reaction scheme, low cost and high efficiency; the reaction is performed at room temperature, the reaction conditions are mild, no catalyst is used, and few subsidiary reaction exists in the reaction, thereby ensuring that the preparation method is green and environment-friendly; and the target product yield is high (up to 80% or above), and the product quality is high (the purity is above 99%). Thus, the preparation method is beneficial to industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and relates to a preparation method of 1-(2-halophenyl)-3-methyl-butanone-1, an important intermediate for synthesizing oral hypoglycemic drug Repaglinide. Background technique [0002] Compound 1-(2-halophenyl)-3-methyl-butanone-1 (Compound II) is a key intermediate in the synthesis of oral hypoglycemic drug Repaglinide. Its structure is as follows: [0003] [0004] At present, there are many reports about the synthetic method of 1-(2-halophenyl)-3-methyl-butanone-1: PCT publications (Nos. WO 03027072 A1, WO 2004103983 A1, WO 2004101540, WO 03027072 A1, WO 2008099286 A2, WO 2009004485 A2) and patent applications (No. 20070123564 A1 and European Patent Nos 0589874, 0147850). Above these methods have used organic solvent, wherein some methods also need to use conditions such as catalyst, low temperature; In addition some methods have many side reactions, low yield, can not be applie...

Claims

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Application Information

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IPC IPC(8): C07C49/807C07C45/45
Inventor 胡雨来A·伊布拉新王克虎张燕黄丹凤
Owner NORTHWEST NORMAL UNIVERSITY
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