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New synthesizing process for modafinil

A technology of compound and reaction temperature, applied in the field of chemical synthesis of modafinil, namely 2-acetamide, can solve the problems of long reaction route, bad smell of diphenylmethane mercaptan, complicated operation and the like, and simplify the preparation and purification methods , Product yield and quality improvement, the effect of mild reaction conditions

Inactive Publication Date: 2007-06-27
浙江华纳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Adopt above method to have following shortcoming: by the synthetic reaction of method (1), its reaction route is long, and the operation of the first step reaction is complicated, and yield is low, and product diphenylmethyl mercaptan has stench, and starting material diphenylmethanol The synthetic difficulty of the method is relatively large, the yield is not high, and the market price is higher, and one of the methods also needs to use highly toxic dimethyl sulfate, chromatographic separation, and complex technology; method (2) needs to be synthesized because of chloroacetamide , so in yield, there is no obvious advantage in synthesis steps and difficulty; method (3) reaction yield obviously reduces, and the whole reaction route is still longer; (75%) is much lower than bibliographical information (92%), and still there is the shortcoming that the cost of starting material diphenylmethanol is higher; Method (5) whole reaction process total yield is low (42%), complex operation, Not suitable for industrial production

Method used

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Examples

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Effect test

Embodiment 1

[0044] 1. Preparation of Diphenylbromomethane (III)

[0045] In a 500mL three-necked flask, add 33.6g (0.2mol) of diphenylmethane, 200mL of dichloromethane, and 8g (0.2mol) of sodium hydroxide, stir vigorously, control the internal temperature at 25-30°C, and slowly add 33.6kg of bromine dropwise (0.21mol) and dichloromethane 30mL solution, the dropwise addition was completed, and the reaction was heated under reflux for 6 hours. Cool to room temperature, wash the reaction solution with 5% sodium bicarbonate solution, and then wash with water until the water layer is neutral, dry the organic layer with anhydrous sodium sulfate, recover dichloromethane under reduced pressure, and pour the oily product diphenylbromomethane into a brown bottle Store in an airtight container for later use. Yield: 98.0%.

[0046] 2. Preparation of diphenylmethylthioacetic acid (V)

[0047]In a 500mL three-necked flask, add 24.7g (0.1mol) of diphenylbromomethane and 250mL of glacial acetic acid, ...

Embodiment 2

[0055] 1. Preparation of Diphenylbromomethane (III)

[0056] In a 250 mL three-necked flask, add 33.6 g (0.2 mol) of diphenylmethane and 8 g (0.2 mol) of sodium hydroxide, and heat to an internal temperature of 95-105°C. Slowly add 33.6 kg (0.21 mol) of bromine dropwise. After the dropwise addition is complete, keep the temperature at 100-110° C. for 3 hours. Cool to room temperature, add 150 mL of dichloromethane, mix well, wash with 5% sodium bicarbonate solution, and then wash with water until the water layer is neutral, dry the organic layer with anhydrous sodium sulfate, recover dichloromethane under reduced pressure, oily product Pour diphenylbromomethane into a brown bottle and seal it for later use. Yield: 92.8%.

[0057] 2. Preparation of diphenylmethylthioacetic acid (V)

[0058] In a 500mL three-neck flask, add 24.7g (0.1mol) of diphenylbromomethane and 250mL of glacial acetic acid, stir and dissolve at room temperature, and add 8.3g (0.9mol) of thioglycolic acid...

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Abstract

The present invention discloses new process of synthesizing Modafinil, or 2-(diphenylmethyl sulfinyl) acetamide. The process includes the reaction of diphenyl methane as main material and bromine to obtain the intermediate diphenyl bromomethane, further condensation with mercapto acetic acid to obtain the intermediate diphenyl methylthio acetic acid, acyl chlorination to obtain the intermediate diphenyl methylthio acetyl chloride, amidation to obtain the intermediate diphenyl methylthio acetamide, and final sulfur-oxidation to obtain ultimate product Modafinil. The synthesis process of the present invention has facile material, mild reaction condition, relatively simple preparation and purification, and high product yield and quality, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a new chemical synthesis method of modafinil (Modafinil, I), namely 2-(diphenylmethylsulfinyl)acetamide. Background technique [0002] Modafinil (Modafinil, I) is the common name of 2-(diphenylmethylsulfinyl) acetamide, and its structural formula is as follows: [0003] [0004] Modafinil is a new type of refreshing drug that acts on the central nervous system developed by the French company Lafon. It was first launched in France in 1994. It is mainly used clinically for the treatment of narcolepsy and spontaneous hypersomnia. [0005] Existing methods for the synthesis of modafinil have the following: [0006] (1) The preparation methods disclosed in the patent Nos. DE 2809625, US 4177290A1 and US2002 / 0045629A1 use diphenylmethanol as a raw material to synthesize modafinil according to the following synthetic route (route 1). [0007] [0008] (2) The preparation method disclosed in the patent No. US 2004 / 002547A1 is c...

Claims

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Application Information

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IPC IPC(8): C07C317/44C07C315/02
Inventor 胡高云相红琳徐利明
Owner 浙江华纳药业有限公司
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