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A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a lorcaserin intermediate

A technology of lorcaserin and intermediates, which is applied in the field of preparation of slimming drug lorcaserin, can solve the problems of equipment causing corrosion, long Friedel-Crafts reaction time, and waste acid polluting the environment, etc., so as to save energy and reduce steps, environment friendly effect

Active Publication Date: 2016-06-22
SICHUAN YIBIN WULIANGYE GROUP YIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] (1) Thionyl chloride needs to be used in the synthesis process, and the waste acid produced will pollute the environment;
[0014] (2) The waste acid produced will also cause corrosion to the equipment;
[0015] (3) The Friedel-Crafts reaction time is long, and the solution after the reaction is viscous, which will adsorb a large amount of products, resulting in low yield

Method used

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  • A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a lorcaserin intermediate
  • A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a lorcaserin intermediate
  • A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, a lorcaserin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] One of the preparation methods of 2-(4-chlorophenyl)N-(2-hydroxypropyl)acetamide (compound 3)

[0050]Compound 1 (100.0g, 0.59mol), boric acid (3.7g, 0.06mol, 0.1eq) and 300ml of toluene were sequentially added to a 1L three-necked flask, heated to 40°C, and then oil compound 2 (47.87g, 0.64mol, 1.1eq) and 200ml of toluene mixed solution, heated to reflux at 135°C, after 24h, the amount of water in the water separator no longer increased, and the reaction temperature dropped to 60°C. The reaction solution was slowly poured into an aqueous solution of sodium carbonate with a weight concentration of 5%, stirred, and a large amount of white solids were precipitated, cooled to room temperature, filtered, and dried in a filter cake blast drying oven for 3 hours to obtain 122.8 g of white granular solids, yield 92.0%, HPLC purity 95.5%. 1 H-NMR (400MHz, DMSO-d6) δ: 8.06 (s, 1H); 7.38 (d, 2H, J = 8.7Hz); 7.30 (m, 2H); 7.82 (d, 2H, J = 8.7Hz); 4.71(d,1H,J=1.8Hz),3.64(m,1H),3....

Embodiment 2

[0051] Example 2 The second preparation method of 2-(4-chlorophenyl)N-(2-hydroxypropyl)acetamide (compound 3)

[0052] Compound 1 (60.0g, 0.35mol), boric acid (1.1g, 0.06mol, 0.05eq) and 180ml of toluene were sequentially added to a 500mL three-necked flask, heated to 40°C, and then oil compound 2 (29.12g, 0.39mol, 1.1eq) and 120ml of toluene, heated to reflux at 135°C, after 24h, the amount of water in the water separator no longer increased, and the reaction temperature dropped to 60°C. The reaction solution was slowly poured into 5% sodium carbonate aqueous solution, stirred, and a large amount of white solids were precipitated, cooled to room temperature, filtered, and dried in a filter cake drying oven for 3 hours to obtain 75.5 g of white granular solids, with a yield of 95.0% , HPLC purity 96.5%.

Embodiment 3

[0054] The third preparation method of 2-(4-chlorophenyl)N-(2-hydroxypropyl)acetamide (compound 3)

[0055] Compound 1 (100.0g, 0.59mol), boric acid (3.7g, 0.06mol, 0.1eq) and 300ml of toluene were sequentially added to a 1L three-necked flask, heated to 40°C, and then oil compound 2 (47.87g, A mixed solution of 0.64mol, 1.1eq) and 200ml toluene was heated to reflux at 135°C. After 48h, the amount of water in the water separator no longer increased, and the reaction temperature dropped to 60°C. The reaction solution was slowly poured into 5% sodium carbonate aqueous solution, stirred, and a large amount of white solids were precipitated, cooled to room temperature, filtered, and dried in a filter cake blast drying oven for 3 hours to obtain 123.6 g of white granular solids, with a yield of 92.3% , HPLC purity 96.0%.

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Abstract

A preparing method of (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine that is a lorcaserin intermediate is disclosed. The method includes (1) dehydrating a compound 1 and a compound 2 under catalysis by boric acid to generate an amide 3, (2) reducing the intermediate 3 with a borane dimethylsulfide complex to obtain a compound 4, and (3) subjecting the compound 4 to direct ring closing with the existence of aluminum chloride to generate the lorcaserin intermediate that is the (R,S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine that is the compound 6. The method avoids use of 3,4,5-trimethoxyphenylboronic acid that is an expensive reagent, thus reducing the cost. The method avoids use of thionyl chloride so that the method is environmental friendly. A step of hydroxy chlorination is reduced so that the method is simple in process. The conversion ratio of raw materials and the total yield of reactions are increased. The yield of the compound 6 is increased from 60% in a patent to 82%. The method is suitable for industrial production. A reaction equation is shown in the description.

Description

technical field [0001] The present invention relates to the preparation method of (R, S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, the intermediate is separated and free , the salt can be used for the preparation of the weight-loss drug lorcaserin. Background technique [0002] With the development of the economy and the improvement of people's living standards, the incidence of obesity is rising rapidly, and it has attracted more and more attention. The 2002 "Nutrition and Health Survey of Chinese Residents" showed that the overweight and obesity rates of Chinese adults were 22.8% and 7.1% respectively. It is estimated that there are currently 60 million obese people in China and more than 200 million overweight people. Compared with the 1992 survey, the adult overweight rate increased by 39% and the obesity rate increased by 97%. Among them, the overweight and obesity rates of adults in big cities are as high as 30.0% and 12.3%, and the obesity rate of child...

Claims

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Application Information

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IPC IPC(8): C07D223/16C07C215/08C07C213/08
Inventor 李建其刘育周爱南张闯丁方石兆勇
Owner SICHUAN YIBIN WULIANGYE GROUP YIBIN PHARMA
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