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Montelukast sodium side chain key intermediate synthesis method

A technology of montelukast sodium and its synthesis method, which is applied in the direction of cyanide reaction preparation and organic chemistry, etc., can solve the problems of hidden dangers in industrial production operation, unstable purity of reaction system, and high content of dicyano impurities, and achieve chemical The effect of stable process conditions, increased yield, and low content of dicyano impurities

Inactive Publication Date: 2015-08-26
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Some problems and defects in the preparation of this intermediate at this stage are reflected in the following points: 1. The reaction stability is poor, and the purity of the reaction system is unstable
2. The reaction time is long, at least 18 hours to complete the reaction, and the energy consumption is high
3. Powdered sodium cyanide must be used, and there are hidden dangers in the safety of industrial production operations
4. The content of the dicyano impurity produced in the reaction process is high, and the content of the dicyano impurity is also getting higher and higher as the reaction proceeds while the raw material is transformed. difficulty

Method used

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Embodiment 1

[0020] A method for synthesizing the key intermediate of the side chain of montelukast sodium, comprising the following steps (1) adding 166Kg N,N-dimethylformamide into a 500L reaction kettle, starting stirring, and adding 50Kg cyclopropyl sulfinate , 10.13Kg sodium iodide, 5.45Kg tetrabutylammonium bromide and 19.88Kg sodium cyanide are put in the reaction kettle, and the system is heated up to 85°C for 15 hours of insulation reaction;

[0021] (2) Cool the system down to 60-70°C, add 9.13Kg of water dropwise to terminate the reaction, add 435Kg of toluene, and keep warm at 60-70°C for 1-2 hours;

[0022] (3) After the reaction is completed, cool down to 20-30°C, add toluene and keep stirring;

[0023] (4) Centrifuge, collect the mother liquor, concentrate the centrifuged mother liquor; purify the concentrated residue by high vacuum vacuum distillation and collect the product at 90~120℃ / 80~200Pa, the product quality is 32.3Kg, the yield is 85%, GC The detection purity is gr...

Embodiment 2

[0025] A method for synthesizing the key intermediate of the side chain of montelukast sodium, comprising the following steps (1) adding 166Kg N,N-dimethylformamide into a 500L reaction kettle, starting stirring, and adding 50Kg cyclopropyl sulfinate , 10.13Kg sodium iodide, 5.45Kg tetrabutylammonium bromide and 19.88Kg sodium cyanide into the reactor, the system was heated to 90 ° C for 10 hours of insulation reaction;

[0026] (2) Cool the system down to 60-70°C, add 9.13Kg of water dropwise to terminate the reaction, add 435Kg of toluene, and keep warm at 60-70°C for 1-2 hours;

[0027] (3) After the reaction is completed, cool down to 20-30°C, add toluene and keep stirring;

[0028] (4) Centrifuge, collect the mother liquor, concentrate the centrifuged mother liquor; purify the concentrated residue by high vacuum vacuum distillation and collect the product at 90~120℃ / 80~200Pa, the product quality is 32.3Kg, the yield is 85%, GC The detection purity is greater than 95%.

Embodiment 3

[0030] A method for synthesizing the key intermediate of the side chain of montelukast sodium, comprising the following steps (1) adding 166Kg N,N-dimethylformamide into a 500L reaction kettle, starting stirring, and adding 50Kg cyclopropyl sulfinate , 10.13Kg sodium iodide, 5.45Kg tetrabutylammonium bromide and 19.88Kg sodium cyanide are put in the reactor, and the system is heated up to 80°C for 20 hours of insulation reaction;

[0031] (2) Cool the system down to 60-70°C, add 9.13Kg of water dropwise to terminate the reaction, add 435Kg of toluene, and keep warm at 60-70°C for 1-2 hours;

[0032] (3) After the reaction is completed, cool down to 20-30°C, add toluene and keep stirring;

[0033] (4) Centrifuge, collect the mother liquor, concentrate the centrifuged mother liquor; purify the concentrated residue by high vacuum vacuum distillation and collect the product at 90~120℃ / 80~200Pa, the product quality is 32.3Kg, the yield is 85%, GC The detection purity is greater th...

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Abstract

The present invention discloses a montelukast sodium side chain key intermediate synthesis method, which comprises: (1) adding N, N-dimethylformamide to a reaction kettle, starting stirring, adding cyclopropyl sulfinic ester, sodium iodide, tetrabutyl ammonium bromide and sodium cyanide to the reaction kettle, and carrying out a thermal insulation reaction for 10-20 h at a temperature of 80-90 DEG C; (2) cooling the system to 60-70 DEG C, adding water in a dropwise manner to terminate the reaction, and carrying out a thermal insulation reaction for 1-2 h at a temperature of 60-70 DEG C after completing the adding; (3) cooling the temperature to 20-30 DEG C after completing the reaction, adding toluene, and carrying out thermal insulation stirring; and (4) carrying out centrifugation, collecting the mother liquor, concentrating, and carrying out pressure reducing distillation. The method of the present invention has characteristics of simple operation, safety, reliability, reaction time shortening due to the use of the phase transfer catalyst, good stability, and low energy consumption.

Description

technical field [0001] The present invention relates to the technical field of heterocyclic compounds. Background technique [0002] The chemical name of Montelukast Sodium is: 1-(((1-(R–(3-(2-(7-chloro-2-quinolinyl)-vinyl)-phenyl)- 3-(2-Hydroxy-1-methylethyl)-phenyl)propyl)mercapto)methyl)cyclopropyl sodium acetate, the structural formula is as follows: [0003] [0004] It is a new type of highly selective LTD4 receptor antagonist developed by Merck Company of the United States. Its trade name is Singular. It was first launched in Finland and Mexico in February 1998. Listed in the United States, and subsequently listed in 71 countries including Canada, Italy, Spain, Sweden, Switzerland, Germany, and France. As a selective leukotriene LTD4 receptor antagonist, the drug can selectively bind to the leukotriene LTD4 receptor on the respiratory mucosa, block the action of allergic mediators, improve respiratory inflammation, and make the airway unobstructed. Anti-inflamma...

Claims

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Application Information

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IPC IPC(8): C07C255/31C07C253/16
Inventor 张少平张基勇王平周文峰张伟
Owner CANGZHOU SENARY CHEM SCI TEC
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