Montelukast sodium preparation technology and intermediates

A kind of technology of montelukast sodium and preparation process, applied in the field of drug synthesis

Active Publication Date: 2015-01-21
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011]Through the synthetic route of montelukast, it is not difficult to find that the construction of the chiral center of montelukast sodium mainly depends on the asymmetric reduction method, and such The asymmetric reduction method has greatly increased the production cost in large-scale industrial production, resulting in a higher price of montelukast sodium and increased medical costs for patients

Method used

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  • Montelukast sodium preparation technology and intermediates
  • Montelukast sodium preparation technology and intermediates
  • Montelukast sodium preparation technology and intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The preparation of embodiment 1 compound A2

[0051] In a 1000ml three-necked flask, first add 300ml of toluene and 4.8ml of glacial acetic acid (0.084mol, 0.3eq), and under mechanical stirring, add 50g (0.28mol, 1eq) of 7-chloro-2-methylquinine, 3-bromobenzene Formaldehyde 77.7g (0.42mol, 1.5eq), after the feeding is complete, heat up to 70°C, add 45ml (0.48mol, 1.71eq) of acetic anhydride after the raw materials are completely dissolved, then heat up to toluene reflux, control the temperature at 120-125°C, reflux After 10 hours, TLC detected the reaction until the raw material point of 7-chloro-2-methylquinine disappeared, the reaction was completed, the heating was stopped, the reaction solution was cooled to room temperature, stirred for 2 hours, left to stand for 1 hour, suction filtered, and the filter cake was used for 30ml Wash with toluene and dry. The product compound A286.8g was obtained, the yield was 90%, MS m / z: 346 (M+1) + .

Embodiment 2

[0052] The preparation of embodiment 2 compound A2

[0053] In a 1000ml three-necked flask, first add 300ml of toluene and 8ml of glacial acetic acid (0.14mol, 0.5eq), under mechanical stirring, add 50g (0.28mol, 1eq) of 7-chloro-2-methylquinine, 3-bromobenzaldehyde 62.16g (0.34mol, 1.2eq), after the addition is complete, heat up to 70°C, add 45ml (0.48mol, 1.71eq) of acetic anhydride after all the raw materials are dissolved, then heat up to toluene reflux, control the temperature at 120-125°C, and reflux for 11 After 1 hour, TLC detects the reaction until the 7-chloro-2-methylquinine raw material point disappears, the reaction ends, the heating is stopped, the reaction solution is cooled to room temperature, and after stirring for 2 hours, it is left to stand for 1 hour, suction filtered, and the filter cake is washed with 30ml toluene Wash and dry. The product compound A282.9g was obtained, the yield was 86%, MS m / z: 346 (M+1) + .

Embodiment 3

[0054] The preparation of embodiment 3 compound A2

[0055] In a 1000ml three-neck flask, first add 350ml xylene and 4.8ml (0.084mol, 0.3eq) of glacial acetic acid, and under mechanical stirring, add 50g (0.28mol, 1eq) of 7-chloro-2-methylquinine, 3-bromo Benzaldehyde 62.16g (0.34mol, 1.2eq), after the feeding is complete, heat up to 70°C, add propionic anhydride 54.6ml (0.42mol, 1.5eq) after the raw materials are completely dissolved, then heat up to toluene reflux, control the temperature at 120-125°C , refluxed for 12 hours, TLC detected the reaction until the raw material point of 7-chloro-2-methylquinine disappeared, the reaction was completed, the heating was stopped, the reaction solution was cooled to room temperature, stirred for 2 hours, left to stand for 1 hour, suction filtered, and the filter cake was Wash with 30 ml of toluene and dry. Obtained product A284.4g, yield 87.5%, MS m / z:346(M+1) + .

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Abstract

The present invention discloses a montelukast sodium preparation technology and intermediates; 7-chloro-2-methylquinine and 3-bromobenzaldehyde are used as raw materials for condensation reaction to obtain a compound A2; by carbon-carbon coupling of the compound A2 and 1-tetralone in the presence of a catalyst, an intermediate compound A3 is obtained; an important intermediate compound A4 is obtained by bio-enzyme catalyzed asymmetric Baeyer-villiger reaction, a chiral center is highly selectively constructed, an important intermediate compound A5 is prepared from the compound A4 by grignard reaction by use of methylmagnesium chloride, finally montelukast sodium (A6) is obtained; according to the technology, the highly chiral important intermediate compound A4 is obtained by bio-enzyme catalyzed asymmetric reaction, the catalyst can be effectively repeatedly used, and the kind of used solvents is less, and the montelukast sodium preparation technology has the characteristics of safety and environmental protection, greatly saves the production cycle, is low in production cost, high in total yield, and simple in operation of production units, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation process of montelukast sodium and an intermediate product thereof, belonging to the technical field of medicine synthesis. Background technique [0002] The chemical name of Montelukast Sodium is: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)-vinyl)phenyl)- Sodium 3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio))methyl)cyclopropylacetate, the structural formula is as follows: [0003] [0004] Montelukast is currently the only strong selective leukotriene receptor antagonist that is taken once a day, and is suitable for the treatment of asthma and allergic rhinitis asthma syndrome in adults and children. The compound first disclosed the chemical structure and preparation method of montelukast in US5565473 by Merck, and reported the preparation method of the compound in detail in process patents CN1046712 and CN1139429. Due to its wide application range and convenient administration, it is currently It has been wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/12C07D215/18
CPCY02P20/582
Inventor 丁尊良王希林
Owner JIANGSU HANSYN PHARMA
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