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Zafirlukast intermediate preparation process

A preparation process and intermediate technology, which is applied in the field of preparation process of the asthma drug zafirlukast intermediate, can solve the problems of increased impurities, expensive raw materials/reagents, difficult purification, etc., and achieve high purity, low production cost, and post-processing Easy to handle effects

Active Publication Date: 2019-08-30
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] To sum up, although there are many technical means to prepare zafirlukast intermediates, these methods have certain shortcomings: raw materials / reagents are too expensive, Lewis acid as a catalyst leads to increased impurities, difficult purification, etc.

Method used

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Examples

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Embodiment 1

[0024] Preparation of (5-nitro-1-toluenesulfonyl-1H-indol-3-yl)methyl acetate:

[0025]

[0026] In a 250mL round bottom flask, add 5-nitroindole-3-carbaldehyde (19g, 0.1mol) dissolved in 150mL of dry dichloromethane, then add p-toluenesulfonyl chloride (19.1g, 0.1mol) and carbonic acid Potassium (27.6g, 0.2mol) was heated under reflux for 12 hours. TLC determined that the raw material disappeared, cooled to room temperature, stood still, and filtered with suction, and the filtrate was distilled off under reduced pressure to remove the organic solvent to obtain 29 g of a yellow solid. In a 250 mL round bottom flask, 29 g of the above yellow solid was dissolved in 100 mL of ethanol, and sodium borohydride (6.4 g, 0.17 mol) was added in batches under stirring, and reacted at room temperature for 6 hours. TLC determined that the starting material disappeared, adjusted the pH to 7 with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate (3×50 mL), combined the ...

Embodiment 2

[0036] Preparation of methyl 3-methoxy-4-[(5-nitro-1-tosyl-1H-indol-3-yl)methyl]benzoate:

[0037] In a 250 mL round bottom flask, methyl (5-nitro-1-tosyl-1H-indol-3-yl)acetate (9.7 g, 0.025 mol) and methyl 3-methoxybenzoate ( 4.2g, 0.025mol) was dissolved in 50mL of chloroform, acidified montmorillonite (8.4g) was added under stirring, and heated to 45°C for reflux reaction for 4 hours. TLC determined that the raw material disappeared, cooled to room temperature, stood still, suction filtered, and the filtrate was distilled off under reduced pressure to remove the organic solvent to obtain a yellow solid, which was recrystallized from ethyl acetate / cyclohexane to obtain a white solid 3-methoxy-4-[(5 -Methyl nitro-1-tosyl-1H-indol-3-yl)methyl]benzoate (8.1 g, 66% yield).

Embodiment 3

[0039] Preparation of methyl 3-methoxy-4-[(5-nitro-1-tosyl-1H-indol-3-yl)methyl]benzoate:

[0040] In a 250 mL round bottom flask, methyl (5-nitro-1-tosyl-1H-indol-3-yl)acetate (9.7 g, 0.025 mol) and methyl 3-methoxybenzoate ( 4.2 g, 0.025 mol) was dissolved in 50 mL of 1,2-dichloroethane, and acidified montmorillonite (8.4 g) was added under stirring, and heated to 45° C. for reflux reaction for 4 hours. TLC determined that the raw material disappeared, cooled to room temperature, left to stand, suction filtered, and the filtrate was distilled off under reduced pressure to remove the organic solvent to obtain a yellow solid, which was recrystallized from ethyl acetate / cyclohexane to obtain a white solid 3-methoxy-4-[(5 -Methyl nitro-1-tosyl-1H-indol-3-yl)methyl]benzoate (7.8 g, 63% yield).

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Abstract

The invention relates to a zafirlukast intermediate preparation process, wherein the compound is an important intermediate for preparing a leukotriene antagonist drug zafirlukast. The process comprises: carrying out a heating reaction in an inert solvent under the action of acidified montmorillonite by using methyl(5-nitro-1-tosyl-1H-indole-3-yl)acetate and methyl 3-methoxybenzoate as raw materials until the raw materials disappear, filtering to obtain 3-methoxy-4-[(5-nitro-1-tosyl-1H-indole-3-yl)methyl] methyl benzoate, and hydrolyzing the 3-methoxy-4-[(5-nitro-1-tosyl-1H-indole-3-yl)methyl]methyl benzoate under alkaline conditions to obtain the target product. According to the present invention, the new process route for synthesizing the important zafirlukast intermediate is provided,has the technical advantages of simple operation, low reaction cost, high product yield and environmental friendliness, and can meet the large-scale production demand of medical products.

Description

technical field [0001] The invention belongs to the production field of fine chemical products, and in particular relates to a preparation process of an intermediate of zafirlukast, a medicine for treating asthma. Background technique [0002] With the continuous development of the industrialization process, the living environment of human beings has also undergone continuous changes, the decline in air quality, coupled with the hundreds of millions of smokers, the number of asthma patients in my country's big cities is increasing year by year. Zafirlukast, chemical name [3-[2-methoxy-4-[(2-methylphenyl)sulfonamidocarbonyl]benzyl]-1-methyl-1H-indole-5 -Methylene]cyclopentyl carbamate is a leukotriene receptor antagonist developed by AstraZeneca, which is clinically used for the prevention and long-term treatment of asthma. At present, the market price of zafirlukast is relatively expensive, and the preparation process is relatively complicated, which is mainly reflected in ...

Claims

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Application Information

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IPC IPC(8): C07D209/18
CPCC07D209/18
Inventor 陈冬寅杨磊李飞陈轩陈超周宇董泽中
Owner NANJING MEDICAL UNIV
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