A kind of preparation technology of zafirlukast intermediate

A preparation process and a technology for intermediates, which are applied in the field of preparation processes for the intermediates of zafirlukast, a drug for treating asthma, can solve the problems of increased impurities, difficult purification, expensive raw materials/reagents, etc. low cost effect

Active Publication Date: 2022-06-14
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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  • A kind of preparation technology of zafirlukast intermediate
  • A kind of preparation technology of zafirlukast intermediate
  • A kind of preparation technology of zafirlukast intermediate

Examples

Experimental program
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Effect test

Embodiment 1

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

[0025]

[0026] In a 250mL round-bottomed flask, add 5-nitroindole-3-carbaldehyde (19g, 0.1mol) and dissolve it in 150mL of dry dichloromethane, then add p-toluenesulfonyl chloride (19.1g, 0.1mol) and carbonic acid in sequence Potassium (27.6 g, 0.2 mol) was heated to reflux for 12 hours. TLC measured the disappearance of the raw materials, cooled to room temperature, allowed to stand, filtered with suction, and distilled the filtrate under reduced pressure to remove the organic solvent to obtain 29 g of a yellow solid. In a 250 mL round-bottomed flask, the above-mentioned 29 g of the yellow solid was dissolved in 100 mL of ethanol, and sodium borohydride (6.4 g, 0.17 mol) was added in batches with stirring, and the reaction was carried out at room temperature for 6 hours. TLC determined the disappearance of the raw materials, 1M aqueous hydrochloric acid was adjusted to pH 7, extracted with e...

Embodiment 2

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

[0037] In a 250 mL round bottom flask, add methyl (5-nitro-1-toluenesulfonyl-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 chloroform, acidified montmorillonite (8.4 g) was added under stirring, and the mixture was heated to 45° C. for reflux reaction for 4 hours. TLC measured the disappearance of the raw materials, cooled to room temperature, left standing, suction filtered, the filtrate was distilled 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 -Nitro-1-toluenesulfonyl-1H-indol-3-yl)methyl]benzoic acid methyl ester (8.1 g, 66% yield).

Embodiment 3

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

[0040] In a 250 mL round bottom flask, add methyl (5-nitro-1-toluenesulfonyl-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, acidified montmorillonite (8.4 g) was added under stirring, and the mixture was heated to 45° C. for reflux reaction for 4 hours. TLC measured the disappearance of the raw materials, cooled to room temperature, left standing, suction filtered, the filtrate was distilled 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 -Nitro-1-toluenesulfonyl-1H-indol-3-yl)methyl]benzoic acid methyl ester (7.8 g, 63% yield).

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Abstract

The invention discloses a process for preparing an intermediate of zafirlukast, and the compound is an important intermediate for preparing the leukotriene antagonist drug zafirlukast. With (5-nitro-1-toluenesulfonyl-1H-indol-3-yl) methyl acetate and 3-methoxybenzoic acid methyl ester as raw materials, under the action of acidified montmorillonite, in an inert solvent In, heat the reaction until the raw materials disappear, filter to obtain 3-methoxy-4-[(5-nitro-1-toluenesulfonyl-1H-indol-3-yl) methyl] methyl benzoate; the above compound Under alkaline conditions, hydrolysis yields the target product. The invention provides a new process route for synthesizing an important intermediate of zafirlukast, which has the technical advantages of simple operation, low reaction cost, high product yield and environmental friendliness, and can meet the demand for large-scale production of pharmaceutical products.

Description

technical field [0001] The invention belongs to the production field of fine chemical products, and particularly 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 air quality has declined, and together with hundreds of millions of smokers, the number of asthma patients in my country's large cities has increased year by year. Zafirlukast, chemical name is [3-[2-methoxy-4-[(2-methylphenyl)sulfonamidocarbonyl]benzyl]-1-methyl-1H-indole-5 Cyclopentyl methylene]carbamate is a leukotriene receptor antagonist developed by AstraZeneca in the United Kingdom. It 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, whic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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