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A kind of preparation method of pranlukast

A reaction and solvent technology, applied in the field of medicine, can solve problems such as long synthetic routes, many synthetic steps, and long routes

Active Publication Date: 2020-07-07
烟台万润药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires many raw material synthesis steps, long route and low yield, resulting in high cost
[0009] And some other reported methods such as patent WO9734885 report are the method for preparing 8-amino-4-oxo-2-tetrazol-5-yl-4H-benzopyran; patent CN104387268A reports for the preparation of 4-butoxy The method of benzoic acid is also all about the preparation method of the two most commonly used starting materials required for the synthesis of pranlukast, and there is also the problem of long synthetic route and high cost

Method used

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  • A kind of preparation method of pranlukast
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  • A kind of preparation method of pranlukast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Synthesis of ethyl 2-iodo-3-(4-bromobenzamide)benzoate

[0035] Add 20.1g (0.1mol) of 4-bromobenzoic acid and 100mL of ethyl acetate to a 250mL three-necked flask, start stirring and heat up to 50-60°C, add 13.1g (0.11mol) of thionyl chloride dropwise, after the dropwise addition is completed , continue to stir for 0.5 hours, then concentrate to dryness, add 100mL ethyl acetate to the residue and shake well for later use, add 29.1g (0.1mol) ethyl 3-amino-2-iodobenzoate and 300mL acetic acid to a 500mL three-necked flask Ethyl ester and 11.85g (0.15mol) pyridine, add the above standby solution dropwise at 20-30°C (dropping temperature is generally in the range value), after the drop is completed, the temperature is raised to 80°C, and the reaction is kept for 5 hours. TLC detects that the reaction is complete. Stir and cool down to 20°C, precipitate the product, and filter to obtain 45.03g of off-white solid with a yield of 95.06% and a purity of 99.2%.

[0036] (2)...

Embodiment 2

[0041] (1) Synthesis of ethyl 2-iodo-3-(4-bromobenzamide)benzoate

[0042] Add 20.1g (0.1mol) of 4-bromobenzoic acid and 100mL of ethyl acetate to a 250mL three-necked flask, start stirring and raise the temperature to 60°C, add 13.1g (0.11mol) of thionyl chloride dropwise, after the dropwise addition is complete, continue Stir for 0.5 hours, then concentrate to dryness, add 100mL ethyl acetate to the residue and shake well for later use, add 29.1g (0.1mol) ethyl 3-amino-2-iodobenzoate and 300mL ethyl acetate to a 500mL three-necked flask and 15.15g (0.15mol) of triethylamine, add the above-mentioned standby solution dropwise between 20 and 30°C, raise the temperature to 80°C after dropping, keep the temperature for 5h, TLC detects that the reaction is complete, stir and cool down to 20°C, precipitate the product, filter , to obtain 40.1 g of off-white solid with a yield of 84.65% and a purity of 98.3%.

[0043] (2) Synthesis of 4-bromo-N-(4-oxo-2-(1H-tetrazol-5-yl)-4H-benzop...

Embodiment 3

[0048] (1) Synthesis of ethyl 2-iodo-3-(4-bromobenzamide)benzoate

[0049] Add 20.1g (0.1mol) of 4-bromobenzoic acid and 100mL of tetrahydrofuran to a 250mL three-necked flask, start stirring and heat up to 60°C, add 13.1g (0.11mol) of thionyl chloride dropwise, and continue stirring for 0.5 hour, and then concentrated to dryness, 100mL tetrahydrofuran was added to the residue and shaken for subsequent use, and 29.1g (0.1mol) ethyl 3-amino-2-iodobenzoate and 300mL tetrahydrofuran and 11.85g (0.15mol ) pyridine, add the above standby solution dropwise at 20-30°C, heat up to 70°C after dropping, keep warm for 4-5 hours, TLC detects that the reaction is complete, stir and cool down to 20°C, precipitate the product, filter to obtain 44.32g off-white Solid, yield 93.56%, purity 99.47%.

[0050] (2) Synthesis of 4-bromo-N-(4-oxo-2-(1H-tetrazol-5-yl)-4H-benzopyrone-8-yl)benzamide

[0051] In a 500mL three-necked flask, add 10.48g (0.093mol) 1-(1H-tetrazol-5-yl)ethanone, 45.03g (0.0...

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Abstract

The invention belongs to the field of medicines and especially relates to a preparation method for pranlukast. The method comprises the following steps: A) adding 4-bromobenzoic acid and thionyl chloride into a solvent and reacting, thereby acquiring 4-bromo-benzoyl chloride; B) adding the 4-bromo-benzoyl chloride acquired in the step A), alkali and 3-amino-2-ethyl iodobenzoate into the solvent and reacting, thereby acquiring 2-iodine-3-(4-bromobenzamide) ethyl benzoate; C) adding the 2-iodine-3-(4-bromobenzamide) ethyl benzoate acquired in the step B), alkali and 1-(1H-tetrazole-5-group) aceton into the solvent and reacting, thereby acquiring 4-bromine-N-(4-oxo-2-(1H-tetrazole-5-group)-4H-benzopyrone-8-group) benzamide; D) adding the 4-bromine-N-(4-oxo-2-(1H-tetrazole-5-group)-4H-benzopyrone-8-group) benzamide acquired in the step C), catalyst and alkali into the solvent and reacting, thereby acquiring the product. The method provided by the invention is simple and practicable in process, low in production cost and high in yield.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a preparation method of pranlukast. Background technique [0002] Pranlukast hemihydrate, the structure is as follows: [0003] [0004] Pranlukast was developed by Ono Company in Japan. It is a leukotriene receptor antagonist. It has clinically good therapeutic effects not only on atopic asthma but also on other types of bronchitis asthma, with low toxicity and no adverse effects. reaction. It went on the market in Japan in 1995, and in 1999 it was found to be able to treat allergic rhinitis. It is one of the hot spots in the development and research of asthma drugs in recent years. [0005] There are two main methods for the commercial production of pranlukast generally adopted at home and abroad at present: [0006] The first method is to use 3-((4-(4-phenylbutoxy) benzoic acid amine)-2-hydroxyacetophenone (PBHA) reported in patent WO9412492 as raw material, in polar solvent, str...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 马志珂马振堂乔仁国杨光程振龙刘德宁张雪易朝辉
Owner 烟台万润药业有限公司
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