Synthesis method of 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran

A technology of tetrazole-based, synthetic method, applied in the field of chemical pharmacy

Active Publication Date: 2014-08-13
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing reported process route of this product (J.M.C, 1988, 31 (1), 84-91) is relatively long, the reaction is cumbersome, and the utilization rate of atoms is low. Not only Wasted a lot of energy and produced many by-products

Method used

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  • Synthesis method of 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran

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preparation example Construction

[0028] The synthetic method of 8-nitro-2-tetrazolyl-4-carbonylbenzopyran of the present invention, such as figure 1 As shown, using o-hydroxyacetophenone as a starting material, it is first nitrated with nitric acid to generate a mixture of 2-hydroxyl-3-nitroacetophenone and 2-hydroxyl-5-nitroacetophenone, followed by Inorganic alkali is formed into salt for separation and purification, and then hydrolyzed with acid to obtain 2-hydroxy-3-nitroacetophenone (A-2); 2-hydroxy-3-nitroacetophenone (A-2) and cyano Ethyl formate undergoes a cyclization reaction to generate 8-nitro-2-cyano-4-carbonylbenzopyran (A-3), and finally reacts with sodium azide to generate 8-nitro-2-tetrazolium Base-4-carbonylbenzopyran (A-6); the specific process steps are:

[0029] 1) Add o-hydroxyacetophenone, acetic acid and an organic solvent into the reactor, add 63% concentrated nitric acid dropwise under stirring, and stir the reaction after the dropwise addition. After the reaction is completed, add...

Embodiment 1

[0035] In the four-necked bottle, add o-hydroxyacetophenone: 175g, acetic acid: 183g and dichloromethane: 800mL in sequence, heat up to 40 degrees under stirring, slowly add 63% concentrated nitric acid: 165g, control the temperature at 40 degrees, The dropping time is 4-6 hours. After the dropping, keep warm at 40°C for 4-6 hours. After the reaction, add water: 500g and stir for 30 minutes, extract and separate layers, and concentrate the organic layer to obtain 200g of crude product.

[0036] Add the above crude product: 200g, toluene: 900g to the four-necked bottle, raise the temperature to 60-70 degrees, add sodium carbonate: 165g, react at 70-80 degrees for 2-4 hours, cool down to 30-50 degrees, filter, and bake the filter cake After drying, add it to a four-necked bottle, add methanol: 100g, water: 800g, heat up to 50-60 degrees, slowly add acetic acid: 150g dropwise, stir at 60-70 degrees for 2 hours after dropping, drop to room temperature and filter, filter The cake w...

Embodiment 2

[0040] In the four-necked bottle, add o-hydroxyacetophenone: 175g, acetic acid: 183g and dichloroethane: 800mL in sequence, heat up to 39 degrees under stirring, slowly add 63% concentrated nitric acid: 168g, control the temperature at 39 degrees , the dropping time is 6 hours, the dropping is completed, and the temperature is kept at 40 degrees for 4-6 hours. After the reaction, add water: 500g and stir for 30 minutes, extract and separate layers, and the organic layer is concentrated to obtain 201g of crude product.

[0041] Add the above crude product: 201g, xylene: 900g to the four-necked bottle, heat up to 60 degrees, add potassium carbonate: 195g, react at 75 degrees for 3 hours, cool down to 30-50 degrees, filter, dry the filter cake and add to four In the mouth bottle, add methanol: 100g, water: 800g, heat up to 50-60 degrees, slowly add 30% hydrochloric acid: 140g dropwise, stir at 60-70 degrees for 2 hours after dropping, drop to room temperature and filter, and dry t...

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Abstract

The invention relates to a synthesis method of 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran. The method comprises the following steps: firstly nitrifying hydroxyacetophenone taken as a starting material with a nitric acid so as to generate a mixture of 2-hydroxy-3-nitroacetophenone and 2-hydroxy-5-nitroacetophenone; salifying the mixture by using an inorganic base, carrying out separation and purification and then hydrolyzing with an acid so as to obtain 2-hydroxy-3-nitroacetophenone (A-2); carrying out a cyclization reaction on the 2-hydroxy-3-nitroacetophenone (A-2) and ethyl cyanoformate so as to generate 8-nirto-2-cyano-4-oxo-4H-1-benzopyran (A-3); and finally, reacting with sodium azide so as to generate the 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran (A-6). According to the method, phosphorus oxychloride with an application risk and large pollution and an ammonia gas with strong stimulating smell are not used, so that the production is safe and environment-friendly; and the generation of waste gases is reduced at the same time, so that the synthesis process is shortened. Thus, the operation is simplified; the production cost is lowered; and the 8-nitro-2-tetrazol-5-yl-4-oxo-4H-1-benzopyran is high in purity.

Description

technical field [0001] The invention relates to a synthesis method of 8-nitro-2-tetrazolyl-4-carbonylbenzopyran, belonging to the technical field of chemical pharmacy. Background technique [0002] Pranlukast (pranlukast), the first oral LTRAs pioneered by Ono Company in Japan, was approved by the Japanese Ministry of Health and Welfare in March 1995, and was first launched in Japan in June of the same year for the treatment of asthma under the trade name Onon. Registered in Europe and America in 1996. Pranlukast (pranlukast) is a new type of anti-asthma drug listed in the mid-1990s, and it is currently one of the three leukotriene receptor antagonists (LTRAs) that are widely valued internationally. Pranlukast has an important intermediate: 8-amino-2-tetrazolyl-4-carbonyl-benzopyran, from 8-nitro-2-tetrazolyl-4-carbonyl-benzopyran Nan restored. [0003] The existing reported process route of this product (J.M.C, 1988, 31 (1), 84-91) is relatively long, the reaction is cum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 余志强曾淼徐剑锋蒋长生
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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