Synthesis method for Nevirapine intermediates

A synthetic method and intermediate technology, applied in the field of intermediate synthesis, can solve the problems of complex reaction processing, environmental damage, etc., and achieve the effects of high yield, reduced pollution, and low cost

Inactive Publication Date: 2013-03-06
上海思协化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by this invention is in order to overcome the preparation method of the intermediate 2-chloro-N-(2-chloro-4-methylpyridin-3-yl) nicotinamide of existing nevirapine, during nitration reaction Produce a large amount of reddish-brown gas and produce two kinds of isomers, thereby cause follow-up reaction processing to be complicated and use noble metal palladium, cause the defect of huge damage to the environment, and provide a kind of synthetic method of the intermediate of nevirapine

Method used

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  • Synthesis method for Nevirapine intermediates
  • Synthesis method for Nevirapine intermediates
  • Synthesis method for Nevirapine intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] (1) Synthesis of 2-amino-3-nitro-4-picoline

[0043] In a reaction flask, add 200ml of toluene and 1000g of 95% concentrated sulfuric acid, start stirring, and slowly add 108g of 2-amino-4-picoline and 10g of barium hydroxide in batches at 25°C, and stir until completely dissolved. Then, 330 g of 20% dilute nitric acid was slowly added dropwise, and after the addition was completed, the mixture was incubated at 25° C. for 5 hours. That is the reaction solution.

[0044] In another reaction bottle, add 1000ml of water, start stirring, cool to 10°C, slowly add the above reaction solution into water, control the temperature at 10°C, after the addition is complete, adjust the pH to 8-8.5 with ammonia water, collect the solid, A mixture of 2-amino-3-nitro-4-picoline and 2-amino-4-methyl-5-nitropyridine is obtained. Its molar ratio is: 2-amino-3-nitro-4-picoline:2-amino-4-methyl-5-nitropyridine=100:5.

[0045] The above mixture was recrystallized from absolute ethanol to o...

Embodiment 2

[0055] (1) Synthesis of 2-amino-3-nitro-4-picoline

[0056] In a reaction flask, add 200ml of xylene and 1000g of concentrated sulfuric acid, start stirring, and slowly add 108g of 2-amino-4-picoline and 10g of zinc hydroxide in batches at 35°C, and stir until completely dissolved. Then, 220 g of 30% dilute nitric acid was slowly added dropwise, and after the addition was completed, the mixture was incubated at 35° C. for 5 hours. That is the reaction solution.

[0057] In another reaction bottle, add 1000ml of water, start stirring, cool to 10°C, slowly add the above reaction solution into water, control the temperature at 10°C, after the addition is complete, adjust the pH to 8-8.5 with ammonia water, collect the solid, A mixture of 2-amino-3-nitro-4-picoline and 2-amino-4-methyl-5-nitropyridine is obtained. Its molar ratio is: 2-amino-3-nitro-4-picoline:2-amino-4-methyl-5-nitropyridine=100:4.

[0058] The above mixture was recrystallized with propanol to obtain 146.50 g ...

Embodiment 3

[0068] (1) Synthesis of 2-amino-3-nitro-4-picoline

[0069] In a reaction flask, add 150ml and 1000g of toluene concentrated sulfuric acid, start stirring, and slowly add 108g of 2-amino-4-picoline and 8g of aluminum hydroxide in batches at 45°C, and stir until completely dissolved. Then, 165 g of 40% dilute nitric acid was slowly added dropwise, and after the addition was completed, it was incubated at 45° C. for 5 hours. That is the reaction solution.

[0070] In another reaction bottle, add 1000ml of water, start stirring, cool to 10°C, slowly add the above reaction solution into water, control the temperature at 10°C, after the addition is complete, adjust the pH to 8-8.5 with ammonia water, collect the solid, A mixture of 2-amino-3-nitro-4-picoline and 2-amino-4-methyl-5-nitropyridine is obtained. Its molar ratio is: 2-amino-3-nitro-4-picoline:2-amino-4-methyl-5-nitropyridine=100:3.

[0071] The above mixture was recrystallized from tert-butanol to obtain 148.0 g of pu...

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Abstract

The invention discloses a synthesis method of a nevirapine intermediate 2-amino-3-nitro-4-methylpyridine shown as the chemical formula I. The synthesis method includes steps: under catalysis of inorganic base or organic base and actions of concentrated sulphuric acid and dilute nitric acid, subjecting the 2-amino-3-nitro-4-methylpyridine shown as the chemical formula I to nitration reaction in organic solvent. The inorganic base can be calcium hydroxide, barium hydroxide, sodium hydroxide or zinc hydroxide; and the organic base can be sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butylate. The invention further discloses a synthesis method of a nevirapine intermediate 2-chloro-N-(2-chloro-4-methylpyridin-3-yl)nicotinamide. The synthesis method is easy and safe in operation, high in yield, low-cost, low in pollution to environments and suitable for industrial production in scale.

Description

technical field [0001] The present invention specifically relates to a synthetic method of an intermediate of nevirapine. Background technique [0002] 2-Chloro-N-(2-chloro-4-methylpyridin-3-yl)nicotinamide is an important intermediate for the synthesis of nevirapine. Nevirapine is an anti-AIDS drug developed by Boehringer Ingelheim in Germany to prevent mother-to-child transmission of HIV. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI) of HIV-1. Nevirapine is directly linked to the reverse transcriptase of HIV-1 and blocks RNA-dependent and DNA-dependent DNA polymerase activity by breaking the catalytic end of the enzyme, thereby effectively reducing the number of viruses in the body and restoring human immune function. Nevirapine is currently one of the most widely used anti-AIDS drugs, mainly for the prevention and treatment of mother-to-child virus transmission. Therefore, it is of great significa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73C07D213/82
Inventor 邱炳开
Owner 上海思协化工科技有限公司
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