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Methods for preparation of nevirapine and intermediate thereof

A technology of nevirapine and an intermediate, which is applied in the field of medicinal chemistry, can solve the problems of harsh process conditions, high production cost, unsuitable for industrialized production and the like, and achieves the effects of high purity, low cost and suitable for large-scale industrialized production

Inactive Publication Date: 2015-07-15
LUNAN BETTER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires low-temperature equipment, the process conditions are harsh, and the production cost is high, so it is not suitable for industrial production

Method used

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  • Methods for preparation of nevirapine and intermediate thereof
  • Methods for preparation of nevirapine and intermediate thereof
  • Methods for preparation of nevirapine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1 crude product preparation

[0043]Weigh compound (Ⅱ) (28.2g 0.1mol), calcium oxide (5.6g 0.1mol), cyclopropylamine (14.3g 0.25mol), KI (8.3g 0.05mol) and 50ml of diethylene glycol dimethyl ether were added to in the reaction vial. Heating in an oil bath to 80°C for reflux reaction, stirring for 12 hours, suction filtration after the reaction, collecting the filtrate, distilling off unreacted cyclopropylamine under reduced pressure, and adding 60% NaH (15.2g 0.38mol) under nitrogen protection Add to 100ml of diethylene glycol dimethyl ether, heat to 130°C, add dropwise the residue after the vacuum distillation, after dropping, continue to keep warm and stir for 1 hour, then evaporate the reaction solvent, add the residue to 150ml of water, stir Then add 65ml of cyclohexane, add glacial acetic acid to adjust the pH to 7-8, continue to stir for 1h and then filter. The filter cake is rinsed twice with ethanol and dried to obtain 20.1g of khaki crude nevirapine...

Embodiment 2

[0044] Embodiment 2 crude product preparation

[0045] Add compound (II) (28.2g 0.1mol), calcium oxide (5.6g 0.1mol), cyclopropylamine (14.3g 0.25mol), NaI (7.5g 0.05mol) and diglyme to the reaction flask in sequence 50ml. Heat the oil bath to 80°C for reflux reaction, stir for 12 hours, filter with suction after the reaction, collect the filtrate, evaporate unreacted cyclopropylamine under reduced pressure, and add 60% NaH (15.2g 0.38mol) under nitrogen protection Add to 100ml of diethylene glycol dimethyl ether, heat to 130°C, add dropwise the residue after the vacuum distillation, after dropping, continue to keep warm and stir for 1 hour, then evaporate the reaction solvent, add the residue to 150ml of water, stir Cyclohexane was added, acetic acid was added to adjust the pH to 7-8, stirring was continued for 1 h and then filtered. The filter cake was rinsed twice with ethanol and dried to obtain 19.8 g of khaki crude nevirapine, with a yield of 84.5% and a purity of 98.2%...

Embodiment 3

[0046] Embodiment 3 crude product preparation

[0047] Add compound (II) (28.2g 0.1mol), calcium oxide (5.6g 0.1mol), cyclopropylamine (14.3g0.25mol), KBr (6.0g 0.05mol) and 50ml of diethylene glycol dimethyl ether into the reaction flask . Heat the oil bath to 80°C for reflux reaction, stir for 12 hours, filter with suction after the reaction, collect the filtrate, evaporate unreacted cyclopropylamine under reduced pressure, and add 60% NaH (15.2g 0.38mol) under nitrogen protection Add to 100ml of diethylene glycol dimethyl ether, heat to 130°C, add dropwise the residue after the vacuum distillation, after dropping, continue to keep warm and stir for 1 hour, then evaporate the reaction solvent, add the residue to 150ml of water, stir Add 65 ml of cyclohexane, add acetic acid to adjust the pH to 7-8, continue to stir for 1 hour, filter, rinse the filter cake twice with ethanol, and dry to obtain 19.7 g of khaki-colored crude nevirapine, with a yield of 84.2% and a purity of 9...

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Abstract

The invention provides methods for high-purity, high-yield, safe and effective preparation of nevirapine and an intermediate thereof. The method for preparation of the intermediate comprises the following specific steps: catalyzing a compound (II) 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridyl amide by KI in the presence of an organic solvent and an alkali, carrying out a reflux reaction with cyclopropylamine, and thus obtaining a compound (III) N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropyl amino)-3-pyridinecarboxamide. In the process of undergoing the reaction of the compound (II) with cyclopropylamine, the KI is added as the catalyst, the heating reflux reaction is carried out to obtain the compound (III), harsh high-temperature and high-pressure reaction conditions can be effectively avoided, risk factors brought by the need for high-pressure reaction kettles and high temperatures are overcome, and the preparation methods are safe and effective, and are convenient to operate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing nevirapine and an intermediate thereof. Background technique [0002] Nevirapine is a non-nucleoside inhibitor of HIV reverse transcriptase, which was approved by the US FDA in September 1996. The mechanism of action is to directly connect with HIV reverse transcriptase and break the catalytic end of this enzyme to block the activity of RNA-dependent and DNA-dependent DNA polymerase, thereby effectively reducing the number of viruses in the body and restoring human immune function. It is clinically used to suppress mother-to-child transmission of AIDS and is currently one of the most widely used anti-AIDS drugs. It has the characteristics of good oral absorption and convenient use. The chemical name of nevirapine is: 11-cyclopropyl-5,11-dihydro-4-methyl-6hydro-bispyrido[3,2-b:2′,3′-e][1,4] Diazepine-6-one. Chemical Molecular Formula: C 15...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14C07D213/82
CPCC07D213/82C07D471/14
Inventor 赵志全翟来生王秀娟薛飞
Owner LUNAN BETTER PHARMA
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