Preparation method of nevirapine intermediate spherical crystal

A spherical crystal, nevirapine technology, applied in the field of medicinal chemistry, to achieve the effects of good reproducibility of the preparation process, high crystallization yield and high crystal purity

Inactive Publication Date: 2017-07-11
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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DSC scanning shows that the mel

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  • Preparation method of nevirapine intermediate spherical crystal
  • Preparation method of nevirapine intermediate spherical crystal
  • Preparation method of nevirapine intermediate spherical crystal

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[0045] The preparation method of the compound II reaction liquid in the present invention refers to the synthesis methods disclosed in patents US5569760, DE4403311, WO2007010352, and US5366972, and the method is as follows:

[0046] 117.5g of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide, 47.5g of cyclopropylamine, 46.7g of calcium oxide, 125-375ml of organic solvent (the organic solvent can be Any one selected from toluene, xylene, dioxane, ethylene glycol dimethyl ether or N,N-dimethylformamide) is added into a pressure reactor, and the temperature is controlled at 135-140° C. to stir and react. After the reaction was completed, the temperature was lowered to 100-120°C, and the calcium oxide filter residue was removed by filtration to obtain 125 g of compound II (11-cyclopropyl-5,11-dihydro-4-methyl-6 hydrogen-bipyridine-[3,2 -b: a reaction solution of 2,3-e][1,4]diazepine).

Embodiment 1

[0048] The xylene (125ml) reaction solution containing 125g of compound II was heated to reflux to dissolve. After dissolving and clearing, the reaction solution was slowly added dropwise to 125ml of xylene at 5-10°C, and the temperature of the crystallization solution was controlled at 20-40°C during the dropping process. After the dropwise addition, the temperature was lowered to -5~5°C. After filtration, vacuum drying at 90°C, and discharge, 114.0 g of spherical Compound II crystals were obtained, with an HPLC purity of 99.1% and a yield of 91.2%. result:

[0049] HPLC test, DSC test and XRD test were performed on the obtained compound II crystal.

[0050] figure 1 It is the compound II crystal HPLC collection of patterns that embodiment 1 obtains, from figure 1 As can be seen in the figure, the purity of the crystal reaches 99.1%.

[0051] figure 2 It is the DSC collection of illustrative plates of the compound II crystal that embodiment 1 obtains, from figure 2...

Embodiment 2

[0056] The xylene (250ml) reaction solution containing 125g of compound II was heated to reflux to dissolve. After dissolving and clearing, the reaction solution was slowly added dropwise into 62.5ml of xylene at 5-10°C, and the temperature of the crystallization solution was controlled at 20-30°C during the dropping process. After the dropwise addition, the temperature was lowered to -5~5°C. After filtration, vacuum drying at 90°C, and discharge, 107.0 g of spherical Compound II crystals were obtained, with an HPLC purity of 99.3% and a yield of 85.6%.

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Abstract

The invention provides a preparation method of a nevirapine intermediate spherical crystal. The method concretely comprises the following steps: heating a reaction solution of a nevirapine intermediate 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2,3-e][1,4]diazepine to make the solution clarified, slowly dropwise adding the reaction solution to a crystallization solvent with the temperature controlled to be 10-40 DEG C, controlling the temperature of the crystallization system to be 0-50 DEG C during the dropwis adding, cooling the system to -10-10 DEG C after the dropwise adding is finished, filtering the solution, and drying the filtered solution to obtain the nevirapine intermediate spherical crystal. The method fills the gap in the prior art, the prepared spherical crystal has the advantages of small density and good fluidity of a crystal slurry, easiness in separation and drying, single solvent, low solvent rate, high crystallization yield, simple preparation method and high purity, and the preparation method has the advantages of easiness in commercial large-scale production, and very high promotion and application values.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a nevirapine intermediate 11-cyclopropyl-5,11-dihydro-4-methyl-6 hydrogen-bipyridine-[3,2-b:2,3-e ][1,4]diazepine spherical crystal and its preparation method. Background technique [0002] Nevirapine, chemical name 11-cyclopropyl-5,11-dihydro-4-methyl-6 hydrogen-bipyridine-[3,2-b:2,3-e][1,4] Diazepine-6-one, its chemical structural formula is: [0003] [0004] Nevirapine is a non-nucleoside reverse transcriptase inhibitor developed by Boehringer Ingelheim, Germany. It was approved by the US FDA in September 1996. Its trade name is Viramune, and it is now on the market in many countries. Nevirapine is a highly selective, non-competitive HIV-1 viral reverse transcriptase inhibitor, and its use with nucleoside reverse transcriptase inhibitors or protease inhibitors can be used to treat AIDS, in the formulation of AIDS cocktail therapy , Nevirapine has always been an indisp...

Claims

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Application Information

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IPC IPC(8): C07D213/82
CPCC07B2200/13C07D213/82
Inventor 钱刚张林祥张文灵
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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