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A kind of preparation method of atazanavir

A technology of phenyl and pyridine, which is applied in the field of preparation of atazanavir, can solve the problems of unsuitability for industrialized production, complex separation and purification of products, and achieve the effects of less pollutants, low equipment and operation requirements, and low price

Active Publication Date: 2015-08-19
瑞博(杭州)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In this patent, DEPBT is used as the condensing agent, reacted in THF and N,N-diisopropylethylamine, the yield is only 55%, and the separation and purification of the product is complicated, and it needs to be separated by a chromatographic column, which is not suitable for industrialization Production

Method used

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Examples

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Effect test

Embodiment 1

[0033] Example 1: Preparation of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane

[0034] In a clean reaction flask, add 11.25g (20mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-bis[( To tert-butoxycarbonyl)amino]-6-phenyl-2-azidine and 45ml of dichloromethane, add 9.3g of hydrochloric acid dropwise; after dropping, raise the temperature to 40~45°C for about 3h; TLC analysis tracking, After the reaction is complete, cool down to 25°C, add 13.2g of N-methylmorpholine, stir at this temperature for 1 h, separate layers, dry the organic layer with anhydrous sodium sulfate for 1 hour, filter, rinse the filter cake with a small amount of solvent, and depressurize Concentration to dryness afforded 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-nitrogen as a solid Heterohexane 6.87g, yield 95.2%.

Embodiment 2

[0035] Example 2: Preparation of atazanavir monomer

[0036] In a clean reaction flask, add 6.87g of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-diamino-6-benzene Base-2-azahexane, 50ml of dichloromethane and 3.83g of N-methylmorpholine, then added 4.16g (22mmol) of N-methoxycarbonyl-L-tert-leucine and 7.2g (24mmol ) of DEPBT, stirred at 35°C for 2h, followed by TLC analysis until the end of the reaction. Add 40ml of 2% sodium hydroxide dropwise, stir for 0.5h, let stand to separate layers, wash the organic layer with 2*40ml of water, remove dichloromethane under reduced pressure, add 2*40ml of ethanol, concentrate to dryness under reduced pressure; in the residual liquid Add 45ml of ethanol and 55ml of water, heat to 60°C, slowly cool down to about 0°C, stir for 3 hours, filter with suction, wash the filter cake with 0°C ethanol and water (1:2), and wash the mixture twice (40ml) , drained, and dried to obtain 11.28 g of solid atazanavir monomer. Yield: 84.1%

Embodiment 3

[0037] Example 3: Preparation of atazanavir sulfate

[0038]At room temperature of 25°C, dissolve 70.5g of atazanavir monomer in 700g of acetone, slowly add 5M 40.4g of concentrated sulfuric acid dropwise under stirring, and keep warm at this temperature for 2h after the dropping; after the heat preservation is over, cool down To 0 ~ 5 ℃, stirring for 2h. After suction filtration, the filter cake was washed twice with 150ml of acetone, and dried to obtain 76.3g of the product atazanavir sulfate, with a yield of 95.4%.

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Abstract

The present invention relates to the field of chemical medicaments. Disclosed is an Atazanavir preparation method, with a reaction formula as represented in figure (I). The present invention uses DEPBT as a condensing agent; 1-[4-(pyridine-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2, 5-diamino-6- phenyl-2-azahexane is reacted with N-methoxycarbonyl-L-tertiary leucine in an organic solvent to give the Atazanavir. The condensing agent normally used in the reaction in existing literatures is TPTU, a combination of carbon diimine compounds and benzotriazole compounds, or only the carbon diimine compounds. However, the compounds are expensive, toxic and heavily pollutive. The present invention uses inexpensive, safe and environment-friendly DEPBT as the condensing agent, and provides an economically feasible, safe and environment-friendly Atazanavir preparation method with high yield and easy product separation.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of atazanavir. Background technique [0002] Atazanavir, the English name Atazanavir, is an open-chain azapeptidomimetic compound developed by Bristol-Myers Squibb, and is a novel HIV-1 protease inhibitor. Its chemical structure is shown in Formula 1 below, [0003] . [0004] The product was launched in the U.S. and Europe on June 20, 2003 and March 2, 2004, respectively. The drug ingredient in the marketed dosage form is atazanavir sulfate (trade name: Reyataz). [0005] Example 46 of patent US5849911 (applied date: April 9, 1997) applied by Swiss Novartis Company first disclosed atazanavir and its preparation method, one of which is the preparation method of atazanavir comprising the following steps, [0006] . [0007] The compound of formula 2 is under the action of condensing agent O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/42
CPCC07D213/42
Inventor 车大庆朱国良
Owner 瑞博(杭州)医药科技有限公司
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