Method for synthesis of atazanavir

A synthetic method and compound technology, applied in the field of preparation of protease inhibitors, can solve the problems of many synthetic steps and high production cost, and achieve the effects of simplified synthetic steps, simple operation and simple process flow

Active Publication Date: 2018-01-05
湖州优研知识产权服务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This preparation method is the same as the original route when constructing the basic skeleton of the compound, but the chiral epoxy intermediate is prepared from the more expensive chiral diol through a 4-step reaction through a protecting group strategy. Compared with the original route, this route has improved The optical purity of intermediates, but more synthesis steps and higher production costs

Method used

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  • Method for synthesis of atazanavir
  • Method for synthesis of atazanavir
  • Method for synthesis of atazanavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]Formula V compound (S)-1-((S)-2-oxiranyl-1-phenylethane-2-yl-amino)-3,3-dimethyl-1-carbonylbutane-2 The synthetic method of -base-carbamate methyl ester comprises the steps:

[0039] 1) Formula I compound L-phenylalanine (74.6g, 451.9mmol) reacts with N-methoxycarbonyl-L-tert-leucine (90.8g, 480.0mmol) in 1000ml of dichloromethane, using a condensing agent of (150 g, 0.5 mol) of 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-one DEPBT and (50 g, 0.26 mol) of 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide DECI mixture, add 20ml triethylamine, and react at 0-20°C for 6-10h to obtain formula II compound (S)-1-((S )-phenylpropanoic acid-2-yl-amino)-3,3-dimethyl-1-carbonylbutan-2-yl-carbamate methyl ester (138.6 g, 412.1 mmol);

[0040] 2) Add 138.6g of the compound of formula II to a mixed solvent of tetrahydrofuran and ether, first add isobutyl chloroformate and react in ice bath for 20min, then add diazomethane for 3h, then add hydrogen bromide and react for 40min at -20...

Embodiment 2

[0046] Under nitrogen protection, triethylamine (21.9 mL, 158.5mmol), stirred at room temperature for 1 hour, added a solution of ethanol (250ml) dissolved in the compound of formula VII 4-(2-pyridyl)-benzaldehyde (65.1g, 355.6mmol), refluxed at 45°C for 5h, and cooled to room temperature , adding LiAlH 4 (8g, 0.25mol), hydrogenated at normal pressure for 12 hours. Filtration, the filtrate was concentrated, and the resulting crude product was recrystallized with isopropanol to obtain formula VIII compound N-1-[N-(methoxycarbonyl)-L-tert-leucine base]-N-2-[4-( 2-pyridyl)-benzyl]hydrazine (122.2g, 330.0mmol);

[0047] The reaction formula is as follows:

[0048]

Embodiment 3

[0050] (102.0g, 305.0mmol) Formula V compound (S)-1-((S)-2-oxiranyl-1-phenylethane-2-yl-amino)-3,3-dimethyl- 1-Carbonylbutane-2-yl-methyl carbamate and (122.2g, 330.0mmol) compound of formula VIII N-1-[N-(methoxycarbonyl)-L-tert-leucine base]-N-2 -[4-(2-Pyridyl)-benzyl]hydrazine was dissolved in 500ml of isopropanol, refluxed at 90°C for 12h, cooled, slowly added 1000ml of distilled water, stirred for 2h, left standing, filtered, washed with water, and then washed with ethanol Water recrystallization, vacuum drying, liquid phase detection, obtain 201.3g formula IX compound 1-[4-(2-pyridyl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl )-L-tert-leucine base]amino}-4(S)-hydroxyl-6-phenyl-2-azahexaneⅧ, which is atazanavir.

[0051] The reaction formula is as follows:

[0052]

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Abstract

The invention discloses a method for synthesis of atazanavir. The method comprises that a compound methyl (S)-1-((S)-2-ethoxyethyl-1-phenylethane-2-yl-amino)-3, 3-dimethyl-1-carbonylbutane-2-yl-carbamate shown in the formula V and a compound N-1-[N-(methoxycarbonyl)-L-tertiary leucine]-N-2-[4-(2-pyridyl)-benzyl]hydrazine shown in the formula VIII undergo a nucleophilic substitution reaction in anorganic solvent to produce a compound 1-[4-(2-pyridyl)phenyl]-5(S)-2, 5-bis{[N-(methoxycarbonyl)-L-tertiary leucine]amino}-4(S)-hydroxy-6-phenyl-2-azahexane VIII shown in the formula IX, wherein the compound shown in the formula IX is atazanavir. The method utilizes raw materials having a wide raw material source, the product is easy to purify, a cost is low, the synthesis processes are simple, the operation is simple, the process is simple, special requirement on equipment is avoided and large-scale production feasibility is realized.

Description

technical field [0001] The invention relates to a preparation method of a protease inhibitor, in particular to a synthesis method of atazanavir. Background technique [0002] Human immunodeficiency virus (HIV) is the pathogen that causes acquired immunodeficiency syndrome (AIDS). During the infection cycle of HIV virions, viral proteases are functional enzymes that cleave polyproteins into structural proteins. Therefore, targeting viral protease inhibitors has become an effective method for the treatment of AIDS. [0003] Atazanavir is an open-chain azapeptidomimetic compound and a novel protease inhibitor. Compared with other protease inhibitors, atazanavir has two significant advantages. First, it is the only protease inhibitor that is allowed to be taken once a day, which will greatly simplify the dosage course; second, atazanavir has not yet been shown to increase the patient's Cholesterol and triglyceride levels, a challenge that all other protease inhibitors encount...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/42
Inventor 陈建华胡磊黄小明
Owner 湖州优研知识产权服务有限公司
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