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Method for preparing A type atazanavir sulfate

A technology of atazanavir sulfate and concentrated sulfuric acid, applied in directions such as organic chemistry, can solve problems such as cumbersome operation, unfavorable for industrialized production, etc., and achieve the effects of low cost and short preparation period

Active Publication Date: 2014-10-15
SHANGHAI DESANO CHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is easy to produce toxic and harmful substances (genotoxic impurities) when preparing A-type atazanavir sulfate. In addition, this method adopts a cubic equation multi-stage dripping method when adding sulfuric acid, which is cumbersome to operate and is not conducive to industrialization. Production

Method used

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  • Method for preparing A type atazanavir sulfate
  • Method for preparing A type atazanavir sulfate
  • Method for preparing A type atazanavir sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Atazanavir free base (150g, 212.8mmol) is added in the mixed solvent that is formed by 2250mL ethyl acetate and 150mL DMSO, stirs and heats up under argon atmosphere, after the system dissolves clear, add 1.5g gac decolorization (system temperature is at 50~60℃), filter to obtain a clear solution; control the temperature at 35±5℃, add concentrated sulfuric acid (11.82mL, 212.8mmol) dropwise to the prepared clear solution; after dropping, keep stirring for 1~2 hours; Slowly (about 30-60 minutes) cool down to 0-15°C, filter, wash the filter cake with ethyl acetate 2-3 times, and vacuum-dry at 40-60°C for 5-8 hours to obtain 158g of atazanavir sulfate , the molar yield was 92.5%, the HPLC purity was >99.5%, and the maximum simplex was <0.1%.

[0030] The FTIR collection of illustrative plates of the atazanavir sulfate that the present embodiment obtains is as figure 1 As shown, the DSC spectrum is as figure 2 As shown, the XRPD pattern is as image 3 Shown; Because the...

Embodiment 2

[0032] Atazanavir free base (10g, 14.19mmol) is added in the mixed solvent that is formed by 120mL ethyl acetate and 10mL DMSO, stirs and heats up under argon atmosphere, after the system dissolves clear, add 0.1g active carbon decolorization (system temperature is at 50~60℃), filter to obtain a clear solution; control the temperature at 35±5℃, add concentrated sulfuric acid (0.8mL, 14.4mmol) dropwise to the prepared clear solution; after dropping, keep stirring for 1~2 hours; Slowly (about 30-60 minutes) cool down to 0-15°C, filter, wash the filter cake with ethyl acetate 2-3 times, and vacuum-dry at 40-60°C for 5-8 hours to obtain atazanavir sulfate 10.6 g, the molar yield is 93.0%, the HPLC purity is >99.5%, and the maximum simplex is <0.1%.

[0033] The atazanavir sulfate that the present embodiment obtains also has figure 1 The FTIR spectrum shown, figure 2 The DSC spectrum shown and image 3 The XRPD pattern shown is for atazanavir sulfate Form A.

Embodiment 3

[0035] Atazanavir free base (10g, 14.19mmol) is added in the mixed solvent that is formed by 120mL isopropyl acetate and 10mL DMSO, stirs and heats up under argon atmosphere, after the system dissolves clear, add 0.1g activated carbon decolorization (system temperature (50-60°C), filter to obtain a clear solution; control the temperature at 35±5°C, add concentrated sulfuric acid (0.8mL, 14.4mmol) dropwise to the prepared clear solution; after dropping, keep stirring for 1-2 hours Slowly (about 30-60 minutes) cool down to 0-15°C, filter, wash the filter cake with isopropyl acetate for 2-3 times, and vacuum-dry at 40-60°C for 5-8 hours to obtain atazanavir sulfate Salt 10.3g, molar yield 90.4%, HPLC purity > 99.5%, maximum simplex < 0.1%.

[0036] The atazanavir sulfate that the present embodiment obtains also has figure 1 The FTIR spectrum shown, figure 2 The DSC spectrum shown and image 3 The XRPD pattern shown is for atazanavir sulfate Form A.

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Abstract

A disclosed method for preparing A type atazanavir sulfate comprises the following steps: step a) adding atazanavir free alkali into an organic solvent to prepare a transparent solution at a controlled temperature of 10-65 DEG C, wherein the organic solvent is at least one selected from dimethyl sulfoxide, ester solvents and ether solvents; step b) dropwise adding concentrated sulfuric acid into the transparent solution prepared in the step a); step c) after adding is finished, stirring for 0.5-10 h under the condition of thermal insulation; and step d) cooling, filtering, washing and drying. By selecting the specific solvent, the high-purity A type atazanavir sulfate is prepared at a high yield through simplest operations. The preparation period is short, the cost is low, no special equipment and no harsh conditions and operations are needed, and the method is extremely suitable for large-scale production and has practical value.

Description

technical field [0001] The invention relates to a method for preparing A-type atazanavir sulfate, which belongs to the technical field of organic chemistry. Background technique [0002] Atazanavir is an oral HIV protease inhibitor developed and marketed by Bristol-Myers Squibb. It was approved by the U.S. FDA in 2003, and its trade name is Rietuo. [0003] Novartis disclosed a group of heterocyclic azahexane derivatives with antiviral activity in patent WO9740029 applied for in 1997, including atazanavir, and Bristol-Myers Squibb disclosed sulfuric acid in patent WO9936404 applied for in 1998 Atazanavir. [0004] At present, reports on the crystal forms of atazanavir sulfate mainly include Type A, Type C, Type E3, Type H1, Type B, Type P and Amorphous Form, among which Type A, Type C and Type E3 are produced by BEST According to the application of My Squibb Company, type A is an ansolvate crystal form, type C is a hydrate crystal form, and type E3 is a solvate containing ...

Claims

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Application Information

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IPC IPC(8): C07D213/42
CPCC07D213/42
Inventor 李金亮赵楠王猛
Owner SHANGHAI DESANO CHEM PHARMA
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