Method for preparing A-type crystal of Atazanavir disulfate

A technology of bisulfate and atazanavir is applied in the field of preparation of type A crystal of atazanavir bisulfate, which can solve the problems of harsh speed requirements, poor process stability and high purity requirements of concentrated sulfuric acid, and is convenient for industrial production. , The effect of high crystal purity and high product yield

Inactive Publication Date: 2016-08-17
SHANGHAI SHYNDEC PHARMA HAIMEN CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above methods all use acetone to directly form a salt to form A-type crystals, which have the following defects: difficult to filter; 1.0%), the speed of adding concentrated sulfuric acid is demanding (three crystallization technology or improved three crystallization technology), adding sulfuric acid at an increased rate according to the cubic equation, the operation is troublesome and difficult to control

Method used

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  • Method for preparing A-type crystal of Atazanavir disulfate
  • Method for preparing A-type crystal of Atazanavir disulfate
  • Method for preparing A-type crystal of Atazanavir disulfate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation method of atazanavir bisulfate type A crystal comprises the steps:

[0044] a) Add the compound atazanavir free base (100.0g, 142mmol) and ethanol (750mL) into a three-necked flask (1000mL) at room temperature (25°C) and maintain the temperature at 25-30 o C stirred for 30 minutes, the reaction solution was a white or off-white suspension, and concentrated sulfuric acid (8.6mL, 0.05mL / s) was slowly added dropwise to the reaction solution, the solution gradually became clear, and the solution was heated to 35-40 o C, add atazanavir ethanolate type E crystal as seed crystal (4.26 mmol), stir for 15-20min, add 750ml of n-heptane (1 hour) and stir, cool to 15-25 o C. Stir the resulting crystalline mixture for 6-8 hours, collect the solid by filtration, wash the filter cake with ethanol / n-heptane=1:1 (10mL), and after drying, obtain about 102g of white or off-white powdery solid Azana Ethanol compound type E crystals, HPLC purity 99.90%, maximum single impu...

Embodiment 2

[0047] a) Add the compound atazanavir free base (100.0g, 142mmol) and ethanol (500mL) into a three-necked flask (1000mL) at room temperature (22°C) and maintain the temperature at 22-30 o C stirred for 30 minutes, the reaction solution was a white or off-white suspension, and concentrated sulfuric acid (8.3mL, 0.05mL / s) was slowly added dropwise to the reaction solution, the solution gradually became clear, and the solution was heated to 30-35 o C, add atazanavir ethanolate type E crystal as seed crystal (2.84 mmol), stir for 15-20min, add 600ml of n-heptane (1 hour) and stir, cool to 15-25 o C. Stir the resulting crystalline mixture for 6-8 hours, collect the solid by filtration, wash the filter cake with ethanol / n-heptane=1:1 (10mL), and after drying, obtain about 100g of white or off-white powdery solid Azana Ethanol compound E crystals. HPLC purity is 99.87%, the maximum single heterogeneity is 0.04%, and diastereomers and enantiomers are not detected; GC solvent residue...

Embodiment 3

[0050] a) Add the compound atazanavir free base (100.0g, 142mmol) and ethanol (2000mL) into a three-necked flask (5000mL) at room temperature (22°C) and maintain the temperature at 22-30 o C stirred for 30 minutes, the reaction solution was a white or off-white suspension, and concentrated sulfuric acid (8.8mL, 0.05mL / s) was slowly added dropwise to the reaction solution, the solution gradually became clear, and the solution was heated to 40-45 o C, add atazanavir ethanolate type E crystal as seed crystal (5.68 mmol), stir for 15-20min, add 1600ml of n-heptane (1 hour) and stir, cool to 15-25 o C. Stir the resulting crystalline mixture for 6-8 hours, collect the solid by filtration, wash the filter cake with ethanol / n-heptane=1:1 (10mL), and after drying, obtain about 100g of white or off-white powdery solid Azana Ethanol compound E crystals. The HPLC purity is 99.80%, the maximum single heterogeneity is 0.05%, and diastereomers and enantiomers are not detected; GC solvent r...

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Abstract

The invention discloses a method for preparing an A-type crystal of Atazanavir disulfate. The method comprises the following steps that a, Atazanavir free alkali is placed in ethyl alcohol, the mixture is stirred at room temperature, then concentrated sulfuric acid is added dropwise, the reaction liquid is heated and stirred, then an inert solvent is added, cooling and crystallization are carried out, drying is carried out after filtering, and an Atazanavir ethyl alcohol compound E-type crystal is obtained, wherein the molar concentration of concentrated sulfuric acid is preferably 15 mol / L to 18.4 mol / L; b, the Atazanavir ethyl alcohol compound E-type crystal obtained in the step a is placed in acetone, heating, refluxing and stirring are carried out, drying is carried out after cooling and filtering, and the A-type crystal of Atazanavir disulfate is obtained. According to the crystal transformation preparation method, the operability of the process is improved, the external properties of the product are improved, and the quality and purity of the product are improved.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing atazanavir bisulfate type A crystals. Background technique [0002] Atazanavir Sulfate, trade name Reyataz, was developed by Bristol-Myers Squibb and was approved by the US FDA in June 2003. It is mainly used in combination with other antiretroviral drugs to treat HIV infection . [0003] Atazanavir sulfate or atazanavir bisulfate, chemical name is (3S, 8S, 9S, 12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4, 11-Dioxo-9-(phenylmethyl)-6-[[4-(2-pyrimidine)phenyl]methyl]-2, 5,6, 10, 13-pentaazatetradecanedioic acid Dimethyl sulfate (1:1), the structure is as follows: [0004] . [0005] Atazanavir hydrogen sulfate exists in various crystal forms including hydrates and solvates. Its pharmaceutical crystal form is anhydrous, non-solvated crystal form A (US 6087383 reported its crystal form and preparation method for the first time). [0006] US...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/42
CPCC07D213/42C07B2200/13
Inventor 黄军海卜永海葛渊源张一凯何康永于振鹏唐祁匀
Owner SHANGHAI SHYNDEC PHARMA HAIMEN CO LTD
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