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Preparation methods of Atazanavir and sulfate of Atazanavir

A technology of intermediates and raw materials, applied in the field of preparation of atazanavir and its sulfate, can solve the problems of multiple impurities, low yield, high product purification cost, etc., and achieve the goal of accelerating reaction rate, reducing production cost and reducing purification The effect of times

Inactive Publication Date: 2014-11-26
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

By optimizing the synthesis process of atazanavir and its sulfate raw material, the method solves the technical problems of low yield and more impurities, product purification and high cost of the existing process route, and improves the production efficiency of atazanavir. Quality and purity of Weiwei and its sulfate API

Method used

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  • Preparation methods of Atazanavir and sulfate of Atazanavir
  • Preparation methods of Atazanavir and sulfate of Atazanavir
  • Preparation methods of Atazanavir and sulfate of Atazanavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The synthesis of the intermediate shown in embodiment 1 formula (I)

[0049]

[0050] In a 500mL three-necked flask, add 50.0g of the intermediate represented by formula (a), 50.5g of the raw material represented by formula (b) and 250mL of tert-butanol, and heat the oil bath to 90°C. After reacting for 3 hours, solids gradually precipitated out. Stirring was continued for 18 hours, and a sample was taken for HPLC detection.

[0051] HPLC analysis method: chromatograph: Dionex v3000DAD

[0052] Column: Inertsil ODS-3

[0053] Chromatographic conditions: acetonitrile: phosphate buffer = 70: 30, where the phosphate buffer is K 2 HPO 3 -KH 2 PO 3 Buffer (0.02M K 2 HPO 3 and 0.02M KH 2 PO 3 )

[0054] Detection wavelength: UV210nm

[0055] Column temperature: 30°C

[0056] Flow rate: 1.5mL / min

[0057] The intermediate shown in formula (a) is detected to be less than 1.5% by HPLC, stop heating, cool down to 30°C, add 750mL water with a constant pressure dro...

Embodiment 2

[0060] The synthesis of the intermediate shown in embodiment 2 formula (II)

[0061]

[0062] In a 250mL three-necked bottle, add the intermediate shown in 50g of the formula (I) prepared in Example 1 and 50mL of methanol, stir, cool down to -5~5°C, and then add dropwise 69.4g of methanol-hydrogen chloride solution (the mass of hydrogen chloride Fraction is 25%), the temperature of the reaction system is controlled at 0~5°C during the dropwise addition, after the dropwise addition is completed, the temperature is raised to 25~30°C, after the reaction is stirred for 12 hours, a sample is taken for HPLC detection, mono-Boc(tert-butoxycarbonyl ) by-product is less than 1%, stop stirring, the reaction solution is added dropwise in 400mL ethyl acetate, a large amount of solids are separated out, filter, and wash the filter cake with ethyl acetate, dry, obtain solid 44.29g, and through routine The method for confirming the structure was confirmed to be an intermediate represented...

Embodiment 3

[0065] The synthesis of the intermediate shown in embodiment 3 formula (II)

[0066] In a 250mL three-necked bottle, add 50g of the intermediate of formula (I) prepared in Example 1 and 50mL of methanol, stir, and cool down to -5 to 5°C, then add dropwise 46.3g of methanol-hydrogen chloride solution (the mass of hydrogen chloride Fraction is 35%), during the dropwise addition process, the temperature of the reaction system is controlled at 0-5°C. After the dropwise addition, the temperature is raised to 25-30°C. After the reaction is stirred for 12 hours, a sample is taken for HPLC detection, and the single Boc by-product is less than 1%. , stop stirring, add the reaction solution dropwise to 400mL ethyl acetate, a large amount of solids precipitate out, filter, and wash the filter cake with ethyl acetate, dry to obtain 44.75g of solids, and through the conventional structure confirmation method, it is confirmed as The yield of the intermediate represented by the above formula...

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Abstract

The invention discloses preparation methods of Atazanavir and a sulfate of the Atazanavir. The preparation method of the Atazanavir comprises the following steps: 1) adding (a) and (b) into an alcohol solvent and reacting so as to obtain an intermediate shown in a formula (I); 2) dissolving the intermediate shown in the formula (I) in an fatty alcohol solvent, cooling, dropwise adding an alcoholic solution of hydrogen chloride and reacting so as to obtain an intermediate shown in a formula (II); 3) dissolving (c) in dichloromethane, cooling, reacting by adding a dehydrating agent, adding an organic alkali and the intermediate shown in the formula (II) and reacting so as to obtain an Atazanavir monomer shown in a formula (III). The Atazanavir monomer can be prepared into an Atazanavir sulfate shown in a formula (IV) according to a conventional method. The Atazanavir monomer has the advantages of high yield, less relevant impurity content, low preparation cost and the like, and can be used for preparing the Atazanavir sulfate with high purity and high yield. The structures of the Atazanavir monomer and the Atazanavir sulfate are as shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of atazanavir and sulfate thereof, in particular to a preparation method of high-purity atazanavir and sulfate thereof. Background technique [0002] Atazanavir (as shown in formula (III)), which is an important raw material for the preparation of Atazanavir Sulfate (Atazanavir Sulfate). [0003] [0004] Atazanavir sulfate, whose trade name is REYATAZ, was developed by Bristol-Myers Squibb in the United States and first launched in the United States in June 2003. It is mainly used in combination with other antiretroviral drugs to treat HIV infection. Atazanavir sulfate is a novel azapeptide protease inhibitor (PI), which is a highly selective and potent inhibitor of HIV-1 protease by blocking the viral gap and gap-pol precursor polyprotein cleavage, thereby inhibiting the generation of viral structural protein reverse transcriptase, integrase and protease, so that HIV-1-infected cells release non-infec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/42
CPCC07D213/42
Inventor 魏彦君张保军
Owner SHANGHAI VIWIT PHARMA CO LTD
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