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Cobicistat raw material impurity preparation method

A technology of comparability and impurities, applied in the field of medicine, can solve problems such as unqualified quality of finished products

Pending Publication Date: 2019-06-21
SHANGHAI AOBO PHARMTECH INC LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] It can be seen that the compound of formula 5 is a key starting material, and it is found through research that it contains hydroxythiazole impurities: when the content of 2-hydroxyisopropyl-4-(methylaminomethyl)thiazole is higher, it will have a significant impact on subsequent processes, such as It is not conducive to the drying of materials, and at the same time, it will lead to the unqualified quality of the finished product of Cobicistat

Method used

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  • Cobicistat raw material impurity preparation method
  • Cobicistat raw material impurity preparation method
  • Cobicistat raw material impurity preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 8.5g of boc-protected 4-ethylaminomethyl-thiazole and 100ml of tetrahydrofuran into a 1L three-necked flask, add 2ml of 2.5M n-butyllithium at -78°C, stir for 30 minutes, add 2ml of acetone, stir for 30 minutes and then Add 10ml of 10% ammonium chloride solution at room temperature, add 500ml ethyl acetate to wash and separate the liquid, and concentrate the ethyl acetate phase to dryness to obtain 5g of 2-isopropyl-4-(methyl-boc aminomethyl)thiazole, M+ H=287, purity 96%.

Embodiment 2

[0035] Add 3g of 2-isopropyl-4-(methyl-bocaminomethyl)thiazole, 10ml of trifluoroacetic acid, and 50ml of ethanol into a 1L three-necked flask, and react at 40°C for 5 hours to obtain 1g of hydroxythiazole, M+H =187, purity 98%.

Embodiment 3

[0037] When the impurity E is 1.0%, the moisture content of bisestat is 0.55% after 24 hours of drying time; when the impurity derivative is 0.15%, the moisture content of bisestat is 0.10% after 3 hours of drying time.

[0038] Example: 4:

[0039] When the impurity E contains 0.5%, after multi-step conversion, it still exists in the cobicistat API in the form of 0.4% structure as shown in the following formula structure F, M+H=792, and the structure is as follows:

[0040]

[0041] This impurity is very similar to the API structure of cobicistat and is difficult to purify.

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Abstract

The invention relates to a preparation method of a cobicistat raw material impurity 2-hydroxyisopropyl-4-(methylaminomethyl)thiazole, wherein the method comprises: amination, protection, ketolysis, and deprotection. According to the present invention, the preparation method has characteristics of mild impurity synthesis reaction condition, simple process, short reaction time, less by-product, goodyield and high product purity.

Description

technical field [0001] The invention relates to cobicistat raw material impurity 2-hydroxyisopropyl-4-(methylaminomethyl)thiazole (molecular formula C 8 h 14 N 2 OS), the preparation method belongs to the field of medicine. Background technique [0002] Cobicistat is a new type of pharmacokinetic enhancer developed by Gilead. The drug increases the required concentration of anti-HIV drugs by inhibiting the main enzyme that metabolizes drugs in the human body-CYP3A. It was approved for marketing by the European Union on September 25, 2013. The dose is 150mg tablet, once a day, suitable for combination with HIV protease inhibitor atazanavir (atazanavir, 300mg, once a day) or darunavir (darunavir). , 800mg, once a day) in combination for the treatment of HIV-1 infection. [0003] The chemical name of cobicistat is (3R,6R,9S)-12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl) )ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-2,7,10,12-tetraazatridecanoic acid-5-thiaz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/28
Inventor 廖文静张继承陶安平黄鲁宁安建国陈茜顾虹
Owner SHANGHAI AOBO PHARMTECH INC LTD
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