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Method for effectively removing isomer of rilpivirine

A technology for rilpivirine and isomers, which is applied in the field of medicinal chemistry synthesis, can solve the problem that the content of Z-isomers and Z-isomers of rilpivirine is not publicly removed, and achieves great practical value and production. Low cost and small loss of product

Active Publication Date: 2016-12-07
宜昌天睿生物医药有限责任公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Patent CN100509801 discloses a compound composed of E-3-(4-amino-3,5-dimethylphenyl)-2-acrylonitrile hydrochloride and 4-[(4-chloro-2-pyrimidinyl)amino] According to the method of benzonitrile, the synthesis of rilpivirine can be carried out according to this method, and the purer rilpivirine finished product can be obtained, and the method is simple and convenient, and the post-treatment operation is easy, but its Z-isomer content is relatively high, about 12%~ About 14%, and the patent does not disclose how to effectively remove rilpivirine Z-isomer

Method used

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  • Method for effectively removing isomer of rilpivirine
  • Method for effectively removing isomer of rilpivirine
  • Method for effectively removing isomer of rilpivirine

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Experimental program
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Effect test

Embodiment 1

[0031] The preparation method of rilpivirine in the present invention is prepared according to the method of the related example B1A in the patent CN100509801C, wherein the Z-isomer content of rilpivirine is about 12%.

[0032] Add 3.66kg of rilpivirine and 1.16kg of maleic acid into 36L of methanol, heat to 60°C, stir at this temperature for 1-2h, cool to room temperature, filter to obtain a white solid, add 43.3L of ethanol and water Mix solvent (ethanol accounts for 95%, water accounts for 5%), heat to reflux, make it completely dissolved, add activated carbon for decolorization, filter, cool to -5 ~ 5°C, crystallize at this temperature for 8 ~ 10h, filter to obtain White solid, the solid was added to 30L of purified water, neutralized by adding 4.2kg of lithium hydroxide monohydrate, filtered, and dried at 40°C to obtain 3.05kg of white solid, yield: 94.8% (based on pure rilpivirine content), HPLC: 99.99%, E-isomer, 0.01%.

[0033] HPLC detection conditions:

[0034] Ins...

Embodiment 2

[0040] Add 3.66kg of rilpivirine and 1.58kg of benzenesulfonic acid into 36L of acetonitrile, heat to 80°C, stir at this temperature for 1-2h, cool to room temperature, filter to obtain a white solid, add 42L of methanol and water to mix Solvent (methanol accounted for 35%, water accounted for 65%), heated to reflux to make it completely dissolved, added activated carbon for decolorization, filtered, cooled to 5-10°C, crystallized at this temperature for 12-15 hours, filtered to obtain a white solid , the solid was added to 30L of purified water, neutralized by adding 8.4kg of sodium bicarbonate, filtered, and dried at 60°C to obtain 2.96kg of white solid, yield: 92.1% (based on pure rilpivirine content), HPLC: 99.93% , E-isomer, 0.07%.

Embodiment 3

[0042]Add 3.66kg of rilpivirine and 1.9kg of p-toluenesulfonic acid monohydrate into 36L of ethanol, heat to 70°C, stir at this temperature for 1-2h, cool to room temperature, filter to obtain a white solid, add 39.5 Mixed solvent of L acetic acid and water (acetic acid accounts for 25%, water accounts for 75%), heat to reflux, dissolve it completely, add activated carbon for decolorization, filter, cool to 10-15°C, and crystallize at this temperature for 5-7 hours , filtered to obtain a white solid, which was added to 30L of purified water, neutralized by adding 13.8kg of potassium carbonate, filtered, and dried at 70°C to obtain 3.04kg of a white solid, yield: 94.1% (based on pure rilpivirine content) , HPLC: 99.95%, E-isomer, 0.07%.

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Abstract

The invention belongs to the field of chemical synthesis of medicines, and in particular discloses a method for effectively removing the isomer of rilpivirine. The method comprises the following steps: synthesizing organic acid salts of rilpivirine from rilpivirine and maleic acid, benzene sulfonic acid, p-methylbenzene sulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid and the like, performing recrystallization on the organic acid salts of the rilpivirine by using mixed solvents of methanol, ethanol, acetonitrile, acetic acid, N,N-dimethyl formamide and the like and water, furthermore freeing recrystallized organic acid salts of the rilpivirine by using alkali such as sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, potassium tert-butoxide and sodium ethoxide, thereby reducing the content of Z-isomer of rilpivirine to be 0.1% or below from about 12%. The method is simple and convenient to operate, gentle in reaction conditions, low in production cost, relatively small in loss of products in the purification process, good in reproducibility, stable in process, applicable to industrial amplification and great in practical values, and the content of the Z-isomer of the rilpivirine can be reduced to be 0.1% or below from 12-14% at a time.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a method for effectively removing isomers of rilpivirine. Background technique [0002] Rilpivirine (Rilpivirine) is a novel non-nucleoside reverse transcriptase inhibitor developed by the U.S. Tibotec company, used for the treatment of AIDS, and its trade name is Edurant. It was approved by the U.S. FDA on May 20, 2011. Synthesis, strong antiviral activity, high oral bioavailability, and good safety. It is a diaryl pyrimidine drug, the Chinese chemical name is 4-[[4-[[4-[(1E)-2-cyanoethylenyl]-2,6-dimethylphenyl]amino ]-2-pyrimidinyl]amino]-benzonitrile, the structural formula is as follows: [0003] [0004] Clinically, rilpivirine is used in combination with other non-nucleoside reverse transcriptase inhibitors, mainly for HIV-1 infected adults with no history of HIV treatment. Rilpivirine cannot cure HIV infection, and patients must adhere to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48
CPCC07B2200/09C07D239/48
Inventor 郭建锋李子元王孟华吕金良符义刚郑华章田峦鸢李仕群李莉娥杜文涛
Owner 宜昌天睿生物医药有限责任公司
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