Intermediate for synthesizing rilpivirine, synthesis method thereof and synthesis method of rilpivirine

A technology of rilpivirine and its synthesis method, which is applied in the field of synthesizing rilpivirine intermediates and rilpivirine, and can solve problems such as reducing the overall yield of rilpivirine

Pending Publication Date: 2021-05-11
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are many reports about the synthesis of rilpivirine, for example, the amino protection of 2-amino-4-chloropyrimidine, and then combined with 4-[(1E)-2-cyanoethenyl]-2,6-dimethyl Aniline is reacted under alkaline conditions, then deaminated and protected, and purified to remove impurities and cis-isomers to obtain an intermediate of the desired configuration, and then the intermediate is reacted to obtain rilpivirine, This method requires amino protection and then deamination protection, reducing the overall yield of rilpivirine

Method used

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  • Intermediate for synthesizing rilpivirine, synthesis method thereof and synthesis method of rilpivirine
  • Intermediate for synthesizing rilpivirine, synthesis method thereof and synthesis method of rilpivirine
  • Intermediate for synthesizing rilpivirine, synthesis method thereof and synthesis method of rilpivirine

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Experimental program
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Embodiment 1

[0050] The embodiment of the present invention provides a synthesis method of 3-(4-(2-aminopyrimidin-4-yl)-3,5-dimethylphenyl)-acrylonitrile:

[0051] Refer to the synthesis path below:

[0052] Specific steps are as follows:

[0053] Put DMF (40ml) into the reaction flask, add the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula II-1 (20.9g, 100mmol), under nitrogen protection, stir, and heat up to 90°C-95°C. This temperature was maintained for 3 hours. After the reaction was completed, the temperature was lowered to room temperature 20±5° C., and 120 ml of 10% potassium carbonate aqueous solution was added dropwise. A solid precipitated, filtered and washed with water. Filter until no filtrate drips, scrape off the filter cake, reflux with 30ml acetonitrile for beating for 1 hour, cool to room temperature 20±5°C, filter, rinse with an appropriate amount of acetonitrile, and dry at 50°C to obtain the intermediate shown in formula...

Embodiment 2

[0057] The embodiment of the present invention provides a synthesis method of 3-(4-(2-aminopyrimidin-4-yl)-3,5-dimethylphenyl)-acrylonitrile:

[0058] Refer to the synthesis path below:

[0059]

[0060] Put DMF (50ml) into the reaction flask, add the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula II-2 (27g, 100mmol), under nitrogen protection, stir, and heat up to 90°C-95°C. This temperature was maintained for 3 hours. After the reaction was completed, the temperature was lowered to room temperature 20±5° C., and 150 ml of 10% potassium carbonate aqueous solution was added dropwise. A solid precipitated, filtered and washed with water. Filter until no filtrate drips, scrape off the filter cake, reflux with 30ml acetonitrile for beating for 1 hour, cool to room temperature 20±5°C, filter, rinse with an appropriate amount of acetonitrile, and dry at 50°C to obtain the intermediate shown in formula III (19.9g , 75%, purity 97.5%,...

Embodiment 3

[0064] The embodiment of the present invention provides a synthesis method of 3-(4-(2-aminopyrimidin-4-yl)-3,5-dimethylphenyl)-acrylonitrile:

[0065] Refer to the synthesis path below:

[0066]

[0067] Put DMF (70ml) into the reaction flask, add the compound represented by formula I (14.3g, 110mmol) and the compound represented by formula II-3 (34.4g, 100mmol), under nitrogen protection, stir, and heat up to 90°C-95°C. This temperature was maintained for 3 hours. After the reaction was completed, the temperature was lowered to room temperature 20±5° C., and 200 ml of 10% potassium carbonate aqueous solution was added dropwise. A solid precipitated, filtered and washed with water. Filter until no filtrate drips, scrape off the filter cake, reflux with 30ml acetonitrile for beating for 1 hour, cool to room temperature 20±5°C, filter, rinse with an appropriate amount of acetonitrile, and dry at 50°C to obtain the intermediate shown in formula III (22.5g , 85%, purity 98.3...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to an intermediate for synthesizing rilpivirine, a synthesis method of the intermediate and a synthesis method of the rilpivirine. The intermediate is synthesized according to the following synthesis route: wherein X is a halogen atom, and M is an acid. According to the method, the compound shown in the formula II can generate acid by itself, and then an acid environment is provided for the reaction, so that the compound shown in the formula I and the compound shown in the formula II can be directly subjected to autocatalytic reaction on the basis of not carrying out amino protection on the compound shown in the formula I; and the compound shown in the formula I and the compound shown in the formula II react to form the required intermediate, and the overall yield of the synthesized rilpivirine is increased.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to an intermediate for synthesizing rilpivirine, a synthesis method thereof and a synthesis method of rilpivirine. Background technique [0002] Rilpivirine is a brand new non-nucleoside reverse transcription inhibitor (NNRTI) developed by Tibotec Pharmaceuticals. So far, only five NNRTI anti-HIV drugs have been marketed, namely nevirapine, efavirenz, delavirdine, etravirine, and rilpivirine. Compared with old drugs such as nevirapine, delavirdine, and etravirine, rilpivirine has the advantages of 1 tablet once a day, the first-line drug, extremely low drug resistance, and high safety. It is as effective as efavirenz and has a better safety profile, so rilpivirine can be used as a new treatment for HIV-1 infected patients. The U.S. Food and Drug Administration (FDA) approved rilpivirine (Rilpivirine, marketed, for the treatment of HIV-1 infected patients in May 2011. Rilpiv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor 郑国君王亚平吕侠王志邦王哲陈小峰朱林晓胡凯凯徐晓鹏张维荣高庆
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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