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Industrial synthesis method of rilpivirine and intermediate compound

A synthesis method and technology of rilpivirine, applied in the field of medicinal chemistry synthesis, can solve the problems of long route, high temperature, unsatisfactory repetition and the like, and achieve the effects of high yield, low production cost and reduced industrialization cost.

Inactive Publication Date: 2017-09-15
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Chinese patent CN100554245C discloses a kind of by 4-[(4-chloro-2-pyrimidinyl) amino] benzonitrile as intermediate preparation 4-[[4-[[4-[(1E)-2-cyanoethylene yl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-benzonitrile, but using 4-[(4-bromo-2-pyrimidinyl)amino]benzonitrile as an intermediate The report of preparation rilpivirine has not been seen yet
[0013] This method has a long route, and the temperature of the third ring-closing reaction and the fourth step decarboxylation reaction is relatively high. Although the patent claims that it is a synthetic route suitable for scale-up, satisfactory results have not been obtained when repeating this method.

Method used

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  • Industrial synthesis method of rilpivirine and intermediate compound
  • Industrial synthesis method of rilpivirine and intermediate compound
  • Industrial synthesis method of rilpivirine and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1, the synthesis of formula II compound

[0040] Dilute 1000 g of ethyl formyl acetate (the compound of formula V in which R is ethyl) with 5 L of methanol, lower the temperature, slowly drop into 510 g of thiomethylisothiourea in 3 L of ethanol, and react at 5°C for 3 h. Concentrate to dryness under reduced pressure, dissolve the residue with hot water, acidify to pH = 4 with acetic acid, precipitate solid after cooling, filter, wash the filter cake with water, and recrystallize with water to obtain 764 g of beige needle-like crystals, yield: 94.9%, that is Compound of formula II;

[0041] 2, the synthesis of formula III compound

[0042] Add 1kg of compound of formula II and 692g of p-aminocyanide into 8L of pyridine, heat to 110°C, react for 8h, cool down to 0-5°C, stir and crystallize for 10h, filter, wash with methanol to obtain 1206g of light yellow solid, yield , 97%, the compound of formula III;

[0043] 3, the synthesis of formula I compound

[0044]Add 1kg...

Embodiment 2

[0065] 1, the synthesis of formula II compound

[0066] Dilute 1000g of methyl formylacetate (compound of formula V in which R is methyl) with 5L of ethanol, lower the temperature, slowly drop into 2.5L of methanol solution of 510g of thiomethylisothiourea, and react at 10°C for 3-5h. Concentrate to dryness under reduced pressure, dissolve the residue with hot water, adjust the pH to 4-5 with acetic acid, precipitate a solid after cooling, filter, wash the filter cake with water, and recrystallize with water to obtain 772 g of beige needle-like crystals, yield: 96%, That is, the compound of formula II;

[0067] 2, the synthesis of formula III compound

[0068] Add 1kg of compound of formula II and 692g of p-aminobenzocyanide into 8L of triethylamine, heat to 60°C, react for 12h, cool down to 0-5°C, stir and crystallize for 15h, filter and wash with methanol to obtain 1157.3g of light yellow solid , yield, 93%, i.e. the compound of formula III;

[0069] 3, the synthesis of f...

Embodiment 3

[0074] 1, the synthesis of formula II compound

[0075] Dilute 1000g of n-propyl formyl acetate (the compound of formula V in which R is n-propyl) with 5L of isopropanol, cool down, slowly drop into 5L of isopropanol solution of 510g of thiomethylisothiourea, and react at 35°C for 5~ 8h. Concentrate under reduced pressure to dryness, dissolve the residue with hot water, adjust the pH to 4-5 with acetic acid, and precipitate a solid after cooling, filter, wash the filter cake with water, and recrystallize with water to obtain 780.5 g of beige needle-like crystals, yield: 97% , the compound of formula II;

[0076] 2, the synthesis of formula III compound

[0077] Add 1kg of the compound of formula II and 692g of p-aminocyanide into 8L of N-methylpyrrolidone, heat to 210°C, react for 3h, cool down to 0-5°C, stir and crystallize for 10h, filter and wash with methanol to obtain a light yellow solid 1107.5 g, yield, 89%, namely formula III compound;

[0078] 3, the synthesis of ...

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Abstract

The invention discloses an industrial synthesis method of rilpivirine. A compound as shown in a formula I and compound hydrochloride as shown in a formula VI react to obtain rilpivirine. The invention further discloses an intermediate compound as shown in the formula I and a synthesis method of the intermediate compound. Compared with the prior art, the synthesis method is simple to operate, mild in condition, high in yield and purity and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to an industrial synthesis method of rilpivirine, an intermediate compound and a synthesis method thereof. 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 c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D239/48
CPCC07D239/42C07D239/48
Inventor 郭建锋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 YICHANG HUMANWELL PHARMA
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