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Preparation method of 4-[(4-Hydroxy-2-pyrimidinyl) amino] benzonitrile

A technology for p-guanidinobenzonitrile and amino, which is applied in the field of synthesis of 4-[amino]benzonitrile, which can solve the problems of unsuitability for large-scale industrial production, large residues of decarboxylation impurities, harsh reaction conditions, etc., and improve safety , less impurity formation, and low reaction temperature

Active Publication Date: 2015-07-22
NINGBO CHEMGOO PHAMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this preparation method, p-guanidinobenzonitrile and diethyl ethoxymethylene malonate are relatively easy to ring-close, but the second-stage decarboxylation is particularly difficult, requiring harsh reaction conditions and expensive solvents, and the decarboxylation is not complete. It will cause the problem of large residues of impurities. In addition, the refining process is quite cumbersome and requires multiple solvents for refining. These shortcomings make this process unsuitable for large-scale industrial production. The reaction formula is as follows:

Method used

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  • Preparation method of 4-[(4-Hydroxy-2-pyrimidinyl) amino] benzonitrile
  • Preparation method of 4-[(4-Hydroxy-2-pyrimidinyl) amino] benzonitrile
  • Preparation method of 4-[(4-Hydroxy-2-pyrimidinyl) amino] benzonitrile

Examples

Experimental program
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Effect test

Embodiment 1

[0018] Add 300 ml of toluene, 30 g of p-guanidinobenzonitrile, and 34.0 g of methyl 3-methoxyacrylate into a 500 ml reaction bottle. Heating to 110-115°C, reflux reaction, HPLC tracking until the reaction is complete, stop the reaction, and react for about 20 hours in total. Remove the heat, cool to about 20°C, and filter to obtain an off-white solid, which is refluxed with 300ml of ethanol for beating, cooled to 20°C, filtered, and dried at 80°C to obtain 29.8 grams of the product, with a yield of 75% and a purity of 99.5%.

Embodiment 2

[0020] Add 500ml of xylene, 65g of p-guanidinobenzonitrile, and 69.5g of ethyl 3-methoxyacrylate into a 1000ml reaction flask. Heating (heating to 144-146 ° C), reflux reaction. After reacting for 14-15 hours, a sample was taken for HPLC detection, and the raw materials basically reacted completely. Stop heating, wait until the temperature is cooled to about 20°C, filter to obtain an off-white solid, and reflux the obtained solid with 500ml of ethanol for beating, cool to 20°C, filter, and dry the product at 80°C to obtain 54.2g of the product, with a yield of 63%. 99.6% purity.

Embodiment 3

[0022] Add 300ml of water, 30g of p-guanidinobenzonitrile, and 40g of ethyl 3-methoxyacrylate into a 500ml reaction bottle. Heating (heating to 100-105 ° C), reflux reaction. After reacting for 24 hours, a sample was taken for HPLC detection, and the raw materials basically reacted completely. Stop heating, wait until the temperature is cooled to about 20°C, filter to obtain a yellow solid, recrystallize the obtained solid with DMF, and then reflux with 300ml ethanol for beating, cool to 20°C, filter, and dry the product at 80°C to obtain 20.5g of the product. The yield is 51.6%, and the purity is 99.8%.

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Abstract

The invention discloses a preparation method of 4-[(4-Hydroxy-2-pyrimidinyl) amino] benzonitrile. The prepration method comprises the following steps of adding N-guanidine and 3-methoxy-acrylate into reaction solvent, heating and controlling the temperature until the end of the reaction, and separating and purifying the reaction solution to obtain 4-[(4-Hydroxy-2-pyrimidinyl) amino] benzonitrile. 3-methoxy-acrylate is 3-methoxy-methyl acrylate or 3-methoxy-ethyl acrylate. Due to the adoption of the preparation method, the yield and the quality of the product can be improved, the cost is reduced, operation is simple, and the preparation method is a synthesis route which is suitable for the industrial production of a Rilpivirine midbody.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical products, and relates to the preparation of an important intermediate of a novel non-nucleoside reverse transcriptase inhibitor rilpivirine (rilpivirine). Specifically, the invention relates to 4-[(4-hydroxy- Synthetic process of 2-pyrimidinyl) amino] benzonitrile. Background technique [0002] Rilpivirine (rilpivirine) is a new type of non-nucleoside reverse transcriptase inhibitor (non-nucleoside reverse tran-scriptase inhibitor, NNRTI) developed by the American company Tibotec. It is used for the treatment of AIDS, and its trade name is Edurant. On May 20, it was approved for marketing by the US FDA. It has the characteristics of easy synthesis, strong antiviral activity, high oral bioavailability, and good safety. [0003] The existing synthetic route is mainly to cyclize p-guanidinobenzonitrile and diethyl ethoxymethylenemalonate in NMP to generate an intermediate state...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
Inventor 吴绍伟吴鹏程楼科侠张达
Owner NINGBO CHEMGOO PHAMA TECH CO LTD
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