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Method for preparing 4-[(4-chloro-2-pyrimidinyl) amino] cyanophenyl

A technology of aminobenzamide and amino group, which is applied in the field of preparation of 4-[amino]benzonitrile, can solve the problems of increased cost of AIDS drug rilpivirine, limited industrialized production, difficult to obtain, etc., and achieves low price. , easy to obtain, the effect of reducing production costs

Active Publication Date: 2014-11-26
NINGBO CHEMGOO PHAMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The advantage of this route is that the steps are short and the operation is simpler, but the disadvantage is that the raw material methylmercaptopyrimidinone (VIII) is expensive and not easy to obtain, while p-aminobenzonitrile (VI) is not avoided
[0014] The shortcomings of the above three routes, due to cost and safety factors, have largely limited its industrial production, thereby increasing the final drug cost of the AIDS drug rilpivirine

Method used

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  • Method for preparing 4-[(4-chloro-2-pyrimidinyl) amino] cyanophenyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The first step: the preparation of 4-guanidine benzamide (II):

[0038]

[0039] Take 15g of 4-aminobenzamide (I), 75ml of water, stir and heat up to 100°C, add dropwise 30g of 50% cyanamide aqueous solution, and at the same time add concentrated hydrochloric acid dropwise to control the pH to 3-4, and continue the reaction for 12h. Add 15 g of sodium chloride, lower the temperature, adjust the pH to weakly alkaline with aqueous sodium hydroxide solution, filter to obtain a solid, and dry to obtain 18.6 g of 4-guanidinobenzamide (II), with a yield of 95%.

[0040] The second step: preparation of compound III:

[0041]

[0042] Add 7.1g of 4-guanidinobenzamide (II), add 9.8g of anhydrous sodium acetate, 60ml of N-methylpyrrolidone and stir to dissolve, add 7.7g of diethyl ethoxymethylenemalonate, and heat up to 100 degrees React for 1.5 hours,

[0043] Add 65 ml of water and heat to reflux, so that the reflux temperature of the reaction solution rises to 155-160 ...

Embodiment 2

[0048] The first step: the preparation of 4-guanidine benzamide (II):

[0049]

[0050]Take 15g of 4-aminobenzamide (I) and 75ml of water, stir and heat up to 100°C, add 30g of 50% cyanamide aqueous solution dropwise in batches, and at the same time add 50% sulfuric acid dropwise to control the pH to 3-4, and continue the reaction for 12h. Add 15 g of sodium chloride, lower the temperature, adjust the pH to weakly alkaline with aqueous sodium hydroxide solution, filter to obtain a solid, and dry to obtain 18.0 g of 4-guanidinobenzamide (II), with a yield of 91.9%.

[0051] The second step: preparation of compound III:

[0052]

[0053] Add 7.1g of 4-guanidinobenzamide (II), add 9.8g of anhydrous sodium acetate, 60ml of DMF and stir to dissolve, add 7.5g of dimethyl ethoxymethylene malonate, heat up to 100 degrees for 1.5 hours, add Heat 65ml of water to reflux, so that the reflux temperature of the reaction solution rises to 150-155 degrees, and continue the reflux reac...

Embodiment 3

[0058] The first step: the preparation of 4-guanidine benzamide (II):

[0059]

[0060] Take 15g of 4-aminobenzamide (I), 75ml of water, stir and heat up to 100°C, add dropwise 30g of 50% cyanamide aqueous solution, and at the same time add dropwise 50% phosphoric acid to control the pH to 3-4, and continue the reaction for 12h. Add 15 g of sodium chloride, lower the temperature, adjust the pH to weakly alkaline with aqueous sodium hydroxide solution, filter to obtain a solid, and dry to obtain 17.8 g of 4-guanidinobenzamide (II), with a yield of 90.9%.

[0061] The second step: preparation of compound III:

[0062]

[0063] 7.1g of 4-guanidinobenzamide (II), add 11.2g of anhydrous potassium acetate, 60ml of DMA and stir to dissolve, add 7.7g of diethyl ethoxymethylene malonate, heat up to 100 degrees for 1.5 hours, add 65ml of water was heated to reflux, so that the reflux temperature of the reaction solution rose to 165-170 degrees, and the reflux reaction was continu...

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Abstract

The invention discloses a method for preparing 4-[(4-chloro-2-pyrimidinyl) amino] cyanophenyl which is a key chloro intermediate of rilpivirine by taking 4-aminobenzamide as a starting raw material. In the method, the 4-aminobenzamide is used as a raw material, aminobenzonitrile which is a highly toxic raw material is not needed, and a product is prepared by a one-pot process, so production operations are safer; the raw material price is low, and reaction steps are shortened, so the production cost is greatly reduced; and the quality of an obtained product is good, the purity is larger than 99.5%, and the content of a single impurity is smaller than 0.1%.

Description

technical field [0001] The invention belongs to the technical field of preparation of fine chemical products such as medicine, and relates to the technical field of preparation of a chlorinated product of a key intermediate of rilpivirine. Specifically, the invention relates to 4-[(4-chloro-2-pyrimidinyl)amino ] The preparation method of benzonitrile. Background technique [0002] Rilpivirine (formula V), a second-generation non-nucleoside reverse transcriptase inhibitor, combined with other antiretroviral drugs, is used for HIV-infected patients. [0003] The structural formula of rilpivirine is as (V): [0004] [0005] The key intermediate for preparing etravirine in production is 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile, and the structural formula is as (Ⅳ) [0006] [0007] 4-[(4-chloro-2-pyrimidinyl) amino] benzonitrile (Ⅳ) is the key intermediate for the preparation of rilpivirine, existing reports (WO2004016581; ChemMedChem, 20094 (9), 1537-1545; Bioorga...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
Inventor 楼科侠何国金吴绍刚张达
Owner NINGBO CHEMGOO PHAMA TECH CO LTD
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