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The preparation technology of rilpivirine intermediate

A technology for rilpivirine and a preparation process, which is applied in the field of preparation technology for synthesizing rilpivirine intermediates, can solve the problems of high catalyst cost, harsh process conditions, troublesome post-processing and the like, and achieves good product quality, simple operation, low cost effect

Active Publication Date: 2017-11-03
苏州莱克施德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to overcome the above-mentioned defects such as harsh process conditions, high catalyst cost, and post-processing troubles, the present invention aims to provide a preparation process for rilpivirine intermediates with simple operation, good product quality, low cost, and convenient large-scale production

Method used

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  • The preparation technology of rilpivirine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] (compound 2 Synthesis)

[0016] A 20L four-neck flask equipped with a thermometer, mechanical stirring, a constant pressure dropping funnel, and an exhaust gas absorption device was replaced with nitrogen three times, and THF (10L), palladium acetate (5.6g, 0.5%mol) and phosphine ligand L (28g, 1% mol), stirred at 20-30°C for 1 hour. Sodium acetate (1.02Kg, 7.5mol), 4-bromo-2,6-dimethylaniline (1.0Kg, 5mol) and acrylonitrile (405g, 7.5mol) were added sequentially. Continue to stir and react at 20-30°C for 4 hours, then add water (5.0 L), let stand to separate the layers, separate the organic phase, and extract the aqueous phase with tertiary methyl ether (5 L) once. The organic phases were combined and concentrated under reduced pressure to obtain 870 g of crude 3-(4-amino-3,5-dimethylphenyl)acrylonitrile (trans:cis=4.6:1), and the crude yield was 102%.

[0017] (compound 3 Synthesis)

[0018] In the 20L four-neck flask equipped with thermometer, mechanical stirrin...

Embodiment 2

[0022] (compound 2 Synthesis)

[0023] A 20L four-necked flask equipped with a thermometer, mechanical stirring, a constant pressure dropping funnel, and an exhaust gas absorption device was replaced with nitrogen three times, and THF (10L), palladium acetate (1.2g, 0.1%mol) and phosphine ligand L (6g, 0.2% mol), stirred at 20-30°C for 1 hour. Sodium acetate (1.02Kg, 7.5mol), 4-bromo-2,6-dimethylaniline (1.0Kg, 5mol) and acrylonitrile (405g, 7.5mol) were added sequentially. Continue to stir and react at 20-30°C for 4 hours, then add water (5.0 L), let stand to separate the layers, separate the organic phase, and extract the aqueous phase with tertiary methyl ether (5 L) once. The organic phases were combined and concentrated under reduced pressure to obtain 870 g of crude 3-(4-amino-3,5-dimethylphenyl)acrylonitrile (trans:cis=4.7:1), and the crude yield was 102%.

[0024] (compound 3 Synthesis)

[0025] In the 20L four-neck flask equipped with thermometer, mechanical stir...

Embodiment 3

[0027] (compound 2 Synthesis)

[0028] A 20L four-neck flask equipped with a thermometer, mechanical stirring, a constant pressure dropping funnel, and an exhaust gas absorption device was replaced with nitrogen three times, and THF (10L), palladium acetate (5.6g, 0.5%mol) and phosphine ligand L (28g, 1% mol), stirred at 20-30°C for 1 hour. Sodium acetate (1.02Kg, 7.5mol), 4-bromo-2,6-dimethylaniline (1.0Kg, 5mol) and acrylonitrile (405g, 7.5mol) were added sequentially. Continue to stir and react at 20-30°C for 4 hours, then add water (5.0 L), let stand to separate the layers, separate the organic phase, and extract the aqueous phase with tertiary methyl ether (5 L) once. The organic phases were combined and concentrated under reduced pressure to obtain 870 g of crude 3-(4-amino-3,5-dimethylphenyl)acrylonitrile (trans:cis=4.6:1), and the crude yield was 102%.

[0029] (compound 3 Synthesis)

[0030] In the 20L four-neck flask equipped with thermometer, mechanical stirrin...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a rilpivirine midbody preparing technology. The technology comprises the steps that 1, 4-bromo-2,6-dimethylaniline and acrylonitrile react under the catalysis of palladium acetate and phosphine ligands to generate 3-(4-amino-3,5-dimethyl phenyl) acrylonitrile (trans-form:cis-form=5:1); 2, the cis-trans mixture is crystallized and purified in hydrochloric acid isopropanol to generate (E)-3-(4-amino-3,5-dimethyl phenyl) acrylonitrile salt. Based on the prior art, raw materials are easy to obtain, cost is low, operation is easy, and the requirement of industrial production is met.

Description

Technical field: [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a preparation process for synthesizing a rilpivirine intermediate with 4-bromo-2,6-dimethylaniline as a starting material. Background technique: [0002] Rilpivirine, the English name is Rilpivirine, the chemical name is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]pyrimidin-2-yl]amino ]benz onitrile is a new type of non-nucleoside reverse transcriptase inhibitor (non-nucleosidereverse tran-scriptase inhibitor, NNRTI) developed by Tibotec Pharmaceutical Company of the United States. It was launched in the United States in May 2011 under the trade name Edurant. It has the characteristics of easy synthesis, strong antiviral activity, high oral bioavailability, and good safety. [0003] About the synthesis of rilpivirine intermediate (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride, synthesis of Org.Process.Res.Dev 2008,530-536 The method is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C255/42C07C253/30
CPCC07C253/30C07C255/42
Inventor 俞菊荣顾志锋孙光明
Owner 苏州莱克施德药业有限公司
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