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Rilpivirine midbody preparing technology

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

Active Publication Date: 2016-05-11
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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  • Rilpivirine midbody preparing technology
  • Rilpivirine midbody preparing technology
  • Rilpivirine midbody preparing technology

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] (compound 2 Synthesis)

[0016] A 20L four-necked flask containing a thermometer, mechanical stirring, a constant pressure dropping funnel and a tail gas absorption device was replaced with nitrogen three times, and THF (10L), palladium acetate (5.6g, 0.5% mol) and phosphine ligand L (28g, were added) were added. 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. The reaction was continued to stir at 20-30°C for 4 hours, then water (5.0L) was added, and the layers were allowed to stand for separation. The organic phase was separated, and the aqueous phase was extracted once with methyl tertiary ether (5L). 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), with a crude yield of 102%.

[0017] (compound 3 Synthesis)

[0018] In a 20L fou...

Embodiment 2

[0022] (compound 2 Synthesis)

[0023] A 20L four-necked flask containing a thermometer, mechanical stirring, a constant pressure dropping funnel and a tail 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), stirring 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. The reaction was continued to stir at 20-30°C for 4 hours, then water (5.0L) was added, and the layers were allowed to stand for separation. The organic phase was separated, and the aqueous phase was extracted once with methyl tertiary ether (5L). 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), with a crude yield of 102%.

[0024] (compound 3 Synthesis)

[0025] In a 20L four-necked flask equippe...

Embodiment 3

[0027] (compound 2 Synthesis)

[0028] A 20L four-necked flask containing a thermometer, mechanical stirring, a constant pressure dropping funnel and a tail gas absorption device was replaced with nitrogen three times, and THF (10L), palladium acetate (5.6g, 0.5% mol) and phosphine ligand L (28g, were added) were added. 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. The reaction was continued to stir at 20-30°C for 4 hours, then water (5.0L) was added, and the layers were allowed to stand for separation. The organic phase was separated, and the aqueous phase was extracted once with methyl tertiary ether (5L). 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), with a crude yield of 102%.

[0029] (compound 3 Synthesis)

[0030] In a 20L fou...

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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 in particular relates to a preparation process for synthesizing a rilpivirine intermediate by using 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 ]benzonitrile, is a new type of non-nucleoside reverse transcriptase inhibitor (non-nucleoside reverse transcriptase inhibitor, NNRTI) developed by Tibotec Pharmaceutical Company of the United States. It was listed 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, the synthetic method of Org.Process.Res.Dev2008,530-536 , ...

Claims

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Application Information

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Patent Type & Authority Applications(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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