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Preparation method of varenicline intermediate and nitroreduction impurity thereof

A technology for varenicline and intermediates, which is applied in the field of preparation of varenicline intermediates and nitro-reduction impurities, can solve the problems of difficult control of hydrogen sulfide equivalent, incomplete reaction, etc., and achieve reduced purification operations and good selectivity The effect of reduction and high purity

Inactive Publication Date: 2015-04-01
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But considering the toxicity of hydrogen sulfide and the degree of pollution to the air, adding the equivalent of hydrogen sulfide is difficult to control, when the equivalent of hydrogen sulfide is insufficient, the reaction is incomplete; if it is slightly excessive, the reaction will continue immediately to produce the product of diamino, and get The product needs to be purified by column chromatography, so in order to minimize air pollution and avoid the operation of column chromatography purification, we abandon this method and find a better method

Method used

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  • Preparation method of varenicline intermediate and nitroreduction impurity thereof
  • Preparation method of varenicline intermediate and nitroreduction impurity thereof
  • Preparation method of varenicline intermediate and nitroreduction impurity thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Embodiment 1: the preparation of varenicline intermediate

[0020] Add trifluoromethanesulfonic acid (1.23g) and dichloromethane (10ml) into the reaction flask, add concentrated nitric acid (0.25g) dropwise and stir, add compound (II) (1g) dropwise at -50~-60°C and react at room temperature After 6 hours, TLC monitored the completion of the reaction, added water, extracted three times with dichloromethane, washed the organic phase with water, dried, and evaporated to dryness to obtain compound (Ⅲ) (1g); Ester = 1:1, Rf = 0.3), and the purity of the product was 97% as detected by HPLC.

Embodiment 2

[0021] Embodiment 2: the preparation of selective nitro reduction impurity

[0022] Compound (Ⅲ) (1g), methanol (10mL) and Pd / C (0.1g) (60% water content) were added to the reaction flask, replaced by hydrogen three times, reacted at room temperature, TLC monitored the completion of the reaction, filtered, and evaporated to dryness to obtain Compound (I); off-white solid, yield 90.5%. The TLC spot plate is a single spot, under TLC conditions (developing agent n-hexane: ethyl acetate = 1:1, Rf = 0.2), and the purity of the product is 98% as detected by HPLC. MS-ESI(m / z):[M+H] + 316.22.

Embodiment 3

[0024] Add compound (III) (1g), methanol (10mL) and Pd / C (0.1g) (50% water content) into the reaction flask, replace with hydrogen three times, react at room temperature, monitor the completion of the reaction by TLC, filter and evaporate to dryness to obtain Compound (I); off-white solid, yield 85.5%. The TLC spot plate is a single point, under TLC conditions (developing agent n-hexane: ethyl acetate = 1:1, Rf = 0.2), and the purity of the product is 93% as detected by HPLC. MS-ESI(m / z):[M+H] + 316.22.

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Abstract

The invention discloses a preparation method of a varenicline intermediate and nitroreduction impurity thereof. The preparation method of the varenicline intermediate and nitroreduction impurity thereof comprises the following steps: nitrifying 2,3,4,5-tetrahydro-3-(trifluoroacetyl)-1,5-methano-1H-3-benazepine, hydrogenating Pd / C, and selectively reducing nitryl, thus obtaining a target compound shown in a formula (I). The preparation method of the varenicline intermediate and nitroreduction impurity thereof has the advantages that no pollution is produced to the environment, column chromatography operation is avoided, and yield and purity of a product are improved. The formula (I) is described in the specification.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of a varenicline intermediate and a nitro-reducing impurity thereof. Background technique [0002] Varenicline, trade name Chantix (FDA), Champix (EMA), is an optional alpha 4 beta 2 A partial agonist of the nicotinic acetylcholine receptor subtype used to help adults quit smoking. Developed and marketed by Pfizer, it was first approved by FDA in January 2006, and was approved for import by SFDA in August 2008. [0003] In terms of market, varenicline tartrate is mainly sold in the United States. After reaching the peak of global sales of 850 million U.S. dollars in 2008, sales have declined. In 2011, global sales reached 760 million U.S. dollars, an increase of 0.05% over 2010. ; China's sales in 2011 were 0.0035 billion US dollars, a decrease of 49.3% compared with 2010. [0004] [0005] In the synthesis process of varenicline, an impur...

Claims

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Application Information

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IPC IPC(8): C07D221/22
CPCC07D221/22
Inventor 范兴宝冯芮茂王珍珍于玲周炳城乔智涛
Owner 连云港恒运药业有限公司
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