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Novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine

A kind of methylamino, benzyl technology

Active Publication Date: 2018-10-02
SULI PHARMA TECH JIANGYIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In order to overcome the shortcoming that the methylation existing in the prior art is too complicated, the present invention provides a novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine

Method used

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  • Novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine

Examples

Experimental program
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preparation Embodiment 1

[0030] Preparation Example 1: Synthesis of Compound 6 and Preparation of Intermediates

[0031] Add 4-amino-3-picoline 10 (10 g, 92.4 mmol) to a 250 ml reaction flask, add methanol (100 g), start stirring, and when the temperature is lower than 30 degrees, add sodium methoxide (7.48 g, 138.6 mmol ), add paraformaldehyde (5.54 g, 184 mmol), and complete the addition. The reaction solution was stirred overnight, and the HPLC detected that the raw material was less than 3%, and it was judged that the first-stage reaction was completed. At a temperature lower than 30°C, sodium borohydride (7.0 g, 184.8 mmol) was added in batches and stirred for 5-8 hours. The HPLC detection of raw materials was less than 3%, and the reaction was judged to be complete. The reaction solution was concentrated under reduced pressure to half, and the reaction was quenched with 3M hydrochloric acid at a temperature lower than 30 degrees, extracted twice with dichloromethane, the organic phases were com...

preparation Embodiment 2

[0034] Preparation Example 2: Synthesis of Compound 6

[0035] Add 4-amino-3-picoline 10 (10 g, 92.4 mmol) to a 250 ml reaction flask, add methanol (100 g), start stirring, and when the temperature is lower than 30 degrees, add sodium methoxide (11.22 g, 207.9 mmol ), add paraformaldehyde (2.77 g, 92 mmol), and complete the addition. The reaction solution was stirred overnight, and the HPLC detected that the raw material was less than 3%, and it was judged that the first-stage reaction was completed. At a temperature lower than 30°C, sodium borohydride (3.5g, 92.4mmol) was added in batches and stirred for 5-8 hours. The HPLC detection of raw materials was less than 3%, and the reaction was judged to be complete. The reaction solution was concentrated under reduced pressure to half, and the reaction was quenched with 3M hydrochloric acid at a temperature lower than 30 degrees, extracted twice with dichloromethane, the organic phases were combined, and concentrated under reduce...

preparation Embodiment 3

[0036] Preparation Example 3: Synthesis of Compound 6

[0037] Add 4-amino-3-picoline 10 (10 g, 92.4 mmol) to a 250 ml reaction flask, add methanol (100 g), start stirring, and when the temperature is lower than 30 degrees, add sodium methoxide (4.99 g, 92.4 mmol ), add paraformaldehyde (8.31 g, 277mmol), and complete the addition. The reaction solution was stirred overnight, and the HPLC detected that the raw material was less than 3%, and it was judged that the first-stage reaction was completed. At a temperature lower than 30°C, sodium borohydride (3.5 g, 92.4 mmol) was added in batches and stirred for 5-8 hours. HPLC detected that the raw material was less than 3%, and the reaction was judged to be complete. The reaction solution was concentrated under reduced pressure to half, and the reaction was quenched with 3M hydrochloric acid at a temperature lower than 30 degrees, extracted twice with dichloromethane, the organic phases were combined, and concentrated under reduce...

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Abstract

The invention provides a novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine. The method has the advantages that aminopyridine is used as the raw material, the original two-step arylamine methylation becomes one-step reaction, unfriendly lithium aluminum hydrogen reduction is avoided, toxic controlled product methyl chloroformate is avoided, the used raw materials are simple and easy to obtain, the method is suitable for industrial production, the generation of a large amount of aluminum-containing wastewater is reduced, production cycle is shortened evidently, and productivity is increased.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine. technical background [0002] Cis-1-benzyl-3-methylamino-4-piperidine is an important pharmaceutical chemical raw material and an important intermediate of the listed drug tofacitinib (see CN1729192A). The specific structure of the compound is as follows: [0003] [0004] The product is an oil and is generally isolated as the dihydrochloride. At present, the schemes reported in the literature can be divided into three categories. The first category is to synthesize cis-products by reductive amination from the corresponding piperidone intermediates, and the second category is to synthesize cis-products from pyridine intermediates by metal-catalyzed methods. The third type is to obtain the cis product by benzylation and reduction from aminopyridine. [0005] The reaction formula of the first typ...

Claims

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Application Information

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IPC IPC(8): C07D211/56
CPCC07D211/56
Inventor 张澎涛杨凯鞠叶明王为磊汪静莉
Owner SULI PHARMA TECH JIANGYIN
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