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Preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt

A technology of toluoyl tartrate and methylpiperidine, applied in the field of organic chemistry, can solve the problems of difficult reaction conditions, high catalyst cost, expensive starting materials, etc., and achieve low cost, high total yield, and easy industrialization Effect

Inactive Publication Date: 2016-01-13
刘卫国
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The technical problem to be solved by this invention is to overcome the deficiencies in the prior art, aiming at the disadvantages of the prior art such as expensive starting materials, low yield, high catalyst cost, difficult control of reaction conditions and difficulty in industrial production, a kind of (3R ,4R)-(1-benzyl-4-methylpiperidin-3-yl)methanamine-L-di-p-toluoyl tartrate is a new preparation method, the whole route is novel, telescopic process is adopted, the total income High yield, in addition, starting materials are cheap and easy to obtain, low cost, strong operability, and easy industrialization

Method used

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  • Preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt
  • Preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt
  • Preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 1kg of formula I compound N-benzyl-4-carbonyl-3-piperidinecarboxylic acid ethyl ester was added in 7kg of ethanol, then 0.9kg of 25% ammonia water was added, the reaction temperature was 33°C, and after 22 hours of reaction, the Most of the ethanol was concentrated under pressure, and 7kg of methyl tert-butyl ether was added for extraction, and the separated organic phase was dried with sodium sulfate for 3 hours, and sodium sulfate was filtered off to obtain the methyl tert-butyl ether of the compound of formula II solution.

[0028]Cool the methyl tert-butyl ether solution of the compound of formula II obtained in the previous step to -55°C, and under the protection of nitrogen, add 2.5 L of 2mol / L tetrahydrofuran solution of methyl Grignard reagent dropwise, and the dropwise addition is completed in 1 hour. The temperature of the system is at -27°C. After reacting for 5 hours, slowly add 3.5 liters of 10% ammonium chloride solution dropwise to terminate the reaction,...

Embodiment 2

[0034] Add 20kg of ethanol in 3kg of formula I compound N-benzyl-4-carbonyl-3-piperidinecarboxylic acid ethyl ester, then add 3.9kg of 25% ammonia water, the reaction temperature is 30 ℃, after reacting for 30 hours, reduce Most of the ethanol was concentrated under pressure, and 20kg of methyl tert-butyl ether was added for extraction, and the separated organic phase was dried with sodium sulfate for 5 hours, and sodium sulfate was filtered off to obtain the methyl tert-butyl ether of the compound of formula II solution.

[0035] Cool the methyl tert-butyl ether solution of the compound of formula II obtained in the previous step to -60°C, and under the protection of nitrogen, add 8.6L 2mol / L of the tetrahydrofuran solution of methyl Grignard reagent dropwise, and the dropwise addition is completed in 1.5 hours. The temperature of the system is at -30°C. After reacting for 7 hours, slowly drop 10 liters of 10% ammonium chloride solution to terminate the reaction, separate the...

Embodiment 3

[0041] 5kg of formula I compound N-benzyl-4-carbonyl-3-piperidinecarboxylic acid ethyl ester was added in 35kg of ethanol, then 2.6kg of 25% ammonia water was added, and the reaction temperature was 40°C. After 16 hours of reaction, the Most of the ethanol was concentrated under pressure, and 35kg of methyl tert-butyl ether was added for extraction, and the separated organic phase was dried with sodium sulfate for 5 hours, and sodium sulfate was filtered off to obtain the methyl tert-butyl ether of the compound of formula II solution.

[0042] Cool the methyl tert-butyl ether solution of the compound of formula II obtained in the previous step to -40°C, and under nitrogen protection, add 10.5 L of 2 mol / L tetrahydrofuran solution of methyl Grignard reagent dropwise, and the dropwise addition is completed in 2 hours. The temperature of the system is at -20°C. After reacting for 4 hours, slowly add 17 liters of 10% ammonium chloride solution dropwise to terminate the reaction, s...

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Abstract

The invention discloses a preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt prepared from the following reaction steps shown in the description. The preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt has the following advantages that the process is novel in design, extremely dangerous chemicals (such as lithium aluminum hydride) are not required to be used, a folding condensation process is adopted, and the total yield is high; more importantly, the starting materials are cheap and easy to obtain, and the cost is low; and the maneuverability is high, and industrialization is easy.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, relates to a preparation process of a pharmaceutical intermediate, in particular to a medicine for treating rheumatoid arthritis-tofacitinib intermediate-(3R,4R)-(1-benzyl- A preparation method of 4-methylpiperidin-3-yl)methanamine-L-di-p-toluoyl tartrate. Background technique [0002] Tofacitinib is an anti-rheumatoid arthritis oral JAK inhibitor developed by Pfizer of the United States; it is the first generation of oral anti-rheumatoid arthritis drug, and it is the first drug of this type to be marketed. The FDA approved the listing on November 6, 2012, for the treatment of moderately to severely active rheumatoid arthritis with insufficient response or intolerance. [0003] [0004] Tofacitinib is a kinase (JAK) inhibitor. JAKs are a kind of intracellular enzymes, whose role is to transmit signals from cytokine or growth factor receptors on the cell membrane, thereby regulating...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCC07D211/56
Inventor 刘卫国
Owner 刘卫国
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