Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride

A technology of dimethylpiperidine and amine dihydrochloride, which is applied to the intermediate cis-1-benzyl-N of tofacitinib, can solve the problems such as difficulty in obtaining raw materials, complex reaction system, pollution, etc. Low equipment requirements, process safety and environmental protection, and the effect of improving reaction yield

Inactive Publication Date: 2021-01-22
甘肃皓天医药科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] Through the analysis of the synthetic route for the preparation of tofacitinib intermediate (I) reported in the above literature, the raw materials used directly in the preparation process are not easy to obtain, or lithium aluminum hydride with high safety risk needs to be used, or it must be combined with benzyl halide Forming pyridinium salt and then reducing it by sodium borohydride, the reaction system is complex, the yield is low, and the amount of three wastes is huge, resulting in a large amount of waste of reagent solvents and great pollution to the environment. The competitiveness is weak, which is not conducive to the economical preparation of I
[0024] With the further development of my country's pharmaceutical industry, the quality requirements for pharmaceutical intermediates are getting higher and higher, and the existing production technology can no longer meet the requirements
Multiple purifications will inevitably greatly increase the cost, and produce a large amount of waste solvents, causing environmental pollution

Method used

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  • Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride
  • Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride
  • Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of compound Ⅲ

[0051]Add compound II (100g, 0.58mol) and 40% methylamine aqueous solution (350g) into the autoclave, add a catalytic amount of copper powder under stirring, slowly raise the temperature to 100-110°C, stir and react for 24h; Dichloromethane (500 mL) was extracted three times, dried and concentrated to obtain compound III (66 g, yield 93%).

[0052] Preparation of compound Ⅳ

[0053] Add compound III (60g, 0.49mol) and dichloromethane (480mL) to the reaction flask, add N,N-dimethylaminopyridine (73g, 0.60mol), then add di-tert-butyl dicarbonate (123g, 0.56 mol); the temperature was raised to 50-55° C., stirred for 20 h, cooled to room temperature, and the organic phase was separated by water, dried and concentrated to obtain compound IV (95 g, yield 87%).

[0054] Preparation of Compound V

[0055] Add compound IV (95g, 0.43mol) to the autoclave, add glacial acetic acid (950mL), add 5% rhodium carbon (48g) after nitrogen replacement three t...

Embodiment 2

[0061] Preparation of compound Ⅲ

[0062] Compound II (100 g, 0.58 mol) and water (350 g) were added to the autoclave, followed by methylamine hydrochloride (196 g, 2.90 mol) and sodium hydroxide (120 g, 3.0 mol). A catalytic amount of copper powder is added with stirring. Slowly raise the temperature to 120-130°C, and stir the reaction for 24h. Cool down to room temperature, extract three times with dichloromethane (500 mL), dry and concentrate to obtain compound III (61.6 g, yield 87%).

[0063] Preparation of compound Ⅳ

[0064] Compound III (60g, 0.49mol) and tetrahydrofuran (480mL) were added to the reaction flask, sodium hexamethyldisilazide (600mL, 0.60mol, 1.0M) was added, and di-tert-butyl dicarbonate (123g, 0.56 mol); heated to 50-55 ° C, stirred for 24 hours, concentrated under reduced pressure to recover tetrahydrofuran, added dichloromethane and water to the residue, separated the organic phase, dried, and concentrated to obtain compound IV (98g, yield 90%) . ...

Embodiment 3

[0072] Preparation of compound Ⅲ

[0073] Add compound II (100g, 0.58mol) and 40% methylamine aqueous solution (300g) into the autoclave, and add a catalytic amount of copper powder under stirring; slowly raise the temperature to 110-120°C, and stir for 24h. Cool down to room temperature, extract three times with dichloromethane (500 mL), dry and concentrate to obtain compound III (65 g, yield 92%).

[0074] Preparation of compound Ⅳ

[0075] Add compound III (60g, 0.49mol) and dichloromethane (480mL) to the reaction flask, add triethylamine (60.7g, 0.60mol) and catalytic amount of N,N-dimethylaminopyridine in turn, then add ethyl Anhydride (57.2 g, 0.56 mol). The reaction was stirred at room temperature for 4h. Water was added to quench the reaction, and the organic phase was separated, dried and concentrated to obtain compound IV (80.5 g, yield 100%).

[0076] Preparation of Compound V

[0077] Compound IV (80 g, 0.49 mol) was added to the autoclave, methanol (800 mL) w...

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Abstract

The invention discloses a preparation method of a tofacitinib intermediate cis-1benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride. The synthetic method comprises the following steps: taking 3-bromo-4-methylpyridine as an initial raw material, performing substitution reaction with amine to obtain a compound III, and performing acetyl or tert-butyloxycarbonyl protection and catalytic hydrogenation on the compound III to obtain a piperidine compound V. The compound V and benzaldehyde are subjected to reductive amination or react with benzyl halide to obtain a compound VI. A protecting groupis removed from the compound VI, and a hydrochloride compound I. 2HCl is formed at the same time. The synthesis method is simple to operate, high in total yield, high in product purity, stable in quality and suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of tofacitinib intermediate cis-1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride, in particular to a cis-1-benzyl The preparation method of base-N,4-dimethylpiperidin-3-amine dihydrochloride. Background technique [0002] Tofacitinib Citrate (Tofacitinib Citrate, see the formula below) was developed by Pfizer of the United States and was approved by the FDA for marketing in the United States in November 2012. The product name is The preparation is a tablet with a specification of 5 mg (calculated as tofacitinib). Indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to or intolerance to methotrexate, as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying agents combination of antirheumatic drugs (DMARDs). [0003] [0004] Tofacitinib citrate [0005] As an important intermedi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCC07D211/56Y02P20/55
Inventor 薛吉军李毅李学海周海明
Owner 甘肃皓天医药科技有限责任公司
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