Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method

A technology of toluyl tartrate and dimethylpiperidine, which is applied in the field of chemical pharmacy, can solve the problems of unsatisfactory cost control and environmental protection, inconvenient transportation and storage, and increased catalyst cost, and achieve effective Conducive to environmental protection, satisfactory product quality and low production cost

Inactive Publication Date: 2015-08-26
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the first step reaction of this method, 3-amino-4-picoline is insoluble in 2-methyltetrahydrofuran, and the heterogeneous reaction causes the reaction to require a large amount of solvent, and the solvent is expensive and the production cost increases
In the third step reaction, lithium aluminum hydride is used as reducing agent to obtain monomethylated products of primary amines. On the one hand, lithium aluminum hydride is active in nature and is easily decomposed by moisture, which is inconvenient for transportation and storage; on the other hand, lithium aluminum hydride The usage amount should be more than 3 times, the cost of the catalyst itself will increase, and a large amount of industrial wastewater will be generated when excessive lithium aluminum hydride is processed; moreover, the reduction reaction requires THF to reflux for more than 3 hours, the reaction conditions are severe, and the reaction time is long
The whole reaction route is unsatisfactory in terms of safety, cost control and environmental protection

Method used

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  • Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019]

[0020] Sodium hydride (8.0g, 200mmol) was suspended in anhydrous tetrahydrofuran, and slowly added dropwise to a solution of compound V (21.6g, 200mmol) in anhydrous tetrahydrofuran (150mL) at -5 ~ 5°C, and the stirring was continued for 60min, then Slowly add dimethyl carbonate (19.80g, 220mmol) dropwise. After the dropwise addition, stir at 40°C for 7h. TLC shows that the reaction is complete. Slowly add 30mL of distilled water, stir for 30min, and evaporate the organic solvent under reduced pressure. Add 20mL of petroleum ether, stir vigorously under ice bath for 30min, filter, wash the filter cake with petroleum ether (30mL×3), and dry to obtain light brown product IV (31.0g), yield: 93.4%, purity (HPLC): 98.7%, 1 H NMR (400MHz, CDCl 3 )δ: 2.27(s, 3H), 3.8(s, 3H), 6.39(s, 1H), 7.10(d, J=5.2Hz, 1H), 8.27(d, J=4.8Hz, 1H), 8.86( s,1H).ESI-HRMS: Calcd for C 8 h 10 N 2 o 2 (M+H) + 167.0815, found 167.0818.

Embodiment 2

[0022]

[0023] Sodium hydride (12.0 g, 300 mmol) was suspended in anhydrous tetrahydrofuran, and slowly added dropwise to a solution of compound V (21.6 g, 200 mmol) in anhydrous tetrahydrofuran (150 mL) at -5 to 5 ° C, and stirring was continued for 60 min, then Slowly add dimethyl carbonate (19.80g, 220mmol) dropwise, stir at room temperature for 10h after the dropwise addition, TLC shows that the reaction is complete, slowly add 50mL of distilled water, stir for 30min, evaporate the organic solvent under reduced pressure, and add 20mL petroleum ether, stirred vigorously for 30min under ice bath, filtered, the filter cake was washed with petroleum ether (30mL×3), dried to obtain light brown product IV (31.2g), yield: 94.1%, purity (HPLC): 97.9% .

[0024] Reference Example 1

[0025]

[0026] The acetic acid solution (200mL) of compound IV (33.2g, 200mmol) was added to the acetic acid (100mL) solution of 5%Rh / C (4.2g), stirred for 15min, and in a hydrogen atmospher...

Embodiment 3

[0031]

[0032] Dissolve compound III (3.0g, 10mmol) in toluene (30mL), slowly add red aluminum toluene solution (8.7g) dropwise under ice-water bath, after the addition is complete, react at room temperature for 2h, then cool the reaction solution below 10°C , slowly added distilled water (30mL) dropwise under vigorous stirring, stirred for 30min, filtered, the filter cake was washed with toluene (20mL×3), the filtrate was extracted with toluene, the organic phases were combined, dried, and the solvent was removed by rotary evaporation, the residue (cis structure Purity (GC): 93.2%) was directly used in the next reaction without purification.

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Abstract

The present invention relates to a novel preparation method of a tofacitinib intermediate bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate. According to the preparation method, 3-amino-4-methyl piperidine is adopted as a starting raw material, is subjected to a N-methoxycarbonylation reaction under the sodium hydride effect, and is subjected to a catalytic hydrogenation reaction, a nucleophilic substitution reaction, an amide reduction reaction under the red aluminum effect, and L-di-p-toluyl tartaric acid (L-DTTA) chiral splitting so as to finally prepare the target compound bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate. The process of the present invention has characteristics of further existing process improving, simple operation, easy post-treatment, high yield, and low cost.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to an intermediate bis-(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine L of a JAK3 kinase inhibitor tofacitinib -The preparation method of di-p-toluoyl tartrate. Background technique [0002] Bis-(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine L-di-p-methylbenzoyl tartrate is an important intermediate in the synthesis of the JAK3 kinase inhibitor tofacitinib body. Tofacitinib is a class of oral drugs developed by Pfizer (Pfizer) for the treatment of rheumatoid arthritis. It was approved for marketing by the FDA in November 2012 under the trade name Xeljanz. The preparation of this product has been reported in the literature at home and abroad, such as the synthesis method provided in the literature Organic Process Research & Development, 2005, 9, 51-56 and patent WO 200829237: [0003] [0004] In the first step of the method, 3-amino-4-picoline is insoluble in 2-methy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56C07C69/78
CPCC07D211/56C07C69/78
Inventor 刘登科刘颖刘冰妮支爽王兵樊梦林
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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