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N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d] pyrimidine-4-amine crystal

A technology of methylpiperidine and methylaminopiperidine dihydrochloride, which is applied in the most critical intermediate field of tofacitinib citrate, can solve the problems affecting the quality of the final product tofacitinib citrate, etc. Achieve the effect of major technical advantages and research value

Inactive Publication Date: 2015-12-16
HUBEI LIYI PHARM TECH CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine is a synthetic citrate The most critical intermediate of tofacitinib citrate directly affects the quality of the final product tofacitinib citrate; however, references at home and abroad have no references to N-[(3R,4R)-1-benzyl- 4-Methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine crystal form has not been reported

Method used

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  • N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d] pyrimidine-4-amine crystal
  • N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d] pyrimidine-4-amine crystal
  • N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d] pyrimidine-4-amine crystal

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preparation example Construction

[0027] Preparation of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine crystals method, including the following steps:

[0028] 1) Weigh 1 to 3 parts of 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 0.4 to 2 parts of 1-benzyl-4-methyl-3 -Methylaminopiperidine dihydrochloride, 0.2 to 2 parts of potassium carbonate, 0.1 to 1.0 parts of sodium hydroxide, 6 to 15 parts of n-butanol, set aside;

[0029] 2) 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 1-benzyl-4-methyl-3-methylaminopiperidine dihydrochloride, potassium carbonate and water were sequentially Add it into a reaction vessel, heat it to 70-90°C, keep it warm for 0.5-2 hours, then lower it to room temperature, filter, wash with ethanol, and dry under reduced pressure at a temperature of 35-45°C to obtain a white solid; set aside;

[0030] 3) Add the white solid, sodium hydroxide and n-butanol to the reaction vessel in turn, heat to 80-100°C, cool down to room temper...

Embodiment 1

[0040] Preparation of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine crystals method, including the following steps:

[0041] 1) Weigh 1 part of 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 0.6 part of 1-benzyl-4-methyl-3-methylaminopiper Pyridine dihydrochloride, 0.6 part of potassium carbonate, 0.4 part of sodium hydroxide, 10 parts of n-butanol, for subsequent use;

[0042] 2) 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 1-benzyl-4-methyl-3-methylaminopiperidine dihydrochloride, potassium carbonate and water were sequentially Add it into a reaction vessel, heat it to 80°C, keep it warm for 1 hour, then lower it to room temperature, filter, wash with ethanol, and dry under reduced pressure at 40°C to obtain a white solid; set aside;

[0043] 3) Add the white solid, sodium hydroxide and n-butanol to the reaction vessel in turn, heat to 90°C, cool down to room temperature, add purified water, extract with dichloromet...

Embodiment 2

[0048] Preparation of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine crystals method, including the following steps:

[0049] 1) Weigh 3 parts of 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 2 parts of 1-benzyl-4-methyl-3-methylaminopiper Pyridine dihydrochloride, 0.2 parts of potassium carbonate, 1.0 parts of sodium hydroxide, 15 parts of n-butanol, for subsequent use;

[0050] 2) 4-chloro-7-p-toluenesulfonylpyrrolo[2,3-d]pyrimidine, 1-benzyl-4-methyl-3-methylaminopiperidine dihydrochloride, potassium carbonate and water were sequentially Add it into a reaction vessel, heat it to 90°C, keep it warm for 0.5h, then lower it to room temperature, filter, wash with ethanol, and dry under reduced pressure at 45°C to obtain a white solid; set aside;

[0051] 3) Add the white solid, sodium hydroxide and n-butanol to the reaction vessel in sequence, heat to 100°C, cool down to room temperature, add purified water, extract with dichlo...

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Abstract

The invention discloses an N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d] pyrimidine-4-amine crystal and a preparation method thereof. The method comprises steps as follows: firstly, 4-chloro-7-(p-tolylsulfonyl) pyrrolo [2,3-d] pyrimidine, 1-benzyl-4-methyl-3-aminomethyl dihydrochloride, potassium carbonate and water are added to a reaction vessel sequentially, heated and subjected to thermal insulation, and white solids are obtained; the white solids, sodium hydroxide and n-butyl alcohol are added to the reaction vessel sequentially, an obtained organic phase is washed with water, then anhydrous magnesium sulfate is added to the organic phase for dehydration, and a dichloromethane extracting solution is obtained; finally, eluting and curing are performed, and the crystal is obtained. The purity of the crystal is higher than 99.9%. According to a final product tofacitinib citrate synthesized with the intermediate, related substances are controlled to be lower than 0.1%, and the preparation of the crystal has great technical advantage and research value.

Description

technical field [0001] The present invention relates to the most critical intermediate of tofacitinib citrate, specifically a kind of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl Cyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (hydrolyzate for short) crystal and preparation method thereof. Background technique [0002] The structural formula of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine is as follows: [0003] [0004] The U.S. Food and Drug Administration approved Pfizer's Xeljanz (tofacitinib, tofacitinib citrate) in November 2012 for moderately to severely active rheumatoid arthritis ( RA) for the treatment of adult patients. [0005] Tofacitinib citrate is used for the treatment of active rheumatoid arthritis (RA), and the patient group is moderate to severe adult patients who have insufficient response or intolerance to methotrexate treatment. RA is an autoimmune disease in which the immune system mistakenly attacks, cau...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/13
Inventor 陈龙刘均均周震张茂刘俊余丹刘婷邵振
Owner HUBEI LIYI PHARM TECH CO LTD
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