Preparation method of tofacitinib citrate starting material

A technology of tofacitinib and raw materials, applied in the field of chemical pharmacy, can solve the problems of large-scale industrial waste water, increase environmental protection pressure, high price, etc., and achieve the effects of reducing production costs, reducing safety risks, and high product yield

Inactive Publication Date: 2017-11-10
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Use a large amount of 2-methyltetrahydrofuran in the first step reaction of this route, this solvent is expensive, and production cost increases
In the second step of catalytic hydrogenation, expensive chiral catalyst rhodium is used, which makes it difficult to realize industrial production
Lithi

Method used

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  • Preparation method of tofacitinib citrate starting material
  • Preparation method of tofacitinib citrate starting material
  • Preparation method of tofacitinib citrate starting material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1. Synthesis of Compound IV

[0036]Add 50g (1eq) of 4-methylpyridine, 200mL of acetone and 102g (1.5eq) of benzyl chloride into a 500mL reaction flask, start stirring, and keep the reaction for 4 hours; TLC monitors that the reaction is basically complete, cool down to room temperature, and store at an external temperature of 40~45°C Concentrate under reduced pressure to dryness, then add 200mL of acetonitrile to the concentrated solution, raise the temperature to reflux until the solution is clear, then slowly cool down to 0~5°C, stir at this temperature for 2h, filter with suction, and filter the cake with cooled acetonitrile Washed twice, dried to obtain a white solid, and the filter cake was vacuum-dried at 40-45°C to obtain 106.1 g of a white powder, with a yield of 90%.

[0037] 2. Synthesis of Compound V

[0038] Add 100g of compound VI (1.0eq) and 400mL of ethanol to a 1L reaction flask, start stirring, and after cooling down to 15°C, add NaBH to the reaction ...

Embodiment 2

[0048] 1. Synthesis of Compound IV

[0049] Add 100g (1eq) of 4-methylpyridine, 400mL of acetone and 204g (1.5eq) of benzyl chloride into a 1L reaction flask, start stirring, and keep the reaction for 4h; TLC monitors that the reaction is basically complete, cool down to room temperature, and store at an external temperature of 40~45°C Concentrate under reduced pressure to dryness, then add 400mL of acetonitrile to the concentrated solution, raise the temperature to reflux until the solution is clear, then slowly cool down to 0~5°C, stir at this temperature for 2h, filter with suction, and filter the cake with a cooled Washed twice with acetonitrile, drained to obtain a white solid, the filter cake was vacuum-dried at 40-45°C to obtain 212.1 g of white powder, yield 90%.

[0050] 2. Synthesis of Compound V

[0051] Add 200g of compound VI (1.0eq) and 800mL of ethanol to a 2L reaction flask, start stirring, and after cooling down to 15°C, add NaBH to the reaction solution 4 ...

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Abstract

The invention discloses a synthesis method of a tofacitinib citrate starting material N-((3R, 4R)-4-methyl-1-benzyl-3-piperidyl)-N-methyl-7-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine-4-amine(I). The method comprises the specific steps that 4-methylpyridine is adopted as the starting material to be subjected to nucleophilic substitution with benzyl chloride to obtain 4-methyl-1-benzyl-pyridinium chloride, a reduction reaction is performed under the effect of sodium borohydride, a hydroboration-oxidation reaction is performed, hydroxyl oxidation is performed, two chiral centers are introduced in a reductive amination stereoselectivity mode, splitting is performed through cheap chiral acid (L-DTTA) easy to obtain to obtain an optically pure intermediate body (3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methyl amine, and finally, the intermediate body and 4-chloropyr are condensed to obtain the tofacitinib citrate starting material. The whole method is easy to implement and low in cost, raw materials are easy to obtain, and aftertreatment is easy. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a starting material N-((3R,4R)-4-methyl-1-benzyl-3- The preparation method of piperidinyl)-N-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidin-4-amine. Background technique [0002] Tofacitinib is a drug for the treatment of rheumatoid arthritis developed by Pfizer. The trade name is Xeljanz, which belongs to a Janus kinase inhibitor and is used for moderate to severe active rheumatoid arthritis who have insufficient response or intolerance to methotrexate treatment Arthritis in adults. N-((3R,4R)-4-Methyl-1-benzyl-3-piperidinyl)-N-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine -4-amine is the key starting material for the synthesis of tofacitinib citrate. [0003] Pfizer announced a preparation route in patent WO2007012953 (see route 1). The preparation method is to use (4-methylpyridin-3-yl) methyl carbamate (1) as the starting material, re...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 孟繁柯陆俊张勇
Owner JIANGSU QINGJIANG PHARMA
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