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Preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, applied in the field of medicinal chemistry, can solve the problems of flammability and explosion of hydrogen, potential safety hazards, incomplete reaction, etc., and achieve the effects of shortening reaction time, easy operation and complete reaction

Active Publication Date: 2018-07-13
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Patent document (CN101233138A) has reported the preparation method of tofacitinib citrate shown in route 2, and this method is in debenzylation and dechlorination process, and reaction time is too long, and hydrogen gas is flammable and explosive, and there is potential safety hazard , and the reaction is not complete, it is easy to produce impurity products of single debenzylation or single dechlorination, which will affect the quality
At the same time, the last two steps of the route are cumbersome and the yield is only 67.3%.

Method used

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  • Preparation method of tofacitinib citrate
  • Preparation method of tofacitinib citrate
  • Preparation method of tofacitinib citrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: the preparation of compound 3

[0039] Add 20g of compound 5 and 13.3g of compound 4 into a 500ml reaction flask, add 266ml of purified water, add a pre-prepared potassium carbonate aqueous solution (20g of potassium carbonate dissolved in 40ml of purified water) under stirring, and heat to reflux. After stirring and refluxing for 10 hours, TLC detection was started until the reaction was complete. Cool down to 20-30°C, add 120ml of dichloromethane, stir and extract, let stand to separate layers, dry, filter, wash to obtain the reaction solution, add n-heptane under stirring at room temperature, cool down to 0-10°C to crystallize for 2-4 hours, Filter and wash. Vacuum drying at 50-60°C for 6 hours gave compound 3, weighing 20.9 g, yield: 82.3%, purity: 99.9%.

Embodiment 2

[0040] Embodiment 2: the preparation of compound 2

[0041]Add 20g of compound 3 into a 500ml beaker, add 300ml of methanol, 7.5g of acetic acid, and 2g of 5% wet palladium carbon and stir until suspended; the reaction module of the microreactor is heated to 30°C, and the cooling module is controlled at 20°C; adjust the flow rate of the feeding pump 30g feed liquid / minute, the mixed feed liquid enters the microreactor from channel A; 15.2g triethylsilane enters the microreactor from channel B, and starts to react after passing through the reaction module, and the reaction liquid is obtained after passing through the cooling module, and the reaction has been detected by TLC (total reaction time 10 minutes), out of the microreactor. Remove the palladium carbon by filtration, at room temperature, add 65g of 10% sodium hydroxide, stir for 1.5 hours, add 80ml of dichloromethane and stir for extraction, stand for layering, add 80ml of dichloromethane to the water phase, stand for la...

Embodiment 3

[0042] Embodiment 3: the preparation of tofacitinib citrate

[0043] Heat up the reaction module of the microreactor to 80°C; add 10g of compound 2 into a 500ml beaker, add 300ml of n-butanol and stir to dissolve, add 9.22g of ethyl cyanoacetate and 6.2g of DBU, and adjust the flow rate of the feeding pump to 30g of feed solution / min Enter the microreactor from channel A; add 15ml purified water and 60ml n-butanol to 21.4g citric acid and stir to dissolve, adjust the flow rate of the feeding pump to 10g feed liquid / min and enter the microreactor from channel B, and react in the reaction module, the total reaction After 10 minutes, the reaction solution was cooled to 20-30°C after leaving the microreactor, stirred and crystallized for 2-3 hours, filtered, washed, and vacuum-dried at 40-50°C for 5 hours to obtain tofacitinib citrate: 19.8g, Yield: 96.4%, purity: 99.98%.

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Abstract

The invention discloses a preparation method of tofacitinib citrate. The preparation method comprises the following steps: stirring an organic solvent, a compound 3, 5 percent wet palladium on carbonand acetic acid until a mixture is suspended; conveying the mixture into a micro-reactor from a channel A; meanwhile, conveying alkylsilane into the micro-reactor from a channel B; controlling the temperature of the micro-reactor to 20 to 30 DEG C and carrying out reaction; carrying out post-treatment to obtain a compound 2; after uniformly mixing an alcohol type solvent, the compound 2, ethyl cyanoacetate and DBU (1,8-Diazabicyclo [5,4,0]undec-7-ene), conveying a mixture into the micro-reactor from the channel A; dissolving citric acid into a mixed solution of water and the alcohol type solvent, conveying a mixture into the micro-reactor from the channel B; controlling the temperature in the micro-reactor to 70 to 80 DEG C and carrying out reaction; cooling and crystallizing to obtain thetofacitinib citrate. The method provided by the invention has the advantages of controllable reaction condition and simplicity in operation; dangers caused by the fact that flammable and explosive gas is used are avoided and the safety is higher; reaction can be finished instantly and the reaction time is greatly shortened; debenzylation reaction and acylation reaction are complete and post-treatment is simple; the preparation method is suitable for industrial large-scale production. A formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib citrate, English name tofacitinib citrate, chemical name: 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino]piperidin-1-yl]-3-oxopropylcyanide citrate (1:1), the chemical structural formula is [0003] [0004] Tofacitinib citrate (tofacitinib) is a JAK inhibitor developed by Pfizer, which can effectively inhibit the activity of JAK1 and JAK3, and block the signal transduction of various inflammatory cytokines. Existing studies have shown that tofacitinib citrate has good therapeutic effects on rheumatoid arthritis, ulcerative colitis, psoriasis and other inflammation-related diseases, and it was launched in the United States on November 7, 2012. [0005] The preparation method of tofacitinib citrate (or tofacitinib) reported in the literature m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C59/265C07C51/41
CPCC07B2200/13C07D487/04
Inventor 李法东吴柯杨庆坤李卓华周显峰潘广鹏
Owner 山东安信制药有限公司
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