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Synthesis method of JAK inhibitor tofacitinib

A technology for the synthesis of tofacitinib and its synthesis method, which is applied in the field of synthesis of the JAK inhibitor tofacitinib, can solve the problems of low yield and long reaction time, and achieve the effects of simple operation, easy control of impurities, and mild reaction conditions

Inactive Publication Date: 2016-06-22
JINAN TIANYU SURVEYING & MAPPING INSTR CO LTD
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Problems solved by technology

[0012] This route is also N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4 -Amine is used as a raw material, debenzylated by palladium hydroxide carbon catalytic hydrogenation, and then acylated with ethyl cyanoacetate to obtain tofacitinib. This route uses hydrogen as a hydrogen donor, and ethyl cyanoacetate for acylating reagents , different from route two is to adopt 1,8-diazabicycloundec-7-ene (DBU) as catalyst, the reaction time is long, and the yield is low

Method used

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  • Synthesis method of JAK inhibitor tofacitinib
  • Synthesis method of JAK inhibitor tofacitinib
  • Synthesis method of JAK inhibitor tofacitinib

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Embodiment 1

[0033] 5% palladium on carbon (1g, 59% water content), N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2, 3-d] Pyrimidin-4-amine (6.7g, 0.02mol), ethanol (50mL), 3mL of formic acid were added to a 100mL three-necked flask, protected by nitrogen, heated to 40°C and reacted for 12h to complete the reaction, adding sodium carbonate to adjust the pH of the system to 7-8, remove the solid by filtration, and evaporate the filtrate to remove ethanol under reduced pressure to obtain N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2, 3-d] Pyrimidin-4-amine 4.0 g, yield 81.6%.

[0034] N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.5g, 0.01mol), Cyanoacetic acid (1.0 g, 0.012 mol), DCC (4.1 g, 0.02 mol), DMAP (0.05 g), tetrahydrofuran (25 mL). Add it into a 50mL three-necked flask, raise the temperature to 35°C and react for 1h, adjust the pH to 7-8 with sodium carbonate, remove the solid by filtration, concentrate the filtrate...

Embodiment 2

[0036] 20% palladium hydroxide on carbon (0.5g, 50% water), N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo [2,3-d]Pyrimidin-4-amine (6.7g, 0.02mol), methanol (50mL), ammonium formate (3.15g, 0.05mol), add to a 100mL three-necked flask, protect with nitrogen, heat up to 60°C for reaction After 6h, the reaction was complete, adding sodium carbonate, adjusting the pH of the system to 7-8, filtering to remove the solid, and distilling the filtrate to remove methanol under reduced pressure to obtain N-[(3R,4R)-4-methylpiperidin-3-yl]-N -Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 4.1 g, yield 93.3%.

[0037] N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.5g, 0.01mol), Cyanoacetic acid (1.0 g, 0.012 mol), DIC (2.5 g, 0.02 mol), 4-PPY (0.05 g), dichloromethane (25 mL). Add it into a 50mL three-necked flask, raise the temperature to 35°C and react for 1h, adjust the pH to 7-8 with potassium carbonate, remove the solid by filtration, ...

Embodiment 3

[0039] 5% palladium on carbon (1.0g, 59% water content), N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2 ,3-d] Pyrimidin-4-amine (6.7g, 0.02mol), ethanol (50mL), hydrazine hydrate (80%, 4g), added to a 100mL three-necked flask, protected by nitrogen, heated to 75°C for 4h and the reaction was complete , filtered to remove the solid, the filtrate was concentrated, and column chromatography was separated to obtain N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d] Pyrimidin-4-amine 3.6g, yield 73.5%.

[0040] N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.5g, 0.01mol), Cyanoacetic acid (1.0 g, 0.012 mol), DCC (4.1 g, 0.02 mol), HOSU (0.05 g), tetrahydrofuran (25 mL). Add it into a 50mL three-necked flask, raise the temperature to 50°C and react for 1h, adjust the pH to 7-8 with sodium bicarbonate, remove the solid by filtration, concentrate the filtrate, and separate by column chromatography to obtain 2.5g of tofa...

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Abstract

The invention relates to a synthesis method of a JAK inhibitor tofacitinib. The method comprises the steps: with N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a raw material, with formic acid, ammonium formate or hydrazine hydrate as a hydrogen donor, carrying out hydrogenation to remove benzyl to obtain N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, and then carrying out a reaction with cyanoacetic acid to obtain tofacitinib. Compared with an original synthesis method, the method provided by the invention has the advantages of mild conditions, simple and convenient operation, high yield, low cost and the like, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for synthesizing JAK inhibitor tofacitinib, which belongs to the technical field of organic synthesis and drug synthesis. Background technique [0002] The chemical name of tofacitinib is 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine- 1-yl]-3-oxopropionitrile is a new type of Janus kinase inhibitor developed by Pfizer of the United States. It was approved by the US FDA on November 6, 2012, and its trade name is Xeljanz. This product can effectively inhibit the activity of JAK1 and JAK3, and block the signal transduction of various inflammatory cytokines. Existing studies have shown that tofacitinib has a good therapeutic effect on rheumatoid arthritis, ulcerative colitis, psoriasis and other inflammation-related diseases. [0003] At present, the synthetic routes of tofacitinib reported in the literature are: [0004] Route 1. The synthetic route reported in patent WO0142246 is as f...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 杨素美
Owner JINAN TIANYU SURVEYING & MAPPING INSTR CO LTD
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