Method for synthesizing citric acid tofacitinib

Abstract

The invention discloses an efficient and safe method for synthesizing citric acid tofacitinib. N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-base]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine is used as the raw material, Pd / C and HCOOH reduction debenzylation is conducted, condensation is conducted under the catalysis of an EDCI or EDCI, HOBT and triethylamine compound system with cyanoacetic acid, and salifying is conducted with citric acid in acetone to obtain citric acid tofacitinib. By the adoption of the synthesis method, potential safety hazards caused by hydrogen and ammonium formate are avoided, debenzylation reaction and amidation are thorough, no side reaction is caused basically, reaction time is shortened greatly, yield is high, aftertreatment is easy, and citric acid tofacitinib can be prepared efficiently and safely.

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to a synthesis method of tofacitinib citrate. Background technique [0002] Tofacitinib citrate, the chemical name is 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)amino]piperidin-1-yl]-3-oxopropionitrile citrate is a new oral Janus kinase (JAK) inhibitor developed by Pfizer, and passed the risk assessment by the US FDA in November 2012 and Mitigation Strategies (REMS) approval for the treatment of adult patients with active and moderate to severe rheumatoid arthritis (RA) who do not respond well to methotrexate, under the trade name Xeljanz. It is also suitable for the treatment of psoriasis, pancreatic disease, leukemia, myelodysplastic syndrome, ankylosing spondylitis, and transplant rejection. [0003] The compound patent (WO2001042246) of tofacitinib citrate was applied for on November 23, 2000, in which the publishe...

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Problems solved by technology

[0005] The patented route of this compound has a stable process, and the raw materials and reagents are cheap and easy to obtain. It is the basic route of the synthesis process of tofacitinib citrate. Many related researchers have made various improvements to the process, but there are still some defects, such as: The debenzylation reaction of raw material 5 basically adopts the original research method, the reaction time of this method is long, and hydrogen is flammable and explosive, which has potential safety hazards

CN105348287 announced the use of Pd / C, HCOONH 4 The method of removing the benzyl group greatly shortens the reaction time, but there is still a potential safety hazard that ammonium formate is easy to sublimate and block the condenser pipe during scale-up production, and if ammonium formate is not removed, by-products will be introduced in the next step of the amide-forming reaction

[0006] The amidation reaction of intermediate 3 mostly uses ethyl cyanoacetate, cyanoacetic acid, cyanoacetic acid-N-hydroxysuccinimide ester, etc., but the cost of cyanoacetic acid-N-hydroxysuccinimide ester Higher, the reaction of ethyl cyanoacetate is incomplete or there are many side reactions. The condensing agent or alkali mostly uses DBU, HOBT, triethylamine, etc., and the reaction time is generally long (10h ~ 48h), and the reaction is not complete. , the problem of low yield

CN105085527 discloses that cyanoacetic acid reacts under DCC condensation, the reaction is very thorough, and there is basically no side reaction, but the by-product DCU of DCC is difficult to be removed in the process of post-treatment, making this method have certain limitations

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