Baricitinib is a novel oral JAK inhibitor that broadly inhibits inflammatory factors delivered via JAK-STAT, which has been associated with the development of a number of autoimmune disorders.It was approved for the treatment of rheumatoid arthritis in China in June 2019, and has also been approved by the U.S. FDA for the treatment of patients with severe pemphigus, moderately severe atopic dermatitis, and adults with severe COVID-19 disease. dermatitis, and adult patients with severe COVID-19.
Chemical Name: Baricitinib
Molecular Formula: C16H17N7O2S
Formula Weight: 371.42
CAS No.: 1187594-09-7
Baricitinib is able to block the synthesis and receptor activity of 5-hydroxytryptamine in the body and can target multiple receptors in the brain, such as 5-HT1A, 5-HT2A, and 5-HT2CR, in order to exert an inhibitory effect. In general, this mechanism of action is to inhibit the secretion of neurotransmitters in neurons by binding to them, thus realizing the function of controlling and regulating neurotransmitters.
Quasi used in the treatment of rheumatoid arthritis (RA) and some other autoimmune diseases. It suppresses the inflammatory response and activation of the immune system by inhibiting the JAK-STAT signaling pathway.
Patent CN105294699A discloses that the intermediate 3-(cyanomethylene)-3-(4-pyrazoleboronic acid pinacol ester)-3-(4-pyrazoleboronic acid pinacol ester)azetidine-1-carboxylic acid tert-butyl ester 27 was produced by Michael addition reaction with 3-(cyanomethylene)azetidine-1-carboxylic acid tert-butyl ester 27 with Boc. tert-butyl 3-(cyanomethylene)-3-(4-pyrazoleboronic acid pinacol ester)azetidine-1-carboxylate27. 27 The intermediate was reacted with Boc-protected 4-chloro-7-(4-pyrazoleboronic acid pinacol ester)azetidine-1-carboxylic acid tert-butyl ester. 27 was reacted with Boc-protected 4-chloro-7-(tert-butyl 1-carboxylate)-7H-pyrrolo[2 ,3-d]pyrimidine28 via a palladium-catalyzed coupling reaction to give the bis-Boc The palladium-catalyzed coupling reaction led to the bis-Boc-protected compound 29, which was prepared by stripping two molecules of the Boc-protecting group to obtain 3-(cyanomethylene)-3-((7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrimidin-4-yl)-3H-pyrimidin-4-carboxylate. -yl)-1H-pyrazol-1-yl)azetidine 30. Finally, a sulfonylation reaction with ethylsulfonyl chloride was carried out to obtain the end product baricitinib.
The raw material used in this method, 3-(cyanomethyl)azetidine-1-carboxylic acid tert-butyl 18, is not readily available, and the intermediate after removal of the Boc protecting group has two reactive amino groups, and the final step of the sulfonylation reaction with ethylsulfonyl chloride is prone to produce a bis-substituted by-product or is more prone to attack the amino group on the pyrrole ring, resulting in the production of bis-substituted by-products. The reaction with ethylsulfonyl chloride in the last step of sulfonylation is prone to produce double-substituted by-products or more easily attack the amino group on the pyrrole ring, resulting in many by-products and not easy to control.
Patent CN 106946917 discloses that 1-amino-3-chloropropan-2-ol hydrochloride31 is used as starting material, and the reaction with ethylsulfonyl chloride protects the amino group under the effect of base, and then the azacyclic ring is cyclized under the effect of base to obtain the azacyclic ring. Cyclization was carried out under the action of a base to obtain azetidine 33, which was oxidized to obtain azetidinone 4, and a wittig reaction between azetidinone 4 and triphenylphosphine acetonitrile was carried out to obtain 2-[1-(ethylsulfonyl)azetidin-3-ylmethylidene] -acetonitrile 20, and the reaction of intermediate 20 with a borate compound gives intermediate 36, which undergoes a coupling reaction and deprotection reaction to give baricitinib. This method directly protects the amino group with ethylsulfonyl group and then directly closes the ring by the action of base to obtain the azetidine intermediate, avoiding the use of other protective groups. However, this method has the problems of long reaction route, difficult to prepare some raw materials, and difficult to separate triphenylphosphine as a by-product of wittig reaction.
Patent CN116375623A discloses a new synthesis method of baricitinib and its intermediates, (1) azetidin-3-one hydrochloride 2 and ethylsulfonyl chloride 3 in the presence of a base under the action of sulfonylation reaction to obtain compound 4; (2) compound 4 and halonitrile 5 in the presence of a catalyst under the action of Reformatsky reaction to obtain compound 4. In the method for the synthesis of baricitinib from intermediate compound 6, compound 8 was obtained by the sulfonylation of compound 6 and sulfonyl chloride 7 in the presence of a base; (2) compound 10 was obtained by the condensation of compound 8 and compound 9; and (3) compound 10 was obtained by the Suzuki coupling reaction of compound 10 with 4-chloropyrrolopyrimidine 11. (3) compound 10 is coupled with 4-chloropyrrolopyrimidine 11 in a Suzuki coupling reaction to obtain compound 1, i.e. baricitinib. This method is simple, easy to obtain raw materials, easy to operate, low cost and suitable for industrialized production.
