477600-70-7Relevant articles and documents
Preparation methods of tofacitinib intermediate amine and dihydrochloride thereof
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Paragraph 0025; 0089-0090, (2020/11/12)
The invention discloses preparation methods of tofacitinib intermediate amine and dihydrochloride thereof. According to the preparation method of the tofacitinib intermediate amine, methyl acetoacetate and cyanoacetamide are taken as starting materials and subjected to condensation, olefinic bond reduction, cyano hydrolysis into amide, N benzylation and Hofmann degradation to prepare primary amine, monomethylation and chiral resolution of the primary amine are performed, and a carbonyl group is reduced with zinc borohydride, so a target product is obtained. The obtained (3R,4R)-1-benzyl-3-methylamino-4-methylpiperidine is subjected to salifying with hydrochloric acid to obtain the dihydrochloride. The methods have the advantages that the whole process avoids a high-pressure hydrogenation reaction under an acidic condition; all the reaction steps adopt conventional reaction reagents and solvents, so raw material sources are not limited, and cost is low; and the method avoids a lithium aluminum hydride reduction reagent with high risk, each step has high selectivity, the reaction product of each step can be easily refined, and the method has advantages in industrialization.
PROCESS FOR THE PREPARATION OF CHIRAL 3-AMINO-PIPERIDINS, USEFUL INTERMEDIATES FOR THE PREPARATION OF TOFACITINIB
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Paragraph 0106; 0107, (2019/01/15)
Object of the present invention is an improved process for the preparation of (3R,4R)-1-benzyl-4-methylpiperidin-3-amine by means of chiral Rhodium catalysts.
Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a Dynamic Kinetic Resolution-Reductive Amination Protocol
Verzijl, Gerard K. M.,Schuster, Christian,Dax, Thomas,De Vries, André H. M.,Lefort, Laurent
, p. 1817 - 1822 (2019/01/04)
We report the first example of a catalytic asymmetric reductive amination under dynamic kinetic resolution (DKR) conditions for the preparation of a chiral amine as a key intermediate toward Tofacitinib, an active pharmaceutical ingredient developed by Pfizer. Such a protocol allows the preferential formation of a single product out of four possible diastereomers of the chiral amine starting from the corresponding racemic ketone. The chiral iridium catalyst able to perform such a feast was discovered through a mix of high-throughput screening, racemization study, and reaction optimization.