Preparation process of Xeljanz intermediate

Abstract

The invention belongs to the technical field of pharmaceutical synthesis, in particular to a preparation process of a Xeljanz intermediate. The preparation process comprises the following steps: 1) adding ethyl cyanoacetate into n-butyl alcohol, and uniformly stirring; 2) dropwise adding DBU into a solution prepared in the step 1) at a temperature of or below 30 DEG C; 3) adding N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine into a solution prepared in the step 2) in batches for reacting; 4) dropwise adding water into a system reacting completely in the step 3), stirring, filtering and washing to obtain the Xeljanz intermediate, namely, (3R,4R)-4-methyl-3-(methyl-1H-pyrrolo[2,3-d]pyridine-4-amino)-beta-oxy-1-piperidine propionitrile. The intermediate prepared by the invention has higher yield and purity, and the decrease of the purity of the intermediate in expanded production is less.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a preparation process of a tofacitinib intermediate, more specifically, to a tofacitinib intermediate ( 3R, 4R )-4-methyl-3-(methyl-1 H -pyrrolo[2,3- d ] The preparation technology of pyrimidine-4-amino)-β-oxygen-1-piperidine propionitrile. Background technique [0002] Tofacitinib citrate (tofacitinib citrate), trade name Xeljanz, is a small molecule oral inhibitor of intracellular tyrosine kinase, approved by the US FDA in November 2012 for adults with moderate to severe activity Treatment of sexual RA. It is indicated for the treatment of active adult patients with moderate to severe rheumatoid arthritis who do not respond well to methotrexate (MTX), and can be used in combination with methotrexate for the treatment of active patients with insufficient response to tumor necrosis factor inhibitor Rheumatoid arthritis. [0003] compound ( 3R, 4R )-4-methyl...

AI Technical Summary

Problems solved by technology

[0005] The existing method for preparing the above-mentioned intermediate has the problem of low purity, especially when preparing in large doses, the purity drops significantly

For example, the literature (Org. Lett., Vol. 11, No. 9, 2009, p2003) mentioned the preparation method of the above-mentioned intermediate, which includes using DBU as a base and n-butanol as a solvent through N-methyl -N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine and ethyl cyanoacetate were reacted at 40°C to obtain intermediate body( 3R, 4R )-4-methyl-3-(methyl-1 H -pyrrolo[2,3- d ] pyrimidine-4-amino)-beta-oxygen-1-piperidine propionitrile, when adopting this method to expand production, the purity of the intermediate declines more obviously

Images