The synthetic method of upadatinib

Abstract

The present invention provides a synthetic method for upatinib, which uses compound 1 as a starting material to obtain compound formula 4 through chlorination, coupling, hydrolysis, and hydrogenation into a salt, and then derivatizes and halogenates with McBurney's acid to obtain intermediate Body compound 6. Next, we use 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine compound 7 as raw material to obtain intermediate compound 9 through ammonolysis reaction and amino protection. The docking reaction of compound 6 and compound 9 obtained chemical formula 10, and then the key nucleus 11 of upadatinib was obtained by cyclization with trifluoroacetic anhydride. Finally, the docking reaction of trifluoroethylamine was optimized, and upadatinib was obtained by both methods. These improvements have greatly improved the route efficiency, reduced the process steps of using noble metal catalysts, reduced the process cost, and greatly reduced the generation of by-chiral products, which is conducive to improving the purity of the final product. The route is:

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a synthetic method for preparing upatinib. Background technique [0002] In early 2018, Upadacitinib (ABT-494), a once-daily oral JAK1 selective inhibitor developed by AbbVie for the treatment of adults with moderate to severe atopic dermatitis, received FDA breakthrough therapy identified. Common symptoms of atopic dermatitis, also known as atopic dermatitis or atopic eczema, include itching, redness, and cracked skin. Clear liquid often flows out of the inflamed area, and the liquid will become thicker as the inflammation lasts longer. The first attack is more common in infants and young children. About 20% of children with asthma will suffer from this disease at the same time. The symptoms of atopic dermatitis can last for several years The pathogenesis of the disease is still unknown at present. Current treatment options for patients with atopic dermatitis are e...

AI Technical Summary

Problems solved by technology

[0005] U.S. Patent US2017129902 reports the synthesis method of upatinib, the synthesis of the key chiral acid intermediate (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid The raw materials are expensive, the synthesis steps are long, and two palladium-catalyzed hydrogenations are required; in addition, the yield of chiral resolution is low, its enantiomers cannot be used, and the synthesis cost is high; another key intermediate of upatinib The multi-step reaction in the synthesis steps of the patented route of p-tert-butyl (5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazin-2-yl) carbonate needs palladium catalysis, and the current market price is relatively high. High; the docking reaction of two key intermediates in the follow-up reaction requires the use of sodium hydride, and the cyclization reaction requires the use of expensive and foul-smelling sulfur-containing Lawson’s reagent, which is difficult to scale up and has a low overall yield; CBZ and Ts removal The protective group uses strong acid-base conditions, and there are many side reactions, which makes the final product difficult to purify. The reaction route is as follows:

Images