Novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine
A technology of tofacitinib and intermediates, applied in the field of medicinal chemistry, can solve the problems of poor stereoselectivity, poor atom economy, and low overall yield, and achieve high reaction yield, high optical purity, and cheap and easy-to-obtain raw materials Effect
Active Publication Date: 2019-03-22
内蒙古京东药业有限公司
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The invention relates to a novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine. The method comprises the following steps: 3-amino-4-methylpyridine is taken as a starting material, amino of 3-amino-4-methylpyridine is subjected to a reaction with ortho-formate, imino formate is generated, and after simple concentration, an N-methyl derivative is obtained by reduction with metal borohydride; after Boc protection, quaternary ammonium salt is generated from a product and benzyl halide and reduced by metal borohydride, a product is subjected to selective hydrogenation with an Rh catalyst, a compound with rich (3R,4R-rel-) configuration is formed, deprotection, salifying and resolution are performed by a hydrochloric acid/alcohol system for removing a (3R,4S-rel-) isomer pair, an obtained (3R,4R-rel-) configuration product is subjected to free treatment and resolved by L-DTTA, and a 3R,4R- configuration product is obtained; after free treatment of salt obtained after resolution, oxalate is formed and purified, a small quantity of remaining 3S,4S-isomers are further removed, and corresponding (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine with high purity and high optical purity is obtained. Through the adoption of the method, safe, simple and industrial large-scale preparation of the tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine oxalate hydrates is better facilitated.
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BorohydrideOxalate salt +13
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