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

Abstract

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.

Description

technical field [0001] The present invention relates to the field of pharmaceutical chemistry, in particular to the synthesis method of Tofacitinib key intermediate (3R, 4R)-N, 4-dimethyl-1-benzyl-3-piperidinamine and salts thereof . The structure of this intermediate (I) and its salt (I-x) general formula is as follows: [0002] [0003] Wherein compound K is (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine monooxalate monohydrate. Background technique [0004] Tofacitinib citrate is a Janus kinases inhibitor developed by Pfizer, which affects the DNA transcription process by interfering with the JAK-STAT signaling pathway. It was first approved for marketing by the U.S. Food and Drug Administration (FDA) on November 6, 2012, and was subsequently approved for marketing by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) on March 25, 2013. It was marketed by Pfizer in the United States and Japan , the product name is Domestically, tofacitinib citrate was app...

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Problems solved by technology

[0023] After investigating various routes, in order to overcome the deficiencies in the preparation of compound I in the prior art (such as the poor stereoselectivity in the preparation of (3R, 4R-rel-) isomers in the process of (II-c) in route one and Cause total yield is not high, atom economy is poor; Need to use very dangerous and expensive aluminum tetrahydrogen lithium or relatively safe some but equally expensive Red-Al) in the route two, the present invention provides a kind of each reaction raw material is cheap and easy Obtaining, the reaction method is simple and safe, especially suitable for industrial production of compound II-c, and then using L-tartaric acid or its O-acyl derivatives to resolve to obtain 3R, 4R-isomers, which are then converted into more suitable subsequent reactions The preparation method of free base and other salts (I-x)

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