Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof

Abstract

The invention relates to a synthesis method for preparing a (2R,4R)-4-methyl-2 -piperidine carboxylic acid compound taking diethyl oxalate as starting materials and an intermediate thereof, and belongs to the field of organic synthesis. The synthesis method comprises the following steps of: taking the diethyl oxalate and 1-bromo-substituted-propylene as the starting materials, performing a Grignard reaction and an addition reaction on the diethyl oxalate and 1-bromo-3-substituted-propylene to obtain intermediate 2-carbonyl-4-substituted-5 cyan ethyl valerate; and then performing a cyclization reaction, a benzyl ester protection reaction and a deprotection reaction on the intermediate 2-carbonyl-4-substituted-5 cyan ethyl valerate to obtain trans-4-substituted-2-piperidine ethyl formate; and finally, splitting the trans-4-substituted-2-piperidine carboxylic acid ethyl ester to obtain a chiral target product (2R,4R)-4-methyl-2-piperidine formic acid compound. The preparation method has the advantages of readily available raw materials, simple process, and mild reaction condition.

Description

technical field [0001] The invention relates to a synthesis method for preparing (2R, 4R)-4-R-2-piperidine carboxylic acid compound by using diethyl oxalate as a starting material, belonging to the field of organic synthesis. Background technique [0002] (2R,4R)-4-substituted-2-piperidinecarboxylic acid compound is a kind of nitrogen-containing heterocyclic compound with good biological activity, especially when 4-substituted with methyl, this compound is the key intermediate of argatroban . Argatroban is a monovalent direct thrombin inhibitor, which directly binds to the catalytic active site of thrombin, not only inactivates liquid phase thrombin, but also inactivates thrombin bound to fibrin thrombus. Heparin-induced thrombocytopenia and thrombosis, percutaneous coronary intervention, stroke thrombolysis and other thrombotic diseases. In vivo and in vitro studies have shown that it also inhibits other effects of thrombin, such as inhibiting tumor metastasis, inflammato...

AI Technical Summary

Problems solved by technology

[0004] 1) Synthesize 4-methyl-2-cyanopiperidine compound with 4-methylpiperidine and sodium cyanide, then hydrolyze and resolve to obtain the target object (S.Okamoto, et al.US4072757, 1978, Mitsubishi Chemical Industries, Japan[1]; S.Okamoto, et al.US4258192, 1981, MitsubishiChemical Industries, Japan[2]), the selectivity of the cis-trans isomers in this process is low, and a large amount of acid and alkali are required in the process, which leads to the reaction before the resolution The compound is mixed with a large amount of inorganic salt, but must be desalted with resin, the operation is complicated and the yield is low

[0005] 2) Literature C.Agami, etal.Eur.J.Org.Chem.2001, 2385-2389[3] and literature C.Alegret, F.Santacana, A.Riera, J.Org.Chem.2007,72,7688 The method of -7692[4], because the starting material cannot be purchased from the market, and its synthetic route is complicated, so the process is difficult to industrialize

[0006] 3) The document K.Tibaudeau, et al.US6440417, 2002, the method of ConjuChem Inc.Canada [4], although the process route is short and does not need to be split, but expensive chemical compounds such as trifluoroacetic acid and chiral catalyst are needed in the process route Reagents, so the process is difficult to industrialize

[0007] 4) The method of the document J.Cossy, D.Belotti, Bioorg.Med.Chem.Lett.11, 1989-1992, 2001[5] needs to use isobutyllithium which is difficult to apply in industrial production, and its process conditions are also difficult to control

[0008] Prior art In the synthetic method of (2R, 4R)-4-substituted-2-piperidinecarboxylic acid, or yield is low, or used raw material is expensive, or operation is complicated, these deficiencies are for their synthesis, especially industrial Production is very inconvenient

Images