A kind of recycling method of 3-(s)-aminobutyric acid derivative

Abstract

The invention provides a recycling method of 3-(S)-amino-4-(2,4,5-trifluorophenyl)-butyric acid derivative shown as a formula (III). The method is as below: conducting chloridization dehydrochlorination on 3-(S)-amino-4-(2,4,5-trifluorophenyl)-butyric acid derivative to obtain a 3-amino-4-(2,4,5-trifluorophenyl) butenoic acid derivative (V); and subjecting the compound (V) to a reduction reaction to obtain a racemic sitagliptin intermediate 3-amino-4-(2,4,5-trifluorophenyl)-butyric acid derivative (VI). The method provided by the present invention has the advantages of simple operation route, mild reaction condition, high atom economy, low cost and less three wastes, and is suitable for industrialization.

Description

(1) Technical field [0001] The invention belongs to the field of pharmaceutical synthetic chemistry, and relates to a by-product 3-(S)-amino-4-(2,4,5-trifluorophenyl)-butyric acid derivative produced during the synthesis of a sitagliptin intermediate recycling methods. (2) Background technology [0002] Sitagliptin phosphate is the first dipeptidyl peptidase-IV (DPP-4) inhibitor approved by the FDA in 2006. Its chemical structure is shown in the following formula: [0003] [0004] Sitagliptin is a dipeptidyl peptidase-IV inhibitor drug used to treat type II diabetes. It can control diabetes by improving the ability of diabetic patients' own pancreatic β cells to produce insulin and increasing insulin secretion when blood sugar rises. The patient's blood sugar level is well tolerated, without weight gain, and without the risk of hypoglycemia. [0005] At present, there are many methods for synthesizing sitagliptin at home and abroad, mainly involving chiral induction an...

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Problems solved by technology

[0008] In 2010, Satyanarayana et al. (WO2010122578) reported that the intermediate (III) was diazotized under the action of sodium nitrite and sulfuric acid to obtain a secondary alcohol, which was then oxidized into an intermediate to achieve the purpose of recovering isomers, but the system There are many waste acids produced, which are not economical and environmentally friendly in practical applications, and the final yield is also relatively low, so the feasibility is not high, as shown in route 1:

[0010] In 2011, Zhang Lipeng et al. (CN102391142) considered to achieve the purpose of racemization by forming an imine structure between an aromatic aldehyde and a primary amine and then performing hydrogenation and debenzylation to protect it. This method will use heavy metal palladium for debenzylation, and the route atom The economy is poor, and there are certain environmental protection problems at the same time, so it is difficult to industrialize, as shown in route 2:

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