Preparation method of sitagliptin

Abstract

The invention provides a preparation method of sitagliptin. The preparation method comprises the following steps of: performing condensation reaction on hydrochloride of 3-trifluoromethyl-[1,2,4] triazol [4,3-a] piperazine serving as a starting raw material and methyl malonyl chloride under a normal temperature condition; reacting an obtained product with 2,4,5-trifluorophenylacetic acid under an alkaline condition and then performing condensation reaction with (S)-phenylglycinamide under normal temperature condition to obtain a product; reducing the obtained product through a reducing agent; removing an ester group through heating reflux; and reacting with a hydrogenation reducing reagent to obtain the sitagliptin. The preparation method has the advantages of low cost, high yield, easiness in operation, all used reagents of conventional reagents, simple post-treatment and convenience for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a preparation method of sitagliptin. Background technique [0002] Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor drug, which is characterized by stimulating insulin secretion and reducing hunger without causing weight gain or Hypoglycemia and edema, suitable for diabetic patients with poor blood sugar control and frequent hypoglycemia. On October 17, 2006, Merck announced that the US Food and Drug Administration had approved sitagliptin phosphate. The drug has become the only dipeptidyl peptidase-4 (DPP-4) inhibitor drug for the treatment of type 2 diabetes in the US market so far. [0003] The chemical name of sitagliptin is: (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[ 4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (CAS NO: 486460-32-6), its chemical structure is as follows: [0004] [0005] At present, the ...

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Problems solved by technology

In addition, this route also has the following disadvantages: platinum oxide needs to be pretreated before use, the high pressure reaction time is long, and some intermediate products are relatively unstable.

[0008]2) Scientific literature First generation process for the prepara-tion of the DPP·IV inhibitor Sitagliptin. (Hansen KB, Balsells J, Dreher S, et a1. Org Pro Res Dev, 2005, 9(5): 634-639.) disclose a preparation method of sitagliptin, the specific route is shown in the figure below, the The asymmetric hydrogenation catalyst (S)-binaphthalene diphenylphosphine-ruthenium chloride used in the route is more expensive and the total yield is lower, which is not conducive to industrial scale-up production

[0010] 3) Scientific literature (2R-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4 , 3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.( Kim D, Wang L B Beconi M. J Med Chem, 2005, 48(11): 141-151.) disclose a preparation method of sitagliptin, the specific route is shown in the figure below, the disadvantage of this method is that the reagents used are relatively expensive , the reaction conditions are relatively harsh. For example, low temperature conditions such as -78°C and -30°C are required, some reactions take a long time and the operation is more cumbersome, and the purification of intermediate products needs to be separated by column chromatography, which is not suitable for the current industrial production conditions.

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