Method and device for continuous preparation of vildagliptin by tubular reaction

Abstract

The invention relates to a method and a device for continuous preparation of Vildagliptin by tubular reaction; 3-amino-1-adamantanol and 1-chloracetyl-2-cyano pyrrolidine are dissolved in a mixed solution of solvents, then dissolved with an alkali and a catalyst in a suspension of the solvents, mixed, and preheated by a preheater, the preheated mixed solution enters into a tubular reactor at 20-100 DEG C, the residence time of a material in the tubular reactor is 30min-180min, and the reaction solution discharged from the tubular reactor is collected, filtered washed and purified to obtain the product. The method greatly improves the response speed, shortens the production cycle, increases the amount of processing, and can effectively improve the production capacity. In addition, by controlling the reaction temperature, material movement speed, dosage ratio, catalyst amount and alkali dosage, the formation of by-products disubstituted compounds can be effectively avoided.

Description

technical field [0001] The invention relates to a method and device for continuously preparing vildagliptin in a tubular reactor. Background technique [0002] Vildagliptin was developed by Novartis and was approved for marketing by the European Union in 2007. On August 15, 2011, CFDA officially approved vildagliptin to be launched in China. Vildagliptin can be used in combination with biguanides, thiazolidinediones, and sulfonylureas to treat type 2 diabetes. Vildagliptin can reduce fasting and postprandial blood glucose levels, postprandial glucagon secretion and improve β-cell function, which provides a new option for the treatment of type Ⅱ diabetes patients. Vildagliptin's sales grew strongly after its launch, reaching US$677 million in 2011, and the total sales in the first three quarters of 2012 were close to US$655 million. [0003] In recent years, as the patent period of vildagliptin is approaching, domestic generic drug manufacturers have accelerated the resear...

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Problems solved by technology

[0007] In the subsequent research, Novartis patent ZL200710090496.6, Spanish Medchem S.A. company patent US2008167479, Czech Zentiva company patent WO2010022690A2, Slovenian KRKA company patent WO2011012322A2 all improved the synthesis method of this route, such as changing the reaction solvent, Change the dehydrating agent to make it more suitable for the requirements of industrial production, but it is impossible to avoid the massive generation of reaction by-products

[0008] In order to effectively control the generation of by-product disubstitutions, Indian SATYA-NARAYANA patent WO2011101861A1 and Italian CHEMELECTIVA SRL patent WO2012004210A1 proposed new synthetic routes. Although the disubstitutions were controlled, the synthetic route was long and the yield was low, greatly improving cost of production

The patent WO2008084383 of MEDICHEM, S.A. discloses a preparation method of highly chemical and enantiomerically pure vildagliptin. Although the purity is improved, liquid phase separation is required, which is costly and unfavorable for large-scale production.

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