Synthesis of Dapagliflozin

Abstract

The synthetic method of dapagliflozin is disclosed, comprising providing a microreactor, the microreactor has at least 4 reaction units connected in series, and 5-bromo-2-chloro-4'-ethoxydiphenylmethane solution and alkyllithium solution into the first reaction unit, the reaction temperature in the first reaction unit is controlled at -5 to -40°C, after the reaction, the reaction solution flows into the second reaction unit, and the trimethylsilyl-protected Gluconolactone or its solution is transported into the second reaction unit. After the reaction, the reaction liquid flows into the third reaction unit. At the same time, the mixed solution of methanol and methanesulfonic acid is transported into the third reaction unit. After the reaction, the reaction liquid flows into the third reaction unit. In the fourth reaction unit, the mixed solution of boron trifluoride ether and triethylhydrogensilane is sent into the fourth reaction unit.

Description

technical field [0001] The invention relates to a method for synthesizing dapagliflozin. The method of the invention can advantageously reduce the synthesis cost. The present invention also relates to the application of the microreactor in the synthesis of dapagliflozin. Background technique [0002] Dapagliflozin is the first approved sodium-glucose cotransporter 2 (SGLT2) inhibitor developed by Bristol-Myers Squibb and AstraZeneca. It was approved in the EU in January 2012 and in the United States in January 2014, respectively Batch marketed drugs for the treatment of type II diabetes. [0003] Dapagliflozin, Chinese chemical name: (2S, 3R, 4R, 5S, 6R)-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6-hydroxymethyl Tetrahydro-2H-pyran-3,4,5-triol, the structural formula is as follows: [0004] [0005] The prior art has publicly reported a variety of Dapagliflozin synthetic routes, for example: [0006] WO2013152476 discloses a synthetic method of dapagliflozin, which uses 2-...

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Problems solved by technology

[0010] Chinese patent CN105061373B discloses a synthetic method of dapagliflozin, its synthetic route is basically the same as Chinese patent CN101628905A, but it adopts batch operation, and its disadvantage is that in the lithium halogen exchange step involving butyllithium, -78°C is required Low temperature reaction for 1-2 hours, high energy consumption, and when gluconolactone is added, a low temperature of -70°C is required, and the reaction lasts for 2-3 hours, not only the overall reaction time is long, but also the low temperature needs to be maintained

[0012] Existing methods either must use low temperature reactions at -70°C to -80°C, or react at relatively mild reaction temperatures with low yields

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