Preparation method of dapagliflozin

Abstract

The invention discloses a preparation method of dapagliflozin. The preparation method comprises the following steps: (1) reacting a compound solution as shown in a formula II and an n-butyllithium solution in a first microreactor in a microchannel reaction device; (2) reacting effluent of the first microreactor with a compound as shown in a formula III in a second microreactor in the microchannel reaction device to obtain a compound as shown in a formula IV; (3) carrying out reduction reaction on the compound shown in the formula IV in a third microreactor in the microchannel reaction device to obtain a compound shown in a formula V; and (4) deprotecting the compound as shown in the formula V to obtain dapagliflozin as shown in the formula I. According to the method disclosed by the invention, benzyl-protected glucolactone is adopted as a starting raw material, so that generation and multiple derivatization of isomer impurities and ring-opening impurities are avoided, the stereoselectivity is relatively high, and post-treatment steps and waste generation are reduced; and meanwhile, the yield is high, the purity is high, the synthesis steps are few, the operation is simple and convenient, and the safety is high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of dapagliflozin. Background technique [0002] Dapagliflozin is a reversible and highly selective hypoglycemic drug named Farxiga, which is mainly used to improve blood sugar control in patients with type 2 diabetes. Its mechanism of action is to reduce the reabsorption of glucose by renal tubules by inhibiting SGLT2 expressed in the kidney, and excrete excess glucose through the urine, thereby reducing plasma glucose levels. Compared with traditional hypoglycemic drugs, Dapagliflozin will not cause adverse reactions such as hypoglycemia and weight gain, and will not cause severe gastrointestinal reactions, and does not require injection, which improves the compliance of patients with medication ,with broadly application foreground. [0003] The chemical name of Dapagliflozin is (2S,3R,4R,5S,6R)-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6-hydroxymethy...

AI Technical Summary

Problems solved by technology

[0011] Anna Sadurní's team and Kuduva's team also successively reported cross-coupling reactions with benzyl-protected gluconolactone and aryllithium derivatives in 2018, with high stereoselectivity, but n-butyllithium was used in the reaction, which is safe Poor performance, cumbersome process, inconvenient operation

[0012] In summary, the main problems in the synthetic route: 1) The gluconolactone protected by the trimethylsilyl and pivaloyl protecting groups used, the hydroxyl on the sugar ring needs to be derivatized multiple times in the process, or a large amount of bromine needs to be used Reagents, easy to produce isomer impurities and a lot of waste, long process steps and unfriendly to the environment

2) The cross-coupling reaction involving n-butyllithium is mostly used in the process, the conditions are relatively harsh, and the production safety is poor

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