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Preparation method of dapagliflozin intermediate

An intermediate and reaction technology, applied in the field of preparation of dapagliflozin intermediates, can solve the problems of highly toxic cyanide, serious pollution, etc., and achieve the effects of high product purity and short synthesis route

Inactive Publication Date: 2017-11-24
安徽省诚联医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The benzylation of this process route uses AIBN, which will produce highly toxic cyanide during the reaction process and cause serious pollution, such as patent CN104478670

Method used

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  • Preparation method of dapagliflozin intermediate
  • Preparation method of dapagliflozin intermediate
  • Preparation method of dapagliflozin intermediate

Examples

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Embodiment Construction

[0021] The present invention will be further described below through the examples, but the examples do not limit the protection scope of the present invention.

[0022] 1, Preparation of 4-ethoxytoluene

[0023] The reaction chemical formula is:

[0024]

[0025] Take 108kg of 4-methylphenol, dissolve in 200kgDMF, 50kg toluene, add potassium carbonate 150kg, at 60°, add dropwise the toluene solution of bromoethane (bromoethane 130kg, toluene 150kg), dropwise in 30 minutes, add dropwise Completed, reacted at 60 ° for 2 hours, after the reaction, filtered to remove potassium bromide and potassium carbonate, recovered the solvent under reduced pressure, added 400kg of water to the residual liquid, extracted with 400kg of ethyl acetate, dried over anhydrous sodium sulfate, filtered, recovered the solvent from the filtrate, and left The product was distilled under reduced pressure to obtain 127.8 kg of a light yellow liquid with a yield of 94%.

[0026] 2, Preparation of 4-eth...

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Abstract

The invention provides a preparation method of a dapagliflozin intermediate. The preparation method comprises the following steps: (1) by taking 4-methylphenol and bromoethane as raw materials, a polar solvent as a reaction solvent and an inorganic base as a catalyst, carrying out reaction for preparing 4-ethyoxyl methylbenzene; (2) by taking N-chlorosuccinimide and 4-ethyoxyl methylbenzene obtained in the step (1) as raw materials, a non-polar solvent as a reaction solvent and dibenzoyl peroxide as an initiator, carrying out reaction, thus obtaining 4-ethyoxyl benzyl chloride; (3) dissolving 4-ethyoxyl benzyl chloride obtained in the step (2) and 4-bromaniline into ethyl acetate, adding a catalyst lewis acid, and carrying out reaction, thus obtaining 5-bromo-2-amino-4-ethyoxyl diphenylmethane; and (4) carrying out diazotization reaction on 5-bromo-2-amino-4-ethyoxyl diphenylmethane obtained in the step (3), and then reacting with cuprous chloride, thus synthesizing 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane. The preparation method provided by the invention has the advantages of low cost, low environmental stress and short synthetic route.

Description

technical field [0001] The invention belongs to the technical field of dapagliflozin synthesis, and in particular relates to a preparation method of a dapagliflozin intermediate. Background technique [0002] Dapagliflozin is a sodium-glucose cotransporter 2 (Sodium-glucosecotransporter-2, SGLT2) inhibitor, C-aryl glucoside compound, chemical name: (2S, 3R, 4R, 5S, 6R )-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol. Dapagliflozin inhibits the reabsorption of blood sugar by inhibiting renal sodium-glucose cotransporter 2, thereby regulating blood sugar levels in the body; at the same time, it can significantly reduce the level of glycosylated hemoglobin and body weight of patients. Dapagliflozin, jointly developed by Bristol-Myers Squibb and AstraZeneca, is the second SGLT2 inhibitor approved by the US FDA for the treatment of type 2 diabetes. [0003] 5-Bromo-2-chloro-4'-ethoxydiphenylmethane is the key intermediate for the preparatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C41/22C07C43/225
Inventor 刘辉
Owner 安徽省诚联医药科技有限公司
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