Preparation method of empagliflozin intermediate

A technology of empagliflozin and intermediates, which is applied in the field of preparation of empagliflozin intermediates, can solve the problems of high cost, high price, and difficult synthesis of starting materials, and achieve short synthetic routes and high product purity. Effect

Inactive Publication Date: 2017-11-03
安徽省诚联医药科技有限公司
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Problems solved by technology

This synthesis scheme is also difficult to synthesize starting materials, and the cost is high and the price is expensive.

Method used

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  • Preparation method of empagliflozin intermediate
  • Preparation method of empagliflozin intermediate
  • Preparation method of empagliflozin intermediate

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Embodiment Construction

[0026] The present invention will be further described below through the examples, but the examples do not limit the protection scope of the present invention.

[0027] 1. Preparation of (S)-3-p-cresyl tetrahydrofuran

[0028] The reaction chemical formula is:

[0029]

[0030] Take 110kg of 4-fluorotoluene and 95kg of (R)-3-hydroxytetrahydrofuran, dissolve them in 300kg of tetrahydrofuran, cool to 0° in an ice bath, and add dropwise a tetrahydrofuran solution of potassium tert-butoxide (potassium tert-butoxide 112kg, Tetrahydrofuran (200kg) was dripped in 30 minutes. After the addition was completed, react at 5-10° for 1 hour. After the reaction, add 300kg of water to quench the reaction, distill and recover THF, add 400kg of ethyl acetate to the residual liquid for extraction, dry over anhydrous sodium sulfate, and filter , the solvent was recovered from the filtrate, and the residue was distilled under reduced pressure to obtain 162 kg of light yellow liquid, with a yie...

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Abstract

The invention provides a preparation method of an empagliflozin intermediate. The preparation method comprises the following steps: 1), taking 4-fluorotoluene and (R)-3-hydroxytetrahydrofuran as raw materials, a polar solvent as a reaction solvent and inorganic alkali as a catalyst, performing a reaction to obtain (S)-3-p-cresyl tetrahydrofuran; 2), with N-chlorosuccinimide and the product obtained in the step 1) as raw materials, a non-polar solvent as a reaction solvent and dibenzoyl peroxide or azobisisobutyronitrile as an initiator, performing a reaction to obtain (S)-3- p-chlorophenol tetrahydrofuran; 3) dissolving 4-bromaniline and the product obtained in the step 2) into ethyl acetate, adding a catalyst Lewis acid, performing a reaction to obtain (S)-3-(4-(5-bromo-2-aminobenzyl)phenoxy) tetrahydrofuran; 4), performing a diazotization reaction on the product obtained in the step 3), and then reacting with cuprous chloride to synthesize (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran. The preparation method has the advantages that the cost is low, the finished product is high in purity and the synthesis route is short.

Description

technical field [0001] The invention belongs to the technical field of empagliflozin, and relates to a preparation method of an empagliflozin intermediate. Background technique [0002] Empagliflozin, chemical name: (2S, 3R, 4R, 5S, 6R)-2-[3-[4-[(3S)-tetrahydrofuran]-3-hydroxyphenyl]methyl]-4 -Chlorophenyl-6-hydroxymethyloxyhexane-3,4,5-triol, a type 2 sodium glucose cotransporter inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly and Company. SGLT-2 (sodium-glucose cotransporter 2) inhibitor is a new type of hypoglycemic drug, which mainly inhibits the expression of SGLT-2 in the kidney, reduces the reabsorption of glucose by the kidney, and increases the excretion of glucose in the urine, thereby reducing Plasma glucose levels, its hypoglycemic effect is independent of β-cell function and insulin resistance. Empagliflozin was first approved for marketing by the European Medicines Agency (EMA) in May 2014, and approved by the US FDA for the treatment of typ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/12
Inventor 刘辉
Owner 安徽省诚联医药科技有限公司
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