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Synthesis method of Empagliflozin intermediate

A synthetic method and intermediate technology, applied in the field of synthesis of empagliflozin intermediate——-3-phenoxy)tetrahydrofuran, can solve the problems of short synthetic route and cumbersome post-treatment steps, and achieve easy reaction and post-processing. Simple processing and high yield

Inactive Publication Date: 2018-06-19
YANGZHOU POLYTECHNIC INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic method adopts simple and easy-to-obtain 4-fluorotoluene as the starting material, and the synthetic route is relatively short, but the first-step reaction and post-treatment steps of the synthetic route are relatively cumbersome and need to be further improved

Method used

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  • Synthesis method of Empagliflozin intermediate
  • Synthesis method of Empagliflozin intermediate
  • Synthesis method of Empagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1) Add 142.5g (1mol) of 4-hydroxybenzyl chloride and 200ml of dichloromethane into the reaction flask, and slowly add 126g (1.1mol) of methanesulfonyl chloride dropwise under temperature control at -5~0°C. Afterwards, the reaction was continued for 2 hours at -5 to 0°C. After the reaction was completed, dichloromethane was recovered by distillation under reduced pressure to obtain an oil; mol) and (S)-3-hydroxytetrahydrofuran 90g (1.03mol), heated and refluxed for 4h, after the reaction was completed, the tetrahydrofuran was recovered by distillation under reduced pressure, 200ml of ethyl acetate and 200ml of water were added, and the pH was adjusted to 4-5 with concentrated hydrochloric acid. Stand still, separate layers, and extract the aqueous phase once with 100 ml of ethyl acetate; the combined organic phases are washed once with water, dried over anhydrous sodium sulfate, and filtered to obtain a feed solution containing the above-mentioned compound III.

[0035] ...

Embodiment 2

[0038]1) Add 142.5g of 4-hydroxybenzyl chloride and 200ml of dichloromethane into the reaction bottle, and slowly add 126g of methanesulfonyl chloride dropwise under temperature control at -5~0°C. React at 0°C for 2 hours. After the reaction is completed, distill under reduced pressure to obtain an oily substance; add 200ml of tetrahydrofuran to dissolve the above oily substance, then add 160g of N,N-diisopropylethylamine and 91g of (S)-3-hydroxytetrahydrofuran, and heat Reflux the reaction for 5 hours. After the reaction is completed, distill under reduced pressure to recover tetrahydrofuran, add 200ml ethyl acetate and 200ml water, adjust the pH to 4-5 with concentrated hydrochloric acid, let it stand, separate layers, and extract the water phase once with 100ml ethyl acetate; The combined organic phases were washed once with water, dried over anhydrous sodium sulfate, and filtered to obtain a feed solution containing the above compound III.

[0039] 2) Add 219g of 4-iodoani...

Embodiment 3

[0041] 1) Add 142.5g of 4-hydroxybenzyl chloride and 200ml of dichloromethane into the reaction bottle, and slowly add 126g of methanesulfonyl chloride dropwise under temperature control at -5~0°C. React at ℃ for 2 hours. After the reaction is completed, the dichloromethane is distilled under reduced pressure to obtain an oily substance; the above oily substance is dissolved in 200ml of tetrahydrofuran, and then 155g of N,N-diisopropylethylamine and (S)-3-hydroxytetrahydrofuran are added. 90g, heated to reflux for 4.5h, after the reaction was completed, the tetrahydrofuran was recovered by distillation under reduced pressure, 150ml of dichloromethane (using the recovered dichloromethane above) and 150ml of water were added, and the pH was adjusted to 4~5 with concentrated hydrochloric acid. , the aqueous phase was extracted once with 100ml of dichloromethane; the combined organic phases were washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate...

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Abstract

The invention discloses a synthesis method of an Empagliflozin intermediate. The synthesis method uses 4-hydroxybenzyl chloride as a starting material to sequentially react with methanesulfonyl chloride and (S)-3-hydroxytetrahydrofuran to obtain compound III, then react with 4-iodoaniline to obtain compound IV, and finally react with cuprous chloride after diazotization to obtain (S)-3-(4-(5-iodine-2-chlorobenzyl)phenoxy) tetrahydrofuran. The raw materials used in the synthesis method are simple and easy to obtain, the operation steps are simple, the post-treatment is simple, the product yieldis high, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing an empagliflozin intermediate (S)-3-(4-(5-iodo-2-chlorobenzyl)phenoxy)tetrahydrofuran, which belongs to the technical field of organic synthesis. Background technique [0002] Empagliflozin, chemical name: (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furyl] Oxy]phenyl]methyl]phenyl]-D-glucitol, molecular formula: C 23 h 27 ClO 7 , molecular weight: 450.91. The chemical structural formula is as follows: [0003] [0004] Empagliflozin is a highly selective SGLT2 inhibitor with a unique insulin-independent hypoglycemic pathway, that is, it directly excretes glucose from the urine by reducing the reabsorption of glucose in the kidney. In addition to having a clear hypoglycemic effect, it can also bring additional benefits of weight loss, lower blood pressure, and lower uric acid. Empagliflozin has good safety and can reduce the risk of cardiovascular events and the progression of kidn...

Claims

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Application Information

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IPC IPC(8): C07D307/20
CPCC07B2200/07C07D307/20
Inventor 封娜王元友周颖
Owner YANGZHOU POLYTECHNIC INST
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