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Preparation method for dapagliflozin

A technology for Grignard reagents and compounds, applied in the field of preparation of dapagliflozin, can solve the problems to be improved, shorten the reaction process steps, etc., and achieve the effects of saving production time and labor cost, shortening reaction time, and high yield

Active Publication Date: 2016-02-03
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction is simple to operate, low in cost, saves the reduction reaction and acetylation reaction in the original method, shortens the reaction process steps, and the reaction conditions are relatively mild, but the highest yield of the reaction is 84%, which still needs to be improved

Method used

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  • Preparation method for dapagliflozin
  • Preparation method for dapagliflozin
  • Preparation method for dapagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the synthesis of compound II

[0042] Dissolve 10.12g (90.8mmol) Mscl in 250ml CH 2 Cl 2 In, add 20.42g (100.5mmol) fresh Ag 2 O, after stirring at room temperature for several minutes, 10.26g (70mmol) of compound I and 3.5g (20.1mmol) of KI were added successively, and stirred at room temperature for 6h. The progress of the reaction was detected by TLC, after the reaction was completed, it was filtered under reduced pressure, and the residue was washed with CH 2 Cl 2 (50ml×3) wash. The filtrate was concentrated to a small volume and separated by silica gel column chromatography (V 石油醚 :V 乙酸乙酯 5:1) was purified to obtain 10.77g (60.86mmol) of compound II with a yield of 98% and a purity of 99.9%.

Embodiment 2

[0043] Embodiment 2: the synthesis of compound II

[0044] Dissolve 10.87g (90.8mmol) Tscl in 250ml CH 2 Cl 2 In, add 20.42g (100.5mmol) fresh Ag 2 O, after stirring at room temperature for several minutes, 10.26g (70mmol) of compound I and 3.5g (20.1mmol) of KI were added successively, and stirred at room temperature for 6h. The progress of the reaction was detected by TLC, after the reaction was completed, it was filtered under reduced pressure, and the residue was washed with CH2 Cl 2 (50ml×3) wash. The filtrate was concentrated to a small volume and separated by silica gel column chromatography (V 石油醚 :V 乙酸乙酯 5:1) was purified to obtain 20.27g (60.79mmol) of compound II with a yield of 97% and a purity of 99.7%.

Embodiment 3

[0045] Embodiment 3: the synthesis of compound IV

[0046] Add 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (40.9g, 150mmol) and 100mL tetrahydrofuran into a 250mL conical flask, stir and cool down to -5~0℃, slowly add n-butylmagnesium chloride dropwise (80mL, 2mol / L), and the system was stirred at 0°C for 2h. Add 10.77g (60.86mmol) compound II (R=-MS), 10.81g (60.94mmol) anhydrous tin tetrachloride and 100ml 2-methyltetrahydrofuran to another 300ml conical flask, and cool the system to 5°C. Slowly add the Grignard reagent in the previous 250ml bottle dropwise, and drop it in about 40 minutes. Return the system to room temperature, keep stirring for 1 hour, quench the system with 1N hydrochloric acid aqueous solution, extract the organic phase with ethyl acetate, wash with saturated brine, and concentrate. Column chromatography (PE / EA=3 / 1) yielded 30.83 g (60.65 mmol) of compound IV with a yield of 97% and a purity of 99.8%.

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Abstract

The invention belongs to the field of medicine chemical industry, and concretely relates to a preparation method for dapagliflozin. 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl hydroxide is taken as a raw material and is subjected to a sulfonylation reaction, a nucleophilic substitution reaction and a acetyl removal reaction, so that dapagliflozin is obtained. The preparation method possesses the advantages of mild reaction conditions, simple and reasonable technological process, short reaction time, simple post-processing, high product quality, high yield and the like.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of dapagliflozin. Background technique [0002] The chemical name of dapagliflozin (ForxigaTM) is (2S, 3R, 4R, 5S, 6R)-2-[3-(4-ethoxyphenyl)-4-chlorophenyl]-6-hydroxymethyl Tetrahydro-2H-pyran-3,4,5-triol. It is a new type of anti-diabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. It was approved for marketing by the European Medicines Agency (EMA) on November 12, 2012. It is the first approved marketing for the treatment of SGLT2 inhibitors in type 2 diabetes. The FDA announced on January 8, 2014 that it approved the use of dapagliflozin for the treatment of type 2 diabetes, and at the same time required the manufacturer to conduct post-marketing research on drug-related risks. [0003] Adults with normal renal function filter about 180 g of glucose through the glomerulus every day, and almost all of the gluc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 陈雨吕会会王依健
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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