Synthesis method of dapagliflozin

A compound and Grignard reagent technology, applied in the field of chemical drug preparation, can solve the problems of large limitations, complex reaction products, low yield, etc., and achieve the effect of simple operation

Inactive Publication Date: 2016-08-17
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the early stage, the substrate of this reaction was limite

Method used

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  • Synthesis method of dapagliflozin
  • Synthesis method of dapagliflozin
  • Synthesis method of dapagliflozin

Examples

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Embodiment 1

[0025] Example 1: 2,3,4,6-tetra-O-acetyl-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-deoxy-β-D-pyridine Synthesis of Glucopyranose (Compound 2)

[0026] Method 1): Take a 500ml three-neck reaction flask, stir it with magnetic force, add 56g (150mmol) of 4-iodo-1-chloro-2-(4-ethoxybenzyl)benzene and 250mL of anhydrous tetrahydrofuran, nitrogen protection, temperature Lowered to -10°C, slowly added isopropylmagnesium chloride (80 mL, 2M tetrahydrofuran solution), and reacted at -5°C for 2 h. Take another 1000mL three-necked flask, add 49g (120mmol) of 2,3,4,6-tetraacetoxy-a-D-bromoglucopyranose, 1.93g (15mmol) of nickel chloride, 5.1g of isoprene ( 75mmol) and 250mL of anhydrous tetrahydrofuran, under nitrogen protection, the temperature dropped to 0°C, slowly added the Grignard reagent (compound 1) prepared in the previous 500mL bottle, added within 1h, kept at 5°C to 10°C for 12h, and saturated Aqueous ammonium chloride solution was used to quench the reaction, the organic phase...

Embodiment 2

[0028] Example 2: Synthesis of 1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-deoxy-β-D-glucopyranose (compound 3, dapagliflozin)

[0029] Take a 1000mL three-neck flask, add 58g (100mmol) of compound 2 crystals, 300mL of methanol and 200mL of tetrahydrofuran, stir mechanically, keep the temperature of the reaction solution at 0°C to 5°C, add dropwise 100mL of lithium hydroxide aqueous solution (containing 2.4g of lithium hydroxide, 200mmol). After dripping, it was raised to room temperature and reacted overnight. After the reaction was completed, the solvent was concentrated under reduced pressure to remove most of the solvent, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, and concentrated under reduced pressure to obtain 38.8 g of a white solid (95% yield). 1 H-NMR (CD3OD, 400MHz): δ7.34~7.25(m, 3H), 7.08(d, J=8.8Hz, 2H), 6.78(d, J=8.8Hz, 2H), 4.10(d, J= 9.2Hz, 1H), 4.06~3.95(m, 4H), 3.88~3.85(m, 1H), 3.72~3.68(m, 1H), 3.47~3.37(m, 3H...

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Abstract

The invention provides a preparation method of dapagliflozin, which uses Grignard reagent prepared by halogenated benzene derivatives and 2,3,4,6-tetraacetoxy-α-D-bromoglucopyranose as raw materials , the pure product of dapagliflozin can be obtained through catalytic coupling and removal of acetyl group, which shortens the reaction process steps, reduces reaction waste and improves the total yield. The reaction temperature of all reaction steps need not be lower than -10°C.

Description

technical field [0001] The invention relates to the field of chemical drug preparation, in particular to a synthesis method of dapagliflozin. technical background [0002] The antidiabetic drug Dapagliflozin (English common name: Dapagliflozin) is an oral selective sodium-glucose cotransporter II (SGLT2) inhibitor developed by Bristol-Myers Squibb and AstraZeneca, January 2012 It was approved for marketing in the European Union, and was approved for marketing in the United States in January 2014 for the treatment of type 2 diabetes. [0003] The chemical name of Dapagliflozin is 1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-deoxy-β-D-glucopyranose, and its chemical structure is as follows: [0004] [0005] At present, the main synthetic methods of dapagliflozin are as follows: [0006] (1) The synthetic route reported by the original manufacturer Bristol-Myers Squibb in patent CN101628905A uses TMS-protected gluconolactone as a raw material, and bromobenzene derivatives are ...

Claims

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Application Information

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IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 张大永马力张亚京许志伟孙英爱
Owner CHINA PHARM UNIV
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