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Purification method of dapagliflozin

A purification method and monohydric alcohol technology, applied in the direction of organic chemistry and the like, can solve the problems of insufficient yield, high cost and low yield, and achieve the effects of good water solubility, low cost and high yield

Active Publication Date: 2019-05-03
JIANGSU SUZHONG PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The purification method uses methods such as applying protective groups, refining purification, and removing protective groups. The route is long, the cost is high, and the yield is low. After multi-step reactions, the yield is less than 50%.

Method used

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  • Purification method of dapagliflozin
  • Purification method of dapagliflozin
  • Purification method of dapagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In a 250ml glass flask, add 120ml of ethyl acetate, add 10.0g (0.0245mol) of Dapagliflozin crude product (purity 75%), stir to dissolve, add 1.86g (0.0245mol) of 1,2-propanediol, stir at 20°C for 30min, If there is solid precipitation, continue to stir for 3h, suction filter, the obtained filter cake is added to the mixed solvent of 100ml ethyl acetate and 50ml purified water, stir, the solid gradually dissolves, separate liquid, wash the organic phase twice with purified water, each time 30ml, The organic phase was concentrated with a rotary evaporator at 45° C. to substantially no liquid dripping out to obtain 6.30 g of Dapagliflozin refined product, according to the formula: yield=Dapagliflozin refined product quality / Dapagliflozin crude product quality (the following examples Same); the net yield of dapagliflozin in this embodiment is calculated to be 63.0%, and the purity is 98.42%. The H-NMR and C-NMR spectra of refined products have less impurity signals, which a...

Embodiment 2

[0038] In a 250ml glass flask, add 120ml ethyl acetate, add 10.0g (0.0245mol) Dapagliflozin crude product (purity 75%), stir to dissolve, add 1.86g (0.0245mol) 1,2-propanediol, purified water 0.44g ( 0.0245mol), stirred for 20min under ice bath conditions, solids precipitated, continued to stir for 3h, filtered with suction, added the obtained filter cake into a mixed solvent of 100ml ethyl acetate and 50ml purified water, stirred, the solids gradually dissolved, separated, and used for the organic phase Purified water was washed twice, 30ml each time, and the organic phase was concentrated to dryness to obtain 7.23g of a refined product of dapagliflozin, with a yield of 72.3% and a purity of 98.36%.

[0039] The obtained dapagliflozin refined product was refined by the same method, and the purity was further improved.

[0040] In a 250ml glass flask, add 120ml of ethyl acetate, 7.23g (0.0177mol) of Dapagliflozin primary refined product, stir to dissolve, add 1.41g (0.019mol, ...

Embodiment 3

[0042]In the 500ml glass flask, add 240ml methyl tert-butyl ether, 30.2g (0.0739mol) dapagliflozin crude product (75%), stir and dissolve, add 6.18g (0.0812mol, 1.1eq) 1,3-propanediol, then Add 1.46g (0.0812mol, 1.1eq) of purified water, stir at 5°C for 10 minutes, solid precipitates out, continue to stir for 2h, filter with suction, add the obtained solid to a mixed solvent of 300ml of isopropyl acetate and 100ml of purified water, the solid dissolves, and The organic phase was washed twice with water, 100ml each time, and the organic phase was concentrated to obtain 22.10g of dapagliflozin refined product, with a yield of 73.2% and a purity of 98.48%.

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Abstract

The invention discloses a purification method of dapagliflozin. The method comprises the following steps: 1) dissolving a crude product of the dapagliflozin into an organic solvent immiscible with water, adding a polar reagent, wherein the polar reagent and hydroxyl easily form a hydrogen bond, performing stirring, and performing crystallization to obtain a solid; and 2) adding the solid into an organic solvent immiscible with water, adding an appropriate amount of water, performing stirring to dissolve the solid and dissolve the polar reagent into the water, allowing the solution to stand forliquid separation, and concentrating an organic phase to obtain the refined product of the dapagliflozin. The method provided by the invention can effectively remove impurities in the dapagliflozin,purity of the purified dapagliflozin can reach 98.0% or more, and purity of the multi-refined dapagliflozin reaches 99.5% or more; the purification method of the dapagliflozin provided by the invention effectively removes the impurities of the dapagliflozin, is simple to operate, safe and convenient, has lower costs, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of purification methods of compounds, in particular to a purification method of dapagliflozin. technical background [0002] Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca for the treatment of type 2 diabetes. Its structural formula is: [0003] [0004] In the preparation process of dapagliflozin, reagents with high activity such as butyllithium and triethylsilane are used to prepare dapagliflozin with low purity. Due to the low melting point of dapagliflozin, it is difficult to purify by recrystallization, and purification by column chromatography requires a large amount of solvent and column chromatography silica gel, which is expensive. The methods reported in patents such as CN101092409A, CN1896088A, CN101628905B, CN102627676B, CN100534997C are purified by changing the melting point and solubility of the product through protecting ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
Inventor 岳永力唐海涛葛海涛赵耕先何爱见孙健王正俊黄骏凯王伟许华宏朱钦权黄杰
Owner JIANGSU SUZHONG PHARM GRP CO LTD
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