Dapagliflozin preparation method

A technology of reaction and chlorobenzaldehyde, which is applied in the field of chemical drug preparation, can solve the problems of serious pollution and achieve the effects of improved purity, short synthetic route and easy process

Inactive Publication Date: 2018-01-05
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The benzylation of this process route uses AIBN, which will produce highly toxic cyanide during the reaction process, causing serious pollution

Method used

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preparation example Construction

[0030] The preparation method of dapagliflozin of the present invention uses 2-chlorobenzaldehyde as a starting material, and synthesizes 5-bromo-2-chlorobenzyl chloride through bromination, reduction, and chlorination, and alkylates with phenetole through K. Reaction to synthesize 5-bromo-2-chloro-4'-ethoxydiphenylmethane, and then condense with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, desorb Trimethylsilyl protection, etherification, and reductive demethoxylation to obtain the hypoglycemic drug dapagliflozin; specifically include the following steps:

[0031] (1) Preparation of 5-bromo-2-chlorobenzaldehyde (I): 2-chlorobenzaldehyde and NBS are dissolved in a polar solvent, and react for 10-12h under the condition of <5°C to prepare 5-bromo- 2-Chlorobenzaldehyde (I); Wherein, the polar solvent can be selected from any one of dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, tetrahydrofuran or acetonitrile, preferred toxicity and low boiling point d...

Embodiment 1

[0044] The preparation of embodiment 1 5-bromo-2-chlorobenzaldehyde (I)

[0045]Take 140kg of 2-chlorobenzaldehyde, dissolve it in 400kg of dichloromethane, stir in ice bath for 30min, then add 180kg of NBS in batches, keep the temperature of the reaction system below 5°C, after the addition, react for 10h, after the reaction, filter , The filtrate was washed with 300kg saturated aqueous sodium bicarbonate solution, then the organic layer was washed with water until neutral, dichloromethane was recovered, and the residual solid was recrystallized with petroleum ether: ethyl acetate (1:1) to obtain 212kg of white solid, with a yield of 98%.

Embodiment 2

[0046] The preparation of embodiment 2 5-bromo-2-chlorobenzyl alcohol (II)

[0047] Take 108 kg of 5-bromo-2-chlorobenzaldehyde, dissolve it in 250 kg of absolute ethanol, add 25 kg of sodium borohydride, and react at room temperature for 4 hours. After the reaction, recover most of the absolute ethanol under reduced pressure, and add dilute hydrochloric acid dropwise under ice bath Quench the reaction system, bring the pH of the system to 4-5, extract with 300kg ethyl acetate, wash with water until neutral, dry over anhydrous sodium sulfate, filter, recover the solvent from the filtrate under reduced pressure, and recrystallize from petroleum ether: ethyl acetate (1:1) Obtain light yellow solid powder 107kg, yield 99%.

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Abstract

The invention relates to a Dapagliflozin preparation method, which comprises the following steps: using 2-chlorobenzaldehyde as a starting material, carrying out bromination, reducing, chlorinating tosynthesize 5-bromo-2-chlorobenzyl chloride, carrying out Friedel-Crafts alkylation reaction between 5-bromo-2-chlorobenzyl chloride and phenetole to synthesize 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane, conducting condensation between 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane and 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone, carrying out trimethylsilyl deprotection, conducting etherification, and reducing for demethylation to obtain a hypoglycemic drug Dapagliflozin. The invention has the following advantages: according to the Dapagliflozin preparation method, 2-chlorobenzaldehyde, whichis used as a starting material, is cheaper and easily available in comparison with 5-bromo-2-chlorobenzoic acid, and the technology is easy for industrialization; during the synthetic process, no rawmaterials which cause severe toxicity will be used and furthermore there is no dangerous process; the synthetic route is short and novel and the operation is simple; and through the synthetic route,purity of the final product can be raised, and the purity can reach 99% and above.

Description

technical field [0001] The invention relates to the field of chemical drug preparation, in particular to a preparation method of dapagliflozin. Background technique [0002] Dapagliflozin (1), the chemical name is (2S,3R,4R,5S,6R)-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6- Hydroxymethyltetrahydro-2H-pyran-3,4,5-triol, jointly developed by Bristol-Myers Squibb and AstraZeneca, is the first sodium-glucose co-transporter approved for the treatment of type 2 diabetes Protein 2 (SGLT2) Inhibitor. The trade name is Farxiga. [0003] There are two main methods for the preparation of Daxigliflozin. One method is to use 5-bromo-2-chlorobenzoic acid as the starting material, undergo acyl chloride, Fockers acylation, reduction, and then combine with 2,3,4,6 -Tetra-O-trimethylsilyl-D-glucopyranosic acid-1,5-lactone condensation, methyl etherification, reduction of methoxyl to prepare dapagliflozin such as patent: PCT Int.Appl., 2010022313, PCTInt.Appl., 2009026537; Documentation Journ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
Inventor 严宾冯成亮
Owner IANGSU COLLEGE OF ENG & TECH
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