Preparation method of 5-bromo-2-chloro-4'-ethoxybenzophenone

Abstract

The invention discloses a preparation method of 5-bromo-2-chloro-4'-ethoxybenzophenone, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps:(1) carrying out direct reflux reaction on 5-bromo-2-chlorobenzoic acid and thionyl chloride in the absence of a solvent under the catalysis of DMF, and evaporating excessive thionyl chloride to obtain 5-bromo-2-chlorobenzoyl chloride after the reaction is finished; (2) adding dichloromethane into the material obtained in the step (1) for dissolving, directly adding silica gel loaded aluminum trichloride, performing reacting with phenethyl ether under a vacuum condition, performing filtering after the reaction is completed, washing the filtrate with a 5% sodium bicarbonate solution and water in sequence, performing evaporating to remove the solvent, and performing recrystallizing with a mixed solvent of ethanol and water to obtain 5-bromo-2-chloro-4'-ethoxybenzophenone. The method providedby the invention has the advantages of the small acid solvent generation amount, less difficult-to-treat wastewater, high product purity and yield, no generation of by-products, environmental protection, simple operation, and suitability for industrial production and popularization.

Description

technical field [0001] The invention relates to the synthesis of 5-bromo-2-chloro-4'-ethoxybenzophenone, an antidiabetic drug dapagliflozin intermediate, and belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Dapagliflozin is a new type of anti-diabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. It is the first SGLT2 inhibitor approved for marketing for the treatment of type 2 diabetes, as a diabetes drug treatment An important option in adults with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Its chemical name is (1S)-1,5-anhydride-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, and its structural formula is: [0003] [0004] 5-Bromo-2-chloro-4'-ethoxybenzophenone is the key intermediate for the synthesis of dapagliflozin, and its structural formula is: [0005] [0006] The synthesis of 5-bromo-2-chloro-4'-ethoxybenzophenone usually adopts the preparation met...

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Problems solved by technology

[0008] The method uses 5-bromo-2-chlorobenzoic acid as a raw material, and reacts with oxalyl chloride in a dichloromethane solvent to prepare the intermediate 5-bromo-2-chlorobenzoyl chloride, and then catalyzes it with phenethyl ether in aluminum trichloride. Carry out Friedel-Crafts acylation reaction below and make 5-bromo-2-chloro-4'-ethoxybenzophenone, this method Friedel-Crafts acylation process has produced more ortho-isomer by-products and has influenced product Yield, and because the by-product is close to the target product, it is difficult to purify the by-product and affect the quality of the subsequent product; at the same time, the process also produces a large amount of waste water containing aluminum trichloride that is difficult to handle and a large amount of acidic solvent recovered , the huge environmental pressure also restricts the application and promotion of this method

[0009] CN107200683A discloses a preparation method of 5-bromo-2-chloro-4'-ethoxybenzophenone: under the catalysis of DMF, 5-bromo-2-chlorobenzoic acid and oxalyl chloride are mixed in dichloromethane The reaction obtains 5-bromo-2-chlorobenzoyl chloride; then, in the presence of tert-butyldimethylsilyl chloride, reacts with phenetole under the catalysis of ferric chloride to obtain the dapagliflozin intermediate 5-bromo-2- Chlorine-4'-ethoxybenzophenone, this method avoids the competition reaction of the ortho-para position in the Friedel-Crafts acylation process, and improves the yield of the product, but there are still a large amount of refractory acid wastewater and solvents in the preparation process problems, and the use of tert-butyldimethylchlorosilane also increases production costs

[0010] CN107417515A discloses another kind of synthetic method: take dichloromethane as solvent, take pyridine as catalyst, 5-bromo-2-chlorobenzoic acid and thionyl chloride react to obtain 5-bromo-2-chlorobenzoyl chloride, and then In dichloromethane system, take solid acid as catalyzer, phenetole and 5-bromo-2-chlorobenzoyl chloride react to obtain 5-bromo-2-chloro-4-ethoxybenzophenone; still in this method product There is a small amount of intractable by-products. At the same time, the process produces acidic waste solvents that are difficult to directly recycle, and neither CN107417515A nor CN107200683A has crystallized the product, so it is difficult to ensure that the high-boiling point phenetole and other salts are completely removed.

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