Preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane

A technology of chlorotoluene and synthetic methods, which is applied in the preparation of organic compounds, chemical instruments and methods, organic chemistry, etc., can solve problems such as post-processing difficulties, and achieve the effects of easy post-processing, mild reaction conditions, and rich synthetic routes

Inactive Publication Date: 2015-04-01
CHINA PHARM UNIV
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Problems solved by technology

[0007] Yu Yankun et al. (Yu Yankun, Chinese Journal of Pharmaceutical Industry, 2011, 42 (2)) reported an improvement to the above route, using sodium borohydride/aluminum chloride system to reduce carbonyl to methylene, yield Reached 92%, but the two-step reaction uses anhydrous aluminum trichloride
Since aluminum trichloride has str...

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  • Preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane
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  • Preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane

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[0024] The present invention will be further described below through the examples, but the examples do not limit the protection scope of the present invention.

[0025] (1) Preparation of 4-bromo-2-methylaniline

[0026] Place 8.1ml (75.4mmol) of o-toluidine in a dry 250ml single-necked bottle, and stir it magnetically under an ice-water bath. Dissolve 13.5g (75.8mmol) of N-bromosuccinimide in 60ml of N,N-dimethylformamide, place it in a dropping funnel and drop it in slowly, keep the reaction liquid at about 0°C, and add it for 5 hours . The reaction solution was poured into 600ml of ice water, the solid was precipitated, and the solid was obtained by suction filtration. The aqueous phase was extracted with 50ml of ethyl acetate and concentrated to obtain a small amount of solid. The combined solid was washed with petroleum ether (25ml*3) to obtain 13.2g of solid. The yield was 95%, and the product was directly used in the next reaction without purification. m.p.50-52℃. 1...

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Abstract

The invention relates to the chemical field and particularly relates to a novel synthesis method for preparing a key intermediate 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane of a drug dapagliflozin for treating diabetes mellitus II. The preparation method comprises the following steps: enabling a starting raw material ortho-toluidine to firstly perform bromization and then perform chlorination after diazotization on a benzene ring with N-bromo-succinimide; then, in the presence of a halogenating agent, performing halogenating reaction of beta-position; and finally, performing Friedel-Crafts alkylation synthesis with phenetole, thereby obtaining the key intermediate. The preparation method is simple and convenient, economical and relatively high in reaction yield in each step, and suitable for industrial production.

Description

Technical field: [0001] The invention relates to a method for synthesizing 5-bromo-2-chloro-4'-ethoxydiphenylmethane, an important intermediate of dapagliflozin. Background technique: [0002] Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor, C-aryl glucoside compound, chemical name: (2S, 3R, 4R, 5S,6R)-2-[3-(4-Ethoxybenzyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol. Dapagliflozin inhibits the reabsorption of blood sugar by inhibiting renal sodium-glucose cotransporter 2, thereby regulating blood sugar levels in the body; at the same time, it can significantly reduce the level of glycosylated hemoglobin and body weight of patients. Dapagliflozin, jointly developed by Bristol-Myers Squibb and AstraZeneca, is the second SGLT2 inhibitor approved by the US FDA for the treatment of type 2 diabetes. [0003] [0004] The existing dapagliflozin synthesis methods are relatively concentrated, all using 5-bromo-2-chloro-4'-ethoxydiphenylme...

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Application Information

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IPC IPC(8): C07C43/225C07C41/22
Inventor 薛晓文刘林义龙劲节宋雅萍李嘉宾
Owner CHINA PHARM UNIV
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