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

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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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 strict requirements on anhydrous, the feeding ratio is twice the equivalent of the reduced substrate, so that a large amount of aluminum hydroxide colloids will be formed in the post-treatment process, especially when the production scale is enlarged, which will greatly increase the quality of the post-treatment process. bring great difficulty

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