Synthetic method of 5-N,N-dibenzylamine acetyl salicylamide

Abstract

The invention discloses a synthetic method of 5-N,N-dibenzylamine acetyl salicylamide. The synthetic method comprises the steps of protecting salicylamide with aldehyde, ketone or acetal and ketal with different substituents, reacting with an alpha-halogenated acylation reagent so as to obtain an intermediate II, substituting halogen atoms with dibenzylamine, and finally carrying out acidificationdeprotection, so as to obtain 5-N,N-dibenzylamine acetyl salicylamide. The synthetic method provided by the invention has the characteristics of high yield, few impurities, low cost, easiness in amplification and the like.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, in particular to a synthesis method of labetalol intermediate 5-N,N-dibenzylamine acetylsalicylamide. Background technique [0002] Labetalol, a drug used to treat high blood pressure, is an alpha-adrenergic blocker and a beta-adrenergic blocker. Its pharmacology is to block adrenergic receptors, slow down sinus rhythm, and reduce peripheral vascular resistance. This drug can be used to treat various types of hypertensive emergencies and hypertensive crises, and is especially effective in treating pregnancy-induced hypertension. [0003] 5-N,N-Dibenzylamine acetylsalicylic amide is an important intermediate in the synthesis of labetalol, and its main synthesis methods include: dibenzylamine method, ammonolysis method and ionic liquid method. Among them, the dibenzylamine method (US4101579,1978, A) is to generate 5-acetylsalicylic amide through the reaction of...

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Problems solved by technology

But this method has two shortcomings: the one, the bromination reaction industrialization condition is difficult for controlling, and by-product is more, thereby seriously affects the yield and the quality of product; , under the action of dibenzylamine, it is easy to undergo a substitution reaction with bromine on another molecule to generate more dimerization impurities, thereby affecting the yield;

[0011] Compared with the dibenzylamine method, this method has a short route and high yield, and can avoid various impurities introduced by bromination. However, because the ionic liquid is not easy to prepare and store, the industrialization prospect of this method is not ideal; Under liquid conditions, the reaction between chloroacetyl chloride and salicylamide is easy to go up to the ortho position of the phenolic hydroxyl group, and the target product cannot be obtained as a result;

[0012] Generally speaking, the synthesis method of 5-N,N-dibenzylamine acetylsalicylic amide that has been reported so far has the disadvantages of high production cost, difficulty in industrialization and difficult removal of impurities.

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