A kind of preparation method of prucalopride intermediate

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a method for preparing a prucalopride intermediate. The method comprises the following steps: performing acylation and demethylation reactions on 2-methoxy-4-acetylamino-5-chloro methyl benzoate (I) serving as an initial raw material at 0-20 DEG C under the action of a proper amount of an acylating agent and lewis acid to obtain an intermediate (II); adding an alkaline reagent into the intermediate (II), and performing cyclization reaction at 0-20 DEG C in a polar solvent to obtain an intermediate (III); adding hydrazine hydrate and absolute ethyl alcohol to the intermediate (III), and performing reduction reaction at 70-80 DEG C to obtain an intermediate (IV); performing hydrolysis reaction on the intermediate (IV) at 90-100 DEG C under the action of a sodium hydroxide solution to obtain sodium salt of an intermediate (V), and acidizing with hydrochloric acid to obtain the intermediate (IV). The synthesizing route has mild reaction condition, low production cost and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a method for preparing prucalopride intermediates. Background technique [0002] Prucalopride, chemical name 4-amino-5-chloro-2,3-dihydro- N -[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide, its succinate is commonly used clinically as a highly selective serotonin receptor agonist. It can stimulate the peristaltic reflex in humans, enhance the contraction of the colon, and accelerate gastric emptying. It can increase the defecation frequency of patients with constipation and reduce the hardness of the stool. It is mainly used to treat various constipation and postoperative gastrointestinal motility and pseudo-obstruction. It is an effective intestinal motility drug. Clinically indicated for the symptomatic treatment of chronic constipation in women not adequately relieved by laxatives. The listing of prucalopride provides a safer, more effective and more sym...

AI Technical Summary

Problems solved by technology

In the existing reports, the intermediate has the following three synthetic routes: (1) Pharmaceutical and Clinical Research, 2011, 19 (4), 306-307. The rearrangement reaction temperature of the second step of this route is nearly 200°C, and the conditions are harsh , a total of seven steps are required, and the synthesis route is rather long, in which the third step oxidation reaction uses osmium tetroxide, and its price is relatively high, so the synthesis cost of this synthesis route is relatively high; (2) J Heterocyclic Chem, 1980, 17( 6): 1333-5. Both the second and sixth steps of this route use butyllithium, which requires anhydrous and oxygen-free low-temperature operation, harsh conditions, and poor industrial feasibility; (3) American Chemical Society, 2003, 125-139 . The third step of this route is a ring-closing reaction catalyzed by zinc powder, which requires anaerobic operation. There is a process of initiating the reaction during the reaction, which is easy to accumulate and release heat, and there are potential safety hazards in industrial production.

[0004] It can be seen that the existing synthetic routes are not easy to industrialized production

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