Dolasetron isomer or salt thereof, preparation method for the Dolasetron isomer or salt thereof and application of the Dolasetron isomer or salt thereof

Abstract

The invention relates to a Dolasetron isomer or salt thereof, a preparation method for the Dolasetron isomer or salt thereof and application of the Dolasetron isomer or salt thereof. In the preparation method, the Dolasetron isomer or salt thereof is prepared from outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone or salt thereof serving as a raw material by esterifying and salifying. The invention also provides two methods for synthesizing outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone. The outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone is prepared from the compound (6) shown in the specification and serving as a raw material by the steps of reducing, protecting hydroxyl, performing Dieckmann condensation and performing hydrolysis and decarboxylation, or by the steps of reducing, performing Mitsunbu esterification, performing hydrolysis, protecting hydroxyl, performing Dieckmann condensation and performing hydrolysis and decarboxylation. The invention also relates to application of the Dolasetron isomer or the salt thereof to preparation of Dolasetron, or application of the salt of the Dolasetron isomer to preparation of control products for detection.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to dolasetron isomers or salts thereof, preparation methods and applications thereof. Background technique [0002] In recent years, the market sales of antiemetic drugs have been increasing year by year, and their market share in digestive system drugs ranks second only to antiulcer drugs. [0003] Dolasetron and its salts are potent and highly selective 5-HT 3 Receptor antagonists are clinically used to prevent and treat nausea and vomiting in tumor patients during chemotherapy and after gynecological operations and surgical operations, with mild adverse reactions. Specifically, the clinical therapeutic applications of dolasetron and its salts mainly include: 1) prevention of nausea and vomiting associated with naïve and re-treated emetogenic tumor chemotherapy (including high-dose cisplatin), strongly inhibiting cisplatin, adriamycin 2) Prevention of postoperative naus...

AI Technical Summary

Problems solved by technology

[0004] European patent EP0329902 discloses the synthetic route of dolasetron mesylate (see Figure 5 ), where R 4 selected from methyl or ethyl, compound The hydroxyl group at the 8-position in (18) is in the configuration of the vertical bond (axial), but isomers in the configuration of the equatorial bond may be produced during the synthesis process (7), which in turn leads to the possible existence of isomers of its flat bond (equatorial) configuration (also known as "dorasetron isomers") in the synthesized dolasetron (2), that is, outside-octahydro-3-oxo-2,6-methylene-2H-quinazin-8-yl-1H-indole-3-carboxylate (Exo-Octahydro-3-oxo- 2,6-methano-2H-quinolizin-8-yl 1H-indole-3-carboxylate)

So far, there are no research reports on the preparation, confirmation and biological activity of dolasetron isomers

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