(R)-praziquantel intermediate and preparation method of (R)-praziquantel

Abstract

The invention relates to a (R)-praziquantel intermediate and a preparation method of (R)-praziquantel. The method comprises the following steps: reacting dihydroisoquinoline and nitromethane serving as raw materials in an enclosed grinding tank under the actions of a chiral catalyst, alkali and a grinding aid by taking 1 to 4 stainless steel grinding balls with diameters of 8 to 14 mm as a grinding medium for 20 to 60 minutes, adding chloroacetyl chloride, and continually reacting for 5 to 30 minutes; after the reaction, leaching the mixture with petroleum ether and ethyl acetate, and recrystallizing to obtain the (R)-praziquantel intermediate; catalytically reducing the intermediate with iron to obtain (R)-1-aminomethyl-2-chloroacetyl tetrahydroisoquinoline, and carrying out an amidation-cyclization reaction on the (R)-1-aminomethyl-2-chloroacetyl tetrahydroisoquinoline and cyclohexaformyl chloride in the enclosed grinding tank under the actions of alkali and the grinding aid by taking 1 to 6 stainless steel grinding balls with diameters of 6 to 14 mm as the grinding medium; after the reaction, directly performing column chromatography separation and purification on the mixture toobtain the (R)-praziquantel. The method has the advantages of mild reaction conditions, easiness and convenience in operation, less pollution, high product yield, high enantioselectivity, and betterpopularization and application prospect.

Description

technical field [0001] The invention belongs to the technical field of preparation of medicines and intermediates, and in particular relates to a (R)-praziquantel intermediate and a preparation method of (R)-praziquantel under the condition of solvent-free mechanical ball milling. Background technique [0002] Praziquantel, also known as ciclopraziquantel, is a broad-spectrum anti-parasitic drug. Because of its high curative effect, short course of treatment, small dose, fast metabolism, low toxicity and convenient oral administration, it has now become a drug for the treatment of various parasites. Drug of choice for disease. Praziquantel drugs are generally administered in the form of racemates, wherein (R)-praziquantel is an effective insecticidal component, and (S)-praziquantel is an ineffective component, which has a bitter taste and certain side effects. Although the World Health Organization called for the use of (R)-form drug delivery and listed the priority product...

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Problems solved by technology

[0027] The purpose of the present invention is to overcome problems such as using a large amount of solvents and toxic reagents, high production cost and low efficiency in the existing (R)-praziquantel preparation process, and to provide a kind of (R)-praziquantel intermediate and ( The preparation method of (R)-praziquantel, which utilizes mechanical ball milling to promote the solvent-free asymmetric Aza-Henry reaction to prepare (R)-praziquantel key intermediate (R)-1-nitromethyl quickly and efficiently -2-Chloroacetyltetrahydroisoquinoline, avoiding the use of solvents and toxic reagents in the reaction process, and then preparing (R)-pyraquine by nitro reduction reaction under mild conditions and one-step solvent-free amidation-cyclization reaction ketone

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