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

A technology of praziquantel and intermediates, applied in the field of preparation of -praziquantel intermediates and -praziquantel, can solve the problems of using a large amount, high production cost, low efficiency, etc. good enantioselectivity

Active Publication Date: 2018-08-03
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 sol

Method used

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

Examples

Experimental program
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Embodiment 1

[0054] Example 1 Preparation of (R)-1-nitromethyl-2-chloroacetyltetrahydroisoquinoline.

[0055]

example 1-1

[0056] Example 1-1: Dihydroisoquinoline (0.655g, 5mmol), nitromethane (0.915g, 15mmol), S-1,1'-bi-2-naphthol catalyst represented by formula (L4) ( 0.299g, 0.5mmol), triethylamine (1.518g, 15mmol), silica gel and sodium chloride (1.6g each) were sequentially added to a 25mL grinding jar, and then two 12mm stainless steel grinding balls were added. After sealing the grinding jar, place the grinding jar in a ball mill and grind at room temperature for 60 minutes at a grinding frequency of 10 Hz, then add chloroacetyl chloride (0.565 g, 5 mmol), and continue grinding for 30 minutes at the same grinding frequency. After the reaction was over, the reaction mixture was rinsed with petroleum ether and ethyl acetate at a volume ratio of 6:1 to obtain (R)-1-nitromethyl-2-chloroacetyltetrahydroisoquinoline 1.115g (yield: 83%, ee: 68%). Then, 10 mL of anhydrous methanol was used as a solvent for recrystallization at 40° C., and the mother liquor was collected and concentrated under redu...

example 1-2

[0058] Example 1-2: Dihydroisoquinoline (0.655g, 5mmol), nitromethane (1.068g, 17.5mmol), quinine-thiourea bifunctional catalyst represented by formula (L2) (0.149g, 0.25 mmol), tert-butylamine (0.365g, 7.5mmol), and neutral alumina (3.2g) were sequentially added to a 25mL grinding jar, and then three 10mm stainless steel grinding balls were added. After the grinding jar was sealed, the grinding jar was placed in a ball mill and ground at room temperature for 20 minutes at a grinding frequency of 30 Hz, then chloroacetyl chloride (1.129 g, 10 mmol) was added, and grinding was continued for 20 minutes at the same grinding frequency. After the reaction was finished, the reaction mixture was rinsed with petroleum ether and ethyl acetate at a volume ratio of 6:1 to obtain (R)-1-nitromethyl-2-chloroacetyl tetrahydroisoquinoline 1.102g (yield: 82%, ee: 72%). Recrystallization was carried out at 50° C. with 15 mL of methanol as a solvent, and the mother liquor was collected and conc...

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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...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D217/14
Inventor 俞静波何召婷江渔彭刚苏为科
Owner ZHEJIANG UNIV OF TECH
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