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A kind of preparation method of (r)-praziquantel

A technology of praziquantel and a synthetic method, applied in the directions of organic chemistry, organic chemistry, etc., can solve the problems of low efficiency and high production cost, and achieve the effects of low reaction cost, easy operation and improved yield

Active Publication Date: 2021-07-30
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the problems of using a large amount of solvents, toxic reagents and corrosive reagents, high production cost and low efficiency in the existing (R)-praziquantel preparation process, and to provide a kind of (R)-praziquantel The preparation method of the intermediate thereof, it utilizes the mechanical ball milling method to promote the solvent-free Aza-Henry reaction to prepare 1-nitromethyl-2-chloroacetyl tetrahydroisoquinoline quickly and efficiently; Nickel catalyzed reduction reaction prepares 1-aminomethyl-2-chloroacetyl tetrahydroisoquinoline intermediate; this intermediate carries out crystal resolution reaction with acidic resolution reagent to prepare (R)-praziquantel intermediate ((R )-1-aminomethyl-2-chloroacetyltetrahydroisoquinoline), and carry out racemization recovery and reuse of the remaining mother liquor after crystallization; Reagent, solvent-free amidation-cyclization reaction promoted by mechanical ball milling to obtain (R)-praziquantel, avoiding the use of corrosive acid chloride reagents

Method used

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  • A kind of preparation method of (r)-praziquantel
  • A kind of preparation method of (r)-praziquantel
  • A kind of preparation method of (r)-praziquantel

Examples

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Embodiment 1

[0042] Preparation of embodiment 11-nitromethyl-2-chloroacetyl tetrahydroisoquinoline

[0043]

example 1-1

[0044] Example 1-1: Add dihydroisoquinoline (6.56g, 50mmol), nitromethane (9.16g, 150mmol), triethylamine (5.06g, 50mmol), and neutral alumina (120g) to 250mL stainless steel in sequence In the grinding tank, add stainless steel grinding balls with a diameter of 6 mm (Φ MB = 0.16). After the grinding jar was sealed, the grinding jar was placed in a planetary ball mill and ground at room temperature for 30 minutes at a grinding speed of 150 rpm, followed by adding chloroacetyl chloride (11.29 g, 100 mmol) and continuing grinding for 30 minutes at the same speed. After the reaction was complete, the reaction mixture was dissolved in ethyl acetate (120 mL) and filtered. The filtrate was successively washed with water (3×30mL), washed with saturated brine (3×30mL), dried and concentrated under reduced pressure to obtain crude 1-nitromethyl-2-chloroacetyltetrahydroisoquinoline, which was washed with acetic acid at reflux temperature Ethyl ester was recrystallized to obtain 11.15 ...

example 1-2

[0046] Example 1-2: Add dihydroisoquinoline (6.56g, 50mmol), nitromethane (3.05g, 50mmol), tert-butylamine (10.95g, 150mmol), and silica gel (120g) into a 250mL stainless steel grinding tank in turn, and then Add a stainless steel grinding ball with a diameter of 10mm (Φ MB = 0.14). After the grinding jar was sealed, the grinding jar was placed in a tumbler ball mill and ground at room temperature for 30 minutes at a grinding speed of 100 rpm, followed by adding chloroacetyl chloride (16.94 g, 150 mmol) and continuing grinding for 30 minutes at the same speed. After the reaction was complete, the reaction mixture was dissolved in ethyl acetate (120 mL) and filtered. The filtrate was successively washed with water (3×30mL), washed with saturated brine (3×30mL), dried and concentrated under reduced pressure to obtain crude 1-nitromethyl-2-chloroacetyltetrahydroisoquinoline, which was washed with ethanol at reflux temperature 10.48 g (78% yield) of pure product was obtained by ...

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Abstract

The invention provides a preparation method of (R)-praziquantel. The method of (R)-praziquantel is: using dihydroisoquinoline and nitromethane as raw materials, undergoing solvent-free Henry reaction under mechanical ball milling and nickel-catalyzed hydrogenation reduction reaction to obtain 1-aminomethyl-2- Chloroacetyl tetrahydroisoquinoline intermediate; said intermediate and acid resolving agent are carried out into salt resolution reaction, obtain (R)-praziquantel intermediate; then (R)-praziquantel intermediate and Cyclohexanecarboxylic acid was subjected to a solvent-free amidation-cyclization reaction under mechanical ball milling to synthesize (R)-praziquantel. The remaining mother liquor after crystallization and resolution of the method can be recovered and reused through racemization, thereby greatly improving the yield of (R)-praziquantel intermediate; the present invention is easy to operate, mild in reaction conditions, environmentally friendly, and the obtained ( The R)-praziquantel product has high optical purity and has a good promotion 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 preparation method of (R)-praziquantel under solventless mechanical ball milling. Background technique [0002] Schistosomiasis is an acute and chronic tropical parasitic disease caused by schistosomes, affecting nearly 240 million people worldwide. According to the "World Health Organization (WHO) 2015 Model List of Essential Drugs", praziquantel (PZQ) is designated as the first-line drug for the treatment of schistosomiasis. This small molecule drug is usually administered in the form of a racemate. However, only the R-enantiomer showed antiparasitic activity, the S-enantiomer was inactive and had a bitter taste. Therefore, it is a wise choice to develop an efficient and feasible enantioselective route to obtain (R)-praziquantel. [0003] So far, the reported methods of (R)-praziquantel mainly include asymmetric synthesis, che...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07B2200/07C07D471/04
Inventor 俞静波何召婷苏为科
Owner ZHEJIANG UNIV OF TECH