Preparation method of levo praziquantel as well as intermediate thereof

A technology of L-praziquantel and intermediates, which is applied in the field of intermediates for the preparation of L-praziquantel, can solve the problems of nitrile hydratase that is difficult to obtain and store, is not easy to use, and is cumbersome to operate, and achieves low production costs and improved yields , the effect of simple reaction route

Active Publication Date: 2015-05-20
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The nitrile hydratase used in this method is difficult to obtain and preserve, the cost is high, the operation is cumbersome, and it is not easy to use

Method used

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  • Preparation method of levo praziquantel as well as intermediate thereof
  • Preparation method of levo praziquantel as well as intermediate thereof
  • Preparation method of levo praziquantel as well as intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] step 1

[0048]

[0049] Dissolve compound HDP100-02 (90g, 361.45mmol) in isopropanol (1800mL), add (+)-α-methylbenzylamine (103g, 361.45mmol), heat to 60°C, the reaction solution is clear, and start to cool down slowly Crystallize overnight, filter with suction, rinse the filter cake with cold isopropanol (150 mL), and dry to obtain a white solid (79 g). Add isopropanol (1700mL) to the above white solid, heat and reflux until the solid is completely dissolved, slowly cool down and crystallize overnight, filter with suction, rinse the filter cake with cold isopropanol (100mL), and dry to obtain a white solid (55g ).

[0050] The white solid obtained by secondary crystallization was washed with saturated NaH 2 PO 4 The solution was freed, extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution (100 mL×1), dried over anhydrous sodium sulfate, and concentrated by suction to obtain an oily liquid (27 g), yield 30%.

[0051] The exp...

Embodiment 2

[0097] step 1

[0098]

[0099] Compound HDP100-02 (50g, 200.59mmol) was dissolved in isopropanol (1000mL), cinchonine (59g, 200.59mmol) was added, the reaction liquid was heated to 80°C, and the reaction liquid was clarified, then slowly cooled down to crystallize overnight, suction filtered, and the filter cake was Rinse with cold isopropanol (120 mL) and dry to give a white solid (72 g). Add isopropanol (1500mL) to the above white solid, heat and reflux until the solid is completely dissolved, slowly cool down and crystallize overnight, filter with suction, rinse the filter cake with cold isopropanol (150mL), and dry to obtain a white solid (50g ).

[0100] The white solid obtained by secondary crystallization was freed with 1N HCl aqueous solution, extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution (100mL×1), dried over anhydrous sodium sulfate, and concentrated by suction to obtain an oily liquid (25g), yield 27.8 %.

[0101] The...

Embodiment 3

[0147] step 1

[0148]

[0149] Compound HDP100-02 (20g, 80.23mmol) was dissolved in isopropanol (400mL), and (R)-(+)-1-(1-naphthyl)ethylamine (11.06g, 64.18mmol) was added and heated to The reaction solution was clarified at 100°C, and the temperature was slowly lowered to crystallize overnight, filtered with suction, the filter cake was rinsed with cold isopropanol (100 mL), and dried to obtain a white solid (29 g). Add isopropanol (600mL) to the above white solid, heat and reflux until the solid is completely dissolved, slowly cool down and crystallize overnight, filter with suction, rinse the filter cake with cold isopropanol (150mL), and dry to obtain a white solid (20g ).

[0150] The white solid obtained by secondary crystallization was washed with 1NH 2 SO 4 The aqueous solution was freed, extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution (100 mL×1), dried over anhydrous sodium sulfate, and concentrated by suction to obtain a...

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Abstract

The invention discloses a preparation method of levo praziquantel as well as an intermediate thereof. The method comprises the following steps of carrying out salt forming reaction onto a compound as shown in formula (I) and an alkaline resolving agent to obtain a levo praziquantel intermediate as shown in formula (II); and carrying out multi-step chemical reaction onto the levo praziquantel intermediate to synthesize the levo praziquantel. According to the preparation method disclosed by the invention, resolution of a racemic mixture is designed at the beginning of the reaction, mother liquor left after crystallization and resolution can be recycled in a racemic manner, and reaction resolution of an initial step is carried out, so that yield of the levo praziquantel intermediate is greatly improved; moreover, the prepared intermediate is high in purity, production cost of the levo praziquantel is lowered, overall reaction route is concise, materials are cheap and easily available, and operation is simple and easy to implement.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to an intermediate for preparing L-praziquantel and a method for preparing L-praziquantel. Background technique [0002] Praziquantel is a broad-spectrum anti-parasitic drug. Most of the praziquantel used in the world at this stage is the racemic praziquantel (i.e. the mixture of L-praziquantel and D-praziquantel), and research has found that the elimination Among the rotatory praziquantel, only L-praziquantel is an effective insecticidal ingredient and tasteless, while D-praziquantel is an invalid or even harmful ingredient and has a severe bitter taste. Therefore, many animals contain dextro-praziquantel Refuse to swallow due to the bitter taste of praziquantel. At the same time, in the case of the same dose, the clinical curative effect of L-praziquantel is better than that of praziquantel, so it has become an inevitable development trend for L-praziquantel to replace praziqu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D217/26
CPCC07D217/26C07D471/04
Inventor 李文森於万松
Owner HEADING NANJING PHARMTECH CO LTD
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