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A kind of preparation method of L-praziquantel

A technology of L-praziquantel and tetrahydroisoquinoline, applied in the directions of organic chemistry, bulk chemical production, etc., can solve problems such as total yield to be improved, complicated operation, large amount of enzyme catalyst, etc., and avoid sodium cyanide. and the use of heavy metals, reducing the amount of organic solvents, and solving the effects of danger and pollution

Active Publication Date: 2019-04-05
TONGLI BIOMEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The method is cumbersome to operate, the yield is low, it needs to use highly toxic raw materials and heavy metals and high temperature and high pressure conditions, and the environment is seriously polluted
[0009] 2. Enzymatic resolution method: Dextromation is required, the process is cumbersome, and the total yield needs to be improved
However, the amount of enzyme catalyst is large, and the amount of enzyme catalyst and raw material reaches 1:1. The post-treatment is complicated and labor-intensive. The optical purity of the product needs to be recrystallized to meet the pharmaceutical needs, and the cost is high.

Method used

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  • A kind of preparation method of L-praziquantel
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  • A kind of preparation method of L-praziquantel

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Example 1, Inducing crystallization to prepare 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate, the synthetic route is as follows:

[0045]

[0046] In the reactor, add acetic acid (25ml), add racemic 1-(R,S)-tetrahydroisoquinoline-1-carboxamide (1.76g, 10.0mmol), (S)-(-)-1- Phenylethanesulfonic acid (1.86g, 10.0mmol) was heated to 45°C and kept warm for 10 minutes to dissolve completely. After adding seed crystals of 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate (0.1 g), the reaction mixture was stirred at 45°C for 4 hours, A pasty liquid was produced. Salicylaldehyde (0.52ml) was added again, stirred at 35°C for 12 hours, then cooled to 5°C, and crystallized under slow stirring for 45 minutes. The precipitated 1-(R)-tetrahydroisoquinoline-1-carboxamide·(S)-(-)-1-phenylethanesulfonate was collected by filtration, washed with ethyl acetate, and dried. 3.03 g (83.5% yield, 94.5% optical purity) of 1-(R)-tetrah...

Embodiment 2

[0047] Example 2, Preparation of 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate by induced crystallization

[0048] In the reactor, add formic acid (25ml), add racemic 1-(R,S)-tetrahydroisoquinoline-1-carboxamide (1.76g, 10.0mmol), (S)-(-)-1- Phenylethanesulfonic acid (1.86g, 10.0mmol) was heated to 25°C and kept warm for 10 minutes to dissolve completely. After adding seed crystals of 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate (0.1 g), the reaction mixture was stirred at 20° C. for 4 hours, A pasty liquid was produced. Then it was cooled to 5° C., and crystallized under slow stirring for 15 minutes. The precipitated 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate was collected by filtration, washed with isopropyl acetate, and dried to obtain 1-( R)-tetrahydroisoquinoline-1-carboxamide · (S)-(-)-1-phenylethanesulfonic acid white crystals 3.42 g (94.3% yield, 99.3% optical purity).

Embodiment 3

[0049] Example 3, Preparation of 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate by induced crystallization

[0050] In the reactor, add propionic acid (25ml), add racemic 1-(R,S)-tetrahydroisoquinoline-1-carboxamide (1.76g, 10.0mmol), (S)-(-)-1 - Phenylethanesulfonic acid (1.86g, 10.0mmol), heated to 100°C, and kept warm for 10 minutes to dissolve completely. After adding seed crystals of 1-(R)-tetrahydroisoquinoline-1-carboxamide (S)-(-)-1-phenylethanesulfonate (0.1 g), the reaction mixture was stirred at 80° C. for 4 hours, A pasty liquid was produced. Then add 3,5-dichlorosalicylaldehyde (0.52ml), stir at 80°C for 12 hours, then cool to 5°C, and carry out crystallization reaction for 35 minutes under slow stirring. The precipitated 1-(R)-tetrahydroisoquinoline-1-carboxamide·(S)-(-)-1-phenylethanesulfonate was collected by filtration, washed with methyl tert-butyl ether, and dried. 3.03 g (83.7% yield, 94.5% optical purity) of 1-(R)-tetrahydroi...

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Abstract

The invention relates to a preparation method of levophenone. The method comprises the following steps: 1, preparing 1-(R)-tetrahydroisoquinoline-1-carboxamide from 1-(R,S)-tetrahydroisoquinoline-1-carboxamide: reacting the 1-(R,S)-tetrahydroisoquinoline-1-carboxamide to generate a sulfonate mixture, adding seed crystals to the sulfonate mixture, carrying out a crystal precipitation reaction to obtain an intermediate 1-(R)-tetrahydroisoquinoline-1-carboxamide sulfonate, and converting the intermediate 1-(R)-tetrahydroisoquinoline-1-carboxamide sulfonate to form the 1-(R)-tetrahydroisoquinoline-1-carboxamide; and 2, preparing the levophenone from the 1-(R)-tetrahydroisoquinoline-1-carboxamide. The method has the advantages of obtaining of the levopraziquantel product with a high optical purity, low cost, and greenness and environmental protection in production.

Description

technical field [0001] The invention relates to a preparation method of L-praziquantel ((R)-praziquantel). Background technique [0002] Praziquantel is an artificially synthesized pyrazine isoquinoline derivative, also known as ciclopraziquantel, white or off-white crystalline powder, bitter in taste, is a world-recognized high-efficiency broad-spectrum antiparasitic drug, and is widely used in the treatment of Schistosoma japonicum , Schistosoma haematobium, Schistosoma mansoni, clonorchiasis, paragonimiasis, sparganosis montesiei, fasciola, echinococcosis, tapeworms and cysticercosis and other diseases. It has the advantages of broad anti-insect spectrum, high curative effect, low toxicity, short course of treatment and convenient use. In addition to being used in humans, it is also widely used in anti-parasitic treatment of animals, poultry, etc. The advent of praziquantel is a major breakthrough in the history of parasitic disease chemotherapy, and praziquantel is cur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCY02P20/55
Inventor 钱明心
Owner TONGLI BIOMEDICAL