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Method of synthetizing levo-praziquantel

A technology of L-praziquantel and a synthesis method, applied in the directions of organic chemistry, fermentation, etc., can solve the problems of low yield of chemical synthesis of L-praziquantel, and achieve the effects of improving quality standards, readily available raw materials, and low cost

Active Publication Date: 2013-06-19
TONGLI BIOMEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the World Health Organization expects to replace praziquantel with L-praziquantel, the technical problem of low chemical synthesis yield of L-praziquantel has been unsolved for many years

Method used

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  • Method of synthetizing levo-praziquantel
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  • Method of synthetizing levo-praziquantel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1 takes following route synthetic tetrahydroisoquinoline carbonitrile

[0030]

[0031] Example 1-1: In a closed container, add compound 3c (78.1g, 0.5mol), ethanol (0.7L) and 10% catalyst Pd / C (6g), after replacing the air in the container with hydrogen, continue to introduce hydrogen ( 1MPa), raised the temperature to 30°C, stirred and reacted for 8 hours, detected that the reaction was complete, recovered the catalyst by filtration, and concentrated the reaction solution under reduced pressure to obtain 74.82g of a solid compound, which was compound 3d (tetrahydroisoquinolinecarbonitrile), with a purity of 97.6 %, yield 94.6%;

[0032] Compound 3d NMR data: 1 H NMR (CDCl 3 ,400MHz,δppm): 3.06–3.10(m,2H,CH 2 ),3.43–3.63(m,2H,CH 2 ), 4.95(s,1H,CH),7.28–7.54(m,4H,ArH), MS(ESI,+ve):m / z:159.1[M+H] + .

example 1-2

[0033] Example 1-2: In a closed container, add compound 3c (78.1g, 0.5mol), methanol (0.7L) and Raney nickel catalyst (12g), replace the air in the container with hydrogen, and continue to introduce hydrogen (1MPa) , stirred and reacted at 25-30 degrees for 8 hours, HPLC detected that the reaction was completely stopped, the catalyst was recovered by filtration, the reaction solution was concentrated under reduced pressure, and the residue was 73.95g of a solid compound, which was compound 3d, with a purity of 94.4% and a yield of 93.5%; It can be directly used in the next reaction without further purification.

[0034] Compound 3d NMR data: 1 H NMR (CDCl 3 ,400MHz,δppm): 3.06–3.10(m,2H,CH 2 ),3.43–3.63(m,2H,CH 2 ), 4.95 (s, 1H, CH), 7.28–7.54 (m, 4H, ArH).

[0035] MS(ESI,+ve):m / z:159.1[M+H] + .

example 1-3

[0036] Example 1-3: Add compound 3c (78.1g, 0.5mol) into 1000mL ethanol, add sodium borohydride (19g, 0.5mol) in batches, stir at 30-40°C for 16 hours, and the system becomes clear. The reaction was completely stopped by HPLC detection, and the organic solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated brine, concentrated under reduced pressure to remove the solvent, and obtained 76.0 g of a white solid compound, which was compound 3d, with a yield of 96.1%. The purity is 94.2%.

[0037] Compound 3d NMR data: 1 H NMR (CDCl 3 ,400MHz,δppm): 3.06–3.10(m,2H,CH 2 ),3.43–3.63(m,2H,CH 2 ), 4.95(s,1H,CH),7.28–7.54(m,4H,ArH), MS(ESI,+ve):m / z:159.1[M+H] + .

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Abstract

The invention relates to a novel method of synthetizing levo-praziquantel. High solid, locus and regioselectivity of enzyme are utilized to catalyze chemosynthesis racemic modification or a certain enantiomer of a derivative to conduct dynamic kinetic splitting and producing an optical homochiral levo-praziquantel midbody, and further the levo-praziquantel is obtained through various mature and high-yield conventional organic chemical reactions. The method is mature in process and low in cost, can be used for producing levo-praziquantel in mass, improves quality standard, establishes foundations for creating quality raw material medicine and preparation, and solves the industrial difficulty of purifying praziquantel which is suspended and unsolved for nearly 30 years. Raw materials can be easily obtained, and product purity can be higher than 98%.

Description

technical field [0001] The invention relates to a synthesis method of L-praziquantel ((R)-praziquantel). Background technique [0002] Praziquantel, also known as cyclic praziquantel, is a broad-spectrum antiparasitic drug. It has a wide anti-helminth spectrum, and has killing effects on Schistosoma japonicum, Schistosoma haematobium, and Schistosoma mansoni. In addition, it also has a killing effect on paragonimus (lung fluke), clonorchis sinensis, hydatid, cysticercosis, sparganus monstii, fasciola, tapeworm, etc. The action characteristics of praziquantel are high curative effect, short course of treatment, small dose, fast metabolism, low toxicity and convenient oral administration. The advent of praziquantel is a major breakthrough in the chemotherapy of parasitic diseases, and now it has become the drug of choice for the treatment of many parasitic diseases. [0003] Praziquantel was first synthesized by Seubere et al. in 1975, and the German E-merck and Bayer two p...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P17/18
CPCC07D471/04C12P17/12C12P17/182C12P41/006
Inventor 钱明心
Owner TONGLI BIOMEDICAL
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