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Method for preparing levo-praziquantel

一种左旋吡喹酮、中间体的技术，应用在左旋吡喹酮-praziquantel)的制备领域，能够解决左旋吡喹酮化学合成收率低等问题，达到提升质量标准、成本低、原料易得的效果

Active Publication Date: 2013-02-06
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 for preparing levo-praziquantel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] This embodiment provides a method for preparing intermediate 5 of L-praziquantel:

[0025] Add compound 3 (2.7g, 10mmol), compound 4 (1.35g, 6.56mmol) and toluene (50mL, water content 20mg) into the reactor, after stirring evenly, add 6mg Candida antarctica lipase CAL-A (6000u / g, L3420, Sigma) to start the reaction, the reaction was carried out with stirring at a temperature of 30°C, the reaction process was detected by HPLC, the reaction was stopped after 46-48 hours of reaction, the enzyme was filtered out, washed with 10mL toluene, the organic layer was concentrated under reduced pressure, and the residue was subjected to Silica gel column chromatography (ethyl acetate / n-hexane = 1:15) yielded 1.16 g of intermediate 5 with a yield of about 43%, a melting point of 111-112°C, and an ee value greater than 99%.

[0026] Intermediate 5 NMR data: 1 H NMR (400MHz, CDCl 3 ): δ1.16-1.27 (m, 4H, CH 2 ), 1.35-1.47 (m, 2H, CH 2 ), 1.64-1.85 (m, 4H, CH 2 ), 2.73-2.85 (m, 2H...

Embodiment 2

[0028] This embodiment provides a method for preparing intermediate 5 of L-praziquantel:

[0029] Add compound 3 (1.36g, 5mmol), compound 4 (0.67g, 3.28mmol) and tert-butyl methyl ether (30mL) into the reactor, after stirring evenly, add 12mg Candida antarctica lipase CAL-A (6000u / g , L3420, Sigma) to start the reaction, the reaction was stirred at a temperature of 0°C, the reaction process was detected by HPLC, the reaction was stopped after 66 to 68 hours of reaction, the enzyme was filtered out, washed with 10mL toluene, the organic layer was concentrated under reduced pressure, and the residue was filtered through silica gel. Column chromatography (ethyl acetate / n-hexane = 1:15) yielded 0.52 g of intermediate 5, with a yield of about 38%, a melting point of 112-114°C, and an ee value greater than 93%.

[0030] Intermediate 5 NMR data: the same as in Example 1.

Embodiment 3

[0032] This embodiment provides a method for preparing intermediate 5 of L-praziquantel:

[0033] Add compound 3 (1.36g, 5mmol), compound 4 (0.67g, 3.28mmol) and diethyl ether (30mL) into the reactor, after stirring evenly, add 20mg Candida antarctica lipase CAL-A (6000u / g, L3420 , Sigma) to start the reaction, the reaction was stirred at a temperature of 5°C, the reaction process was detected by HPLC, the reaction was stopped after 46 to 48 hours of reaction, the enzyme was filtered out, washed with 10mL of toluene, the organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography Column separation (ethyl acetate / n-hexane = 1:15) yielded 0.61 g of intermediate 5 with a yield of about 45%, a melting point of 111-112°C, and an ee value greater than 96%.

[0034] Intermediate 5 NMR data: the same as in Example 1.

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Abstract

The invention relates to a method for preparing levo-praziquantel. The method includes resolving certain antipode in raceme under actions of characteristics of high stereoscopic property, locus and regioselectivity of biological enzymes to obtain a mixture of optical isomers which are reacted or unreacted; and further separating and synthesizing the optical isomers to obtain the target product. The raceme is chemically synthesized. The method has the advantages that raw materials are easy to obtain, the cost is low, the purity of the product can be higher than 98%, quality standards are improved, a foundation is laid for manufacturing high-quality bulk drugs and preparations, and the difficult problem, which cannot be solved in the past 30 years, of purifying praziquantel is solved.

Description

technical field [0001] The invention relates to a preparation 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P17/12C07D471/04
CPCC07D471/04C12P17/12C07D217/12C12P17/182C12P41/00
Inventor 钱明心
Owner TONGLI BIOMEDICAL
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