Preparation method of (R)-praziquantel

A technology of L-praziquantel and intermediates, which is applied in the field of preparation of L-praziquantel (praziquantel), can solve the problems of high cost, cumbersome operation, and high labor intensity, and achieve the effect of low cost and high optical purity

Active Publication Date: 2015-04-29
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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  • Preparation method of (R)-praziquantel
  • Preparation method of (R)-praziquantel
  • Preparation method of (R)-praziquantel

Examples

Experimental program
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Embodiment 1

[0037] The preparation of embodiment 1 recombinant D-amino acid oxidase

[0038] Inoculate a single colony of recombinant Escherichia coli containing the D-amino acid oxidase gene from a glycerol tube or transformation plate into 4mL liquid LB medium containing (100ug / mL) ampicillin resistance, and activate overnight at 37°C for 12-16 hours , the culture obtained after activation was transferred to 100mL liquid LB medium containing (100ug / mL) ampicillin resistance with 2% inoculum, and cultured at 37°C and 220rpm until OD 600 When the value reaches about 0.6, add the inducer isopropyl-β-D-thiogalactopyranoside to a final concentration of 0.8mmol / L, and continue culturing overnight at 30°C. Collect the cells by centrifugation (4°C, 5000 rpm, 15 min), and suspend the cells with 10 mL of phosphate buffer (100 mM, pH 7.0). Place the cell suspension in an ice bath for 10 minutes, then centrifuge (4°C, 12000rpm, 15min), pre-freeze the supernatant at -20°C overnight, and then freez...

Embodiment 2

[0039] Preparation of embodiment 2 intermediate 1-(R)-tetrahydroisoquinoline formic acid ammonium salt

[0040] Dissolve 1.77g (0.01mol) DL-tetrahydroisoquinoline-1-carboxylic acid in 5ml ammonia water (adjust pH to 8.0), add 1.5g (0.05mol) borane-ammonia complex, feed oxygen at a uniform speed, add 88.5 mg of recombinant D-amino acid oxidase and 18 mg of catalase were started to react at 28° C. under stirring, and the reaction progress was detected by HPLC. After about 28 hours, the HPLC test results showed that the ammonium salt of 1-(S)-tetrahydroisoquinoline-1-carboxylate was less than 1%. Stop the reaction, heat to 50-60°C, denature the enzyme protein for more than half an hour, filter the heated reaction through diatomaceous earth to remove the enzyme, add acetone twice the volume of the reaction solution to the filtrate to dilute, collect the precipitated crude solid by filtration, and then pass through Water / acetone (volume ratio 1 / 2) recrystallized to obtain 1.8 g ...

Embodiment 3

[0042] Preparation of embodiment 3 intermediate 1-(R)-tetrahydroisoquinoline formic acid potassium salt

[0043] 1.77g (0.01mol) DL-tetrahydroisoquinoline-1-carboxylic acid was dissolved in 5ml K 2 HPO 4 -KH 2 PO 4 In the buffer solution (adjust the pH to 8.2), add 2.61g (0.03mol) borane-tert-butylamine complex, feed oxygen at a uniform speed, add 35.5mg recombinant D-amino acid oxidase, 9mg catalase, stir The reaction was started at 35°C, and the reaction progress was detected by HPLC. After about 30 hours, the HPLC test results showed that the potassium salt of 1-(S)-tetrahydroisoquinoline-1-carboxylate was less than 1%. Stop the reaction, heat to 50-60°C, denature the enzyme protein for more than half an hour, filter the heated reaction through diatomaceous earth to remove the enzyme, extract the filtrate with toluene (3x5ml), and recover tert-butylamine (2.1g) from the toluene phase. Add 2 times the volume of acetone to the extracted water phase to dilute the reacti...

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Abstract

The present invention relates to an (R)-praziquantel preparation method, comprising steps of using (R,S)-tetrahydroisoquinoline-1-formate or salts thereof, or 1-(S)-tetrahydroisoquinoline-1-formate or salts thereof as a raw material to prepare 1-(R)-tetrahydroisoquinoline-1-formate salts, and steps of preparing (R)-praziquantel from said 1-(R)-tetrahydroisoquinoline-1-formate salts. The preparation method for 1-(R)-tetrahydroisoquinoline-1-formate or salts thereof is as follows: perform an oxidation reaction between the raw material described above and oxygen in the presence of recombinant D-amino acid oxidase and catalase, then perform a reduction reaction on the resulting product under the effect of a borane-amine complex, thus successively converting 1-(S)-tetrahydroisoquinoline-1-formate or salts thereof into the 1-(R)-tetrahydroisoquinoline-1-formate or salts thereof isomer. The present method not only produces an (R)-praziquantel product with a high optical purity, but is also low-cost and environmentally friendly in terms of 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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IPC IPC(8): C07D471/04C07D217/16
CPCC07D217/16C07D471/04C12P13/04C12P17/12C12P41/002C07D217/26C12P17/182
Inventor 钱明心
Owner TONGLI BIOMEDICAL
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