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 t

Method used

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  • Preparation method of (R)-praziquantel
  • Preparation method of (R)-praziquantel
  • Preparation method of (R)-praziquantel

Examples

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Example Embodiment

[0037] Example 1 Preparation of recombinant D-amino acid oxidase

[0038] Inoculate a single colony of recombinant E. coli containing the D-amino acid oxidase gene from a glycerol tube or transformation plate into 4 mL liquid LB medium containing (100ug / mL) ampicillin resistance, and activate it at 37°C overnight for 12-16 hours , The culture obtained after activation was transferred to 100mL liquid LB medium containing (100ug / mL) ampicillin resistance at 2% inoculum, and cultured with shaking at 37℃ and 220rpm to OD 600 When the value reached about 0.6, the inducer isopropyl-β-D-thiogalactoside was added to the final concentration of 0.8mmol / L, and the culture was continued overnight at 30°C. The cells were collected by centrifugation (4°C, 5000 rpm, 15 min), and the cells were suspended in 10 mL of phosphate buffer (100 mM, pH 7.0). The cell suspension was sonicated in an ice bath for 10 minutes, then centrifuged (4℃, 12000rpm, 15min), the supernatant was pre-frozen at -20℃ ove...

Example Embodiment

[0039] Example 2 Preparation of intermediate 1-(R)-tetrahydroisoquinoline ammonium salt

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

Example Embodiment

[0042] Example 3 Preparation of intermediate 1-(R)-tetrahydroisoquinoline carboxylate potassium salt

[0043] 1.77g (0.01mol) DL-tetrahydroisoquinoline-1-carboxylic acid 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) of borane-tert-butylamine complex, add oxygen at a uniform rate, add 35.5mg recombinant D-amino acid oxidase, 9mg catalase, and stir The reaction started at 35°C, and the progress of the reaction was monitored by HPLC. About 30 hours HPLC test results showed that 1-(S)-tetrahydroisoquinoline-1-carboxylic acid potassium salt was less than 1%. Stop the reaction and heat to 50-60°C for more than half an hour to denature the enzyme protein. The heated reaction is filtered through Celite to remove the enzyme. The filtrate is extracted with toluene (3x5ml), and tert-butylamine (2.1g) is recovered from the toluene phase. The extracted aqueous phase is diluted by adding 2 times the volume of the reaction solution wi...

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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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