A kind of synthetic method of L-praziquantel and its intermediate
A technique for the synthesis of L-praziquantel, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of time-consuming energy consumption, cumbersome process, and the total yield needs to be improved, and achieves mature conditions, simple operation, and high yield. rate-enhancing effect
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Embodiment 1
[0046] The preparation of embodiment 1 recombinant D-amino acid oxidase
[0047] Inoculate a single colony of recombinant Escherichia 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 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 free...
Embodiment 2
[0048] Preparation of embodiment 2 intermediate 1-(R)-tetrahydroisoquinoline formic acid ammonium salt
[0049] 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. About 28 hours HPLC test result shows that 1-(S)-tetrahydroisoquinoline-1-formic acid ammonium salt is 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 of pure white solid, ...
Embodiment 3
[0051] Preparation of embodiment 3 intermediate 1-(R)-tetrahydroisoquinoline formic acid potassium salt
[0052] 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. About 30 hours of HPLC detection results showed that 1-(S)-tetrahydroisoquinoline-1-carboxylic acid potassium salt was less than 1%. Stop the reaction, heat to 50-60°C, and denature the enzyme protein for more than half an hour. The heated reaction is filtered through diatomaceous earth to remove the enzyme, and the filtrate is extracted with toluene (3x5ml), and tert-butylamine (2.1g) is recovered from the toluene phase. Add 2 times the volume of acetone to the extracted water phase to ...
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