Enzymatic resolution method of isavuconazole intermediate
A technology for the separation of isavuconazole intermediates and enzymatic methods, which is applied in fermentation and other directions, can solve the problems of poor reproducibility and inability to crystallize, and achieve simple operation, mild enzymatic separation conditions, and high chiral purity of products Effect
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[0027] Example 1
[0028] Add 100.0g of racemic isaconazole intermediate I of formula I to a 500ml flask, then add 400ml of ethyl acetate, heat to 60°C and stir for 20 minutes, cool to room temperature, and filter to obtain filtrate A. Add 10g of commercially available AK226 nitrilase and 300ml of water into a 1000ml beaker, mechanically stir, slowly pour the filtrate A into the enzymolysis solution, stir slowly at 32℃, maintain the two-phase stratification state, and add 5% hydrogen dropwise Sodium oxide solution, control the pH value from 8 to 8.5. After the pH is stable and the sodium hydroxide solution is no longer consumed, the liquids are separated, the organic layer is filtered, and the solvent is evaporated under reduced pressure at 50°C to obtain the crude product of the structure compound (2S, 3R)-Intermediate I represented by formula IV. The crude product of the structure compound (2S,3R)-Intermediate I of formula IV is slurried by adding 60ml methyl tert-butyl ether,...
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[0029] Example 2
[0030] Add 1.00 kg of racemic isaconazole intermediate I of the structure compound represented by formula I into a 5000 ml flask, and then add 3.0 L of ethyl acetate, heat to 70° C. and stir for 10 minutes, cool to room temperature, and filter to obtain filtrate A. Mix 120g of commercially available AK226 nitrilase with 2.0L of water, mechanically stir, slowly pour the filtrate A into the enzymolysis solution, stir slowly at 35°C, maintain the two-phase stratification state, and add saturated sodium carbonate solution dropwise. Control the pH value from 7.5 to 8.0. When the pH is stable and the sodium carbonate solution is no longer consumed, separate the liquids, strip the aqueous layer with 1.0L ethyl acetate, combine the organic layers and filter, remove the enzyme from the aqueous layer, and evaporate the solvent under reduced pressure at 55°C to obtain the structure shown in formula IV Compound (2S, 3R)-Intermediate I crude product. Add 1.5L of isopropan...
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[0032] Example 3
[0033] Add 1.00kg of racemic isaconazole intermediate I of the structure compound represented by formula I in a 5000ml flask, then add 5.0L ethyl acetate, heat to 50°C and stir for 30 minutes, cool to 10°C, and filter to obtain filtrate A. The recovered nitrilase stored in the buffer in Example 2 was filtered, the filter cake was mixed with 3.0L of water, and mechanically stirred. The filtrate A was slowly poured into the enzymatic hydrolysis solution, and stirred slowly at 40°C to maintain the two In the state of phase stratification, saturated 5% potassium hydroxide solution was added dropwise to control the pH value of 8.4-8.6. HPLC monitoring the structure compound (2R, 3S)-intermediate Ⅰ enantiomer shown in formula IV has hydrolyzed remaining ≤0.2% (area normalization method), separate the liquids, back-extract the aqueous layer with 2.0L ethyl acetate, and combine the organic The layer was filtered, the water layer was deenzyme-recovered, and the solvent...
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