Enzymatic method for synthesizing the intermediate of Imitasvir
A synthetic method and lipase technology, applied in the field of medicine, can solve the problem of low selectivity
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Embodiment 1
[0077] Take 1 g of CALB lipase enzyme powder (obtained commercially) and add 90 mL of phosphate buffer (100 mM, pH 7.4) to dissolve to obtain an enzyme solution. 4 g of diester (compound of formula 5, wherein R is ethyl) was dissolved in methyl tert-butyl ether (MTBE), and the final volume was 10 mL of substrate solution. The 10 mL substrate solution was added into the enzyme solution to obtain an enzyme reaction system. Add condensing reflux to the enzyme reaction system (to reduce the loss of organic solvents), stir magnetically at 40°C for 18 hours, extract the reaction solution with dichloromethane after the conversion of the substrate is complete, and detect the reaction product by HPLC. The HPLC detection result shows that the monoester B is The reaction conversion rate is 98%, and the ee value reaches 95%.
Embodiment 2-6
[0079] Except changing the solvent in the enzyme reaction system, other conditions are all the same as in Example 1, and the HPLC detection results are shown in the following table 1:
[0080] Table 1: Effect of solvents on reactions
[0081]
[0082] As can be seen from the results in Table 1, when substrate concentration 40g / L, enzyme amount 10g / L, organic solvent consumption 10% (v / v), 40 ℃ reacted 18h, reacted with methyl tert-butyl ether (MTBE) When being an organic solvent, the conversion rate and ee value of the reaction are optimal, so the best solvent in the present invention is methyl tert-butyl ether (MTBE).
Embodiment 7-10
[0084] Except changing temperature of reaction, other conditions are all identical with embodiment 1, and HPLC detection result is shown in table 2 below:
[0085] Table 2: Effect of Temperature on Reaction
[0086]
[0087]
[0088] As can be seen from the results in Table 2, when the substrate concentration is 40g / L, the amount of enzyme is 10g / L, MTBE is an organic solvent (10%v / v), the reaction is 18h, and the conversion rate of the reaction is the highest when the reaction temperature is 40°C Excellent, so the optimum reaction temperature in the present invention is 40 ℃.
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