Efficient Preparation of (R)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid by Dynamic Kinetic Resolution
1. College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China;
2. Tongli Biomedical Co, Ltd, Zhang jiagang 215600, China
Abstract：Immobilized Candida Antarctica lipase B (CAL-B) was used to prepare (R)-1,2,3,4-tetrahydroisoquinoline
1-carboxylic acid ((R)-1-TIC) by dynamic kinetic resolution of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic
ester ((±)-1). The catalytic efficiency of CAL-B preparations from different sources and the effects of key reaction conditions on stability of (±)-1 and enzymatic efficiency were investigated. The results showed that QLlip-9 was of the best catalytic efficiency. When the temperature was raised to 30 ℃ and initial pH value of the ammonium acetate buffer was 8.0, the time for complete conversion was greatly shortened and the overall catalytic efficiency was significantly improved, regardless of a slight decrease in the stability of (±)-1. In addition, the constant-pH controlling strategy increased the racemization rate of ineffective substrates at the last period of the reaction, which further improved the catalytic efficiency. When the concentration of (±)-1 was 20 g/L, reducing the concentration of QLlip-9 to 10 g/L did not affect the catalytic efficiency, and the optimum enzyme/substrate ratio reached to 1:2. Under the optimum conditions above, the reaction time was shortened to 6 h, the conversion rate was over 99% and the enantiomeric excess of product (e.e.p) was 96%. What’s more, the productivity was up to 0.24 g/(h·genzyme), which was 8 times of the highest level as reported before. On this basis, QLlip-9 could be reused to catalyze 8 batches, and the scale-up was achieved step by step in volumes of 300 mL, 1 000 mL and 20 L. Finally, crystals of (R)-1-TIC (e.e.p≥99%) were obtained from concentrated solutions (isolated yield≥80%). This study not only greatly improves the overall catalytic efficiency of the reaction, but also reduces the amounts of enzymes.
