Enantioseparation of racemic bupivacaine via ultrasonic-assisted diastereomeric crystallization using 12,14-dinitrodehydroabietic acid

Abstract

12,14-Dinitrodehydroabietic acid (12,14-dinitroDHAA), a chiral acid obtained by the nitration of optical dehydroabietic acid (DHAA), was successfully employed as resolving agent. The resolution of racemic bupivacaine by ultrasonic-assisted diastereomeric crystallization in ethanol was investigated. The results indicated that ultrasonic-assist can well facilitate resolution of (R,S)-bupivacaine and a higher enantiomeric excess (ee) and yield was obtained for (S)-bupivacaine, and while without ultrasound, the ee value decreases by increasing the crystallization time. A Box-Behnken experimental design with four factors (amount of 12,14-dinitroDHAA, ethanol amount, ultrasonic power and crystallization temperature) combined with response surface methodology (RSM) was applied to explore resolution effects. A second-order polynomial equation was adequate to model the relationship between the ee (or yield) and the dependent variables. When maintaining a lower limit of 90% for the yield of (S)-bupivacaine, the optimal resolution conditions by RSM were 12,14-dinitroDHAA/bupivacaine molar ratio of 1.6, solvent/propranolol ratio of 16.5 mL/g, 63.2 W ultrasonic power and crystallization temperature of 0 °C, respectively. Under the optimal conditions, the experimental ee and yield of (S)-bupivacaine were 69.8% and 87.5%.