Tandem crystallization strategies for resolution of 3,3,3‐trifluorolactic acid [CF3CH(OH)COOH] by chiral benzylamines

Resolution of rac‐3,3,3‐trifluorolactic acid by diastereomeric salt formation was reinvestigated. The use of (S)‐1‐phenylethylamine gives coprecipitation of two diastereomeric phases, 1 (S)‐NH₃CH(CH₃)Ph](S)‐CF₃CH(OH)COO] and 2 (S)‐NH₃CH(CH₃)Ph](R)‐CF₃CH(OH)COO]·H₂O. Pure phase 1 may be obtained using molecular sieves as desiccants. Resolution by (S,S)‐2‐amino‐1‐phenylpropan‐1,3‐diol gives monoclinic (S,S)‐NH₃CH(CH₂OH)CHOHPh] (R)‐CF₃CH(OH)‐COO] 3 with minor (S)‐3,3,3‐trifluorolactate contamination, which is precluded in the recrystallized orthorhombic form 4 . A new resolution using inexpensive phenylglycinol gives pure phase 5 (S)‐NH₃CH(CH₂OH)Ph] (S)‐CF₃CH(OH)COO] in 76% yield, 94% ee in a single step, in preference to its (S)‐(R) diastereomer 6 . Overall efficient resolution for both enantiomers of the trifluorolactic acid (each ca. 70% yield, 99% ee) may be achieved by various two‐step “tandem” crystallizations, involving direct addition of either water or a second base to the filtrate from the initial reaction.