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

Abstract

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.

Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam

“…Up to now, formation of diastereomeric salt [23][24][25][26][27] and chiral chromatography [28][29][30][31] are two commonly applied chiral resolution methods in industry. For those compounds of interest that are easy to form salts, the formation of diastereomeric salt is the most suitable method, as a chiral resolving agent can form a pair of diastereomer salts with two enantiomers that show difference in their physical properties, promoting the success of the resolution [32].…”

Chiral anionic layers in tartramide spiroborate salts and variable solvation for [NR 4][B(TarNH2)2] (R = Et, Pr or Bu)

“…Spiroborate anions (Vogels & Westcott, 2011) may have application as bulky noncoordinating counter-ions for crystallization (Clegg et al, 1998) or resolution in the case of chiral spiroborate anions (Periasamy et al, 1999;Loewer et al, 2011). The use of diastereomeric salts for resolution is a classical method still of much value and for which modern X-ray diffractometry can shed new insights (Kellogg, 2017;Wong et al, , 2019. One example of this we reported is the chiral spiroborate anion bis(mandelato)borate, [B(R-Man) 2 ] À , which can be used for the efficient resolution of a wide range of racemic cations (Wong et al, 2015).…”