Study On Selective Separation Of Enantiomers Of Halogenated Mandelic Acid

In this paper,several halogenated mandelic acids were separated by high performance liquid chromatography(HPLC),diastereomeric salt formation and co-crystal resolution.Firstly,the enantiomers of mandelic acid(MA),2-chloromandelic acid(2-ClMA),3-chloromandelic acid(3-ClMA),4-chloromandelic acid(4-ClMA),4-bromomandelic acid(4-BrMA)and 4-fluoromandelic acid(4-FMA)were separated by HPLC using L-leucine as a chiral additive.The law of resolution of racemic 3-chloromandelic acid((R,S)-3-ClMA)by diastereomer salt formation using threo-(1S,2S)-2-amino-1-p-nitrophenyl-1,3-propanediol((S)-SA)as a resolving agent was studied emphatically,and the optimal conditions were determined.The efficiency of resolution was up to 93.3%.At the same time,(R)-SA resolved(R,S)-2-ClMA and(R,S)-4-ClMA to obtain less soluble salts(R)-2-ClMA·(R)-SA and(R)-4-ClMA·(R)-SA,respectively,but resolved(R,S)-3-ClMA to obtain less soluble salt(S)-3-ClMA·(R)-SA,which shows that meta-chlorine substituted benzene ring has a special law.(R)-α-phenylethylamine((R)-PEA)and(R)-N-Benzyl phenethylamine((R)-BPA)resolved(R,S)-3-ClMA to obtain less soluble salts(R)-3-ClMA·(R)-PEA and(R)-3-ClMA·(R)-BPA,respectively.The crystal structures of less soluble salts(R)-3-ClMA·(S)-SA,(R)-3-ClMA·(R)-PEA and(R)-3-ClMA·(R)-BPA were studied to reveal the resolution law.Finally,the law of co-crystal resolution of(R,S)-2-ClMA,(R,S)-3-ClMA,(R,S)-4-ClMA,(R,S)-4-BrMA and(R,S)-4-FMA by levetiracetam(LEV)was studied.It was found that LEV can be used as a co-crystal resolving agent to resolve the above halogenated mandelic acid.Taking(R,S)-3-ClMA as an example,the factors affecting co-crystal resolution were investigated:equilibrium time,molar ratio,the amount solvent and cooling temperature.The efficiency of resolution was as high as 94.3%.