A process for resolving a compd. in racemic form comprising the following steps is described: (a) reacting an org. acid or base compd. in racemic form with a resolving agent, (b) forming a diastereoisomeric complex of the resolving agent and an enantiomer of interest, (c) sepg. the enantiomer of interest from the obtained diastereoisomer, wherein such a process is characterized in that said resolving agent is a compd. of formula (I; C* = a chiral center; n, p = 0-1; R1 = C1-3 alkyl; R2 = CO2H, NH, NH2, Ph, or CH2OH; or R1, C* and R2 form a nitrogenous five-membered ring; R3 = C:O or CH2; R4 = H or CH2; CR = C6-C12 arom. group optionally substituted with one or more halogens; A = a substituent selected from the group consisting of CH2, SO2 and C:O; with the proviso that when n = 0 and p = 1, R1 = C1-C3 alkyl and R2 = CH2OH, Ph, COOH or R1, C*, N and R4 form a five-membered ring). A diastereoisomeric complex between the resolving agent of formula I and the enantiomer of interest is also described. The process according to the invention allows acid and basic racemic mixts. to be sepd. A group of resolving agents has been identified and synthesized from L-amino acids such as L-alanine, L-valine, and L-proline, whose structure results from the combination of three different structural elements: (a) a chiral center formable from enantiomerically pure compds., which are com. available in both enantiomeric forms and at low costs; (b) a functional group (an acid or a basic group) capable to allow the conjugation with the components of the racemic mixt.; and (c) a group capable of imparting crystallinity and allowing the modulation of the soly. of the diastereoisomeric conjugates. Thus, a soln. of tert-butoxycarbonyl-L-alanine in THF was cooled to 0°, treated sequentially with N-methylmorpholine and tert-Bu chloroformate, stirred at room temp. for 6 h, treated with 1,1'-biphenyl-4-amine, and stirred for one night at room temp. to give 95% [(1S)-1-(1,1'-biphenyl-4-ylcarbamoyl)ethyl]carbamic acid (II). A soln. obtained by adding in portions acetyl chloride to MeOH was cooled 0°, treated with II, heated to reflux in order to bring all components to soln., and then left at room temp. for a night to give, after workup, 95.9% 2-amino-N-(1,1'-biphenyl-4-yl)propionamide (III). A soln. of racemic tetrahydrofuran-2-carboxylic (1 g) in 10 mL Et2O was treated with the amine III (1.15 g) and heated to give a soln., which was slowly left to be cooled. The formed ppt. was filtered and washed by small portions of ether to give 1.4 g (R)-tetrahydrofuran-2-carboxylic acid-III salt in 85% yield. E.e. of the free acid was 95% which is comparable to the optical purity obtained by enzymic resoln.
A process for resolving racemic mixtures and a diastereoisomeric complex of a resolving agent and an enantiomer of interest
FIASCHI, RITA;
2007-01-01
Abstract
A process for resolving a compd. in racemic form comprising the following steps is described: (a) reacting an org. acid or base compd. in racemic form with a resolving agent, (b) forming a diastereoisomeric complex of the resolving agent and an enantiomer of interest, (c) sepg. the enantiomer of interest from the obtained diastereoisomer, wherein such a process is characterized in that said resolving agent is a compd. of formula (I; C* = a chiral center; n, p = 0-1; R1 = C1-3 alkyl; R2 = CO2H, NH, NH2, Ph, or CH2OH; or R1, C* and R2 form a nitrogenous five-membered ring; R3 = C:O or CH2; R4 = H or CH2; CR = C6-C12 arom. group optionally substituted with one or more halogens; A = a substituent selected from the group consisting of CH2, SO2 and C:O; with the proviso that when n = 0 and p = 1, R1 = C1-C3 alkyl and R2 = CH2OH, Ph, COOH or R1, C*, N and R4 form a five-membered ring). A diastereoisomeric complex between the resolving agent of formula I and the enantiomer of interest is also described. The process according to the invention allows acid and basic racemic mixts. to be sepd. A group of resolving agents has been identified and synthesized from L-amino acids such as L-alanine, L-valine, and L-proline, whose structure results from the combination of three different structural elements: (a) a chiral center formable from enantiomerically pure compds., which are com. available in both enantiomeric forms and at low costs; (b) a functional group (an acid or a basic group) capable to allow the conjugation with the components of the racemic mixt.; and (c) a group capable of imparting crystallinity and allowing the modulation of the soly. of the diastereoisomeric conjugates. Thus, a soln. of tert-butoxycarbonyl-L-alanine in THF was cooled to 0°, treated sequentially with N-methylmorpholine and tert-Bu chloroformate, stirred at room temp. for 6 h, treated with 1,1'-biphenyl-4-amine, and stirred for one night at room temp. to give 95% [(1S)-1-(1,1'-biphenyl-4-ylcarbamoyl)ethyl]carbamic acid (II). A soln. obtained by adding in portions acetyl chloride to MeOH was cooled 0°, treated with II, heated to reflux in order to bring all components to soln., and then left at room temp. for a night to give, after workup, 95.9% 2-amino-N-(1,1'-biphenyl-4-yl)propionamide (III). A soln. of racemic tetrahydrofuran-2-carboxylic (1 g) in 10 mL Et2O was treated with the amine III (1.15 g) and heated to give a soln., which was slowly left to be cooled. The formed ppt. was filtered and washed by small portions of ether to give 1.4 g (R)-tetrahydrofuran-2-carboxylic acid-III salt in 85% yield. E.e. of the free acid was 95% which is comparable to the optical purity obtained by enzymic resoln.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
