Dutch Resolution of Racemates and the Roles of Solid Solution Formation and Nucleation Inhibition

Abstract

An overview is given of the principles of Pasteur resolutions via separation of diastereomeric salts.Thereafter, primary nucleation processes of (chiral) organic compounds in supersaturated solution are consideredfollowed by crystal growth in the presence of tailor-made additives. A representative example of a DutchResolution is presented, the concept of families of resolving agents is defined and examples are given.The phenomenon of reversed Dutch Resolution, resolution of mixtures of families of racemates, is illustrated.The roles of both solid solution formation and nucleation inhibition in Dutch Resolution are discussed.The work is concluded with the results of a broadly based search for nucleation inhibitors for phenylethylamine as resolving agent. This search can serve as a model for the discovery of nucleation inhibitorsfor other resolving agents. The specific role of bifunctional family members of resolving agents as possiblenucleation inhibitors is also discussed.

Chiral Symmetry Breaking Phenomenon Caused by a Phase Transition

“…The methods for enantiomeric resolution of racemates comprising nonracemizable enantiomers by crystallization are classified into two categories [9]; one is an indirect method using an external chiral element, such as a diastereomeric salt formation followed by fractional crystallization [10][11][12][13] or a diastereoselective host-guest inclusion complexation [14], and the other is a straightforward method to separate enantiomers by crystallization in the absence of an external chiral element. As the typical example of this latter category, well known is the "preferential crystallization" method to resolve a racemic conglomerate composed of a mixture of homochiral R and S crystals, in which by repeating crystallization from the supersaturated solution with the aid of its enantiopure seed crystals the enantiomerically enriched crystals are efficiently deposited in the alternating chirality sense [15][16][17][18].…”

Partial resolution of racemic trans‐4‐[5‐(4‐alkoxyphenyl)‐2,5‐dimethylpyrrolidine‐1‐oxyl‐2‐yl]benzoic acids by the diastereomer method with (R)‐ or (S)‐1‐phenylethylamine

“…As resolving agent candidates for the enantiomeric resolution of the typical carboxylic acid (6)-1j (n 5 13) by the diastereomer method, four commercially available, optically-active amines namely (R)-1-phenylethylamine (2), (S)-1-(1-naphthalenyl)ethylamine (11), (1R,2R)-1,2-diaminocyclohexane (12), and (R)-2-methylpiperazine (13) were examined (Scheme 1). To a saturated ethereal solution of (6)-1j was added 1 equiv of the optically active amine, and the resulting deposited diastereomeric salts were collected and hydrolyzed with aqueous 2 N HCl to give free 1j.…”

“…9 To obtain both (R)-and (S)-3 or -4 efficiently, enantiomeric resolution of any of the racemic intermediates is supposed to be appropriate. Nowadays, diastereoselective enantiomeric resolution methods have significantly advanced; a number of resolving agents are listed 10,11 and the logical improvement and extension for efficient resolution, such as the Dutch resolution method, 12 the dielectrically controlled resolution (DCR) method, 13,14 and the host-guest inclusion complexation method, 15 have emerged. Here we report the successful enantiomeric resolution of a series of racemic trans-4-[5-(4-alkoxyphenyl)-2,5-dimethylpyrrolidine-1-oxyl-2-yl]benzoic acids [(6)-1], which are the key intermediate carboxylic acids for the synthesis of enantiomerically enriched 4, by the conventional diastereomeric salt formation using a chiral amine as the resolving base.…”

Dutch Resolution of a configurationally stable [5]helquat

“…55,56 The use of family of resolving agents for the racemate resolution effectively changes trial-anderror resolution method into an acceptable and almost routine practice. [55][56][57][58][59][60][61][62][63][64][65][66] The extremely high success rate, defined in terms of yield and enantiomeric excess in a first trial, is the most attractive feature of this method. Out of the 1000 tested racemate resolutions, 95% have been reported as successful.…”