Towards Diastereomeric Pure Salts with Antisolvent Methods

Abstract

Chiral molecules, especially enantiomers and diastereomers of purity > 99 %, present a significant market share within the chemical, pharmaceutical, and flavor industries. Antisolvent precipitations, both batch and semicontinuous operations to serve the current trends in flow chemistry were demonstrated to be environmentally benign and efficient tools in achieving high optical purities. Although salts are known to be insoluble in supercritical CO 2 , instabilities of the nascent salts were detected and applied for increasing efficiency. Diastereomeric excess values of the crystalline products exceeded 99 % in maximum of three consecutive steps both by repeated resolution with half molar equivalent of the amine to the acid and by direct recrystallization of the salts.

Gas antisolvent fractionation based optical resolution of ibuprofen with enantiopure phenylglycinol

“…The amount of diastereomeric salt used to prepare the organic solution was set by changing the amount of racemic ibuprofen and (S)-phenylglycinol while the amount of methanol was kept constant. The mass of the precipitated salt is determined either by the apparent solubility of the salt, or as reported in previous papers [32] [46], by the dissociation of the salts. Figure 3.…”

Hatékonyságnövelés szub- és szuperkritikus oldószerekkel

“…Más szóval a diasztereomer sóképzési reakció lejátszódhat szuperkritikus szén-dioxid oldószerben is. A különbözõ rendszereken [17][18][19][20] végzett részletes vizsgálatokból arra következtetésre jutottunk, hogy ha az egyik reagens jól oldódik szén-dioxidban (>1 tömeg%) a másik akárcsak kismértékben, de kimutathatóan oldódik (>0,05 tömeg%) akkor a diasztereomer sóképzési reakció lejátszódik, bár ettõl még nem szükségszerûen enantioszelektív. Amennyiben az egyik reagens oldhatatlanak tekinthetõ, akkor a reakció megvalósítható idõtartományon belül (<1 hét) nem játszódik le jó konverzióval.…”

“…Enantioselective enzyme catalyzed kinetic resolutions [21][22] and partial diastereomeric salt formation based optical resolutions [17][18][19][20] are possible and in some cases are efficient in supercritical carbon dioxide. While enantioselectivities and reaction rate might be increased by working at the optimal operational parameters, the major advantage of allying supercritical fluids is the possibility of coupling the reaction with a selective separation as supercritical fluid extraction followed by sequential pressure drop based recovery of the solutes.…”

Gas Antisolvent Fractionation: A New Approach for the Optical Resolution of 4-chloromandelic Acid

“…Carbon dioxide-involving experiments have even been conducted using the supercritical fluid as an antisolvent and as a reaction medium in diastereomeric salt formation as well [14][15][16][17][18][19]. Antisolvent methods have been studied in the production of enantiomerically pure compounds too [6,14,[20][21][22]. Also, supercritical carbon dioxide was used as the reaction medium of enzymatic kinetic resolutions [23].…”