Optical Resolution and Optimization of (R,S)‐Propranolol Using Dehydroabietic Acid Via Diastereomeric Crystallization

Abstract

The optical resolution of (R,S)-propranolol by the diastereomeric crystallization method was successfully performed using dehydroabietic acid (DHAA) as the resolving agent in methanol. The three important parameters: DHAA amount, solvent (methanol) amount, and crystallization temperature of diastereomeric salts were optimized employing the response surface methodology (RSM). When maintaining a lower limit of 95% for the purity of (S)-propranolol, the optimal resolution conditions were a DHAA/(R,S)-propranolol molar ratio of 1.1, solvent/(R,S)-propranolol ratio of 16.2 mL.g(-1) , and crystallization temperature of -5 °C. The desired (S)-propranolol was prepared with 94.8% optical purity and 72.2% yield under the optimal conditions.

Experimental Determination and Computational Prediction of Dehydroabietic Acid Solubility in (−)-α-Pinene + (−)-β-Caryophyllene + P-Cymene System

“…The differential scanning calorimetry (DSC) curve of dehydroabietic acid in its pure form is included in Figure 2. The onset melting temperature of dehydroabietic acid (T m ) is 443.22 K, which is in general agreement with the literature values [15] (442.65 to 443.55 K in the literature). The melting enthalpy (∆ fus H) value for pure dehydroabietic acid is 17.19 kJ/mol as obtained by analyzing the DSC curve with the analysis software.…”

Optical Resolution of Rimantadine

“…For example, the recent asymmetric synthesis of enantiomerically pure 1 [55] involves the reductive amination of the corresponding ketone using rather expensive Ellman’s chiral sulfinimide [56,57,58] as a chiral auxiliary. Accordingly, with the aim to develop an economically sound process, and drawing inspiration from the recent publications of optical resolutions of various chiral amines [59,60,61,62,63] and, in particular, patent data [64], we focused our attention on the optical resolution approach, the science of which is well understood and can be performed on an industrial scale [65,66,67,68].…”

New Opportunities to Improve the Enantiomeric and Diastereomeric Separations

“…During cooling, the reaction mixture was seeded with (R)-ETO.CIN diastereomer, which was then sonicated for 5 min, resulting in (R)-ETO enantiomer mixture of 99% enantiomer purity (Scheme 12). In the case of room temperature stirring, the product was received with low yield and low optical purity (~ee: 40%), which indicates the almost simultaneous crystallization of the two diastereomers [37]. Comparative experiments were executed to determine the effect of the ultrasound treatment compared with conventional stirring.…”