Impact of Entropic Effects in the Classical Resolution of a 2-Arylpyrrolidine

Abstract

The impact of entropic effects on the classical salt resolution of a 2-arylpyrrolidine is described. We have found that the crystallization of a racemic mixture of the base with tartaric acid led to a salt in which the undesired enantiomer is incorporated into the crystal lattice as a solid solution. The product enantiomer ratio was later determined to be at the thermodynamic well when the racemate is crystallized. In order to circumvent this effect, an efficient two-crystallization resolution was developed. The bulk of the undesired enantiomer is removed in the first crystallization so that the second crystallization can result in material of acceptable optical purity. † This paper is dedicated to the memory of Chris Schmid.

Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals

“…Researchers at Abbott incorporated a Suzuki coupling into the synthesis of optically pure benzoic acid 74 (Scheme ) . 2-Arylpyrrole intermediate 73 was prepared via the coupling of commercially available bromide 71 and Boc-pyrrole-2-boronic acid ( 72 ) in the presence of PdCl 2 (1,1′-di- tert -butylphosphinoferrocene) and a combination of K 2 HPO 4 and K 3 PO 4 in DME/H 2 O/EtOH at rt for 4 h. The mild conditions, including ambient temperature and phosphate buffer, likely minimized decomposition of the boronic acid.…”

Synthesis, Catalytic Activity and Comparative Leaching Studies of Calix[8]arene‐Supported Pd‐NHC Complexes for Suzuki‐Miyaura Cross‐Couplings

“…Finally, the catalysts were engaged in an even more challenging coupling reaction between ethyl 2-fluoro-4-bromobenzoate and N-Boc-2-pyrrolylboronic acid (Tables 7 and SI-6). [21] The nature of the base had to be adjusted to respect the integrity of the functional Table 4. Catalysts activity and Pd contamination for the Suzuki-Miyaura reaction between 2-amino-5-chloropyrazine and phenylboronic acid.…”

“…Finally, the catalysts were engaged in an even more challenging coupling reaction between ethyl 2-fluoro-4-bromobenzoate and N-Boc-2-pyrrolylboronic acid (Tables 7 and SI-6). [21] The nature of the base had to be adjusted to respect the integrity of the functional groups on both substrates. Thus, the use of K 2 CO 3 afforded the best results allowing the use of Cat.…”

Tandem crystallization strategies for resolution of 3,3,3‐trifluorolactic acid [CF3CH(OH)COOH] by chiral benzylamines

“…It is likely that due to entropic factors, upon cooling, anhydrous phase 1 is first formed at a higher temperature. Subsequently, 2 , which having a smaller volume with an extra water is more efficiently packed, is then favoured at lower temperatures closer to ambient.…”