Developing Processes for Crystallization-Induced Asymmetric Transformation

Abstract

Crystallization-induced dynamic resolution (CIDR) is an adaptation of dynamic resolution, a process that can afford in principle a quantitative yield of chiral product from a racemic starting material through in situ resolution. Crystallizationinduced asymmetric transformation (CIAT) includes CIDR and the preparation of diastereomers and olefins that are driven by crystallization. The history of CIAT and CIDR processes is reviewed, along with key observations made by researchers. Recommendations are made for identifying opportunities for and developing CIAT processes.

Design, Preparation, and Implementation of an Imidazole-Based Chiral Biaryl P,N-Ligand for Asymmetric Catalysis

“…To achieve this, rac-7 was treated with complex 14 and KPF 6 in refluxing acetone for 24 h to provide 15 in 81% yield as a single diastereomer whose structure was confirmed by X-ray crystallography (Scheme 2). 19,20 The free ligand was then obtained in high yield and 98% ee after treatment with dppe. 21 Interestingly, the inclusion of KPF 6 is vital to the success of the reaction, as two non-interconverting diastereomers are observed in the absence of this additive.…”

Discovery Process and Characterization of Novel Carbohydrazide Derivatives as Potent and Selective GHSR1a Antagonists

“…3-Pyridinecarbaldehyde 12 j was subjected to the Strecker reaction in the presence of chiral (8aR)-octahydropyrrolo[1,2-a]pyrazine (19), [17] the resulting cyano derivative 21 was hydrolyzed to the corresponding amide 22, which was subsequently transformed into the bis-N-Boc derivative 23 that was not isolated but used immediately and without further purification for the final coupling with 3,5-bistrifluoromethylphenylhydrazine to give enantiomerically pure desired compound 18 a (d2), obtained after precipitation from the reaction mixture. Notably, the other isomer, 18 a (d1), present as the major component in the mother liquors, could be converted into the desired diastereoisomer by crystallization-induced asymmetric transformation (CIAT), [18] mediated by 1,4-diazabicyclo[2.2.2]octane (DABCO) in diisopropyl ether (step d in Scheme 6).…”

A practical synthesis of enantiopure β-methyltryptophan ethyl ester for a preparation of diabetes drug

“…We have focused our attention on the development of an efficient and facile synthesis of optically active b-methyltryptophan ethyl ester (b-MeTrp-OEt, 2) as a key-step of a manufacturing process for 1. We investigated a straightforward route to (2R,3S)-2 including two chirality control processes: crystallization-induced diastereomer transformation (CIDT), which is a hybrid process involving selective crystallization and in situ epimerization, 24,25 and optical resolution via diastereomeric salt formation. The drug candidate 1 contains an unsymmetrical urea structure with two chiral centers derived from 2.…”