142921-58-2Relevant articles and documents
Synthesis, characterization and hplc analysis of the (1S,2S,5R)-diastereomer and the enantiomer of the clinical candidate ar-15512
Abás, Sònia,Escolano, Carmen,Galdeano, Carles,Pujol, Eugènia,Rodríguez-Arévalo, Sergio,Vázquez, Santiago
, (2021)
AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.
Synthesis of (Racemization Prone) Optically Active Thiols by SN2 Substitution Using Cesium Thiocarboxylates
Strijtveen, Bert,Kellogg, Richard M.
, p. 3664 - 3671 (2007/10/02)
The cesium salt of thioacetic acid is prepared by treatment with cesium carbonate.This salt has a solubility of about 0.7 M in DMF (even higher in Me2SO) at 50 deg C.The mesylates of (R)-2-octanol, the ethyl ester and N,N-dimethyl amide of (R)-mandelic acid, (S)-ethyl lactate, (S)-methyl 3-phenyllactate, and (S)-diethyl malate underwent clean SN2 substitution in DMF solution.Racemization occured only in the case of the mesylate of ethyl mandelate when allowed to react in DMF, but complete inversion was achieved on use of absolute ethanol as solvent.Hydrolysis or aminolysis is used to deacylate the thiols (except for aliphatic thioacetates, which are deprotected by treatment with lithium aluminum hydride) to afford 2-mercapto esters or amides.Owing to the sensitivity of mercapto-bearing carbon, some racemization (0-20percent depending on the system) occurs during deprotection.An alternate route to the same materials prepared by the cesium thiocarboxylate method involves treatment of the free alcohol with thioacetic acid in the presence of twofold amount of the preformed salt from diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.This method works well except for ethyl mandelate and N,N-dimethylmandelamide.Scale-up of the reaction is difficult, however, owing to the need for a chromatographic separation.Various NMR methods for determining the enantiomeric excesses of the various products are described.Particularly useful for determination of the high enantiomeric excesses is an internal calibration method based on the use of 13C satellite peaks in the presence of a chiral shift reagent.The enantiomeric excesses of the thiols were determined by conversion to the phosphonodithioates followed by measurement of the meso/d,l ratios obtained from 31P NMR spectra.Attempts to hydrolyze 2-acetylthio esters to the free 2-mercapto carboxylic acids lead to 10-40percent racemization depending on the compound.A partial solution to this problem was found by use of optically pure S bromides obtained from diazotation of (S)-alanine, (S)-phenylalanine, and (S)-valine in the presence of bromide.These bromides, on treatment with cesium thiobenzoate, underwent clean SN2 substitution, and debenzoylation could be brought about without significant racemization
