RESUMEN
Flow chemistry was initially used for speed to early phase material delivery in the development laboratories, scaling up chemical transformations that we would not or could not scale up batch for safety reasons. Some early examples included a Newman Kwart Rearrangement, Claisen rearrangement, hydroformylation, and thermal imidazole cyclization. Next, flow chemistry was used to enable safe scale up of hazardous chemistries to manufacturing plants. Examples included high pressure hydrogenation, aerobic oxidation, and Grignard formation reactions. More recently, flow chemistry was used in Small Volume Continuous (SVC) processes, where highly potent oncolytic molecules were produced by fully continuous processes at about 10 kg/day including reaction, extraction, distillation, and crystallization, using disposable equipment contained in fume hoods.
RESUMEN
An optimized route to enantiopure tetra-carboxylic acid and tetra-carboxamide bis(diazaphospholane) ligands that obviates chromatographic purification is presented. This synthesis, which is demonstrated on 15 and 100 g scales, features a scalable classical resolution of tetra-carboxylic acid enantiomers with recycling of the resolving agent. When paired with a rhodium metal center, these bis(diazaphospholane) ligands are highly active and selective in asymmetric hydroformylation applications.
RESUMEN
A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
Asunto(s)
Benzopiranos/síntesis química , Antagonistas de Estrógenos/síntesis química , Sofocos/tratamiento farmacológico , Naftalenos/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Adenocarcinoma , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Densidad Ósea/efectos de los fármacos , Neoplasias de la Mama , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colesterol/sangre , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Morfina/farmacología , Naftalenos/química , Naftalenos/farmacología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Estereoisomerismo , Neoplasias Uterinas , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
The asymmetric hydrogenation of tetrasubstituted α,ß-unsaturated ketones has been accomplished using an in situ formed rhodium-Josiphos catalyst. The reaction is enhanced by addition of catalytic zinc(II) triflate, which significantly improves turnover frequency while suppressing epimerization of the products.