RESUMEN
The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCîCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCîCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCîCCH(OH)CH3 and TMSCîCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner.
Asunto(s)
Alquinos/química , Cobre/química , Flurbiprofeno/síntesis química , Indicadores y Reactivos/química , Propanoles/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Catálisis , Flurbiprofeno/química , Flurbiprofeno/farmacología , EstereoisomerismoRESUMEN
The regioselectivity (r.s.) and enantiospecificity (e.s.) of the substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts were studied. First, the picolinate, 3-methylpicolinate, and diethylphosphonate derivatives of Ph(CH2 )2 CH(OH)C≡CTMS were reacted with PhMgBr/CuCN in ratios of 2.5:2.7-2.5:0.25. The use of 2.5:0.25 ratio in THF/DME (6:1) at 0 °C for 1â h afforded the α-substitution product from the phosphate with ≥98 % r.s. and 99 % e.s. CuBrâ Me2 S gave similar selectivity. The reaction system was then applied to phosphates derived from R1 CH(OH)C≡CR2 and ArMgBr to obtain synthetically sufficient r.s. and e.s. values with R2 =TMS, Ph, whereas iPr was borderline in terms of size as an R1 substituent. The presence of a substituent at the o-position of Ar marginally affected the selectivity. We also found that the use of PhMgBr/Cu(acac)2 in a 2:1 ratio in THF produced the γ-substitution products (allenes) with high r.s. and e.s.