AR-R25859

Chemical Name: N-[1-Azabicyclo[2.2.2]oct-3(R)-yl]-3-(2-thienyl)-2-propenamide; N-[Quinuclidin-3(R)-yl]-3-(2-thienyl)-2-propenamide
CAS No. 340682-16-8 (E-isomer)
项目整合开发状态: Biological Testing
项目研究机构: AstraZeneca (Originator)
合成路线:The reaction of 3-bromophenol (I) with 2,2,2-trichloro-1,1-dimethylethanol (II) by means of NaOH in acetone gives 2-(3-bromophenoxy)-2-methylpropionic acid (III),which is esterified with isobutylene and H2SO4,yielding the corresponding tert-butyl ester (IV).The condensation of (IV) with N-allylphthalimide (V) by means of Pd(OAc)2,tri(o-tolyl)phosphine and DIEA in acetonitrile,followed by hydrogenation with H2 over Pd/C,affords the adduct (VI).The reaction of (VI) with hydrazine in refluxing ethanol cleaves the phthalimido group to provide the amino derivative (VII),which is treated with 3,5-dinitrophenylsulfonyl chloride (VIII) and TEA in dichloromethane to give the sulfonamide (IX).The cleavage of the tert-butyl ester group of (IX) with TFA in dichloromethane yields the carboxylic acid (X),which is esterified with SASRIN resin (XI) by means of 1,3-dimethyl-2-fluoro p-toluenesulfonate (DMFPT) in dichloromethane to afford the resin-anchored polyester (XII).The N-alkylation of (XII) with 2,4-bis(trifluoromethyl)benzyl alcohol (XIII) by means of PPh3 and DIAD in THF provides the disubstituted sulfonamide (XIV).The cleavage of the sulfonamido group of (XIV) by means of mercaptoacetic acid and TEA in dichloromethane gives the resin-bound secondary amine (XV),which is acylated with 2-[4-(trifluoromethyl)phenyl]acetic acid (XVI) by means of HATU and DIEA to yield the acetamide precursor (XVII).Finally,the title product is cleaved from the resin (XVII) by treatment with TFA in dichloromethane.