Hydrochloric Acid → (S)-2-(3,4-Difluorophenylamino)-N-[2-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetamide, trihydrochloride

Participants

Reaction Conditions

Reaction Steps

To a solution of (3,4-difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.200 g) from Example 3b) in dry 1-methyl-2-pyrrolidinone (2 ml) was added N,N-diisopropylethylamine (0.52 ml) followed by methanesulfonyl chloride (0.16 ml) in a single portion. After 3 hours the reaction was poured into ethyl acetate/water. The organic layer was separated and washed with aqueous KHSO4, aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to a pale red oil which was dissolved in 1-methyl-2-pyrrolidinone (8 ml) and N,N-diisopropylethylamine (0.52 ml) and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (0.41 ml) were added, and the reaction heated at 95° C. overnight. After cooling to room temperature, the reaction was poured into ethyl acetate/water. The organic layer was separated and washed with aqueous KHSO4, aqueous K2CO3 and brine, dried (Na2SO4) and concentrated to a pale red oil. Purification by NPHPLC (eluting with 0-25% methanol in dichloromethane) gave a white solid which was dissolved in methanol (2 ml) and HCl (1 ml of a 4M solution in dioxane) added. After 2 hours, the solvent was removed and the residue recrystalised from isopropanol/acetonitrile to give the title compound as a white powder (0.071 g).

Provenance & Evidence