反应详情

The process of the invention for the manufacture of N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfon-amide having the formula I comprises the steps, where in the first step (S)-1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one of formula II and N-(2-aminoethyl)methanesulfonamide of formula III are contacted with trimethylsilyl cyanide in the presence of an agent capable of capturing water molecules, in an organic solvent, followed by adding hydrogen chloride to obtain (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]ethyl]methanesulfon-amide dihydrochloride, in the second step (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]-ethyl]methanesulfonamide dihydrochloride is contacted with 1,1′-carbonyldiimidazole in the presence of a hydrogen chloride acceptor in an organic solvent to obtain (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzo-furo[2,3-a]quinolizine-2-carbonitrile, and in the third step (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzofuro[2,3-a]quinolizine-2-carbonitrile is contacted with hydrogen in the presence of Raney nickel catalyst and sodium methoxide or potassium tert-butoxide in methanol solvent to yield N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexa-hydrospiro-[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfonamide.