S-31411(racemate), S-32504

Chemical Name: (+)-(4aR,10bR)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-carboxamide
CAS No. 220932-72-9
项目整合开发状态: Preclinical
项目研究机构: Servier (Originator)
合成路线:Nitrosation of 7-methoxy-2-tetralone (I) using isoamyl nitrite and potassium tert-butoxide provided the oximino ketone (II).Catalytic hydrogenation of the oxime function of (II) in the presence of propionic anhydride gave rise to the propionamide (III).Ketone reduction by means of NaBH4 produced a mixture of cis- and trans-hydroxy amides from which the pure trans-isomer (IV) was isolated after two recrystallizations from EtOAc.The amide function of (IV) was subsequently reduced with LiAlH-4 to the N-propyl amine (V).Acylation of amino alcohol (V) with chloroacetyl chloride (VI) afforded the corresponding chloroacetamido alcohol (VII),which was further cyclized to compound (VIII) upon treatment with NaH.The lactam carbonyl group of (VIII) was then reduced with borane-dimethyl sulfide complex to the cyclic amine (IX).Methyl ether cleavage in (IX) to produce phenol (X) was then achieved by heating with pyridine hydrochloride (1).Phenol (X) was converted to the aryl triflate (XI) by treatment with trifluoromethanesulfonic anhydride.Displacement of the triflate group of (XI) with zinc cyanide in the presence of Pd catalyst furnished nitrile (XII).Partial hydrolysis of the nitrile (XII) under basic conditions produced the corresponding racemic amide.The title dextro-enantiomer was then isolated by preparative chiral HPLC.