Lusaperidone, R-107474

2-甲基-3-[2-(1,2,3,4-四氢苯并呋喃并[3,2-c]吡啶-2-基)乙基]-4H-吡啶并[1,2-A]嘧啶-4-酮Chemical Name: 2-Methyl-3-[2-(1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one
CAS No. 214548-46-6
项目整合开发状态: Phase II
项目研究机构: Janssen (Originator)
合成路线:The intermediate 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (VIII) has been obtained by three different ways:1) The cyclization of 2-hdroxybenzaldehyde (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives ethyl benzofuran-2-carboxylate (III),which is reduced with LiAlH4 in refluxing THF to the carbinol (IV).The reaction of (IV) with acetone cyanohydrin (V),PPh3 and DEAD yields the acetonitrile (VI),which is reduced with H2 over Raney-Ni to afford the ethylamine (VII).Finally,this compound is cyclized with formaldehyde in refluxing water to provide the desired intermediate (VIII).2) The intermediate ethyl benzofuran-2-carboxylate (III),is hydrolyzed with NaOH to the corresponding free acid (IX),which is decarboxylated with Cu at 240 C in quinoline to yield benzofuran (X).The reaction of (X) with oxirane (XI) by means of n-BuLi in ethyl ether affords 2-(2-benzofuryl)ethanol (XII),which is treated first with MsCl and TEA,and then with NaI in refluxing acetone to provide the 2-(2-iodoethyl)benzofuran (XIII).The reaction of (XIII) with hexamethylenetetramine (HMT) gives the adduct (XIV),which is finally cyclized to the target intermediate (VIII) by means of HCl in refluxing ethanol.3) The target intermediate (VIII) can also be obtained by cyclization of O-phenylhydroxylamine (XV) with 4-piperidone (XVI) in refluxing isopropanol.Finally,intermediate (VIII) is condensed with 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine (XVII) by means of Na2CO3 and KI in a refluxing organic solvent such as 4-methyl-2-pentanone.