RS-100329

Chemical Name: 5-Methyl-3-[3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl]propyl]pyrimidine-2,4(1H,3H)-dione hydrochloride
CAS No. 186386-15-2 (as dihydrochloride)
项目整合开发状态: Preclinical
项目研究机构: Roche (Originator)
合成路线:The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III),which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV).The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI),which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII).Finally,this compound is deprotected by hydrogenation with ammonium formate and Pd/C.The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X),which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).

合成路线:The intermediate arylpiperazine (VI) was prepared as follows: Reaction of 2,4-difluoronitrobenzene (I) with trifluoroethanol (II) in the presence of potassium tert-butoxide yielded the trifluoroethyl ether (III).After catalytic hydrogenation of the nitro group of (III),the resultant aniline (IV) was cyclized with bis(2-chloroethyl) amine hydrochloride (V) in a refluxing mixture of o-dichlorobenzene and n-hexanol to afford the target piperazine (VI).

合成路线:5-Methyluracil (VII) was protected with SEM-Cl (VIII) to yield the 1-SEM derivative (IX),which was subsequently alkylated with 1-bromo-3-chloropropane (X) under phase-transfer conditions to provide chloride (XI).Alkylation of piperazine (VI) with chloride (XI) in the presence of NaI and K2CO3 furnished adduct (XII).The title compound was then obtained by deprotection of (XII) upon treatment with tetrabutylammonium fluoride in THF.