BMS-181101

Chemical Name: 1-[3-(5-Fluoro-1H-indol-3-yl)propyl]-4-(5-methoxypyrimidin-4-yl)piperazine; 5-Fluoro-3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1H-indole
CAS No. 141071-67-2
项目整合开发状态: Phase II
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:The cyclization of dimethyl 2-methoxymalonate (I) with formamidine (II) by means of sodium methoxide in methanol gives the dihydroxypyrimidine (III),which by reaction with POCl3 is converted into the dichloropyrimidine (IV).The condensation of (IV) with 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) by means of DIPEA in refluxing acetonitrile affords intermediate (VI),which is finally dechlorinated by hydrogenation with H2 over Pd/C in aqueous ethanol.

合成路线:The target compound can also be obtained by condensation of 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) with 4-chloro-5-methoxypyrimidine (VII) by means of K2CO3 in toluene/ethyl acetate.

合成路线:The intermediate 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) has been obtained as follows:a) The condensation of 5-fluoro-1H-indole (VIII) with acrylic acid (IX) by means of acetic anhydride gives 3-(1H-indol-5-yl)propionic acid (X),which is reduced with LiAlH4 to 3-(1H-indol-5-yl)-1-propanol (XI).The tosylation of (XI) with tosyl chloride yields the tosylate (XII),which is condensed with 1-benzylpiperazine (XIII) in refluxing butyl acetate affording 3-[3-(4-benzylpiperazin-1-yl)propyl]-5-fluoro-1H-indole (XIV).Finally,this compound is debenzylated by hydrogenation with H2 over Pd/C yielding the target intermediate (V).b) The tosylate intermediate (XII) can also be condensed with ethyl piperazine-1-carboxylate (XVII) in refluxing butyl acetate giving 4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine-1-carboxylic acid ethyl ester (XVIII),which is then decarboxylated with NaOH to the target intermediate (V).The intermediate 3-(1H-indol-5-yl)-1-propanol (XI) can also be obtained by direct cyclization of 4-fluorophenylhydrazine (XV) with dihydropyran (XVI) in hot propyleneglycol.