Napitane mesilate, ABT-200, A-75200

萘吡坦 Chemical Name: (?-1-[5,6-(Methylenedioxy)-1,2,3,4-tetrahydronaphth-1(R*)-ylmethyl]-3(R*)-phenylpyrrolidine methanesulfonate; (?-3(R*)-Phenyl-1-[6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6(R*)-ylmethyl]pyrrolidine methanesulfonate
CAS No. 149189-73-1, 148152-63-0 (free base), 125067-61-0 (undefined stereochem.)
项目整合开发状态: Phase II
项目研究机构: Abbott (Originator)
合成路线:This compound has been obtained by several different ways:1) The reaction of 6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-one (I) with trimethylsilyl cyanide gives 8,9-dihydronaphtho[1,2-d][1,3]dioxole-6-carbonitrile (II),which is hydrogenated with NaBH4 and hydrolyzed with KOH yielding the carboxylic acid (III).The condensation of (III) with 3-phenylpyrrolidine (IV) by means of DCC in THF affords the acylated pyrrolidine (V),which is reduced with BH3 in THF giving intermediate (VI) as a mixture of the cis and trans racemic diastereomers.Finally,the reaction of this mixture with methanesulfonic acid yields the corresponding mixture of mesylates that is separated by crystallization to afford the target cis racemate.2) The reduction of carbonitrile (II) with H2 over Raney-Ni gives the corresponding amine (VII),which is cyclized with 2-phenylsuccinic anhydride (VIII) to yield the succinamic acid derivative (IX).The cyclization of (IX) by means of acetyl chloride affords the succinimide (X) as a mixture of the cis and trans racemic diastereomers,which are separated by crystallization giving the cis racemate (cis)(X).Finally,this racemate is reduced with BH3.THF or BH3.Dimethyl sulfide and treated with methanesulfonic acid to afford the target compound.3) The cyclization of amine (VII) with the dimesylate (XI) by means of DIEA in ethanol gives also the previously described mixture of the cis and trans racemic diastereomers (VI).

合成路线:The reaction of 6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-one (I) with nitromethane by means of butylamine in refluxing toluene/methylcyclohexane/acetic acid gives the nitromethyl derivative (XIII),which is reduced with H2 over Pd/C in methanol to yield the previously described amine (VII).Amine (VII) can be condensed with 2-phenylsuccinic acid by means of acetyl chloride in refluxing xylene yielding directly the previously reported succinimide (X) as a mixture of the cis and trans racemic diastereomers.