BMS-181168, BMY-21502

2-吡咯利二酮,1-[[1-[2-(三氟甲基)-4-嘧啶酰]-4-哌啶基]-Chemical Name: 1-[2-(Trifluoromethyl)pyrimidin-4-yl]piperidin-4-ylmethyl]pyrrolidin-2-one
CAS No. 123259-91-6
项目整合开发状态: Phase II
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:Synthesis of the intermediate 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (IV) is accomplished by condensation of 3-amino-2-chloropyridine (I) and the anthranilic ester (II) using potassium tert-butoxide as a catalyst.The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid.Treatment of (IV) with chloroacetylchloride in toluene furnishes the corresponding chloroacetamide (V).The diamine part of AF-DX 116 is prepared starting from 2-(hydroxymethyl)piperidine (VI).Reaction with thionylchloride in dichloromethane affords the pipecolylchloride hydrochloride (VII),which is converted with diethylamine to the required 2-[(diethylamino)methyl]piperidine (IX) via nucleophilic ring opening of the intermediate aziridine (VIII).Minor amounts of 3-(diethylamino)hexahydroazepine (X),formed by a side reaction,are separated by thorough fractional distillation of the diamine (IX) and/or recrystallization of its hydrochloride (XI).Coupling of (V) and (XI) in the presence of sodium carbonate yields AF-DX 116 as its free base.

合成路线:Alkylation of 2-pyrrolidinone with 4-chloromethylpyridine and base provides the pyridine (I).Catalytic hydrogenation of (I) with platinum oxide yields the piperidine (II).Condensation of 4-chloro-2-trifluoromethylpyrimidine,which is obtained in two steps from trifluoroacetamidine and the sodium salt of ethyl formylacetate,with (II) then affords BMY-21502.