4-Piperidinecarboxylic acid → 6-Fluoro-2-(piperidin-4-yl)-1H-benzimidazole
Reaction equation
[NH:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]2[NH:17][C:7]([CH:4]3[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)=[N:18][C:13]=2[CH:12]=1Participants
3
Conditions
- Temperature
- 180 °C
Procedure
To a mixture of piperidine-4-carboxylic acid (18.33 g, 0.14 mol) and 4-fluoro-benzene-1,2-diamine (18.01 g, 0.14 mol) was added polyphosphoric acid (138.39 g) and the mixture heated at 180° C. (internal temperature) for 2 h 45 minutes. The reaction mixture was cooled, reheated to 80° C. and the reaction was quenched by cautious addition to water (300 mL). The mixture was made basic (pH 8) by the addition of concentrated aqueous NaOH. The aqueous phase was extracted sequentially with 3:7 isopropanol:CH2Cl2 (2×200 mL) and CH2Cl2 (150 mL) and the combined organic phase dried (Na2SO4) and concentrated. The aqueous phase was reextracted with n-butanol (2×200 mL), the organic layer dried (Na2SO4) and concentrated. The crude product was stirred in diethyl ether, filtered and dried to give crude 5-fluoro-2-piperidin-4-yl-1H-benzoimidazole. Further purification was achieved by preparing the hydrochloride salt.