4-Piperidinecarboxylic acid → 6-Fluoro-2-(piperidin-4-yl)-1H-benzimidazole

Temperature

180 °C

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.

1. temperatureThe reaction mixture was cooled
2. customreheated to 80° C.
3. customthe reaction was quenched by cautious addition to water (300 mL)
4. additionby the addition of concentrated aqueous NaOH
5. extractionThe aqueous phase was extracted sequentially with 3:7 isopropanol
6. dry with materialCH2Cl2 (2×200 mL) and CH2Cl2 (150 mL) and the combined organic phase dried (Na2SO4)
7. concentrationconcentrated
8. dry with materialthe organic layer dried (Na2SO4)
9. concentrationconcentrated
10. filtrationfiltered
11. customdried

ORD record

ord-ae6b75d287f440d0a4a8949b427bd857

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08957064B2