Acetic Acid → tert-Butyl 4-[4-(4-fluorophenyl)-2-methyl-5-pyrimidin-4-yl-1H-imidazol-1-yl]piperidine-1-carboxylate

Temperature

37.5 °C

According to the method of J. A. Murry et al., J. Am. Chem. Soc. 2001, 123, 9696-9697, N-{(4-fluorophenyl)[(4-methylphenyl)sulfonyl]methyl}acetamide (C28) (250 mg, 0.778 mmol) and 5-(2-hydroxyethyl)-3,4-dimethyl-1,3-thiazol-3-ium iodide (44.5 mg, 0.156 mmol) were combined, and the reaction flask was evacuated and refilled with nitrogen gas twice. Dichloromethane (4 mL) was added, followed by pyrimidine-4-carbaldehyde (92.5 mg, 0.856 mmol), and the reaction mixture was heated to 35-40° C., then treated with triethylamine (1.63 mL, 11.7 mmol); the reaction was stirred at 35° C. for 1 hour, then cooled to room temperature. Aliquot: LCMS m/z 274.5 [(M+1) for N-[1-(4-fluorophenyl)-2-oxo-2-pyrimidin-4-ylethyl]acetamide (C29)]. After 2 hours at room temperature, the mixture was concentrated in vacuo, dissolved in ethanol (4 mL) and treated with acetic acid (0.22 mL, 3.8 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (358 mg, 1.79 mmol). The reaction was heated to reflux for 3 hours, then concentrated under reduced pressure and diluted with ethyl acetate and aqueous sodium bicarbonate solution until the mixture was basic. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (Eluant: 5% methanol in ethyl acetate) provided the product. Yield: 60 mg, 0.14 mmol, 18%. LCMS m/z 438.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.95-2.00 (m, 2H), 2.12-2.23 (m, 2H), 2.61 (s, 3H), 2.68-2.77 (m, 2H), 4.21-4.33 (m, 2H), 4.65 (tt, J=12.4, 3.9 Hz, 1H), 6.97 (dd, J=8.7, 8.7 Hz, 2H), 7.12 (dd, J=5.2, 1.4 Hz, 1H), 7.29 (dd, J=8.8, 5.5 Hz, 2H), 8.54 (d, J=5.3 Hz, 1H), 9.27 (d, J=1.3 Hz, 1H).

1. customthe reaction flask was evacuated
2. additionrefilled with nitrogen gas twice
3. additionDichloromethane (4 mL) was added
4. temperaturecooled to room temperature
5. waitAfter 2 hours at room temperature
6. concentrationthe mixture was concentrated in vacuo
7. dissolutiondissolved in ethanol (4 mL)
8. temperatureThe reaction was heated
9. temperatureto reflux for 3 hours
10. concentrationconcentrated under reduced pressure
11. additiondiluted with ethyl acetate and aqueous sodium bicarbonate solution until the mixture
12. extractionThe mixture was extracted with ethyl acetate
13. dry with materialthe combined organic layers were dried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customPurification of the residue by silica gel chromatography (Eluant: 5% methanol in ethyl acetate)
17. customprovided the product

ORD record

ord-1a94c17c754549529d409ec92763784f

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08518944B2