Pyridine → HCID 54490302, compound

Temperature

-15 °C

In a 5-l round bottom flask combine 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-1-hydroxymethyl-2-oxoethyl] amide (100 g, 0.296 mole) and acetonitrile (1.4 l) and cool to -15° C. To the solution is added trifluoroacetic acid (22.8 mL, 0.296 mole) at such a rate as to maintain a temperature below -10° C. The resulting suspension is stirred at -10° C. to -15° C. for 10 minutes, then trifluoroacetic anhydride (125.6 mL, 0.890 mole) is charged at such a rate as to maintain a temperature below -10° C. After the addition is complete, a solution of pyridine (96.0 mL, 1.19 mole) in acetonitrile (50 mL) is added over 30 minutes maintaining a temperature of -15° C. The reaction mixture is warmed to room temperature, water (100 mL) is added then the reaction temperature is increased to 40° C. and the solution is stirred for 1.5 hours. The reaction mixture is concentrated to about 250 mL and a 1:1 mixture of saturated aqueous sodium chloride:water (1.5 l) is added. The aqueous suspension is washed with ethyl acetate (4×800 mL) and to the combined organic extracts is added sodium sulfate (100 g) and Dacro brand activated carbon (100 g). After sitting 1 hour, the slurry is filtered through sintered glass and concentrated to an oil. The oil is dissolved in acetonitrile (200 mL) and saturated aqueous sodium bicarbonate (1.2 l) is added in portions to effect crystallization of the free base. The resulting slurry is cooled to 0° C., the solids are collected by filtration and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl} acetonitrile (85 g, 0.255 mole) as a monohydrate 1H NMR (400 MHz, CDCl3) d 1.91 (m, 2H), 2.25 (m, 2H), 2.47 (m, 2H), 2.70 (m, 1H), 2.85 (m, 3H), 3.55 (s, 2H), 4.68 (d, 2H), 7.03 (t, 2H), 7.58 (q, 2H).

1. customIn a 5-l round bottom flask combine
2. temperatureto maintain a temperature below -10° C
3. temperatureto maintain a temperature below -10° C
4. additionAfter the addition
5. temperatureThe reaction mixture is warmed to room temperature
6. temperaturethe reaction temperature is increased to 40° C.
7. stirringthe solution is stirred for 1.5 hours
8. concentrationThe reaction mixture is concentrated to about 250 mL
9. additiona 1:1 mixture of saturated aqueous sodium chloride
10. additionwater (1.5 l) is added
11. washThe aqueous suspension is washed with ethyl acetate (4×800 mL) and to the combined organic extracts
12. additionis added sodium sulfate (100 g) and Dacro brand activated carbon (100 g)
13. waitAfter sitting 1 hour
14. filtrationthe slurry is filtered through sintered glass
15. concentrationconcentrated to an oil
16. dissolutionThe oil is dissolved in acetonitrile (200 mL)
17. additionsaturated aqueous sodium bicarbonate (1.2 l) is added in portions
18. customcrystallization of the free base
19. temperatureThe resulting slurry is cooled to 0° C.
20. filtrationthe solids are collected by filtration
21. customdried to constant weight

ORD record

ord-314331635e034ca08904d7b976a27924

Source dataset

uspto-grants-2000_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06090825