Ammonium Acetate → HCID 178451792, compound

Temperature

140 °C

Combine 4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (100 g, 231 mmol), ammonium acetate (178.3 g; 2.31 mol, 10 eq), and methanol (1000 mL). The reactor used for this transformation is a coiled 1/16″ I.D. stainless steel tube (total internal volume of tubing in oven is 541 mol). Heat the reactor in an oven to 140° C. Control the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point. Pump the solution prepared above continuously through the heated tube under pressure at 6.01 mL/min (affording a total residence time in the heated tube of 90 minutes). As the solution exits the oven, cool it back to 20° C. in a tube-in-tube heat exchanger. Once the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL. Add ACN (200 mL) and heat the solution to 50° C. Add water (700 mL) drop wise with seeding over 2 hours to crystallize the product. Cool the resulting slurry to 20° C. and filter the solid, then wash with 20% MeOH in water (2×200 mL). Dry the resulting solid under vacuum at 50° C. Re-slurry the solid in ACN (200 mL) at 50° C. Cool the slurry to ambient temperature, filter the solid and wash with ACN (100 mL) to afford 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (54.43 g, 132 mmol, 57%) as an off white solid. 1H NMR (300 MHz, DMSO): 12.01 (s, 1H), 8.08-8.04 (m, 2H), 7.70 (d, J=1.4 Hz, 1H), 7.49-7.43 (m, 1H), 3.99 (d, J=12.6 Hz, 2H), 2.92-2.85 (m, 3H), 1.91-1.87 (m, 2H), 1.64-1.51 (m, 2H), 1.41 (s, 9H).

1. temperatureControl the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point
2. customprepared above continuously through the heated tube under pressure at 6.01 mL/min (
3. customaffording a total residence time in the heated tube of 90 minutes)
4. temperaturecool it back to 20° C. in a tube-in-tube
5. temperatureheat exchanger
6. concentrationOnce the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL
7. temperatureAdd ACN (200 mL) and heat the solution to 50° C
8. customto crystallize the product
9. temperatureCool the resulting slurry to 20° C.
10. filtrationfilter the solid
11. washwash with 20% MeOH in water (2×200 mL)
12. customDry the resulting solid under vacuum at 50° C
13. customat 50° C
14. temperatureCool the slurry to ambient temperature
15. filtrationfilter the solid
16. washwash with ACN (100 mL)

ORD record

ord-a17f2126a18145bba1c69cfaa7c4b4a0

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08148387B2