Isopropyl Acetate → 1-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic Acid

Temperature

5 °C

A reactor was charged with 1,1,-cyclopropanedicarboxylic acid (28.3 Kg, 218 mol) and tetrahydrofuran (177 Kg) and stirred with cooling to 5° C. The reactor was charged with triethylamine (22.0 Kg, 217 mol) at a rate to maintain reaction at <10° C.; the line was rinsed with 2 Kg of THF and stirring was continued at <10° C. for 30 min. The reactor was charged with thionyl chloride (25.9 Kg, 217 mol) and the line was rinsed with an additional 2 Kg of THF and stirring was continued at <10° C. for 2 h. The reactor was charged with a solution of 4-fluoroaniline (26.6 Kg, 239 mol) in THF (70.8 Kg) and allowed to stir at <10° C. for approximately 10 h. The reactor was then charged with isopropyl acetate (246 Kg) followed by a solution of 4 wt % NaOH in water (146 Kg) and stirred for 15 min. The lower aqueous layer was drained and the organic layer washed with water. The lower aqueous layer was drained again and the organic layer washed with a solution of 20 wt % sodium chloride (141.5 Kg). The aqueous layer was drained and the organic layer distilled in vacuo to approximately 110 L. The product was treated with heptane (192 Kg) and the contents were cooled and stirred at 20° C. for 3 h. The resulting solids were filtered and washed with heptane (113 Kg) to provide crude 1-{[(4-fluorophenyl)amino]carbonyl}cyclopropanecarboxylic acid (35.5 Kg). A glass column packed with 1 Kg sand was filled with 63-200 mesh silica gel (17 Kg) and methanol (80 Kg). The crude product was dissolved in methanol (283 Kg) and passed through the silica gel bed collecting the UV active eluent. Remaining product was flushed off the silica gel with additional methanol (25 Kg). The combined fractions were stirred in a vessel and treated with water (340 Kg); the contents were stirred at 20° C. for approximately 30 min.

1. additionA reactor was charged with 1,1
2. temperatureto maintain
3. customreaction at <10° C.
4. washthe line was rinsed with 2 Kg of THF
5. washthe line was rinsed with an additional 2 Kg of THF
6. stirringstirring
7. waitwas continued at <10° C. for 2 h
8. stirringto stir at <10° C. for approximately 10 h
9. stirringstirred for 15 min
10. washthe organic layer washed with water
11. washthe organic layer washed with a solution of 20 wt % sodium chloride (141.5 Kg)
12. distillationthe organic layer distilled in vacuo to approximately 110 L
13. additionThe product was treated with heptane (192 Kg)
14. temperaturethe contents were cooled
15. stirringstirred at 20° C. for 3 h
16. filtrationThe resulting solids were filtered
17. washwashed with heptane (113 Kg)

ORD record

ord-0ee25a4963e940e6a11d17ca96534c2d

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08314232B2