Diisopropylamine → 3-(Trifluoromethyl)-1,2-oxazol-5-amine

Temperature

0 °C

A 15% solution of n-butyllithium in n-hexane (500 ml) was added to diisopropylamine (116.5 ml) dissolved in dry tetrahydrofuran (720 ml), keeping below 0° C. After being stirred at 0° C. for 30 minutes, the solution was cooled below -72° C. A solution of methyl trifluoroacetate (46.28 g, 0.3614 mole), acetonitrile (29.67 g) and dry tetrahydrofuran (300 ml) were added dropwise, keeping below -72° C., and the solution, after being kept at -75° C. for additional 45 minutes, was warmed to room temperature over 1 hour. Ice-water (360 ml) was added to the solution and tetrahydrofuran and n-hexane were then evaporated under reduced pressure in a water bath at 40° C. The resulting residue was extracted with diethylether to remove neutral and basic components. It was adjusted to pH 1 with 36% HCl and then extracted with methylene chloride to remove by-products such as acetoacetonitrile. The solution was extracted with diethyl ether. p-Toluenesulfonic acid (0.07 g, 0.0003614 mole) was added to the extract and diethyl ether was distilled off at atmospheric pressure (in a water bath at 60° C.) by using a distillation apparatus equipped with a fractionating column. The resulting residue was distilled under reduced pressure at room temperature to give a crude product (56.44 g, 114%). Methanol (651 ml) and 97% hydroxylamine hydrochloride (33.66 g, 0.4698 mole) were added to this product and the mixture was heated under reflux for 68 hours. Methanol was distilled off under reduced pressure and ice-water (240 ml) was added to the resulting residue. This was adjusted above pH 11 with a 48% solution of sodium hydroxide and after being extracted with methylene chloride, the solvent was evaporated. The resulting residue was then distilled under reduced pressure to give the title compound (34.13 g, 62.1%) as pale red crystals, b.p. 85°-88° C./3.5 mmHg. This compound was recrystallized from benzene-cyclohexane to give colorless plates, m.p. 57°-58° C. The structure of this compound was confirmed by IR, NMR, UV and elemental analysis.

1. customkeeping below 0° C
2. temperaturethe solution was cooled below -72° C
3. customkeeping below -72° C.
4. waitthe solution, after being kept at -75° C. for additional 45 minutes
5. temperaturewas warmed to room temperature over 1 hour
6. customwere then evaporated under reduced pressure in a water bath at 40° C
7. extractionThe resulting residue was extracted with diethylether
8. customto remove neutral
9. extractionextracted with methylene chloride
10. customto remove by-products such as acetoacetonitrile
11. extractionThe solution was extracted with diethyl ether
12. extractionextract
13. distillationdiethyl ether was distilled off at atmospheric pressure (in a water bath at 60° C.)
14. customequipped with a fractionating column
15. distillationThe resulting residue was distilled under reduced pressure at room temperature
16. customto give a crude product (56.44 g, 114%)
17. temperaturethe mixture was heated
18. temperatureunder reflux for 68 hours
19. distillationMethanol was distilled off under reduced pressure and ice-water (240 ml)
20. additionwas added to the resulting residue
21. extractionafter being extracted with methylene chloride
22. customthe solvent was evaporated
23. distillationThe resulting residue was then distilled under reduced pressure

ORD record

ord-873a270de3024aac887d75d5529ba215

Source dataset

uspto-grants-1989_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04797492