Hexamethylenetetramine → HCID 58444085, compound

Temperature

80 °C

101.8 g (453 mmole) 1-(2-Chloro-phenyl)-4,4-dimethyl-pentan-1-one, 133.4 g (2.1 eq.) urotropine and 124.7 g (2.7 eq.) of acetic anhydride were placed in a 1000 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 200 ml water and 200 ml 2M NaOH were added and the mixture was extracted two times with 250 ml dichloromethane each. The organic layer was washed two times with 150 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 250 ml volume and the solution was added dropwise over a period of 2.5 h to 1000 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was poured onto approx. 800 g of ice and extracted three times with 250 ml dichloromethane each. The organic layer was washed twice with 250 ml of a saturated sodium bicarbonate solution and once with 200 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 1:1) to yield 79.4 g (74%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.44 (t, 1H, aromatic), 7.30 (d, 1H, aromatic), 7.27 (d, 1H, aromatic), 3.38 (dd, 1H, COCH), 2.79, 2.60 (2×m, 2H, benzylic), 2.10, 1.21 (2×m, 1H, CH2-t-Bu), 0.90 (s, 9H, t-Bu) ppm.

1. extractionthe mixture was extracted two times with 250 ml dichloromethane each
2. washThe organic layer was washed two times with 150 ml saturated aqueous ammonium chloride
3. dry with materialdried over magnesium sulphate
4. additionthe solution was added dropwise over a period of 2.5 h to 1000 g of hot (70-75° C.) concentrated sulphuric acid
5. stirringAfter stirring for an additional 30 min at 75° C. the mixture
6. waitto stand overnight at room temperature
7. additionThe mixture was poured onto approx. 800 g of ice
8. extractionextracted three times with 250 ml dichloromethane each
9. washThe organic layer was washed twice with 250 ml of a saturated sodium bicarbonate solution and once with 200 ml of a saturated sodium chloride solution
10. dry with materialAfter drying over magnesium sulphate the solvent
11. customwas removed in vacuo
12. customThe product was purified by column chromatography on silica (heptane/dichloromethane 1:1)

ORD record

ord-5628ee5d807d4c76baccb9e26f30e10b

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08415492B2