Hexamethylenetetramine → HCID 616437, compound

Temperature

100 °C

2,2,7,8-Tetramethylchroman-6-ol (2.0 g, 9.7 mmol) and hexamethylene tetramine (680 mg, 4.05 mmol) were weighed into a 20-mL scintillation vial, after which TFA (640 μL) and acetic acid (6.4 mL) were added. The vial was sealed, and the resulting mixture heated to 100° C. for 90 min, during which time a deep red color developed. The mixture was then concentrated to a red oil at 55° C. in vacuo. The darkly-colored residue was stirred in a biphasic mixture of 50 mL ethylacetate (EtOAc) and 50 mL 1 M aqueous sodium bicarbonate for 1 hr. At this time, the organic layer was removed, and successively washed with 1 M aqueous sodium bicarbonate (2×50 mL), 1 M aqueous citric acid (2×50 mL), and brine (50 mL). The residual organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 2.1 g yellow oil. Crude purification was accomplished by silica gel chromatography (gradient elution 0→10% EtOAc/Heptane) to obtain 1.0 g 6-hydroxy-2,2,7,8-tetramethylchroman-5-carbaldehyde product, which was immediately dissolved in DMF (88 mL) and treated with MOMCl (670 μL, 8.8 mmol) and Di-isopropyl ethyl amine (DiPEA) (2.2 mL, 13.2 mmol). The reaction mixture was heated to 50° C. for 2 hr and then subsequently diluted in EtOAc (75 mL). The organics were washed successively with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (25 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient elution 0→15% EtOAc/Heptane) afforded the 6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (920 mg) as a colorless oil. 1H NMR (CDCl3, 400 MHz) 10.4 (s, 1H), 4.93 (s, 2H), 3.56 (s, 3H), 3.06 (t, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.72 (t, 2H), 1.28 (s, 6H) ppm.

1. customThe vial was sealed
2. concentrationThe mixture was then concentrated to a red oil at 55° C. in vacuo
3. customAt this time, the organic layer was removed
4. washsuccessively washed with 1 M aqueous sodium bicarbonate (2×50 mL), 1 M aqueous citric acid (2×50 mL), and brine (50 mL)
5. dry with materialThe residual organics were dried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo to 2.1 g yellow oil
8. customCrude purification
9. washwas accomplished by silica gel chromatography (gradient elution 0→10% EtOAc/Heptane)

ORD record

ord-64e9945fd06341f8a5bb7a9a6bbc58fb

Source dataset

uspto-grants-2014_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08716527B2