Hexamethylenetetramine → 3-Chloro-4-hydroxy-5-methylbenzaldehyde

Temperature

85 °C

Hexamethylenetetramine (19.60 g, 139.8 mmol) was added in portions to a solution of 2-chloro-6-methylphenol (20.00 g, 117.2 mmol) in trifluoroacetic acid (200 mL). There was a slight exotherm and effervescence was noted. The reaction mixture was heated in an oil-bath at 84-86° C. for 5 h, then it was cooled and evaporated (˜50° C., 0.2 mm) under reduced pressure. The residue was evaporated from hexane, then ice-water (500 mL) was added and the mixture was stirred for 20 min. Diethyl ether (100 mL) was added and the reaction was adjusted to approximately pH 5 by the careful portionwise addition of solid sodium bicarbonate (49 g). The resulting mixture was extracted with diethyl ether (2×250 mL) and the organic layers were washed with brine, dried (MgSO4), filtered and concentrated to about 100 mL. The mixture was then left to crystallize over the weekend to give a solid that was collected by filtration and washed with cold diethyl ether to give 3-chloro-4-hydroxy-5-methylbenzaldehyde (6.9 g, 35% yield) as a yellow solid. The mother liquor was evaporated and dichloromethane (30 mL) was added. The yellow solid was filtered off (2.9 g, 14% yield). The remaining solution was purified by HPLC (7% ethyl acetate/hexanes) to give the aldehyde as a yellow solid (7.8 g, 39% yield). The overall yield was 17.6 g (88% yield).

1. temperatureit was cooled
2. customevaporated (˜50° C., 0.2 mm) under reduced pressure
3. customThe residue was evaporated from hexane
4. additionice-water (500 mL) was added
5. additionDiethyl ether (100 mL) was added
6. additionthe reaction was adjusted to approximately pH 5 by the careful portionwise addition of solid sodium bicarbonate (49 g)
7. extractionThe resulting mixture was extracted with diethyl ether (2×250 mL)
8. washthe organic layers were washed with brine
9. dry with materialdried (MgSO4)
10. filtrationfiltered
11. concentrationconcentrated to about 100 mL
12. waitThe mixture was then left
13. customto crystallize over the weekend
14. customto give a solid
15. filtrationthat was collected by filtration
16. washwashed with cold diethyl ether

ORD record

ord-6349ac78dde745bdbe4a09f00a1851bd

Source dataset

uspto-grants-2003_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06515124B2