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). The residue was evaporated from hexane, then ice-water (500 mL) was added and the mixture was stirred for 20 min. Ether (100 mL) was added and the reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g). The resulting mixture was extracted with ether (2×250 mL), and the ether 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 which was filtered off and washed with ice-cold ether to give 3-chloro-4-hydroxy-5-methylbenzaldehyde (6.9 g, 35%) 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%). The remaining solution was purified by HPLC (7% ethyl acetate/hexanes) to give a yellow solid (7.8 g, 39%). The overall yield was 17.6 g (88%).

1. temperatureit was cooled
2. customevaporated (˜50° C., 0.2 mm)
3. customThe residue was evaporated from hexane
4. additionice-water (500 mL) was added
5. additionEther (100 mL) was added
6. additionthe reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g)
7. extractionThe resulting mixture was extracted with ether (2×250 mL)
8. washthe ether 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 which
15. filtrationwas filtered off
16. washwashed with ice-cold ether

ORD record

ord-d7e8a0fff7ad4a0c9f87debba3774f90

Source dataset

uspto-grants-2009_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07491741B2