4-Hydroxybenzyl Alcohol → 4-(2-Methyl-2-nitropropyl)phenol

Temperature

132 °C

A mixture of 4-hydroxybenzyl alcohol (100.08 g, 806 mmol), 2-nitropropane (400 mL, 4.45 mol) and diglyme (800 mL) was heated to 38 0C. Potassium t-butoxide (45.29 g, 403.6 mmol) was added, and the mixture was heated to reflux at 132° C. with a Dean-Stark trap. Water began collecting in the trap, and continued at a high rate for approximately 1.5 h. When water collection slowed (around 2.5 h) then portions of solvent (30-40 mL each) were removed every thirty minutes. During the water collection and solvent removal the temperature rose from 132° C. to 149° C. After 4 h less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis. The heating mantle was removed, and the reaction mixture was allowed to cool. When the temperature was 100° C. water (200 mL) was added, and the solution was allowed to cool to room temperature. Solvent was removed on a rotary evaporator under vacuum until 593 g of solution remained. Water (500 mL) and EtOAc (500 mL) were added and the layers were separated (layer separation was poor, but addition of 20% aqueous NaCl was ineffectual). The aqueous layer was extracted with EtOAc (200 mL), and the combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL). The organic layer was distilled in vacuo to 261 g of oil to which EtOAc was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 min, and the product crystallized to yield a beige solid (112.36 g, 71% yield, >98% purity by HPLC analysis). Another crop of crystals may be obtained from the filtrate by concentrating and filtering the solids, or by concentrating more fully to a solution and adding heptane to crystallize. NMR. E.A.

1. temperaturethe mixture was heated
2. customWater began collecting in the trap
3. customWhen water collection
4. custom(around 2.5 h)
5. customportions of solvent (30-40 mL each) were removed every thirty minutes
6. customDuring the water collection and solvent removal the temperature
7. customrose from 132° C. to 149° C
8. waitAfter 4 h less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis
9. customThe heating mantle was removed
10. temperatureto cool
11. customwas 100° C.
12. additionwas added
13. temperatureto cool to room temperature
14. customSolvent was removed on a rotary evaporator under vacuum until 593 g of solution
15. additionWater (500 mL) and EtOAc (500 mL) were added
16. customthe layers were separated
17. custom(layer separation was poor, but addition of 20% aqueous NaCl was ineffectual)
18. extractionThe aqueous layer was extracted with EtOAc (200 mL)
19. extractionthe combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL)
20. distillationThe organic layer was distilled in vacuo to 261 g of oil to which EtOAc
21. additionwas added (160 mL)
22. additionHeptane (3.4 L) was added rapidly
23. customthe product crystallized
24. customto yield a beige solid (112.36 g, 71% yield, >98% purity by HPLC analysis)
25. customAnother crop of crystals may be obtained from the filtrate
26. concentrationby concentrating
27. filtrationfiltering the solids
28. concentrationby concentrating more fully to a solution
29. additionadding heptane
30. customto crystallize

ORD record

ord-d91e896b59894049967908e64ed1b956

Source dataset

uspto-grants-1999_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05977154