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

Temperature

38 °C

A mixture of 4-hydroxybenzyl alcohol (100.08 grams, 806 mmol), 2-nitropropane (400 mL, 4.45 mol) and diglyme (800 mL) was heated to 38° C. Potassium t-butoxide (45.29 grams, 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 hours. When water collection slowed (around 2.5 hours), 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 hours 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 grams of solution remained. Water (500 mL) and ethyl acetate (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 ethyl acetate (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 ethyl acetate was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 minutes, and the product crystallized to yield a beige solid (112.36 grams, 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—and adding heptane to crystallize.

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

ORD record

ord-a99d6189727640209babbabcb2934fb2

Source dataset

uspto-grants-2003_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06534504B1