反应详情

A 20 gallon glass-lined vessel was charged with N,N-dimethylformamide (15.9 1) and 4-hydroxyphenylacetic acid (3.969 kg, 26.09 moles). When solution was obtained, lithium carbonate (2.12 kg, 28.7 moles, 1.1 equivs.) was added in one portion and the resulting mixture stirred at room temperature for 10 minutes. Benzyl bromide (3.723 l, 31.3 moles, 1.2 equivs.) was added in one portion and the mixture heated to 100° C. (internal temperature) and held for 3 hours, when LC (40/60, 0.0025 M H3PO4 /CH3CN, 220 nm, 1.5 mlmin-1, Hypersil column) showed approx. 5% starting acid remained. The reaction was cooled to approx. 60° C. and 2N aqueous HCl solution (20 l ) was added and the solution extracted with ethyl acetate (2×10 l). The combined organic extracts were washed with saturated NaHCO3 solution (16 l) and water (3×16 l). Emulsions were encountered during water washing, which could be broken by the addition of toluene (20 l total). The ethyl acetate was removed by distillation until the level of residual ethyl acetate was<0.3% [additional toluene (5 l) was added during distillation]. The volume of the mixture was adjusted to approx. 16 l (by further distillation) and allowed to cool to room temperature when crystallisation occurred. The slurry was diluted by the addition of hexane (20 l) and aged at ambient temperature overnight. The slurry was cooled to 0° C., held for 1 hour and the product filtered, washed with a cold (0° C.) 1:1 toluene/hexane mixture (4 l) and dried in vacuo at 50° C. to give the product as a white solid. Yield: 5.283 kg, 83%. LC/GC>98%. NMR confirmed structure; only trace impurities noted.

1. customWhen solution was obtained
2. temperaturethe mixture heated to 100° C. (internal temperature)
3. waitheld for 3 hours
4. temperatureThe reaction was cooled to approx. 60° C.
5. extractionthe solution extracted with ethyl acetate (2×10 l)
6. washThe combined organic extracts were washed with saturated NaHCO3 solution (16 l) and water (3×16 l)
7. additioncould be broken by the addition of toluene (20 l total)
8. customThe ethyl acetate was removed by distillation until the level of residual ethyl acetate
9. addition<0.3% [additional toluene (5 l) was added during distillation]
10. distillationThe volume of the mixture was adjusted to approx. 16 l (by further distillation)
11. temperatureto cool to room temperature
12. customwhen crystallisation
13. additionThe slurry was diluted by the addition of hexane (20 l)
14. waitaged at ambient temperature overnight
15. temperatureThe slurry was cooled to 0° C.
16. waitheld for 1 hour
17. filtrationthe product filtered
18. washwashed with a cold (0° C.) 1:1 toluene/hexane mixture (4 l)
19. customdried in vacuo at 50° C.