4-Hydroxybenzyl Alcohol → 3,4-Dihydro-2-hydroxy-4-phenyl-2H-1-benzopyran-6-methanol

4-(Hydroxymethyl)phenol (2.515 kg, 20.26 mol, 1 eq) was stirred with N-methylpiperazine (5.06 kg, 50.52 mol, 2.5 eq) in toluene (17.74 kg, 20.5 L, 8.15 mL/g) and then heated to reflux. trans-Cinnamaldehyde (3.35 kg, 25.35 mol, 1.25 eq) was then added over 2 hours maintaining the reaction mixture at reflux. The transfer line was washed with toluene (0.9 Kg, 0.35 ml/g). Once the addition was complete the reaction mixture continued to be heated at reflux for 19 h. Then some toluene was distilled off, reducing the volume to approximately 18.5 L. The mixture was then allowed to cool to room temperature and EtOAc was added (13.5 Kg 15 L, 6 mL/g). The organic phase was washed with HCl 2M (46.4 kg, 46.4 L 18.5 mL/g). The phases were separated, and ethyl acetate (27.1 kg, 30 L, 12 ml/g) was added to dilute the organic layer. The organic phase was washed with 1M HCl (17.75 kg, 17.75 L 7.1 mL/g), 5% w/w NaHCO3 (17.5 L, 7 mL/g) and water (25 L, 10 mL/g). The phases were separated, and toluene (6.5 Kg, 7.5 L, 3 ml/g) was added to the organic layer, and the mixture was distilled to approximately 8 L. Additional toluene (7 kg) was charged followed by ethyl acetate (3.9 L). The mixture was heated to reflux then cooled to 22° C. at 1° C./minute, then stirred for 20 hrs. The suspension was cooled to 2° C. and granulated for 2 hrs. The slurry was filtered and the cake was washed with cold toluene (2×4.3 Kg, 5 L). The resulting pale tan solid was dried in vacuum for 68 h at 40° C., to provide 2.76 Kg of product (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (53.4% yield) which was used in the following example without purification:

1. temperatureheated to reflux
2. temperaturemaintaining the reaction mixture
3. temperatureat reflux
4. washThe transfer line was washed with toluene (0.9 Kg, 0.35 ml/g)
5. additionOnce the addition
6. temperatureto be heated
7. temperatureat reflux for 19 h
8. distillationThen some toluene was distilled off
9. additionEtOAc was added (13.5 Kg 15 L, 6 mL/g)
10. washThe organic phase was washed with HCl 2M (46.4 kg, 46.4 L 18.5 mL/g)
11. customThe phases were separated
12. additionethyl acetate (27.1 kg, 30 L, 12 ml/g) was added
13. additionto dilute the organic layer
14. washThe organic phase was washed with 1M HCl (17.75 kg, 17.75 L 7.1 mL/g), 5% w/w NaHCO3 (17.5 L, 7 mL/g) and water (25 L, 10 mL/g)
15. customThe phases were separated
16. additiontoluene (6.5 Kg, 7.5 L, 3 ml/g) was added to the organic layer
17. distillationthe mixture was distilled to approximately 8 L
18. additionAdditional toluene (7 kg) was charged
19. temperatureThe mixture was heated
20. temperatureto reflux
21. temperaturethen cooled to 22° C. at 1° C./minute
22. temperatureThe suspension was cooled to 2° C.
23. waitgranulated for 2 hrs
24. filtrationThe slurry was filtered
25. washthe cake was washed with cold toluene (2×4.3 Kg, 5 L)
26. customThe resulting pale tan solid was dried in vacuum for 68 h at 40° C.

ORD record

ord-b890b8d85bed46cbbb2cb5a218a84f26

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08067594B2