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

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Reaction Steps

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:

Provenance & Evidence