Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.
Procedure: Thionyl chloride (5.5 mL, 75.5 mmol) was added smoothly over 1 hour to a clear solution of 4-hydroxyphenylethanol (10.0 g, 70.9 mmol) and triethylamine (10.5 mL, 74.5 mmol) dissolved in toluene (37.2 mL) and acetonitrile (10.0 mL) at or below 60° C., followed by a line wash of toluene (1.4 mL). A light yellow to light brown coloured solution resulted which was held at 60° C. for 2 hours, during which time some SO2 was evolved. A saturated solution of sodium bicarbonate (20 mL) was added carefully at 60° C., stirred for 15 minutes, allowed to settle and the lower aqueous phase removed and discarded. The bicarbonate wash was repeated, followed by a water wash (20 mL). The organic phase was heated to toluene reflux under Dean and Stark conditions to a constant head temperature to remove residual dissolved gases and water. The total distillate was measured and fresh toluene added to replace it (30 mL on this scale). The reaction mixture was cooled back to 80° C. and thiobenzoic acid (10.5 g, 74.5 mmol) added slowly from a warmed measure vessel (alternatively, the thiobenzoic acid can be dissolved in the fresh toluene required to make up the volume). Triethylamine (10.5 mL, 74.5 mmol) was added smoothly over 30 minutes, followed by a toluene line wash (11.4 mL), and the reaction mixture stirred at 80° C. for 8 hours. Dilute aqueous hydrochloric acid (20 mL of 0.5 M) was added, stirred vigorously for 15 minutes, allowed to settle and the lower aqueous phase removed and discarded. The procedure was repeated with water (20 mL). The organic phase was cooled to 60° C. and given a second water wash. Iso-hexane (65 mL) was added to the toluene phase over 1 hour, and the resulting solution cooled smoothly to 0° C. over 4 hours with good stirring. The product crystallized at ˜33° C. The resulting slurry was chilled at 0° C. for at least 1 hour before being isolated by filtration and washed by displacement with the recycled mother liquors (as a vessel rinse) and then with fresh iso-hexane (20 mL), to yield the title compound as a light buff-coloured solid (14.7 g, 77%). HPLC (Rt 10.1 min); m.p. 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (2H, d, J=7.2 Hz), 7.57 (1H, t, J=7.4 Hz), 7.44 (2H, t, J=7.8 Hz), 7.13 (2H, d, J=8.8 Hz), 6.79 (2H, d, J=8.4 Hz), 5.0 (1H, bs), 3.28 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=7.8 Hz); 13C NMR (100.6 MHz, CDCl3) δ 192.26, 154.23, 137.09, 133.51, 132.23, 129.78, 128.59, 127.19, 115.35, 34.99, 30.71; MS (ES+) 259 (M+H+, 100%), 182 ((M+H-Ph)+, 60%).
below 60° C.
wash of toluene (1.4 mL)
A light yellow to light brown coloured solution resulted which
the lower aqueous phase removed
The bicarbonate wash
wash (20 mL)
The organic phase was heated to toluene
reflux under Dean and Stark conditions to a constant head temperature
to remove residual
dissolved gases and water
fresh toluene added
wash (11.4 mL)
the reaction mixture stirred at 80° C. for 8 hours
Dilute aqueous hydrochloric acid (20 mL of 0.5 M) was added
stirred vigorously for 15 minutes
the lower aqueous phase removed
The organic phase was cooled to 60° C.
wash
Iso-hexane (65 mL) was added to the toluene phase over 1 hour
the resulting solution cooled smoothly to 0° C. over 4 hours with good stirring
The product crystallized at ˜33° C
The resulting slurry was chilled at 0° C. for at least 1 hour
before being isolated by filtration
washed by displacement with the recycled mother liquors (as a vessel rinse)
Source ID: ord-2f292fc10f26438abb9acf5f82d022dd