3-hydroxybenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Bromosuccinimide (2.13 g, 12 mmol) and subsequently α,α′-azoisobutyronitrile (16 mg, 0.1 mmol) were added to a solution of 3,5-lutidine (1.14 ml, 10 mmol) in CCl4 (40 ml). The reaction mixture was stirred at reflux for 2 hrs. After cooling, succinimide was removed by filtration and the filtrate was evaporated to smaller volume (10 ml). To this filtrate, a mixture of 3-hydroxybenzenecarboxamide (550 mg, 4 mmol) and K2CO3 (830 mg, 6 mmol) in DMF (5 ml) was added and the new reaction mixture was stirred at 60° C. for 24 h. After diluting with CH2Cl2 (100 ml), the solution was washed with Na2CO3 solution (40 ml) and water (40 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The brown oil residue was extracted by trituration with Et2O (2×10 ml), and from the Et2O extracts, the precipitant solid was filtered and washed with pentane, to give 70 mg (7.2% yield) of the desired product. Mp 152-154° C., HPLC-MS: m/z 243 [M+H]+, Rt=2.28 min. at reflux for 2 hrs After cooling succinimide was removed by filtration the filtrate was evaporated to smaller volume (10 ml) was added the new reaction mixture was stirred at 60° C. for 24 h the solution was washed with Na2CO3 solution (40 ml) and water (40 ml) dried (Na2SO4) evaporated to dryness, under reduced pressure The brown oil residue was extracted by trituration with Et2O (2×10 ml) the precipitant solid was filtered washed with pentane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesised from 3-hydroxybenzenecarboxamide and 10-undecyn-1-ol according to Method C, scheme 3; mp 111-112° C., HPLC-MS (method 1): m/z 274 [M+H]+, Rt=4.61 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Method D) K2CO3 (1.38 g, 10 mmol, 1 equiv.) was added to a suspension of 3-hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) in CH3CN (100 ml). The mixture stirred for 10 min at room temperature, before 1,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) was added. The resulting mixture was stirred at 60° C. for 16 h. After this time, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate evaporated under reduced pressure to dryness. The residue was taken-up in EtOAc and water. The organic phase was separated and washed consecutively with K2CO3 solution, water and brine. Dried with MgSO4 and evaporated under reduced pressure to a small volume. The precipitant solid was filtered and washed with EtOAc/pentane, to give the desired compound as a white solid (2.0 g, 67%), mp 115-117° C. HPLC-MS (method 1): m/z 300 [M]+, 302 [M+2H]+, Rt=4.08 min. was added After this time, the reaction was cooled to room temperature any undissolved solids were filtered off the filtrate evaporated under reduced pressure to dryness The organic phase was separated washed consecutively with K2CO3 solution, water and brine Dried with MgSO4 evaporated under reduced pressure to a small volume The precipitant solid was filtered washed with EtOAc/pentane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of polymer-supported triphenyl phosphine (1.4 g, 3 mmol, based on a loading of 2.15 mmol/g [purchased from Argonaut], 1.5 equiv.) swollen in THF (20 ml) at room temperature was added diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.). The mixture was shaken for 5 min before 3-hydroxybenzamide (274 mg, 2 mmol, 1 equiv.), triethylamine (0.28 ml, 2 mmol, 1 equiv.) and cis-5-decenol (313 mg, 2 mmol, 1 equiv.) were added. The resulting suspension was shaken at room temperature for 16 h and then filtered. The resin was washed with additional THF (×3) and then the combined filtrate and washings were concentrated under reduced pressure, to give the crude product as a colourless semi-solid. It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient) to give the desired compound as a white solid (390 mg, 71%), mp 98-100° C. HPLC-MS (method 1): m/z 276 [M+H]+, Rt=5.00 min. 1H NMR (CDCl3) δ=7.35 (s, 1H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 (t, J=6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34-1.28 (m, 4H), 0.88 (t, J=7.0 Hz, 3H). were added filtered The resin was washed with additional THF (×3) the combined filtrate and washings were concentrated under reduced pressure to give the crude product as a colourless semi-solid It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-hydroxybenzenecarboxamide (200 mg, 1.46 mmol, 1 equiv.) in DMF (3 ml) was added K2CO3 (302 mg, 2.19 mmol, 1.5 equiv.) and NaI (43.5 mg, 0.29 mmol, 0.2 equiv). The suspension was stirred for 5 min before n-nonyl chloride (0.32 ml, 1.61 mmol, 1.1 equiv) was introduced. The resulting mixture was warmed to 60° C. where it was maintained for 16 h. After this time, the reaction was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with additional water (×2), dried (MgSO4), filtered and concentrated in vacuo to reveal a colourless solid. In the case of 3-n-nonyloxybenzamide this colourless solid was stirred for 5 min with MeOH (˜0.5 ml) [NB: 3-n-nonyloxybenzamide partially soluble in MeOH] and then filtered to reveal the desired compound as a colourless solid (116 mg, 30%). HPLC-MS (method 3): m/z 264 [M+H]+, Rt=1.80 min. 1H NMR (d6-DMSO) δ=7.95 (s, 1H), 7.44-7.31 (m, 4H), 7.06 (ddd, J=8 Hz, J=2 Hz, J=1 Hz, 1H), 3.99 (t, J=6.5 Hz, 2H), 1.72 (quintet, J=6.5 Hz, 2H), 1.42 (m, 2H), 1.34-1.26 (m, 10H), 0.86 (t, J=6.5 Hz, 3H). was introduced was maintained for 16 h After this time, the reaction was cooled to room temperature partitioned between EtOAc and water The organic phase was separated washed with additional water (×2) dried (MgSO4) filtered concentrated in vacuo 3-n-nonyloxybenzamide partially soluble in MeOH] and then filtered

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-hydroxybenzamide (21.6 g) in methyl ethyl ketone ("MEK") was added 2-chloroethyl p-toluenesulphonate (55.46 g) and potassium carbonate (16.0 g). After starting at reflux for 6 hours, the resultant mixture was poured onto water and a colourless solid filtered off. Crystallisation from ethanol gave the title compound, (22.2 g), m.p. 125°-126°. at reflux for 6 hours a colourless solid filtered off Crystallisation from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.0 g (21.9 mmol) of the 3-hydroxybenzamide prepared in Example 1 and 5.7 g (41.2 mmol) of anhydrous potassium carbonate were added to a round bottom flask followed by 40 ml anhydrous DMF added by syringe. To this mixture was added 11.85 g (70.9 mmol, 7.8 cc) of 2-acetoyl ethyl bromide, also using a syringe to maintain anhydrous conditions. The suspension was stirred for 48 hr and the mixture filtered. The solid was washed with 6×5 ml DMF and the filtrate evaporated in vacuo to a solid. The resulting solid was recrystallized from 90% aqueous alcohol and the solid from the filtration was washed with cold 90% alcohol and ether. The desired product, 3-(2-acetoylethoxy)benzamide was obtained in 65% yield (3.2 g), mp 121°-122° C. Identity of the product was confirmed by TLC and by elemental analysis. Calculated for C11H13NO4 ; C: 59.18; H: 5.87; N: 6.28; Found: C: 59.03; H: 5.83; N: 6.58. added by syringe to maintain anhydrous conditions the mixture filtered The solid was washed with 6×5 ml DMF the filtrate evaporated in vacuo to a solid The resulting solid was recrystallized from 90% aqueous alcohol the solid from the filtration was washed with cold 90% alcohol and ether