methyl 2,4-dihydroxy-5-propan-2-ylbenzoate

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

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (332 mg, 2.4 mmol) in acetonitrile (12 ml) was treated with chloromethyl methyl ether (0.16 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours whereupon further anhydrous potassium carbonate (1.38 g, 10.0 mmol) and chloromethyl methyl ether (0.76 ml, 10.0 mmol) were added and the mixture was stirred and held at 50° C. for a further 4 days. Upon cooling to room temperature the solvent was removed in vacuo and the residue treated with water (30 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford methyl 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoate (580 mg, 97%) as a pale yellow oil. 1H NMR (DMSO-d6) 7.57 (1H, s), 6.88 (1H, s), 5.32 (2H, s), 5.20 (2H, s), 3.78 (3H, s), 3.41 (6H, s), 3.21 (1H, m), 1.17 (6H, d). MS: [M+Na]+ 321. were added was removed in vacuo the residue treated with water (30 ml) The organic material was extracted with dichloromethane (2×20 ml) the combined organic extracts were evaporated in vacuo

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (10 ml) was treated with allyl bromide (0.364 ml, 4.2 mmol) and the mixture was stirred at room temperature for 16 hours. A further portion of allyl bromide (0.364 ml, 4.2 mmol) was added and the mixture was stirred and held at reflux for a further 16 hours. Upon cooling to room temperature the solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (20 ml). The organic material was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford methyl 2,4-bis-allyloxy-5-isopropylbenzoate (480 mg, 83%) as a pale yellow oil. 1H NMR (DMSO-d6) 7.56 (1H, s), 6.68 (1H, s), 6.07 (2H, m), 5.51 (1H, dm), 5.44 (1H, dm), 5.28 (2H, m), 4.68 (2H, m), 4.64 (2H, m), 3.75 (3H, s), 3.18 (1H, m), 1.16 (6H, d). MS: [M+Na]+ 313. the mixture was stirred at reflux for a further 16 hours Upon cooling to room temperature the solvent was removed in vacuo the residue acidified by the addition of 2M hydrochloric acid (20 ml) The organic material was extracted with ethyl acetate (2×20 ml) the combined organic extracts were evaporated in vacuo

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (10 ml) was treated with allyl bromide (0.35 ml, 4.0 mmol) and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with dichloromethane (2×20 ml), the combined organic extracts were evaporated in vacuo and the residue subjected to column chromatography on silica. Elution with 2-10% ethyl acetate in petroleum ether afforded methyl 4-allyloxy-2-hydroxy-5-isopropylbenzoate (330 mg, 60%) as a colourless solid. 1H NMR (DMSO-d6) 10.68 (1H, s), 7.55 (1H, s), 6.54 (1H, s), 6.06 (1H, m), 5.42 (1H, dm), 5.29 (1H, dm), 4.65 (2H, m), 3.88 (3H, s), 3.16 (1H, m), 1.16 (6H, d). The solvent was removed in vacuo the residue acidified by the addition of 2M hydrochloric acid (10 ml) The organic material was extracted with dichloromethane (2×20 ml) the combined organic extracts were evaporated in vacuo Elution with 2-10% ethyl acetate in petroleum ether

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (1.05 g, 5.0 mmol) and anhydrous potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (25 ml) was treated with chloromethyl methyl ether (0.4 ml, 5.27 mmol) and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue treated with water (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (1.02 g, 80%) as a colourless solid. 1H NMR (DMSO-d6) 10.61 (1H, br s), 7.58 (1H, s), 6.62 (1H, s), 5.30 (2H, s), 3.88 (3H, s), 3.42 (3H, s), 3.17 (1H, m), 1.17 (6H, d). MS: [M+H]+ 255. The solvent was removed in vacuo the residue treated with water (30 ml) The solid material was collected by suction filtration rinsed with water (2×20 ml) sucked dry under reduced pressure

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (10 ml) was treated with dimethyl sulphate (0.4 ml, 4.2 mmol) and the mixture was stirred at room temperature for 16 hours and then held at reflux for 6 hours. Upon cooling to room temperature the solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford methyl 5-isopropyl-2,4-dimethoxybenzoate (350 mg, 74%) as a colourless solid. 1H NMR (DMSO-d6) 7.53 (1H, s), 6.67 (1H, s), 3.92 (3H, s), 3.86 (3H, s), 3.75 (3H, s), 3.13 (1H, m), 1.14 (6H, d). MS: [M+Na]+ 261. at reflux for 6 hours Upon cooling to room temperature the solvent was removed in vacuo the residue acidified by the addition of 2M hydrochloric acid (10 ml) The solid material was collected by suction filtration rinsed with water (2×10 ml) sucked dry under reduced pressure

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (331 mg, 2.4 mmol) in acetonitrile (10 ml) was treated with dimethyl sulphate (0.2 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (440 mg, 98%) as a colourless solid. 1H NMR (DMSO-d6) 10.70 (1H, br s), 7.54 (1H, s), 6.53 (1H, s), 3.87 (3H, s), 3.84 (3H, s), 3.12 (1H, m), 1.13 (6H, d). MS: [M+H]+ 225. The solvent was removed in vacuo the residue acidified by the addition of 2M hydrochloric acid (10 ml) The solid material was collected by suction filtration rinsed with water (2×10 ml) sucked dry under reduced pressure

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (1.05 g, 5.0 mmol) and anhydrous potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (25 ml) was treated with benzyl bromide (0.655 ml, 5.5 mmol) and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was treated with water (50 ml). The solid material was collected by suction filtration, rinsed with water (2×50 ml) and sucked dry under reduced pressure to afford methyl 4-benzyloxy-2-hydroxy-5-isopropylbenzoate (1.25 g, 83%) as colourless needles. 1H NMR (DMSO-d6) 10.68 (1H, br s), 7.57 (1H, s), 7.48-7.40 (4H, m), 7.34 (1H, m), 6.64 (1H, s), 5.20 (2H, s), 3.87 (3H, s), 3.18 (1H, m), 1.17 (6H, d). MS: [M+H]+ 301. The solvent was removed in vacuo the residue was treated with water (50 ml) The solid material was collected by suction filtration rinsed with water (2×50 ml) sucked dry under reduced pressure

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

Procedure: 10% Palladium on carbon (350 mg) was added to a suspension of methyl 2,4-bis-benzyloxy-5-isopropenylbenzoate [prepared as per WO 2006/109085 A1] (3.88 g, 10.0 mmol) in ethanol (30 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. Methanol (20 ml) was added to aid dissolution and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, the catalyst was rinsed with methanol (3×20 ml) and the combined filtrates were evaporated in vacuo to afford methyl 2,4-dihydroxy-5-isopropylbenzoate (2.10 g, 100%) as a colourless solid. 1H NMR (DMSO-d6) 10.54 (1H, s), 10.44 (1H, br s), 7.52 (1H, s), 6.37 (1H, s), 3.85 (3H, s), 3.08 (1H, m), 1.13 (6H, d). MS: [M+H]+ 211. the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours The mixture was filtered the catalyst was rinsed with methanol (3×20 ml) the combined filtrates were evaporated in vacuo

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

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (332 mg, 2.4 mmol) in acetonitrile (12 ml) was treated with chloromethyl methyl ether (0.16 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours whereupon further anhydrous potassium carbonate (1.38 g, 10.0 mmol) and chloromethyl methyl ether (0.76 ml, 10.0 mmol) were added and the mixture was stirred and held at 50° C. for a further 4 days. Upon cooling to room temperature the solvent was removed in vacuo and the residue treated with water (30 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford methyl 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoate (580 mg, 97%) as a pale yellow oil. 1H NMR (DMSO-d6) 7.57 (1H, s), 6.88 (1H, s), 5.32 (2H, s), 5.20 (2H, s), 3.78 (3H, s), 3.41 (6H, s), 3.21 (1H, m), 1.17 (6H, d). MS: [M+Na]+ 321. were added was removed in vacuo the residue treated with water (30 ml) The organic material was extracted with dichloromethane (2×20 ml) the combined organic extracts were evaporated in vacuo

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

Procedure: A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (332 mg, 2.4 mmol) in acetonitrile (12 ml) was treated with chloromethyl methyl ether (0.16 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours whereupon further anhydrous potassium carbonate (1.38 g, 10.0 mmol) and chloromethyl methyl ether (0.76 ml, 10.0 mmol) were added and the mixture was stirred and held at 50° C. for a further 4 days. Upon cooling to room temperature the solvent was removed in vacuo and the residue treated with water (30 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford methyl 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoate (580 mg, 97%) as a pale yellow oil. 1H NMR (DMSO-d6) 7.57 (1H, s), 6.88 (1H, s), 5.32 (2H, s), 5.20 (2H, s), 3.78 (3H, s), 3.41 (6H, s), 3.21 (1H, m), 1.17 (6H, d). MS: [M+Na]+ 321. were added was removed in vacuo the residue treated with water (30 ml) The organic material was extracted with dichloromethane (2×20 ml) the combined organic extracts were evaporated in vacuo