methyl 5-iodo-2-methoxybenzoate

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: A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), methyl 5-iodo-2-methoxybenzoate (0.056 g, 0.20 mmol) were coupled according to the general procedure and the resulting methyl 3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)-4-methoxybiphenyl-3-carboxylate was hydrolyzed using LiI (0.019 g, 0.14 mmol) in refluxing pyridine (2 mL) to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as a pale yellow solid (0.013 g, over two steps 10%). δ1 NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.87 (d, 1H, J=8.2 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.63 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.41-7.39 (m, 1H), 7.28-7.24 (m, 2H), 7.14 (d, 1H, J=8.7 Hz), 5.26 (s, 2H), 4.63-4.59 (m, 1H), 3.89 (s, 3H), 2.16-2.04 (m, 2H), 2.04-1.58 (m, 6H). LC-MS (ESI) Calcd for C27H25NO5S [M+H]+: 475.14. Found: 475.80.

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

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

Procedure: Methyl iodide (2.40 mL, 38.48 mmol) and K2CO3 (10.60 g, 76.96 mmol) were added to a solution of 5-iodo-2-methoxybenzoate (5.37 g, 19.24 mmol) in DMF (20 mL) and stirred at rt under Ar for 24 h. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (3:1 hexane:ethyl acetate) to afford methyl-5-iodo-2-methoxybenzoate (4.93 g, 88%) as a white solid. See, for example, Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574-5576, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.90 (d, 1H, J=2.4 Hz), 7.80 (dd, 1H, J=8.8, 2.4 Hz), 6.96 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.79 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 164.7, 158.0, 141.6, 138.5, 122.2, 115.2, 82.1, 55.9, 52.0. HREIMS calculated for C9H9IO3 (M+) 291.9608, found 291.9596. the reaction was washed with 1% HCl (2×20 mL), brine (1×) dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (3:1 hexane:ethyl acetate)

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

Procedure: Methyl iodide (2.40 mL, 38.48 mmol) and K2CO3 (10.60 g, 76.96 mmol) were added to a solution of 5-iodo-2-methoxybenzoate (5.37 g, 19.24 mmol) in DMF (20 mL) and stirred at rt under Ar for 24 h. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (3:1 hexane:ethyl acetate) to afford methyl-5-iodo-2-methoxybenzoate (4.93 g, 88%) as a white solid. See, for example, Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574-5576, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.90 (d, 1H, J=2.4 Hz), 7.80 (dd, 1H, J=8.8, 2.4 Hz), 6.96 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.79 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 164.7, 158.0, 141.6, 138.5, 122.2, 115.2, 82.1, 55.9, 52.0. HREIMS calculated for C9H9IO3 (M+) 291.9608, found 291.9596. the reaction was washed with 1% HCl (2×20 mL), brine (1×) dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (3:1 hexane:ethyl acetate)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Iodo-2-methoxy-benzoic acid methyl ester (500 mg, 1.7 mmol), morpholine (223 μl, 2.5 mmol), cesium carbonate (850 mg, 2.7 mmol), xantphos (60 mg, 0.1 mmol) and bis(dibenzylideneacetone)dipalladium (35 mg, 0.04 mmol) were suspended in dioxane (5 ml) and heated at 100° C. for 5 h. The mixture was then cooled, filtered and the residue was purified by flash column chromatography [SiO2, EtOAc] to give 2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (170 mg) as a colourless solid. (LC/MS (basic method): Rt 2.35 min, [M+H]+ 252). The mixture was then cooled filtered the residue was purified by flash column chromatography [SiO2, EtOAc]

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

Procedure: 5-iodo-2-hydroxybenzoic acid (2.81 g, 10.6 mmol) was suspended in acetone (50 ml) and K2CO3 (6.77 g, 49.0 mmol) was added. The reaction was cooled in an ice water bath, and dimethylsulfate (2.4 ml, 25 mmol) was added via syringe. The reaction was warmed to room temperature, then heated to reflux, and stirred overnight. After 14.75 hours, the reaction was cooled to room temperature, diluted with water (150 ml), and stirred for 30 minutes. It was then extracted with EtOAc (3×50 ml), and the organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel (Biotage instrument, 5% EtOAc/hexanes->100% EtOAc) to give methyl 5-iodo-2-methoxybenzoate (3.08 g, 99%). The reaction was cooled in an ice water bath heated to reflux After 14.75 hours the reaction was cooled to room temperature stirred for 30 minutes It was then extracted with EtOAc (3×50 ml) dried over magnesium sulfate filtered concentrated purified on silica gel (Biotage instrument, 5% EtOAc/hexanes->100% EtOAc)

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

Procedure: 5-iodo-2-hydroxybenzoic acid (2.81 g, 10.6 mmol) was suspended in acetone (50 ml) and K2CO3 (6.77 g, 49.0 mmol) was added. The reaction was cooled in an ice water bath, and dimethylsulfate (2.4 ml, 25 mmol) was added via syringe. The reaction was warmed to room temperature, then heated to reflux, and stirred overnight. After 14.75 hours, the reaction was cooled to room temperature, diluted with water (150 ml), and stirred for 30 minutes. It was then extracted with EtOAc (3×50 ml), and the organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel (Biotage instrument, 5% EtOAc/hexanes->100% EtOAc) to give methyl 5-iodo-2-methoxybenzoate (3.08 g, 99%). The reaction was cooled in an ice water bath heated to reflux After 14.75 hours the reaction was cooled to room temperature stirred for 30 minutes It was then extracted with EtOAc (3×50 ml) dried over magnesium sulfate filtered concentrated purified on silica gel (Biotage instrument, 5% EtOAc/hexanes->100% EtOAc)

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

Procedure: A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), methyl 5-iodo-2-methoxybenzoate (0.056 g, 0.20 mmol) were coupled according to the general procedure and the resulting methyl 3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)-4-methoxybiphenyl-3-carboxylate was hydrolyzed using LiI (0.019 g, 0.14 mmol) in refluxing pyridine (2 mL) to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as a pale yellow solid (0.013 g, over two steps 10%). δ1 NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.87 (d, 1H, J=8.2 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.63 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.41-7.39 (m, 1H), 7.28-7.24 (m, 2H), 7.14 (d, 1H, J=8.7 Hz), 5.26 (s, 2H), 4.63-4.59 (m, 1H), 3.89 (s, 3H), 2.16-2.04 (m, 2H), 2.04-1.58 (m, 6H). LC-MS (ESI) Calcd for C27H25NO5S [M+H]+: 475.14. Found: 475.80.

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

Procedure: A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), methyl 5-iodo-2-methoxybenzoate (0.056 g, 0.20 mmol) were coupled according to the general procedure and the resulting methyl 3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)-4-methoxybiphenyl-3-carboxylate was hydrolyzed using LiI (0.019 g, 0.14 mmol) in refluxing pyridine (2 mL) to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as a pale yellow solid (0.013 g, over two steps 10%). δ1 NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.87 (d, 1H, J=8.2 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.63 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.41-7.39 (m, 1H), 7.28-7.24 (m, 2H), 7.14 (d, 1H, J=8.7 Hz), 5.26 (s, 2H), 4.63-4.59 (m, 1H), 3.89 (s, 3H), 2.16-2.04 (m, 2H), 2.04-1.58 (m, 6H). LC-MS (ESI) Calcd for C27H25NO5S [M+H]+: 475.14. Found: 475.80.