methyl 6-hydroxy-1H-indole-2-carboxylate

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: 0.144 ml (2.70 mmol) of concentrated sulfuric acid is added, at ambient temperature, to a solution of 5.98 g (33.75 mmol) of 6-hydroxy-1H-indole-2-carboxylic acid in 350 ml of methanol. The mixture is refluxed for 9 days and the reaction mixture is then concentrated to dryness under reduced pressure. The residue obtained is taken up in water and alkalinized to pH9 with a 38% potassium hydroxide solution, and the product is then extracted 6 times with ethyl acetate. The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 5.81 g of methyl 6-hydroxy-1H-indole-2-carboxylate in the form of a brown solid. The mixture is refluxed for 9 days the reaction mixture is then concentrated to dryness under reduced pressure The residue obtained the product is then extracted 6 times with ethyl acetate dried over anhydrous magnesium sulfate filtered concentrated to dryness under reduced pressure

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

Procedure: 0.144 ml (2.70 mmol) of concentrated sulfuric acid is added, at ambient temperature, to a solution of 5.98 g (33.75 mmol) of 6-hydroxy-1H-indole-2-carboxylic acid in 350 ml of methanol. The mixture is refluxed for 9 days and the reaction mixture is then concentrated to dryness under reduced pressure. The residue obtained is taken up in water and alkalinized to pH9 with a 38% potassium hydroxide solution, and the product is then extracted 6 times with ethyl acetate. The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 5.81 g of methyl 6-hydroxy-1H-indole-2-carboxylate in the form of a brown solid. The mixture is refluxed for 9 days the reaction mixture is then concentrated to dryness under reduced pressure The residue obtained the product is then extracted 6 times with ethyl acetate dried over anhydrous magnesium sulfate filtered concentrated to dryness under reduced pressure

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a light brown, homogeneous solution of methyl 6-hydroxy-1H-indole-2-carboxylate (1.4862 g, 7.77 mmol) and 1-bromo-2-methoxyethane (0.731 mL, 7.77 mmol) in DMF (38.9 mL) under nitrogen was added cesium carbonate (2.53 g, 7.77 mmol). The reaction was heated to 55° C. and stirred overnight. The reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through CELITE®. The filtrate was washed with water (4×50 mL) and brine (2×50 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 20-60% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give desired product (0.8592 g) as a white solid. Mixed fractions were combined and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 80 g column eluting with 20-60% EtOAc/hexanes to give another crop of desired product (0.1673 g) as a white solid. The reaction was cooled to room temperature filtered through CELITE® The filtrate was washed with water (4×50 mL) and brine (2×50 mL) dried over MgSO4 concentrated in vacuo to give a residue which was purified by flash chromatography eluting with 20-60% EtOAc/hexanes Appropriate fractions were collected concentrated in vacuo

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

Procedure: To a solution 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (4.0 g, 21 mmol) and 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (4.3 g, 21 mmol) in MeCN:DMF (4:1, 250 mL) was added Cs2CO3 (13.8 g, 42 mmol) and the reaction mixture was heated (60° C., 4 h). The reaction mixture was cooled (rt) and partitioned between EtOAc (300 mL) and saturated NH4Cl (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as a brown solid (3.6 g, 53%). MS (ESI): mass calcd. for C16H11N3O3S, 325.1; m/z found, 326.0[M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.18 (s, 1H), 8.52 (dd, J=4.8, 1.7, 1H), 8.39 (dd, J=8.0, 1.7, 1H), 7.82 (d, J=8.7, 1H), 7.53 (d, J=2.2, 1H), 7.34 (dd, J=8.0, 4.8, 1H), 7.26 (dd, J=2.2, 0.9, 1H), 7.19 (dd, J=8.7, 2.2, 1H), 3.88 (s, 3H). The reaction mixture was cooled (rt) partitioned between EtOAc (300 mL) and saturated NH4Cl (200 mL) The organic layer was separated the aqueous layer was extracted with EtOAc (2×200 mL) The organic layer was dried filtered concentrated in vacuo The resulting residue was purified by silica gel flash chromatography

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (4.7 g, 24.5 mmol) in DMF (250 mL) was added Cs2CO3 (8.0 g, 24.5 mmol) followed by 2-chloro-benzothiazole (3.0 mL, 4.2 g, 24.5 mmol) and the reaction mixture was heated (70° C., 12 h). The reaction mixture was cooled (rt) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (200 mL) and brine (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×300 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-40%) to provide the title compound as a colorless foam (3.6 g, 45%). MS (ESI): mass calcd. for O17H12N2O3S, 324.1; m/z found, 325.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.17 (s, 1H), 7.77-7.63 (m, 3H), 7.46-7.42 (m, 1H), 7.42-7.34 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.19 (m, 1H), 7.14 (dd, J=8.7, 2.1, 1H), 3.94 (s, 3H). The reaction mixture was cooled (rt) concentrated in vacuo The resulting residue was partitioned between EtOAc (200 mL) and brine (100 mL) The organic layer was separated the aqueous layer was extracted with EtOAc (2×300 mL) The organic layer was dried filtered concentrated in vacuo The resulting residue was purified by silica gel flash chromatography

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-hydroxy-1H-indole-2-carboxylic acid (5.0 g, 28.2 mmol) in MeOH (250 mL) was added concentrated HCl (3 mL) and the reaction mixture was heated (90° C., 3 h). The reaction mixture was cooled (rt) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and H2O (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a yellow solid (4.2 g, 77%). MS (ESI): mass calcd. for C10H9NO3, 191.1; m/z found, 192.1 [M+H]+. The reaction mixture was cooled (rt) concentrated in vacuo The resulting residue was partitioned between EtOAc (50 mL) and H2O (200 mL) The organic layer was separated the aqueous layer was extracted with EtOAc (2×200 mL) The organic layer was dried filtered concentrated in vacuo

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

Procedure: A 2M solution of trimethylsilyldiazomethane in hexanes was added to a solution of 6-hydroxy-1H-indole-2-carboxylic acid (0.500 g, 2.82 mmol) in MeOH until the solution remained yellow in color. The solution was stirred at RT until the starting material was consumed as evident by TLC. The reaction mixture was partitioned between water and EtOAc then the organic layer was separated, dried over MgSO4, filtered and concentrated. Purification was accomplished by column chromatography (EtOAc/hexanes) to afford the title compound (0.464 g, 86% yield). 1H NMR (400 MHz, Acetone-d6): δ ppm 10.55 (br. s., 1H), 8.32 (s, 1H), 7.50 (d, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 6.74 (dd, 1H), 3.85 (s, 3H). MS m/z=191.9 (M+1). was consumed as evident by TLC The reaction mixture was partitioned between water and EtOAc the organic layer was separated dried over MgSO4 filtered concentrated Purification

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

Procedure: To a tetrahydrofuran (8 mL) solution of 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (395 mg, 2.07 mmol) described in Production Example 73-1-1 was added 5 N aqueous sodium hydroxide solution (414 μL, 2.07 mmol), which was concentrated under a reduced pressure. To an N,N-dimethylformamide (8 mL) solution of the residue was added cyclopropylmethyl bromide (241 μL, 2.48 mmol) at room temperature followed by stirring at room temperature for 12 hours. Moreover, after stirring at 50° C. for 4 hours, water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (297 mg, 59%) as a white solid. was concentrated under a reduced pressure Moreover, after stirring at 50° C. for 4 hours followed by extraction with ethyl acetate The organic layer was washed with water and sat. NaCl by drying over anhydrous magnesium sulfate filtering The filtrate was concentrated under a reduced pressure the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1)