METHYL 4-AMINO-6-INDOLECARBOXYLATE

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

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

Procedure: To a mixture of methyl 4-amino-1H-indole-6-carboxylate (EXAMPLE SP-216, step 3) (3.2 g) in water (50 mL) was added concentrated hydrochloric acid (5 mL). The mixture was chilled to below 5° C. with the addition of ice. To this was added sodium nitrite (1.16 g) dissolved in water (10 mL). The mixture was stirred chilled for 1 h followed by addition of sodium iodide (3 g) in water (20 mL). The mixture was stirred for 30 minutes, filtered and the solids collected by filtration were washed with water and dried at 50° C. The solids turned black and gas evolved rapidly upon drying. Column chromatography on silica gel (200 mL) using 20% hexanes in CH2Cl2 as eluent to give 0.82 g of the title compound: 1H NMR (CDCl3) δ 3.94, 6.55, 7.43, 8.14, 8.22, 8.62. The mixture was chilled to below 5° C. with the addition of ice chilled for 1 h The mixture was stirred for 30 minutes filtered the solids collected by filtration were washed with water dried at 50° C upon drying

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

Procedure: To a mixture of methyl 4-amino-1H-indole-6-carboxylate (1.0 g) in DMF (10 mL) was added 4-dimethylaminopyridine (1.46 g) and methanesulfonyl chloride (0.6 g). The mixture was heated to 60° C. for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous sodium sulfate and concentrated to give 0.71 g of the title compound: 1H NMR (CDCl3) δ 3.02, 3.94, 6.69, 7.42, 7.81, 8.04. cooled to room temperature partitioned between water and ethyl acetate The layers were separated the organic layer washed three times with brine dried over anhydrous sodium sulfate concentrated

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

Procedure: To a mixture of methyl 4-[(E)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate (19.3 g) in ethyl acetate (200 mL) was added 5% palladium on carbon (1.5 g). The mixture was placed under 45 PSI H2 and shaken overnight. The mixture was filtered through celite and concentrated. The residue was dissolved in CH2Cl2 to which was added ((1:1) H2O:conc. HCl (250 mL)). The resulting solids were collected by filtration, dissolved in ethyl acetate and washed with 2N NaOH. The ethyl acetate layer with anhydrous magnesium sulfate, filtered and concentrated to give 7.4 g if the title compound: 1H NMR (CDCl3) δ 3.91, 4.01, 6.51, 7.09, 7.27, 8.40. The mixture was filtered through celite concentrated The residue was dissolved in CH2Cl2 to which was added ((1:1) H2O:conc. HCl (250 mL)) The resulting solids were collected by filtration dissolved in ethyl acetate washed with 2N NaOH The ethyl acetate layer with anhydrous magnesium sulfate, filtered concentrated

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

Procedure: To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (1.0 g, 5.3 mmol, 1 equiv) in CH2Cl2 (50 ml) were added pyridine (0.55 g, 6.5 mmol, 1.2 equiv), 4-chloro-1-butanesulfonyl chloride (1.14 g, 6 mmol, 1.1 equiv) and DMAP (300 mg, 2.45 mmol, 0.5 equiv) and the resulting mixture was stirred at room temperature for 5 h. NEt3 (1 ml, 7.2 mmol, 1.3 equiv) was added and the resulting solution stirred for 2 h then diluted with AcOEt, washed with a 2N aqueous solution, a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 ml) and treated with a 2N aqueous NaOH solution (10 ml, 20 mmol, excess). The resulting solution was stirred at room temperature for 15 h then most of the MeOH was removed in vacuo. The residue was partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (CH2Cl2/MeOH: 9/1) gave 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-indole-6-carboxylic acid (A155) (320 mg, 20%) as a pale pink solid. [M+H]=295.0, RT=1.90 min. the resulting solution stirred for 2 h washed with a 2N aqueous solution a saturated aqueous NaHCO3 solution, dried over MgSO4 concentrated in vacuo The residue was dissolved in MeOH (20 ml) The resulting solution was stirred at room temperature for 15 h most of the MeOH was removed in vacuo The residue was partitioned between AcOEt The two layers were separated the organic phase was dried over MgSO4 concentrated in vacuo Purification of the residue by flash chromatography on silica gel (CH2Cl2/MeOH: 9/1)

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

Procedure: To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (1.0 g, 5.3 mmol, 1 equiv) in CH2Cl2 (50 ml) were added pyridine (0.55 g, 6.5 mmol, 1.2 equiv), 4-chloro-1-butanesulfonyl chloride (1.14 g, 6 mmol, 1.1 equiv) and DMAP (300 mg, 2.45 mmol, 0.5 equiv) and the resulting mixture was stirred at room temperature for 5 h. NEt3 (1 ml, 7.2 mmol, 1.3 equiv) was added and the resulting solution stirred for 2 h then diluted with AcOEt, washed with a 2N aqueous solution, a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 ml) and treated with a 2N aqueous NaOH solution (10 ml, 20 mmol, excess). The resulting solution was stirred at room temperature for 15 h then most of the MeOH was removed in vacuo. The residue was partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (CH2Cl2/MeOH: 9/1) gave 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-indole-6-carboxylic acid (A155) (320 mg, 20%) as a pale pink solid. [M+H]=295.0, RT=1.90 min. the resulting solution stirred for 2 h washed with a 2N aqueous solution a saturated aqueous NaHCO3 solution, dried over MgSO4 concentrated in vacuo The residue was dissolved in MeOH (20 ml) The resulting solution was stirred at room temperature for 15 h most of the MeOH was removed in vacuo The residue was partitioned between AcOEt The two layers were separated the organic phase was dried over MgSO4 concentrated in vacuo Purification of the residue by flash chromatography on silica gel (CH2Cl2/MeOH: 9/1)

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

Procedure: To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (900 mg, 4,74 mmol, 1 equiv) in DMF (25 ml) at room temperature was added NaH (60% dispersion in mineral oil, 200 mg, 5 mmol, 1.05 equiv) and after 15 min ethyl iodide (400 μl, 5 mmol, 1.05 equiv). The resulting mixture was stirred for 30 min then most of the solvent was removed in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave an oil which was diluted with Et2O and treated with a 4N HCl solution in Et2O. The precipitate obtained was filtrated off to give methyl 4-amino-1-ethyl-1H-indole-6-carboxylate hydrochloride salt (D202) (800 mg, 66%) as a white solid. [M+H]+=219.0, RT=2.50 min. most of the solvent was removed in vacuo The residue was diluted with AcOEt the organic phase was washed with a 2N aqueous HCl solution dried over MgSO4 concentrated in vacuo Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave an oil which The precipitate obtained was filtrated off

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

Procedure: To a solution of methyl 4-[(E)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate (D200) (10 g, 34 mmol, 1 equiv) in MeOH (250 ml) was added 10% palladium on charcoal (50% wet, 1.0 g, 5% w/w) and the resulting mixture was stirred under an atmosphere of hydrogen for 7 h. The catalyst was removed by filtration through a pad of celite and the solution concentrated in vacuo. The residue was triturated with AcOEt/iso-hexane to give methyl 4-amino-1H-indole-6-carboxylate (D201) (5 g, 77%) as a dark pink solid. [M+H]+=191.0, RT=1.20 min. The catalyst was removed by filtration through a pad of celite the solution concentrated in vacuo The residue was triturated with AcOEt/iso-hexane

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

Procedure: To a solution of methyl 4-[(E)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate (D200) (10 g, 34 mmol, 1 equiv) in MeOH (250 ml) was added 10% palladium on charcoal (50% wet, 1.0 g, 5% w/w) and the resulting mixture was stirred under an atmosphere of hydrogen for 7 h. The catalyst was removed by filtration through a pad of celite and the solution concentrated in vacuo. The residue was triturated with AcOEt/iso-hexane to give methyl 4-amino-1H-indole-6-carboxylate (D201) (5 g, 77%) as a dark pink solid. [M+H]+=191.0, RT=1.20 min. The catalyst was removed by filtration through a pad of celite the solution concentrated in vacuo The residue was triturated with AcOEt/iso-hexane

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

Procedure: To a mixture of methyl 4-amino-1H-indole-6-carboxylate (EXAMPLE SP-216, step 3) (3.2 g) in water (50 mL) was added concentrated hydrochloric acid (5 mL). The mixture was chilled to below 5° C. with the addition of ice. To this was added sodium nitrite (1.16 g) dissolved in water (10 mL). The mixture was stirred chilled for 1 h followed by addition of sodium iodide (3 g) in water (20 mL). The mixture was stirred for 30 minutes, filtered and the solids collected by filtration were washed with water and dried at 50° C. The solids turned black and gas evolved rapidly upon drying. Column chromatography on silica gel (200 mL) using 20% hexanes in CH2Cl2 as eluent to give 0.82 g of the title compound: 1H NMR (CDCl3) δ 3.94, 6.55, 7.43, 8.14, 8.22, 8.62. The mixture was chilled to below 5° C. with the addition of ice chilled for 1 h The mixture was stirred for 30 minutes filtered the solids collected by filtration were washed with water dried at 50° C upon drying

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

Procedure: To a mixture of methyl 4-amino-1H-indole-6-carboxylate (1.0 g) in DMF (10 mL) was added 4-dimethylaminopyridine (1.46 g) and methanesulfonyl chloride (0.6 g). The mixture was heated to 60° C. for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous sodium sulfate and concentrated to give 0.71 g of the title compound: 1H NMR (CDCl3) δ 3.02, 3.94, 6.69, 7.42, 7.81, 8.04. cooled to room temperature partitioned between water and ethyl acetate The layers were separated the organic layer washed three times with brine dried over anhydrous sodium sulfate concentrated

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

Procedure: To a mixture of methyl 4-[(E)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate (19.3 g) in ethyl acetate (200 mL) was added 5% palladium on carbon (1.5 g). The mixture was placed under 45 PSI H2 and shaken overnight. The mixture was filtered through celite and concentrated. The residue was dissolved in CH2Cl2 to which was added ((1:1) H2O:conc. HCl (250 mL)). The resulting solids were collected by filtration, dissolved in ethyl acetate and washed with 2N NaOH. The ethyl acetate layer with anhydrous magnesium sulfate, filtered and concentrated to give 7.4 g if the title compound: 1H NMR (CDCl3) δ 3.91, 4.01, 6.51, 7.09, 7.27, 8.40. The mixture was filtered through celite concentrated The residue was dissolved in CH2Cl2 to which was added ((1:1) H2O:conc. HCl (250 mL)) The resulting solids were collected by filtration dissolved in ethyl acetate washed with 2N NaOH The ethyl acetate layer with anhydrous magnesium sulfate, filtered concentrated