7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester

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

Procedure: Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.11 g, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ 13.206 (bs, 1H), δ 11.876 (s, 1H), δ 7.498-7.445 (m, 2H), δ 7.19 (d, J=2.0 Hz, 1.0H). mixed with a magnetic stirrer This mixture was refluxed for 1 hour The THF was removed via rotary evaporator extracted with ethyl acetate

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

Procedure: To a stirred mixture of sodium hydride [disp. 55-65%] (175 mg, 4.37 mmol) in DMF (5.6 ml) was added drop wise at room temperature under argon atmosphere a solution of commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [CAS No. 396076-60-1] (1.04 g, 3.64 mmol) in DMF (2.8 ml). Afterwards the mixture was allowed to stir for 5 min at room temperature, then commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (975 mg, 4.37 mmol) was added and the solution was allowed to stir at room temperature for 15 h. The solution was cooled in an ice bath, and citric acid (10%, 62 ml) was added drop wise. The mixture was allowed to stir at room temperature for 1 h, and was afterwards extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (80 ml), dried (MgSO4) and evaporated. The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%) to yield 7-bromo-1-(2-tert-butoxycarbonylamino-ethyl)-5-fluoro-1H-indole-2-carboxylic acid ethyl ester as a light yellow oil (1.37 g, 88%), MS (ISN) m/z=431.2 [(M+H)+]. 459817-82-4] (975 mg, 4.37 mmol) was added to stir at room temperature for 15 h The solution was cooled in an ice bath to stir at room temperature for 1 h was afterwards extracted with ethyl acetate (2×70 ml) The combined organic layers were washed with brine (80 ml) dried (MgSO4) evaporated The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%)

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

Procedure: To a stirred mixture of sodium hydride [disp. 55-65%] (175 mg, 4.37 mmol) in DMF (5.6 ml) was added drop wise at room temperature under argon atmosphere a solution of commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [CAS No. 396076-60-1] (1.04 g, 3.64 mmol) in DMF (2.8 ml). Afterwards the mixture was allowed to stir for 5 min at room temperature, then commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (975 mg, 4.37 mmol) was added and the solution was allowed to stir at room temperature for 15 h. The solution was cooled in an ice bath, and citric acid (10%, 62 ml) was added drop wise. The mixture was allowed to stir at room temperature for 1 h, and was afterwards extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (80 ml), dried (MgSO4) and evaporated. The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%) to yield 7-bromo-1-(2-tert-butoxycarbonylamino-ethyl)-5-fluoro-1H-indole-2-carboxylic acid ethyl ester as a light yellow oil (1.37 g, 88%), MS (ISN) m/z=431.2 [(M+H)+]. 459817-82-4] (975 mg, 4.37 mmol) was added to stir at room temperature for 15 h The solution was cooled in an ice bath to stir at room temperature for 1 h was afterwards extracted with ethyl acetate (2×70 ml) The combined organic layers were washed with brine (80 ml) dried (MgSO4) evaporated The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%)

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

Procedure: The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscous yellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)+

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

Procedure: The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscous yellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)+

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-4-fluoro-phenylhydrazine (20 g, 0.097 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (11.3 ml, 0.101 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield 24.4 g, 82%. The hydrazone mixture (22 g, 0.073 mol) was dissolved in Eaton's reagent (230 ml) and the mixture heated 3 h at 50° C. The mixture was cooled to room temperature, diluted with dichloromethane and added to saturated aqueous sodium hydrogen carbonate. The phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in diethyl ether, and hexane added whereupon part of the product precipitated. This was filtered and the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant) to afford the product as a light yellow solid (14.1 g, 68%). Mp: 125° C., EI MS: 285.0 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 3 h at 50° C The mixture was cooled to room temperature The phases were separated the aqueous phase extracted twice with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate evaporated hexane added whereupon part of the product precipitated This was filtered the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant)

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

Procedure: The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035 mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscous yellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)+

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

Procedure: The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035 mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscous yellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)+

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-4-fluoro-phenylhydrazine (20 g, 0.097 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (11.3 ml, 0.101 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield 24.4 g, 82%. The hydrazone mixture (22 g, 0.073 mol) was dissolved in Eaton's reagent (230 ml) and the mixture heated 3 h at 50° C. The mixture was cooled to room temperature, diluted with dichloromethane and added to saturated aqueous sodium hydrogen carbonate. The phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in diethyl ether, and hexane added whereupon part of the product precipitated. This was filtered and the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant) to afford the product as a light yellow solid (14.1 g, 68%). Mp: 125° C., EI MS: 285.0 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 3 h at 50° C The mixture was cooled to room temperature The phases were separated the aqueous phase extracted twice with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate evaporated hexane added whereupon part of the product precipitated This was filtered the mother liquor purified by column chromatography on silica gel (5:1 toluene/hexane eluant)

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

Procedure: Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.1 μg, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ 13.206 (bs, 1H), δ 11.876 (s, 1H), δ 7.498-7.445 (m, 2H), δ 7.19 (d, J=2.0 Hz, 1.0H). mixed with a magnetic stirrer This mixture was refluxed for 1 hour The THF was removed via rotary evaporator extracted with ethyl acetate

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

Procedure: Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.1 μg, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ 13.206 (bs, 1H), δ 11.876 (s, 1H), δ 7.498-7.445 (m, 2H), δ 7.19 (d, J=2.0 Hz, 1.0H). mixed with a magnetic stirrer This mixture was refluxed for 1 hour The THF was removed via rotary evaporator extracted with ethyl acetate

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

Procedure: Tetrahydrofuran (35.2 ml), water (23.5 ml), lithium hydroxide (2.61 g, 10.9 mmol), and 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (3.11 g, 10.9 mmol) were added to a round bottom flask and mixed with a magnetic stirrer. This mixture was refluxed for 1 hour. The THF was removed via rotary evaporator, and the aqueous solution was acidified with 1M HCL, and extracted with ethyl acetate. 1H NMR (DMSO-d6): δ 13.206 (bs, 1H), δ 11.876 (s, 1H), δ 7.498-7.445 (m, 2H), δ 7.19 (d, J=2.0 Hz, 1.0H). mixed with a magnetic stirrer This mixture was refluxed for 1 hour The THF was removed via rotary evaporator extracted with ethyl acetate