2-bromo-1H-indole

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:

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

Procedure: The 2-bromoindole derivative 19-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. MeI (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0-15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 20-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 20-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 20-2 in 96% yield: MS-ES m/z 258.1 (MH+). was added dropwise stirring was continued for an additional 30 min volatiles removed under reduced pressure The residue was dissolved in TBME (100 mL) the solution washed with brine (2×25 mL) The extract was dried (MgSO4) concentrated under reduced pressure the residue purified by flash chromatography

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

Procedure: A mixture of intermediate 1-5 (4.02 g, 12 mmol), 2-(2,4-dimethyl-thiazol-5-yl)-quinoline-6-boronic acid 16-1 (4.58 g, 1.19 eq, synthesized as described in WO2006/076529), K2CO3 (5.13 g, 3.1 eq) and dichloro-bis(triphenylphosphino)-Pd(II) (0.86 g, 0.10 eq) in ethanol/toluene (1:1, 80 mL) was stirred at room temperature under N2 overnight. After concentration under reduced pressure, the reaction mixture was redissolved in ethyl acetate and washed with a 5 M NaHCO3 solution. The obtained yellow precipitate was filtered off, washed with water, then isopropanol to give 4.13 g (67%) of 3-Cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole-6-carboxylic acid methyl ester 16-2 as a yellow solid; m/z=496 (M+H+). After concentration under reduced pressure the reaction mixture was redissolved in ethyl acetate washed with a 5 M NaHCO3 solution The obtained yellow precipitate was filtered off washed with water

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

Procedure: To a stirred solution of ethyl 1-phenylsulfonylindole-2-carboxylate (1 eq.) in DMF (2.5 ml/mmol) under N2, was added a solution of bromine (4 eq.) in DMF (0.5 ml/mmol). This reaction mixture was stirred at room temperature for about 4 hours, following which water was added and the mixture was extracted with dichloromethane (×3). The organic layer was washed with a saturated solution of Na2SO5, dried and evaporated to give a crude yellow oil. Purification by chromatography on silica gel (eluent: C6H12/EtOAc 9/1) afforded 3-brominated indole 11. was added the mixture was extracted with dichloromethane (×3) The organic layer was washed with a saturated solution of Na2SO5 dried evaporated to give a crude yellow oil Purification by chromatography on silica gel (eluent: C6H12/EtOAc 9/1)

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

Procedure: To a stirred solution of ethyl 1-phenylsulfonylindole-2-carboxylate (1 eq.) in DMF (2.5 ml/mmol) under N2, was added a solution of bromine (4 eq.) in DMF (0.5 ml/mmol). This reaction mixture was stirred at room temperature for about 4 hours, following which water was added and the mixture was extracted with dichloromethane (×3). The organic layer was washed with a saturated solution of Na2SO5, dried and evaporated to give a crude yellow oil. Purification by chromatography on silica gel (eluent: C6H12/EtOAc 9/1) afforded 3-brominated indole 11. was added the mixture was extracted with dichloromethane (×3) The organic layer was washed with a saturated solution of Na2SO5 dried evaporated to give a crude yellow oil Purification by chromatography on silica gel (eluent: C6H12/EtOAc 9/1)

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

Procedure: A mixture of intermediate 1-5 (4.02 g, 12 mmol), 2-(2,4-dimethyl-thiazol-5-yl)-quinoline-6-boronic acid 16-1 (4.58 g, 1.19 eq, synthesized as described in WO2006/076529), K2CO3 (5.13 g, 3.1 eq) and dichloro-bis(triphenylphosphino)-Pd(II) (0.86 g, 0.10 eq) in ethanol/toluene (1:1, 80 mL) was stirred at room temperature under N2 overnight. After concentration under reduced pressure, the reaction mixture was redissolved in ethyl acetate and washed with a 5 M NaHCO3 solution. The obtained yellow precipitate was filtered off, washed with water, then isopropanol to give 4.13 g (67%) of 3-Cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole-6-carboxylic acid methyl ester 16-2 as a yellow solid; m/z=496 (M+H+). After concentration under reduced pressure the reaction mixture was redissolved in ethyl acetate washed with a 5 M NaHCO3 solution The obtained yellow precipitate was filtered off washed with water

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 2-bromoindole from above (1.53 g, 4.55 mmol, 1.0 equiv.) was dissolved in anhydrous THF (20 mL) and the solution was cooled to −78° C. under an argon atmosphere. N-BuLi (solution in hexane, 4.78 mmol, 1.05 equiv.) was added dropwise and the mixture was stirred 30 min in the cold. Trimethylborate (0.62 mL, 5.46 mmol, 1.2 equiv.) was added dropwise and the solution stirred at −78° C. for 40 min and then at 0° C. for 1 h. Finally the reaction mixture was allowed to warm up to room temperature and additional THF (20 mL) was added. para-Tolylphosphine (0.083 g, 0.27 mmol, 0.06 equiv.) and 2-bromopyridine (0.86 g, 5.46 mmol, 1.2 equiv.) were then added and the solution was degassed by bubbling argon through for 30 min. Palladium acetate (10 mg, 0.046 mmol, 0.01 equiv.), anhydrous potassium carbonate (1.26 g, 9.1 mmol, 2 equiv.) and MeOH (20 mL) were added and the mixture was refluxed overnight under an argon atmosphere. After cooling to RT, TBME (12 mL) and water (12 mL) were added, the organic phase was separated and the aqueous phase extracted with additional TBME (2×25 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a residue that was purified by flash chromatography on silica gel using 5–10% EtOAc in hexane as eluent: 1.21 g (79%). the solution stirred at −78° C. for 40 min at 0° C. for 1 h to warm up to room temperature the solution was degassed by bubbling argon through for 30 min the mixture was refluxed overnight under an argon atmosphere After cooling to RT the organic phase was separated the aqueous phase extracted with additional TBME (2×25 mL) The combined organic layers were washed with brine dried (Na2SO4) concentrated to give a residue that was purified by flash chromatography on silica gel using 5–10% EtOAc in hexane as eluent

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 intermediate 1-5 (4.02 g, 12 mmol), 2-(2,4-dimethyl-thiazol-5-yl)-quinoline-6-boronic acid 16-1 (4.58 g, 1.19 eq, synthesized as described in WO2006/076529), K2CO3 (5.13 g, 3.1 eq) and dichloro-bis(triphenylphosphino)-Pd(II) (0.86 g, 0.10 eq) in ethanol/toluene (1:1, 80 mL) was stirred at room temperature under N2 overnight. After concentration under reduced pressure, the reaction mixture was redissolved in ethyl acetate and washed with a 5 M NaHCO3 solution. The obtained yellow precipitate was filtered off, washed with water, then isopropanol to give 4.13 g (67%) of 3-Cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole-6-carboxylic acid methyl ester 16-2 as a yellow solid; m/z=496 (M+H+). After concentration under reduced pressure the reaction mixture was redissolved in ethyl acetate washed with a 5 M NaHCO3 solution The obtained yellow precipitate was filtered off washed with water