ethyl 3-bromo-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:

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

Procedure: To a solution of EXAMPLE 101A (5.9 g) in N,N-dimethylformamide (50 mL) was added 1-(bromomethyl)-4-methoxybenzene (4.85 g) and Cs2CO3 (25 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether twice. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration of the solvent gave EXAMPLE 101B. The aqueous layer was extracted with ether twice The combined extracts were washed with water (×3), brine dried over Na2SO4 Concentration of the solvent gave EXAMPLE 101B

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

Procedure: To a stirred solution of ethyl 1H-indole-2-carboxylate (9.45 g) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (8.89 g, 50 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was dissolved with water (100 ml) and diethyl ether (300 ml). The organic layer was washed with water brine and dried over Na2SO4. After filtration, concentration of solvent afforded the title compound. The mixture was concentrated under vacuum the residue was dissolved with water (100 ml) and diethyl ether (300 ml) The organic layer was washed with water brine dried over Na2SO4 After filtration, concentration of solvent

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

Procedure: To a stirred solution of ethyl 1H-indole-2-carboxylate (9.45 g) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (8.89 g, 50 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was dissolved with water (100 ml) and diethyl ether (300 ml). The organic layer was washed with water brine and dried over Na2SO4. After filtration, concentration of solvent afforded the title compound. The mixture was concentrated under vacuum the residue was dissolved with water (100 ml) and diethyl ether (300 ml) The organic layer was washed with water brine dried over Na2SO4 After filtration, concentration of solvent

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

Procedure: A mixture of EXAMPLE 31B (1.08 g), ortho-tolylboronic acid (1.1 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (140 mg) in dimethoxyethane:2N aqueous Na2CO3 (25 mL:5 mL) was stirred under nitrogen at 80° C. for 16 hours, diluted with ethyl acetate and was washed with water and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes. was washed with water and brine The organic phase was dried (MgSO4) filtered concentrated The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes

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

Procedure: A mixture of ethyl-2-indole carboxylate (1.89 g) and N-bromosuccinimide (1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL) and filtered. The filtrant was washed with THF, dried under vacuum at 60° C., and recrystallized from ethyl acetate/hexanes. filtered The filtrant was washed with THF dried under vacuum at 60° C. recrystallized from ethyl acetate/hexanes

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

Procedure: A solution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151°; NMR δ (CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 11H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (bs, 1H); M/z (−) 268 (M+), 266, 196, 194. to precipitate a pale yellow solid which was filtered off recrystallized from ethyl acetate to give the

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

Procedure: Powdered sodium hydroxide (0.5 g) was added in a single portion to a vigorously stirred solution of ethyl 3-bromoindole-2-carboxylate (0.3 g), 3,4-dichlorobenzyl bromide (0.32 g) and tetra-n-butylammonium hydrogensulphate (50 mg) in dichloromethane. The reaction was stirred for 3 hours then partitioned between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the desired end product as a colourless oil (0.35 g, 73%); NMR δ (CDCl3) 1.42 (t, 3H), 4.41 (q, 2H), 5.73 (s, 2H), 6.84 (d, 1H), 7.18-7.40 (m, 5H), 7.74 (d, 11H); M/z (+) 428 (MH+), 426, 346, 159. then partitioned between 2M HCl and ethyl acetate Combined organic extracts were dried (MgSO4) concentrated in vacuo the residue purified by column chromatography

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

Procedure: Synthesis of 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (Froshauer, S. A. et al., U.S. Pat. No. 5,981,762 (1999)): 3-Bromo-1H-indole-2-carboxylic acid ethyl ester (536 mg, 2.0 mmol), is prepared by following the method given by Elliott, J. D. et al., (U.S. Pat. No. 5,684,032 (1997)) is dissolved in nitromethane (10 mL) and cooled to 0° C. AlCl3 is added to the flask. Then a solution of isovaleryl chloride (0.295 mL, 2.4 mmol) in nitromethane (2 mL) was added dropwise to the flask. The mixture is allowed to come to room temperature and stirred for 18 hours, and then cooled to 0° C. 20 mL ice-water is added and extracted with CH2Cl2 (4×20 mL). The combined organic phase is washed with saturated brine (20 mL), 1N NaHCO3 (20 mL) and saturated brine (2×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give yellow solid. It is then purified by flash column chromatography eluted with hexane:ethyl acetate (6:1) to give 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (468 mg, 67%) as light yellow solid. 1H NMR (300 MHz, DMSO-d6) 612.60 (brs, 1H); 8.20 (d, J=1.2 Hz, 1H), 7.97 (dd, J=8.7, 1.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 4.41 (q, J=6.9 Hz, 2H), 2.98 (d, J=6.9 Hz, 2H), 2.20 (m, 1H), 1.39 (t, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 6H). EIMS m/z 352.0 (M++H). to come to room temperature cooled to 0° C extracted with CH2Cl2 (4×20 mL) The combined organic phase is washed with saturated brine (20 mL), 1N NaHCO3 (20 mL) and saturated brine (2×20 mL) dried over anhydrous Na2SO4 filtered concentrated under vacuum to give yellow solid It is then purified by flash column chromatography eluted with hexane:ethyl acetate (6:1)