methyl 4-amino-3-iodobenzoate

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:

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

Procedure: A solution of diisopropylamine (2.8 ml) in tetrahydrofuran (25 ml), under nitrogen, cooled to −10° C. was treated with butyl lithium in hexane (12.4 ml, 1.6M). The solution was added slowly via a syringe to a cooled to solution of methyl 4-amino-3-iodobenzoate (5 g, prepared according to the procedure of M. L. Hill, Tetrahedron, 1990, 46, page 4587) in tetrahydrofuran (100 ml), under nitrogen and at −78° C. The mixture was allowed to warm to 0° C. and after stirring for a further 10 minutes the mixture was cooled to −78° C. and then treated with 4-bromo-2-methyl-2-butene (2.49 ml). The reaction mixture was allowed to warm to room temperature over 1.5 hours then poured into saturated brine (100 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 ml). the combined organic phases were evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:9, v/v) to give the title compound (5 g). The solution was added slowly via a syringe to prepared at −78° C was cooled to −78° C. to warm to room temperature over 1.5 hours The organic layer was separated the aqueous phase was extracted with ethyl acetate (100 ml) the combined organic phases were evaporated the residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:9, v/v)

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

Procedure: A solution of diisopropylamine (2.8 ml) in tetrahydrofuran (25 ml), under nitrogen, cooled to −10° C. was treated with butyl lithium in hexane (12.4 ml 1.6M). The solution was added slowly via a syringe to a cooled to solution of methyl 4-amino-3-iodobenzoate (5 g, prepared according to the procedure of M. L. Hill, Tetrahedron, 1990, 46, page 4587) in tetrahydrofuran (100 ml), under nitrogen and at −78° C. The mixture was allowed to warm to 0° C. and after stirring for a further 10 minutes the mixture was cooled to −78° C. and then treated with 4-bromo-2-methyl-2-butene (2.49 ml). The reaction mixture was allowed to warm to room temperature over 1.5 hours then poured into saturated brine (100 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 ml). the combined organic phases were evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:9, v/v) to give the title compound (5 g). The solution was added slowly via a syringe to prepared at −78° C was cooled to −78° C. to warm to room temperature over 1.5 hours The organic layer was separated the aqueous phase was extracted with ethyl acetate (100 ml) the combined organic phases were evaporated the residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:9, v/v)

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrahydro-4H-pyran-4-one (1.3 g, 13 mmol), 4-amino-3-iodobenzoic acid methyl ester (3.46 g, 12.5 mmol), DABCO (4.37 g, 39 mmol), MgSO4 (2.35 g, 19.5 mmol) and Pd(OAc)2 (0.15 g, 0.00065 mol) were dissolved in DMF (18 mL) and heated under nitrogen at 105° C. for 2 days. The reaction mixture was then partitioned between ethyl acetate and water, and extracted. The crude was purified by column chromatography (98/2 DCM/MeOH) to give 0.62 g of title compound. The reaction mixture was then partitioned between ethyl acetate and water extracted The crude was purified by column chromatography (98/2 DCM/MeOH)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 4-amino-3-iodobenzoate (0.5 g, 1.8 mmol), 1-(4-fluorophenyl)piperidin-4-one (1.05 g, 5.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.61 g, 5.4 mmol) and palladium (II) acetate (20 mg, 0.09 mmol) in DMF (10.0 mL) was degassed, filled with argon (3×) and allowed to stir at 110° C. for 3.5 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (40 mL) and water (40 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), filtered and concentrated. Column chromatography (25% EtOAc/hexane) provided, upon trituration with ethyl ether, methyl 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (23 in Scheme 1(k)) as a yellow solid (0.23 g, 39%). 1H NMR (CDCl3, 300 MHZ) 8.17 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 3H), 7.09 (t, J=8.1 Hz, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 3.73 (t, J=5.6 Hz, 2H), 3.12 (br s, 2H) ppm; MS (ES) 325 (M+H). filled with argon (3×) to cool to room temperature partitioned between EtOAc (40 mL) and water (40 mL) the aqueous layer was extracted with EtOAc (2×20 mL) The combined organic layers were washed with water (2×20 mL), brine (1×20 mL) dried (MgSO4) filtered concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 4-amino-3-iodobenzoate (0.5 g, 1.8 mmol), 1-(4-fluorophenyl)piperidin-4-one (1.05 g, 5.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.61 g, 5.4 mmol) and palladium (II) acetate (20 mg, 0.09 mmol) in DMF (10.0 mL) was degassed, filled with argon (3×) and allowed to stir at 110° C. for 3.5 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (40 mL) and water (40 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), filtered and concentrated. Column chromatography (25% EtOAc/hexane) provided, upon trituration with ethyl ether, methyl 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (23 in Scheme 1(k)) as a yellow solid (0.23 g, 39%). 1H NMR (CDCl3, 300 MHZ) 8.17 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 3H), 7.09 (t, J=8.1 Hz, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 3.73 (t, J=5.6 Hz, 2H), 3.12 (br s, 2H) ppm; MS (ES) 325 (M+H). filled with argon (3×) to cool to room temperature partitioned between EtOAc (40 mL) and water (40 mL) the aqueous layer was extracted with EtOAc (2×20 mL) The combined organic layers were washed with water (2×20 mL), brine (1×20 mL) dried (MgSO4) filtered concentrated

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

Procedure: A solution of 25 g 4-Amino-3-iodo-benzoic acid methyl ester, 19 ml 2-Oxo-propionic acid, 30.4 g 1,4-Diaza-bicyclo[2.2.2]octane and 1 g Pd(OAc)2 was heated under argon to 100° C. After 5 h the reaction mixture was concentrated under reduced pressure and the residue was partitioned between 300 ml ethyl acetate and 200 ml 1 M hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to yield a yellow solid (6.4 g). From the aqueous layer additional product slowly precipitated as a white solid (7.9 g) which was collected by filtration. Both fractions were combined, dried in vacuo and used in the next reaction without further purification. Yield: 14.3 g MS (ES+): m/e=220. After 5 h the reaction mixture was concentrated under reduced pressure the residue was partitioned between 300 ml ethyl acetate and 200 ml 1 M hydrochloric acid The organic layer was dried over MgSO4 the solvent removed under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 4-amino-3-iodobenzoate (0.5 g, 1.8 mmol), 1-(4-fluorophenyl)piperidin-4-one (1.05 g, 5.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.61 g, 5.4 mmol) and palladium (II) acetate (20 mg, 0.09 mmol) in DMF (10.0 mL) was degassed, filled with argon (3×) and allowed to stir at 110° C. for 3.5 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (40 mL) and water (40 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), filtered and concentrated. Column chromatography (25% EtOAc/hexane) provided, upon trituration with ethyl ether, methyl 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (23 in Scheme 1(k)) as a yellow solid (0.23 g, 39%). 1H NMR (CDCl3, 300 MHZ) 8.17 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 3H), 7.09 (t, J=8.1 Hz, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 3.73 (t, J=5.6 Hz, 2H), 3.12 (br s, 2H) ppm; MS (ES) 325 (M+H). filled with argon (3×) to cool to room temperature partitioned between EtOAc (40 mL) and water (40 mL) the aqueous layer was extracted with EtOAc (2×20 mL) The combined organic layers were washed with water (2×20 mL), brine (1×20 mL) dried (MgSO4) filtered concentrated