Methyl 2-amino-5-chloro-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:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized in analogy to 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (described in example S85) using 1-butyne (excess ca 3 ml), 2-amino-5-chloro-3-iodo-benzoic acid methyl ester (prepared as described in example S85) (430 mg, 1.38 mmol), copper (I) iodide (19 mg, 0.10 mmol) and bis(triphenyl-phosphine) palladium (II) chloride (71 mg, 0.10 mmol) in triethylamine (10 ml). The final compound was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-3-but-1-ynyl-5-chlorobenzoic acid methyl ester (120 mg, 37%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.49 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). The final compound was purified by flash column chromatography (9:1 cyclohexane:EtOAc)

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

Procedure: Propyne (excess ca 3 ml) was condensed onto a cold (−78° C.) solution of 2-amino-5-chloro-3-iodobenzoic acid methyl ester (500 mg, 1.61 mmol) in triethylamine (10 ml) in a Parr pressure reaction vessel. To this solution was added copper (I) iodide and bis(triphenylphosphine)palladium (II) chloride and the pressure tube was then sealed and stirred at rt for 4 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (340 mg, 95%) as an off white solid. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.13 (s, 3H). in a Parr pressure reaction vessel the pressure tube was then sealed The solvent was then removed in vacuo the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc)

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

Procedure: Propyne (excess ca 3 ml) was condensed onto a cold (−78° C.) solution of 2-amino-5-chloro-3-iodobenzoic acid methyl ester (500 mg, 1.61 mmol) in triethylamine (10 ml) in a Parr pressure reaction vessel. To this solution was added copper (I) iodide and bis(triphenylphosphine)palladium (II) chloride and the pressure tube was then sealed and stirred at rt for 4 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (340 mg, 95%) as an off white solid. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.13 (s, 3H). in a Parr pressure reaction vessel the pressure tube was then sealed The solvent was then removed in vacuo the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc)

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrabutylammonium chloride (100 mg, 0.4 mmol), trimethyl(prop-1-ynyl)silane (1.1 ml, 7.2 mmol), methyl 2-amino-5-chloro-3-iodobenzoate (1.0 g, 3.6 mmol), triphenylphosphine (47.2 mg, 0.1 mmol), palladium(II) acetate (20 mg, 0.1 mmol) and sodium carbonate (1.9 g, 18 mmol) in DMF were added to a sealed tube and the reaction was stirred at 100° C. for 15 h: After cooling to room temperature, the reaction mixture was diluted with ether and washed with saturated aqueous ammonium chloride and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 5-chloro-3-methyl-2-(trimethylsilyl)-1H-indole-7-carboxylate (620 mg, 59%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.72 (d, J=1.0 Hz, 1H), 3.98 (s, 3H), 2.37 (s, 3H), 0.40 (t, 9H); MS (ESI+) m/z 296 (M+H). After cooling to room temperature washed with saturated aqueous ammonium chloride and water The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrabutylammonium chloride (100 mg, 0.4 mmol), trimethyl(prop-1-ynyl)silane (1.1 ml, 7.2 mmol), methyl 2-amino-5-chloro-3-iodobenzoate (1.0 g, 3.6 mmol), triphenylphosphine (47.2 mg, 0.1 mmol), palladium(II) acetate (20 mg, 0.1 mmol) and sodium carbonate (1.9 g, 18 mmol) in DMF were added to a sealed tube and the reaction was stirred at 100° C. for 15 h: After cooling to room temperature, the reaction mixture was diluted with ether and washed with saturated aqueous ammonium chloride and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 5-chloro-3-methyl-2-(trimethylsilyl)-1H-indole-7-carboxylate (620 mg, 59%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.72 (d, J=1.0 Hz, 1H), 3.98 (s, 3H), 2.37 (s, 3H), 0.40 (t, 9H); MS (ESI+) m/z 296 (M+H). After cooling to room temperature washed with saturated aqueous ammonium chloride and water The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrabutylammonium chloride (100 mg, 0.4 mmol), trimethyl(prop-1-ynyl)silane (1.1 ml, 7.2 mmol), methyl 2-amino-5-chloro-3-iodobenzoate (1.0 g, 3.6 mmol), triphenylphosphine (47.2 mg, 0.1 mmol), palladium(II) acetate (20 mg, 0.1 mmol) and sodium carbonate (1.9 g, 18 mmol) in DMF were added to a sealed tube and the reaction was stirred at 100° C. for 15 h. After cooling to room temperature, the reaction mixture was diluted with ether and washed with saturated aqueous ammonium chloride and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 5-chloro-3-methyl-2-(trimethylsilyl)-1H-indole-7-carboxylate (620 mg, 59%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.72 (d, J=1.0 Hz, 1H), 3.98 (s, 3H), 2.37 (s, 3H), 0.40 (t, 9H); MS (ESI+) m/z 296 (M+H). After cooling to room temperature washed with saturated aqueous ammonium chloride and water The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Added successively to a solution of 3 g of methyl 2-amino-5-chloro-3-iodobenzoate in 100 cm3 of toluene, under an inert atmosphere and at a temperature close to 20° C., are 2.2 g of 4-aminoheptane then 12 cm3 of a 2M solution of trimethylaluminum in toluene. The reaction mixture is heated, while stirring, for 16 h at 100° C., then it is cooled to 20° C. in order to then be poured over a mixture of 250 g of water/ice and 150 cm3 of ethyl acetate. The suspension obtained is filtered over a Celite 545 pellet. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined then washed with 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 12 g of crude product obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 3.21 g of 2-amino-5-chloro-3-iodo-N-(1-propylbutyl)benzamide are obtained. close to 20° C. The reaction mixture is heated it is cooled to 20° C. in order The suspension obtained is filtered over a Celite 545 pellet The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate The organic phases are combined then washed with 100 cm3 of a saturated aqueous solution of sodium chloride dried over magnesium sulfate concentrated a rotary evaporator under reduced pressure (5 kPa)

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

Procedure: The title compound was synthesized in analogy to 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (described in example S85) using 1-butyne (excess ca 3 ml), 2-amino-5-chloro-3-iodo-benzoic acid methyl ester (prepared as described in example S85) (430 mg, 1.38 mmol), copper (I) iodide (19 mg, 0.10 mmol) and bis(triphenyl-phosphine) palladium (II) chloride (71 mg, 0.10 mmol) in triethylamine (10 ml). The final compound was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-3-but-1-ynyl-5-chlorobenzoic acid methyl ester (120 mg, 37%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.49 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). The final compound was purified by flash column chromatography (9:1 cyclohexane:EtOAc)

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

Procedure: Propyne (excess ca 3 ml) was condensed onto a cold (−78° C.) solution of 2-amino-5-chloro-3-iodobenzoic acid methyl ester (500 mg, 1.61 mmol) in triethylamine (10 ml) in a Parr pressure reaction vessel. To this solution was added copper (I) iodide and bis(triphenylphosphine)palladium (II) chloride and the pressure tube was then sealed and stirred at rt for 4 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (340 mg, 95%) as an off white solid. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.13 (s, 3H). in a Parr pressure reaction vessel the pressure tube was then sealed The solvent was then removed in vacuo the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc)