4-bromo-2-methyl-1H-indole

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-2-methyl-1H-indole (22 mg, 0.104 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with DCM:methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v), passed through a 1 g C18 cartridge washing with acetonitrile and evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method G). Pure fractions were combined, evaporated to dryness, the residue suspended in 3 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as an off-white solid (17 mg). cooled was washed with DCM The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 washing with acetonitrile evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method G) evaporated to dryness v/v) and freeze dried

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-2-methyl-1H-indole (22 mg, 0.104 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with DCM:methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v), passed through a 1 g C18 cartridge washing with acetonitrile and evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method G). Pure fractions were combined, evaporated to dryness, the residue suspended in 3 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as an off-white solid (17 mg). cooled was washed with DCM The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 washing with acetonitrile evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method G) evaporated to dryness v/v) and freeze dried

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-methyl-1H-indole (572 mg, 2.72 mmol), Zn(CN)2 (351 mg, 3.0 mmol), Zn (35 mg, 0.54 mmol), dppf (606 mg, 1.09 mmol), and Pd2(dba)3 (498 mg, 0.54 mmol) in NMP (10 mL) under argon atmosphere was heated at 120° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford 2-methyl-1H-indole-4-carbonitrile as a yellow oil (408 mg, 96%). MS (ESI): m/z=157.2 [M+1]+. After cooling to RT the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL) The organic layer was washed with brine dried (MgSO4) filtered concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of 2-(2-bromophenyl)-3-methyl-2H-azirine (758 mg, 3.61 mmol) in xylene (20 mL) was stirred at 160° C. for 7 d. The reaction mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 4-bromo-2-methyl-1H-indole as yellow oil (572 mg, 75.5%). MS (ESI): m/z=210.1 [M+1]+. The reaction mixture was concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of 2-(2-bromophenyl)-3-methyl-2H-azirine (758 mg, 3.61 mmol) in xylene (20 mL) was stirred at 160° C. for 7 d. The reaction mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 4-bromo-2-methyl-1H-indole as yellow oil (572 mg, 75.5%). MS (ESI): m/z=210.1 [M+1]+. The reaction mixture was concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-2-methyl-1H-indole (22 mg, 0.104 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with DCM:methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v), passed through a 1 g C18 cartridge washing with acetonitrile and evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method G). Pure fractions were combined, evaporated to dryness, the residue suspended in 3 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as an off-white solid (17 mg). cooled was washed with DCM The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 washing with acetonitrile evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method G) evaporated to dryness v/v) and freeze dried

反応条件: temp:14.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.99 g of sodium cyanoborohydride are gradually added to a solution of 8.90 g of 4-bromo-2-methylindole (which can be prepared according to patent US2010/160647 A1, 2010) in 310 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is stirred at a temperature of about 14° C. for 15 minutes, and it is then allowed to warm up to ambient temperature. After 2 hours, the reaction mixture is poured into an Erlenmeyer flask containing ice-cold water (200 ml) and then the pH is brought to 9 with an aqueous ammonia solution. The reaction medium is extracted with dichloromethane (2×200 ml) and then the organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (90/10), 5.92 g of 4-bromo-2-methylindoline are obtained, the characteristics of which are the following: to warm up to ambient temperature After 2 hours the reaction mixture is poured into an Erlenmeyer flask The reaction medium is extracted with dichloromethane (2×200 ml) washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (90/10), 5.92 g of 4-bromo-2-methylindoline are obtained

反応条件: temp:14.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.99 g of sodium cyanoborohydride are gradually added to a solution of 8.90 g of 4-bromo-2-methylindole (which can be prepared according to patent US2010/160647 A1, 2010) in 310 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is stirred at a temperature of about 14° C. for 15 minutes, and is then left to warm back up to ambient temperature. After 2 hours, the reaction mixture is poured into an Erlenmayer flask containing ice-cold water (200 ml) and the pH is then brought to 9 with an aqueous ammonia solution. The reaction medium is extracted with dichloromethane (2×200 ml) and then the organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (90/10), 5.92 g of 4-bromo-2-methylindoline are obtained. is then left to warm back up to ambient temperature After 2 hours the reaction mixture is poured into an Erlenmayer flask The reaction medium is extracted with dichloromethane (2×200 ml) washed with water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (90/10), 5.92 g of 4-bromo-2-methylindoline are obtained

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-methyl-1H-indole (containing 25% of the 6-bromo isomer) (8.30 g), palladium (II) acetate (0.45 g), tri-o-tolylphosphine (1.22 g), benzyl acrylate (9.76 g) and triethylamine (8.36 ml) in acetonitrile (8 ml) was heated in an oil bath at 140° C. under an atmosphere of nitrogen for 2 hours. The mixture was cooled and partitionedbetween dichloromethane and water. The organic layer was separated, washed three times with water and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/hexane (1:1) first gave impurity followed by pure product.The product fractions were evaporated and the residue was triturated with ether to give the title compound (6.60 g), m.p. 135°-136° C.Found: C,77.98; H,6.10; N,4.71. C19H17NO2 requires: C,78.33; H,5.88; N,4.81%. Further elution with dichloromethane/hexane (4:1) gave benzyl (E)-3-(2-methyl-1H-indol-6-yl)-2-propenoate (2.0 g), m.p. 164°-165° C. Found: C,78.53; H,6.06; N,4.74. C19 H17NO2 requires: C,78.33; H,5.88; N,4.81%. The mixture was cooled The organic layer was separated washed three times with water dried (MgSO4) Evaporation of the solvent gave an oil which was chromatographed on silica gel Elution with dichloromethane/hexane (1:1) first gave impurity were evaporated the residue was triturated with ether

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-methyl-1H-indole (572 mg, 2.72 mmol), Zn(CN)2 (351 mg, 3.0 mmol), Zn (35 mg, 0.54 mmol), dppf (606 mg, 1.09 mmol), and Pd2(dba)3 (498 mg, 0.54 mmol) in NMP (10 mL) under argon atmosphere was heated at 120° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford 2-methyl-1H-indole-4-carbonitrile as a yellow oil (408 mg, 96%). MS (ESI): m/z=157.2 [M+1]+. After cooling to RT the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL) The organic layer was washed with brine dried (MgSO4) filtered concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The solution of 2-(2-bromophenyl)-3-methyl-2H-azirine (758 mg, 3.61 mmol) in xylene (20 mL) was stirred at 160° C. for 7 d. The reaction mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 4-bromo-2-methyl-1H-indole as yellow oil (572 mg, 75.5%). MS (ESI): m/z=210.1 [M+1]+. The reaction mixture was concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-2-methyl-1H-indole (22 mg, 0.104 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with DCM:methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v), passed through a 1 g C18 cartridge washing with acetonitrile and evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method G). Pure fractions were combined, evaporated to dryness, the residue suspended in 3 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as an off-white solid (17 mg). cooled was washed with DCM The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 washing with acetonitrile evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method G) evaporated to dryness v/v) and freeze dried