* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iron; ammonium chloride In ethanol; water at 80℃; for 1 h;
Step 2: Preparation of l-methyl-lH-indazol-5-amine Iron powder (5.04 g, 0.0903 mol) is added portionwise to a solution of l-methyl-5- nitro-lH-indazole (4.00 g, 0.0226 mol) and ammonium chloride (12.1 g, 0.225 mol) in ethanol (225 mL) and water (100 mL) at 8O0C. The mixture is stirred and heated for Ih, diluted with dichloromethane (500 mL) and filtered. The organic layer is separated, dried (Mg2SO4) and evaporated to afford the title compound (3.29 g, 99percent); HPLC (SYMMETRY C18 3.5 μM, 4.6 x 30 mm column; gradient elution 2percent-98percent MeCN with 0.1percent TFA over 10 min; 2 mL/min rate): retention time = 1.06 min; MS for C1OHnN3 m/z 147.2(M+H)+.
71%
With hydrogenchloride; iron In ethanol; waterReflux
Iron (3.62 g, 64.7 mmol) and concentrated hydrochloric acid (0.1 mL) were added to ethanol/water (20 mL/20 mL), and refluxed for 1 hour. The mixed reaction solution was added with l-methyl-5-nitro-lH-indazole (2.29 g, 12.9 mmol) obtained in above, and further refluxed for 3 hours or more. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with chloroform/2-propanol = 4/l(v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol = 4/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.35 g, 71percent). -NMR Spectrum (300 MHz, OMSO-d6): δ 7.65 (d, 1H), 7.31 (d, 1H), 6.80 (d, 1H), 6.71 (d, 1H), 4.78 (s, 2H), 3.89 (s, 3H) MS(ESI+, m/z): 148 [M+H]+
71%
With hydrogenchloride; iron In ethanol; waterReflux
Iron (3.62 g, 64.7 mmol) and concentrated hydrochloric acid (0.1 mL) were added to ethanol/water (20 mL/20 mL), and refluxed for 1 hour. The mixed reaction solution was added with 1-methyl-5-nitro-1H-indazole (2.29 g, 12.9 mmol) obtained in <Step 1> above, and further refluxed for 3 hours or more. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with chloroform/2-propanol=4/1(v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol=4/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.35 g, 71percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 7.65 (d, 1H), 7.31 (d, 1H), 6.80 (d, 1H), 6.71 (d, 1H), 4.78 (s, 2H), 3.89 (s, 3H) MS (ESI+, m/z): 148 [M+H]+
18%
With ammonium chloride; acetic acid; zinc In ethanol; water; ethyl acetate at 20℃; for 1 h;
Zinc powder (194 mmol), ammonium chloride (388 mmol), and acetic acid (33.3 mmol) were added, successively, to a solution of l-methyl-5-nitro-1H-indazole (19.1 mmol) in ethanol (50 mL), water (20 mL), and ethyl acetate (5 mL) and the resulting suspension was maintained at rt for 1 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (5/1 petroleum ether/ethyl acetate) to provide 1 -methyl- 1H-indazol-5-amine in 18percent yield as a brown solid.
18%
With ammonium chloride; acetic acid; zinc In ethanol; water; ethyl acetate at 20℃; for 1 h;
2. Synthesis of 1 -methyl- lH-indazol-5-amine.Zinc powder (194 mmol), ammonium chloride (388 mmol), and acetic acid (33.3 mmol) were added, successively, to a solution of l-methyl-5-nitro-lH-indazole (19.1 mmol) in ethanol (50 mL), water (20 mL), and ethyl acetate (5 mL) and the resulting suspension was maintained at rt for 1 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (5/1 petroleum ether/ethyl acetate) to provide 1- methyl-lH-indazol-5-amine in 18percent yield as a brown solid.
18%
With ammonium chloride; acetic acid; zinc In ethanol; water; ethyl acetate at 20℃; for 1 h;
2. Synthesis of l-methyl-lH-indazol-5-amine.Zinc powder (194 mmol), ammonium chloride (388 mmol), and acetic acid (33.3 mmol) were added, successively, to a solution of l-methyl-5-nitro-lH-indazole (19.1 mmol) in ethanol (50 mL), water (20 mL), and ethyl acetate (5 mL) and the resulting suspension was maintained at rt for 1 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (5/1 petroleum ether/ethyl acetate) to provide 1- methyl-lH-indazol-5-amine in 18percent yield as a brown solid.
Reference：
[1] Patent: WO2007/88478, 2007, A1, . Location in patent: Page/Page column 19
[2] Tetrahedron, 2008, vol. 64, # 28, p. 6711 - 6723
[3] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
[4] Patent: WO2013/100632, 2013, A1, . Location in patent: Page/Page column 95
[5] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0662; 0663; 0664
[6] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[7] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 132
[8] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 97
[9] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 115
[10] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
[11] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000407
[12] Patent: WO2004/108663, 2004, A1, . Location in patent: Page 106-107
Stage #1: With caesium carbonate In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 0℃;
General procedure: Cesium carbonate (12.26mmol) was added to a solution of 5-nitroindazole 1 (6.13 mmol) in tetrahydrofuran (THF;25mL)cooledat 0°C. After 15 mn at 0°C, MeI or allyl bromide(6.13mmol) was added dropwise. Upon disappearance of the starting materialas indicated by TLC,the resulting mixture was evaporated.The crude material was dissolved with EtOAc(50mL),washed with water and brine,and dried over MgSO4; and the solvent was removed in vacuo.The resulting residue was purified by column chromatography on silica gel using EtOAc=hexane(3:7) to afford the desired products,1-alkyl-5-nitroindazole followed by2-alkyl-5-nitroindazole.
42%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; Stage #2: at 0 - 20℃; for 3 h;
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS (ESI+, m/z): 178 [M+H]+
Reference：
[1] Heterocycles, 2006, vol. 68, # 12, p. 2595 - 2605
[2] Journal of Chemical Research, Miniprint, 1990, # 11, p. 2601 - 2615
[3] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
6
[ 5401-94-5 ]
[ 74-88-4 ]
[ 5228-48-8 ]
[ 5228-49-9 ]
Yield
Reaction Conditions
Operation in experiment
58%
Stage #1: With caesium carbonate In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 0℃;
General procedure: Cesium carbonate (12.26mmol) was added to a solution of 5-nitroindazole 1 (6.13 mmol) in tetrahydrofuran (THF;25mL)cooledat 0°C. After 15 mn at 0°C, MeI or allyl bromide(6.13mmol) was added dropwise. Upon disappearance of the starting materialas indicated by TLC,the resulting mixture was evaporated.The crude material was dissolved with EtOAc(50mL),washed with water and brine,and dried over MgSO4; and the solvent was removed in vacuo.The resulting residue was purified by column chromatography on silica gel using EtOAc=hexane(3:7) to afford the desired products,1-alkyl-5-nitroindazole followed by2-alkyl-5-nitroindazole.
42%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; Stage #2: at 0 - 20℃; for 3 h;
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS (ESI+, m/z): 178 [M+H]+
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h; Stage #2: at 0 - 20℃; for 18 h;
Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-1H-indazole (18.40 mmol) inN,N-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 °C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5-nitro-1H-indazole in 83percent yield as a yellow solid.
83%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h; Stage #2: at 0 - 20℃;
Intermediate 40: Synthesis of l-methyl-lH-indazole-5-sulfonyl chloride.1. Synthesis of 1 -methγl-5-nitro- lH-indazole.Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-lH-indazole (18.40 mmol) in N.jV-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 0C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5- nitro-1/f-indazole in 83percent yield as a yellow solid.
83%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h; Stage #2: at 20℃; for 18 h;
Intermediate 40: Synthesis of l-methyl-l//-indazole-5-sulfonyl chloride. 1. Synthesis of l-methyl-5-nitro-lH-indazole.Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-lH-indazole (18.40 mmol) in N,N-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 0C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5- nitro-l//-indazole in 83percent yield as a yellow solid.
55%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 20℃;
Step 1: Preparation of l-methyl-5-nitro-lH-indazoleSodium hydride (5.40 g, 0.135 mol) is added portionwise to a solution of 5- nitroindazole (20.0 g, 0.122 mol) in DMF (250 mL) at room temperature. The reaction is <n="20"/>stirred for 30 minutes, iodomethane (8.40 mL, 0.135 mol) added dropwise, and the mixture allowed to react overnight at room temperature. The solvent is then removed in vacuo and the residue diluted with ethyl acetate, washed with water and brine, the organic layer dried (Mg2SO4) and evaporated. The residue is purified by flash chromatography (20percent EtOAc/Hexanes) to give the title compound (12.0 g, 55percent); HPLC (SYMMETRY C18 3.5 μM, 4.6 x 30 mm column; gradient elution 2percent-98percent MeCN with 0.1percent TFA over 10 min; 2 mL/min rate): retention time = 4.29 min; MS for C8H7N3O2 m/z 178.2(M+H)+.
42%
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 3 h;
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0°C. Separately, 5- nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1 -methyl added (Rf = 0.3), 2-methyl added (Rf = 0.1)) was purified using silica gel chromatography (ethyl acetate:hexane = 1 : 1 (v/v)) to obtain the title compound (Rf = 0.3, 2.29 g, 42percent). -NMR Spectrum (300 MHz, DMSO- ): δ 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS(ESI+, m/z): 178 [M+H]+
Reference：
[1] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 132
[2] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 97
[3] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 114; 115
[4] Journal of Organic Chemistry, 2014, vol. 79, # 16, p. 7286 - 7293
[5] Patent: WO2007/88478, 2007, A1, . Location in patent: Page/Page column 18-19
[6] Patent: WO2013/100632, 2013, A1, . Location in patent: Page/Page column 94; 95
[7] Journal of Chemical Research, 2014, vol. 38, # 4, p. 202 - 207
[8] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2015, vol. 136, # PC, p. 1484 - 1490
[9] Journal of Molecular Structure, 2016, vol. 1119, p. 151 - 156
8
[ 7597-18-4 ]
[ 74-88-4 ]
[ 6850-23-3 ]
[ 5228-49-9 ]
Yield
Reaction Conditions
Operation in experiment
59%
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1 h;
General procedure: Procedure E: NaH (1.1 equiv) was added to the solution of amine (1 equiv) in anhydrous N,N-dimethylformamide. Iodomethane (1.1 equiv) was added dropwise to the reaction mixture at 0°C.The reaction was continued at room temperature until the starting material was consumed. The resulting mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure.The product was carried on to the next reaction without further purification or was isolated by column chromatography.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3821 - 3830
9
[ 73105-48-3 ]
[ 5228-49-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
With tert.-butylnitrite In tetrahydrofuran for 1 h; Reflux
General procedure: A mixture of 3-amino-1-methyl-1H-indazole 2 (3.0 mmol) and tert-butyl nitrite (1.0 mL, 8.1 mmol, 2.7 equiv) in THF (12.0 mL) was heated to reflux for 1 h. The mixture was cooled to rt and then concentrated. H2O (10.0 mL) and EtOAc (20.0 mL) were added to the residue. The organic layer was washed with H2O (10.0 mL), brine (10.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to silica-gel chromatography by using Et2O/hexanes (1:4) as eluent to give the product 3.#10;
With iron; ammonium chloride; In ethanol; water; at 80℃; for 1h;
Step 2: Preparation of l-methyl-lH-indazol-5-amine Iron powder (5.04 g, 0.0903 mol) is added portionwise to a solution of l-methyl-5- nitro-lH-indazole (4.00 g, 0.0226 mol) and ammonium chloride (12.1 g, 0.225 mol) in ethanol (225 mL) and water (100 mL) at 8O0C. The mixture is stirred and heated for Ih, diluted with dichloromethane (500 mL) and filtered. The organic layer is separated, dried (Mg2SO4) and evaporated to afford the title compound (3.29 g, 99%); HPLC (SYMMETRY C18 3.5 muM, 4.6 x 30 mm column; gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min rate): retention time = 1.06 min; MS for C1OHnN3 m/z 147.2(M+H)+.
71%
With hydrogenchloride; iron; In ethanol; water;Reflux;
Iron (3.62 g, 64.7 mmol) and concentrated hydrochloric acid (0.1 mL) were added to ethanol/water (20 mL/20 mL), and refluxed for 1 hour. The mixed reaction solution was added with l-methyl-5-nitro-lH-indazole (2.29 g, 12.9 mmol) obtained in above, and further refluxed for 3 hours or more. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with chloroform/2-propanol = 4/l(v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol = 4/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.35 g, 71%). -NMR Spectrum (300 MHz, OMSO-d6): delta 7.65 (d, 1H), 7.31 (d, 1H), 6.80 (d, 1H), 6.71 (d, 1H), 4.78 (s, 2H), 3.89 (s, 3H) MS(ESI+, m/z): 148 [M+H]+
71%
With hydrogenchloride; iron; In ethanol; water;Reflux;
Iron (3.62 g, 64.7 mmol) and concentrated hydrochloric acid (0.1 mL) were added to ethanol/water (20 mL/20 mL), and refluxed for 1 hour. The mixed reaction solution was added with 1-methyl-5-nitro-1H-indazole (2.29 g, 12.9 mmol) obtained in <Step 1> above, and further refluxed for 3 hours or more. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with chloroform/2-propanol=4/1(v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol=4/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.35 g, 71%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 7.65 (d, 1H), 7.31 (d, 1H), 6.80 (d, 1H), 6.71 (d, 1H), 4.78 (s, 2H), 3.89 (s, 3H) MS (ESI+, m/z): 148 [M+H]+
18%
With ammonium chloride; acetic acid; zinc; In ethanol; water; ethyl acetate; at 20℃; for 1h;
Zinc powder (194 mmol), ammonium chloride (388 mmol), and acetic acid (33.3 mmol) were added, successively, to a solution of l-methyl-5-nitro-1H-indazole (19.1 mmol) in ethanol (50 mL), water (20 mL), and ethyl acetate (5 mL) and the resulting suspension was maintained at rt for 1 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (5/1 petroleum ether/ethyl acetate) to provide 1 -methyl- 1H-indazol-5-amine in 18% yield as a brown solid.
18%
With ammonium chloride; acetic acid; zinc; In ethanol; water; ethyl acetate; at 20℃; for 1h;
2. Synthesis of 1 -methyl- lH-indazol-5-amine.Zinc powder (194 mmol), ammonium chloride (388 mmol), and acetic acid (33.3 mmol) were added, successively, to a solution of l-methyl-5-nitro-lH-indazole (19.1 mmol) in ethanol (50 mL), water (20 mL), and ethyl acetate (5 mL) and the resulting suspension was maintained at rt for 1 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (5/1 petroleum ether/ethyl acetate) to provide 1- methyl-lH-indazol-5-amine in 18% yield as a brown solid.
18%
With ammonium chloride; acetic acid; zinc; In ethanol; water; ethyl acetate; at 20℃; for 1h;
2. Synthesis of l-methyl-lH-indazol-5-amine.Zinc powder (194 mmol), ammonium chloride (388 mmol), and acetic acid (33.3 mmol) were added, successively, to a solution of l-methyl-5-nitro-lH-indazole (19.1 mmol) in ethanol (50 mL), water (20 mL), and ethyl acetate (5 mL) and the resulting suspension was maintained at rt for 1 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (5/1 petroleum ether/ethyl acetate) to provide 1- methyl-lH-indazol-5-amine in 18% yield as a brown solid.
With iron; ammonium chloride; In ethanol; water; for 2h;Reflux;
[000407j To a stirred solution of compound 2 (1 g, 1 eq) in ethanol (20 mL), iron powder (1.19 g, 4 eq), water (10 mL) and ammonium chloride (1.19 g, 4 eq) were added slowly. The reaction mixture was refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 X 25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 60% EtOAc-hexane to afford the title compound 3. LCMS (mlz): 147.95 (M +1).
With hydrogenchloride; iron; In water; at 20 - 75℃; for 19.1667h;
To a stirred solution of l-methyl-5-nitroindazole (3.24g, commercially available)in concentrated hydrochloric acid (75ml) was added iron powder (3.53g) in portions over10 minutes, allowing the reaction temperature to gradually rise to 52C. On complete ?addition, the reaction mixture was heated to 70-75C for 1 hour, cooled to ambienttemperature and stored for 18 hours. The mixture was chilled by the addition of ice thentaken to pH 9 with aqueous sodium hydroxide filtered and the filtrate and insoluble solidsextracted with ethyl acetate (three times). The extracts were combined, washed with brineand dried over magnesium sulphate then evaporated under reduced pressure to give 5-amino-1-methylindazole as a pale brown solid..H NMR (CDC13) 5 ppm: 3.92 (3H,s); 4.80 (2H,s); 6.74(lH,m); 6.82 (lH,dd); 7.32(lH,d); 7.66 (lH,s).
General procedure: Cesium carbonate (12.26mmol) was added to a solution of 5-nitroindazole 1 (6.13 mmol) in tetrahydrofuran (THF;25mL)cooledat 0C. After 15 mn at 0C, MeI or allyl bromide(6.13mmol) was added dropwise. Upon disappearance of the starting materialas indicated by TLC,the resulting mixture was evaporated.The crude material was dissolved with EtOAc(50mL),washed with water and brine,and dried over MgSO4; and the solvent was removed in vacuo.The resulting residue was purified by column chromatography on silica gel using EtOAc=hexane(3:7) to afford the desired products,1-alkyl-5-nitroindazole followed by2-alkyl-5-nitroindazole.
42%
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0 C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS (ESI+, m/z): 178 [M+H]+
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;
[0004061 To a stirred solution of compound 1 (2 g, 1 eq) in DMF (20 mL), NaH (1.47 g,3 eq) was added slowly at 0 C followed by the addition of methyl iodide (2.3 mL, 3 eq) at same temperature. The reaction mixture was stirred at room temperature for 30 mm. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3 X 25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 50% EtOAc-hexane to afford the title compounds 2 and 5 (confirmed by NOE). LCMS (mlz):178.00(M+ 1).
Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-1H-indazole (18.40 mmol) inN,N-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5-nitro-1H-indazole in 83% yield as a yellow solid.
83%
Intermediate 40: Synthesis of l-methyl-lH-indazole-5-sulfonyl chloride.1. Synthesis of 1 -methgammal-5-nitro- lH-indazole.Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-lH-indazole (18.40 mmol) in N.jV-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 0C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5- nitro-1/f-indazole in 83% yield as a yellow solid.
83%
Intermediate 40: Synthesis of l-methyl-l//-indazole-5-sulfonyl chloride. 1. Synthesis of l-methyl-5-nitro-lH-indazole.Sodium hydride (55.0 mmol) was added to a solution of 5-nitro-lH-indazole (18.40 mmol) in N,N-dimethylformamide (50 mL) and the mixture was maintained for 60 min at 0 0C. To the mixture was added Methyl iodide (22.12 mmol) was added and the reaction mixture was allowed to warm to rt and was maintained for 18 h. The reaction mixture was quenched with water (60 mL), filtered through Celite, and the filtrate was concentrated to provide l-methyl-5- nitro-l//-indazole in 83% yield as a yellow solid.
55%
Step 1: Preparation of l-methyl-5-nitro-lH-indazoleSodium hydride (5.40 g, 0.135 mol) is added portionwise to a solution of 5- nitroindazole (20.0 g, 0.122 mol) in DMF (250 mL) at room temperature. The reaction is <n="20"/>stirred for 30 minutes, iodomethane (8.40 mL, 0.135 mol) added dropwise, and the mixture allowed to react overnight at room temperature. The solvent is then removed in vacuo and the residue diluted with ethyl acetate, washed with water and brine, the organic layer dried (Mg2SO4) and evaporated. The residue is purified by flash chromatography (20% EtOAc/Hexanes) to give the title compound (12.0 g, 55%); HPLC (SYMMETRY C18 3.5 muM, 4.6 x 30 mm column; gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min rate): retention time = 4.29 min; MS for C8H7N3O2 m/z 178.2(M+H)+.
42%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0C. Separately, 5- nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1 -methyl added (Rf = 0.3), 2-methyl added (Rf = 0.1)) was purified using silica gel chromatography (ethyl acetate:hexane = 1 : 1 (v/v)) to obtain the title compound (Rf = 0.3, 2.29 g, 42%). -NMR Spectrum (300 MHz, DMSO- ): delta 8.74 (d, 1H), 8.31 (dd, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 4.15 (s, 3H) MS(ESI+, m/z): 178 [M+H]+
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: To a solution of KOH (13.3 g, 238 mmol) in methanol (50mL) the appropriate 1-alkyl-5-nitro-1H-indazoles (10 mmol) and arylacetonitrile (12 mmol) were added with stirring. The mixture was stirred at rt for 24 h. After concentration at reduced pressure, the precipitate was collected by filtration, washed with water, following with EtOH, and then air dried to give crude 3a-e and 4a-d.
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: To a solution of KOH (13.3 g, 238 mmol) in methanol (50mL) the appropriate 1-alkyl-5-nitro-1H-indazoles (10 mmol) and arylacetonitrile (12 mmol) were added with stirring. The mixture was stirred at rt for 24 h. After concentration at reduced pressure, the precipitate was collected by filtration, washed with water, following with EtOH, and then air dried to give crude 3a-e and 4a-d.
With tert.-butylnitrite; In tetrahydrofuran; for 1h;Reflux;
General procedure: A mixture of 3-amino-1-methyl-1H-indazole 2 (3.0 mmol) and tert-butyl nitrite (1.0 mL, 8.1 mmol, 2.7 equiv) in THF (12.0 mL) was heated to reflux for 1 h. The mixture was cooled to rt and then concentrated. H2O (10.0 mL) and EtOAc (20.0 mL) were added to the residue. The organic layer was washed with H2O (10.0 mL), brine (10.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to silica-gel chromatography by using Et2O/hexanes (1:4) as eluent to give the product 3.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
General procedure: Procedure E: NaH (1.1 equiv) was added to the solution of amine (1 equiv) in anhydrous N,N-dimethylformamide. Iodomethane (1.1 equiv) was added dropwise to the reaction mixture at 0C.The reaction was continued at room temperature until the starting material was consumed. The resulting mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure.The product was carried on to the next reaction without further purification or was isolated by column chromatography.
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: Compound 1a or 1b (10 mmol) and thiophene-2-acetonitrile 2 (12 mmol) were added to a stirred solution of KOH (20 g, 357 mmol) in methanol (50 mL). The mixture was stirred at ambient temperature for 24 h. The solvent was distilled off under reduced pressure, and the precipitate was collected by filtration, washed with water and EtOH, dried in air, and crystallised from EtOH. The following compounds were prepared by this method.
2-(5-hydroxyimino-1-methyl-4,5-dihydro-1H-4 indazolyliden)-2-phenylacetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium hydroxide; In methanol; for 2h;Reflux;
General procedure: To a solution of KOH (20 g, 357 mmol) in methanol (80 mL) compounds 1a-d (10 mmol) and 2a-c (12 mmol) were added with stirring. The mixture was refluxed with stirring for 2 h, and then poured into water and then it was neutralized with dilute HCl solution. The precipitate was collected by filtration, washed with water, following with n-hexane-dichloromethane (50:50), and then air dried to give practically pure 3a-f. More purification was achieved by crystallization from suitable solvent such as n-hexane-ethyl acetate or acetone.
2-(5-hydroxyimino-1-methyl-4,5-dihydro-1H-4 indazolyliden)-2-(4 methylphenyl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium hydroxide; In methanol; for 2h;Reflux;
General procedure: To a solution of KOH (20 g, 357 mmol) in methanol (80 mL) compounds 1a-d (10 mmol) and 2a-c (12 mmol) were added with stirring. The mixture was refluxed with stirring for 2 h, and then poured into water and then it was neutralized with dilute HCl solution. The precipitate was collected by filtration, washed with water, following with n-hexane-dichloromethane (50:50), and then air dried to give practically pure 3a-f. More purification was achieved by crystallization from suitable solvent such as n-hexane-ethyl acetate or acetone.
2-(4-chlorophenyl)-2-(5-hydroxyimino-1-methyl-4,5-dihydro-1H-4 indazolyliden)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium hydroxide; In methanol; for 2h;Reflux;
General procedure: To a solution of KOH (20 g, 357 mmol) in methanol (80 mL) compounds 1a-d (10 mmol) and 2a-c (12 mmol) were added with stirring. The mixture was refluxed with stirring for 2 h, and then poured into water and then it was neutralized with dilute HCl solution. The precipitate was collected by filtration, washed with water, following with n-hexane-dichloromethane (50:50), and then air dried to give practically pure 3a-f. More purification was achieved by crystallization from suitable solvent such as n-hexane-ethyl acetate or acetone.
3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: The appropriate 1-alkyl-5-nitro-1H-indazoles 1a-e (10 mmol) andarylacetonitriles 2a-b (12 mmol) were added with stirring to a solutionof KOH (13 g, 238 mmol) in methanol (50 mL). The mixture was stirredat room temperature for 24 h. After concentration at reduced pressure,the precipitate was collected by filtration, washed with water, followedby EtOH, and then air dried to give crude 3a-h.
8-bromo-3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: The appropriate 1-alkyl-5-nitro-1H-indazoles 1a-e (10 mmol) andarylacetonitriles 2a-b (12 mmol) were added with stirring to a solutionof KOH (13 g, 238 mmol) in methanol (50 mL). The mixture was stirredat room temperature for 24 h. After concentration at reduced pressure,the precipitate was collected by filtration, washed with water, followedby EtOH, and then air dried to give crude 3a-h.
3,7-dimethyl-3,7-dihydropyrazolo[4,3-a]quinindoline-12-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: Compounds 1a,b (10mmol) and 2a,b (12mmol) were added with stirring to a of KOH (13g, 238mmol) in methanol (50mL). The mixture was stirred at rt for 24h. After concentration of the solution at reduced pressure, the precipitate was collected by filtration, washed with water, following with acetone, and then air dried to give practically pure 3a-d.
7-ethyl-3-methyl-3,7-dihydropyrazolo[4,3-a]quinindoline-12-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: Compounds 1a,b (10mmol) and 2a,b (12mmol) were added with stirring to a of KOH (13g, 238mmol) in methanol (50mL). The mixture was stirred at rt for 24h. After concentration of the solution at reduced pressure, the precipitate was collected by filtration, washed with water, following with acetone, and then air dried to give practically pure 3a-d.
General procedure: A mixture of 1-alkyl-5-nitroindazoles 2a,b (0.66 mmol) and anhydrous SnCl2 (3.3 mmol) in 25 mL of absolute alcohol was heated at 60 C. After reduction the solution was allowed to cool down. The pH was made slightly basic (pH 7-8) by addition of 5% aqueous potassium bicarbonate before being extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed to afford the amine, which was immediately dissolved in pyridine (5 mL) and then reacted with arylsulfonyl chloride (0.72 mmol) at room temperature overnight. After the reaction mixture was concentrated in vacuo, the resulting residue was purified by flash chromatography (eluted with EtOAc/hexane).
5-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With acetic acid; tin(ll) chloride; In tetrahydrofuran; at 80℃;
General procedure: Method A. N-alkyl-6-nitroindazoles(1.0 mmol) were added to a mixture of anhydrous SnCl2 powder (460mg, 4.0 mmol), and acetic acid (0.572 mL, 10 mmol) in tetrahydrofuran (10 mL),followed by the addition of 2,5-hexadione (1.0 mmol) in THF (15 mL). Thereaction mixture was stirred at 80 C for 3 to 5 h. After the reaction wascompleted, the mixture was diluted with ethyl acetate (30 mL), poured into 10%NaHCO3 (30 mL), and then extracted with ethyl acetate (50 mL x 3).The combined organic extracts were dried over MgSO4, filtered, andconcentrated. The residue was purified by column chromatography on silica gelusing ethyl acetate/hexane (3:7) to afford the desired products N-alkyl-6-pyrrolyl-indazolesin good to excellent yields.
1-(4-methoxyphenyl)-6-methyl-6H-isoxazolo[4,3-e]-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%; 45%
With potassium hydroxide; In methanol; for 48h;Reflux;
General procedure: 1-Alkyl-5-nitro-1H-indazole 1 (1.77 g, 10 mmol) andnitrile 2a-e (12 mmol) were added with stirring to asolution of KOH (30 g, 535 mmol) in methanol (70 ml).The mixture was refluxed for 48 h and then poured intowater. The precipitate was filtered off, washed with water,and air-dried to give crude product 5a-e with admixture ofside product 4a-e. Washing the crude product withacetone, evaporation of the filtrate, and recrystallization ofthe residue from MeOH gave pure compound 5a-e, whilecrude compound 4a-e remained as precipitate on the filter.Compound 4a-e was purified by recrystallization fromEtOH
8-chloro-3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile[ No CAS ]
1-(4-chlorophenyl)-6-methyl-6H-isoxazolo[4,3-e]-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%; 63%
With potassium hydroxide; In methanol; for 48h;Reflux;
General procedure: 1-Alkyl-5-nitro-1H-indazole 1 (1.77 g, 10 mmol) andnitrile 2a-e (12 mmol) were added with stirring to asolution of KOH (30 g, 535 mmol) in methanol (70 ml).The mixture was refluxed for 48 h and then poured intowater. The precipitate was filtered off, washed with water,and air-dried to give crude product 5a-e with admixture ofside product 4a-e. Washing the crude product withacetone, evaporation of the filtrate, and recrystallization ofthe residue from MeOH gave pure compound 5a-e, whilecrude compound 4a-e remained as precipitate on the filter.Compound 4a-e was purified by recrystallization fromEtOH
8-bromo-3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile[ No CAS ]
1-(4-bromophenyl)-6-methyl-6H-isoxazolo[4,3-e]-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%; 55%
With potassium hydroxide; In methanol; for 48h;Reflux;
General procedure: 1-Alkyl-5-nitro-1H-indazole 1 (1.77 g, 10 mmol) andnitrile 2a-e (12 mmol) were added with stirring to asolution of KOH (30 g, 535 mmol) in methanol (70 ml).The mixture was refluxed for 48 h and then poured intowater. The precipitate was filtered off, washed with water,and air-dried to give crude product 5a-e with admixture ofside product 4a-e. Washing the crude product withacetone, evaporation of the filtrate, and recrystallization ofthe residue from MeOH gave pure compound 5a-e, whilecrude compound 4a-e remained as precipitate on the filter.Compound 4a-e was purified by recrystallization fromEtOH
3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile[ No CAS ]
6-methyl-1-phenyl-6H-isoxazolo[4,3-e]indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%; 65%
With potassium hydroxide; In methanol; for 48h;Reflux;
General procedure: 1-Alkyl-5-nitro-1H-indazole 1 (1.77 g, 10 mmol) andnitrile 2a-e (12 mmol) were added with stirring to asolution of KOH (30 g, 535 mmol) in methanol (70 ml).The mixture was refluxed for 48 h and then poured intowater. The precipitate was filtered off, washed with water,and air-dried to give crude product 5a-e with admixture ofside product 4a-e. Washing the crude product withacetone, evaporation of the filtrate, and recrystallization ofthe residue from MeOH gave pure compound 5a-e, whilecrude compound 4a-e remained as precipitate on the filter.Compound 4a-e was purified by recrystallization fromEtOH
6-methyl-1-(p-tolyl)-6H-isoxazolo[4,3-e]indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%; 56%
With potassium hydroxide; In methanol; for 48h;Reflux;
General procedure: 1-Alkyl-5-nitro-1H-indazole 1 (1.77 g, 10 mmol) andnitrile 2a-e (12 mmol) were added with stirring to asolution of KOH (30 g, 535 mmol) in methanol (70 ml).The mixture was refluxed for 48 h and then poured intowater. The precipitate was filtered off, washed with water,and air-dried to give crude product 5a-e with admixture ofside product 4a-e. Washing the crude product withacetone, evaporation of the filtrate, and recrystallization ofthe residue from MeOH gave pure compound 5a-e, whilecrude compound 4a-e remained as precipitate on the filter.Compound 4a-e was purified by recrystallization fromEtOH
3-methyl-3H-benzo[a]pyrazolo[3,4-j]acridine-13-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium hydroxide; In methanol; at 20℃; for 48h;
General procedure: 1-alkyl-5-nitro-1H-indazoles 1a-d (10 mmol) and 1-naphthylacetonitrile (2) (13 mmol) were added with stirring to a solution of KOH(20 g, 357 mmol) in methanol (40 mL). The mixture was stirred at r.t. for 48 h. After concentration at reduced pressure, the precipitate wascollected by filtration, washed with water, followed by cold EtOH and acetone, and then air dried to give the crude products 3a-d. Further purification was achieved by crystallisation from a suitable solvent such as EtOH or acetone. 3-Methyl-3H-benzo[a]pyrazolo[3,4-j]acridine-13-carbonitrile(3a): Shiny yellow needles (acetone); m.p. 320-322 C; yield 73%;IR (KBr) (numax cm-1): 2223 (CN); 1H NMR (300 MHz, CDCl3): delta 4.17(3H, s, NCH3), 7.78-7.99 (7H, m, ArH), 8.09 (1H, d, J = 9.3 Hz, ArH),9.42 (1H, s, ArH), 9.98 (1H, d, J = 7.5 Hz, ArH); 13C NMR (75 MHz,CDCl3): delta 36.2, 107.3, 115.3, 116.4, 120.5, 123.2, 124.1, 126.0, 127.5,128.1, 128.3, 129.0, 129.3, 129.3, 132.5, 133.4, 135.5, 137.4, 145.7,147.6; MS (m/z) 308 [M]+ found: C, 78.05; H, 3.94; N, 17.90; calcd forC20H12N4 (308.3): C, 77.91; H, 3.92; N, 18.17%.
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 3h;
To a solution of 9.78 g (60 mmol) of 1-methyl-1H-indazole in 20 mL of dimethylsulfoxide were successively added 3.53 g (63 mmol) of powdered KOH and 8.52 g (60 mmol) of methyl iodide. The mixture was stirred at room temperature for 3 h, after which it was diluted with 200 mL of water. The precipitate was separated and crystallized from 2-propanol. Yield 9.45 g (mixture of isomers), yellowish crystals.
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