* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4632 - 4640
[2] Journal of the Chemical Society, 1955, p. 2412,2419
[3] Bulletin de la Societe Chimique de France, 1958, p. 152,156
[4] Patent: US2009/54425, 2009, A1, . Location in patent: Page/Page column 22
[5] Patent: EP2226315, 2010, A1, . Location in patent: Page/Page column 40
2
[ 6494-19-5 ]
[ 201286-99-9 ]
Reference：
[1] Journal of the Chemical Society, 1955, p. 2412,2419
3
[ 20191-74-6 ]
[ 6494-19-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
With tert.-butylnitrite In acetic acid at 20℃; for 0.75 h; Inert atmosphere
Intermediate Example 1 Preparation of 3-methyl-1H-indazol-6-amine To a solution of 10 g (.06 mol) of 2-ethyl-5-nitroaniline (prepared by nitration of 2-ethylaniline:) in 300 ml of glacial acetic acid, at room temperature, was added a solution of 8.98 ml (.06 mol) of tert-butyl nitrite in 40 ml of acetic acid dropwise over 15 min. After the addition was complete the solution was allowed to stir for 30 min. The acetic acid was removed in vacuo to afford an orange solid. The solid was dissolved in approximately 120 ml of ethyl acetate and washed with 3 x 100 ml sat. aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to afford 3-methyl-6-nitroindazole as a yellow solid (10.4 g, 98percent). To a stirred solution of 10 g (.06 mol) of 3-methyl-6-nitroindazole in 100 ml of 2-methoxyethyl ether, at 0 °C, was added a solution of 45 g (.24 mol) of tin(II) chloride in 86 ml of concentrated HCl dropwise over 15 min, in order to keep the reaction temperature below 100 °C. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 20 min. Approximately 70 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (10 g, 92 percent), the HCl salt of 3-methyl-1H-indazol-6-amine.
98%
for 0.5 h;
A solution of tert-butyl nitrite (12.5ml, 0.075mol) in glacial aceticacid (50ml) was added dropwise to a 2-1 (12.5g, 0.075mol) in glacial aceticacid (375mL) solution. Continue stirring the reaction 30min. The reactionsolution was concentrated to dryness, the resulting orange solid was dissolvedin ethyl acetate (150 mL), and saturated aqueous sodium bicarbonate (125mL ×3), dried, filtered, and concentrated to give 13.0 g of a yellow solid, yield98percent,
40.5%
at 0 - 25℃;
Step 1 3-Methyl-6-nitro-1H-indazole Following generally the procedure reported by Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73, 2-ethyl-5-nitroaniline (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 424 mg) in water (1 ml) was added all at once. Stirring was continued for 15 minutes at 25° C. After 3 hours, residual solids were filtered off and discarded, and the filtrate was allowed to stand for 3 days at room temperature. The solution was concentrate in vacuo, and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was filtered and washed thoroughly with cold water, dried and purified by flash chromatography (4:1 hexanes/ethyl acetate) to give 3-methyl-6-nitro-1H-indazole (436 mg, 40.5percent) as a solid.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4632 - 4640
[2] Patent: EP2311825, 2015, B1, . Location in patent: Paragraph 0157 - 0159
[3] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0125-0126; 0130-0132
[4] Letters in Organic Chemistry, 2012, vol. 9, # 4, p. 276 - 279
[5] Patent: US2010/160388, 2010, A1, . Location in patent: Page/Page column 54
[6] Patent: US2009/54425, 2009, A1, . Location in patent: Page/Page column 22
[7] Patent: EP2226315, 2010, A1, . Location in patent: Page/Page column 39-40
[8] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
4
[ 578-54-1 ]
[ 6494-19-5 ]
Reference：
[1] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
[2] Patent: CN103739550, 2016, B,
5
[ 6494-19-5 ]
[ 616-38-6 ]
[ 444731-73-1 ]
Yield
Reaction Conditions
Operation in experiment
81.1%
Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: for 6 h; Reflux
3-methyl-6-nitro-1H-indazole (1a, 10.00 g, 56 mmol) and triethylenediamine (DABCO, 6.40 g, 56 mmol) were dissolved in 100 mL of DMF. The mixture was stirred for 15 min at room temperature, then dimethyl carbonate (DMC) (6.04 g, 67 mmol) was added dropwise to it. After the addition, the reaction mixture was heated to reflux and stirred for 6 h. After cooling to room temperature, 120 mL of water was added and stirred for 15 min, a large amount of light-yellow solid appeared, the solid was filtered and dried to give 2a (8.66 g, 81.1percent yield). Mp: 187~187.6 C. 1HNMR (400MHz, DMSO-d6) δ: 2.67 (s, 3H), 4.14 (s, 3H), 7.73 (d, J=9.2 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.51 (s, 1H).
70.6%
With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide; isopropyl alcohol at 70℃; for 20 h;
In a 250 ml three-necked flask,40 ml of DMF was added,5 ml of isopropanol,17.7 g (0.1 mol) of 3-methyl-6-nitro-1H-indazole,Stirring dissolved,Further, 18 g (0.2 mol) of dimethyl carbonate was added,12.3 g (0.11 mol) of triethylenediamine.The reaction was heated to 70 ° C for 20 h,To room temperature,Poured into 900ml of ice water,Stirring 30mins,A large amount of yellow solid precipitated,Filtration,Dried in vacuo to give 13.5 g of a yellow solid,Yield 70.6percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1108 - 1110
[2] Patent: CN103319410, 2016, B, . Location in patent: Paragraph 0035; 0036
[3] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 989 - 994
6
[ 6494-19-5 ]
[ 149-73-5 ]
[ 444731-73-1 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at -30 - 0℃; for 0.25 h; Stage #2: at 20℃; for 17 h;
Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period [TO A] solution of boron [TRIFLUORIDE] etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been [COOLED TO-30 C.] The mixture was warmed to 0 [C] for 15 min and was then cooled to-70 [C.] The nitro [INDAZOLE] (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at-70 [C] for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until-10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2, 3-dimethyl-6-nitro-2H-indazole (65 percent, [7MMOL,] 1.25 g) as a light yellow [POWDER.APOS;H] NMR (300 MHz, [DMSO-D6)] 8 8.51 (s, [1 H),] 7.94 (d, [J =] 9.1 Hz, [1 H),] 7.73 [(D, J] = 8.9 Hz, [1 H),] 4.14 (s, [3H),] 2.67 (s, [3H).] MS (ES+, m/z) 192 (M+H).
65%
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at -30 - 0℃; for 0.25 h; Stage #2: at -70 - 20℃; for 17.25 h; Stage #3: With sodium hydrogencarbonate In dichloromethane; water
Procedure 2: Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30° C. The mixture was warmed to 0° C. for 15 min and was then cooled to -70° C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70° C. for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6-nitro-2H-indazole (65percent, 7 mmol, 1.25 g) as a light yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
65%
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at -30 - 0℃; for 0.283333 h; Stage #2: at -70 - 20℃; for 17.25 h;
Procedure 2: Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to-30 °C. The mixture was warmed to 0 °C for 15 min and was then cooled to-70 °C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at-70 °C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until - 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6-nitro-2H- indazole (65 percent, 7mmol, 1.25 g) as a light yellow powder.
65%
With boron trifluoride diethyl etherate In dichloromethane at -70 - 20℃; for 17.5333 h;
Thmethyl orthoformate (1 1 mmol, 1 .17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30 0C. The mixture was warmed to 0 0C for 15 min and was then cooled to -70 0C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70 0C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until ~ 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6- nitro-2H-indazole (65 percent, 7mmol, 1.25 g) as a light yellow powder. 1H NMR (300 MHz, DMSOd6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
Example 1 Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was stirred at 25° C. to 30° C. for 16 hours. The solvent was recovered under reduced pressure. A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4:1 mixture of dichloromethane isopropyl alcohol (1080 mL*5). The solvent was recovered under reduced pressure. Methyl tert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45° C. to 50° C. The reaction mixture was cooled to 25° C. to 30° C. and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert-butyl ether (100 mL*2), and dried in an air oven at 50° C. for 12 hours to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid. Yield: 82.4percent w/w
73%
at 20℃; for 3 h;
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-7H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added <n="26"/>saturated aqueous NaHCO3 (600 mL) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro- 2tf-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73%
at 20℃; for 3 h;
To a stirred solution of 18.5 g (0.11 mol) of [3-METHYL-6-NITRO-1H-INDAZOLE] in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of [TRIMETHYLOXONIUM] [TETRAFLOUROBORATE.] After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous [NAHC03] (600 mL) and a 4: 1 mixture of chloroform-isopropanol (200 [ML),] the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried [(NA2S04).] Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2, 3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 [G,] 73 [percent).APOS;H] NMR (300 MHz, [DMSO-D6)] 8 8.51 (s, [1 H),] 7.94 (d, [J= 9.] 1 Hz, [1 H),] 7.73 (d, [J =] 8.9 Hz, [1 H),] 4.14 (s, 3H), 2.67 (s, 3H). MS [(ES+,] [M/Z)] 192 (M+H).
73%
at 20℃; for 3 h;
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml_) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H)1 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73%
at 20℃; for 3 h; Inert atmosphere
Intermediate Example 11 Preparation of 2,3-dimethyl-2H-indazol-6-amine To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, d6DMSO) δ 8.51 (s, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).; To a stirred solution of 2,3-dimethyl-6-nitro-2H-indazole (1.13 g) in 2-methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(II) chloride in 8.9 ml of concentrated HCl dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 percent), the HCl salt 2,3-dimethyl-2H-indazol-6-amine. 1H NMR (300 MHz, d6DMSO) δ 7.77 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 7.88 (m, 1H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).
73%
at 20℃; for 3 h; Inert atmosphere
18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole was dissolved in 350 ml of acetone,20 g (0.14 mol) of trimethyloxonium tetrafluoroborate was added with stirring at room temperature,The reaction solution was filled with argon for 3 h,The solvent was removed under reduced pressure,The solid was added with 600 ml of aqueous NaHCO3 solution,200 ml of a mixture of chloroform and isopropanol (4: 1)The organic phase was dried over anhydrous sodium sulfate,filter,The solvent was distilled off,To give a brown solid,Washed with ether,15.85 g of 2,3-dimethyl-6-nitro-2H-indazole was obtained in a yield of 73percent.
73%
Stage #1: at 20℃; for 3 h; Stage #2: With sodium hydrogencarbonate In chloroform; water; isopropyl alcohol
Intermediate Example 1 Preparation of 2,3-dimethyl-6-nitro-2H-indazole Procedure 1: To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetrafluoroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 mL) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4*200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73percent). 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73%
at 20℃; for 3 h;
Intermediate Example 1 Preparation of 2,3-dimethyl-6-nitro-2H-indazole Procedure 1: To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H- indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 mL) and a 4: 1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2S04). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent).
73%
at 20℃; for 3 h;
To a stirred solution of 18.5 g (0.1 1 mol) of 3-methyl-6-nitro-7/-/-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of thmethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml_) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2/-/-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSOd6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
32%
Stage #1: at 20℃; for 7.5 h; Inert atmosphere Stage #2: With sodium hydrogencarbonate In water
Example 50: Process for preparation of DMND[000167] To a stirred solution of 3-methyl-6-nitro- l H-indazole (MNID) (5.0 g, 28.2 mmol) in acetone (95 mL, 19V) at ambient temperature was added trimethyloxonium tetrafluoroborate (5.3 g, 35.8 mmol, 1 .27 eq). Stirring was continued under nitrogen and the reaction was monitored by TLC. After 5.5 h another 1 g of trimethyloxonium tetrafluoroborate was added to the reaction in an attempt to push it to completion. After 7.5 h total reaction time the solvent was removed and saturated sodium bicarbonate ( 162 mL) was added to the residue, followed by a 4: 1 mixture of CHC : IPA (54 mL). The resulting mixture was agitated and the layers were separated. The aqueous phase was washed with additional CHCI3: IPA 4: 1 (4x54 mL) and the combined organic phases were dried ( a2SO,)), filtered and evaporated to dryness. The resulting brown solid was washed with diethylether (about 160 mL) and dried on the filter under nitrogen/vacuum to afford crude DMND (3.2 g, 87.5percent purity). The crude material (2.9 g) was then dissolved in EtOH (50 mL) at reflux and the solution was gradually cooled to ambient temperature and then to 5 °C, and was kept at this temperature for 1 h. The resulting precipitate was isolated by filtration and the filter cake was washed with cold EtOH ( 10 mL) and dried in a vacuum oven (35 mbar) at 55°C for 4 h to give 2,3-dimethyl-6-nitro-2H-indazole ( 1 .57g, ca 32percent) as a yellow solid.
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h;
In a 25 ml round bottom flask 3-methyl-6-nitroindazole (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 0C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was <n="27"/>extracted with methylene chloride (2 x 20 ml_). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.94 (d, J= 9.1 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h;
In a 25 ml round bottom flask 3-methyl-6-nitroindazole (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 [MMOL,] 2.66 g). The mixture was heated under nitrogen at 50 [C] for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2 x 20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2, 3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow [SOLID.APOS;H] NMR (300 MHz, DMSO- [D6)] [6 8.] 51 (s, [1 H),] 7.94 (d, [J=] 9.1 Hz, [1 H),] 7.73 (d, [J= 8.] 9 Hz, [1 H),] 4.14 (s, 3H), 2.67 (s, 3H). MS [(ES+,] m/z) 192 (M+H).
70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h;
In a 25 ml round bottom flask 3-methyl-6-nitroindazole (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 0C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2 x 20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h; Inert atmosphere
A solution of 1.28 g (0.00727 mol) of 3-methyl-6-nitro-1H-indazole was dissolved in 4 ml of DMSO,(0.00727 mol) of concentrated sulfuric acid to give a thick slurry,Further, 2.66 g (0.0211 mol) of dimethyl sulfate was added,The mixture was heated at 50 ° C under nitrogen for 72 hours,A thick yellow slurry was obtained,After cooling,10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added slowly,Extracted twice with 20 ml of dichloromethane,The organic layers were combined,Reverse extraction with 20 ml of water,The methylene chloride layer was added with 10 ml of propanol,The methylene chloride was distilled off under reduced pressure,Filtration,To give a yellow solid,Washed with 5 ml of heptane,dry,To give 2,3-dimethyl-6-nitro-2H-indazole, 0.97 g, yield 70percent.
70%
Stage #1: With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h; Stage #2: With sodium hydrogencarbonate In water; dimethyl sulfoxide
In a 25 ml round bottom flask 3-methyl-6-nitroindazole (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50° C. for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2.x.20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h;
Procedure 3: In a 25 ml round bottom flask 3-methyl-6-nitroindazole (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 °C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2 x 20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid.
70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72 h;
In a 25 ml round bottom flask 3-methyl-6-nitroindazole (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric <n="30"/>acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 0C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 ml_). The mixture was extracted with methylene chloride (2 x 20 ml_). The methylene chloride layers were combined and back extracted with water (20 ml_). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2/-/-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSOd6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
Stage #1: With sodium In isopropyl alcohol for 3 h; Reflux Stage #2: for 5 h; Reflux
Sodium (3.2g, 0.14mol) was addedportionwise to refluxingisopropanol (140ml)and stirred until the whole solution, was added 2-2 (13.0g, 0.073mol), plus complete reflux wascontinued for 3h. Iodomethane (30.0g,0.21mol) in isopropanol (45 ml of) the solution was refluxed for 5h. Cooled, allowed to stand overnight. Andfiltered to give a pale yellow solid 12.0g, yield 87.6percent.
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at -70 - 0℃; for 0.25 h; Stage #2: at -70 - 20℃; for 17.25 h;
Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30 0C. The mixture was warmed to 0 0C for 15 min and was then cooled to -70 0C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70 0C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until ~ 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6-nitro-2H-indazole (65 percent, 7mmol, 1.25 g) as a light yellow powder. 1H NMR (300 MHz, DMSO-d6) 58.51 (s, 1 H), 7.94 (d, J= 9.1 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
With ammonium formate In methanol; water at 25 - 30℃; for 6 h;
Procedure 2: A 2-L 3-necked round bottom flask was fitted with nitrogen inlet and outlet and with mechanical stirring. A moderate nitrogen flow was initiated and the reactor was charged with 10percent Pd/C (50percent water wet, 6.0 g). Stirring was initiated and the reactor was charged with methanol (750 mL) and the product of Intermediate Example 1 (50 g). Ammonium formate (82.54 g) was dissolved in water (120 mL). The water solution of ammonium formate was added to the reaction solution at an addition rate, which kept the reaction temperature at or between 25 and 30° C. The reaction was allowed to proceed at 25° C. After 6 h the reaction was judged to be finished based on HPLC analysis. The mixture was filtered and the catalyst washed with methanol (50 mL). The methanol layers were combined and the solvent removed under reduced pressure. The residue was dissolved in water (200 mL) and was extracted with methylene chloride (3*250 mL). The methylene chloride layers were combined and solvent removed under vacuum to remove approximately half the solvent. Heptane (400 mL) was added and the vacuum distillation continued until approximately 300 mL reaction product slurry remained. The product was isolated by filtration and dried under vacuum at 50° C. for 4 h. to yield 2,3-dimethyl-6-amino-2H-indazole as the free base. (40.76 g, 96.7percent). 1H NMR (300 MHz, DMSO-d6) δ 7.31 (d, J=8.9 Hz, 1H), 6.45 (d, J=8.9 Hz, 1H), 6.38 (s, 1H), 4.95 (s, br, 2H), 3.85 (s, 3H), 2.44 (s, 3H) MS (ES+, m/z) 162 (M+H).
With ammonium formate; iron; In ethanol; water; at 90℃; for 2h;
To a solution of <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (0.4 g, 2.24 mmol) in ethanol (EtOH) (10 mL) and H2O (5 mL) was added Iron (0.63 g, 11.22 mmol) and ammonium formate (1.4 g, 22.4 mmol). After heating at 90° C. for 2 h, the mixture was diluted with EtOAc, excess iron was removed by filtration, and the filtrate was washed sequentially with water, sat. NaHCO3, and brine, before it was dried and concentrated to give 6-amino-3-methylindazole (0.27 g).
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 10h;
Second Step [Show Image] To an ethyl acetate solution (50 mL) of the product (1.17 g, 6.60 mmol) of the first step, 10percent Pd-C (0.46 g) was added, followed by stirring under a hydrogen gas flow at room temperature for 10 hours. The insoluble substances were filtered through cerite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:n-hexane = 3:1) to obtain 0.57 g of 6-amino-3-methylindazole. 1H-NMR (CDCl3) d: 2.50 (s, 3H), 6.4-6.65 (m, 2H), 7.43 (d, 1H, J = 8.4 Hz), 9.35 (br, 1H).
With hydrogenchloride; potassium carbonate; In water; nitrobenzene;
Step A 3-Methyl-6-nitroindazole (5.31 g), 6.93 g of 2-bromo-6-methoxybenzoic acid, 4.71 g of potassium carbonate and 0.218 g of copper (II) oxide were stirred in 60 ml of nitrobenzene at 180° C. for 50 minutes. After cooling, 300 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform. The aqueous layer was decolored with active charcoal and filtered, and 40 ml of 1 N hydrochloric acid aqueous solution was added to the filtrate. The crystals precipitated were separated by filtration and dried under reduced pressure to obtain 7.45 g (75.9percent) of 1-(2-carboxy-3-methoxyphenyl)-<strong>[6494-19-5]3-methyl-6-nitroindazole</strong>.
Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period [TO A] solution of boron [TRIFLUORIDE] etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been [COOLED TO-30 C.] The mixture was warmed to 0 [C] for 15 min and was then cooled to-70 [C.] The nitro [INDAZOLE] (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at-70 [C] for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until-10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2, 3-dimethyl-6-nitro-2H-indazole (65 percent, [7MMOL,] 1.25 g) as a light yellow [POWDER.APOS;H] NMR (300 MHz, [DMSO-D6)] 8 8.51 (s, [1 H),] 7.94 (d, [J =] 9.1 Hz, [1 H),] 7.73 [(D, J] = 8.9 Hz, [1 H),] 4.14 (s, [3H),] 2.67 (s, [3H).] MS (ES+, m/z) 192 (M+H).
65%
Procedure 2: Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30° C. The mixture was warmed to 0° C. for 15 min and was then cooled to -70° C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70° C. for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6-nitro-2H-indazole (65percent, 7 mmol, 1.25 g) as a light yellow powder. 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
65%
Procedure 2: Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to-30 °C. The mixture was warmed to 0 °C for 15 min and was then cooled to-70 °C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at-70 °C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until - 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6-nitro-2H- indazole (65 percent, 7mmol, 1.25 g) as a light yellow powder.
65%
With boron trifluoride diethyl etherate; In dichloromethane; at -70 - 20℃; for 17.5333h;Product distribution / selectivity;
Thmethyl orthoformate (1 1 mmol, 1 .17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30 0C. The mixture was warmed to 0 0C for 15 min and was then cooled to -70 0C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70 0C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until ~ 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6- nitro-2H-indazole (65 percent, 7mmol, 1.25 g) as a light yellow powder. 1H NMR (300 MHz, DMSOd6) delta 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
1.77 g (0.0125 mol) of boron trifluoride etherate was added to the dichloromethane solution,The mixture was cooled to -30 ° C,1.17 g (0.011 mol) of trimethyl orthoformate were added over 2 minutes,The mixture was warmed to 0 ° C,After 15 minutes, the temperature was lowered to -70 ° C,A solution of 1.77 g (0.01 mol) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> in 30 ml of methylene chloride was added,Stirred for 15 minutes,The mixture was stirred at room temperature for 17 hours,20 ml of saturated sodium bicarbonate solution was added,Liquid separation,The aqueous layer was extracted with dichloromethane,The organic layers were combined,Vacuum distillation to retain about 10ml,10 ml of propanol was added,The residual methylene chloride was distilled off under reduced pressure,To give a yellow syrup,filter,To give 2,3-dimethyl-6-nitro-2H-indazole.
Example 1 Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of <strong>[6494-19-5]3-methyl-6-nitro-indazole</strong> (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was stirred at 25° C. to 30° C. for 16 hours. The solvent was recovered under reduced pressure. A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4:1 mixture of dichloromethane isopropyl alcohol (1080 mL*5). The solvent was recovered under reduced pressure. Methyl tert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45° C. to 50° C. The reaction mixture was cooled to 25° C. to 30° C. and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert-butyl ether (100 mL*2), and dried in an air oven at 50° C. for 12 hours to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid. Yield: 82.4percent w/w
73%
In acetone; at 20℃; for 3h;Product distribution / selectivity;
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-7H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added <n="26"/>saturated aqueous NaHCO3 (600 mL) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro- 2tf-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73%
In acetone; at 20℃; for 3h;
To a stirred solution of 18.5 g (0.11 mol) of [3-METHYL-6-NITRO-1H-INDAZOLE] in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of [TRIMETHYLOXONIUM] [TETRAFLOUROBORATE.] After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous [NAHC03] (600 mL) and a 4: 1 mixture of chloroform-isopropanol (200 [ML),] the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried [(NA2S04).] Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2, 3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 [G,] 73 [percent).APOS;H] NMR (300 MHz, [DMSO-D6)] 8 8.51 (s, [1 H),] 7.94 (d, [J= 9.] 1 Hz, [1 H),] 7.73 (d, [J =] 8.9 Hz, [1 H),] 4.14 (s, 3H), 2.67 (s, 3H). MS [(ES+,] [M/Z)] 192 (M+H).
73%
In acetone; at 20℃; for 3h;Product distribution / selectivity;
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml_) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H)1 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73%
In acetone; at 20℃; for 3h;Inert atmosphere;
Intermediate Example 11 Preparation of 2,3-dimethyl-2H-indazol-6-amine To a stirred solution of 18.5 g (0.11 mol) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, d6DMSO) delta 8.51 (s, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).; To a stirred solution of 2,3-dimethyl-6-nitro-2H-indazole (1.13 g) in 2-methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(II) chloride in 8.9 ml of concentrated HCl dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 percent), the HCl salt 2,3-dimethyl-2H-indazol-6-amine. 1H NMR (300 MHz, d6DMSO) delta 7.77 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 7.88 (m, 1H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).
73%
In acetone; at 20℃; for 3h;Inert atmosphere;
18.5 g (0.11 mol) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> was dissolved in 350 ml of acetone,20 g (0.14 mol) of trimethyloxonium tetrafluoroborate was added with stirring at room temperature,The reaction solution was filled with argon for 3 h,The solvent was removed under reduced pressure,The solid was added with 600 ml of aqueous NaHCO3 solution,200 ml of a mixture of chloroform and isopropanol (4: 1)The organic phase was dried over anhydrous sodium sulfate,filter,The solvent was distilled off,To give a brown solid,Washed with ether,15.85 g of 2,3-dimethyl-6-nitro-2H-indazole was obtained in a yield of 73percent.
73%
Intermediate Example 1 Preparation of 2,3-dimethyl-6-nitro-2H-indazole Procedure 1: To a stirred solution of 18.5 g (0.11 mol) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetrafluoroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 mL) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4*200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73percent). 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73%
In acetone; at 20℃; for 3h;Product distribution / selectivity;
Intermediate Example 1 Preparation of 2,3-dimethyl-6-nitro-2H-indazole Procedure 1: To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H- indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 mL) and a 4: 1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2S04). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent).
73%
In acetone; at 20℃; for 3h;Product distribution / selectivity;
To a stirred solution of 18.5 g (0.1 1 mol) of 3-methyl-6-nitro-7/-/-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of thmethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml_) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2/-/-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSOd6) delta 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
32%
Example 50: Process for preparation of DMND[000167] To a stirred solution of 3-methyl-6-nitro- l H-indazole (MNID) (5.0 g, 28.2 mmol) in acetone (95 mL, 19V) at ambient temperature was added trimethyloxonium tetrafluoroborate (5.3 g, 35.8 mmol, 1 .27 eq). Stirring was continued under nitrogen and the reaction was monitored by TLC. After 5.5 h another 1 g of trimethyloxonium tetrafluoroborate was added to the reaction in an attempt to push it to completion. After 7.5 h total reaction time the solvent was removed and saturated sodium bicarbonate ( 162 mL) was added to the residue, followed by a 4: 1 mixture of CHC : IPA (54 mL). The resulting mixture was agitated and the layers were separated. The aqueous phase was washed with additional CHCI3: IPA 4: 1 (4x54 mL) and the combined organic phases were dried ( a2SO,)), filtered and evaporated to dryness. The resulting brown solid was washed with diethylether (about 160 mL) and dried on the filter under nitrogen/vacuum to afford crude DMND (3.2 g, 87.5percent purity). The crude material (2.9 g) was then dissolved in EtOH (50 mL) at reflux and the solution was gradually cooled to ambient temperature and then to 5 °C, and was kept at this temperature for 1 h. The resulting precipitate was isolated by filtration and the filter cake was washed with cold EtOH ( 10 mL) and dried in a vacuum oven (35 mbar) at 55°C for 4 h to give 2,3-dimethyl-6-nitro-2H-indazole ( 1 .57g, ca 32percent) as a yellow solid.
With sulfuric acid; In dimethyl sulfoxide; at 50℃; for 72h;Product distribution / selectivity;
In a 25 ml round bottom flask <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 0C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was <n="27"/>extracted with methylene chloride (2 x 20 ml_). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1 H), 7.94 (d, J= 9.1 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
70%
With sulfuric acid; In dimethyl sulfoxide; at 50℃; for 72h;
In a 25 ml round bottom flask <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 [MMOL,] 2.66 g). The mixture was heated under nitrogen at 50 [C] for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2 x 20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2, 3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow [SOLID.APOS;H] NMR (300 MHz, DMSO- [D6)] [6 8.] 51 (s, [1 H),] 7.94 (d, [J=] 9.1 Hz, [1 H),] 7.73 (d, [J= 8.] 9 Hz, [1 H),] 4.14 (s, 3H), 2.67 (s, 3H). MS [(ES+,] m/z) 192 (M+H).
70%
With sulfuric acid; In dimethyl sulfoxide; at 50℃; for 72h;Product distribution / selectivity;
In a 25 ml round bottom flask <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 0C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2 x 20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
70%
With sulfuric acid; In dimethyl sulfoxide; at 50℃; for 72h;Inert atmosphere;
A solution of 1.28 g (0.00727 mol) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> was dissolved in 4 ml of DMSO,(0.00727 mol) of concentrated sulfuric acid to give a thick slurry,Further, 2.66 g (0.0211 mol) of dimethyl sulfate was added,The mixture was heated at 50 ° C under nitrogen for 72 hours,A thick yellow slurry was obtained,After cooling,10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added slowly,Extracted twice with 20 ml of dichloromethane,The organic layers were combined,Reverse extraction with 20 ml of water,The methylene chloride layer was added with 10 ml of propanol,The methylene chloride was distilled off under reduced pressure,Filtration,To give a yellow solid,Washed with 5 ml of heptane,dry,To give 2,3-dimethyl-6-nitro-2H-indazole, 0.97 g, yield 70percent.
70%
In a 25 ml round bottom flask <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50° C. for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2.x.20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
70%
With sulfuric acid; In dimethyl sulfoxide; at 50℃; for 72h;Product distribution / selectivity;
Procedure 3: In a 25 ml round bottom flask <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 °C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with methylene chloride (2 x 20 mL). The methylene chloride layers were combined and back extracted with water (20 mL). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2H-indazole product (70percent, 0.97 g) was obtained as a light yellow solid.
70%
With sulfuric acid; In dimethyl sulfoxide; at 50℃; for 72h;Product distribution / selectivity;
In a 25 ml round bottom flask <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (7.27 mmol, 1.28 g) was dissolved with stirring in DMSO (4.0 mL) and was treated with concentrated sulfuric <n="30"/>acid (7.27 mmol, 0.73 g) to yield a thick slurry. The slurry was treated with dimethyl sulfate (21.1 mmol, 2.66 g). The mixture was heated under nitrogen at 50 0C for 72 h. After 72 h a thick yellow slurry was obtained. The slurry was cooled and was slowly treated with saturated sodium bicarbonate solution (10 ml_). The mixture was extracted with methylene chloride (2 x 20 ml_). The methylene chloride layers were combined and back extracted with water (20 ml_). The methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure. The solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried. The 2,3-dimethyl-6-nitro-2/-/-indazole product (70percent, 0.97 g) was obtained as a light yellow solid. 1H NMR (300 MHz, DMSOd6) delta 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
Trimethyl orthoformate (11 mmol, 1.17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30 0C. The mixture was warmed to 0 0C for 15 min and was then cooled to -70 0C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70 0C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated. The aqueous layer was extracted with methylene chloride (30 mL). The methylene chloride layers were combined and extracted with water (30 mL). The methylene chloride layer was distilled under reduced pressure until ~ 10 mL remained. Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry. The product was isolated by filtration to give 2,3-dimethyl-6-nitro-2H-indazole (65 percent, 7mmol, 1.25 g) as a light yellow powder. 1H NMR (300 MHz, DMSO-d6) 58.51 (s, 1 H), 7.94 (d, J= 9.1 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h;
2,6-Difluorobenzonitrile (5.89 g), <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (5.00 g) and powdered potassium carbonate (11.7 g) were stirred in DMF (85 mL) in an atmosphere of nitrogen at 90°C for 5 hours. The reaction mixture was cooled to room temperature, and a precipitated insoluble substance was removed by filtration. The DMF was distilled away from the resulting filtrate under reduced pressure. The resulting residue was dissolved in ethyl acetate, water was added to the solution, and then the mixture was separated. The organic layer was sequentially washed with water and a saturated brine solution and was dried over anhydrous magnesium sulfate. The ethyl acetate was distilled away under reduced pressure. Subsequently, the resulting residue was purified by silica gel column chromatography (eluate: ethyl acetate/hexane = 40/60) to give Compound 3 (2.72 g, yield 32.5percent) as crystals. Melting point: 199.7°C 1H-NMR (300 MHz, CDCl3) delta (ppm): 8.41 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 2.0, 8.8 Hz), 7.89 (1H, d, J = 8.8 Hz), 7.81 (1H, dt, J = 6.0, 8.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.35 (1H, dt, J = 0.9, 8.3 Hz), and 2.73 (3H, s). 13C-NMR (75 MHz, CDCl3) delta(ppm): 164.5 (d, 1J = 262 Hz), 147.7, 146.5, 141.8 (d, 3J = 2.5 Hz), 139.1, 135.3 (d, 3J = 10.0 Hz), 128.4, 121.9, 121.1 (d, 4J = 3.8 Hz), 116.9, 115.6 (d, 2J = 19.9 Hz), 111.2, 106.6, 99.3 (d, 2J = 17.4 Hz), and 12.0. IR (KBr, cm-1): 2,233 (CN), 1,535 and 1,350 (NO2).
A 1-Boc-<strong>[6494-19-5]3-methyl-6-nitroindazole</strong> By methods substantially equivalent to those described in Example 1-A, 1-Boc-<strong>[6494-19-5]3-methyl-6-nitroindazole</strong> (3 g, 64percent) was prepared from <strong>[6494-19-5]3-methyl-6-nitro-indazole</strong> (Chem. Abstr., (1966), 65, p 2245).
1-(2-carboxyphenyl)-3-methyl-6-nitroindazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.6 g (69.4%)
With potassium carbonate;
EXAMPLE 11 5-Amino-2-methyl-6H-pyrazolo[4,5,1-d,e]acridin-6-one (Compound 11): 3-Methyl-6-nitroindazole (64.5 g), 46.0 g of 2-iodobenzoic acid, 40.8 g of potassium carbonate and 1.89 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 53.6 g (69.4percent) of 1-(2-carboxyphenyl)-<strong>[6494-19-5]3-methyl-6-nitroindazole</strong>.
Step 2 3-Methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole 3-Methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong> (436 mg, 2.46 mmol) was dissolved in 25 ml of dichloromethane at room temperature. DMAP (5 mg) and pyridine (1.1 eq, 0.38 ml) were added followed by tosyl chloride (1.1 eq, 516 mg). The mixture was allowed to stir at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 Hexanes/Ethyl Acetate) to give 3-methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole (850 mg, quant) as a light brown crystalline solid.
With dmap; triethylamine; In dichloromethane; at 20℃; for 192h;
Step A: teri-Butyl 3-methyl-6-nitro-l/7-indazole-l-carboxylateTo a flask was added 3-methyl-6-nitro-l//-indazole (5.00 g, 28.2 mmol, ArkPharm), TEA (3.93 mL, 28.2 mmol), DMAP (0.345 g, 2.82 mmol) and DCM (282 mL). Boc20 (6.47 g, 29.6 mmol) was added and the mixture was stirred at rt for about 8 d. The mixture was washed with 1 N HC1 (100 mL) and the layers separated. The aqueous layer was extracted with DCM (20 mL). The combined extracts were washed with brine (50 mL), dried over MgS04, filtered, and concentrated under reduced pressure to remove most of the DCM and leave a suspension. Heptane (100 mL) was added and the mixture concentrated to about 50 mL to remove as much of the DCM as possible. The resulting precipitate was collected by vacuum filtration and washed with heptane (15 mL) to provide teri-butyl 3-methyl-6-nitro-l//-indazole-l-carboxylate (7.4 g, 95percent): LC/MS (Table 2, Method c) R, = 2.62 min.; MS m/z: 278 (M+H)+. .H NMR (400 MHz, DMSO-i3/4 delta 8.82 (d, J= 1.5 Hz, 1H), 8.18 (dd, J= 8.7, 2.0 Hz, 1H), 8.12 - 8.08 (m, 1H), 2.58 (s, 3H), 1.65 (s, 9H).
With triethylamine;dmap; In dichloromethane; at 20℃; for 3h;
First Step [Show Image] To a dichloromethane solution (10 mL) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> (see the first step of Example 34) (985 mg, 5.56 mol) , di-tert-butyl dicarbonate (1.58 g, 7.23 mmol), triethylamine (1.16 mL, 8.34 mmol) and a catalytic amount of N,N-dimethyl-4-aminopyridine (10 mg) were added, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with water and then extracted with dichloromethane. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.23 g of tert-butyl <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong>-1-carboxylate.
<strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong> (1a, 10.00 g, 56 mmol) and triethylenediamine (DABCO, 6.40 g, 56 mmol) were dissolved in 100 mL of DMF. The mixture was stirred for 15 min at room temperature, then dimethyl carbonate (DMC) (6.04 g, 67 mmol) was added dropwise to it. After the addition, the reaction mixture was heated to reflux and stirred for 6 h. After cooling to room temperature, 120 mL of water was added and stirred for 15 min, a large amount of light-yellow solid appeared, the solid was filtered and dried to give 2a (8.66 g, 81.1percent yield). Mp: 187~187.6 C. 1HNMR (400MHz, DMSO-d6) delta: 2.67 (s, 3H), 4.14 (s, 3H), 7.73 (d, J=9.2 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.51 (s, 1H).
70.6%
With 1,4-diaza-bicyclo[2.2.2]octane; In N,N-dimethyl-formamide; isopropyl alcohol; at 70℃; for 20h;
In a 250 ml three-necked flask,40 ml of DMF was added,5 ml of isopropanol,17.7 g (0.1 mol) of <strong>[6494-19-5]3-methyl-<strong>[6494-19-5]6-nitro-1H-indazole</strong></strong>,Stirring dissolved,Further, 18 g (0.2 mol) of dimethyl carbonate was added,12.3 g (0.11 mol) of triethylenediamine.The reaction was heated to 70 ° C for 20 h,To room temperature,Poured into 900ml of ice water,Stirring 30mins,A large amount of yellow solid precipitated,Filtration,Dried in vacuo to give 13.5 g of a yellow solid,Yield 70.6percent.
3-methyl-1H-indazol-6-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With hydrogenchloride; tin(ll) chloride; In diethylene glycol dimethyl ether; water; at 0 - 100℃; for 0.583333h;Cooling with ice; Inert atmosphere;
Intermediate Example 1 Preparation of 3-methyl-1H-indazol-6-amine To a solution of 10 g (.06 mol) of 2-ethyl-5-nitroaniline (prepared by nitration of 2-ethylaniline:) in 300 ml of glacial acetic acid, at room temperature, was added a solution of 8.98 ml (.06 mol) of tert-butyl nitrite in 40 ml of acetic acid dropwise over 15 min. After the addition was complete the solution was allowed to stir for 30 min. The acetic acid was removed in vacuo to afford an orange solid. The solid was dissolved in approximately 120 ml of ethyl acetate and washed with 3 x 100 ml sat. aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to afford <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> as a yellow solid (10.4 g, 98percent). To a stirred solution of 10 g (.06 mol) of <strong>[6494-19-5]3-methyl-6-nitroindazole</strong> in 100 ml of 2-methoxyethyl ether, at 0 °C, was added a solution of 45 g (.24 mol) of tin(II) chloride in 86 ml of concentrated HCl dropwise over 15 min, in order to keep the reaction temperature below 100 °C. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 20 min. Approximately 70 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (10 g, 92 percent), the HCl salt of 3-methyl-1H-indazol-6-amine.
Sodium (3.2g, 0.14mol) was addedportionwise to refluxingisopropanol (140ml)and stirred until the whole solution, was added 2-2 (13.0g, 0.073mol), plus complete reflux wascontinued for 3h. Iodomethane (30.0g,0.21mol) in isopropanol (45 ml of) the solution was refluxed for 5h. Cooled, allowed to stand overnight. Andfiltered to give a pale yellow solid 12.0g, yield 87.6percent.
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