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CAS No. : | 289483-82-5 | MDL No. : | MFCD17779298 |
Formula : | C10H7N3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XDNBPEYPQDBCIK-UHFFFAOYSA-N |
M.W : | 201.18 | Pubchem ID : | 11622527 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.1 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 56.8 |
TPSA : | 85.4 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.14 cm/s |
Log Po/w (iLOGP) : | 1.49 |
Log Po/w (XLOGP3) : | 1.96 |
Log Po/w (WLOGP) : | 2.26 |
Log Po/w (MLOGP) : | 0.09 |
Log Po/w (SILICOS-IT) : | 0.75 |
Consensus Log Po/w : | 1.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.7 |
Solubility : | 0.401 mg/ml ; 0.00199 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.38 |
Solubility : | 0.0842 mg/ml ; 0.000418 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.14 |
Solubility : | 0.145 mg/ml ; 0.000719 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.08 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.6% | Stage #1: at 0℃; for 0.5 h; Stage #2: at 0 - 60℃; for 2 h; Stage #3: With hydroxylamine hydrochloride In N,N-dimethyl-formamide at 60 - 80℃; for 0.666667 h; |
To 740 mL of dimethylformamide was added 235 mL (2.52 mol) of phosphorous oxychloride at 0°C, followed by stirring at 0°C for 0.5 hour. To the reaction mixture was then added a solution of 370 g (2.10 mol) of 4-methyl-7-nitro-1H-indole (WO00/50395) in dimethylformamide (1110 mL) at 0°C, followed by heating and stirring at 60°C for 2 hours. To the reaction mixture was then added dropwise a solution of 292 g (4.20 mol) of hydroxylamine hydrochloride in dimethylformamide (1850 mL) with keeping the internal temperature below 80°C, followed by heating and stirring at 60°C for 40 minutes. After adding 11.1 L of ice water to the reaction mixture while cooling in an ice bath, the mixture was further stirred overnight. The precipitated crystals were collected by filtration and washed with water. The crystals were suspended in 11.1 L of water, 1N solution of sodium hydroxide was added to the suspension for adjustment to pH 7, and then the crystals were collected by filtration and washed with water to give 412 g of the title compound (yield: 97.6percent). HPLC analysis confirmed that the obtained compound was identical to the 3-cyano-4-methyl-7-nitro-1H-indole described in WO00/50395.(HPLC conditions) Mobile phase: CH3CN/H2O/70percent HClO4 = 500/500/1 (v/v/v)Flow rate: 1.0 mL/minDetection: UV (254 nm)Column: YMC-Pack Pro C18 250 x 4.6 mm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | Stage #1: With pyridine; hydroxylamine hydrochloride In N,N-dimethyl-formamide at 60℃; for 0.666667 h; Stage #2: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 60℃; for 0.5 h; Stage #3: With triethylamine In N,N-dimethyl-formamide at 60℃; for 1 h; |
Reference Example 2A Synthesis of 3-cyano-4-methyl-7-nitro-1H-indole After dissolving 2.21 g (10.8 mmol) of the 3-formyl-4-methyl-7-nitro -1H-indole obtained in Reference Example 1A in 100 mL of dimethylformamide, 900 mg (13.0 mmol) of hydroxylamine hydrochloride and 1.05 mL (13.0 mmol) of pyridine were added. The mixture was heated and stirred at 60° C. for 40 minutes, and then 1,1'-carbonyldiimidazole (53.9 mmol) was added to the reaction mixture while cooling in an ice bath. The mixture was further heated and stirred at 60° C. for 30 minutes, and then 3.0 mL (21.5 mmol) of triethylamine was added to the reaction mixture, and heating and stirring were continued at the same temperature for 1 hour. To the reaction mixture was added 50 mL of ice water while cooling in an ice bath and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order, dried over magnesium sulfate, and concentrated to dryness. A mixture of tert-butyl methyl ether and hexane was added to the residue, and the crystals were collected by filtration to give 1.95 g of the title compound (yield: 89.7percent). 1H-NMR (DMSO-d6) δ (ppm): 2.78 (3H, s), 7.22 (1H, d, J=8.0Hz), 8.14 (1H, d, J=8.0Hz), 8.41 (1H, s), 12.76 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.6% | Stage #1: at 0℃; for 0.5 h; Stage #2: at 0 - 60℃; for 2 h; |
Example 1A; Synthesis of 3-cyano-4-methyl-7-nitro-1H-indole; To 740 mL of dimethylformamide was added 235 mL (2.52 mol) of phosphorous oxychloride at 0° C., followed by stirring at 0° C. for 0.5 hour. To the reaction mixture was then added a solution of 370 g (2.10 mol) of 4-methyl-7-nitro-1H-indole (WO00/50395) in dimethylformamide (1110 mL) at 0° C., followed by heating and stirring at 60° C. for 2 hours. To the reaction mixture was then added dropwise a solution of 292 g (4.20 mol) of hydroxylamine hydrochloride in dimethylformamide (1850 mL) with keeping the internal temperature below 80° C., followed by heating and stirring at 60° C. for 40 minutes. After adding 11.1 L of ice water to the reaction mixture while cooling in an ice bath, the mixture was further stirred overnight. The precipitated crystals were collected by filtration and washed with water. The crystals were suspended in 11.1 L of water, 1 N solution of sodium hydroxide was added to the suspension for adjustment to pH 7, and then the crystals were collected by filtration and washed with water to give 412 g of the title compound (yield: 97.6percent). HPLC analysis confirmed that the obtained compound was identical to the 3-cyano-4-methyl-7-nitro -1H-indole described in W00/50395. (HPLC conditions) Mobile phase: CH3CN/H2O/70percent HClO4=500/500/1 (v/v/v) Flow rate: 1.0 mL/min Detection: UV (254 nm) Column: YMC-Pack Pro C18 250.x.4.6 mm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.8% | With hydrogen In tetrahydrofuran; methanol at 20℃; | Reference Example 3A; Synthesis of 7-amino-3-cyano-4-methyl-1H-indole; After suspending 12.6 g (62.6 mmol) of the 3-cyano-4-methyl-7-nitro-1H-indole obtained in Reference Example 2A in a mixture of 100 mL of tetrahydrofuran and 100 mL of methanol, the suspension was subjected to hydrogenation in the presence of 430 mg (1.87 mmol) of platinum oxide at ordinary temperature, 3 atmospheres. The catalyst was removed by filtration, the filtrate was concentrated to dryness, and then a mixture of tert-butyl methyl ether and hexane was added to the residue and the crystals were collected by filtration to give 10.7 g of the title compound (yield: 99.8percent). 1H-NMR (DMSO-d6) δ (ppm): 2.47 (3H, s), 5.07 (2H, s), 6.34 (1H, d, J=7.6Hz), 6.64 (1H, d, J=7.6Hz), 8.10 (1H, s), 11.70 (1H, br s). |
84.8% | With hydrogen In methanol; ethyl acetate at 20℃; | After suspending 400 g (1.99 mol) of the 3-cyano-4-methyl-7-nitro-1H-indole obtained in Example 1A in a mixture of 6 L of ethyl acetate and 6 L of methanol, the suspension was subjected to hydrogenation in the presence of 40 g of 10percent palladium-carbon at ordinary temperature, 4 atmospheres. After removing the catalyst by filtration, the filtrate was treated with activated carbon and concentrated to give crude crystals. The crude crystals were dissolved in 6 L of 1,2-dimethoxyethane at an external temperature of 60°C, and then 12 L of water was added dropwise. Upon confirming precipitation of crystals, the mixture was stirred for 1.5 hours while cooling in an ice bath and filtered, and the crystals were washed twice with water (1 L). The crystals were air-dried at 50°C for 16 hours to give 289 g of the title compound (yield: 84.8percent). HPLC analysis confirmed that the obtained compound was identical to the 7-amino-3-cyano-4-methyl-1H-indole described in WO00/50395.(HPLC conditions) Mobile phase: CH3CN/H2O/70percent HClO4 = 400/600/1 (v/v/v)Flow rate: 1.0 mL/minDetection: UV (282 nm)Column: YMC-Pack Pro C18 250 x 4.6 mm |
84.8% | With hydrogen In methanol; ethyl acetate at 20℃; | Example 2A; Synthesis of 7-amino-3-cyano-4-methyl-1H-indole; After suspending 400 g (1.99 mol) of the 3-cyano-4-methyl-7-nitro-1H-indole obtained in Example 1A in a mixture of 6 L of ethyl acetate and 6 L of methanol, the suspension was subjected to hydrogenation in the presence of 40 g of 10percent palladium-carbon at ordinary temperature, 4 atmospheres. After removing the catalyst by filtration, the filtrate was treated with activated carbon and concentrated to give crude crystals. The crude crystals were dissolved in 6 L of 1,2-dimethoxyethane at an external temperature of 60° C., and then 12 L of water was added dropwise. Upon confirming precipitation of crystals, the mixture was stirred for 1.5 hours while cooling in an ice bath and filtered, and the crystals were washed twice with water (1 L). The crystals were air-dried at 50° C. for 16 hours to give 289 g of the title compound (yield: 84.8percent). HPLC analysis confirmed that the obtained compound was identical to the 7-amino-3-cyano-4-methyl-1H-indole described in WO00/50395. (HPLC conditions) Mobile phase: CH3CN/H2O/70percent HClO4=400/600/1 (v/v/v) Flow rate: 1.0 mL/min Detection: UV (282 nm) Column: YMC-Pack Pro C18 250.x.4.6 mm |
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