6494-19-5|3-Methyl-6-nitro-1H-indazole| Ambeed

Structure of 6494-19-5

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Quality Control of [ 6494-19-5 ] Purity: 97% SDS Specification

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Product Details of [ 6494-19-5 ]

CAS No. :	6494-19-5
Formula :	C₈H₇N₃O₂
M.W :	177.16
SMILES Code :	CC1=N[NH]C2=CC(=CC=C12)[N+](=O)[O-]
MDL No. :	MFCD07082704
InChI Key :	FUNWSYKLFDLUIZ-UHFFFAOYSA-N
Pubchem ID :	10921054

Safety of [ 6494-19-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302+H312+H332-H315-H319-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 6494-19-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	49.88
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	74.5 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.88
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.78
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.78
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.37
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.27
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.02

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.51
Solubility	0.552 mg/ml ; 0.00312 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.96
Solubility	0.193 mg/ml ; 0.00109 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.68
Solubility	0.373 mg/ml ; 0.0021 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.12 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.77

Application In Synthesis of [ 6494-19-5 ]

* 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.

Upstream synthesis route of [ 6494-19-5 ]
Downstream synthetic route of [ 6494-19-5 ]

[ 6494-19-5 ] Synthesis Path-Upstream 1~1

1
[ 6494-19-5 ]
[ 635702-60-2 ]

References: [1] Patent: US2008/293691, 2008, A1, .
[2] Patent: US2008/293691, 2008, A1, .
[3] Patent: WO2005/105094, 2005, A2, .
[4] Patent: WO2007/143483, 2007, A2, .
[5] Patent: US2008/293691, 2008, A1, .
[6] Patent: WO2005/105094, 2005, A2, .
[7] Patent: WO2007/143483, 2007, A2, .
[8] Patent: WO2005/105094, 2005, A2, .

[ 6494-19-5 ] Synthesis Path-Downstream 1~35

1
[ 6494-19-5 ]
[ 99584-38-0 ]

References: [1]Ind.chim. belge Sonderband 31. Congr. int. Chim. ind. Luettich 1958, Bd. 2, S. 469,.

2
[ 6494-19-5 ]
[ 79173-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	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).

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,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.

3
[ 6494-19-5 ]
[ 16883-16-2 ]
[ 62235-34-1 ]

References: [1]Pharmazie,1976,vol. 31,p. 775 - 777.

4
[ 6494-19-5 ]
[ 91182-77-3 ]
[ 62235-33-0 ]

References: [1]Pharmazie,1976,vol. 31,p. 775 - 777.

5
[ 6494-19-5 ]
[ 25629-50-9 ]
[ 62235-35-2 ]

References: [1]Pharmazie,1976,vol. 31,p. 775 - 777.

6
[ 6494-19-5 ]
[ 4462-55-9 ]
[ 62235-36-3 ]

References: [1]Pharmazie,1976,vol. 31,p. 775 - 777.

7
[ 6494-19-5 ]
[ 31786-45-5 ]
[ 126955-75-7 ]

Yield	Reaction Conditions	Operation in experiment
7.45 g (75.9%)	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>.

References: [1]Synthesis,1994,p. 73 - 76.
[2]Patent: US5220026,1993,A .

8
diazotized 2-ethyl-5-nitro-aniline [ No CAS ]
[ 6494-19-5 ]

References: [1]Journal of the Chemical Society,1955,p. 2412,2419.

9
[ 6494-19-5 ]
[ 149-73-5 ]
[ 444731-73-1 ]

Yield	Reaction Conditions	Operation in experiment
65%		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.

References: [1]Patent: WO2003/106416,2003,A2 .Location in patent: Page 40-41.
[2]Patent: US2008/293691,2008,A1 .Location in patent: Page/Page column 8.
[3]Patent: WO2005/105094,2005,A2 .Location in patent: Page/Page column 27-28.
[4]Patent: WO2007/143483,2007,A2 .Location in patent: Page/Page column 28.
[5]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[6]Patent: CN103319410,2016,B .Location in patent: Paragraph 0020; 0021.

10
[ 6494-19-5 ]
[ 142854-00-0 ]