6494-19-5

Basic information

• Product Name: 3-Methyl-6-nitroindazole
• Synonyms: 1H-Indazole, 3-Methyl-6-nitro-;3-Methyl-6-Nitro-1H-;6-Nitro-3-Methylindazole;3-Methyl-6-nitro-1H-indazole≥ 99% (HPLC);3-methyl-6-nitro-1h-indazole;3-Methyl-6-nitroindazole;3-Methyl-6-nitroindole;3-Methyl-6-Nitro-1h-Indole
• CAS NO: 6494-19-5
• Molecular Formula: C₈H₇N₃O₂
• Molecular Weight: 177.16
• EINECS: 1592732-453-0
• Product Categories: Heterocyclic Compound;Indole
• Mol File: 6494-19-5.mol
• Article Data: 13

Chemical Properties

• Melting Point: 187-188°C
• Boiling Point: 225.226 °C at 760 mmHg
• Flash Point: 90.014 °C
• Appearance: /
• Density: 1.437
• Vapor Pressure: 0.00684mmHg at 25°C
• Refractive Index: 1.704
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 11.47±0.40(Predicted)
• CAS DataBase Reference: 3-Methyl-6-nitroindazole(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Methyl-6-nitroindazole(6494-19-5)
• EPA Substance Registry System: 3-Methyl-6-nitroindazole(6494-19-5)

Safety Data

• Statements: 20/21/22
• Safety Statements: 24/25-36/37
• Hazardous Substances Data: 6494-19-5(Hazardous Substances Data)

Usage

Chemical Properties

Brown solid

Uses

3-Methyl-6-nitroindazole a reactant used in the preparation of Pazopanib (P210925), an oral angiogenesis inhibitor targeting VEGFR and PDGFR.

InChI:InChI=1/C8H7N3O2/c1-5-7-3-2-6(11(12)13)4-8(7)10-9-5/h2-5H,1H3

Synthetic route

2-ethyl-5-nitroaniline (20191-74-6) → 3-methyl-6-nitro-1H-indazole (6494-19-5)

Conditions	Yield
With acetic acid; isopentyl nitrite at 20℃; for 0.75h;	98%
With tert.-butylnitrite In acetic acid at 20℃; for 0.75h; Inert atmosphere;	98%
With tert.-butylnitrite; acetic acid for 0.5h;	98%

diazotized 2-ethyl-5-nitro-aniline → 3-methyl-6-nitro-1H-indazole (6494-19-5)

Conditions	Yield
With acetic acid

ortho-ethylaniline (578-54-1) → 3-methyl-6-nitro-1H-indazole (6494-19-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid; potassium nitrate / 1.5 h / 0 °C 2: acetic acid; isopentyl nitrite / 1.5 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / 0.5 h / 0 - 5 °C 2: tert.-butylnitrite; acetic acid / 0.5 h View Scheme

3-methyl-6-nitro-1H-indazole (6494-19-5) + p-toluenesulfonyl chloride (98-59-9) → 3-methyl-6-nitro-1-(toluene-4-sulfonyl)-1H-indazole (62271-21-0)

Conditions	Yield
With pyridine; dmap In dichloromethane at 20℃;	100%

3,4-dihydro-2H-pyran (110-87-2) + 3-methyl-6-nitro-1H-indazole (6494-19-5) → 3-methyl-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Conditions	Yield
With toluene-4-sulfonic acid In dichloromethane at 20℃; for 12h;	98%
With methanesulfonic acid In tetrahydrofuran at 80℃; for 8h; Inert atmosphere;	74%

3-methyl-6-nitro-1H-indazole (6494-19-5) → 2,3-dimethyl-6-amino-2H-indazole (444731-72-0)

Conditions	Yield
With ammonium formate; palladium 10% on activated carbon In methanol; water at 25 - 30℃; for 6h;	96.7%
Multi-step reaction with 2 steps 1: sulfuric acid / N,N-dimethyl-formamide; toluene / 3 h / Reflux 2: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; methanol View Scheme
Multi-step reaction with 2 steps 1.1: 1,4-diaza-bicyclo[2.2.2]octane / N,N-dimethyl-formamide / 0.25 h / 20 °C 1.2: 6 h / Reflux 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 12 h / 20 °C View Scheme

3-methyl-6-nitro-1H-indazole (6494-19-5) + di-tert-butyl dicarbonate (24424-99-5) → tert-butyl 3-methyl-6-nitro-1H-indazole-1-carboxylate (219507-74-1)

Conditions	Yield
With dmap; triethylamine In dichloromethane at 20℃; for 192h;	95%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;	70.28%
With triethylamine; dmap In dichloromethane at 20℃; for 3h;

3-methyl-6-nitro-1H-indazole (6494-19-5) → 3-methyl-1H-indazol-6-amine (79173-62-9)

Conditions	Yield
With hydrogenchloride; tin(ll) chloride In diethylene glycol dimethyl ether; water at 0 - 100℃; for 0.583333h;	92%
With nickel Hydrogenation;
With hydrogenchloride; water; iron Hydrogenation;
With ammonium formate; iron In ethanol; water at 90℃; for 2h;
With hydrogen; palladium 10% on activated carbon In ethyl acetate at 20℃; for 10h;

3-methyl-6-nitro-1H-indazole (6494-19-5) → 3-methyl-1H-indazol-6-amine hydrochloride

Conditions	Yield
With hydrogenchloride; tin(ll) chloride In diethylene glycol dimethyl ether; water at 0 - 100℃; for 0.583333h; Cooling with ice; Inert atmosphere;	92%

3-methyl-6-nitro-1H-indazole (6494-19-5) + methyl iodide (74-88-4) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1)

Conditions	Yield
Stage #1: 3-methyl-6-nitro-1H-indazole With sodium In isopropyl alcohol for 3h; Reflux; Stage #2: methyl iodide In isopropyl alcohol for 5h; Reflux;	87.6%

3-methyl-6-nitro-1H-indazole (6494-19-5) + 2-fluoro-6-methoxybenzonitrile (94088-46-7) → 1-(2-cyano-3-methoxyphenyl)-3-methyl-6-nitroindazole

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 6h; Product distribution / selectivity;	86.7%

3-methyl-6-nitro-1H-indazole (6494-19-5) + dimethyl sulfate (77-78-1) → 1,2,3-trimethyl-6-nitro-1H-indazol-2-ium perchlorate

Conditions	Yield
Stage #1: 3-methyl-6-nitro-1H-indazole; dimethyl sulfate In toluene for 48h; Reflux; Stage #2: With sodium perchlorate In water	86%

3-methyl-6-nitro-1H-indazole (6494-19-5) + 2-bromo-6-methoxybenzoic acid (31786-45-5) → 1-(2-carboxy-3-methoxy)phenyl-3-methyl-6-nitro-1H-indazole (126955-75-7)

Conditions	Yield
With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 6h;	84%
With hydrogenchloride; potassium carbonate In water; nitrobenzene	7.45 g (75.9%)

3-methyl-6-nitro-1H-indazole (6494-19-5) + trimethoxonium tetrafluoroborate (420-37-1) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1)

Conditions	Yield
In ethyl acetate at 25 - 30℃; for 20h;	82.4%
In acetone at 20℃; for 3h; Product distribution / selectivity;	73%
In acetone at 20℃; for 3h;	73%

3-methyl-6-nitro-1H-indazole (6494-19-5) + carbonic acid dimethyl ester (616-38-6) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1)

Conditions	Yield
Stage #1: 3-methyl-6-nitro-1H-indazole With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: carbonic acid dimethyl ester In N,N-dimethyl-formamide for 6h; Reflux;	81.1%
With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide; isopropyl alcohol at 70℃; for 20h; Concentration; Reagent/catalyst; Temperature; Solvent;	70.6%
With sodium hydride for 5h; Reflux;

3-methyl-6-nitro-1H-indazole (6494-19-5) + dimethyl sulfate (77-78-1) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1)

Conditions	Yield
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72h; Product distribution / selectivity;	70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72h;	70%
With sulfuric acid In dimethyl sulfoxide at 50℃; for 72h; Product distribution / selectivity;	70%

3-methyl-6-nitro-1H-indazole (6494-19-5) + trimethyl orthoformate (149-73-5) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1)

Conditions	Yield
Stage #1: trimethyl orthoformate With boron trifluoride diethyl etherate In dichloromethane at -30 - 0℃; for 0.25h; Stage #2: 3-methyl-6-nitro-1H-indazole In dichloromethane at 20℃; for 17h;	65%
Stage #1: trimethyl orthoformate With boron trifluoride diethyl etherate In dichloromethane at -30 - 0℃; for 0.25h; Stage #2: 3-methyl-6-nitro-1H-indazole In dichloromethane at -70 - 20℃; for 17.25h; Stage #3: With sodium hydrogencarbonate In dichloromethane; water Product distribution / selectivity;	65%
Stage #1: trimethyl orthoformate With boron trifluoride diethyl etherate In dichloromethane at -30 - 0℃; for 0.283333h; Stage #2: 3-methyl-6-nitro-1H-indazole In dichloromethane at -70 - 20℃; for 17.25h; Product distribution / selectivity;	65%

3-methyl-6-nitro-1H-indazole (6494-19-5) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1)

Conditions	Yield
Stage #1: trimethyl orthoformate With boron trifluoride diethyl etherate In dichloromethane at -70 - 0℃; for 0.25h; Stage #2: 3-methyl-6-nitro-1H-indazole In dichloromethane at -70 - 20℃; for 17.25h; Product distribution / selectivity;	65%

3-methyl-6-nitro-1H-indazole (6494-19-5) + carbonic acid dimethyl ester (616-38-6) → 2,3‑dimethyl‑6‑nitro‑2H‑indazole (444731-73-1) + 1,3-dimethyl-6-nitro-1H-indazole

Conditions	Yield
Stage #1: 3-methyl-6-nitro-1H-indazole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: carbonic acid dimethyl ester In N,N-dimethyl-formamide at 120℃; for 5h;	A 61% B 33%

3-methyl-6-nitro-1H-indazole (6494-19-5) + 2,6 difluorobenzonitrile (1897-52-5) → 1-(2-cyano-3-fluorophenyl)-3-methyl-6-nitroindazole (786658-39-7)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 5h;	32.5%

3-methyl-6-nitro-1H-indazole (6494-19-5) + ethanol (64-17-5) → 1-(1-ethoxyethyl)-3-methyl-6-nitro-1H-indazole

Conditions	Yield
With tert.-butylhydroperoxide In decane at 120℃; for 12h; Schlenk technique; Sealed tube;	20%

3-methyl-6-nitro-1H-indazole (6494-19-5) → 3-methyl-6-nitro-1(2)H-indazol-7-ylamine (99584-38-0)

Conditions	Yield
With hydrogenchloride; propan-1-ol; sodium hydroxide; hydroxylamine

3-methyl-6-nitro-1H-indazole (6494-19-5) + 5-methyl-3-phenylisoxazole-4-carbonyl chloride (16883-16-2) → 3-methyl-1-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-6-nitro-1H-indazole (62235-34-1)

Conditions	Yield
With triethylamine In benzene

3-methyl-6-nitro-1H-indazole (6494-19-5) + 3-methyl-5-phenylisoxazole-4-carbonyl chloride (91182-77-3) → 3-methyl-1-(3-methyl-5-phenyl-isoxazole-4-carbonyl)-6-nitro-1H-indazole (62235-33-0)

Conditions	Yield
With triethylamine In benzene

3-methyl-6-nitro-1H-indazole (6494-19-5) + 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (25629-50-9) → 1-[3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-3-methyl-6-nitro-1H-indazole (62235-35-2)

Conditions	Yield
With triethylamine In benzene

3-methyl-6-nitro-1H-indazole (6494-19-5) + 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl chloride (4462-55-9) → 1-[3-(2,6-dichloro-phenyl)-5-methyl-isoxazole-4-carbonyl]-3-methyl-6-nitro-1H-indazole (62235-36-3)

Conditions	Yield
With triethylamine In benzene

3-methyl-6-nitro-1H-indazole (6494-19-5) → 5-bromo-7-hydroxy-2-methyl-6H-pyrazolo<4,5,1-de>acridin-6-one (142854-00-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 84 percent / K2CO3, CuI / dimethylformamide / 6 h / 100 °C 2: 88 percent / NH2NH2*H2O / 10percent Pd-C / H2O; ethanol / 2 h / Heating 3: 47percent aq. HBr, NaNO2 / methanol 4: 47percent HBr, CuBr / methanol 5: NaOMe / methanol; H2O 6: CF3SO3H / 4 h / 100 °C View Scheme

3-methyl-6-nitro-1H-indazole (6494-19-5) → 5-bromo-7-methoxy-2-methyl-6H-pyrazolo<4,5,1-de>acridin-6-one (142853-99-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 84 percent / K2CO3, CuI / dimethylformamide / 6 h / 100 °C 2: 88 percent / NH2NH2*H2O / 10percent Pd-C / H2O; ethanol / 2 h / Heating 3: 47percent aq. HBr, NaNO2 / methanol 4: 47percent HBr, CuBr / methanol 5: NaOMe / methanol; H2O 6: CF3SO3H / 4 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1: 84 percent / K2CO3, CuI / dimethylformamide / 6 h / 100 °C 2: 88 percent / NH2NH2*H2O / 10percent Pd-C / H2O; ethanol / 2 h / Heating 3: 47percent aq. HBr, NaNO2 / methanol 4: 47percent HBr, CuBr / methanol 5: NaOMe / methanol; H2O 6: 1.) CF3SO3H; 2.) K2CO3 / 1.) 100 deg C, 4 h; 2.) acetone, 10 h, reflux View Scheme

3-methyl-6-nitro-1H-indazole (6494-19-5) → 2-(6-Bromo-3-methyl-indazol-1-yl)-6-methoxy-benzoic acid (791559-34-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 84 percent / K2CO3, CuI / dimethylformamide / 6 h / 100 °C 2: 88 percent / NH2NH2*H2O / 10percent Pd-C / H2O; ethanol / 2 h / Heating 3: 47percent aq. HBr, NaNO2 / methanol 4: 47percent HBr, CuBr / methanol View Scheme

3-methyl-6-nitro-1H-indazole (6494-19-5) → 6-amino-1-(2-carboxy-3-methoxyphenyl)-3-methylindazole (142854-09-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / K2CO3, CuI / dimethylformamide / 6 h / 100 °C 2: 88 percent / NH2NH2*H2O / 10percent Pd-C / H2O; ethanol / 2 h / Heating View Scheme

3-methyl-6-nitro-1H-indazole (6494-19-5) → 6-bromo-1-(2-carboxy-3-methoxy)phenyl-3-methyl-1H-indazole sodium salt

Conditions	Yield
Multi-step reaction with 5 steps 1: 84 percent / K2CO3, CuI / dimethylformamide / 6 h / 100 °C 2: 88 percent / NH2NH2*H2O / 10percent Pd-C / H2O; ethanol / 2 h / Heating 3: 47percent aq. HBr, NaNO2 / methanol 4: 47percent HBr, CuBr / methanol 5: NaOMe / methanol; H2O View Scheme

Upstream product

• 612-22-6 2-nitro(ethylbenzene) 
• 578-54-1 ortho-ethylaniline 
• 20191-74-6 2-ethyl-5-nitroaniline 

Downstream Products

• 79173-62-9 3-methyl-1H-indazol-6-amine 
• 1620059-11-1 5-[[4-[N-(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]amino]-2-methyl-benzenesulfonamide 
• 1620843-77-7 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]amino]-2-methyl-benzenesulfonamide 
• 1620059-12-2 3-[[4-[N-(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]amino]-benzenesulfonamide 
• 1620843-78-8 3-[[4-[(2,3-dimethyl-2H-indazol-6-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]amino]-benzenesulfonamide 
• 1620843-79-9 3-[[4-[N-(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]amino]-4-methoxy-benzenesulfonamide 
• 1620059-14-4 N²-(3,4-dimethoxyphenyl)-N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine 
• 1620059-15-5 N²-(3-bromohenyl)-N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine 
• 1620059-16-6 N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N²-(3-fluorohenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine 
• 1620843-80-2 5-[[4-[N-(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-5,6,7,8-tetrahydroquinazolin-2-yl]amino]-2-methyl-benzenesulfonamide 
• 1620843-82-4 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)amino]-5,6,7,8-tetrahydroquinazolin-2-yl]amino]-2-methyl-benzenesulfonamide 
• 1620059-24-6 3-[[4-[N-(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-5,6,7,8-tetrahydroquinazolin-2-yl]amino]-benzenesulfonamide 
• 1620059-26-8 N²-(3,4-dimethoxyphenyl)-N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine 
• 1620059-27-9 N²-(3-bromophenyl)-N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine 

Relevant articles and documents

Preparation method of pazopanib intermediate

The invention provides a preparation method of a pazopanib key intermediate 2,3-dimethyl-N-(2-chloropyrimidin-4-yl)-N-methyl-2H-indazole-6-amine. The method comprises the following steps: by taking 6-halogenated-2,3-dimethyl-2H-indazole as a raw material, conducting reacting to obtain N,2,3-trimethyl-2H-indazole-6-amine; and further carrying out a reaction to obtain the 2,3-dimethyl-N-(2-chloropyrimidin-4-yl)-N-methyl-2H-indazole-6-amine. The method has the advantages of short synthesis route, accessible raw materials, low cost, mild reaction conditions, high safety and high yield, and is suitable for industrial mass production.

Method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride

The invention discloses a method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride. The method comprises the steps of reacting a glacial acetic acid solution of tert-butyl nitrite and a glacial acetic acid solution of 5-nitro-2-ethylaniline in a first microreactor to generate 3-methyl-6-nitro-1H-indazole; reacting a homogeneous solution formed by mixing the 3-methyl-6-nitro-1H-indazole and a dimethyl sulfoxide solution of methyl iodide and a dimethyl sulfoxide solution of sodium ethoxide in a second microreactor to generate 2,3-dimethyl-6-nitro-2H-indazole; then reacting withmixed liquor formed by stirring a concentrated hydrochloric acid solution of stannous chloride and ethyl alcohol in a third microreactor to generate the 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride. The method provided by the invention has the advantages of less side reaction, high yield, simplification of a complicated multi-step synthesis process, low toxicity and pollution, low production cost, good product quality, environment friendliness, energy saving and high efficiency, and is suitable for industrialized application.

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