Indazole 7-methyl-6-nitro

The basicities of indazole (1.31), 1-methyl (0.42) and 2-methyl (2.02) derivatives and of eight other substituted indazoles have been measured (67BSF261 The effect of substituents in the 3-position is similar in pyrazoles and indazoles with Api values as follows Me, 0.80 and 0.86 Cl, -3.01 and -2.98 Br, -2.85 and -2.82, respectively. A nitro group in the homocycle has an expected base-weakening effect of -2 pK units, whether it is at the 5- or the 6-position. 

Studies of the alkylation of indazoles (67HC(22)1) have been updated by Nunn (73JCS(PD2371) and Palmer (75JCS(P1)1695). The ratio of methylation at positions 1 and 2 is relatively sensitive to the steric effect of substituents at positions 3 and 7 as shown by the results obtained in basic medium for unsubstituted indazole (55 45) and its 3-phenyl (74 26) and7-nitro derivatives (29 71). 

Formyl-3-methyl-2-( 2-methoxy-4-nitro-anilino)-2,3-dihydro-indazol wenig (bei pH = 6 42%)... 

The synthesis of pazopanib (1) involves sequential animation of 2,4-dichloropyrimidine 25 with 6-amino-2,3-dimethylindazole 24 and 5-amino-2-methyl-benzenesulfonamide 28. The 6-amino-2,3-dimethylindazole 24, on the other hand, was prepared from 2-ethylphenylamine 20 via 5-nitration with fuming nitric acid and concentrated sulfuric acid, followed by treatment with isoamyl nitrite and acetic acid to produce 6-nitro-3-methylindazole 22. The 6-nitro group was reduced with stannous chloride and concentrated HC1 in glyme and subsequently methylated at the C2 position of the indazole ring with trimethyloxonium tetrafluoroborate in acetone to produce 6-amino-2,3-dimethylindazole 24. The resultant indazole 24 was condensed with 2,4-dichloropyrimidine 25 in the presence of sodium bicarbonate in ethanol/THF and subsequent iV-methylation with iodomethane and cesium carbonate to produce 27. The 2-chloro group of pyrimidine was then allowed to react with 5-amino-2-methyl-benzenesulfonamide 28 in catalytic HCl/isopropanol and heated to reflux to deliver pazopanib hydrochloride (1) in good yield. 

In this case the activation of the methyl group by the nitro group is a necessary reaction condition. Moreover, the nitro group has to be in the ortho- or para-position to the methyl group [294, 295], If it is in the meta-position, no indazole is formed. This is in good agreement with larger yields of 6-nitroindazole in comparison with the ones of 5-nitroindazole (Scheme 2.26) [296],... 

NMR spectra of vicarious /V-alkylation products of 7-nitroinduzoles [672], l-benzylamino-3-nitroindazole [673], 1- and 6-nitroglucosylindazoles [674], l-acetyl-3-chloro-6-nitroindazole [675], the products of methylation and acetylation of 5- and 6-nitroindazoles in various solvents (CDC13, DMSO, acetone) [676], 5-nitro-7-methylindazole [677], 2-substituted 4,6-dinitroindazole [678], several dinitro indazoles [679], 6-nitroindazole derivatives [680], 44 nitrated 1- and 2-methylindazoles having H, Cl, and Br substituents in position 3 [681] have been obtained. II NMR data of some nitroindazoles are presented in a few studies [682-684],... 

Certain nuclear substituents ortho to a newly formed diazonium group may interact to form a cyclic structure with or without retention of the nitrogen atoms. Such is the case in the diazotization of o-phenylene-diamine in aqueous solution, the product being 1,2,3-benzotriazole (81%). If the ortho substituent is an activated methyl group, an indazole is formed. Hydroxyl groups ortho or para to the diazonium group may interact to form internal condensation products called diazo oxides. These compounds may also form in the reaction of halo- and nitro-substituted aminophenols. 

In view of the importance of 2-nitroimidazoles as antibiotics e.g. 2-nitroimidazoIe azomycin ) and the problems involved in their synthesis (usually via the 2-aminoimidazole) it seemed worthwhile to attempt to prepare these compounds by thermal rearrangement of the (V-nitro compounds (by analogy with the well-known reactions of 1-nitro-pyrazoles and -indazoles) (Chapter 4.04). Thus, when 1,4-dinitroimidazole (16) is heated at 140 °C in chlorobenzene, benzonitrile or anisole there is conversion into 2,4- and 4,5-dinitroimidazoles, but considerable denitration can also occur, giving 4-nitroimidazole (Scheme 6). 2-Methyl-l,4-dinitroimidazole rearranges smoothly to 2-methyl-4,5-dinitroimidazole, but 5-methyl-l,4-dinitroimidazole appears to denitrate in preference to any other reaction. Further study of these reactions is indicated. 

The best method for preparing large quantities of very pure 1-methylpyrazole uses PTC without solvent (yield of methylation with methyl iodide 90%) <90SC2849>. For 1-arylpyrazoles where the aryl is not activated by a nitro group, the best procedure uses aryl-lead triacetates <92TL659> (with indazole, a mixture of isomers is obtained, the 1//-derivative being the most abundant one). 

Durch Einwirkung von waBriger Kaliumhydroxid-Losung auf 4-[Ethoxycarbonyl-(2-phenyl-hydrazono)-methyl]-l, 3-dinitro-benzol (R = OC2H5) tritt Cyclisierung unter Abspaltung der Nitro-Gruppe zu 3-Carboxy-6-nitro-1 -phenyl-1 H-indazol (R = OH)176, l7X- 57°-571 ein. 

Analog erhalt man aus 6-Nitro-l H-indazol J-(4-Methyl-benzolsulfonyl )-6-nitro-1 H-indazol659 (Schmp. 105-109°) sowie /-Trichlormethansulfonyl-6-nitro-1H-indazof66 (Schmp. 195-201°). 

Methylamin ergibt so mit 1-Methyl-4-nitro-lH-indazol nach saulenchromalographischer Auf-arbeitung (Kieselgel Dichlormethan) l-Methyl-3-methylamino-4-nitro-lH-indazol293 [56% Schmp. 114 116° (Methanol)] ... 

Wird die Photolyse ohne Zusatz von Aminen durchgefuhrt, so kann in einigen Fallen die Einfuhrung eines Ethoxy-Restes in der 3- oder 7-Stelle beobachtet werden293. So wird z. B. aus 2-Methyl-6-nitro-2H-indazol in Ethanol 3-Ethoxy-2-methyl-6-nitro-2H-indazol [15% Schmp. 112-115° (Methanol)] nach saulenchromatographischerReinigung (Kieselgel Aceton-Benzol =1 1) isoliert ... 

Durch elektronische Einfliisse beeinfluBt die Nitro-Gruppe sehr stark das Isomerenverhaltnis 5-Nitro-lH-indazol reagiert in Dimcthylsulfoxid zu einem Isomerengemisch (/-Methyl-5-nitro-lH-j2-Methyl-5-nitro-2H-indazol) von 50 10, 6-Nitro-lH-indazol liefert dagegen das umgekehrte Verhaltnis 10 50 (l-Methyl-6-nitro-lH-/2-Methyl-6-nitro-2H-in-dazol). Weitere Beispiele s. Tab. 90 (S. 824). 

Eine nukleophile Photosubslilution an 3-Halogen-lH-indazolen wird bei der Photolyse in Aminen beobachtet, wobei aus 3-Brom-l-methyl-5-nitro-l H-indazol in Dimethylamin 3-Dimethyl-amino-I-metkyl-5-nitro-lH-indazol292, (20% Schmp. 253-255°) gebildet wird. 

Aus l-Methyl-4-nitro-1 II-indazol wird dabei durch Bcstrahlcn bei 254 nm 4-Amino-1-methyl-lH-indazol293 (23% Schmp. 108-110 ) gebildet. 

Bei der Photooxidation von 3,7-Dimethyl-l-(4-nitro-phenyl)-lH-indazol wird neben dem als Hauptprodukt (15%) isolierten 7-Formyl-3-methyl-l-(4-nitro-phenyl)-l H-indazol) in geringer Menge 2-Methyl-9-nilro-6H-(1,5-benzoxazepino[3,4,5-h,i]indazol)1> 9 [1,5% Schmp. 233-235° (Ethanol)] isoliert ... 

Amino-l-(butyl-ethoxycarbonyI-aminocarb-onyl)-5-trifluormcthyl-aus 3-Amino-2-ethoxycarbonyl-5-trifluor-methyl-2H-indazol/Butylisocyanat 851 3-Aminocarbonyl- 809 l-Aminocarbonyl-3-benzyl- 851 l-(2-Aminocaibonyl-ethyl)- 831 1 -(2-Aminocarbonyl-ethyl)-5-chlor 831 1 -(2-Aminocarbonyl-ethyl)-5-nitro- 831 7-Amino-6-dicthylamino- 843... 

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