Amino acids, 410 indazoles

The Wittig-Horner reaction of protected 3-formylindazoles with iV-(benzyloxycarbonyl)-a-phosphonoglycine trimethyl ester has been developed as a new practical synthesis of dehydro 2-azatryptophans and amino acid derivatives <2007TL2457>. Nucleophilic addition of Grignard or lithiated reagents of 3-A -methoxy-A -methyl-amides of indazole afforded a library of 3-keto and 3-formylindazoles <2007T419>. 

The p/fa for benzimidazole is 12.3 and for indazole, the value is 13.9. The benzimidazolyl and indazolyl anions react straightforwardly on nitrogen with electrophiles, though mixtures of N-1- and N-2-substituted products can result in the latter case. For example, amination with hydroxylamine 0-suIfonic acid gives a 2 1 ratio of 1-amino-l//-indazole and 2-amino-2//-indazole ° or to take another example, the ratio of N-1-to N-2-ethylated products from methyl indazol-3-ylcarboxylate can vary from 1 1 to 18 1 depending on the base and the solvent. The N-arylation of benzimidazoles and indazoles can be achieved with palladium or copper catalysis (See 4.2.10). 

The (R)-amino acid, (R)-2-amino-3-(7-methyl-l H-indazol-5-yl)propanoicacid (R)-88a, (Figure 11.25) is a key intermediate for preparing antagonists of calcitonin gene-related peptide receptors (GGRP receptor) 89 [152] Such antagonists are potentially useful for the treatment of migraine and other maladies [153,154]. 

Amination at an azole ring nitrogen is known for Af-unsubstituted azoles. Thus 4,5-diphenyl-1,2,3-triazole with hydroxylamine-O-sulfonic acid gives approximately equal amounts of the 1- (104) and 2-amino derivatives (105) (74AHC(16)33). Pyrazole affords (106) and indazole gives comparable amounts of the 1- and 2-amino derivatives. 

N-Amination of indazole affords a mixture of 60% (271) and 40% (272), which compares with the 55 45 ratio obtained in methylation (Section 4.04.2.1.3(viii)). A camphopyrazole derivative (a mixture of tautomers 275 and 276) when treated with hydroxylamine O-sulfonic acid yields exclusively the (4S,7i )-4,7-methano-2-amino-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-indazole (277) (79YZ699). 

Substituents in the indazole ring may direct a given reaction towards another position either by their R and I electronic properties or simply by protecting the most reactive position. Examples of both types are found in sulfonation studies (67HC(22)l). As indicated before (Section 4.04.2.3.2(i)), sulfonation takes place at position 7. However, the presence of an amino group at positions 5 or 7 directs the attack towards the 4-position (Scheme 40). To obtain the indazole-5-sulfonic acid a more complicated procedure has been used but it is still based on the same ideas. 

Most of the pharmacologically active indazole derivatives are useful as antiinflammatory drugs, e.g. bendazac or [(1-benzyl-l J/-indazol-3-yl)oxy]acetic acid (LDso in mice and rats of 355 and 388mgkg i.p., respectively) and benzydamine or l-benzyl-3-[3-(dimethyl-amino)propoxy]-l//-indazole (LDso in mice and rats of 110 and lOOmgkg" i.p., respectively). The last cited compound also has analgesic and antipyretic properties (B-76MI40404). 

Dinitro>6>amino, (OaN)a C7HsNa NHa, mw 223-15, N 31.39%. Brn-yel scales, mp—melted with decompn on heating on Pt foil in flame very diff sol in w, easier in boiling AcOH. Was prepd by heating 5,7-dinitro-6-indazolesulfonic acid with ammonia... 

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. 

To simplify the synthetic technology of 3-amino-5-nitroindazole and to improve the target product quality it is reasonable to use 2-cyano-4-nitroaniline. The latter is subjected to diazotization, and the azo compound thus formed is reduced with simultaneous closure of the indazole cycle with sulfur dioxide in 5-15% sulfuric acid [315],... 

Amino-l-methylindazolium salt reacts with acetylacetone differently in comparison with TV-aminobenzimidazolium salts [Eq. (91)] (76CPB2 267). This is explained partly by the decreased CH-acidity of the pyrazole ring and partly because the product of the primary cyclization (376) is not stabilized by ring opening, but is aromatized by the oxidant to pyraz-olo[l,5-/)]indazole (377). 

The 3-(A -acyl-JV-benzylamino-2-(triphenylphosphoranylidene)-amino-2/f-indazoles (228) on treatment with concentrated hydrochloric acid cyclize to 2-alkyl-1-benzyl-l/f-[l,2,4]triazolo-[l,5-h]indazoles (229) (Equation (61)) <90JOC4724>. 

CGRP receptors antagonist enzymatic preparation of (A)-2-amino-3-(7-methyl-1 H-indazol-5-yl)propanoic acid. 

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