4- Aminopyrazole carboxamide

Heteropolyacids Hi4[NaPsW29MoOno] and H3PMO12O4 have been shown to be efficient catalysts for consecutive condensation of aldehydes with 5-aminopyrazole -carboxamide and cyclization into pyrazolo[3,4-t4pyrimidines <2007MI1467>. The reaction of ethyl 5-acylaminopyrazoles with hexachloroethane and triphenylphosphine in the presence of a base has been recently reported to afford an imidoyl chloride that reacted in situ with ethylamine yielding an amidine in 71% yield that cyclized readily in DMF in the presence of potassium carbonate to yield pyrazolopyrimidines in 65% yield <2007TL3983>. 

The stable triazolotriazine anionic cr-adducts (44) can be prepared by reacting nitroacetaldehyde with hydrazinotriazines [94KGS52], whilst pyrazolotriazinones (45) are readily obtained from aminopyrazole carboxamides [94S1437],... 

The methods of synthesis of both these systems are very similar and are almost exclusively by the treatment of the corresponding aminopyrazole carboxamide with nitrous acid (Equation (8)). 

These are generally obtained by diazotization of 5-aminopyrazole 4-carboxamides, e.g., conversion of 156 to 157 (38G49 59GEP1058519 83EUP127028 86JMCI544). 

In some cases a choice of multicomponent or linear protocol for the treatment of pyruvic acids, aminoazole, and aldehydes allows obtaining different heterocycles. For instance, MCR involving 5-aminopyrazoles or sequence pathway via preliminary synthesis of arylidenpyruvic acids led to positional isomers 36 and 37, respectively (Scheme 15) [4, 61, 68]. It is interesting to note that the same strategy applied to 3-amino-l,2,4-triazole or to amino-W-aryl-lH-pyrazole-4-carboxamide reactions gave no effect and the final compound for both the protocols were the same [52, 61, 62]. 

Interesting reagents for such MCRs from the viewpoint of selectivity tuning are 5-aminopyrazoles containing carboxamide substituent. In the first article concerning the behavior of these aminozoles in the reactions with cyclic 1,3-diketone and aldehydes, it was found that only one direction of the treatment leads to tricyclic Biginelli-like heterocycles 61 (Scheme 30) [96]. 

Scheme 30 Tuning of selectivity of MCRs involving carboxamide containing 5-aminopyrazoles...

Analogous to the synthesis of imidazo[4,5-,y [l,2,3]triazin-4-ones (Scheme 41), diazotization is the method of choice for making this ring system, and involves treatment of the 5-aminopyrazole-4-carboxamides with nitrous acid (Scheme 43) <1995JHC1417, 1996CHEC-II(7)489>. 

Reaction of 5-aminopyrazole-4-carboxamides with acid amides gives pyrazolo[3,4-d] pyrimidines (56JA784 58JOC191 61GEP1106331 ... 

Thus, it is clear that in the case of 3-amino-1,2,4-triazole and 5-aminotetra-zole, reactions with arylidenepyruvic acids and their synthetic precursors lead to identical reaction products [199, 201], while applying sequential or multi-component procedures for interaction with 3-substituted 5-aminopyrazoles allows for the isolation of heterocycles of different structures [202]. However, it is interesting to note that, according to publication [202], reactions of 5-amino-7V-arylpyrazolo-4-carboxamides 213 with arylidenepyruvic acids 236 or with pyruvic acid 239 and aldehydes 240 also yielded identical reaction products—pyrimidine heterocycles 255 (Scheme 3.70). 

The 4-aminopyrazole-5-carboxamide (381) cyclizes to give compound (383) on heating with chloroformamidine hydrochloride in DMSO it is most likely that intermediate amidine (382) is first formed (Scheme 35) <78NJC357>. 

Formamide is a powerful C-N-heterocyclization reagent. 2-Formamidino derivatives are intermediates. Robins transformed 3-aminopyrazole-4-carboxamide to a 4-oxopyrazolo[3,4-d]pyrimidine (155)95 by heating in formamide. In boiling formamide, 155 was obtained from ethyl 3-aminopyrazole 4-carboxylate (38)31 (Scheme 35). From the enamino ester 59 and formamide a 5,6,7,8-tetrahydrobenzo [b] thieno [2,3-d ] pyrimidin-4-one (156) was obtained,96 as well as the aromatic thionaphtheno[2,3-d]-pyrimidine (157).97 This heterocyclization method shows broad applicability... 

The formamide reaction has been successfully used to convert a 2-amino-pyridine-3-carboxamide to pyrido[2,3-d]pyrimidin-4-ones (see 3)220 3-aminopyrazole-4-carboxamide (see 15) to pyrazolo[3,4-rf ] pyrimidin-4-ones (see 16)118 4-aminopyrazole-3-carboxamide to pyrazolo[4,3-d]pyrimi-din-7-ones (see 17)221 many 4-amino-1,2,3-triazole-5-carboxamides (see 20) to 8-azapurin-6-ones (see 21)157,217-222—226 and 4-aminoimidazole-5-car-boxamides (see 18) to purin-6-ones (see 19).124-202-227 228 Secondary amines are suitable starting materials, as in the conversion of 4-amino-l,2,3-triazole-5-(jV-methyl)carboxamide and its 3-benzyl63 and... 

Amidines were first condensed with o-aminoamides in 1965 when Baker and Kozma fused benzamide, 4-aminopyrazole-5-carboxamide, and sodium... 

Aminopyrazole-4-carboxamide hemisulfate To water (253 ml) at 60°C was added 3-morpho-lino-2-cyanoacrylamIde (63.4g) and85% technical hydrazine hydrate (22.7 g). Themixture was rapidiy heated to 95°C and the temperature was maintained at >90°C for 20 minutes. The mixture was then cooied to 60°C and the pH carefully adjusted to 1.5 by the addition of a mixture of sulfuric acid (45.7 g) and ice (45.7 g). The acidified reaction was cooled to 5°C and the crystalline product collected and washed with cold water (2 X 100 ml) and acetone (2X50ml). Theproductwasdried invacuoat80°C. Wt = 5.8g. Yield =95%,MP237 -239 C. 

Hydroxypyrazolo[3,4-d] pyrimidine A suspension of 3-aminopyrazole-4-carboxamide hemisulfate (113 g) in formamide (325 g) was stirred and heated to 145°C. The reaction was held at 145°C for 5 hours. The reaction was then cooled to 30t and the product collected and washed with formamide (2 X 50 ml), water (2 X 150 ml) and acetone (2 X 100 ml). Wt of crude product = 79 g. The crude product was recrystallized by dissolution in a solution made from sodium hydroxide (25 g) in water (1,200 mi) with treatment at 25% with char-coai (8 g),foilowed by reprecipitation by the addition of concentrated hydrochloric acid to pH 5. The product was coilected and washed with cold water (2 X 300 ml), acetone (2 X 200 ml) and dried in vacuo at 60°C. Wt = 70 g. Yield = 80%. 

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