Nitropyrazoles, synthesis

Poullain and co-workers ° synthesized Af-substituted-3,5-diamino-4-nitropyrazoles by treating substituted pyrimidines with Af-alkylhydrazines. 3,5-Diamino-4-nitropyrazole (14) has been synthesized by treating the pyrimidine (13) with hydrazine hydrate. This methodology is limited in scope but the products are useful intermediates for the synthesis of insensitive high explosives. 

Fig. 2.4.10. Synthesis of oligomeric aminopyrazoles starting from 3-nitropyrazole-5-carboxylic acid 15 (i) HCI, MeOH ...

The construction of a heterocyclic ring from two reagents, one of which contains a nitro group, is widely used in the synthesis of the nitro derivatives of pyrazole, isoxazole, and 1,2,3-triazole. Thus, for example, the reaction of sodionitromalonal-dehyde with substituted hydrazines leads to the corresponding derivatives of 4-nitropyrazole [33, 61, 471 173] (Scheme 63). 

Nitroalkenes are valuable starting reagents for the synthesis of nitroazoles [479], Thus, l,3-diphenyl-4-nitropyrazole is formed in the reaction of l-nitro-2-morpholinoethene with a-chlorobenzylidenephenyl hydrazine [480], However, the yield is not greater than 20% (Scheme 64). 

The reaction of sodium azide with l-bromo-l-nitro-2-arylethenes takes place by a formal 1,3-cycloaddition Scheme leading to 4(5)-aryl-5(4)-nitro-l,2,3-triazoles [487-489], During the synthesis of nitrotriazoles the bromonitroarylethenes can be replaced successfully by the more readily obtainable l,2-dibromo-l-nitro-2-arylethanes [489], The intermediate product in the synthesis of 3-nitropyrazoles from 2,2-dinitroethanol and diazo ketones or diazoacetic ester is 1,1-dinitroethene [490,491] (Scheme 68). 

Nitroketene aminals react with organic thiocyanates to form the amides of /J/)-bis-amino-a-nitrothioacrylic acid [501], The latter proved valuable starting compounds for the synthesis of various heterocycles [502], It was not possible to obtain nitropy-razoles by the direct action of hydrazine hydrate on these amides [502,503], However, the corresponding derivatives of 3,5-diamino-4-nitropyrazole were synthesized after previous methylation of the hydrazine hydrate with methyl iodide or dimethyl sulfate (without isolating the 5-methyl intermediate) [504] (Scheme 75). 

The action of hydrazine or hydroxylamine on certain other nitropyrimidine systems leads to 4-nitropyrazoles and 4-nitrooxazoles [549], When 1,5-disubstituted 4-nitro-6-pyridazinone derivatives are heated in an alkaline medium the derivatives of 4-nitropyrazole are formed with high yields. 1-Substituted 4-nitropyrazole-5-carboxyiic acids [550, 551] or 1-substituted 4-nitropyrazoles [552-554] can be obtained, depending on the conditions. Another promising method of synthesis has been opened up for the production of 4-nitropyrazole derivatives. 4-Nitropyrazole is obtained with a high yield in the reaction of 3,5-dinitro-2-pyridone with hydrazine [555] (Scheme 99). 

Nitropyrazole derivatives such as 4-nitropyrazole, l-methyl-4-nitropyrazole and 4,4 -dinitro-l,r-methylene dipyrazole are known as antiparasitic agents <88Mi 30i-02>. It has been shown that 3,4-bis(2,4-dinitrobenzoyl-hydroxymethyl) pyrazole has remarkable antimicrobial activity it is more efficient than penicillin, levomycetin, and polymyxin <92Ml 30i-03>. The synthesis of A -pyrazoline-... 

As previously mentioned, nitropyrazole 5 is one of the regulatory starting materials for sildenafil citrate, so not surprisingly the compound has attracted the attention of fine chemical companies and within Pfizer. The optimization of the condensation reaction to make intermediate 1 has been previously reported. In the medicinal chemistry synthesis, conversion of 1 to compound 3 was accomplished via reaction with hydrazine followed by a methylation reaction. Clearly a more efficient way of making this transformation is to use a regioselective condensation reaction with methylbydrazine. " " ... 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

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