5-Methylpyrazole-3-carboxylic acid

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

Pyrazoles and Isoxazoles- Further in vitroand in vivo25, 26 studies have been conducted with 5-methylpyrazole-3-carboxylic acid (VIII). This compound is known to depress blood sugar levels in fastedi glucose-primed rats by a mechanism which may be secondary to its depression of plasma... 

We have already noted (Section 4.04.2.1.4(xi)) that alkyl groups on pyrazoles are oxidized with permanganate to carboxylic acids. Silver nitrate and ammonium persulfate transform 4-ethyl-1-methylpyrazole (436) into the ketone (437) (72JHC1373). The best yield was obtained starting with the alcohol (438) and using an acid dichromate solution as oxidizing agent. 

The reaction of the isomeric 3-iodo-l-methylpyrazole-4-carboxylic acid with copper phenyl- and p-amylacetylide also leads to closure of the pyranopyrazole... 

For this reason, the heterocyclization of acetylenic derivatives of pyrazolecar-boxylic acids with different arrangements in the ring of the interacting groups was studied (Table XXVI). The reaction is carried out in boiling pyridine in the presence of catalytic amounts of PhC=CCu (81IZV1342). 4-Acetylenyl-l-methylpyrazole-5-carboxylic acids (Scheme 121) are fully isomerized into the pyranopyrazoles in 20 min in 62-84% yields. 

The cyclocondensation of 4-iodo-l-methylpyrazole-5-carboxylic acid with PhC=CCu under similar conditions is over in 1.5 h. Thus, the cyclization of the... 

In the heterocyclization reactions of 4-acetylenyl-l-methylpyrazole-3-carbox-ylic acids and 4-acetylenyl-l-methylpyrazole-5-carboxylic acids the behavior is the same. Isomeric l-methyl-4-phenylethynylpyrazole-3-carboxylic acid forms... 

Such an easy isomerization of acetylenylbenzoic acid amides implies the formation of a five-membered nonaromatic ring condensed with the pyrazole ring. However, the pyrazole analog of o-iodobenzamide (amide of 4-iodo-l-methylpyrazole-3-carboxylic acid) formed under heating with CuC=CPh in pyridine for 9 h only the disubstituted acetylene in 71 % yield is identical in all respects to the compound obtained from the corresponding acid by successive action of SOCI2 and NH3 (90IZV2089) (Scheme 126). 

The same strategy had application in several other heterocyclic compounds, to obtain either amine or carboxylic acid derivatives. A process for the production of 4-amino-5-methylpyrazole derivative 325 using the Beckmann rearrangement as a key step was the subject of a new patent ° (equation 119). 

The hydrogen atoms of the methyl and carboxyl groups of 1 -phenyl-3-methylpyrazole-5-carboxylic acid are replaced by deuterium under mildly alkaline conditions.538 No other example of hydrogen exchange in a methylpyrazole seems to have been recorded. 

The introduction of other electron-withdrawing or -donating groups enables nitration of one or another of the rings to be accomplished selectively. Thus, l-phenyl-3-methylpyrazole is nitrated only in the pyrazole ring, whereas 1 -phenylpyrazole-3-carboxylic acid nitrates only in the para position of the benzene ring.586 The only dinitro-pyrazole recorded was obtained from 3-nitro-5-(pyrid-3-yl)-pyrazole.249,587 In the nitration product (54) the nitro group at... 

Snyder703 was the first to obtain an organo-lithium derivative of pyrazole, when he treated l-phenyl-3-methylpyrazole with butyl-lithium and then carbon dioxide, and isolated l-phenyl-3-methyl-pyrazole-5-carboxylic acid. Subsequently, Alley704 showed that 1-phenyl- and 1-methyl-pyrazoles are also metallated in the 5-position by the treatment with organo-lithium compounds. Hiittell and Schon705 studied the pyrazolyl lithium derivatives in detail, and showed that in pyrazole itself the 3- and 5-hydrogen atoms were more... 

The proton spectra of 1-substituted 3-nitropyrazoles [296], 5-substituted 3-methyl-l-aryl-4-nitropyrazoles [297, 298], 1,3- and l,5-diphenyl-4-nitropyra-zoles [281], 5-iodo-4-nitro-l,3-dimethylpyrazole [299], l-methyl-3-nitro-4- and l,3-methyl-4-nitro-5-phenylethynylpyrazoles [300], l-methyl-3-nitro-5-methoxy-carbonylpyrazole [301], l-methyl-3-nitro- and l-methyl-5-nitro-4-cyanopyrazoles [302], A-(2,4-dinitrophenyl)nitropyrazoles [303], a- and [3-anomers of 3-nitro-and4-nitropyrazolyl-l-ribonucleosides [304, 305], 3-substituted 1,5-dimethyl- [306] and 5-substituted l,3-dimethyl-4-nitropyrazoles [279], l-acetyl-3-anilino-4-nitro-5-dimethylaminopyrazoles [307], 3-substituted 4-nitro-5-carboxylic acid derivatives [308, 309], 4-nitropyrazolo[4,3-e][l, 4]diazepin-5,8-diones showing antimicrobial activity [310], l-heteryl-4-nitropyrazole derivatives [311], 3-nitro- and 5-nitro-l-methylpyrazole [312], 4-nitro-5-(trimethylsilyl)pyrazole [313], 3-methyl-4-nitro-pyrazol-5-ones [298], and some other nitropyrazoles [248, 314-320] have been examined. 

Natural products containing pyrazole rings are practically nonexistent. It seems that the evolution of organisms has produced few enzymes capable of forming an N-N bond. However, a methanol extract of the sponge Tedania anhelans yielded the two unusual heteroaromatic acids, pyrazole-3(5)-carboxylic acid 905 and 4-methylpyrazole-3(5)-car-boxylic acid 906, which are reported for the first time as natural products <1997JNP802>. 

Transformation of 4-methylpyrazoles into 4-carboxylic acids takes place readily by cobalt-manganese bromide mediated oxidation <91CL585>. Begtrup <92JCS(P1)2555> has developed a method to activate methyl groups at positions 3 and 5 using 2-alkoxy-pyrazohum derivatives (181) in this way pyrazoles (182) were prepared (X = D, I, OMe). 

Ethyl l-methyl-5-fluoropyrazole-4-carboxylate 12 and ethyl l-fluoromethyl-5-flu-oropyrazole-4-carboxylate 13 are the products of electrochemical fluorination of ethyl l-methylpyrazole-4-carboxylic acid 11 on a platinum anode in 70% HF/Py/ EtsN (99TL7819) (Scheme 24). The maximum yield is 40% (selectivity of fluorine attack at position 5 is 83%) (Table 8). 

The cyclocondensation of 4-iodo-l-methylpyrazole-5-carboxylic acid with PhC CCu under similar conditions is over in 1.5 h. Thus, the cyclization of the 4-phenylethynyl-l-methylpyrazole-5-carboxylic acids and the cyclocondensation of the iodine acid with PhC CCu give the same products pyranopyrazoles. However, the formation rate of the first reaction is much higher. 

In the heterocyclization reactions of 4-acetylenyl-l-methylpyrazole-3-carbox-ylic acids and 4-acetylenyl-l-methylpyrazole-5-carboxylic acids the behavior is the same. Isomeric I-methyI-4-phenyIethynyIpyrazole-3-carboxylic acid forms 3 -lactones, 2-methyl-7-oxo-5-phenylpyrano[3,4-c]pyrazole, in 71 % yield (20 min) (Scheme 122). The same ester is obtained by acetylenic condensation (3 h) of 4-iodo-l-methylpyrazole-3-carboxylic acid with copper phenylacetylide. 

Methylpyrazole-l-carboxylate (or Pyrazole-1-carboxylic acid methyl ester)... 

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