Pyrazolone Compounds

As anti-inflammatory drugs, pyrazolone preparations have been used topically for superficial phlebitis and similar inflammatory conditions. Krook (1975) described three cases of contact allergy, one sensitive to oxyphenbutazone, the two others sensitive to phenylbutazone. Phenylbutazone did not cause cross-sensitivity to oxyphenbutazone, while cross-sensitivity the opposite way was found. Vooys and Van Ketel (1977) added one more case of phenylbutazone allergy, and Thormann and Kaaber (1978) recorded four, emphasizing the increased risk of developing hypersensitivity in patients with preexisting skin disorders. 

Another report describes the conversion of methyl 3-azido-4,6-0-benzylidene-2,3-dideoxy-o(-D-glucopyranoside to the -lactam (15) (glucose numbering), another precursor for thienamycin. In this 

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The last group of metal-free azo pigments are the pyrazolone compounds, the most commonly used examples being made from the coupling component l-phenyl-3-methylpyrazol-5-one, also used in making azo dyes. The two most important pigments are... 

In an analysis of 447 adverse effects in 194 patients worldwide (5), 20 had blood abnormahties, including two cases of agranulocytosis and one of granulocytopenia. One of these patients, who was sensitive to pyrazolone, had taken a pyrazolone compound as well. Immune-mediated agranulocytosis and thrombocytopenia have been reported (SEDA-16,110). 

Pyrazolone compounds with pharmaceutical applicability are, in UV spectrophotometry, a relatively limited, clearly defined group in which phenylbutazone [701] can be included. They are characterised by 2 relatively broad maxima with different wavelengths and intensities, 234-246 nm and 265-275 nm (see figure 7). In the base-substituted compounds (dimethylamino phenazone [103], metamizole sodium [109]) in acid solution the longwave maximum occurs at approximately the point of the minimum in methanol solution. The curves are slightly flattened in alkaline solution. is around 10000 in methanolic solution. 

Vooys RC, Van Ketel WG (1977) Allergic drug eruption from pyrazolone compounds. Contact Dermatitis 3 57-58... 

Vermeulen CW, Malten KE (1963) Contact eczeem door 6-alpha-chloorprednison en ne-omycine. Ned Tijdschr Geneeskd 107 548-551 Vooys RC, Van Ketel WG (1977) Allergic drug eruption from pyrazolone compounds. Contact Dermatitis 3 57-58... 

P Keto esters (t.g., ethyl ocetoacetate) are soluble in solutions of caustic alkalis but not in sodium carbonate solution. They give colours with freshly prepared ferric chloride solution a little alcohol should be added to bring the ester into solution. Sodium ethoxide solution reacts to yield sodio compounds, which usually crystallise out in the cold. Phenylhydrazine yields pyrazolones. They are hydrolysed by boiling sulphuric acid to the Corresponding ketones, which can be identified as usual (Section 111,74). 

When ethyl acetoacetate is warmed with an equivalent quantity of phenyl-hydrazine, the compound (I), which is not a true hydrazone, is first formed this undergoes ring formation (II) with loss of ethyl alcohol upon further heating. The product (II) is N or l-phenyl-3-methyl-5-pyrazolone. 

These latter compounds can also be obtained by direct cyclization in a Hantzsch s reaction of the selenosemicarbazone of a /3-ketoester, that is, a l-selenocarbamoyl-3-alkyl-5-pyrazolone (Scheme 21). 

The tautomeric character of the pyrazolones is also illustrated by the mixture of products isolated after certain reactions. Thus alkylation normally takes place at C, but on occasion it is accompanied by alkylation on O and N. Similar problems can arise during acylation and carbamoylation reactions, which also favor C. Pyrazolones react with aldehydes and ketones at to form a carbon—carbon double bond, eg (41). Coupling takes place when pyrazolones react with diazonium salts to produce azo compounds, eg (42). 

In mordant dyes, phenols, naphthols, and enolizable carbonyl compounds, such as pyrazolones, are generally the couplers. As a rule, 2 1 metal complexes are formed ia the afterchroming process. A typical example of a mordant dye is Eriochrome Black T (18b) which is made from the important dyestuff iatermediate nitro-l,2,4-acid, 4-amiQO-3-hydroxy-7-nitro-l-naphthalenesulfonic acid [6259-63-8]. Eriochrome Red B [3618-63-1] (49) (Cl Mordant Red 7 Cl 18760) (1, 2,4-acid — l-phenyl-3-methyl-5-pyrazolone) is another example. The equiUbrium of the two tautomeric forms depends on the nature of the solvent. 

AminothiaZoles. In contrast to the pyrazolones, pyridones, and indoles just described, aminotliiazoles are used as diazo components. As such they provide dyes that ate more bathochromic than their benzene analogues. Thus aminothiazoles are used chiefly to provide dyes in the red-blue shade areas. The most convenient synthesis of 2-aminothiazoles is by the condensation of thiourea with an a-chlorocarbonyl compound for example, 2-aminothiazole [96-50A-] (94) is prepared by condensing thiourea [62-56-6J with a-chloroacetaldehyde [107-20-0J both readily available intermediates. 

Neither (71PMH(3)67) nor (B-76MI40402) contains information on non-aromatic derivatives of pyrazole. Table 21 gives some references to these compounds, including aromatic pyrazolones. 

A parallel exists between the results of protonation and alkylation of pyrazolones since there is an alkyl derivative for each tautomer. The main difference is that the percentage of the different tautomers is thermodynamically controlled whereas that of alkyl derivatives is kinetically controlled. One has to remember that the alkyl derivatives thus obtained are the fixed compounds used in tautomeric studies. 

The reaction is very common in pyrazolone chemistry. Since alkoxypyrazoles and tautomerizable pyrazolones undergo this reaction and 3-pyrazolin-5-ones, like antipyrine, do not, it is assumed that the reaction takes place at C-4 of the OH tautomer. Pyrazolone diazo coupling is an important industrial reaction since the resulting azo derivatives are used as dyestuffs. For instance, tartrazine (Section 4.04.4.1.3) has been prepared this way. 3,5-Pyrazolidinediones react with aryldiazonium salts resulting in the introduction of a 4-arylazo group. As has been described in Section 4.04.2.1.4(v), diazonium salts couple in the 3-position with indazole to give azo compounds. 

Pyrazolones show a great variety of reactions with carbonyl compounds (B-76MI40402). For instance, antipyrine is 4-hydroxymethylated by formaldehyde and it also undergoes the Mannich reaction. Tautomerizable 2-pyrazolin-5-ones react with aldehydes to yield compound (324) and with acetone to form 4-isopropylidene derivatives or dimers (Scheme 8 Section 4.02.1.4.10). 

The title compounds also undergo the Claisen rarrangement (5-allyloxypyrazoles 4-allyl-5-pyrazolones) and are readily transformed into 5-chloropyrazoles by means of phosphorus oxychloride (8OCHE1). In the presence of aluminum chloride 5-acyloxypyrazoles (481) undergo the Fries rearrangement affording 4-acyl-5-hydroxypyrazoles (482). 

The acetyl transfer reactions of acetylated pyrazolones (acylotropy) have been carefully studied by Arakawa and Miyasaka (74CPB207,74CPB214) (Section 4.04.2.1.3(x)). Methylation of 3-methyl-l-phenyl-4-phenylazo-5-pyrazolone (402) yields, depending on the experimental conditions, the N- and the O-methylated derivatives (483) and (484) (66BSF2990). These derivatives have been used as model compounds in a study of the tautomerism of (402) (structure 139 Section 4.04.1.5.2). 

Pigments derived from pyrazolones include Hansa Yellow R, l-phenyl-3-methyl-4-[(2,5-dichlorophenyl)azo]-5-hydroxypyrazole and Pigment Chrome Yellow, 1-phenyl-3-methyl-4-[(o-tolylazo]-5-hydroxypyrazole, as examples of monoazo compounds. 

Analytical applications of pyrazolones have been reviewed by Busev et al. (65RCR237). Organic bases are easily characterized by formation of highly crystalline salts with picrolonic acid (l-(4-nitrophenyl-3-methyl-4-nitro-5-hydroxypyrazole). The last-named compound is used as a reagent for alkaloids, tryptophan, phenylalanine and for the detection and estimation of calcium (B-76MI40404). 

In hexadeuteriodimethyl sulphoxide the compound which is labelled as 3-methyl-pyrazolone gives NMR spectra 16. In what form is this compound present in this solution ... 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

Knorr reported the first pyrazole derivative in 1883. The reaction of phenyl hydrazine and ethylacetoacetate resulted in a novel stmcture identified in 1887 as l-phenyl-3-methy 1-5-pyrazolone 9. His interest in antipyretic compounds led him to test these derivatives for antipyretic activity which led to the discovery of antipyrine 10. He introduced the name pyrazole for these compounds to denote that the nucleus was derived from the pyrrole by replacement of a carbon with a nitrogen. He subsequnently prepared many pyrazole analogs, particularly compounds derived from the readily available phenyl hydrazine. The unsubstituted pyrazole wasn t prepared until 1889 by decarboxylation of liT-pyrazole-3,4,5-tricarboxylic acid. ... 

The only major comprehensive work on pyrazolones that includes pyrazolidi-nones was published by Wiley and Wiley in the Chemistry of Heterocyclic Compounds series of monographs (64MI1) and is now obsolete. Since then, pyrazolones have been mentioned only briefly in other major works such as Comprehensive... 

The preparation of the selenazolyl-pyrazolones was then effected by a second method, in which first the pyrazolone ring and afterward the selenazole ring was formed. For this purpose -ketoester seleno-semicarbazones were first converted to the corresponding 1-seleno-carbamoyl-3-aIkylpyrazol-5-one. These, by condensation with a-halo-genocarbonyl compounds according to the Hantzsch synthesis, formed the selenazole ring as a second step (17). 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

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