Pyrazolones antipyrine

When the methyl-phenyl-pyrazolone is heated with methyl iodide in methano-lie solution, it acts in the form (D), the — NH— group undergoing methy lation, with the formation of the hydriodide of 2,3-dimethyl- l-phenyl-5 Pyrazolone, or antipyrine (F), a drug used (either as the free base or as the... 

This substance may be conveniently methylated with dimethyl sulphate to 3deld 1-phenyl-2 3-dimethyl-5-pyrazolone or antipyrin (III) ... 

Scheme 19 contains all the reactions observed in different examples, none being so complex (B-76MI40402). Most studies deal with the methylation of 3-methyl-1-phenyl-pyrazolone, since in this case one of the products obtained is antipyrine (2,3-dimethyl-l-phenyl-3-pyrazolin-5-one), one of the classical antipyretic agents (Section 4.04.4.1.1). 

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). 

Some active 5-pyrazolone derivatives (707) and (708) in which the 1-phenyl substituent of antipyrine was replaced by 2 -, 3 - and 4 -pyridyl groups have been prepared (66HCA272). A series of aminoesters substituted at the nitrogen atom of the ester grouping with an antipyryl residue (709) were found to possess local anesthetic properties (69MI40400). 

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. ... 

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). ... 

Pyrazolone derivatives are analgesic substances that have been known for a long time. The use of antipyrine (phenazone) and aminopyrine was sharply curtailed after their bone marrow toxicity was reported. Other derivatives, however, like phenylbutazone. 

DERIVATIVES OF PYRAZOLE Pyrazolones rank among some of the more venerable nonsteroidal antiinflammatory agents. The activity of antipyrine (154) was discovered not too long after that of aspirin. The preparation of a plethora of analogues of that compound, all bearing additional substitution at the 4-position, was described in some detail in the earlier volume. 

Antipyrine (l,5-dimethyl-2-Phenyl-3-Pyrazolone) is known to form hexakis complexes with the lanthanides and yttrium salts 38). The bright green fluores-... 

Antipyrine 2t3- imetbyl-l pkenyl-3 pyrazolin 3 one or Pbenazone, listed in Beil as 1-Phenyl-2.3 dimethyI-pyrazolon-(5) or... 

Preparation 404.—Antipyrine, Phenazone (l-Phenyl-2 3-dimethyl-5-pyrazolone). 

Phenylmethyl pyrazolone (see Preparation 252) is methylated with a methyl alcoholic solution of methyl chloride or bromide at 90°—100°, a slight excess of methylating agent being employed. The methylation can he conveniently carried out in an autoclave fitted with an agitator. The alcohol is distilled off, and the reaction product dissolved in water made slightly alkaline with caustic soda. The antipyrine is then extracted with benzene, and crystallised from benzene, and finally from water, animal charcoal being used to decolorise. 

Antipyrine or 2,5-Dimethyl-l-phenyl-4-pyrazoline-3-one, listed in Beil as 1-Phenyl-2.5-dimethyl-pyrazolon-(3),(HjC)C-N(C6H5)-N(CHj)... 

The phenyl-methyl-pyrazolon is then methyl by heating with the calculated amount of me iodide in methyl alcohol at 100°—150°, in a sealed 1 for one or two hoars. The hydriodide of antipy present in the contents, is decomposed by aqu< potash, and the antipyrine obtained is then cryi lised from toluene or ether. M.p. 114°. Yi about 10 gms. 

ANTIPYRINYLMETHYLAMINO)METHANESULFONIC ACID SODIUM SALT METHYLAMINO-ANTIPYRINE SODIUM METHANESULFONATE 4-METHYLA NO-1,5-DIMETHYL-2-PHENYL-3-PYRAZOLONE SODIUM METHANESULFONATE ... 

METHYLAMINOPHENYLDIMETHYLPYRAZOLONE METHANESULFONATE SODIUM l-PHENYL-2,3-DIMETHYL-5-PYRAZOLONE-4-METHYLA nNO-METHANESULFONATESODIUM l-PHENYL-2,3-DIMETHYLPYRAZOLONE-(5)-4-METHYLA.MINO-METHANESULFONICACID SODIUM PHENYL DIMETHYL PYRAZOLON METHYL AMINOMETH-ANE SODIUM SULFONATE 4-SODIUM METHANESULFONATE METHYLAMINE-ANTIPYRINE SODIUM METHYLAMINO-ANTIPYRINE METHANESULFONATE... 

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