Antipyrine derivatives

The photochemistry of antipyrine derivatives (Scheme 11) involves, depending on the substituent in position 4, ring opening fragmentations and rearrangements. In all cases the N—N bond is cleaved. Irradiation of the 4-unsubstituted derivative (163 = H) in alcohols... 

Although requiring high temperatures and long reaction times for the fluorination of aromatic compounds, A-fluoro-2,4,6-tri-methyl triflate (2) was also used for the fluorination of estrone, methyl /J-hydroxyphenylacetate, and some heteroaromatic rings such as indoles or antipyrine derivatives. However, furan, pyrrole, A -benzylpyrrole, ethyl 2-thienylacetate, or methyl 2-thio-phenecarboxylate could not be lluorinated with reagent 2. ... 

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). 

Derivatives like (491 R = Me) can be de-5-methylated by Raney nickel in ethanol or concentrated hydrochloric acid. Acid hydrolysis of (491 R = acyl) also affords 5-mercap-topyrazoles, whereas alkaline hydrolysis of the pyrazolium salt (495) furnishes methanethiol and antipyrine. 

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. ... 

Some offier pyrazol-3-one derivatives studied by biological chemistry are muscimol analogs and bacterial metabolites of antipyrine [77ZN(C)557 79ACSA (B)294]. 

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. 

Oxo-derivatives of pyrazole also contain an amide group replacing two carbon atoms in the aromatic pyrrole ring. Antipyrine [146] is... 

The structural feature of aminopyrine is similar to antipyrine except that aminopyrine has a substituent (dimethylamino group) at the C-4 position (Fig. 4). The exceptional efficacy of the aminopyrine breath test derives from the presence of multiple N-methyl groups that are readily removed by oxidative N-demethyla-tion. Hence, further oxidation of several formaldehyde molecules produced by demethylation of aminopyrine gives large volumes of labeled COj that is readily quantified. Some of the metabohtes of aminopyrine are given in Fig. 4 [30, 85, 87-90]. 

Unsaturated 5(4//)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride/ antipyrine/ " chromone/ indoles/ pyridines/" ° quinolines/" diazines/" benzoxazoles/" and benzimidazoles " " have been prepared. Reaction with nitrogen nucleophiles and subsequent cycliza-tion leads to the expected 5(477)-imidazolones. 

Table 36 Complexes of Actinide(IV) Compounds with Lactams, Antipyrine (2,3-Dimethyl-l-phenylpyrazol-5-one, ATP) and its Derivatives, and Dicarboxylic Acid Amides...

Nikelly (49) performed a similar separation without the need for derivatives. The column was 0.25% Carbowax 20M/0.4% isophthalic acid on acid-washed microbeads. Included in Kern s work (39) was a description of a separation of aspirin and salicylic acid as the TMS derivatives on 3% OV-17 on Chromosorb W-HP at 130 C°as well as the separation of phenacetin, antipyrine, and aminopyrine without derivatization on SE-30, 3% on VarAport 30 at 180°C. 

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