4- antipyrine

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-p)U azolone. 

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

Section IV,49). Reflux the mixture for 1 hour and allow to cool, with continuous stirriug. Distil off the methyl alcohol. Add hot water to the residue, filter from impurities, extract the antip3rrine with benzene, and evaporate the solvent. Recrystallise the crude product from benzene or benzene - light petroleum or from hot water with the addition of a little decolourising carbon. The yield of antipyrin (white crystalline sohd, m.p. 113°) is 36 g. 

Equip a 1 litre bolt-head flask with dropping fuuncl and a double surface reflux condenser to the top of the latter attach a device (e.g.. Fig. II, 8, 1, c) for tbe absorption of the hydrogen bromide evolved. Place 100 g. (108 ml.) of dry iso-valeric acid (Section 111,80) and 12 g. of purified red phosphorus (Section 11,50,5) in the flask. Add 255 g. (82 ml.) of dry bromine (Section 11,49,5) slowly through the dropping funnel at such a rate that httle or no bromine is lost with the hydrogen bromide evolved the addition occupies 2-3 hours. Warm the reaction mixture on a water bath until the evolution of hydrogen bromide is complete and the colour of the bromine has disappeared. Pour off the liquid reaction product into a Claisen flask and distil under the reduced pressure of a water pump. Collect the a-bromo-iso-valeryl bromide at 117-122°/25-30 mm. The yield is 150 g. 

In a 500 ml. bolt-head flask provided with a thermometer (reaching almost to the bottom) and a calcium chloride (or cotton wool) guard tube, place 100 g. of a-bromo-iso-valerj l bromide and 50 g. of dry, finely-divided urea. Start the reaction by warming the flask on a water bath the temperature soon rises to about 80°. Maintain this temperatme for about 3 hours the mass will liquefy and then resolidify. Transfer the sticky reaction product to a large beaker containing saturated sodium bicarbonate solution, stir mechanically and add more saturated sodium bicarbonate solution in small quantities until effervescence ceases. Filter at the pump, suck as dry as possible and dry the crude bromural upon filter paper in the air. Recrystallise the dry product from toluene. Alternatively, recrystallise the moist product from hot water (co. 700 ml.). The yield of pure bromm-al, m.p. 154-155°, is 28 g. 

MO-Valeric acid is converted by phosphorus and bromine into a-bromo-tso-valeryl bromide the latter upon beating with urea gives bromural  

Benzocaine (or anaesthesine) is conveniently prepared from p-nitrobenzoio acid by either of the following methods  

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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... 

Alternatively, the experiment may be conducted with acetanilide (113°) and antipyrin (113°). 

XXIV XXIV, 1st 1936 3555-3633 Two Cyclic Nitrogens (continued). j Carbonyl compounds Antipyrin, 27. 

Naphthol Antipyrine, camphor, phenol, iron(III) salts, menthol, oxidizing materials, permanganates, urethane... 

Thymol Acetanilide, antipyrine, camphor, chlorohydrate, menthol, quinine sulfate, ure-thene... 

The concentration of phenol in a water sample is determined by separating the phenol from nonvolatile impurities by steam distillation, followed by reacting with 4-aminoantipyrine and K3Ee(CN)g at pH 7.9 to form a colored antipyrine dye. A phenol standard with a concentration of... 

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). 

Sulfonation of 2- and 3-pyrazolin-5-ones occurs at position 4. Thus 3-methyl-1-phenyl-pyrazolin-5-one with 20% oleum at 10-15 °C yields the corresponding 4-sulfonic acid (304) (64HC(20)l). Higher temperatures cause sulfonation not only of the heterocycle but also of the phenyl group. Antipyrine treated with sulfuric acid and acetic anhydride yields (305). 

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. 

Forbisen, 2,2, 3,3 -tetramethyl-l,l -diphenyl-4,4 -bi-3,3 -pyrazoline-5,5 -dione (706) (B-76MI40404), a by-product obtained in the manufacture of antipyrine, has been used in bovine anaplasmosis. 

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). 

Antipyrine [2,3-dihydro-l,5-dimethyl-3-oxo-2-phenylpyrazole] [60-80-0] M 188.2, m 114 , b 319 , pK 1.45. Crystd from EtOH/water mixture, bcnzene, bcnzene/pet ether or hot water (charcoal), and dried under vacuum. 

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. ... 

An interesting result has been observed when 4-formylantipyrine 89 was converted into the corresponding pyridinium salt 90 and reacted with alkyl 3-aminobut-2-enoates. Tire expected 1,4-dihydropyridines 91 are transient species in these syntheses and readily lose the 4-substituent (antipyrine, 93) so that dialkyl 2,6-dimethylpyridine-3,5-dicarboxylates 92 are obtained (85-95%) (94H815). Protonation of the pyrazole ring by the evolved hydrochloric acid accounts for this particular behavior (Scheme 29). 

A thin-layer chromatography assay was developed for ffie simultaneous determination of the three major hydroxylated metabolites of antipyrine 409,410, and 411 in urine of humans and other animals (82JPP168) (Scheme 95). 

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). ... 

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