Pyrazolidin-3,5-diones

A Hammett relationship of the form ApK = 5.8am has been proposed for 4-substituted pyrazoles (74TL1609) in order to explain the effect of 4-nitro ApK = 4.5, am = 0.71) and 4-diazo groups (Apiifa = 10.0, am = 1.76). The acidity constants of a series of pyrazolidine-3,5-diones have been determined (75AJC1583) and the 4- -butyl-1,2-diphenyl derivative phenylbutazone has a pK of 4.33. 

Pyrazolidine-3,5-dione, 4,4-diethyl-1,2-dimethyl- CNMR, 5, 194 (80CB3910) Pyrazolidine-3,5-dione, 4-(dimethylaminomethylene)-1,2-diphenyl-... 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

Voigt-Martin et al. [13] have used MICE to solve the stmcture of 4-(4 -(N,N-dimethyl)aminobenzylidene)-pyrazolidine-3,5-dione at 1.4A in projection using 42 reflections. The potential maps do not resolve atoms with these data and models have to be fitted to the map density in a way reminiscent of macromolecular crystallography. This can pose problems in structure validation which were overcome in this case by simulation calculations. There is an excellent agreement between the solution and independent model building and high resolution electron microscopy studies. 

Treatment of phenylbutazone and sulfinpyrazone with one equivalent of iV-fluorobis(trifluoro-methylsulfonyl)amine (1 d) in acetic acid and chloroform solution, respectively, results in clean fluorination at position four, and the corresponding 4-butyl-4-fluoro-l, 2-diphenylpyrazolidine-3,5-dione (22a) and 4-fluoro-1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]pyrazolidine-3,5-dione (22b) are obtained in 95 and 90% isolated yield.148... 

Acidic enolic compounds (pyrazolidine-3,5-diones, oxicams)... 

Synthesis Feprazone is prepared by the condensation of acetic acid 3-methyl-but-2-enyl ester with the lithium salt of 1,2-diphenyl-pyrazolidine-3,5-dione in the presence of tetrakis(triphenylphosphin)palladium in anhydrous tetra-hydrofuran. 

Butyl-1-phenyl-pyrazolidine-3,5-dione, C13H16N202, Mr 232.28, mp 102-103 °C sodium salt [41468-34-2], C13Hi5N2Na02, Mr 254.27... 

Comm. Farmaceutica Milanese Preparation of 4-n-butyl-2-phenyl-pyrazolidine-3,5-dione and 1-alkyl substituents thereof, GB 839 057,1957. 

A mixture comprising 108 g of phenyl hydrazine and 216 g of the diethyl ester of n-butylmalonic acid is heated on an oil bath at 170°-180°C for 12 hours. The residue is taken up with water in which an alkaline compound has been dissolved and acetic acid is added to precipitate 4-n-butyl-2-phenyl-pyrazolidine-3,5-dione. The product is a white crystalline solid having a MP 103°C. It is soluble in acetone and benzene, soluble in hot condition in methanol and ethanol and insoluble in water. 

The C—N bond of (56 A = B = O) is easily cleaved in alkaline media to form pyrazolidine-3,5-diones (58) (71CHE1028). The product of the reaction of hydroxide ion with a typical syn-bimane was shown to be the 2-pyrazolinonylacrylic acid (82JOC4222). 

A large number of diazetidinones 15 have been synthesized by an intramolecular cyclization of haloacetylhydrazones 14 with suitable bases (Scheme 11) . A photochemical Wolff rearrangement of 4-diazo-pyrazolidine-3,5-diones 16 in the presence of some nucleophiles (H20 or alcohols) leads to diazetidinones 17 in moderate yields (Scheme 12) <1987J(P1)899>. 

The corresponding 4-ketopyrazol-3-ones 347a-s (Scheme 79) were prepared from pyrazolidine-3,5-dione 345b under the conditions described in Scheme 78 except that acid chlorides 346a-s were used in place of isocyanates. 

Earlier, Kutterer et al. (05BMCL2527) (Scheme 80) reported that 4-methyl-1,2-fazs(4-chlorophenyl)pyrazolidine-3,5-dione 348 with 2-bromo-l-(2,4-difluoro-phenyl)ethanone 349 in toluene containing DIPEA under MW heating (900 W) for 1 min gave 4 -alkyl-4-methyl-pyrazolidine-3,5-dione 350 and 4-methyl-5-alkyloxy-pyrazol-3-one 351. Although compound 351 was evaluated as new inhibitor of bacterial cell wall biosynthesis, no separation and yields of 350 and 351 were reported. 

The effect of the general toxicity of compounds on the development of oedema seems to have been completely overlooked by many workers. Winter, Risley and Nuss rightly emphasize that doses of drugs that have been used to demonstrate inhibition of oedema have often been within the toxic range. Domenjoz notes that the doses of phenylbutazone and l,2-diphenyl-4-(phenylmercaptoethyl)pyrazolidine-3,5-dione (G 25671), which suppress formalin oedema by 50 per cent, are lethal in 23 per cent of the animals. The implications of these findings must be borne in mind when interpreting the... 

It is convenient to divide the anti-inflammatory pyrazolones into two groups pyrazol-5-ones XXVII), typified by amidopyrine, and pyrazolidine-3,5-diones XXVIII), of which the principal member is phenylbutazone. 

Several oxo compounds are derived from pyrazolidine, a cyclic iy,iV-disubstituted hydrazine. Pyra-zolidin-3-ones, as well as pyrazolidin-4-ones are known [141]. The anti-inflammatory phenylbutazone 1 is a substituted pyrazolidine-3,5-dione. It is made by C-alkylation of l,2-diphenylpyrazolidin-3,5-dione. For the industrial synthesis, cyclocondensation of 1,2-diphenylhydrazine with diethyl 2-butyl-malonate is preferred ... 

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