Patent GB-433053-A (GB)
Title: Manufacture of 5-pyrazolone-derivatives
Filed: 1934-02-08
Abstract: 1-Aryl-2-alkyl-5-pyrazolones which contain at least at one nitrogen atom a partially or wholly hydrogenated cyclic hydrocarbon radicle and have the general formula <FORM:0433053/IV/1> wherein R1 stands for phenyl or a wholly or partially hydrogenated cyclic hydrocarbon radicle, R2 for alkyl or a wholly or partially hydrogenated cyclic hydrocarbon radicle, R3 for alkyl, R4 for hydrogen, alkyl or the group <FORM:0433053/IV/2> (wherein X1 or X2 stand for hydrogen, alkyl, aralkyl, or a wholly or partially hydrogenated cyclic hydrocarbon radicle) are distinguished by a good febrifuge and sedative action.  They are prepared (a) by condensing an acylacetic ester with a hydrazine mono-substituted by a wholly or partially hydrogenated cyclic hydrocarbon radicle and causing an alkylating agent or an agent capable of introducing the radicle of a wholly or partially hydrogenated cyclic hydrocarbon radicle to act upon the resulting product; (b) by condensing an acylacetic ester with a symmetrically disubstituted hydrazine containing at least one wholly or partially hydrogenated cyclic hydrocarbon radicle; (c) condensing a hydrazine mono substituted by a wholly or partially hydrogenated cyclic hydrocarbon radicle with an a :b -unsaturated carboxylic acid or an ester thereof, oxidizing the pyrazolidone thus obtained and causing an alkylating agent or an agent capable of introducing the radicle of a wholly or partially hydrogenated cyclic hydrocarbon to act upon the resulting product; (d) a pyrazolone obtained by (a), (b) or (c) is nitrated or treated with nitrous acid, followed by reduction in each case and the resulting amino derivative may be reacted with an alkylating agent or with a halogen substitution product of a wholly or partially hydrogenated cyclic hydrocarbon; (e) by reacting one molar proportion of a halogen substitution product of a wholly or partially hydrogenated cyclic hydrocarbon with one molar proportion of a known 5-pyrazolone compound substituted in 1- and 2-positions and containing a primary or secondary amino group in 4-position; the product may be further alkylated; (f) by causing an aldehyde bisulphite or an aldehydesulphoxylate to act upon the pyrazolones obtained according to (d) and (e) and containing a replaceable hydrogen atom attached to nitrogen; solubility of the products in water is thus effected.  In examples: (1) cyclohexylhydrazine is condensed with acetoacetic ester and the product methylated by means of methyl iodide or dimethylsulphate to give 1-cyclohexyl-2.3-dimethyl-5-pyrazolone; this is converted to the 4-nitroso derivative by means of nitrous acid and reduced by means of zinc dust in hydrochloric acid or by means of catalytically activated hydrogen to the 4-amino derivative; this is converted to the 4-dimethylamino derivative by means of formaldehyde and formic acid, while the monomethylamino derivative is prepared by the action of dimethylsulphate on the 4-benzylidene compound; p symm.-dicyclohexylhydrazine is condensed with acetoacetic ester and treated with nitrous acid followed by reduction as in (1); the resulting 1.2 - dicyclohexyl - 3 - methyl - 4 - amino - 5-pyrazolone is converted to the corresponding dimethylamino and monomethylamino derivatives as in (1) and the latter, by reaction with formaldehyde bisulphite, yields a water-soluble compound; (3) 1-phenyl-2.3-dimethyl-4-amino-5-pyrazolone is reacted with 1-bromocyclohexene - 2.3-; 1 - phenyl - 2.3 - dimethyl - 4-methylamino-5-pyrazolone and 1-phenyl-2.3-dimethyl - 4 - cyclohexenylamino - 5 - pyrazolone may be similarly reacted; (4) 1-cyclohexyl-2.3-dimethyl-5-pyrazolone is nitrated by a nitricsulphuric acid mixture and the 4-nitro compound reduced by hydrogen in the presence of a nickel catalyst at 80 DEG  C.; (5) cyclohexylhydrazine is condensed with crotonic acid, the pyrazolidone oxidized by air in the presence of ferric and copper chlorides and the resulting 1 - cyclohexyl - 3 - methyl - 5 - pyrazolones methylated in 2 - position by means of methyliodide.  The Specification as open to inspection under Sect. 91 also comprises the manufacture of compounds of the above formula unsubstituted in the 2-position (R2 standing for hydrogen) by application of the foregoing methods of manufacture suitably modified as regards starting materials or by omission of the final step of alkylation &c. to introduce a 2-substituent.  This subject-matter does not appear in the Specification as accepted.