Patent GB-843691-A (GB)
Title: Substituted 3, 5-diketo-pyrazolidines
IPC: C07D401/04
Filed: 1957-10-02
Abstract: The invention comprises 3:5-dioxopyrazolidines having in one tautomeric form the general formula:  <FORM:0843691/IV(b)/1> (wherein R1 represents an alkyl, alkenyl, aryl, cycloalkyl or aralkyl radical, R2 represents hydrogen or an alkyl, aralkyl or acyl radical, and R3 represents an alkyl radical of up to 4 carbon atoms, with the proviso that R1, R2 and R3 need not be dissimilar), and their salts with hydrochloric, hydrobromic, sulphuric, citric, tartaric, succinic, maleic, acetic, benzoic and hexahydrobenzoic acids, and the production thereof by condensing a piperidyl-4-hydrazine of the general formula:  <FORM:0843691/IV(b)/2> with a reactive derivative of malonic acid, of the general formula:  <FORM:0843691/IV(b)/3> (wherein X and Y may be similar or dissimilar, and each represents bromine, chlorine or an azide, amino or alkoxy group), R2 when an acyl group being optionally split off during or after the condensation, and the products being, if desired, converted into acid addition salts.  The condensation is advantageously carried out in the absence of a solvent at 150-200 DEG C. or in an anhydrous inert organic solvent in the neighbourhood of the boiling temperature.  The products are useful as antipyretics and analgesics for the treatment of rheumatism.  In examples: (1) N-methylpiperidyl-4-hydrazine is refluxed with ethylmalonic acid diethyl ester in benzonitrile to produce 1-(N-methylpiperidyl-41) - 4 - ethyl - 3:5 - dioxopyrazolidine;(2)-(9) similarly prepared are the corresponding 4-isopropyl-, 4-n-butyl-, 4-phenyl-, 4-benzyl-, 2-methyl-4-phenyl-, 2-methyl-4-n-butyl-, 2-isopropyl-4-n-butyl- and 4-methyl-compounds; (10) ethylmalonyl dichloride is reacted with 1 - (N - methylpiperidyl - 41) - 2 - acetylhydrazine in chloroform in the presence of triethylamine to form 1 - (N - methylpiperidyl-41) - 2 - acetyl-4 - ethyl - 3:5 - dioxopyrazolidine; (11) ethyl-malonic and dihydrazide is treated with hydrochloric acid and sodium nitrite and the resulting diazide is reacted with N - methylpiperidyl - 4-hydrazine to give 1-(N-methylpiperidyl-41)-4-ethyl-3:5-dioxopyrazolidine; (12) n-propyl-malonic acid diethyl ester is heated with N-methylpiperidyl-4-hydrazine to produce 1-(N - methylpiperidyl - 41) - 4 - n - propyl - 3:5 - dioxopyrazolidine; (13) n-butylmalonyl dichloride is reacted as in (10) to give 1-(N-methylpiperidyl - 41) - 2 - acetyl - 4 - m - butyl - 3:5 - dioxopyrazolidine, from which (14) the acetyl group is removed by heating with aqueous methanol; (15) the product of (14) is prepared by heating 1 - (N - methylpiperidyl - 41) - 2 - acetylhydrazine with n-butylmalonic acid diethyl ester, the acetyl group being split off during the condensation; (16) N - methylpiperidyl - 4 - hydrazine is reacted as in (13) to produce 1-(N-methylpiperidyl - 41) - 4 - n - butyl - 3:5 - dioxopyrazolidine; (17) phenylmalonyl dichloride is reacted as in (10) to form 1-(N-methylpiperidyl-41) - 2 - acetyl - 4 - phenyl - 3:5 - dioxopyrazolidine, from which (18) the acety group is split off as in (14) or by heating with dilute hydrochloric acid (the product in the latter clase being in the form of its hydrochloride): (19) the product of (18) is prepared by a process analogous to that of (15); (20) and (21) N-methylpiperidyl-4-hydrazine is heated with phenylmalonic acid diamide or ethyl ester-amide to produce 1-(N-methylpiperidyl - 41) - 4 - phenyl - 3:5 -dioxopyrazolidine; (22) 1 - (N - methylpiperidyl - 41) - 2 - methylhydrazine is heated with ethylmalonic acid diethyl ester to give 1-(N-methylpiperidyl-41)-2-methyl - 4 - ethyl - 3:5 - dioxopyrazolidine; (23)-(35) similarly prepared are the corresponding 2 - methyl - 4 - isopropyl-, 2 - methyl - 4 - benzyl-, 2 - ethyl - 4 - phenyl-, 2 - ethyl - 4 - n - butyl-, 2 - ethyl - 4 - alkyl -, 2 - isopropyl - 4 - phenyl-, 2 - isopropyl - 4 - methyl-, 2 - isopropyl - 4-ethyl-, 2 - isopropyl - 4 - n - propyl-, 2:4 - diisopropyl-, 2 - isopropyl - 4 - hexyl-, 2 - isopropyl - 4 - cyclohexyl- and 2-benzyl-4-phenylcompounds; (36)-(45) by methods analogous to one or other of the foregoing are prepared 1-(N-methylpiperidyl-41)-2-isopropyl-4-phenyl, -2-methy-4 - benzyl-, - 2 - ethyl - 4 - phenyl, - 2 - isopropyl-4 - phenyl-, - 2 - isopropyl - 4 - ethyl-, - 2 - ethyl-4 - n - butyl-, - 2 - isopropyl - 4 - n - butyl-, - 4 - n - butyl-, and - 2:4 - dimethyl - 3:5 - dioxopyrazolidine and 1-(N-n-butylpiperidyl-41)-4 - phenyl - 3:5 - dioxopyrazolidine.  Salts of some of the products are described. Specifications 843,688 and 843,689 are referred to.