Patent GB-776136-A (GB)
Title: Improvements in and relating to 3:5-dioxopyrazolidines bicyclically substituted in the 4-position
Filed: 1955-11-16
Abstract: The invention comprises compounds of the general formula <FORM:0776136/IV(b)/1> (wherein R1 and R2 represent hydrogen or, methyl, R3 represents hydrogen or an alkyl cycloalkyl, aralkyl or aryl radical, R4 represents hydrogen or an alkyl, cycloalkyl or aralkyl radical, any aromatic ring in R3 and/or R4 being, if desired, substituted by alkyl, alkoxy or alkylmercapto groups of at most 4 carbon atoms or by halogen atoms, and n is 0-3), and the preparation thereof by (a) condensing, in the presence of an alkaline condensing agent, a substituted malonic acid diester of the general formula <FORM:0776136/IV(b)/2> (wherein X represents a hydrocarbon radical, preferably an alkyl radical of not more than 4 carbon atoms) with hydrazine or a hydrazine derivative of the general formula <FORM:0776136/IV(b)/3> (wherein one Z represents hydrogen or an acyl radical which can be easily split off and the other represents hydrogen), or (b) condensing, in the presence of an acid-binding agent (which may be an excess of the hydrazine when this is aliphatic, araliphatic or cycloaliphatic), a substituted malonic acid derivative of the general formula <FORM:0776136/IV(b)/4> (wherein Y represents chlorine, bromine or an acyloxy radical) with hydrazine or a hydrazine derivative of the general formula <FORM:0776136/IV(b)/5> or (c) condensing, as in (a), a substituted cyanoacetic acid ester of the general formula <FORM:0776136/IV(b)/6> with hydrazine or a hydrazine derivative of the general formula given in (a) and hydrolysing the resulting 3-imino-5-oxopyrazolidine, or (d) first condensing, as in (b), a substituted malonic acid derivative of the general formula <FORM:0776136/IV(b)/7> with hydrazine or a hydrazine derivative of the general formula given in (a) and then condensing the resulting substituted malonic acid monoester monohydrazide as in (a), followed in each case, if desired, by treatment of the products, if either or both of R3 and R4 represent hydrogen, with alkylation, aralkylation or cycloalkylation agents in the presence of acid-binding agents, and/or conversion of the products into their salts with inorganic or organic bases.  The products possess antipyretic, antiphlogistic and analgesic activity.  Examples describe the condensation of: (1) (2:5 - endomethylene - D 3 - cyclohexenyl) - malonic acid dibutyl ester with phenylhydrazine in n-butanol in the presence of sodium n-butoxide; the phenylhydrazine may be replaced by its p-methyl, o-methoxy, p-ethoxy, p-methylmercapto, 2:4-dichloro or p-bromo derivative; (2) (2:5-endomethylene-D 3-cyclohexenylmethyl)-malonic acid diethyl ester with phenylhydrazine similarly; the substituted malonic ester may be replaced by its 1- or 6-methyl drivative or by g -(2:5-endomethylene-D 3 - cyclohexenyl) - propylmalonic acid diethyl ester; (3) (2:5-endomethylene-D 3-cyclohexenylmethyl)-malonic acid diethyl ester with hydrazine hydrate in ethanol in the presence of sodium ethoxide; (4) and (5) (2:5-endomethylene - D 3 - cyclohexenyl) - malonyl dichloride in ether with an excess of (4) methyl- or isopropylhydrazine, and (5) 1:2-dimethyl- or 1:2-dibenzyl-hydrazine; (6) the same malonic acid derivative with 1-phenyl-2-benzylhydrazine in ether in the presence of dimethylaniline; (7) the same malonic acid derivative with an excess of cyclohexylhydrazine in ether; (8) (2:5-endomethylene - D 3 - cyclohexenylmethyl) - cyano - acetic acid ethyl ester with phenylhydrazine in ethanol in the presence of sodium ethoxide, followed by hydrolysis of the product with dilute hydrochloric acid; (9) the first product of (1) with dimethyl sulphate in aqueous caustic soda; (10) (2:5 - endomethylene - D 3 - cyclohexenyl)-malonic acid ethyl ester chloride with phenylhydrazine in ether in the presence of dimethylaniline, followed by ring closure by heating with sodium n-butoxide in n-butanol.  Additional starting materials are listed.  Starting materials.  1 - Phenyl - 2 - benzylhydrazine and cyclohexylhydrazine are prepared by reducing respectively benzalphenylhydrazine with sodium amalgam in ethanol, and cyclohexanone hydrazone with sodium amalgam in a 1:4 mixture of ethanol and benzene.