Patent GB-768813-A (GB)
Title: Substituted 1.2-diphenyl-3.5-dioxo-pyrazolidines and processes for the production thereof
IPC: A61K31/00
Filed: 1955-04-28
Abstract: The invention comprises compounds of the general formula <FORM:0768813/IV(b)/1> wherein Ar1 and Ar2 are phenyl radicals which may be substituted by alkyl, alkoxy or alkyl mercapto groups of 1 to 4 carbon atoms or by halogen, R1 and R2 are hydrogen or methyl and n is 0-3, their salts with inorganic or organic bases, and their preparation by (a) condensing, preferably in the presence of an alkaline condensation agent, a diester of the appropriately mono-substituted malonic acid with the appropriate 1,2-diarylhydrazine or an N-acyl derivative thereof or (b) condensing in the presence of an acid binding agent, a dichloride, dibromide or mixed anhydride of the appropriately monosubstituted malonic acid with the appropriate 1 : 2-diarylhydrazine or (c) condensing an appropriately mono-substituted malonic acid mono-ester mono-chloride, bromide or mixed anhydride first, corresponding to (b), with the appropriate diarylhydrazine to form a substituted malonic acid hydrazide ester and then condensing, corresponding to (a), to form the required product, and, if desired, converting the products so obtained into their salts with inorganic or organic bases.  Alkaline condensation agents referred to are alkali metals, their alcoholates, amides, hydroxides and hydrides, the condensation preferably being performed in an organic solvent at a raised temperature.  Acid binding agents referred to are tertiary organic bases, the condensation being effected with or without organic solvents at temperatures near 0 DEG  C., with subsequent heating if desired. Salts according to the invention are prepared by reacting the free pyrazolidinediones in aqueous solution or an organic solvent with an inorganic or organic base, e.g. sodium or potassium hydroxide or carbonate, sodium alcoholate or mono-, di- or tri-ethanolamine or ethylene diamine.  Examples describe the preparation of the following 3.5-dioxo-pyrazolidines: 1 : 2 - diphenyl - 4 - (21 : 51 - endomethylene - D 31 - cyclohexenyl - methyl)-, 1 : 2 - di - phenyl - 4 - (21 : 51 - endomethylene - D 31-cyclo-hexenyl)-, 1 : 2 - diphenyl - 4 - (61 - methyl - 21 : 51-endomethylene - D 31 - cyclohexenyl - methyl)-, 1 : 2 - diphenyl - 4 [31 - (211 : 511 - endomethyleneD 311-cyclohexenyl) - propyl - (11)]-, 1 : 2 - di - (p - methyl - phenyl) - 4 - (21 : 51 - endomethylene - D 31 - cyclohexenyl)-, 1 : 2 - di - (p - chlor - phenyl) - 4 - 21 : 51 - endomethylene - D 31 - cyclohexenyl)-, 1 : 2-di-(m-brom-phenyl)-4-(21 : 51-endomethylene - D 31 - cyclohexenyl)-, 1 : 2 - di - (m-methylmercapto) - 4 - [21 : 51 - endomethylene - D 31-cyclohexenyl - (11)]- and 1 : 2 - di - (p - methoxy-phenyl) - 4 - [21 : 51 - endomethylene-D 31-cyclohexenyl - (11)]-; a  - (2 : 5 - endomethylene - D 3-cyclohexenyl) - a  - carbethoxyacetylhydrazo - benzene is an intermediate in one preparation of the second of the above compounds.  The preparation of sodium salts of some of the above compounds is also described. A list of further starting materials is also given, including 4-ethoxy-41-bromo-hydrazobenzene.  Starting materials.  Compounds of the general formula <FORM:0768813/IV(b)/2> where X is a hydrocarbon radical, are prepared by condensation of sodium malonic acid diesters with the appropriate 21 : 51-endomethylene-D 31-cyclohexenyl-alkyl halides, themselves prepared by the addition of cyclopentadiene to unsaturated aliphatic halogen compounds such as vinyl bromide, allyl chloride or methallyl chloride.  Acid halides are obtained from the above esters by alkaline saponification, liberation of the acids and treatment thereof with inorganic acid halides. Mixed anhydrides, when X is an acetyl radical, are obtained from the free acid and excess acetic anhydride.  In the examples, the following compounds are prepared by the above methods: malonic acid diethyl esters, free acids and dichlorides substituted by [(6-methyl-2 : 5-endomethylene-D 3-cyclohexenyl - methyl)]- and [2 : 5 - endomethylene - D 3 - cyclohexenyl - (1)] - radicals, [3-(21 : 51 - endomethylene - D 31 - cyclohexenyl)-propyl-(1)]-malonic acid diethyl ester and 6-methyl - 2 : 5 - endomethylene - D 3 - cyclo - hexenyl - methyl bromide. 1-Bromobutene-(2) is prepared from butadiene and hydrogen bromide in glacial acetic acid.  3-(21 : 51-Endomethylene - D 3 - cyclohexenyl) - propyl bromide is obtained from PBr3 and the corresponding propanol, itself obtained by converting 2 : 5-endomethylene - D 3 - cyclohexenyl - (1) - methyl bromide into the corresponding Grignard compound and reacting this with ethylene oxide.  p.p1 - Dimethyl-, p.p1-dichloro-, m.m1-dibromo- and m.m1 - dimethylmercapto - hydrazo - benzenes are produced by reduction with zinc dust and alkali of p-nitrotoluene, p-nitrochlorobenzene, m-bromonitrobenzene and mi-nitrothioanisole respectively.  Specification 646,597 is referred to.