Patent GB-814228-A (GB)
Title: 3.5-dioxo-pyrazolidines bicyclically substituted in the 4-position and a process fortheir preparation
Filed: 1957-03-21
Abstract: The invention comprises compounds of the formula <FORM:0814228/IV (b)/1> (wherein R1 and R2 are hydrogen or C1-4 alkyl radicals, n is zero, 1, 2 or 3 and R3 and R4 are hydrogen or alkyl, cycloalkyl, aralkyl or aryl radicals in which any aromatic rings may be substituted by C1-4 alkyl, alkoxy or alkylmercapto radicals or by halogen atoms), their salts with inorganic or organic bases and their preparation by condensing the appropriate 2 : 5-endomethylene-cyclohexyl- or cyclohexyl-alkyl-substituted malonic acid diester with hydrazine or the appropriately substituted hydrazine or N-acyl derivatives of such compounds, preferably in the presence of an alkaline condensing agent; or by condensing a similarly substituted malonic acid dihalide or di-(mixed anhydride) with hydrazine or the appropriately substituted hydrazine, preferably in the presence of an acid-binding agent, or, when R3 and R4 are aryl radicals, with a lithium compound of the substituted hydrazine, or by condensing the appropriate 2 : 5-endomethylene-cyclohexyl- or cyclohexyl-alkyl-substituted cyanacetic acid ester with hydrazine or the appropriately substituted hydrazine (in which, however, R4 may not represent an aryl radical) with subsequent hydrolysis of the substituted tautomeric 3-imino-5-oxopyrazolidine or 3-amino-pyrazol-5-one obtained, or by reacting the appropriate 2 : 5-endomethylene-cyclohexyl- or cyclohexyl-alkyl-substituted malonic acid mono-ester-mono-acid chloride with hydrazine or the appropriately substituted hydrazine in the cold in the presence of an acid binding agent and then ring-closing the resulting compound of the formula <FORM:0814228/IV (b)/2> by means of an alkaline condensing agent in the warm.  Suitable alkaline condensing agents for the above condensations, which can be performed in the presence or absence of organic solvents, preferably at temperatures between 80 DEG  and 160 DEG  C., are alkali metals or their amides, alcoholates, hydrides or hydroxides. Suitable acid-binding agents for the above condensations are an excess of the hydrazine or tertiary organic bases such as pyridine, dimethylaniline and trialkylamines, used advantageously at temperatures near 0 DEG  C. in the presence or absence of additional organic solvents.  The above condensation with a substituted cyanacetic acid ester can be performed in the warm and the tautomeric imino compound so obtained hydrolysed by heating with dilute mineral acid.  In examples: (1) 1 : 2-diphenyl-4-(21 : 51 - endomethylene - cyclohexylmethyl) 3 : 5 - dioxo - pyrazolidine is prepared from the appropriately substituted malonic acid diethyl ester and hydrazobenzene; (2) 1 : 2-bis-(p-methyl - phenyl) - 4 - (21 : 51 - endomethylenecyclohexylmethyl) - 3 : 5 - dioxopyrazolidine is prepared from the appropriately substituted malonyl chloride and p : p1-dimethyl-hydrazobenzene, and it is stated that the corresponding 1 : 2 - bis - (p - chlorophenyl) - compound, 1 : 2-bis - (m - bromo - phenyl) - compound, 1 - phenyl - 2 - benzyl - compound and 1 : 2 - dibenzyl compound may be similarly prepared and that 1 : 2-diphenyl-4-(21 : 51-endomethylenecyclohexyl) - 3 : 5 - dioxo - pyrazolidine and the corresponding 1 : 2 - di - (m - bromophenyl)-compound are prepared from (2 : 5-endomethylenecyclohexyl)-malonic acid dichloride and the appropriate hydrazobenzene; (3) 1-phenyl-4-(21 : 51 - endomethylene - cyclohexylmethyl)- and 1 - phenyl - 4 - (21 : 51 - endomethylenecyclohexyl)- 3 : 5-dioxo-pyrazolidines are prepared by the method of (1); (4) 4-(21 : 51-endomethylene - cyclohexylmethyl) - 3 : 5 - dioxopyrazolidine and the corresponding 1-methyl- and 1 : 2 - dimethyl - compounds and 1-methyl - 4 - (21 : 51 - endomethylene - cyclo hexyl) - 3 : 5 - dioxopyrazolidine and the corresponding 1 : 2-dimethyl-compound are obtained by the method of (2); (5) 1-benzyl-4-(21 : 51-endomethylenecyclohexylmethyl) - 3 : 5 - dioxopyrazolidine is similarly prepared; (6) and (7) 2 : 5 - endomethylene - cyclohexylmethyl) - cyanacetic acid ethyl ester and phenyl hydrazine give 1 - phenyl - 3 - amino - 4 - (21 : 51 - endomethylene - cyclohexylmethyl) - 5 - pyrazolone which on hydrolysis with HCl gives the first-named product of (3), and this on methylation with dimethyl sulphate in caustic soda gives 1 - phenyl - 2 - methyl - 4 - (21 : 51 - endomethylene - cyclohexylmethyl) - 3 : 5 - dioxo - pyrazolidine; and (8) (2 : 5-endomethylene-cyclohexylmethyl)-malonic acid ethyl ester chloride and phenyl hydrazine are reacted at 0 DEG  C. in ether containing dimethylaniline, the solvent is removed and the residue is heated with sodium butylate in n-butanol to give, on working up, the first-named product of (3).  Reference is also made to other substituted malonic acid esters and substituted hydrazines which may be used in the processes of the invention, in which R1 has the additional value of methyl, R2 has the additional value of methyl, n has the additional values of 2 and 3, and R3 and R4 have the additional values of ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, a -ethylpropyl, n-heptyl, n-octyl, allyl, cyclohexyl, 2 - 3 - and 4 - methyl - cyclohexyl, cyclohexylmethyl, menthyl, bornyl, 3- and 4-chlorobenzyl, 4-methylbenzyl, 2 : 4- and 3 : 4-dimethylbenzyl, 2-, 3- and 4-methoxybenzyl, a -methyl- and a -ethyl-benzyl, b -phenylethyl, a -ethyl-4-methyl-benzyl, a -ethyl-4-methoxy-benzyl, benzhydryl, a  : b -diphenylethyl, various mono- and di-chloro, mono- and di-bromo- and mono- and dimethylphenyls, 2 : 4 : 5-trimethylphenyl, 4-ethyl- and 4-t-butyl-phenyl, 2-methyl-4-bromo- and 2-bromo-4-methyl-phenyl, various methoxy- and ethoxy-phenyls, 3-ethoxy-4-methyl-phenyl, various methyl- and ethyl-mercaptophenyls, 1 - methyl - 4 - iso - propyl - phenyl-(2) p-diphenylyl, a - and b -naphthyl, 1-methyl-b -, naphthyl and 5 : 6 : 7 : 8 - tetrahydro - naphthyl-(2).  Substituted malonic acid diesters of the formula <FORM:0814228/IV (b)/3> (wherein X is a hydrocarbon radical) are prepared from the unsubstituted malonic acid diesters and the appropriate bicyclic halides, which may be unsaturated in the 3 : 4 position of the bicyclic ring, the product in this case being subsequently hydrogenated; or by diene synthesis from cyclopentadiene and an unsaturated substituted malonic acid diester, e.g. allyl malonic acid diethyl ester, with subsequent hydrogenation of the product. The halides referred to above may also be prepared by diene synthesis from cyclopentadiene and an unsaturated aliphatic halogen compound, e.g. allyl chloride, methallyl chloride or vinyl bromide, with subsequent hydrogenation if the saturated halide is required. Esters of the above formula may be converted to the corresponding dihalides by alkaline saponification to the di-carboxylic acids and treatment of these with halides such as SOCl2, PCl5 or POBr3.