Patent GB-788393-A (GB)
Title: Process for the manufacture of pyridazone compounds
Filed: 1954-04-26
Abstract: The invention comprises 4-cyano-pyridazone-(3) compounds, particularly 4-cyano-pyridazone-(3), 4-cyano-6-methyl-pyridazone-(3), 4-cyano-5 - methyl - pyridazone - (3), 5:6 - cyclohexano - 4 - cyano - pyridazone - (3), 5:6-(91:101 - phenanthreno) - 4 - cyano - pyridazone-(3) and compounds of the formula: <FORM:0788393/IV (b)/1> (wherein R1 is hydrogen or a phenyl, halogenophenyl or alkyl residue and R2 and R3 are phenyl, halogenophenyl or alkyl residues, the alkyl residues containing at most 5 carbon atoms); pyridazone-(3)-compounds of the formula: <FORM:0788393/IV (b)/2> (wherein R1 is hydrogen or a phenyl, halogenophenyl or alkyl residue, R2 is a free or esterified carboxyl group or an acetyl group, and each of R3 and R4 are phenyl, halogenophenyl or alkyl residues or R3 is hydrogen or an alkyl residue and R4 hydrogen, the alkyl residues containing at most 5 carbon atoms); 4 : 5 : 6-triphenylpyridazone - (3); 4 - benzoyl - 5 : 6 - diphenylpyridazone - (3); and 4 - benzoylamino - 5 : 6-diphenyl - pyridazone - (3), and the preparation of pyridazone-(3) compounds by condensing a hydrazine containing at least 3 hydrogen atoms attached to the nitrogen atoms directly or in stages with 2 components, viz: (a) an organic a -dicarbonyl compound or a reactive functional carbonyl mono- or di-derivative thereof; and (b) a carboxylic acid of which the a -carbon atom is part of a reactive methylene group or a reactive nitrogen-free functional derivative of such acid, ring closure to a pyridazone-(3) compound being achieved by the use of a basic condensing agent, and, if desired, hydrolysing a nitrile group or an esterified carboxyl group in 4-position of the pyridazone-(3) to a free carboxyl group and/or, if desired, removing a free carboxyl group in 4-position by decarboxylation and/or, if desired, alkylating the nitrogen atom in 2-position, e.g. with a dialkyl sulphate or an alkyl halide, and/or, if desired, converting the products into salts. Hydrazines which may be used include hydrazine itself or monoalkyl-, monoaryl- or monoheterocyclic-hydrazines, if desired as their salts. Suitable a -dicarbonyl compounds include diacetyl, benzils, pyridils, glyoxal or alkyl- or aryl-glyoxals and o-quinones or their acetals, thioacetals, ketals, thioketals, acylates, bisulphite compounds or oximes.  Advantageously, esters of carboxylic acids are used as the acid components, particularly those in which the a  - methylene group is activated by a carbonyl, carboxyl, carbalkoxy or cyano group or esters such as those of phenyl- or pyridyl-acetic acid, glycollic acid or acylamino-acetic acids. Solvents are preferably used in the condensations, agents for which include hydroxides, alcoholates, hydrides, amides or hydrocarbon compounds of alkali or alkaline earth metals, or strong organic bases such as triethylamine or trimethylbenzyl ammonium hydroxide.  The process may be carried out by reaction of all 3 components together at once, by first forming the mono-hydrazone of the carbonyl compound and condensing this with the carboxylic acid or by first forming the carboxylic acid hydrazide and then condensing this with the dicarbonyl compound, the condensing agent being added at either stage in the last 2 processes.  It is stated that pyridazone-(3) compounds containing a free or esterified carboxyl group or an acetyl group in position-4 can be converted by known methods into corresponding 4-amino- or 4-cyano-compounds, e.g. for the latter, by conversion into a 4-carbamoyl compound and then splitting off water.  In examples: (1) the monohydrazone of benzil is prepared from benzil and hydrazine hydrate and is then condensed with diethyl malonate to give 4-carbethoxy-5 : 6-diphenyl - pyridazone - (3); (2) 4 - carbethoxy-2 : 5 : 6 - triphenyl - pyridazone - (3) is similarly prepared; (3) benzil monohydrazone and ethyl aceto acetate give 4-acetyl-5 : 6-diphenyl-pyridazone - (3); (4) 4 - benzoyl - 5 : 6 - diphenylpyridazone-(3) is similarly prepared; (5) benzil monohydrazone and ethyl cyanacetate give 4-cyano - 5 : 6 - diphenylpyridazone - (3); (6) cyanacetic acid hydrazide is prepared from hydrazine hydrate and methyl cyanacetate and is then condensed with diacetyl to give diacetyl monocyanacetyl hydrazone and this is cyclized to give 4 - cyano - 5 : 6 - dimethyl - pyridazone-(3); (7) cyanacetic acid hydrazide and benzoyl acetyl give benzoyl-acetyl-mono-cyan-acetyl-hydrazone C6H5-CO-C(CH3) = N-NH-CO-CH2CN and this is cyclized to 4-cyano-5-phenyl-6-methyl-pyridazone-(3); (8) benzil monohydrazone and ethyl phenylacetate give 4 : 5 : 6-triphenyl-pyridazone-(3); (9) benzil monohydrazone and ethyl hippurate give 4-benzoylamino - 5 : 6 - diphenyl - pyridazone - (3); (10) benzil, ethyl cyanacetate and hydrazine hydrate are condensed in a one-stage reaction to give the product of Example (5); (11) diacetyl replaces the benzil of Example (10), the product of Example (6) being formed; (12) ethyl malonate and p : p1-dichlorbenzil monohydrazone give 5 : 6 - di - (p - chlorophenyl) - 4 - carbethoxy-pyridazone-(3); (13) 1 : 2-cyclohexanedione and cyanacetic acid hydrazide give 5 : 6-cyclohexano - 4 - cyano - pyridazone - (3); (14) 5 : 6 - (91 : 101 - phenanthreno) - 4 - cyanopyridazone-(3) is similarly prepared; (15) the product of Example (1) is hydrolysed to give 4-carboxy - 5 : 6 - diphenyl - pyridazone - (3); (16) the product of Example (2) is hydrolysed to give the sodium salt of 4-carboxy-2 : 5 : 6-triphenylpyridazone-(3) from which the free acid is isolated; (17) the free acid of Example (16) is decarboxylated; (18) the product of Example (6) is hydrolysed to give 4-carboxy-5 : 6-dimethylpyridazone-(3) and this is decarboxylated; (19) to (21) the product of Example (6) is methylated to give 4-cyano-2 : 5 : 6-trimethyl-pyridazone-(3), this is hydrolysed to give 4-carboxy-2 : 5 : 6-trimethyl-pyridazone-(3), and this is decarboxylated; (22) to (24) the product of Example (1) is methylated to give 2-methyl-4-carbethoxy-5 : 6-diphenyl-pyridazone-(3), this hydrolysed to 2 - methyl - 4 - carboxy - 5 : 6 - diphenylpyridazone-(3) and this is decarboxylated; (25) the product of Example (12) is methylated to give 2 - methyl - 5 : 6 - bis - (p - chlorophenyl)-4-carbethoxypyridazone-(3); (26) the product of Example (5) is methylated to give 2-methyl-5 : 6 - diphenyl - 4 - cyano - pyridazazone - (3); (27) the product of Example (3) is methylated to give 2 - methyl - 5 : 6 - diphenyl - 4 - acetylpyridazone-(3); (28) the product of Example (12) is hydrolysed to give 5 : 6-bis-(p-chlorophenyl) - 4 - carboxy - pyridazone - (3), this is decarboxylated and the product is methylated to give 2 - methyl - 5 : 6 - bis - (p - chlorophenyl)pyridazone - (3); (29) to (31) glyoxal sodium bisulphite and cyanacetic acid hydrazide give 4-cyano-pyridazone-(3), this is hydrolysed to 4-carboxy - pyridazone - (3) and this is decarboxylated; (32) to (34) 4-cyano-pyridazone-(3) is methylated to give 2 - methyl - 4 - cyanopyridazone-(3), this is hydrolysed to give 2-methyl - 4 - carboxy - pyridazone - (3) and this is decarboxylated; (35) the product of Example (6) is ethylated to give 2-ethyl-4-cyano-5 : 6-dimethyl - pyridazone - (3); (36) the product of Example (7) is methylated to give 2 : 6-dimethyl - 4 - cyano - 5 - phenyl - pyridazone - (3); (37) and (38) the product of Example (25) is hydrolysed to give 2-methyl-5 : 6-bis-(p-chlorophenyl) - 4 - carboxy - pyridazone - (3) and this is decarboxylated; (39) a composition is described (Abridgment Group VI); and (40) aqueous methyl-glyoxal and sodium hydrosulphite solution are mixed and the resulting solution is reacted with cyanacetic acid hydrazide to give 4-cyano-5-methyl-pyridazone-(3) and 4 - cyano - 6 - methyl - pyridazone - (3), separated by extraction with boiling benzene. In addition to the compounds specifically referred to above reference is also made to compounds of the general formula: <FORM:0788393/IV (b)/3> wherein R1, R2 and R3 are phenyl or halogenophenyl residues or alkyl residues of 1 to 5 carbon atoms.ALSO:Pharmaceutical preparations comprise a pyridazone-(3) compound or a salt thereof in admixture with a pharmaceutical organic or inorganic carrier.  Specified carriers include water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, polyalkylene glycols, " Vaseline " (Registered Trade Mark) and cholesterine.  The preparations may be in the form of tablets, drag<\>ees, ointments, creams, solutions, suspensions or emulsions and may contain preservatives, stabilizers, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers.  They may also contain other therapeutically valuable substances.  It is stated that compounds of the formula <FORM:0788393/VI/1> (wherein R1 is phenyl, halogenophenyl or alkyl of 1 to 5 carbon atoms) may be used as solution promoters, particularly for medicaments such as 1 - phenyl - 2 : 3 - dimethyl - 4 - dimethylamino - pyrazolone.  An example describes the preparation of a solution of the latter compound in water with the aid of 2-methyl-4-carboxy - 5 : 6 - diphenyl - pyridazone - (3).  A further example describes a pharmaceutical preparation containing 2 : 5 : 6-trimethyl-4-cyano-pyridazone-(3), lactose, gelatin, starch, magnesium stearate and talcum.