Patent GB-785185-A (GB)
Title: Improvements in the production of 4-hydroxypyrazoles
Filed: 1956-03-14
Abstract: 4-Hydroxypyrazoles are produced by reacting a b -halogen-a -diketone of general formula R-CHX-CO-CO-R1, in which R and R1 are alkyl, aralkyl, cycloalkyl or aryl groups and R can also be a hydrogen atom, and X is chlorine, bromine or iodine, with hydrazine or a monosubstitution product of hydrazine and cyclizing the resultant monohydrazone by splitting off hydrogen halide at an elevated temperature, advantageously in the presence of an agent which binds the hydrogen halide.  When 4-bromohexane-dione-(2.3) and phenyl hydrazine are used as starting materials the reaction proceeds as follows <FORM:0785185/IV (a)/1> Other suitable diketones are, for example, monochlordiacetyl, monobromdiacetyl, 1-brom-1 - phenylbutanedione - (2.3), 5 - bromohexane dione - (3.4), 4 - chloro - octanedione - (2.3), 6-phenyl - 4 - bromohexanedione - (2.3), 3 - bromo-1 - p - tolyl - propanedione - (1.2) and 5 - cyclo - hexyl - 4 - bromohexanedione - (2.3).  Instead of phenyl hydrazine there may be used, for example, hydrazine, semicarbazide, monomethyl, butyl cyclohexyl, benzyl, acetyl, p-toluenesulphonyl and benzoyl hydrazines, the isomeric chlorophenylhydrazines, nitrophenyl hydrazines and naphthylhydrazines to give a 4-hydroxypyrazole unsubstituted on the N-atom 1 or substituted by the corresponding group.  It is advantageous to allow the whole process to proceed in one stage by reacting the monohalogen diketone with the hydrazine in the presence of a hydrogen halide acceptor such as alkali metal hydroxides or carbonates, alkaline earth metal oxides or hydroxides, or tertiary amines and an inert solvent at elevated temperature. Suitable solvents are, for example, benzene, toluene or tetrahydrofurane in which the hydrogen halide salt of the tertiary amine is insoluble.  Suitable tertiary amines are, for example, pyridine and trimethyl amine.  If desired, an excess of the hydrazine compound may be used as a hydrogen halide acceptor or, in some cases, a special cyclization agent can be dispensed with because the 4-hydropyrazoles themselves exhibit a weakly basic function.  It is advantageous to carry out the process in an inert atmosphere, free from molecular oxygen, such as nitrogen.  In the examples: (a) 4-bromohexanedione-(2.3) is led into a mixture of phylhydrazine, triethylamine and toluene, the resulting mixture is heated and 1-phenyl-3-methyl-5-ethyl-4-hydroxypyrazole is separated; (6) 4-bromohexanedione-(2.3) is reacted with phenylhydrazine in benzene; the resulting monophenyl hydrazone is boiled with triethylamine in toluene to give 1-phenyl-3-methyl-5-ethyl-4-hydroxypyrazole; (c) monobromodiacetyl, dissolved in toluene, is passed into a mixture of phenylhydrazine, triethylamine and toluene and the resulting mixture is heated to give 1-phenyl-3-methyl-4-hydroxypyrazole; (d) 4-bromohexanedione-(2.2) is passed into a mixture of hydrazine hydrate, triethylamine and tetrahydrofurane; the mixture is heated and 3 - methyl - 5 - ethyl - 4 - hydroxypyrazole is obtained; (e) 4-bromohexanedione mixed with methanol is passed into a mixture of semicarbazide hydrochloride, sodium acetate and methanol to give 4-bromo-hexane dione-(2.3)-monosemicarbazone which is boiled with triethylamine and n-propanol to give 1-carbamido-3 - methyl - 5 - ethyl - 4 - hydroxypyrazole; (f) phenylhydrazine hydrochloride is mixed with sodium acetate solution and monochlordiacetyl is added to give monochlordiacetyl-monophenyl-hydrazone which is added to a mixture of sodium hydroxide solution and methanol; 1 - phenyl - 3 - methyl - 4 - hydroxypyrazole is obtained; and (g) 3-chlorophenylhydrazine sulphate is mixed with sodium acetate solution and methanol; a mixture of monochlorodiacetyl and methanol is added and the 3-chlorophenyl hydrazone of the monochlor diacetyl is formed; this hydrazone is heated with sodium hydroxide solution to give 1-(31-chlorophenyl)-3-methyl-4-hydroxypyrazole.