Patent GB-563279-A (GB)
Title: Manufacture of 3-amino pyrazolones or of their carbalkoxy or carbamide derivatives
IPC: C07D231/22
Filed: 1942-07-30
Abstract: 3-Amino pyrazolones or their carbalkoxy or carbamide derivatives are made by treating 2-alkyl-5-pyrazolone-3-carboxylic acids of the formula <FORM:0563279/IV/1> wherein R1 is an aliphatic, araliphatic, hydroaromatic or aromatic residue, R2 is an aliphatic residue, and R3 is hydrogen, halogen, an aliphatic, cycloaliphatic, aromatic or araliphatic residue, or functional derivatives of these acids, such as the acid amides, esters or hydrazides, by the Hofmann or Curtius process, for conversion of a carboxyl group into an amino group.  An alkyl ester of the pyrazolone carboxylic acid may be converted to the hydrazide and this by the action of nitrous acid to the azide or the azide may be prepared from a halide of the acid and sodium azide.  It is preferred to isolate the azide, but it may be converted directly to the urethane by boiling with an alcohol.  The 3-amino pyrazolone is obtained therefrom by saponification.  In the Hofmann process it can be obtained directly although the intermediate halogenamides may be isolated if desired.  The 2-alkyl-5-pyrazolone-3-carboxylic acids or their esters, amides or hydrazides can be made by alkylation of the unsubstituted compounds which may be prepared from the corresponding oxalacetic esters.  The 1-phenyl-4-isopropyl-5-pyrazolone-3-carboxylic acid ester may be obtained from the 4-unsubstituted ester by hydrogenation in the presence of acetone, and the corresponding 4-sec. butyl derivative in analogous manner.  The 1-phenyl-2-methyl-4-bromo-5-pyrazolone-3-carboxylic acid ester can be prepared directly from the bromine-free ester.  The 1-phenyl-4-allyl ester can be made by direct allylation, but preferably from allyl acetic ester through the oxal-allyl acetic ester.  In examples: (1) 1 - phenyl - 2 - methyl - 5 - pyrazolone - 3 - carboxylic acid hydrazide made from the ethyl ester and hydrazine hydrate, is treated at -5 DEG  C. with acid and sodium nitrite to precipitate the azide. The dry azide is heated in absolute alcohol to give 1-phenyl-2-methyl-3-carbethoxy-amino-5-pyrazolone.  This urethane yields the 3-amino pyrazolone on refluxing with caustic soda; (2) the absolute alcohol of (1) is replaced by n-butyl alcohol giving the corresponding urethane; (3) glycol in place of alcohol gives the 3-carbo-hydroxyethoxy-amino derivative; (4) the 2-ethyl derivative replaces the 2-methyl of (1) as starting material and is converted into the azide from which is obtained with ethyl or isopropyl alcohol respectively the 3-carbethoxy-amino or 3-carbo-isopropyloxy-amino pyrazolone and, on hydrolysis, 1-phenyl-2-ethyl-3-amino-5-pyrazolone; (5) the 4-bromo-derivative of the hydrazide of (1) is converted to the azide which with methyl alcohol gives 1-phenyl-2-methyl-3-carbomethoxy-amino-4-bromo-5-pyrazolone; (6) the 1-phenyl - 2.4 - dimethyl pyrazolone carboxylic acid ethyl ester is converted to the hydrazide which gives the 3-carbomethoxy-amino or 3-carbo-isopropyloxy-amino pyrazolone derivative and, on hydrolysis, the 3-amino pyrazolone; (7) 1-phenyl-2-methyl-4-ethyl-5-pyrazolone-3-carboxylic acid by way of the hydrazide and azide gives the corresponding 3-carbomethoxy-amino with methanol and finally the 3-amino pyrazolone; (8) the 4-isopropyl derivative made by hydrogenation of 1-phenyl-5-pyrazolone-3-carboxylic acid ethyl ester by hydrogenation in acetone is methylated and converted by way of the hydrazide and azide and subsequent heating with the corresponding alcohol to 1-phenyl-2-methyl-4-isopropyl-5-pyrazolones having in the 3-position carbomethoxy - amino, carboethoxy - amino, carbo - allyloxy - amino, carbo - isopropyloxy - amino, carbo - chlorethoxy - amino or carbo - hydroxy - ethoxy - amino as substituent.  These urethanes all yield 1-phenyl-2-methyl-3-amino-4 - isopropyl - 5 - pyrazolone; (9) the same hydrazide as in (8) is reacted with hydrochloric acid and methyl nitrite in methanol, the latter slowly distilled off, and water added to give 1-phenyl-2-methyl-3-carbomethoxy-amino-4-isopropyl-5-pyrazolone; (10) the corresponding azide is dried and heated with methanol giving the same urethane; (11) 1-phenyl-4-sec. butyl-5-pyrazolone-3-carboxylic acid ethyl ester, produced from the 4-unsubstituted ester by hydrogenation in methyl ethyl ketone, is methylated in the 2-position with dimethyl sulphate, heated with hydrazine to form the hydrazide and the latter converted into the azide.  With methanol, the 3-carbomethoxy-amino derivative is formed giving the amine on hydrolysis; (12) 1.4 - diphenyl - 5 - pyrazolone - 3 - carboxylic acid ethyl ester, prepared from phenyloxal acetic acid diethyl ester and phenyl hydrazine, is converted into the 2-methyl derivative with dimethyl sulphate.  The hydrazide is prepared and from this the 3-carbomethoxy-amino derivative and finally the amine. 1.2-dimethyl-4 - phenyl - 3 - amino - 5 - pyrazolone is obtained similarly; (13) as in (12) but using benzyloxal acetic ester, 1-phenyl-2-methyl-3-carbomethoxy-amino - 4 - benzyl - 5 - pyrazolone, and finally the 3-amino pyrazolone is obtained.  The 4-allyl derivatives are obtained similarly; (14) p-tolyl hydrazine with oxal acetic ester gives 1-(41-methylphenyl) - 5 - pyrazolone - 3 - carboxylic acid ethyl ester which, on hydrogenation in acetone, yields 1-(41-methylphenyl)-4-isopropyl-5-pyrazolone-3-carboxylic acid ethyl ester.  This is methylated in the 2-position and converted through the hydrazide and azide into the urethane and finally the 3-amino pyrazolone. p-methyl-cyclohexyl or cyclohexyl hydrazine in place of p-tolyl hydrazine gives analogous products; (15) 1-methyl-5-pyrazolone-3-carboxylic acid ethyl ester with dimethyl sulphate gives the 1.2-dimethyl derivative which is converted to the hydrazide, thence to the azide and to 1.2-dimethyl-3-carbomethoxy-amino-5-pyrazolone.  The 1-benzyl-2-methyl substituted ester reacts similarly; (16) 1-phenyl-2-methyl-4-isopropyl-5-pyrazolone-3-carboxylic acid azide is heated with toluene and a little water to produce mainly the 3-amino pyrazolone and some di-(1-phenyl-5-oxo-2-methyl-4-isopropylpyrazolyl-3) urea which can be saponified with caustic soda.  The azide may also be heated with water-containing alcohol giving the amino pyrazolone, its urethane and its urea.  The azides of the other examples react similarly; (17 1 - phenyl - 2 - methyl - 5 - pyrazolone - 3 - carboxylic acid amide, made by the action of alcoholic ammonia on the ester, is treated with ice-cold hypochlorite solution. Heating with caustic soda precipitates the 3-amino pyrazolone; (18) 1.4-diphenyl-2-methyl-5-pyrazolone-3-carboxylic acid amide is treated with hypochlorite solution and heated with caustic soda to give the amine.