US2068790A - Pyrazolones containing wholly or - Google Patents

Description

Patented Jan. 26, 1937 UNITED STATES FATENT OFFICE PYRAZOLONES CONTAINING WHOLLY OR PARTIALLY HYD R GENATED CYCLIC the-Main- Hochst,

Germany,

assignors to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York No Drawing. Application January 31,

Serial No. 709,232. 1933 l Claims.

As is known, the 1-ary1-2-alky1-5-pyrazolones or their derivatives being substituted in 4-posi'- tion by amino. groups show febrifuge and sedative properties.

Now we have found that when in the process usual for obtaining 5-pyrazo1ones and their 4-amino-derivatives, there are used parent materials, intermediate products or adjuvants which contain at least at one nitrogen atom a partially or wholly hydrogenated cyclic hydrocarbon radical, or allow of the introduction of such a radical at nitrogen atoms, there are obtained S-pyrazolones and 4-amino-derivatives thereof, which contain at least at one nitrogen atom a parls tially or wholly hydrogenated cyclic hydrocarbon radical and are distinguished by a good febrifuge and sedative action. The products have the following general formula:

tially hydrogenated cyclic hydrocarbon radical, R2 for alkyl or a wholly or partially hydrogenated cyclic hydrocarbon radical, R3 for alkyl, and R4 for hydrogen, alkyl or the group wherein X1 and X2 stand for hydrogen, alkyl, aralkyl, or a wholly or partially hydrogenated cyclic hydrocarbon radical, at least one wholly or partially hydrogenated cyclic hydrocarbon radical being present in the molecule.

When starting from the hydrazines, the process may, for instance, follow the known methods for producing 5-pyrazolones and 4-amino-derivatives thereof. If, for example, cyclohexylhydrazine is condensed with acetoacetic ester there is obtained the 1-cyclohexyl-3-methyl-5-pyrazolone which is transformed by methylation into the 1-cyclohexy1-2.3-dimethyl5-pyrazolone. When starting from symmetrically disubstituted hydrazines, there are directly obtained in one operation, by condensation with acetoacetic ester the 5-pyrazo1ones trisubstituted in 1-2-3-position.

1934, In Germany February 8,

Thus, by condensing symmetrical dicyclohexylhydrazine with acetoacetic ester there is obtained the l.2-dicyclohexyl-3-methyl-5-pyrazo1one or from symmetrical cyclohexyl-cyclohexenylhydrazine the cyclohexyl-cyclohexenyl-3-methyl-5- pyrazolone. The same or similar pyrazolone derivatives may be obtained when starting from the monoor symmetrically disubstituted hydrazines by condensation with, for instance, unsaturated acids, such as crotonic acid or esters thereof, oxidation of the pyrazolidones obtained and, if desired, subsequent alkylation of the products containing no substituent in the Z-position.

Furthermore the new compounds may be obtained by introducing into the pyrazolones obtainable according to the process of this invention an amino group which contains as substituent or substituents at least one alkyl group or a Wholly or partially hydrogenated cyclic hydro- H carbon radical or both. By treating, for instance, the 1-cyclohexyl-2.3-dimethyl-5-pyrazolone 0btainable according to the present invention with nitrous acid and methylating the reduction prodnot of the resultant nitroso compound, the 1- cyc1ohexyl-2.3-dimethyl-4- dimethylamino- 5 -pyrazolone is obtained. Finally, the process may also be carried out by introducing into known pyrazolone derivatives, for instance, into 1-phenyl-2.3-dimethy1-4-amino-5-pyrazolone, a wholly or partially hydrogenated cyclic hydrocarbon radical. Thus, from 1-pheny1-2.3-dimethyl-4- methylamino-ii-pyrazolone there is obtained with bromocyclohexene the 1-phenyl-2.3-dimethyl- 4-methylcyclohexenylamino-5-pyrazolone.

The compounds of this invention, in so far as they contain a hydrogen atom capable of being exchanged may be rendered soluble in water by introduction of suitable groups, such as by conversion into aldehydebisulfites or sulfoxylates.

The following examples illustrate the invention, the parts being by weight unless otherwise stated:

(1) parts of cyclo-hexylhydrazine and parts of acetoacetic ester are mixed, while cooling; the mixture is heated for half an hour on a steam bath and is then dissolved in acetic ester;

on cooling the solution the 1-cyclohexyl-3- methyl-B-pyrazolone crystallizes; it melts at 152 C. By methylating the product with methyl iodide at 120 C. or with dimethylsulfate at 170 C. there is obtained the l-cyclohexyl-2.3-dimethyl-S-pyrazolone which is recrystallized from acetic ester and then melts at 66 C. It is very readily soluble in water and organic solvents.

33 parts of 1-cyclohexyl-2.3-dimethyl-5-pyrazolone are dissolved in a small portion of water; the solution is mixed with 100 parts by volume of 2N-hydrochloric acid, and to the mixture cooled to 0 C. 100 parts by volume of 2N-sodium nitrite solution are added, drop by drop. The green 4-nitroso-compound is thus precipitated; it is filtered by suction and converted by the action of the usual reducing agents, such as zinc dust in hydrochloric acid solution or catalytically activated hydrogen, into the 4-amino compound; the latter is recrystallized from acetic ester and then melts at 104 C.; it is readily soluble in water and alcohol. With the aid of methylating agents, such as formaldehyde and formic acid, there is obtained from it the 1-cyclohexyl-2.3- dimethyl 4 dimethylamino-5-pyrazolone. The latter is recrystallized from benzine or hexahydrobenzene and then melts at 77 C.; it is readily soluble in water and alcohol and sparingly soluble in cold benzine and cold hexahydrobenzene.

By causing 2 molecular proportions of l-cyclohexyl-2.3-dimethyl-4-amino 5-pyrazolone to react in a benzene solution with 1 molecular proportion of bromocyclohexene, eliminating the precipitated hydrobromide of l-cyclohexyl-2.3- dimethyl-4-amino-5-pyrazolone by filtration and distilling the benzene, the l-cyclohexyl-ZB-dimethyl-4-cyclohexenylamino-5-pyrazolone is obtained.

Instead of the methyl groups there may be introduced into the 4-amino group one or two benzyl groups, cyclohexyl groups or hexyl groups, and, for instance, one benzyl group and one methyl group or one cyclohexyl group and one methyl group. At the 2-nitrogen atom there may be attached instead of the methyl group also another alkyl group or ethyl or isopropyl. When starting from a'higher homologue of acetoacetic ester, pyrazolones are obtained which contain a substituent in 'B-position, for instance, ethyl or propyl.

The compound monomethylated in 4-position is obtainable from 1-cyclohexyl-2.3dimethyl-4- amino-5-pyrazolone by adding dimethylsulfate to the 4-benzylidene-compound and splitting off benzaldehyde. It melts, after redissolution from a mixture of hexahydrobenzene and benzine, at 102 C. and shows solubilities similar to those of the dimethyl compound.

(2) 100 parts of symmetrical dicyclohexylhydrazine and 70 parts of acetoacetic ester are heated for 6 hours to a temperature between 160 C. and 180 C. After cooling, the whole is mixed with acetic ester and alcoholic hydrochloric acid until there is a strongly acid reaction to Congo paper; the hydrochloride of 1.2-dicyclohexyl-3- methyl-S-pyrazolone is thus precipitated. The free base is recrystallized from benzine and then melts at 85 C.; it is sparingly soluble in water and readily soluble in alcohol. By treatment with nitrous acid and reduction 'in a manner analogous to that described in Example 1, the compound is converted into the 1.2-dicyclohexyl-3- methyl-4amino-5-pyrazolone, the hydrochloride of which melts, after recrystallization from alcohol containing hydrochloric acid, at 205 C.

20 parts of 1.2-dicyclohexyl-3-methy1-4-amino 5-pyrazolone hydrochloride are heated for 3 hours on a steam bath with formaldehyde and formic acid. After cooling, the base is separated by addition of alkali and is dissolved in ether; the ethereal residue is mixed with acetic ester and an excess of alcoholic hydrochloric acid. The hydrochloride of 1.2-dicyclohexyl-3-methyl- 4-dimethylamino-5-pyrazolone crystallizes; it is recrystallized from alcohol containing hydrochloric acid and then melts at 206 C. The free base melts at 83 C., when recrystallized from petroleum ether; it is sparinglysoluble in water and readily soluble in alcohol. In this case, too, the groups mentioned in Example 1 may be introduced in like manner into the 4-amino group and into the 3-position.

From the 1.2-dicyclohexyl-3methyl-4-amino- 5-pyrazolone there is obtained, in a manner analogous to that described in Example 1, the 1.2- dicyclohexyl-3-methyl-4-methylamino-5-pyrazolone, and by reaction with formaldehyde-bisulfite, its water soluble formaldehydebisulfite-compound.

(3) 203 parts of 1-phenyl-2.3-dimethyl-4-amino-5-pyrazolone are dissolved in about ten times their weight of benzene; to this solution there are added 80.5 parts of l-bromocyclohexene-2.3 of the formula:

H CH JJH! CHBr and the mixture is boiled on a steam bath until the separation of salt which soon sets in has ceased. After cooling the salt is eliminated by filtering with suction; the benzene solution is shaken with dilute hydrochloric acid and the hydrochloric acid solution is made alkaline by means of potassium carbonate. The 1-phenyl-2.3 dimethyll-cyclohexenylamino-5-pyrazo1one which first separates in the form of an oil soon solidifies. When recrystallized from alcohol and hexahydrobenzene it forms compact crystals which melt at 93 C. The new compound is readily soluble in most of the organic solvents, with the exception of petroleum ether. It is sparingly soluble in water and readily soluble in dilute mineral acids.

(4) In the same manner as described in Example 3 there is obtained from 217 parts of 1-phenyl 2.3-dimethyl-4-methylamino 5 pyrazolone and 80.5 parts of bromocyclohexene the 1-phenyl-2.3- dimethyll- (methylcyclohexenyl) -amino 5 pyrazolone, which when recrystallized from dilute alcohol, melts at 84 C. to 86 C. It shows about the same solubility as the compound described in Example 3.

(5) The 1-phenyl-2.3-dimethyl-4 -dicyclohexenylamino-5-pyrazolone is prepared in a manner analogous to that described in Example 3 from 283 parts of 1-phenyl-2.B-dimethyll-cyclohexenylamino-S-pyrazolone and 80.5 parts of bromocyclohexene. When recrystallized from dilute alcohol, it melts at 94 C. to 95 C. It is sparingly soluble in water and readily soluble in most of the organic solvents.

In the same manner as described in Examples 3, 4 and 5 there may be introduced into the 4- amino group cyclohexyl and cyclohexadienyl radicals or both radicals simultaneously.

(6) Equimolecular quantities of sodium acetate and cyclopentylhydrazine hydrochloride (melting point 130 C.) are well stirred at 80 C. for 2 hours in ten times their weight of water with the calculated quantity of acetoacetic ester. The 1- cyclopentyl-3-methyl-5 pyrazolone obtained is filtered with suction; when recrystallized from alcohol it melts at 139 C. By methylating it with methyl iodide at C. or with dimethylsulfate at 170 C. the 1-cyclopentyl-2.3-dimethyl-5-pyrazolone is obtained which boils under 3 mm. pressure at 161 C. to 163 C.

36 parts of l-cyclopentyl-Z.3-dimethyl-5-pyrazolone are dissolved in a small portion of water; 120 parts by volume of 2N-hydrochloric acid are added; the solution is cooled to 0 C. and 100 parts by volume of 2N-sodium nitrite solution are gradually added thereto, drop by drop. The green 4-nitroso-compound is filtered with suction and converted with the aid of the usual reducing agents into the l-cyclopentyl-Z.3-dimethyl-4-amino-5-pyrazolone, which boils under 4 mm. pressure at 178 C. to 182 C. and, when recrystallized from a mixture of acetic ester and hexahydrobenzene, melts at 63 C. By the action of methylating agents, such as formaldehyde and formic acid, there is obtained from the 4-amino-compound the 1-cyclopentyl-2.3-dimethyl-4 dimethylamino 5- pyrazolone which boils under 3 mm. pressure at C. The radicals mentioned in Example 1 may be introduced into the 4-amino group or into the 2- or 3-position.

(7) 28 parts of methylacetoacetic ester and 22 parts of cyclohexylhydrazine are heated together for one hour on a steam bath. 100 parts of acetic ester are then added and the mixture is allowed to cool. The 1-cyclohexyl3.4-dimethy1-5-pyrazolone crystallizes. 19 parts thereof are heated for 8 hours at 170 C. with 13 parts of dimethylsulfate. After cooling, the whole is mixed with water and caustic potash solution and shaken with benzene; distillation follows after drying and distilling the benzene in a vacuum. The l-cyclohexyl-2.3.4-trimethyl-5-pyrazolone obtained boils under 4 mm. pressure at 163 C. to C. It is readily soluble in water and the usual organic solvents.

(8) 32 parts of 1-cycl0hexy1-3-methyl-5-pyrazolone (obtained according to Example 1) are dissolved in 150 parts of alcohol and hydrogenated at 80 C. in the presence of 3 parts of a nickel catalyst and 20 parts of acetone under a hydrogen pressure of 40 atmospheres. When the absorption of hydrogen is complete, the alcohol is distilled; the residue is dissolved in a small amount of acetic ester; the solution is allowed to cool and the 1-cyclohexyl-3-methyl-4- isopropyl-5-pyrazolone which has separated is filtered by suction. It melts at 102 C. and is sparingly soluble in water. 22 parts of the 4-isopropyl compound obtained are heated for 8 hours at C. with 13 parts of dimethylsulfate. After working up according to Example '7 the l-cyclohexyl-2.3-dimethyl-4-isopropy1-5-pyrazolone is obtained which boils under 4 mm. pressure at 165 C. to 170 C. It solidifies on some standing; when recrystallized from benzine it melts at 7 3 C.

We claim:

1. The compounds of the following general formula:

R4-C=C-R$ wherein R1 stands for phenyl or a wholly or partially hydrogenated 5- or 6-membered cyclic hydrocarbon radical, R2 for alkyl or a wholly or partially hydrogenated 5- or 6-membered cyclic hydrocarbon radical, R3 for alkyl, and R4 for hydrogen, alkyl or the group mo 0: N-CH:

s C CH In H,

said compound being colorless, readily soluble in water and alcohol and having a feebly alkaline reaction.

3. The compound of the following formula:

said compound being colorless and of a feebly alkaline reaction.

4. The compound of the following formula:

said compound being colorless and of a feebly alkaline reaction.

MAX BocKMiiHL. WALTER KROHS.