DE1445750A1 - Process for the preparation of aminooxadiazoles - Google Patents

Description

Process for the preparation of aminooxadiazoles Aminooxadiazoles can by oxidation of substituted semicarbazones or substituted thiosemicarbazones as well as by reacting aoyl semicarbazides with phosphorus oxychloride (Journal for Chemistry, Leipzig, Vol. 2 (1962)).

It is also known that one aminooxadiazoles by reaction of Can produce acid hydrazides with cyanogen halide (see. US Pat. No. 2,883,391 and Ann. 563, 185 (1949) in connection with Ann.

638: 136 (1960)). In this process, intercepting the A base can be added to the reaction liberated hydrohalic acid. By the presence of the base is always created by saponification from the acid hydrazide small amounts of carboxylic acid that are difficult to remove from the end product. Furthermore, the resulting hydrohalic acid salt of the base must be removed from the reaction mixture removed.

There has now been a particularly advantageous method of manufacture of aminooxadiazoles found by using cyanic acid esters of the general formula R - OCN, where R is an aliphatic, denotes an optionally substituted aromatic or heterocyclic radical, with Acylhydrazines of the general formula R1 - (CO - NH - NH2) y in which R1 is hydrogen, an optionally substituted aliphatic, cycloaliphatic, aromatic or heterocyclic radical and y is an integer from 1 to 3, optionally in a solvent at temperatures from -60 to +15000.

With this procedure, no auxiliary chemical is added, it is superfluous So its separation after the implementation and, moreover, no saponification conditions occur on, which eliminates the contamination with carboxylic acid. The split off in the reaction ROH remains in solution and is automatic when the precipitated end product is suctioned off removed with.

The process according to the invention proceeds according to the following reaction equation, which also reproduces the general formula (II) of the aminooxadiazole In these formulas, R and R1 have the meaning given above.

Intermediate I is not isolated.

The radical R can in particular a by, for example, halogen, acyl, Ketone, carboxylic acid, carboxylic acid ester, sulfonic acid, Sulfonic acid ester, Nitro, cyano and acetylene residues, especially in or ß-position to the oxygen bonded carbon atom substituted alkyl radical, or an aromatic hydrocarbon radical with up to 20 carbon atoms, as well as a 5- or 6-membered heterocyclic Radical containing oxygen, nitrogen and / or sulfur atoms mean. These aromatic and heterocyclic radicals can also, for. B. by alkyl, aryl, arkylamino, Aoylamino, nitro, halogen, alkoxy, aroyx, acyloxy, carbonyl, carboxyl, ester, -amid, sulfonyl-, -ester, -amid, acyl-, cyano, rhodanid, alkylmercapto, acylmeroapto be substituted.

The cyanic acid meters used can according to our own, older proposals by reaction of compounds containing hydroxyl groups with halogenocyanides Temperatures preferably below 650c, optionally in a solvent in Presence of a base.

It can ftlr there. inventive method z. B. the following cyanic acid esters are used: phenyl cyanate, mono- and polyalkylphenyl cyanates such as 3-methyl-, 4-isodedecyl-, 4-cyclohexyl-, 2-tert. Butyl, 3-trifluoromethyl, 2,4-dimethyl, 3,5-dimethyl-, 2,6-diethyl-, 4-allyl-2-methoxyphenylcyanatg lrylphenylcyanate like 4-cyanatodiphenyl, 4,4'-biscyanatodiphenyl; Dialkylaminophenylcyanates such as 4-dimethylamino, 4-dimethylamino3-methyl-phenylcyanate; Acylaminophenyl cyanates such as acetylaminophenyl cyanate; Nitrophenyl cyanates such as 4-nitro, 3-nitro, 4-nitro-3-methyl, 3-nitro-6-methyl-phenyl cyanate; Halophenyl cyanates such as 2-chloro, 3-chloro, 4-chloro, 2,4-dichloro, 2,6-dichloro, 3-bromo-, 2 = chloro-6-methyl-phenyl-cyanate; Cyanatophenyl carboxylic acids, esters, amides such as 4-cyanatobenzoic acid, 2-cyanatobenzoic acid ethyl ester, 2-cyanatobenzoic acid morphofide and diethylamide; Cyanatophenylsulfonic acid, esters, amides such as 4-cyanatobenzenesulfonic acid; Alkoxyphenyl cyanates such as 2-methoxy, 3-methoxy, 4-isopropoxyphenyl cyanate; Phenoxyphenyl cyanate such as 4-cyanatodiphenyl ether; Acyloxyphenyl cyanates such as 3-acetoxyphenyl cyanate; Acyl phenyl cyanates such as 4-acetylphenyl cyanate; Cyanatophenyl cyanates such as 2,3-dicyano-1,4-dicyanatobenzene; # - and ß-naphthyl cyanate, anthrachinyl cyanates such as 1,4-dicyanatoanthraquinone; Quinoline cyanates such as 5-cyanatoquinoline; Cyanatopyrazoles such as 5-cyanato-1-phenyl-3-methyl-pyrazole, 1,4-enylenedicyanate, 1,5-naphthylenedicyanate, 1,3,5-tricyanatobenzene, 4,4'-biscyanatodiphenyldimethylmethane, 4,4'-biscyanatodiphenyl-cyclohexane-1,1, 2,2'-biscyanatodinaphthyl, 4-methyl mercaptophenyl cyanate, 3-N, N-dimethylcarbamylphenyl cyanide and the cyanic acid esters of the following alcohols: ß, ß, ß-trichloroethanol, ß, ß, ß-trifluoroethanol, ß, ß, ß-tribromoethanol, butyne- (2) -diol-1,4, acetylacetone (EnolSorm reacts), aoetoacetic ester (enol form), cyclohexen- (1) -ol- (1) -one- (3) hydroxyacetone, 2-nitroethanol, ß, ß-dichloroethanol, hydroxyacetonitrile, ethyl hydroxyacetate.

The radical R1 can in particular be hydrogen, an aromatic or heterocyclic radical according to the definition given for R or an alkyl or cycloalkyl radical, for example by the for the aromatic R radicals indicated substituents can be substituted.

As acylhydrazines, inter alia. are used: formylhydrazine, Acetic acid hydrazide, propionic acid hydrazide, phenylacetic acid hydrazide, phenoxyacetic acid hydrazide, Chlorophenoxyacetic acid hydrazide, benzhydrazide, p-chlorobenzhydrazide, p-methoxybenzhydrazide, m-nitrobenzhydrazide, naphthoic acid hydrazide, cyclohexanecarboxylic acid hydrazide, isonicotinic acid hydrazide, Carbazole carboxylic acid hydrazide, succinic acid dihydrazide and adipic acid dihydrazide.

The following solvents can be used, for example: water, Alcohols, ethers, ketones, nitriles, esters, amides, aromatic and aliphatic, optionally halogenated or nitrated hydrocarbons.

The process according to the invention is carried out at temperatures between -600C and + 150 ° C, preferably -200 to + 1000C carried out.

You can carry out the process, the reactants in one dissolve the solvents mentioned and heat to the reaction temperature. Included it is preferable to use equivalent amounts of the reaction partner. The resulting Aminooxadiazole precipitates - if necessary after concentration of the solvent and can be isolated by filtration.

The present method has compared to the known method Advantage that no acid-binding agents have to be added and thus one There is no separation of the reaction product from the products of the neutralization. Rather, the aminooxydiazoles are directly pure because they are the second reaction product resulting OH compound remains in solution.

The aminooxadiazoles are useful and have as muscle relaxants anti-tuberculous effectiveness.

Example 1 13.6 g of benzhydrazide are placed in 100 ml of benzene and 13.3 g of 4-methylphenyl cyanate between 40 and 60 ° C. were slowly added dropwise.

After brief stirring at 70 ° C. and cooling, the precipitated product becomes with a melting point of 2460C obtained by filtration with suction and washed with benzene.

Yield: 14 g (= 87% 0 of theory). The split off p-cresol remains dissolved in the filtrate and can be recovered by evaporation.

Analysis: C fl N O calculated 59.6% 4.35% 26.1% 9.95 ffi found: 59.68% 4.51 26.02% 10.08 s Example 2 In an ethanolic solution of 11.9 g of phenyl cyanate a solution of 13.6 g of benzhydrazide in ethanol is added dropwise. The mixture heats up falls to about 50 to 60 ° C, the 2-amino-5-phenyl-1,3,4-oxadiazole drops suddenly and is obtained by suction. The phenol remains dissolved in the filtrate. Yield: 14.5 g (= 90 ffi d. Th.). The end product is identical to that obtained according to Example 1 (Mixed melting point, identical IR spectrum).

Example 3 When performing an analogous approach as in Example 2, but in an aqueous suspension instead of an ethanol solution, the same is obtained Product, which in this case was removed by washing with alcohol or benzene Phenol must be freed.

Example 4 When reacting benzhydrazide suspended in ligroin, with ß, ß, ß-Trichloräthylcyanat one obtains the same product as in Example 1.

Identification: mixed melting point, identical IR spectrum.

Example 5 13.7 g of isonicotinic acid hydrazide are initially charged in a mixture of 100 ml of benzene and 100 ml of isopropanol. After adding 11.9 g of phenyl cyanate and heating to 40 ° C. for one hour, the precipitated product becomes of melting point 2620C (dec .; from methanol) obtained by suction.

Yield: 15.5 g (= 95% of theory). w Analysis: ENT calculated; 51.85% 3.7% 34.6% 9.88% found: 51.63% 4.19% 34.2 s 10.13% Example 6 6 g of formhydrazide are dissolved in 150 ml of dioxane at 400C and 13, 3 g of 3-methylphenyl cyanate were slowly added. The temperature rises and is held at 600C for a short time. After cooling, the dioxane is drawn off, isopropanol is added and the precipitated product is isolated from 150 to 152 ° C by suction, yield 4.5 g.

(= 53% of theory).

Example 7 -14.8 g of acetic acid hydrazide are suspended in 70 ml of benzene.

23.8 g of phenyl cyanate, diluted with 20 ml of benzene, are slowly added dropwise. Exothermic reaction. The temperature is kept at 30.degree. C. by means of a water bath. After four hours of stirring, the mixture is cooled and 10 g of des is isolated by suction of m.p. 186-188 ° C. Another 6 g can be obtained by concentrating the filtrate or by precipitation from the filtrate with ether.

Total yield: 16 g (= 81 s of theory).

Example 8 Analogously to Example 2, 3-chlorophenyl cyanate and Phenylacetic acid hydrazide, 2-amino-5-benzyl-1,3,4-oxadiazole, melting point 158-159 ° C. Yield: 71 s d. Th.

Example 9 Analogously to Example 2, 2,4-dimethylphenyl cyanate is obtained and CyclohexanecarbonsGurehydrazid 2-Amino-5-cyclchexyl-1,3,4-oxadiazole of m.p. 219-221 ° C. Yield: 58% of theory th.

Example 10 Analogously to Example 2, phenyl cyanate and phenoxyacetic acid hydrazide are obtained 2-amino-5-phenoxymethyl-1,3,4-oxadiazole with a melting point of 157-158 ° C. Yield: 61% d. Th.

Example 11 Analogously to Example 1, instead of 13.3 g of 4-methylphenyl cyanate are added 17.5 g of 13, ß, ß-trichloroethyl cyanate are used. The same thing happens with a yield of 80% Product from, as in Example 1 (identical I.R. spectra; mixed melting point without Depression).

Example 12 1.4 g of 4-methylphenyl cyanate and 1.4 g of benzhydrazide become converted analogously to Example 1 in a) acetonitrile b) dimethylformamide c) carbon tetrachloride, while in a) and b) the components immediately go into solution and the end product is exothermic Reaction with 65% or 78% yield precipitates, the solution in c) takes place only after Heat. Then, however, the end product precipitates with a yield of 82%. In all three balls the end product is isolated by suction. The identity of all three products with that obtained according to Example 1 is demonstrated by the misoh melting point.

Example 13 Analogously to Example 1, with otherwise the same amounts used, 16.5 g of 4-methylmercaptophenylcyanate are obtained instead of 13.3 g of 4-methylphenylcyanate, 12 g (= 74% of theory) of des from Ft 245 ° C. Identification by mixed melting point.

Example 14 Analogous to Example 1, the amounts used are otherwise the same with 16. 1 g of 4-acetylphenyl cyanate instead of 13. 3 g of 4-methylphenyl cyanate 10.5 g (= 65 ffi of theory) of the same product as in Example 1 or 13.

Identificationr mixed melting point, IR spectra comparison.

Claims (1)

Claim: Process for the preparation of Aminooxadiazolen, thereby characterized in that cyanic acid esters of the general formula B - OCN wherein R is a optionally by halogen, nitro, cyano, the remainder of a lower aliphatic or aromatic carboxylic acid, carboxylic acid ester, sulfonic acid ester, ketone or acetylene radicals, substituted aliphatic hydrocarbon radical, R further for one optionally by alkyl, aryl, alkylamino, dialkylamino, acylamino, nitro, alkoxy, Aroxy, acyloxy, carbonyl, carboxyl ester, carboxylamide, sulfonyl ester, sulfonylamide, the remainder of a lower aliphatic or aromatic carboxylic acid, cyano, rhodanide, Alkyl mercapto, acyl mercapto, substituted, aromatic or heterocyclic The remainder is, with acylhydrazines of the general formula R1 CO - NH - NH2) y in which R1 Hydrogen or one which is optionally substituted by the substituents mentioned for R. means aliphatic, cycloaliphatic, aromatic or heterocyclic radical and y is an integer from 1 to 3, optionally in a solvent, at temperatures from -60 to + 1500C.