DE2426878A1 - 3,5-Substd-1,2,4-oxadiazoles prodn - from acylamidine or guanidine salts by N-halogenation then cyclising with base - Google Patents

Abstract

Oxadiazoles of formula (I): are prepd. by reacting acylamidine salts (II) first with a hypohalite (III) MOX and secondly with a NH4 or alkali(ne earth) cpd. in presence of a solvent. In the formulae R1 and R2 are each H, aliphatic, cycloaliphatic araliphatic, aromatic or heterocyclic gps. or R3NH; R3= aliphatic or aromatic gp. and R2 may also be (R3)2N or R3O; X is halo and M is a cation esp. Na or K. (I) are inters. for dyes, pesticides, optical brighteners and pharmaceuticals, Some have insecticidal, fungicidal, herbicidal, antibacterial, anti-inflammatory, sedative, convulsive and coronary-dilating activity.

Description

Process for the preparation of 1,2,4-oxadiazoles The invention relates to a new process for the preparation of 1,2,4-oxadiazoles by reacting acylamidines with hypohalites and then with alkali or alkaline earth compounds.

It is from Advances in Chemical Research, Volume 4 (1964), pages 810 to 829, known that 1,2,4-oxadiazoles can be obtained from amidoximes by cyclization of O-acylated oximes or carboxylic acid derivatives of oximes, by the reaction of hydroxylamine with N-acylated amidines, iminochlorides, imino ethers, acylimidothiocarbonates, Acyl dicyandiamides or by reacting amidoximes with acid amides, imino ether hydrochlorides or B-keto carboxylic acid esters. All of these procedures are difficult accessible or uneconomical raw materials; also hydrolyzes one large number of amidoximes easily. The processes are especially on an industrial scale with reference to simple, easily controllable operation, yield and purity of the end product unsatisfactory.

It was found that 1,2,4-oxadiazoles of the formula where R1 and R2 can be the same or different and each denotes a hydrogen atom, an aliphatic, cycloaliphatic, araliphatic, aromatic, heterocyclic radical or the radical R3-NH-, in which R3 denotes an aliphatic or aromatic radical, and also R2 for the rest or R in which R3 has the abovementioned meaning, can advantageously be obtained if a hydrohalide of acylamidines of the formula wherein R1 and R2 have the aforementioned meaning, reacted in a first step with a hypohalite and in a second step with an ammonium compound, alkali compound or alkaline earth compound in the presence of a solvent.

In the event that sodium hypochlorite and N-benzoylbenzoic acid amidine are used, the reaction can be represented by the following formulas: Preferred starting materials II and correspondingly preferred end products I are those in whose formulas R1 and R2 can be identical or different and each have a hydrogen atom, an alkyl radical with 1 to 7 carbon atoms, a cyclopentyl radical, a cyclohexyl radical, an aralkyl radical with 7 to 12 carbon atoms, a Aralkenyl radical with 9 to 12 carbon atoms, a phenyl radical, a 5- or 6-membered heterocyclic ring, which can contain one or two nitrogen atoms or an oxygen atom, or the radical R-NH-, in which R3 is an alkyl radical with 1 to 7 carbon atoms or one Phenyl radical means, denote, moreover also R2 for the radical or RDO-, in which R3 has the aforementioned preferred meaning. The aforementioned radicals and rings can also be replaced by groups and / or atoms which are inert under the reaction conditions, e.g. Nitro groups, dialkylamino groups with 2 to 8 carbon atoms, cyano groups, alkyl groups, or alkoxy groups each with 1 to 4 carbon atoms, chlorine atoms bonded to aromatic rings, bromine atoms, hydroxyl groups, trifluoromethyl groups can be substituted. The starting materials II can be prepared, for example, by reacting amidines or guanidines with corresponding acid chlorides, acid anhydrides or chlorocarbonic acid esters.

There are, for example, the following acylamidines as starting materials II suitable: N-acetyl-formamidine, -acetamidine, -benzamidine, -o-methyl-benzamidine, -p-chlorobenzamidine, -3,4-dichlorobenzamidine, -phenylguanidine, -o-chlorophenylguanidine, -m-chlorophenyl-guanidine, -p-chlorophenyl-guanidine, -3,5-dichlorophenylguanidine, -, 5-dichloro-4-methoxyphenyl-guanidine, -m-hydroxyphenyl-guanidine, -p-hydroxyphenyl-guanidine, -2,6-diethylphenylguanidine, -2, 6-dinitro-4-trifluoromethylphenyl-guanidine, -2,4,5-trichlorophenyl-guanidine, -methyl-guanidine, -äthyl-guanidine, -1, l-diethyl-guanidine, -isopropyl-guanidine, -cyclohexylcarboxamide, -cyclopentylcarboxamide, -pyrrole- (2) -carboxamide, -pyrrolidine- (2) -carboxamide, -phenylacetamidine, -pyridine- (2) -carboxamide, -pyrazine- (2) -carboxamide, -piperidine- (2) -carboxamide, -imidazole- (2) -carboxamide, -imidazolidine- (2) -carboxamide, -furan- (2) -carboxamide, -p-methyl-benzamidine, -cinnamic acid amidine; appropriate N-propionyl-, N- (chloro-acetyl) -, N- (carb-3-chlorophenoxy) -, N- (dimethylaminoacetyl) -, N- (dimethylaminopropionyl) -, N- (cyanoacetyl) -, N- (diethylaminoacetyl) -, N-benzoyl, N-isopropylcarbonyl-, N-butylcarbonyl-, N-formyl-, N-cyclohexylcarbonyl-, N-styrylcarbonyl-, N-phenylacetyl-, N-pyrrole- (2) -carbonyl-, N-pyrrolidine- (2) -carbonyl-, N-pyridine- (2) -carbonyl-, N-furan (2) carbonyl, N-piperidine (2) carbonyl, N-imidazole (2) carbonyl, N-pyrazine (2) carbonyl, N- (N ', N'-dimethylcarbamoyl) -, N- (N', N'-diethylcarbamoyl) -, N- (N'-methylcarbamoyl) -, N- (N, N'-Diphenylcarbamoyl) -, N- (N'-Phenylcarbamoyl) -, N- (Carbmethoxy) -, N- (Carbisopropoxy) -, N- (carbphenoxy), N- (carb-2, 4-dichlorophenoxy) compounds.

The starting materials II are preferably in the form of their hydrohalides their hydrochloride, implemented. The first one is used as further starting materials Step of the reaction hypohalites, usually hypochlorites and hypobromites in aqueous medium, usually in the form of corresponding aqueous, alkaline Solutions. The aqueous hypochlorite solutions generally contain from 5 to 15, preferably from 12 to 14% by weight of hypohalite, preferably hypochlorite, and can additionally from 0.2 to 2.5 moles, preferably 1 to 2.1 moles, of alkali metal hydroxide per mole Contain hypohalite, preferably hypochlorite. In the starting mixture of both starting materials in general amounts from 0.9 to 1.5 in total, preferably from 0.95 to 1.1 Moles of hypochlorite and expediently from a total of 0.2 to 2.5 moles, preferably 1 to 2.1 moles of alkali hydroxide (not counting the alkali contained in the hypohalite), based on 1 mole of starting material II in question. Contains the aqueous hypohalite solution no free alkali metal hydroxide, so are appropriate at the beginning or in the course of the reaction from 0.2 to 2, preferably 1 to 2 moles of alkali metal hydroxide per mole of hypohalite fed. Preferred alkali hypohalites are the sodium or potassium salt.

One can use the N-halogen compound obtained in the first step of the reaction Isolate the starting material II from the mixture and carry out the reaction in a new medium perform with the basic compound. Usually you will do both steps single-stage and so carry out the cyclization with the addition of the base. In the second Step of the reaction is the reaction mixture with the basic compound in a Amount less than 1.5 times, preferably 0.6 to 1.4 times, in particular 0.9 to 1.1 times the equivalent weight, based on starting material II, implemented. Advantageous alkali, ammonium and alkaline earth compounds are the hydroxides, oxides, Carbonates, bicarbonates, salts of weak or polybasic acids, alcoholates of Calcium, barium, lithium and especially ammonium, sodium and potassium. There come e.g. as basic compounds in question: potassium hydroxide, sodium hydroxide, potassium carbonate, Sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, Barium oxide, barium hydroxide, Calcium carbonate, ammonium hydroxide, ammonium carbonate, Sodium acetate, propionate, ethylene glycolate, methylate, ethylate, tripropylene glycolate.

The reaction usually takes place in the first step at one temperature from -20 to + 500C, preferably from +10 to + 300C, in the second step at one Temperature from 0 to 1200C, preferably from +10 to +70 0C, under reduced or elevated pressure or preferably without pressure, continuously or discontinuously carried out. The solvent used is water and, if appropriate, alcohols such as methanol, ethanol, isopropanol, tert-butanol, ethylhexanol, cyclohexanol; or corresponding mixtures. The solvent generally comes in an amount of 500 to 5,000 percent by weight, based on starting material II, in use.

The reaction can be carried out as follows: A mixture of the hydrohalide of starting material II, hypohalite, water and optionally organic solvent is for 5 minutes to an hour at the reaction temperature of the first reaction step held. Then in the second step you add di <z basic compound and hold the mixture for 15 minutes to 2 hours at the reaction temperature of the second Reaction step. Then, after the mixture has cooled, the end product becomes more customary Manner, e.g. by filtration, optionally with concentration of the filtrate and again Filtration, separated.

The compounds preparable by the process of the invention are valuable raw materials for the production of dyes, pesticides, optical brighteners and pharmaceutica. They have partly insecticidal, fungicidal and herbicidal properties as well as partially antibacterial, anti-inflammatory, sedative, convulsive and coronary dilatory effects (progress. chem. research 4 (1964), 849-850).

The use of 1,2,4-oxadiazoles as optical brighteners is described in DOS 1 955 374 and DOS 1 958 778. Regarding further synthesis possibilities reference is made to the literature cited for the prior art.

The parts listed in the following examples are parts by weight. The parts by weight relate to the parts by volume like the kilogram to the liter.

Example 1 19.3 parts of 1-phenyl-5-methoxycarbonyl-guanidine become for conversion into the hydrochloride with 100 parts of 1-n HC1 and mixed in one Mixture of 200 parts of methanol and 200 parts of water was added. Afterward is filtered. 53 parts of a 14 percent strength by weight are added to the clear solution at 20 ° C. run in aqueous sodium hypochlorite solution. The reaction mixture is then added with 11 parts of Na2CO3, which are dissolved in 100 parts of water, and then heated the Reaction mixture to reflux temperature (650C) until the control reaction with potassium iodide starch paper negative. After cooling, the crystals formed are suctioned off and dried. When the filtrate is concentrated, crystals precipitate again, and these too to be isolated. The precipitate (19 parts) is recrystallized from toluene, whereby 16 parts (84% of theory) of 3-phenylamino-5-methoxy-1,2,4-oxadiazole are obtained. M.p. 1470C.

Example 2 56 parts of 1- (4'-chlorophenyl) -3-methoxycarbonyl-guanidine are dissolved in a mixture of 1,100 parts of methanol and 490 parts of water and mixed with 246 parts of 1-nBHCl. The mixture is filtered. Become the filtrate at 150C 131 parts of 14 weight percent aqueous sodium hypochlorite solution and then 26 parts of Na2CO3 (dissolved in 200 parts of water) were also added. The reaction mixture is heated for 2 hours at reflux temperature (650C) and cooled to room temperature. The crystals formed are filtered off, and the filtrate is concentrated and filtered. A total of 52 parts of crude product are obtained with the recrystallization Toluene 48 parts (87% of theory) of pure 5- (4'-chlorophenyl) -5-methoxy-1,2,4-oxadiazole result. M.p. 149 ° C.

Example 3 23 parts of 1 (2-chlorophenyl) -3-methoxycarbonyl-guanidine are dissolved in a mixture of 300 parts of methanol and 200 parts of water. To the To convert into the hydrochloride, 100 parts of 1-n HCl are added, the mixture is filtered. At 200C first 53 parts of a 14 percent by weight aqueous Sodium hypochlorite solution and then 55 parts of 20 weight percent aqueous soda solution fed. After two hours of heating at reflux temperature (650C), the mixture is brought to room temperature cooled and filtered. The filter material is recrystallized with toluene.

There are 19.5 parts (85 of theory) of 3- (2'-chlorophenyl) -5-methoxy-1,2,4-oxadiazole obtain. M.p. 930C.

Examples 4 to 20 As in Example 1, 1,2,4-oxadiazoles of the formula are used manufactured. Details of the implementation are given in the following table: Table Example parts R1 R2 Yield in mp (bp) Starting% of theory substance II (based on implemented Starting fabric II) 4 23 to to 82 1100C 5 CH3-OH- 56 570c 3 6 "to ClH2C-73 3900 7 "to 0H30- 76 1160C 8 "to b 85 1140C 9 0 87 1180C 9 11 10 (OH) tr (CH3) 2N-CH2-73 bp 12100 (0.2 torr) 11 "> (CH3) 2N-CH2-CH2 72 16000 (ion Ge stalt des Hydrochloride) 12 "3 + OH3 0H30-85 1010C 13 3 t OH3 NC-CH2- 81 720C 14> OH2-OH30- 76 113 ° C 15 "to CH = CH-OH 3-72780c 16 C1-CH2 "CH2" 63 Kp 116-1180C (0.2 torr) 17 "Ol> (C2H5) 2N-cH2 -OH 71 bp 13700 (0.8 Torr) 18 to OH - 75 11700 H0 3 19 "toNH- to 86 1400C C1 20 "to H-OH30- 88 13500

Claims (1)

Process for the preparation of 1,2,4-oxadiazoles of the formula where R1 and R2 can be the same or different and each denotes a hydrogen atom, an aliphatic, cycloaliphatic, araliphatic, aromatic, heterocyclic radical or the radical R3-NH-, in which R5 denotes an aliphatic or aromatic radical, and also R for the rest or R30-, in which R3 has the abovementioned meaning, can be, characterized in that a hydrohalide of acylamidines of the formula wherein R1 and R2 have the aforementioned meaning, reacted in a first step with a hypohalite and in a second step with an ammonium compound, alkali compound or alkaline earth compound in the presence of a solvent.