DE1445409C3 - - Google Patents

Description

example 1

R,

Cl - Λ - N

in which A, Ri and R2 have the meanings mentioned, and, if necessary, the bases obtained are converted into salts in a manner known in the art.

3-Phenyl-5 - ((2-diethylamino-ethyl) -amino) -1,2,4-oxadiazole

16 g 3-phenyl-5-amino-l, 2,4-oxadiazole are dissolved in 100 ml of xylene, and 5 _V 6 g KOH. The mixture is boiled for 3 hours. Then 13.5 g of diethylaminoethyl chloride, dissolved in 25 ml of xylene, are added. The resulting mixture is boiled for a further 8 hours. After the KCI formed has been filtered off, the xylene is stripped off under reduced pressure. The end product is then distilled over at 0.27 ° C and 165 ° C. The oily, pale yellowish 3-phenyl-5 - ((2-diethylamino-ethyl) -amino) -l, 2,4-oxadiazole is in a yield of 96% of the theoretical yield

receive. The Hydrochloric! of the product obtained Melts from 54 to l55 ° C.

Example 2

3-phenyl-5 - ((2-dimethylamino-ethyl) -amino) -1,2,4-oxadiazole

The procedure described in Example 1 is repeated with the modification that instead of the Diethylaminoethyl chloride solution uses a solution of 1 mole of dimethylaminochloroethane in xylene

The product is obtained in a yield of 85% of the theoretical yield and boiling under a pressure of 0.13 mbar at 130 ° C. The Hydrochkirid has a melting point of 189-190 ⁰ C. It is hygroscopic and discolored on exposure to light.

Example 3

3-phenyl-5 - ((3-dimethylamino-propyl) -amino) -1,2,4-oxadiazole

1 mole of 3-phenyl-5-amino-l, 2,4-oxadiazole and 1 mole of powdered potassium hydroxide are mixed with one another in xylene mixed. The mixture is heated to the boil. A solution of 1 mol of dimethylaminopropyl chloride is added with stirring added in xylene. It is boiled for 8 h and then proceed in the manner described in Example 1. The liquid end product boils under a pressure of 0.13 mbar at 165 ° C and falls in a yield of 80% of the theoretical Yield to.

Alternatively, the dimethylaminopropyl derivative can also be produced as follows:

16 g of 3-phenyl-5-amino-1.2.4-oxadiazole are in 200 ml of anhydrous toluene dissolved. 4 g of sodium amide are quickly added to this solution. Then will Boiled under reflux for 2 h. The heating is interrupted and 12.2 g of dimethylaminopropyl chloride are added, dissolved in 20 ml of anhydrous toluene, gradually adding to the mixture. The mixture is taken again for 5 h Stir cooked.

After standing overnight, excess sodium amide is slowly added by adding water Stirring destroyed. A further 100 ml of water are then added and the aqueous solution is decanted Solution is extracted with 100 ml of toluene. After stripping off the toluene in vacuo, the end product is receive.

The monohydrochloride, which forms easily in the usual way, is hygroscopic and melts at 135 to 140 ° C.

Example 4

3-Phenyl-5 - ((3-diethylamino-propyl) -amino) -1,2,4-oxadiazole

The procedure is in the manner described in Example 1 using 1 mole of sodium amide carried out in xylene and using 1 mole of diethylaminopropyl chloride. It is heated for 8 h. The liquid end product is obtained in a yield of 75% of theory and has a boiling point vr> n 180 ° C under a pressure of 0.13 mbar.

55

60

Example 5

3-Phenyl-5 - ((1-methyl-2-dimethylamino-ethyl) -amino) -1,2,4-oxadiazole

The procedure is carried out in the manner described in Example 1. It is taken in xylene Use of sodium amide and a solution of dimethylaminoisopropyl chloride worked

The liquid product obtained in 95% yield boils under a pressure of 0.13 mbar at a Temperature of 195 ° C.

Example 6

3-phenyl-5 - ((2-piperidinoamino-ethyl) -amino-1,2,4-oxadiazole

The procedure is carried out in the manner described in Example 3. It will be in the presence of

1 mol of KOH worked using a solution of 1 mol of piperidinoethyl chloride in xylene. That in one Yield of 84% of the theoretical yield of liquid end product has at a pressure of 0.13 mbar a boiling point of 210 ° C.

20 g of this product are dissolved in absolute ethanol and anhydrous ether saturated with hydrogen chloride is added. After the precipitation is complete, it is filtered, dried and then recrystallized from anhydrous ethanol. 20.7 g of the hydrochloride, corresponding to a yield of 91%, are obtained. The hydrochloride has a melting point of 190 to 196 ⁰ C.

Example 7

3-phenyl-5 - ((3-di-n-butylamino-propyl) -amino) -1,2,4-oxadiazole

32 g of 3-phenyl-5-amino-1,2,4-oxadiazole are dissolved in toluene and, with stirring, with 7.8 g of sodium amide offset. The mixture is then heated to boiling temperature for 2 h. After adding 39 g of dibutylaminopropyl hydrochloride the mixture is boiled in toluene for a further 4 hours.

After removing the solvent on the water bath under reduced pressure, the Product in the form of a pale yellow oil in a yield of 60 g, corresponding to 90.1% of the theoretical Yield obtained. The product boils under a pressure of 0.13 mbar at 185 ° C.

Example 8

3-phenyl-5 - ((2-di-n-butylamino-ethy!) -Amino) -1,2,4-oxadiazole

32 g of 3-phenyl-5-amino-l, 2,4-oxadiazole are dissolved in 150 ml of anhydrous xylene and 7.8 g Sodium amide added. The solution is stirring

Cooked for 2 h. Then 38.3 g of dibutylaminochloroethane are added, which are dissolved in about 50 ml of xylene. The mixture is then boiled for a further 4 hours while stirring.

After the solvent has been stripped off in vacuo, 56 g, corresponding to 89% of the theoretical Yield, obtained from the oily product.

To produce the hydrochloride, the oily product is dissolved in ethanol and treated with a dry Hydrogen chloride saturated anhydrous ether was added. That obtained in a yield of 82% Monohydrochloride has a melting point of 136 ° C. after recrystallization.

Claims (1)

Claim: Process for the preparation of 3-phenyl-5-amino-1,2,4-oxadiazole derivatives the general formula -N C-NH-A-N in which A is an alkylene group with 2 to 4 carbon atoms and Ri and R _{2 represent} a straight-chain alkyl group, where Ri and R2 can also form a piperidino group with the nitrogen atom, and their salts with acids, characterized in that 1 mol of 3-phenyl 5-amino-l, 2,4-oxadiazole in toluene or xylene with 1 mole of sodium amide or potassium hydroxide and then the heated mixture with 1 mole of a chloroalkylamine of the general formula Cl-A -N in which A, Ri and R2 have the meanings mentioned have converted, and optionally convert the bases obtained into salts in a manner known per se. The invention relates to a process for the preparation of 3-phenyl-5-amino-1,2,4-oxadiazole derivatives of the general formula C-NH-A -N in which A is an alkylene group with 2 to 4 carbon atoms and Ri and R _{2 are} a straight-chain alkyl group, where Ri and R ₂ can also form a piperidino group with the nitrogen atom, and their salts with acids, characterized in that 1 mole of 3-phenyl -5-amino-1,2,4-oxadiazole in toluene or xylene with 1 mole of sodium amide or potassium hydroxide and then the heated mixture with 1 mole of a chloroalkylamine of the general formula and acute or chronic coronary insufficiency are indicated, as well as proving effective in certain cases as local anesthetics. 3-Amino-5-aryi-oxadiazoIe are known compounds which are stable to acids and bases, in which the Amino group in 3-position all properties and ίο Characteristics of an amino group shows amino derivatives these compounds are available in a simple and customary manner. In contrast to this, however, the likewise known 3-phenyl-5-amino-1,2,4-oxadiazole has fundamentally different properties. The amino group in the 5-position is bonded to a carbon atom, which in turn forms both a double bond to a hetero nitrogen atom and a single bond to a hetero oxygen atom. As a result of this constellation, the 5-position NH ₂ group loses its typical amino functions. From Chem. Abstr. 27 (1933), p. 705, in particular lines 24 to 26, it emerges that 3-aryl-5-amino-1,2,4-oxadiazoles are decomposed in the presence of NaOH or HCl to form hydroxyl derivatives. The prior art therefore shows no way of substituting the NHj group in the 5-position. The method according to the invention described at the beginning opens up this possibility of substitution. The products made by the process of the invention are new substances. The substances prepared by the process of the invention can, in contrast to the unsubstituted 3-Phenyl-5-amino-1,2,4-oxadiazole in the usual way convert into salts without difficulty. When carrying out the process of the invention, particular care must be taken that the 3-phenyl-5-amino-1,2,4-oxadiazole, the sodium amide or potassium hydroxide and the chloroalkylamine are used in a molar ratio of 1: 1: 1. In particular, if the proportions of the base are too low, an incomplete reaction and by-products occur, whereas if the proportions of the base are higher, undesired disubstitution of the nitrogen of the NH ₂ group in the 5-position occurs. The process of the invention is preferably carried out in such a way that the three reaction ^{components are heated to 140 °} C. for 6 to 40 hours in the solvent, then cooled and the reaction product obtained is separated off in a manner known per se. The invention is described in more detail below on the basis of exemplary embodiments.