DE1193054B - Process for the preparation of aminopyrazines - Google Patents

Description

Process for the preparation of aminopyrazines The invention relates to a process for the preparation of aminopyrazines of the general formula in which R is a lower alkyl group, R1 and R2 together with the nitrogen atom to which they are bonded is a piperidino, pyrrolidino, morpholino or hexamethyleneimino group or a piperazino group substituted in the S position by a lower alkyl group and R3 and R4 are hydrogen atoms or lower alkyl groups mean, and of their non-toxic salts with acids.

These compounds are valuable intermediates that lead to Preparation of other pyrazine derivatives can be used. Besides, they own a remarkable, the enzyme monoamine oxidase inhibiting activity and are thereby useful as a stimulant. They also show muscle relaxants and gastric secretions inhibitors Activity.

The products of the process are, when used, as monoamine oxidase inhibiting agents to the known, equally effective ß-phenylethylhydrazine dihydrogen sulfate think about it, as can be seen from the following test report: In groups of ten each Adult mice with a body weight of 20 to 25 g were given 2-piperidino-3-methylpyrazine orally (A: Example 1) and B-phenethylhydrazine dihydrogen sulfate administered and the animals Observed for 1 week. The dose in mglkg was used for 500/0 of the test mice survived, determined as acute toxicity or LD50.

The investigation of the inhibitory effect against the monoamine oxidase was carried out according to that of Chessin and coworkers in Fed. Proc., 15, p. 409 (1956). In this procedure, female mice with a body weight of 18 to 24 g each were caged in groups of five animals and treated as follows: Group treatment stimulus L Reserpine controls Reserpine none 5 mglkg iv II. Test substance (A) Test substance (A) none Controls 50 to 100 mglkg ip III. Test substance (A) Test substance (A) reserpine 50 to 100 mg / kg ip 5 mg / kg iv 3 hours after Administration of substance A IV. Test Substance (A) Test Substance (A) Reserpine 50 to 100 mg / kg ip 5 mg / kg iv 24 hours after Administration of substance A The animals of group I showed the usual reserpine stimulus, manifesting itself in depression, about 20 minutes after the injection. The animals of group II, which were administered the test substance (A), showed a stimulation in comparison to the controls, which was expressed in overactivity and increased pilomotor activity. The animals of groups III and IV received reserpine in addition to the compound prepared according to the invention. They were observed with regard to the stimulating effect which occurs in this experiment if the test substance is an effective inhibitor against monoamine oxidase. Both groups showed a stimulation expressed as overactivity and increased pilomotor activity compared to the control animals to which only reserpine was administered and to the animals to which nothing was administered at all.

The inhibitory effect of compound A against monoamine oxidase was compared in a further experiment on mice with the mixture of the known comparison substance. The dose in mg / kg at which a stimulating effect is shown in 50% of the test animals was referred to as the effective dose 50 or AEDso. The results are shown in the following table: 2-piperidino- B-phenylethylhydrazine- 3-methylpyrazine dihydrogen sulfate Acute toxicity (LDc) - 600 mg / kg oral 156 mg / kg oral Inhibitory effect against monamine oxidase (AEDso) 5 mg / kg 15 mg / kg intraperitoneally The aminopyrazines of the general formula given above are prepared by using a halopyrazine of the general formula in a manner known per se in which Hal is a halogen atom, such as a chlorine, bromine or iodine atom, with an amine of the general formula reacted and optionally then converted the aminopyrazine obtained with a non-toxic acid into a salt.

The reaction mixture is brought to the boil while stirring Heat to reflux until reaction is complete, which is usually 2 to 6 days requires. The reaction can also be carried out in the presence of an alkali metal hydroxide, e.g. B. sodium or potassium hydroxide. The product is made by extraction and subsequent fractional distillation separated.

The bases obtained can be converted into their non-toxic ones by customary methods Salts are converted with acids. These salts include, for example, those those made from maleic, fumaric, amber, lemon, vinegar, sulfamine, sulfur, hydrogen chloride, Hydrobromic, phosphoric or nitric acid can be obtained.

The halopyrazines required as starting materials are, for example by G. K a r m a s and colleagues in Journ. Amer. Chem. Soc., 74 (1952), p. 1580, has been described.

The following examples illustrate the invention.

Example 1 2-Piperidino-3-methylpyrazine In one with mechanical 100 ccm three-necked round bottom flask equipped with a stirrer, condenser and electrically heated Ulbad 10 g (0.078 mol) of 2-chlorine 3-methylpyrazine, 15.4 cc (0.156 moles) piperidine and a solution of 4.36 g (0.078 mol) of potassium hydroxide in 15 cc of water is added. This mixture is heated to reflux for 4 days with stirring, then cooled and filled with about 50 ccm of water and 30 ccm of ether 250 cc separating funnel transferred. The aqueous layer is drained off and three times extracted with 25 cc of ether each. The combined ether extracts are over potash dried, filtered and evaporated on the steam bath to a U1. After that will be twice in succession each 5 cc of toluene was added and using a from the rotating evaporator at 0.5 mm pressure and a bath temperature of 700 C, to remove any remaining piperidine.

The remaining 131 is dissolved in 75 cc of ethyl acetate and carefully treated with 20 cc of ether containing 0.02 mol of hydrogen chloride. One a small amount of a yellow by-product, melting point 159 to 165 "C, precipitates and is filtered off. Further treatment of the filtrate with essential hydrochloric acid gives 13.65 g (82% of theory) of impure product with a melting point of 95 to 111.degree. Pure 2-piperidino-3-methylpyrazine hydrochloride is obtained by recrystallization from ethyl acetate obtained in the form of yellow needles or flakes with a melting point of 112.2 to 114.2 "C.

Analysis: Calculated C 56.200 / o, H 7.550 / 0, N 19.660 / o, Cl 16.590 / o; found C 56.430 / o, H 7.400 / 0, N 19.780 / o, Cl 16.570 / o.

Example 2 2-Pyrrolidino-3-methylpyrazine In a with mechanical Stirrer, condenser and electrically heated 13-bath equipped 125 ccm three-necked round bottom flask 5 g (0.039 mol) of 2-chloro-3-methylpyrazine and 16 cc (about 0.2 mol) of pyrrolidine are added Heated to reflux with stirring for 4 days, then the mixture cooled and placed in a 250 cc separating funnel filled with about 50 cc of water and 20 cc of ether convicted. Then 10 ccm of 10 n-potassium hydroxide solution are added and the mixture extracted four times with 25 com ether each time.

The combined ether extracts are dried over potash and the ether is distilled off on the steam bath at atmospheric pressure. The leftover Oil is then distilled at 0.05 mm pressure. Following a minor Amount of first runnings are 5.36 g (86% of theory) of 2-pyrrolidino-3-methylpyrazine as colorless oil with a boiling point of 69 ° to 71 ° C. was obtained.

Analysis: Calculated ... C 66.23%, H 8.02%, N 25.75%; found ... C 66.33%, H 8,000 / o, N 25.74%.

The free base is then dissolved in 175 cc of ethyl acetate and the resulting solution treated with ethereal hydrochloric acid, yielding 5.8 g of yellow Crystals are obtained. By recrystallization from methyl chloride-ethyl acetate the pure hydrochloride is obtained; Mp 191.8 to 193.8 ° C.

Analysis: Calculated ... C 54.130 / 0, H 7.070 / o, N 21.040 / o; found . . C 54.340 / 0, H 7.33%, N 20.89%.

Example 3 2-Hexamethyleneimino-3-methylpyrazine A mixture of 15.6 g (0.156 mol) of hexamethyleneimine, 10 g (0.078 mol) of 2-chloro-3-methylpyrazine and a solution of 0.78 mol of potassium hydroxide in 15 cc of water is boiled for 24 hours heated under reflux, the mixture then cooled, with twice the volume strong potassium hydroxide solution and extracted four times with 25 ccm of ether each time. The United Extracts are dried over potash and then the ether is distilled off.

The residue is distilled at 0.5 to 1.0 mm pressure and delivers 10.45 g of 2-hexamethyleneimino-3-methylpyrazine; Bp 97-103 ° C. 5.3 g of the base will be dissolved in 100 cc of ethyl acetate and treated the solution with hydrogen chloride gas. A yellow solid substance is deposited, which is cleaned by sublimation will. 3.7 g of the sublimate formed are recrystallized from benzene. You get 1.5 g of 2-hexamethyleneimino-3-methylpyrazine hydrochloride; M.p. 118 to 120 ° C.

Analysis: Calculated ... C 58.010 / 0, H 7.960 / o, N 18.45%; found . . C 58.220 / 0, H 8.010 / o, N 18.550 / 0.

Example 4 2-piperidino-3,6-dimethylpyrazine A mixture of 5.0 g (0.035 mol) of 2-chloro-3,6-dimethylpyrazine and 20 ccm of piperidine are taken for 30 hours Boiled to reflux, then cooled and diluted with an equal volume of ether. That precipitating piperidine hydrochloride is filtered off.

After evaporation of the solvent, the filtrate leaves 2-piperidino-3,6-dimethylpyrazine in the form of a dark pulse that is dissolved in ether.

The solution is filtered and then with gaseous hydrogen chloride treated, whereby the yellow 2-piperidino-3,6-dimethylpyrazine hydrochloride separates. The hydrochloride is obtained by recrystallizing twice from ethyl acetate cleaned. Mp 136.2-137.4 ° C.

Analysis: Calculated C 58.01%, H 7.97%, N 18.450 / 0, Cl 15.570 / o; found C 58.09%, H 8.09%, N 18.57%, Cl 15.37%.

Example 5 2-Piperidino-3,6-diethylpyrazine A mixture of 17 g (0.1 mole) 2-chloro-3,6-diethylpyrazine, 20.5 cc (0.21 mole) piperidine, 10 drops Dimethyl sulfoxide and 3 mg cupric acetate are refluxed for 96 hours. The piperidine hydrochloride which separates out is filtered off.

The filtrate is evaporated: a dark, oily residue is obtained. This dark oil is distilled at 0.04-0.05 mm pressure; 14.8 g are obtained 2-piperidino-3,6-diethylpyrazine, which boils between 86 and 94 ° C at this pressure, as yellow 131.

Analysis: Calculated ... C 71.190 / 0, H 9.650 / 0, N 19.160 / o; found ... C 71.41%, H 9.880 / 0, N 18.990 / o.

Example 6 2-Piperidino-3-ethylpyrazine A mixture of 6 g of 2-chloro-3-ethylpyrazine and 30 cc of piperidine is refluxed for 24 hours. After cooling it will the piperidine hydrochloride formed is filtered off and the filtrate by evaporation concentrated to a heavy 131. The oil becomes ether in the multiple volume taken up and washed twice with 20 cc of water. The essential solution will dried over magnesium sulfate and freed from the ether by evaporation. The leftover Oil is purified by distillation at 0.3 mm pressure, under which it is between 88 and 90 ° C passes. Another distillation at 0.25 mm pressure gives 4.0 g 2-piperidine-3-ethylpyrazine boiling at 85 ° C. was obtained.

Analysis: Calculated ... C 69.07%, H 8.960 / 0, N 21.970 / o; found ... C 69.200 / 0, H 9.11%, N21.700 / o.

Example 7 2- (4'-Methyl-piperazino) -3-methylpyrazine A mixture from 20 g of 2-chloro-3-methylpyrazine and 50 cc of 4-methylpiperazine is 27 hours under Boiled under reflux, then cooled, diluted with about twice the volume of ether and filtered. The filtrate is washed with dilute, aqueous potassium hydroxide solution. the Ether solution is dried over potash and freed from ether by distilling off. With further distillation under 0.5 mm pressure, 3.6 g of 2- (4'-methyl-piperazino) -3-methylpyrazine go at 89 to 91 ° C above. The base is dissolved in 25 cc of ethyl acetate and the solution mixed with 3.2 g of cyclohexanesulfamic acid in 150 cc of ethyl acetate. So become 5.6 g of the cyclohexanesulfamic acid salt having a melting point of 121.8 to 123.4 ° C. were obtained.

Analysis: Calculated. C 51.72%, H 7.87%, N 18.85%; found ... C 51.80%, H 7.97%, N 18.57%.

Claims (1)

Claim: Process for the preparation of aminopyrazines of the general formula in which R is a lower alkyl group, R1 and R2 together with the nitrogen atom to which they are bonded are a piperidino, pyrrolidino, m orpholino or hexamethyleneimino group or a piperazino group substituted in the 4-position by a lower alkyl group and R3 and R4 are hydrogen atoms or lower alkyl groups, and of their non-toxic salts with acids, characterized in that a halopyrazine of the general formula is used in a manner known per se in which Hal denotes a halogen atom, with an amine of the general formula reacted and optionally then converted the aminopyrazine obtained with a non-toxic acid into a salt. Documents considered: J. org. chem., 26 (1961), pp. 4981 off.