| PATENT ASSIGNEE'S COUNTRY | CH |
| UPDATE | 05.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 23.05.00 |
| PATENT TITLE |
Process for preparing alkoxypyrazine derivatives |
| PATENT ABSTRACT |
A process for preparing alkoxypyrazine derivatives of the general formula: ##STR1## These alkoxypyrazine derivatives are obtained by reacting a glyoxal derivative of the general formula: ##STR2## and an aminomidiate of the general formula: ##STR3## The alkoxypyrazine derivatives are important intermediates for preparing pharmaceutically active compounds. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 29.06.98 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
M. Botta et al., J. Of heterocyclic Chemistry, vol. 16, (1979), pp. 193-194 (Botta et al.). Hideki Hirano et al., J. Of Heterocyclic Chemistry, vol. 19, (1982), pp. 1409 to 1413, (Hirano et al.). Katritzky, Comprehensive Het. Chem., vol. 3, (1984), 179-197. Hirano, H. et al. Journal of Heterocyclic Chemistry 19(6), 1409-1413 (1982) . |
| PATENT CLAIMS |
What is claimed is: 1. An alkoxypyrazine derivative of the formula: ##STR13## in which R.sup.1 denotes alkyl, R.sup.3 denotes alkyl or aryl, and R.sup.2 denotes CONH.sub.2 and COOR.sup.4, in which R.sup.4 denotes alkyl. 2. The alkoxypyrazine derivative of the formula Ia according to claim 1, which is selected from the group consisting of: 3-methoxy-5-methylpyrazine-2-carboxamide; and 3-ethoxy-5-methylpyrazine-2-carboxamide. 3. The alkoxypyrazine derivative of the formula Ia according to claim 1, which is selected from the group consisting of: methyl 3-methoxy-5-methylpyrazine-2-carboxylate; methyl 3-ethoxy-5-methylpyrazine-2-carboxylate; ethyl 3-methoxy-5-methylpyrazine-2-carboxylate; and ethyl 3-ethoxy-5-methylpyrazine-2-carboxylate. 4. An alkoxypyrazine derivative which is 3-methoxy-5-phenylpyrazine-2-carboxamide; and 3-ethoxy-5-phenylpyrazine-2-carboxamide. 5. An alkoxypyrazine derivative of the formula: ##STR14## in which R.sup.1 and R.sup.3 denote alkyl or aryl and R.sup.2 denotes C(NH)OR.sup.4, in which R.sup.4 denotes alkyl. 6. The alkoxypyrazine derivative of the formula Ia according to claim 5, which is methyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate or methyl 3-ethoxy-5-methylpyrazine-2-imidocarboxylate. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to a novel process for preparing alkoxypyrazine derivatives of the general formula: ##STR4## in which R.sup.1 denotes hydrogen, alkyl or aryl, R.sup.2 denotes hydrogen, alkyl, --CONH.sub.2, --COOR.sup.4, in which R.sup.4 denotes alkyl, or --C(NH)OR.sup.4, in which R.sup.4 is as defined above, and R.sup.3 denotes alkyl or aryl. Moreover, the invention relates to a novel process for preparing alkoxypyrazineamine derivatives of the general formula: ##STR5## in which R.sup.1 and R.sup.3 are as defined above. 2. Background Art Both the alkoxypyrazine derivatives of the general formula Ia and the alkoxypyrazineamine derivatives of the general formula V are important intermediates for preparing pharmaceutically active compounds [Katritzky, Comprehensive Het. Chem.,Vol. 3, (1984), 179-197]. A number of processes for preparing pyrazine derivatives are known from the above-mentioned literature reference. British Published Patent Application No. 922,725, for example, describes a process for preparing 3-methoxy-5-methylpyrazine-2-amine by reaction of 3-chloro-5-methylpyrazine-2-amine with sodium methoxide. BROAD DESCRIPTION OF THE INVENTION It is an object of the present invention to provide a novel alternative access to alkoxypyrazine and alkoxypyrazineamine derivatives. This object is successfully achieved by the novel process according to the invention. The key step of the synthesis according to the invention according to the first process of the invention is the reaction of a glyoxal derivative of the general formula: ##STR6## in which R.sup.1 is as defined above with an aminoimidate of the general formula: ##STR7## in which R.sup.2 and R.sup.3, are as defined above to give the alkoxypyrazine derivative of the general formula: ##STR8## in which R.sup.1 denotes hydrogen, alkyl or aryl, R.sup.2 denotes hydrogen, alkyl, --CONH.sub.2, --COOR.sup.4, in which R.sup.4 denotes alkyl, or --C(NH)OR.sup.4, in which R.sup.4 is as defined above, and R.sup.3 denotes alkyl or aryl. The radicals R.sup.1 to R.sup.5 are as defined below: Alkyl denotes a C.sub.1 -C.sub.6 -alkyl group, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl and its isomers Alkyl preferably denotes a C.sub.1 -C.sub.4 -alkyl group. The alkyl group can optionally be substituted by one of the alkyl groups mentioned, by aryl, by a halogen, by an alkoxy group, by an amino, by an alkylamino or by a dialkylamino group. For the purpose of the invention, aryl is to be understood as an optionally substituted phenyl or naphthyl group. Suitable substituents are the above-mentioned alkyl groups, halogen, alkoxy, amino, alkylamino or dialkylamino. The preferred aryl group is phenyl. The preferred aryl-substituted alkyl group is benzyl. For the purpose of the invention, halogen denotes fluorine, chlorine, bromine or iodine, preferably chlorine. Depending on the substitution pattern of the reactants, the group R.sup.1 can be positioned regioselectively in position 5 or position 6 of the alkoxypyrazine derivative. Generally and also preferably, an alkoxypyrazine derivative of the general formula: ##STR9## results in which R.sup.1 is in position 5. The glyoxal derivatives of the general formula II are generally available commercially. This is true in particular for the preferably used compounds glyoxal (R.sup.1 =H), methylglyoxal (R.sup.1 =CH.sub.3) and phenylglyoxal (R.sup.1 =phenyl). However, it is also possible to employ other glyoxal compounds of the general formula II where R.sup.1 =t-butyl or haloalkyl, such as, for example, di- or triflhalomethyl, in particular di- or trifluoromethyl or di-trichloromethyl. The aminoimidate of the general formula III used as reaction partner of the glyoxal derivative of the general formula II is a compound whose presence can be reaffirmed unambiguously, but which can usually not be isolated in stable form. According to one subembodiment of the invention, the aminoimidate of the general formula III is therefor advantageously prepared by reacting an aminonitrile of the general formula: ##STR10## in which R.sup.5 has the meaning of R.sup.2 or of cyano, with an alkali metal alkoxide or alkaline earth metal alkoxide and then reacted further, directly and without isolation, with the glyoxal derivative of the general formula II to give the alkoxypyrazine derivative of the general formula Ia. The reaction is advantageously carried out by initially charging the amino nitrile of the general formula IV in a suitable solvent, preferably in an aliphatic alcohol, followed by reaction with the alkali metal alkoxide or alkaline earth metal alkoxide in question at a temperature of advantageously -30.degree. C. to 150.degree. C. Preference is given to using alkali metal alkoxides, such as sodium methoxide or potassium methoxide or sodium ethoxide or potassium ethoxide. Depending on the group R.sup.2 in the resulting aminoimidate of the general formula III, it may be advantageous to neutralize the reaction mixture with a suitable acid beforehand. Suitable acids are simple carboxylic acids, such as acetic acid, or mineral acids, such as, sulfuric acid or hydrochloric acid. The aminoimidate of the general formula III usually can not be isolated in stable form, but its presence can be reaffirmed unambiguously by spectroscopic methods such as .sup.13 C NMR. Consequently, further reaction with the glyoxal derivative usually follows. This is advantageously carried out at a temperature of -30.degree. C. to 150.degree. C., preferably of -10.degree. C. to 10.degree. C. The glyoxal derivative of the general formula II is usually employed in a slight excess, based on the aminonitrile of the general formula IV. The reaction has usually ended after 0.1 hour to 40 hours, and the alkoxypyrazine of the general formula I can then be isolated in a customary manner, for example by extraction from the reaction mixture. Alkoxypyrazine derivatives of the general formula Ia where R.sup.1 and R.sup.3 denote alkyl or aryl and R.sup.2 denotes --CONH.sub.2, COOR.sup.4, where R.sup.4 denotes alkyl, or --C(NH)OR.sup.4 , where R.sup.4 is as defined above, are novel and not known from the literature and are therefore also part of the subject-matter of the present invention. Specifically, such novel alkoxypyrazine derivatives are: 3-methoxy-5-methylpyrazine-2-carboxamide; 3-ethoxy-5-methylpyrazine-2-carboxamide; methyl 3-methoxy-5-methylpyrazine-2-carboxylate; methyl 3-ethoxy-5-methylpyrazine-2-carboxylate; 3-methoxy-5-phenylpyrazine-2-carboxamide; 3-ethoxy-5-phenylpyrazine-2-carboxamide; methyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate; methyl 3-ethoxy-5-methylpyrazine-2-imidocaroxylate; ethyl 3-methoxy-5-methylpyrazine-2-carboxylate; and ethyl 3-ethoxy-5-methylpyrazine-2-carboxylate. The reaction according to the invention is preferably suitable for preparing 3-methoxy-5-methylpyrazine-2-carboxamide (general formula Ib where R.sup.1 denotes methyl, R.sup.2 denotes --CONH.sub.2, and R.sup.3 denotes methyl). To this end, either 2-amino-2-cyanoacetamide (general formula IV where R.sup.5 denotes --CONH.sub.2) or 2-aminomalononitrile (general formula IV where R.sup.5 denotes --CN), or a salt thereof, can be used as the starting material. Starting from 2-amino-2-cyanoacetamide, the target compound is obtained by the above-described reaction with the alkali metal alkoxide or alkaline earth metal alkoxide and subsequent neutralization via the aminoimidate intermediate (general formula III where R.sup.2 denotes --CONH.sub.2 and R.sup.3 denotes methyl) and after reaction with methylglyoxal (general formula II where R.sup.1 denotes methyl). Starting from 2-aminomalononitrile, or a salt thereof, the target compound is obtained by the above-described reaction with the alkali metal alkoxide or alkaline earth metal alkoxide and subsequent neutralization via the aminoimidate intermediate (general formula III where R.sup.2 denotes --C(NH)OCH.sub.3 and R.sup.3 denotes methyl), after its reaction with methylglyoxal (general formula II where R.sup.1 denotes methyl) via methyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate, after its acidification to give methyl 3-methoxy-5-methylpyrazine-2-carboxylate and finally after its amidation. In the last variant, methyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate is not isolated but directly converted into the carboxylic ester mentioned by acidification of the reaction mixture. The acidification and the amidation is carried out in a known manner using a mineral acid and ammonia, respectively. The alkoxypyrazine derivatives of the general formula Ia preparable according to the invention where R.sup.2 denotes --CONH.sub.2 and R.sup.1 and R.sup.3 are defined as above, can, according to a further aspect of the invention, be converted, according to the principles of the Hofmann degradation, into alkoxypyrazineamine derivatives of the general formula: ##STR11## where R.sup.1 and R.sup.3 are as defined above, using an alkali metal hypohalite. Preference is given to preparing, starting from the alkoxypyrazine derivatives of the general formula Ib, the alkoxypyrazineamine derivatives of the general formula: ##STR12## in which R.sup.1 and R.sup.3 are as defined above. The Hofmann degradation is known from the literature. The reaction is usually carried out using an alkali metal hypobromite solution, which is customarily prepared from the corresponding alkali metal hydroxide and bromine, at a reaction temperature between -20.degree. C. and 100.degree.C. The alkoxypyrazineamine derivative can be isolated from the reaction mixture in a customary manner known to the person skilled in the art, for example, by extraction. DETAILED DESCRIPTION OF THE INVENTION |
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