Method for the preparation of 5-methylpyrazine-2-carboxylic acid-4-oxide and its salts
View Patent ↗Methods for the preparation of pharmaceutically acceptable salts of 5-methylpyrazine-carboxylic acid-4-oxide by using the oxidizing agent OXONE® for the N-oxidation of C 1-4 methylpyrazinecarboxylic acid esters. The pharmaceutically acceptable salts are then formed by the saponification of the esters followed by alcohol precipitation.
1. A method for the preparation of a 5-methylpyrazinecarboxylic acid ester-4-oxide comprising:
reacting 5-methylpyrazinecarboxylic acid with a C 1-4 alcohol in the presence of an acidic cation exchange resin to obtain the ester of 5-methylpyrazine-carboxylic acid; and
oxidizing the 5-methylpyrazinecarboxylic ester in the presence of potassium monopersulfate present as a component of a triple salt having the formula
2KHSO 5 .KHSO 4 .K 2 SO 4
in a halogenated solvent to obtain the isolated ester oxide.
2. A method for the preparation of the pharmaceutically acceptable inorganic salts of 5-methylpyrazinecarboxylic acid-4-oxide comprising oxidizing an ester of 5-methylpyrazine-carboxylic acid-4-oxide in a biphasic system consisting of a halogenated solvent and an aqueous solution of peroxymonosulfate present as a component of a triple salt having the formula
2KHSO 5 .KHSO 4 .K 2 SO 4
and saponifying said oxidized ester with an aqueous alkali or alkaline earth hydroxide to obtain the sodium or potassium salts of 5-methylpyrazine-carboxylic acid-4-oxide.
3. A method for the preparation of a pharmaceutically acceptable inorganic salt of a 5-methylpyrazinecarboxylic acid-4-oxide having the formula I
wherein
M is a cation of a metal selected from the group consisting of Na, K, Mg and Ca, comprising the steps of:
reacting 5-methylpyrazinecarboxylic acid or esters thereof, having the formula II
wherein
R is H or an alkyl group having from 1 to 4 carbon atoms, with a C 1-4 alcohol in the presence of an acidic cation exchange resin to obtain an ester of the formula III
wherein
R is H or C 1-4 alkyl;
oxidizing the ester of formula III in a biphasic system consisting of a halogenated solvent and an aqueous solution of peroxymonosulfate present as a component of a triple salt having the formula
2KHSO 5 .KHSO 4 .K 2 SO 4
to obtain an oxidation product; and
saponificating the oxidation product to obtain the salt of formula I.
4. A method for the preparation of a pharmaceutically acceptable inorganic salt of a 5-methylpyrazinecarboxylic acid-4-oxide having the formula I
wherein:
M is selected from the group consisting of cations of alkali or alkaline earth metals selected from the group consisting of Na, K, Mg and Ca, comprising the steps of:
heating 5-methylpyrazinecarboxylic acid in a halogenated solvent in the presence of 20 to 40% w/w mineral acid selected from the group consisting of sulfuric acid and hydrochloric acid or an acidic cation exchange resin, and 20 to 25% w/w of an aqueous solution of peroxymonosulfate, KHSO5, present as a component of a triple salt having the formula
2KHSO 5 .KHSO 4 .K 2 SO 4
to obtain a solution;
stirring the solution until the reaction is complete;
separating the aqueous layer and extracting it with a solvent to obtain the ester oxide of 5-methylpyrazinecarboxylic acid;
drying said ester oxide;
saponifying said ester oxide;
precipitating a salt of said ester oxide by the addition of a pharmaceutically acceptable alcohol selected from the group consisting of ethanol, isopropanol and denatured alcohol;
collecting said salt by filtration;
washing said salt with alcohol; and
drying said salt under vacuum.