Method for the preparation of 5-methylpyrazine-2-carboxylic acid-4-oxide and its salts
AssigneeISP Investments Inc.
InventorsJonathan Caudill, Mark Cooney, Satish Nigam
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Abstract
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 C1-4 methylpyrazinecarboxylic acid esters. The pharmaceutically acceptable salts are then formed by the saponification of the esters followed by alcohol precipitation.
Claims7
A method for the preparation of a 5-methylpyrazinecarboxylic acid ester-4-oxide comprising:
- reacting 5-methylpyrazinecarboxylic acid with a C1-4 alcohol in the presence of the ion exchange resin AMBERLYST® to obtain the ester of 5-methylpyrazine-carboxylic acid;
- and
- oxidizing the 5-methylpyrazinecarboxylic ester in the presence of OXONE® in a halogenated solvent to obtain the isolated ester oxide.
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 OXONE®.
A method for the preparation of the sodium or potassium salts of 5-methylpyrazine-carboxylic acid-4-oxide comprising:
- reacting 5-methylpyrazinecarboxylic acid esters with sodium or potassium silanolates in a solvent.
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 an inorganic salt selected from the group consisting of Na, K, Mg and Ca, comprising the steps of:
- reacting 5-methylpyrazinecarboxylic acid having the formula II
- wherein
- R is H or an alkyl group having from 1 to 4 carbon atoms, with a C1-4 alcohol in the presence of AMBERLYST® to obtain an ester of the formula III
- wherein
- R is H or C1-4 alkyl;
- oxidizing the ester of formula III in a biphasic system consisting of a halogenated solvent and an aqueous solution of OXONE® to obtain an oxidation product;
- and
- saponificating the oxidation product to obtain the salt of formula I.
A method for the preparation of a pharmaceutically acceptable inorganic salt of a 5-methylpyrazinecarboxylic acid having the formula I
- wherein:
- M is 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 AMBERLYST® and 20 to 25% w/w of an aqueous-solution of OXONE® 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.
Dependencies are inferred from the claim text.