Purification of substituted diaminopyrazine dicarboxylic acids

A method for purifying a compound of Formula (I) or salt thereof from a precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents,

• the method comprising:
• (a) contacting the precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents with a first solvent comprising a mixture of ethyl acetate, iso-propanol, and water, thereby forming a first reaction mixture wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 2:1 to about 25:1;
• (b1) performing a first distillation of the first reaction mixture under vacuum maintaining a temperature below 40° C. forming a second reaction mixture, wherein the vacuum is less than 50 inches of Hg and the volume of the first reaction mixture after distillation is less than 50% as compared to the initial volume of the first reaction mixture;
• (b2) adding a second solvent to the distilled first reaction mixture to form a second reaction mixture, the second solvent comprising isopropanol, wherein the second solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 2:1 to about 25:1;
• (b3) performing a second distillation of the second reaction mixture under vacuum maintaining a temperature below 20° C. forming a third reaction mixture, wherein the vacuum is less than 50 inches of Hg and the volume of the first reaction mixture after distillation is less than 50% as compared to the initial volume of the first reaction mixture;
• (c) cooling the third reaction mixture to a temperature of about 0° C.;
• and
• (d) isolating the compound of Formula (I) from the third reaction mixture;
• wherein “AA ester” is an ester amino acid comprising an ester portion and an amino acid portion, and
• wherein the AA ester is

A method for purifying a compound of Formula (I) or salt thereof from a precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents,

• the method comprising:
• (a) contacting the precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents with a first solvent comprising a mixture of ethyl acetate, iso-propanol, and water, thereby forming a first reaction mixture wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 15:1 to about 20:1;
• (b1) performing a first distillation of the first reaction mixture under vacuum maintaining a temperature below 40° C. forming a second reaction mixture, wherein the vacuum is less than 50 inches of Hg and the volume of the first reaction mixture after distillation is less than 50% as compared to the initial volume of the first reaction mixture;
• (b2) adding a second solvent to the distilled first reaction mixture to form a second reaction mixture, the second solvent comprising isopropanol, wherein the second solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 4:1 to about 6:1;
• (b3) performing a second distillation of the second reaction mixture under vacuum maintaining a temperature below 20° C. forming a third reaction mixture, wherein the vacuum is less than 25 inches of Hg and the volume of the first reaction mixture after distillation is less than 25% as compared to the initial volume of the first reaction mixture;
• (c) cooling the third reaction mixture to a temperature of about 0° C.;
• and
• (d) isolating the compound of Formula (I) from the third reaction mixture;
• wherein “AA ester” is an ester amino acid comprising an ester portion and an amino acid portion, and
• wherein the amino acid portion of the AA ester is (R)-serine.