Manufacture of pure hydralazine salts
The present invention provides an improved process of preparing hydralazine hydrochloride, which involves the preparation of 1-chlorophthalazine salt and further reacting with hydrazine followed by purification of hydralazine hydrochloride, which is free of phosphate, does not contain any individual impurities more than 0.05%, total impurities less than 0.5%, and a hydrazine content of not more than 0.001%, and preferably less than 0.0003%. One benefit of improved purity is enhanced storage stability.
1. A process of preparing purified hydralazine hydrochloride comprising the steps of: (a) reacting 1-2H-phthalazinone with less than about 3 mole equivalents of phosphorous oxychloride and then precipitating with a mineral acid or a strong organic acid in the presence of a first solvent to recover one or more 1-chlorophthalazine salts; (b) reacting the recovered one or more 1-chlorophthalazine salts with hydrazine hydrate and then precipitating hydralazine base by the addition of a second solvent; and (c) converting the precipitated hydralazine base to hydralazine hydrochloride in a third, organic solvent.
2. The process of claim 1 , further comprising distilling phosphorous oxychloride prior to precipitating, and wherein the acid is a mineral acid.
3. The process of claim 1 , wherein step (a) further comprises filtering the one or more 1-chlorophthalazine salts.
4. The process of claim 1 , wherein the acid is a mineral acid.
5. The process of claim 4 , wherein the mineral acid is hydrochloric acid, sulfuric acid, or a mixture thereof.
6. The process of claim 1 , wherein the strong organic acid is selected from the group consisting of oxalic acid, citric acid, an alkyl sulfonic acid, trifluoroacetic acid, trifluromethane sulfonic acid or a mixture thereof.
7. The process of claim 1 , wherein the first solvent is toluene, ethyl acetate, methyl acetate, tetrahydrofuran, or a mixture thereof.
8. The process of claim 1 , wherein the second solvent is water miscible.
9. The process of claim 8 , wherein the solvent is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or a mixture thereof.