Method for synthesizing pirfenidone
View Patent ↗A process for synthesizing pirfenidone from bromobenzene having less than about 0.15% by weight dibromobenze is disclosed. Also disclosed are processes of synthesizing pirfenidone without using ethyl acetate or n-butanol, and pirfenidone having controlled levels of ethyl acetate, n-butanol, di(5-methyl-2-pyridinone)benzenes, and other impurities having specified retention times. Also disclosed are formulated dosage forms including the disclosed pirfenidone.
1. A method of synthesizing pirfenidone comprising
admixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and an organic solvent under conditions sufficient to form pirfenidone,
wherein the bromobenzene comprises less than about 0.15% by weight or molar ratio dibromobenzene, and
wherein the pirfenidone has a purity of at least 99% by weight or molar ratio and no impurity greater than 0.05% by weight or molar ratio.
2. The method of claim 1 , further comprising washing the pirfenidone with a saline solution.
3. The method of claim 1 , further comprising extracting the pirfenidone from the organic solvent mixture with an extracting organic solvent.
4. The method of claim 3 , wherein the extracting organic solvent comprises toluene.
5. The method of claim 1 , further comprising admixing a base with the bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and organic solvent.
6. The method of claim 5 , wherein the base comprises a carbonate.
7. The method of claim 6 , wherein the carbonate comprises potassium carbonate.
8. The method of claim 1 , wherein the organic solvent comprises dimethyl formamide.
9. The method of claim 1 , further comprising crystallizing the pirfenidone from a solvent mixture comprising heptanes and toluene to form purified pirfenidone.
10. The method of claim 9 , further comprising recrystallizing the purified pirfenidone by
dissolving at least a portion of the purified pirfenidone in an acidic aqueous solution at an elevated temperature to form a pirfenidone solution;
adding a base to the pirfenidone solution until the pH is at least about 11 to form a basic pirfenidone solution; and
cooling the basic pirfenidone solution to a temperature below about 20° C. to form recrystallized pirfenidone.
11. The method of claim 9 , comprising performing the crystallizing in the absence of ethyl acetate and in the absence of butanol.
12. The method of claim 11 , further comprising milling the pirfenidone to a particle size of less than 150 μm.
13. The method of claim 1 , wherein the bromobenzene comprises less than about 0.1% by weight or molar ratio dibromobenzene.
14. The method of claim 1 , wherein the bromobenzene comprises less than about 0.05% by weight or molar ratio dibromobenzene.
15. The method of claim 1 , further comprising formulating the pirfenidone into a pharmaceutical composition by combining it with a pharmaceutically acceptable excipient.
16. The method of claim 15 , wherein the pharmaceutical composition is in the form of a solid, liquid solution, emulsion, suspension, powder, syrup, elixir, cream, ointment, tablet, capsule, troche, lozenge, or granule.
17. The method of claim 15 , wherein the pharmaceutical composition is suitable for oral administration.
18. The method of claim 16 , wherein the pharmaceutical composition is in the form of a granule, capsule or tablet.