Crystalline inhibitor of 4-hydroxyphenylpyruvate dioxygenase, and a process of synthesis and crystallization thereof

A process of synthesis of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione crystalline Form A, comprising:

• a) reacting 2-nitro-4-(trifluoromethyl) benzoyl chloride and 1,3-cyclohexanedione in a CH3CN solution in the presence of potassium carbonate;
• b) acidifying by means of HCl 37% to about pH=1 and warming to about 55° C.;
• c) washing the organic phase and concentrating it to about half the initial volume of CH3CN used in a);
• d) adding the crude nitisinone from c) to about an 3/1 (w/w) binary acetonitrile/toluene mixture, wherein the ratio nitisinone/binary mixture is around ¼ (w/v) and heating the resultant combination at a temperature of about 55° C. until complete dissolution;
• e) concentrating the solution from d) to a final volume of about twice the initial volume of toluene added in d) at a temperature below 50° C. to obtain a solution of nitisinone in toluene containing about 0.5-0.6 g of nitisinone per ml of solvent;
• f) adding toluene to the mixture obtained in e) in order to double the final volume obtained from e);
• g) repeating e);
• h) heating the product of g) to about 55° C. for about 1 hour;
• i) cooling the product resulting from h) to about 10° C. in about 10 to about 12 h;
• j) filtering off the solid thus obtained in i) and rinsing it with toluene pre-cooled to 0° C.;
• and
• k) drying the resulting crystals under vacuum at a temperature of about 60° C. for about 4 hours,
• wherein 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione crystalline Form A has a X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.4, 14.7, 15.7, 22.9, and 29.7, wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 30%.