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

  • US 9,783,485 B1
  • Filed: 11/30/2016
  • Issued: 10/10/2017
  • Est. Priority Date: 11/30/2016
  • Status: Active Grant
First Claim
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1. 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%.

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