Crystalline inhibitor of 4-hydroxyphenylpyruvate dioxygenase, and a process of synthesis and crystallization thereof
DC
First Claim
Patent Images
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%.
1 Assignment
Litigations
0 Petitions
Accused Products
Abstract
The present invention relates to an improved synthesis and crystallization process of the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC.
5 Citations
13 Claims
-
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.; andk) 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%. - View Dependent Claims (2, 3, 11)
-
-
4. 2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione crystalline Form A which 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%.
- View Dependent Claims (5, 6, 7, 8, 9, 10, 12, 13)
Specification
-
- Resources
Litigation Campaign Assessment
Thank you for your request. You will receive a custom alert email when the Litigation Campaign Assessment is available.
×
Litigation Data
-
Current AssigneeDipharma S.A.
-
Original AssigneeDipharma S.A.
-
InventorsAttolino, Emanuele
-
Primary Examiner(s)Katakam, Sudhakar
-
Application NumberUS15/364,576Time in Patent Office314 DaysField of SearchUS Class CurrentCPC Class CodesA61K 31/12 KetonesA61K 31/122 having the oxygen directly ...C07B 2200/13 Crystalline forms, e.g. pol...C07C 205/46 the carbon skeleton contain...C07D 311/78 Ring systems having three o...
