Polymorphs of a mPGES-1 inhibiting triazolone compound
The present application relates to solid state forms of a triazolone compound which exhibit mPGES-1 enzyme inhibition activity, specifically N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (Compound of formula II), and process for preparation thereof.
1. A process for the preparation of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (Compound of formula II) or a salt thereof,
which process comprises the steps of:
a) reacting 2-chloro benzoic acid with 2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain a substantially pure compound of formula (VI)
b) converting the compound of formula (VI) to a compound of formula (IV)
c) reacting the compound of formula (IV) with oxalyl chloride and a compound of formula (V)
to obtain the compound of formula (III)
and
d) converting the compound of formula (III) to the compound of formula (II),
wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide is crystalline, having a characteristic X-ray diffraction pattern comprising peaks expressed in terms of 2θ±0.2 at 5.66, 6.55 and 13.05.
2. The process according to claim 1 , wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide has a characteristic X-ray diffraction pattern further comprising peaks expressed in terms of 2θ±0.2 at, 6.55, 12.51, 15.01, 16.59 and 25.69.
3. A process for the preparation of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (Compound of formula II) or a salt thereof,
which process comprises the steps of:
a) reacting 2-chloro benzoic acid with 2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain a substantially pure compound of formula (VI)
b) converting the compound of formula (VI) to a compound of formula (IV)
c) reacting the compound of formula (IV) with oxalyl chloride and a compound of formula (V)
to obtain the compound of formula (III)
and
d) converting the compound of formula (III) to the compound of formula (II),
wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide is crystalline, having a characteristic X-ray diffraction pattern comprising peaks expressed in terms of 2θ±0.2 at 24.57 and 30.85.
4. The process according to claim 3 , wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide has a characteristic X-ray diffraction pattern further comprising peaks expressed in terms of 2θ±0.2 at 7.02, 12.54, 16.64, 18.31, and 25.74.
5. A process for the preparation of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (Compound of formula II) or a salt thereof,
which process comprises the steps of:
a) reacting 2-chloro benzoic acid with 2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain a substantially pure compound of formula (VI)
b) converting the compound of formula (VI) to a compound of formula (IV)
c) reacting the compound of formula (IV) with oxalyl chloride and a compound of formula (V)
to obtain the compound of formula (III)
and
d) converting the compound of formula (III) to the compound of formula (II),
wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide is crystalline, having a characteristic X-ray diffraction pattern comprising peaks expressed in terms of 2θ±0.2 at 13.92, 31.01, 35.13 and 38.54.
6. The process according to claim 5 , wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide has a characteristic X-ray diffraction pattern further comprising peaks expressed in terms of 2θ±0.2 at 7.00, 12.60, 16.71, 20.89, and 24.55.
7. A process for the preparation of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (Compound of formula II) or a salt thereof,
which process comprises the steps of:
a) reacting 2-chloro benzoic acid with 2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain a substantially pure compound of formula (VI)
b) converting the compound of formula (VI) to a compound of formula (IV)
c) reacting the compound of formula (IV) with oxalyl chloride and a compound of formula (V)
to obtain the compound of formula (III)
and
d) converting the compound of formula (III) to the compound of formula (II),
wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide is amorphous.
8. A process for the preparation of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (Compound of formula II) or a salt thereof,
which process comprises the steps of:
a) reacting 2-chloro benzoic acid with 2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain a substantially pure compound of formula (VI)
b) converting the compound of formula (VI) to a compound of formula (IV)
c) reacting the compound of formula (IV) with oxalyl chloride and a compound of formula (V)
to obtain the compound of formula (III)
and
d) converting the compound of formula (III) to the compound of formula (II),
wherein the N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide has an average particle size value (D 50 ) in the range from about 1 μm to about 100 μm.