Polymorphs of a mPGES-1 inhibiting triazolone compound

Patent metadata

Field	Value
Publication number	US-10457649-B2
Application number	US-201816119306-A
Country	US
Kind code	B2
Filing date	Aug 31, 2018
Priority date	Jun 12, 2015
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

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.

First claim

We claim:

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)

Assignees

• Glenmark Pharmaceuticals Sa

Inventors

• Muthukaman Nagarajan
• Gharat Laxmikant A
• Kadam Suresh M
• Gavhane Sachin
• Khandagale Sandeep B
• Nirgude Sunil P

Classifications

• G01N2021/3595

  using FTIR · CPC title

• G01N23/20075

  by measuring interferences of X-rays, e.g. Borrmann effect · CPC title

• C07D249/12 Primary

  Oxygen or sulfur atoms · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title