Hydrochloric Acid → Mavacoxib

HRID 1994279Notes

Reaction equation

HRID 1994279 reaction equation
[F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.C[O-].[Na+].CO.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=O.Cl.[CH:26]1[C:31]([NH:32][NH2:33])=[CH:30][CH:29]=[C:28]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:27]=1.Cl>O.CC(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:32]([C:31]3[CH:26]=[CH:27][C:28]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:29][CH:30]=3)[N:33]=[C:3]([C:2]([F:1])([F:8])[F:9])[CH:15]=2)=[CH:19][CH:20]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 887MethanolHCID 9794Ethyl trifluoroacetateHCID 98284'-FluoroacetophenoneHCID 27945674-Hydrazinylbenzenesulfonamide hydrochlorideHCID 10942334Sodium Methoxide

Product 1

HCID 9843089Mavacoxib

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
55 °C

Procedure

The following procedure describes a method of preparing the crystal Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide without isolating the crystal Form II. 2-propanol (70 ml) and ethyl trifluoroacetate (27.15 g, 0.191 moles) are added to a first vessel, followed by a line wash of 2-propanol (10 ml). Next, 25% sodium methoxide in methanol (37.5 g, 0.174 moles) is added to the vessel, followed by a line wash of 2-propanol (10 ml). Next, 4-fluoroacetophenone (20 g, 0.145 moles) is added followed by a line wash of 2-propanol (10 ml). The contents of vessel are heated to 55° C. and held at that temperature for 2 hours, then cooled to ambient temperature. Water (110 ml), concentrated hydrochloric acid (20.0 g, 0.203 moles), and 4-sulfonamidophenylhydrazine hydrochloride (32.4 g, 0.145 moles) are added to a second vessel, followed by a line wash of water (10 ml). The contents of the first vessel are added to the second vessel, followed by a line wash of 2-propanol (60 ml). The combined contents are heated at 70° C. for 2 hours, then cooled to 55° C. and seeded with 10 mg (0.05% wt/wt relative to 4-fluoroacetophenone) of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide. The contents are held at 55° C. for 6 hours, then cooled to ambient temperature and filtered. The product is washed with 50% aqueous 2-propanol (120 ml) and water (60 ml), then dried under vacuum at 55° C. to give 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide of the desired Form I polymorph (44.8 g, 80%).

Workup

  1. washwash of 2-propanol (10 ml)
  2. washwash of 2-propanol (10 ml)
  3. washwash of 2-propanol (10 ml)
  4. temperaturecooled to ambient temperature
  5. washwash of water (10 ml)
  6. additionThe contents of the first vessel are added to the second vessel
  7. washwash of 2-propanol (60 ml)
  8. temperatureThe combined contents are heated at 70° C. for 2 hours
  9. temperaturecooled to 55° C.
  10. waitThe contents are held at 55° C. for 6 hours
  11. temperaturecooled to ambient temperature
  12. filtrationfiltered
  13. washThe product is washed with 50% aqueous 2-propanol (120 ml) and water (60 ml)
  14. customdried under vacuum at 55° C.

Sources & evidence

ORD record
ord-88a090fe4b4a4db8ac8d0e40168d9142
Source dataset
uspto-grants-2010_01
Patent number
US07652149B2

Reaction notes

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