Sulfuric Acid → 2-(3-Difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine

HRID 479865Notes

Reaction equation

HRID 479865 reaction equation
[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].OS(O)(=O)=O.[F:18][CH:19]([F:31])[C:20](=O)[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(O)(C)C.FC(F)C(=O)CC(C1C=CC=CC=1)=O>C(O)(C)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][C:20]([CH:19]([F:18])[F:31])=[N:12]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 27742054,4-Difluoro-1-phenylbutane-1,3-dione2×HCID 99642932-Hydrazino-5-(methanesulfonyl)-pyridine3×HCID 86588270Isopropanol 4,4-difluoro-1-phenyl-1,3-butanedione

Product 1

HCID 99682152-(3-Difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
24 °C

Procedure

To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged: 500 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (2.67 moles), 10 L water (20 volumes) and 579 mL of concentrated H2SO4 (0.063 volumes). In a separate 12 L 3-neck round-bottomed flask was prepared a solution of 7500 mL of isopropanol (15 volumes) and 508 g (2.56 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the mixture containing the 5-(methylsulfonyl)-2-hydrazinyl-pyridine, keeping the pot temperature below 30° C. After addition of the 4,4-difluoro-1-phenyl-1,3-butanedione solution, the mixture was stirred at 24° C. for 1.0 hour and sampled for disappearance of 5-(methylsulfonyl)-2-hydrazinyl-pyridine by HPLC. The pot was then heated to 40° C. for 2 hours until disappearance of the intermediate compound of formula 4 and the resulting slurry was filtered and washed with water to achieve a pH of the filtrate of from about 6-7. The solids were then charged to a 5L 3-neck round-bottom flask. To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes). The mixture was heated to reflux (85° C.) for 2 hours. The pot was then cooled to 40° C. and then stirred overnight. The solids were isolated by filtration, washed with 2 L isopropanol, and dried in a vacuum oven at 45° C. The compound of formula 6 was present at a level of 1.2% by HPLC (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.

Workup

  1. customTo a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere
  2. additionwas charged
  3. customthe pot temperature below 30° C
  4. filtrationthe resulting slurry was filtered
  5. washwashed with water
  6. additionThe solids were then charged to a 5L 3-neck round-bottom flask
  7. additionTo the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes)
  8. temperatureThe mixture was heated
  9. temperatureto reflux (85° C.) for 2 hours
  10. temperatureThe pot was then cooled to 40° C.
  11. stirringstirred overnight
  12. customThe solids were isolated by filtration
  13. washwashed with 2 L isopropanol
  14. customdried in a vacuum oven at 45° C
  15. customHPLC retention time (title compound) 8.4 minutes

Sources & evidence

ORD record
ord-311879bc6f914e239e466ac8e67591d5
Source dataset
uspto-grants-2003_11
Patent number
US06646128B2

Reaction notes

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