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

HRID 479862Notes

Reaction equation

HRID 479862 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].C(O)(C)C.[F:17][CH:18]([F:30])[C:19](=O)[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O.S(=O)(=O)(O)O>O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:20][C:19]([CH:18]([F:17])[F:30])=[N:12]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]

Participants

6

Reactant 4

HCID 1118Sulfuric AcidHCID 3776Isopropanol3×HCID 27742054,4-Difluoro-1-phenylbutane-1,3-dioneHCID 99642932-Hydrazino-5-(methanesulfonyl)-pyridine

Product 1

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

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
75 °C

Procedure

To 12.2 kg of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (64.1 moles) was charged isopropanol (45 gallons) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (12.0 kg, 61.5 moles, 0.96 eq.) as a melt, followed by 45 gallons of isopropanol. The slurry was stirred for 15 minutes, then 3.6 L of concentrated sulfuric acid was added (slight exotherm) (30V of isopropanol total). The reaction was heated to 75° C. and held for 1 hour. The pot was then cooled to 20-30° C. After reaction completion assay, 126 gallons (40V) of water was added (slight exotherm, reaction temp kept below 45° C.) and the reaction product was granulated for 2 hours. The product was filtered on a 36-inch nutche filter dressed with a poly cloth in less than 2 hours. The filter cake was rinsed with an additional 12 gallons (4V) of water, and the cake was blown dry for 12 hours. The product contained 2.2% of compound 6 as the major impurity (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. waitheld for 1 hour
  2. temperatureThe pot was then cooled to 20-30° C
  3. additionwas added
  4. custom(slight exotherm, reaction temp kept below 45° C.)
  5. waitthe reaction product was granulated for 2 hours
  6. filtrationThe product was filtered on a 36-inch
  7. filtrationnutche filter
  8. waitdressed with a poly cloth in less than 2 hours
  9. washThe filter cake was rinsed with an additional 12 gallons (4V) of water
  10. customthe cake was blown dry for 12 hours
  11. customHPLC retention time (title compound) 8.4 minutes

Sources & evidence

ORD record
ord-269e5965ddf24ed2a155ad11fb7caf91
Source dataset
uspto-grants-2003_11
Patent number
US06646128B2

Reaction notes

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