Citric Acid → 1-[6-(2-t-Butylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid

HRID 1803793Notes

Reaction equation

HRID 1803793 reaction equation
[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27]([C:29]1[CH:33]=[C:32]([CH2:34][CH2:35][CH3:36])[N:31]([CH2:37][C:38]2[CH:39]=[N:40][C:41](Br)=[CH:42][CH:43]=2)[N:30]=1)=[O:28])C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(C)(C)C>[Li+].[OH-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:41]1[N:40]=[CH:39][C:38]([CH2:37][N:31]2[C:32]([CH2:34][CH2:35][CH3:36])=[CH:33][C:29]([C:27]([OH:28])=[O:26])=[N:30]2)=[CH:43][CH:42]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]

Participants

10

Reactant 7

HCID 311Citric AcidHCID 962Water2×HCID 1140TolueneHCID 6386tert-ButanolHCID 11430Potassium CarbonateHCID 574695852-(tert-butylaMino)sulfonyl-phenylboronic acid pinacol esterHCID 581029001-(6-Bromopyridin-3-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester

Product 1

HCID 667579881-[6-(2-t-Butylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acidYield 98.6%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 3939Lithium HydroxideSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of N-t-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide (722 mg, 2.1 mmol) and 1-(6-bromopyridin-3-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 1.4 mmol) in toluene (4.0 mL, 37 mmol) was added a solution of potassium carbonate (392 mg, 2.84 mmol) in water (530 μL, 30 mmol). The resulting solution was sparged shortly with nitrogen before tetrakis(triphenylphosphine)-palladium(0) (328 mg, 284 μmol) was added. The mixture heated in the microwave at 100° C. for 30 minutes, then cooled to room temperature. Aqueous 1% citric acid was added, the mixture was extracted with EtOAc. The combined organics were partially concentrated, filtered through Celite® (EtOAc rinse), and concentrated. The crude residue was diluted with t-butyl alcohol (21.6 mL, 226 mmol), and 0.20 M LiOH in water (42.6 mL, 8.5 mmol) was added. The mixture was stirred overnight, then concentrated and extracted with EtOAc. The EtOAc was back-extracted with 1 N LiOH. The combined aqueous layers were acidified with 1 N HCl to pH 4-5. The acidic aqueous layer was extracted with EtOAc and DCM to yield 1-[6-(2-t-butylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (630 mg).

Workup

  1. additionwas added
  2. temperaturecooled to room temperature
  3. extractionthe mixture was extracted with EtOAc
  4. concentrationThe combined organics were partially concentrated
  5. filtrationfiltered through Celite® (EtOAc rinse)
  6. concentrationconcentrated
  7. additionwas added
  8. concentrationconcentrated
  9. extractionextracted with EtOAc
  10. extractionThe EtOAc was back-extracted with 1 N LiOH
  11. extractionThe acidic aqueous layer was extracted with EtOAc and DCM

Sources & evidence

ORD record
ord-f03403165dfe4cdfa6db22605be76c66
Source dataset
uspto-grants-2013_01
Patent number
US08350027B2

Reaction notes

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