Diisopropylethylamine → N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide

HRID 1685938Notes

Reaction equation

HRID 1685938 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[Cl:15])[CH:3]=1.[F:16][C:17]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[Cl:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:17]=2[F:16])[CH:7]=[CH:6][C:5]=1[OH:8]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 27745422-Fluoro-4-methoxybenzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1363880184-Amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenol

Product 1

HCID 136388017N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamideYield 85.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

4-Amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenol (2.0 g, 8.94 mmol) was suspended in anhydrous CH2Cl2 (75 mL). The suspension was made to dissolve by the adding anhydrous DMF (5 mL) and briefly heating the solution using a heat gun (˜50° C.). 2-Fluoro-4-methoxybenzoic acid (1.52 g, 8.94 mmol), DIEA (2.34 mL, 13.4 mmol) and HATU (4.08 g, 10.7 mmol) were added to the solution. The reaction was stirred at room temperature for 2 hours. After this time, the reaction was extracted (120 mL each of H2O/CH2Cl2). The aqueous layer was extracted once more with CH2Cl2 (120 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (0,20,40,50,70% EtOAc/Hexanes) to yield N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (2.88 g, 7.66 mmol, 77.1%) as a colorless oil that turned solid upon standing. LCMS m/z 376.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 3.76 (s, 3 H), 3.90 (s, 3 H), 6.87 (dd, J=33.09, 2.53 Hz, 1 H), 6.87 (dd, J=11.49, 2.40 Hz, 1H), 7.00 (d, J=8.59 Hz, 1 H), 7.54 (s, 1 H), 7.55 (d, J=2.53 Hz, 1 H), 7.66 (dd, J=8.84, 2.53 Hz, 1 H), 7.76 (t, J=8.72 Hz, 1 H).

Workup

  1. temperaturebriefly heating the solution
  2. customa heat gun (˜50° C.)
  3. extractionAfter this time, the reaction was extracted (120 mL each of H2O/CH2Cl2)
  4. extractionThe aqueous layer was extracted once more with CH2Cl2 (120 mL)
  5. dry with materialThe combined organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe product was purified by column chromatography (0,20,40,50,70% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-db4d5fe18cd94bbf8ecdf64f4d453d3d
Source dataset
uspto-grants-2012_04
Patent number
US08148417B2

Reaction notes

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