Cesium carbonate → methyl 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoate

HRID 915590Notes

Reaction equation

HRID 915590 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 7706433-tert-Butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine2×HCID 7210837Methyl 2-bromo-4-fluorobenzoate

Product 1

HCID 58958586methyl 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoateYield 89.3%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
110 °C

Procedure

To a dried 25 mL flask was introduced 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C, 110 mg, 0.48 mmol), methyl 2-bromo-4-fluorobenzoate (93.1 mg, 0.40 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), BINAP (24.9 mg, 0.04 mmol), and Cs2CO3 (182 mg, 0.56 mmol). The flask was degassed followed by the addition of toluene (1 mL), and the mixture was heated to 110° C. for 20 h. The mixture was then cooled to rt, and diluted with ethyl acetate. The solid was filtered off, and the solvent was removed under reduced pressure. The residue was redissolved in methanol/THF (4:1, v/v) and filtered through a C8-silica plug. HPLC purification using gradient elution from 30% to 90% acetonitrile in water afforded 136.2 mg (89%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.42 (s, 1H), 7.85 (dd, 1H), 7.21-7.30 (m, 4H), 6.86 (dd, 1H), 6.44 (dt, 1H), 6.11 (s, 1H), 3.70 (s, 3H), 2.04 (s, 3H), 1.30 (s, 9H). ES-MS m/z 381.9 (MH+); HPLC RT (min) 4.50.

Workup

  1. customThe flask was degassed
  2. additionfollowed by the addition of toluene (1 mL)
  3. temperatureThe mixture was then cooled to rt
  4. additiondiluted with ethyl acetate
  5. filtrationThe solid was filtered off
  6. customthe solvent was removed under reduced pressure
  7. dissolutionThe residue was redissolved in methanol/THF (4:1
  8. filtrationv/v) and filtered through a C8-silica plug
  9. customHPLC purification
  10. washelution from 30% to 90% acetonitrile in water

Sources & evidence

ORD record
ord-3b979a270ce5401d9a8e5cb7bf0c7514
Source dataset
uspto-grants-2007_09
Patent number
US07265144B2

Reaction notes

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