Sodium Carbonate → 3-[4-Chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-one

HRID 522309Notes

Reaction equation

HRID 522309 reaction equation
F[C:2]1[CH:7]=CC(N2C(I)=C(N)C=N2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[C:17]([C:41]([F:44])([F:43])[F:42])=[N:18][N:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[C:31]=3[I:32])[C:23]2=[O:40])[C:20]=1[CH3:21].C/C(/[B-](F)(F)F)=C\C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:16]1[C:17]([C:41]([F:43])([F:42])[F:44])=[N:18][N:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[C:31]=3[I:32])[C:23]2=[O:40])[C:20]=1[CH3:21].[Cl:15][C:16]1[C:17]([C:41]([F:44])([F:43])[F:42])=[N:18][N:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[C:31]=3/[C:2](/[CH3:7])=[CH:3]/[CH3:4])[C:23]2=[O:40])[C:20]=1[CH3:21]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 71310868Potassium (Z)-but-2-en-2-yltrifluoroborateHCID 867230213-[4-Chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-oneHCID 867230231-(4-Fluorophenyl)-5-iodo-pyrazol-4-amine

Product 2

HCID 867230213-[4-Chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-oneHCID 867230223-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-[(E)-1-methylprop-1-enyl]pyrazol-4-yl]pyrrolidin-2-one

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

The starting material 3-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-one was prepared from a procedure analogous to Example 2, substituting 1-(4-fluorophenyl)-5-methyl-pyrazol-4-amine for 1-(4-fluorophenyl)-5-iodo-pyrazol-4-amine in step 2a. A solution containing 3-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-iodo-pyrazol-4-yl]pyrrolidin-2-one (90 mg, 0.16 mmol), potassium (2Z)-2-butene-2-yltrifluoroborate (32 mg, 0.20 mmol), PdCl2(dppf) (6.0 mg, 0.0080 mmol), and aqueous 2 M sodium carbonate (0.25 mL, 0.49 mmol) in dioxane (5 mL) was heated to 80° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (SiO2, 20-50% EtOAc/hexanes) afforded the titled compound (33 mg, 0.070 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.45 (dd, J=8.9, 4.8 Hz, 2H), 7.11 (dd, J=8.0, 8.0 Hz, 2H), 5.73 (dddd, J=8.4, 6.8, 6.8, 1.6 Hz, 1H), 5.02 (dd, J=9.2, 6.9 Hz, 1H), 3.94 (ddd, J=9.6, 8.8, 4.8 Hz, 1H), 3.76 (ddd, J=9.6, 7.9, 6.2 Hz, 1H), 2.92 (dddd, J=13.6, 13.6, 8.8, 6.4 Hz, 1H), 2.67 (dddd, J=13.6, 9.2, 8.0, 4.4 Hz, 1H), 2.41 (s, 3H), 1.69 (dd, 6.8, 1.2 Hz, 3H), 1.60 (dd, J=1.2, 1.2 Hz, 3H); MS: (ES) m/z calculated for C22H20ClF4N5O [M+H]+482.1. found 482.1.

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionextracted with CH2Cl2 (2×10 mL)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification of the crude material by flash chromatography (SiO2, 20-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-e975b628e4244bf09847d4c5e52f576d
Source dataset
uspto-grants-2016_05
Patent number
US09328116B2

Reaction notes

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