Triethylamine → Tert-butyl 4-(4-((4-((3-carbamoylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

HRID 1485281Notes

Reaction equation

HRID 1485281 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39])#[CH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:38]([C:37]1[CH:36]=[C:35]([C:33]#[C:34][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:32]=[CH:31][C:16]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:15][CH:14]=3)[N:3]=2)[CH:43]=[CH:42][CH:41]=1)(=[O:39])[NH2:40]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 120650003-EthynylbenzamideHCID 86675725tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

Product 1

HCID 71208949Tert-butyl 4-(4-((4-((3-carbamoylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylateYield 29%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.30 g, 0.64 mmol), 3-ethynylbenzamide (I144) (102 mg, 0.70 mmol), copper(I) iodide (12 mg, 10 mol %), triphenylphosphine (17 mg, 10 mol %), bis(triphenylphosphine)palladium(II) chloride (22 mg, 5 mol %), DMF (3 mL) and triethylamine (0.443 mL, 3.18 mmol) were loaded into a microwave tube and degassed with nitrogen for five minutes. The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then cooled to room temperature. The cooled mixture was added to 5% aqueous potassium carbonate (150 mL) and the resulting mixture extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phases were washed with water (200 mL), brine (200 mL), dried then evaporated. The residue was chromatographed (Biotage Isolera: 12 g silica cartridge, 20-100% ethyl acetate/petroleum benzine 40-60° C. then 0-10% methanol/ethyl acetate) to give the title compound (I145) (107 mg, 29% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.46 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 8.09 (t, J=1.7 Hz, 1H), 8.04 (dt, J=7.9, 1.4 Hz, 1H), 7.77 (dt, J=7.8, 1.3 Hz, 1H), 7.71-7.66 (m, 2H), 7.66-7.52 (m), 7.27 (d, J=8.6 Hz, 2H), 3.44 (s, 2H), 2.33-2.26 (m, 4H), 1.38 (s, 9H). LCMS Method C: rt 5.06 min; m/z 581.1 [M+H]+, 525.1 [M-tBu+2H]+; m/z 579.2 [M−H]−.

Workup

  1. customdegassed with nitrogen for five minutes
  2. temperaturethen cooled to room temperature
  3. additionThe cooled mixture was added to 5% aqueous potassium carbonate (150 mL)
  4. extractionthe resulting mixture extracted with ethyl acetate (3×150 mL)
  5. washThe combined ethyl acetate phases were washed with water (200 mL), brine (200 mL)
  6. customdried
  7. customthen evaporated
  8. customThe residue was chromatographed (Biotage Isolera

Sources & evidence

ORD record
ord-b0028d489ff2417c9f80c7ad72798991
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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