Potassium Carbonate → Isopropyl 4-(3-(2-fluoropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate

HRID 1844352Notes

Reaction equation

HRID 1844352 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.O.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[N:7][C:6]=23)=[CH:29][CH:28]=[CH:27][N:26]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 2783269(2-fluoropyridin-3-yl)boronic Acid HydrateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86697433Isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate

Product 1

HCID 86697439Isopropyl 4-(3-(2-fluoropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylateYield 21.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

Isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (4 g, 10.86 mmol), 2-fluoropyridine-3-boronic acid hydrate (3.44 g, 21.7 mmol), potassium carbonate (4.5 g, 32.6 mmol), Pd(OAc)2 (24 mg, 0.1086 mmol), and x-Phos (146 mg, 0.217 mmol) were taken up in dioxane and water under nitrogen and stirred at 80° C. for 2 hours. Reaction then cooled to room temperature, filtered through celited plug with ethyl acetate. Reduced in vacuo and run through an isco silica column with hexane:ethyl acetate 75-100%. Product plus desbromo co elute, reduced in vacuo. Product recrystallized 3 times from IPAC, washed with heptanes dried to get 889 mg product. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (t, J=2.15 Hz, 1 H), 8.78 (d, J=7.83 Hz, 1 H), 8.29 (d, J=4.29 Hz, 1 H), 8.00 (d, J=4.80 Hz, 1 H), 7.43 (dt, J=2.40, 4.99 Hz, 1 H), 6.85 (d, J=7.83 Hz, 1 H), 4.78-4.87 (m, 1 H), 3.73-3.83 (m, 4 H), 3.48-3.58 (m, 4 H), 3.31 (s, 1 H), 1.22 (d, J=6.06 Hz, 6 H) LRMS (ESI) m/z 385 [(M+H)]+, calc'd for C19H21FN6O2: 384.42.

Workup

  1. customReaction
  2. filtrationfiltered through celited plug with ethyl acetate
  3. washProduct plus desbromo co elute
  4. customProduct recrystallized 3 times from IPAC
  5. washwashed with heptanes
  6. customdried

Sources & evidence

ORD record
ord-32c2e11a9a0e4378b8ca106bcfc44005
Source dataset
uspto-grants-2015_02
Patent number
US08946415B2

Reaction notes

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