Potassium Phosphate, Tribasic → HCID 86698333, compound

HRID 1187354Notes

Reaction equation

HRID 1187354 reaction equation
I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:51]1[CH:52]=[C:53]([NH:57][C:58](=[O:63])[CH2:59][CH:60]([CH3:62])[CH3:61])[CH:54]=[N:55][CH:56]=1>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].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(C=O)C>[CH:17]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:63])[CH2:59][CH:60]([CH3:61])[CH3:62])[CH:54]=[N:55][CH:56]=3)[CH:3]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=1)=[O:18]

Participants

10

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 205807365-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehydeHCID 68195779N-(5-Bromo-3-Pyridinyl)-3-Methylbutamide

Product 1

HCID 86698333HCID 86698333, compound

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) (498 mg, 1.4 mmol), bis(pinacolato)diboron (426 mg, 1.6 mmol), KOAc (412 mg, 4.2 mmol) and dry DMF (10 mL) was purged with nitrogen. Pd(dppf)2Cl2 (68 mg, 0.08 mmol) was added to the reaction and purged again with nitrogen. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (II), the solution was cooled to room temperature. To this solution was added K3PO4 (446 mg, 2.1 mmol), N-(5-bromopyridin-3-yl)-3-methylbutanamide (XXVIII) (358 mg, 1.4 mmol), Pd(PPh3)4 (48 mg, 0.042 mmol) and water (2 mL). The solution was purged with nitrogen and heated at 90° C. for 4 h. The reaction was passed through a pad of Celite® and then concentrated under reduced pressure. The residue was suspended in water, sonicated, filtered and dried. The crude product was purified on a silica gel column (100% DCM→3:97 MeOH:DCM) to give N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide (LXXXIV) as an off white solid (239 mg, 0.59 mmol, 42% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.96 (d, 6H), 1.60-1.67 (m, 1H), 1.75-1.84 (m, 1H), 2.05-2.15 (m, 3H), 2.26 (d, 2H), 2.39-2.47 (m, 1H), 3.80-3.86 (m, 1H), 3.89-3.93 (m, 1H), 6.13 (dd, 1H), 7.91 (dd, 1H), 8.06 (d, 1H), 8.36 (s, 1H), 8.39 (s, 1H), 8.63 (d, 1H), 8.81 (d, 1H), 10.23 (s, 1H); ESIMS found C23H26N4O3 m/z 407.3 (M+H).

Workup

  1. custompurged again with nitrogen
  2. temperaturethe solution was cooled to room temperature
  3. customThe solution was purged with nitrogen
  4. temperatureheated at 90° C. for 4 h
  5. concentrationconcentrated under reduced pressure
  6. customsonicated
  7. filtrationfiltered
  8. customdried
  9. customThe crude product was purified on a silica gel column (100% DCM→3:97 MeOH:DCM)

Sources & evidence

ORD record
ord-86c8e9ebb1874794a34d0b70d7011c6c
Source dataset
uspto-grants-2014_03
Patent number
US08673936B2

Reaction notes

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