Potassium Phosphate, Tribasic → HCID 71251270, compound

HRID 2171878Notes

Reaction equation

HRID 2171878 reaction equation
Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([NH:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15])[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[C:24]2=[N:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.O.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]>[F:10][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[C:2]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([F:20])[CH:22]=3)[NH:27][CH:28]=2)=[N:3][C:4]=1[NH:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 672856905-fluoro-1-((4-methylphenyl)sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo(2,3-b)pyridine2×HCID 86714759HCID 86714759, compound2×

Product 1

HCID 71251270HCID 71251270, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
135 °C

Procedure

To a racemic solution of 2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile, 95a, (0.20 g, 0.70 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 7a, (0.44 g, 1.05 mmol) in THF (15 mL) was added a solution of potassium phosphate (0.45 g) in 3 mL of water. The resulting mixture was degassed under a stream of nitrogen for 15 minutes. To the mixture was then added X-Phos (0.03 g, 0.07 mmol) and Pd2(dba)3 (0.02 g, 0.04 mmol). The reaction was warmed to 135° C. via microwave irradiation for 15 minutes and then extracted into EtOAc (3×15 mL) vs. water. The organic layers were combined and concentrated in vacuo to a dark oil which was redissolved in 20 mL of THF. To the solution was added 5 mL of 2 N LiOH and the reaction was warmed to 65° C. for 12 hrs and then concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc) to afford 108 mg of the desired product, 41, as a yellow solid: 1H NMR (300 MHz, d6-DMSO) δ 12.40 (s, H), 8.63 (dd, J=2.8, 10.1 Hz, H), 8.37-8.32 (m, H), 7.83 (d, J=11.4 Hz, H), 7.31 (d, J=9.7 Hz, H), 4.56-4.50 (m, H), 4.41 (dd, J=4.1, 5.2 Hz, H), 3.69 (s, H), 3.57 (s, H), 3.49 (t, J=6.6 Hz, H), 3.48 (s, H), 3.36-3.28 (m, H), 2.50 (qn, J=1.8 Hz, H), 1.86-1.67 (m, 2H), 1.21 (dd, J=7.0, 16.1 Hz, H) and 0.94 (s, 9H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.09 minutes (M+H) 386.39.

Workup

  1. customThe resulting mixture was degassed under a stream of nitrogen for 15 minutes
  2. extractionextracted into EtOAc (3×15 mL) vs
  3. concentrationconcentrated in vacuo to a dark oil which
  4. dissolutionwas redissolved in 20 mL of THF
  5. additionTo the solution was added 5 mL of 2 N LiOH
  6. temperaturethe reaction was warmed to 65° C. for 12 hrs
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified via silica gel chromatography (EtOAc)

Sources & evidence

ORD record
ord-3d2121b29068402ebfaeb62dc94763c8
Source dataset
uspto-grants-2015_06
Patent number
US09051319B2

Reaction notes

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