Potassium Phosphate, Tribasic → Ethyl 3-[[5-cyano-3-fluoro-6-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-pyridyl]amino]-4,4-dimethyl-hexanoate

HRID 1055124Notes

Reaction equation

HRID 1055124 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[F:24][C:25]1[CH:26]=[C:27]2[C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:28]2=[N:29][CH:30]=1.[O-]P([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>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].O>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][CH:9]([C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]=1[C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([F:24])[CH:26]=2)[N:31]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)(=[O:44])=[O:45])[CH:32]=1)#[N:23]

Participants

7

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 86714774Ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate2×

Product 1

HCID 71251266Ethyl 3-[[5-cyano-3-fluoro-6-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-pyridyl]amino]-4,4-dimethyl-hexanoate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
125 °C

Procedure

A solution of ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate, 158a, (0.21 g, 0.600 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.30 g, 0.72 mmol) and K3PO4 (0.51 g, 2.40 mmol) in 2-methyl THF (20.5 mL) a n d H2O (2.7 mL) was degassed for 45 minutes and treated with X-phos (0.03 g, 0.07 mmol) and Pd2(dba)3 (0.01 g, 0.02 mmol). The reaction vessel was sealed and heated to 125° C. for 90 minutes. After cooling to room temperature, the aqueous phase was removed and the organic phase was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to provide 270 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.51 (dd, J=9.1, 2.7 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.41 (d, J=10.3 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 5.28-5.22 (m, 1H), 4.92 (td, J=10.4, 3.2 Hz, 1H), 4.03-3.91 (m, 2H), 2.75 (dd, J=14.9, 3.5 Hz, 1H), 2.45 (dd, J=12.6, 8.2 Hz, 1H), 2.40 (s, J=4.7 Hz, 3H), 1.36 (q, J=7.4 Hz, 2H), 1.01 (t, J=7.1 Hz, 3H), 0.92 (d, J=8.8 Hz, 6H), 0.88 (t, J=7.5 Hz, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.86 minutes (M+H) 596.02.

Workup

  1. customThe reaction vessel was sealed
  2. temperatureAfter cooling to room temperature
  3. customthe aqueous phase was removed
  4. filtrationthe organic phase was filtered
  5. concentrationconcentrated in vacuo
  6. customThe crude residue was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient)

Sources & evidence

ORD record
ord-bb9586510c0441b695ccb229654ba264
Source dataset
uspto-grants-2016_07
Patent number
US09394302B2

Reaction notes

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