Dichloromethane → 3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine

HRID 2095691Notes

Reaction equation

HRID 2095691 reaction equation
I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C@H:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[NH:22][CH:21]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].ClCCl>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].O1CCOCC1>[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C@H:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)[CH:27]=2)[NH:22][CH:21]=1)[CH3:19]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 12776685-Iodo-1-methyl-1H-imidazoleHCID 670040713-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

Product 1

HCID 546743643-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 5-iodo-1-methyl-1H-imidazole (0.0217 g, 0.104 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.030 g, 0.070 mmol), potassium carbonate (0.0289 g, 0.209 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.84 mg, 0.00348 mmol) in previously degassed 4:1 dioxane:water (1.50 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. The reaction mixture was partitioned between EtOAc and H2O and separated. The aqueous was back extracted with EtOAc (3×) and the combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude brown oil. The crude was purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, eluting with 100% DCM→8% MeOH in DCM]. This resulted in the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.82 (d, J=7.3 Hz, 3H), 3.51 (s, 3H), 3.66 (br. s., 3H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=4.2, 9.0 Hz, 1H), 6.95 (s, 1H), 7.08 (dd, J=8.8, 8.8 Hz, 1H), 7.41 (d, J=1.0 Hz, 1H), 7.51 (s, 1H), 7.69 (s, 1H), 8.17 (d, J=2.0 Hz, 1H). MS (ES+): m/z 385.11, 387.07 (76/24) [MH+]. HPLC: tR=2.87 min (polar—5 min, ZQ3).

Workup

  1. customwater (1.50 mL) was evacuated
  2. additioncharged with N2 (2×)
  3. customThe reaction mixture was partitioned between EtOAc and H2O
  4. customseparated
  5. extractionThe aqueous was back extracted with EtOAc (3×)
  6. dry with materialthe combined organic fractions were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customresulting in a crude brown oil
  10. customThe crude was purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, eluting with 100% DCM→8% MeOH in DCM]

Sources & evidence

ORD record
ord-1852773fa4f34628973ea903fd002e5c
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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