Dichloromethane → HCID 54674512, compound

HRID 2095685Notes

Reaction equation

HRID 2095685 reaction equation
Br[C:2]1[C:3]([O:8][CH3:9])=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21].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].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.O1CCOCC1>[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:2]3[C:3]([O:8][CH3:9])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 670039094-bromo-3-methoxy-1-methyl-1H-pyrazoleHCID 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 54674512HCID 54674512, compound

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 4-bromo-3-methoxy-1-methyl-1H-pyrazole (0.0399 g, 0.209 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 (0.0300 g, 0.0697 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 charged with an additional amount of 4-bromo-3-methoxy-1-methyl-1H-pyrazole (0.0399 g, 0.209) followed by Pd(PPh3)4 (4.02 mg, 0.00348 mmol) and evacuated and charged with N2 gas (3×) and heated under microwave conditions [Biotage, 100° C., 45 min, high absorption]. The dioxane layer was removed and diluted with CHCl3 and charged with silica gel. The sample was then dry loaded and purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, 100% DCM→5% MeOH in DCM]. This resulted in the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.78 (d, J=7.1 Hz, 3H), 3.75 (s, 3H), 3.93 (s, 3H), 5.07 (q, J=6.8 Hz, 1H), 6.83-6.91 (m, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.27 (d, J=1.0 Hz, 1H), 7.65 (s, 1H), 7.83 (br. s., 1H), 8.27 (d, J=2.0 Hz, 1H). MS (ES+): m/z 415.06, 417.07 (76/24) [MH+]. HPLC: tR=3.97 min (polar—5 min, ZQ3).

Workup

  1. customwater (1.50 mL) was evacuated
  2. additioncharged with N2 (2×)
  3. additionThe reaction mixture was charged with an additional amount of 4-bromo-3-methoxy-1-methyl-1H-pyrazole (0.0399 g, 0.209)
  4. customevacuated
  5. additioncharged with N2 gas (3×)
  6. temperatureheated under microwave conditions [Biotage, 100° C., 45 min, high absorption]
  7. customThe dioxane layer was removed
  8. additiondiluted with CHCl3
  9. additioncharged with silica gel
  10. customThe sample was then dry loaded
  11. custompurified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, 100% DCM→5% MeOH in DCM]

Sources & evidence

ORD record
ord-789e127f7d4f4f4b9c3f4238eb8b5bba
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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