Water → 6-Cyano-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-3-carboxylic acid methyl ester

HRID 1888527Notes

Reaction equation

HRID 1888527 reaction equation
C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[C:31](Br)[CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1C[CH2:57][O:56][CH2:55]C1.N12CCCN=C1CCCCC2.[OH2:70]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].CO>[CH3:55][O:56][C:57]([C:31]1[CH:32]=[N:33][C:11]2[NH:10][C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]=2[CH:30]=1)=[O:70]

Participants

8

Reactant 5

HCID 962WaterHCID 312751,4-DioxaneHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 582668389-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-6-carbonitrile

Product 1

HCID 582664306-Cyano-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4',3'-d]pyrrole-3-carboxylic acid methyl esterYield 28%

Reagents, catalysts & solvents 2

HCID 98885Molybdenum carbonyl (Mo(CO)6)CatalystHCID 887MethanolSolvent

Conditions

Temperature
150 °C

Procedure

9-Benzenesulfonyl-3-bromo-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (150 mg, 0.278 mmol), molybdenum hexacarbonyl (73 mg, 0.278 mmol), Herman's catalyst (trans-di(μ-acetato)bis[(2-di-o-tolylphosphino)benzyl]dipalladium(II), 26 mg, 0.028 mmol) and tri-tert-butylphosphonium tetrafluoroborate (20 mg, 0.069 mmol) were placed in a 5 mL microwave vial. Dioxane (3 mL), methanol (1.5 mL) followed by 1,8-diazabicyclo(5.4.0)undec-7-ene (0.12 mL, 0.833 mmol) were added to the mixture, the tube sealed and heated under microwave irradiation at 150° C. for 15 min. The cooled reaction mixture was diluted with water and extracted into ethyl acetate (4×50 mL). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% MeOH in DCM). The resultant material was triturated with MeOH and collected by filtration to afford the title compound as a pale yellow powder (29 mg, 28%). 1H NMR (CDCl3, 300 MHz): 9.35 (d, J=2.1 Hz, 1H), 9.23 (s, 1H), 8.83 (s, 1H), 5.21-5.06 (m, 1H), 4.05 (s, 3H), 3.07-2.88 (m, 2H), 2.59-2.44 (m, 2H), 2.41-2.06 (m, 6H), 1.20-1.07 (m, 3H). LCMS (Method H): RT=6.56 min, M+H+=380.

Workup

  1. additionwere added to the mixture
  2. customthe tube sealed
  3. customThe cooled reaction mixture
  4. extractionextracted into ethyl acetate (4×50 mL)
  5. washThe combined organic phase was washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customto afford a residue that
  9. customwas purified by flash chromatography (silica, 12 g column, ISCO, 0-10% MeOH in DCM)
  10. customThe resultant material was triturated with MeOH
  11. filtrationcollected by filtration

Sources & evidence

ORD record
ord-6e5cdb18e92148b8b53fa1ae128809f0
Source dataset
uspto-grants-2013_08
Patent number
US08501765B2

Reaction notes

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