Dimethylformamide → 7-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)furo[3,2-c]pyridin-6-amine

HRID 911989Notes

Reaction equation

HRID 911989 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20](Br)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28]([Sn](C)(C)C)[CH2:29]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C>C(Cl)Cl.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].CO.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:28]3[CH2:29][CH:30]4[N:25]([CH3:24])[CH:26]([CH2:32][CH2:31]4)[CH:27]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11]

Participants

9

Reactant 4

HCID 6228DimethylformamideHCID 80271Tri-o-tolylphosphineHCID 235329158-Methyl-3-(trimethylstannyl)-8-azabicyclo[3.2.1]oct-2-eneHCID 578127253-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine

Product 1

HCID 578124167-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)furo[3,2-c]pyridin-6-amine

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
115 °C

Procedure

In a two necked RB flask (50 mL), equipped with a N2 inlet, a water condenser and a magnetic stirrer, were placed 7-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-3-bromofuro[3,2-c]pyridine-6-amine (200 mg, 0.48 mmol), 8-methyl-3-(trimethylstannyl)-8-azabicyclo[3.2.1]oct-2-ene (216 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (100 mg, 0.11 mmol), tri-o-tolylphosphine (26 mg, 0.085 mmol), DMF (10 mL) and triethylamine (1.0 mL). This reaction mixture was heated at 114-116° C. for 4 h. TLC (10% MeOH in DCM) indicated that the starting material was consumed. DMF was removed under reduced pressure; water was added to the residue and extracted with DCM (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified on silica gel column chromatography eluting with 2-5% methanol in dichloromethane to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=1.2 (m, 1H), 2.85 (d, J=6.6 Hz, 3H), 2.31 (m, 2H), 2.58 (br, m, 2H), 2.70 (s, 3H), 3.10 (br, d, 1H), 3.90 (d, br, 2H), 4.77 (br, 2H), 6.40 (d, J=6.0 Hz, 1H), 6.55 (m, 1H), 7.01 (t, J=6.6 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.40 (s, 1H), 8.21 (s, 1H).

Workup

  1. customIn a two necked RB flask (50 mL), equipped with a N2 inlet, a water condenser and a magnetic stirrer
  2. customwas consumed
  3. customDMF was removed under reduced pressure
  4. additionwater was added to the residue
  5. extractionextracted with DCM (3×10 mL)
  6. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified on silica gel column chromatography
  10. washeluting with 2-5% methanol in dichloromethane

Sources & evidence

ORD record
ord-6d2c479aba2642d8aeec13830fbe5111
Source dataset
uspto-grants-2011_09
Patent number
US08022206B2

Reaction notes

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