Sodium Bicarbonate → tert-Butyl ((6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)(2-methoxyethyl)carbamate

HRID 1475539Notes

Reaction equation

HRID 1475539 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:17])[CH3:18]

Participants

8

Reactant 4

HCID 516892Sodium BicarbonateHCID 112752517-Chlorothieno[3,2-b]pyridineHCID 57919609tert-Butyl [(6-Bromopyridin-3-yl)methyl](2-methoxyethyl)carbamateHCID 178418339Butyllithium

Product 1

HCID 57919613tert-Butyl ((6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)(2-methoxyethyl)carbamateYield 72%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 7-chlorothieno[3,2-b]pyridine (6) (8.84 g, 52.1 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1 mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether) was added at −78° C. and the reaction mixture was allowed to warm to r.t. After 1 h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and tert-butyl(6-bromopyridin-3-yl)methyl(2-methoxyethyl)carbamate (10) (6 g, 17.38 mmol) in THF (25.00 mL) were added and the mixture was heated to reflux for 1 h and cooled to room temperature. To the cooled reaction mixture were added NaHCO3 (sat. aq.) (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduce pressure. The residue was purified by flash column chromatography (eluent hexane/EtOAc: 5/5, 3/7, 0/100), to afford intermediate 11 (5.41 g, 72% yield). MS (m/z): 434.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H).

Workup

  1. waitAfter 1 h
  2. temperaturethe mixture was heated
  3. temperatureto reflux for 1 h
  4. temperaturecooled to room temperature
  5. customTo the cooled reaction mixture
  6. customThe organic layer was collected
  7. extractionthe aqueous layer was extracted with EtOAc (3×100 mL)
  8. washThe combined organic solutions were washed with brine
  9. dry with materialdried over anhydrous Na2SO4
  10. customevaporated
  11. customThe residue was purified by flash column chromatography (eluent hexane/EtOAc: 5/5, 3/7, 0/100)

Sources & evidence

ORD record
ord-5446deff96994701a0c03971684d391f
Source dataset
uspto-grants-2015_04
Patent number
US09018378B2

Reaction notes

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