Hydrochloric Acid → Hydrochloric Acid

HRID 1897608Notes

Reaction equation

HRID 1897608 reaction equation
[Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=1[CH:26]([OH:31])[CH2:27][O:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[ClH:39]>C(OCC)(=O)C.C(Cl)Cl.O1CCOCC1.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([F:32])[C:25]=2[CH:26]([OH:31])[CH2:27][O:28][CH2:29][CH3:30])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:39]

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 579261132-Chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 67155130HCID 67155130, compound

Product 2

HCID 313Hydrochloric AcidHCID 69938040HCID 69938040, compound

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 25 mL round bottom flask was charged with 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (74 mg, 0.282 mmol), 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-ethoxy-ethanol (62 mg, 0.235 mmol), 2M aqueous sodium carbonate (0.235 mL, 0.470 mmol) and DMF (5 mL). The reaction mixture was evacuated and flushed with N2 twice, followed by addition of PdCl2(dppf). CH2Cl2 adduct (9.6 mg, 0.012 mmol). The reaction was stirred under N2 at 100° C. for 30 min. The reaction mixture was cooled to room temperature diluted with ethyl acetate and washed with water twice. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in DMF (5 mL) and purified by HPLC using an Xbridge Shield RP18 column and gradient 0.1% aqueous NH4OH in acetonitrile to afford a solid, which was dissolved in DCM (2 mL) and 4N HCl in dioxane (0.5 mL). The solvents were evaporated and the product was lyophilized to afford the product 2-chloro-4-[4-(2-ethoxy-1-hydroxy-ethyl)-5-fluoro-pyridin-3-yl]-benzonitrile as an HCl salt. 1H NMR (400 MHz, MeOD, HCl salt) δ ppm 1.17 (t, J=6.9 Hz, 3H), 3.46-3.57 (m, 2H), 3.81 (dd, J=6.7, 1.4 Hz, 2H), 4.90 (t, J=6.8 Hz, 1H), 7.61 (dd, J=8.0, 1.6 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 8.36 (s, 1H), 8.60 (d, J=2.8 Hz, 1H); HRMS: (ESI) m/z 321.0801 [(M+H)+ Calcd for C16H14ClFN2O2 321.0806].

Workup

  1. customThe reaction mixture was evacuated
  2. customflushed with N2 twice
  3. additionfollowed by addition of PdCl2(dppf)
  4. temperatureThe reaction mixture was cooled to room temperature
  5. washwashed with water twice
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. dissolutionThe crude was dissolved in DMF (5 mL)
  9. custompurified by HPLC
  10. customto afford a solid, which
  11. customThe solvents were evaporated

Sources & evidence

ORD record
ord-7781022fe5da4ac181465ebf8868a592
Source dataset
uspto-grants-2013_08
Patent number
US08519134B2

Reaction notes

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