Triethylamine → HCID 86699654, compound

HRID 929541Notes

Reaction equation

HRID 929541 reaction equation
[O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH:10]([CH3:13])[CH2:11][NH2:12])[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CCN(CC)CC.CCOC(C)=O>CC(O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:12][CH2:11][CH:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]3[CH2:3][CH2:2][O:1][C:9]=23)[CH3:13])[CH:20]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 709434,6-DichloropyrimidineHCID 86699655HCID 86699655, compound

Product 1

HCID 86699654HCID 86699654, compoundYield 81%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

As shown in step 6-iv of Scheme 6, to a suspension of 2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propan-1-amine.2HCl and 4,6-dichloropyrimidine (456.0 mg, 3.061 mmol) in i-PrOH (17.01 mL) was added Et3N (1.291 g, 1.778 mL, 12.76 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature, and partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined organics were washed with H2O (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes, then isocratic EtOAc) to afford 6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine (600.3 mg, 81% yield over two steps). Chiral SFC purification (20% MeOH at 5 mL/min on a ChiralPak® AD-H (4.6 mm×100 mm) column, 100 bar, 35° C., 220 nm) provided (S)-6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine (Compound 2021, 300 mg, SFC retention time 1.05 minutes): LCMS=291.04 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.00 (d, J=4.5 Hz, 1H), 6.92 (d, J=4.4 Hz, 1H), 6.36 (s, 1H), 5.24 (s, 1H), 4.71 (t, J=8.9 Hz, 2H), 3.61-3.35 (m, 4H), 3.23 (dd, J=14.0, 6.9 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H). The corresponding (R)-enantiomer had a retention time of 1.25 minutes).

Workup

  1. temperaturecooled to room temperature
  2. custompartitioned between saturated aqueous NaHCO3 and EtOAc
  3. extractionThe aqueous layer was further extracted with EtOAc (2×50 mL)
  4. washthe combined organics were washed with H2O (50 mL) and brine (50 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography (0-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-6f3136137fac41989c8c359554034c7a
Source dataset
uspto-grants-2016_03
Patent number
US09296701B2

Reaction notes

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