Sodium Carbonate → (2-Chloro-5-(4-(4-morpholinyl)-6-quinolinyl)-3-pyridinyl)methanol

HRID 1963773Notes

Reaction equation

HRID 1963773 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([CH2:34][OH:35])[C:30]([Cl:33])=[N:31][CH:32]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:30]1[C:29]([CH2:34][OH:35])=[CH:28][C:27]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[C:7]3[N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:32][N:31]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 23091039(5-Bromo-2-chloropyridin-3-yl)methanolHCID 670704324-Morpholinoquinolin-6-ylboronic acid

Product 1

HCID 44609230(2-Chloro-5-(4-(4-morpholinyl)-6-quinolinyl)-3-pyridinyl)methanolYield 94%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
95 °C

Procedure

(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) A mixture of 4-morpholinoquinolin-6-ylboronic acid (500 mg, 1937 μmol), PdCl2(dppf) (70.9 mg, 96.9 μmol), Na2CO3 (616 mg, 5812 μmol) and (5-bromo-2-chloropyridin-3-yl)methanol (431 mg, 1937 μmol) in DME (8 mL) and water (3 mL) was heated to 95° C. under nitrogen. After 2 h, the mixture was concentrated and the residue was partitioned between water and DCM containing iPrOH (1%). The aqueous layer was extracted several times with DCM containing iPrOH (1%). The combined organic phase was concentrated and suspended in DMSO-MeOH (1:1). This mixture was then filtered, washed with MeOH to give the desired product (230 mg, 94% pure based on LCMS). The filtrate was purified with HPLC and concentrated to an oil. This was partitioned between DCM and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated to a white solid (100 mg). LCMS (ESI, pos. ion): calc'd for C19H18ClN3O2: 355.1; found: 356.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.19-2.39 (m, 1 H) 3.21-3.33 (m, 4 H) 3.95-4.06 (m, 4 H) 4.91 (d, J=5.02 Hz, 2 H) 6.93 (d, J=4.52 Hz, 1 H) 7.88 (d, J=9.03 Hz, 1 H) 8.13-8.27 (m, 3 H) 8.63 (d, J=2.01 Hz, 1 H) 8.79 (d, J=5.02 Hz, 1 H)

Workup

  1. concentrationthe mixture was concentrated
  2. customthe residue was partitioned between water and DCM
  3. additioncontaining iPrOH (1%)
  4. extractionThe aqueous layer was extracted several times with DCM
  5. additioncontaining iPrOH (1%)
  6. concentrationThe combined organic phase was concentrated
  7. filtrationThis mixture was then filtered
  8. washwashed with MeOH

Sources & evidence

ORD record
ord-ebd8d34f30734225898d1d5305a13c06
Source dataset
uspto-grants-2013_04
Patent number
US08415376B2

Reaction notes

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