Triethylamine → {6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinic acid ethyl ester

HRID 1430985Notes

Reaction equation

HRID 1430985 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:13]=[C:12]([O:24][CH:25]([CH3:27])[CH3:26])[CH:11]=2)=[N:6][CH:7]=1.[CH2:29]([O:31][PH:32]([CH3:34])=[O:33])[CH3:30].CCN(CC)CC>C1(C)C=CC=CC=1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:29]([O:31][P:32]([C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:13]=[C:12]([O:24][CH:25]([CH3:27])[CH3:26])[CH:11]=2)=[CH:4][CH:3]=1)([CH3:34])=[O:33])[CH3:30]

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 58528906N-(5-bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamideHCID 178476777HCID 178476777, compound

Product 1

HCID 58528997{6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinic acid ethyl esterYield 92.3%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of N-(5-bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (1.69 g, 3.66 mmol) in toluene (40 mL) was added a solution of methylphosphinic acid ethyl ester (0.475 g, 4.40 mmol), palladium tetrakis(triphenylphosphine) (0.846 g, 0.733 mmol), and Et3N (1.54 mL, 10.9 mmol) in DCM (5.0 mL) at rt. The mixture was heated at 90° C. overnight. Cooled to rt and concentrated. EtOAc and water were added and the mixture was filtered through a pad of Celite to remove the insoluble solids. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (6×25 cm, hexane/EtOAc, v/v=1:3, EtOAc, 1% MeOH in EtOAc). Fractions containing the product were pooled and concentrated to give {6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinic acid ethyl ester (1.65 g, 92%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.74 (br, 1H), 8.68 (ddd, J=6, 2, 1 Hz, 1H), 8.49 (ddd, J=9, 2, 1 Hz, 1H). 8.10 (ddd, J=11, 9, 2 Hz, 1H), 7.63-7.70 (m, 1H), 7.43-7.47 (m, 1H), 7.29 (dd, J=5.3 Hz, 1H), 7.09-7.10 (m, 1H), 7.04 (dd, J=5, 1 Hz, 1H), 6.99-7.03 (m, 2H), 6.64 (m, 1H), 4.60 (m, 1H), 4.22 (t, J=7 Hz, 2H), 4.07-4.15 (m, 1H), 3.84-3.92 (m, 1H), 3.14 (t, J=7 Hz, 2H), 1.70 (d, J=15 Hz, 3H), 1.35 (d, J=6 Hz, 6H), 1.23-1.31 (m, 3H).

Workup

  1. temperatureCooled to rt
  2. concentrationconcentrated
  3. additionEtOAc and water were added
  4. filtrationthe mixture was filtered through a pad of Celite
  5. customto remove the insoluble solids
  6. customThe organic layer was separated
  7. washwashed with brine (1×)
  8. dry with materialdried with anhydrous MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by silica gel flash chromatography (6×25 cm, hexane/EtOAc, v/v=1:3, EtOAc, 1% MeOH in EtOAc)
  12. additionFractions containing the product
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-09a5c6d1837e47baa2e615ca8cb126b6
Source dataset
uspto-grants-2015_01
Patent number
US08940927B2

Reaction notes

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