Phosphorus trichloride → HCID 135440360, compound

HRID 2245567Notes

Reaction equation

HRID 2245567 reaction equation
[H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([NH2:15])=[O:14])[CH:10]=2)[NH:5]1.[Cl:16][C:17]1[N+:22]([O-])=[CH:21][C:20]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.P(Cl)(Cl)Cl>CN(C)C=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[ClH:16].[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:17]1[CH:18]=[CH:19][C:20]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][N:22]=1)=[CH:10][C:9]([C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=2

Participants

8

Reactant 4

HCID 24387Phosphorus trichlorideHCID 24758Sodium hydrideHCID 21717249HCID 21717249, compoundHCID 85873132HCID 85873132, compound

Product 1

HCID 135440360HCID 135440360, compound

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (0.090 g of 60% suspension in mineral oil, 2.25 mmol) was added to a cooled (0° C.) solution of 2-oxoindoline-5-carboxamide (0.315 g, 1.79 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 0° C. for 15 min under an N2 atmosphere, followed by the addition of 4-[(6-chloro-1-oxidopyridin-3-yl)methyl]morpholine (0.345 g, 1.51 mmol) in N,N-dimethylformamide (2 mL). The reaction vessel was closed, immediately warmed up to 130° C., and the reaction was stirred at this temperature for 0.5 h. The cooled mixture was diluted with a saturated NaHCO3 solution (30 mL), and extracted with ethyl acetate (containing 5% methanol). The combined organic extracts were dried (Na2SO4), and the solvents were removed in vacuo. The residue was dissolved in toluene (100 mL), and re-evaporated. The material was dried, dissolved in ethyl acetate (75 mL), and phosphorus trichloride (0.6 mL, 6 mmol) in ethyl acetate (5 mL) was added dropwise under vigorous stirring. The reaction mixture was heated to reflux for 2 h, cooled to room temperature, and quenched with an excess of saturated sodium hydrogen carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (containing 5% methanol). The combined organic extracts were dried (Na2SO4), the solvents were removed in vacuo, and the residue was purified on a silica gel column using chloroform/methanol/aqueous NH3, (100:10:1), as the eluent to afford the title compound as the base, yield 0.013 g (2.5%). This material was dissolved in chloroform/methanol (1:1), and treated with HCl in diethyl ether (1 M) followed by addition of diethyl ether. The resulting yellow crystals were collected by filtration and washed with diethyl ether to afford 0.010 g of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 14.70 (br s, 1H), 11.08 (br s, 1H), 10.68 (s, 1H), 8.21 (s, 1H), 8.05-7.95 (m, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.10 (br s, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.26 (s, 2H), 3.97-3.92 (m, 2H), 3.80-3.72 (m, 2H), 3.40-3.33 (m, 2H), 3.13-3.07 (m, 2H); MS (ES) m/z 354 (M++1).

Workup

  1. customThe reaction vessel was closed
  2. temperatureimmediately warmed up to 130° C.
  3. stirringthe reaction was stirred at this temperature for 0.5 h
  4. extractionextracted with ethyl acetate (containing 5% methanol)
  5. dry with materialThe combined organic extracts were dried (Na2SO4)
  6. customthe solvents were removed in vacuo
  7. dissolutionThe residue was dissolved in toluene (100 mL)
  8. customre-evaporated
  9. customThe material was dried
  10. dissolutiondissolved in ethyl acetate (75 mL)
  11. temperatureThe reaction mixture was heated
  12. temperatureto reflux for 2 h
  13. temperaturecooled to room temperature
  14. customquenched with an excess of saturated sodium hydrogen carbonate
  15. customThe organic layer was separated
  16. extractionthe aqueous layer was extracted with ethyl acetate (containing 5% methanol)
  17. dry with materialThe combined organic extracts were dried (Na2SO4)
  18. customthe solvents were removed in vacuo
  19. customthe residue was purified on a silica gel column

Sources & evidence

ORD record
ord-d932ed5d5a254c068e6f25842a7f4f3b
Source dataset
uspto-grants-2010_03
Patent number
US07683067B2

Reaction notes

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