Phosphorus oxychloride → HCID 16058688, compound

HRID 1686071Notes

Reaction equation

HRID 1686071 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:23](=O)[CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.O=P(Cl)(Cl)Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][C:9]2[C:10]([N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:22]=[C:23]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 67265230HCID 67265230, compound

Product 1

HCID 16058688HCID 16058688, compoundYield 103.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a solution of N-(2-{[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]amino}phenyl)-3,3,3-trifluoropropanamide (127 mg) in 6 mL of dioxane was added 500 uL of POCl3. Immediate precipitation was observed. The reaction was heated at 100 C for 24 h, giving a sluggish reaction. The reaction was cooled to 0 C and carefully quenched with saturated aqueous sodium bicarbonate. then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and concentrated. The resulting crude mixture of starting material and desired product was dissolved in 4 mL of dioxane. This solution was added dropwise to 10 mL of POCl3 stirring at 50 C. The mixture was heated at 100 C for 8 h, then cooled to room temperature and concentrated in vacuo. CH2Cl2 was added to the residue, and the resulting solution was cooled to 0 C and neutralized slowly with saturated aqueous sodium bicarbonate, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and purified by flash chromatography. A second purification by reverse phase HPLC provided 127 mg of 1-[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]-2-(2,2,2-trifluoroethyl)-1H-benzimidazole as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (dd, J=4.6, 1.7 Hz, 1H), 8.43 (d, J=4.4 Hz, 2H), 8.31 (d, J=1.7 Hz, 1H), 8.24 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.69 (dd, J=7.8, 1.5 Hz, 1H), 7.40-7.35 (m, 2H), 7.31-7.28 (m, 1H), 7.22-7.20 (m, 1H), 7.18-7.11 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 4.08 (t, J=7.8 Hz, 1H), 3.73-3.64 (m, 1H), 3.52-3.43 (m, 1H), 3.29-3.21 (m, 2H).

Workup

  1. customImmediate precipitation
  2. temperatureThe reaction was heated at 100 C for 24 h
  3. customgiving
  4. customa sluggish reaction
  5. temperatureThe reaction was cooled to 0 C
  6. customcarefully quenched with saturated aqueous sodium bicarbonate
  7. customthen partitioned between saturated aqueous sodium bicarbonate and CH2Cl2
  8. extractionThe aqueous solution was extracted with CH2Cl2 (2×)
  9. dry with materialthe combined organic solutions were dried (Na2SO4)
  10. concentrationconcentrated
  11. additionThe resulting crude mixture of starting material and desired product
  12. dissolutionwas dissolved in 4 mL of dioxane
  13. additionThis solution was added dropwise to 10 mL of POCl3 stirring at 50 C
  14. temperatureThe mixture was heated at 100 C for 8 h
  15. concentrationconcentrated in vacuo
  16. additionCH2Cl2 was added to the residue
  17. temperaturethe resulting solution was cooled to 0 C
  18. custompartitioned between saturated aqueous sodium bicarbonate and CH2Cl2
  19. extractionThe aqueous solution was extracted with CH2Cl2 (3×)
  20. dry with materialthe combined organic solutions were dried (Na2SO4)
  21. custompurified by flash chromatography
  22. customA second purification by reverse phase HPLC

Sources & evidence

ORD record
ord-92ba619449f64f71a624616833f4b4fe
Source dataset
uspto-grants-2012_04
Patent number
US08148535B2

Reaction notes

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