Hydrochloric Acid → HCID 66884657, compound

HRID 915371Notes

Reaction equation

HRID 915371 reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17](=O)[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].Cl.ClC1C=CC=C2C=1C(=O)OC(C1C=CC(OC3C=CC=CC=3)=CC=1)=C2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:31]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=3[F:27])[C:17](=[O:16])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 27332442,4-DifluorobenzylamineHCID 66882846HCID 66882846, compoundHCID 66884082HCID 66884082, compound

Product 1

HCID 66884657HCID 66884657, compoundYield 73%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Procedure

A suspension of 3-(4-benzyloxyphenyl)-8-chloro-isochromen-1-one (1.7 g, 4.7 mmol) and 2,4-difluorobenzylamine (0.75 mL, 6.3 mmol) was prepared in toluene (25 mL) in a 100 mL round-bottomed flask under nitrogen. To the resulting suspension was added a solution of methyl aluminoxane (5.0 mL, of a 1.5 M solution in toluene, 7.5 mmol). Gas evolution was observed as the aluminoxane solution was added. The resulting suspension was then heated to reflux. As the solution came to reflux the solids dissolved to afford a brown solution. After stirring at reflux for 16 hours, an aliquot of the reaction was worked up with aqueous HCl, and analyzed by TLC. There was no visible 8-chloro-3-(4-phenoxyphenyl)-isochromen-1-one, and there were two product spots visible. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (50 mL), and diluted with EtOAc (100 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (50 mL), saturated aqueous NaHCO3 (30 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white foam. The crude foam was purified by silica gel column chromatography eluting with a gradient from 0% to 30% EtOAc/hexane. Two product peaks were collected from the column: The first peak that eluted was concentrated to afford 3-(4-benzyloxyphenyl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one, a compound of formula (Id), (1.68 g, 73% yield); 1H-NMR (400 MHz, CDCl3): δ 7.51-7.48 (2H, m), 7.46-7.33 (6H, m), 7.11-7.07 (2H, m), 7.04-6.96 (1H, m), 6.95-6.91 (2H, m), 6.78-6.71 (1H, m), 6.66-6.59 (1H, m), 6.39 (1H, s), 5.17 (2H, s), 5.10 (2H, s); and the second peak that eluted was concentrated to afford 2-[2-(4-benzyloxyphenyl)-2-oxoethyl]-6-chloro-N-(2,4-difluorobenzyl)benzamide, a compound of formula (W) (533 mg, 22% yield); 1H-NMR (400 MHz, CDCl3): δ 7.78 (2H, d, J=8.8 Hz), 7.45-7.30 (5H, m), 7.26-7.14 (3H, m), 7.00-6.93 (3H, m), 6.71 (1H, t, J=6.3 Hz), 6.56-6.49 (1H, m), 6.45-6.37 (1H, m), 5.12 (2H, s), 4.40 (2H, d, J=6.3 Hz), 4.16 (2H, s).

Workup

  1. additionwas added
  2. temperatureThe resulting suspension was then heated to reflux
  3. temperatureto reflux the solids
  4. dissolutiondissolved
  5. customto afford a brown solution
  6. temperatureat reflux for 16 hours
  7. temperatureHeating
  8. customThe reaction was then quenched by the addition of 1N HCl (aq.) (50 mL)
  9. additiondiluted with EtOAc (100 mL)
  10. customThe layers were separated
  11. extractionthe acidic aqueous layer was extracted with EtOAc (3×30 mL)
  12. washThe combined organic layers were washed with H2O (50 mL), saturated aqueous NaHCO3 (30 mL)
  13. dry with materialThe organic layer was dried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated under reduced pressure
  16. customto afford a white foam
  17. customThe crude foam was purified by silica gel column chromatography
  18. washeluting with a gradient from 0% to 30% EtOAc/hexane
  19. customTwo product peaks were collected from the column
  20. washThe first peak that eluted
  21. concentrationwas concentrated

Sources & evidence

ORD record
ord-be28f20101104cfdb48d56445b52ad54
Source dataset
uspto-grants-2007_09
Patent number
US07265131B2

Reaction notes

Loading…