Dimethylformamide → 3-{2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester

HRID 1181055Notes

Reaction equation

HRID 1181055 reaction equation
[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:42][CH2:41][C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH3:29])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 120517392-(5-Methyl-2-phenyloxazol-4-yl)ethyl 4-methylbenzenesulfonateHCID 58979464HCID 58979464, compound

Product 1

HCID 589791833-{2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

A 2 L 3-neck flask was charged with 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (67.9 g, 0.178 mol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (76.6 g, 0.214 mol) and DMF (680 mL). Cesium carbonate (75.4 g, 0.231 mol) was added, and the reaction mixture was heated at 55° C. for 18 h. After cooling, ethyl acetate (890 mL) and DI water (1200 mL) were added, the mixture was agitated, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (740 mL). The organic layers were combined and washed with 1N NaOH (375 mL) then saturated NaCl solution (2×375 mL). The organic solution was dried (Na2SO4), filtered, and concentrated to an oil (107 g). The crude oil was dissolved in toluene (50 mL), and heptane was added (˜100 mL) until cloudiness remained even with agitation. The mixture was warmed to 50° C. on a rotary evaporator to yield a solution. Seed crystals were added, and rotation was continued at ambient temperature overnight. The product slurry was placed in the freezer overnight and filtered. The title compound was dried in a vacuum oven at 35° C. (71.4 g, 70.8%).

Workup

  1. temperatureAfter cooling
  2. customthe layers were separated
  3. extractionThe aqueous layer was back-extracted with ethyl acetate (740 mL)
  4. washwashed with 1N NaOH (375 mL)
  5. dry with materialThe organic solution was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated to an oil (107 g)
  8. dissolutionThe crude oil was dissolved in toluene (50 mL)
  9. additionheptane was added (˜100 mL) until cloudiness
  10. temperatureThe mixture was warmed to 50° C. on a rotary evaporator
  11. customto yield a solution
  12. additionSeed crystals were added
  13. customwas placed in the freezer overnight
  14. filtrationfiltered
  15. dry with materialThe title compound was dried in a vacuum oven at 35° C. (71.4 g, 70.8%)

Sources & evidence

ORD record
ord-4d1d9ff3e5584f22933875f679885da5
Source dataset
uspto-grants-2007_10
Patent number
US07282501B2

Reaction notes

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