Toluene → Ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate

HRID 2361345Notes

Reaction equation

HRID 2361345 reaction equation
[NH2:1][CH2:2][CH:3]([C:19]1[C:20]([CH3:36])=[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCOCC1.CC1C=CC(C)=CC=1.[Pd]>[CH2:28]([O:27][C:26]([NH:25][C:21]1[C:20]([CH3:36])=[C:19]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][CH:2]=2)[CH:24]=[CH:23][CH:22]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 70211Ethyl oxoacetate2×HCID 204431481,4-Dioxane hydrochlorideHCID 67995166Benzyl 3-(2-amino-1-(5-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate

Product 1

HCID 67994745Ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylateYield 23.4%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 7809P-XyleneSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
40 °C

Procedure

To a solution of benzyl 3-(2-amino-1-(5-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.713 g, 1.471 mmol) and 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol)/toluene in 1,4-dioxane (61.3 mL) was added 4 N hydrochloric acid/1,4-dioxane (0.736 mL, 2.94 mmol)/dioxane under nitrogen. After stirring overnight, more 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol) was added. After 2 hr, the reaction was heated to 40° C. After another 2 hr, the reaction was cooled to room temperature, concentrated in vacuo, and dissolved in water (50 mL) and EtOAc (50 mL). The mixture was basified with saturated NaHCO3 solution to pH ˜10. The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo to give crude product used in subsequent step. This was added to 10% Pd/C (0.377 g, 0.354 mmol) in p-xylene (39.4 mL), and the reaction was heated at 125° C. After 9 h, the reaction was cooled to room temperature, filtered through a wad of CELITE®, rinsed with EtOAc, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 40 g column eluting with 0-50% EtOAc/CH2Cl2 to give the desired product (0.1558 g, 0.276 mmol, 23.4% yield) as a light orange foam.

Workup

  1. waitAfter 2 hr
  2. waitAfter another 2 hr
  3. temperaturethe reaction was cooled to room temperature
  4. concentrationconcentrated in vacuo
  5. dissolutiondissolved in water (50 mL)
  6. customThe layers were separated
  7. extractionthe aqueous layer was extracted with EtOAc (3×50 mL)
  8. washwashed with brine
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated in vacuo
  11. customto give crude product
  12. temperaturethe reaction was heated at 125° C
  13. waitAfter 9 h
  14. temperaturethe reaction was cooled to room temperature
  15. filtrationfiltered through a wad of CELITE®
  16. washrinsed with EtOAc
  17. concentrationthe filtrate was concentrated in vacuo
  18. dissolutionThe residue was dissolved in EtOAc (100 mL)
  19. washwashed with brine (25 mL)
  20. dry with materialdried over MgSO4
  21. concentrationconcentrated in vacuo
  22. customThe residue was purified by flash chromatography
  23. washeluting with 0-50% EtOAc/CH2Cl2

Sources & evidence

ORD record
ord-e5e17af2e65d4727adcef7ec02652b42
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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