Hydrochloric Acid → HCID 22676736, compound

HRID 1006271Notes

Reaction equation

HRID 1006271 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=C[CH:32]=1.C(Cl)(Cl)=[O:38].C1(N)CC1.Cl>ClCCl>[CH:36]1([NH:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C:9]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][CH:7]=2)=[O:38])[CH2:34][CH2:35]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 6371PhosgeneHCID 69828CyclopropylamineHCID 22676829HCID 22676829, compound

Product 1

HCID 22676736HCID 22676736, compoundYield 53%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a 25 mL round-bottomed flask at rt was charged with ethyl 3-(3-aminophenyl)-1-[(3-methoxyphenyl)methyl]indole-2-carboxylate (Example 93, 222 mg, 0.55 mmol) and dichloromethane (1.5 mL). The resulting solution was cooled to 0° C., to which was added pyridine (0.09 mL, 1.1 mmol) and phosgene (20% in toluene, 0.35 mL, 0.66 mmol). The mixture was left stirred at 0° C. for 2 hours and rt for 2 hours before it was concentrated in vacuo. The residue was dissolved in dichloromethane (2 mL) and cyclopropylamine (0.11 mL, 1.65 mmol) was added. The mixture was left at rt for 15 minutes before it was mixed with hydrochloric acid (1 N) and extracted with dichloromethane (10 mL). The organic layer was washed with aqueous sodium bicarbonate, brine, and dried over anhydrous magnesium sulfate. The crude mixture was purified with silica gel flash chromatography using hexane/ethyl acetate (3/1) as the eluant to give ethyl 3-{3-[(cyclopropylamino)carbonylamino]phenyl}-1-[(3-methoxyphenyl)methyl]indole-2-carboxylate (140 mg, 53%): MS (electrospray, MH+) calcd for C29H30N3O4 484.2, found 484.1; 1H NMR (DMSO-d6) δ 8.36 (s, 1H), 7.52-7.64 (m, 3H), 7.15-7.38 (m, 5H) 6.95 (ddd, J=6.9 Hz, 1H), 6.79 (dd, J=8.1, 1.9 Hz, 1H), 6.65 (dd, 1H), 6.59 (d, J=7.6 Hz, 1H), 6.38 (d, J=2.6 Hz, 1H), 5.77 (s, 2H), 4.10 (q, J=7.1 Hz), 3.68 (s, 3H), 2.50-2.60 (m, 1H), 0.97 (t, J=7.1 Hz), 0.60-0.64 (m, 2H), 0.39-0.41 (m. 2H).

Workup

  1. waitThe mixture was left
  2. concentrationwas concentrated in vacuo
  3. dissolutionThe residue was dissolved in dichloromethane (2 mL)
  4. waitThe mixture was left at rt for 15 minutes before it
  5. extractionextracted with dichloromethane (10 mL)
  6. washThe organic layer was washed with aqueous sodium bicarbonate, brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. customThe crude mixture was purified with silica gel flash chromatography

Sources & evidence

ORD record
ord-7243d5ba81554f06938b0d0688ffd228
Source dataset
uspto-grants-2004_09
Patent number
US06787651B2

Reaction notes

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