Sodium Bicarbonate → 3-(4-Fluorobenzoyl)-8-(3-methoxyphenyl)-1,2,3,6-tetrahydroazepino[4,5-B]indole-5-carboxylic acid ethyl ester

HRID 37949Notes

Reaction equation

HRID 37949 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 2734370(3-Methoxyphenyl)boronic acidHCID 575591468-Bromo-3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester

Product 1

HCID 575591333-(4-Fluorobenzoyl)-8-(3-methoxyphenyl)-1,2,3,6-tetrahydroazepino[4,5-B]indole-5-carboxylic acid ethyl esterYield 93.6%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6344DichloromethaneSolventHCID 21863594Toluene ethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 8-bromo-3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (compound in Example 37A, 70 mg, 0.15 mmol), 3-methoxyphenylboronic acid (58 mg, 0.38 mmol), and (o-tolyl)3P (24 mg, 0.077 mmol) in toluene/EtOH (2:1, 3 mL) was added 0.55 mL of 1M NaHCO3 solution and Pd(OAc)2 (7 mg) at ambient temperature. The reaction mixture was heated at 80° C. under N2 for 1.5 hours and samples monitored by LC-MS. The solution was diluted with DCM (10 mL) and washed with brine. The aqueous phase was extracted with DCM (10 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (68 mg) as a light yellow solid; 1H-NMR (CDCl3): δ 10.76 (1H, s), 8.20 (1H, s), 7.78 (4H, m), 7.52 (2H, m), 7.42 (1H, d), 7.36 (3H, m), 7.04 (1H, m), 4.43 (4H, m), 4.05 (3H, s), 3.45 (2H, m), 1.39 (3H, t). MS (ESI): 485 (MH+).

Workup

  1. washwashed with brine
  2. extractionThe aqueous phase was extracted with DCM (10 mL) twice
  3. dry with materialThe combined organic phase was dried over Na2SO4
  4. concentrationconcentrated
  5. customThe crude product was purified by flash chromatograph on silica gel
  6. washeluting with EtOAc-hexane (0-30%)

Sources & evidence

ORD record
ord-8dda85203ab345528a91eb0b26ef9e96
Source dataset
uspto-grants-2013_09
Patent number
US08524704B2

Reaction notes

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