Potassium Carbonate → Benzoate

HRID 2364621Notes

Reaction equation

HRID 2364621 reaction equation
[CH2:1]([O:3][C:4](C1C=CC(B(O)O)=CC=1)=[O:5])[CH3:2].NC1CC(C(N(CCC)CCC)=O)=CC2C=CC(Br)=CC=2N=1.C[O:38][C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)=[O:40].C(=O)([O-])[O-].[K+].[K+].C(OC([NH:63][C:64]1[CH2:65][C:66]([C:86](=[O:102])[N:87]([CH2:91][CH2:92][CH2:93][O:94][Si](C(C)(C)C)(C)C)[CH2:88][CH2:89][CH3:90])=[CH:67][C:68]2[CH:74]=[CH:73][C:72]([C:75]3[CH:85]=[CH:84][C:78]([C:79](OCC)=O)=[CH:77][CH:76]=3)=[CH:71][C:69]=2[N:70]=1)=O)(C)(C)C>C(#N)C.CCOC(C)=O.ClCCl.C(O)(C(F)(F)F)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:63][C:64]1[CH2:65][C:66]([C:86](=[O:102])[N:87]([CH2:91][CH2:92][CH2:93][OH:94])[CH2:88][CH2:89][CH3:90])=[CH:67][C:68]2[CH:74]=[CH:73][C:72]([C:75]3[CH:85]=[CH:84][C:78]([CH2:79][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:77][CH:76]=3)=[CH:71][C:69]=2[N:70]=1.[C:39]([O-:40])(=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1

Participants

12

Reactant 5

HCID 11430Potassium CarbonateHCID 27343504-Ethoxycarbonylphenylboronic acid2×HCID 27343694-Methoxycarbonylphenylboronic acid2×HCID 66960277HCID 66960277, compoundHCID 66961446(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide2×

Product 2

HCID 242BenzoateYield 44%HCID 50943616HCID 50943616, compoundYield 40%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

Ethyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate (40%) was prepared as follows, substituting 4-(2-ethoxy-2-oxoethyl)phenylboronic acid for 4-(ethoxycarbonyl)phenylboronic acid. Ethyl 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (44%) was prepared as follows, substituting tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate for 1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide and 4-(ethoxycarbonyl)phenylboronic acid for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. Ethyl 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.050 g, 0.075 mmol) was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) was used. 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 2H), 7.20-7.41 (m, 5H), 6.73-6.85 (m, 3H), 4.42-4.52 (m, 1H), 4.05-4.16 (m, 2H), 3.71 (s, 2H), 3.24-3.52 (m, 6H, partially obscured by water peak), 2.75 (s, 2H), 1.66-1.78 (m, 2H), 1.50-1.65 (m, 2H), 1.15-1.23 (m, 3H), 0.75-0.92 (m, 3H); m/z (APCI-pos) M+1=464.2.

Workup

  1. washwashed twice with brine
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated under reduced pressure
  4. concentrationthe mixture was concentrated under reduced pressure
  5. dissolutionthe resulting residue was then re-dissolved in dichloromethane
  6. addition1 ml of concentrated ammonium hydroxide added
  7. additionThis mixture was then diluted with water
  8. extractionextracted with dichloromethane (2×)
  9. dry with materialextracts dried over sodium sulfate
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-c578cbe5155042b894ffa9e6883c9022
Source dataset
uspto-grants-2014_04
Patent number
US08691809B2

Reaction notes

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