Bromide ion → N-[4-(1-{1-(4-Chlorophenyl)-2-[5-(2-methoxypyridin-3-yl)-1,3-dihydro-2H-isoindol-2-yl]-2-oxoethyl}butyl)benzoyl]-beta-alanine

HRID 2190893Notes

Reaction equation

HRID 2190893 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](=[O:40])[CH:12]([CH:20]([C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:26][CH:25]=1)[CH2:21][CH2:22][CH3:23])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:5]2.[CH3:41][O:42][C:43]1[C:48](B(O)O)=[CH:47][CH:46]=[CH:45][N:44]=1.C([O-])([O-])=O.[Na+].[Na+].[Br-]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C=O)C.C(#N)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([CH:20]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:38][CH:39]=2)[CH2:21][CH2:22][CH3:23])[C:11]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:48]4[C:43]([O:42][CH3:41])=[N:44][CH:45]=[CH:46][CH:47]=4)[CH:3]=3)[CH2:7]2)=[O:40])=[CH:18][CH:17]=1

Participants

8

Reactant 4

HCID 259Bromide ionHCID 10340Sodium CarbonateHCID 2762709(2-Methoxypyridin-3-yl)boronic acidHCID 58553818Ethyl N-(4-{1-[2-(5-bromo-1,3-dihydro-2H-isoindol-2-yl)-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-beta-alaninate

Product 1

HCID 46870236N-[4-(1-{1-(4-Chlorophenyl)-2-[5-(2-methoxypyridin-3-yl)-1,3-dihydro-2H-isoindol-2-yl]-2-oxoethyl}butyl)benzoyl]-beta-alanine

Reagents, catalysts & solvents 3

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
125 °C

Procedure

Ethyl N-(4-{1-[2-(5-bromo-1,3-dihydro-2H-isoindol-2-yl)-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (30 mg, 0.048 mmol), trans-bis(triphenylphospine)palladium(II) chloride (3.4 mg, 4.8 μmol), 2-methoxypyridine-3-boronic acid (9.5 mg, 0.062 mmol), acetonitrile (2.0 mL) and Na2CO3 (2.0 M in H2O, 2.0 mL, 4.0 mmol) were added to a microwave vial. DMF (0.3 mL) was added to increase the solubility of the bromide. The vial was flushed with nitrogen, sealed, then heated to 125° C. for 10 minutes in a microwave reactor. The mixture was diluted with 1N HCl (aq) then extracted twice with EtOAc. The organic layers were dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by reverse-phase HPLC. Following lyophilization, this afforded the title compound as a white solid. The characterization data provided are for a single stereoisomer (of the possible four) that was the most potent glucagon receptor antagonist. 1H NMR (500 MHz, CD3OD): δ 8.09 (ddd, J=13.2, 5.1, 1.8 Hz, 1 H); 7.72 (d, J=8.1 Hz, 2 H); 7.67-7.58 (m, 1 H); 7.61 (dd, J=8.6, 2.4 Hz, 2 H); 7.49 (d, J=8.0 Hz, 2 H); 7.43-7.35 (m, 2 H); 7.37 (d, J=8.0 Hz, 1 H); 7.32 (s, 1 H); 7.23 (dd, J=13.9, 8.0 Hz, 1 H); 7.01 (ddd, J=14.0, 7.3, 5.0 Hz, 1 H); 4.90 (obs, 1 H); 4.79 (d, J=14.5 Hz, 1 H); 4.47 (d, J=16.2 Hz, 1 H); 4.31 (d, J=16.2 Hz, 1 H); 4.26 (dd, J=11.1, 2.3 Hz, 1 H); 3.90 (d, J=15.6 Hz, 3 H); 3.56 (t, J=7.0 Hz, 2 H); 3.47 (dd, J=11.2, 3.4 Hz, 1 H); 2.58 (t, J=7.0 Hz, 2 H); 1.55-1.49 (m, 1 H); 1.30 - 1.23 (m, 1 H); 1.00-0.91 (m, 2 H); 0.69 (t, J=7.3 Hz, 3 H). LC2 1.43 min. (M+H)+ 626.

Workup

  1. customThe vial was flushed with nitrogen
  2. customsealed
  3. additionThe mixture was diluted with 1N HCl (aq)
  4. extractionthen extracted twice with EtOAc
  5. dry with materialThe organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting residue was purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-e60026e2390a4b8f98f6b77cdb7aca0a
Source dataset
uspto-grants-2012_12
Patent number
US08324384B2

Reaction notes

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