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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 2190893
ノート
印刷プレビュー

反応式

HRID 2190893 の反応式
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
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

8

反応物 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

生成物 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

試薬・触媒・溶媒 3

HCID 6102075Dichlorobis(triphenylphosphine)palladium触媒HCID 6228Dimethylformamide溶媒HCID 6342Acetonitrile溶媒

反応条件

温度
125 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-e60026e2390a4b8f98f6b77cdb7aca0a
出典データセット
uspto-grants-2012_12
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08324384B2

反応ノート

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このページの内容参加物反応条件実験手順後処理出典と根拠反応ノート