Diisopropylethylamine → (E)-6-{2-[methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester

HRID 2097055Notes

Reaction equation

HRID 2097055 reaction equation
[CH3:1][N:2]([CH2:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])[C:3](=[O:6])[CH:4]=[CH2:5].[CH2:18]([O:20][C:21]([C:23]1[C:24](=[O:34])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:22])[CH3:19].CCN(C(C)C)C(C)C>C(C#N)C.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:20][C:21]([C:23]1[C:24](=[O:34])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](/[CH:5]=[CH:4]/[C:3](=[O:6])[N:2]([CH3:1])[CH2:7][C:8]1[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=1[CH3:17])=[CH:28][N:27]=2)=[O:22])[CH3:19]

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 17930139N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamideHCID 53396436HCID 53396436, compound

Product 1

HCID 59277530(E)-6-{2-[methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl esterYield 56.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 7854PropionitrileSolvent

Procedure

A suspension of N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide (500 mg, 2.04 mmol), 6-bromo-2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (665 mg, 2.24 mmol), (o-tol)3P (135 mg, 0.44 mmol) and DIEA (0.4 mL, 2.45 mmol) in EtCN (10 mL) and DMF (10 mL) was deoxygenated with argon for 30 min. Pd(OAc)2 (50 mg, 0.22 mmol) was added, the mixture was deoxygenated with argon for 20 min and then heated to reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was partitioned between CH2Cl2 and H2O. The organic layer was washed with satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 89:10:1 CH2Cl2/MeOH/conc NH4OH) gave the title compound (530 mg, 56%) as a yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.98 (d, J=2.1 Hz, 1H), 8.67 (s, 1H), 8.44-8.42 (m, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.75-7.52 (m, 2H), 7.43-7.31 (m, 3H), 5.14-4.91 (m, 2H), 4.32-4.25 (m, 2H), 3.18-2.96 (m, 3H), 2.43 (s, 3H), 1.33-1.27 (m, 3H); MS (ESI) m/e 462 (M+H)+.

Workup

  1. customwas deoxygenated with argon for 30 min
  2. customthe mixture was deoxygenated with argon for 20 min
  3. temperatureheated
  4. temperatureto reflux overnight
  5. concentrationconcentrated
  6. customThe residue was partitioned between CH2Cl2 and H2O
  7. washThe organic layer was washed with satd NaCl
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customPurification by column chromatography (silica gel, 89:10:1 CH2Cl2/MeOH/conc NH4OH)

Sources & evidence

ORD record
ord-bdba28917cd14d748cc203c733dfbcda
Source dataset
uspto-grants-2013_05
Patent number
US08450307B2

Reaction notes

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