Dichloromethane → {4-[(Pyrid-3-yl)ethynyl]-2-phenylbenzoyl]methionine methyl ester

HRID 2121191Notes

Reaction equation

HRID 2121191 reaction equation
[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClCCl.[C:29]([Sn](CCCC)(CCCC)CCCC)#[CH:30].[I-].Br[C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.C(N(CC)CC)C>CN(C=O)C.CCOCC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:29]#[C:30][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1

Participants

11

Reactant 6

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 122863-BromopyridineHCID 30165Iodide IonHCID 621176EthynyltributyltinHCID 53801632(4-Iodo-2-phenylbenzoyl)methionine methyl ester

Product 1

HCID 20622839{4-[(Pyrid-3-yl)ethynyl]-2-phenylbenzoyl]methionine methyl esterYield 24%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (4-iodo-2-phenylbenzoyl)methionine methyl ester, prepared as in Example 210D, (469 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed to dichloromethane (1:1) (82 mg, 0.10 mmol), and ethynyltributyltin (315 mg, 1.0 mmol) in DMF (5 mL) was heated at 80° C. for 6 hours at which point thin layer chromatography indicated no starting iodide left. 3-Bromopyridine (0.114 mL, 1.2 mmol) and triethylamine (0.42 mL, 3.0 mmol) were added and the reaction mixture was heated at 100° C. for 14 hours. The reaction mixture was diluted with ether (50 mL) and ethyl acetate (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. To the filtrate was added 3 drops of water, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) with swirling. The resulting milky mixture was filtered through silica gel (15 g), rinsed with ethyl acetate, and concentrated in vacuo. The residue was then purified by column chromatography (50% ethyl acetate-hexane, then ethyl acetate) to give {4-[(pyrid-3-yl)ethynyl]-2-phenylbenzoyl}methionine methyl ester (109 mg, 24%). 1H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 8.58 (dd, 1H), 7.82 (dt, 1H), 7.74 (d, 1H), 7.59 (dd, 1H), 7.57 (s, 1H), 7.45 (m, 5H), 7.31 (dd, 1H), 5.93 (br d, 1H), 4.69 (m, 1H), 3.68 (s, 3H), 2.08 (m, 2H), 2.02 (s, 3H), 1.93 (m, 1H), 1.76 (m, 1H). MS (CI+) m/e 445 (M+H)+.

Workup

  1. waitleft
  2. temperaturethe reaction mixture was heated at 100° C. for 14 hours
  3. washwashed with water and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. additionTo the filtrate was added 3 drops of water
  7. filtrationThe resulting milky mixture was filtered through silica gel (15 g)
  8. washrinsed with ethyl acetate
  9. concentrationconcentrated in vacuo
  10. customThe residue was then purified by column chromatography (50% ethyl acetate-hexane

Sources & evidence

ORD record
ord-f581f5f8742d4882aecd016f46288241
Source dataset
uspto-grants-2004_02
Patent number
US06693123B2

Reaction notes

Loading…