Dimethylbarbituric acid → Ethyl tert-butoxy[4-(2-hydroxy-4-methylphenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

HRID 2406400

Reaction equation

HRID 2406400 reaction equation
C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:29])[N:15]=[C:14]2[S:30][C:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:13]=12)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:25]([O:24][CH:18]([C:17]1[C:12]([C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[OH:4])=[C:13]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=3[S:30][C:14]2=[N:15][C:16]=1[CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:26])[CH3:27]

Participants

5

Reactant 2

HCID 69860Dimethylbarbituric acidHCID 67890974Ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(tert-butoxy)acetate

Product 1

HCID 136372356Ethyl tert-butoxy[4-(2-hydroxy-4-methylphenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetateYield 63%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalyst2×HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(tert-butoxy)acetate (Step 8, 370 mg, 729 μmol) in dichloromethane (10 mL) was added 1,3-dimethylbarbituric acid (569 mg, 3.64 mmol), and the reaction was evacuated and filled with nitrogen. Palladium tetrakis(triphenylphosphine) (17 mg, 15 μmol) was added and the reaction was heated to reflux for 16 hours. Further palladium tetrakis(triphenylphosphine) (17 mg, 15 μmol) was added and the reaction was heated to reflux for a further 4 hours. The reaction was concentrated in vacuo and preabsorbed onto silica. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 20%). Product containing fractions were concentrated in vacuo to give the title compound as a pair of diastereoisomers as a colourless oil, 214 mg, in a 63% yield. The other pair of minor diastereoisomers co-eluted with unreacted starting material and were not isolated. LC-MS (12 min acidic) 6.89 mins 100% pure by UV, ES+/APCI+ 468, ES−/APCI− 466 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (s, 9H) 1.20 (t, 3H) 1.62-1.85 (m, 4H) 2.02-2.14 (m, 2H) 2.41 (s, 3H) 2.74 (s, 3H) 2.78-2.85 (m, 2H) 4.08-4.18 (m, 2H) 5.14 (s, 1H) 6.78 (s, 1H) 6.82 (d, 1H) 7.17 (d, 1H).

Workup

  1. customthe reaction was evacuated
  2. additionfilled with nitrogen
  3. temperaturethe reaction was heated
  4. temperatureto reflux for 16 hours
  5. temperaturethe reaction was heated
  6. temperatureto reflux for a further 4 hours
  7. concentrationThe reaction was concentrated in vacuo
  8. custompreabsorbed onto silica
  9. customThe residue was purified
  10. additionProduct containing fractions
  11. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-c78316d5d9054bad9618db45e1d1ab7f
Source dataset
uspto-grants-2014_08
Patent number
US08809363B2

Linked notes

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