Sodium Carbonate → 5-Hydroxymethyl-2-(2-oxo-1,2-dihydro-quinolin-3-yl)-indole-1-carboxylic acid tert-butyl ester

HRID 431165Notes

Reaction equation

HRID 431165 reaction equation
I[C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([SiH2][O:18][C:19](C)(C)[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2)(C)(C)C.[C:31]([O:35][C:36](N1C2C(=CC=CC=2)C=C1B(O)O)=[O:37])([CH3:34])([CH3:33])[CH3:32].[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+].B(O)O>O1CCOCC1.[Pd].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>[C:31]([O:35][C:36]([N:25]1[C:26]2[C:22](=[CH:21][C:20]([CH2:19][OH:18])=[CH:28][CH:27]=2)[CH:23]=[C:24]1[C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:37])([CH3:34])([CH3:33])[CH3:32]

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 61668Boronic Acid3×HCID 433294Lithium ChlorideHCID 114145753-iodo-1H-quinolin-2-one2×HCID 157380136tert-butyl-[2-(1H-indol-5-yl)propan-2-yloxy]silane;[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-2-yl]boronic acid

Product 1

HCID 121116885-Hydroxymethyl-2-(2-oxo-1,2-dihydro-quinolin-3-yl)-indole-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A stirred mixture of the iodoquinolinone (1-6, 10 g, 36.9 mmol, 1 equiv), the boronic acid (1-4, 7.5 g, 18.45 mmol, 0.5 equiv), tetrakis (triphenyl-phosphine) palladium (1.71 g, 1.48 mmol, 0.04 equiv), and lithium chloride (4.69 g, 110.7 mmol, 3 equiv) in dioxane/2M-aqueous Na2CO3 was degassed and heated at 80° C. until the boronic acid is not detected by thin layer chromatography. Additional boronic acid (0.2 equiv at a time) was added to the reaction mixture until all the iodoquinolinone (1-6) was consumed completely (1.5 equivalent of the boronic acid, 1-4, in total, was required). The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude oil (1-7) was dissolved in tetrahydrofuran (100 mL), transferred to the PEG bottle, treated at 0° C. with HF-pyridine (15 mL) and stirred for 1 hour at ambient temperature. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude solid was trituated with ethyl acetate and hexanes, collected by filtration and air-dried to afford the desired product (1-8) as a light yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 12.1 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=8.5 Hz), 7.74 (d, 1H, J=7.5 Hz), 7.55 (s, 1H), 7.52 (t, 1H, J=7.5 Hz), 7.35 (d, 1H, J=8.5 Hz), 7.30 (d, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 6.77 (s, 1H), 5.21 (t, 1H, J=5.5 Hz), 4.60 (d, 2H, J=5.5 Hz), 1.35 (s, 9H).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3
  2. washThe organic layer was washed with brine
  3. customseparated
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. dissolutionThe crude oil (1-7) was dissolved in tetrahydrofuran (100 mL)
  7. additiontreated at 0° C. with HF-pyridine (15 mL)
  8. customThe reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3
  9. washThe organic layer was washed with brine
  10. customseparated
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated in vacuo
  13. filtrationcollected by filtration
  14. customair-dried

Sources & evidence

ORD record
ord-f0f41681170e4c34a6fd660472a677ab
Source dataset
uspto-grants-2003_12
Patent number
US06656942B2

Reaction notes

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