Potassium bis(trimethylsilyl)amide → 2-{[2-(Benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid

HRID 577523Notes

Reaction equation

HRID 577523 reaction equation
[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH2:8][CH2:7][C:6]=2[C:5]([C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[O:17][CH:18]([CH3:20])[CH3:19].[CH2:21]([O:28][C:29]1[C:34]([CH2:35]Cl)=[C:33]([CH3:37])[CH:32]=[C:31]([CH3:38])[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCOCC1>[CH2:21]([O:28][C:29]1[C:34]([CH2:35][N:9]2[CH2:8][CH2:7][C:6]3[C:5]([C:13]([OH:15])=[O:14])=[CH:4][C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:2]([Cl:1])[C:11]=3[C:10]2=[O:12])=[C:33]([CH3:37])[CH:32]=[C:31]([CH3:38])[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

5

Reactant 3

HCID 3251421Potassium bis(trimethylsilyl)amideHCID 612578682-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridineHCID 86723680Methyl 8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate

Product 1

HCID 867237502-{[2-(Benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acidYield 33%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of methyl 8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd F, 92.0 mg, 0.310 mmol) and 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 97.1 mg, 0.371 mmol) in 1,4-dioxane (3 mL) was added KHMDS (308 mg, 1.54 mmol). The reaction mixture was heated at 100° C. for 1 hour. The solvent was removed under vacuum and the residue diluted with EtOAc (10 mL) and water (10 mL). The pH of the aqueous layer was adjusted to 3-4 using 1N HCl. The aqueous layer was extracted with EtOAc (25 mL) and the organic layer concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (90a, 52 mg, 33% yield) as an oil.

Workup

  1. customThe solvent was removed under vacuum
  2. additionthe residue diluted with EtOAc (10 mL) and water (10 mL)
  3. extractionThe aqueous layer was extracted with EtOAc (25 mL)
  4. concentrationthe organic layer concentrated under vacuum
  5. customThe residue was purified by column chromatography (silica gel, heptanes/EtOAc)

Sources & evidence

ORD record
ord-2b0f8efae24d49a9be6d2a37161b56b2
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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