Sodium hydride → 1,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

HRID 2383298Notes

Reaction equation

HRID 2383298 reaction equation
CC([CH:5]1[C:14]2[C:9](=[C:10]([C:15]([NH:17][OH:18])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:19]([O-:21])=[O:20])(C)C.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:28](OC)=O>O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[O:18][N:17]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:9]=3[CH2:8][CH2:7][N:6]([C:19]([O:21][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:20])[CH2:5]4)[N:16]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 22597811Methyl 3-chloro-4-isopropoxybenzoateHCID 178440558HCID 178440558, compound

Product 1

HCID 593704861,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylateYield 159.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1,1-dimethylethyl5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinoline carboxylate (Preparation 1) (2 g, 6.86 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) and stirred with sodium hydride (60% dispersion, 0.302 g, 7.55 mmol) under argon at room temperature for 30 minutes. Then methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (Preparation 2, 2.355 g, 10.30 mmol) was added and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 mL) and water (100 mL). The water layer was washed with DCM (50 mL) and the combined DCM layers dried (hydrophobic frit) and evaporated. The crude product was purified by chromatography through a small silica pad, eluting with DCM to yield 1,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinoline carboxylate (2.57 g, 5.47 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, s), 8.05 (1H, d), 7.95 (1H, d), 7.34 (1H, t), 7.27 (1H, d), 7.06 (1H, d), 4.76-4.63 (1H, m), 4.66 (2H, br.s), 3.67 (2H, br.t), 3.25 (2H, br.t), 1.51 (9H, s), 1.45 (6H, d); m/z (API-ES) 414, 416 [M+H-56]+.

Workup

  1. temperaturethe reaction heated
  2. temperatureat reflux temperature for 1.5 hours
  3. customThe cooled reaction
  4. customwas evaporated
  5. custompartitioned between DCM (100 mL) and water (100 mL)
  6. washThe water layer was washed with DCM (50 mL)
  7. dry with materialthe combined DCM layers dried (hydrophobic frit)
  8. customevaporated
  9. customThe crude product was purified by chromatography through a small silica pad
  10. washeluting with DCM

Sources & evidence

ORD record
ord-13a3ecab869045009124527f122b98b1
Source dataset
uspto-grants-2012_09
Patent number
US08263620B2

Reaction notes

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