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 2059924Notes

Reaction equation

HRID 2059924 reaction equation
[OH:1][NH:2][C:3](=[NH:21])[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2.[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:1][N:2]=[C:3]([C:4]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:5]=3[CH2:6][CH2:7][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)[N:21]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:37])[CH3:38]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 22597811Methyl 3-chloro-4-isopropoxybenzoateHCID 178451585HCID 178451585, 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 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1,1-dimethylethyl 5-[(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-453de59988f549868a008fbecac89128
Source dataset
uspto-grants-2012_10
Patent number
US08278324B2

Reaction notes

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