Triethylamine → 1,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate

HRID 2059941Notes

Reaction equation

HRID 2059941 reaction equation
C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])[C:12]([OH:14])=O)#[N:8].O[NH:23][C:24](=[NH:43])[C:25]1[C:26]([CH3:42])=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]2.C(N(CC)CC)C>ClCCl.CN(C=O)C.C(#N)C>[C:7]([C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:23]=[C:24]([C:25]3[C:26]([CH3:42])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][N:30]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:29][CH2:28]4)[N:43]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])#[N:8]

Participants

9

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chloride2×HCID 21956832RP-101124HCID 178428722HCID 178428722, compound

Product 1

HCID 547570061,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylateYield 34.1%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

Oxalyl chloride (571 mg, 4.5 mmol) was added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (available from AK Scientific Product Catalog; 800 mg, 3.90 mmol) in dichloromethane (15 ml) followed by DMF (catalytic amount). The reaction mixture was stirred for 45 minutes, further oxalyl chloride (0.1 ml) and DMF (1 drop) were added and stirring continued for 20 minutes. The solvent was evaporated, the residue was co-evaporated with toluene then dried under high vacuum for 30 minutes. The crude acid chloride was dissolved in acetonitrile (10 ml) and added to a suspension of 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 916 mg, 3.00 mmol) and triethylamine (607 mg, 6.00 mmol) in acetonitrile (15 ml). The reaction mixture was stirred at room temperature for 40 minutes then heated under reflux for 24 hours. The reaction mixture was cooled and the solvent evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated to give the crude product (1.3 g). The residue was purified by chromatography, eluting with 8-38% ethyl acetate in cyclohexane, to give the title compound (486 mg).

Workup

  1. stirringstirring
  2. waitcontinued for 20 minutes
  3. customThe solvent was evaporated
  4. customthen dried under high vacuum for 30 minutes
  5. dissolutionThe crude acid chloride was dissolved in acetonitrile (10 ml)
  6. stirringThe reaction mixture was stirred at room temperature for 40 minutes
  7. temperaturethen heated
  8. temperatureunder reflux for 24 hours
  9. temperatureThe reaction mixture was cooled
  10. customthe solvent evaporated
  11. customThe residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution
  12. customThe organic phase was separated
  13. washwashed with brine
  14. dry with materialdried (MgSO4)
  15. customevaporated
  16. customto give the crude product (1.3 g)
  17. customThe residue was purified by chromatography
  18. washeluting with 8-38% ethyl acetate in cyclohexane

Sources & evidence

ORD record
ord-71b96ce103d548bebe5be011f0ac59ef
Source dataset
uspto-grants-2012_10
Patent number
US08278324B2

Reaction notes

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