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

HRID 2059925Notes

Reaction equation

HRID 2059925 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.O[NH:23][C:24](=[NH:42])[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:23]=[C:24]([C:25]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:26]=3[CH2:27][CH2:28][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:42]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 21956832RP-101124HCID 178451585HCID 178451585, compound

Product 1

HCID 575059191,1-dimethylethyl 5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylateYield 37%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent3×HCID 6344DichloromethaneSolvent

Procedure

To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848, 737 mg, 3.59 mmol) and oxalyl chloride (360 μl) in DCM (20 mL) was added DMF (20 μl). The solution was stirred at room temperature for 90 min, then concentrated in vacuo, and redissolved in dry DMF (6 mL). Separately, 1,1-dimethylethyl 5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 1, 1.05 g, 3.60 mmol), N,N-dimethyl-4-pyridinamine (DMAP) (20 mg) and N,N-diisopropylethylamine (DIPEA) (1.31 ml, 7.50 mmol) were dissolved in DMF (10 mL). 5 mL of the first DMF solution was added to the second solution, and the yellow solution stirred at room temperature for 1 h and then at 95° C. for 18 h. The reaction was concentrated in vacuo then partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (50 mL). The organics were washed with saturated aqueous NaHCO3 (50 mL), then the combined aqueous extracted with DCM (20 mL). The combined organics were concentrated in vacuo to give a crude brown oil. Flash chromatography (gradient [0.5-4%] MeOH in DCM) and concentration in vacuo gave the title compound as a pale yellow solid (512 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 8.42 (1H, d), 8.34 (1H, dd), 7.96 (1H, d), 7.34 (1H, t), 7.29 (1H, d), 7.13 (1H, d), 4.80 (1H, sept), 4.67 (2H, s), 3.68 (2H, t), 3.24 (2H, t), 1.51 (9H, s), 1.48 (6H, d); m/z (ES) 361 [M+H-100]+.

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionredissolved in dry DMF (6 mL)
  3. stirringthe yellow solution stirred at room temperature for 1 h
  4. waitat 95° C. for 18 h
  5. concentrationThe reaction was concentrated in vacuo
  6. customthen partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (50 mL)
  7. washThe organics were washed with saturated aqueous NaHCO3 (50 mL)
  8. extractionthe combined aqueous extracted with DCM (20 mL)
  9. concentrationThe combined organics were concentrated in vacuo
  10. customto give a crude brown oil
  11. concentrationFlash chromatography (gradient [0.5-4%] MeOH in DCM) and concentration in vacuo

Sources & evidence

ORD record
ord-fc02a96407ad415ca817668dcddf7299
Source dataset
uspto-grants-2012_10
Patent number
US08278324B2

Reaction notes

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