1,2-Dichloroethane → 2-Isopropoxy-5-(3-(3-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

HRID 1053782Notes

Reaction equation

HRID 1053782 reaction equation
C(C1C=C(C=CC=1OC(C)C)C(O)=O)#N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.ONC(=N)C1C=CN=CC=1C.[C:41]([C:43]1[CH:44]=[C:45]([CH:59]=[CH:60][C:61]=1[O:62][CH:63]([CH3:65])[CH3:64])[C:46]([O:48][NH:49][C:50](=[NH:58])[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][C:52]=1[CH3:57])=O)#[N:42].Cl>CN(C=O)C.CCOCC>[CH:63]([O:62][C:61]1[CH:60]=[CH:59][C:45]([C:46]2[O:48][N:49]=[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][C:52]=3[CH3:57])[N:58]=2)=[CH:44][C:43]=1[C:41]#[N:42])([CH3:65])[CH3:64]

Participants

9

Reactant 6

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 757711-HydroxybenzotriazoleHCID 21956832RP-101124HCID 178430466HCID 178430466, compoundHCID 178430467HCID 178430467, compound

Product 1

HCID 583550152-Isopropoxy-5-(3-(3-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrileYield 45%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

Prepared using General Procedure 2. To a solution of 3-cyano-4-isopropoxybenzoic acid (0.122 g, 0.60 mmol) in DMF (1.5 mL) was added HOBt (0.132 g, 0.86 mmol) and EDC (0.165 g, 0.86 mmol) at room temperature. The reaction was stirred for 0.5 h until the complete formation of the HOBt-acid complex. N-hydroxy-3-methylisonicotinimidamide INT-69 (0.100 g, 0.66 mmol) was added and the mixture was stirred at room temperature for 0.5 h until formation of the intermediate N-(3-cyano-4-isopropoxybenzoyloxy)-3-methylisonicotinimidamide was observed. The reaction mixture was then heated at 80° C. for 4 h. Upon cooling, the mixture was extracted with DCM and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to produce a brown oil. The crude product recrystallized from MeOH (3 mL) and the resulting crystals were filtered and washed with cold MeOH to yield product as a white crystalline solid. To the product was added Et2O (0.5 mL) followed by 2N HCl in Et2O (0.6 mL). The mixture was stirred at room temperature for 10 minutes then dried under nitrogen and subsequently under vacuum to afford 0.087 g (45%) of 2-isopropoxy-5-(3-(3-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 70 as the HCl salt. LCMS-ESI (m/z) calculated for C18H16N4O2: 320.3; found 321.1 [M+H]+, tR=8.82 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=17.5, 2H), 8.70 (d, J=5.7, 1H), 8.44 (d, J=2.2, 1H), 8.36 (dd, J=8.9, 2.2, 1H), 7.18 (d, J=9.1, 1H), 4.83 (dt, J=12.2, 6.1, 1H), 2.95 (s, 3H), 1.49 (d, J=6.1, 6H). 13C NMR (101 MHz, DMSO) δ 173.90, 166.58, 162.81, 147.11, 142.99, 137.55, 135.01, 134.79, 134.06, 125.00, 115.42, 115.17, 115.00, 102.57, 72.66, 21.48, 18.69.

Workup

  1. customPrepared
  2. addition(0.100 g, 0.66 mmol) was added
  3. temperatureUpon cooling
  4. extractionthe mixture was extracted with DCM and brine
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customto produce a brown oil
  9. customThe crude product recrystallized from MeOH (3 mL)
  10. filtrationthe resulting crystals were filtered
  11. washwashed with cold MeOH
  12. customto yield product as a white crystalline solid
  13. stirringThe mixture was stirred at room temperature for 10 minutes
  14. customthen dried under nitrogen and subsequently under vacuum

Sources & evidence

ORD record
ord-5efa52bfd1c44236a5fd6262ee66bf4b
Source dataset
uspto-grants-2016_07
Patent number
US09394264B2

Reaction notes

Loading…