2-Methyltetrahydrofuran → 1(3H)-Isobenzofuranone, 6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitro-, (3Z)-

HRID 1617263Notes

Reaction equation

HRID 1617263 reaction equation
CC1CCCO1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][O:13][C:14]2=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1.[CH3:21][N:22]1[C:26]([CH:27]=O)=[N:25][CH:24]=[N:23]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>>[F:7][C:8]1[CH:16]=[C:15]2[C:11](/[C:12](=[CH:27]/[C:26]3[N:22]([CH3:21])[N:23]=[CH:24][N:25]=3)/[O:13][C:14]2=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1

Participants

6

Reactant 5

HCID 73012-MethyltetrahydrofuranHCID 7918Acetic AnhydrideHCID 8471TriethylamineHCID 136242781-methyl-1H-1,2,4-triazole-5-carbaldehydeHCID 575191766-Fluoro-4-nitro-2-benzofuran-1(3H)-one2×

Product 1

HCID 533535091(3H)-Isobenzofuranone, 6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitro-, (3Z)-Yield 75.3%

Conditions

Temperature
90 °C

Procedure

To a 80 L jacketed glass reactor equipped with a chiller, mechanical stirrer, thermocouple, and nitrogen inlet/outlet, at 15-25° C., anhydrous 2-methyl-tetrahydrofuran (22.7 kg), 6-fluoro-4-nitroisobenzofuran-1(3H)-one (2) (2.4 kg, 12.2 mol, 1.00 eq.), and 2-methyl-2H-1,2,4-triazole-3-carbaldehyde (49.6-52.6% concentration in dichloromethane by GC, 3.59-3.38 kg, 16.0 mol, 1.31 eq.) were charged consecutively. Triethylamine (1.50 kg, 14.8 mol, 1.21 eq.) was then charged into the above reaction mixture. The reaction mixture was stirred for another 10 minutes. Acetic anhydride (9.09-9.10 kg, 89.0-89.1 mol, 7.30 eq.) was charged into the above reaction mixture at room temperature for 20-30 minutes. The reaction mixture was heated from ambient to reflux temperatures (85-95° C.) for 80-90 minutes, and the mixture was refluxed for another 70-90 minutes. The reaction mixture was monitored by HPLC, indicating compound (2) was reduced to ≦5%. The resulting slurry was cooled down to 5-15° C. for 150-250 minutes. The slurry was aged at 5-15° C. for another 80-90 minutes. The slurry was filtered, and the wet cake was washed with ethyl acetate (2 L×3). The wet cake was dried under vacuum at 40-50° C. for 8 hours to give 2.65-2.76 kg of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroisobenzofuran-1(3H)-one (3) as a yellow solid (2.66 kg, yield: 75.3%, purity: 98.6-98.8% by HPLC). LC-MS (ESI) m/z: 291 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.94 (s, 3H), 7.15 (s, 1H), 8.10 (s, 1H), 8.40-8.42 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H), 8.58-8.61 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H).

Workup

  1. customequipped with a chiller, mechanical stirrer
  2. temperatureThe reaction mixture was heated from ambient
  3. temperaturethe mixture was refluxed for another 70-90 minutes
  4. temperatureThe resulting slurry was cooled down to 5-15° C. for 150-250 minutes
  5. waitThe slurry was aged at 5-15° C. for another 80-90 minutes
  6. filtrationThe slurry was filtered
  7. washthe wet cake was washed with ethyl acetate (2 L×3)
  8. customThe wet cake was dried under vacuum at 40-50° C. for 8 hours

Sources & evidence

ORD record
ord-5acbe35aafd0458cbf691ed1cbcd65f3
Source dataset
uspto-grants-2014_07
Patent number
US08765945B2

Reaction notes

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