Chlorosuccinimide → tert-butyl 5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

HRID 1508319

Reaction equation

HRID 1508319 reaction equation
[OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:33]=[C:34]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH:35]=[C:36]([Cl:39])[C:37]=1[F:38].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:31][C:32]1[CH:33]=[C:34]([C:40]2([C:41]([F:43])([F:44])[F:42])[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[C:9]3([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[O:8][CH2:7]4)[O:45]2)[CH:35]=[C:36]([Cl:39])[C:37]=1[F:38]

Participants

6

Reactant 4

HCID 31398ChlorosuccinimideHCID 516892Sodium BicarbonateHCID 755300231-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanoneHCID 131734382tert-butyl 5'-((hydroxyimino)methyl)-3'H-spiro[azetidine-3,1-isobenzofuran]-1-carboxylate

Product 1

HCID 89994607tert-butyl 5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylateYield 35.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
55 °C

Procedure

To a stirred solution of tert-butyl 5′-((hydroxyimino)methyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 43) (0.5 g, 1.645 mmol, 1 eq) in DMF (6.5 mL) was added NCS (0.218 g, 1.645 mmol, 1 eq). Reaction mixture was stirred at 55° C. for 1 hour under nitrogen atmosphere. After 1 hour (chloro intermediate formation), 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (0.437 g, 1.678 mmol, 1.02 eq) was added followed by addition of sodium bicarbonate (0.140 g, 1.678 mmol, 1.02 eq) at room temperature. Resulting reaction mixture was stirred at 55° C. for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (3×50 mL). Combined organic phase was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.6 g, crude). Crude compound was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as colorless thick oil (0.33 g, impure). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 4.11 (d, J=10.04 Hz, 2H), 4.32 (d, J=9.92 Hz, 2H), 5.15 (s, 2H), 7.56-7.58 (m, 1H), 7.64-7.68 (m, 3H), 7.86 (d, J=8.04 Hz, 1H), 8.02-8.04 (dd, J1=6.12 Hz, J2=0.64 Hz, 1H). LC-MS (m/z): No ionization.

Workup

  1. customReaction mixture
  2. customResulting
  3. customreaction mixture
  4. stirringwas stirred at 55° C. for 3 hours under nitrogen atmosphere
  5. customAfter complete consumption of starting material, reaction mixture
  6. customwas quenched by water (10 mL)
  7. extractionextracted with ethyl acetate (3×50 mL)
  8. washCombined organic phase was washed with brine solution (20 mL)
  9. dry with materialdried over anhydrous Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. customto get brown thick oil (0.6 g, crude)
  12. customCrude compound was purified by Combiflash
  13. washDesired compound was eluted in 25% ethyl acetate in hexane

Sources & evidence

ORD record
ord-ed7e159352d046308b4ea14d039148d0
Source dataset
uspto-grants-2015_12
Patent number
US09221835B2

Linked notes

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