Chlorosuccinimide → 3-{4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester

HRID 1520792Notes

Reaction equation

HRID 1520792 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:21])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:19][OH:20])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:30][C:31]1[CH:32]=[C:33]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:44][C:39]([C:33]4[CH:34]=[C:35]([Cl:38])[C:36]([F:37])=[C:31]([Cl:30])[CH:32]=4)([C:40]([F:43])([F:42])[F:41])[O:20][N:19]=3)=[CH:14][CH:13]=2)([F:21])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 31398ChlorosuccinimideHCID 516892Sodium BicarbonateHCID 755300231-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanoneHCID 76661477Tert-butyl 3-fluoro-3-(4-((hydroxyimino)methyl)phenyl)azetidine-1-carboxylate

Product 1

HCID 900139003-{4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl esterYield 39.32%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
55 °C

Procedure

To a stirred solution of 3-fluoro-3-[4-(hydroxyimino-methyl)-phenyl]-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.7 mmol, 1 eq) in DMF (6.5 mL) was added N-chloro succinimide (0.227 g, 1.7 mmol, 1 eq). Reaction mixture was stirred at 55° C. for 1 hour. After 1 hour (chloro intermediate formation), 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (0.45 g, 1.73 mmol, 1.02 eq) was added followed by addition of sodium bicarbonate (0.146 g, 1.74 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 Na2SO4and concentrated under reduced pressure to get brown thick oil (0.6 g, Crude). Crude 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 (0.37 g, 39.32%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.16-4.24 (m, 2H), 4.38-4.47 (m, 2H), 7.59 (d, J=8.44 Hz, 2H), 7.66 (d, J=5.88 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 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. customdried over anhydrous Na2SO4and
  10. concentrationconcentrated under reduced pressure
  11. customto get brown thick oil (0.6 g, Crude)
  12. customCrude was purified by Combiflash
  13. washDesired compound was eluted in 25% ethyl acetate in hexane

Sources & evidence

ORD record
ord-8d03097a21114e05b003473ff25e5ceb
Source dataset
uspto-grants-2015_07
Patent number
US09073912B2

Reaction notes

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