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 1520792

반응식

HRID 1520792 반응식
[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]

참가 물질

6

반응물 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

생성물 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 ester수율 39.32%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
55 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-8d03097a21114e05b003473ff25e5ceb
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09073912B2

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