Hydrochloric Acid → (4R,5R)-4-(5-Bromo-2-fluoropyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one

HRID 2362415노트

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HRID 2362415 반응식
[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:20][C:21](=[O:27])[O:22]C(C)(C)C)[C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])O)[C:5]([F:8])=[N:6][CH:7]=1.Cl.C(N(CC)C(C)C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[O:27][C:21](=[O:22])[NH:20]2)[C:5]([F:8])=[N:6][CH:7]=1

참가 물질

7

반응물 4

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 521913N,N-Diethyl-2-propanamineHCID 69281853tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate

생성물 1

HCID 69082811(4R,5R)-4-(5-Bromo-2-fluoropyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매

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온도
0 °C

실험 절차

To a solution of optically-enriched tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (380 mg, 0.850 mmol) in dichloromethane (6 mL) at room temperature was added hydrochloric acid (4M in dioxane, 10 mL, 40.0 mmol). The resulting solution was placed in a 45° C. bath. After 20 min, the reaction was concentrated. The resulting viscous oil was dissolved in and reconcentrated from tetrahydrofuran (3×) to give a white solid. The resulting residue was suspended in tetrahydrofuran (15 mL), and treated with diethylisopropylamine (0.297 mL, 1.70 mmol). After stirring briefly, the mixture was cooled to 0° C. and treated with carbonyldiimidazole (207 mg, 1.27 mmol) as a solid in one portion. The ice bath was removed and stirring continued for 1.5 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The material was purified by column chromatography (EtOAc/Hex) to give the product as a mixture of regioisomers. The material was re-purified by chiral prep HPLC (Chiralcel OJ, 30% EtOH/heptane/0.1% DEA) to afford 88 mg (25%). 1H NMR (CDCl3) δ: 8.33 (dd, J=2.3, 1.4 Hz, 1H), 8.11 (dd, J=8.2, 2.1 Hz, 1H), 7.21-7.27 (m, 1H), 7.09-7.17 (m, 2H), 6.48 (br. s., 1H), 5.58 (d, J=5.8 Hz, 1H), 5.04 (d, J=5.5 Hz, 1H). 19F NMR (CDCl3) δ: −74.27 (br. s., 1F), −116.97 (d, J=17.3 Hz, 1F), −123.78-123.41 (m, 1F). Mass spec.: 373.0 (MH)+.

후처리

  1. customwas placed in a 45° C.
  2. concentrationthe reaction was concentrated
  3. dissolutionThe resulting viscous oil was dissolved in and
  4. customto give a white solid
  5. customThe ice bath was removed
  6. stirringstirring
  7. waitcontinued for 1.5 h
  8. customThe reaction was quenched by addition of 2M ammonia in methanol
  9. concentrationconcentrated
  10. customThe material was purified by column chromatography (EtOAc/Hex)
  11. customto give the product
  12. additionas a mixture of regioisomers
  13. customThe material was re-purified by chiral prep HPLC (Chiralcel OJ, 30% EtOH/heptane/0.1% DEA)
  14. customto afford 88 mg (25%)

출처 및 근거

ORD 기록
ord-0250011c2abc48b98358a8b4897fdec6
출처 데이터셋
uspto-grants-2014_04
특허 번호
US08691821B2

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