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

HRID 2362415Notes

Reaction equation

HRID 2362415 reaction equation
[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

Participants

7

Reactant 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

Product 1

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

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

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)+.

Workup

  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%)

Sources & evidence

ORD record
ord-0250011c2abc48b98358a8b4897fdec6
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

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