Hydrochloric Acid → HCID 86673447, compound

HRID 2362425Notes

Reaction equation

HRID 2362425 reaction equation
[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:25])[O:20]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])O)[CH:5]=[CH:4][CH:3]=1.Cl.C(N(C(C)C)CC)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[O:25][C:19](=[O:20])[NH:18]2)[CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 86673446HCID 86673446, compound

Product 1

HCID 86673447HCID 86673447, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
45 °C

Procedure

To a solution of optically-enriched tert-butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-(2-fluorophenyl)-2-hydroxyethylcarbamate (375 mg, 0.912 mmol) in dichloromethane (4 mL) at room temperature was added hydrogen chloride (4M in dioxane, 3 mL, 12 mmol). After 15 min at room temperature, the reaction was warmed to 45° C. and held at that temperature for 15 min. The reaction was cooled and concentrated. The reaction was concentrated twice more from tetrahydrofuran. The resulting residue was suspended in tetrahydrofuran (10 mL), cooled to 0° C., and treated with diisopropylethylamine (0.319 mL, 1.82 mmol) and carbonyldiimidazole (222 mg, 1.368 mmol). After 5 min, the ice bath was removed and stirring continued for 3 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was suspended in dichloromethane, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% EtOAc/Hex) gave 75 mg. 1H NMR (CDCl3) δ: 7.60-7.68 (m, 1H), 7.46-7.56 (m, 2H), 7.35-7.45 (m, 2H), 7.24 (td, J=7.7, 1.0 Hz, 1H), 7.12 (ddd, J=10.3, 8.3, 1.0 Hz, 1H), 7.03 (s, 1H), 5.80 (d, J=5.3 Hz, 1H), 4.93 (d, J=5.3 Hz, 1H). 13C NMR (CDCl3) δ: 160.9, 158.9, 158.4, 142.0, 139.2, 130.5, 127.8, 127.2, 125.0, 124.3, 119.6, 115.6, 78.5, 63.1. 19F NMR (CDCl3) δ: −121.48-113.54 (m, 1F). Mass spec.: 337.1 (MH)+.

Workup

  1. waitheld at that temperature for 15 min
  2. temperatureThe reaction was cooled
  3. concentrationconcentrated
  4. concentrationThe reaction was concentrated twice more from tetrahydrofuran
  5. temperaturecooled to 0° C.
  6. waitAfter 5 min
  7. customthe ice bath was removed
  8. waitcontinued for 3 h
  9. customThe reaction was quenched by addition of 2M ammonia in methanol
  10. concentrationconcentrated
  11. additiondiluted with ethyl acetate
  12. washwashed with brine
  13. dry with materialdried over magnesium sulfate
  14. concentrationconcentrated
  15. customColumn chromatography (25%→50% EtOAc/Hex) gave 75 mg

Sources & evidence

ORD record
ord-5314fc2907d3425680ea3e3452819d67
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

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