Lithium diisopropylamide → HCID 178451148, compound

HRID 2272648Notes

Reaction equation

HRID 2272648 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:21]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:26][CH2:25]1)(=[O:23])[CH3:22]>O1CCCC1.C(OCC)(=O)C.O.[Cl-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]([C:8]2[S:12][C:11]([C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:26][CH2:25]3)([OH:23])[CH3:22])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 867153342-Bromo-6-(thiazol-5-yl)pyridineHCID 178451155HCID 178451155, compound

Product 1

HCID 178451148HCID 178451148, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent2×

Procedure

To a solution of 2-bromo-6-(1,3-thiazol-5-yl)pyridine (457 mg, 1.895 mmol) in tetrahydrofuran (20 mL) at −78° C. was added lithium diisopropyl amide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 1.106 mmol, 1.990 mmol) over three minutes. After 30 minutes, a solution of butyl trans-4-acetylcyclohexanecarboxylate (450 mg, 1.990 mmol) in tetrahydrofuran (3 mL) was added to the reaction mixture. After an additional 70 minutes, a saturated aqueous ammonium chloride solution (10 mL) was added. Then, the reaction mixture was allowed to warm to room temperature before being diluted with ethyl acetate (50 mL), water (2 mL), and saturated aqueous ammonium chloride solution (10 mL). The layers were separated and the organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-20% ethyl acetate/dichloromethane) to give butyl trans-4-{1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexanecarboxylate. MS ESI calc'd. for C21H27BrN2O3S [M+H]+ 467 and 469. found 467 and 469. Two enantiomers were separated by chiral super critical fluid chromatography (Chiral Technology IC-H, 2.1×25 cm, 5 uM, 70/30 ethanol/CO2, Flow Rate: 70 mL/min, 6 min run time, WL: 220 nm) Elution was observed at 3.98 min and 4.76 min. Pooled fractions of each peak were concentrated under reduced pressure.

Workup

  1. waitAfter an additional 70 minutes
  2. customThe layers were separated
  3. washthe organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by chromatography on silica gel (0-20% ethyl acetate/dichloromethane)

Sources & evidence

ORD record
ord-847cb9ce4b0347a983877419569a66c2
Source dataset
uspto-grants-2015_09
Patent number
US09120785B2

Reaction notes

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