Lithium diisopropylamide → tert-butyl 4-[[2-[[(2S)-2-bicyclo[2.2.1]heptanyl]amino]-5-methyl-4-oxo-1,3-thiazol-5-yl]methyl]piperidine-1-carboxylate

HRID 852796

Reaction equation

HRID 852796 reaction equation
[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH3:15])[C:12](=[O:14])[N:13]=1.C([N-]C(C)C)(C)C.[Li+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]Br)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:37][CH:34]2[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]2)([CH3:15])[C:12](=[O:14])[N:13]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 15512811tert-Butyl 4-(bromomethyl)piperidine-1-carboxylateHCID 178435106HCID 178435106, compound

Product 1

HCID 178451850tert-butyl 4-[[2-[[(2S)-2-bicyclo[2.2.1]heptanyl]amino]-5-methyl-4-oxo-1,3-thiazol-5-yl]methyl]piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one in anhydrous THF (30 mL) at −78° C. under N2 was added lithium diisopropylamide (Aldrich, 2.0 M in heptane/THF/ethylbenzene, 9.2 mL, 18.4 mmol). After stirring the reaction mixture at −78° C. for 1 h, a solution of 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (Pharma Core, 5.12 g, 18.4 mmol, 4.0 eq) in anhydrous THF (10 mL) was added under N2. The resulting reaction mixture was stirred at −78° C. for 4 h. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for ca. 18 h. Saturated NH4Cl was then added, and the THF was removed in vacuo. The residue was extracted with EtOAc (3×180 mL), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 0-60% EtOAc in hexane) afforded the title compound as an off-white solid (1.42 g). MS (ESI, neg. ion) m/z: 420 (M−H).

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at −78° C. for 4 h
  3. customThe cooling bath was removed
  4. stirringthe reaction mixture was stirred at ambient temperature for ca. 18 h
  5. additionSaturated NH4Cl was then added
  6. customthe THF was removed in vacuo
  7. extractionThe residue was extracted with EtOAc (3×180 mL)
  8. washthe combined organic layers were washed with saturated NaCl
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-9e3ec1b110c449f0874fc311739c9969
Source dataset
uspto-grants-2007_08
Patent number
US07253196B2

Linked notes

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