4-Acetylpyridine → 4-(3,5-Dioxo-5-pyridin-4-ylpentyl)piperidine-1-carboxylic acid tert-butyl ester

HRID 221352Notes

Reaction equation

HRID 221352 reaction equation
C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)(=[O:33])[CH3:32].[Li+].CC([N-]C(C)C)C>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.CCOC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][C:28](=[O:30])[CH2:32][C:31](=[O:33])[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]

Participants

8

Reactant 4

HCID 142824-Acetylpyridine2×HCID 682631,1'-CarbonyldiimidazoleHCID 15125403-(1-((Tert-butoxy)carbonyl)piperidin-4-yl)propanoic acidHCID 2724682Lithium diisopropylamide

Product 1

HCID 579544124-(3,5-Dioxo-5-pyridin-4-ylpentyl)piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 22742125Tetrahydrofuran heptane ethylbenzolSolvent

Conditions

Temperature
-78 °C

Procedure

CDI (0.63 g, 3.9 mmol) was added to a solution of 4-(2-carboxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.9 mmol) in anhydrous THF (7.6 ml), then the mixture was stirred for 45 min. In a separate vessel, 4-acetylpyridine (0.49 g, 4.1 mmol) was added slowly to a stirred solution of LDA (2.04 ml of a 2.0M solution in heptane-THF-ethylbenzene, 4.1 mmol) in anhydrous THF (15.3 ml) at −78° C. After 45 min, the solution of the acylimidazole was added slowly via cannula to the lithiated 4-acetylpyridine while maintaining the temperature at −78° C. The reaction was allowed to warm to rt over 2 h, before being diluted with EtOAc (150 ml). The solution was washed with 10% aqueous citric acid (2×15 ml), saturated aqueous NaHCO3 (2×15 ml), and brine (20 ml), before being dried (MgSO4). Filtration, concentration, and purification by RP-HPLC afforded the title compound: m/z (ES+)=261.2 [M-Boc+H]+.

Workup

  1. waitAfter 45 min
  2. temperatureto warm to rt over 2 h
  3. washThe solution was washed with 10% aqueous citric acid (2×15 ml), saturated aqueous NaHCO3 (2×15 ml), and brine (20 ml)
  4. dry with materialbefore being dried (MgSO4)
  5. filtrationFiltration, concentration, and purification by RP-HPLC

Sources & evidence

ORD record
ord-8833dd7c913d423a984ff547c2ebb809
Source dataset
uspto-grants-2012_06
Patent number
US08207147B2

Reaction notes

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