1-N-Boc-4-Piperidinecarboxylic acid methyl ester → 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester

HRID 657282Notes

Reaction equation

HRID 657282 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=2)[N:37]=[CH:36][N:35]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:34]2[C:43]3[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]

Participants

5

Reactant 3

HCID 3928701-N-Boc-4-Piperidinecarboxylic acid methyl esterHCID 210882784-Chloro-6,7-difluoroquinazolineHCID 23714775LiHMDS tetrahydrofuran

Product 1

HCID 595517644-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl esterYield 37%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.27 g, 5.23 mmol) in dry THF (2 mL) was added dropwise over 2 minutes with stirring to 1.01M LiHMDS/THF (5.75 mL, 5.81 mmol) at −78° C. under argon. After 5 min at −78° C., the cold bath was removed and the reaction was allowed to stir at “rt” for 30 min. A portion of this enolate solution (5.1 mL, ˜3 mmol enolate) was added dropwise over 2-3 min to a stirred homogeneous solution of 4-chloro-6,7-difluoroquinazoline (600 mg, 2.99 mmol) in dry THF (3 mL) at 0° C. under argon. The reaction was stirred for 30 min at 0° C., and was then quenched with 1M NaH2PO4 (50 mL) and extracted with EtOAc (1×50 mL). The organic layer was washed with 4M NaCl (1×50 mL), dried (Na2SO4), and concentrated. The residue was purified with silica flash chromatography (3:1 hexanes/EtOAc) to afford the title compound as a yellow oil (451 mg, 37%). LC/MS (ESI): calcd mass 407.2, found 408.2 (MH)+.

Workup

  1. customthe cold bath was removed
  2. stirringThe reaction was stirred for 30 min at 0° C.
  3. customwas then quenched with 1M NaH2PO4 (50 mL)
  4. extractionextracted with EtOAc (1×50 mL)
  5. washThe organic layer was washed with 4M NaCl (1×50 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe residue was purified with silica flash chromatography (3:1 hexanes/EtOAc)

Sources & evidence

ORD record
ord-ce82453024564e358aa71fa69b6c5763
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

Loading…