Water → 1,1-Dimethylethyl 4-[[(4-amino-5-chloro-2-methoxy-benzoyl)oxy]methyl]-1-piperidine-carboxylate

HRID 392064Notes

Reaction equation

HRID 392064 reaction equation
[H-].[Na+].[C:3]([N:10]1[CH:14]=[CH:13]N=[CH:11]1)(N1C=CN=C1)=[O:4].[NH2:15][C:16]1[C:24]([Cl:25])=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=1.[OH2:28]>C1COCC1.C(#N)C>[NH2:15][C:16]1[C:24]([Cl:25])=[CH:23][C:19]([C:20]([O:22][CH2:17][CH:16]2[CH2:24][CH2:11][N:10]([C:3]([O:4][C:19]([CH3:23])([CH3:20])[CH3:18])=[O:28])[CH2:14][CH2:13]2)=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=1

Participants

7

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 816264-Amino-5-chloro-2-methoxybenzoic acid

Product 1

HCID 226627611,1-Dimethylethyl 4-[[(4-amino-5-chloro-2-methoxy-benzoyl)oxy]methyl]-1-piperidine-carboxylateYield 42%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Procedure

Sodium hydride (5.8 g) was added to a solution of 1,1-dimethylethyl 1-piperidine-4-methanolcarboxylate (25 g) in THF (800 ml). The mixture was stirred and refluxed for 3 hours (H2 gas evolution), then cooled (solution I). 1,1′-Carbonylbis-1H-imidazole (19.5 g) was added to a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (24 g) in ACN (800 ml), stirred at room temperature. This mixture was stirred for 2 hours at room temperature (solution II). At room temperature, solution (II) was poured out into solution (I) and the reaction mixture was stirred for 20 hours at room temperature. Water (±10 ml) was added. The organic solvent was evaporated. The residue was partitioned between DCM and H2O. The insoluble solid was filtered off. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from ACN (0° C.). The precipitate was filtered off and dried, filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried (vacuum; 50° C.), yielding 20 g (42%) 1,1-dimethylethyl 4-[[(4-amino-5-chloro-2-methoxy-benzoyl)oxy]methyl]-1-piperidine-carboxylate (intermediate 10).

Workup

  1. temperaturerefluxed for 3 hours (H2 gas evolution)
  2. stirringstirred at room temperature
  3. stirringthe reaction mixture was stirred for 20 hours at room temperature
  4. customThe organic solvent was evaporated
  5. customThe residue was partitioned between DCM and H2O
  6. filtrationThe insoluble solid was filtered off
  7. customThe organic layer was separated
  8. customdried
  9. filtrationfiltered
  10. customthe solvent was evaporated
  11. customThe residue was crystallized from ACN (0° C.)
  12. filtrationThe precipitate was filtered off
  13. customdried
  14. filtrationfiltered
  15. customthe solvent was evaporated
  16. customThe residue was crystallized from ACN
  17. filtrationThe precipitate was filtered off
  18. customdried (vacuum; 50° C.)

Sources & evidence

ORD record
ord-d28a384793b446a5a3887aa54f13922d
Source dataset
uspto-grants-2004_10
Patent number
US06800628B2

Reaction notes

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