Hydrochloric Acid → 1-{[(9H-fluoren-9-yl)methoxy]carbonyl}-4-methylpiperidine-3-carboxylic acid

HRID 1854328Notes

Reaction equation

HRID 1854328 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.C([O-])(O)=O.[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>O1CCOCC1.O>[CH:36]1[C:35]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]3)=[O:7])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:39]=[CH:38][CH:37]=1

Participants

7

Reactant 4

HCID 313Hydrochloric Acid2×HCID 134122N-(9-Fluorenylmethoxycarbonyloxy)succinimideHCID 516892Sodium BicarbonateHCID 450431571-(tert-Butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid

Product 1

HCID 580102161-{[(9H-fluoren-9-yl)methoxy]carbonyl}-4-methylpiperidine-3-carboxylic acidYield 31.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.50 g, 6.17 mmol, Example #13, Step G) in 1,4-dioxane (10 mL) was added aqueous HCl (4N in 1,4-dioxane (4.62 mL, 18.5 mmol). The reaction mixture was heated at about 60° C. for about 16 h before being allowed to cool to ambient temperature. To the mixture was added NaHCO3 (2.07 g, 24.7 mmol) and water (10.0 mL) followed by (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (4.16 g, 12.3 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was acidified to about pH 1 with aqueous 1N HCl and was extracted with EtOAc (75 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g column) eluting with a gradient of 1-5% MeOH in DCM to give 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylic acid (0.72 g, 31%) as a clear oil: LC/MS (Table 2, Method a) Rt=2.44 min; MS m/z: 366 (M+H)+.

Workup

  1. temperatureto cool to ambient temperature
  2. extractionwas extracted with EtOAc (75 mL)
  3. washThe organic layer was washed with brine (50 mL)
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe product was purified by silica gel chromatography (40 g column)
  8. washeluting with a gradient of 1-5% MeOH in DCM

Sources & evidence

ORD record
ord-c0e2492d7f5b4d8293cf631feb7415e2
Source dataset
uspto-grants-2015_02
Patent number
US08962629B2

Reaction notes

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