Potassium Carbonate → Methyl 2-[4-((2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-3-[(phenylmethyl)oxy]propanoate

HRID 1943143Notes

Reaction equation

HRID 1943143 reaction equation
[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH:27]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH:20]3[CH2:25][CH2:24][N:23]([CH:27]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 11011152Propanoic acid, 2-bromo-3-(phenylmethoxy)-, methyl esterHCID 578154611,1-Dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate

Product 1

HCID 68597436Methyl 2-[4-((2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-3-[(phenylmethyl)oxy]propanoateYield 36.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)4-piperidinylcarbamate (1.087 g, 3.11 mmol) (for a synthesis see WO2004/058144 Example 99(h)), methyl 2-bromo-3-[(phenylmethyl)oxy]propanoate (1.0 g, 3.66 mmol) and potassium carbonate (0.860 g, 6.22 mmol) in DMF (50 ml) was heated to 80° C. and stirred under argon for 2.5 h. The solvents were removed under reduced pressure and the residue treated with saturated aqueous sodium bicarbonate. The aqueous was extracted with DCM (5×100 ml) dried MgSO4, filtered and concentrated under reduced pressure. The crude product was chromatographed, eluting with 0-100% EtOAc/40-60 petroleum ether. Appropriate fractions were combined and evaporated under reduced pressure. The residue was then dissolved in DCM (50 ml) and washed with water (20 ml). The organic layer was separated, dried MgSO4 and evaporated under reduced pressure to afford product (618 mg, 35% yield).

Workup

  1. customThe solvents were removed under reduced pressure
  2. additionthe residue treated with saturated aqueous sodium bicarbonate
  3. extractionThe aqueous was extracted with DCM (5×100 ml) dried MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was chromatographed
  7. washeluting with 0-100% EtOAc/40-60 petroleum ether
  8. customevaporated under reduced pressure
  9. dissolutionThe residue was then dissolved in DCM (50 ml)
  10. washwashed with water (20 ml)
  11. customThe organic layer was separated
  12. customdried MgSO4 and evaporated under reduced pressure

Sources & evidence

ORD record
ord-b616ad3c0df44d30a827f6b96f5b92a3
Source dataset
uspto-grants-2013_03
Patent number
US08389524B2

Reaction notes

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