Hydrochloric Acid → tert-Butyl 3-methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-1,3-dicarboxylate

HRID 255294Notes

Reaction equation

HRID 255294 reaction equation
[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]1[C:37]([O:39][CH3:40])=[O:38])(=O)=O.Cl>CN(C)C=O.C(OCC)(=O)C.O>[C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[N:7]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH:25]3[C:37]([O:39][CH3:40])=[O:38])[C:6]=2[CH:8]=1)#[N:13]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 106548133-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile2×HCID 866525391-Tert-butyl 3-methyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1,3-dicarboxylate

Product 1

HCID 66773991tert-Butyl 3-methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-1,3-dicarboxylateYield 64%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent3×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (265 mg, 1.53 mmol) in dry dimethylformamide (DMF) (5 mL) was treated at 0° C. with sodium hydride (105 mg, 60% in oil, 2.63 mmol) and then stirred for 30 minutes at room temperature. A solution of 1-tert-butyl 3-methyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1,3-dicarboxylate in DMF (Intermediate 132, 0.31 mmol/mL, 5 mL, 1.53 mmol) was then added and the resulting mixture was stirred at room temperature for 96 hours. The reaction was diluted with ethyl acetate and water. The aqueous layer was adjusted to pH3 with 1N HCl. The layers were separated. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed four times with water, dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel with (10-35%) acetone in hexanes gave 445 mg (64%) of the product as a white semi-solid (as a mixture of diastereomers).

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 96 hours
  2. customThe layers were separated
  3. extractionThe aqueous phase was extracted once with ethyl acetate
  4. washThe combined organic phases were washed four times with water
  5. dry with materialdried over magnesium sulfate
  6. customevaporated at reduced pressure

Sources & evidence

ORD record
ord-789919d950fa41989c8f52cf9f1eb5cb
Source dataset
uspto-grants-2011_01
Patent number
US07875715B2

Reaction notes

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