4-Methoxypiperidine → N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-methoxypiperidine-1-carboxamide

HRID 930328Notes

Reaction equation

HRID 930328 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[CH3:42][O:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>ClCCl>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([N:47]3[CH2:48][CH2:49][CH:44]([O:43][CH3:42])[CH2:45][CH2:46]3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:28])([CH3:27])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 776664-MethoxypiperidineHCID 821294-Nitrophenyl chloroformateHCID 86732123N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Product 1

HCID 86732157N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-methoxypiperidine-1-carboxamideYield 61.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a cooled (0° C.) solution of N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (4l, 0.200 g, 0.506 mmol) in dichloromethane (4 mL) was added 4-nitrophenyl chloroformate (0.111 g, 0.551 mmol) as a solid. After 10 min the reaction was allowed to warm to room temperature. After 3 h 4-methoxy-piperidine (0.100 mL, 1.036 mmol) was added dropwise via syringe and the reaction was stirred overnight. The reaction was evaporated onto silica gel and purified by flash chromatography (Isco, 25 g) eluting with (25% EtOH/EtOAc):hexanes (0:1→2:3) to give N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-methoxypiperidine-1-carboxamide (166 mg. 61% yield) of a clear, colorless tar. MS m/z=537 [M+H]+. Calculated for C26H28F4N4O4: 536

Workup

  1. customThe reaction was evaporated onto silica gel
  2. custompurified by flash chromatography (Isco, 25 g)
  3. washeluting with (25% EtOH/EtOAc)

Sources & evidence

ORD record
ord-a419775cb47b47b9a22e3166984f357a
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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