Diisopropylethylamine → (3S,9aR)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester

HRID 1502001Notes

Reaction equation

HRID 1502001 reaction equation
C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[C:15]([CH3:23])=[C:16]([C:19]([F:22])=[CH:20][CH:21]=1)[C:17]#[N:18])=[O:13].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:37][OH:38])[CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CCOC(C)=O>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][N:34]2[C@@H:33]([CH2:37][O:38][C@:12]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[C:16]([C:17]#[N:18])[C:15]=3[CH3:23])([OH:13])[CH2:11]2)[CH2:32]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 24820286tert-Butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylateHCID 867270493-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile

Product 1

HCID 117690253(3S,9aR)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Diisopropylethylamine (156 mL, 894 mmol) was added to a stirred, room temperature mixture of 3-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile (176 g, 688 mmol) and (R)-4-N-Boc-2-hydroxymethyl-piperazine (149 g, 688 mmol) in THF (3500 mL) and the mixture was stirred at room temperature for 18 h. The reaction was diluted with 3 L EtOAc, washed 2× with 1500 mL 10% w/w NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (40-80% EtOAc/Hexanes, linear gradient), to provide the title compound.

Workup

  1. washwashed 2× with 1500 mL 10% w/w NaHCO3 aqueous solution
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by column chromatography on silica gel (40-80% EtOAc/Hexanes, linear gradient)

Sources & evidence

ORD record
ord-ff26bbb95ed4417d9ba7c5cae8ee91bb
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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