(S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester → tert-Butyl (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HRID 1501995Notes

Reaction equation

HRID 1501995 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]#[N:26])[C:19]=3[CH3:27])=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C([O-])([O-])=O.[Ca+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C@@H:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]#[N:26])[C:19]=3[CH3:27])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 1

HCID 71271720(S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester

Product 1

HCID 71273581tert-Butyl (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Reagents, catalysts & solvents 2

HCID 12000666Calcium Palladium CarbonateCatalystHCID 887MethanolSolvent

Conditions

Temperature
40 °C

Procedure

To a 1 L 3 neck RB was charged 5% Pd/CaCO3 (10.0 g., 4.02 mmol), MeOH (405 mL), and (S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (15.0 g., 40.2 mmol). The solution was sparged with N2 for 5 min, then put under an atmosphere of hydrogen with balloon pressure and warmed to 40° C. with stirring. After 38 h, HPLC shows full conversion of the olefin, with a 5:1 cis:trans ratio of diastereomers. The suspension was cooled to room temperature, filtered through a pad of Celite and concentrated. The residue was purified via column chromatography (60-100% EtOAc/Hexanes, linear gradient), to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 8.18 (m, 1H), 7.03 (t, J=7.9 Hz, 1H), 4.87 (s, 1H), 4.10-3.60 (m, 2H), 3.56 (d, J=10.5 Hz, 1H), 3.25-2.88 (m, 3H), 2.80-2.35 (m, 8H), 1.50 (s, 9H).

Workup

  1. customThe solution was sparged with N2 for 5 min
  2. temperatureThe suspension was cooled to room temperature
  3. filtrationfiltered through a pad of Celite
  4. concentrationconcentrated
  5. customThe residue was purified via column chromatography (60-100% EtOAc/Hexanes, linear gradient)

Sources & evidence

ORD record
ord-21a28216a54e490b98e08d8c5c6b99b0
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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