Trifluoroacetic acid → Carbon Dioxide

HRID 1501996Notes

Reaction equation

HRID 1501996 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:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])(O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[C:6](=[O:7])=[O:5].[C:26]([C:21]1[C:20]([CH3:28])=[C:19]([C@H:13]2[O:12][CH2:11][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:17][CH2:16][N:15]3[CH2:14]2)[CH:24]=[CH:23][C:22]=1[F:25])#[N:27]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 90495Di-tert-butyl dicarbonateHCID 86727050(3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester

Product 2

HCID 280Carbon DioxideHCID 71273580tert-butyl(3R,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A three-necked, round-bottomed flask equipped with a nitrogen inlet adapter, thermocouple, and a septum was charged with (3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (330 g, 840 mmol), TFA (1.65 L, 21 mol), and 3300 mL of DCM. Et3SiH (292 g, 2.52 mol, 3 equiv) was added in one portion and the reaction mixture stirred at room temperature for 24 h. The reaction mixture was concentrated and azeotroped with toluene (100 mL) to remove the TFA. The resulting material was dissolved in DCM (1.7 L) and carefully charged with 2.5 M Na2CO3 (pH should be basic). Boc2O (218 g, 1.2 equiv) was added in one portion and the reaction mixture was stirred at room temperature for 2 h. The organic layer was separated, concentrated, and purified via column chromatography (0-30% acetone-hexanes) to give a mixture of product cis/trans isomers. Chiral SFC purification (Berger MultiGram™ SFC, Mettler Toledo Co, LTD, AD 250 mm*50 mm, 5 um column, A: supercritical CO2, B: methanol, A:B=85:15 at 150 mL/min) afforded the major trans diastereomer 17A as well as the cis diastereomer 17B.

Workup

  1. customA three-necked, round-bottomed flask equipped with a nitrogen inlet adapter
  2. concentrationThe reaction mixture was concentrated
  3. customazeotroped with toluene (100 mL)
  4. customto remove the TFA
  5. dissolutionThe resulting material was dissolved in DCM (1.7 L)
  6. additioncarefully charged with 2.5 M Na2CO3 (pH should be basic)
  7. stirringthe reaction mixture was stirred at room temperature for 2 h
  8. customThe organic layer was separated
  9. concentrationconcentrated
  10. custompurified via column chromatography (0-30% acetone-hexanes)
  11. customto give
  12. additiona mixture of product cis/trans isomers
  13. customChiral SFC purification (Berger MultiGram™ SFC, Mettler Toledo Co, LTD, AD 250 mm*50 mm, 5 um column

Sources & evidence

ORD record
ord-6c7bccf25aed4b0986288fd459c3086c
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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