Triethylamine → [(S)-1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a, 5-diazaphenalen-9-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

HRID 10333Notes

Reaction equation

HRID 10333 reaction equation
[NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 1514396(3S)-(-)-3-(tert-Butoxycarbonylamino)pyrrolidineHCID 219788755-Amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione

Product 1

HCID 69073124[(S)-1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a, 5-diazaphenalen-9-yl)pyrrolidin-3-yl]carbamic acid tert-butyl esterYield 104.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of 0.2 g (0.75 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.58 g (2.0 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.5 g (0.5 mmol) of triethylamine and 20 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane-water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.34 g of the title compound, mp 114–116° C.

Workup

  1. temperatureat reflux for 18 hours
  2. customThe solvent is removed in vacuo
  3. customthe residue is partitioned between dichloromethane-water
  4. washThe organic layer is washed with water
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue is chromatographed over flash grade silica gel (230–400 mesh)
  8. washeluting with dichloromethane/ethanol (95:5)

Sources & evidence

ORD record
ord-e85e2ebb798446ffac97f400cdc25983
Source dataset
uspto-grants-2006_08
Patent number
US07094780B1

Reaction notes

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