Diisopropylethylamine → tris(1,1-dimethylethyl) 2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate

HRID 1366563Notes

Reaction equation

HRID 1366563 reaction equation
Cl.Cl.[CH2:3]1[C@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][O:4]1.[CH3:13][C:14]([O:17][C:18]([N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:21]([C:29]1[C:34]([F:35])=[C:33](Cl)[N:32]=[C:31]([Cl:37])[N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:16][C:14]([O:17][C:18]([N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:21]([C:29]1[C:34]([F:35])=[C:33]([N:10]2[CH2:11][CH2:12][N:7]3[C@@H:8]([CH2:3][O:4][CH2:5][CH2:6]3)[CH2:9]2)[N:32]=[C:31]([Cl:37])[N:30]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:19])([CH3:13])[CH3:15]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 58000755Tris(1,1-dimethylethyl) 2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylateHCID 66936480(R)-Octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride

Product 1

HCID 86636987tris(1,1-dimethylethyl) 2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylateYield 90.2%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of crude (9aR)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (1.7185 g, 7.99 mmol) in DMF (40 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (3.97 g, 7.98 mmol) and N,N-diisopropylethylamine (4.60 mL, 26.41 mmol). The solution was stirred overnight and then diluted with Et2O (200 mL). The mixture was washed with water (2×100 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (100 mL). The combined organic phase was washed with a fresh portion of water (50 mL), and then dried over anhydrous Na2SO4. The mixture was filtered, concentrated in vacuo, and the residue was dissolved in DCM (200 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the solution was concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to afford tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (4.34 g, 90%) as a white foam. LCMS: (M+H)+: 603.3.

Workup

  1. washThe mixture was washed with water (2×100 mL)
  2. extractionthe combined aqueous phase was extracted with a fresh portion of Et2O (100 mL)
  3. washThe combined organic phase was washed with a fresh portion of water (50 mL)
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationThe mixture was filtered
  6. concentrationconcentrated in vacuo
  7. dissolutionthe residue was dissolved in DCM (200 mL)
  8. dry with materialdried over anhydrous Na2SO4
  9. filtrationThe mixture was filtered
  10. concentrationthe solution was concentrated in vacuo
  11. customThe residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N)

Sources & evidence

ORD record
ord-ca12ed211d45448db72fc3c86705357b
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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