Diisopropylethylamine → tris(1,1-dimethylethyl) 2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate

HRID 1366682Notes

Reaction equation

HRID 1366682 reaction equation
Cl.[CH3:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[CH3:9][C:10]([O:13][C:14]([N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:17]([C:25]1[C:30]([F:31])=[C:29](Cl)[N:28]=[C:27]([Cl:33])[N:26]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:12][C:10]([O:13][C:14]([N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:17]([C:25]1[C:30]([F:31])=[C:29]([N:4]2[CH2:5][CH2:6][O:7][CH2:8][C@@H:3]2[CH3:2])[N:28]=[C:27]([Cl:33])[N:26]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:15])([CH3:9])[CH3:11]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 53486469(3S)-3-methylmorpholine hydrochlorideHCID 58000755Tris(1,1-dimethylethyl) 2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate

Product 1

HCID 86637029tris(1,1-dimethylethyl) 2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylateYield 79%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (3S)-3-methylmorpholine hydrochloride (0.2059 g, 1.496 mmol) in DMF (7.5 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.7451 g, 1.498 mmol), and N,N-diisopropylethylamine (0.575 mL, 3.301 mmol). The solution was stirred overnight, and then diluted with Et2O (150 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This Et2O layer was washed with a fresh portion of water (50 mL), and the combined organic phase was diluted with DCM (50 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and azeotroped with EtOAc. The solid was collected by vacuum filtration and washed with hexanes. The supernatant was concentrated in vacuo, and purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N). The desired fractions were concentrated in vacuo, and the resulting solid was collected by vacuum filtration, washed with hexanes, and combined with the first crop of solid to give tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.6610 g, 79%) as a white solid. LCMS: (M+H)+: 562.2.

Workup

  1. washThe mixture was washed with water (2×50 mL)
  2. extractionthe combined aqueous phase was extracted with a fresh portion of Et2O (50 mL)
  3. washThis Et2O layer was washed with a fresh portion of water (50 mL)
  4. additionthe combined organic phase was diluted with DCM (50 mL)
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customazeotroped with EtOAc
  9. filtrationThe solid was collected by vacuum filtration
  10. washwashed with hexanes
  11. concentrationThe supernatant was concentrated in vacuo
  12. custompurified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N)
  13. concentrationThe desired fractions were concentrated in vacuo
  14. filtrationthe resulting solid was collected by vacuum filtration
  15. washwashed with hexanes

Sources & evidence

ORD record
ord-da3ce1630d764954bb0bd07755695c60
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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