Diisopropylethylamine → Racemic tris(1,1-dimethylethyl) 2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate

HRID 1366547Notes

Reaction equation

HRID 1366547 reaction equation
Cl.Cl.[CH3:3][N:4]([CH3:11])[C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2.[Cl:12][C:13]1[N:18]=[C:17]([N:19]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:16]([F:42])=[C:15](Cl)[N:14]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:27][C:24]([O:23][C:21]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:19]([C:17]1[C:16]([F:42])=[C:15]([N:7]2[CH2:8][CH:9]3[C:5]([N:4]([CH3:11])[CH3:3])([CH2:10]3)[CH2:6]2)[N:14]=[C:13]([Cl:12])[N:18]=1)[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:22])([CH3:25])[CH3:26]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 58000755Tris(1,1-dimethylethyl) 2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylateHCID 66936286n,n-Dimethyl-3-azabicyclo[3.1.0]hexan-1-amine dihydrochloride

Product 1

HCID 87210351Racemic tris(1,1-dimethylethyl) 2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylateYield 84.5%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of racemic N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine dihydrochloride (assumed 0.5339 g, 2.681 mmol) in DMF (13 mL) was added tris(1,1-dimethylethyl) 2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.33 g, 2.674 mmol) and N,N-diisopropylethylamine (1.87 mL, 10.74 mmol). The solution was stirred overnight and then diluted with Et2O (100 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). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to afford racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (1.3261 g, 84%) as a white foam. LCMS: (M+H)+: 587.3.

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. dry with materialThe combined organic phase was dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N)

Sources & evidence

ORD record
ord-8e21a69a16954c45bbbc9eb61d520e5f
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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