Diethyl Oxalate → HCID 54692278, compound

HRID 1162826Notes

Reaction equation

HRID 1162826 reaction equation
[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:9]([CH2:20][CH2:21][N:22]([O:24][CH3:25])[CH3:23])[CH2:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:43](OCC)(=[O:49])[C:44](OCC)=[O:45]>CN(C=O)C.CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH:9]([CH2:20][CH2:21][N:22]([O:24][CH3:25])[CH3:23])[N:10]3[C:14](=[O:15])[N:16]([CH:17]([CH3:19])[CH3:18])[C:44](=[O:45])[C:43]([OH:49])=[C:11]3[C:12]2=[O:13])=[CH:26][CH:27]=1

Participants

8

Reactant 4

HCID 7268Diethyl OxalateHCID 8028Tetrahydrofuran2×HCID 2733832Lithium Hexamethyldisilazide2×HCID 86617475HCID 86617475, compound

Product 1

HCID 54692278HCID 54692278, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

4-(4-Fluorobenzyl)-N-isopropyl-2-{2-[methoxy(methyl)amino]ethyl}-5-oxopiperazine-1-carboxamide (777 mg, 2.04 mmol) was azeotroped with anhydrous toluene (10 μL) and dissolved in anhydrous DMF (10 mL). The solution was cooled to 0° C. under inert atmosphere and treated with 1.0 M lithium bis(trimethylsilyl)amide in THF (2.45 mL, 2.45 mmol). After stirring for 10 min, diethyl oxalate (416 μL, 3.06 mmol) was added. The mixture was stirred at 0° C. for an additional 15 min and then allowed to warm to ambient temperature. Following addition of excess 1.0 M lithium bis(trimethylsilyl)amide in THF (7.30 mL, 7.30 mmol), the reaction was stirred at ambient temperature for 18 h. The mixture was treated with MeOH and concentrated in vacuo to give a dark oil. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)] afforded the title compound as tan foam. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (br s, 1H), 7.44-7.41 (m, 2H), 7.24-7.19 (m, 2H), 5.04 (dt, J=6.4, 13.6 Hz, 1H), 4.84 (d, J=14.8 Hz, 1H), 4.72 (br s, 1H), 4.51 (d, J=14.4 Hz, 1H), 3.77 (dd, J=3.6, 13.2 Hz, 1H), 3.43 (d, J=13.6 Hz, 1H), 3.31 (s, 3H), 2.36 (s, 3H), 2.33-2.31 (m, 2H), 1.71-1.62 (m, 1H), 1.51-1.43 (m, 1H), 1.37 (d, J=6.8 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C21H27FN4O5)+ 435.2038. found 435.2038.

Workup

  1. stirringThe mixture was stirred at 0° C. for an additional 15 min
  2. temperatureto warm to ambient temperature
  3. stirringthe reaction was stirred at ambient temperature for 18 h
  4. concentrationconcentrated in vacuo
  5. customto give a dark oil
  6. customPurification by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)]

Sources & evidence

ORD record
ord-6c324a467ca641f3a026f5116e7710d9
Source dataset
uspto-grants-2010_10
Patent number
US07820680B2

Reaction notes

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