Diisopropylethylamine → 4-{5-[(6,7-Dichloro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl)methyl]-2-fluorophenyl}-1-methyl-3,5-dioxopiperazin-1-ium trifluoroacetate

HRID 1172803Notes

Reaction equation

HRID 1172803 reaction equation
[CH3:1][N:2]1[CH2:7][C:6](=[O:8])O[C:4](=[O:9])[CH2:3]1.[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13].[Cl:17][C:18]1[N:22]2[C:23]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([NH3+:35])[CH:34]=3)=[CH:24][NH:25][C:26](=[O:27])[C:21]2=[CH:20][C:19]=1[Cl:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O.CC#N>[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13].[Cl:17][C:18]1[N:22]2[C:23]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([N:35]4[C:4](=[O:9])[CH2:3][NH+:2]([CH3:1])[CH2:7][C:6]4=[O:8])[CH:34]=3)=[CH:24][NH:25][C:26](=[O:27])[C:21]2=[CH:20][C:19]=1[Cl:37]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 143203244-Methylmorpholine-2,6-dioneHCID 866334295-[(6,7-Dichloro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl)methyl]-2-fluorobenzenaminium trifluoroacetate

Product 1

HCID 866334344-{5-[(6,7-Dichloro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl)methyl]-2-fluorophenyl}-1-methyl-3,5-dioxopiperazin-1-ium trifluoroacetate

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 6342AcetonitrileSolvent

Procedure

To a solution of 4-methylmorpholine-2,6-dione (1 eq) (see for Ref. WO 03/093261) in toluene (0.06 M) was added N2 (Example 14, step 2). The reaction mixture was refluxed for 2 h and then allowed to stand at RT overnight. The solvent was removed under reduced pressure. The resulting crude was dissolved in DMF (0.2 M) and to the resulting solution were added sequentially TBTU (1.3 eq), DIPEA (2.2 eq) and DMAP (0.3 eq). The mixture was stirred at RT for 2 h and then the product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the desired compound as a white powder. 1H NMR (400 MHz, DMSO-d6+TFA) δ: 7.41-7.27 (2H, m), 7.14 (1H, s), 7.08 (1H, d, J=6.8 Hz), 6.59 (1H, br. s), 4.38 (2H, s), 4.25 (4H, m), 2.85 (3H, s). MS (ES) C19H15Cl2FN4O3 requires: 436/438, found: 437/439 (M+H)+.

Workup

  1. temperatureThe reaction mixture was refluxed for 2 h
  2. customThe solvent was removed under reduced pressure
  3. dissolutionThe resulting crude was dissolved in DMF (0.2 M) and to the resulting solution
  4. customthe product was isolated by purification at prep RP-HPLC

Sources & evidence

ORD record
ord-c1f1a265a458444ba2cfc89ec791758f
Source dataset
uspto-grants-2010_11
Patent number
US07834015B2

Reaction notes

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