Methylamine → 2-[2-(3,5-dimethoxyphenyl)ethyl]-N-methyl-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 1052271Notes

Reaction equation

HRID 1052271 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:27][CH:26]=4)[N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:46][N:47](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:22]([NH:47][CH3:46])=[O:24])=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1

Participants

7

Reactant 5

HCID 6329MethylamineHCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 899630612-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid

Product 1

HCID 730571552-[2-(3,5-dimethoxyphenyl)ethyl]-N-methyl-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 21.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of crude 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (20 mg, 31.6 μmol) in N,N-dimethylformamide (2 mL), HATU (12.0 mg, 31.6 μmol), 2.0 M methylamine in THF (15.8 μL, 31.6 μmol) and N,N-diisopropylethylamine (11.0 μL, 63.3 mmol) were added sequentially at ambient temperature. After 1 hour, the reaction was quenched with saturated aqueous NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated. The residue was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL) was added at ambient temperature. After 2 hours, the volatiles were removed under vacuum and the residue was dissolved in methanol (1 mL), followed by the addition of ethylenediamine (0.1 mL). After another 1 hour, the reaction mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.5 mg) as its TFA salt. LCMS calculated for C29H35N6O3 (M+H)+: m/z=515.3. Found: 515.2.

Workup

  1. customthe reaction was quenched with saturated aqueous NH4Cl
  2. extractionextracted with methylene chloride
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. concentrationconcentrated
  5. dissolutionThe residue was dissolved in methylene chloride (1 mL)
  6. additiontrifluoroacetic acid (1 mL) was added at ambient temperature
  7. waitAfter 2 hours
  8. customthe volatiles were removed under vacuum
  9. dissolutionthe residue was dissolved in methanol (1 mL)
  10. additionfollowed by the addition of ethylenediamine (0.1 mL)
  11. waitAfter another 1 hour
  12. customthe reaction mixture was purified on RP-HPLC (XBridge C18 column
  13. washeluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min)

Sources & evidence

ORD record
ord-44fedcc95fdf4c7596f43bffb8b6a333
Source dataset
uspto-grants-2016_07
Patent number
US09388185B2

Reaction notes

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