Cyanogen Bromide → 7-(2-Amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)Methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

HRID 1890820Notes

Reaction equation

HRID 1890820 reaction equation
[N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([C:13]2[N:18]=[C:17]3[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:20](=[O:23])[CH2:21][NH:22][C:16]3=[N:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11]>CN(C)C=O.CO>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[C:7]([C:13]3[N:18]=[C:17]4[N:19]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:20](=[O:23])[CH2:21][NH:22][C:16]4=[N:15][CH:14]=3)[CH:8]=[C:9]([CH3:12])[C:10]=2[N:11]=1

Participants

5

Reactant 2

HCID 10476Cyanogen BromideHCID 666070657-(3,4-Diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

Product 1

HCID 582983117-(2-Amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)Methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-oneYield 62.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent2×

Procedure

Cyanogen bromide (0.059 g, 0.556 mmol) in N,N-dimethylformamide (0.5 mL) was added to a stirred solution of 7-(3,4-diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.195 g, 0.529 mmol) in N,N-dimethylformamide (3 mL) at 0° C. The resulting dark brown mixture was capped and stirred at room temperature for 16 h. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (5-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The residue was loaded onto a Strata X-C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure and dried under high vacuum at 50° C. to give the desired product (0.130 g, 0.331 mmol, 62% yield) as an orange solid. 1H NMR (400 MHz, D2O and DMSO-d6) δ (ppm) 8.13 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 4.18 (s, 2H), 4.03 (d, J=6.64 Hz, 2H), 3.84-3.90 (m, 2H), 3.24 (t, J=11.32 Hz, 2H), 2.40 (s, 3H), 2.04-2.19 (m, 1H), 1.59 (d, J=12.10 Hz, 2H), 1.25-1.41 (m, 2H); MS (ESI) m/z 394.2 [M+1]+.

Workup

  1. customThe resulting dark brown mixture was capped
  2. filtrationfiltered
  3. custompurified
  4. customreverse-phase preparatory HPLC (5-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min)
  5. additionFractions containing the desired product
  6. customremoved under reduced pressure
  7. washThe column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol
  8. washThe product eluted with the 5% ammonium hydroxide in methanol eluent
  9. concentrationwas concentrated under reduced pressure
  10. customdried under high vacuum at 50° C.

Sources & evidence

ORD record
ord-8f46a54659294a43b4e50cd7beaf9786
Source dataset
uspto-grants-2013_08
Patent number
US08507492B2

Reaction notes

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