Methanol → HCID 118161065, compound

HRID 928697Notes

Reaction equation

HRID 928697 reaction equation
C(OC([N:8]([C:16]1[C:21]([CH3:22])=[N:20][CH:19]=[C:18]([C:23]2[N:24]=[C:25]([N:32](C(OC(C)(C)C)=O)[C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:41][CH2:40]4)=[C:35]([O:49][CH2:50][CH2:51][O:52]C4CCCCO4)[CH:34]=3)[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CO.O>C(Cl)Cl>[NH2:8][C:16]1[N:17]=[C:18]([C:23]2[N:24]=[C:25]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:40][CH2:41][N:42]([CH:45]5[CH2:48][O:47][CH2:46]5)[CH2:43][CH2:44]4)=[C:35]([CH:34]=3)[O:49][CH2:50][CH2:51][OH:52])[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)[CH:19]=[N:20][C:21]=1[CH3:22]

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 6422Trifluoroacetic acidHCID 118187817HCID 118187817, compound

Product 1

HCID 118161065HCID 118161065, compoundYield 60.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of tert-butyl tert-butoxycarbonyl(6-(8-((tert-butoxycarbonyl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)imidazo[1,2-a]pyrazin-6-yl)-3-methylpyrazin-2-yl)carbamate XXXV (165 mg, 0.18 mmol) in DCM (2.2 mL) was added TFA (1.1 mL, 0.11 mmol). The mixture was stirred at rt for 16 h. The reaction was diluted with 9:1 DCM:MeOH and H2O. The aqueous layer was separated and extracted with 9:1 DCM:MeOH. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of 100% 75/18/7 DCM/Et2O/MeOH—100% 70/20/10 DCM/Et2O/MeOH to provide the desired compound 2-(5-((6-(6-amino-5-methylpyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-(4-(oxetan-3-yl)piperazin-1-yl)phenoxy)ethanol (7, 56 mg, 59%). LCMS-ESI+ (m/z): [M+H]+: 518.2. 1H NMR (300 MHz, d6-DMSO) δ: 9.49 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 8.13 (d, J=1.1 Hz, 1H), 7.85-7.66 (m, 2H), 7.62 (d, J=1.1 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 6.25 (s, 2H), 4.87-4.77 (m, 1H), 4.50 (dt, J=25.2, 6.3 Hz, 4H), 4.04 (t, J=5.1 Hz, 2H), 3.74 (q, J=5.2 Hz, 2H), 3.51-3.39 (m, 1H), 3.10-2.95 (m, 4H), 2.45-2.35 (m, 4H), 2.34 (s, 3H). Alternatively, compound XXXIV could be taken directly to this step and similarly de-protected to provide the 5-chloropyrazine substituted analog.

Workup

  1. customThe aqueous layer was separated
  2. extractionextracted with 9:1 DCM
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was purified by column chromatography
  8. washeluting with a gradient of 100% 75/18/7 DCM/Et2O/MeOH—100% 70/20/10 DCM/Et2O/MeOH

Sources & evidence

ORD record
ord-8c27804193884f1e9824a96fb164b199
Source dataset
uspto-grants-2016_03
Patent number
US09290505B2

Reaction notes

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