Diisopropylethylamine → HCID 178463567, compound

HRID 243384Notes

Reaction equation

HRID 243384 reaction equation
C(O[C:6](=O)[NH:7][CH:8]([C:10]1[N:14]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.ClC1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2C1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)CCC.CO>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([CH:8]([NH:7][C:6]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:9])[N:14]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[CH:22]=1

Participants

8

Reactant 3

HCID 81531DiisopropylethylamineHCID 977406-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 68156913{1-[6-Fluoro-1-(3-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester

Product 1

HCID 178463567HCID 178463567, compoundYield 16.2%

Reagents, catalysts & solvents 4

HCID 2631-ButanolSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

A mixture of {1-[6-fluoro-1-(3-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethyl}-carbamic acid tert-butyl ester (84 mg, 0.22 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford a dark orange oil. A mixture of this residue, 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (53 mg, 0.22 mmol) and DIPEA (110 μL, 0.63 mmol) in n-butanol (0.5 mL) was heated at 100° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 238 as a white solid (14 mg, 16%). LCMS (Method K): RT 3.09 min [M+H]+ 393.01. 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, s), 8.07-7.81 (4H, m), 7.73 (1H, dd, J=8.86, 4.85 Hz), 7.56 (1H, s), 7.18-7.04 (2H, m), 5.68 (1H, s), 1.70 (3H, d, J=6.75 Hz)

Workup

  1. washwashed with MeOH
  2. concentrationconcentrated in vacuo
  3. customto afford a dark orange oil
  4. temperaturewas heated at 100° C. in a sealed vial for 16 h
  5. temperatureAfter cooling to RT
  6. washThe cartridge was washed with MeOH
  7. concentrationconcentrated in vacuo
  8. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM)

Sources & evidence

ORD record
ord-50f9061a88214287adbe7db343814bb3
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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