Hydrochloric Acid → HCID 178461932, compound

HRID 243352Notes

Reaction equation

HRID 243352 reaction equation
[NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]2)[C:7]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl>C(O)CCC.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([C@@H:2]([NH:1][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:3])[N:8]([CH:9]3[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]3)[C:7]=2[CH:17]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 977406-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 68157889HCID 68157889, compound

Product 1

HCID 178461932HCID 178461932, compoundYield 18.4%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of 4-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]cyclohexanecarbonitrile (100 mg, 0.35 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (91 mg, 0.38 mmol) and DIPEA (0.10 mL, 0.72 mmol) in n-butanol (0.7 mL) was heated for 48 h at 105° C. After cooling to RT, the crude reaction mixture was treated with 4N HCl in dioxane (0.5 mL) and stirred for 1 h at RT. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and 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 0-8% MeOH in DCM), then triturated with hot EtOAc and purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 0-40%, 0.1% HCO2H in acetonitrile/water) to afford 174 as a white solid (26 mg, 18%). LCMS (Method K): RT 2.93 min [M+H]+ 405.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.45 (1H, s), 8.34-7.94 (3H, m), 7.71-7.56 (2H, m), 7.05-6.96 (1H, m), 5.96 (1H, bs), 4.62-4.59 (1H, m), 3.09-2.95 (1H, m), 2.38-2.25 (1H, m), 2.21-2.07 (2H, m), 1.93 (1H, bd, J=12.75 Hz), 1.84 (1H, bd, J=12.00 Hz), 1.73-1.65 (5H, m), 1.02 (1H, bs). Broad signals due to presence of rotamers/tautomers

Workup

  1. temperatureAfter cooling to RT
  2. customthe crude reaction mixture
  3. washwashed with MeOH
  4. concentrationconcentrated in vacuo
  5. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-8% MeOH in DCM)
  6. customtriturated with hot EtOAc
  7. custompurified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 0-40%, 0.1% HCO2H in acetonitrile/water)

Sources & evidence

ORD record
ord-96579aa4039e4b948cd5e875a4dfc3c0
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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