Acetyl chloride → HCID 178473831, compound

HRID 243286Notes

Reaction equation

HRID 243286 reaction equation
[NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:37](=[O:39])[CH3:38])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1

Participants

6

Reactant 3

HCID 6367Acetyl chlorideHCID 81531DiisopropylethylamineHCID 178461903HCID 178461903, compound

Product 1

HCID 178473831HCID 178473831, compoundYield 19.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred suspension of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (46 mg, 0.127 mmol) and DIPEA (26 μL, 0.152 mmol) in anhydrous THF (3 mL) and anhydrous DCM (1 mL) was added acetyl chloride (9 μL, 0.127 mmol). Stirring at RT was continued for 3 h then volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc and water. The aqueous layer was further washed with DCM and the organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residues were combined, purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-70% 0.1% HCO2H in acetonitrile/water) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure affording 115 as a white solid (10 mg, 19%). LCMS: RT 2.13 min [M+H]+ 405.1. 1H NMR (CDCl3, 400 MHz): δ 8.35 (1H, s), 7.88 (1H, s), 7.78-7.70 (1H, m), 7.49-7.42 (1H, m), 7.28-7.20 (3H, m), 6.05 (1H, s), 4.98-4.82 (1.5H, m), 4.71-4.61 (0.5H, m), 4.09-3.99 (0.5H, m), 3.90-3.78 (0.5H, m), 3.42-3.37 (0.5H, m), 3.32-3.18 (0.5H, m), 2.88-2.37 (1H, m), 2.20-2.10 (4H, m), 2.06-1.96 (1H, m), 1.90-1.69 (5H, m). Signals split due to presence of rotamers

Workup

  1. customwere removed under reduced pressure
  2. customthe resulting residue was partitioned between EtOAc and water
  3. washThe aqueous layer was further washed with DCM
  4. washthe organic layers were then washed with brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. custompurified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-70% 0.1% HCO2H in acetonitrile/water) and
  8. washThe cartridge was washed with MeOH
  9. washthe product eluted with 2M NH3/MeOH
  10. additionThe product containing fractions
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-e19f9521803b4bb3b11f53e030a607c6
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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