Acetamide → HCID 44438909, compound

HRID 2373924Notes

Reaction equation

HRID 2373924 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[N:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=23)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([NH2:39])(=[O:38])[CH3:37].CNCCNC>O1CCOCC1.[Cu]I>[NH2:22][C:18]1[C:17]2[N:16]([C:15]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[N:14][C:13]=2[C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:39][C:36](=[O:38])[CH3:37])[CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][N:19]=1

Participants

7

Reactant 4

HCID 178AcetamideHCID 8070N,N'-DimethylethylenediamineHCID 11430Potassium CarbonateHCID 59852808HCID 59852808, compound

Product 1

HCID 44438909HCID 44438909, compound

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
170 °C

Procedure

Argon was bubbled through a suspension of 1-[3-(3-bromobenzyloxy)-phenyl]-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine (1, 25 mg, 0.056 mmol), potassium carbonate (15 mg, 0.109 mmol), copper(I) iodide (10 mg, 0.052 mmol), acetamide (40 mg, 0.68 mmol) and N,N′-dimethylethylenediamine (5 mg, 0.057 mmol), in dioxane (0.5 ml) in a thick walled 5 ml microwave tube. The tube was sealed and heated to 170° C. for 2 hours using the CEM Discover microwave oven at a maximum power of 250 W. The reaction mixture was then partitioned between water (3 ml) and ethyl acetate (3 ml) and the aqueous layer was extracted with further ethyl acetate (2×3 ml). The combined organic extracts were washed with water (2×3 ml) and brine (3 ml) then evaporated in vacuo. The residues after evaporation were dissolved in methanol and loaded on to 1 g SCX cartridges, then eluted with methanol and methanol/ammonia (concentrated aqueous ammonia in methanol, 3% v/v). Fractions containing product were combined and evaporated to furnish N-{3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-phenyl}-acetamide as an off white solid (10 mg, 0.023 mmol, 42%, 85% pure). This was purified further using preparative mass directed HPLC purification (conditions) to afford 2 as an off white solid (6.3 mg, 0.015 mmol, 27%; (M+H)+ m/z 428.2; Retention Time; 2.87 min; 1H-NMR (D4-MeOH) δ 7.72 (1H, br t), 7.53 (1H, br d, J=8 Hz), 7.49 (1H, t, J=8 Hz), 7.43 (1H, d, J=5.1 Hz), 7.35 (1H, t, 7.8 Hz), 7.29 (1H, br t), 7.25-7.22 (2H, m), 7.17 (1H, dd, J=2.8, 8.2 Hz), 7.01 (1H, d, J=5.1 Hz), 5.21 (2H, s), 4.00 (1H, p, J=8.4 Hz), 2.55 (4H, m), 2.22 (1H, m), 2.15 (3H, s), 2.10-2.02 (1H, m).

Workup

  1. customThe tube was sealed
  2. customThe reaction mixture was then partitioned between water (3 ml) and ethyl acetate (3 ml)
  3. extractionthe aqueous layer was extracted with further ethyl acetate (2×3 ml)
  4. washThe combined organic extracts were washed with water (2×3 ml) and brine (3 ml)
  5. customthen evaporated in vacuo
  6. customThe residues after evaporation
  7. dissolutionwere dissolved in methanol
  8. washeluted with methanol and methanol/ammonia (concentrated aqueous ammonia in methanol, 3% v/v)
  9. additionFractions containing product
  10. customevaporated

Sources & evidence

ORD record
ord-dca2fd5e2bcb4ab3b7c7247596f9deae
Source dataset
uspto-grants-2008_12
Patent number
US07459554B2

Reaction notes

Loading…