Ammonia → HCID 46216227, compound

HRID 1880033Notes

Reaction equation

HRID 1880033 reaction equation
Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[N:21](C4CCCCO4)[C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[N:18]=3)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C(F)(F)F)=O.N>CO.C1(C)C=CC=CC=1>[NH:18]1[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[N:21]=[C:17]1[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1)=[O:16]

Participants

9

Reactant 6

HCID 222AmmoniaHCID 6422Trifluoroacetic acidHCID 8082PiperidineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 59326998HCID 59326998, compound

Product 1

HCID 46216227HCID 46216227, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A heavy-walled vial was charged with (4-(3-bromopyridin-2-yloxy)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-2-yl)methanone (0.150 g, 0.314 mmol), piperidine (0.041 mL, 0.470 mmol), cesium carbonate (0.204 g, 0.627 mmol), (r)-binap (0.020 g, 0.031 mmol), Pd3 dba3 (0.014 g, 0.016 mmol) and Toluene (4 mL). Nitrogen was bubbled into the flask for 5 mins. The vial was capped and heated to 80° C. After 12 hours, the reaction was partitioned with ethyl acetate and water. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give a clear residue. The residue was dissolved in MeOH (10 mL) and treated with 1 mL of TFA. The mixture was allowed to stir at room temperature. 10 ml of 2N ammonia in MeOH was added to the reaction with was reduced in vacuo. The residue was partitioned in water and EtOAc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and reduced. The residue obtained was triturated in 1:1 ethyl acetate:ether and then dried in a vacuum oven to give product as solid. MS (ESI, pos. ion) m/z: 398.8 (M+1). IC50 (uM) ++++.

Workup

  1. customNitrogen was bubbled into the flask for 5 mins
  2. customThe vial was capped
  3. customthe reaction was partitioned with ethyl acetate and water
  4. washThe organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate
  5. dry with materialThe organic layer was then dried with sodium sulfate
  6. custompurified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes
  7. customto give a clear residue
  8. customThe residue was partitioned in water
  9. washThe organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate
  10. dry with materialThe organic layer was then dried with sodium sulfate
  11. customThe residue obtained
  12. customwas triturated in 1:1 ethyl acetate
  13. dry with materialether and then dried in a vacuum oven
  14. customto give product as solid

Sources & evidence

ORD record
ord-ea0ea9ff05d148bba13181d442160fdf
Source dataset
uspto-grants-2012_11
Patent number
US08318718B2

Reaction notes

Loading…