Benzene, ((2-bromoethoxy)methyl)- → Umeclidinium bromide

HRID 533886Notes

Reaction equation

HRID 533886 reaction equation
[N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([CH2:29][O:30][CH2:31][CH2:32][Br:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[Br-:33].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:32][CH2:31][O:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2

Participants

4

Reactant 2

HCID 73833Benzene, ((2-bromoethoxy)methyl)-HCID 239923851-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol

Product 1

HCID 11519069Umeclidinium bromideYield 43.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (3.30 g, 11.2 mmol) in 2 CH3CN/3 CHCl3 (200 mL) was added 2-bromoethyl phenylmethyl ether (2.31 mL, 14.6 mmol). The solution was stirred at 60° C. for 16 h. The reaction was cooled down to room temperature and concentrated. EtOAc (200 mL) was added to the solid, and the mixture was allowed to stir for 1 hour then filtered. The resulting solid was taken up in MeOH (125 mL) and heated to 60° C. The solution was filtered hot, and then cooled back to room temperature. The reaction was concentrated to a low volume of MeOH (˜20 mL) and filtered. Water (75 mL) was then added and the resulting mixture was heated at 55° C. with brisk stirring for 40 min. After cooling to room temperature, the solid was filtered off, washed with water (20 mL) and dried in a vacuum oven at 45° C. for 16 hours to give the title compound (2.47 g, 43.3%). EI-MS m/z 428(M+) Rt (1.90 min) 1H NMR (DMSO-d6) δ 7.56 (d, 4H, J=1.2), 7.28 (m, 11H), 5.95 (s, 1H), 4.50 (s, 2H), 3.81 (d, 2H, J=4.0), 3.48 (t, 6H, J=7.2), 3.38 (d, 2H, J=4.0), 2.01 (t, 6H, J=7.2); Elemental analysis (C29H34NO2Br) C, H, N: calculated, 68.50, 6.74, 2.75. Found, 68.28, 6.68, 2.73.

Workup

  1. temperatureThe reaction was cooled down to room temperature
  2. concentrationconcentrated
  3. additionEtOAc (200 mL) was added to the solid
  4. stirringto stir for 1 hour
  5. filtrationthen filtered
  6. temperatureheated to 60° C
  7. filtrationThe solution was filtered hot
  8. temperaturecooled back to room temperature
  9. concentrationThe reaction was concentrated to a low volume of MeOH (˜20 mL)
  10. filtrationfiltered
  11. additionWater (75 mL) was then added
  12. temperaturethe resulting mixture was heated at 55° C.
  13. stirringwith brisk stirring for 40 min
  14. temperatureAfter cooling to room temperature
  15. filtrationthe solid was filtered off
  16. washwashed with water (20 mL)
  17. customdried in a vacuum oven at 45° C. for 16 hours

Sources & evidence

ORD record
ord-af190d175b1c4c6ebf903e1658168220
Source dataset
uspto-grants-2014_10
Patent number
US08853404B2

Reaction notes

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