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

HRID 919038Notes

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.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)CC>[Br-:23].[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]([CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2

Participants

Conditions

Temperature: 52.5 °C

Procedure

A solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (31.7 kg) and benzyl 2-bromoethyl ether (25.7 kg) in n-propanol (257.5 kg) was refluxed for 13 hours. The solution was cooled to 50-55° C. over not less than an hour and stirred for 40 minutes to induce crystallisation. The slurry was cooled to 17-23° C. over not less than 1 hour and stirred for 60 minutes. The slurry was then cooled to 0-5° C. over not less than 1 hour and aged for 2 hours. The product was filtered and washed twice with n-propanol (34.8 kg and 33.8 kg). Drying under vacuum at 50° C. gave a white solid (47.95 kg, 87%).

Workup

customcrystallisation
temperatureThe slurry was cooled to 17-23° C. over not less than 1 hour
stirringstirred for 60 minutes
temperatureThe slurry was then cooled to 0-5° C. over not less than 1 hour and aged for 2 hours
filtrationThe product was filtered
washwashed twice with n-propanol (34.8 kg and 33.8 kg)
customDrying under vacuum at 50° C.

Sources & evidence

ORD record: ord-4ec7bfbd9d1e481398b7a011681d74d0
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09273001B2

Reaction notes

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