Hydrochloric Acid → rac Nebivolol hydrochloride

HRID 1424695Notes

Reaction equation

[NH:1]([CH2:16][C@@H:17]([C@H:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=2[O:20]1)[OH:18])[CH2:2][C@@H:3]([C@@H:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)[OH:4].[ClH:30]>CC(O)CC.O>[ClH:30].[NH:1]([CH2:16][C@@H:17]([C@H:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=2[O:20]1)[OH:18])[CH2:2][C@@H:3]([C@@H:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)[OH:4]

Participants

Conditions

Temperature: 70 °C

Procedure

(±)[R*,S*,S*,S*]-α,α′-[imino-bis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (3.106 g; 96.6% w/w; 0.00740 mol) was dissolved in a mixture of 2-butanol (33.1 g) and water (2.0 g). Aq. conc. (about 31%) hydrochloric acid (1.1 g; 0.00903 mol) was added to the solution under stirring at 70±2° C. The resulting mixture was heated at 70±2° C. for 2 hours, then cooled to 20±2° C. over 2 hours and maintained at this temperature for further 2 hours obtaining the product precipitation. The solid was isolated by filtration, washing with 2-butanol (2×2 g), and dried under vacuum at 60° C. to give the title compound as a white solid (3.1 g, 98.3% w/w assay (HPLC); 93.2% molar yield). Purity Profile (HPLC): Sum of Impurities=0.224% w/w; Max Single Impurity (“de-F” Nebivolol)=0.178% w/w.

Workup

temperatureThe resulting mixture was heated at 70±2° C. for 2 hours
temperaturecooled to 20±2° C. over 2 hours
temperaturemaintained at this temperature for further 2 hours
customobtaining
customthe product precipitation
customThe solid was isolated by filtration
washwashing with 2-butanol (2×2 g)
customdried under vacuum at 60° C.

Sources & evidence

ORD record: ord-c6eeb6422bb649d5ab8e30cc7ad16b56
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08927742B2

Reaction notes

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