Toluene → Vernakalant Hydrochloride
Reaction equation
[CH3:1][O:2][CH2:3][CH2:4][O:5][AlH2-:6][O:7][CH2:8][CH2:9][O:10][CH3:11].[Na+:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][O:25]/[C:26](=N/[H])/[C:27](Cl)(Cl)[Cl:28])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].[CH:33]([NH2:36])([CH3:35])C.[C:37]1(C)[CH:42]=CC=[CH:39][CH:38]=1>>[CH3:11][O:10][CH2:9][CH2:8][O:7][AlH2-:6][O:5][CH2:4][CH2:3][O:2][CH3:1].[Na+:12].[ClH:28].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][O:25][C@@H:26]2[CH2:27][CH2:39][CH2:38][CH2:37][C@H:42]2[N:36]2[CH2:33][CH2:35][C@@H:9]([OH:10])[CH2:8]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]Participants
Procedure
To a refluxing solution of Red-Al (65 wt % in toluene, 1.86 g, 1.80 mL, 6 mmol, Aldrich cat #19, 619-3) in toluene (2 mL) was added dropwise (over 5 min) a solution of crude (36) in toluene (3 mL). After the resultant solution was refluxed for 1 h, TLC analysis (EtOAc-hexanes, 2:1 v/v, +0.5% v/v iPrNH2) revealed the absence of (36) and the appearance of a new polar spot (reduction of (36) with Red-Al at room temperature provided a very complex mixture (HPLC) from which (19) could not be isolated). The cooled (0° C.) reaction mixture was cautiously quenched by addition of 6M aq NaOH (3 mL). After separation of the layers, the organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give (19) free base as an oil (195 mg, 37% yield). Alternatively, the reduction of (36) was performed using LiAlH4.THF2 1.0M in toluene (3 mL, 3 mmol, Aldrich cat #243949) at room temperature. After carefully quenching the reaction by successive addition of water (100 μl), 6M aq NaOH (100 μL) and water (300 μL), the free base of (19) (423 mg, 80% yield) was obtained.
Sources & evidence
- ORD record
- ord-d6705040c7ca474bb873370261d24aa4
- Source dataset
- uspto-grants-2014_04
- Patent number
- US08692002B2
Reaction notes
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