Dimethylformamide → Buprenorphine component OF alks-5461
Reaction equation
[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.C(=O)(O)[O-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1.CN(C=O)C>CO.O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1Participants
Conditions
- Temperature
- 90 °C
Procedure
A mixture of 11.5 g of norbuprenorphine, 4.6 g of sodium bicarbonate, 4.85 g of cyclopropylmethyl bromide (1% butenyl bromide in it by GC) and 46 ml of dry DMF is heated in an oilbath at 80-100° C. for 4 hours until the reaction is substantially complete. The reaction mixture is transferred to a dropping funnel, with minimal DMF as a wash. The reaction mixture is added over 5 minutes to 160 ml of water, with mechanical stirring. (Adding water to the reaction yields a gum). The mixture is stirred for about 10 minutes and filtered. The filter cake is washed with 20 ml water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, yielding about 12 g. The resulting product is boiled in 30 ml of methanol for about 30 minutes, cooled, and filtered to yield about 7.3 g buprenorphine.
Workup
- customyields a gum)
- filtrationfiltered
- washThe filter cake is washed with 20 ml water
- customThe resulting product is dried
- customyielding about 12 g
- temperaturecooled
- filtrationfiltered
Sources & evidence
- ORD record
- ord-665878874a614695aa8a58ab4b5d41f8
- Source dataset
- uspto-grants-2015_03
- Patent number
- US08993764B2
Reaction notes
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