Bromomethylcyclopropane → Buprenorphine component OF alks-5461

HRID 881991Notes

Reaction equation

HRID 881991 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.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>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]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1

Participants

4

Reactant 2

HCID 81503BromomethylcyclopropaneHCID 114976Norbuprenorphine

Product 1

HCID 9848990Buprenorphine component OF alks-5461

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

In an illustrative embodiment, a mixture of norbuprenorphine, a mild base, and cyclopropylmethyl bromide are heated in an oilbath at about 80-100° C. until the reaction is substantially complete. The reaction mixture is then added over 5 minutes to 160 ml of water, with mechanical stirring, yielding a gum. The mixture is stirred and filtered, and the filter cake is washed with 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, and then boiled in alcohol, cooled, and filtered to yield buprenorphine.

Workup

  1. customyielding a gum
  2. filtrationfiltered
  3. washthe filter cake is washed with water
  4. customThe resulting product is dried
  5. temperaturecooled
  6. filtrationfiltered

Sources & evidence

ORD record
ord-ac2eb24660be4b1797a91d05ec0059fe
Source dataset
uspto-grants-2015_03
Patent number
US08993764B2

Reaction notes

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