Bromomethylcyclopropane → Buprenorphine component OF alks-5461

HRID 524835Notes

Reaction equation

HRID 524835 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>CN1CCCC1.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]1

Participants

6

Reactant 3

HCID 81503BromomethylcyclopropaneHCID 114976NorbuprenorphineHCID 516892Sodium Bicarbonate

Product 1

HCID 9848990Buprenorphine component OF alks-5461Yield 86%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 84541-MethylpyrrolidineSolvent

Procedure

To the solution of norbuprenorphine (Example 4, 0.07 g; 0.169 mmol) in N-methylpyrrolidine (1 mL) was added NaHCO3 (0.017 g; 0.203 mmol) and cyclopropylmethyl bromide (0.034 g; 0.253 mmol). The reaction mixture was placed into a pre-heated oil bath at 80° C. and stirred over 18 h. It was then diluted with water (10 mL), extracted three times with EtOAc, and the combined organic layers were washed with water (2×5 mL), brine, dried over Na2SO4 and concentrated. Column chromatography (eluent EtOAc:hexane/1:2) afforded 0.068 g (86%) of buprenorphine.

Workup

  1. customThe reaction mixture was placed into a pre-heated oil bath at 80° C.
  2. extractionextracted three times with EtOAc
  3. washthe combined organic layers were washed with water (2×5 mL), brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-c42415a8f0e647acab1be377b8f3d6bc
Source dataset
uspto-grants-2016_05
Patent number
US09340550B2

Reaction notes

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