Adipic Acid → 951123-35-6

HRID 2424640Notes

Reaction equation

HRID 2424640 reaction equation
[CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@:8]2([O:28][CH3:29])[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]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[C:35](O)(=[O:43])[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].O.[ClH:46]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@@:8]2([O:28][CH3:29])[C@@H:9]3[O:23][C:18]4=[C:19]([O:22][C:35]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:43])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[ClH:46]

Participants

7

Reactant 4

HCID 196Adipic AcidHCID 313Hydrochloric AcidHCID 962WaterHCID 9848990Buprenorphine component OF alks-5461

Product 1

HCID 57383390951123-35-6Yield 69.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Alternate Method: To a stirred solution of 4-dimethylaminopyridine (1.232 g, 0.010 mol, acylation catalyst) in tetrahydrofuran (1.5 L, THE) was added buprenorphine free base (93.534 g, 0.20 mol) followed by adipic acid (239.952 g, 1.64 mol). The suspension was stirred for 20 minutes and dicyclohexylcarbondiimide (45.409 g, 0.22 mol) was added over approx 30 minutes whilst maintaining the internal temperature between 16-21° C. with cold water cooling. Stirring was continued overnight. The insoluble precipitate (mostly dicyclohexylurea) was removed by filtration under vacuum and washed with more THF. Solvent was removed under vacuum from the filtrate (960 ml recovered). The precipitate (mainly adipic acid) was removed by filtration and washed with a little more THF and dried in air. The combined filtrates were stirred at room temperature and treated with concentrated hydrochloric acid (20.606 g, 0.20 mol). The resulting precipitate was removed by filtration, washed with THF and dried in air. This crude product was crystallized from ethanol/dichloromethane with a hot filtration and removal of solvents under vacuum to concentrate the suspension. The solid was removed by filtration, washed with ethanol and dried to give buprenorphine hemiadipate hydrochloride (87.525 g). The identity of the material was confirmed by full assignment of the 1H and 13C NMR spectrum and by comparison of these spectra with the NMR spectra of buprenorphine hydrochloride.

Workup

  1. additiondicyclohexylcarbondiimide (45.409 g, 0.22 mol) was added over approx 30 minutes
  2. stirringStirring
  3. waitwas continued overnight
  4. customThe insoluble precipitate (mostly dicyclohexylurea) was removed by filtration under vacuum
  5. washwashed with more THF
  6. customSolvent was removed under vacuum from the filtrate (960 ml recovered)
  7. customThe precipitate (mainly adipic acid) was removed by filtration
  8. washwashed with a little more THF
  9. customdried in air
  10. stirringThe combined filtrates were stirred at room temperature
  11. customThe resulting precipitate was removed by filtration
  12. washwashed with THF
  13. customdried in air
  14. customThis crude product was crystallized from ethanol/dichloromethane with a hot filtration and removal of solvents under vacuum
  15. concentrationto concentrate the suspension
  16. customThe solid was removed by filtration
  17. washwashed with ethanol
  18. customdried

Sources & evidence

ORD record
ord-733bd0e5f1e24b319ed3ec12542e48ce
Source dataset
uspto-grants-2011_06
Patent number
US07964610B2

Reaction notes

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