Hydrochloric Acid → HCID 56846972, compound

HRID 2384596Notes

Reaction equation

HRID 2384596 reaction equation
[H-].[Na+].[CH:3]1([CH2:6][N:7]2[CH2:27][CH2:26][C@@:14]34[C:15]5[C:16]([OH:25])=[C:17]([C:22]([NH2:24])=[O:23])[CH:18]=[CH:19][C:20]=5[CH2:21][C@@H:8]2[C@:9]3([OH:29])[CH2:10][CH2:11][C:12](=O)[CH2:13]4)[CH2:5][CH2:4]1.Cl.[CH3:31]CCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH:3]1([CH2:6][N:7]2[CH2:27][CH2:26][C@@:14]34[C:15]5[C:16]([OH:25])=[C:17]([C:22]([NH2:24])=[O:23])[CH:18]=[CH:19][C:20]=5[CH2:21][C@@H:8]2[C@:9]3([OH:29])[CH2:10][CH2:11][C:12](=[CH2:31])[CH2:13]4)[CH2:5][CH2:4]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8058HexaneHCID 24758Sodium hydrideHCID 11667832Samidorphan

Product 1

HCID 56846972HCID 56846972, compoundYield 30%

Reagents, catalysts & solvents 2

HCID 74505Methyltriphenyliphosphonium bromideCatalystHCID 679Dimethyl SulfoxideSolvent2×

Conditions

Temperature
60 °C

Procedure

Sodium hydride (324 mg, 8.1 mmol, 60% dispersion in mineral oil) was washed under an argon atmosphere with hexane. DMSO (5 mL) was added and the mixture heated at 60° C. for 1 hour. Methyltriphenylphosphonium bromide (2.89 g, 8.1 mmol) was added and stirred at the same temperature for 1 hour. A solution of 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxomorphinan-3-carboxamide [P4] (0.6 g, 1.62 mmol) in DMSO (10 mL) was added and the mixture heated at 65° C. for 42 hours (A further 5 equivalents of Wittig reagent was added after 18 hours). The reaction was allowed to return to room temperature and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was washed with brine and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave a residue that was stirred with hydrochloric acid (5%) for 30 minutes before washing with ethyl acetate. The aqueous phase was adjusted to pH8 by the addition of 2N sodium hydroxide solution and then extracted with DCM and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave a residue that was purified by prep-HPLC [Xbridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile Phase A: 10 mM NH4HCO3 (pH10), Phase B: MeCN; Flow: 50 ml/min; Column Temperature: 30° C.; Runtime: 25 min.] giving 17-(cyclopropylmethyl)-4,14-dihydroxy-6-methylenemorphinan-3-carboxamide [11] (180 mg, 30% yield); LC/MS (r.t. 13.3 minutes [5 to 95% B]), 369 (M+H)+.

Workup

  1. additionwas added after 18 hours)
  2. customto return to room temperature
  3. custompartitioned between ethyl acetate (300 mL) and water (300 mL)
  4. washThe organic phase was washed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationFiltration and removal of the solvent under reduced pressure
  7. customgave a residue that
  8. washbefore washing with ethyl acetate
  9. additionThe aqueous phase was adjusted to pH8 by the addition of 2N sodium hydroxide solution
  10. extractionextracted with DCM
  11. dry with materialdried (MgSO4)
  12. filtrationFiltration and removal of the solvent under reduced pressure
  13. customgave a residue that
  14. customwas purified by prep-HPLC [Xbridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile Phase A: 10 mM NH4HCO3 (pH10), Phase B: MeCN; Flow: 50 ml/min; Column Temperature: 30° C.; Runtime: 25 min.]

Sources & evidence

ORD record
ord-b7d1735a75c445bb8122976479121470
Source dataset
uspto-grants-2012_09
Patent number
US08263807B2

Reaction notes

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