Sodium borohydride → 1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2-(1-(S)-phenyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine

HRID 458868Notes

Reaction equation

HRID 458868 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([N:14]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[P+]=O.[BH4-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][C@H:12]1[C:31]2[CH:30]=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23][N:14]1[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]

Participants

5

Reactant 3

HCID 4311764Sodium borohydrideHCID 693539142-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-N-(1-(S)-phenyl-ethyl)-acetamideHCID 178527006HCID 178527006, compound

Product 1

HCID 184425701-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2-(1-(S)-phenyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepineYield 20.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of 2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-N-(1-(S)-phenyl-ethyl)-acetamide (7.0 g, 14.65 mmol) and phosphorus oxide chloride (13.4 ml, 146.5 mmol) in anhydrous acetonitrile, (160 ml) was heated at reflux for 6.5 h, under nitrogen. After cooling to RT, the volatiles were removed under vacuum and the resulting oil was dissolved in anhydrous methanol before evaporation to dryness (repeated twice). The resulting brown oil was dissolved again in anhydrous methanol (122 ml) and cooled at −78° C., under nitrogen. Then, sodium borohydride (3.02 g, 79.99 mmol) was added portionwise in 5 h to the reaction mixture kept at −78° C. The reaction was quenched by dropwise addition of aqueous 1N HCl (8 ml) and the mixture was allowed to warm to RT before the solvent was removed under vacuum and water (175 ml) was added. After extraction with CH2Cl2 (4×150 ml), the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under vacuum. The resulting crude oil was purified by flash chromatography (CH2Cl2/CH3OH: 36/1) giving the pure diastereoisomer 1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2-(1-(S)-phenyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow oil (1.36 g, 20%).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 6.5 h, under nitrogen
  3. customthe volatiles were removed under vacuum
  4. dissolutionthe resulting oil was dissolved in anhydrous methanol before evaporation to dryness (
  5. dissolutionThe resulting brown oil was dissolved again in anhydrous methanol (122 ml)
  6. temperaturecooled at −78° C., under nitrogen
  7. customkept at −78° C
  8. customThe reaction was quenched by dropwise addition of aqueous 1N HCl (8 ml)
  9. temperatureto warm to RT before the solvent
  10. customwas removed under vacuum and water (175 ml)
  11. additionwas added
  12. extractionAfter extraction with CH2Cl2 (4×150 ml)
  13. dry with materialthe organic layer was dried over anhydrous magnesium sulfate
  14. customthe solvent was removed under vacuum
  15. customThe resulting crude oil was purified by flash chromatography (CH2Cl2/CH3OH: 36/1)

Sources & evidence

ORD record
ord-a2810d2920904c4cb9c0a1a552ca14f1
Source dataset
uspto-grants-2007_03
Patent number
US07192950B2

Reaction notes

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