Hydrochloric Acid → (S)-4-Chloro-1-methoxy-2-nitro-6,7-dihydro-5H-benzocyclohepten-7-ylamine

HRID 1687475Notes

Reaction equation

HRID 1687475 reaction equation
[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13]C(=O)C)[CH2:8][CH:7](O)[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH2:13])[CH:8]=[CH:7][C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 131729599n-((s)-4-Chloro-9-(r,s)-hydroxy-1-methoxy-2-nitro-6,7,8,9-tetrahydro-5h-benzocyclohepten-7-yl)-acetamide

Product 1

HCID 67263587(S)-4-Chloro-1-methoxy-2-nitro-6,7-dihydro-5H-benzocyclohepten-7-ylamineYield 50%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of the crude N—((S)-4-Chloro-9-(R,S)-hydroxy-1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide and 6 M of Hydrogen Chloride in Water (15 mL) were warmed to 95° C. for 3 days. The reaction mixture was then cooled and treated slowly with 30% aqueous NaOH. When the pH proved >10, the reaction mixture was extracted with Et2O (3×). The organic phases were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2, dried over Na2SO4, filtered, and then chromatographed on a normal phase column eluting with a gradient of 100% CH2Cl2 to 5:1 CH2Cl2:MeOH to give 42 mg (50% over two steps) of (S)-4-Chloro-1-methoxy-2-nitro-6,7-dihydro-5H-benzocyclohepten-7-ylamine as an oil, which was used for subsequent steps without further manipulation. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 6.68 (d, J=12.37 Hz, 1H), 6.23-6.19 (dd, J=4.29 Hz, 11.98 Hz, 1H), 3.89 (s, 3H), 3.56 (m, 1H), 3.15 (m, 1H), 2.74-2.66 (m, 1H), 2.28 (m, 1H), 2.01 (m, 1H); MS (m/e) weak parent at 269 (M+H).

Workup

  1. temperatureThe reaction mixture was then cooled
  2. extractionthe reaction mixture was extracted with Et2O (3×)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe resulting residue was dissolved in CH2Cl2
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customchromatographed on a normal phase column
  10. washeluting with a gradient of 100% CH2Cl2 to 5:1 CH2Cl2

Sources & evidence

ORD record
ord-42767cfe120a40fd94e45f9435eda05e
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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