Hydrochloric Acid → Aplindore

HRID 1259461Notes

Reaction equation

HRID 1259461 reaction equation
[CH2:1]([NH:8][CH2:9][C@H:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:24]([O-])=O)=[C:19]([CH2:20][C:21](O)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CO.[OH-].[Na+]>CC1CCCO1.O.C(O)C.[Pt]>[CH2:1]([NH:8][CH2:9][C@@H:10]1[O:11][C:12]2=[C:19]3[C:18](=[CH:17][CH:16]=[C:13]2[O:14][CH2:15]1)[NH:24][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 313Hydrochloric Acid2×HCID 887MethanolHCID 14798Sodium HydroxideHCID 59456457{(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetic acid

Product 1

HCID 158784Aplindore

Reagents, catalysts & solvents 4

HCID 23939PlatinumCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
45 °C

Procedure

A 50 mL two necked flask equipped with a magnetic stir bar, gas inlet adapter and gas outlet adapter is charged with {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetic acid.HCl (1.00 g, 2.53 mmol), methanol (20 mL), 1 N hydrochloric acid (2.53 mL, 2.53 mmol) and platinum (5% on carbon, 62% w/w water, 0.20 g). The flask head space is flushed with hydrogen gas (200 mL), the gas outlet adapter is closed and the slurry is stirred under a hydrogen atmosphere. After ˜1 h, no solid {(3S)-3-[benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetic acid.HCl is visible. The mixture is stirred for an additional 1 h under hydrogen, at which point the reaction is complete by LCMS. The catalyst is removed by vacuum filtration, and the resulting solution is heated to 45° C. (external) in an oil bath for 8 h. The volatiles are removed by rotary evaporation to give a pink solid. The solids are suspended in 2-methyl tetrahydrofuran (18 mL) and water (3 mL). 1 N NaOH is added until the solids dissolved and the pH of the aqueous phase is 10 (pH paper), about 6 mL is required. The aqueous layer is removed, and the organic phase is washed with water (4 mL) and half saturated brine (3 mL). The volatiles are removed by rotary evaporation to give a brown syrup. The syrup is dissolved in absolute ethanol (3 mL) and evaporated to dryness. Absolute ethanol (3 mL) is added to the residue and removed by rotary evaporation to give crude (2S)-2-[(benzylamino)methyl]-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-8-one as a brown syrup.

Workup

  1. customThe flask head space is flushed with hydrogen gas (200 mL)
  2. customthe gas outlet adapter is closed
  3. stirringThe mixture is stirred for an additional 1 h under hydrogen, at which
  4. customThe catalyst is removed by vacuum filtration
  5. customThe volatiles are removed by rotary evaporation
  6. customto give a pink solid
  7. dissolutiondissolved
  8. customThe aqueous layer is removed
  9. washthe organic phase is washed with water (4 mL) and half saturated brine (3 mL)
  10. customThe volatiles are removed by rotary evaporation
  11. customto give a brown syrup
  12. customevaporated to dryness
  13. additionAbsolute ethanol (3 mL) is added to the residue
  14. customremoved by rotary evaporation

Sources & evidence

ORD record
ord-0457369c800148e49c5c539af247712b
Source dataset
uspto-grants-2013_06
Patent number
US08466296B2

Reaction notes

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