Phosphoric Acid → Aplindore

HRID 1259463Notes

Reaction equation

HRID 1259463 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+:26]([O-])=O)=[C:19]([CH2:20][C:21](OCC)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP(O)(O)=O>[Pt].C(O)C>[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:26][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 2

HCID 1004Phosphoric AcidHCID 59456459ethyl {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetate

Product 1

HCID 158784AplindoreYield 55.6%

Reagents, catalysts & solvents 2

HCID 23939PlatinumCatalystHCID 702EthanolSolvent

Conditions

Temperature
40 °C

Procedure

In a 500 mL Parr shake flask is charged crude ethyl {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetate (6.02 g, 14.5 mmol), ethanol (50 mL) and Pt—C (5% on carbon, 50% w/w water, 1.0 g). The flask is pressurized to 30 psig and shaken for 18 h. The pressure is released, the catalyst is removed by filtration through celite, and ethanol (20 mL) is used to rinse the filter cake. To the solution is added 85% H3PO4 (1.21 mL, 17.4 mmol) and the mixture is heated to 40° C. for 36 h. The solution is filtered through celite and the volatiles are removed. The residue is suspended in isopropyl acetate (50 mL), THF (25 mL) and 1 N NaOH is added until pH 10 is obtained. The organic extracts are washed with water and then with brine treated with Darco 12-20Li (0.5 g), filtered through celite and evaporated giving crude title compound (2.50 g, 55%) as a red-orange syrup. LCMS (Basic Method): 1.84 min, 311 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.4 (br s, 1H), 7.35-7.27 (m, 5H), 6.73 (d, J=8.3 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 4.37-4.35 (m, 1H), 4.25 (dd, J=2.2, 11.5 Hz, 1H), 4.03 (dd, J=7.3, 11.5 Hz, 1H), 3.88 (s, 2H), 3.44 (s, 2H), 2.97-2.88 (m, 2H), 8.9 (br s, 1H).

Workup

  1. customthe catalyst is removed by filtration through celite, and ethanol (20 mL)
  2. washto rinse the filter cake
  3. filtrationThe solution is filtered through celite
  4. customthe volatiles are removed
  5. additionTHF (25 mL) and 1 N NaOH is added until pH 10
  6. customis obtained
  7. washThe organic extracts are washed with water
  8. additionwith brine treated with Darco 12-20Li (0.5 g)
  9. filtrationfiltered through celite
  10. customevaporated

Sources & evidence

ORD record
ord-92166c07e6424431abd7dfc421253784
Source dataset
uspto-grants-2013_06
Patent number
US08466296B2

Reaction notes

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