Methanol → (R)-2-(5-Nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate

HRID 1161262Notes

Reaction equation

HRID 1161262 reaction equation
[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][C@H:16]([CH3:19])[CH2:17][OH:18].CO.C(Cl)Cl.CN(C)C=O.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)C(C)C)(C)C.C(NC(C)C)(C)C>C(OCC)(=O)C.C(N(CC)CC)C>[C:30]([O:18][CH2:17][C@H:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH3:19])(=[O:32])[CH3:31]

Participants

11

Reactant 8

HCID 887MethanolHCID 6228DimethylformamideHCID 6344DichloromethaneHCID 6367Acetyl chloride3×HCID 7912DiisopropylamineHCID 80308(R)-(-)-2-Amino-1-propanolHCID 81531Diisopropylethylamine2×HCID 100127605-nitro-1H-isochromen-1-one

Product 1

HCID 59515745(R)-2-(5-Nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate

Reagents, catalysts & solvents 2

HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 5-nitro-isochromen-1-one (6.81 g, 0.0320 mol), (2R)-2-Aminopropan-1-ol (5.0 mL, 0.064 mol) and methanol (210 mL, 5.1 mol) was heated at reflux for 1 hour. 10 ml of Triethylamine was added and the reaction temperature was lowered to 60° C. and stirred at this temperature for 3 hours. LC-MS analysis showed the starting material was consumed. The reaction mixture was reduced in vacuo and the reaction flask was placed under high vacuum for 1 hour. The black residue was taken up in a mixture of methylene chloride (200 mL, 2 mol) and N,N-dimethylformamide (7.6 mL, 0.098 mol). Acetyl chloride (9.1 mL, 0.13 mol) and N,N-diisopropylethylamine (14 mL, 0.078 mol) were added and the reaction was allowed to stir at 40° C. for 5 hours. LC-MS analysis showed that the reaction did not go to completion. Two equivalents of acetyl chloride and 1 equivalent of N,N-Diisopropylamine were added and the reaction was left to stir overnight at room temperature. After analysis showed that less than 50% of the starting material was consumed, 4 more equivalents of acetyl chloride and 2 equivalents of N,N-diisopropylethylamine were added and the reaction temperature raised to 40° C. The reaction was allowed to stir for 4 more hours. LC-MS analysis showed the presence of approximately 5% of unreacted material. The flask was cooled to room temperature and reduced in vacuo. The dark yellow residue was taken up in 300 ml ethyl acetate and washed 3 times with 50 ml water. Saturated sodium chloride solution was added to remove any emulsion formed between the layers. Most of the desired product stayed in the organic layer although a minimal amount was in the aqueous layer. The organic layer was dried with sodium sulfate and reduced in vacuo to produce a brownish-yellow oil which was purified via flash chromatography using a 120 g normal phase silica column and an Ethyl acetate:Hexane gradient (0-60%). The pure fractions were collected and volatiles were removed under reduced pressure to give a yellow oil. M+1=291.0 1H-NMR (400 MHz, DMSO-d6) δ 8.63 (dq, 1H), 8.48 (dd, 1H), 7.83 (d, 1H, J=8.02 Hz), 7.69 (t, 1H, J=8.02 Hz), 7.09 (dd, 1H, J=8.02 Hz), 5.32-5.22 (m, 1H), 4.33 (d, 2H, J=6.26 Hz), 1.93 (s, 3H), 1.40 (d, 3H, J=7.11 Hz).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 1 hour
  3. customwas lowered to 60° C.
  4. customwas consumed
  5. waitthe reaction flask was placed under high vacuum for 1 hour
  6. stirringto stir at 40° C. for 5 hours
  7. waitthe reaction was left
  8. stirringto stir overnight at room temperature
  9. customwas consumed
  10. stirringto stir for 4 more hours
  11. temperatureThe flask was cooled to room temperature
  12. washwashed 3 times with 50 ml water
  13. additionSaturated sodium chloride solution was added
  14. customto remove any emulsion
  15. customformed between the layers

Sources & evidence

ORD record
ord-a18c91ab1a554ae98a1ed998f60f3de1
Source dataset
uspto-grants-2010_10
Patent number
US07816371B2

Reaction notes

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