Nitric Acid → Naproxen ethyl ester

HRID 1873614Notes

Reaction equation

HRID 1873614 reaction equation
C(OC(=O)C)(=O)C.[N+]([O-])(O)=O.C(=O)(O)[O-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@H:29]([CH3:40])[C:30]([O:32][CH2:33][CH2:34]S(CCO)=O)=[O:31])[CH:23]=[CH:22]2>C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@H:29]([CH3:40])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[CH:22]2

Participants

6

Reactant 4

HCID 944Nitric AcidHCID 7918Acetic AnhydrideHCID 516892Sodium BicarbonateHCID 21075926HCID 21075926, compound

Product 1

HCID 711615Naproxen ethyl esterYield 22%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

To acetic anhydride (9.1 mL, 98.1 mmol) at 0° C. was added fuming nitric acid (90%, 2.86 mL, 61.3 mmol) with stirring. After addition was complete, the mixture was stirred at 0° C. for 5 minutes, then added drop-wise to a solution of the product of Example 1a (4.10 g, 12.3 mmol) in ethyl acetate (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then poured into a pre-cooled (0° C.) mixture of 25 mL of ethyl acetate and 50 mL of sodium bicarbonate. The mixture was stirred cold for 20 minutes, and then warmed to room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with sodium bicarbonate, water, and brine, and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica, eluting with methanol/ethyl acetate (gradient, 0% to 20%), gave 2-((2-nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate as a pale yellow solid (1.07 g, 22% yield) and 2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate as a white solid. 2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate (1.87 g, 44% yield). Mp 74-86° C. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.65 (d, J=1.0 Hz, 1H), 7.37 (dt, J=1.9, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 4.52 (m, 2H), 3.91 (s, 3H), 3.87 (q, J=7.2 Hz, 1H), 2.97 (m, 2H), 2.84 (br.s, 1H), 2.62 (m, 2H), 1.59 (d, J=7.2 Hz, 3H) Mass spectrum (API-TIS) m/z 351 (MH+). 2-((2-(nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate. Mp 72-88° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.64 (br s, 1H), 7.35 (dt, J=2.1, 8.5 Hz, 1H), 7.16 (dd, J=2.5, 8.9 Hz, 1H), 7.11 (br s, 1H), 4.54-4.29 (m, 4H), 3.91 (s, 3H), 3.86 (q, J=7.2 Hz, 1H), 3.01-2.83 (m, 2H), 2.64-2.46 (m, 2H), 1.60 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 396 (MH+), 413 (M+18+).

Workup

  1. additionAfter addition
  2. stirringthe mixture was stirred at 0° C. for 5 minutes
  3. stirringThe reaction mixture was stirred at 0° C. for 10 minutes
  4. additionpoured into
  5. temperaturea pre-cooled
  6. stirringThe mixture was stirred cold for 20 minutes
  7. customThe reaction mixture was partitioned between ethyl acetate and water
  8. washwashed with sodium bicarbonate, water, and brine
  9. dry with materialdried over sodium sulfate
  10. customThe solvent was evaporated
  11. customthe residue was purified by column chromatography on silica
  12. washeluting with methanol/ethyl acetate (gradient, 0% to 20%)

Sources & evidence

ORD record
ord-ed0aefb4ae10430e919ef098f4433f6e
Source dataset
uspto-grants-2012_11
Patent number
US08304409B2

Reaction notes

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