Oxidative Decarboxylation of Naproxen FRANCISCO BoscA*, R A M ~ MART~NEZ-MANEZ~, N MIGUELA. MIRANDA*', JAIME PRIMO*, JUAN SOTO', AND LIRIOSVAN@ Received February 15,1991,from the 'Departamento de Quimica, Universidad Polit6cnica de Valencia, Camino de Vera s/n, Apartado 22012, 46071-Valencia, and the 'Departamento de Quimica Orghnica, Facultad de Farmacia, Universidad de Valencia, Avda Blasco Ibaiiez, 13, Accepted for publication July 15, 1991. 46010-Valencia, Spain. Abstract 0 The decarboxylation of naproxen (1H) and its salt (1-) was achieved by means of chemical [Ce(lV) or S,Oi-] and electrochemical oxidation. The product patterns were compatible with mechanisms involving single-electron transfer from the pi-system or the carboxylate
moiety. The results are discussed in connection with the involvement of electron-transfer processes in the reported phototoxicity of naproxen.
Table CChemlcal Oxldatlon of Naproxen (1H) and Its Salt (1-) wlth Ce(IV) In Methanol Product Distribution Molar Ratio: 1(YO)" Conversion or 1H/Ce(lV) ("4 3
4
6
111 112 1 13 114
38 1 4 12 13
9 4 6 4 8 0 2 85 3 84
111 1 I2 113 114
65 16 12 9
15 18 4 77 3 85 2 8 9
7
~~
1H
The oxidative nature of the atmosphere is one of the main causes of instability of various chemicals, including drugs.' Our understanding of the oxidation processes still remains rather unsatisfactory, mainly because of the complexity of the mechanistic pathways and the multiplicity and instability of the reactive intermediates. Single-electron transfer can be the basis of a number of processes leading to toxicity, including phototoxicity.2 We have recently found that photodecarboxylation of 6-methoxya-methyl-2-naphthaleneacetic acid (naproxen, 1H;Scheme I) leads to products derived from a carbenium ion (V),' whose formation can be explained by homolysis of a radical cation (111) a h r photoionization. This new photodecarboxylation pathway is interesting in connection with the mechanisms currently accepted for one-electron oxidation of carboxylates and also as a photochemical key to explain the observed in vivo phototoxicity exhibited by naproxen,4.6a property shared by other nonsteroidal anti-inflammatory drugs of the same structural group.616 We studied the oxidative decarboxylation of naproxen as an alternative method of drug degradation. Reactions were performed chemically (by means of well-established singleelectron-transfer oxidants) or electrochemically. Results of oxidative decarboxylation were compared with photolysis results.3J7.18
Results and Discussion Table 1 summarizes the results obtained for the chemical oxidation of naproxen (1H)and its salt (1-1 with Ce(1V) a t different substrate/oxidant molar ratios. The isolated products were 2-acetyl-6-methoxynaphthalene (3),179'8 241hydroxyethyl)-6-methoxynaphthalene(4),'73 24-methoxyethyl)-6-methoxynaphthalene(6),3 and methyl 6-methoxy-amethyl-2-naphthaleneacetate (7).19920
oO22-3H9/9Y05oO-#79$02.50/0 0 1992, American Pharmaceutical Association
1-
7 2 1 -b
2 3
-
-
15 68 72 61 65 66 74 67
a Values are in mole percent. The compounds listed account for >96% of the total products. - indicates that the product was not measurable at the given molar ratio.
Scheme I shows a plausible mechanistic rationalization of the results and is the basis for the discussion, which will be concerned mainly with the generation of the radical IV and the carbenium ion V from the primary intermediate I, 11, or 111 through routes a-f. In general, salts of arylacetic acids contain two electronactive centers: the carboxylate moiety and the aromatic nucleus.21Formation of benzylic radicals occurs by removal of one electron from either the carboxylate group (Kolbe reaction) or the pi-system of the aromatic ring (pseudo-Kolbe reaction), whereas formation of carbenium ions takes place by further oxidation of the radicals in an overall two-electron process.2-8 Inner-sphere mechanisms also have been proposed for some oxidations with metal ions.1g We compared the oxidation of naproxen and that of its salt. With an equimolar amount of Ce(IV),different proportions of radical-derived (the ketone 3 and the alcohol 4) and carbenium-ion-derived (the methyl ether 6) products were obtained depending on the dissociation state, even though the oxygen concentration in the medium remained nearly constant, close to the saturation level. The results show that the intermediate I11 can directly yield the carbenium ion V without consuming a second mole of Ce(IV). This behavior of I11 explains the enhanced formation of the methyl ether, via route e, when the free acid is used as starting substrate and the amount of Ce(1V) is limiting. Table I also shows that, when the molar ratio of Ce(1V) was increased, oxidation of the radical IV to the carbenium ion V (route 0 became the dominant process, and the methyl ether 6 was always obtained as the major product. In another experiment, the naproxen salt (1-1 was oxidized in water with S20:-. The isolated products were 3 (31%),4 (40%)) and 1,1'-bis(6-methoxy-2-naphthyl)ethoxyethane(5; 21%).The product 5 , obtained as a mixture of diastereomers, was identified on the basis of spectroscopic data. The most Journal of Pharmaceutical Sciences I 479 Vol. 81. No. 5, May 1992
salient features of the mass spectrum were the molecular ion at mlz 386 and the base peak at mlz 185, assignable to the benzylic cation V. The NMR spectrum of the isomeric mixture showed a characteristic multiplet a t S 4.1-3.7, corresponding to the benzylic protons, and two singlets at 6 2.8, corresponding to the methoxy groups. The latter signals appear to be abnormally shielded when compared with the reported ranges for related protons.39 This shielding suggests that 5 adopts a "sandwichlike" conformation (see structure) so that the protons of each half-moleculeare affected by the anisotropic effect of the parallel naphthalene rings. The dimeric ether 5 would be produced by reaction between the alcohol 4 and the carbenium ion V. Previously, no evidence existed for the formation of compounds such as 5 in related oxidations with S,O:-, in which mainly radicalderived products have been detected.30-33. Electrochemical oxidations offer, in general, many advantages over conventional oxidation methods. One example is the possibility of ruling out the involvement of inner-sphere electron-transfer mechanisms that may compete with outersphere mechanisms in the oxidation of arylacetic acids with metal salts. We also performed electrochemical oxidations of naproxen and its salt under different conditions to obtain more data about the oxidation process. Table I1 gives the oxidation potentials of naproxen and its salt in different solvents, obtained by plotting the corresponding voltammetric curves (Figure 1). In all c w s , totally irreversible curves were recorded, a fact making evident that a fast chemical reaction is coupled with the oxidation process. The type of solvent did not affect significantly the potential of the oxidation peak of either naproxen (1H)or its salt (1-1, However, oxidation is more favorable for the carboxylate ion than for the free acid, presumably becam? of the greater electron density of the carboxylate moiety. Thus oxidation through the intermediate I must be the preferred pathway when the salt 1- is the starting substrate. Nonetheless, when electron-rich aryl groups are present, withdrawal of one electron from the pi-system of the aromatic nucleus also occurs to a significant extent to give intermediates of the type 11.21
We performed the electrolysis at controlled potential of
Ar-CHMe-C0; I'
Ar-CHMe-C02'
\ -
\
Table Il-Anodic
Solvent Compound HzOe CH,OHh
1H
111H
Ep (VP
Eap (v)=
1.07' 1.19 1.45
1.10 1.20 1.47
-' -
76 21 3 7 17 76 3 1 7 89
-
-
-
54 31 33
compounds 1- and 1H over the oxidation peak with water and methanol as solvents. In related oxidations, the current density and the concentrations of added ions affect the relative extent of the different reaction paths and change noticeably the ratio of radical-derived products to carbenium ion-derived products.21-26 Hence, we attempted to maintain constant the current density and the concentration of the supporting electrolyte. The products 3-7 (Table II), previously described, were characterized by their physical and spectroscopic properties. The data indicate that the solvent is important in connection with the route followed in the oxidation (carbenium ion or radical formation). The alcohol can be obtained by two different routes: splitting of the hydroperoxide 2 or trapping of the carbenium ion V with water. However, we have previously observed that splitting of the hydroperoxide affords mixtures of the ketone 3 and the alcohol 4, for which the ratio of ketone to alcohol is approximately 4.3 Thus for
(a) -*
I
\ Ar-CHMeOOH
-
Product Distribution (YO)" Current Yield 3 4 5 6 7 ('/Id
a Values are in mole percent. The compounds listed account for >96% of the total products. Ep is electrode potential;V is applied voltage. The supporting electrolyteswere 0.1 M tetrabutylammonium hexafiuorophosphate (for CH,OH) and 0.1 M sodium sulfate (for H,O), referenced to the saturated calomel electrode (SCE). In all cases graphite was used as electrode; V = 200 mV/s. Eap is electrolysis anode potential (referenced to SCE with graphite as electrode). Current yield was calculated with the following data: 3,l F/mol; &7,2 F/mol; and 4 , l or 2 F/mol (see text). 'Na,SO, (0.1 M) was the supporting electrolyte. 'The value was obtained at pH 8-9. 9- indicates that the product was not measurable at the given conditions. Tetrabutylammonium hexafluorophosphate (0.1 M) was the supporting electrolyte.
(f)
Ar-CHh4e-C02H
Oxldatlon of Naproxen (1H) and Its Salt (1-)
-
Ar-COMe 3
Ar-CHMeOH 4
? Ar-CHMe-C02H Ar-CHhle-0-CEIMe-Ar
111
\
5 Ar-CHMeOMe 6
Ar-CHMe-C02Me
Ar =
7 Scheme I
480 I Journal of PharmaceuticalSciences Vol. 81, No. 5,May 1992
//
//
EN)
1.5
vs. S.C.E.
I
Figure l4yclic voltammogramsof naproxen salt (1-) in water ( 8 )and in CH,OH (b) and of naproxen (1H) in CH,OH (c). Starting potential,0.0 V; sweep rate, 200 rnV/s. i is electric current, E(V.) is electrode potential, and S.C.E. is saturated calomel electrode.
electrolysis in water, we assume that the alcohol arises mainly from the radical intermediate. Finally, when the electrolysis of the acid form (1H)was performed with methanol as solvent, the major product (about 90%)was the methyl ester of naproxen (7). This result can be rationalized by assuming that oxidation occurs with H,O consumption and consequent shift of the esterification equilibrium toward the ester side by electrochemical oxidation of water with simultaneous generation of H' ions. In fact we have obaeerved that, in methanol with a graphite electrode, water can be oxidized at the electrode potential value of 1.47 V used in the electrolysis experiments.
Experimental Section General M e t h o d e ' H NMR spectra were measured in CCl, with a 60-MHz instrument (Varian 360 EM); chemical shifte (6)are reported in ppm values, referenced to tetramethyleilane as internal standard. Mass spectra were obtained with a Hewlett-Packard 5988 A spectrometer; the ratios m/z and the relative intensities (%) are reported. GLC (gas-liquid chromatographic) analyses were performed with a Hewlett-Packard 5890 A instrument connected to a Hewlett-Packard 3390 A integrator. The electrochemical studies were conducted in methanol with tetrabutylammonium hexafhorophmphate (0.1 M) as supporting electrolyte or in distilled water with sodium sulfate as supporting electrolyte. Cyclic voltammograms were obtained with a programming function generator (Tacussel IMT-1) connected to a potentiostat (Tacuwl PJT 120-1).The working electrode was graphite with a saturated calomel reference electrode, separated from the test solution by a salt bridge containing the solvent and supporting electrolyte. The auxiliary electrode was a platinum wire. The electrochemical cell used for potential-controlled electrolysis was a conventional
H-type design with anodic and cathodic compartments separated by a porous glass frit. Isolation and purification were done by flash column chromatography on silica gel (Merck 60,76230mesh) with hexane as eluent or by high-performance liquid chromatography (HPLC) (Waters isocratic HPLC equipment) with a semipreparative silica gel (Microporasil column and hexane-ethyl acetate as eluent. Materials-Naproxen, obtained from Naproval (Lab. Vallen Heutre), was purified by chromatography on a short silica gel column with CH2Cl, as eluent, followed by recrystallization from CH,Cl,n-hexane. The sodium salt of naproxen was obtained by addition of an equimolar amount of CH,ONa to a solution of naproxen in CH30H. The solid remaining after evaporation of the resulting solution was dried under vacuum and washed with dichloromethane and ether. Ce(1V) Oxidatione-Oxidatwn of Naproxen (1H)in Methanol-A mixture of naproxen (30 mg) and the indicated amount of ceric ammonium nitrate (Table I) in methanol (5 mL) was stirred vigorously for 30 min, and then sodium hydroxide solution (10%;5 mL) was added. After extraction with n-hexane:ethyl acetate (1:11, the organic layer was dried (NaaO,) and analyzed by GLC. Oxiahtion of Naproxen Salt ( I - ) in MethanobA mixture of naproxen (30mg), a n equimolar amount of KOH, and the indicated amount of ceric ammonium nitrate (Table I) in methanol (6 mL) was stirred vigorously. After 30 min, n-hexane:ethyl acetate (1 : 1)was added. The organic layer was dried (Na,SO,) and analyzed by GLC. S,Oi- Oxidations-A solution of naproxen (1.5g, 6.5 mmol), KOH (2.2g, 39.3 mmol), and potassium peroxydisulfate (1.65g, 61 mmol) in water (275 mL) was heated a t 80°C for 24 h, with magnetic stirring. The mixture was extracted with n-hexane:ethyl acetate (1 :l), and the organic layer was dried (NaaO,) and evaporated under reduced pressure. Column chromatography of the products yielded the ketone 4 (0.41g, 31%), the alcohol 5 (0.52g, 40961,and l,l'-bis(6methoxy-2-naphthy1)ethoxyethane (6; 0.53 g, 21%). 'H NMR: 6 7.00-6.20(12H, m, Ar-HI, 3.95(2H, q + q, J = 7 Hz, CH), 2.80 (6H, s + 8, OMe), 0.95 (6H, d, J = 7 Hz,Me); MS:mlz 386 (M+, 26),186 (881,185 (loo), 171 (30).(For MS data, values in parentheses are percent relative intensities.) Electrochemical Oxidation-A typical electrolysis was performed as follows: 750 mg of naproxen (1H)or its salt (l-)waa dissolved in 35 mL of water (pH 8-9) or methanol, and the solution was electrolyzed for several hours at low current intensity (initially about 20 mA). Electrolysis was stopped when current intensity was about 1% of the initial value. The total charge was obtained by integration of the curve of intensity versus time. After electrolysis in methanol, the solvent was removed with a rotary evaporator, and the residue was partitioned between aqueous d i u m hydroxide and ether. The organic phaee was dried (NaaO,), filtered, and evaporated. After electrolysis in water, ether was added for extraction and then the organic layer was dried (Na,SO,), filtered, and evaporated. The product mixtures were analyzed by GLC and mass spectrometry.
Conclusions The data show that naproxen (1H)and its conjugate salt (1-1 undergo oxidative decarboxylation chemically, by treatment with known one-electron oxidizing reagents, or electrochemically. The product patterns can be related to the fate of intermediates I, 11, and 111, when they are generated by ejection of one electron in the photolysis of 1- and 1H. Presumably, this behavior is involved in the photobiological reactions of naproxen and reflects the low oxidation potential of this drug.
References and Notes 1. Connors, K. A.; Amidon, G. L.; Stella, V.J. Chemical Stability of Phurmaceuticals; Wiley: New York, 1986;pp 82-114. 2. Paillous, N.; Contat, M. In PhotoinducedElectron Tramfer; Fox, M.A.; Chanon, M., Eds.; Elsevier: Amsterdam, 1988;Part D, p 578. 3. Bo&, F.:Miranda, M. A.; Vaiio, L; Vargas, F. J. Photochem. Photobwl. A: Chem. 1990,54, 131-134. 4. Diffey, B. L.;Daymond, T. J.; Fairgreaves, H. Br. J.Rheumatol. 1983,22,239-242. Journal of Pharmaceutical Sciences I 481 Vol. 81, No. 5, May 1992
5. Ljunggren, B.; Lundberg, K. Photoakrmatol. 1985,2,377382. 6. Biebv. M.; Stern. R. J . Am. Acad. Dermatol. 1985,12,866-876. 7. W i b k r , .G. F.; .Kaidbey, K. H.; Kligman, A. M. Photochem. Photobwl. 1982,36,5!3-64. 8. Ijung en, B * B’ellerup, M.; Mdller, M. Arch. Dermatol. Res. 1983,%5,31&!43 9. Ferguson, J.; Addo, H. A.; M d i l l , P. E.; Woodcock, K. R.; Johnson, B. E.; Frain-Bell, W. Br. J . Dermatol. 1982, 107,
__
429-441. - - .- .
10. Ljunggren, B. Photodermatol. 1985,2,3-9. 11. McCormack, L. S.;Elgart, M. L.; Turner, M. L. J . Am. Acad. Dermatol. 1982,7,67&680. 12. Caatell, J. V.; Gomez, M. L.; Miranda, M. A.; Morera, I. M. Photochem. Photobwl. 1987,46,991-996. 13. Merot, Y.; Harms. M.; Saurat, J . H. Dermatol. 1983,166,301307. 14. Goh, C.L.; Kwok, S. F. Dermatol. 1985,170,74-76. 15. Przybilla, B.; Ring, J.; Schwab, U.; Born, M. Allergologie 1986,9, 8-15. 16. Przybilla, B.; Ring, J.; Schwab, U.; Galosi, A.; Braun-Falco, 0. Hautarzt 1987,38.18-25. 17. Moore, D. E.;Chappuis, P. P. Photochem.Photobwl. 1988,47, 173-180. 18. Coetanzo, L. L.; de Guidi, G.; Condorelli, G.; Cambria, A.; Fama, M. J . Photochem. Photobwl. B: Bwl. 1989;3,223-235. 19. Hiyama, T.; Inoue, M. Synthesis 1986,689-691. Spreafico, F.; Visentin, G. J . Org. Chem. 1987,52, 20. Picolo, 0.; 10-14. 21. Coleman, J. P.; Lines, R.; Utley, J. H. P.; Weedon, B. C. L. J . Chem.Soc. Perkrn Tram. II1974,1064-1069. 22. Linstead, R. D.; Shephard, B. R.; Weedon, B. C. L. J . Chem.Soc. 1952,3624-3627.
482 I Journal of Pharmaceutical Sciences Vol. 81, No. 5, May 1992
23. Wladislaw, B.; Giora, A. J . Chem. Soc. 1964,1037-1040. 24. Coleman, J. P.; Eberson, L. J . Chem. Soc. Chem. Commun. 1971; 1300-1301. 25. Masumizu, T.; Nozawa, K.; Kawai, K . ; Nakajima, S. Tetrahedron Lett. 1986,27,5556. 26. Trahanovsky, W. S.;Cramer, J.; Brixius, D. W. J . Am. Chem. SOC.1974,96,1077-1081. 27. Eberson. L.: Wistrand. L. Acta Chem. Scand. 1980.34.349-357. . . 28. J6neson,’J. Acta Chem.Scand. 1981,35,683-689. 29. Jdnsson, J. Acta Chem. Scand. 1983;35,761-768. 30. Tanner, D.D.;Osman, S. A. J . Am. Chem. Soc. 1968,90,65736574. 31. Norman. R.0.C.; Storev, P. M. J . Chem. Sm. 1970.1099-1106. 32. Walling; C.; Camaioni, M.;Kim, S. S. J . Am. Chem. Soc. 1978, 100,48144818. 33. Tanner, D. D.;Osman, S. A. J . Org. Chem.1987,52,46894693. 34. Mei gs, T. 0.;Miller, S. I. J . Am. Chem. Soc. 1972,94, 19891d. 35. Eplina, G. A.:Loves,A. J . Am. Chem. Soc. 1977,99,2700-2704. 36. Mei is,T. 0.; Giossweiner, L. I.; Miller, S. I. J . Am. Chem. Soc. 197j.94,7981-7986. 37. Joschek, H. I.; Groeeweiner, L. I. J . Am. Chem.Soc. 1966, 88, 326132(i8. - - - - - - - -.
38. Wan, P.; Yaks, K. J . Chem. Soc. Chem. Commun. 1982,275-276. 39.Pretach, E.; Clerc, T.; Seibl, J.; Simon, W. Tabellen zur StruktumufiMrung Organischer Verbindungen mit Spektroskopzschen Methoden; Springer: Berlin, 1976.
Acknowledgments We thank the Direccidn General de Investigaci6n Cientffica y T6cnica (grant no. PB 88-0494)for financial support.
moiety. The results are discussed in connection with the involvement of electron-transfer processes in the reported phototoxicity of naproxen.
Table CChemlcal Oxldatlon of Naproxen (1H) and Its Salt (1-) wlth Ce(IV) In Methanol Product Distribution Molar Ratio: 1(YO)" Conversion or 1H/Ce(lV) ("4 3
4
6
111 112 1 13 114
38 1 4 12 13
9 4 6 4 8 0 2 85 3 84
111 1 I2 113 114
65 16 12 9
15 18 4 77 3 85 2 8 9
7
~~
1H
The oxidative nature of the atmosphere is one of the main causes of instability of various chemicals, including drugs.' Our understanding of the oxidation processes still remains rather unsatisfactory, mainly because of the complexity of the mechanistic pathways and the multiplicity and instability of the reactive intermediates. Single-electron transfer can be the basis of a number of processes leading to toxicity, including phototoxicity.2 We have recently found that photodecarboxylation of 6-methoxya-methyl-2-naphthaleneacetic acid (naproxen, 1H;Scheme I) leads to products derived from a carbenium ion (V),' whose formation can be explained by homolysis of a radical cation (111) a h r photoionization. This new photodecarboxylation pathway is interesting in connection with the mechanisms currently accepted for one-electron oxidation of carboxylates and also as a photochemical key to explain the observed in vivo phototoxicity exhibited by naproxen,4.6a property shared by other nonsteroidal anti-inflammatory drugs of the same structural group.616 We studied the oxidative decarboxylation of naproxen as an alternative method of drug degradation. Reactions were performed chemically (by means of well-established singleelectron-transfer oxidants) or electrochemically. Results of oxidative decarboxylation were compared with photolysis results.3J7.18
Results and Discussion Table 1 summarizes the results obtained for the chemical oxidation of naproxen (1H)and its salt (1-1 with Ce(1V) a t different substrate/oxidant molar ratios. The isolated products were 2-acetyl-6-methoxynaphthalene (3),179'8 241hydroxyethyl)-6-methoxynaphthalene(4),'73 24-methoxyethyl)-6-methoxynaphthalene(6),3 and methyl 6-methoxy-amethyl-2-naphthaleneacetate (7).19920
oO22-3H9/9Y05oO-#79$02.50/0 0 1992, American Pharmaceutical Association
1-
7 2 1 -b
2 3
-
-
15 68 72 61 65 66 74 67
a Values are in mole percent. The compounds listed account for >96% of the total products. - indicates that the product was not measurable at the given molar ratio.
Scheme I shows a plausible mechanistic rationalization of the results and is the basis for the discussion, which will be concerned mainly with the generation of the radical IV and the carbenium ion V from the primary intermediate I, 11, or 111 through routes a-f. In general, salts of arylacetic acids contain two electronactive centers: the carboxylate moiety and the aromatic nucleus.21Formation of benzylic radicals occurs by removal of one electron from either the carboxylate group (Kolbe reaction) or the pi-system of the aromatic ring (pseudo-Kolbe reaction), whereas formation of carbenium ions takes place by further oxidation of the radicals in an overall two-electron process.2-8 Inner-sphere mechanisms also have been proposed for some oxidations with metal ions.1g We compared the oxidation of naproxen and that of its salt. With an equimolar amount of Ce(IV),different proportions of radical-derived (the ketone 3 and the alcohol 4) and carbenium-ion-derived (the methyl ether 6) products were obtained depending on the dissociation state, even though the oxygen concentration in the medium remained nearly constant, close to the saturation level. The results show that the intermediate I11 can directly yield the carbenium ion V without consuming a second mole of Ce(IV). This behavior of I11 explains the enhanced formation of the methyl ether, via route e, when the free acid is used as starting substrate and the amount of Ce(1V) is limiting. Table I also shows that, when the molar ratio of Ce(1V) was increased, oxidation of the radical IV to the carbenium ion V (route 0 became the dominant process, and the methyl ether 6 was always obtained as the major product. In another experiment, the naproxen salt (1-1 was oxidized in water with S20:-. The isolated products were 3 (31%),4 (40%)) and 1,1'-bis(6-methoxy-2-naphthyl)ethoxyethane(5; 21%).The product 5 , obtained as a mixture of diastereomers, was identified on the basis of spectroscopic data. The most Journal of Pharmaceutical Sciences I 479 Vol. 81. No. 5, May 1992
salient features of the mass spectrum were the molecular ion at mlz 386 and the base peak at mlz 185, assignable to the benzylic cation V. The NMR spectrum of the isomeric mixture showed a characteristic multiplet a t S 4.1-3.7, corresponding to the benzylic protons, and two singlets at 6 2.8, corresponding to the methoxy groups. The latter signals appear to be abnormally shielded when compared with the reported ranges for related protons.39 This shielding suggests that 5 adopts a "sandwichlike" conformation (see structure) so that the protons of each half-moleculeare affected by the anisotropic effect of the parallel naphthalene rings. The dimeric ether 5 would be produced by reaction between the alcohol 4 and the carbenium ion V. Previously, no evidence existed for the formation of compounds such as 5 in related oxidations with S,O:-, in which mainly radicalderived products have been detected.30-33. Electrochemical oxidations offer, in general, many advantages over conventional oxidation methods. One example is the possibility of ruling out the involvement of inner-sphere electron-transfer mechanisms that may compete with outersphere mechanisms in the oxidation of arylacetic acids with metal salts. We also performed electrochemical oxidations of naproxen and its salt under different conditions to obtain more data about the oxidation process. Table I1 gives the oxidation potentials of naproxen and its salt in different solvents, obtained by plotting the corresponding voltammetric curves (Figure 1). In all c w s , totally irreversible curves were recorded, a fact making evident that a fast chemical reaction is coupled with the oxidation process. The type of solvent did not affect significantly the potential of the oxidation peak of either naproxen (1H)or its salt (1-1, However, oxidation is more favorable for the carboxylate ion than for the free acid, presumably becam? of the greater electron density of the carboxylate moiety. Thus oxidation through the intermediate I must be the preferred pathway when the salt 1- is the starting substrate. Nonetheless, when electron-rich aryl groups are present, withdrawal of one electron from the pi-system of the aromatic nucleus also occurs to a significant extent to give intermediates of the type 11.21
We performed the electrolysis at controlled potential of
Ar-CHMe-C0; I'
Ar-CHMe-C02'
\ -
\
Table Il-Anodic
Solvent Compound HzOe CH,OHh
1H
111H
Ep (VP
Eap (v)=
1.07' 1.19 1.45
1.10 1.20 1.47
-' -
76 21 3 7 17 76 3 1 7 89
-
-
-
54 31 33
compounds 1- and 1H over the oxidation peak with water and methanol as solvents. In related oxidations, the current density and the concentrations of added ions affect the relative extent of the different reaction paths and change noticeably the ratio of radical-derived products to carbenium ion-derived products.21-26 Hence, we attempted to maintain constant the current density and the concentration of the supporting electrolyte. The products 3-7 (Table II), previously described, were characterized by their physical and spectroscopic properties. The data indicate that the solvent is important in connection with the route followed in the oxidation (carbenium ion or radical formation). The alcohol can be obtained by two different routes: splitting of the hydroperoxide 2 or trapping of the carbenium ion V with water. However, we have previously observed that splitting of the hydroperoxide affords mixtures of the ketone 3 and the alcohol 4, for which the ratio of ketone to alcohol is approximately 4.3 Thus for
(a) -*
I
\ Ar-CHMeOOH
-
Product Distribution (YO)" Current Yield 3 4 5 6 7 ('/Id
a Values are in mole percent. The compounds listed account for >96% of the total products. Ep is electrode potential;V is applied voltage. The supporting electrolyteswere 0.1 M tetrabutylammonium hexafiuorophosphate (for CH,OH) and 0.1 M sodium sulfate (for H,O), referenced to the saturated calomel electrode (SCE). In all cases graphite was used as electrode; V = 200 mV/s. Eap is electrolysis anode potential (referenced to SCE with graphite as electrode). Current yield was calculated with the following data: 3,l F/mol; &7,2 F/mol; and 4 , l or 2 F/mol (see text). 'Na,SO, (0.1 M) was the supporting electrolyte. 'The value was obtained at pH 8-9. 9- indicates that the product was not measurable at the given conditions. Tetrabutylammonium hexafluorophosphate (0.1 M) was the supporting electrolyte.
(f)
Ar-CHh4e-C02H
Oxldatlon of Naproxen (1H) and Its Salt (1-)
-
Ar-COMe 3
Ar-CHMeOH 4
? Ar-CHMe-C02H Ar-CHhle-0-CEIMe-Ar
111
\
5 Ar-CHMeOMe 6
Ar-CHMe-C02Me
Ar =
7 Scheme I
480 I Journal of PharmaceuticalSciences Vol. 81, No. 5,May 1992
//
//
EN)
1.5
vs. S.C.E.
I
Figure l4yclic voltammogramsof naproxen salt (1-) in water ( 8 )and in CH,OH (b) and of naproxen (1H) in CH,OH (c). Starting potential,0.0 V; sweep rate, 200 rnV/s. i is electric current, E(V.) is electrode potential, and S.C.E. is saturated calomel electrode.
electrolysis in water, we assume that the alcohol arises mainly from the radical intermediate. Finally, when the electrolysis of the acid form (1H)was performed with methanol as solvent, the major product (about 90%)was the methyl ester of naproxen (7). This result can be rationalized by assuming that oxidation occurs with H,O consumption and consequent shift of the esterification equilibrium toward the ester side by electrochemical oxidation of water with simultaneous generation of H' ions. In fact we have obaeerved that, in methanol with a graphite electrode, water can be oxidized at the electrode potential value of 1.47 V used in the electrolysis experiments.
Experimental Section General M e t h o d e ' H NMR spectra were measured in CCl, with a 60-MHz instrument (Varian 360 EM); chemical shifte (6)are reported in ppm values, referenced to tetramethyleilane as internal standard. Mass spectra were obtained with a Hewlett-Packard 5988 A spectrometer; the ratios m/z and the relative intensities (%) are reported. GLC (gas-liquid chromatographic) analyses were performed with a Hewlett-Packard 5890 A instrument connected to a Hewlett-Packard 3390 A integrator. The electrochemical studies were conducted in methanol with tetrabutylammonium hexafhorophmphate (0.1 M) as supporting electrolyte or in distilled water with sodium sulfate as supporting electrolyte. Cyclic voltammograms were obtained with a programming function generator (Tacussel IMT-1) connected to a potentiostat (Tacuwl PJT 120-1).The working electrode was graphite with a saturated calomel reference electrode, separated from the test solution by a salt bridge containing the solvent and supporting electrolyte. The auxiliary electrode was a platinum wire. The electrochemical cell used for potential-controlled electrolysis was a conventional
H-type design with anodic and cathodic compartments separated by a porous glass frit. Isolation and purification were done by flash column chromatography on silica gel (Merck 60,76230mesh) with hexane as eluent or by high-performance liquid chromatography (HPLC) (Waters isocratic HPLC equipment) with a semipreparative silica gel (Microporasil column and hexane-ethyl acetate as eluent. Materials-Naproxen, obtained from Naproval (Lab. Vallen Heutre), was purified by chromatography on a short silica gel column with CH2Cl, as eluent, followed by recrystallization from CH,Cl,n-hexane. The sodium salt of naproxen was obtained by addition of an equimolar amount of CH,ONa to a solution of naproxen in CH30H. The solid remaining after evaporation of the resulting solution was dried under vacuum and washed with dichloromethane and ether. Ce(1V) Oxidatione-Oxidatwn of Naproxen (1H)in Methanol-A mixture of naproxen (30 mg) and the indicated amount of ceric ammonium nitrate (Table I) in methanol (5 mL) was stirred vigorously for 30 min, and then sodium hydroxide solution (10%;5 mL) was added. After extraction with n-hexane:ethyl acetate (1:11, the organic layer was dried (NaaO,) and analyzed by GLC. Oxiahtion of Naproxen Salt ( I - ) in MethanobA mixture of naproxen (30mg), a n equimolar amount of KOH, and the indicated amount of ceric ammonium nitrate (Table I) in methanol (6 mL) was stirred vigorously. After 30 min, n-hexane:ethyl acetate (1 : 1)was added. The organic layer was dried (Na,SO,) and analyzed by GLC. S,Oi- Oxidations-A solution of naproxen (1.5g, 6.5 mmol), KOH (2.2g, 39.3 mmol), and potassium peroxydisulfate (1.65g, 61 mmol) in water (275 mL) was heated a t 80°C for 24 h, with magnetic stirring. The mixture was extracted with n-hexane:ethyl acetate (1 :l), and the organic layer was dried (NaaO,) and evaporated under reduced pressure. Column chromatography of the products yielded the ketone 4 (0.41g, 31%), the alcohol 5 (0.52g, 40961,and l,l'-bis(6methoxy-2-naphthy1)ethoxyethane (6; 0.53 g, 21%). 'H NMR: 6 7.00-6.20(12H, m, Ar-HI, 3.95(2H, q + q, J = 7 Hz, CH), 2.80 (6H, s + 8, OMe), 0.95 (6H, d, J = 7 Hz,Me); MS:mlz 386 (M+, 26),186 (881,185 (loo), 171 (30).(For MS data, values in parentheses are percent relative intensities.) Electrochemical Oxidation-A typical electrolysis was performed as follows: 750 mg of naproxen (1H)or its salt (l-)waa dissolved in 35 mL of water (pH 8-9) or methanol, and the solution was electrolyzed for several hours at low current intensity (initially about 20 mA). Electrolysis was stopped when current intensity was about 1% of the initial value. The total charge was obtained by integration of the curve of intensity versus time. After electrolysis in methanol, the solvent was removed with a rotary evaporator, and the residue was partitioned between aqueous d i u m hydroxide and ether. The organic phaee was dried (NaaO,), filtered, and evaporated. After electrolysis in water, ether was added for extraction and then the organic layer was dried (Na,SO,), filtered, and evaporated. The product mixtures were analyzed by GLC and mass spectrometry.
Conclusions The data show that naproxen (1H)and its conjugate salt (1-1 undergo oxidative decarboxylation chemically, by treatment with known one-electron oxidizing reagents, or electrochemically. The product patterns can be related to the fate of intermediates I, 11, and 111, when they are generated by ejection of one electron in the photolysis of 1- and 1H. Presumably, this behavior is involved in the photobiological reactions of naproxen and reflects the low oxidation potential of this drug.
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Acknowledgments We thank the Direccidn General de Investigaci6n Cientffica y T6cnica (grant no. PB 88-0494)for financial support.
