Naproxen esters

F Harboe, C Larsen, MJ Johansen, HP Olesen. Macromolecular prodrugs. XV. Colon-targeted delivery—Bioavailability of naproxen from orally administered dextran-naproxen ester prodrugs varying in molecular size in the pig. Pharm Res 6(11) 919—923, 1989. 

Figure 18 Kinetic resoiution of racemic naproxen ester 28 by antibody 15G2 raised against hapten 27.

The lipase enzyme stereospecifically hydrolyzes the (+) isomer of naproxen ester. The enzyme is immobilized in the wall of an inside-skinned hollow fiber membrane. The racemic d and / naproxen ester mixture, dissolved in methyl isobutyl ketone, is introduced on the shell side of the fiber and an aqueous buffer solution is circulated through the fiber lumen. The lipase enzyme hydrolyzes the d form of naproxen ester, forming ethanol and naproxen d. Naproxen d is a carboxylic acid soluble in aqueous buffer but insoluble in methyl isobutyl ketone. Consequently naproxen d is removed from the reactor with the buffer solution. The naproxen / ester remains in the methyl isobutyl ketone solution. This technique achieves an essentially complete separation of the d and Z forms. In a clever final step... 

An (/ ,S)-naproxen ester 96 is obtained through regioselective hydrocarbalkoxylation of 6-methoxy-2-naphthylethene (95) catalyzed by PdCl2[P(c-C6Hn)Ph2l2 with 100% regioselectivity in 95% yield (Eq. 52)." ... 

Other interesting appUcations regard (S)-Naproxen through biphasic EMRs. In these cases, the presence of the emulsion combined with the enzyme bioreactor improves the catalytic activity and enantiose-lectivity of the immobilized enzyme, along with the mass transfer of the hydrophobic reagent (Naproxen esters and triglycerides) note that the immobilization procedure preserves enzyme stability without altering its enantioselectivity. 

Table 6B Enantioselective Esterification of rac-2-(6-methoxy-2-naphthyl)Propionic Acid Obtaining the Naproxen Esters... 

The first point to be mentioned is that usually the structure of the alcohol moiety of the starting profen ester does not have a dramatic influence on the yield and/or the enantioselectivity in hydrolytic processes (see Table lA [83,84] or Table 2A [77,85]) on the contrary, the alcohol specificity of the lipase might be the key in the yield achieved in the esterification. This fact is shown in Tables 6B ([100,103], resolution of naproxen esters... 

Table using 3-3. Enantioseparation of l-methylnaphthoyl-A. A -diethylamide and naproxene CSPs 1-11. methyl ester... 

C16H14O6S3 84449-65-0) see Raloxifene hydrochloride (S)-2-[(methylsulfonyl)oxy]propanoic acid ethyl ester (QHijOjS 63696-99-1) see Naproxen (5)-2-[(methylsulfonyl)oxy]propanoyl chloride (C4H7CIO4S 85277-55-0) see Naproxen 2-methylsulfonylphenothiazine (C13H11NO2S2 23503-68-6) see Metopimazine Sulforidazine... 

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

These studies have been extended and confirmed with A-monosubsti-tuted and A, A-di substituted carbamoylmethyl esters of 6-methoxy-2-naph-thylacetic acid [38], This compound, a close analogue of naproxen (8.26), is the active metabolite of the anti-inflammatory agent nabumetone. The A-substituents investigated were mostly lower alkyl and oxygenated alkyl groups. The compounds were quite stable in buffer under physiological... 

In Sect. 8.2.3, we have discussed 1-alkyl-l-azacycloalkan-2-ones (8.32, n = 1 or 2 m = 3, 4, 5 or 6) as a group of amidoalkyl esters, taking prodrugs of indomethacin (8.9, R = OH) and naproxen (8.26) as examples [43a,b]. For both compounds, the prodrugs in the series n = 1 were rapidly hydrolyzed (tm ca. 0.5-1 h in pH 7.4 buffer at 32°). Furthermore, the carbinolamides liberated were not fully stable and broke down by hydrolysis to produce the toxic formaldehyde (Fig. 8.3) [62], Thus, the half-life of decomposition of A-(hydroxymethyl)benzamide (HOCH2-NH-CO-C6H5), a pro-moiety of 8.56 discussed below, was 160 h at pH 7.4 and 37° [69]. This means that a small amount of formaldehyde may be formed in vivo. 

J. Rautio, H. Taipale, J. Gynther, J. Vepsalainen, T. Nevalainen, T. Jarvinen, In vitro Evaluation of Acyloxyalkyl Esters as Dermal Prodrugs of Ketoprofen and Naproxen , J. Pharm. Sci. 1998, 87, 1622-1628. 

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