Of naproxene

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

Fig. 2-5. Examples showing the eomplementary separations on glyeopeptide CSPs. (A) Separation of N-CBZ-norvaline on vaneomyein (left) and teieoplanin (right). The mobile phase was methanol 1 % triethylammonium aeetate (20/80 v/v) pH 4.1. (B) Separation of warfarin on teieoplanin (left) and vaneomyein (right) CSPs. The mobile phase was aeetonitrile 1 % triethylammonium aeetate (10/90 v/v) pH 4.1. (C) Separation of naproxen on teieoplanin (left) and ristoeetin A (right). The mobile phase was methanol 0.1 % triethylammonium aeetate (30/70 v/v) pH 4.1. All eolumns were 250 x 4.6 mm i.d. The flow rate for all the separations was 1 mL min at ambient temperature (23 °C).

TABLE 28.2 An Example of a Capsule Eormnlation of Naproxen as Generated by the Sanofi System... 

A potentially attractive route for the production of -naproxen is ba.sed on the following reaction ... 

Fig. 3 Intrinsic compressibility of nonagglomerated naproxen (control) and of naproxen that has been spherically agglomerated with different solvents. (From Ref. 21.)...

Table 7.23 shows the results for 47 specific PAMPA models tested at pION, according the the scheme in Fig. 7.58. The two columns on the right are the r2 values in the comparisons. The neutral-lipid models (1.0, 1A.0, 2.0, 3.0, and 4.0) at pH 7.4 do not explain the permeability trend indicated in the human jejunal permeabilities [56]. Octanol was least effective, with r2 0.01. This should not be too surprising, since we did note that the appearance of naproxen, ketoprofen, and piroxicam at the top of the HJP ordering was unexpected. Our expectations were based on the octanol-water lipophilicity scale, which clearly does not correlate with the HJP trend. Adding a sink condition to the 2% DOPC model (model 1.1) improves correlation (r1 increases from 0.33 to 0.53). The addition of cholesterol to the 2% DOPC/dodecane system made the model unstable to the surfactant-created sink condition. 

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. 

The phase transformation relationships for the solvatomorphs of naproxen sodium have been reported [71], The dihydrate phase is obtained upon crystallization from water, and a monohydrate phase could be prepared by the dehydration of the dihydrate phase in a desiccator (RH = 0%) for two days. The anhydrate phase could be obtained from either the monohydrate or dihydrate by drying the substance in an oven at 120 °C for two hours. Thermal analysis data was used to demonstrate the existence of two types of water in the dihydrate phase, and that each could be removed at a characteristic temperature. 

The introduction of electronic asymmetry into this class of bis(diaryl)phosphinites has been used to design catalysts that can afford both enantiomers of naproxen nitrile. If the carbohydrate scaffold is based on methyl o-D-fructol uranosidc (29), (i )-naproxen nitrile is produced. In a similar manner to the results above, electron-donating aryl substituents on phosphorus afford... 

Thus, [HRh(C0)(TPPTS)3]/H20/silica (TPPTS = sodium salt of tri(m-sulfophenyl)phopshine) catalyzes the hydroformylation of heavy and functionalized olefins,118-122 the selective hydrogenation of a,/3-unsaturated aldehydes,84 and the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic add (a precursor of naproxen).123,124 More recently, this methodology was tested for the palladium-catalyzed Trost Tsuji (allylic substitution) and Heck (olefin arylation) reactions.125-127... 

In contrast, the opposite result was observed when these materials were used in the acylation of a bulky substrate (2-methoxynaphthalene, 2-MN). In this case, l-acetyl-2-metoxynaphthalene (1-A,2-MN) and 6-acetyl-2-metoxynaphthalene (6-A,2-MN) are the main reaction products (Scheme 2). The latter is an intermediate for the preparation of Naproxen (antiinflammatory drug) and, therefore, the most interesting product. Initially, 2-MN acylation leads to 1-A,2-MN (the kinetically controlled product). However, at long times, the selectivity to 6-A,2-MN usually increases due to two secondary reactions transacylation of 1-A,2-MN with a molecule of 2-MN and protodeacylation of 1-A,2-MN yielding 2-MN [7],... 

Applications. In the last decade a lot of research has been devoted to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acetamido ligand as additional functionality. In Figure 4.17 four are listed, which are important as anaesthetics for rheumatic diseases. Their sales in beat many bulk chemicals the turnover of Naproxen (retail) in 1990 was 700 million for 1000 tons. S-Naproxen is now being produced by Syntcx via resolution with a chiral auxiliary. The main patents from Syntex expired in the U.S. in 1993, the reason for a lot of activity to study alternative synthetic routes. Routes leading to an asymmetric centre are o asymmetric hydrogenation of an unsaturated acid, o asymmetric carbohydroxylation of a styrene precursor, o asymmetric hydroformylation of a styrene precursor and oxidation. 

Several important industrial applications of the Heck reactions are known. The world s largest producer of Naproxen is Albemarle and they make Naproxen using two homogeneously catalysed steps, a Heck reaction and a palladium catalysed hydroxycarbonylation. The last step is carried out using palladium without chiral ligand and the enantiomers obtained are separated, see Figure 13.18. 

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... 

A comparable approach was used to design (piperazine-1-yl)alkyl prodrugs of naproxen (8.26), some of which improved severalfold the skin permeability of the drug [42],... 

An example is provided by the renal delivery of naproxen coupled to lysozyme via an L-lactic acid spacer [261b]. Here, the terminal amino group... 

Fig. 22 In-situ EDXRD data for the intercalation of naproxen into hexagonal LiAl - Cl. a 3D stacked plot for the reaction at 31 °C. b Plot of extent of reaction vs time for the (004) reflection of the intercalate over a range of temperatures...

Figure 4.3. The chemical synthesis of naproxen-HSA. Naproxen is first converted to an ester and is then coupled to the free E-NH2 of the lysine residues in human serum albumin (HSA). NHS N-hydroxysuccinimide, DCC dicyclohexylcarbodiimide.

The coupling of 2 moles of naproxen to 1 mole of lysozyme did not affect the catabolism of lysozyme in rat kidney [66,75]. After delivery to the kidney, naproxen in the form of naprox-... 

No detectable amounts of naproxen or its lysine conjugates were found in the plasma after administration of the conjugate and it can be inferred that excretion into the urine is the crucial process which determines the elimination rate fi. The lack of diffusion into the bloodstream is a favourable property in relation to unwanted extra-renal effects. 

Effects of Targeted Drugs Using an LMWP as Carrier 5.3.4.1 Renal Effects of Naproxen-Lysozyme... 

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