Naproxen carrying

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. 

Analysis is carried out on tablets containing naproxen 100 mg and aspirin 250 mg per tablet. A narrow range calibration curve is constructed within 20% of the expected concentration of the diluted tablet extract. UV monitoring of the column effluent is carried out at 278 nm. Suggest a column and mobile phase for this analysis both aspirin and naproxen are discussed earlier in this chapter. Suggest a suitable column and mobile phase for this analysis. The following data were obtained for the analysis ... 

B-deuterated naproxen (4) was the dominant species (>60%) when the hydrogenation of concentrated 1 (>5%) in CH3OD was carried out under low H2 pressure (<10 psig) and in the absence of a base (such as triethylamine). 

A typical procedure is a follows An esterification solution was prepared by dissolving 3.5 g(+)-menthol,0.12 g DCC, 3 mg 4-dimethylaminopyridine (4-DMAP), and 3 mg 4-DMAP-HCI in one mL dry CH2CI2. For the analysis of a product sample, about 0.05mg of the compound in about 10 microliter dichloromethane is mixed well with 10(0.1 esterification solution at ambient temperature for 30 minutes. The final solution was analyzed on a Varian 370 GC with a 25-meter Chirasil-L-Val column at 195°C isothermally. Excellent baseline separations of the diasteromers are usually obtained. A calibration with naproxen of known optical purity is carried out before using this method for analysis. 

Over HBEA zeolites, acetylation of 2-methoxynaphthalene with acetic anhydride leads mainly to l-acetyl-2-methoxynaphthalene. However, the desired product, i.e. 2-acetyl-6-methoxynaphthalene, precursor of Naproxen is obtained at long reaction time by an intermolecular irreversible isomerization process. A very selective production of II (83%) can be obtained by acetylation of 2-methoxynaphthalene over a commercial HBEA zeolite (Si/Al = 15) at 170°C, with nitrobenzene as a solvent. With dealuminated HBEA samples (framework Si/Al ratio between 20 and 40), better results could be expected. Furthermore, preliminary experiments showed that this selective synthesis of 2-methoxynaphthalene can be carried out in a flow reactor system. 

The reaction can be carried out asymmetrically, using nickel complexes of chiral phosphite ligands. Examples are the enantioselective hydrocyanation of norbomene using ligand (22-XVIII),48 and of vinylnaphthalene derivatives with (22-XIX).49 The latter is a precursor for the anti-inflammatory drug naproxen. 

Hydrolysis of conjugated naproxen has been reported during storage of urine samples, and assays carried out immediately after collection suggested that only very small amounts of unchanged drug were excreted (R. A. Upton etal., J. pharm. Sci., 1980, 69,1254-1257). 

Sulfamethoxazole failed to produce any trappable radicals with an array of different spin traps, but naproxen afforded the EPR spectrum shown in Figure 2.11 when irradiated with 330 nm UV-R in the instrument cavity in the presence of 2-methyl-2-nitroso-propane (MNP). The spectrum contains contributions from di-t-butyl nitroxide, a known photoproduct of MNP. The H-atom adduct MNP-H also evident can arise by several different mechanisms, including the trapping of an H atom by MNP the reaction of MNP with an electron followed by protonation and the direct reduction of MNP by an excited state species. In view of the flash photolysis results, it was concluded that photoionization was the major precursor of MNP-H. The third radical corresponded to a C-centered radical carrying a single H atom, leading to the postulate of a decarboxylation reaction as the primary photochemical step. Confirmation of the participation of free radical intermediates came from the initiation of the free radical polymerization of acrylamide with rates as shown in Table 2.1. 

Owing to the simplicity, selectivity and economy of this new procedure, the a-bromo alkyl aryl acetals have been proposed as starting materials for the industrial production of some 2-aryl propionic acids such as the important pharmaceutical drugs, Ibuprofen and Naproxen. For instance, the preparation of enantiomerically pure Naproxen has been carried out, in one step, by means of the highly stereoselective Lewis acid catalyzed rearrangement of a starting a-bromo acetal, involving a 1,2-aryl shift (ref. 3) (Fig. 3) ... 

Acylation of 2-methoxynaphthalene with acetic anhydride was carried out using different solid acid catalysts such as zeolites, acid activated clays, ion exchange resins and sulphated zirconia. The products of the reaction are precursors of many organic and pharmaceutical intermediates. For example, the para isomer of the reaction product, 6-methoxy-2-naphthalene-a-methyl ketone is useful as a raw material for the manufacture of well-known anti-inflammatory dru called naproxen. The reaction products were isolated and confirmed by their melting points, H-NMR, gas chromatography, etc. 

Irradiation of 2-[N-(pentafluorophenyI)amino]-3-phenylcyclopropenone promotes decarbonylation to give N-(pentafluorophenyl)phenylethynamine and 2-phenyl-3-[N-(pentafluorophenyl)amino]acrylic acid by a process for which there is no known precedent,and the photoextrusion of carbon monoxide from l,3-bis(ethylenedioxy)indan-2-one has been used as the first step in a new synthesis of 1,2-dioxobenzocyclobutene. This represents an unusual example of the decarbonylation of a five-membered cyclic ketone in the preparation of a highly strained and functionalised cyclobutane derivative. The photolysis of a-naphthaleneacetic acid in aqueous solution proceeds by decarboxylation and oxidation of the aromatic ring, and has been carried out at a variety of different wavelengths. The primary step occurs by pseudo-first order kinetics and the optimum photolysis rate has been observed using Ti02 as photocatalyst. Within the cavity of P-cyclodextrin, naproxene (129) has been photodecarboxylated to... 

Thus, the assertion that rofecoxib could have been known to be worse than placebo by 2000 is based entirely on an auxiliary hypothesis that naproxen and placebo are identical. This hypothesis may or may not have been reasonable at the time, but the meta-analysis as carried out by Juni et cd. (2004) cannot prove it. To be fair to these authors, they did carry out some independent investigation of this hypothesis by looking at studies that had compared naproxen with placebo but here they assumed that absence of evidence was evidence of absence and did not use methods that have been developed for formally incorporating evidence regarding previous trials of comparators. (See the discussion of the approaches of Hasselblad and Kong (2001) and Hlrotsu and Yamada (1999) in Chapter 15). 

Naproxen and its metabolites were measured (31) in urine. 1-2 ml of sample was acidified with 0.1 ml of 0.1M-HCI and extracted with 5 ml of CHCI3. The extract was evaporated, and the residue was dissolved in 100 p.1 of ethanol. 10 pi portions were spotted on to silica gel 60 F254 plates and TLC was carried out with CHClsimethanol (17 3) as mobile phase. Spots corresponding to naproxen and its 6-demethylmetabolite (Rf 0.54 and 0.41, respectively) were visualized under 254 nm radiation, scraped off and extracted with aq. 95% ethanol (4x5 ml). The extracts were diluted to 25 ml, and the absorbance was measured at 232 nm. The calibration graph covered the range 0.2-0.3 pg mT in the final solution. 

Commenls The preparation of alcoholic HCl can also be carried out in silu by the addition of acetyl chloride to the dry chiral alcohol [8]. Although the conditions used for these reactions are harsh, the authors reported no evidence of racemization during the derivatization of naproxen [54] even after an extended reaction time of 23 h. Lee el al. [64], however, observed a small peak, corresponding to approximately 2%, when enantiomeri-cally pure ibuprofen was derivatized under the conditions described in procedure C the results could have been attributed to either racemization or the presence of impurities in the substrates or reagents. 

---