Naproxen Ethanol

Carbonylation of IBPE and other 2-arylethanols with various organosoluble Pd-catalysts was studied in detail with special emphasis on the role of the promoters p-toluenesulfonic acid and LiCl [55], Some of the catalytic species, such as [PdCl(PPh3)2] formed from [Pd(PPh3)4] or from Pd(II) precursors in aqueous methylethylketone (MEK) under reaction conditions (54 bar CO, 105 °C) were identified by P NMR spectroscopy. Ibuprofen was obtained in a fast reaction (TOP = 850 h" ) with 96% yield (3-IPPA 3.9 %), while the carbonylation of l-(6-methoxynaphtyl)ethanol gave 2-(6-methoxynaphtyl)propionic acid (Naproxen) with high selectivity (97.2 %) but with moderate reaction rates (TOP = 215 h" ). 

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... 

Type I CSPs have also been used with aqueous mobile phases. Pirkle et al. (32) have reported on the resolution of N-(3,5-dinitrobenzoyl) derivatives of M-amino adds and 2-aminophosphonic adds on an (l )-N-(2-naphthyl)-alanine-derived CSP using a mobile phase composed of methanol-aqueous phosphate buffer. The utility of achiral alkyltrimethylammoruum ion-pairing reagents was also investigated. Other examples include the following (1) The recently commercialized ot-Burke 1 CSP resolves the enantiomers of a number of underivatized p-blockers using an ethanol-dichlorornethane-ammonium acetate mobile phase (33) (2) an (R)-l-naphthylethylurea CSP was used to resolve N-(3,5-dinitrobenzoyI)-substituted amino adds and 3,5-dinitrobenzoyl amide derivatives of ibuprofen, naproxen, and fenoprofen with acetonitrile-sodium acetate mobile phases (34). 

ASA = aspirin NSAIDs = non-steroidal anti-inflammatory drugs, such as ibuprofen, naproxen, and diclofenac CNS stimulants include drugs such as pseudoephedrine, dextroamphetamine, theophylline, and caffeine MAO = monoamine oxidase CNS depressants include drugs such as benzodiazepines, barbiturates, and ethanol SSRIs = selective serotonin reuptake inhibitors, such as fluoxetine, sertraline, and paroxetine. Antidiabetic agents include drugs such as insulin, glipizide, glyburide, and metformin. 

Nonsteroidal anti-inflammatory drugs (naproxen and ibuprofen) Penicillins Phenylbutazone Probenecid Salicylates Sulfonamides Barbitu rates Phenytoin Probenecid Retinoids Salicylates Sulfonamides Sulfonylureas Tetracycline Ethanol Retinoids Dipyridamole... 

Eqn. (b) shows the interaction between (I) and two moles of ethyl-2-bromopropionate in the presence of THF, at 20°C for 24 hours followed by hydrolysis in the presence of metbanolic NaOH to yield the desired product naproxen with the elimination of one mole of CdBrg and two moles of ethanol. 

Physical Parameters. Naproxen is obtained as bitter crystals from acetone hexane having mp 152-154°C. It has specific optical rotation [a]p + 66° (in chloroform). It is found to be soluble in 25 parts ethanol (96%) 20 parts methanol 15 parts chloroform 40 parts ether and almost insoluble in water. It has apparent pKa 4.15. 

UV spectra of Naproxen (12) in Ethanol (6 mg%) was scanned from 200-400 nm (Fig. 1) using LKB 4054 UV/vis spectrophotometer. Naproxen exhibited the following UV data (Table 1). 

Spectrophotometric determination of naproxen in tablets form was done by Tosunoglu, S. (24). A portion of the crushed tablets containing about 250 mgs of naproxen was shaken with 50 ml of 96% ethanol for 30 minutes and the mixture was diluted to 100 ml with 96% ethanol and filtered. A 1 ml portion of diluted solution was mixed with 4 mM-rosaniline in 20% ethanol (3 ml) and extracted with 5 ml of CHCI3 and the absorbance was measured at 545 nm against blank. The calibration range was 1 to 15 pg per ml. Recovery was 99.9%. 

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. 

Benzylic alcohols are reactive in the presence of an acid as an activator. Asymmetric carbonylation of l-(6-methoxy-2-naphthyl)ethanol (20) by using DDPPI as a chiral ligand in the presence of CuCb and / -TsOH as activators afforded the methyl ester of (5)-naproxen (21) with 81 % ee [12], Benzyl alcohol was carbonylated to phenylacetic acid under somewhat harsh conditions in the presence of HI. Presumably the carbonylation of benzyl iodide, generated by the reaction of benzyl alcohol with HI, occurred. 1,2-Di(hydroxymethyl)benzene (22) was carbonylated to give 3-isochromanone 25 in 88 % yield. In this reaction, one of the benzylic alcohols is converted to benzylic iodide 23 and the lactone 25 was obtained via acylpalladium 24 [13]. 

Scheme 5.6, Equation 5.1) [19]. Although the acidity of the a-proton is much greater than that of the oxoesters, the presence of a tertiary amine has been shown to be indispensable for quantitative conversion. Biochemical transesterification has also been reported for the DKR of a variety of chiral trifluoroethyl thioesters [20]. The DKR of trifluoroethyl thioesters, using either lipase-catalysed hydrolysis [20b,d,e] or transesteriflcation with 4-morpholine ethanol [20c], has allowed the isolation of enantiomerically pure profen esters based on (S)-naproxen, (S)-fenoprofen and (S)-suprofen in >75% yield with up to 95% ee. Some oxoester with relatively higher... 

The standard compounds will all be available as solutions of 1 g of each dissolved in 20 mL of a 50 50 mixture of methylene chloride and ethanol. The purpose of the first reference plate is to determine the order of elution (R values) of the known substances and to index the standard reference mixture. Several of the substances have similar Revalues, but you will note a different behavior for each spot with the visualization methods. On the sample plate, the standard reference mixture will be spotted, along with Naproxen sodium and several solutions that you will prepare from commercial analgesic tablets. These tablets will each be crushed and dissolved in a 50 50 methylene chloride-ethanol mixture for spotting. 

As vinylaromatics, used as substrates in the synthetic routes toward 2-arylpropionic acids described in the previous chapters, are often obtained by the dehydration of the corresponding alcohols, direct carbonylation of 1-arylethanols provides a shorter access to ibuprofen or naproxen. However, in the presence of the PdCl2(PPh3)2 catalyst, the use of strongly addic medium is necessary to obtain ibuprofen from l-(4-isobutylphenyl)ethanol with good (>98%) selectivity [55]. A significant improvement in catalytic activity (with turnover frequendes up to 850 h ) has been achieved by... 

Fig. 23 Fluorescence emission and mean centered spectral plots of 10 jtM R- and S- (a) tri-fluoroanthryl ethanol (TFAE), (b) warfarin, and (c) naproxen enantiomers in the presence of L-AlaCaNTfz CIL. The emission spectra of TFAE, warfarin, tmd naproxen were monitored at excitation wavelength of 365, 306, and 280 nm, respectively, at room temperature. Adapted from [24]...

Cosolvent effect on aqueous solubility at different temperatures have been reported mostly in pharmaceutical studies, which report the thermodynamics of drug dissolution for ibuprofen, naproxen, oxolinic acid, probenecid, phenacetin, etc. in water mixed with cosolvents such as ethanol, propylene glycol, or dioxane. " " " Few such studies have been done in environmental research, although many have focused on either the effect of cosolvents at a specific temperature or the effect of temperature on solubility in water without involving cosolvents. Due to the needs of environmental remediation, cosolvent effects on the sorption and Henry s law constant under different temperatures have been reported. " ... 

The following chiral reagents were employed for diastereomer formation before sample application and chromatography on silica gel or silica gel G TLC plates (L)-leucine Af-carboxyanhydride for D,L-dopa-carboxyl- " C separated with ethyl acetate/formic acid/water (60 5 35) mobile phase and detected by ninhydrin [7 f 0.38 (d)/0.56 (l)] [43] Af-trifluoroacetyl-L-prolyl chloride for D,L-amphetamine separated with chloroform/methanol (197 3) and detected by sulfuric acid/formaldehyde (10 1) (Rf 0.49 (d)/0.55 (l)) [44] Af-benzyloxycarbonyl-L-prolyl chloride for D,L-methamphetamine separated with n-hexane/ethyl acetate/acetonitrile/diisopropyl ether (2 2 2 1) and detected by sulfuric acid/formaldehyde (10 1) [/ f 0.57 (l)/0.61 (d)] [44] (l/ ,2/ )-(-)-l-(4-nitrophenyl)-2-amino-1,3-propanediol (levobase) and its enantiomer dextrobase for chiral carboxylic acids separated with chloroform/ethanol/acetic acid (9 1 0.5) and detected under UV (254 nm) light R[ values 0.63 and 0.53 for 5- and / -naproxen, respectively) [45] (5)-(4-)-a-methoxyphenylacetic acid for R,S-ethyl-4-(dimethylamino)-3-hydroxybutanoate (carnitine precursor) with diethyl ether mobile phase [/ f 0.55 R)/0J9 (5)] [46] and (5)-(4-)-benoxaprofen chloride with toluene/acetone (100 10, ammonia atmosphere) mobile phase and fluorescence visualization (Zeiss KM 3 densitometer 313 nm excitation, 365 nm emission) (respective R values of R- and 5-isomers of metoprolol, oxprenolol, and propranolol were 0.24/0.28, 0.32/0.38, and 0.32/0.39) [47]. 

The same technique was used by Kowalska and coworkers [29] to investigate the oscillatory transenantiomerization of some profens [i.e., S-(-l-)-ibuprofen, 5-(-l-)-naproxen, and S,/ -( )-2-phenylpropionic acid] when stored in 70% ethanol at two different temperatures (6 C and 22°C). In this work, the instability of various optical antipodes was pointed out and attributed to change their steric configurations from the S-form to the i -form, and vice versa. Such phenomenon, which took place by a keto-enol tautomerism, was much more remarkable at low temperatures. 

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