Ketoprofen resolution

Y. Oda, N. Asakawa, Y. Yoshida and T. Sato, On-line determination and resolution of the enantiomers of ketoprofen in plasma using coupled achiral-cliiral high-performance liquid chromatography , 7. Pharm. Biomed. Anal. 10 81-87 (1992). 

Pehourcq, R, Jarry, C., and Bannwarth, B., Chiral resolution of flurbiprofen and ketoprofen enantiomers by HPLC on a glycopeptide-type column chiral stationary phase, Biomed. Chromatogr, 15, 217, 2001. 

Table 2 gives chromatographic data for different classes of enantiomeric dmgs resolved by P-CD bonded phases (8). Drugs for which resolution factors (R) greater than 1.0 were obtained include mephenytoin, ketoprofen, chlorpheniramine, and the barbiturates mephobarbital and hexobarbital. Cyclodextrin-bonded phases provide a rapid and specific technique for the pharmacological evaluation of racemic dmgs. 

FIGURE 12 Chromatograms of the chiral resolution of (a) ibuprofen and (b) ketoprofen on Whelk-01 CSP using SFC. (From Ref. 158.)... 

S)-3-Methyl-2-phenylbutylamine, a new versatile synthetic resolving agent we have proposed, is effective for the resolution of chrysanthemic acid, ibuprofen, ketoprofen, naproxen and others.19... 

Another major benefit of the purity of CLCs relates to the fact that many commercially available enzyme products actually contain more than one enzyme, and these contaminating enzymes can often lead to undesired side reactions. In the case of a resolution this can mean the difference between success and failure. For example, in the resolution of racemic ketoprofen by ester hydrolysis (Fig. 1), the enantioselectivity using crude Candida rugosa lipase is poor (E = 5). 

Figure 1 Resolution of racemic ketoprofen by enzyme catalyzed ester hydrolysis.

Sotalol, metoprolol, propranolol, carvedilol, nifedipine, captopril, cilazapril, milrinone, ticlopidine, acenocoumarol, furosemide, acetylsalicylic acid, salicylic acid, ibuprofen, naproxen, ketoprofen, diclofenac, paracetamol, dipyrone, mildronate, sildenafil, dexa-methasone, carbamazepine, terbinafine/urine UHPLC MS/MS Column Zorbax Rapid Resolution High Definition SB-C18 (50 x 2.1 mm, 1.8 pm) Mobile phase Solvent A 0.1 % HCOOH in water Solvent B MeOH (gradient elution) Detection MS/MS, ionization ESI Protein precipitation LOQ 0.05-0.60 ng/mL [71]... 

Cross-linked crystals of lipase from Candida rugosa (CRL) were applied in the resolution of racemic ketoprofen chloroethyl ester. In batch-wise operation, the half-life of the catalyst was reached after about 18 cycles or, in terms of enzyme consumption, about 5.6 g of enzyme protein were consumed to prepare 1 kg of (S)-ketoprofen. CRL suffers from a low specific activity towards this poorly water-soluble substrate which may explain the high enzyme input [117]. 

Typical kinetic resolutions of the arylpropionic acids are those of flurbiprofen 16 and ketoprofen 18 with a cell-free extract of Pseudomonas fluorescens. Note the special ester (trifluoroethyl) selected for maximum efficiency and how successful that is perfect ee in the hydrolysed products at close to 50% conversion.8 The unreacted esters 15 and 17 can of course be racemised by enolisation and added to the next resolution. 

Hermansson, J. Erikson, M. Direct liquid chromatographic resolution of acidic drugs using a chiral al-acid glycoprotein column (Enantiopac). J.Liq.Chromatogr., 1986, 9, 621-639 [chiral also bendroflu-methiazide, disopyramide, ethotoin, hexobarbital, ketoprofen, naproxen, 2-phenoxypropionic acid, RAC 109]... 

H5fun, M.H. Ryoo, J.-J. Cho, Y.J. Jin, J.S. Unusual examples of the liquid chromatographic resolution of racemates. Resolution of n-donor analytes on a ir-donor chiral stationary phase. J.ChromatognA, 1995, 692, 91-96 [chiral also alminoprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen]... 

The production of other profens as well, like the enantiospecific esterification of racemic ketoprofen in non-aqueous solvent under reduced pressure (De Crescenzo et al. 2000 Ong et al. 2005) and the anti-inflammatory drug naproxen by kinetic resolution of the racemic ester in a in an aqueous-organic biphasic system in a stirred tank membrane bioreactor (Xin et al. 2001)... 

An example of an industrial Heck reaction of an aryl bromide is the announced synthesis of Naproxen by Albermarle. Toward that end, 2-bromo-6-methoxynaphthalene is reacted with ethylene in the presence of a homogeneous palladium catalyst. Apparently, as a ligand a sterically hindered basic phosphine is used. Known Pd-catalyzed hydro-carboxylation of 2-methoxy-6-vinylnaphthalene and subsequent resolution give access to Naproxen (Scheme 3). In addition, it was shown that Ketoprofen can be produced by a similar reaction sequence. 

Although the catalytic activity of T. brassicae CGMCC0574 whole cells in the enantioselective hydrolysis of ketoprofen ester was initially moderate, it was significantly promoted after the cells were pretreated for a few hours in a buffer containing an alcohol as the modulator. This suggested a possible permeability barrier from the cell membrane against the mass transfer of substrates and/or products. Therefore, the permeabilization of the yeast cells was considered to be favorable for the enzymatic resolution of ketoprofen. 

Lipase- or esterase-catalyzed hydrolytic resolution of ketoprofen esters was usually employed for the preparation of (isolated microorganisms or commercial lipases have been applied for the enantioselective hydrolysis of racemic ketoprofen esters. A commercial enzyme. Lipase OF from Candida rugosa (Meito Sangyo, Japan), was found to be a good biocatalyst for kinetically resolving the 2-chloroethyl ester of ketoprofen (2-(3-benzoylphenyl)propionic acid). ... 

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