Rac-ibuprofen

Supercooling has been observed in an extreme form in molten ibuprofen if the molten solid is allowed to cool from the melting point to room temperature without vibration in a smooth-lined container [48]. For instance, undisturbed rac-ibuprofen can exist as an oil phase for several hours to a few days. If disturbed, however, an exothermic recrystallization proceeds and bulk crystalline material rapidly grows vertically out of the oil phase so energetically that the system emits an audible cracking sound. 

Table 3 Enautioselective Hydrolysis of rac-Ibuprofen Esters Obtaining the S(+)-Acid... 

The nature of the solvent plays an important role both in the yield and in the en-antioselectivity of the reaction. Thus, in Table 6B we can observe how the presence of CI4C reduces the yield and the enantiomeric excess in the resolution of esters of tri-methylsilyl methyl estem of rac-2-(6-methoxy-2-naphthyl)propionic acid with Candida cylindracea lipase [ICK)] another example is shown in Table 7B, where the synthesis of butyl esters of rac-ibuprofen is carried out in different organic media [98], obtaining the best results with solvents possessing log P (partition coefficient in the mixture n-octanol/ water) higher than 2.5. In the same table can be found another, similar example the esterification with methanol of rac-ibuprofen with lipase from C. cylindracea [108]. 

Table 7A Enantioselective Resolution of rac-Ibuprofen Propionic Esters Obtaining the 5(+) Pure Enantiomer... 

Table 7B Enantioselective Esterification of rac-Ibuprofen Obtaining Ibuprofen Esters... 

Figure 5.6 Production of S(+)-ibuprofen from rac. 2-(4 -isobutylphenyt)-propionitrile using an S-specific nitrilase irora. Acinetobacter (Yamamoto eta/., 1990).

Analytical Properties Separation of the drugs ibuprofen, ketoprofen, naproxen, 2-phenoxypropionic acid, bendroflumethiazide, ethotoin, hexobarbital, disopyramide, and RAC 109 retention and selectivity of the solutes can be regulated by addition of the tertiary amine /V,/V-dimethyloctylamine (DMOA) to the mobile phase DMOA decreases retention time and the enantioselectivity of the weaker acids but has opposite effects on the stronger acids Reference 3... 

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, ibuprofen, naproxen, 2-phenoxypropionic acid, RAC 109]... 

Many kinetic resolutions of rac-nitriles were performed in search of a method to produce (S)-configurated a-arylpropionic acids, such as ketoprofen, ibuprofen, or naproxen, which are widely used as nonsteroidal antiinflammatory agents. Overall, enantioselectivities depended on the strain used, and whether a nitrilase- or nitrile hydratase-amidase pathway was dominant, which determines the nature of (enantiomeric) products consisting of a mixture of nitrile/carboxylic acid or amide/ carboxylic acid, respectively [687, 693-696]. 

Preparative-scale resolution of rac-4-isobutyl- -methylstyrene oxide using an enzymatic extract of Aspergillus niger LCP 521. A four-step enantioconvergent procedure enabled the synthesis of (S)-ibuprofen. 

This last tyj of nonsteroidal anti-inflammatory drugs, such as ibuprofen ([rac-2-(4-iso-butylphenyl) propionic acid], 5), flurbiprofen ([rac-2-((3-fluoro-4-phenyl)phenyl)propionic acid], 6), fenoprofen ([rac-2-(3-phenoxyphenyl)propionic acid], 7), suprofen ([rac-2-(4(2-fliienyloxo)phenyl)propionic acid, 8], carprofen ([rac-2-(6-chloro-9H-cabazolyl) propionic acid], 9), naproxen ([5(+)-2-(6-methoxy-2-naphthyl)propionic acid], 10), Dexketoprofen ([S(+)-2-(3-benzoylphenyl)propionic acid], 11), flunoxaprofen ([S(+)-2-(2(4-fluoro-phenyl)benzoxazol-5-yl)propionic acid], 12), or ketorolac ([5(+)-5-benzoyl-2,3-dihidro-1/i-pyrrolizine-l-carboxylic acid], 13, thromethamine salt marketed as Toradol), have a more promising future. 

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