Ibuprofen methyl ester

A wide variety of substituents are tolerated. The group R can be alkyl, halogen, alkoxy, -amido, azi-domethyl, ester, aryl, aryloxy and aryloyl, and at least one ortho substituent is permissible with no loss in yield. TTie aromatic ring can also be 2-naphthyl, 9,10-dihydro-2-phenanthryl, 3-pyridyl, thiophen-2-yl or pyrrol-3-yl. The group R can be hydrogen, yl, acyl or acetic acid. Beyond Ae antiinflammatory targets, successful reaction substrates include the methyl ketones of a binaphthyl crown ether, a morphinane and a polyaromatic hydrocarbon. The preparation of ibuprofen methyl ester (38) is shown in equation (37) as a typical example. ... 

More recently acids have been resolved with enzymes cloned and over-expressed in their own organisms, such as an esterase from Bacillus subtilis that resolves ibuprofen methyl ester 138 to give ibuprofen 139 of 99% ee. A range of anti-inflammatory arylpropionic esters, including 138, could also be resolved with a cell-free extract from Pseudomonas fluorescens showing that purified enzymes are not essential.34... 

Compound 157 has been used in a short synthesis of (/ )-ibuprofen methyl ester (161) [58] (Scheme 24). Acetalization of optically pure aryl ketone 159 under basic conditions produces hydroxy acetal 160 (74% ee), where the configuration at the asymmetric carbon is inverted. Treatment of 160 with sulfuryl chloride in pyridine at —50 °C causes facile 1,2-aryl migration and affords the target molecule 161 stereospecifically. 

A new and promising way of combining reaction and extraction are supported liquid membranes (SLM). Miyako et al. used SLMs on the basis of different water-immiscible ionic liquids and aliphatic hydrocarbons to achieve pure (S)-ibuprofen together with an enzymatic resolution step (Scheme 8-6). Only the (S)-enantiomer is esterified by the enzyme attached to the feed interface and able to enter the membrane. The ionic-liquid phase allows the selective transport of the more hydrophobic ibuprofen methyl ester from the aqueous-feed phase to the receiving phase. At the inter ce of the receiving phase, the (S)-ibuprofen methyl ester is hydrolysed to (S)-ibuprofen by another lipase. As (S)-ibuprofen is more hydrophilic it is not transported back through the supported ionic-Hquid phase. Best results were achieved with [BMIM]( (CFjSOijiN] as liquid membrane phase and the enzyme combination mentioned in Table 8-3 [85,86]. 

Fig. 6.3.1 Production of S-ibuprofen (S-Ibu) by kinetic resolution of the ester racemate (R-S IbuME) with lipase (L) in organic medium in a membrane bioreactor (1), with product separation (2) and racemization (3) of the unreacted R-ibuprofen methyl ester (R-IbuME)...

Figure 28. Enantiomeric excess of ibuprofen methyl ester and ibuprofen ethyl ester in dependence of the conversion (p = 100 bar. T = 50 X) [20],...

The enantiomeric excess in dependence of the conversion for the interesterification of ibuprofen methyl ester with ethanol is shown in Figure 28. The data were correlated with the above given equations. The data were in good correlation for a enantioselective conversion with a reversible reverse reaction that occurs above 50 % conversion. 

The enantiomeric excess of the interesterification of ibuprofen methyl ester with ethanol in supercritical carbon dioxide at different pressures shows a linear decrease of the enantiomeric excess with increasing pressure. From experiments in organic solvents it is known that penetration into the hydrophobic core of the enzymes can occur. Therefore penetration of carbon dioxide into the enzyme molecule probably takes place with increasing pressure and alters the conformation of the enzyme and hence reduces its affinity to the substrates. 

CO 630-08-0) see Ibuprofen Retinol Rofecoxib carbonochloridic acid (4-nitrophenyl)methyl ester... 

C13H17NO 63367-12-4) see Ibuprofen a-hydroxy-a-methyl-4-(2-methylpropyl)benzeneethan-imidic acid methyl ester hydrochloride... 

C24H,2N2 147770-02-3) see Repaglinide a-methyl-4-(2-methylpropyl)benzeneacetaldehyde oxime (C,Hi9NO 58609-72-6) see Ibuprofen a-methyl-4-(2-methylpropyl)benzeneacetamide (C13H19NO 59572-77-3) see Ibuprofen a-methyl-4-(2-methylpropyl)benzeneacetonitrile (C, H 7N 58609-7J-7) see Ibuprofen a-methyl-4-(2-methylpropyl)benzeneethanimidic acid methyl ester hydrochloride (C14H22CINO) see Ibuprofen... 

An intEiesting variant on the Wilgerodt reaction offers a simple three-step procedure that avoids the wastage involved in the schemes above, which require the incorporation of an extra carbon atom that must later be eliminated. The sequence starts with the acylation of isobutylbenzene (49-1) with propionyl chloride to give propiophenone (49-2). Reaction of that with thallium 111 nitrate and methyl ortho-formate in methanol leads in high yield to the methyl ester (49-3) of ibuprofen [50]. This would be the method of choice for preparing the dmg but for two unfortunate facts the extreme toxicity of thallium and the very high sensitivity of analytical methods for the detection of metals. It proved to be virtually impossible, in practice, to produce samples that showed zero residues of thallium. 

Recent studies in the pharmaceutical field using MBR technology are related to optical resolution of racemic mixtures or esters synthesis. The kinetic resolution of (R,S)-naproxen methyl esters to produce (S)-naproxen in emulsion enzyme membrane reactors (E-EMRs) where emulsion is produced by crossflow membrane emulsification [38, 39], and of racemic ibuprofen ester [40] were developed. The esters synthesis, like for example butyl laurate, by a covalent attachment of Candida antarctica lipase B (CALB) onto a ceramic support previously coated by polymers was recently described [41]. An enzymatic membrane reactor based on the immobilization of lipase on a ceramic support was used to perform interesterification between castor oil triglycerides and methyl oleate, reducing the viscosity of the substrate by injecting supercritical CO2 [42],... 

C,H]7NO 63367-12-4) see Ibuprofen cx-hydroxy-a-methyl-4-(2-methylpropyl)benzeneethan-imidic acid methyl ester hydrochloride (C 4H22C1N02) see Ibuprofen 2-hydroxymethyl-5-methylpyrazine (C,H8N20 61892-95-3) see Acipimox... 

Figure 13 Enantiomer separation of analgesic drug ibuprofen as methyl ester (esterification with diazometh-ane). 25-m Pyrex glass capillary with per-pentyl-p-CD and per-methyl-p-Cd (1 1, w/w) at 140 C,...

Three 4-thiazolidinone libraries were prepared and assayed for inhibition of the enzyme cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonic acid to prostaglandins [421, 422], From the carboxylic acid, ester and carboxamides libraries only the methyl ester library showed significant activity. A series of three rounds of testing and deconvolution led to a compound (library 37 IC50 3.7 fiM) with equivalent in vitro activity to the commercially available COX-1 inhibitors ibuprofen and phenylbutazone. 

As it is seen from Eq. (62b) and (62e), the method allowed for the synthesis of moderately enantioenriched methyl esters of the commercially available drugs ibuprofen (224), 60% ee [136] or naproxen (230), 47% ee [136], from optically active carbamates 222 or 228, respectively. The final step is a reductive removal of the carbamoyloxy group by Pd-catalyzed hydrogenolysis, which proceeds with inversion [138-140] but some erosion of the enantiomeric purity results. 

Detailed structure-activity studies showed that small structural differences in the agents determined whether or not they caused irreversible inactivation. Particularly striking was the conversion of the free carboxylic acid to the methyl ester which gave an agent that had a similar binding affinity [86], but appeared to be completely devoid of ability to irreversibly inactivate the cyclooxygenase activity. The value of the apparent inactivation constants (K ) for the acidic forms of the compounds ranged from zero for ibuprofen and mefenamic acid to 0.0003, 0.04, 0.4 and 1.1 M min for aspirin, indomethacin, meclofenamate and flurbiprofen, respectively [86]. 

Photodecarboxylation of NSAIDs Inside Cyclodextrin Diastereoselective Photodecarboxylation of 2-Phenylpropionic Acid in Zeolite Medium Photolysis of Ibuprofen and the Methyl Ester of Naproxen 64.5 Conclusion.65-11... 

An interesting effect was found whilst studying the enantioselectivity of these reactions. Although several esters (ethyl-2-chloropropionate, ethyl lactate, ethyl-2-hydroxy hexanoate and ethyl-2-methyl butyrate) were converted into the amides with only low to moderate ee values, the ammoniolysis of ibuprofen (2 -chloro-ethyl)ester was highly enantioselective. At 56 % conversion the ee of the remaining (S)-ester was 96% (Scheme 12.2-3), corresponding with an E value of the ammoniolysis of 28. 

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]. 

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