Transition-metal catalyzed synthesis of Ketoprofen

Journal of the Brazilian Chemical Society

Lando, Vanusa R.¹  Zim, Danilo¹  Ramminger, Carolina¹  Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil¹  Monteiro, Adriano L.¹  Fassina, Viviane¹ 

关键词: ketoprofen;    carbonylation;    hydrovinylation;    hydrogenation;   

DOI  :  10.1590/S0103-50532000000200002

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Homogeneous catalysis has been responsible for many major recent developments in synthetic organic chemistry1,2. The combined use of organometallic and coordination chemistry has led to a number of new powerful synthetic methods involving the selective formation and/or cleavage of C-C and C-heteroatom bonds. An appropriate choice of central metal and a careful molecular design of coordinated ligands, especially with regard to electronic and steric properties, have resulted in the development of active and selective (chemo-, regio- and enantioselective) catalytic systems. Over the past years we have focused our attention on the synthesis of transition metal complexes3, and their application in the selective transformation of organic unsatured substrates4-10.a-Arylpropionic acids are an important class of non-steroidal anti-inflammatory agents with a multibillion-dollar market11. Among the numerous methodologies12,13 for the synthesis of this class of drug, metal-catalyzed reactions appear to be of general utility and are very promising in racemic and asymmetric synthesis. In this work we show the application of homogeneous metal-based catalytic systems for the synthesis of Ketoprofen (Scheme 1).Ketoprofen was developed by Rhône-Poulenc14 and is commercialized in its racemic form in Brazil by Rhodia as Profenid. The synthesis of ketoprofen generally involves a multi-step reaction procedure12. Although many asymmetric syntheses for a-arylpropionic acids have been developed, most of them are not amenable to Ketoprofen. In terms of enantioselective catalytic reactions, asymmetric hydrogenation15 and epoxidation16 reactions have been used as key steps. The hydrogenation of a-(3-benzoylphenyl) acrylic acid using a chiral rhodium catalyst gave Ketoprofen in moderate enantiomeric excess (up to 69%)15. Another catalytic approach made use of a combination of Sharpless epoxidation followed by a stereoselective hydrogenolysis of a benzylic carbon-oxygen bond to establish the stereochemistry16. Using this approach, (S)-Ketoprofen was obtained in 98% ee in 11 steps starting from 3-bromoacetophenone. The other asymmetric syntheses described are not catalytic reactions and the stereoselectivity is achieved using a stoichiometric chiral auxiliary. For instance, a-(3-benzoylphenyl)acetic acid was transformed into a chiral imide using oxazolidines as chiral auxiliaries17. Thereafter, the chiral imide was alkylated with methyliodide. Racemizing amide cleavage conditions did not afford (S)-Ketoprofen of sufficient enantiomeric purity and a later separation by recrystallisation of diastereoisomers resulting from reaction with (R)-methylbenzylamine was necessary in order to obtain (S)-Ketoprofen in 96% ee. Another approach started from racemic Ketoprofen which was transformed into a ketene18,19. Diastereoselectivities for the addition of a chiral hydroxyl compound were, after saponication, Ketoprofen up to 71% for the chiral lactate18 and up to 99% for (R)-pantolactone19. Finally, a photochemical rearrangement of a-chloropropiophenones was used to obtain a-arylpropionic acids in low optical yield in the

【 授权许可】

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