Naproxene synthesis

With a rhodium complex catalyst containing a chiral ligand dispersed in [BMIM]SbFg, the enantioselective hydrogenation of a-acetamidocinnamic acid to (5)-phenylalanine was achieved with 64% enantiomeric excess 112). [RuCl2( S)-BINAP]2 NEt3 in [BMIM]BF4 for (5)-naproxen synthesis gave 80% ee from 2-(6-methoxy-2-naphthyl) acrylic acid and isopropyl alcohol 214). 

Shanbhag, V. R., Crider, A. M., Gokhale, R., et al. Ester and amide prodrugs of ibuprofen and naproxen Synthesis, anti-inflammatory activity, and gastrointestinal toxicity. J. Pharm. Sci. 81 149—154, 1992. 

Fig. 35. The optimization of S-Naproxen synthesis using Ru-BINAP asymmetric hydrogenation...

Nanocrystals, anatase Nanocrystals, offretite Nanoemulsion template Nanoparticles agglomerates, MFI Nanoparticles, Au Nanoparticles, Fe203 in MCM-41 Nanoparticles, Sn02 Nanoparticles, surfactant stabilized Nanoparticles, Zr02 in SBA-15 Nanoscopic precursor particles Nanoslabs, silicalite-1 Nanowires in FSM-16 Nanowires, Se in MFI Naphtha isomerisation Naphthalene isopropylation Naphthalene alkylation 25-0-03 25-P-Naphthene ring opening S-Naproxen synthesis... 

NAP ligand. The resulting chiral polymeric phosphine was then used to form a Ru(BINAP)-type complex by reaction with [Ru(cymene)Cl2]2 this complex formed in situ and was used to hydrogenate the naproxen precursor shown in Eq. 75. The activity of this complex in naproxen synthesis in this biphasic system was higher than in pure ethyl acetate or in miscible methanol-water mixtures. This in situ formed catalyst was also more active than a low molecular weight Ru(4-Na03S-BINAP) catalyst in a similar asymmetric hydrogenation of... 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Hydroformylation has been extensively studied since it produces optically active aldehydes which could be important precursors for pharmaceutical and fine chemical compounds. Thus, asymmetric hydroformylation of styrene (Scheme 27) is a model reaction for the synthesis of ibuprofen or naproxen. Phosphorus ligands were used for this reaction with excellent results, espe-... 

The use of an analogous (S)-BINAP-Ru-diacetate catalyst with axial chirality has led to important industrial applications, such as the synthesis developed by Monsanto where the asymmetric hydrogenation is involved in the last step to yield naproxen, a widely prescribed, non-steroidal, anti-inflammatory drug (Equation (9)).96... 

With a BINAP-Ru [3d,104], Hg-BINAP-Ru [102], or P-Phos-Ru [25] catalyst, the anti-inflammatory drugs (S)-ibuprofen and (S)-naproxen could be efficiently synthesized via enantioselective hydrogenation (Scheme 26.9). In these cases, high hydrogenation pressure and low temperature are required to achieve good enantioselectivity. With an (R)-BIPHEMP-Ru catalyst, (S)-2-(4-fluorophenyl)-3-methylbutanoic acid, a key intermediate for the synthesis of the calcium antago-... 

One of the first applications of the then newly developed Ru-binap catalysts for a,/ -unsaturated acids was an alternative process to produce (S)-naproxen. (S)-Naproxen is a large-scale anti-inflammatory drug and is actually produced via the resolution of a racemate. For some time it was considered to be one of the most attractive goals for asymmetric catalysis. Indeed, several catalytic syntheses have been developed for the synthesis of (S)-naproxen intermediates in recent years (for a summary see [14]). The best results for the hydrogenation route were obtained by Takasago [69] (Fig. 37.15), who recently reported that a Ru-H8-binap catalyst achieved even higher activities (TON 5000, TOF 600 h 1 at 15 °C, 50 bar) [16]. 

Monsanto [117] has developed a way to electrosynthesize by reductive carboxylation the optically active precursor to Naproxen, (S)-2-(6 -methoxy-2 -naphthyl)propionic acid, a drug used to treat arthritis. A more economical route was needed since the US patent expires in 1993 while the market is growing. The electrochemical process is said to cut manufacturing costs by over 50%. Since it uses CO 2 instead of the hazardous HCN used in conventional synthesis, it is also safer. 

Example 1, the Willgerodt-Kindler reaction was a key operation in the initial synthesis of racemic Naproxen ... 

Figure 4.3. The chemical synthesis of naproxen-HSA. Naproxen is first converted to an ester and is then coupled to the free E-NH2 of the lysine residues in human serum albumin (HSA). NHS N-hydroxysuccinimide, DCC dicyclohexylcarbodiimide.

---