Naproxen precursor

The potential naproxen precursor 23 is accessible in 96 % yield and in 85 % ee by asymmetric hydrocyanation (cf. Section 2.5) of the aromatic olefin 22 catalyzed by a Ni° complex with a glucose-derived phosphinite ligand (Scheme 6) [27]. 

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... 

Naproxen precursor nitrile. The best reported results are >90% ee at 25°C. Over 4000 turnovers of catalyst have been shown, without deactivation at 100% conversion. After recrystallization, over 99% optical purity of the nitrile was observed. Although this is only one example, there are many other fine examples of asymmetric catalysis being developed that illustrate the power of catalysis in this area, longer term, particularly for chiral drugs and agrichemicals. 

AHF of a naproxen precursor was conducted with (5,5,5)-Bisdiazaphos with a CO/H2 ratio of 8 3 bar, which gave the branched aldehyde with 96% ee at a TON = 500, without no detectable linear isomer (Scheme 4.62). 

Scrivanti, A. Matteoli, U. (1995) A convenient synthesis of 2-(6-methoxy-2-naphthyl)propenoic acid (a naproxen precursor). Tetrahedron Lett., 56,9015-18. 

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-... 

Mixtures of a nematic liquid crystal (LC or LC ) with small quantities of gold nanoparticles coated with alkylthiolates (<5 wt%) including an alkylthiolate functionalized with a chiral group have been studied (Figure 8.29) [72]. All mixtures show nematic mesophases with transition temperatures and phase stability very similar to those oftheliquid crystal precursors LC or LC. The introduction ofachiral center into the mixtures (mixtures of Au ) produce chiral nematic mesophases. A similar result is obtained in mixtures of Au and LC doped with the chiral dopant (s)-Naproxen. 

Thus, [HRh(C0)(TPPTS)3]/H20/silica (TPPTS = sodium salt of tri(m-sulfophenyl)phopshine) catalyzes the hydroformylation of heavy and functionalized olefins,118-122 the selective hydrogenation of a,/3-unsaturated aldehydes,84 and the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic add (a precursor of naproxen).123,124 More recently, this methodology was tested for the palladium-catalyzed Trost Tsuji (allylic substitution) and Heck (olefin arylation) reactions.125-127... 

The asymmetric hydroformylation of aryl ethenes such as substituted styrene or naphthylethene is of industrial interest because the hydroformylation products of these substrates are precursors to important nonsteroidal antiinflammatory drugs such as (S )-ibuprofen and (S )-naproxen. Strong efforts have been made to improve the branched/linear ratio, as well as the enantioselectivity of the product. 

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. 

Applications. In the last decade a lot of research has been devoted to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acetamido ligand as additional functionality. In Figure 4.17 four are listed, which are important as anaesthetics for rheumatic diseases. Their sales in beat many bulk chemicals the turnover of Naproxen (retail) in 1990 was 700 million for 1000 tons. S-Naproxen is now being produced by Syntcx via resolution with a chiral auxiliary. The main patents from Syntex expired in the U.S. in 1993, the reason for a lot of activity to study alternative synthetic routes. Routes leading to an asymmetric centre are o asymmetric hydrogenation of an unsaturated acid, o asymmetric carbohydroxylation of a styrene precursor, o asymmetric hydroformylation of a styrene precursor and oxidation. 

Carbonylation of IBPE and other 2-arylethanols with various organosoluble Pd-catalysts was studied in detail with special emphasis on the role of the promoters p-toluenesulfonic acid and LiCl [55], Some of the catalytic species, such as [PdCl(PPh3)2] formed from [Pd(PPh3)4] or from Pd(II) precursors in aqueous methylethylketone (MEK) under reaction conditions (54 bar CO, 105 °C) were identified by P NMR spectroscopy. Ibuprofen was obtained in a fast reaction (TOP = 850 h" ) with 96% yield (3-IPPA 3.9 %), while the carbonylation of l-(6-methoxynaphtyl)ethanol gave 2-(6-methoxynaphtyl)propionic acid (Naproxen) with high selectivity (97.2 %) but with moderate reaction rates (TOP = 215 h" ). 

Isobutylphenyl)propanal with 92% ee is obtained from p-isobutylstyr-ene using the Rh-BINAPHOS catalyst, which is the precursor of anti-inflammatory drug (5)-ibuprofen. " In a similar manner, the precursor of (5)-naproxen is obtained... 

Other similar lipase/esterase resolution processes have been developed such as the use of Bacillus that esterase to produce the substituted propanoic acids that are precursors of non-steroidal anti-inflammatory drags, snch as naproxen and ibuprofen etc., and the formation of chiral amines by Celgene. Other methods start from prochiral precursors and have the advantage that enantioselective synthesis allows the production of particular isomers in yields approaching 100%, rather than the 50% yields characteristic of resolution processes. For instance Hoechst have patented the production of enantiomers using Pseudomonas fluorescens lipase to either acylate diols or hydrolyse diacetate esters. 

These cross-coupling reactions were successfully applied to a synthesis of the precursor of naproxen and cicloprofen, non-steroidal anti-inflammatory agents11. 

V)-2-(4-Isobutylphenyl)propanal (17b) with 92% ee is obtained from p-isobutylstyrene (16b) by using the Rh-BINAPHOS catalyst, which is the precursor of antiinflammatory drug (S)-ibuprofen (entry 15) [19,64,65]. In a similar manner, the precursor of (S)-naproxen is obtained with 85% ee and excellent regioselectivity in the reaction of 16c catalyzed by Rh-(diphosphite 9) complex (entry 16) [25], Pentafluorostyrene (16e) is converted to the corresponding branched aldehyde 17e by the catalysis of the Rh-BINASPHOS complex with... 

RajanBabu and Casalnuovo [19, 20] tested diphosphinite ligand systems (5 and 6 in Figure 4) based on carbohydrate backbones. The steric and electronic properties depended on the substituents on the aryl groups on the phosphorus atoms. The use of different chlorophosphine precursors led to the electronically asymmetric ligand 6. This approach resulted in both enantiomers of naproxen nitrile from MVN in 91 % ee (S)-nitrile (ligand 5) and 95 % ee (R)-nitrile (ligand 6) at 0 °C. 

Monsanto also uses a similar process to produce a single enantiomer of the arthritis drug Naproxen, a nonsteroidal anti-inflammatory drug (NSAID). Note that this asymmetrical hydrogenation produces only the (.S )-cnantiomer of the drug in a yield of 98.5% from an achiral precursor ... 

Compared to the above success story, the selective 6-acylation of 2-methoxynaphthalene - a precursor for the drug Naproxene - is in a much earlier state of development (Scheme 2). Here the kinetically favored substitution is at the 1-position. Two approaches can be applied to enhance the yield of the 6-isomer ... 

This paper deals with the selective synthesis of 2-acetyl-6-methoxynaphthalene, precursor of Naproxen, over zeolite catalysts and especially over HBEA zeolites. As has been previously observed3 8, acetylation of 2-methoxynaphthalene occurs preferentially at the kinetically controlled 1-position with formation of l-acetyI-2-methoxynaphthalene (I). The desired isomer, 2-acetyl-6-methoxynaphthalene (II) and the minor isomer, l-acetyl-7-methoxynaphthalene (HI), are the other primary products. However, it will be shown that in presence of 2MN, isomerization of I can occur allowing a selective production of II, the desired product the effect of the operating conditions (solvent, temperature) and of the acidity and porosity of the zeolite catalyst will be presented. 

Over HBEA zeolites, acetylation of 2-methoxynaphthalene with acetic anhydride leads mainly to l-acetyl-2-methoxynaphthalene. However, the desired product, i.e. 2-acetyl-6-methoxynaphthalene, precursor of Naproxen is obtained at long reaction time by an intermolecular irreversible isomerization process. A very selective production of II (83%) can be obtained by acetylation of 2-methoxynaphthalene over a commercial HBEA zeolite (Si/Al = 15) at 170°C, with nitrobenzene as a solvent. With dealuminated HBEA samples (framework Si/Al ratio between 20 and 40), better results could be expected. Furthermore, preliminary experiments showed that this selective synthesis of 2-methoxynaphthalene can be carried out in a flow reactor system. 

Acetylation of 2-methoxynaphthalene (2MN) with acetic anhydride (AA) was also investigated over various molecular sieves FAU (19, 20), MFI, MOR (20), MTW (19), MCM41 (21) and especially BEA (19, 22-30). With this acetylation, there is an additional problem because of the simultaneous formation of 2-acety]-6-methoxynaphthalene (II, Figure 14.3), which is the desired product (precursor of naproxen), and of its isomers. Generally, acetylation occurs preferentially at the kinetically controlled 1-position with formation of l-acetyl-2-methoxynaphthalene (I, Figure 14.3). 

The reaction can be carried out asymmetrically, using nickel complexes of chiral phosphite ligands. Examples are the enantioselective hydrocyanation of norbomene using ligand (22-XVIII),48 and of vinylnaphthalene derivatives with (22-XIX).49 The latter is a precursor for the anti-inflammatory drug naproxen. 

There are very numerous synthetic applications of the Heck reaction, notably in the coupling of naphthyl bromide with ethylene to give a precursor to naproxen 88... 

Recently, ee s of 85-90% have been obtained for the asymmetric hydrocyanation of 6-methoxy-2-vinyhiaphthalene using nickel complexes of chiral bidentate phosphinites derived from glucose (abbreviated PP, equation 12). This reaction is of great interest to the pharmaceutical industry because the (S) enantiomer of the product nitrile is a useful precursor for the widely marketed antiinflammatory dmg naproxen (equation 13). The same reaction can be applied to a number of other vinyl aromatic compounds, including the precursor for the antiinflammatory drug ibuprofen (6) however, the ee is not as high. 

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