Naproxen hydroformylation

Considerable advances in asymmetric hydroformylation, a process which, among other things, provides a potential route to enantiomericaHy pure biologically active compounds, have occurred. Of particular interest are preparations of nonsteroidal antiinflammatory (NSAI) pharmaceuticals such as Naproxen (8) and Ibuprofen (9), where the represents a chiral center. 

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-... 

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. 

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. 

Asymmetric Hydroformylation of Vinylarenes a-Arylpropanals, the products of asymmetric hydroformylation of vinylarenes, serve as useful intermediates for pharmaceutical drugs. For example, (5)-2-arylpropanals can be oxidized to the corresponding (5)-2-arylpropanoic acids, such as (5)-ibuprofen (Ar = 4-isobutylphe-nyl), (5)-naproxen (Ar = 6-methoxynaphthalen-2-yl), and (5)-suprofen (Ar = 4-(2-thienylcarbonyl)phenyl) (see later in chapter. Scheme 4.4). Styrene is thus one of the most popular substrates used to test new catalyst systems. Representative ligands and their use as Pt or Rh complexes in the asymmetric hydroformylation are summarized in Figure 4.1 and Table 4.1. (See also Scheme 4.3.)... 

An analgesic with greater antiinflammatory and antipyretic activity than Naproxen is a-methyl-4-(2-thienylcarbonyl)benzeneacetic acid, Suprofen.63 This compound has been tested only as a racemic mixture, and any difference in the activity of the enantiomers is not known. Hydroformylation of 4-(2-thienylcarbonyl)styrene (entry 3, Table 4) to the 2-aiylpropanal was achieved in 78% ee for the branched aldehyde [(-t-)-enantiomer in excess], which can be converted to Suprofen by oxidation. 

In spite of extensive studies on the asymmetric hydroformylation of olefins using chiral rhodium and platinum complexes as catalysts in early days, enantioselectivity had not exceeded 60% ee until the reaction of styrene catalyzed by PtCl2[DBP-DIOP (l)]/SnCl-> was reported to attain 95% ee in 1982 [8]. Although the value was corrected to 73% ee in 1983 [9], this result spurred further studies of the reaction in connection to possible commercial synthesis of antiinflammatory drugs such as (S)-ibuprofen and (S)-naproxen. The catalyst PtCl2[BPPM... 

S)-ibuprofen (44b Ar = 4-isobutylphenyl), (S)-naproxen (44c Ar = 6-MeO-naphthyl), and (S)-suprofen (44d Ar = 4-(2-thienylcarbonyl)phenyl) (Eq. 7.11) (10]. Thus, the asymmetric hydroformylation of vinylarenes discussed above provides potentially efficient route to these drags. 

Other approaches that have been suggested include catalytic asymmetric hydroformylation of 2-methoxy-6-vinylnaphthalene (6) using a rhodium catalyst on BINAPHOS ligand followed by oxidation of the resultant aldehyde 7 to yield 5-naproxen (Scheme 6.3).22 However, the tendency of the aldehyde to racemize and the co-generation of the linear aldehyde isomer make the process less attractive. Other modifications related to this process include catalytic asymmetric hydroesterification,23 hydrocarboxylation,24 and hydrocyanation.25... 

The asymmetric hydroformylation of vinyl arenes can provide a route to the preparation of the profen class of drugs. Naproxen and ibuprofen, two examples in the profen class, are NSAIDs on the market.50... 

The alternative potential synthetic routes for the drug Naproxen neatly illustrate the industrial significance of asymmetric hydroformylation and asymmetric hydrocyanation reactions. This is shown in Fig. 9.12. Regio- and en-antioselective hydroformylation or hydrocyanation of 6-methoxy 2-vinyl naphthalene can give the desired enantiomers of the branched aldehyde or nitrile. These two intermediates can be oxidized or hydrolyzed to give 5-Naproxen. 

Hydroformylation of styrene and its analogues has attracted particular attention, since this provides a general method for the preparations of optically pure arylpropionic acids. Apart from Naproxen , the drug ibuprofen is another ar-ylpropionic acid-based nonsteroidal anti-inflammatory agent. As shown by 9.9, ibuprofen may in principle be synthesized by enantioselective hydroformylation reactions followed by oxidation of the aldehydic functionality. 

Figure 9.12 Two alternative synthetic routes for 5-Naproxen. The left-hand route involves asymmetric hydroformylation, while the right-hand one uses asymmetric hydrocyanation.

Rhodium complexes of the ligand a,a-TREDIP (2) give very high iso regioselectivity in the hydroformylation of styrene under mild conditions, and this has been extended to the synthesis of 2 -(2-methoxy-6-naphthyl)propanal (3), a precursor of the antiinflammatory drug naproxen." ... 

A Chiral Synthesis Route to Naproxen Using Asymmetric Hydroformylation... 

Rhone-Poulenc developed ketoprofen [66]. A few synthetic routes have been reported that involving multi-step syntheses [67, 68]. Ketoprofen is produced by similar reaction sequences that were described for naproxen [69]. Transition metal-catalyzed reactions including carbonylations, hydroformylations, and hydrogenations have been applied to the synthesis of ketoprofen. 3-Vinylbenzophenone (4) was obtained from 3-bromo-benzophenone (3) by a Heck reaction. Palladium-catalyzed carbonylation of 4 provided the isopropyl-a-(3-benzoylphenyl)propionate in 95% yield. Ketoprofen was then obtained in 90% yield by hydrolysis of the isopropyl ester [69]. 

Other asymmetric synthetic processes used for the manufacturing of (S)-(-l-)-naproxen can also be applied to the production of (S)-(-l-)-ibuprofen these include the Rh-phosphite catalyzed hydroformylation [33], hydrocyanation [21], and hydrocarboxylation reactions [20],... 

Naproxen. In addition, the use of chiral bisphosphites in asymmetric olefin hy-drocyanation is described. Details of the structural features responsible for hi b/1 and %ee in asymmetric hydroformylation and hydrocyanation are presented. 

We describe the extension of this class of bisphosphite catalysts to asymmetric hydroformylation and hydrocyanation of vinylarenes.(3) These enantiose-lective catalytic transformations are employed for the asymmetric synthesis of S-Naproxen, a widely used non-steroidal anti-inflammatory drug (NSAID). Factors which influence regioselectivity and enantioselectivity, as well as characterization of the catalyst resting states, are discussed. 

The optical purity of S-Naproxen produced by asymmetric hydroformylation with 1 can be increased by recrystallization. The solid aldehyde (87 %ee) from asymmetric hydroformylation of 6-methoxynaphthalene was recrystallized from acetone with an increase in enantiomeric purity to >98 %ee. In addition, the regiopu-rity of this aldehyde increased from 90 1 to >200 1 after one recrystallization.(5)... 

The complete regioselectivity, the absence of byproducts, the ready availability at low cost of the ligand employed, and the chemical and stereochemical efficiency of this reaction make it a good candidate to become the first catalytic, stereoselective industrial manufacturing of naproxen, even if the use of HCN can be a drawback. In this context, it must be remembered that Union Carbide Co. has recently patented a route to (S)-ibuprofen based on a Rh(CO)2(acac)/chiral phosphite-catalyzed hydroformylation of 4-isoutylstyrene that occurs in 82% e.e. [63,80]. 

The hydrocarboxylation of vinylarenes has also been studied extensively as a simple, clean route to the ot-aryl carboxylic acids that are common non-steroidal anti-inflamatory medicines, such as ibuprofen and naproxen. " By this process, a vinylarene undergoes hydrocarboxylation to form the branched a-aryl carboxylic acid. A series of patents and papers describe this hydrocarboxylation process " and the related hydroesteri-fication. Like the hydrosilylations and hydrocyanations presented in Qiapter 16 and the hydroformylations described in this chapter, the regioselectivity for reactions of vinylarenes contrasts with that for reactions of alkenes. The reactions of vinylarenes form branched hydrocarboxylation products. 

Branched hydroformylation inttoduces a new stereogenic centre and, therefore, there is the opportunity to control the new centre by the use of chiral ligands. An early application of this concept is in an industrial synthesis of the anti-inflammatory drug, naproxen 4.193 from the corresponding styrene (Scheme 4.69). The ligand for the hydroformylation reaction, chiraphite 4.194, consisted of two bulky phosphates linked by a chiral tether. Many other chiral ligands have been developed. A problem with generating aldehydes with an a-chiral centre is their facile racemization via their enol or enolate form. One solution to this problem is to protect the product as its acetal 4.195 in situ (Scheme 4.70). ... 

SCHEME 14.6. Asymmetric hydroformylation of vinyl arenes allows access to profen dmgs such as naproxen and flurbiprofen. 

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