Naproxen amide

Internal proton return to lithium enolates from secondary amines which are coordinated to the lithium ion has been used for diastereoselective (Sections 2.1.3.6. and 2.1.4.2.) and enantioselec-tive (Section 2.1.6.1.2.) protonations. A remarkable example of enantioselective internal proton return, with the exclusion of any additional proton source, occurs with racemic Naproxen amides 1l63a. 

PAMAM GO Naproxen Naproxen Amide or ester Anti-inflammatory Yes Yes No 335... 

The use of chiral lithium amide bases in combination with achiral protonating agents provides as striking argument for the internal proton return in mixed eno-late aggregates. The concept was verified first by Hogeveen and Zwart [233] and thereafter studied intensively by Vedejs and coworkers who used Lewis acids for reprotonation [234]. The method is illustrated for the deracemization of naproxen amide 466 that is converted into a mixture of cis- and traws-enolates 468 in the ratio of 93 7 by treatment with 2 equiv. of s-butyllithium, followed by 2 equiv. of... 

Naproxen amide (T -Ibuprofen amide (79-Flurbiprofen amide... 

Naproxen, (S)-2-(6-methoxy-2-naphthyl)propanoic acid 126 is a nonsteroidal anti-inflammatory and analgesic agent first developed by Syntex [220,221]. Biologically active desired S-naproxen has been prepared by enantioselective hydrolysis of the methyl ester of naproxen by esterase derived from Bacillus subtilis Thai 1-8 [222]. The esterase was subsequently clone in Escherichia coli with over 800-fold ipcrease in activity of enzyme. The resolution of racemic naproxen amide and ketoprofen amides has been demonstrated by amidases from Rhodococcus erythropolis MP50 and Rhodococcus sp. C311 (223-226). 5-Naproxen 126 and 5-ketoprofen 127 (Fig. 44) were obtained in 40% yields (theoretical maximum yield is 50%) and 97% e.e. Recently, the enantioselective esterification of naproxen has been demonstrated using lipase from Candida cylindraceae in isooctane as solvent and trimethylsilyl as alcohol. The undesired isomer of naproxen was esterified leaving desired S isomer unreacted [227]. 

Together with R. rhodochrous ATCC 21197 [43] and Pseudomonas putida NRRL 18668 [51], also Rhodococcus sp. C3II md Rhodococcus erythropolis MP 50 were used for the enantiospecific preparation of (S)-naproxen [65]. Rhodococcus sp. C3II lacks a nitrilase but exhibits nitrile hydratase and amidase activities, both of which are constitutive and prefer the (5 )-enantiomers of naproxen derivatives. On the other hand, the enzymes from R. erythropolis MP 50 were induced by nitriles and its nitrile hydratase was (R)-specific [44]. Due to the presence of a strictly (5)-specific amidase, both strains finally formed (5)-naproxen with high enantioselectivity (Fig. 18). Evidence for the enantioselectivity of the nitrile hydratases of both strains was obtained by the formation of optically active amides in the presence of the amidase inhibitor diethyl phosphoramidate [63,65]. The nitrile hydratase of Rhodococcus sp. C3II whole cells was used for the sjmthesis of (>S)-naproxen amide with 94% e.e. after 30% conversion in the presence of the amidase inhibitor [63]. In addition, the highly stereoselective amidases of these two strains were used to prepare (5)-ketoprofen (Fig. 28), and the amidase from R. erythropolis MP 50 was used to prepare (5)-2-phenylpropionic acid with more than 99% e.e. and more than 49% conversion [66,67]. 

Naproxen amide (C3II) ffl -Naproxen amide (MP50)... 

Most of the reactions applied to amines can also be transferred to alcohols (Eig. 7-5). One large group of chiral alcohols are the (i-adrenoreceptor blockers, for which a variety of derivatization agents was developed. One highly versatile reagent for the separation of (i-blockers is A-[(2-isothiocyanato)cyclohexyl]3,5-dinitrobenzoyl-amide (DDITC) [11]. Alternatively, unichiral drugs such as (3-blockers or (S)-naproxen [12] may be used in a reciprocal approach to derivatize racemic amine compounds. 

The hydrolysis of racemic non-natural amides has led to useful products and intermediates for the fine chemical industry. Thus hydrolysis of the racemic amide (2) with an acylase in Rhodococcus erythrolpolis furnished the (S)-acid (the anti-inflammatory agent Naproxen) in 42 % yield and > 99 % enantiomeric excess1201. Obtaining the 7-lactam (—)-(3) has been the subject of much research and development effort, since the compound is a very versatile synthon for the production of carbocyclic nucleosides. An acylase from Comamonas acidovor-ans has been isolated, cloned and overexpressed. The acylase tolerates a 500 g/ litre input of racemic lactam, hydrolyses only the (+)-enantiomer leaving the desired intermediate essentially optically pure (E > 400)[211. 

Firstly, the system will also hydrogenate enamides with high e.e., provided that the amide substituent and the one substituent at the other carbon are cis to one another. Secondly, the Ru(BINAP)(RC02)2 catalyst gives enantioselective hydrogenation of acrylic derivatives, see the examples below for Naproxen and the like. 

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. 

The highly water-soluble 2-hydroxypropyl-/i-cyclodextrin (2-HP-/1-CD) is a commercially useful general complexing agent. Inclusion complexes of poorly water-soluble Naproxen with 2-HP-/1-CD were useful to increase its solubility and dissolution rate, and resulted in an enhancement of bio-availability and minimized the gastrointestinal toxicity of the drug [69]. The water solubility of melatonin, which is an indole amide neurohormone, was also enhanced in a complex with 2-HP-/J-CD [70]. 

Although nitrile hydratases tend not to be stereoselective, examples of enantioselective enzymes are known [103, 106, 107, 114]. Of particular interest is the possibility to selectively hydrolyse 2-phenylproprionitriles, the core structure for ibuprofen and many other profens [103, 107, 114, 115]. This enables the enantioselective synthesis of the amides of ketoprofen and naproxen (Scheme 6.39). 

Type I CSPs have also been used with aqueous mobile phases. Pirkle et al. (32) have reported on the resolution of N-(3,5-dinitrobenzoyl) derivatives of M-amino adds and 2-aminophosphonic adds on an (l )-N-(2-naphthyl)-alanine-derived CSP using a mobile phase composed of methanol-aqueous phosphate buffer. The utility of achiral alkyltrimethylammoruum ion-pairing reagents was also investigated. Other examples include the following (1) The recently commercialized ot-Burke 1 CSP resolves the enantiomers of a number of underivatized p-blockers using an ethanol-dichlorornethane-ammonium acetate mobile phase (33) (2) an (R)-l-naphthylethylurea CSP was used to resolve N-(3,5-dinitrobenzoyI)-substituted amino adds and 3,5-dinitrobenzoyl amide derivatives of ibuprofen, naproxen, and fenoprofen with acetonitrile-sodium acetate mobile phases (34). 

Several variations of these CSPs have been developed, such as the phosphonate ester CSP 30 and the tetrahydrophenanthryl amide CSP 33. These compounds are used in pharmaceutical studies. The former CSP is a good resolving agent for the (3-adrenergic blocker class of compounds, such as propanolol, whereas the latter is a good CSP for separation of NSAIDs, such as naproxen and ibuprofen. ... 

In contrast to facile a-alkylation of carbonyl compounds, a-arylation or alkenylation of carbonyl compounds has been considered to be a difficult reaction. Recently, a big breakthrough has occurred, and methods for the smooth a-arylation or alkenylation of carbonyl compounds have been developed [1]. Active methylene compounds, ketones, aldehydes, esters, amides and nitriles are now a-arylated easily not only with aryl iodides, but also with bromides and even chlorides. These reactions will lead to wide-ranging applications. A typical example of a synthetic application of the innovative reactions is a new preparative method for a-arylated carboxylic acids, such as ibuprofen (1) and naproxen, by direct a-arylation of acetate or propionate. 

In order to broaden the capabilities of the Pirkle concept, both polar and polarizable groups were introduced into the molecule. The most popular of this type of chiral stationary phase are the (R,R) Whelk-01 and the (S,S)Whelk-01 phases, the structures of which are shown below. These phases are more versatile and have a wider field of application than the phases previously described. The phases are covalently bonded to the silica and so they can be used with almost any type of solvent. However, they have been found to operate most effectively in the normal phase mode. It should be noted that the polarizable character of the aromatic ring is essential for the stationary phase to function well. As the Pirkle phases are generally available in both the (R) and (S) configurations, the reversal of the elution order of a pair of enantiomers is possible. This stationary phase was originally designed for the separation of the Naproxen enantiomers but has found a wide application to the separation of epoxides, alcohols, diols, amides, imides and carbamates. 

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