Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-02-15
2004-01-27
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06683205
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the synthesis of non-steroidal anti-inflammatory drugs (“NSAIDs”). More particularly, the invention relates to the synthesis of 2-aryl-3-hydroxy-propenoic acid esters and 2-aryl propenoic acid esters, which are key intermediates in the production of certain NSAIDs and their pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Efficient practical routes to pharmaceutically-active compounds are in great demand. Manufacturers constantly seek synthetic routes that are environmentally friendly with respect to solvent volume, purity, yield and waste reduction. In addition, the cost of manufacturing drugs generally decreases as the number of steps in the synthetic route decreases. This is particularly true with respect to (S)-2-(6-methoxy-2-naphthyl)propanoic acid, which is also known as naproxen.
Naproxen is one of the most potent NSAIDs currently available, and as a result is extremely popular with consumers, generating sales of over one billion dollars annually.
Unfortunately, naproxen is difficult to synthesize in an efficient and environmentally friendly manner. Since naproxen is the optically active (S) form of 2-(6-methoxy-2-naphthyl)propanoic acid, and is presently marketed in a composition free of the (R) stereoisomer, it has been proposed to produce naproxen using a catalytic asymmetric hydrogenation process.
Specifically, it has been proposed to synthesize naproxen from 2-(6-methoxy-2-naphthyl)propenoic acid in a catalytic asymmetric hydrogenation reaction using a ruthenium (S)-BINAP catalyst or a tol-BINAP-based catalyst. This synthesis route is generally shown in FIG. 1 below.
While this is an extremely efficient and effective process, it has not been utilized to date on a commercial scale due to the difficulty and high cost involved in producing the 2-(6-methoxy-2-naphthyl)propenoic acid precursor compound. Therefore, an efficient, cost-effective and environmentally-friendly process for making 2-(6-methoxy-2-naphthyl)propenoic acid is needed.
SUMMARY OF THE INVENTION
An efficient, cost-effective and environmentally-friendly process for making 2-(6-methoxy-2-naphthyl) propenoic acid ester, which can then easily be converted to 2-(6-methoxy-2 naphthyl) propenoic acid, and then from there to naproxen, using known techniques, has been discovered. Moreover, this process can be used to make other 2-aryl substituted propenoic acid esters, which in turn can be used to produce a wide variety of NSAIDs, including, but not limited to, ibuprofen, ketoprofen, flurbiprofen, fenaprofen, indoprofen, cicloprofen, carprofen, pirprofen, suprofen, and tiaprofenic acid.
For the production of NSAIDs, an aryl aldehyde, where the aryl group is a substituted or unsubstituted aromatic or heteroaromatic group, is reacted with an alkyldiazoacetate in the presence of a catalytic amount of fluoroboric acid or an iron Lewis acid to provide a 2-aryl-3-hydroxy-propenoic acid ester. The 2-aryl-3-hydroxy-propenoic acid ester is then reduced to provide a 2-aryl-propenoic acid ester, which can be converted to the desired NSAID by hydrolysis and hydrogenation.
Preferably, the substituted or unsubstituted aromatic or heteroaromatic group is (a) a phenyl group; (b) a phenyl group substituted with one, two or three substituents independently selected from alkyl halogen, cyano, carboxy, cycloalkyl, nitro, alkoxy, phenyl or substituted phenyl, alkylcarbonyl of one to ten carbon atoms, benzoyl or substituted benzoyl, 1-oxo-isoindolyl, phenoxy or substituted phenoxy, azoline or thienylcarbonyl; (c) a naphthyl group; (d) a naphthyl group substituted with one or more of the substituents from (b) above; (e) a fluorenyl group; (f) a carbazoyl group; (g) a carbazoyl group substituted with one or more of the substituents from (b) above; (h) a thienyl group; (i) a thienyl group substituted with one or more of the substituents from (b) above; (j) a pyrrolyl group; (k) a pyrrolyl group substituted with one or more of the substituents from (b) above; (l) a furyl group; and (m) a furyl group substituted with one or more of the substituents from (b) above.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to the synthesis of compounds of the formula:
where Ar is a substituted or unsubstituted aromatic or heteroaromatic group. The term “aromatic” refers to a ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, tetrahydronaphthyl, indanyl, indenyl and the like. Aromatic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, dialkylamino, aminocarbonyl, aminocarbonylalkoxy, aryl, arylalkyl, arylalkoxy, aryloxy, cyano, nitro, carboxy, cycloalkyl, cycloalkylalkyl, carboxyalkoxy and phenyl.
The term “alkyl” as used herein refer to straight or branched chain containing from one to ten carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term “alkoxy” as used herein refers to RO—, wherein R is a alkyl group, as defined above.
The term “cycloalkyl” as used herein refers to an aliphatic ring system having three to ten carbon atoms and one to three rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and like.
The term “halogen” or “halo” refers to one of the electronegative elements of group VIIA of the periodic table, such as fluorine, chlorine, bromine, iodine and astatine.
The term “heteroaromatic” refers to any 5-, 6-, 7-membered aromatic ring containing one or more nitrogen, oxygen, or sulfur atoms, or any combination thereof. The term “heteroaromatic” also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic ring (for example, indolyl, quinolyl, benzofuryl or benzothienyl and the like).
Heteroaromatics include, but are not limited to, pyrrolyl, pyrrolinyl, imidazolyl, pyridyl, indolyl, furyl, thienyl, isoindolyl.
Preferably, the substituted or unsubstituted aromatic or heteroaromatic group is (a) a phenyl group; (b) a phenyl group substituted with one, two or three substituents independently selected from alkyl, halogen, cyano, carboxy, cycloalkyl, nitro, alkoxy, phenyl or substituted phenyl, alkylcarbonyl of one to ten carbon atoms, benzoyl or substituted benzoyl, 1-oxo-isoindolyl, phenoxy or substituted phenoxy, azoline or thienylcarbonyl; (c) a naphthyl group; (d) a naphthyl group substituted with one or more of the substituents from (b) above; (e) a fluorenyl group; (f) a carbazoyl group; (g) a carbazoyl group substituted with one or more of the substiuents from (b) above; (h) a thienyl group; (i) a thienyl group substituted with one or more of the substituents from (b) above; (j) a pyrrolyl group; (k) a pyrrolyl group substituted with one or more of the substituents from (b) above; (l) a furyl group; and (m) a fturyl group substituted with one or more of the substituents from (b) above.
More preferably, the process of the present invention is used to produce NSAID compounds of formula (IV) above such as naproxen (Ar is 6-methoxy-2-naphthalenyl), ibuprofen (Ar isp-isobutylphenyl), ketoprofen (Ar is m-benzoylphenyl), flurbiprofen (Ar is 2-fluoro-4-biphenyl), fenaprofen (Ar is m-phenoxyphenyl), indoprofen (Ar is p-(1-oxo-2-isoindolinyl)-phenyl), cicloprofen (Ar is fluorenyl), carprofen (Ar is 6-chlorocarbazolyl), pirprofen (Ar is 3-chloro-4-(3-pyrrolin-1-yl)-phenyl), tiaprofenic acid (Ar is 5-benzoyl-2-thienyl), and suprofen (Ar is p-2-thienoyl-phenyl).
Most preferably, the process of the present invention is used to manufacture naproxen.
The compounds of formula (IV) are produced by reacting an aldehyde of the formula:
where Ar is as described above, with an alkyldiazoacetate of the formula N
2
CHCOOR, w
Gerstl Robert
Michael & Best & Friedrich LLP
WiSYS Technology Foundation, Inc.
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