Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1995-05-22
2003-04-29
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C546S087000, C560S056000, C562S466000
Reexamination Certificate
active
06555704
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a novel process for the production of alpha-arylpropionic acids. The invention is particularly useful for the production of anti-inflammatory drugs such as 2-(4′-isobutylphenyl)propionic acid, more commonly known as ibuprofen.
Ibuprofen is a well-known non-steroidal anti-inflammatory drug which has been converted from ethical, i.e., prescription, to over-the-counter status. Various processes are known for the production of ibuprofen using 4-isobutylacetophenone as a starting material. Thus, for example, British Patent 971,700 and corresponding U.S. Pat. No. 3,385,886, both assigned to Boots Pure Drug Company, PLC, show the production of phenylalkane derivatives such as ibuprofen in which the first step of the process is the reaction of an alkylbenzene with acetyl chloride in the presence of aluminum chloride to produce an alkylacetophenone which is then subjected to any of various series of subsequent reactions to produce the desired derivative.
Arylpropionic acids have been formed by the carbonylation of the respective arylethyl alcohol. For example, Japanese Kokai Patent No. SHO 55 [1980]-27147, published Feb. 27, 1980 and assigned to Mitsubishi Petrochemical Co., discloses the formation of ibuprofen by reacting 1-(4′-isobutylphenyl)ethanol with carbon monoxide and water in the presence of a hydrogen fluoride catalyst. Japanese Kokai Patent No. SHO 59 [1984]-95238, published Jun. 1, 1984 and assigned to Mitsubishi Petrochemical Co., teaches the formation of alpha-aryl-substituted propionic acids, by reacting an alpha-aryl-substituted ethanol with carbon monoxide and water, alcohol, or phenol, in the presence of a palladium catalyst. An acidic compound such as hydrogen chloride may be added as an auxiliary catalyst and a solvent such as benzene may also be used. The disclosure includes a comparative example in which ibuprofen (not included within the invention) is obtained in very low yield, i.e., 17.1%, when made utilizing the described process. Japanese Kokai Patent No. SHO 59 [1984]-95239, published Jun. 1, 1984 and assigned to Mitsubishi Petrochemical Co., discloses the formation of alpha-(6′-methoxy-2′-naphthyl)propionic acid by reacting alpha-(6′-methoxy-2′-naphthyl)ethanol with carbon monoxide and water in the presence of a palladium catalyst and an acidic compound, e.g., hydrogen chloride. The patent publication also states that if a non-halogen-containing acidic compound is used, it is desirable to add an ionizable metal halide to the reaction.
Japanese Kokai Patent No. SHO 56[1981]-35659, published Sep. 4, 1978 and assigned to Ferrel International Societe Annonim, discloses an anhydrous method of producing a 2-(4′-isobutylphenyl)propionic acid ester by treating 1-(4′-isobutylphenyl)ethanol (IBPE) with carbon monoxide in a solution containing an alkanol and a catalyst such as palladium bis(triphenylphosphine) dichloro complex. The solution may also contain up to 10% of a mineral acid such as hydrogen chloride.
British Patent 1,565,235, assigned to Mitsubishi Petrochemical Co. discloses a process for producing alpha-arylpropionic acids which have an anti-inflammatory, analgesic or antipyretic effect. The process comprises reacting an arylethylene with carbon monoxide under pressure in the presence of a carbonylation catalyst and in the presence of water and/or a lower alcohol to carbonylate the arylethylene into the alpha-arylpropionic acid. The starting materials for the arylethylenes can be prepared such as by the dehydration of arylethyl alcohols or by the dehydrohalogenation of arylethyl halides. The arylethylenes can be purified by means of a single distillation or re-crystallization to obtain the products with a sufficiently high purity to be used as the starting material for the subsequent carbonylation step. An example in the patent describes the dehydrohalogenation of alpha-(4-isobutylphenyl)ethyl chloride to obtain 4-isobutylstyrene and then carbonylating 4-isobutylstyrene in the presence of water, methyl alcohol, hydrogen chloride, and bis(triphenolphosphine)dichloropalladium (II).
In copending, commonly assigned U.S. Ser. No. 158,141, filed Mar. 4, 1988, 2-(4′-isobutylphenyl)propionic acid, i.e., ibuprofen, is prepared by carbonylating 1-(4′-isobutylphenyl)ethanol (IBPE) with carbon monoxide in an acidic aqueous medium at a temperature of at least about 10° C. and a carbon monoxide pressure of at least about 500 psig, and in the presence of 1) a catalyst consisting essentially of a palladium compound in which the palladium is complexed with at least one acid stable, monodentate phosphine ligand freely miscible with the organic phase of the reaction medium; 2) dissociated hydrogen ions from an acid which is substantially completely ionizable in a dilute aqueous solution such that the molar ratio of hydrogen ions to IBPE added to the reaction zone is at least about 0.15 and the mole ratio of hydrogen ions to water is at least 0.026; and 3) dissociated halide ions such that the molar ratio of halide ions to IBPE added to the reaction zone is at least about 0.15.
the process is immediately described above for preparing ibuprofen by carbonylating 1-(4′-isobutylphenyl)ethanol is generally a multi-stage process in which the carbonylation reaction to produce ibuprofen is integrated with a method of producing IBPE from isobutylbenzene. Thus, isobutylbenzene is subjected to Friedel-Crafts reaction with an acetylating agent such as acetic acid, acetic anhydride, acetyl fluoride, acetyl chloride, acetyl bromide, methyl acetate in the presence of the Friedel-Crafts catalyst such as hydrogen fluoride to produce 4′-isobutylacetophenone (IBAP) which is subsequently reduced with hydrogen in the presence of a hydrogenation catalyst or with a reducing agent containing available hydrogen, to obtain IBPE.
An alternative process for producing alpha-aryl-propionic acids from the carbonylation of the respective 1-aryl ethyl alcohols is the carbonylation of secondary benzyl halides to the corresponding carboxylic acid. In such a known process, the secondary benzyl halides are carbonylated in the presence of a carbonylation catalyst in a basic medium. For example, in an article “Cobalt-Catalyzed Synthesis of Alpha-Arylpropionic and Diarylacetic Acids”,
Journal of Organometallic Chemistry
282 (1985) 277-282, there is disclosed the cobalt-catalyzed carbonylation of ArCH(R)X (R═CH
3
, C
6
H
5
; X═Cl, Br) in alcoholic solvents under atmospheric pressure of CO. It is stated therein that selective, high yield synthesis of the corresponding acids can be achieved within a very narrow range of experimental conditions. Similarly, U.S. Pat. No. 4,536,595 and related European Patent Applications 76,721 and 76,722 disclose forming alpha-arylpropionic acids such as ibuprofen by carbonylating the respective secondary benzyl halides in the presence of a cobalt hydrocarbonyl catalyst and an anhydrous alcoholic solvent. U.S. Pat. Nos. 4,152,352 and 4,351,952 disclose the formation of arylpyruvic acids by reacting an arylmethyl halide with carbon monoxide in the presence of a cobalt carbonyl catalyst and a base. U.S. Pat. No. 3,974,202 discloses producing an alkyl ester of arylacetic acid by reacting the arylmethyl halide with CO and an alcohol in basic reaction medium in the presence of a cobalt catalyst. U.S. Pat. No. 4,713,484 discloses the formation of carboxylic acid salts by carbonylating an organic halide with an alcohol, CO, and a base in the presence of a palladium catalyst and an excess of tertiary phosphine.
The process for carbonylating the arylalkyl halides to carboxylic acids in base medium has several disadvantages. For one, the carboxylic acid salt of an alkali metal is formed instead of the acid. Consequently, the acid has to be obtained in a separate step by acidification of the salt such as with mineral acids. Additionally, reactions on the arylalkyl halides under carbonylation conditions often result in d
BASF Corporation
Maurer Barbara V.
Meyers, Esq. Kenneth J
Rotman Alan L.
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