Catalytic process for preparing the alkyl esters of ibuprofen
AssigneeEthyl Corporation
InventorsThanikavelu Manimaran, Tse-Chong Wu, Felix M. Orihuela
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Abstract
A process for preparing alkyl esters of ibuprofen is provided. A 1-halo-1-(4-isobutylphenyl)ethane is reacted in an anhydrous medium with carbon monoxide in the presence of an alkoxide source at a temperature between about 10.degree. C. and about 200.degree. C. An excess of several moles of alcohol is preferred. An acid such as hydrogen chloride may also be added. As catalyst, a palladium compound having at least one acid-stable ligand is present; however, an excess of ligand over palladium is advantageous.
Claims42
A process for preparing an alkyl ester of ibuprofen which comprises carbonylating a 1-halo-1-(4-isobutylphenyl)ethane with carbon monoxide in a neutral or acidic anhydrous medium containing at least about 1 mol of a source of alkoxide ions selected from the group consisting of RC(OR.sub.1).sub.3, (R).sub.2 C(OR.sub.1).sub.2, Ti(OR.sub.1).sub.4, Al(OR.sub.1).sub.3, B(OR.sub.1).sub.3, HC(O)OR.sub.1, P(O)(R.sub.1).sub.3 and P(OR.sub.1) where R is hydrogen or individually the same or different than R.sub.1 and R.sub.1 is alkyl per mol of 1-halo-1-(4-isobutylphenyl)ethane at a temperature between about 10.degree. C. and about 200.degree. C. and a carbon monoxide pressure of at least about one atmosphere in the presence of (a) a palladium metal or palladium compound in which the palladium has a valence of 1 or 2 and (b) at least one acid-stable ligand.
A process for preparing the methyl ester of ibuprofen which comprises carbonylating 1-chloro-1-(4-isobutylphenyl)ethane with carbon monoxide in an anhydrous, acidic medium containing methyl ethyl ketone as a solvent and about 8-24 mols of anhydrous trimethyl orthoformate per mol of said 1-chloro-1-(4-isobutylphenyl)ethane at a temperature in the range of about 50.degree.-150.degree. C. and a carbon monoxide pressure in the range of about 800-1000 psig in the presence of (a) a palladium(II) compound and (b) at least one acid-stable monodentate phosphine ligand and in the presence of an amount of hydrogen chloride such as to provide an amount up to about 10 mols of hydrogen chloride per mol of 1-chloro-1-(4-isobutylphenyl)ethane.
A process for preparing the methyl ester of ibuprofen which comprises carbonylating 1-chloro-1-(4-isobutylphenyl)ethane with carbon monoxide in an anhydrous, neutral or acidic medium containing methyl ethyl ketone as a solvent and about 8-24 mols of trimethyl orthoformate per mol of said 1-chloro-1-(4-isobutylphenyl)ethane and no added acid at a temperature in the range of about 50.degree.-150.degree. C. and a carbon monoxide pressure in the range of about 800-2000 psig (about 5-14 MPa), in the presence of (a) a palladium(II) compound and (b) at least one acid-stable monodentate phosphine ligand.
Dependencies are inferred from the claim text.