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US 6,555,704 B1Granted
Process for the carbonylation of arylalkyl halides
AssigneeBASF SE
InventorVaradaraj Elango
Life of this patent
Estimating the term…
Abstract
A method is provided for the preparation of alpha-aryl-propionic acids such as ibuprofen by carbonylating the corresponding 1-arylethyl halide in an acidic aqueous medium containing a palladium catalyst. In the preparation of ibuprofen, 1-(4′-isobutylphenyl)ethyl halide is reacted with carbon monoxide in an acidic aqueous medium containing a palladium catalyst.
Claims71
A process for preparing ibuprofen from a corresponding halide substrate, which consists essentially of:
- combining an initial reactant consisting of a 1-(4′-isobutylphenyl)ethyl halide with carbon monoxide in an acidic medium containing water, which is present in an amount of about 1% to 600% based on the weight of the halide initial reactant, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl halide is from about 1:25 to 1:20,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and halide ions such that the molar ratios of dissociated hydrogen ions and halide ions to 1-(4′-isobutylphenyl)ethyl halide initial reactant are each about 0.1 to 5, at a temperature in the range of about 10° C. to 225° C., and a carbon monoxide pressure of about 100 to 5,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
A process for preparing ibuprofen from a corresponding halide substrate, which consists essentially of:
- charging a reactor with 1-(4′-isobutylphenyl)ethyl halide;
- and
- carbonylating said halide with carbon monoxide;
- wherein the carbonylation takes place in an acidic medium containing water, which is present in an amount of about 10% to 300% based on the weight of the halide charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl halide is from about 1:75 to 1:10,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and halide ions such that the molar ratios of dissociated hydrogen ions and halide ions to 1-(4′-isobutylphenyl)ethyl halide charged are each about 0.2 to 2, at a temperature in the range of about 70° C. to 175° C. and a carbon monoxide pressure of about 600 to 3,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing ibuprofen from a corresponding halide substrate, which consists essentially of:
- charging a reactor with a 1-(4′-isobutylphenyl)ethyl halide;
- and
- carbonylating said halide with carbon monoxide;
- wherein the carbonylation takes place in an acidic medium containing methyl ethyl ketone and water, which is present in an amount of about 10% to 300% based on the weight of the halide charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl halide is from about 1:100 to 1:6,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and chloride ions such that the molar ratios of dissociated hydrogen ions and chloride ions to 1-(4′-isobutylphenyl)ethyl halide charged are each about 0.2 to 2.0, at a temperature in the range of about 70° C. to 175° C., and a carbon monoxide pressure of about 600 to 3,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing ibuprofen from an ibuprofen substrate, which consists essentially of:
- charging a reactor with said ibuprofen substrate, wherein said ibuprofen substrate consists of 1-(4′-isobutylphenyl)ethyl chloride;
- and
- carbonylating said substrate with carbon monoxide;
- wherein said carbonylation takes place in an acidic medium containing water, which is present in an amount of about 10% to 300% based on the weight of the chloride charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl chloride is from about 1:100 to 1:6,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and chloride ions such that the molar ratios of dissociated hydrogen ions and chloride ions to 1-(4′-isobutyl-phenyl)ethyl chloride charged are each about 0.2 to 2, at a temperature in the range of about 70° C. to 175° C., and a carbon monoxide pressure of about 600 to 3,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A method of preparing ibuprofen comprising:
- (A) charging a reactor with 1-(4′-isobutylphenyl)ethyl halide;
- and
- (B) carbonylating the 1-(4′-isobutylphenyl)ethyl halide with carbon monoxide in an acidic aqueous medium in the reactor in the presence of (a) a palladium catalyst in which the palladium has a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction, complexed with the palladium.
A process for preparing ibuprofen, which comprises carbonylating a 1-(4′-isobutylphenyl)ethyl halide with carbon monoxide in an acidic medium containing water in an amount of about 1% to 600% based on the weight of the halide at a temperature in the range of about 10° C. to 225° C. and carbon monoxide pressure in the range of about 100 to 5,000 psig in the presence of (a) a palladium catalyst in which the palladium has a valence of 0-2 and (b) at least one ligand, which can tolerate conditions of reaction, complexed with the palladium.
A process for preparing ibuprofen, which comprises:
- (A) charging a reactor with 1-chloro-1-(4-isobutylphenyl)ethane;
- and
- (B) carbonylating the 1-chloro-1-(4-isobutylphenyl)ethane in the reactor with carbon monoxide in an acidic medium containing methyl ethyl ketone as a solvent and about 10% to 300% of water based on the weight of 1-chloro-1-(4-isobutylphenyl)ethane at a temperature in the range of about 10° C.-225° C. and a carbon monoxide pressure in the range of about 100-5,000 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 of about 0.1 to 5 mols of hydrogen chloride per mol of 1-chloro-1-(4-isobutylphenyl)ethane.
A process for preparing ibuprofen, which comprises:
- (A) charging a reactor with 1-chloro-1-(4-isobutylphenyl)-ethane;
- and
- (B) carbonylating the 1-chloro-1-(4-isobutylphenyl)ethane in the reactor with carbon monoxide in an acidic medium containing methyl ethyl ketone as a solvent and about 10% to 300% of water based on the weight of 1-chloro-1-(4-isobutylphenyl)ethane and added hydrogen halide at a temperature in the range of about 10°-225° C. and a carbon monoxide pressure in the range of about 100-5,000 psig, in the presence of (a) a palladium(II) compound, and (b) at least one acid-stable monodentate phosphine ligand.
A process for preparing ibuprofen from a corresponding halide substrate, which consists essentially of:
- combining an initial reactant consisting of a 1-(4′-isobutylphenyl)ethyl halide with carbon monoxide in an acidic medium containing water, which is present in an amount of about 1% to 600% based on the weight of the halide initial reactant, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl halide is from about 1:25 to 1:20,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and halide ions such that the molar ratios of dissociated hydrogen ions and halide ions to 1-(4′-isobutylphenyl)ethyl halide initial reactant are each about 0.1 to 5, at a temperature in the range of about 10° C. to 225° C., and a carbon monoxide pressure of about 100 to 5,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
A process for preparing ibuprofen from a corresponding halide substrate, which consists essentially of:
- charging a reactor with 1-(4′-isobutylphenyl)ethyl halide;
- and
- carbonylating said halide with carbon monoxide;
- wherein said carbonylation takes place in an acidic medium containing water, which is present in an amount of about 10% to 300% based on the weight of the halide charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl halide is from about 1:75 to 1:10,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and halide ions such that the molar ratios of dissociated hydrogen ions and halide ions to 1-(4′-isobutylphenyl)ethyl halide charged are each about 0.2 to 2, at a temperature in the range of about 70° C. to 175° C. and a carbon monoxide pressure of about 600 to 3,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing ibuprofen from a corresponding halide substrate, which consists essentially of:
- charging a reactor with a 1-(4′-isobutylphenyl)ethyl halide;
- and
- carbonylating said halide with carbon monoxide;
- wherein said carbonylation takes place in an acidic medium containing methyl ethyl ketone and water, which is present in an amount of about 10% to 300% based on the weight of the halide charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl halide is from about 1:100 to 1:6,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and chloride ions such that the molar ratios of dissociated hydrogen ions and chloride ions to 1-(4′-isobutylphenyl)ethyl halide charged are each about 0.2 to 2.0, at a temperature in the range of about 70° C. to 175° C., and a carbon monoxide pressure of about 600 to 3,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing ibuprofen from an ibuprofen substrate, which consists essentially of:
- charging a reactor with said ibuprofen substrate, wherein said ibuprofen substrate consists of 1-(4′-isobutylphenyl)ethyl chloride;
- and
- carbonylating said substrate with carbon monoxide;
- wherein said carbonylation takes place in an acidic medium containing water, which is present in an amount of about 10% to 300% based on the weight of the chloride charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(4′-isobutylphenyl)ethyl chloride is from about 1:100 to 1:6,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and chloride ions such that the molar ratios of dissociated hydrogen ions and chloride ions to 1-(4′-isobutylphenyl)ethyl chloride charged are each about 0.2 to 2, at a temperature in the range of about 70° C. to 175° C., and a carbon monoxide pressure of about 600 to 3,000 psig, to form said ibuprofen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing naproxen, which comprises:
- (A) charging a reactor with 1-(6′-methoxy-2′-napthyl)ethyl chloride;
- and
- (B) carbonylating the 1-(6′-methoxy-2′-napthyl)ethyl chloride in the reactor with carbon monoxide in an acidic medium containing methyl ethyl ketone as a solvent and about 10% to 300% of water based on the weight of 1-(6′-methoxy-2′-napthyl)ethyl chloride at a temperature in the range of about 10° C.-225° C. and a carbon monoxide pressure in the range of about 100-5,000 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 of about 0.1 to 5 mols of hydrogen chloride per mol of 1-(6′-methoxy-2′-napthyl)ethyl chloride.
A process for preparing naproxen, which comprises:
- (A) charging a reactor with 1-(6′-methoxy-2′-napthyl)ethyl chloride;
- and
- (B) carbonylating the 1-(6′-methoxy-2′-napthyl)ethyl chloride in the reactor with carbon monoxide in an acidic medium containing methyl ethyl ketone as a solvent and about 10% to 300% of water based on the weight of 1-(6′-methoxy-2′-napthyl)ethyl chloride and added hydrogen halide at a temperature in the range of about 10°-225° C. and a carbon monoxide pressure in the range of about 100-5,000 psig, in the presence of (a) a palladium(II) compound, and (b) at least one acid-stable monodentate phosphine ligand.
A process for preparing naproxen from a corresponding halide substrate, which consists essentially of:
- combining an initial reactant consisting of a 1-(6′-methoxy-2′-napthyl)ethyl halide with carbon monoxide in an acidic medium containing water, which is present in an amount of about 1% to 600% based on the weight of the halide initial reactant, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(6′-methoxy-2′-napthyl)ethyl halide is from about 1:25 to 1:20,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and halide ions such that the molar ratios of dissociated hydrogen ions and halide ions to 1-(6′-methoxy-2′-napthyl)ethyl halide initial reactant are each about 0.1 to 5, at a temperature in the range of about 10° C. to 225° C., and a carbon monoxide pressure of about 100 to 5,000 psig, to form said naproxen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
A process for preparing naproxen from a corresponding halide substrate, which consists essentially of:
- charging a reactor with 1-(6′-methoxy-2′-napthyl)ethyl halide;
- and
- carbonylating said halide with carbon monoxide;
- wherein the carbonylation takes place in an acidic medium containing water, which is present in an amount of about 10% to 300% based on the weight of the halide charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(6′-methoxy-2′-napthyl)ethyl halide is from about 1:75 to 1:10,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and halide ions such that the molar ratios of dissociated hydrogen ions and halide ions to 1-(6′-methoxy-2′-napthyl)ethyl halide charged are each about 0.2 to 2, at a temperature in the range of about 70° C. to 175° C. and a carbon monoxide pressure of about 600 to 3,000 psig, to form said naproxen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing naproxen from a corresponding halide substrate, which consists essentially of:
- charging a reactor with 1-(6′-methoxy-2′-napthyl)ethyl halide;
- and
- carbonylating said halide with carbon monoxide;
- wherein the carbonylation takes place in an acidic medium containing methyl ethyl ketone and water, which is present in an amount of about 10% to 300% based on the weight of the halide charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(6′-methoxy-2′-napthyl)ethyl halide is from about 1:100 to 1:6,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and chloride ions such that the molar ratios of dissociated hydrogen ions and chloride ions to 1-(6′-methoxy-2′-napthyl)ethyl halide charged are each about 0.2 to 2.0, at a temperature in the range of about 70° C. to 175° C., and a carbon monoxide pressure of about 600 to 3,000 psig, to form said naproxen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
A process for preparing naproxen from a naproxen substrate, which consists essentially of:
- charging a reactor with said naproxen substrate, wherein said naproxen substrate consists of 1-(6′-methoxy-2′-napthyl)ethyl chloride;
- and
- carbonylating said substrate with carbon monoxide;
- wherein the carbonylation takes place in an acidic medium containing water, which is present in an amount of about 10% to 300% based on the weight of the chloride charged, in the presence of a palladium catalyst, wherein the mole ratio of palladium to 1-(6′-methoxy-2′-napthyl)ethyl chloride is from about 1:100 to 1:6,000, and wherein said acidic aqueous medium further includes dissociated hydrogen ions and chloride ions such that the molar ratios of dissociated hydrogen ions and chloride ions to 1-(6′-methoxy-2′-napthyl)ethyl chloride charged are each about 0.2 to 2, at a temperature in the range of about 70° C. to 175° C., and a carbon monoxide pressure of about 600 to 3,000 psig, to form said naproxen;
- and
- wherein said palladium catalyst includes (a) palladium having a valence of 0-2, and (b) at least one ligand, which can tolerate conditions of reaction and which is complexed with the palladium.
3 more elements
Dependencies are inferred from the claim text.