Hydrogenation of precursors to thiazolidinedione antihyperglycemics
AssigneeTeva Pharmaceutical Industries Ltd.
InventorBen-Zion Dolitzky
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Abstract
Provided is a method of hydrogenating the exocyclic double bond of a thiazolidinedione precursor in a method of making a thiazolidinedione antihyperglycemic, for example pioglitazone, including work-up steps to afford pure thiazolidinedione antihyperglycemic.
Claims45
A method of catalytically hydrogenating the exocyclic double bond of a penultimate thiazolidinedione precursor comprising the steps of:
- a) providing a solution of the penultimate thiazolidinedione precursor in a high capacity solvent,
- b) combining the solution with a supported metal hydrogenation catalyst in a reactor, and
- c) exposing the combination of solution and hydrogenation catalyst to hydrogen gas.
A method of catalytically hydrogenating the exocyclic double bond of a penultimate thiazolidinedione precursor comprising the steps of:
- a) providing a solution of the penultimate thiazolidinedione precursor in formic acid solvent,
- b) combining the solution with a supported metal hydrogenation catalyst in a reactor, wherein the supported metal hydrogenation catalyst comprises a metal selected from the group consisting of platinum, palladium, ruthenium, rhodium, osmium, and iridium, and
- c) heating the combination to a temperature of about 40° C. to about 100° C.
A method of making a thiazolidinedione antihyperglycemic comprising the step of catalytically hydrogenating a penultimate thiazolidinedione precursor in solution in a high capacity solvent using a supported metal hydrogenation catalyst comprising a metal selected from platinum, palladium, ruthenium, rhodium, osmium, and iridium, wherein essentially all of the product of hydrogenation is in solution in the high capacity solvent when hydrogenation is completed.
A method of making a pure thiazolidinedione antihyperglycemic comprising the steps of:
- a) catalytically hydrogenating a penultimate thiazolidinedione precursor in solution in a high capacity solvent using a supported metal hydrogenation catalyst comprising a metal selected from platinum, palladium, ruthenium, rhodium, osmium, and iridium, wherein essentially all of the product of hydrogenation is in solution in the high capacity solvent when hydrogenation is completed,
- b) separating the supported metal catalyst from the solution,
- c) combining the solution from which catalyst has been separated with a crystallization solvent that is acetone or a lower aliphatic alcohol,
- d) cooling the combination, and
- e) isolating the solid pure thiazolidinedione antihyperglycemic formed.
Pioglitazone having a purity of 99.7 area percent as determined by HPLC.
Rosiglitazone having a purity of 99.7 area percent as determined by HPLC.
Troglitazone having a purity of 99.7 area percent as determined by HPLC.
In a method of making pioglitazone, the step of catalytically hydrogenating 5-[4-[2-[5ethylpyridin-2-yl]ethoxy]phenyl]methenyl-2,4-thiazolidinedione in formic acid solution using a palladium-on-charcoal supported hydrogenation catalyst wherein the concentration of the precursor in the solution is at least about 0.2 g/mL and wherein the amount of supported catalyst used is such that the ratio of the weight of palladium metal to weight of 5-[4-[2-[5ethylpyridin-2-yl]ethoxy]phenyl]methenyl-2,4-thiazolidinedione is about 0.02:1 or less.
In a method of making rosiglitazone, the step of catalytically hydrogenating 5-[4-[2-[N-methyl-N-(pyridin-2-yl)aminoethoxy]phenyl]methenyl-2,4-thiazolidinedione in formic acid solution using a palladium-on-charcoal supported hydrogenation catalyst wherein the concentration of the precursor in the solution is at least about 0.2 g/mL and wherein the amount of supported catalyst used is such that the ratio of the weight of palladium metal to weight of 5-[4-[2-[5ethylpyridin-2-yl]ethoxy]phenyl]methenyl-2,4-thiazolidinedione is about 0.02:1 or less.
In a method of making troglitazone, the step of catalytically hydrogenating 5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman72-yl)methoxy]phenyl]methenyl-2,4-thiazolidinedione in formic acid solution using a palladium-on-charcoal supported hydrogenation catalyst wherein the concentration of the precursor in the solution is at least about 0.2 g/mL and wherein the amount of supported catalyst used is such that the ratio of the weight of palladium metal to weight of 5-[4-[2-[5ethylpyridin-2-yl]ethoxy]phenyl]methenyl-2,4-thiazolidinedione is about 0.02:1 or less.
Dependencies are inferred from the claim text.