Processes for making thiazolidinedione derivatives and compounds thereof

A compound and alkyl technology, applied in the field of producing thiazolidinedione derivatives, can solve the problems of troublesome purification, low chemical yield and the like

Inactive Publication Date: 2006-08-02
SYNTHON BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The close ratio of N- and O-alkylated products of compound (9) causes troubles in purification and leads to low chemical yields

Method used

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  • Processes for making thiazolidinedione derivatives and compounds thereof
  • Processes for making thiazolidinedione derivatives and compounds thereof
  • Processes for making thiazolidinedione derivatives and compounds thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Preparation of 2-amino-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- by alkylation of L-tyrosine sodium salt in DMSO Propionic acid (compound (11), R=H)

[0130] 10 g of L-tyrosine was dissolved in 43 mL of 1M NaOH, 245 mL of dimethylsulfoxide was added, followed by 14 g of 2-(5-ethyl-pyridin-2-yl)-ethyl methanesulfonate (Preparation 3). The reaction mixture was stirred for more than 72 hours, the solvent was removed under vacuum and the residue was dissolved in 100 mL of water. The aqueous solution was neutralized with 6N hydrochloric acid. The precipitate was filtered off and washed with water. Recrystallization from hot methanol-water solution gave 3.1 g of 2-amino-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid (R =H).

Embodiment 2

[0132] Preparation of 2-amino-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- by alkylation of L-tyrosine lithium salt in DMSO Propionic acid (compound (11), R=H)

[0133] 14 g of L-tyrosine were dissolved in a mixture of 12 g of lithium hydroxide and 120 mL of water. Then, 400 mL of dimethylsulfoxide was added, followed by a solution of 23.5 g of 2-(5-ethyl-pyridin-2-yl)-ethyl methanesulfonate (Preparation 3) in 100 mL of toluene. The reaction mixture was stirred at ambient temperature for 48 hours, after which time it was extracted 5 times with 20 mL of toluene. The pH of the dimethylsulfoxide layer was adjusted to 8 with 6N aqueous hydrochloric acid (1:1). The mixture was stirred, the precipitate (8.9 g lithium salt of L-tyrosine) was filtered off, and the filter cake was washed with hot ethanol. Ethanol was evaporated and the residue was added to the filtrate. The filtrate was acidified to pH 2 with hydrochloric acid and the solvent was removed under vacuum at 50°C. T...

Embodiment 3

[0135] Preparation of 2-amino-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzene by alkylation of L-tyrosine benzyltrimethylammonium salt in DMSO Base}-propionic acid (compound (11), R=H)

[0136] Mix 10 g of L-tyrosine with 25 mL of 40% benzyltrimethylammonium hydroxide in methanol. The mixture was heated and methanol was removed under vacuum. Then, 50 mL of dimethyl sulfoxide was added and the mixture was heated until all solids were dissolved (90°C). The solution was allowed to cool and an additional 3.0 g of sodium hydride was added. Then, a solution of 2.3 g of 2-(5-ethyl-pyridin-2-yl)-ethyl methanesulfonate (Preparation 3) in dimethylsulfoxide and 2.5 g of solid sodium hydride were added portionwise over 6 hours. The reaction mixture was stirred overnight at ambient temperature. Then, 150 mL of acetone was added, and the precipitate was filtered off, dissolved in 50 mL of water and acidified with hydrochloric acid. The solution was extracted with ethyl acetate, and the ...

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Abstract

The present invention provides a compound of the formula (I): wherein A represents a ring group connected to the oxygen atom by a C1 to C6 hydrocarbon chain, R is hydrogen or a C1-C4 alkyl, and Q is hydrogen, or an amine protecting group such as acetyl, trifluoroacetyl, benzoyl, benzyl, or trityl, is useful in making thiazolidinedione derivatives (formula (II)), such as pioglitazone, rosiglitazone and troglitazone.

Description

Background of the invention [0001] The present invention relates to a process for the production of thiazolidinedione derivatives such as pioglitazone and to compounds suitable for use in the process. [0002] A number of thiazolidinedione derivatives or "glitazones" are known to exhibit hypoglycemic and / or hypolipidemic activity and are suggested, inter alia, for the treatment of diabetes. Some of the more well-known and / or investigated glitazones include pioglitazone, troglitazone, and rosiglitazone. The chemical name of formula (1) is 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxyl]phenyl]methyl]-2, the pioglitazone of 4-thiazolidinedione [0003] is a commercially licensed antidiabetic agent. Pharmaceutical compositions containing pioglitazone in hydrochloride form are marketed under the trade name ACTOS(R) (Takeda Chemical Ind.) for the treatment of type II diabetes. [0004] Pioglitazone and its hydrochloride are disclosed in EP 193256 and the corresponding US Patent No. 4,687...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D213/30C07D213/74C07D311/72
CPCC07D213/74C07D311/72C07D417/12C07D213/30Y02P20/55A61P3/10
Inventor K·波斯皮司里克朱杰F·皮察
Owner SYNTHON BV
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