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A process for the preparation of substituted phenyl ether compounds and rosiglitazone

A compound, phenyl technology, applied in the field of acid addition salts, key intermediates of thiazolidinedione derivatives, and pyridyl-substituted ethoxybenzaldehyde, which can solve problems such as low yields

Inactive Publication Date: 2008-07-23
SANDOZ AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In existing literature methods for the preparation of pyridyl-substituted ethoxybenzaldehydes (ether compounds), the presence of even small amounts of water in aromatic formaldehyde compounds causes their conversion to the corresponding acids and unavoidable amounts resulting in lower Yield of the acid

Method used

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  • A process for the preparation of substituted phenyl ether compounds and rosiglitazone
  • A process for the preparation of substituted phenyl ether compounds and rosiglitazone
  • A process for the preparation of substituted phenyl ether compounds and rosiglitazone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Preparation of 2-(N-methyl-N-(2-pyridyl)amino)ethanol

[0062] A mixture of 1.5 kg (13.21 mol) of 2-chloropyridine and 12.75 l (158.7 mol) of 2-(N-methylamino)ethanol was stirred at 120-125° C. for about 22 hours. Excess 2-(N-methylamino)ethanol (approximately 9.1 l) was then distilled off under reduced pressure. To the oily residue was added 3.0 1 of water at 25-35°C and the solution was stirred for 30 minutes, then 3.0 1 of toluene was added and stirred for 30 minutes. The aqueous layer was separated and extracted twice with 3.0 1 toluene. The combined organic layers were washed twice with 1.5 l of water. The organic solvent was evaporated under reduced pressure at 50-55°C. 1.82 kg (90.55%) of the title compound were obtained as an oil.

Embodiment 2

[0064] Preparation of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde

[0065] 450ml of toluene, 300ml of water, 91g of potassium hydroxide, 50g of 2-(N-ethyl-N-(2-pyridyl)amino)ethanol, 60g of 4-fluorobenzaldehyde and 56g of tetra-n-butylammonium bisulfate in 49- Heat at 52°C and stir vigorously at the same temperature for about 20 hours. 300ml of water was added to the reaction and stirred for 10-15 minutes and the aqueous layer was separated. The organic layer was washed with 300ml of water. The combined aqueous layers were extracted with 200ml of toluene and the layers were separated. The combined toluene layers were extracted with a mixture of 600 ml of water and 40 ml of concentrated hydrochloric acid. The aqueous extract was separated and 80 ml of 12% aqueous ammonium hydroxide were added with stirring. The precipitated product was isolated by filtration, washed with water and dried in vacuo to give 60.2 g of the title compound as a light yellow solid.

[006...

Embodiment 3

[0073] Preparation of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione

[0074] Add 12.0l of toluene, 2.0kg (7.8mol) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde and 1.0g (8.78mol) at 25-30°C ) in the mixture of 2,4-thiazolidinedione was added 14.4g piperidine and 10g acetic acid. The water was removed azeotropically by using a Dean Stark apparatus. The reaction mixture was heated at reflux temperature for 5 hours and the resulting orange reaction was cooled to 25-30°C. The solid separated was filtered and washed with 5.0 1 methanol. The obtained solid was dried under reduced pressure at 68-72° C. for 12 hours to obtain 2.16 g (75.8%) of the title compound.

[0075] Example 3(a)

[0076] Purification of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione

[0077] 2.1kg 5-[4-[2-[N-methyl-N-(2-pyridyl) amino) ethoxy] benzylidene] thiazolidine-2,4-dione (obtained in Example 3 ) was dissolved in 9.0 l of N,N...

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Abstract

A novel process for the preparation of a compound of the formula (II), which is useful as intermediate compound for the preparation of thiazolidinedione derivatives, such as rosiglitazone, pioglitazone, troglitazone and ciglitazone, is disclosed. The novel process comprising reacting a compound of the formula (III) with a compound of the formula (IV) in a mixture of a non-polar water immiscible organic solvent and water (two phase system) with an alkali metal hydroxide or an alkali metal carbonate as a base in the presence of a phase transfer catalyst. In the first aspect of the present invention comprising reacting 2-(N-methyl-N-(2- pyridyl) ethanol with 4-fluorobenzaldehyde in the mixture of a non-polar water immiscible organic solvent, preferably toluene, and water with an alkali metal hydroxide or an alkali metal carbonate as a base, preferably potassium hydroxide, in the presence of a phase transfer catalyst, e.g. tetra n-butylammonium hydrogensulphate or benzyltriethylammonium chloride, to obtain 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzaldehyde, which is the key intermediate for preparing rosiglitazone and its salts, e.g. maleate salt or phosphate salt, useful in the treatment of Type II diabetes.

Description

technical field [0001] The present invention relates to a novel process for the preparation of substituted phenyl ether compounds, which can be used as key intermediates for the preparation of thiazolidinedione derivatives useful in the treatment of type II diabetes. [0002] More precisely, the present invention relates to a process for the preparation of certain pyridyl-substituted ethoxybenzaldehydes (ether compounds) that can be used as intermediates for the synthesis of thiazolidinedione derivatives, such as rosiglitazone , pioglitazone, troglitazone and ciglitazone or pharmaceutically acceptable acid addition salts, which have hypoglycemic and hypolipidemic effects. Background of the invention [0003] EP 0257781 B1 describes a process for the preparation of 4-[2-(5-ethylpyridyl)ethoxy]benzaldehyde for the preparation of pioglitazone. The method described in this patent requires long reaction times and results in the desired compound with uncontrolled impurities. [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/74C07D417/12A61K31/435A61P3/10
CPCC07D213/74C07D417/12A61P3/10
Inventor J·卢德谢尔R·A·R·坎A·保罗
Owner SANDOZ AG
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