WO2004000810A1

WO2004000810A1 - A process for the production of substituted phenyl ethers

Info

Publication number: WO2004000810A1
Application number: PCT/TR2002/000025
Authority: WO
Inventors: Mustafa Adiyaman; Didem Guner; Aycil Yurdakul; Nurten Ridvanoglu
Original assignee: Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S.
Priority date: 2002-06-19
Filing date: 2002-06-19
Publication date: 2003-12-31
Also published as: TR200302265T1; AU2002345524A1

Abstract

The present invention provides a process to prepare substituted phenyl ethers. More particularly the present invention provides a process to produce a compound represented by the Formula I: wherein H1 is a substituted pyridyl group and R1 can be an aldehyde, cyano or nitro group.The compound I is a key intermediate in the preparation of pharmaceutically useful thiazolidinedione derivatives such as pioglitazone, rosiglitazone, etc.

Description

APROCESS FORTHEPRODUCTIONOF SUBSTITUTED

PHENYLETHERS

FIELD OF INVENTION Present invention relates to a novel process for producing substituted phenyl ethers such as 4-[2-(5-ethylpyridyl)ethoxy]benzaldehyde which are useful intermediates in the synthesis of thiazolidinedione derivatives known as anti-diabetic agents. BACKGROUND

Thiazolidinedione derivatives such as pioglitazone (Curr. Med. Res. Opin. 2001, 17, 166), rosiglitazone (Diabetes. Technol. Ther. 2000 Autumn, 2, 429), etc. are pharmaceutically active compounds used as insulin sensitising agents in the treatment of diabetes.

Pioglitazone hydrochloride possesses hypoglycemic and hypolipidemic properties and one of the most widely used anti-diabetic agents among these thiazolidinedione derivatives. 4-[2-(5-Ethylpyridyl)ethoxy]benzaldehyde is one of the key intermediates in the synthesis of pioglitazone.

There has been reported methods for the preparation of 4-[2-(5- ethylpyridyl)ethoxy]benzaldehyde . One method, EP 0257 781 Al uses a two layer solvent system consisting of halogeneted aliphatic hydrocarbon such as dichloromethane, chloroform, carbontetrachloride etc. and water. A phase transfer catalyst is employed since the reaction is conducted in immiscible solvents. In this method the reaction takes long time, the yield and the purity of the resulting phenyl ether is affected by the generated by-products.

In another method, EP 0506273 Bl potassium salt of hydroxybenzaldehyde is prepared and isolated in advance. The resulting potassium 4-formylphenolate is reacted with 2-(5- ethylpyridyl)ethyl methanesulfonate. Thus an additional reaction step is involved. Adding an additional step extends the production time and the cost of production.

A recent method, US Pat. 6,100,403 uses a mixture of toluene/ethanol as the reaction solvent and the potassium carbonate as the base. Two drawbacks can be acquainted for this method: 1) the recovery of ethanol and toluene will be difficult; 2) the cost of potassium carbonate and potassium hydroxide is comparable in terms of industrial production of the desired phenyl ether. SUMMARY OF THE INVENTION

The present invention provides a process for producing a compound represented by the formula: -

I

Wherein Hi stands for an aryl or a heterocyclic ring residue. An aryl is a substituted phenyl or naphthyl group. The substituents on the phenyl or naphthyl ring can be alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, propyl; alkoxy groups having 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy; a halogen such as fluorine, chlorine, bromine; an amino group; a nitro group; a sulfonyl group; alkyl amino groups having 1 to 3 carbon atoms such as methyl amino, ethyl amino or propyl amino.

A heterocyclic ring residue is a 5- or 6-membered unsaturated ring containing from one to three heteroatom selected from the group consisting of nitrogen; oxygen; or sulfur such as furyl group (2-furyl, 3-furyl), thienyl group (2-thienyl, 3-thienyl), pyridyl group (2-pyridyl,

3-pyridyl), etc. and including any bicyclic group in which any of the above heterocyclic ring is fused to a phenyl ring.

The compound represented by the Formula I is prepared by reacting a compound represented by the formula:

Xi Formula II

wherein Hi has the same meaning as described above, and Xi stands for a leaving group including a halogen such as iodine, bromine, chlorine, alkyl sulfonyloxy groups such methylsulfonyloxy, ethylsulfonyloxy, and aryl sulfonyloxy groups such as phenylsulfonyloxy or j9-toluenesulfonyloxy with a compound represented by the formula:

wherein Rj. is an aldehyde, cyano or nitro group. The reaction is conducted in an alcohol such as methanol, ethanol, propanol, 2-propanol in the presence of an alkali metal hydroxide and alkali metal iodide. DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention refers to the preparation of the compound represented by the Formula I:

wherein Hi is a heterocyclic, pyridinyl ring substituted at the five position by an ethyl group and wherein Ri is an aldehyde group. Scheme 1

This process comprises reacting the compound of Formula II with the compound represented by Formula LTI to obtain a compound of the formula I as shown in Scheme 1. In Formula II, Hi can be an aryl or a heterocyclic ring residue, preferably a substituted pyridinyl ring such as 5-ethylpyridinyl group. Xi is a leaving group which can be a halogen such as iodine, bromine, or chlorine, alkyl sulfonyloxy groups having 1 to 3 carbon atoms such as methylsulfonyloxy, ethylsulfonyloxy, or propylsulfonyloxy, and aryl sulfonyloxy groups such as phenylsulfonyloxy andp-toluenesulfonyloxy. In this process, the preferred leaving group is methylsulfonyloxy group.

In Formula HI, Ri can be an aldehyde, cyano or nitro group. The preferred group is the aldehyde. Scheme 2

Compound represented by the Formula II wherein Hi is 5-ethylpyridinyl and Xi is methylsulfonyloxy groups is prepared from 2-(5-ethylpyridyl)ethanol Ila as shown in Scheme 2. The hydroxyl group in compound Ila is protected according to the known methods as described in "Protective Groups in Organic Synthesis, 2^nd Edition" edited by T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc. (1991). Compound Ila is made to react with methanesulfonyl chloride in dichloromethane or toluene in the presence of a base such as triethylamine, pyridine, pyrolidine, or piperidine at temperatures ranging from 10 °C to 25 °C to give compound Tib. The preferred solvent is toluene. On the long-standing at room temperature 2-(5-ethylpyridyl)ethyl methanesulfonate undergoes a β-elimination to give 5- ethyl-2-vinylpyridine. Present inventors have observed that β-elimination is much slower or not taking place when 2-(5-ethylpyridyl)ethyl methanesulfonate is kept in toluene.

In the process of this invention, the reaction between compound II and compound III is carried out in an alcoholic solvent. Examples of the said solvents include alcohols having 1 to 3 carbon atoms such as methanol, ethanol, and 2-propanol. Ethanol and 2-propanol are the preferred solvents. The volume of the solvent to be used ranges with respect to the amount of the compound II from 10-30 weight part.

In this invention, the reaction of compound II and compound LT is carried out in the presence of a base. Examples of the base include alkali metal hydroxides (MOH) such as sodium hydroxide, lithium hydroxide, or potassium hydroxide. The preferred base is potassium hydroxide. The amount of the base to be used is equivalent to the amount of the reacting phenolic substrate.

Present inventors have observed that the use of a catalytic amount of alkali metal iodides such as potassium or sodium iodide has enhanced the reaction in terms of purity and the yield of the product. Present inventors reports here that 4-formylphenyl methanesulfonate V is formed in large amounts in the early stage of the reaction in the absence of the alkali metal iodide. However, when potassium iodide is employed, formation of 4-formylphenyl methanesulfonate decreases dramatically. HPLC analysis of reactions shows that formation of compound V increases by four fold when potassium iodide is not employed. The amount of the potassium iodide ranges from 0.01 mol equivalent to 1.0 mol equivalent with respect to the amount of pyridinyl sulfonate.

In this process, the amount of the compound HI to be used ranges from 1 to 3, preferably 1.5 to 2 times mol equivalent relative to the compound H

The reaction is conducted at temperatures ranging from 40 °C to 90 °C, preferably at 82 °C to 85 °C. In the present invention, the reaction of compound T and compound HI is also carried out in the solvent mentioned above employing potassium hydroxide as IN, 3N, and ION aqueous solutions. Best results are obtained when the reaction is conducted in 2-propanol using potassium hydroxide as neat.

In the process of this invention, the compound I to be produced can be obtained by conventional work-up procedures such as extraction, concentration under reduced pressures in relatively pure form. The product can be used as such in the subsequent reaction without further purifications. Jf desired, the compound I can be purified by column chromatography using ethyl acetate/hexanes as an eluent.

The compound I produced by the process of this invention can be used to synthesise pharmaceutically useful thiazolidinedione derivatives such as pioglitazone which is used in the treatment of diabetes. The thiazolidinedione benzylidine derivative VII can be obtained by using the method described in E.P. No. 0257 781 Bl. The thiazolidinedione benzylidine derivative VII can then be transformed to the antidiabetic agent pioglitazone by using the method described in U.S. P. No. 5 587495 as shown in Scheme 3.

The compound I wherein Hi is 5-ethylpyridiene and Ri is a formyl is reacted with compound VI in ethanol in the presence of base such as pyrolidine, piperidine etc. at reflux temperature to give compound VII. The reduction of the double bond in compound VEI is performed using sodium borohydride, cobaltous chloride, dimethyl glyoxime to give pharmaceutically useful drug agent pioglitazone. Pioglitazone is reacted with hydrochloric acid to obtain pioglitazone hydrochloride. The process of this invention is industrially useful for the production of the compound I and has the following advantages than the methods described previously. Firstly, in this process compound I is obtained in one step. Therefore this process does not require the preparation of potassium 4-formylphenolate in advance. Then, this process does not require the employment of a mixture of solvents, thus the solvent used in the reaction can be easily recovered and there is no need to use any phase catalyst. Finally, the use of the minute amount of potassium iodide or sodium iodide gives better results with respect to yield and the purity of the product.

Below are detailed examples illustrating the process of this invention. EXAMPLE la

Production of 2-(5-ethyl-2-pyridyl)ethyl methanesulfonate

A 500 ml two-necked flask equipped with a magnetic stirring bar and thermometer was charged with 10 g (0.0661 mol) of 2-(5-ethyl-2-pyridyl) ethanol, 200 ml of toluene and 9.82 g (0.09 mol) of triethylamine at room temperature. The mixture was cooled to 5 °C and to the cooled mixture was added slowly 12.43 g (0.086 mol) of methanesulfonyl chloride at 5 °C over 20 minutes. The reaction mixture was stirred at temperatures ranging from 15 to 20 °C for 30 minutes. The precipitate was filtered off and the filtrate was washed first with 100 ml of water, then 100 ml of 5 wt % of sodium hydrogen carbonate, and 100 ml of water. The organic layer was dried over 10 g of anhydrous sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give 14.8 g of the product, 2- (5-ethyl-2-pyridyl)ethyl methanesulfonate, as an oil (yield 98%).

1HNMR (CDC1₃) δ 8.4 (s, 1H), 7.48 (d, J= 5.86 Hz, 1H), 7.15 (d, J= 7.62, 1H), 4.62 (t, J= 6.45, 2H), 3.18 (t, J= 6.45, 2H), 2.89 (s, 3H), 2.63 (q, J= 7.6 Hz, 2H), 1.23 (t, J= 7.62, 3H). ¹³C NMR (CDC1₃) δ 165, 148, 139, 137, 124, 69, 37, 36, 26, 15. EXAMPLE lb

Production of 2-(5-ethyl-2-pyridyl)ethyl methanesulfonate

A 500 ml two-necked flask equipped with a magnetic stirring bar and thermometer was charged with 10 g (0.0661 mol) of 2-(5-ethyl-2-pyridyl)ethanol, 130 ml of methylene chloride, and 9.82 g (0.09 mol) of triethylamine at room temperature. The mixture was cooled to 5 °C and to the cooled mixture was added slowly 12.43 g (0.086 mol) of methanesulfonyl chloride at 5 °C over 30 minutes. The reaction mixture was stirred at temperatures ranging from 15 to 20 °C for 1 hour. The precipitate was filtered off and the filtrate was washed first with 100 ml of water, then 100 ml of 5 wt % of sodium hydrogen carbonate, and 100 ml of water. The organic layer was dried over 10 g of anhydrous sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give 15 g of the product, 2-(5-ethyl-2-pyridyl)ethyl methanesulfonate, as an oil (yield 99%). EXAMPLE 2a

Production of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde

A I L two-necked flask, equipped with a magnetic stirring bar and thermometer was charged with 14.06 g (61.62 mmol) of 2-(5-ethyl-2-pyridyl)ethyl methanesulfonate, 300 ml of z^'so-propyl alcohol, 11.88 g (97.36 mmol) ofp-hydroxybezalhedyde, 5.45 g (97.36 mmol) of potassium hydroxide and 0.65 g (3.9 mmol) of potassium iodide. The reaction mixture was heated to reflux temperature and stirred at reflux for 12 hours. Upon completion of the reaction the solvent was removed in vacuo. The residue was dissolved in 500 ml of ethyl acetate. The resulting solution was washed with 250 ml of 0.5N sodium hydroxide, 2 x 250 ml of water, and dried over 25 g of sodium sulfate. Sodium sulfate was filtered off and the filtrate was removed under reduced pressure to give 15.74 g of an oily residue (product content measured by HPLC: 74%). The product can be used as it is in the next step without further purification. Alternately the resulting oily residue can be purified by column chromatography using ethyl acetate/hexane (4:6) as an eluent.

1HNMR (CDC1₃) δ 9.84 (s, IH), 8.38 (s, IH), 7.8 (d, J= 8.8 Hz, 2H), 7.43 (d, J= 7.6 Hz, IH), 7.2 (d, J= 8.2, IH), 7.0 (d, J= 8.8 Hz, IH), 4.4 (t, J= 7.0 Hz, 2H), 3.2 (t, J= 6.4 Hz, 2H), 2.6 (q, J= 7.6 Hz, 2H), 1.23 (t, J= 7.6 Hz, 3H). ¹³C NMR (CDCI3) δ 209, 164.3, 154.4, 149.5, 137.6, 136.1, 132.2 (2xC), 123.6, 115.1 (2xC), 68.8, 37.8, 26.1, 16.

EXAMPLE 2b

Production of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde A 500 ml two-necked flask, equipped with a magnetic stirring bar and thermometer was charged with 6.99 g (30.64 mmol) of 2-(5-ethyl-2-pyridyl)ethyl methanesulfonate, 200 ml of wo-propyl alcohol, 5.9 g (48.41 mmol) ofj?-hydroxybezalhedyde, and 4.8 ml (48.41 mmol) of ION potassium hydroxide and 0.32 g (1.93 mmol) of potassium iodide. The reaction mixture was heated to reflux temperature and stirred at reflux for 12 hours. Upon completion of the reaction the solvent was removed in vacuo. The residue was dissolved in 300 ml of ethyl acetate. The resulting solution was washed with 200 ml of 0.5N sodium hydroxide, 2 x 200 ml of water, and dried over 15 g of sodium sulfate. Sodium sulfate was filtered off and the filtrate was removed under reduced pressure to give 7.86 g of an oily residue (product content measured by HPLC: 68%).

EXAMPLE 3

Production of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4- thiazolidinedione

A 250 ml three-necked flask, equipped with a magnetic stirring bar and thermometer was charged with 8.12 g (21.62 mmol) of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde, 120 ml of ethanol, 2.79 g (23.78 mmol) of 2,4-thiazolidinedione, and 1.93 ml (19.46 mol) of piperidine. The reaction mixture was heated at reflux temperature for 15 h. The reaction mixture was cooled to room temperature and then poured into 100 ml of ice-water. The reaction mixture was acidified to pH=6.5 by the addition 4 ml of acetic acid. The product precipitated out upon acidification. The resulting crystals were collected by filtration give 6.2 g of product as pale yellow crystals (yield 81%).

EXAMPLE 4 Production of 5-{4-[2-(5-ethyl-2-pyridyl)emoxy]benzyl}-2,4-thiazolidinedione A 2 L three-necked flask, equipped with a mechanical stirrer and thermometer is charged with 53.16 g (150 mmol) of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4 thiazolidinedione, 750 ml of water, 180 ml of tetrahydrofuran, and 60 ml of 1.0N sodium hydroxide. The mixture is stirred at room temperature for 10 minutes and cooled to 15 °C. To the cooled mixture is added slowly 15 ml of catalyst solution, prepared by dissolving 0.696 g (6 mmol) of dimethylglyoxime and 0.036 g (0.15 mmol) of cobaltous chloride hexahydrate in 15 ml ofdimethylformamide. A solution of 11.34 g (300 mmol) of sodium borohydride in 15 ml of 1.0N sodium hydroxide diluted with 70 ml of water is added dropwise to the resulting mixture at 15 °C over 3 hours. The reaction mixture is stirred at 15 °C for 3 hours. The reaction mixture is quenched by dropwise addition of 78 ml of acetone to destroy any remaining of sodium borohydride. The resulting solution is acidified by the dropwise addition of 24 ml of glacial acetic acid diluted with 52 ml of water at room temperature (22- 24 °C) until the pH of the solution becomes 6.0-6.5. Upon acidification, the product precipitates as off white solids. The slurry is cooled to 0-5 °C in an ice bath and stirred for 30 minutes prior to filtration. The collected product is washed with three 450 ml portions of water and dried at 55 °C in the vacuum oven for 18 hours to give 53 g of product as off- white solid (yield 99%). EXAMPLE 5

Production of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2.4-thiazolidinedione.

Hydrochloride A I L two-necked flask, equipped with a magnetic stirring bar and thermometer was charged with 50.63 g (142 mmol) of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4- thiazolidinedione, 310 ml of methanol, and then treated with 14.3 ml of cone, hydrochloric acid (%37) in 137 ml of methanol. The reaction mixture was stirred at room temperature until all of the solid was dissolved (30 minutes) and further stirred at room temperature for 2 hours. Half of the solvent was evaporated in vacuo, diluted with 150 ml of ethyl acetate, reconcentrated in vacuo up to 175 ml. To this solution was added 150 ml of ethyl acetate. The reaction flask was kept in 5 °C in an ice bath for 1 hour and then the solidified product was collected by filtration, washed with 50 ml of cold ethyl acetate, dried in vacuum oven at 55 °C for 18 h to give 44.9 g and the filtrate was concentrated up to one third of the solvent volume. The precipitated product was collected by filtration to give 6.88 g of white solid product (yield: 89).

FT-IR (KBr, cm^-1): 1742, 1884, 1508. 1HNMR (CDC1₃) δ 12.05 (s, IH), 8.7 (s, IH), 8.4 (d, J= 8.2 Hz, IH), 7.9 (d, J= 8.2 Hz, IH), 7.1 (d, J= 8.8 Hz, 2H), 6.8 (d, J= 8.7 Hz, 2H), 4.86 (m, IH), 4.36 (t, J= 5.8 Hz, 2H), 3.48 (t, J= 5.3 Hz, 2H), 3.28 (dd, J= 9.4 and 14.1 Hz, IH), 3.1 (dd, J= 5.3 and 14.1 Hz, IH), 2.75 (q, J= 1.6 Hz, 2H), 1.2 (t, J= 7.6 Hz, 3H). 13C NMR (CDC1₃) δ 176.4, 172.4, 157.7, 151.9, 145.9, 141.9, 140.8, 131.1, 129.8 (2xC), 127.8, 115.1 (2xC), 66.1, 53.6, 36.8, 32.9, 25.3, 15.3. MS (ES) m/z: 357 (M+Cl).

Claims

1. A process for producing the compound represented by the Formula I:

wherein Hi stands a heterocyclic ring residue such as compounds of the formula LX, X, XI

Formula XI

and Ri is an aldehyde group. The compound represented by Formula I comprises reacting a compound of Formula LI

^■"My.

X] Formula II

wherein Hi has the same meaning as described above and Xi stands for a leaving group including iodine, bromine, chlorine, methylsulfonyloxy, ethylsulfonyloxy, orp- toluenesulfonyloxy with a compound represented by the formula:

wherein Ri is an aldehyde or nitro group.

2. The process of claim 1 wherein the solvent is 2-propanol, propanol, ethanol, or methanol.

3. The process of claim 1 wherein the reaction is conducted at a temperature ranging from 50 to 90° C.

4. The process of claim 1 wherein alkali metal hydroxides are potassium hydroxide and sodium hydroxide.

5. The process of claim 4 wherein alkali metal hydroxides are employed in the reaction as IN, 3N, and ION aqueous solutions as well as neat forms.

6. The process of claim 1 wherein the reaction is conducted in the presence of alkali metal iodides.

7. A compound represented by the formula

Wherein R₂ is methylsulfonyloxy or ?-toluenesulfonyloxy and i is an aldehyde or nitro group 8. The process of claim 6 wherein alkali metal iodides are potassium iodide and sodium iodide in an amount ranging from 0.01 mol equivalent to 1 mol equivalent with respect to the amount of compound II of claim 1.