WO2004108721A1

WO2004108721A1 - Process for the preparation of 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl] methyl]-2,4-thiazolidinedione

Info

Publication number: WO2004108721A1
Application number: PCT/IN2004/000087
Authority: WO
Inventors: Vijay Chhangamal Chhabada; Rashminkumar Rameshchandra Pandya; Rajeev Budhdev Rehani; Rajamannar Thennati
Original assignee: Sun Pharmaceutical Industries Limited
Priority date: 2003-04-01
Filing date: 2004-04-01
Publication date: 2004-12-16

Abstract

A process for the preparation of 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (formula 1) comprising a. reacting diazonium salt of 4-[2-(5-Ethyl-2-pyridyl) ethoxy] amino- benzene, compound of formula 2, with acrylamide, aqueous HX (wherein X is Br or Cl), under meerwein arylation conditions to yield compound of formula 3; b. condensing compound of formula 3 with thiourea to obtain compound of formula 4; and c. converting compound of formula 4 to compound of formula 1.

Description

PROCESS FOR THE PREPARATION OF 5-[[4-[2-(5-ETHYL-2- PYRIDINYL)ETHOXY]PHENYL]METHYL]-2,4-THIAZOLIDINEDIONE

The present invention relates to a process for the preparation of 5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione. 5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione commonly known as pioglitazone (LNN Name), compound of formula 1, is used in the management of type 2 diabetes.

Formula 1

PRIOR ART:

United States patent No. 4687777 (Assignee : Takeda; Indian Reference not available). This patent discloses preparation of compound of formula 1 as follows:

(a) reaction of 2-(5-ethyl-2-pyridyl)ethanol with 4-fluoronitrobenzene to give 4-[2-(5- Ethyl-2-pyridyl)ethoxy]nitrobenzene which is reduced to yield the corresponding amino compound, 4-[2-(5-Ethyl-2-pyridyl)ethoxy]aminobenzene; (b) 4-[2-(5-Ethyl-2- pyridyl)ethoxy]aminobenzene is diazotised and treated with aqueous HBr and methylacrylate to give methyl- 2-Bromo-3-{4-[2-(5-Ethyl-2 pyridyl) ethoxy]phenyl} propionate; and (c) methyl- 2-Bromo-3-{4-[2~(5-Ethyl-2 pyridyl) ethoxy phenyl} propionate is treated with thiourea to yield 5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy] benzyl}-2- imino-4-thiazolidinone which is converted to compound of formula 1. The process of the present invention uses environmentally friendly reaction conditions like usage of acrylamide instead of methylacrylate. Further, the process of the present invention uses the sodium salt of p-nitrophenol which is a cheaper alternative to 4-fluoronitrobenzene and sodium hydride as used herein. United States patent No. 5952509 (Assignee : Takeda ; Indian Reference not available) This invention claims a reduction process for the preparation of compound of formula 1 wherein the substrate is the unsaturated precursor of compound of formula 1 viz. 5-[[4- [2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methylidene]-2,4-thiazolidinedione and the ' reducing agent is borohydride. ■

Also, United States patent application No. 20030153765 (Inventor : Ben-Zion Dolitzky ; Indian Reference not available) carries out catalytic hydrogenation of the precursor 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methylidene]-2,4- thiazolidinedione to yield compound of formula 1. The process of the present invention uses a different route to prepare compound of formula 1.

We have developed a new process for the preparation of compound of formula 1 using compound of formula 2 as the starting material to prepare a new intermediate, compound of formula 3, hitherto not reported in any of the synthetic schemes in literature.

formula 3 (wherein X is Br or CI)

OBJECTIVE OF THE INVENTION: An object of the present invention is to provide a novel process for the preparation of 5- [[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, compound of formula 1.

Another object of the present invention is to provide novel compound of formula 3 and its process of preparation.

SUMMARY OF INVENTION :

A process for the preparation of 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]- 2,4-thiazolidinedione (formula 1) comprising

formula 1 a. reacting diazonium salt of 4-[2-(5-Ethyl-2-pyridyl) ethoxy] amino- benzene, compound of formula 2, with acrylamide, aqueous HX (wherein X is Br or CI), under meerwein arylation conditions to yield compound of formula 3;

formula 2

Formula 3 b. condensing compound of formula 3 with thiourea to obtain compound of formula 4; and

Formula 4 c. converting compound of formula 4 to compound of formula 1.

Novel compound of formula 3

(wherein X is Br or CI) formula 3

Further, the process for the preparation of compound of formula 3 comprises reacting diazonium salt of 4-[2-(5-Ethyl-2-pyridyl) ethoxy] aminobenzene, compound of formula 2, with acrylamide, aqueous HX (wherein X is Br or CI), under meerwein arylation conditions. DETAILED DESCRIPTION OF THE INVENTION:

According to step (a) of the process, of the present invention compound of formula 3 may be prepared by reacting diazonium salt of compound of formula 2 with acrylamide, aqueous HX (wherein X is Br or CI), under meerwein arylation conditions such as in the presence of metal halide like copper bromide or chloride. The reaction may be carried out at temperature ranging from 10 to 100°C, preferably 10 to 70°C.

According to step (b) of the process of the present invention condensation of compound of formula 3 with thiourea may be carried out in polar aprotic solvent selected from dimethylamine, hexamethylphosphoramide, N-methylpyrrolidine, dimethylsulphoxide and the like, preferably dimethylsulphoxide.

In the process of the present invention compound of formula 2 may be prepared by reducing compound of formula 5 with a hydrogen source which is cheap as compared to Pd/C used in prior art. The hydrogen source being compounds which liberate (with or without heating) or contain nascent hydrogen such as sulphides or polysulphides, sodium borohydride with various catalysts like NiCl or CoCl₂; preferably sulphides like NaHS, (NHι)₂S, NaBH₂S₃. .

Formula 5

In the process of the present invention compound of formula 5 may be prepared by adding p-toluene sulphonyl chloride to 2-(5-ethyl-2-pyridyl)ethanol to yield compound of formula 6; followed by reacting compound of formula 6 with alkali or alkaline earth metal salt of p-nitrophenol.

In the process of the present invention addition of p-toluene sulphonyl chloride may be carried out in the presence of a base. The base may be selected from an organic or an inorganic base. Preferably, an organic base selected from mono, di or tri substituted or unsubstituted amines, quaternary ammonium salts, the most preferred being 4-dimethyl amino pyridine and triethylamine. This step yields 95-97% compound of formula 6.

The reaction of compound of formula 6 with sodium salt of p-nitrophenol gives better yield 70-75% of 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (formula 5) as compared to 62% obtained in prior art. Compared to prior art the process of the present invention uses the sodium salt of p-nitrophenol which is a cheaper alternative to 4-fluoronitrobenzene and sodium hydride.

Compound of formula 4 may be converted to 5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (formula 1) and its pharmaceutically acceptable salts using standard methods reported in the literature, preferably as disclosed in our co-pending Indian patent application 1026/MUM/2003.

The compound of formula 1 contains both basic nitrogen and acid nitrogen in its molecule, and can be converted to pharmacologically acceptable salt, when desired, by using a suitable acid or base.

The acid salts may be mineral salts (e.g. hydrochloride, hydrobromide, sulfate, etc.), organic acid salts (e.g. succinate, maleate, fumarate, malate, tartrate, etc.) and sulfonates (e.g. methanesulfonate, benzenesulfonate, toluenesulfonate, etc.). Such basic salts are exemplified by alkali metal salts e.g. sodium salt, potassium salt, alkaline earth metal salts, e.g. calcium salt, etc. All of these salts can be prepared by methods known to those skilled in the art.

EXAMPLES EXAMPLE 1 a) Preparation of Toluene-4-sulfonic acid-2-(5-ethylpyridin-2-yl)-ethyl ester, compound of formula 6 150 g of 2-(5-ethyl-2-pyridyl)ethanol was added to 300 ml of methylene dichloride in a 3

necked round bottom flask at 30 + 2 °C and stirred for 15 minutes to obtain a clear

yellowish solution. 12 g of 4-Dimethylaminopyridine (DMAP) and 202ml triethylamine in a single charge were added to the above solution. The contents of flask were cooled to 0-3 °C. A solution of 236.4 g of p-toluene sulphonyl chloride in 800 ml of methylene dichloride was prepared and about 940 ml of this solution was gradually added to the reaction flask by maintaining reaction temperature between 0-5 °C, over a period of 1-2 hours. The reaction mixture was maintained at 0-5 °C for 2 hours. After completion of

the reaction the temperature was gradually raised to 15 ± 2 °C . To the reaction mixture

750 ml of D. M. water was added and stirred for 30_minutes and was allowed to settle for 10 minutes and the organic layer was separated. The methylene dichloride from product enriched organic layer was distilled out completely to obtain Toluene-4-sulfonic acid-2- (5-ethylpyridin-2-yl)-ethyl ester, compound of formula 6, as a syrup.

(b) Preparation of 4-r2-(5-Ethyl-2-pyridyl)ethoxy1nitrobenzene, compound of formula 5

In a 3 necked round bottom flask 82. lg of sodium hydroxide was added to 1.2 L

methanol 30 ± 2 °C and stirred for 30 minutes, to obtain a homogenous solution. To the above reaction mixture at 25-40 ° C was added 300g p-nitrophenol & 2.4 L toluene. The contents of flask were heated to 78 °C. The reaction mixture was maintained for 30 minutes at 76-78 °C. The temperature was raised and toluene and methanol were distilled out completely to obtain a thick slurry. The residual mass was degassed for 1 hour at 100-

110 °C under vacuum to obtain sodium salt of p-nitrophenol. It was cooled to 30 ± 2 °C and 750 ml of DMSO was added to obtain a clear yellowish brown solution. One lot of 150g of compound of formula 6 in a single charge was added to the above reaction mixture at 25-30 ° C and the contents of flask were heated to 40 °C. The reaction mixture was maintained for 3 hours at 38-40 °C, under nitrogen blanketing. To the reaction mixture, was added 2^nd lot of 150g of compound of formula 6 in a single charge at 40 °C. The reaction mixture was maintained for 4 hours at 38-40 °C. After completion of the

reaction, the reaction mixture was cooled to 30 ± 2 °C and the contents of the flask were

transferred to a 10 L 3 necked round bottomed flask. D.M. water was added followed by addition of toluene. The contents of flask were stirred for 30 minutes, at room temperature and allowed to settle and upper product enriched toluene layer was separated. The product enriched toluene layer was subjected to distillation to obtain compound of formula 5 as a syrup. 150 ml hexane was added, at 25-28 °C and stirred for 1 hour at 25-28 °C. The product was filtered and dried.

(c)Preparation of 4-r2-(5-Ethyl-2-pyridvI)ethoxy1aniline, compound of formula 2

In a 3 necked round bottom flask 617g of (52 %) sodium sulphide was added to 2.0 1 of D.M water and stirred for 10 minutes to obtain a clear solution. 217g of sodium bicarbonate (3-5 lots) was slowly added at 25-40 ° C over a period of 15-30 minutes. The contents of flask were cooled to 18 - 20 °C and the reaction mixture was stirred. 2.0 L of methanol was added and the reaction mixture stirred for 30 minutes at 18-20 ° C. The solid was filtered at 18-20 °C and washed with methanol. The filtrate was collected and transferred to 10 L, 3-necked round bottom flask. The contents of flask were heated to 76-78 °C. A solution of 200g of compound of formula 5 in 400ml of methanol was separately prepared and gradually added to reaction mixture. The reaction mixture was maintained for 2 hours at 76-78 °C. After completion of the reaction, the reaction mixture

was cooled to 30 ± 2 °C. 800ml of D.M.water was added into the reaction mixture

followed by 800ml of methylene dichloride and the contents of the flask were stirred for 15 minutes. The product enriched methylene dichloride layer was separated The aqueous layer was washed with methylene dichloride and the methylene dichloride layers were pooled up. The methylene dichloride layer was subjected to distillation to obtain compound of formula 2.

(d) Preparation of 2-Bromo-3 4-r2-(5-Ethyl-2 pyridyl) ethoxylphenylj propionamide, compound of formula 3 18 g of copper sulphate and 6.75 g of sodium bromide were added to 150 ml of D.M water in a 3 necked round bottom flask. The contents of flask were heated to 76-78 °C to obtain a clear solution. 6g of sodium metabisulphite was then added to it in portions and

stirred for 15 min. The reaction mixture was cooled to 30± 2 °C. CuBr solid was filtered.

To 150 g of compound of formula 2 was added 1.5 1 of acetone and 600 ml of methanol. The contents of the flask were cooled to 18-20 °C. 245 ml of aqueous HBr was added to the above reaction mixture at 18-20 ° C in a single charge. Cool the contents of the flask to 0-2 °C. 120ml of 50% w/v aqueous sodium nitrite solution was added slowly to the reaction mixture by maintaining the temperature between 0-2 °C, over a period of 30 ^■ minutes. The reaction mixture was maintained for 15 minutes at 0-2 C. The temperature was raised to 20-22 °C. A solution of 246g of acrylamide in 900ml of acetone was added at 22-23 °C in single charge. The reaction mixture was stirred for 10 minutes at 23-24 °C, 4.6g of cuprous bromide was added in a single charge under vigorous stirring and the reaction mixture maintained for 2 hours at 30-35 ^°C. After completion of the reaction, acetone and methanol were distilled off completely to obtain thick liquid mass. A solution of 150 g of sodium bicarbonate in 3.0 1 of D.M water was prepared. 600ml of hexane was added to it and stirred to get a clear biphasic solution. The reaction mixture was gradually quenched into above flask containing aqueous sodium bicarbonate and hexane solution over a period of 30 minutes at 23-35 °C followed by stirring for 2 hours. The product was filtered and the product cake washed with D.M. Water followed by hexane and dried . The crude product obtained was suspended in water and stirred for 1 hour at 25-30 °C. The product was filtered and cake washed with D.M. Water followed by hexane. The product thus obtained was suspended in hexane and stirred for 2 hours at 35- 40°C. It was filtered and washed with hexane and dried to get compound of formula 3.

(e) Preparation of 5-{4-r2-(5-Ethyl-2-pyridyl)ethoxy1 benzyU-2-imino-4- thiazolidinone, compound of formula 4

150 g of compound of formula 3 and 31.77g of thiourea were added to 750 ml of DMSO

at 30 + 2 °C in a 3-necked round bottom flask. The reaction mixture was heated to 65-70

°C and maintained for 8 hours. The reaction mixture was cooled to 25-30°C and gradually quenched in D M water and hexane biphasic solution, over a period of 30 minutes at 23-30 °C followed by stirring for 2 hours.The product was filtered and washed with D. M. water followed by hexane and dried. 190 g of crude thus obtained was suspended in 2.0 1 of methanol flask and heated to 55-60 °C to obtain a clear solution. To the hot solution was added activated charcoal and stirred for 15 minutes and filtered. The filtrate was collected and methanol was distilled out completely under vacuum at 50-55 °C to obtain compound of formula 4 as a syrupy mass. To the syrupy mass was added 600ml of hexane which was distilled out completely under vacuum at 40-45 °C. 600ml of hexane was added again and the contents were cooled to 25-30°C under stirring followed by filtration and washing with hexane and drying to get compound of formula 4.

(f) Preparation of 5-{4-r2-(5-Ethyl-2-pyridyl)ethoxyl benzyl}-2,4- thiazolidinedione, compound of formula 1

283g of oxalic acid was added to 2.0 1 of D. M water at 30 ± 2 °C to obtain a

homogeneous solution. 80g of compound of formula 4 was added and stirred for 10 minutes. The reaction mixture was heated to 98-102 °C and maintained for 12-14 hours.

The reaction mixture was then cooled to 30 ± 2 °C and gradually quenched in 1 1 aqueous

ammonia (Liq. Ammonia : D.M. Water) (1:1), over a period of 30 minutes at 23-35 °C. The pH was adjusted to 7 to 7.3 using 200ml of (1:1) HC1 and stirred for 2 hours at 27- 30 °C. The product was filtered and the product cake washed with D.M. water followed by washing with hexane and dried. The crude product obtained was suspended in water and heated to 55-60°C and maintained for 1 hour at that temperature. The product was filtered at 55-60 °C and washed with D.M.water and dried. The product thus obtained was suspended in ethyl acetate and heated to 55-60°C and maintained for 1 hour at that temperature. The product was filtered at 55-60 °C and washed with ethylacetate and dried. To the product thus obtained was added 375 ml of methanolic ammonia followed by stirring to get a homogeneous solution. To the clear solution was added activated charcoal and stirred for 15 minutes. The solution was filtered. The filtrate was collected

5 and methanolic ammonia was distilled out completely to obtain compound of formula 1 as a thick slurry. To the slurry 160 ml of methanol was added and subjected to distillation. To the residual slurry was added 600 ml of D. M. water to obtain a homogeneous suspension and stirred for 1 hour at 28-30°C. Filter and wash the cake with D. M. water to get compound of formula 1.

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Claims

We claim :

1. A process for the preparation of 5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (formula 1) comprising

formula 1 a. reacting diazonium salt of 4-[2-(5-Ethyl-2-pyridyl) ethoxy] aminobenzene, compound of formula 2, with acrylamide, aqueous HX (wherein X is Br or CI), under meerwein arylation conditions to yield compound of formula 3 ;

formula 2

(wherein X is CI or Br) formula 3 b. condensing compound of formula 3 with thiourea to obtain compound of formula 4; and

Formula 4 c. converting compound of formula 4 to compound of formula 1.

2. A process as claimed in claim 1 wherein the compound of formula 1 is further optionally converted to its hydrochloride salt.

3. A process as claimed in claim 1 wherein step (b) is carried out in polar aprotic solvent.

4. A process as claimed in claim 1 wherein the compound of formula 2 is prepared by reducing compound of formula 5 with hydrogen source.

Formula 5 A process as claimed in claim 4 wherein the compound of formula 5 is prepared by adding p-toluene sulphonyl chloride to 2-(5-ethyl-2- pyridyl)ethanol to yield compound of formula 6 followed by reaction of compound of formula 6 with alkali or alkaline earth metal salt of p- nitrophenol.

Formula 6

6. A process as claimed in claim 5 wherein addition of p-toluene sulphonyl chloride to 2-(5-ethyl-2-pyridyl)ethanol is carried out in the presence of organic base(s).

7. A process as claimed in claim 6 wherein the organic base is a mixture of 4- dimethylamino pyridine and triethylamine.

8. A process as claimed in claim 5 wherein the alkali metal salt of p-nitrophenol is sodium salt.

9. Compound of formula 3

(wherein X is Br or CI) formula 3

10. A process for the preparation of compound of formula 3 comprising reacting diazonium salt of 4-[2-(5-Ethyl-2-pyridyl) ethoxy] aminobenzene, compound of formula 2, with acrylamide, aqueous HX (wherein X is Br or CI), under meerwein arylation conditions.

(wherein X is Br or CI) formula 3

formula 2

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