FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1.- Title of the invention. - An improved process for the preparation of 4-[2-(substituted-2-pyridyl)ethoxy] nitrobenzene
2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :

ALEMBIC LIMITED

An Indian Company.

Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of invention:
The present invention relates to an improved method for producing a 4-| 2-(substituted-2-pyridyl)ethoxy]nitrobenzene compound of formula (II), wherein R| is selected from group of-H, C1-6 alkyl or C1-6 acyl. These intermediates are useful for synthesis of well known antihyperglycemic agent like Pioglitazone of formula (I) or pharmaceutical^ acceptable salts thereof.

Background of the invention and prior art:
The process of preparing compound of formula (II) has been disclosed in US Patent No. 4,687,777; US Patent No. 4,443,246; US Patent No. 6,414,001 etc.
The process as disclosed in US Patent No. 4,687,777 and US Patent No. 4,443,246 involves reaction of 2-(substututed-2-pyridyl)ethanol of formula (III), wherein R1 stands for lower alkyl group and 4-fluoronitrobenzene (compound of formula (IV), wherein L is fluoro), in dirnethylformamide or tetrahydrofuran as solvent and in presence of sodium hydride at low temperature. Sodium hydride is an expensive reagent and highly hygroscopic in nature and explodes violently on exposure to moisture. Thus, it is difficult to handle on commercial scale. Moreover, this reaction is low yielding as 62.9%.
The process in accordance with US Patent No. 6,414,001 involves reaction between 2-(subslituted-2-pyridyl) ethanol of formula (III), wherein R| is ethyl and 4-fluoronitribenzene of formula (IV) in presence of sodium hydroxide using dirnethylformamide as a solvent. In this reaction, sodium hydroxide slowly hydrolyses dirnethylformamide into dimethylamine which reacts with 4-fluoronitrobenzene to
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form about 5-10% w/w of undesired compound 4-(N-dimethyl)nitrobenzene of the formula (V) as an impurity, which results in decreased purity and yield of the final product. The reported yield is around 74.4% after chromatographic separation.

Also this process involves the purification of the compound of formula (0) by tedious and cumbersome chromatographic technique. If the impurity of formula (V) is not removed at this stage, then it proceeds further in reaction resulting in impure compound (I). Separation of compound of formula (V) from compound of formula (II) is very difficult. Hence, it is necessary to avoid the formation of this impurity during the reaction.
The inventors of the present invention have surprisingly found that reaction of compound of formula (III) with compound of formula (IV) in presence of alkali or alkaline earth metal hydroxides and in lower alkyl sulfoxides as solvents gives compound of formula (II), which is substantially free from compound of formula (V).
Object of the invention:
Therefore it is the primary object of the present invention to provide a process for preparing compound of formula (II), which avoids use of expensive and hazardous reagent, sodium hydride.
Another object of the present invention is to provide compound of formula (II) substantially free from compound of formula (V).
Yet another object of the present invention is to provide a process for preparing compound of formula (II) which is simple, easy to handle, cost-effective and avoids use of cumbersome chromatographic technique.
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Therefore, it is the object of the present invention to provide a simple process for preparing Pioglitazone of formula (I).
Summary of the invention:

comprising reacting compound of formula (III),

In accordance with the primary object of the present invention, there is provided a process for preparation of compound of formula (II), being substantially free of compound of formula (V)
wherein R1 is selected from group of-H, C1-6 alkyl or C1-6 acyl, with compound of formula (IV),

wherein L is a leaving group selected from halogen like CI, F, Br and I; tosylate or mesylate, in lower alkyl sulfoxides in the .presence of alkali or alkaline earth metal hydroxides.
According to other aspect of the present invention, there is provided a compound of formula (II), which is substantially free from compound of formula (V).
Yet another aspect of the present invention is to provide an improved process for preparing Pioglitazone of formula (I) by using compound of formula (II) prepared in accordance with the present invention.
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Detail description of the invention:
The inventors of the present invention have surprisingly found that reaction of compound of formula (III) with compound of formula (IV) in presence of alkali or alkaline earth metal hydroxides and in lower alkyl sulfoxides as solvents gives compound of formula (II), which is substantially free from compound of formula (V). According to the process of the present invention, the use of lower alkyl sulfoxide as solvent, avoids formation of compound of formula (V), which is formed as an impurity in the prior art process.

R1 in compound of formula (II) and (III), is selected from group of-H, C1-6 alkyl or
C1-6 acyl, which include C1-6 straight chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, preferably methyl and ethyl and most preferably ethyl or Ci-6 acyl group such as formyl, acetyl, propionyl, butyryl and iso-butyryl, preferably formyl and acetyl and most preferably acetyl. L in compound of formula (IV) is a leaving group selected from halogen like CI, F, Br and I; tosylate or mesylate.
The alkali and alkaline earth metal hydroxides are selected from group of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, preferably sodium and potassium hydroxide. The preferred lower alkyl sulfoxide is dimethyl sulphoxide.
The reaction is generally carried out at temperature of about -30 to about 120°C, preferably from about -10 to about 50°C, and reaction time is from about 1 to about 30 hours.
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Preferably, reaction of compound of formula (III) with compound of formula (IV) is conducted at about -5 to about 20°C in dimethylsulfoxide as solvent, in the presence of sodium hydroxide.
The compound of formula (II) prepared in accordance with the present invention is further converted to Pioglitazone of formula (I) by the method know perse or known in the literature. The Pioglitazone of formula (I) as referred herein description and claims means to include is pharmaceutically acceptable salts such as hydrochloride.
The compound of formula (II) obtained in accordance with the present invention does not require to further purify and remove impurity of formula (V). The purity level of the compound of formula 11 of the present invention is at least 99%. .Also, it eliminates the use of costlier and hazardous material such as sodium hydride. Moreover, it is high yielding.
The compound of formula (II) can be isolated and purified by means of conventional isolation and refining process such as dilution, concentration, concentration under reduced pressure, solvent extraction, crystallization or any method know in art.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example:
Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxyl] nitrobenzene
In a 3 liter 3 necked round bottom flask 2-(5-ethy!-2-pyridyl) ethanol (250g, 1.655 moles), dimethylsulfoxide (1250 ml) and 4-fluonitrobenzene (245g, 1.737 moles) were charged. The mixture was cooled to 10°C under stirring. Powdered sodium hydroxide (86g, 2.151 moles) was added in portions over a period of an hour. The reaction mixture was stirred at 10°C for an hour and then allowed to attain room temperature. The reaction mixture was then stirred for 30 hours at room temperature. The reaction mixture was monitored by thin layer chromatography. The reaction mixture was poured in chilled water (10 liter) under stirring and the slurry was stirred for 1 hour. The product was filtered and washed thoroughly with water. The product
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was dried at 30°C under a stream of air to get the title compound as light yellow solid, (yield: 388g, 86.2%, HPLC purity: 99.7%) Melting Range: 45-50°C.
IR(KBr): 1597, 1521, 1491, 1343,1260,1009,836.
1H NMR (CDCL3)  ppm: 1.16 (t;3H,-C2H5); 2.57 (q,2H,-C2H5); 3.18 (t,2H,-CH2-); 4.48 (t,2H,-CH2-); 7.12 (d,2H, aromatic); 7.27 (d,lH, pyridine); 7.5 (d-d,lH,pyridine); 8.16 (d,2H, aromatic); 8.36 (d,lH, Pyridine)
Preparation of Pioglitazone hydrochloride:
4-[2-(5-Ethy]-2-pyridyl)ethoxyl] nitrobenzene is added to methanol and stirred at RT. 10% Pd/C is added to the reaction mixture and hydrogenated at RT. The reaction mixture is filtered after completion of reaction and methanol is distilled out. Acetone and DM water is added to the reaction mass and cooled under stirring. Hydrobromic acid is added to the reaction mixture and cooled. Further, sodium nitrite solution in water is slowly added to the reaction mixture. Methyl acrylate is added to the reaction mixture and heated to 38-40°C. Cuprous oxide is slowly added to the reaction mixture and stirred for 4-5 hrs. at 40-42°C. The reaction mixture is stirred for 16 hours at RT. Solvent is distilled out after completion of reaction. Reaction mass is poured in DM water and basified by adding ammonia solution.
Ethyl acetate is added to the reaction mixture and stirred and product organic layer extracted out. Ethyl acetate is distilled out and residue is treated with hexane and ethyl acetate and solvent is distilled out to give Methyl 2-bromo-3-{4-[2-(5-ethyI-2-pyridyl)ethoxy] phenyljpropionate.
Methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl} propionate, thiourea and sodium acetate is added to ethanol in the reactor. The reaction mixture is refluxed for 8 hours under stirring. After completion of reaction, reaction mixture is cooled and stirred, filtered and dried to give 5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyU-2-imino-4-thiazolidinone
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5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4-thiazolidinone is added to 12% HC1 in reactor and refluxed for 9-10 hrs. After completion of reaction, reaction mixture is cooled and stirred at 27-30°C for 2-3 hrs. Further it is treated with sodium bicarbonate solution and purified from Dimethylfromamide to obtain Pioglitazone base, which is converted to Pioglitazone hydrochloride by treatment with ethanolic hydrochloride.
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We claim:

comprising reacting compound of formula (III),

1. A process for preparation of compound of formula (II), being substantially free of compound of formula (V)
wherein R1 is selected from group of-H, C1-6 alkyl or C1-6 acyl, with compound of formula (IV),

wherein L is a leaving group selected from halogen like CI, F, Br and 1; tosylate or mesylate, in lower alkyl sulfoxides in presence of alkali or alkaline earth metal hydroxides.

comprising reacting compound of formula (III),

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2. A process for preparation of compound of formula (II), being substantially free of compound of formula (V )

wherein R1 is -C2H5,
with compound of formula (IV),

wherein L is fluoro, in dimethyl sulfoxide in presence of sodium hydroxide
3. A process as claimed in claim 2, wherein -C2H5 is at 5-position.
4. A process as claimed in claim 1, wherein the said alkali or alkaline earth metal hydroxides are selected from group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, preferably sodium and potassium hydroxide.
5. A process as claimed in claim 1, wherein lower alkyl sulfoxides is
dimethylsulphoxide.
wherein R1 is selected from group of-H, C1-6 alkyl or C1-6 acyl, substantially free
from compound of formula (V).

6. A compound of formula (II)

7. Use of compound of formula (II) prepared in accordance with any of the preceding
claims, in the synthesis of Pioglitazone.
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8. A process for the preparation of Pioglitazone of formula (I), wherein the compound of formula (II) is prepared in accordance with any of the preceding claims and converted to pioglitazone by method known perse.
9. A process for the preparation of compound of formula (II) and Pioglitazone of formula (I) such as herein described by accompanying description, text and examples.
Dated this 5th day of October 2005

Dr. Sanchita Ganguli
Of S.Majumdar & Co. Applicant's Agent

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ABSTRACT
Title: An improved process for the preparation of 4-[2-(substituted-2-pyridyl)ethoxyl nitrobenzene
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The present invention relates to an improved method for producing a 4-[2-(sub.-2-pyridyl)ethoxy]nitrobenzene compound of formula (II), wherein R1 is selected from group of-H, C1-6 alkyl or C1-6 acyl, substantially free from impurity of formula (V).