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(12) Patent Application Publication (10) Pub. No.: US 2007/0191611 A1 Rao Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0191611 A1 Rao Et Al US 2007.019 1611A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0191611 A1 Rao et al. (43) Pub. Date: Aug. 16, 2007 (54) SYNTHESIS OF ANTIDIABETIC Publication Classification ROSGLTAZONE DERVATIVES (51) Int. Cl. (75) Inventors: Dharmaraj Ramachandra Rao, C07D 417/02 (2006.01) Maharashtra (IN); Rajendra C07D 213/72 (2006.01) Narayanrao Kankan, Maharashtra (IN) (52) U.S. Cl. ......................................... 546/269.7: 546/304 Correspondence Address: (57) ABSTRACT CONLEY ROSE, PC. A process of preparing rosiglitaZone, or a pharmaceutically 5700 GRANITE PARKWAY, SUITE 330 acceptable salt thereof, which process employs an interme PLANO, TX 75024 (US) diate metabisulphite complex of 4-2-(N-methyl-N-(2-py ridyl)amino) ethoxybenzaldehyde, which metabisulphite (73) Assignee: CIPLA LIMITED, MAHARASHA- complex is represented by following formula (III); where X TRA, INDIA (IN) represents an alkali metal. The present invention further provides rosiglitaZone, or a pharmaceutically acceptable salt (21) Appl. No.: 11/568,610 thereof, prepared by the above process. (22) PCT Filed: May 3, 2005 (III) (86). PCT No.: PCT/GBOS/O1671 N OH S 371(c)(1), O SOX (2), (4) Date: Jan. 11, 2007 4. 1N1 3 (30) Foreign Application Priority Data hi, H May 5, 2004 (GB)......................................... O41OO13.7 US 2007/019 1611 A1 Aug. 16, 2007 SYNTHESIS OF ANTDABETIC ROSIGLTAZONE thiazolidine-2,4-dione, which is then reduced with Pd/C to DERVATIVES obtain rosiglitazone free base. We have now developed an improved synthesis of rosiglitaZone, or a pharmaceutically 0001. The present invention describes a novel process for the synthesis of the antidiabetic compound, 5-4-2-(N- acceptable salt thereof, which alleviates many problems methyl-N-(2-pyridyl)amino)ethoxybenzyl)thiazolidine-2, associated with the prior art preparation of rosiglitaZone 4-dione, namely rosiglitaZone, especially as the maleate salt substantially as hereinafter described in greater detail. 0007 According to the present invention, therefore, there thereof, which is the preferred drug for non-insulin depen is provided a process of preparing 5-4-2-(N-methyl-N-(2- dent diabetes mellitus (NIDDM). pyridyl)amino) ethoxy benzyl thiazolidine-2,4-dione, 0002 Rosiglitazone maleate, 5-4-2-(N-methyl-N-(2- namely rosiglitaZone, of formula (I), or a pharmaceutically pyridyl)amino)ethoxybenzylthiazolidine-2,4-dione male acceptable salt thereof, especially rosiglitaZone maleate, ate, has the following general structural formula (I) Sa O N 2 1N-1 O Y Ol NH 4N 1-9 S NH CH3 0008 which process employs an intermediate metabisul CO2H phite complex of 4-2-(N-methyl-N-(2-pyridyl)amino) ethoxybenzaldehyde, which metabisulphite complex is represented by following formula (III) 0003 Rosiglitazone is a member of the thiazolidinedione class of compounds and is one of the most potent com pounds of this class. The thiazolidinedione class of antidia (III) betics, such as pioglitaZone, englitaZone, rosiglitaZone, tro glitaZone and ciglitaZone, has been shown to alleviate insulin resistance in humans. RosiglitaZone is, therefore, a known antidiabetic compound, and more particularly is the H preferred drug for non-insulin dependent diabetes mellitus CH3 (NIDDM). Diabetes mellitus is a complex, chronically pro gressive disease, which affects the function of the kidneys, eyes, vascular and nervous systems. 0009 where X represents an alkali metal, such as sodium or potassium, especially sodium. 0004 EP 0306228B describes the synthesis of 5-4-2- (N-methyl-N-(2-pyridyl)amino) ethoxybenzylidene thia 0010. According to a process of the present invention, a metabisulphite complex of formula (III) is converted to Zolidine-2,4-dione rosiglitaZone free base, or a pharmaceutically acceptable salt thereof, by reacting the metabisulphite complex of formula (III) with thiazolidine 2,4 dione. Suitably, the reaction is carried out in toluene in the presence of a catalytic amount Sa O of piperidine and acetic acid. Alternatively, the reaction is 4. 1n- N Y carried out in a C alcohol (preferably ethanol), or in a NH mixture of water and a C alcohol, and at a temperature in the range of about 40° C. to about reflux temperature, O preferably at about 80° C., in presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate, so 0005 by condensing 4-2-(N-methyl-N-(2-pyridyl)ami as to yield a benzylidene intermediate of formula (II) no)ethoxybenzaldehyde (which is an impure oil) (II) s/Ne Ol4. ---. ) to Ol4. ~ y CH3 O 0006 with 2,4-thiazolidinedione, to obtain above 5-4- 0011 Benzylidene intermediate of formula (II) can be 2-(N-methyl-N-(2-pyridyl)amino) ethoxy benzylidene Subsequently converted to rosiglitaZone free base of formula US 2007/019 1611 A1 Aug. 16, 2007 (I) by appropriate reduction techniques, and optionally con l)amino)ethoxybenzaldehyde. A metabisulphite complex verting rosiglitaZone free base to a pharmaceutically accept of formula (III) is a very fine crystalline solid in nature, able salt thereof, particularly rosiglitazone maleate. Suitable having HPLC purity of about 96-99%, with a defined reducing techniques can comprise reduction in the presence melting point making it easy to handle and as indicated of palladium on charcoal as described in EP 0306228B as above alleviating the prior art problems related to handling referred to above. Alternatively, reduction can be carried out of viscous oils on an industrial scale. in the presence of a cobaltion, a ligand and a reducing agent, wherein the cobalt ion is provided in the form of any of the 0016 Intermediate benzaldehyde compound of formula following—cobaltous chloride, cobaltous diacetate and (IV) is in turn prepared from an intermediate compound of cobaltic chloride; the ligand is selected from the group formula (V) in a process according to the present invention consisting of dimethylglyoxime, 2,2'-bipyridyl and 1.10 phenanthroline; the reducing agent is selected from the group consisting of Sodium borohydride, lithium borohy (V) dride, potassium borohydride, tetraalkylammonium borohy dride and Zinc borohydride; and optionally converting the thus formed rosiglitaZone free base to a pharmaceutically Ol acceptable salt thereof. Preferably the above reduction step % 1-N-O is carried out in the presence of cobaltous chloride as the CH Source of the cobalt ion, dimethylglyoxime as the ligand and Sodium borohydride as the reducing agent. 0012. A metabisulphite complex of formula (III) is suit 0017 wherein intermediate compound of formula (V) ably prepared by a process of the present invention from and a 4-Hal benzaldehyde, where Hal represents bromo, 4-2-(N-methyl-N-(2-pyridyl)amino)ethoxybenzaldehyde chloro, fluoro or iodo, preferably fluoro, are dissolved in a (known from the prior art as indicated above and referred to polar aprotic solvent, preferably DMF, followed by sequen in the context of the present invention as an intermediate tial additions of sodium hydride in increasing molar quan benzaldehyde compound of formula (IV)) tities, suitably carried out at a temperature of below about 40° C., and Subsequent stirring of the reaction mass at a temperature in the range of about 0 to 40°C., preferably at (IV) ambient temperature for a time period of not more than about 3 hrs. Intermediate benzaldehyde compound of for mula (IV) isolated by this process has HPLC purity of more Cl than about 80%. 4. ---( )—cio 0018 4-2-(N-methyl-N-(2-pyridyl)amino) ethoxyben CH3 Zaldehyde has hitherto been prepared by processes known in the art, for example by reaction of 2-(N-methyl-N-(2-py ridyl)amino) ethanol with 4-fluoro benzaldehyde in pres 0013 by reacting the intermediate benzaldehyde com ence of sodium hydride. EP 0306228B discloses a process pound of formula (IV) with an alkali metal metabisulphite wherein sodium hydride is added to a stirred solution of salt, such as sodium or potassium metabisulphite, in par 2-(N-methyl-N-(2-pyridyl) amino) ethanol in DMF fol ticular sodium metabisulphite, in an aqueous Solution com lowed by addition of 4-fluorobenzaldehyde and the reaction prising Calcohols, typically at a temperature in the range mixture was heated to 80° C. for 16 hrs. The crude viscous of -10° C. to reflux. oil of 4-2-(N-methyl-N-(2-pyridyl)amino)ethoxybenzal 0014. The prior art synthesis of 4-2-(N-methyl-N-(2- dehyde was then isolated and purified by column chroma pyridyl)amino)ethoxybenzaldehyde has hitherto led to a tography. It has been seen that by following this prior art number of in situ generated impurities, with the compound process, impurities were observed to an extent of about being prepared as a viscous oil and as Such being difficult to 30-40% and 4-2-(N-methyl-N-(2-pyridyl)amino) ethoxy isolate and purify. The purity of 4-2-(N-methyl-N-(2-py benzaldehyde exhibited a purity not more than about ridyl)amino)ethoxybenzaldehyde as prepared by prior art 50-55%. As can be seen from the 80% purity of 4-2-(N- processes has generally not been more than about 50-55%. methyl-N-(2-pyridyl)amino) ethoxybenzaldehyde as pre According to the present invention, however, 4-2-(N-me pared by a process according to the present invention, the thyl-N-(2-pyridyl)amino)ethoxybenzaldehyde is isolated present invention thus discloses an improvement in the and purified in the form of a solid metabisulphite complex process of preparing 4-2-(N-methyl-N-(2-pyridyl)amino) of formula (III), which in addition to the associated ethoxybenzaldehyde compared to the prior art. improved purity obviates the handling properties of the Viscous oil employed in the prior art reaction with thiazo 0019. It can be appreciated from the above that the present invention essentially provides modification of three lidine 2,4 dione. process stages in the preparation of rosiglitaZone, or a 0.015 The present invention thus provides a process for pharmaceutically acceptable salt thereofas follows.
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