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. the synthesis of 4-2-(N-methyl-N-(2-pyridyl)amino) ethoxybenzaldehyde, whereby the benzaldehyde forms an 0020. According to the present invention, therefore, there addition complex with an alkali metal metabisulphite salt, is provided a process of preparing 5-4-2-(N-methyl-N-(2- leading to the formation of metabisulphite complex of pyridyl)amino) ethoxy benzyl thiazolidine-2,4-dione, formula (III). This intermediate process step also provides namely rosiglitaZone, of formula (I), or a pharmaceutically means for purification of 4-2-(N-methyl-N-(2-pyridy acceptable salt thereof, especially rosiglitaZone maleate, US 2007/019 1611 A1 Aug. 16, 2007
0024 which process includes an intermediate process step wherein a metabisulphite complex of formula (III) (I) (III) Ol4N 1-9 S y NH H CH3 O CH which process comprises reacting a metabisulphite complex 0025 where X represents an alkali metal, such as sodium of formula (III) or potassium, especially sodium, is prepared from an inter mediate benzaldehyde compound of formula (IV) (III) (IV)
H Ol CH3 4. ---( )—ci CH3 0021 where X represents an alkali metal, such as sodium or potassium, especially sodium with thiazolidine 2,4 dione. 0026 by reacting the intermediate benzaldehyde com Suitably, the reaction is carried out in toluene in the presence pound of formula (IV) with an alkali metal metabisulphite of a catalytic amount of piperidine and acetic acid. Alter salt, such as sodium or potassium metabisulphite, in par natively, the reaction is carried out in a C alcohol (pref ticular sodium metabisulphite, in an aqueous Solution com erably ethanol), or in a mixture of water and a C alcohol, typically at a temperature in the range of about 40° C. to prising Calcohols, typically at a temperature in the range about reflux temperature, preferably at about 80° C., in of -10° C. to reflux. presence of an alkali or alkaline earth metal hydroxide, 0027 According to the present invention there is further alkoxide or carboxylate, so as to yield a benzylidene inter provided a process of preparing 5-4-2-(N-methyl-N-(2- mediate of formula (II) pyridyl)amino) ethoxy benzyl thiazolidine-2,4-dione, namely rosiglitaZone, of formula (I), or a pharmaceutically acceptable salt thereof, especially rosiglitaZone maleate, (II) (I) Sa O N 2 1N-1 O N Y Ol% 1n S y NH NH O CH O
0022 which can be subsequently converted to rosiglita 0028 which process includes an intermediate process Zone free base of formula (I) by appropriate reduction step wherein an intermediate benzaldehyde compound of techniques, and optionally converting rosiglitaZone free base formula (IV) to a pharmaceutically acceptable salt thereof particularly rosiglitaZone maleate. (IV) 0023. According to the present invention there is further provided a process of preparing 5-4-2-(N-methyl-N-(2- Ol pyridyl)amino) ethoxy benzyl thiazolidine-2,4-dione, % ---( )—ci namely rosiglitaZone, of formula (I), or a pharmaceutically CH3 acceptable salt thereof, especially rosiglitaZone maleate, 0029) is prepared from an intermediate compound of (I) formula (V) (V) Sa O N 2 1n-1 O Y r 2 OH NH N 1N1 US 2007/019 1611 A1 Aug. 16, 2007
0030 wherein intermediate compound of formula (V) and a 4-Hal benzaldehyde, where Hal represents bromo, -continued chloro, fluoro or iodo, preferably fluoro, are dissolved in a polar aprotic solvent, preferably DMF, followed by sequen tial additions of Sodium hydride in increasing molar quan Ol4N-1- S y tities, suitably carried out at a temperature of below about NH 40° C., and Subsequent stirring of the reaction mass at a CH3 temperature in the range of about 0 to 40° C., preferably at (I) ambient temperature for a time period of not more than about 3 hrs. 0032 where X represents an alkali metal, such as sodium 0031. There is still further provided by the present inven or potassium, especially sodium, wherein for intermediate tion an overall process for the preparation of 5-4-2-(N- process step (a) intermediate compound of formula (V) is methyl-N-(2-pyridyl)amino)ethoxybenzyl)thiazolidine-2, reacted with a 4-Hal benzaldehyde, where Hal represents 4-dione, namely rosiglitaZone, of formula (I), or a bromo, chloro, fluoro or iodo, preferably fluoro, dissolved in pharmaceutically acceptable Salt thereof, especially rosigli a polar aprotic solvent, preferably DMF, followed by taZone maleate, which can be represented by the following sequential additions of Sodium hydride in increasing molar reaction scheme quantities, 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 ambient temperature for a time period of not more than about 3 hrs; for intermediate process step (b) intermediate r benzaldehyde compound of formula (IV) is reacted with an 2 OH alkali metal metabisulphite salt, Such as sodium or potas N ~ sium metabisulphite, in particular sodium metabisulphite, in CH an aqueous Solution comprising C alcohols, typically at a (V) temperature in the range of -10° C. to reflux; for interme diate process step (c) a metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione suitably either in | toluene in the presence of a catalytic amount of piperidine and acetic acid, or in a C alcohol (preferably ethanol), or in a mixture of water and a C alcohol, typically at a temperature in the range of about 40° C. to about reflux 2 O CHO temperature, preferably at about 80° C., in presence of an r K) alkali or alkaline earth metal hydroxide, alkoxide or car N ~ boxylate; for intermediate process step (d) a benzylidene CH3 intermediate compound of formula (II) is converted to (IV) rosiglitaZone free base of formula (I) by appropriate reduc tion techniques, and optionally converting rosiglitaZone free base to a pharmaceutically acceptable salt thereof, particu larly rosiglitaZone maleate. 0033. There is also provided by the present invention a N OH metabisulphite complex of formula (III) 4. 1N1 O-K } Hox3 H (III) CH3 (III)
H CH
N 0034 where X represents an alkali metal, such as sodium 2 O N-N4 or potassium, especially sodium, and the use of this met N 1n-1 Y abisulphite complex in the manufacture of rosiglitaZone, or NH a pharmaceutically acceptable salt thereof. CH O 0035. The present invention further provides rosiglita (II) Zone free base, or a pharmaceutically acceptable salt thereof, prepared by a process as hereinbefore described. l 0036 Rosiglitazone free base, or a pharmaceutically acceptable salt thereof, as provided by the present invention, US 2007/019 1611 A1 Aug. 16, 2007
is useful in the treatment of Type II diabetes mellitus. adjuvant or additive colourings, aroma, preservatives or the RosiglitaZone as provided by the present invention can also like may also be used provided that they are compatible with be indicated to be of particular use for the treatment and/or the rosiglitaZone as provided by the present invention. prophylaxis of other diseases including hyperlipidaemia, hypertension and cardiovascular disease, especially athero 0043 Solutions for injections may be prepared by dis Sclerosis. In addition, rosiglitaZone as provided by the Solving rosiglitaZone as provided by the present invention present invention is considered to be useful for treating and possible additives in a part of the solvent for injection, certain eating disorders, in particular the regulation of appe typically sterile water, adjusting the Solution to the desired tite and food intake in subjects suffering from disorders volume, sterilisation of the solution and filling in suitable associated with under-eating, such as anorexia nervous, and ampoules or vials. Any suitable additive conventionally used disorders associated with over-eating. Such as obesity and in the art may be added. Such as tonicity agents, preserva anorexia bulimia. tives, antioxidants and the like. 0044) The present invention further provides a method 0037. The present invention accordingly provides, there for the treatment and/or prophylaxis of hyperglycaemia in a fore, for use in therapy rosiglitaZone free base, or a phar patient, which method comprises administering a therapeu maceutically acceptable salt thereof, as provided by a pro tically effective amount of rosiglitazone free base, or a cess according to the present invention Substantially as pharmaceutically acceptable salt thereof, as provided by a hereinbefore described. process according to the present invention to a hypergly 0038 Accordingly, the present invention provides for use caemic patient in need thereof. In particular, the present in the treatment of and/or prophylaxis of hyperglycaemia, invention provides a method for the treatment and / or rosiglitaZone free base, or a pharmaceutically acceptable salt prophylaxis of diabetes mellitus in a patient, which method thereof, as provided by a process according to the present comprises administering a therapeutically effective amount invention. In particular, there is provided rosiglitaZone free of rosiglitaZone free base, or a pharmaceutically acceptable base, or a pharmaceutically acceptable Salt thereof, as pro salt thereof, as provided by a process according to the vided by a process according to the present invention for use present invention to a patient Suffering from, or Susceptible in the treatment of diabetes mellitus. to, diabetes mellitus. 0.039 The present invention further provides for use in 0045. The present invention further provides a method the treatment and/or prophylaxis of hyperlipidaemia, rosigli for the treatment of hyperlipidaemia in a patient, which taZone free base, or a pharmaceutically acceptable salt comprises administering a therapeutically effective amount thereof, as provided by a process according to the present of rosiglitaZone free base, or a pharmaceutically acceptable invention. salt thereof, as provided by a process according to the present invention to a hyperlipidaemic patient in need 0040. The present invention also further provides for use thereof. in the treatment of hypertension, cardiovascular disease and certain eating disorders, rosiglitaZone free base, or a phar 0046) The present invention further provides a method maceutically acceptable salt thereof, as provided by a pro for the treatment of hypertension, cardiovascular disease or cess according to the present invention. Cardiovascular certain eating disorders Substantially as hereinbefore disease includes in particular atherosclerosis. Certain eating described, which comprises administering a therapeutically disorders include in particular the regulation of appetite and effective amount of rosiglitaZone free base, or a pharmaceu food intake in, Subjects Suffering from disorders associated tically acceptable salt thereof, as provided by a process with under-eating, such as anorexia nervosa and disorders according to the present invention to a patient in need associated with over-eating. Such as obesity and anorexia thereof. bulimia. 0047. In a further aspect the present invention provides 0041 Accordingly, the present invention also provides a the use of rosiglitaZone free base, or a pharmaceutically pharmaceutical composition comprising rosiglitaZone free acceptable Salt thereof, as provided by a process according base, or a pharmaceutically acceptable Salt thereof, as pro to the present invention, for the manufacture of a medica vided by a process according to the present invention, and a ment for the treatment and/or prophylaxis of hyperglycae pharmaceutically acceptable carrier therefor. Preferably a mia. In particular, the present invention provides use of composition as provided by the present invention can be for rosiglitaZone free base, or a pharmaceutically acceptable salt oral administration. The pharmaceutical compositions of the thereof, as provided by a process according to the present invention may, however, be administered in any Suitable invention for the manufacture of a medicament for the way and in any suitable form, for example orally in the form treatment and/or prophylaxis of diabetes mellitus. of tablets, capsules, liquid preparations, granules, lozenges, 0048. The present invention also provides the use of or parenterally in the form of injectable, or infusible, solu rosiglitaZone free base, or a pharmaceutically acceptable salt tions or Suspensions. thereof, as provided by a process according to the present 0042. The pharmaceutical compositions of the invention invention for the manufacture of a medicament for the may be prepared by conventional methods in the art. For treatment and/or prophylaxis of hyperlipidaemia. example, tablets may be prepared by mixing the active 0049. The present invention also provides the use of ingredient with ordinary adjuvants and/or diluents and Sub rosiglitaZone free base, or a pharmaceutically acceptable salt sequently compressing the mixture in a conventional tablet thereof, as provided by a process according to the present ting machine. Examples of adjuvants or diluents can com invention for the manufacture of a medicament for the prise: corn starch, potato starch, talcum, magnesium treatment and/or prophylaxis of hypertension, cardiovascu Stearate, gelatine, lactose, gums, and the like. Any other lar disease or certain eating disorders. US 2007/019 1611 A1 Aug. 16, 2007
0050. The particular dosage form of rosiglitazone as Example 4 provided by the present invention required for therapeutic use or treatment in accordance with the present invention Preparation of 5-(4-2-(N-methyl-N-(2-pyridyl) aminoet will depend on the particular disease state being treated, and hoxybenzylidene)-2,4-thiazolidinedione the symptoms and severity thereof. Dosage, routes of admin 0055) 4--(N-methyl-N-(2-pyridyl)amino)ethoxyben istration, and frequency of dosing are best decided by an Zaldehyde Sodium metabisulphite complex (10gms, attending physician. 0.027M) from Example 3 was suspended in toluene (100 ml) 0051) The present invention will now be further illus with 2,4-thiazolidine dione (3.2gms, 0.0273M) at ambient trated by the following Examples, which do not limit the temperature. A catalytic amount of piperidine (0.2 ml) and Scope of the invention in any way. acetic acid (0.1 ml) was added to the reaction mixture under stirring. The reaction mass was then refluxed using Dean EXAMPLES Stark apparatus for 5 to 6 hours. The reaction mass was then cooled to 60° C. and concentrated to half of its volume under Example 1 vacuum. Methanol (50 ml) was added drop wise to the Preparation of 4-(2-(N-methyl-N-(2-pyridyl)amino ethoxy) reaction mass at 60° C. and cooled gradually to room benzaldehyde temperature. The Suspension was stirred at room tempera ture for about 2 hours and the solid filtered and washed with 0.052 2-(N-methyl-N-(2-pyridyl)amino ethanol (50gms, methanol (25 ml), followed by water (200 ml). The resulting 0.32M) and 4-fluorobenzaldehyde (68gms, 0.547M) were solid was then dried under vacuum oven at 60° C. to obtain dissolved in DMF (500 ml) and sodium hydride (2gms) was added. The reaction mass was stirred for 15 minutes and the the title compound (6.5gms, 98% HPLC purity). temperature was maintained below 35° C. Sodium hydride (4gms) was added again and the reaction mass stirred for 15 Example 5 minutes. Subsequently 8 and 10gms of sodium hydride were Preparation of 5-(4-2-(N-methyl-N-(2-pyridyl) aminoet sequentially added at 15 minute intervals. The reaction was hoxybenzylidene)-2,4-thiazolidinedione monitored by HPLC. After completion of reaction, the reaction mass was cooled to 5°C., and methanol (30 ml) was 0056 4-2-(N-methyl-N-(2-pyridyl)amino) ethoxyben added slowly. The reaction mass was then quenched into Zaldehyde Sodium metabisulphite complex (10gms, water (approx 2ltrs) and extracted with ethyl acetate (4x500 0.027M) from Example 3 was suspended in industrial spirit ml). The combined organic layers were washed with water (150 ml) with 2,4-thiazolidine dione (6.4gms, 0.0546M) at (6x500 ml). The organic layer was dried over sodium ambient temperature. Sodium hydroxide pellets (6.0gms Sulphate and concentrated to obtain the title compound as an 0.15 moles) were added to the reaction mixture under oil (105 gms, 84% HPLC purity). stirring. The reaction mass was then refluxed for 18 hours, the reaction mass was then cooled to 0° C. and neutralized Example 2 with (1:1) hydrochloric acid water mixture. The suspension Preparation of 4-2-(N-methyl-N-(2-pyridyl)amino)ethoxy was stirred at 10° C. for 1 hour. The solid was filtered and benzaldehyde sodium metabisulphite complex washed with demineralised water (50 ml). The resulting solid was then dried under vacuum oven at 60° C. to obtain 0053 4-2-(N-methyl-N-(2-pyridyl)amino)ethoxyben the title compound (9gms, 98% HPLC purity). Zaldehyde (10gms, 0.039M) was stirred with industrial spirit (150 ml) and cooled to 15° C. A solution of sodium metabisulphite (11gms, 0.057M) in water (20 ml) was added Example 6 drop wise to the above solution over a time period of about Preparation of 5-(4-2-(N-methyl-N-(2-pyridyl) amino 15 to 20 minutes, whilst maintaining the temperature below ethoxybenzyl)-2,4-thiazolidinedione (in accordance with about 20°C. The reaction mixture was further cooled to 10° C. and stirred for 1 to 2 hours. The resulting precipitate was EP 0306228B) then filtered and washed with industrial spirit (25 mlx2) 0057 5-(4-2-(N-methyl-N-(2-pyridyl) amino ethoxy followed by water (25 ml). The solid obtained was then dried benzylidene)-2,4-thiazolidinedione (20gms) in dry 1,4-di in a vacuum oven at 40° C. to obtain the title complex oxane (700 ml) was reduced under hydrogen in the presence (10gms, HPLC purity 98.5%). of 10% Palladium on charcoal (30gms) at ambient tempera ture and atmospheric pressure until hydrogen uptake was Example 3 ceased. The reaction mass was filtered through celite. The Preparation of 4-2-(N-methyl-N-(2-pyridyl)amino)ethoxy clear filtrate was evaporated to dryness under vacuum. The benzaldehyde sodium metabisulphite complex product obtained was crystallized from methanol. 0054 4-2-(N-methyl-N-(2-pyridyl)amino)ethoxyben Example 7 Zaldehyde (20gms, 84% HPLC purity) was stirred with methanol (200 ml) and cooled to 15°C. A solution of sodium Preparation of 5-(4-2-(N-methyl-N-(2-pyridyl) amino metabisulphite (22gms, 0.115M) in water (40 ml) was added ethoxybenzyl)-2,4-thiazolidinedione drop wise to the above solution over a time period of about 15 to 20 minutes, whilst maintaining the temperature below 0058 5-(4-2-(N-methyl-N-(2-pyridyl) amino ethoxy about 20°C. The reaction mixture was then cooled to 10° C. benzylidene)-2,4-thiazolidinedione (10gms) was suspended and stirred for about 2 hours. The resulting solid precipitate in water (30 ml) and tertahydrofuran (30 ml), and to this was then filtered and washed with methanol (25 ml) and suspension was added 4% sodium hydroxide (25 ml). The water (25 ml). The solid was then dried in a vacuum oven at resulting mixture was cooled to 10° C. and to this was added 40° C. to obtain the title compound (20gms, 98% HPLC a catalyst solution prepared by dissolving dimethyl gly purity). oxime (1.88gms) and cobaltous chloride (0.200gms) in US 2007/019 1611 A1 Aug. 16, 2007 tetrahydrofuran (30 ml). Then a solution of sodium boro lidine 2,4 dione so as to yield a benzylidene intermediate of hydride (3.2gms) in water (30 ml), and 4% sodium hydrox formula (II): ide (9.4 ml), was slowly added at 10°C. over a period of 90 minutes. The resulting reaction mixture was stirred at 25°C. for 16 hours and later was acidified with 60% glacial acetic (II) acid, which was added very slowly over a period of 1-2 hours. The resulting suspension was further stirred for 1.5 hours. The solid obtained was filtered and washed with s-N4 water and dried under vacuum at 60° C. to obtain 9.3gms of Ol% 1n 5-(4-2-(N-methyl-N-(2-pyridyl)amino ethoxybenzyl)-2, Y 4-thiazolidinedione (rosiglitazone free base). CH O 1. A process of preparing rosiglitazone of formula (I), or a pharmaceutically acceptable salt thereof, which is subsequently reduced to yield rosiglitazone free base of formula (I), and optionally converting rosigli (I) tazone free base to a pharmaceutically acceptable salt thereof. 11. A process according to claim 1, wherein said met abisulphite complex of formula (III) is prepared from 4-2- Ol4N1 S y (N-methyl-N-(2-pyridyl)amino) ethoxybenzaldehyde of NH CH3 formula (IV):
(IV) which process employs an intermediate metabisulphite complex of 4-2-(N-methyl-N-(2-pyridyl)amino) ethoxybenzaldehyde, which metabisulphite complex is represented by following formula (III): Cl-----. ) to CH (III) by reacting the intermediate benzaldehyde compound of formula (IV) with an alkali metal metabisulphite salt. 12. A process according to claim 11, wherein said alkali H metal metabisulphite salt is sodium or potassium metabisul CH3 phite. 13. A process according to claim 12, wherein said alkali metal metabisulphite salt is sodium metabisulphite. where X represents an alkali metal. 14. A process according to claim 11, wherein said inter 2. A process according to claim 1, wherein X is sodium or mediate benzaldehyde compound of formula (IV) is reacted potassium. with said alkali metal metabisulphite salt in an aqueous 3. A process according to claim 2, wherein X is sodium. solution comprising C. alcohols. 4. A process according to claim 1, wherein said metabisul 15. A process according to claim 11, wherein said inter phite complex of formula (III) is reacted with thiazolidine mediate benzaldehyde compound of formula (IV) is reacted 2.4 dione in toluene in the presence of a catalytic amount of with said alkali metal metabisulphite salt at a temperature in piperidine and acetic acid. the range of -10° C. to reflux. 5. A process according to claim 1, wherein said metabisul 16. A process according to claim 11, wherein said inter phite complex of formula (III) is reacted with thiazolidine mediate benzaldehyde compound of formula (IV) is pre 2.4 dione in a C alcohol or in a mixture of water and a Ca pared from an intermediate compound of formula (V): alcohol. 6. A process according to claim 5, wherein said C. alcohol is ethanol. (V) 7. A process according to claim 5, wherein said metabisul phite complex of formula (III) is reacted with thiazolidine 2.4 dione at a temperature in the range of about 40° C. to Cl about reflux temperature. 4N-N-OH 8. A process according to claim 7, wherein said tempera CH ture is about 80° C. 9. A process according to claim 5, wherein said metabisul phite complex of formula (III) is reacted with thiazolidine where in said intermediate compound of formula (V) and 2.4 dione in the presence of an alkali or alkaline earth metal a 4-Hal benzaldehyde, where Hal represents bromo, hydroxide, alkoxide or carboxylate. chloro, fluoro or iodo, are dissolved in a polar aprotic 10. A process according to claim 1, wherein said met solvent followed by sequential additions of sodium abisulphite complex of formula (III) is reacted with thiazo hydride in increasing molar quantities. US 2007/019 1611 A1 Aug. 16, 2007
17. A process according to claim 16, wherein Hal repre wherein intermediate compound of formula (V) and a sents fluoro. 4-Hal benzaldehyde, where Hal represents bromo, 18. A process according to claim 16, wherein said polar chloro, fluoro or iodo, are dissolved in a polar aprotic aprotic solvent is DMF. solvent followed by sequential additions of sodium 19-21. (canceled) hydride in increasing molar quantities. 22. A process according to claim 10, wherein said met 34. A process according to claim 33, wherein Hal repre abisulphite complex of formula (III) is reacted with thiazo sents fluoro. lidine 2,4 dione in toluene in the presence of a catalytic 35. A process according to claim 33, wherein said polar amount of piperidine and acetic acid. aprotic solvent is DMF. 23. A process according to claim 10, wherein said met 36. A process according to claim 1, represented by the abisulphite complex of formula (III) is reacted with thiazo following reaction Scheme: lidine 2,4 dione in a Calcohol or in a mixture of water and a C alcohol. 24. A process according to claim 23, wherein said C. alcohol is ethanol. 25. A process according to claim 23, wherein said met r 2 OH abisulphite complex of formula (III) is reacted with thiazo lidine 2,4 dione at a temperature in the range of about 40° N ~ C. to about reflux temperature. CH 26. A process according to claim 25, wherein said tem (V) perature is about 80° C. 27. A process according to claim 23, wherein said met abisulphite complex of formula (III) is reacted with thiazo lidine 2,4 dione in the presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate. 28-32. (canceled) r 2 O ( ) CHO 33. A process of preparing rosiglitaZone of formula (I), or N ~ a pharmaceutically acceptable salt thereof, CH3 (IV) (I)
Sa O N OH N 2 1N1 O Y NH N2 1N1 O-K } Hox3 H CH3 (III) which process includes an intermediate process step wherein an intermediate benzaldehyde compound of formula (IV): e N s/Ne (IV) N 2 1N1 O Y NH CH O Ol% ---( )-n (II) CH3 l N is prepared from an intermediate compound of formula Sa O (V): 21\1\-2 O Y NH CH3 (V) O (I)
where X represents an alkali metal and wherein for intermediate process step (a) intermediate compound of formula (V) is reacted with a 4-Hall benzaldehyde, where Hal represents bromo, chloro, fluoro or iodo, US 2007/019 1611 A1 Aug. 16, 2007
dissolved in a polar aprotic solvent, followed by 44. A process according to claim 36, wherein for inter sequential additions of sodium hydride in increasing mediate process step (c) said metabisulphite complex of molar quantities; for intermediate process step (b) formula (III) is reacted with thiazolidine 2,4 dione in a Ca intermediate benzaldehyde compound of formula (IV) alcohol or in a mixture of water and a C alcohol. is reacted with an alkali metal metabisulphite salt; for 45. A process according to claim 44, wherein for inter intermediate process step (c) a metabisulphite complex mediate process step (c) said C. alcohol is ethanol. of formula (III) is reacted with thiazolidine 2,4 dione: 46. A process according to claim 44, wherein for inter for intermediate process step (d) a benzylidene inter mediate process step (c) said metabisulphite complex of mediate compound of formula (II) is reduced to yield formula (III) is reacted with thiazolidine 2,4 dione at a rosiglitaZone free base of formula (I), and optionally temperature in the range of about 40° C. to about reflux converting rosiglitaZone free base to a pharmaceuti temperature. cally acceptable salt thereof. 47. A process according to claim 46, wherein said tem 37. A process according to claim 36, wherein for inter perature is about 80° C. mediate process step (a) Hal represents fluoro. 48. A process according to claim 44, wherein for inter 38. A process according to claim 36, wherein for inter mediate process step (c) said metabisulphite complex of mediate process step (a) said polar aprotic solvent is DMF. formula (III) is reacted with thiazolidine 2,4 dione in the 39. A process according to claim 36, wherein for inter presence of an alkali or alkaline earth metal hydroxide, mediate process step (b) X is sodium or potassium and said alkoxide or carboxylate. alkali metal metabisulphite salt is sodium or potassium 49. A metabisulphite complex of formula (III): metabisulphite. 40. A process according to claim 39, wherein for inter mediate process step (b) X is sodium and said alkali metal (III) metabisulphite salt is sodium metabisulphite. N OH 41. A process according to claim 36, wherein for inter mediate process step (b) said intermediate benzaldehyde compound of formula (IV) is reacted with said alkali metal N 2 1N1 O-K } Hox metabisulphite salt in an aqueous Solution comprising Ca H alcohols. CH3 42. A process according to claim 36, wherein for inter mediate process step (b) said intermediate benzaldehyde compound of formula (IV) is reacted with said alkali metal where X represents an alkali metal. metabisulphite salt at a temperature in the range of -10°C. 50. A metabisulphite complex of formula (III) according to reflux. to claim 49, wherein X is sodium or potassium. 43. A process according to claim 36, wherein for inter 51. A metabisulphite complex of formula (III) according mediate process step (c) said metabisulphite complex of to claim 50, wherein X is sodium. formula (III) is reacted with thiazolidine 2,4 dione in toluene 52-64. (canceled) in the presence of a catalytic amount of piperidine and acetic acid.