Novel preparation method of lobeglitazone

Abstract

The invention relates to a novel preparation method of a thiazolidinedione derivative, namely, lobeglitazone. Specifically, the invention relates to a preparation method of lobeglitazone, which comprises the following steps: synthesizing an intermediate; coupling the intermediates; and a step of crystallization. According to the method provided by the invention, the solid intermediate is synthesized, so that the high-purity lobeglitazone can be prepared without column chromatography. The method provides a preparation process suitable for large-scale industrial production. In addition, when the method of the present invention is used, uniform crystallization can be achieved, and the generation of impurities in the preparation of the lobeglitazone sulfate can be minimized.

Description

Technical Field

[0001] This invention relates to a novel method for preparing lobeglitazone, a thiazolidinedione derivative. Specifically, this invention relates to a method for preparing lobeglitazone, comprising the steps of synthesizing intermediates; coupling the intermediates; and crystallization. Background Technology

[0002] Thiazolidinediones (TZDs) are representative drugs for improving insulin resistance. Pioglitazone is widely used to treat metabolic syndromes such as hypertension, hyperlipidemia, chronic inflammation, and microalbuminuria, and plays a positive role in the prevention of cardiovascular diseases.

[0003] Meanwhile, lobeglitazone is a thiazolidinedione compound used for the oral treatment of diabetes with insulin resistance-improving effects, particularly for type 2 diabetes. Furthermore, lobeglitazone may be very useful for obese diabetic patients because it lacks cardiovascular side effects, which are a controversial side effect of conventional glitazones, especially rosiglitazone from GlaxoSmithKline.

[0004] Lobeglitazone, namely 5-[(4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidin-2,4-dione, can be represented by the following chemical formula I, which contains a 2,4-thiazolidinedione moiety and is structurally linked by an N-methylaminoethoxybenzyl group. This compound is a white to pale yellow powder, almost odorless.

[0005] <Chemical Formula I>

[0006]

[0007] In response, Korean Patent No. 10-0450700 and the document Organic Process Research &

[0008] Development 2007, 11, 190-199 discloses a method for preparing lobeglitazone, as shown in reaction formula 1.

[0009] <Reaction Formula 1>

[0010]

[0011] Thus, the known conventional methods for preparing lobeglitazone involve obtaining an oily intermediate and purifying it using column chromatography until the synthesis of the thiazolidinedione intermediate. However, these methods are based on stepwise total synthesis, which is complex, expensive, and time-consuming due to the need for column chromatography purification.

[0012] Therefore, there is still a need to develop a synthetic method that simplifies the synthesis of lobeglitazone while producing high-purity lobeglitazone.

[0013] In view of this, through unremitting efforts, the inventors have overcome the problems of the prior art and developed a novel intermediate synthesis method, which involves coupling two intermediates after synthesis. The inventors have confirmed that high-purity lobeglitazone can be prepared by crystallization of the intermediates without the use of column chromatography, thus completing this invention.

[0014] [Existing Technical Documents]

[0015] [Patent Literature]

[0016] (Patent Document 0001) Korean Patent Registration No. 10-0450700

[0017] [Non-patent literature]

[0018] (Non-Patent Document 0001) Organic Process Research & Development 2007, 11, 190-199 Summary of the Invention

[0019] Technical issues

[0020] The purpose of this invention is to solve the problems associated with conventional preparation methods by developing a novel intermediate synthesis method and providing a process for producing high-purity lobeglitazone without using column chromatography.

[0021] Problem-solving methods

[0022] This invention provides a method for preparing lobeglitazone, comprising coupling a compound of formula II with a compound of formula III using a base to obtain a compound of formula I:

[0023] <Chemical Formula I>

[0024]

[0025] <Chemical Formula II>

[0026]

[0027] <Chemical Formula III>

[0028]

[0029] The present invention also provides a method for preparing lobeglitazone, which further includes the step of crystallizing a compound of chemical formula II, a compound of chemical formula III, or both.

[0030] The present invention also provides lobeglitazone prepared by the above method.

[0031] Furthermore, the present invention provides a method for preparing lobeglitazone sulfate, comprising: 1) adding a compound of chemical formula I to a solvent and cooling it; 2) adding sulfuric acid to the cooled compound to dissolve it; and 3) adding the dissolved compound to a cooled acetate to crystallize it.

[0032] The present invention also provides lobeglitazone sulfate prepared by the above method.

[0033] Invention Effects

[0034] When using the preparation method of this invention, high-purity lobeglitazone can be prepared by synthesizing a solid intermediate without the need for column chromatography. This method provides a preparation process suitable for large-scale industrial production. Attached Figure Description

[0035] Figure 1 A schematic diagram illustrating the preparation process of lobeglitazone according to an embodiment of the present invention.

[0036] Figure 2 The NMR spectrum of the compound of chemical formula II obtained according to the present invention is shown.

[0037] Figure 3 The NMR spectrum of the compound of chemical formula III obtained according to the present invention is shown.

[0038] Figure 4 The NMR spectrum of the compound of chemical formula I obtained according to the present invention is shown.

[0039] Figure 5 The XRD diffraction pattern of the compound of chemical formula I obtained according to the present invention is shown.

[0040] Figure 6 The DSC curves of the crystal form of the compound of chemical formula I obtained according to the present invention are shown.

[0041] Figure 7 The HPLC spectrum of the compound of chemical formula I obtained according to the present invention is shown.

[0042] Figure 8 The NMR spectrum of lobeglitazone sulfate obtained according to the present invention is shown.

[0043] Figure 9 The XRD diffraction pattern of lobeglitazone sulfate obtained according to the present invention is shown.

[0044] Figure 10 The HPLC chromatogram of lobeglitazone sulfate obtained according to the present invention is shown. Detailed Implementation

[0045] The embodiments of the present invention will be described in detail below to enable those skilled in the art to readily implement the invention. The embodiments of the present invention are provided to explain the invention more completely to those skilled in the art. Therefore, the embodiments of the present invention can be modified into several different forms, and the scope of the invention is not limited to the embodiments described below. Unless specifically defined herein, the terminology used herein should also be understood to have the conventional meaning known in the art.

[0046] Throughout this specification, when a component is described as "comprising" certain elements, it is intended that, unless otherwise specifically stated, it may also include additional elements and does not exclude other elements.

[0047] Unless otherwise specified, the singular form used herein is intended to include the plural form.

[0048] The preparation method of the present invention can be chemically synthesized using the methods described below, but is not limited to this example. Appropriate variations of reagents and starting materials known to those skilled in the art can also be used.

[0049] Unless otherwise specified herein, the term "lobeglitazone" refers to the free base form of 5-[(4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidin-2,4-dione, which may exist in crystalline, amorphous, or mixture of amorphous and crystalline forms.

[0050] In the preparation method of this invention, "coupling" refers to a method of obtaining monomeric compounds or polymers through carbon-carbon, carbon-oxygen, carbon-sulfur, and other bonding processes. This includes conventional coupling reactions such as nickel-catalyzed coupling reactions, Suzuki reactions, Negishi reactions, and Stille reactions.

[0051] An embodiment of the present invention provides a method for preparing lobeglitazone, comprising coupling a compound of chemical formula II with a compound of chemical formula III using a base to obtain a compound of chemical formula I:

[0052] <Chemical Formula I>

[0053]

[0054] <Chemical Formula II>

[0055]

[0056] <Chemical Formula III>

[0057]

[0058] In the above reactions, the base can be an organic base or an inorganic base. Specifically, the base can be an organic base selected from the group consisting of amidine, methylamine, alkylamine, and heterocyclic amine; or an inorganic base selected from the group consisting of metal salts of lithium, sodium, and potassium, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and metal alkoxides. More specifically, the base can be DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), triethylamine, pyridine, Na2CO3, NaHCO3, NaOH, or sodium methoxide. Even more specifically, the base can be DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), but the choice is not limited to this.

[0059] The amount of base used relative to 1 part by weight of the compound of formula II can range from 0.1% to 2% by weight. Specifically, the range of said amount can be 0.2% to 2% by weight, 0.3% to 2% by weight, 0.4% to 2% by weight, 0.5% to 2% by weight, 0.6% to 2% by weight, 0.7% to 2% by weight, 0.8% to 2% by weight, 0.9% to 2% by weight, 1.0% to 2% by weight, 1.1% to 2% by weight, 1.2% to 2% by weight, 1.3% to 2% by weight, 1.4% to 2% by weight, 1.4% to 1.9% by weight, 1.4% to 1.8% by weight, 1.4% to 1.7% by weight, or 1.5% to 1.7% by weight, but is not limited thereto.

[0060] Furthermore, in the above reaction, the solvent can be water or an organic solvent. The organic solvent that can be used can be at least one selected from the group consisting of: alcohols such as ethanol and methanol; saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as isopropyl acetate; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; ketones such as methyl isobutyl ketone; nitriles such as acetonitrile; and amides such as dimethylacetamide, dimethylformamide, and cyclic amides such as N-methyl-2-pyrrolidone. One or more solvents can be selected from the group consisting of the above-mentioned organic solvents. Specifically, acetonitrile can be used, but it is not limited to this; conventional solvents can also be used.

[0061] In the above reactions, the reaction temperature is 20 to 100°C, specifically 30 to 100°C, 40 to 100°C, 50 to 100°C, 60 to 100°C, 60 to 90°C, and more specifically 65 to 90°C, 70 to 90°C, 75 to 90°C, or 75 to 85°C. The time required for the reaction to complete may vary depending on the reaction temperature and the amount of base used, but is at least 1 hour, specifically at least 2 hours, at least 3 hours, at least 4 hours, or at least 5 hours, but is not limited to these.

[0062] In one embodiment of the invention, the preparation method may further include the step of crystallizing a compound of chemical formula II, a compound of chemical formula III, or both.

[0063] The solvent that can be used for the above crystallization can be water or an organic solvent. Suitable organic solvents can be at least one selected from the group consisting of: alcohols such as ethanol and methanol; saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as isopropyl acetate; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; ketones such as methyl isobutyl ketone; nitriles such as acetonitrile; and amides such as dimethylacetamide, dimethylformamide, and cyclic amides such as N-methyl-2-pyrrolidone. At least one solvent selected from the group consisting of the above can be used. Specifically, methanol or ethanol can be used; however, the choice is not limited to these solvents, as long as they allow the crystallization of compounds of formula II and compounds of formula III.

[0064] Crystallization can be achieved using conventional separation and purification methods, such as solvent reflux followed by solvent cooling to obtain the target compound. During this process, the crystallization solvent can be cooled to temperatures of -30 to -5°C, specifically -25 to -5°C, -20 to -10°C, or -15 to -10°C; however, the choice is not limited to these temperature ranges.

[0065] In one embodiment of the invention, the compound of formula II can be obtained by coupling the compound of formula IV with the compound of formula V using a base:

[0066] <Chemical Formula IV>

[0067]

[0068] <Chemical Formula V>

[0069]

[0070] In the above reactions, the base can be an organic base or an inorganic base. Specifically, the base can be an organic base selected from the group consisting of amidine, methylamine, alkylamine, and heterocyclic amine; or an inorganic base selected from the group consisting of metal salts of lithium, sodium, and potassium, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and metal alkoxides. More specifically, the base can be DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), triethylamine, pyridine, Na2CO3, NaHCO3, NaOH, or sodium methoxide. Even more specifically, the base can be DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), but the choice is not limited to this.

[0071] In this case, the amount of base used relative to 1 part by weight of the compound of formula IV can be 0.1 to 2 wt%. Specifically, the amount of base used can be 0.2 to 1.9 wt%, 0.3 to 1.8 wt%, 0.4 to 1.7 wt%, 0.5 to 1.6 wt%, 0.6 to 1.5 wt%, 0.7 to 1.4 wt%, 0.8 to 1.4 wt%, 0.9 to 1.4 wt%, 1 to 1.4 wt%, 1.1 to 1.4 wt%, 1.2 to 1.4 wt%, or 1.3 to 1.4 wt%, but is not limited thereto.

[0072] Furthermore, in the above reaction, the solvent can be water or an organic solvent. Suitable organic solvents can be at least one selected from the group consisting of: alcohols such as ethanol and methanol; saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as ethyl acetate and isopropyl acetate; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; ketones such as methyl isobutyl ketone; nitriles such as acetonitrile; and amides such as dimethylacetamide, dimethylformamide, and cyclic amides such as N-methyl-2-pyrrolidone. At least one solvent selected from the above group can be used. Specifically, ethyl acetate can be used; however, the choice is not limited to this, and conventional solvents can also be used.

[0073] In the above reaction, the reaction temperature can be from 0 to 50°C, specifically 20 to 50°C, 25 to 45°C, 26 to 44°C, 27 to 43°C, 28 to 42°C, 29 to 41°C, or 30 to 40°C. The time required for the reaction to complete can vary depending on the reaction temperature and the amount of alkali used, but approximately 1 to 5 hours is sufficient.

[0074] In one embodiment of the invention, a compound of formula III can be obtained by deprotecting a compound of formula VI:

[0075] <Chemical Formula VI>

[0076]

[0077] In the above reactions, deprotection may vary depending on the type of protecting group, but conventional deprotection methods can be used. Specifically, deprotection can be carried out under acidic conditions, and more specifically, hydrochloric acid can be used for deprotection; however, the choice is not limited to these.

[0078] In the above reaction, the amount of acid used relative to 1 part by weight of the compound of chemical formula VI can be 0.1 to 1 wt%, specifically 0.2 to 0.9 wt%, 0.3 to 0.8 wt%, 0.4 to 0.7 wt%, or 0.5 to 0.6 wt%; however, the choice is not limited to this.

[0079] In the above reaction, the reaction temperature can be from 0 to 100°C, specifically 30 to 100°C, 40 to 100°C, 50 to 100°C, 60 to 100°C, 60 to 90°C, 60 to 80°C, and more specifically 61 to 79°C, 62 to 78°C, 63 to 77°C, 64 to 76°C, 64 to 75°C, 64 to 74°C, 64 to 73°C, 64 to 72°C, 64 to 71°C, or 65 to 70°C. The time required for the reaction to complete can vary depending on the reaction temperature and the amount of acid used, but approximately 1 to 4 hours is sufficient.

[0080] In one embodiment of the present invention, a compound of chemical formula VI can be obtained by reducing a compound of chemical formula VII with a reducing agent:

[0081] <Chemical Formula VII>

[0082]

[0083] In the above reaction, the reducing agent can be at least one selected from the group consisting of sodium borohydride (NaBH4), lithium borohydride, potassium borohydride, tetraalkylammonium borohydride, zinc borohydride, and cobalt chloride (CoCl2). Specifically, cobalt chloride hexahydrate and sodium borohydride can be used; however, the choice is not limited to these, and conventional reducing agents can also be used.

[0084] In the above reaction, the reaction temperature can be from 0 to 50°C, specifically 10 to 30°C, 11 to 30°C, 12 to 30°C, 13 to 30°C, 14 to 30°C, 15 to 30°C, 16 to 30°C, 17 to 30°C, 18 to 30°C, 19 to 30°C, 20 to 30°C, 20 to 29°C, 20 to 28°C, 20 to 27°C, 20 to 26°C, or 20 to 25°C. The time required for the reaction to complete can vary depending on the reaction temperature and the amount of reducing agent used, but approximately 1 to 4 hours is sufficient.

[0085] In one embodiment of the invention, a compound of formula VII can be obtained by coupling a compound of formula VIII with a compound of formula IX:

[0086] <Chemical Formula VIII>

[0087]

[0088] <Chemical Formula IX>

[0089]

[0090] In the above reaction, the solvent can be water or an organic solvent. Suitable organic solvents can be at least one selected from the group consisting of: alcohols such as ethanol and methanol; saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as isopropyl acetate; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; ketones such as methyl isobutyl ketone; nitriles such as acetonitrile; and amides such as dimethylacetamide, dimethylformamide, and cyclic amides such as N-methyl-2-pyrrolidone. At least one solvent selected from the above group can be used. Specifically, toluene can be used; however, the choice is not limited to this, and conventional solvents can also be used.

[0091] In the above reactions, the reaction temperatures range from 40 to 200°C, specifically 50 to 190°C, 60 to 180°C, 70 to 170°C, 80 to 160°C, 90 to 150°C, 90 to 140°C, 90 to 130°C, and 90 to 120°C, more specifically 91 to 120°C, 92 to 120°C, 93 to 120°C, 94 to 120°C, 95 to 120°C, 96 to 120°C, 97 to 120°C, 98 to 120°C, 99 to 120°C, 100 to 120°C, 100 to 119°C, 100 to 118°C, 100 to 117°C, 100 to 116°C, or 100 to 115°C. The time required for the reaction to complete may vary depending on the reaction temperature and the amount of base used, but approximately 1 to 5 hours is sufficient.

[0092] In one embodiment of the invention, a compound of chemical formula VIII can be obtained by coupling a compound of chemical formula X with a compound of chemical formula XI:

[0093] <Chemical Formula X>

[0094]

[0095] <Chemical Formula XI>

[0096]

[0097] In the above reaction, the solvent can be water or an organic solvent. Suitable organic solvents can be at least one selected from the group consisting of: alcohols such as ethanol and methanol; saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as isopropyl acetate; chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; ketones such as methyl isobutyl ketone; nitriles such as acetonitrile; and amides such as dimethylacetamide, dimethylformamide, and cyclic amides such as N-methyl-2-pyrrolidone. At least one solvent selected from the above group can be used. Specifically, dimethylformamide can be used; however, the choice is not limited to this, and conventional solvents can also be used.

[0098] In the above reactions, the reaction temperature ranges from 0 to 50°C, specifically 10 to 40°C, 11 to 39°C, 12 to 38°C, 13 to 37°C, 14 to 36°C, 15 to 35°C, 16 to 34°C, 17 to 33°C, 18 to 32°C, 19 to 31°C, or 20 to 30°C. The time required for the reaction to complete may vary depending on the reaction temperature and the amount of base used, but approximately 1 to 4 hours is sufficient.

[0099] In one embodiment of the invention, a compound of chemical formula X can be obtained by protecting a compound of chemical formula XII with a protecting group:

[0100] <Chemical Formula XII>

[0101]

[0102] As used in this article, the term "protecting group" refers to a portion or functional group introduced into a molecule through chemical modification to achieve chemoselectivity in subsequent chemical reactions. Standard protecting groups are provided in the literature [Greene and Wuts: "Greene's Protective Groups in Organic Synthesis" 4th Ed, Wuts, PGM and Greene, TW, Wiley-Interscience, New York: 2006].

[0103] In the above reactions, the protecting group can be selected from groups that deprotect under acidic conditions, such as Boc (tert-butyloxycarbonyl), Trt (triphenylmethyl), Ddz (3,5-dimethoxyphenylisopropylcarbonyl), Bpoc (2-(4-biphenyl)isopropyloxycarbonyl), and Nps (2-nitrophenylsulfinyl) groups; and groups that deprotect under basic conditions, such as Fmoc (9-fluorenylmethoxycarbonyl), Nsc (2-(4-nitrophenylsulfonyl)ethoxycarbonyl), and Bsmoc (1,1-dioxo-benzo[b]thiophene-2-yl)methoxycarbonyl) groups. Specifically, the Boc protecting group can be used, and more specifically, Boc2O can be used. However, the invention is not limited to these examples, and any general protecting group applicable to compounds of formula XII can be used without limitation.

[0104] According to the preparation method of the present invention, the purity of lobeglitazone can be above 99%, specifically above 99.1%, above 99.2%, above 99.3%, above 99.4%, above 99.5%, above 99.6%, above 99.7%, above 99.8%, or above 99.9%.

[0105] Furthermore, one embodiment of the present invention provides lobeglitazone produced by the above-described preparation method.

[0106] Furthermore, one embodiment of the present invention provides a method for preparing lobeglitazone sulfate, comprising:

[0107] 1) the step of adding the compound of chemical formula I to a solvent and cooling it; 2) the step of adding sulfuric acid to the cooled compound to dissolve it; and 3) the step of adding the dissolved compound to a cooled acetate to crystallize it.

[0108] In one embodiment of the present invention, the solvent in step 1) can be water or an organic solvent. The organic solvent may include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), amides (e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), and alcohols (e.g., methanol, ethanol, 2-propanol, etc.). These solvents may be used alone or in combination in appropriate proportions (e.g., 1:1 to 1:100) of two or more. Specifically, alcohols may be used, and more specifically, methanol may be used, but the choice is not limited thereto.

[0109] In one embodiment of the present invention, the cooling temperature in step 1) can be -20 to 0°C, specifically -19 to 0°C, -18 to 0°C, -17 to 0°C, -16 to 0°C, -15 to 0°C, -14 to 0°C, -13 to 0°C, -12 to 0°C, -11 to 0°C, -10 to 0°C, -9 to 0°C, -8 to 0°C, -7 to 0°C, -6 to 0°C, or -5 to 0°C, but the choice is not limited to these.

[0110] In one embodiment of the invention, the amount of sulfuric acid added in step 2) may be 1 to 50% by weight relative to 100% by weight of the compound of formula I, specifically 1 to 45% by weight, 1 to 40% by weight, 1 to 35% by weight, 1 to 30% by weight, 5 to 30% by weight, 10 to 30% by weight, 10 to 25% by weight, 15 to 25% by weight, more specifically 16 to 24% by weight, 17 to 23% by weight, 18 to 22% by weight, 19 to 21% by weight or 20% by weight, but the choice is not limited thereto.

[0111] In one embodiment of the present invention, the acetate in step 3) may be methyl acetate, ethyl acetate (EA), propyl acetate, isopropyl acetate, isobutyl acetate, sec-butyl acetate, amyl acetate, pentyl acetate, isoamyl acetate, octyl acetate, benzyl acetate, phenyl acetate, ethoxyethyl acetate, or methoxybutyl acetate (MBA), or propylene glycol monomethyl ether acetate (PGMEA), and specifically may be ethyl acetate or isopropyl acetate; however, it is not limited thereto.

[0112] Acetates can be used under cooling conditions in the range of -30 to -5°C, specifically in the range of -25 to -5°C, -20 to -10°C, or -15 to -10°C; however, they are not limited thereto.

[0113] According to the above preparation method, uniform crystallization of lobeglitazone sulfate can be achieved while minimizing the generation of impurities.

[0114] Furthermore, the preparation method of lobeglitazone sulfate disclosed in Organic Process Research & Development 2007, 11, 190-199 uses isopropyl ether as a solvent, which is not mentioned in the ICH guidelines. In contrast, the preparation method of this invention satisfies the ICH guidelines by using ethyl acetate instead of isopropyl ether.

[0115] The embodiments of the present invention provide lobeglitazone sulfate prepared by the above preparation method.

[0116] The present invention will be described in more detail below through embodiments and experimental examples. However, the following embodiments and experimental examples are only for the purpose of helping to understand the present invention and are not intended to limit the scope of the present invention.

[0117] <Example 1> Preparation of (2-hydroxyethyl)(methyl)carbamate tert-butyl ester (chemical formula X)

[0118]

[0119] At room temperature, 1.0 kg of 2-(methylamino)ethanol (compound of formula XII) was added to 10.0 L of dichloromethane and stirred. The solution was then cooled to 10–15 °C, and 2.8 kg of di-tert-butyl dicarbonate was added while maintaining this temperature. The mixture was stirred at room temperature for 2 hours, followed by the addition of 5.0 L of distilled water. Hydrochloric acid was added to adjust the pH to 2.0–3.0. The aqueous layer was discarded, and the organic layer was washed with 6.0 kg of 20% brine. Sodium sulfate (1.0 kg) was then added to the organic layer, stirred, and filtered. The filtrate was concentrated under reduced pressure to prepare tert-butyl (2-hydroxyethyl)(methyl)carbamate (formula X).

[0120] -Amount obtained: 2.3kg

[0121] - Yield: 97.7%

[0122] - 1 H NMR(CDCl3,ppm)δ1.47(9H,s)2.92(3H,s)3.40(2H,t)3.75(2H,q)

[0123] <Example 2> Preparation of (2-(4-formylphenoxy)ethyl)(methyl)carbamate tert-butyl ester (Chemical Formula VIII)

[0124]

[0125] At room temperature, 2.3 kg of (2-hydroxyethyl)(methyl)carbamate tert-butyl ester (compound of formula X) was added to 11.5 L of dimethylformamide and stirred. The mixture was then cooled to below -10°C, and 2.2 kg of potassium hydroxide was added, followed by 1.5 kg of p-fluorobenzaldehyde (compound of formula XI). After the addition was complete, the mixture was stirred at room temperature for more than 3 hours. The mixture was then cooled to 10–15°C, and 11.5 L of distilled water was added, followed by 23.0 L of ethyl acetate, and stirred for 10 minutes. The aqueous layer was discarded, and the organic layer was washed twice with 13.8 kg of 20% brine. Sodium sulfate (2.3 kg) was added to the organic layer, and after stirring for 1 hour, the mixture was filtered. The organic layer was washed with 1.2 L of ethyl acetate, concentrated under reduced pressure, to prepare (2-(4-formylphenoxy)ethyl)(methyl)carbamate tert-butyl ester (formula VIII).

[0126] -Amount obtained: 3.0kg

[0127] - Yield: 81.4%

[0128] - 1 H NMR(CDCl3,ppm)δ1.47(9H,s)2.99(3H,s)3.64(2H,s)4.20(2H,bs)7.01(2H,d)7.84(2H,d)9.89(1H,s)

[0129] <Example 3> Preparation of (Z)-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)(methyl)carbamate tert-butyl ester (Chemical Formula VII)

[0130]

[0131] At room temperature, 3.0 kg of (2-(4-formylphenoxy)ethyl)(methyl)carbamate tert-butyl ester (compound of formula VIII) and 9.0 L of toluene were added and stirred. Then, 1.3 kg of 1,3-thiazolidin-2,4-dione (compound of formula IX), 0.2 L of AcOH, and 0.3 L of piperidine were added and the mixture was stirred. A separator (Dean-Stark apparatus) was installed, and the mixture was refluxed and stirred for more than 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. 9.0 L of isopropanol was added, the mixture was refluxed and stirred for 1 hour, and then cooled to 0-5 °C to crystallize. The mixture was filtered, washed with 1.5 L of isopropanol, and dried under reduced pressure at 40-50 °C for more than 12 hours to give (Z)-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)(methyl)carbamate tert-butyl ester (formula VII).

[0132] -Amount obtained: 2.5kg

[0133] - Yield: 60.6%

[0134] - 1 H NMR(DMSO-d6,ppm)δ1.46(9H,s)2.98(3H,s)3.67(2H,bs)

[0135] 4.26(2H,bs)7.14(2H,d)7.59(2H,d)7.73(1H,s)

[0136] <Example 4> Preparation of 5-(4-(2-(methylamino)ethoxy)benzyl)thiazolidin-2,4-dione hydrochloride (Formula III)

[0137]

[0138] 2.5 kg of (Z)-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)(methyl)carbamate tert-butyl ester (compound of formula VII), 40.0 g of cobalt(II) hexahydrate, 0.2 kg of dimethylglyoxime, and 0.3 kg of sodium hydroxide were added to 50.0 L of distilled water and stirred at 15–20 °C. While maintaining the temperature at 15–20 °C, 0.5 kg of sodium borohydride was added. The mixture was stirred at 20–25 °C for more than 4 hours. Extraction was performed with ethyl acetate (25.0 L) and acetic acid (1.5 L). The aqueous layer was discarded, and the upper organic layer was treated with 2.5 kg of sodium sulfate and 70.0 g of activated carbon, then stirred, filtered, and washed with 12.5 L of acetone. Hydrochloric acid (1.2 L) was added to the filtrate, and the mixture was refluxed at 65–70 °C for more than 2 hours. Cool the mixture to 20-30°C and stir for 1-2 hours to allow crystals to precipitate. Then cool to -5 to 0°C and stir for 1-2 hours. Filter the mixture, wash with 5.0 L of acetone, and dry under reduced pressure at 40-50°C to give 5-(4-(2-(methylamino)ethoxy)benzyl)thiazolidin-2,4-dione hydrochloride (Formula III).

[0139] Harvest yield: 1.8kg

[0140] - Yield: 89.2%

[0141] - 1 H NMR(DMSO-d6,ppm)δ2.60(3H,s)3.09(1H,dd)3.28-3.33(4H,m)4.22(2H,t)4.88(1H,dd)6.94(2H,m)7.19(2H,m)

[0142] <Example 5> Preparation of 4-chloro-6-(4-methoxyphenoxy)pyrimidine (Chemical Formula II)

[0143]

[0144] 1.0 kg of 4,6-dichloropyrimidine (compound of formula IV) and 0.8 kg of 4-methoxyphenol (compound of formula V) were added to 8.0 L of ethyl acetate and stirred at 30–40 °C. Then, 1.3 L of 1,8-diazabicyclo[5.4.0]undec-7-ene (diluted in 2.0 L of ethyl acetate) was added to the mixture, and the mixture was stirred at 30–40 °C for more than 3 hours. After confirming the reaction was complete, 5.0 kg of distilled water was added, and the pH was adjusted to 2.0–4.0 with 0.2 kg of hydrochloric acid while stirring. The aqueous layer was discarded, and 1.0 kg of sodium sulfate was added to the organic layer and stirred. The mixture was filtered, washed with 2.0 L of ethyl acetate, and concentrated under reduced pressure. 4.0 L of ethanol was added to the concentrated residue, and the mixture was refluxed and stirred until dissolved. After confirming dissolution, the mixture was cooled to 35–45 °C and stirred for more than 4 hours to allow crystals to precipitate. The mixture was then cooled to -10 to -5°C and stirred continuously. The mixture was filtered and washed with 2.0 L of ethanol. The product was dried under reduced pressure at 25–35°C for more than 12 hours to give 4-chloro-6-(4-methoxyphenoxy)pyrimidine (formula II).

[0145] -Amount obtained: 1.3kg

[0146] - Yield: 86.7%

[0147] - 1 H NMR(DMSO-d6,ppm)δ3.78(3H,s)7.00-7.03(2H,m)7.15-7.19(2H,m)7.31(1H,d)8.64(1H,d)

[0148] <Example 6> Preparation of 5-[(4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl]methyl]-1,3-thiazolidin-2,4-dione (Chemical Formula I)

[0149]

[0150] 1.3 kg of 4-chloro-6-(4-methoxyphenoxy)pyrimidine (a compound of formula II) and 1.7 kg of 5-(4-(2-(methylamino)ethoxy)benzyl)thiazolidin-2,4-dione hydrochloride (a compound of formula III) were added to 6.5 L of acetonitrile and stirred under reflux. Then, 2.0 L of 1,8-diazabicyclo[5.4.0]undec-7-ene was diluted in 13.0 L of acetonitrile and added to the reaction mixture, which was stirred under reflux for more than 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. 6.5 kg of distilled water and 13.0 L of ethyl acetate were added to the concentrated residue, and the pH was adjusted to 2.0–6.0 with 0.5 kg of hydrochloric acid while stirring. The aqueous layer was discarded, and 0.7 kg of sodium sulfate and 40.0 g of activated carbon were added to the organic layer and stirred. The mixture was filtered, washed with 2.6 L of ethyl acetate, and concentrated under reduced pressure. Add 5.2 L of tetrahydrofuran and reflux the mixture with stirring until dissolved. Add 5.2 L of ethanol, cool the mixture to 20-30 °C, and stir. After crystallization, further cool to -15 to -10 °C and continue stirring. Filter the mixture and wash it with 2.6 L of ethanol. Dissolve the wet cake by adding 5.2 L of tetrahydrofuran and refluxing. Add 5.2 L of ethanol, cool the mixture to 20-30 °C, and stir. After crystallization, further cool to -15 to -10 °C and continue stirring. Filter the mixture and wash it with 2.6 L of ethanol. Dry the product under reduced pressure at 40-50 °C for more than 12 hours to give 5-[(4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl]methyl]-1,3-thiazolidin-2,4-dione (Formula I).

[0151] -Amount obtained: 2.0kg

[0152] - Yield: 80.0%

[0153] Purity: 99.9%

[0154] - 1 H NMR(DMSO-d6,ppm)δ3.02-3.08(4H,m)3.27-3.32(1H,dd)

[0155] 3.75(3H,s)3.91(2H,bs)4.10-4.13(2H,t)4.84-4.88(1H,q)6.06(1H,s)

[0156] 6.86-6.88(2H,m)6.92-6.97(2H,m)7.03-7.08(2H,m)7.13-7.16(2H,m)

[0157] 8.17(1H,d) 11.99(1H,s)

[0158] <Example 7> Preparation of 5-[(4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl]methyl]-1,3-thiazolidin-2,4-dione sulfate (sulfate of formula I)

[0159]

[0160] While stirring, 2.0 kg of 5-[(4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl]methyl]-1,3-thiazolidin-2,4-dione (a compound of formula I) was added to 6.0 L of methanol, and the mixture was cooled to -5 to 0 °C. While maintaining this temperature, 0.4 kg of sulfuric acid was added, and stirring continued. After confirming dissolution, the solution was filtered through a membrane filter, and the filtrate was slowly added to 200 L of ethyl acetate. The mixture was then cooled to -15 to -10 °C to allow crystallization. After addition, heat the mixture to 20-30°C and stir for 1-2 hours. Filter the mixture while adding nitrogen into a filter and wash with 20 L of ethyl acetate. Dry the product under reduced pressure at 20-30°C for more than 3 hours, and further dry under reduced pressure at 75-80°C for more than 15 hours to give 5-[4-[2-([6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl]methyl]-1,3-thiazolidin-2,4-dione sulfate.

[0161] Harvest yield: 1.8kg

[0162] - Yield: 75.0%

[0163] Purity: 99.9%

[0164] 1 H NMR(DMSO-d6,ppm)δ3.02-3.08(4H,m)3.27-3.32(1H,dd)3.75(3H,s)3.91(2H,bs)4.10-4.13(2H,t)4.84-4.88(1 H,q)6.06(1H,s)6.86-6.88(2H,m)6.92-6.97(2H,m)7.03-7.08(2H,m)7.13-7.16(2H,m)8.17(1H,d)11.99(1H,s)

[0165] <Comparative Example 1> Lobexiglitazone was synthesized via a stepwise reaction and column chromatography.

[0166] To compare with lobeglitazone prepared by the method of this invention, lobeglitazone was synthesized using a stepwise reaction and column chromatography. Specifically, the operations were performed in the following order.

[0167] 4-(4-methoxy)phenoxy-6-chloropyrimidine

[0168] 4-Methoxyphenol (2.3 g) was dissolved in dimethylformamide (20 mL), and sodium hydride (60%, 805 mg) was slowly added at 0 °C, followed by stirring at the same temperature for 30 minutes. Then, 4,6-dichloropyrimidine (2.5 g) was added to the reaction mixture, and the mixture was stirred at 25 °C for 1 hour. Subsequently, a saturated aqueous solution of ammonium chloride (20 mL) was added. The mixture was diluted with ethyl acetate (50 mL), washed with brine (30 mL × 3), the organic layer was separated, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography with ethyl acetate / n-hexane = 1 / 10 to give the title compound (2.1 g).

[0169] 1 H NMR δ(CDCl3)

[0170] 3.85(3H,s),6.90(1H,m),6.98(2H,m),7.07(2H,m),8.60(1H,s)

[0171] 2-[N-methyl-N-(6-(4-(4-methoxy)phenoxy)pyrimidinyl)amino]ethanol

[0172] 4-(4-methoxy)phenoxy-6-chloropyrimidine (3.2 g) was dissolved in ethanol (30 mL), and 2-methylaminoethanol (30 mL) was added. The mixture was refluxed and stirred for 24 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate (50 mL), washed with brine (30 mL × 3), the organic layer was separated, and dried over magnesium sulfate. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate / n-hexane = 1 / 1 to give the title compound (3.02 g).

[0173] 1 H NMR δ(CDCl3)

[0174] 3.05(3H,s),3.79(2H,m),3.83(3H,m),3.87(2H,m),5.84(1H,s),6.29(2H,m),7.06(2H,m),8.27(1H,s)

[0175] 4-[2-(N-methyl-N-(6-(4-(4-methoxy)phenoxy)pyrimidinyl)amino)ethoxy]benzaldehyde

[0176] Dissolve 530 mg of 2-[N-methyl-N-(6-(4-(4-methoxy)phenoxy)pyrimidin-2-yl)amino]ethanol (40 mL) in dimethylformamide, and slowly add sodium hydride (60%, 333 mg) at 0 °C. Stir the mixture at the same temperature for 30 minutes. Then, add 430 mg of p-fluorobenzaldehyde dropwise to the reaction mixture. Stir the reaction mixture at 25 °C for 5 hours. After completion, add 20 mL of saturated ammonium chloride aqueous solution. Then extract the reaction mixture with ethyl acetate (50 mL × 2). Dry the separated organic layer with magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. Perform silica gel column chromatography on the residue with ethyl acetate / n-hexane = 1 / 3 to give the title compound (490 mg).

[0177] 1 H NMR δ(CDCl3)

[0178] 3.14(3H,s),3.83(3H,s),4.06(2H,m),4.29(2H,m),5.86(1H,s),7.02(6H,m),7.84(2H,m),8.32(1H,s),9.91(1H,s)

[0179] 5-(4-[2-(N-methyl-N-(6-(4-(4-methoxy)phenoxy)pyrimidinyl)amino)ethoxy]benzylidene)-2,4-thiazolidinedione

[0180] To a solution of 290 mg of 4-[2-(N-methyl-N-(6-(4-(4-(4-methoxy)phenoxy)pyrimidinyl)amino)ethoxy]benzaldehyde in 30 mL of ethanol, piperidine (0.3 g) and 0.4 g of 2,4-thiazolidinedione (0.4 g) were added. The mixture was refluxed and stirred for 24 hours. After the reaction was complete, the reaction mixture was cooled to 25 °C and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography with a dichloromethane / methanol ratio of 50 / 1 to give the title compound (230 mg).

[0181] 1 H NMR δ(CDCl3)

[0182] 3.13(3H,s),3.83(3H,m),4.04(2H,m),4.26(2H,m),5.86(1H,s),7.01(6H,m),7.46(2H,m),7.81(1H,s),8.32(1H,s),8.68(1H,width s)

[0183] Melting point: 180℃

[0184] 5-(4-[2-(N-methyl-N-(6-(4-(4-methoxy)phenoxy)pyrimidinyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione

[0185] 5-(4-[2-(N-methyl-N-(6-(4-(4-(4-methoxy)phenoxy)pyrimidinyl)amino)ethoxy]-benzylidene)-2,4-thiazolidinedione (1.3 g) was dissolved in dimethylformamide (100 mL) and stirred for 24 h under a hydrogen atmosphere (1 atm) in the presence of 20% palladium hydroxide / carbon (1.5 g). The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using dichloromethane / methanol = 50 / 1 to give the title compound (1.1 g).

[0186] 1 H NMR δ(CDCl3)

[0187] 3.16(3H,s),3.46(1H,m),3.83(3H,s),4.01(2H,m),4.19(2H,m),4.51(1H,m),5.85(1H,s),7.02(8H,m),8.31(1H,s),8.33(1H,width s)

[0188] Melting point: 148℃

[0189] <Comparative Example 2> Synthesis of Lobeglitazone Sulfate via Stepwise Reaction and Column Chromatography

[0190] Lobeglitazone sulfate was synthesized according to the following reaction formula 5.

[0191] <Reaction Formula 5>

[0192]

[0193] Specifically: 4,6-dichloropyrimidine (3) was reacted with p-methoxyphenol and KF in DMF at 80°C, and then reacted with 2-methylaminoethanol to obtain pyrimidine amino alcohol (6) with a purity of 98% and a yield of 90%; in the presence of KOH in DMF, the amino alcohol (6) was O-arylated with p-fluorobenzaldehyde to obtain aldehyde (7) without purification, with a yield of 80%; the aldehyde (7) was reacted with 2,4-thiazolidinedione (TZD) in the presence of piperidine-HOAc and toluene, and recrystallized in ethanol to obtain benzylidene-2,4-thiazolidinedione (10) with a purity of 95% and a yield of 90%. Using SiO2 as an acidic catalyst, in the presence of toluene, the olefinic portion of benzylidene-2,4-thiazolidinedione (10) was reduced to Hantzsch ester, and recrystallized to obtain benzylidene-2,4-thiazolidinedione (lobeglitazone (1)) with a purity of 98% and a yield of 90%. Subsequently, by reacting with sulfuric acid in methanol at 0 °C and crystallizing with isopropyl ether, lobeglitazone sulfate (2) with a purity of 98.5% and a yield of 90% was obtained.

[0194] <Experimental Example 1> Confirmation of the purity of lobeglitazone

[0195] The purity was confirmed using lobeglitazone and lobeglitazone sulfate prepared in Examples 6, 7 and Comparative Example 2.

[0196] [Table 1]

[0197]

[0198] In summary, the preparation method according to the present invention simplifies the synthetic steps by generating two intermediates, followed by crystallization of these intermediates, making it suitable for large-scale production. It has been confirmed that high-purity lobeglitazone can be synthesized without column chromatography.

Claims

1. A method of preparing rosiglitazone, comprising coupling a compound of Chemical Formula II with a compound of Chemical Formula III using a base to obtain a compound of Chemical Formula I: Chemical Formula I Chemical Formula II Chemical Formula III the base being at least one selected from the group consisting of amidine bases, methylamines, alkylamines, heterocyclic amines, metal salts consisting of lithium, sodium or potassium, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and metal alkoxides. The amount of the base is 0.1 to 2% by weight with respect to 1 part by weight of the compound of Chemical Formula II. 4.The method of preparing rosiglitazone according to claim 1, further comprising a crystallization step of the compound of Chemical Formula II, the compound of Chemical Formula III, or both. The crystallization is performed by solvent reflux using water or an organic solvent.

2. The process for the preparation of lobeglitazone according to claim 1, wherein, The organic solvent is at least one selected from the group consisting of ethanol, methanol, hexane, heptane, benzene, toluene, xylene, isopropyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, methyl isobutyl ketone, acetonitrile, dimethylacetamide, dimethylformamide, and N-methyl-2-pyrrolidone.

3. The process for the preparation of lobeglitazone according to claim 1, wherein, The crystallization step further comprises cooling the solvent to a temperature range of -30°C to -5°C. The compound of Chemical Formula II is obtained by coupling a compound of Chemical Formula IV with a compound of Chemical Formula V using a base:

5. The process for the preparation of Lobeglitazone as claimed in claim 4 wherein, Chemical Formula IV Chemical Formula V 6. The process for the preparation of lobeglitazone according to claim 5, wherein, The base is at least one selected from the group consisting of amidine bases, methylamines, alkylamines, heterocyclic amines, metal salts consisting of lithium, sodium or potassium, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and metal alkoxides.

7. The process for the preparation of Lobeglitazone as claimed in claim 5 wherein, The amount of the base is 0.1 to 2% by weight with respect to 1 part by weight of the compound of Chemical Formula IV.

8. The process for the preparation of Lobeglitazone as claimed in claim 1 wherein, The compound of Chemical Formula III is obtained by deprotecting a compound of Chemical Formula VI: Chemical Formula VI The deprotection is performed under acidic conditions using an acid in an amount of 0.1 to 1% by weight with respect to the weight of the compound of Chemical Formula VI.

9. The process for the preparation of lobeglitazone according to claim 8, wherein, The compound of Chemical Formula VI is obtained by reducing a compound of Chemical Formula VII using a reducing agent:

10. The process for the preparation of lobeglitazone according to claim 8, wherein, Chemical Formula VII 11. The process for the preparation of Lobeglitazone as claimed in claim 1 wherein, The reducing agent is at least one selected from the group consisting of sodium borohydride (NaBH4), lithium borohydride, potassium borohydride, tetraalkylammonium borohydride, zinc borohydride, and cobalt chloride (CoCl2). The compound of Chemical Formula VII is obtained by coupling a compound of Chemical Formula VIII with a compound of Chemical Formula IX:

12. The process for the preparation of Lobeglitazone as claimed in claim 11 wherein, Chemical Formula VIII Chemical Formula IX 13. The method of preparing rosiglitazone according to claim 11, wherein, The compound of Chemical Formula VIII is obtained by coupling a compound of Chemical Formula X with a compound of Chemical Formula XI: Chemical Formula X Chemical Formula XI 14. The process for the preparation of lobeglitazone according to claim 13, wherein, The compound of Chemical Formula X is obtained by protecting a compound of Chemical Formula XII using a protecting group:

15. The process for the preparation of Lobeglitazone as claimed in claim 13 wherein, Chemical Formula XII ​ ​ 16. The process for the preparation of lobeglitazone according to claim 15, wherein, ​ ​ ​ 17. The process for the preparation of lobeglitazone according to claim 16, wherein, ​ ​ 18. The process for the preparation of Lobeglitazone as claimed in claim 17 wherein, the protecting group is at least one selected from the group consisting of a group which is deprotected under acidic conditions, including Boc (tert-butyloxycarbonyl), Trt (trityl), Ddz (3,5-dimethoxyphenylisopropylcarbonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl), and Nps (2-nitrophenylsulphenyl); and a group which is deprotected under basic conditions, including Fmoc (9-fluorenylmethoxycarbonyl), Nsc (2-(4-nitrophenylsulfonyl)ethoxycarbonyl), and Bsmoc (1,1-dioxo-benzo[b]thiophene-2-yl)methoxycarbonyl).

19. The process for preparing lobeglitazone of claim 1, wherein, The purity of the rosiglitazone is 99% or more.

20. Rosiglitazone prepared by the method of any one of claims 1 to 19.

21. A method of preparing rosiglitazone sulfate salt, comprising: 1) a step of adding a compound of Chemical Formula I to a solvent and cooling; 2) a step of adding sulfuric acid to the cooled compound to dissolve it; and 3) a step of adding the dissolved compound to a cooled acetate to crystallize it, <Chemical Formula I> The solvent in step 1) is water or an organic solvent.

22. The method of preparing rosiglitazone sulfate according to claim 21, wherein, The organic solvent is methanol.

23. The method of preparing rosiglitazone sulfate according to claim 22, wherein, The cooling in step 1) is performed to a temperature range of -20°C to 0°C.

24. The method of preparing rosiglitazone sulfate according to claim 21, wherein, The amount of sulfuric acid added in step 2) is 1 to 50% by weight with respect to 100% by weight of the compound of Chemical Formula I.

25. The method of preparing rosiglitazone sulfate according to claim 21, wherein, The acetate in step 3) is ethyl acetate or isopropyl acetate.

26. The method of preparing rosiglitazone sulfate according to claim 21, wherein, The acetate in step 3) is cooled to a temperature range of -30°C to -5°C.

27. The method of preparing rosiglitazone sulfate according to claim 21, wherein, 28. Rosiglitazone sulfate salt prepared by the method of any one of claims 21 to 27. ​

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