Method for preparing substituted fused imidazole derivative

Abstract

The present invention relates to a method for preparing a novel substituted fused imidazole derivative compound. The preparation method according to the present invention has the advantages of shortening the preparation process to secure process convenience, improving the reaction rate and reactivity, and obtaining an intermediate as a solid, thus enabling the preparation of a high-purity compound with high yields. Thus, it is useful for industrial mass production.

Description

METHOD FOR PREPARING SUBSTITUTED FUSED IMIDAZOLE DERIVATIVE

[0001] The present invention relates to a method for preparing a glucagon-like peptide-1 receptor (GLP-1R) agonist compound having a substituted fused imidazole derivative structure.

[0002] Glucagon-like peptide-1 (GLP-1) is a hormone known to be effective in increasing insulin secretion and lowering blood sugar by acting on a receptor called the glucagon-like peptide-1 receptor (GLP-1R). The hormone is also known to have effects such as decreased motility in the upper digestive system and appetite suppression, and to be able to proliferate existing pancreatic beta cells. These characteristics of GLP-1 shows promise as a potential treatment for type 2 diabetes, but its short half-life of less than two minutes in the bloodstream poses a significant challenge for its development as a pharmaceutical product. Recently, to overcome the short duration of action of GLP-1, therapies have been developed in two ways: GLP-1 analogs and DPP-4 inhibitors that are resistant to Dipeptidyl Peptidase Ⅳ (DPP-Ⅳ), which destroys GLP-1 in the bloodstream.

[0003] Currently, a number of GLP-1 analogs have been developed that are resistant to the DPP-4 enzyme, which destroys GLP-1 in the bloodstream, and are used as treatments for type 2 diabetes. These GLP-1 analogs have a substantially longer half-life than natural GLP-1, enabling them to sustain their blood glucose-lowering effects for extended periods. However, they are not orally available and must be administered via injection, which can lead to poor patient compliance. Therefore, research is underway to discover small molecule GLP-1R agonists capable of being administered orally and developed as a treatment for diabetes.

[0004] For example, Korean Patent Registration No. 10-2344561 discloses a novel GLP-1R agonist compound with superior glucose tolerance improvement in both intravenous and oral administration. Specifically, Korean Patent No. 10-2344561 describes a method for preparing a novel GLP-1R agonist compound comprising: (I) introducing a suitably substituted nicotinonitrile group to a pyridinyl group of the starting material in the presence of a base and an organic solvent; (II) introducing a piperazine group to the pyridinyl group under metal catalysis; (III) removing a protecting group of the piperazine group by reacting a deprotecting reagent; (IV) introducing a substituted benzimidazole group to the piperazine group in the presence of a base and an organic solvent; and (V) hydrolyzing an ester to a carboxylic acid in the presence of a metal salt and a base. However, the preparation method disclosed in the above patent requires separation and purification using column chromatography, which is difficult to apply to industrial mass production, and has very low economic efficiency due to low reactivity and low yield.

[0005] In order to solve the above problems, the present inventors have developed a method suitable for mass production by improving the reaction rate and reactivity of the method above disclosed in Korean Patent No. 10-2344561, shortening the preparation process to secure process convenience, and obtaining an intermediate as a solid, which facilitates superior purification to maximize purity while significantly increasing the production level of the target substance. Therefore, the present invention has been completed by providing a preparation process for a novel GLP-1R agonist compound.

[0006] An object of the present invention is to provide a method for preparing a substituted fused imidazole derivative compound.

[0007] To solve the above-mentioned problems, there is provided the method for preparing the substituted fused imidazole derivative compound comprising:

[0008] 1) treating a compound represented by the following Chemical Formula 6 with an acid to prepare an acid salt represented by the following Chemical Formula 7;

[0009] 2) adding a desalting agent to the compound represented by Chemical Formula 7, followed by reacting with a compound represented by the following Chemical Formula 8, thereby preparing a compound represented by the following Chemical Formula 9; and

[0010] 3) hydrolyzing the compound represented by Chemical Formula 9 to prepare a compound represented by the following Chemical Formula 1:

[0011] [Chemical Formula 1]

[0012]

[0013] [Chemical Formula 6]

[0014]

[0015] [Chemical Formula 7]

[0016]

[0017] [Chemical Formula 8]

[0018]

[0019] [Chemical Formula 9]

[0020]

[0021] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0022] in Chemical Formula 8 above, X3is F, Cl, Br or I; and

[0023] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0024] In one general aspect, there is provided a preparation method as shown in the following Reaction Scheme 1:

[0025] [Reaction Scheme 1]

[0026]

[0027] Specifically, the present invention provides a method for preparing the compound represented by Chemical Formula 1 above, comprising steps 1 to 3 below:

[0028] 1) treating the compound represented by Chemical Formula 6 above with an acid to prepare the acid salt represented by Chemical Formula 7 above;

[0029] 2) adding a desalting agent to the compound represented by Chemical Formula 7 above, followed by reacting with the compound represented by Chemical Formula 8 above, thereby preparing the compound represented by Chemical Formula 9 above; and

[0030] 3) hydrolyzing the compound represented by Chemical Formula 9 above to prepare the compound represented by Chemical Formula 1 above:

[0031] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0032] in Chemical Formula 8 above, X3is F, Cl, Br or I; and

[0033] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0034] In addition, the present invention provides a preparation method shown as Reaction Scheme 2, optionally further comprising the following Step B to prepare the compound represented by Chemical Formula 1 above:

[0035] [Reaction Scheme 2]

[0036]

[0037] B) reacting a compound represented by the following Chemical Formula 4 with a compound represented by the following Chemical Formula 5 to prepare the compound represented by Chemical Formula 6 above;

[0038] 1) treating the compound represented by Chemical Formula 6 above with an acid to prepare the acid salt represented by Chemical Formula 7 above;

[0039] 2) adding a desalting agent to the compound represented by Chemical Formula 7 above, followed by reacting with the compound represented by Chemical Formula 8 above, thereby preparing the compound represented by Chemical Formula 9 above; and

[0040] 3) hydrolyzing the compound represented by Chemical Formula 9 above to prepare the compound represented by Chemical Formula 1 above:

[0041] [Chemical Formula 4]

[0042]

[0043] [Chemical Formula 5]

[0044]

[0045] in Chemical Formula 4 above, X2is F, Cl, Br or I;

[0046] in Chemical Formula 5 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0047] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0048] in Chemical Formula 8 above, X3is F, Cl, Br or I; and

[0049] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0050] In addition, the present invention provides a preparation method shown as Reaction Scheme 3, optionally further comprising the following Steps A and B to prepare the compound represented by Chemical Formula 1 above:

[0051] [Reaction Scheme 3]

[0052]

[0053] A) reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3 to prepare the compound represented by Chemical Formula 4 above;

[0054] B) reacting the compound represented by Chemical Formula 4 above with the compound represented by Chemical Formula 5 above to prepare the compound represented by Chemical Formula 6 above;

[0055] 1) treating the compound represented by Chemical Formula 6 above with an acid to prepare the acid salt represented by Chemical Formula 7 above;

[0056] 2) adding a desalting agent to the compound represented by Chemical Formula 7 above, followed by reacting with the compound represented by Chemical Formula 8 above, thereby preparing the compound represented by Chemical Formula 9 above; and

[0057] 3) hydrolyzing the compound represented by Chemical Formula 9 above to prepare the compound represented by Chemical Formula 1 above:

[0058] [Chemical Formula 2]

[0059]

[0060] [Chemical Formula 3]

[0061]

[0062] in Chemical Formula 3 above, X1and X2are each independently F, Cl, Br or I,

[0063] in Chemical Formula 4 above, X2is F, Cl, Br or I,

[0064] in Chemical Formula 5 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide,

[0065] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide,

[0066] in Chemical Formula 8 above, X3is F, Cl, Br or I, and

[0067] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0068] In addition, the present invention provides a preparation method shown as Reaction Scheme 4, optionally further comprising the following Step 4 to prepare a salt compound of the compound represented by Chemical Formula 1 above:

[0069] [Reaction Scheme 4]

[0070]

[0071] 1) treating the compound represented by Chemical Formula 6 above with an acid to prepare the acid salt represented by Chemical Formula 7 above;

[0072] 2) adding a desalting agent to the compound represented by Chemical Formula 7 above, followed by reacting with the compound represented by Chemical Formula 8 above, thereby preparing the compound represented by Chemical Formula 9 above;

[0073] 3) hydrolyzing the compound represented by Chemical Formula 9 above to prepare the compound represented by Chemical Formula 1 above; and

[0074] 4) adding a salt to the compound represented by Chemical Formula 1 above to prepare a salt compound of the compound represented by Chemical Formula 1.

[0075] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0076] in Chemical Formula 8 above, X3is F, Cl, Br or I, and

[0077] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0078] Hereinafter, an embodiment of the present invention will be described in detail for each of the above steps.

[0079] [Step 1]

[0080] Step 1 above is a step of treating the compound represented by Chemical Formula 6 with an acid to remove the protecting group and prepare an acidic salt represented by Chemical Formula 7.

[0081] The type of acid capable of being used in Step 1 above is not particularly limited and may be either Brønsted acid or Lewis acid.

[0082] Specifically, the Brønsted acid may be any one selected from the group consisting of hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, hydriodic acid, and fluoroboric acid. Specifically, the Lewis acid may be any one selected from the group consisting of aluminum chloride, iron chloride, boron trifluoride ether complexes, boron trichloride (BCl3), chlorotrimethylsilane (TMSCl), tetra-n-butylammonium fluoride (TBAF), zinc bromide (ZnBr2), zinc chloride (ZnCl2), and magnesium bromide (MgBr2).

[0083] Preferably, hydrogen chloride, sulfuric acid, and trifluoroacetic acid may be used. More preferably, hydrogen chloride may be used.

[0084] The reaction in Step 1 may be performed in an organic solvent. The organic solvent may be, for example, ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, acetonitrile, dichloromethane, normal hexane, dimethyl sulfoxide, or a mixture of two or more thereof. Preferably, isopropyl alcohol or acetone may be used.

[0085] The reaction of Step 1 may be performed at 60 to 120℃. It is not desirable that when the reaction temperature is lower than 60℃, there is a problem that the production yield is lowered, and when the reaction temperature is higher than 120℃, side reactions may occur. More specifically, the reaction may be performed at 80 to 100℃.

[0086] The reaction of Step 1 above may be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 8 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 5 hours.

[0087] According to a preferred embodiment of the present invention, the compound represented by Chemical Formula 7 may be precipitated as a solid HCl salt by using hydrogen chloride as the acid and isopropyl alcohol as the reaction solvent in Step 1 above. Thus, Step 1 has the advantage of being able to obtain a high-purity product only through filtration and washing without a work-up process, thereby achieving excellent purification effect and simplifying the process.

[0088] In an embodiment, when hydrogen chloride is used in Step 1, the compound represented by Chemical Formula 7 may be a compound represented by the following Chemical Formula 7-1:

[0089] [Chemical Formula 7-1]

[0090]

[0091] [Step 2]

[0092] Step 2 is a step of adding a desalting agent to the compound represented by Chemical Formula 7, followed by reacting with the compound represented by Chemical Formula 8, thereby preparing the compound represented by Chemical Formula 9, which is a step of introducing a substituted benzimidazole group to the piperazine group of the compound represented by Chemical Formula 7 above.

[0093] More specifically, Step 2 above facilitates the coupling reaction by desalting the compound represented by Chemical Formula 7 before adding the compound represented by Chemical Formula 8. Step 2 above may comprise Step 2-1 of adding the desalting agent and Step 2-2 of adding the compound represented by Chemical Formula 8:

[0094] [Reaction Scheme 5]

[0095]

[0096] In Reaction Scheme 5 above, the preparation method is as follows:

[0097] 2-1) adding a desalting agent to the compound represented by Chemical Formula 7 above to desalt the compound;

[0098] 2-2) adding the compound represented by Chemical Formula 8 to the desalted compound to induce conversion to the compound represented by Chemical Formula 9; wherein the compound represented by Chemical Formula 8 may be added to the reaction solution after Step 2-1 so that Steps 2-1 and 2-2 are performed in-situ.

[0099] In Step 2-1 above, the desalting agent refers to various compounds used in the art to remove acid salts, and may be an alkali metal hydroxide, an alkali metal salt, or a low molecular weight amine.

[0100] Specifically, the alkali metal hydroxide may be any one selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0101] In detail, the alkali metal salt may be any one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium citrate, disodium tartrate, sodium hydrogen tartrate, and sodium oleate.

[0102] Specifically, the low molecular weight amine may be any one selected from the group consisting of triethylamine, N,N-diisopropylethylamine, and diisopropylamine.

[0103] Preferably, potassium carbonate may be used as the desalting agent of Step 2-1.

[0104] The treatment with the desalting agent in Step 2-1 may be performed in at least any one organic solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate, and 2-methyltetrahydrofuran. Preferably, dichloromethane may be used.

[0105] The reaction of Step 2-1 may be performed at 10 to 90℃. Preferably, the reaction may be performed under room temperature conditions.

[0106] Further, the reaction of Step 2-1 may be performed for 10 minutes to 5 hours. Preferably, the reaction may be performed for 10 minutes to 1 hour.

[0107] For example, the reaction of Step 2-1 may be performed by mixing the compound represented by Chemical Formula 7 above with dichloromethane at room temperature, slowly adding an aqueous potassium carbonate solution dropwise, and then stirring for 30 minutes.

[0108] Step 2-2 above is a step of adding the compound represented by Chemical Formula 8 to the desalted compound to prepare the compound represented by Chemical Formula 9 above.

[0109] The reaction of Step 2-2 above may be performed in the presence of a base and an organic solvent. Here, the base may be triethylamine (TEA), N,N-diisopropylethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, cesium carbonate, or a mixture of two or more thereof. Preferably, potassium carbonate may be used.

[0110] In the reaction in Step 2-2, a reaction solvent may be any one or more selected from the group consisting of dichloromethane (DCM), acetonitrile (ACN), tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, ethyl acetate, 2-methyltetrahydrofuran, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Preferably, acetonitrile may be used as the reaction solvent of Step 2-2.

[0111] In Step 2-2 above, a molar ratio between the compound represented by Chemical Formula 7 and the compound represented by Chemical Formula 8 above may be 10 : 1 to 1 : 10, more preferably 5 : 1 to 1 : 5, and more preferably 3 : 1 to 1 : 3.

[0112] The reaction of Step 2-2 may be performed at 60 to 90℃. It is not desirable that when the reaction temperature is lower than 60℃, there is a problem that the production yield is lowered, and when the reaction temperature is higher than 90℃, side reactions may occur. More specifically, the reaction may be performed at 70 to 80℃.

[0113] The reaction of Step 2-2 above may be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 8 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 5 hours.

[0114] Thereafter, the present invention may further comprise, as needed, a step of extracting the reaction product 1 to 3 times using an organic solvent to obtain an organic layer, and purifying the compound represented by Chemical Formula 9 from the organic layer.

[0115] For the extraction, the organic solvent may be methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 2-propanol, 1-butanol, dichloromethane, acetone, or a mixture of two or more thereof. Preferably, ethyl acetate may be used.

[0116] The above purifying step may be performed by crystallizing the compound represented by Chemical Formula 9 above from the reaction product of Step 2 above. A solvent for crystallizing the compound represented by Chemical Formula 9 from the reaction product of Step 2-2 above may be an organic solvent which is acetone, ethyl acetate, methyl acetate, isopropyl acetate, acetonitrile, diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, n-hexane, and n-heptane or a mixture of two or more thereof.

[0117] Preferably, the crystallization solvent may be a mixture of ethyl acetate and n-heptane. For example, the process may be performed by adding ethyl acetate and n-heptane to the concentrated residue of Step 2-2 at a temperature range of 50℃ to 60℃, stirring for 30 minutes or more, slowly cooling to room temperature, and then stirring for 16 hours or more.

[0118] After purifying the compound represented by Chemical Formula 9 above, the purified compound may be dried to lower the moisture content contained in the compound represented by Chemical Formula 9. For example, the moisture content of the compound represented by Chemical Formula 9 may be significantly lowered by drying for 12 hours or more at a temperature range of 40 to 60℃.

[0119] [Step 3]

[0120] Step 3 is a step of hydrolyzing the compound represented by Chemical Formula 9 to prepare the compound represented by Chemical Formula 1.

[0121] The hydrolyzing in Step 3 may be performed in the presence of a hydrolysis reagent and a base.

[0122] In Step 3 above, the hydrolysis reagent may be specifically at least any one selected from the group consisting of sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li2SO4), lithium nitrate (LiNO3), lithium tetrafluoroborate (LiBF4), lithium trifluoroacetate (CF3CO2Li), lithium trifluoromethanesulfonate (CF3SO3Li), and lithium p-toluenesulfonate (C7H7LiO3S).

[0123] Preferably, lithium bromide may be used. In particular, the hydrolysis reagent described above may be used to suppress the oxetane opening reaction or amide formation reaction of the compound represented by Chemical Formula 9, which may occur when using a metal hydroxide, thereby minimizing the generation of related substances and increasing the yield and purity of the final product.

[0124] In Step 3 above, the base may be a low molecular weight amine. Specifically, the low molecular weight amine may be at least any one selected from the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, and diisopropylamine. Preferably, triethylamine may be used.

[0125] In Step 3 above, a molar ratio of the compound represented by Chemical Formula 9, and the hydrolysis reagent and the base may be from 10 : 1 to 1 : 20, respectively. In other words, the reaction of Step 2 above may be performed so that a molar ratio of the compound represented by Chemical Formula 9 and the hydrolysis reagent satisfies a range from 10 : 1 to 1 : 20 and, at the same time, a molar ratio of the compound represented by Chemical Formula 9 and the base satisfies a range from 10 : 1 to 1 : 20. Preferably, each molar ratio may be 1 : 1 to 1 : 20.

[0126] In the reaction in Step 3, a reaction solvent may be any one or more selected from the group consisting of water, acetonitrile, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide. Specifically, acetonitrile may be used as the reaction solvent in Step 3 above.

[0127] The reaction of Step 3 may be performed at 60 to 90℃. Specifically, the reaction within the reaction temperature range of Step 3 above may contribute to increasing a conversion rate of Step 3 and reducing a content of related substances in the final material.

[0128] The reaction of Step 3 above may be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 8 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 5 hours.

[0129] After completion of the reaction, as needed, a step of purifying the compound represented by Chemical Formula 1 may be further included. The purification may be performed by precipitating a lithium salt of the compound represented by Chemical Formula 1 from a reaction solution in which the reaction is terminated, washing with an acidic aqueous solution, and crystallizing the compound represented by Chemical Formula 1.

[0130] A solvent for precipitating the lithium salt of the compound represented by Chemical Formula 1 above, C2-C4 alcohol or alkyl acetate and water may be mixed to be used. Specifically, the C2-C4 alcohol may be at least any one selected from the group consisting of ethanol, propanol, isopropanol, butanol and tert-butanol. Specifically, the alkyl acetate may be at least any one selected from the group consisting of methyl acetate, ethyl acetate, and isopropyl acetate. Preferably, a mixed solvent of ethyl acetate and water may be used. This precipitation process may be very effective in removing related substances that dissolve in organic solvents.

[0131] The acidic aqueous solution may be an inorganic acid or an organic acid. Specifically, the acidic aqueous solution may be any one or more inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. In detail, the acidic aqueous solution may be any one or more organic acids selected from the group consisting of acetic acid, citric acid, tartaric acid, glutamic acid, malonic acid, succinic acid, oxalic acid, fumaric acid, and methanesulfonic acid. Preferably, a citric acid aqueous solution may be used. This washing process may be very effective in removing amidated related substances.

[0132] The crystallization solvent of the compound represented by Chemical Formula 1 above may be any one solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, and tetrahydrofuran, or a mixed solvent thereof. Preferably, a mixed solvent of methanol, ethyl acetate, and acetonitrile may be used.

[0133] After the crystallization of the compound represented by Chemical Formula 1 above, additional purification may be performed. A solvent for the additional purification may be any one solvent or mixed solvent selected from the group consisting of 2-methyltetrahydrofuran, ethanol, methanol, methyl acetate, methyl isobutyl ketone (MIBK), a mixed solvent of tetrahydrofuran and water, a mixed solvent of dichloromethane and ethyl acetate, a mixed solvent of dichloromethane and methanol, a mixed solvent of tetrahydrofuran and toluene, a mixed solvent of tetrahydrofuran and methanol, a mixed solvent of dimethylformamide and methanol, and a mixed solvent of potassium carbonate and water. Preferably, a mixed solvent of tetrahydrofuran and methanol may be used. The additional purification may further improve the purity of the compound represented by Chemical Formula 1.

[0134] After purifying the compound represented by Chemical Formula 1 through the above steps, the compound may be dried at 40℃ to 60℃ to reduce the moisture content in the compound and obtain a high-purity product.

[0135] [Step 4]

[0136] After Step 3 above, the following step 4 may be optionally further included.

[0137] This four-step process may comprise the following step:

[0138] 4) adding a salt to the compound represented by Chemical Formula 1 to prepare a salt compound of the compound represented by Chemical Formula 1.

[0139] Step 4 above is a step of adding a salt to the compound represented by Chemical Formula 1 in order to supply the compound represented by Chemical Formula 1 in the form of a pharmaceutically acceptable salt, which is performed simultaneously with or after Step 3 above, to thereby obtain a pharmaceutically acceptable salt compound of the compound represented by Chemical Formula 1 above.

[0140] Specifically, Step 4 may comprise a step of supplying an organic solvent to the compound represented by Chemical Formula 1 and then supplying a salt or a mixed solution with an organic solvent thereof, thereby crystallizing a salt compound of the compound represented by Chemical Formula 1.

[0141] More specifically, an organic solvent may be supplied to the compound represented by Chemical Formula 1. Here, the organic solvent to be supplied may be one or a combination of two or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, normal propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyl tetrahydrofuran. Preferably, the organic solvent may be one or a combination of two or more organic solvents selected from methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and ethyl acetate. More preferably, a mixed solvent of methanol and ethyl acetate may be used. In particular, the crystallization under organic solvent conditions according to the present invention has the advantage of minimizing the generation of related substances and preparing the desired salt without an additional purification process.

[0142] Pharmaceutically acceptable salt compounds in the salt compound represented by Chemical Formula 1 above include acid addition salts and base addition salts.

[0143] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples thereof may include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphthalenedisulfonic acid, and xinafoate salts.

[0144] Suitable base addition salts are formed from bases which form non-toxic salts. Examples thereof may include aluminum, L-arginine, L-histidine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine(diolamine), glycine, L-lysine, magnesium, meglumine, 2-aminoethanol(olamine), potassium, sodium, tromethamine, L-cysteine, L-glutamine, t-butylamine, ammonia, and zinc salts.

[0145] Preferably, the pharmaceutically acceptable salt compound in the salt compound represented by Chemical Formula 1 above may be at least any one selected from the group consisting of L-lysine, L-arginine, L-histidine, choline hydroxide, meglumine, ammonia, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, L-arginine, L-cysteine, tromethamine (TRIS), L-glutamine, tert-butylamine, citrate, malate, and fumarate.

[0146] The salt compound of the compound represented by Chemical Formula 1 above may be crystallized by supplying the organic solvent to the compound represented by Chemical Formula 1 above, controlling the internal temperature of the reactor to 15℃ to 35℃, preferably 20℃ to 30℃, and stirring the mixed solution of the salt and the organic solvent.

[0147] The salt and the organic solvent may be provided as a mixed solution, and the organic solvent in the mixed solution may be selected from the organic solvents presented above.

[0148] In an embodiment, when the salt used to crystallize the salt compound of the compound represented by Chemical Formula 1 is tromethamine, the crystal has a chemical structure of the following Chemical Formula 1-1:

[0149] [Chemical Formula 1-1]

[0150]

[0151] After the above salt is prepared, the salt may be dried at 45 to 55℃ to reduce the moisture content contained in the salt compound of the compound represented by Chemical Formula 1 above. This can significantly reduce the moisture content of the salt, thereby maximizing the yield of the target compound.

[0152] Optionally, in Step 4 above, the crystallization of the salt compound of the compound represented by Chemical Formula 1 may be performed two or more times.

[0153] For example, after crystallizing the salt compound of the compound represented by Chemical Formula 1 above, the salt compound of the compound represented by Chemical Formula 1 may be extracted using the above organic solvent, followed by supplying the salt or a mixed solution with an organic solvent thereof, thereby crystallizing the salt compound represented by Chemical Formula 1.

[0154] A washing step using a solvent used after completion of the reaction in each step may be further included.

[0155] According to an embodiment of the present invention, the compound represented by Chemical Formula 6 may be prepared by the reaction of Step B below.

[0156] [Step B]

[0157] Step B is a step of reacting the compound represented by Chemical Formula 4 with the compound represented by Chemical Formula 5 to prepare the compound represented by Chemical Formula 6.

[0158] The reaction of Step B above may proceed in the presence of a palladium catalyst, a metal catalyst ligand, and a base.

[0159] The palladium catalyst may be any one selected from the group consisting of Pd(0) and Pd(II) complexes, such as allylchloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]palladium(II), (ethylenediamine)palladium(II) chloride, palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCl2), palladium pivalate, palladium(II) acetylacetonate, bis(benzonitrile)palladium(II) chloride, bis(acetonitrile)dichloropalladium(II), diaminedichloropalladium(II), dichloro(1,5-cyclooctadiene)palladium(II), palladium(II) nitrate, palladium(II) oxide, palladium(II) oxide hydrate, dihydrogentetrachloropalladate(II) (H2[PdCl4]), diaminedinitritopalladium(II), palladium(II) sulfate, tetraamminepalladium(II) sulfate ([Pd(NH3)4]SO4), tetraamminepalladium(II) hydrogen carbonate, tetraamminepalladium(II) chloride ([Pd(NH3)4]Cl2), potassium tetrachloropalladate(II) (K2[PdCl4]), sodium tetrachloropalladate(II) (Na2[PdCl4]), ammonium tetrachloropalladate(II) ((NH4)2[PdCl4]), tetraamminepalladium(II) nitrate, 1,3-divinyl-1,1,3,3-tetramethyldisiloxanepalladium(0), and bis(dibenzylideneacetone)palladium(0) (Pd(dba)2).

[0160] The metal catalyst ligand may be any one selected from the group consisting of phosphine or aza / phosphine ligands, such as tris-ortho-tolylphosphine, tricyclohexylphosphine, 1-(2-diphenylphosphino-1-naphthyl)isoquinoline (QUINAP), 1,8-bis(dimethylamino)naphthalene, 1,1-bis(diphenylphosphino)methane (DPPM), tri-tert-butylphosphine (P(t-Bu)3), 1,1'-bis(diphenylphosphano)ferrocene (DPPF), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 1-(2-di-tert-butylphosphanylphenyl)-ethyldimethylamine, 1-(N,N-dimethylamino)-1'-(dicyclohexylphosphino)-biphenyl, 1-(di-t-butylphosphino)biphenyl, 1,1'-bis(di-t-butylphosphino)biphenyl, and 1,1'-bis(di-tert-butylphosphino)ferrocene (DBPF).

[0161] In the reaction of Step B above, a base may be used together to improve the yield, and the base may be any one selected from the group consisting of cesium carbonate (Cs2CO3), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium phosphate (K3PO4), sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium tert-butoxide (KOtBu), sodium tert-butoxide (NaOtBu), triethylamine (Et3N), N,N-diisopropylethylamine ((i-Pr)2NEt), and cesium fluoride (CsF).

[0162] In the method according to the present invention, the palladium catalyst is preferably palladium (II) acetate, the metal catalyst ligand is preferably 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), and the base is preferably cesium carbonate.

[0163] In Step B above, the palladium catalyst and the metal catalyst ligand may each be used in an amount of 0.01 to 1 equivalent relative to the compound represented by Chemical Formula 4. Preferably, the palladium catalyst and the metal catalyst ligand may each be used in an amount of 0.01 to 0.5 equivalents. When the amount of the copper catalyst, metal catalyst ligand, co-catalyst, and base used is less than the lower limit, the reaction rate and yield may decrease, and when the amount thereof exceeds the upper limit, the economic effect during preparation may be reduced.

[0164] A reaction solvent of Step B above may be at least any one selected from the group consisting of methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, acetone, diethyl ether, tert-butyl ethyl ether, tert-butyl methyl ether, dioxane ethylene glycol dimethyl ether, bis(2-methoxyethyl) ether, ethyl acetate, benzene, toluene, xylene, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Preferably, toluene may be used as the reaction solvent in Step B above.

[0165] The reaction of Step B above may be performed at a reaction temperature of 90 to 120℃. When the reaction temperature is lower than 90℃, there is a problem that the production yield is lowered, and when the reaction temperature is higher than 120℃, the production yield does not substantially increase. More specifically, the reaction may be performed at 100 to 120℃.

[0166] The reaction of Step B above may be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 8 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 5 hours.

[0167] After the reaction is completed, a step of washing the reaction solution with an acidic aqueous solution may be performed. The acidic aqueous solution may be an inorganic acid or an organic acid.

[0168] Specifically, the acidic aqueous solution may be any one or more inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. In detail, the acidic aqueous solution may be any one or more organic acids selected from the group consisting of acetic acid, citric acid, tartaric acid, glutamic acid, malonic acid, succinic acid, oxalic acid, fumaric acid, and methanesulfonic acid. Preferably, an aqueous acetic acid solution may be used. This washing process may effectively remove residual byproducts, such as starting materials that do not participate in the reaction, including the compound represented by Chemical Formula 5, and palladium catalyst, etc.

[0169] According to an embodiment of the present invention, the compound represented by Chemical Formula 6 may proceed to the next step (Step 1) without further separation so that Step B and Step 1 are performed in-situ.

[0170] In the present reaction, X2in Chemical Formula 4 may be Br. The Br functional group may further enhance the rate and efficiency of metal-catalyzed reactions.

[0171] The present invention may optionally further comprise Step B above to prepare the compound represented by Chemical Formula 1. In this case, there is provided a preparation method shown as the following Reaction Scheme 2:

[0172] [Reaction Scheme 2]

[0173]

[0174] B) reacting a compound represented by the following Chemical Formula 4 with a compound represented by the following Chemical Formula 5 to prepare the compound represented by Chemical Formula 6;

[0175] 1) treating the compound represented by Chemical Formula 6 above with an acid to prepare the acid salt represented by Chemical Formula 7 above;

[0176] 2) adding a desalting agent to the compound represented by Chemical Formula 7 above, followed by reacting with the compound represented by Chemical Formula 8 above, thereby preparing the compound represented by Chemical Formula 9 above; and

[0177] 3) hydrolyzing the compound represented by Chemical Formula 9 above to prepare the compound represented by Chemical Formula 1 above:

[0178] [Chemical Formula 4]

[0179]

[0180] [Chemical Formula 5]

[0181]

[0182] in Chemical Formula 4 above, X2is F, Cl, Br or I;

[0183] in Chemical Formula 5 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0184] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0185] in Chemical Formula 8 above, X3is F, Cl, Br or I; and

[0186] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0187] Further, according to an embodiment of the present invention, the compound represented by Chemical Formula 4 may be prepared by the reaction of Step A below:

[0188] [Step A]

[0189] Step A is a step of adding the compound represented by Chemical Formula 3 above to the compound represented by Chemical Formula 2 above to prepare the compound represented by Chemical Formula 4 above.

[0190] The reaction of Step A above may be performed in the presence of a base and an organic solvent. Here, the base may be triethylamine, N,N-diisopropylethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, cesium carbonate, or a mixture of two or more thereof. Preferably, potassium hydroxide or sodium hydroxide may be used.

[0191] In the reaction in Step A, a reaction solvent may be any one or more selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, acetone, ethyl acetate, 2-methyltetrahydrofuran, N,N-dimethylformamide (DMF), N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Preferably, N,N-dimethylformamide may be used as the reaction solvent in Step A above.

[0192] In Step A above, a molar ratio between the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 may be 10 : 1 to 1 : 10, more preferably 5 : 1 to 1 : 5, and more preferably 3 : 1 to 1 : 3.

[0193] The reaction of Step A above may be performed at a reaction temperature of -20 to 5℃. When the reaction temperature is lower than -20℃, there is a problem that the production yield is lowered, and when the reaction temperature is higher than 5℃, the production yield does not substantially increase. More specifically, the reaction may be performed at -15 to 0℃. As described above, Step A above has the advantage of suppressing side reactions as the reaction proceeds at a low temperature, minimizing the generation of related substances, and securing safety against heat that may occur during mass production.

[0194] The reaction of Step 4 above may be performed for 4 hours to 24 hours. When the reaction time is less than 4 hours, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 24 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 5 hours to 10 hours.

[0195] After completion of the reaction, as needed, a step of purifying the compound represented by Chemical Formula 4 may be further included. The above purification may be performed by crystallizing the compound represented by Chemical Formula 4 above from the reaction product of Step A above.

[0196] A solvent for crystallizing the compound represented by Chemical Formula 4 from the reaction product of Step A above may be water or C1-C4 alcohol. More specifically, the crystallization solvent may be water, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixture of two or more thereof. Specifically, water may be used. For example, water may be added to the reaction product of Step A above at a temperature range of 20 to 30℃ and stirred for 16 hours or more.

[0197] After purifying the compound represented by Chemical Formula 4 above, the purified compound may be dried to lower the moisture content contained in the compound represented by Chemical Formula 4. For example, the moisture content of the compound represented by Chemical Formula 4 may be significantly lowered by drying at a temperature range of 40 to 60℃.

[0198] The present invention may optionally further comprise the following Steps A and B to prepare the compound represented by Chemical Formula 1. In this case, there is provided a preparation method shown as the following Reaction Scheme 3:

[0199] [Reaction Scheme 3]

[0200]

[0201] A) reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3 to prepare the compound represented by Chemical Formula 4;

[0202] B) reacting a compound represented by the following Chemical Formula 4 with a compound represented by the following Chemical Formula 5 to prepare the compound represented by Chemical Formula 6;

[0203] 1) treating the compound represented by Chemical Formula 6 above with an acid to prepare the acid salt represented by Chemical Formula 7 above;

[0204] 2) adding a desalting agent to the compound represented by Chemical Formula 7 above, followed by reacting with the compound represented by Chemical Formula 8 above, thereby preparing the compound represented by Chemical Formula 9 above; and

[0205] 3) hydrolyzing the compound represented by Chemical Formula 9 above to prepare the compound represented by Chemical Formula 1 above:

[0206] [Chemical Formula 2]

[0207]

[0208] [Chemical Formula 3]

[0209]

[0210] in Chemical Formula 3 above, X1and X2are each independently F, Cl, Br or I;

[0211] in Chemical Formula 4 above, X2is F, Cl, Br or I;

[0212] in Chemical Formula 5 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0213] in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;

[0214] in Chemical Formula 8 above, X3is F, Cl, Br or I; and

[0215] in Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.

[0216] In an embodiment, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the compound represented by Chemical Formula 1 above, or the pharmaceutically acceptable salt thereof (preferably Chemical Formula 1-1).

[0217] The present invention provides the compound represented by Chemical Formula 1 as defined in any embodiment described herein, or the pharmaceutically acceptable salt thereof, for use as a medicament.

[0218] The present invention provides the compound represented by Chemical Formula 1 as defined in any embodiment described herein, or the pharmaceutically acceptable salt thereof, for use in the prevention or treatment of metabolic diseases.

[0219] The present invention provides a method for treating a metabolic disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0220] Specifically, the metabolic disease may be at least any one selected from the group consisting of diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), juvenile-onset atypical diabetes (YOAD), adult-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, visual impairment, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, symptoms of impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcers, ulcerative colitis, hyper-apo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

[0221] In detail, the non-alcoholic fatty liver disease may be at least any one selected from the group consisting of, for example, steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The exemplary non-alcoholic fatty liver diseases described above encompass a category of metabolic diseases that have significant associations with several medical diseases excluding the category of alcoholic liver disease.

[0222] The pharmaceutical composition may comprise the compound of the present invention together with a pharmaceutically acceptable carrier. Other pharmacologically active ingredients may also be present. The term "pharmaceutically acceptable carrier" in the present invention includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents.

[0223] The composition of the present invention may be in various forms. These forms may include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The above form depends on the intended mode of administration and therapeutic use.

[0224] Typical compositions are in the form of compositions similar to injectable and infusible solutions. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular administration).

[0225] Oral administration in the form of a solid dosage form may be provided, for example, as a hard or soft capsule, pill, sachet, lozenge, or tablet, each containing a predetermined amount of one or more compounds of the present invention. In another embodiment, the oral administration may be in the form of a powder or granule.

[0226] In another embodiment, the oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration may include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent (e.g., water) conventionally used in the field.

[0227] In still another embodiment, the present invention includes parenteral dosage forms. As used herein, the term "parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. The injectable preparation (i.e., sterile injectable aqueous or oily suspension) may be formulated according to known techniques, using suitable dispersants, wetting agents and / or suspending agents.

[0228] Other carrier materials and modes of administration known in the art of pharmaceutical technology may also be utilized. The pharmaceutical composition of the present invention may be prepared by any well known pharmaceutical technique, e.g., by effective formulation and administration procedures.

[0229] Typically, the compound of the present invention is administered in an amount effective to treat the symptoms described herein. The compound of the present invention may be administered as the compound itself or, alternatively, as a pharmaceutically acceptable salt thereof. For purposes of administration and dosage, the compound itself or a pharmaceutically acceptable salt thereof will be referred to simply as the compound of the present invention.

[0230] The compound of the present invention is administered by any suitable route, in the form of a pharmaceutical composition suitable for the route, and in a dosage effective for the intended treatment. The compound of the present invention may be administered orally, rectally, intravaginally, parenterally, or topically.

[0231] The compound of the present invention may preferably be administered orally. Oral administration may involve swallowing the compound so that it enters the gastrointestinal tract.

[0232] In still another embodiment, the compound of the present invention may also be administered directly into the bloodstream, muscles, or internal organs. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intramuscular, and subcutaneous administration.

[0233] The dosing regimen of the compound of the present invention or the composition containing the compound is based on a variety of factors, including the type of patient, age, weight, gender, and medical condition; severity of the condition; route of administration; and activity of the specific compound used. Therefore, the dosing regimen may vary widely. In an embodiment, the total daily dosage of the compound of the present invention is typically from about 0.001 to about 100 mg / kg (i.e., mg of the compound of the present invention per kg of body weight) for the treatment of the presented symptoms discussed herein.

[0234] The preparation method according to the present invention is a method for preparing a glucagon-like peptide-1 receptor (GLP-1R) agonist that can be mass-produced, which has the advantage of shortening the preparation process through salt preparation to achieve process convenience, while minimizing the generation of related substances and increasing yield and purity. The preparation method according to the present invention can have an advantage of omitting a column chromatography purification process. This allows for improved process efficiency with superior yields, and provides a useful advantage for industrial mass production.

[0235] Hereinafter, the present invention will be described in more detail through the following Examples. However, the following Examples are only provided to illustrate the present invention, and the content of the present invention is not limited to these Examples.

[0236] The preparation process according to an embodiment of the present invention is schematically described in Reaction Scheme 6 below:

[0237] [Reaction Scheme 6]

[0238]

[0239] Example 1. Preparation of tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid

[0240] (Step A) Synthesis of (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile

[0241]

[0242] 200.0 g of 6-(hydroxymethyl)pyridine-3-carbonitrile, 275.50 g of 2-bromo-6-fluoropyridine, and 2.0 L of DMF were added and stirred at 20 to 30℃ to dissolve. After cooling the internal temperature to -12℃, 100.39 g of KOH was added and stirred for 5 hours or more at an internal temperature of -12 to -5℃ to complete the reaction. Once the addition was complete, acetic acid dissolved in DMF at an internal temperature of -6 to -5℃ was added to terminate the reaction. After the reaction was complete, 3.0 L of water was added to the reaction mixture to precipitate crystals. After stirring at an internal temperature of 20 to 30℃ for 16 hours or more, the resulting crystals were filtered and washed with water. The resulting product was subjected to vacuum drying at 55℃ to obtain 410.3 g of (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile. According to the present preparation method, (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile was prepared simply, rapidly, and in high yield in a one-step reaction. In addition, the low-temperature reaction was used to suppress the formation of related substances, and to improve safety, and the direct precipitation into solids could provide a more desirable form of intermediate for subsequent manufacturing process (94.8% yield, 94.73% purity).

[0243] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (d, 1 H), 8.34 (dd, 1 H), 7.72 (t, 1 H), 7.67 (d, 1 H), 7.28 (d, 1 H), 7.03 (d, 1 H), 5.49 (s, 2 H)

[0244] (Step B) Synthesis of tert-butyl 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-carboxylate

[0245]

[0246] The (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (405.0 g) synthesized in Step A above, 1-tert-butyl piperazin-1-carboxylate (390.0 g), Cs2CO3(909.67 g), Pd(OAc)2(6.45 g), and BINAP (36.74 g) were placed in a reactor and stirred under reflux at 115℃ for 2 to 3 hours in the presence of toluene (4.05 L) solvent. When the reaction was complete, a temperature of the reaction solution was cooled to room temperature, water (1.22 L) was then added to terminate the reaction, and the resulting product was filtered through celite. The aqueous layer was removed, and acetic acid (48 mL) was added to the organic layer, followed by stirring for 15 minutes. Then, water (1.22 L) was added, stirred for 30 minutes, and allowed to stand to remove the aqueous layer. A 10% aqueous sodium chloride solution (4.0 L) was added to the organic layer, stirred for 10 minutes, and the organic layer of the mixture was separated and filtered through celite. The filtrate was concentrated under reduced pressure at 55℃ to obtain tert-butyl 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-carboxylate as a brown oil, which was then proceeded to the next step (Step 1) without further separation. The reaction rate was improved through the method of the present preparation process. Further, the preparation of the intermediate capable of minimizing the occurrence of side reactions was completed by removing the residue remaining in the reaction solution as much as possible.

[0247] (Step 1) Synthesis of 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile hydrochloride

[0248]

[0249] Isopropyl alcohol (4.05 L) was added to the tert-butyl 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-carboxylate synthesized in Step B above, and the internal temperature was heated up to 70℃. Here, hydrochloric acid (37% w / w, 172 mL) was slowly added dropwise over 30 minutes while maintaining the internal temperature at 70℃. Then, the reaction solution was raised to 90℃ and stirred for 3 hours. When the reaction was completed, the reaction solution was cooled to room temperature and stirred for 2 hours. The precipitated crystals were filtered and washed with isopropyl alcohol. The washed filtrate was vacuum-dried at 50℃ for 16 hours to obtain 348 g of 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile hydrochloride. The preparation of the hydrochloride simplified the reaction process by obtaining the substance by filtration without an additional purification process. In addition, through this process, the substance was secured with high purity. (Yield: 75.1%, Purity: 98.43%)

[0250] 1H NMR (600 MHz, DMSO-d6) δ ppm 9.27 (br s, 2 H), 9.00 (d, 1 H), 8.29 (dd, 1 H), 7.51 - 7.62 (m, 2 H), 6.43 (d, 1 H), 6.28 (d, 1 H), 5.44 (s, 2 H), 3.51 - 3.65 (m, 4 H), 3.04 (br s, 4 H).

[0251] (Step 2) Synthesis of methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylate

[0252]

[0253] The 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile hydrochloride (320.0 g) obtained in Step 1 above and dichloromethane (1.92 L) were added and stirred at room temperature. Here, potassium carbonate (199.94 g) was dissolved in water (960 mL) and added dropwise to the reaction solution over 20 minutes. The reaction solution was stirred for 30 minutes and the water layer was separated and removed. A 5% aqueous sodium chloride solution (1.28 L) was added to the organic layer, stirred for 30 minutes, and then allowed to stand to remove the aqueous layer. The remaining organic layer was concentrated under reduced pressure at 45℃. Acetonitrile (1.9 L) was dissolved in the concentrated residue, and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (255.82 g) and potassium carbonate (399.88 g) were added. The reaction solution was stirred at an internal temperature of 75℃ for 2 hours. Once the reaction was complete, the internal temperature was allowed to cool to room temperature, and ethyl acetate (2.9 L) and water (1.28 L) were added to the reaction solution and stirred for 30 minutes. After allowing the reaction solution to stand, the water layer was separated and removed. Water (1.28 L) was added to the remaining organic layer, stirred for 30 minutes, and allowed to stand to separate the aqueous layer. The remaining organic layer was concentrated under reduced pressure at 55℃. To the concentrated residue, ethyl acetate (1.6 L) and n-heptane (640 mL) were added, stirred at an internal temperature of 50 to 60℃ for 30 minutes, slowly cooled to room temperature over 3 hours, and stirred for 16 hours. The precipitated crystals were filtered and washed twice with ethyl acetate / n-heptane (1:1 mixture, 640 mL). The washed product was dried under vacuum at 50℃ to obtain 360 g of methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylate as a light brown solid. By performing coupling after the desalting reaction of salt, the reaction rate was not only greatly increased, but also the purity was greatly improved by precipitation into crystals (Yield: 74.9%, Purity: 98.95%).

[0254] 1H NMR (600 MHz, DMSO-d6) δ ppm 8.91 - 9.02 (m, 1 H), 8.30 (d, 1 H), 8.27 (dd, 1 H), 7.82 (dd, 1 H), 7.68 (d, 1 H), 7.55 (d, 1 H), 7.48 (t, 1 H), 6.32 (d, 1 H), 6.18 (d, 1 H), 5.41 (s, 2 H), 5.08 (qd, 1 H), 4.79 (dd, 1 H), 4.65 (dd, 1 H), 4.44 - 4.53 (m, 1 H), 4.36 (dt, 1 H), 3.95(d, 1 H), 3.87 (s, 3 H), 3.77 (d, 1 H), 3.30 - 3.34 (m, 4 H), 2.65- 2.73 (m, 1 H), 2.35 - 2.49 (m, 5 H)

[0255] (Step 3) Synthesis of free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid

[0256]

[0257] The methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylate (353.0 g) obtained in Example 2 above, lithium bromide (840.27 g), water (211.8 mL), triethylamine (445 mL), and acetonitrile (3.53 L) were added and stirred under reflux for 2 hours. When the reaction was completed, the reaction solution was concentrated under reduced pressure at 55℃. Water (3.53 L) and ethyl acetate (1.77 L) were added to the concentrated residue and stirred at room temperature for 12 hours or more to precipitate a lithium salt. The precipitated lithium salt was filtered and washed with ethyl acetate. Water (3.53 L) was added to the washed lithium salt and the pH was adjusted to 4 using a 15% aqueous citric acid solution. The reaction mixture was extracted twice with dichloromethane / methanol (4:1 mixture, 2.12 L). The organic layer was collected and washed twice with 0.09 N aqueous hydrochloric acid solution (2.82 L). The washed organic layer was washed with water (2.82 L), and the organic layer was separated and concentrated under reduced pressure. To the concentrated residue, acetonitrile (1.06 L), methanol (1.06 L), and ethyl acetate (706 mL) were added, and heated and stirred at an internal temperature of 65℃ for 30 minutes. The reaction solution was slowly cooled to room temperature and stirred for 12 hours or more. The precipitated solid was washed with ethyl acetate and dried in vacuo at 50℃ to obtain 279.5 g of the free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid as a white solid (Yield 81.24%, Purity 98.41%).

[0258] 1H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br s, 1 H), 8.97 (d, 1 H), 8.21 - 8.33 (m, 2 H), 7.80 (dd, 1 H), 7.65 (d, 1 H), 7.56 (d, 1 H), 7.48 (t, 1 H), 6.32 (d, 1 H), 6.18 (d, 1 H), 5.42 (s, 2 H), 5.08 (qd, 1 H), 4.78 (dd, 1 H), 4.63 (dd, 1 H), 4.48 (td, 1 H), 4.37 (dt, 1 H), 3.94 (d, 1 H), 3.77 (d, 1 H), 3.32 (br s, 4H), 2.65 - 2.76 (m, 1 H), 2.37 - 2.49 (m, 5 H).

[0259] (Step 3-b) Purification of free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid

[0260] To the free base (200.0 g) of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid obtained in Step 3 above, methanol (1.6 L) and tetrahydrofuran (400 mL) were added, and stirred under reflux at 60℃ for 2 hours. The reaction solution was slowly cooled to room temperature and stirred for 12 hours or more. The precipitated solid was filtered, washed with methanol, and dried in vacuo at 50℃ to obtain 186 g of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid as a white solid.

[0261] A preparation process for synthesizing a high-purity free base with high reproducibility was established by removing related substances through the above-described lithium salt separation process (in step 3) and further removing related substances in a subsequent purification process (step 3, step 3-b) (Yield 93.0%, Purity 99.51%).

[0262] (Step 4) Synthesis of tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid

[0263]

[0264] To the free base (180.0 g) of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid prepared according to Step 3, EtOAc (1.8 L) was added and heated to 30℃. When the internal temperature reached 30℃, 42.43 g of 2-amino-2-(hydroxymethyl)propane-1,3-diol (tromethamine) and 720 mL of methanol were added. The reaction solution was stirred at 55 to 60℃ for 4 hours, then cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with ethyl acetate, and dried in vacuo at 50℃ to obtain 202.8 g of white tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (Yield 92.0%, Purity 99.55%).

[0265] 1H NMR (500 MHz, CD3OD) δ ppm 8.84 (d, 1 H), 8.20 (d, 1 H), 8.11 (dd, 1 H), 7.95 (dd, 1 H), 7.62-7.57 (m, 2 H), 7.46 (t, 1 H), 6.27 (d, 1 H), 6.20 (d, 1 H), 5.45 (s, 2 H), 5.26 (qd, 1 H), 4.88-4.82 (m, 1 H), 4.70 (dd, 1 H), 4.62 (td, 1 H), 4.46 (dt, 1 H), 3.98 (d, 1 H), 3.89 (d, 1 H), 3.66 (s, 6 H), 3.39 (br t, 4H), 2.77 (dtd, 1 H), 2.57 - 2.47 (m, 5 H).

[0266] It should be appreciated that the above Examples are merely examples of the above-described embodiments, and it is also possible to achieve improvements in yield and process efficiency of the final material, while controlling the quality.

[0267] With reference to these exemplary embodiments, it will be appreciated that improvements in yield and process efficiency of the final material can be achieved while controlling its quality by adjusting the process temperature, time of execution, etc., of each step within the scope of the above-described embodiments.

Claims

1.A method for preparing a compound represented by the following Chemical Formula 1:1) treating a compound represented by the following Chemical Formula 6 with an acid to prepare an acid salt represented by the following Chemical Formula 7;2) adding a desalting agent to the compound represented by Chemical Formula 7, followed by reacting with a compound represented by the following Chemical Formula 8, thereby preparing a compound represented by the following Chemical Formula 9; and3) hydrolyzing the compound represented by Chemical Formula 9 to prepare the compound represented by Chemical Formula 1:[Chemical Formula 1][Chemical Formula 6][Chemical Formula 7][Chemical Formula 8][Chemical Formula 9]in Chemical Formula 6 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide;in Chemical Formula 8 above, X3is F, Cl, Br or I; andin Chemical Formulas 8 and 9 above, Pg2is methyl, ethyl, benzyl, or tert-butyl.2.The method of claim 1, wherein the Pg1in the Chemical Formula 6 above is a tert-butyloxycarbonyl group (Boc).3.The method of claim 1, wherein the X3in the Chemical Formula 8 above is Cl.4.The method of claim 1, wherein the Pg2in the Chemical Formulas 8 and 9 is methyl.5.The method of claim 1, wherein the acid in Step 1 above is any one selected from the group consisting of hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, hydriodic acid, fluoroboric acid, aluminum chloride, iron chloride, boron trifluoride ether complex, boron trichloride (BCl3), chlorotrimethylsilane (TMSCl), tetra-n-butylammonium fluoride (TBAF), zinc bromide (ZnBr2), zinc chloride (ZnCl2), and magnesium bromide (MgBr2).6.The method of claim 1, wherein the desalting agent in Step 2 above is any one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium citrate, disodium tartrate, sodium hydrogen tartrate, sodium oleate, triethylamine, N,N-diisopropylethylamine, and diisopropylamine.7.The method of claim 1, wherein the Step 2 above is performed in the presence of a base and an organic solvent.8.The method of claim 7, wherein the base in Step 2 above is at least any one selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, and cesium carbonate.9.The method of claim 7, wherein the organic solvent in Step 2 is at least any one selected from the group consisting of dichloromethane (DCM), acetonitrile (ACN), tetrahydrofuran, methanol, ethanol, propanol, isopropyl alcohol, butanol, tert-butanol, acetone, ethyl acetate, 2-methyltetrahydrofuran, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.10.The method of claim 1, wherein the hydrolyzing of Step 3 above is performed in the presence of a hydrolysis reagent and a base, wherein the hydrolysis reagent is at least any one selected from the group consisting of sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li2SO4), lithium nitrate (LiNO3), lithium tetrafluoroborate (LiBF4), lithium trifluoroacetate (CF3CO2Li), lithium trifluoromethanesulfonate (CF3SO3Li), and lithium p-toluenesulfonate (C7H7LiO3S).11.The method of claim 10, wherein the hydrolysis reagent is lithium bromide.12.The method of claim 10, wherein the base is at least any one selected from the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, and diisopropylamine.13.The method of claim 1, further comprising, after Step 3 above,4) adding a salt to the compound represented by Chemical Formula 1 to prepare a salt compound of the compound represented by Chemical Formula 1.14.The method of claim 13, wherein the salt is at least any one selected from the group consisting of L-lysine, L-arginine, L-histidine, choline hydroxide, meglumine, ammonia, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, L-arginine, L-cysteine, tromethamine (TRIS), L-glutamine, tert-butylamine, citrate, malate, and fumarate.15.The method of claim 13, wherein the salt is tromethamine.16.The method of claim 1, further comprising:the following Step B to prepare the compound represented by Chemical Formula 1:B) reacting a compound represented by the following Chemical Formula 4 with a compound represented by the following Chemical Formula 5 to prepare the compound represented by Chemical Formula 6;[Chemical Formula 4][Chemical Formula 5]in Chemical Formula 4 above, X2is F, Cl, Br or I; andin Chemical Formula 5 above, Pg1is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.17.The method of claim 16, further comprising:the following Step A to prepare the compound represented by Chemical Formula 1:A) reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3 to prepare the compound represented by Chemical Formula 4;[Chemical Formula 2][Chemical Formula 3]in Chemical Formula 3 above, X1and X2are each independently F, Cl, Br or I.

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