Process for preparation of substituted fused imidazole derivatives

Abstract

The present invention relates to a process for the preparation of novel substituted fused imidazole derivative compounds. The preparation method of the present invention has the advantages of shortening the preparation process to ensure process convenience, improving the reaction rate and reactivity, and obtaining a solid intermediate, thereby being able to prepare a high-purity compound at a high yield. Therefore, the method is suitable for industrial large-scale production.

Description

Technical Field

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

[0002] Glucagon-like peptide-1 (GLP-1) is a hormone known to effectively increase insulin secretion and lower blood glucose by acting on a receptor called the glucagon-like peptide-1 receptor (GLP-1R). This hormone is also believed to have effects such as reducing motility and suppressing appetite in the upper digestive system, and proliferating existing pancreatic β-cells. These properties of GLP-1 show 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 to its development as a pharmaceutical product. Recently, to overcome the problem of the short duration of action of GLP-1, therapies have been developed in two ways: GLP-1 analogs and DPP-4 inhibitors, which are resistant to dipeptidyl peptidase IV (DPP-Ⅳ), a enzyme that destroys GLP-1 in the bloodstream.

[0003] Currently, several GLP-1 analogues resistant to the DPP-4 enzyme, which destroys GLP-1 in the bloodstream, have been developed and used to treat type 2 diabetes. These GLP-1 analogues have a significantly longer half-life than natural GLP-1, allowing them to maintain their glycemic-lowering effects for an extended period. However, they are not available orally and must be administered by injection, which may lead to poor patient adherence. Therefore, ongoing research aims to discover and develop small-molecule GLP-1R agonists that can be administered orally for the treatment of diabetes.

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

[0005] To address the aforementioned problems, the inventors improved the reaction rate and reactivity of the method disclosed in Korean Patent No. 10-2344561, shortened the preparation process to ensure convenience, and obtained a solid intermediate that facilitates excellent purification to maximize purity, while significantly improving the production level of the target substance, thereby developing a method suitable for large-scale production. Therefore, this invention is accomplished by providing a novel method for preparing GLP-1R agonist compounds. Summary of the Invention

[0006] [Technical Issues] The purpose of this invention is to provide a method for preparing substituted fused imidazole derivative compounds.

[0007] To address the above problems, a method for preparing substituted fused imidazole derivative compounds is provided, the method comprising: 1) Treat the compound represented by the following chemical formula 6 with acid to prepare the acid salt represented by the following chemical formula 7; 2) Adding a desalting agent to the compound represented by chemical formula 7, followed by reaction with the compound represented by chemical formula 8, yields the compound represented by chemical formula 9; and 3) Hydrolyze 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 the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0008] [Technical Solution] In general, the preparation method shown in reaction scheme 1 is provided below: [Reaction Scheme 1] Specifically, the present invention provides a method for preparing the compound represented by the above-mentioned chemical formula 1, the method comprising steps 1 to 3: 1) Treat the compound represented by chemical formula 6 with acid to prepare the acid salt represented by chemical formula 7; 2) Add a desalting agent to the compound represented by chemical formula 7, and then react it with the compound represented by chemical formula 8 to prepare the compound represented by chemical formula 9; and 3) Hydrolyze the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1 above: In the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0009] Furthermore, the present invention provides a preparation method as shown in reaction scheme 2, which optionally further includes step B to prepare the compound represented by the above chemical formula 1: [Reaction Scheme 2] B) React the compound represented by chemical formula 4 below with the compound represented by chemical formula 5 below to prepare the compound represented by chemical formula 6 above; 1) Treat the compound represented by chemical formula 6 with acid to prepare the acid salt represented by chemical formula 7; 2) Add a desalting agent to the compound represented by chemical formula 7, and then react it with the compound represented by chemical formula 8 to prepare the compound represented by chemical formula 9; and 3) Hydrolyze the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1 above: [Chemical Formula 4] [Chemical Formula 5] In the above chemical formula 4, X2 is F, Cl, Br or I; In the above chemical formula 5, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or trifluoroacetamide; In the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0010] Furthermore, the present invention provides a preparation method as shown in reaction scheme 3, which optionally further includes steps A and B to prepare the compound represented by the above chemical formula 1: [Reaction Scheme 3] A) React the compound represented by chemical formula 2 below with the compound represented by chemical formula 3 below to prepare the compound represented by chemical formula 4 above; B) React the compound represented by chemical formula 4 with the compound represented by chemical formula 5 to prepare the compound represented by chemical formula 6. 1) Treat the compound represented by chemical formula 6 with acid to prepare the acid salt represented by chemical formula 7; 2) Add a desalting agent to the compound represented by chemical formula 7, and then react it with the compound represented by chemical formula 8 to prepare the compound represented by chemical formula 9; and 3) Hydrolyze the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1 above: [Chemical Formula 2] [Chemical Formula 3] In the above chemical formula 3, X1 and X2 are each independently F, Cl, Br, or I. In the above chemical formula 4, X2 is F, Cl, Br, or I. In the above chemical formula 5, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or trifluoroacetamide; In the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0011] Furthermore, the present invention provides a preparation method as shown in reaction scheme 4, which optionally further includes step 4 to prepare a salt compound of the compound represented by the above chemical formula 1: [Reaction Scheme 4] 1) Treat the compound represented by chemical formula 6 with acid to prepare the acid salt represented by chemical formula 7; 2) Add a desalting agent to the compound represented by chemical formula 7 above, and then react it with the compound represented by chemical formula 8 above to prepare the compound represented by chemical formula 9 above; 3) Hydrolyze the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1; and 4) Add a salt to the compound represented by the above chemical formula 1 to prepare a salt compound of the compound represented by chemical formula 1.

[0012] In the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0013] In the following text, embodiments of the present invention will be described in detail for each of the above steps.

[0014] [Step 1] Step 1 above is the step of treating the compound represented by chemical formula 6 with acid to remove the protecting group and preparing the acid salt represented by chemical formula 7.

[0015] There are no particular limitations on the type of acid that can be used in step 1 above; it can be Brønsted (Br (nsted) acid or Lewis acid.

[0016] Specifically, the Brønsted acid can be any one selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, hydroiodic acid, and fluoroboric acid. Specifically, the Lewis acid can be any one selected from aluminum chloride, ferric chloride, boron trifluoride ether complex, boron trichloride (BCl3), trimethylchlorosilane (TMSCl), tetrabutylammonium fluoride (TBAF), zinc bromide (ZnBr2), zinc chloride (ZnCl2), and magnesium bromide (MgBr2).

[0017] Preferably, hydrochloric acid, sulfuric acid, and trifluoroacetic acid can be used. More preferably, hydrochloric acid can be used.

[0018] The reaction in step 1 can be carried out in an organic solvent. The organic solvent can be, for example, ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, acetonitrile, dichloromethane, n-hexane, dimethyl sulfoxide, or a mixture of two or more of these. Preferably, isopropanol or acetone can be used.

[0019] The reaction in step 1 can be carried out at temperatures between 60°C and 120°C. Below 60°C, the production yield decreases, while above 120°C, side reactions may occur, which is undesirable. More specifically, the reaction can be carried out at temperatures between 80°C and 100°C.

[0020] The reaction in step 1 above can proceed from 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction is not complete enough, resulting in a lower production yield; while when the reaction time exceeds 8 hours, the production yield does not increase substantially. More specifically, the reaction can proceed from 1 hour to 5 hours.

[0021] According to a preferred embodiment of the present invention, in step 1 above, by using hydrochloric acid as the acid and isopropanol as the reaction solvent, the compound represented by chemical formula 7 can be precipitated as a solid HCl salt. Therefore, the advantage of step 1 is that a high-purity product can be obtained simply by filtration and washing, without the need for post-processing, thereby achieving excellent purification results and simplifying the process.

[0022] In one embodiment, when hydrochloric acid is used in step 1, the compound represented by chemical formula 7 can be a compound represented by chemical formula 7-1: [Chemical Formula 7-1] .

[0023] [Step 2] Step 2 is the step of adding a desalting agent to the compound represented by chemical formula 7, and then reacting it with the compound represented by chemical formula 8 to prepare the compound represented by chemical formula 9. This step involves introducing a substituted benzimidazole group onto the piperazine group of the compound represented by chemical formula 7.

[0024] More specifically, step 2 above promotes the coupling reaction by desalting the compound represented by formula 7 before adding the compound represented by formula 8. Step 2 above may include step 2-1 of adding a desalting agent and step 2-2 of adding the compound represented by formula 8: [Reaction Scheme 5] In reaction scheme 5 above, the preparation method is as follows: 2-1) Add a desalting agent to the compound represented by the above chemical formula 7 to desalt the compound; 2-2) Add the compound represented by chemical formula 8 to the desalted compound to induce the conversion of 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 can be carried out in situ.

[0025] In step 2-1 above, the desalting agent refers to various compounds in the art used to remove acid salts, which may be alkali metal hydroxides, alkali metal salts or low molecular weight amines.

[0026] Specifically, the alkali metal hydroxide can be any one selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0027] Specifically, the alkali metal salt can be selected from any one of 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, and sodium oleate.

[0028] Specifically, the low molecular weight amine can be any one selected from triethylamine, N,N-diisopropylethylamine, and diisopropylamine.

[0029] Preferably, potassium carbonate can be used as a desalting agent in step 2-1.

[0030] In step 2-1, the desalting agent treatment can be carried out in at least one organic solvent selected from methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate, and 2-methyltetrahydrofuran. Preferably, dichloromethane can be used.

[0031] The reaction in step 2-1 can be carried out at temperatures ranging from 10°C to 90°C. Preferably, the reaction can be carried out at room temperature.

[0032] Furthermore, the reaction in step 2-1 can proceed from 10 minutes to 5 hours. Preferably, the reaction can proceed from 10 minutes to 1 hour.

[0033] For example, the reaction in step 2-1 can be carried out by mixing the compound represented by the above chemical formula 7 with dichloromethane at room temperature, slowly adding an aqueous solution of potassium carbonate, and then stirring for 30 minutes.

[0034] Step 2-2 above is the step of adding the compound represented by chemical formula 8 to the desalted compound to prepare the compound represented by chemical formula 9 above.

[0035] The reaction in step 2-2 above can be carried out in the presence of a base and an organic solvent. In this document, the base can be triethylamine (TEA), N,N-diisopropylethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, cesium carbonate, or a mixture of two or more of these. Preferably, potassium carbonate can be used.

[0036] In step 2-2, the reaction solvent can be one or more selected from 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 can be used as the reaction solvent in step 2-2.

[0037] In step 2-2 above, the molar ratio between the compound represented by chemical formula 7 and the compound represented by chemical formula 8 can be 10:1 to 1:10, more preferably 5:1 to 1:5, and even more preferably 3:1 to 1:3.

[0038] The reaction in step 2-2 can be carried out at 60°C to 90°C. Below 60°C, the production yield decreases, while above 90°C, side reactions may occur, which is undesirable. More specifically, the reaction can be carried out at 70°C to 80°C.

[0039] The reaction in step 2-2 above can proceed from 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction is not complete enough, resulting in a lower production yield; while when the reaction time exceeds 8 hours, the production yield does not increase substantially. More specifically, the reaction can proceed from 1 hour to 5 hours.

[0040] Subsequently, the present invention may further include, as needed, the steps of extracting the reaction product with an organic solvent one to three times to obtain an organic layer, and purifying the compound represented by formula 9 from the organic layer.

[0041] For extraction, the organic solvent can be methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 2-propanol, 1-butanol, dichloromethane, acetone, or a mixture of two or more of these. Preferably, ethyl acetate can be used.

[0042] The purification steps described above can be performed by crystallizing the compound represented by chemical formula 9 from the reaction product of step 2 above. The solvent used to crystallize the compound represented by chemical formula 9 from the reaction product of step 2-2 above can be an organic solvent, such as acetone, ethyl acetate, methyl acetate, isopropyl acetate, acetonitrile, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, n-hexane, and n-heptane, or a mixture of two or more of these.

[0043] Preferably, the crystallization solvent can be a mixture of ethyl acetate and n-heptane. For example, the process can be carried out by adding ethyl acetate and n-heptane to the concentrated residue of step 2-2 at a temperature range of 50°C to 60°C, stirring for 30 minutes or longer, slowly cooling to room temperature, and then stirring for 16 hours or longer.

[0044] After purifying the compound represented by Formula 9, the purified compound can be dried to reduce its water content. For example, drying at a temperature between 40°C and 60°C for 12 hours or longer can significantly reduce the water content of the compound represented by Formula 9.

[0045] [Step 3] Step 3 is the step of hydrolyzing the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1.

[0046] In step 3, hydrolysis can be carried out in the presence of a hydrolysis reagent and a base.

[0047] In step 3 above, the hydrolysis reagent may be specifically selected from at least one 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).

[0048] Preferably, lithium bromide can be used. In particular, the above-mentioned hydrolysis reagent can be used to suppress the oxetane ring-opening reaction or amide formation reaction of the compound represented by Formula 9, which may occur when metal hydroxides are used, thereby minimizing the formation of related substances and improving the yield and purity of the final product.

[0049] In step 3 above, the base can be a low molecular weight amine. Specifically, the low molecular weight amine can be at least one selected from triethylamine (TEA), N,N-diisopropylethylamine, and diisopropylamine. Preferably, triethylamine can be used.

[0050] In step 3 above, the molar ratio of the compound represented by formula 9 to the hydrolysis reagent and the base can be from 10:1 to 1:20. In other words, the reaction in step 2 above can be carried out so that the molar ratio of the compound represented by formula 9 to the hydrolysis reagent is in the range of 10:1 to 1:20, and simultaneously, the molar ratio of the compound represented by formula 9 to the base is also in the range of 10:1 to 1:20. Preferably, each molar ratio can be from 1:1 to 1:20.

[0051] In step 3, the reaction solvent can be any one or more selected from water, acetonitrile, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Specifically, in step 3 above, acetonitrile can be used as the reaction solvent.

[0052] The reaction in step 3 can be carried out at temperatures between 60°C and 90°C. Specifically, the reaction within the temperature range of step 3 described above can help improve the conversion rate of step 3 and reduce the content of related substances in the final material.

[0053] The reaction in step 3 above can proceed from 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction is not complete enough, resulting in a lower production yield; while when the reaction time exceeds 8 hours, the production yield does not increase substantially. More specifically, the reaction can proceed from 1 hour to 5 hours.

[0054] After the reaction is complete, a further step of purifying the compound represented by Formula 1 may be included, if necessary. Purification can be performed by precipitating the lithium salt of the compound represented by Formula 1 from the reaction solution from which the reaction has been terminated, washing with an acidic aqueous solution, and crystallizing the compound represented by Formula 1.

[0055] The solvent used to precipitate the lithium salt of the compound represented by Formula 1 above can be a mixture of C2-C4 alcohol or alkyl acetate and water. Specifically, the C2-C4 alcohol can be at least one selected from ethanol, propanol, isopropanol, butanol, and tert-butanol. Specifically, the alkyl acetate can be at least one selected from methyl acetate, ethyl acetate, and isopropyl acetate. Preferably, a mixture of ethyl acetate and water can be used. This precipitation process can very effectively remove substances dissolved in organic solvents.

[0056] The acidic aqueous solution can be an inorganic acid or an organic acid. Specifically, the acidic aqueous solution can be any one or more inorganic acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. More specifically, the acidic aqueous solution can be any one or more organic acids selected from acetic acid, citric acid, tartaric acid, glutamic acid, malonic acid, succinic acid, oxalic acid, fumaric acid, and methanesulfonic acid. Preferably, an aqueous solution of citric acid can be used. This washing process can very effectively remove amidation-related substances.

[0057] The crystallization solvent for the compound represented by the above chemical formula 1 can be any solvent selected from methanol, ethanol, isopropanol, acetone, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, and tetrahydrofuran, or a mixture thereof. Preferably, a mixture of methanol, ethyl acetate, and acetonitrile can be used.

[0058] After crystallization of the compound represented by Formula 1, further purification can be performed. The solvent used for this additional purification can be any one or a mixture selected from 2-methyltetrahydrofuran, ethanol, methanol, methyl acetate, methyl isobutyl ketone (MIBK), a mixture of tetrahydrofuran and water, a mixture of dichloromethane and ethyl acetate, a mixture of dichloromethane and methanol, a mixture of tetrahydrofuran and toluene, a mixture of tetrahydrofuran and methanol, a mixture of dimethylformamide and methanol, and a mixture of potassium carbonate and water. Preferably, a mixture of tetrahydrofuran and methanol can be used. This additional purification can further improve the purity of the compound represented by Formula 1.

[0059] After purifying the compound represented by chemical formula 1 through the above steps, the compound can be dried at 40°C to 60°C to reduce the water content in the compound and obtain a high-purity product.

[0060] [Step 4] Following step 3 above, step 4 may optionally be included.

[0061] This fourth step may include the following steps: 4) Add salt to the compound represented by chemical formula 1 to prepare a salt compound of the compound represented by chemical formula 1.

[0062] Step 4 above is the step of adding a salt to the compound represented by chemical formula 1, thereby providing the compound represented by chemical formula 1 in the form of a pharmaceutically acceptable salt. This step is performed simultaneously with or after step 3 above, thereby obtaining a pharmaceutically acceptable salt compound of the compound represented by chemical formula 1.

[0063] Specifically, step 4 may include providing an organic solvent to the compound represented by Formula 1, followed by providing a salt or a mixture thereof with the organic solvent, thereby causing the salt compound of the compound represented by Formula 1 to crystallize.

[0064] More specifically, an organic solvent can be provided to the compound represented by Formula 1. In this document, the organic solvent to be provided can be one or a combination of two or more selected from methanol, ethanol, isopropanol, acetonitrile, n-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran. Preferably, the organic solvent can be one or a combination of two or more selected from methanol, ethanol, isopropanol, acetonitrile, acetone, and ethyl acetate. More preferably, a mixed solvent of methanol and ethyl acetate can be used. In particular, crystallization under organic solvent conditions according to the invention has the advantage of minimizing the formation of related substances and preparing the desired salt without additional purification processes.

[0065] Pharmaceutically acceptable salt compounds among those represented by the above chemical formula 1 include acid addition salts and base addition salts.

[0066] Acids that form non-toxic salts can be used to form suitable acid addition salts. Examples may include acetate, adipic acid salt, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphor sulfonate, citrate, cyclohexylsulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucohepanoate, gluconate, glucuronate, hexafluorophosphate, benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthylate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, 1,5-naphthalenedisulfonate, and xinafoatesalts.

[0067] Suitable base addition salts are formed from bases that form non-toxic salts. Examples may include aluminum salts, L-arginine salts, L-histidine salts, benzylethylenediamine salts, calcium salts, choline salts, diethylamine salts, bis(2-hydroxyethyl)amine (diethanolamine) salts, glycine salts, L-lysine salts, magnesium salts, meglumine salts, 2-aminoethanol (ethanolamine) salts, potassium salts, sodium salts, tromethamine salts, L-cysteine ​​salts, L-glutamine salts, tert-butylamine salts, ammonium salts, and zinc salts.

[0068] Preferably, the pharmaceutically acceptable salt compound represented by the above-mentioned chemical formula 1 may be selected from at least one 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.

[0069] The salt compound of the compound represented by the above chemical formula 1 can be crystallized by providing an organic solvent to the compound, controlling the internal temperature of the reactor at 15°C to 35°C, preferably 20°C to 30°C, and stirring the mixture of salt and organic solvent.

[0070] The salt and organic solvent may be provided in the form of a mixed solution, and the organic solvent in the mixed solution may be selected from the aforementioned organic solvents.

[0071] In an embodiment, when the salt used to crystallize the salt compound of the compound represented by Formula 1 is tromethamine, the crystal has the following chemical structure of Formula 1-1: [Chemical Formula 1-1] .

[0072] After the salt is prepared as described above, it can be dried at 45°C to 55°C to reduce the water content in the salt compound of the compound represented by Formula 1. This can significantly reduce the water content in the salt, thereby maximizing the yield of the target compound.

[0073] Optionally, in step 4 above, the crystallization of the salt compound of the compound represented by chemical formula 1 can be carried out two or more times.

[0074] For example, after crystallizing the salt compound of the compound represented by Formula 1, the salt compound of the compound represented by Formula 1 can be extracted with the organic solvent described above, and then the salt or a mixture thereof with the organic solvent is provided, thereby crystallizing the salt compound represented by Formula 1.

[0075] After each reaction step is completed, a washing step using the solvent used may be further included.

[0076] According to an embodiment of the present invention, the compound represented by chemical formula 6 can be prepared by the reaction in step B.

[0077] [Step B] Step B is the 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.

[0078] The reaction in step B above can be carried out in the presence of a palladium catalyst, a metal catalyst ligand, and a base.

[0079] The palladium catalyst can be any of the Pd(0) and Pd(II) complexes, such as allyl chloride [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-yl]palladium(II), (ethylenediamine)palladium(II) chloride, palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCl2), palladium neopentanoate, 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, tetrachloropalladium(II) dihydrogen salt (H2[PdCl4]), diaminedinitropalladium(II), palladium(II) sulfate, tetraaminepalladium(II) sulfate ([Pd(NH3)4]SO4). 4) Tetraamine palladium bicarbonate (II), tetraamine palladium chloride (II) ([Pd(NH3)4]Cl2), potassium tetrachloropalladate (II) (K2[PdCl4]), sodium tetrachloropalladate (II) (Na2[PdCl4]), ammonium tetrachloropalladate (II) ((NH4)2[PdCl4]), tetraamine palladium nitrate (II), 1,3-divinyl-1,1,3,3-tetramethyldisiloxane palladium (0) and bis(dibenzylideneacetone)palladium (0) (Pd(dba)2).

[0080] The metal catalyst ligand can be selected from any of the phosphine or aza / phosphine ligands, such as tri-o-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(diphenylphosphino)ferrocene (DPPF), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 1-(2-di-tert-butylphosphinophenyl)-ethyldimethylamine, 1-(N,N-dimethylamino)-1'-(dicyclohexylphosphino)biphenyl, 1-(di-tert-butylphosphino)biphenyl, 1,1'-bis(di-tert-butylphosphino)biphenyl, and 1,1'-bis(di-tert-butylphosphino)ferrocene (DBPF).

[0081] In the reaction of step B above, a base can be used simultaneously to increase the yield. The base can be any one selected from 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).

[0082] In the method according to the 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.

[0083] In step B above, the palladium catalyst and the metal catalyst ligand are each used in amounts of 0.01 to 1 equivalent relative to the compound represented by Formula 4. Preferably, the palladium catalyst and the metal catalyst ligand are each used in amounts of 0.01 to 0.5 equivalents. When the amounts of the copper catalyst, the metal catalyst ligand, the co-catalyst, and the base are below the lower limit, the reaction rate and yield may decrease; when their amounts exceed the upper limit, the economic benefits during preparation may decrease.

[0084] The reaction solvent in step B above can be selected from at least one of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, diethyl ether, tert-butyl ethyl ether, tert-butyl methyl ether, dioxane 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 can be used as the reaction solvent in step B above.

[0085] The reaction in step B above can be carried out at a reaction temperature of 90°C to 120°C. When the reaction temperature is below 90°C, there is a problem of reduced production yield, while when the reaction temperature is above 120°C, the production yield does not increase significantly. More specifically, the reaction can be carried out at 100°C to 120°C.

[0086] The reaction in step B above can proceed from 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction is not complete enough, resulting in a lower production yield; while when the reaction time exceeds 8 hours, the production yield does not increase substantially. More specifically, the reaction can proceed from 1 hour to 5 hours.

[0087] After the reaction is complete, the reaction solution can be washed with an acidic aqueous solution. The acidic aqueous solution can be an inorganic acid or an organic acid.

[0088] Specifically, the acidic aqueous solution can be any one or more inorganic acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. More specifically, the acidic aqueous solution can be any one or more organic acids selected from acetic acid, citric acid, tartaric acid, glutamic acid, malonic acid, succinic acid, oxalic acid, fumaric acid, and methanesulfonic acid. Preferably, an aqueous solution of acetic acid can be used. This washing process can effectively remove residual byproducts, such as unreacted starting materials, including compounds represented by Formula 5, and palladium catalysts, etc.

[0089] According to an embodiment of the present invention, the compound represented by chemical formula 6 can proceed to the next step (step 1) without further separation, so that steps B and step 1 can be carried out in situ.

[0090] In this reaction, X2 in chemical formula 4 can be Br. The Br functional group can further enhance the rate and efficiency of metal-catalyzed reactions.

[0091] The present invention may optionally further include step B above to prepare the compound represented by chemical formula 1. In this case, the preparation method shown in reaction scheme 2 is provided: [Reaction Scheme 2] B) React the compound represented by chemical formula 4 with the compound represented by chemical formula 5 to prepare the compound represented by chemical formula 6; 1) Treat the compound represented by chemical formula 6 with acid to prepare the acid salt represented by chemical formula 7; 2) Add a desalting agent to the compound represented by chemical formula 7, and then react it with the compound represented by chemical formula 8 to prepare the compound represented by chemical formula 9; and 3) Hydrolyze the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1 above: [Chemical Formula 4] [Chemical Formula 5] In the above chemical formula 4, X2 is F, Cl, Br or I; In the above chemical formula 5, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or trifluoroacetamide; In the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0092] Furthermore, according to embodiments of the present invention, the compound represented by chemical formula 4 can be prepared by the reaction in step A: [Step A] Step A is the step of adding the compound represented by ...

[0093] The reaction in step A above can be carried out in the presence of a base and an organic solvent. In this document, the base can be triethylamine, N,N-diisopropylethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, cesium carbonate, or a mixture of two or more of these. Preferably, potassium hydroxide or sodium hydroxide can be used.

[0094] In step A, the reaction solvent can be any one or more selected from dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, ethyl acetate, 2-methyltetrahydrofuran, N,N-dimethylformamide (DMF), N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Preferably, in step A above, N,N-dimethylformamide can be used as the reaction solvent.

[0095] In step A above, the molar ratio between the compound represented by chemical formula 2 and the compound represented by chemical formula 3 can be from 10:1 to 1:10, more preferably from 5:1 to 1:5, and even more preferably from 3:1 to 1:3.

[0096] The reaction in step A above can be carried out at a reaction temperature ranging from -20°C to 5°C. When the reaction temperature is below -20°C, there is a decrease in production yield, while when the reaction temperature is above 5°C, the production yield essentially does not increase. More specifically, the reaction can be carried out at temperatures ranging from -15°C to 0°C. As described above, step A has the advantages of suppressing side reactions, minimizing the formation of related substances, and ensuring thermal safety during large-scale production because the reaction is carried out at low temperatures.

[0097] The reaction in step 4 above can proceed for 4 to 24 hours. When the reaction time is less than 4 hours, the reaction is not complete enough, resulting in a lower production yield; while when the reaction time exceeds 24 hours, the production yield does not increase substantially. More specifically, the reaction can proceed for 5 to 10 hours.

[0098] After the reaction is complete, a further step of purifying the compound represented by chemical formula 4 may be included, if necessary. This purification can be carried out by crystallizing the compound represented by chemical formula 4 from the reaction product of step A above.

[0099] The solvent used to crystallize the compound represented by Formula 4 from the reaction product of step A above can be water or a C1-C4 alcohol. More specifically, the crystallization solvent can be water, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixture of two or more of these. Specifically, water can be used. For example, water can be added to the reaction product of step A above at a temperature range of 20°C to 30°C and stirred for 16 hours or longer.

[0100] After purifying the compound represented by Formula 4, the purified compound can be dried to reduce its water content. For example, drying at a temperature range of 40°C to 60°C can significantly reduce the water content of the compound represented by Formula 4.

[0101] The present invention may optionally further include steps A and B to prepare the compound represented by chemical formula 1. In this case, the preparation method shown in reaction scheme 3 is provided: [Reaction Scheme 3] A) React the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to prepare the compound represented by chemical formula 4; B) React the compound represented by chemical formula 4 with the compound represented by chemical formula 5 to prepare the compound represented by chemical formula 6; 1) Treat the compound represented by chemical formula 6 with acid to prepare the acid salt represented by chemical formula 7; 2) Add a desalting agent to the compound represented by chemical formula 7, and then react it with the compound represented by chemical formula 8 to prepare the compound represented by chemical formula 9; and 3) Hydrolyze the compound represented by chemical formula 9 to prepare the compound represented by chemical formula 1 above: [Chemical Formula 2] [Chemical Formula 3] In the above chemical formula 3, X1 and X2 are each independently F, Cl, Br, or I. In the above chemical formula 4, X2 is F, Cl, Br or I; In the above chemical formula 5, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or trifluoroacetamide; In the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

[0102] In an embodiment, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, comprising a compound represented by the above-described chemical formula 1, or a pharmaceutically acceptable salt thereof (preferably chemical formula 1-1).

[0103] This invention provides compounds represented by Formula 1 as defined in any of the embodiments described herein, or pharmaceutically acceptable salts thereof, for use as medicines.

[0104] This invention provides compounds represented by Formula 1 as defined in any of the embodiments described herein, or pharmaceutically acceptable salts thereof, for the prevention or treatment of metabolic diseases.

[0105] The present invention provides a method for treating metabolic diseases, comprising administering to a subject in need a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0106] Specifically, metabolic diseases can be selected from at least one of the following: diabetes mellitus, idiopathic type 1 diabetes mellitus, latent autoimmune diabetes mellitus in adults (LADA), early-onset type 2 diabetes mellitus (EOD), adolescent-onset atypical diabetes mellitus (YOAD), juvenile-onset diabetes mellitus (MODY), malnutrition-associated diabetes mellitus, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis. Arteriosclerosis, 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 lipolipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, visual impairment, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, glucose metabolism disorder, impaired fasting glucose symptoms, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

[0107] In detail, non-alcoholic fatty liver disease can be selected from at least one of, for example, steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The above-described exemplary non-alcoholic fatty liver disease covers a class of metabolic diseases that are significantly associated with several medical conditions other than alcoholic liver disease.

[0108] The pharmaceutical composition may include the compounds of this invention and a pharmaceutically acceptable carrier. Other pharmacologically active ingredients may also be present. In this invention, the term "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents.

[0109] The compositions of the present invention can 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 infusionable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The above forms depend on the intended method of administration and therapeutic use.

[0110] Typical compositions are in the form of injectable and infusion-compatible solutions. One route of administration is extra-enteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).

[0111] Oral administration in solid dosage forms is possible, for example, as hard capsules or soft capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of one or more compounds of the present invention. In another embodiment, oral administration may be in the form of powder or granules.

[0112] In another embodiment, oral administration may be in the form of a liquid dosage form. Liquid dosage forms for oral administration may include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (e.g., water) commonly used in the field.

[0113] In another embodiment, the invention includes parenteral administration dosage forms. As used herein, the term "parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile injectable aqueous or oily suspensions) can be formulated using appropriate dispersants, wetting agents, and / or suspending agents according to known techniques.

[0114] Other carrier materials and administration methods known in the pharmaceutical technology field can also be utilized. The pharmaceutical compositions of the present invention can be prepared by any well-known pharmaceutical technique, such as through efficient formulation and administration procedures.

[0115] Typically, the compounds of this invention are administered in doses effective in treating the symptoms described herein. The compounds of this invention may be administered in their natural form or as pharmaceutically acceptable salts thereof. For purposes of administration and dosage, the compounds themselves or their pharmaceutically acceptable salts will be simply referred to as compounds of this invention.

[0116] The compounds of the present invention can be administered via any suitable route, in the form of a pharmaceutical composition suitable for that route, and at a dose appropriate for intended therapeutic efficacy. The compounds of the present invention can be administered orally, rectally, vaginally, over the intestines, or topically.

[0117] The compounds of the present invention can preferably be administered orally. Oral administration may involve swallowing the compound so that it enters the gastrointestinal tract.

[0118] In another embodiment, the compounds of the present invention can also be administered directly into the bloodstream, muscles, or internal organs. Suitable methods for non-enteric administration include intravenous, intra-arterial, intraperitoneal, intramuscular, and subcutaneous administration.

[0119] The dosing regimens of the compounds of the present invention or compositions containing such compounds are based on a variety of factors, including patient type, age, weight, sex, and medical condition; severity of the condition; route of administration; and the activity of the specific compound used. Therefore, dosing regimens can vary considerably. In embodiments, for the treatment of the symptoms discussed herein, the total daily dose of the compounds of the present invention is typically from about 0.001 to about 100 mg / kg (i.e., milligrams of the compounds of the present invention per kilogram of body weight).

[0120] [Beneficial Effects] The preparation method of this invention is a method for preparing glucagon-like peptide-1 receptor (GLP-1R) agonists that can be produced on a large scale. Its advantages include shortening the preparation process through salt preparation, achieving process convenience, minimizing the formation of related substances, and improving yield and purity. The preparation method of this invention can omit the column chromatography purification process. This allows for improved process efficiency with excellent yields and provides beneficial advantages for large-scale industrial production. Detailed Implementation

[0121] In the following description, the present invention will be further detailed through the following embodiments. However, the following embodiments are provided for illustrative purposes only, and the scope of the present invention is not limited to these embodiments.

[0122] According to an embodiment of the present invention, the preparation process is illustratively described in the following reaction scheme 6: [Reaction Scheme 6] Example 1. Preparation of the aminobutane glycerol salt of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (Step A) Synthesis of (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-nitrile) 200.0 g of 6-(hydroxymethyl)pyridine-3-onitrile, 275.50 g of 2-bromo-6-fluoropyridine, and 2.0 L of DMF were added and stirred at 20°C to 30°C to dissolve. After cooling the internal temperature to -12°C, 100.39 g of KOH was added, and the mixture was stirred at an internal temperature of -12°C to -5°C for 5 hours or longer to complete the reaction. Once the addition was complete, the reaction was terminated by adding a DMF solution of acetic acid at an internal temperature of -6°C to -5°C. 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°C to 30°C for 16 hours or longer, the resulting crystals were filtered and washed with water. The product was vacuum dried at 55 °C to obtain 410.3 g of (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-onitrile]. According to this method, (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-onitrile was prepared simply, rapidly, and in high yield in a one-step reaction. Furthermore, the use of low-temperature reaction inhibited the formation of related substances and improved safety; direct precipitation into a solid provided a more desirable intermediate form for subsequent manufacturing processes (94.8% yield, 94.73% purity).

[0123] 1 H 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).

[0124] (Step B) Synthesis of 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester The 6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-onitrile (405.0 g), piperazine-1-carboxylic acid 1-tert-butyl ester (390.0 g), Cs₂CO₃ (909.67 g), Pd(OAc)₂ (6.45 g), and BINAP (36.74 g) synthesized in step A above were placed in a reactor and stirred under reflux at 115 °C for 2 to 3 hours in the presence of toluene (4.05 L). After the reaction was complete, the reaction solution was cooled to room temperature, and water (1.22 L) was added to terminate the reaction. The resulting product was filtered through diatomaceous earth. 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, and the mixture was 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, and the mixture was stirred for 10 minutes. The organic layer of the mixture was separated and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure at 55°C to give a brown, oily tert-butyl 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid, which was then directly proceeded to the next step (step 1) without further separation. This preparation method improves the reaction rate. Furthermore, by removing as much residue as possible from the reaction solution, the preparation of an intermediate with minimized side reactions was achieved.

[0125] (Step 1) Synthesis of 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile hydrochloride To the 4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester synthesized in step B above, isopropanol (4.05 L) was added, and the internal temperature was heated to 70 °C. Hydrochloric acid (37% w / w, 172 mL) was then slowly added dropwise over 30 minutes while maintaining the internal temperature at 70 °C. The reaction solution was then raised to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and stirred for 2 hours. The precipitated crystals were filtered and washed with isopropanol. The filtrate was dried under vacuum at 50 °C for 16 hours to obtain 348 g of 6-(((6-(piperazine-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile hydrochloride. The preparation of the hydrochloride by filtration simplifies the reaction process by eliminating the need for additional purification. Furthermore, this process yields the substance with high purity. (Yield: 75.1%, Purity: 98.43%) 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).

[0126] (Step 2) Synthesis of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester Add 320.0 g of 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile hydrochloride and 1.92 L of dichloromethane obtained in step 1 above and stir at room temperature. Dissolve 199.94 g of potassium carbonate in 960 mL of water and add it dropwise to the reaction solution over 20 minutes. Stir the reaction solution for 30 minutes, then separate and remove the aqueous layer. Add 1.28 L of a 5% aqueous sodium chloride solution to the organic layer, stir for 30 minutes, and then allow to stand to remove the aqueous layer. Concentrate the remaining organic layer under reduced pressure at 45 °C. Dissolve 1.9 L of acetonitrile in the concentrated residue and add methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (255.82 g) and 399.88 g of potassium carbonate. The reaction solution was stirred at an internal temperature of 75°C for 2 hours. Once the reaction was complete, the internal temperature was cooled 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 the reaction solution was allowed to stand, the aqueous 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°C. Ethyl acetate (1.6 L) and n-heptane (640 mL) were added to the concentrated residue, and the mixture was stirred at an internal temperature of 50°C to 60°C for 30 minutes, slowly cooled to room temperature over 3 hours, and stirred for 16 hours. The precipitated crystals were then filtered and washed twice with ethyl acetate / n-heptane (1:1 mixture, 640 mL). The washed product was vacuum dried at 50 °C to obtain 360 g of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester, which was a light brown solid. Coupling after the desalting reaction of the salt not only greatly increased the reaction rate but also significantly improved the purity by precipitation into crystals (yield: 74.9%, purity: 98.95%).

[0127] 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).

[0128] (Step 3) Synthesis of the free base of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid The following were added: (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (353.0 g), lithium bromide (840.27 g), water (211.8 mL), triethylamine (445 mL), and acetonitrile (3.53 L), obtained in Example 2 above. The mixture was stirred and refluxed for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 55 °C. Water (3.53 L) and ethyl acetate (1.77 L) were added to the concentrated residue, and the mixture was stirred at room temperature for 12 hours or longer to precipitate the 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 with a 15% citric acid aqueous 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 hydrochloric acid aqueous solution (2.82 L). The washed organic layer was washed with water (2.82 L), then separated and concentrated under reduced pressure. Acetonitrile (1.06 L), methanol (1.06 L), and ethyl acetate (706 mL) were added to the concentrated residue, and the mixture was heated and stirred at an internal temperature of 65 °C for 30 min. The reaction solution was slowly cooled to room temperature and stirred for 12 h or longer. The precipitated solid was washed with ethyl acetate and dried under vacuum at 50 °C 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-(oxepane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, which was a white solid (yield 81.24%, purity 98.41%).

[0129] 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).

[0130] (Step 3-b) Purification of the free base of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid Methanol (1.6 L) and tetrahydrofuran (400 mL) were added 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-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid obtained in step 3 above, and the mixture was stirred and refluxed at 60 °C for 2 hours. The reaction solution was slowly cooled to room temperature and stirred for 12 hours or longer. The precipitated solid was filtered, washed with methanol, and dried under vacuum at 50 °C to obtain 186 g of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, which was a white solid.

[0131] By removing relevant substances through the lithium salt separation process described above (step 3), and further removing relevant substances in the subsequent purification process (step 3, step 3-b), a preparation process for synthesizing high-purity free base was established. This process has high reproducibility (yield 93.0%, purity 99.51%).

[0132] (Step 4) Synthesis of the aminobutanetriol salt of (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid EtOAc (1.8 L) was added 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-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid prepared according to step 3, and the mixture was heated to 30 °C. When the internal temperature reached 30 °C, 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 °C to 60 °C for 4 hours, then cooled to room temperature and stirred for 12 hours. The filtered solid was washed with ethyl acetate and dried under vacuum at 50 °C to give 202.8 g of a white (S)-2-((4-(6-(((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid aminobutane glycerol salt (yield 92.0%, purity 99.55%).

[0133] 1 H 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).

[0134] It should be recognized that the above embodiments are merely examples of the implementation methods described above, and it is possible to improve the yield of the final material and the efficiency of the process while controlling quality.

[0135] With respect to these exemplary embodiments, it will be appreciated that by adjusting the process temperature, execution time, etc. of each step within the scope of the above embodiments, improvements in yield and process efficiency can be achieved while controlling the final material quality.

Claims

1. A method for preparing a compound represented by the following chemical formula 1: 1) Treat the compound represented by the following chemical formula 6 with acid to prepare the acid salt represented by the following chemical formula 7; 2) Adding a desalting agent to the compound represented by chemical formula 7, followed by reaction with the compound represented by chemical formula 8, yields the compound represented by chemical formula 9; and 3) Hydrolyze 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 the above chemical formula 6, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide; In the above chemical formula 8, X3 is F, Cl, Br, or I; and In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl or tert-butyl.

2. The method according to claim 1, wherein Pg1 in the above-described chemical formula 6 is tert-butyloxycarbonyl (Boc).

3. The method according to claim 1, wherein X3 in the above-described chemical formula 8 is Cl.

4. The method according to claim 1, wherein Pg2 in the above chemical formulas 8 and 9 is a methyl group.

5. The method according to claim 1, wherein the acid in step 1 is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, hydroiodic acid, fluoroboric acid, aluminum chloride, ferric chloride, boron trichloride ether complex, boron trichloride (BCl3), trimethylchlorosilane (TMSCl), tetrabutylammonium fluoride (TBAF), zinc bromide (ZnBr2), zinc chloride (ZnCl2), and magnesium bromide (MgBr2).

6. The method according to claim 1, wherein the desalting agent in step 2 is selected from 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 according to claim 1, wherein step 2 is carried out in the presence of an alkali and an organic solvent.

8. The method according to claim 7, wherein the base in step 2 is selected from at least one of triethylamine, N,N-diisopropylethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, and cesium carbonate.

9. The method according to claim 7, wherein the organic solvent in step 2 is selected from at least one 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.

10. The method according to claim 1, wherein the hydrolysis in step 3 is carried out in the presence of a hydrolysis reagent and an alkali, wherein the hydrolysis reagent is selected from at least one 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 according to claim 10, wherein the hydrolysis reagent is lithium bromide.

12. The method according to claim 10, wherein the base is selected from at least one of triethylamine (TEA), N,N-diisopropylethylamine, and diisopropylamine.

13. The method according to claim 1, further comprising, after step 3: 4) Add 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 according to claim 13, wherein the salt is selected from at least one 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 according to claim 13, wherein the salt is tromethamine.

16. The method of claim 1, further comprising: Step B is for the preparation of the compound represented by chemical formula 1: B) React the compound represented by chemical formula 4 with the compound represented by chemical formula 5 to prepare the compound represented by chemical formula 6; [Chemical Formula 4] [Chemical Formula 5] In the above chemical formula 4, X2 is F, Cl, Br, or I; and In the above chemical formula 5, Pg1 is benzyl (Bn), diphenylmethyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

17. The method of claim 16, further comprising: Step A is for preparing the compound represented by chemical formula 1: A) React the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to prepare the compound represented by chemical formula 4; [Chemical Formula 2] [Chemical Formula 3] In the above chemical formula 3, X1 and X2 are each independently F, Cl, Br or I.

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