Method for producing substituted condensed imidazole derivatives

Abstract

The present invention relates to a method for producing novel substituted condensed imidazole derivative compounds. The manufacturing method according to the present invention has the advantage of shortening the manufacturing process to ensure process efficiency, improving reaction rate and reactivity, and obtaining the intermediate as a solid, thereby enabling the production of high-purity compounds in high yield. This provides advantages that are useful for industrial mass production.

Description

TECHNICAL FIELD

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

BACKGROUND ART

[0002] Glucagon-like peptide-1 (GLP-1) is known as a hormone that acts on the receptor GLP-1R (Glucagon-like peptide-1 Receptor) to increase insulin secretion and is effective in lowering blood glucose. This hormone is also known to have effects such as reducing upper gastrointestinal motility and suppressing appetite, and to be capable of proliferating the existing pancreatic β cells. Due to these characteristics, GLP-1 is applicable as a therapeutic approach for type 2 diabetes, but its blood half-life is only 2 minutes, leading to various inconveniences for its development as a pharmaceutical agent. Recently, to solve the problem of the short duration of action of GLP-1, therapeutic agents have been developed in two approaches: GLP-1 analogs with resistance to dipeptidyl peptidase 4 (DPP-IV) that degrades GLP-1 in blood, and DPP-4 inhibitors.

[0003] Currently, various GLP-1 analogs with resistance to the DPP-4 enzyme that degrades GLP-1 in blood have been developed and are used as therapeutic agents for type 2 diabetes. Such GLP-1 analogs have a considerably longer half-life compared to native GLP-1, thus having the advantage of maintaining a hypoglycemic effect for a long period of time, but they cannot be orally administered and must be used in the form of injections, which poses the problem of low medication convenience. Therefore, studies are being actively conducted to discover orally available small-molecule GLP-1R agonists and develop them as therapeutic agents for diabetes.

[0004] For example, Korean Patent Registration No. 10-2344561 discloses a novel GLP-1R agonist compound that has excellent glucose tolerance improving effects in both intravenous and oral administration. Specifically, Korean Patent No. 10-2344561 discloses a method for producing a novel GLP-1R agonist compound via the following steps: (I) introducing appropriately substituted nicotinonitrile groups to the pyridinyl groups of a starting material in the presence of a base and an organic solvent; (II) introducing piperazine groups to the pyridinyl groups under a metal catalyst; (III) removing the protecting group of the piperazine group by reacting it with a deprotection reagent; (IV) introducing substituted benzimidazole groups to the piperazine groups 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 manufacturing method disclosed in the aforementioned patent requires separation and purification using column chromatography, making it difficult to apply to large-scale industrial production. Furthermore, it suffers from low reactivity and low yields, resulting in very poor economic viability.

[0005] To resolve the above-mentioned problems, the present inventors have developed a manufacturing method suitable for mass production by improving the reaction rate and reactivity of the manufacturing method disclosed in Korean Patent No. 10-2344561, shortening the manufacturing process to ensure process convenience, obtaining the intermediate as a solid to maximize purity with excellent purification function, and significantly increasing the production level of the target substance. Accordingly, the present invention is completed by providing a novel manufacturing process for a GLP-1R activator compound. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present invention provides a method for producing substituted condensed imidazole derivative compounds.

[0007] To solve the above-mentioned problems, a method for producing a substituted condensed imidazole derivative compound,

[0008] 1) A step of treating a compound represented by the following chemical formula 6 with an acid to produce an acidic salt represented by the following chemical formula 7,

[0009] 2) A step of adding a desalting agent to the compound represented by the following chemical formula 7, and then reacting it with the compound represented by the following chemical formula 8 to produce the compound represented by the following chemical formula 9,

[0010] 3) The step of hydrolyzing a compound represented by the following chemical formula 9 to produce a compound represented by the following chemical formula 1.

[0011] [Chemical formula 1]

[0012] JPEG2026534193000001.jpg38170

[0013] [Chemical formula 6]

[0014] JPEG2026534193000002.jpg24170

[0015] [Chemical formula 7]

[0016] JPEG2026534193000003.jpg24170

[0017] [Chemical formula 8]

[0018] JPEG2026534193000004.jpg37170

[0019] [Chemical formula 9]

[0020] JPEG2026534193000005.jpg32170

[0021] In the above chemical formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0022] In the above Chemical Formula 8, X3 is F, Cl, Br or I,

[0023] In the above Chemical Formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl. [Means for Solving the Problems]

[0024] In order to solve the above problems, the present invention provides a production method as shown in the following Reaction Scheme 1.

[0025] [Reaction Scheme 1]

[0026] JPEG2026534193000006.jpg56170

[0027] Specifically, the present invention provides a method for producing the compound represented by the above Chemical Formula 1, comprising the following steps 1 to 3.

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

[0029] 2) a step of adding a desalting agent to the compound represented by the above Chemical Formula 7, then reacting the resultant with the compound represented by the above Chemical Formula 8 to produce the compound represented by the above Chemical Formula 9;

[0030] 3) a step of hydrolyzing the compound represented by the above Chemical Formula 9 to produce the compound represented by the above Chemical Formula 1.

[0031] In the above Chemical Formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz) or trifluoroacetamide,

[0032] In the above Chemical Formula 8, X3 is F, Cl, Br or I,

[0033] In the above Chemical Formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl.

[0034] Furthermore, the present invention provides a method for producing the compound represented by chemical formula 1, as shown in reaction formula 2, which optionally further comprises step B below.

[0035] [Reaction Equation 2]

[0036] JPEG2026534193000007.jpg72170

[0037] B) A step of reacting a compound represented by the following chemical formula 4 with a compound represented by the following chemical formula 5 to produce the compound represented by the chemical formula 6;

[0038] 1) A step of treating the compound represented by chemical formula 6 with an acid to produce an acidic salt represented by chemical formula 7;

[0039] 2) A 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 produce the compound represented by chemical formula 9;

[0040] 3) A step of hydrolyzing the compound represented by chemical formula 9 to produce the compound represented by chemical formula 1.

[0041] [Chemical formula 4]

[0042] JPEG2026534193000008.jpg24170

[0043] [Chemical formula 5]

[0044] JPEG2026534193000009.jpg24170

[0045] In the aforementioned chemical formula 4, X2 is F, Cl, Br, or I.

[0046] In the above chemical formula 5, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0047] In the above chemical formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0048] In the aforementioned chemical formula 8, X3 is F, Cl, Br, or I.

[0049] In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl.

[0050] Furthermore, the present invention provides a method for producing the compound represented by chemical formula 1, as shown in reaction formula 3, which optionally further comprises steps A and B below.

[0051] [Reaction Equation 3]

[0052] JPEG2026534193000010.jpg95170

[0053] A) A step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce the compound represented by the chemical formula 4;

[0054] B) A step of reacting the compound represented by chemical formula 4 with the compound represented by chemical formula 5 to produce the compound represented by chemical formula 6;

[0055] 1) A step of treating the compound represented by chemical formula 6 with an acid to produce an acidic salt represented by chemical formula 7;

[0056] 2) A 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 produce the compound represented by chemical formula 9;

[0057] 3) A step of hydrolyzing the compound represented by chemical formula 9 to produce the compound represented by chemical formula 1.

[0058] [Chemical formula 2]

[0059] JPEG2026534193000011.jpg22170

[0060] [Chemical formula 3]

[0061] JPEG2026534193000012.jpg22170

[0062] In the aforementioned chemical formula 3, X1 and X2 are each independently F, Cl, Br, or I.

[0063] In the aforementioned chemical formula 4, X2 is F, Cl, Br, or I.

[0064] In the above chemical formula 5, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0065] In the above chemical formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0066] In the aforementioned chemical formula 8, X3 is F, Cl, Br, or I.

[0067] In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl.

[0068] Furthermore, the present invention provides a method for producing a salt compound of the compound represented by chemical formula 1, as shown in reaction formula 4, which optionally further comprises step 4 below.

[0069] [Reaction Equation 4]

[0070] JPEG2026534193000013.jpg86170

[0071] 1) A step of treating the compound represented by chemical formula 6 with an acid to produce an acidic salt represented by chemical formula 7;

[0072] 2) A 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 produce the compound represented by chemical formula 9;

[0073] 3) A step of hydrolyzing the compound represented by chemical formula 9 to produce the compound represented by chemical formula 1;

[0074] 4) A step of adding a salt to the compound represented by chemical formula 1 to produce a salt compound of the compound represented by chemical formula 1.

[0075] In the above chemical formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0076] In the aforementioned chemical formula 8, X3 is F, Cl, Br, or I.

[0077] In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl.

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

[0079] [Step 1]

[0080] Step 1 is a step of treating the compound represented by chemical formula 6 with an acid to remove the protecting group and produce an acidic salt represented by chemical formula 7.

[0081] The type of acid that can be used in step 1 is not particularly limited and may be a Brønsted acid or a 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, hydroiodic 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 complex, 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, or trifluoroacetic acid can be used. More preferably, hydrogen chloride can be used.

[0084] The reaction in step 1 can be carried out under an organic solvent, which 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, n-hexane, dimethyl sulfoxide, or a mixture of two or more of these. Preferably, isopropyl alcohol or acetone can be used.

[0085] The reaction in step 1 can be carried out at a temperature of 60°C to 120°C. If the reaction temperature is below 60°C, there is a problem of low production yield, and if the reaction temperature is above 120°C, side reactions may occur, which is undesirable. More specifically, the reaction can be carried out at a temperature of 80°C to 100°C.

[0086] The reaction in step 1 can be carried out for 30 minutes to 8 hours. If the reaction time is less than 30 minutes, the reaction will not be sufficient, resulting in a low production yield. If the reaction time exceeds 8 hours, the production yield will not substantially increase. More specifically, the reaction can be carried out for 1 hour to 5 hours.

[0087] According to a preferred embodiment of the present invention, in step 1, by using hydrogen chloride as the acid and isopropyl alcohol as the reaction solvent, the compound of chemical formula 7 can be precipitated as a solid HCl salt. Therefore, step 1 has the advantage of obtaining a high-purity product by filtration and washing alone, without a work-up process, resulting in excellent purification efficiency and simplified processing.

[0088] In one embodiment, when hydrogen chloride is used in step 1, the compound of chemical formula 7 may be the compound represented by the following chemical formula 7-1.

[0089] [Chemical formula 7-1]

[0090] JPEG2026534193000014.jpg24170

[0091] [Step 2]

[0092] Step 2 is a 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 produce the compound represented by chemical formula 9, wherein a benzimidazole group substituted for the piperazine group of the compound represented by chemical formula 7 is introduced.

[0093] More specifically, step 2 involves desalting the compound represented by chemical formula 7 before adding the compound represented by chemical formula 8 to facilitate the coupling reaction. Step 2 can consist of step 2-1, which involves adding a desalting agent, and step 2-2, which involves adding the compound represented by chemical formula 8.

[0094] [Reaction Equation 5]

[0095] JPEG2026534193000015.jpg48170

[0096] In the case of reaction equation 5, the manufacturing method is as follows.

[0097] 2-1) A step of desalting the compound represented by chemical formula 7 by adding a desalting agent;

[0098] 2-2) Adding the compound represented by chemical formula 8 to the desalted compound to convert it to the compound represented by chemical formula 9; here, so that steps 2-1 and 2-2 are carried out in situ, the compound represented by chemical formula 8 may be added to the reaction mixture after step 2-1.

[0099] In step 2-1, the desalting agent refers to various compounds used in the industry to remove acidic salts, and may be alkali metal hydroxides, alkali metal salts, or low molecular weight amines.

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

[0101] Specifically, the alkali metal salt may be any one selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, sodium lactate, sodium citrate, disodium tartrate, sodium bitartrate, 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 can be used as the desalting agent in step 2-1.

[0104] The desalting treatment in step 2-1 can be carried out in an organic solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate, and 2-methyltetrahydrofuran. Preferably, dichloromethane can be used.

[0105] The reaction in step 2-1 can be carried out at a temperature of 10 to 90°C. Preferably, it can be carried out under room temperature conditions.

[0106] Furthermore, the reaction in step 2-1 can be carried out for 10 minutes to 5 hours. Preferably, the reaction can be carried out for 10 minutes to 1 hour.

[0107] For example, the reaction in step 2-1 can be carried out by mixing the compound represented by chemical formula 7 with dichloromethane at room temperature, gradually adding an aqueous potassium carbonate solution dropwise, and then stirring for 30 minutes.

[0108] Step 2-2 is a step of adding the compound represented by chemical formula 8 to the desalted compound to produce the compound represented by chemical formula 9.

[0109] The reaction in step 2-2 can be carried out in the presence of a base and an organic solvent. Here, as the base, 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 of these can be used. Preferably, potassium carbonate can be used.

[0110] As the reaction solvent in step 2-2, one or more 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 can be used. Preferably, acetonitrile can be used as the reaction solvent in step 2-2.

[0111] In step 2-2, the molar ratio of the compound represented by chemical formula 7 to the compound represented by chemical formula 8 may be 10:1 to 1:10, more preferably 5:1 to 1:5, and even more preferably 3:1 to 1:3.

[0112] The reaction in step 2-2 can be carried out at a temperature of 60°C to 90°C. If the reaction temperature is below 60°C, there is a problem of low production yield, and if the reaction temperature is above 90°C, side reactions may occur, which is undesirable. More specifically, the reaction can be carried out at a temperature of 70°C to 80°C.

[0113] The reaction in step 2-2 can be carried out for 30 minutes to 8 hours. If the reaction time is less than 30 minutes, the reaction will not be sufficient, resulting in a low production yield. If the reaction time exceeds 8 hours, the production yield will not substantially increase. More specifically, the reaction can be carried out for 1 hour to 5 hours.

[0114] The process may further include, if necessary, obtaining the organic layer by extracting it 1 to 3 times with an organic solvent, and purifying the compound represented by chemical formula 9 from this organic layer.

[0115] For the extraction, an organic solvent such as 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 of these can be used. Preferably, ethyl acetate can be used.

[0116] The purification step can be carried out by crystallizing the compound represented by chemical formula 9 from the reaction product of step 2. As the solvent for crystallizing the compound represented by chemical formula 9 from the reaction product of step 2-2, organic solvents such as acetone, ethyl acetate, methyl acetate, isopropyl acetate, acetonitrile, diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, n-hexane and n-heptane, or mixtures of two or more of these may be used.

[0117] Preferably, the crystallization solvent can be a mixture of ethyl acetate and n-heptane. For example, this can be carried out by adding ethyl acetate and n-heptane to the concentrated residue from step 2-2 at a temperature range of 50°C to 60°C, stirring for 30 minutes or more, then gradually cooling to room temperature, and stirring for 16 hours or more.

[0118] After purifying the compound represented by chemical formula 9, it can be dried to reduce its water content. For example, drying it at a temperature range of 40°C to 60°C for 12 hours or more can significantly reduce the water content of the compound represented by chemical formula 9.

[0119] [Step 3]

[0120] Step 3 is a step of hydrolyzing the compound represented by chemical formula 9 to produce the compound represented by chemical formula 1.

[0121] The hydrolysis in step 3 can be carried out in the presence of a hydrolysis reagent and a base.

[0122] In step 3, the hydrolysis reagent can be one or more selected from the group consisting of sodium bromide, sodium potassium iodide, 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 can be used. In particular, by using the hydrolysis reagent, the oxetane salt reaction or amide formation reaction of the compound represented by chemical formula 9 that may occur when metal hydroxides are used can be suppressed, minimizing the generation of related substances and increasing the yield and purity of the final product.

[0124] In step 3, the base may be a low molecular weight amine. Specifically, one or more selected from the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, and diisopropylamine can be used. Preferably, triethylamine can be used.

[0125] In step 3, the molar ratio of the compound represented by chemical formula 9 to the hydrolysis reagent and the base can be 10:1 to 1:20, respectively. That is, the reaction in step 2 can be used such that the molar ratio of the compound represented by chemical formula 9 to the hydrolysis reagent is 10:1 to 1:20, and the molar ratio of the compound represented by chemical formula 9 to the base is 10:1 to 1:20. Preferably, each molar ratio may be 1:1 to 1:20.

[0126] The reaction in step 3 can use one or more of the following as the reaction solvent: water, acetonitrile, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. Specifically, acetonitrile can be used as the reaction solvent in step 3.

[0127] The reaction in step 3 can be carried out at 60-90°C. Specifically, the reaction within the temperature range of step 3 can help increase the conversion rate of step 3 and reduce the content of related substances in the final product.

[0128] The reaction in step 3 can be carried out for 30 minutes to 8 hours. If the reaction time is less than 30 minutes, the reaction will not be sufficient, resulting in a low production yield. If the reaction time exceeds 8 hours, the production yield will not substantially increase. More specifically, the reaction can be carried out for 1 hour to 5 hours.

[0129] After the reaction is complete, the process may optionally include a step of purifying the compound represented by chemical formula 1. This purification can be carried out by precipitating the lithium salt of the compound represented by chemical formula 1 from the reaction solution after the reaction is complete, washing it with an acidic aqueous solution, and then crystallizing it into the compound represented by chemical formula 1.

[0130] As a solvent for precipitating the lithium salt of the compound represented by chemical formula 1, a mixture of a carbon-2 to carbon-4 alcohol or alkyl acetate and water can be used. Specifically, the carbon-2 to carbon-4 alcohol may be one or more selected from the group consisting of ethanol, propanol, isopropanol, butanol, and tert-butanol. Specifically, the alkyl acetate may be one or more selected from the group consisting of methyl acetate, ethyl acetate, and isopropyl acetate. Preferably, a mixed solvent of ethyl acetate and water can be used. Through such a precipitation process, it can be shown to have an excellent effect in removing related substances that dissolve in organic solvents.

[0131] The acidic aqueous solution may be an inorganic acid or an organic acid. Specifically, it may be one or more inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Specifically, it may be 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 solution of citric acid can be used. Such a washing process can be very effective in removing amidated related substances.

[0132] The crystallization solvent for the compound represented by chemical formula 1 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 mixture thereof. Preferably, a mixture of methanol, ethyl acetate, and acetonitrile can be used.

[0133] After crystallization of the compound represented by chemical formula 1, further purification can be performed. The additional purification solvent may be any one or a mixture of solvents 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, or a mixed solvent of potassium carbonate and water. Preferably, a mixed solvent of tetrahydrofuran and methanol can be used. Such additional purification can 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 water content of the compound can be reduced by drying it at 40°C to 60°C to obtain a high-purity product.

[0135] [Step 4]

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

[0137] This four-step process can be carried out through the following steps:

[0138] 4) A method for producing a salt compound of the compound represented by chemical formula 1, further comprising the step of adding a salt to the compound represented by chemical formula 1 to produce a salt compound of the compound represented by chemical formula 1.

[0139] Step 4 is a step of adding a salt to the compound represented by chemical formula 1, either simultaneously with or after Step 3, in order to supply the compound represented by chemical formula 1 in the form of a pharmaceutically acceptable salt, thereby obtaining a pharmaceutically acceptable salt compound of the compound represented by chemical formula 1.

[0140] Specifically, step 4 may include supplying an organic solvent to the compound represented by chemical formula 1, followed by supplying a salt or a mixed solution of the salt and the organic solvent to crystallize the salt compound of the compound represented by chemical formula 1.

[0141] More specifically, an organic solvent can be supplied to the compound represented by chemical formula 1. The organic solvent supplied may be a combination of one or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, n-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran. Preferably, the organic solvent may be a combination of one or more organic solvents composed of methanol, ethanol, isopropyl alcohol, 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 present invention has excellent advantages in that it minimizes the generation of related substances and allows for the production of the target salt without additional purification steps.

[0142] Among the salt compounds of the compound represented by the chemical formula 1, pharmaceutically acceptable salt compounds include acid addition salts and base addition salts.

[0143] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspatate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edicelate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hypenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, This includes maleates, maleates, malonates, mesylates, methyl sulfates, naphthylates, 2-naphthylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, 1,5-naphthalenedisulfonic acid, and xinafoate salts.

[0144] Suitable base addition salts are formed from bases that form non-toxic salts. Examples 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 salts of the compounds represented by chemical formula 1 may be one or more selected from the group consisting of L-lysine, L-arginine, L-histidine, choline hydroxide, meglumine, ammonia, sodium hydroxide, potassium hydroxide, potassium hydroxide, magnesium hydroxide, L-arginine, L-cysteine, tromethamine (TRIS), L-glutamine, tert-butylamine, citrate, malate, and fumarate.

[0146] By supplying the organic solvent to the compound represented by chemical formula 1, adjusting the internal temperature of the reactor to 15°C to 35°C, preferably 20°C to 30°C, and stirring the mixed solution of salt and organic solvent, the salt compound of the compound represented by chemical formula 1 can be crystallized.

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

[0148] In one embodiment, when the salt used to crystallize the salt compound of the compound represented by chemical formula 1 is tromethamine, the crystal has the chemical structure of chemical formula 1-1 shown below.

[0149] [Chemical formula 1-1]

[0150] JPEG2026534193000016.jpg31170

[0151] After the salt is produced, it can be dried at 45-55°C to reduce the water content in the salt compound of the compound represented by chemical formula 1. This significantly reduces the water content of the salt, maximizing the yield of the target compound.

[0152] If necessary, in step 4, the crystallization of the salt compound of the compound represented by chemical formula 1 may be carried out two or more times.

[0153] For example, after crystallizing a salt compound of the compound represented by chemical formula 1, the salt compound of the compound represented by chemical formula 1 is extracted using the organic solvent, and then a mixed solution of the salt or the organic solvent is supplied to recrystallize the salt compound represented by chemical formula 1.

[0154] The process may further include a washing step using the solvent used after the reaction has been completed in each of the above steps.

[0155] According to one embodiment of the present invention, compound 6 can be produced by the reaction in 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 produce the compound represented by chemical formula 6.

[0158] The reaction in step B can be carried out in the presence of a palladium catalyst, a metal catalyst ligand, and a base.

[0159] The palladium catalyst is a Pd(0) and Pd(II) complex, such as allylchloro[1,3-bis(2,4,6-trimethylphenyl)imidazole-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, dihydrogentetrachloropalladium(II)(H2[P It may be any one selected from the group consisting of [dCl4]), diamine dinitritopalladium(II), palladium(II) sulfate, tetraamine palladium(II) sulfate ([Pd(NH3)4]SO4), tetraamine palladium(II) hydrogen carbonate, tetraamine palladium(II) chloride ([Pd(NH3)4]Cl2), potassium tetrachloropalladium(II) (K2[PdCl4]), sodium tetrachloropalladium(II) (Na2[PdCl4]), ammonium tetrachloropalladium(II) ((NH4)2[PdCl4]), tetraamine palladium(II) nitrate, 1,3-divinyl-1,1,3,3-tetramethyldisiloxanepalladium(0) and bis(dibenzylideneacetone)palladium(0) (Pd(dba)2).

[0160] The metal catalyst ligand is a phosphine or aza / phosphine ligand, for example, 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 Any one selected from the group consisting of (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 in step B, 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, it is preferable to use palladium(II) acetate as the palladium catalyst, 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (BINAP) as the metal catalyst ligand, and cesium carbonate as the base.

[0163] In step B, the palladium catalyst and the metal catalyst ligand can each be used in amounts of 0.01 to 1 equivalent compared to the compound represented by chemical formula 4. Preferably, the palladium catalyst and the metal catalyst ligand can each be used in amounts of 0.01 to 0.5 equivalents. If the amounts of the copper catalyst, metal catalyst ligand, co-catalyst, and base used are below the lower limit, the reaction rate and yield may decrease, and if they exceed the upper limit, the economic benefits during production may decrease.

[0164] As the reaction solvent in step B, one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, diethyl ether, tert-butyl ethyl ether, tert-butyl methyl ether, dioxaneethylene 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 can be used. Preferably, toluene can be used as the reaction solvent in step B.

[0165] The reaction temperature in step B may be 90 to 120°C. If the reaction temperature is below 90°C, there is a problem of low production yield, and if the reaction temperature is above 120°C, the production yield does not substantially increase. More specifically, the reaction can be carried out at 100 to 120°C.

[0166] The reaction in step B can be carried out for 30 minutes to 8 hours. If the reaction time is less than 30 minutes, the reaction will not be sufficient, resulting in a low production yield. If the reaction time exceeds 8 hours, the production yield will not substantially increase. More specifically, the reaction can be carried out for 1 to 5 hours.

[0167] After the reaction is complete, the reaction solution may be washed with an acidic aqueous solution. The acidic aqueous solution may be an inorganic acid or an organic acid.

[0168] Specifically, it may be one or more inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Specifically, it may be 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 solution of acetic acid can be used. Such a washing process can effectively remove residual by-products, such as starting materials that do not participate in the reaction, for example, the compound represented by chemical formula 5, palladium catalysts, etc.

[0169] According to one embodiment of the present invention, the next step (step 1) can be performed without additional separation of the compound represented by chemical formula 6, so that steps B and 1 are performed in situ.

[0170] In this reaction, X2 in chemical formula 4 may be Br. The Br functional group can further increase the rate and efficiency of the metal-catalyzed reaction.

[0171] The present invention can optionally further include step B to produce a compound represented by chemical formula 1. In this case, a production method as shown in reaction formula 2 below is provided.

[0172] [Reaction Equation 2]

[0173] JPEG2026534193000017.jpg72170

[0174] B) A step of reacting a compound represented by the following chemical formula 4 with a compound represented by the following chemical formula 5 to produce the compound represented by the chemical formula 6;

[0175] 1) A step of treating the compound represented by chemical formula 6 with an acid to produce an acidic salt represented by chemical formula 7;

[0176] 2) A 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 produce the compound represented by chemical formula 9;

[0177] 3) A step of hydrolyzing the compound represented by chemical formula 9 to produce the compound represented by chemical formula 1.

[0178] [Chemical formula 4]

[0179] JPEG2026534193000018.jpg24170

[0180] [Chemical formula 5]

[0181] JPEG2026534193000019.jpg24170

[0182] In the aforementioned chemical formula 4, X2 is F, Cl, Br, or I.

[0183] In the above chemical formula 5, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0184] In the above chemical formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0185] In the aforementioned chemical formula 8, X3 is F, Cl, Br, or I.

[0186] In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl.

[0187] Furthermore, according to one embodiment of the present invention, compound 4 can be produced by the reaction in step A below.

[0188] [Step A]

[0189] Step A is a step of adding the compound represented by chemical formula 3 to the compound represented by chemical formula 2 to produce the compound represented by chemical formula 4.

[0190] The reaction in step A can be carried out in the presence of a base and an organic solvent. Here, as the base, 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 of these can be used. Preferably, potassium hydroxide or sodium hydroxide can be used.

[0191] As the reaction solvent in step A, one or more selected from the group consisting of 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 can be used. Preferably, N,N-dimethylformamide can be used as the reaction solvent in step A.

[0192] In step A, the molar ratio of the compound represented by chemical formula 2 to the compound represented by chemical formula 3 may be 10:1 to 1:10, more preferably 5:1 to 1:5, and even more preferably 3:1 to 1:3.

[0193] The reaction temperature in step A may be -20 to 5°C. If the reaction temperature is below -20°C, there is a problem of low production yield, and if the reaction temperature is above 5°C, the production yield does not substantially increase. More specifically, the reaction can be carried out at -15 to 0°C. Thus, step A has the advantage of suppressing side reactions and minimizing the generation of related substances by carrying out the reaction at a low temperature, and ensuring safety against heat that may be generated during mass production.

[0194] The reaction in step A can be carried out for 4 to 24 hours. If the reaction time is less than 4 hours, the reaction will not be sufficient, resulting in a low production yield. If the reaction time exceeds 24 hours, the production yield will not increase substantially. More specifically, the reaction can be carried out for 5 to 10 hours.

[0195] After the reaction is complete, the process may optionally further include a step of purifying the compound represented by chemical formula 4. This purification can be carried out by crystallizing the compound represented by chemical formula 4 from the reaction product of step A.

[0196] As the solvent for crystallizing the compound represented by chemical formula 4 from the reaction product of step A, water or an alcohol having 1 to 4 carbon atoms can be used. More specifically, as the crystallization solvent, water, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixture of two or more of these can be used. Specifically, water can be used. For example, this can be done by adding water to the reaction product of step A at a temperature range of 20 to 30°C and stirring for 16 hours or more.

[0197] After purifying the compound represented by chemical formula 4, it can be dried to reduce its water content. For example, drying it in a temperature range of 40°C to 60°C can significantly reduce its water content.

[0198] The present invention can selectively further comprise steps A and B to produce a compound represented by chemical formula 1. In this case, a production method like the one shown in reaction formula 3 below is provided.

[0199] [Reaction Equation 3]

[0200] JPEG2026534193000020.jpg72170

[0201] A) A step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce the compound represented by the chemical formula 4;

[0202] B) A step of reacting the compound represented by chemical formula 4 with the compound represented by chemical formula 5 to produce the compound represented by chemical formula 6;

[0203] 1) A step of treating the compound represented by chemical formula 6 with an acid to produce an acidic salt represented by chemical formula 7;

[0204] 2) A 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 produce the compound represented by chemical formula 9;

[0205] 3) A step of hydrolyzing the compound represented by chemical formula 9 to produce the compound represented by chemical formula 1.

[0206] [Chemical formula 2]

[0207] JPEG2026534193000021.jpg22170

[0208] [Chemical formula 3]

[0209] JPEG2026534193000022.jpg22170

[0210] In the aforementioned chemical formula 3, X1 and X2 are each independently F, Cl, Br, or I.

[0211] In the aforementioned chemical formula 4, X2 is F, Cl, Br, or I.

[0212] In the above chemical formula 5, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0213] In the above chemical formula 6, Pg1 is a benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

[0214] In the aforementioned chemical formula 8, X3 is F, Cl, Br, or I.

[0215] In the above chemical formulas 8 and 9, Pg2 is methyl, ethyl, benzyl, or tert-butyl.

[0216] On the other hand, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, comprising the compound of chemical formula 1, or a pharmaceutically acceptable salt thereof (preferably chemical formula 1-1).

[0217] The present invention provides compounds of chemical formula 1 as defined in any embodiment described herein, or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0218] The present invention provides compounds of chemical formula 1 as defined in any embodiment described herein, or pharmaceutically acceptable salts thereof, for use in the prevention or treatment of metabolic diseases.

[0219] The present invention provides a method for treating a metabolic disease, comprising the step of administering a therapeutically effective amount of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject requiring it.

[0220] Specifically, the metabolic diseases mentioned above include diabetes mellitus, idiopathic type 1 diabetes mellitus, latent autoimmune diabetes mellitus in adulthood (LADA), early-onset type 2 diabetes mellitus (EOD), early-onset atypical diabetes mellitus (YOAD), early-onset adult-onset diabetes mellitus (MODY), malnutrition-related 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 syndrome, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, and lung disease. One or more conditions may be selected from the group consisting of hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, decreased vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, carbohydrate metabolism disorders, fasting blood glucose disorders, hyperuricemia, gout, erectile dysfunction, psoriasis, lower extremity ulcers, ulcerative colitis, hyper-apo-B lipid proteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

[0221] Specifically, the non-alcoholic fatty liver disease may be one or more selected from the group consisting of, for example, dyslipidemia, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The exemplary non-alcoholic fatty liver diseases mentioned above include a category of metabolic diseases that have a significant association with various medical conditions other than alcoholic liver disease.

[0222] The aforementioned pharmaceutical composition may contain the compound of the present invention together with a pharmaceutically acceptable carrier. Other pharmacologically active ingredients may also be present. In the present invention, “pharmaceutically acceptable carrier” includes any and all physiologically miscible solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic formulations and absorption retarders, and the like.

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

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

[0225] The oral administration in solid form may be provided, for example, as hard or soft capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of one or more compounds of the present invention. In yet another embodiment, the oral administration may be in the form of a powder or granules.

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

[0227] In yet another embodiment, the present invention includes forms of parenteral administration. "Pareral 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 formed into dosage forms according to known techniques using suitable dispersants, wetting agents and / or suspending agents.

[0228] Other carrier substances and administration methods known in the pharmaceutical technology field may also be used. The pharmaceutical compositions of the present invention can be manufactured by any widely known pharmaceutical technology, such as effective dosage form and administration procedures.

[0229] Typically, the compounds of the present invention are administered in amounts effective to treat the symptoms described herein. The compounds of the present invention can be administered as the compounds themselves or, otherwise, as pharmaceutically acceptable salts. For administration and dosage purposes, the compounds themselves or pharmaceutically acceptable salts thereof are simply referred to as the compounds of the present invention.

[0230] The compounds of the present invention are administered by any preferred route, in the form of a pharmaceutically appropriate composition for that route, and in a dose effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally, or topically.

[0231] 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.

[0232] In yet another embodiment, the compounds of the present invention can also be administered directly into the bloodstream, muscles, or internal organs. Preferred means of parenteral administration include intravenous, intra-arterial, intraperitoneal, intramuscular, and subcutaneous.

[0233] Therapeutic administration of the compound of the present invention or a composition containing the compound depends on various factors, including the patient's type, age, weight, sex, and medical symptoms; the severity of the symptoms; the route of administration; and the activity of the specific compound used. Therefore, therapeutic administration can vary widely. In one embodiment, the total daily dose of the compound of the present invention is typically 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 in the present invention. [Effects of the Invention]

[0234] The manufacturing method according to the present invention is a method for producing a GLP-1 receptor agonist that can be mass-produced, and has the advantages of shortening the manufacturing process by using a salt, ensuring process convenience, minimizing the generation of related substances, and increasing yield and purity. Furthermore, the manufacturing method according to the present invention has the advantage of eliminating the column chromatography purification step. As a result, it is possible to improve process efficiency with excellent yield and obtain advantages useful for industrial mass production. [Modes for carrying out the invention]

[0235] The present invention will be described in more detail below with reference to the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

[0236] The manufacturing process according to an embodiment of the present invention is schematically described as shown in reaction equation 6 below.

[0237] [Reaction Equation 6]

[0238] JPEG2026534193000023.jpg127170

[0239] Example 1. Preparation of tromethamine salt of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

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

[0241] JPEG2026534193000024.jpg24170

[0242] 200.0 g of 6-(hydroxymethyl)pyridine-3-carbonitride, 275.50 g of 2-bromo-6-fluoropyridine, and 2.0 L of DMF were added and stirred at 20-30°C until dissolved. After cooling the internal temperature to -12°C, 100.39 g of KOH was added, and the reaction was terminated by stirring at an internal temperature of -12 to -5°C for at least 5 hours. Once the reaction was complete, acetic acid dissolved in DMF was added at an internal temperature of -6 to -5°C 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 20-30°C for at least 16 hours, the resulting crystals were filtered and washed with water. Vacuum drying at 55°C yielded 410.3 g of (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitride. According to this manufacturing method, (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitride was produced simply, rapidly, and in high yield in a single-step reaction. Furthermore, the low-temperature reaction suppressed the formation of related substances, improving safety, and direct precipitation onto a solid provided a more favorable intermediate for subsequent manufacturing processes (yield 94.8%, purity 94.73%).

[0243] 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)

[0244] (Step B) Synthesis of tert-butyl 4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-carboxylate

[0245] JPEG2026534193000025.jpg30170

[0246] The (6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (405.0 g), 1-tert-butylpiperazine-1-carboxylate (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 2-3 hours under toluene (4.05 L) solvent. After the reaction was completed, the reaction mixture was cooled to room temperature, water (1.22 L) was added to terminate the reaction, and the mixture was filtered through Celite. The aqueous layer was removed, acetic acid (48 mL) was added to the organic layer and stirred for 15 minutes, then water (1.22 L) was added. The mixture was stirred for 30 minutes and then allowed to stand before removing the aqueous layer. 4.0 L of 10% sodium chloride aqueous solution was added to the organic layer and stirred for 10 minutes. The organic layer of the mixture was then separated and filtered through Celite. The filtrate was concentrated under reduced pressure at 55°C to obtain a brown, oily tert-butyl 4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-carboxylate, and the process proceeded immediately to the next step (Step 1) without further separation. This manufacturing process improved the reaction rate. Furthermore, by minimizing the removal of residual substances remaining in the reaction solution, the intermediate was successfully produced, minimizing the occurrence of side reactions.

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

[0248] JPEG2026534193000026.jpg30170

[0249] To the tert-butyl 4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-carboxylate synthesized in step B, isopropyl alcohol (4.05 L) was added and the internal temperature was heated to 70°C. Hydrochloric acid (37% w / w, 172 mL) was gradually added dropwise over 30 minutes while maintaining the internal temperature at 70°C. The temperature of the reaction mixture was then raised to 90°C and stirred for 3 hours. Once the reaction was complete, the temperature of the reaction mixture 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°C for 16 hours to obtain 348 g of 6-(((6-(piperazine-1-yl)pyridine-2-yl)oxy)methyl)nicotinonitrile hydrochloride. The production of the hydrochloride simplified the reaction process by allowing the substance to be obtained by filtration without additional purification steps. Furthermore, this process ensured that the substance was obtained with high purity (yield: 75.1%, purity: 98.43%).

[0250] 1 H 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-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0252] JPEG2026534193000027.jpg57170

[0253] 320.0 g of 6-(((6-(piperazin-1-yl)pyridine-2-yl)oxy)methyl)nicotinonitrile hydrochloride (obtained in step 1) and 1.92 L of dichloromethane were added and stirred at room temperature. 199.94 g of potassium carbonate dissolved in 960 mL of water was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred for 30 minutes, and the aqueous layer was separated and removed. 1.28 L of 5% sodium chloride aqueous solution was added to the organic layer and stirred for 30 minutes, after which it was allowed to stand and the aqueous layer was removed. The remaining organic layer was concentrated under reduced pressure at 45°C. The concentrated residue was dissolved in acetonitrile (1.9 L), 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 mixture was stirred at an internal temperature of 75°C for 2 hours. Once the reaction was complete, the internal temperature was lowered to room temperature, and ethyl acetate (2.9 L) and water (1.28 L) were added to the reaction mixture and stirred for 30 minutes. After standing, the aqueous layer was separated and removed. Water (1.28 L) was added to the remaining organic layer and stirred for 30 minutes, then allowed to stand and the aqueous layer was separated. 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 50-60°C for 30 minutes. After that, it was gradually cooled to room temperature for 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). Vacuum drying was performed at 50°C to obtain 360 g of pale brown solid methyl(S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. After the desalting reaction of the salt, coupling was performed not only to significantly increase the reaction rate, but also to greatly improve the purity through 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 the free base of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0256] JPEG2026534193000028.jpg41170

[0257] Methyl(S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (353.0 g), lithium bromide (840.27 g), water (211.8 mL), triethylamine (445 mL), and acetonitrile (3.53 L) were added and the mixture was stirred under reflux for 2 hours. Once 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 at least 12 hours to precipitate the lithium salt. The precipitated lithium salt was filtered and washed with ethyl acetate. The washed lithium salt was mixed with water (3.53 L) and the pH was adjusted to 4 using a 15% 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 in a 0.09 N hydrochloric acid solution (2.82 L). The washed organic layer was washed with water (2.82 L), 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 minutes. The reaction mixture was gradually cooled to room temperature and stirred for at least 12 hours. The precipitated solid was washed with ethyl acetate and vacuum-dried at 50°C to obtain 279.5 g of the free base of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-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, 1H), 2.37 - 2.49 (m, 5H).

[0259] (Step 3-b) Purification of the free base of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0260] To the free base (200.0 g) of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid obtained in step 3, methanol (1.6 L) and tetrahydrofuran (400 mL) were added and the mixture was stirred under reflux at 60°C for 2 hours. The temperature of the reaction mixture was gradually cooled to room temperature and stirred for at least 12 hours. The precipitated solid was filtered, washed with methanol, and then vacuum-dried at 50°C to obtain 186 g of a white solid ((S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0261] By removing related substances through the lithium salt separation process described above (Step 3), and further removing related substances in subsequent purification steps (Step 3, Step 3-b), a manufacturing process for synthesizing high-purity free base with reproducibility was established (yield 93.0%, purity 99.51%).

[0262] (Step 4) Synthesis of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0263] JPEG2026534193000029.jpg39170

[0264] 180.0 g of the free base of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, prepared in Step 3, was mixed with 1.8 L of butyl and 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 mixture was stirred at 55-60°C for 4 hours, then cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with ethyl acetate, and then vacuum-dried at 50°C to obtain 202.8 g of the white tromethamine salt of (S)-2-((4-(6-((5-cyanopyridine-2-yl)methoxy)pyridine-2-yl)piperazine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-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, 1H), 2.57 - 2.47 (m, 5H).

[0266] On the other hand, the above-described embodiment is merely an example of one embodiment, and it is also possible to improve the yield and process efficiency of the final product and to control the quality.

[0267] By referring to such embodiments and adjusting the process temperature, execution time, etc., of each step within the scope of the above-described embodiment, the yield and process efficiency of the final substance can be improved, and the quality can be controlled.

Claims

1. 1) A step of treating a compound represented by the following chemical formula 6 with an acid to produce an acidic salt represented by the following chemical formula 7, 2) A step of adding a desalting agent to the compound represented by the following chemical formula 7, and then reacting it with the compound represented by the following chemical formula 8 to produce the compound represented by the following chemical formula 9, 3) The step of hydrolyzing a compound represented by the following chemical formula 9 to produce a compound represented by the following chemical formula 1, A method for producing the compound represented by the following chemical formula 1. [Chemical formula 1] [Chemical formula 6] [Chemical formula 7] [Chemical formula 8] [Chemical formula 9] In the aforementioned chemical formula 6, Pg １ These are benzyl group (Bn), benzhydryl, tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide. In the aforementioned chemical formula 8, X ３ is F, Cl, Br, or I, In the above chemical formulas 8 and 9, Pg ２ These are methyl, ethyl, benzyl, or tert-butyl.

2. Pg of the aforementioned chemical formula 6 １ The manufacturing method according to claim 1, wherein is a tert-butyloxycarbonyl group (Boc).

3. X of the aforementioned chemical formula 8 ３ The manufacturing method according to claim 1, wherein is Cl.

4. Pg of chemical formulas 8 and 9 mentioned above ２ The manufacturing method according to claim 1, wherein is methyl.

5. The acid in the aforementioned step 1 is hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, hydroiodic acid, fluoroboric acid, aluminum chloride, iron chloride, boron trifluoride ether complex, boron trichloride (BCl ３ ), chlorotrimethylsilane (TMSCl), tetra-n-butylammonium fluoride (TBAF), zinc bromide (ZnBr ２ ), zinc chloride (ZnCl ２ ) and magnesium bromide (MgBr ２ ), the production method according to claim 1, wherein the acid is any one selected from the group consisting of the foregoing.

6. The manufacturing method according to claim 1, wherein the desalting agent in step 2 is 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, dipotassium dihydrogen phosphate, sodium lactate, sodium citrate, disodium tartrate, sodium bitartrate, sodium oleate, triethylamine, N,N-diisopropylethylamine, and diisopropylamine.

7. The manufacturing method according to claim 1, wherein step 2 is carried out in the presence of a base and an organic solvent.

8. The manufacturing method according to claim 7, wherein the base in step 2 is one or more 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 manufacturing method according to claim 7, wherein the organic solvent in step 2 is one or more 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 hydrolysis in step 3 is carried out in the presence of a hydrolysis reagent and a base, the hydrolysis reagent being sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li ２ SO ４ ), lithium nitrate (LiNO) ３ ), lithium tetrafluoroborate (LiBF ４ ), lithium trifluoroacetate (CF ３ CO ２ Li), lithium trifluoromethanesulfonate (CF ３ SO ３ Li), and lithium p-toluenesulfonate (C ７ H ７ LiO ３ The manufacturing method according to claim 1, wherein one or more of the group consisting of S) are selected.

11. The manufacturing method according to claim 10, wherein the hydrolysis reagent is lithium bromide.

12. The manufacturing method according to claim 10, wherein the base is one or more selected from the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, and diisopropylamine.

13. After step 3, 4) The manufacturing method according to claim 1, further comprising the step of adding a salt to the compound represented by chemical formula 1 to produce a salt compound of the compound represented by chemical formula 1.

14. The method for producing the product according to claim 13, wherein the salt is one or more selected from the group consisting of L-lysine, L-arginine, L-histidine, choline hydroxide, meglumine, ammonia, sodium hydroxide, potassium hydroxide, potassium hydroxide, magnesium hydroxide, L-arginine, L-cysteine, tromethamine (TRIS), L-glutamine, tert-butylamine, citrate, malate, and fumarate.

15. The manufacturing method according to claim 13, wherein the salt is tromethamine.

16. The manufacturing method according to claim 1, further comprising step B below, to produce a compound represented by chemical formula 1. B) A step of producing the compound represented by the chemical formula 6 by reacting the compound represented by the chemical formula 4 with the compound represented by the chemical formula 5 below; [Chemical formula 4] [Chemical formula 5] In the aforementioned chemical formula 4, X ２ is F, Cl, Br, or I, In the above chemical formula 5, Pg １ This is a benzyl group (Bn), benzhydryl, t-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Cbz), or trifluoroacetamide.

17. The manufacturing method according to claim 16, further comprising step A below, to produce a compound represented by chemical formula 1. A) A step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce the compound represented by the chemical formula 4; [Chemical formula 2] [Chemical formula 3] In the above chemical formula 3, X １ and X ２ These are, independently, F, Cl, Br, or I.

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