Method for producing triazolopyrimidinone derivatives

Abstract

The present invention relates to a method for producing triazolopyrimidinone derivatives and intermediates exhibiting tankyrase inhibitory activity. The production method of the present invention is economical and suitable for mass production because it can produce triazolopyrimidinone derivative compounds with high purity and high yield by improving reaction efficiency through the development of efficient processes.

Description

[Technical Field]

[0001] The present invention relates to a method for producing triazolopyrimidinone derivatives that exhibit tankirase inhibitory activity. [Background technology]

[0002] Tankyrases belong to the poly(ADP-ribose) polymerase (PARP) protein family, which consists of 17 members that share a catalytic PARP domain. Recently, it has been reported that intracellular axinomic levels are influenced by tankyrase-1 and tankyrase-2 (also known as PARP5a and PARP5b, respectively), which are members of the PARP enzyme family (Huang et al., 2009, Nature, 461(7264):614-620).

[0003] Tankirase-1 and tankirase-2 inhibitors are known to have therapeutic potential for a variety of cancers, including solid tumors such as colorectal carcinoma, colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, medulloblastoma, melanoma, non-small cell lung cancer, pancreatic adenocarcinoma, and prostate cancer. Furthermore, tankirase-1 and tankirase-2 inhibitors have therapeutic potential in addition to the aforementioned cancers, including osteoporosis, osteoarthritis, polycystic kidney disease, pulmonary fibrosis, diabetes, schizophrenia, vascular disease, cardiac disease, non-oncogenic proliferative disease, and neurodegenerative diseases such as Alzheimer's disease.

[0004] As mentioned above, there is a persistent need for novel therapeutic agents that can be used for cancer and hyperproliferative conditions, and attempts are being made to develop new pharmaceutical compounds that can selectively inhibit the tankyrase enzyme. In particular, triazolopyrimidinone derivatives of chemical formula I shown below are known as selective tankyrase inhibitors and are being developed as colorectal cancer treatments for patients with colorectal cancer-inducing gene (KRAS) mutations or patients who do not respond to Erbitux. [ka]

[0005] International Publication WO2016 / 006974 discloses a method for producing triazolopyrimidinone derivatives, including the compound of chemical formula I mentioned above. However, this production method involves a reaction step using microwaves and column purification, and is therefore not suitable for mass production; thus, process improvements are necessary.

[0006] Therefore, it is necessary to improve the aforementioned inefficient manufacturing methods and develop new manufacturing methods that can produce triazolopyrimidinone derivative compounds of chemical formula I with high purity. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2016 / 006974 [Non-patent literature]

[0008] [Non-Patent Document 1] Huang et al., 2009, Nature, 461(7264):614-620 [Overview of the project] [Problems that the invention aims to solve]

[0009] The objective of the present invention is to provide a manufacturing method suitable for mass production through efficient process steps, which allows for the production of triazolopyrimidinone derivatives with high purity and high yield, thereby lowering production costs.

[0010] Another object of the present invention is to provide a novel intermediate used in the above-mentioned manufacturing method. [Means for solving the problem]

[0011] The present invention provides a method for producing a triazolopyrimidinone derivative represented by the following chemical formula I. [ka]

[0012] According to a specific example of the present invention, the triazolopyrimidinone derivative represented by the above chemical formula I can be produced through the following synthetic route A or B.

[0013] <Synthetic Route A> Among the production methods of the present invention, synthetic route A includes the following steps (A-1) to (A-8). (A-1) The first step of producing a compound represented by the following chemical formula 2 from a compound represented by the following chemical formula 1 or a salt thereof through a protection reaction; (A-2) The second step of producing a compound represented by the following chemical formula 3 from the compound represented by the above chemical formula 2 through an oxidation reaction; (A-3) The third step of producing a compound represented by the following chemical formula 5 from a compound represented by the following chemical formula 4 through an amination reaction; (A-4) The fourth step of producing a compound represented by the following chemical formula 6 from the compound represented by the above chemical formula 5 through a Dakin reaction; (A-5) The fifth step of producing a compound represented by the following chemical formula 7 from the compound represented by the above chemical formula 6 through an alkylation reaction; (A-6) The sixth step of producing a compound represented by the following chemical formula 8 or a salt thereof from the compound represented by the above chemical formula 7 through a deprotection reaction; (A-7) The seventh step of producing a compound represented by the following chemical formula Ia from the compound represented by the above chemical formula 3 and the compound represented by the above chemical formula 8 or a salt thereof through an amination reaction; and (A-8) The eighth step of producing a compound represented by the following chemical formula I from the compound represented by the above chemical formula Ia through a deprotection reaction;

Chemical Formula

Chemical Formula

[43] ] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] In the above chemical formula, R is an O-protecting group; A is an N-protecting group.

[0014] Below, we will explain each of the aforementioned stages (A-1) to (A-8) separately.

[0015] <(A-1) Stage> In the present invention, step (A-1) is a step in which a triazolopyrimidinone derivative compound represented by chemical formula 1 or a salt thereof is used as a starting material and a protective reaction is performed to produce a compound represented by chemical formula 2 (reaction formula 1). [ka] In the above chemical formula, R is an O-protecting group.

[0016] According to a specific example of the present invention, the reaction provides protection for the triazolopyrimidinone derivative. For example, R may be a C1-C6 alkyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, MOM (methoxymethyl acetal), THP (tetrahydropyran), or silyl ether. According to a specific example of the present invention, the reaction can be carried out by reacting the compound of chemical formula 1 with an alkyl halide to produce the compound represented by chemical formula 2. For example, R may be isopropyl and can be carried out by an alkylation reaction with 2-iodopropane, but is not limited thereto.

[0017] The reaction can use a base commonly used in protective reactions. For example, the base can be sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, or cesium fluoride. Specifically, cesium fluoride (CsF) can be used, but is not limited to this.

[0018] The reaction can use organic solvents commonly used in protective reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, or mixtures thereof. Specifically, dimethylformamide can be used, but is not limited to this.

[0019] Furthermore, the reaction can be carried out at 30 to 110°C, more specifically at 60 to 90°C, but is not limited to this range. After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. In the embodiment of the present invention, the product of the above reaction was stirred in isopropanol, an organic solvent, to obtain a high-purity product.

[0020] <(A-2) Stage> In the present invention, step (A-2) is a step in which a triazolopyrimidine derivative compound represented by chemical formula 2 is used as a starting material and a compound represented by chemical formula 3 is produced by an oxidation reaction (reaction formula 2). [ka] In the above chemical formula, R is as defined above.

[0021] According to a specific example of the present invention, the reaction can be carried out by an oxidation reaction in which a compound represented by chemical formula 2 is reacted with an oxidizing agent.

[0022] The aforementioned reaction can use oxidizing agents commonly used in oxidation reactions. For example, hydrogen peroxide, benzoyl peroxide, metachloroperbenzoic acid, or oxone can be used as the oxidizing agent. Specifically, oxone can be used, but is not limited to it.

[0023] The reaction can use organic solvents commonly used in oxidation reactions. For example, the solvent can be tetrahydrofuran, 1,4-dioxane, acetone, methanol, ethanol, isopropanol, water, or a mixture thereof. Specifically, a mixture of tetrahydrofuran and methanol can be used, but is not limited to this.

[0024] Furthermore, the reaction can be carried out at 0 to 70°C, more specifically at 30 to 50°C, but is not limited to this range.

[0025] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. In the embodiment of the present invention, the product of the above reaction was stirred in isopropanol, an organic solvent, to obtain a high-purity product.

[0026] <(A-3) Stage> In the present invention, step (A-3) is a step in which a trifluorobenzaldehyde derivative compound represented by chemical formula 4 is used as a starting material and a compound represented by chemical formula 5 is produced by an amide reaction (reaction formula 3). [ka] In the above chemical formula, A is an N-protecting group.

[0027] According to a specific example of the present invention, the reaction can be carried out using a trifluorobenzaldehyde derivative and a protected piperazine derivative. For example, A may be -Boc, -Cbz, -Fmoc, -benzyl, p-methoxybenzyl, trityl, or DMT (dimethoxytrityl). According to a specific example of the present invention, the reaction can be carried out by an amination reaction in which 3,4,5-trifluorobenzaldehyde is reacted with N-Boc-piperazine, but is not limited thereto.

[0028] The reaction can use bases commonly used in amide reactions. For example, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, or cesium carbonate can be used as the base. Specifically, lithium carbonate can be used, but is not limited to this.

[0029] The reaction can use organic solvents commonly used in amination reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, or mixtures thereof. Specifically, dimethyl sulfoxide can be used, but is not limited to this.

[0030] Furthermore, the reaction can be carried out at 80-150°C, more specifically at 110-130°C, but is not limited to this range.

[0031] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited to this.

[0032] <(A-4) Stage> In the present invention, step (A-4) is a step in which a compound represented by chemical formula 6 is produced by a Dakin reaction using a phenylpiperazine derivative compound represented by chemical formula 5 as a starting material (reaction formula 4). [ka] In the above chemical formula, A is as defined above.

[0033] According to a specific example of the present invention, the reaction can be carried out by adding an oxidizing agent to a compound represented by chemical formula 5.

[0034] The Dakin reaction described above can use commonly used oxidizing agents. For example, hydrogen peroxide, ammonium persulfate, metachloroperbenzoic acid (mCPBA), or mixtures thereof can be used. Specifically, metachloroperbenzoic acid can be used, but is not limited to this.

[0035] After the above reaction has proceeded, a commonly used base can be used when hydrolyzing the resulting intermediate (phenyl formate). For example, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or calcium carbonate can be used as the base. Specifically, sodium hydroxide can be used, but is not limited to this.

[0036] The reaction can use commonly used solvents. For example, the solvent can be dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetone, methanol, ethanol, isopropanol, water, or mixtures thereof. Specifically, dichloromethane can be used, but is not limited to it.

[0037] Furthermore, the reaction can be carried out at -20 to -30°C, and more specifically, at -15 to -15°C, but is not limited to this range.

[0038] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. For example, in the embodiment of the present invention, the product of the above reaction was stirred in isopropanol, an organic solvent, to obtain a high-purity product.

[0039] <(A-5) stage> In the present invention, step (A-5) is a step in which a compound represented by chemical formula 7 is produced by an alkylation reaction using a phenylpiperazine derivative compound represented by chemical formula 6 as a starting material (reaction formula 5). [ka] In the above chemical formula, A is as defined above.

[0040] According to a specific example of the present invention, the reaction can be carried out by an alkylation reaction in which the compound of chemical formula 6 is reacted with 1-halo-2-methoxyethane (e.g., 1-bromo-2-methoxyethane).

[0041] The reaction can use organic solvents commonly used in alkylation reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, or mixtures thereof. Specifically, acetonitrile can be used, but is not limited to this.

[0042] Furthermore, the reaction can be carried out at 50-100°C, more specifically at 75-85°C, but is not limited to this range.

[0043] <(A-6) Stage> In the present invention, step (A-6) is a step in which a phenylpiperazine derivative compound represented by chemical formula 7 is used as a starting material, and a compound represented by chemical formula 8 or a salt thereof is produced by a deprotection reaction (reaction formula 6). [ka] In the above chemical formula, A is as defined above.

[0044] According to a specific example of the present invention, the reaction can be carried out by a deprotection reaction of the compound of chemical formula 7 under acidic conditions.

[0045] The reaction can use solvents commonly used in deprotection reactions. For example, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, water, or mixtures thereof can be used as the solvent. Specifically, methanol can be used, but is not limited to this.

[0046] Furthermore, the reaction can be carried out at 0 to 60°C, and more specifically, at 30 to 50°C, but is not limited to this range.

[0047] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. In the embodiments of the present invention, the product of the above reaction was stirred with an organic solvent such as dichloromethane, tert-butyl methyl ether, or a mixture thereof to obtain a high-purity product.

[0048] <(A-7) Stage> In the present invention, step (A-7) is a compound represented by chemical formula 3 and a compound represented by chemical formula 8. The following chemical formula can be obtained by an amination reaction from the compound or its salt. It This is the step in producing the compound represented by (reaction equation 7).

[0049] According to a specific example of the present invention, the reaction can be carried out by an amination reaction using, for example, 7-isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazine hydrochloride.

[0050] The reaction can use bases commonly used in amide reactions. For example, the bases that can be used are lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU). Specifically, diisopropylethylamine can be used, but is not limited to this.

[0051] The reaction can use organic solvents commonly used in amination reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, or mixtures thereof. Specifically, ethanol can be used, but is not limited to it.

[0052] Furthermore, the reaction can be carried out at 50-100°C, more specifically at 60-80°C, but is not limited to this range.

[0053] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. In the embodiments of the present invention, the product of the above reaction was stirred with an organic solvent such as dichloromethane, diisopropyl ether, or a mixture thereof to obtain a high-purity product.

[0054] <(A-8) Stage> In the present invention, step (A-8) is a chemical formula ItThis is the step of producing the compound represented by chemical formula I from the compound represented by (reaction formula 8) by a deprotection reaction.

[0055] According to a specific example of the present invention, the reaction can be carried out, for example, by a deprotection reaction from 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

[0056] The above reaction may use an acid commonly used in deprotection reactions as a solvent. In this case, the acid may be acetic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or a mixture thereof. Specifically, acetic acid, sulfuric acid, or a mixture thereof may be used, but is not limited to these.

[0057] Furthermore, the reaction can be carried out at 30-80°C, more specifically at 40-60°C, but is not limited to this range.

[0058] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. In the embodiment of the present invention, the product of the above reaction was stirred with acetone, water, or a mixture thereof to obtain a high-purity product.

[0059] <Synthesis Path B> Of the manufacturing methods of the present invention, synthesis route B includes the following steps (B-1) to (B-7). (B-1) The first step of producing a compound represented by chemical formula 2 from a compound represented by chemical formula 1 or a salt thereof by a protective reaction; (B-2) The second step involves producing a compound represented by the following chemical formula 3 from the compound represented by the chemical formula 2 by an oxidation reaction; (B-3) The third step involves producing the compound represented by chemical formula 9 from the compound represented by chemical formula 4 by an amination reaction; (B-4) The fourth step involves producing a compound represented by the following chemical formula 10 from the compound represented by chemical formula 3 and the compound represented by chemical formula 9 or a salt thereof by an amication reaction; (B-5) The fifth step involves producing the compound represented by the following chemical formula 11 from the compound represented by the following chemical formula 10 via the Dakin reaction; (B-6) The sixth step of producing the compound represented by chemical formula Ia from the compound represented by the chemical formula 11 below by an alkylation reaction; and (B-7) The seventh step involves producing a compound represented by the following chemical formula I from the compound represented by the chemical formula Ia by a deprotection reaction; [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] In the above chemical formula, R is an O-protecting group.

[0060] Below, we will explain each of the aforementioned stages (B-1) to (B-7) separately. Of these, stages (B-1), (B-2), and (B-7) are the same as the aforementioned stages (A-1), (A-2), and (A-8), respectively, and we will only consider stages (B-3) to (B-6) in detail.

[0061] <(B-3) stage> In the present invention, step (B-3) is a trifluorobenzaldehyde represented by chemical formula 4. Starting with a hydride derivative compound, the chemical formula is obtained through an amination reaction. 9 Compounds represented by This is the stage for producing the salt thereof (reaction equation 9).

[0062] According to a specific example of the present invention, the reaction can use a trifluorobenzaldehyde derivative and piperazine.

[0063] The reaction can use bases commonly used in amide reactions. For example, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, or cesium carbonate can be used as the base. Specifically, potassium carbonate can be used, but is not limited to this.

[0064] The reaction can use organic solvents commonly used in amination reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, isopropyl alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, ethylene glycol, diethylene glycol, dimethyl ether, dimethoxyethane, or mixtures thereof. Specifically, dimethoxyethane can be used, but is not limited to it.

[0065] Furthermore, the reaction can be carried out at 60-150°C, more specifically at 70-90°C, but is not limited to this range.

[0066] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited to this.

[0067] <(B-4) Stage> In the present invention, the (B- 4 The stage involves a compound represented by chemical formula 3 and a compound represented by chemical formula 9. A compound represented by the following chemical formula 10 is obtained from a compound or a salt thereof by an amination reaction. This is the manufacturing stage (reaction equation 10).

[0068] According to a specific example of the present invention, the reaction can be carried out by an amination reaction using, for example, 7-isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,5-difluoro-4-(piperazin-1-yl)benzaldehyde.

[0069] The reaction can use bases commonly used in amination reactions. For example, the base can be, but is not limited to, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU).

[0070] The reaction can use organic solvents commonly used in amination reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, or mixtures thereof. Specifically, dimethylacetamide can be used, but is not limited to this.

[0071] Furthermore, the reaction can be carried out at 50-150°C, more specifically at 80-120°C, but is not limited to this range.

[0072] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. In the embodiments of the present invention, the product of the above reaction was stirred with an organic solvent such as diethyl ether, isopropanol, or a mixture thereof to obtain a high-purity product.

[0073] <(B-5) stage> In the present invention, step (B-5) is a step in which a compound represented by chemical formula 10 is used as a starting material to produce a compound represented by chemical formula 11 by a Dakin reaction (reaction formula 11). [ka] In the above chemical formula, R is as defined above.

[0074] According to a specific example of the present invention, the reaction can be carried out by adding an oxidizing agent to a compound represented by chemical formula 10.

[0075] The Dakin reaction described above can use commonly used oxidizing agents. For example, hydrogen peroxide, ammonium persulfate, metachloroperbenzoic acid (mCPBA), or mixtures thereof can be used. Specifically, metachloroperbenzoic acid can be used, but is not limited to this.

[0076] After the above reaction has proceeded, a commonly used base can be used when hydrolyzing the resulting intermediate (phenyl formate). For example, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or calcium carbonate can be used as the base. Specifically, sodium hydroxide can be used, but is not limited to this.

[0077] The reaction can use commonly used solvents. For example, the solvent can be dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetone, methanol, ethanol, isopropanol, water, or mixtures thereof. Specifically, dichloromethane can be used, but is not limited to it.

[0078] Furthermore, the reaction can be carried out at -20 to -30°C, and more specifically, at -15 to -15°C, but is not limited to this range.

[0079] After the above reaction, one or more steps of separating or purifying the product may be carried out, but are not limited thereto. For example, in the embodiment of the present invention, the product of the above reaction was stirred with organic solvents such as isopropanol and tert-butyl methyl ether or a mixture thereof to obtain a high-purity product.

[0080] <(B-6) stage> In the present invention, step (B-6) is a step in which a compound represented by chemical formula Ia is produced by an alkylation reaction using a compound represented by chemical formula 11 as a starting material (reaction formula 12). [ka]

[0081] According to a specific example of the present invention, the reaction can be carried out by an alkylation reaction in which the compound of chemical formula 11 is reacted with 1-halo-2-methoxyethane (e.g., 1-bromo-2-methoxyethane).

[0082] The reaction can use organic solvents commonly used in alkylation reactions. For example, the solvent can be acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, or mixtures thereof. Specifically, dimethylformamide can be used, but is not limited to this.

[0083] Furthermore, the reaction can be carried out at 50-100°C, more specifically at 60-80°C, but is not limited to this range.

[0084] According to the manufacturing method disclosed in International Publication WO2016 / 006974, the compound represented by chemical formula I is produced through 11 steps. Furthermore, because it involves the use of microwaves and several column purification steps, it was not suitable for mass production. However, according to the manufacturing method of the present invention, synthesis routes A or B each consist of 8 or 7 steps, eliminating the need for numerous steps. Moreover, steps (A-1) to (A-8) in synthesis route A and all of steps (B-1) to (B-7) in synthesis route B are omitted, and microwave and column purification steps are omitted, allowing for the efficient production of compounds in high yield and high purity, making it suitable for mass production.

[0085] Furthermore, the compounds represented by chemical formulas 1 to 11 and chemical formula Ia, which were produced and used in steps (A-1) to (A-8) and (B-1) to (B-7), are all useful intermediates for producing the triazolopyrimidinone derivative compound represented by chemical formula I. [Effects of the Invention]

[0086] The manufacturing method of the present invention has fewer steps than conventional manufacturing methods, and through the development of an efficient process, it is possible to produce triazolopyrimidinone derivative compounds in high purity and high yield through crystallization without using microwave reactions or column purification. Therefore, the production cost can be significantly reduced, making it economical and suitable for mass production. [Modes for carrying out the invention]

[0087] The following are preferred embodiments to aid in understanding the present invention. However, these embodiments are provided only to facilitate understanding the present invention and do not limit the scope of the invention. [Examples]

[0088] In Example 1 of the present invention, a triazolopyrimidinone derivative compound represented by chemical formula I was produced according to the following reaction formula I. [ka]

[0089] <Step 1: Production of 7-isopropoxy-3-methyl-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine>

[0090] 3-Methyl-5-(methylthio)-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-one (15 g, 76.1 mmol) was diluted in 76 mL of dimethylformamide. Cesium fluoride (46.2 g, 304.2 mmol) and isopropyl iodide (38.1 g, 228.2 mmol) were added, and the internal temperature was raised to 75-80°C and stirred for 2 hours. Once the reaction was complete, it was cooled to room temperature, 300 mL of ethyl acetate was added, and the mixture was stirred for 10 minutes. The formed crystals were filtered through Celite filtration, and 120 mL of 5% saline solution was added to the filtrate and stirred for 10 minutes. The organic layer was washed twice more with 120 mL of 5% saline solution. After dehydration with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. 50 mL of isopropanol was added to the concentrated residue, and the temperature was raised to 40°C and stirred for 30 minutes. The precipitated crystals were stirred at 5-10°C for 30 minutes, then filtered and dried under reduced pressure to obtain the title compound as a pale yellow solid (11.3 g, 62%).

[0091] 1H-NMR 400 Hz (DMSO-d6): 5.62 (m, 1H), 4.15 (s, 3H), 2.61 (s, 3H), 1.44 (d, J = 8 Hz, 6H). LCMS (ESI, m / z): 240.1[M+H + ].

[0092] <Step 2: Production of 7-isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine>

[0093] 7-Isopropoxy-3-methyl-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (10 g, 41.8 mmol) prepared in step 1 was diluted in 70 mL of tetrahydrofuran, cooled to an internal temperature of 5-10°C, and stirred. Oxon (38.5 g, 125.3 mmol) was dissolved in 200 mL of purified water and then added dropwise to the reaction mixture for 30 minutes. After the addition was complete, the internal temperature was raised to 35-40°C and stirred for 2 hours. Once the reaction was complete, the reaction mixture was concentrated under reduced pressure, 100 mL of dichloromethane was added, and the organic layer was extracted. 100 mL of dichloromethane was added to the aqueous layer for extraction, and after combining the organic layers, the mixture was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 50 mL of isopropanol was added to the concentrated residue, the temperature was raised to 75°C, and stirred for 30 minutes. The precipitated crystals were stirred at 5-10°C for 30 minutes, then filtered and dried under reduced pressure to obtain a slightly white solid of the title compound (9.9 g, 87%).

[0094] 1 H-NMR 400 Hz (DMSO-d6): 5.74 (m, 1H), 4.30 (s, 3H), 3.47 (s, 3H), 1.50 (d, J = 6.4 Hz, 6H). LCMS(ESI, m / z):272.0[M+H + ].

[0095] <Step 3: Preparation of tert-butyl 4-(2,6-difluoro-4-homylphenyl)piperazine-1-carboxylate>

[0096] 3,4,5-Trifluorobenzaldehyde (5 g, 31.2 mmol), Boc-piperazine (5.8 g, 31.2 mmol), and lithium carbonate (7.3 g, 94 mmol) were diluted in dimethyl sulfoxide (25 mL) and then stirred at an internal temperature of 115-120°C for 3 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature, diluted with a mixture of 125 mL of cold water and 50 mL of ethyl acetate, and stirred for 10 minutes. Insoluble materials were removed by Celite filtration. The organic layer of the filtrate was separated, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was not purified before proceeding to the next reaction.

[0097] <Step 4: Preparation of tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate>

[0098] The tert-butyl 4-(2,6-difluoro-4-homylphenyl)piperazine-1-carboxylate prepared in step 3 was dissolved in 102 mL of dichloromethane, then cooled to an internal temperature of -15 to -10°C and stirred. Metachloroperbenzoic acid (8.08 g, 46.8 mmol) was slowly added dropwise, and the mixture was stirred for 2 hours while maintaining an internal temperature of -10 to 10°C. 2N sodium hydroxide aqueous solution (78 mL, 156 mmol) was added dropwise to the reaction mixture, and the temperature was gradually raised to room temperature and stirred for 2 hours. Once the reaction was complete, the aqueous layer was separated, and the pH was adjusted to 6 using 1N hydrochloric acid aqueous solution at 0 to 5°C. Then 90 mL of tert-butyl methyl ether was added and stirred for 10 minutes. The organic layer was extracted and washed with 30 mL of sodium bicarbonate aqueous solution. The mixture was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 35 mL of isopropanol was added to the residue, and the mixture was stirred at room temperature for 3 hours. The sample was filtered and dried under reduced pressure to obtain the title compound as a pale yellow solid (3.9 g, 40%).

[0099] 1 H-NMR 400 Hz (MeOD): 6.33 (d, J = 8.2 Hz, 2H), 4.63 (S, 1H), 3.52 (S, 4H), 3.00 (S, 4H), 1.49 (S, 9H). LCMS (ESI, m / z): 315.1[M+H +].

[0100] <Step 5: Preparation of tert-butyl 4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazine-1-carboxylate>

[0101] The tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate (20 g, 63.6 mmol) prepared in step 4 was diluted with acetonitrile. Calcium carbonate (26.4 g, 190.9 mmol) and 1-bromo-2-methoxyethane (13.3 g, 95.5 mmol) were added, and the mixture was heated to 75-85°C and stirred under reflux for 8 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and 140 mL of purified water and 280 mL of ethyl acetate were added to the residue. The mixture was stirred at room temperature for 15 minutes. The organic layer was separated, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was not purified, and the next reaction proceeded.

[0102] <Step 6: Manufacturing of 1-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazine hydrochloride>

[0103] 240 mL of methanol was added to the reactor, and after cooling to below 5°C, acetyl chloride (31.3 mL, 439 mmol) was slowly added and stirred for 15 minutes. The tert-butyl 4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazine-1-carboxylate prepared in step 5 was dissolved in 64 mL of dichloromethane and gradually added to the reactor, the internal temperature was raised to 40-45°C, and stirred for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, 60 mL of methanol was added to the residue, and it was stirred at room temperature to dissolve. The internal temperature was cooled to 15-20°C, 180 mL of tert-butyl methyl ether was added dropwise, and stirred for 30 minutes. The precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (14.2 g, 72%) as a slightly white solid.

[0104] 11H-NMR 400 Hz (DMSO-d6): 9.25 (brs, 2H), 6.85 - 6.64 (m, 2H), 4.12 - 4.02 (m, 2H), 3.65 - 3.58 (m, 2H), 3.28 (s, 3H), 3.25 - 3.18 (m, 4H), 3.17 - 3.09 (m, 4H). LCMS (ESI, m / z): 273.0 [M+H + . (Free form)

[0105] <Step 7: Preparation of 5-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine>

[0106] Dilute 7-isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (10 g, 36.9 mmol) prepared in Step 2 in 146 mL of ethanol, add diisopropylethylamine (19.3 mL, 110.5 mmol) and 1-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazine hydrochloride (13.1 g, 42.4 mmol) prepared in Step 6, heat to 60 - 80 °C, and reflux with stirring for 3 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, add 150 mL of dichloromethane and 53 mL of water to the residue, and separate the layers. Extract the aqueous layer twice with 50 mL of dichloromethane. Combine the organic layers, wash with 50 mL of 1N hydrochloric acid aqueous solution and 50 mL of 5% brine, dehydrate with anhydrous sodium sulfate, and then filter. Add 2 g of activated carbon to the filtrate and stir for 30 minutes. Proceed with celite filtration and concentrate the filtrate under reduced pressure. Add 30 mL of dichloromethane to the concentrated residue, dissolve it, then dropwise add 200 mL of diisopropyl ether, and stir at 5 - 10 °C for 1 hour. Filter the precipitated crystals and dry under reduced pressure to obtain the title compound (15.1 g, 89%) as a slightly white solid.

[0107] 1H-NMR 400 Hz(DMSO-d6):6.77-6.69(m, 2H), 5.55(m, 1H), 4.09-4.06(m, 2H), 3.99(s, 3H), 3.93(t, J = 4.8 Hz, 4H), 3.64-3.62(m, 2H), 3.28(s, 3H), 3.09(t, J = 4.8 Hz, 4H), 1.42(d, J = 6.4 Hz, 6H). LCMS (ESI, m / z): 464.1[M+H + ].

[0108] <Step 8: Preparation of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-one>

[0109] 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (15 g, 32.4 mmol) prepared in step 7 was mixed with 92 mL of acetic acid and 16.1 mL of sulfuric acid, and the internal temperature was raised to 45-50°C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 230 mL of purified water was added dropwise for 30 minutes while stirring. After the dropwise addition was complete, the internal temperature was cooled to 5-10°C and stirred for 1 hour. The precipitated crystals were filtered and diluted with 150 mL of acetone, and the internal temperature was raised to 40-45°C and stirred for 1 hour. The reaction mixture was gradually cooled to 5-10°C and 150 mL of purified water was added. The precipitated crystals were stirred for 30 minutes, then filtered and dried under reduced pressure to obtain the title compound as a slightly white solid (11.5 g, 84%).

[0110] 1 H-NMR 400 Hz (DMSO-d6): 11.29(brs, 1H), 6.74(d, J = 11.2 Hz, 2H), 4.08(t, J = 4.4 Hz, 2H), 3.92(s, 3H), 3.82-3.76(m, 4H), 3.62(t, J = 4.4 Hz, 2H), 3.29(s, 3H), 3.12-3.06(m, 4H). LCMS(ESI, m / z):422.1[M+H + ]. [Examples]

[0111] In Example 2 of the present invention, a triazolopyrimidinone derivative compound represented by chemical formula I was prepared according to the following reaction formula II. [ka]

[0112] <Step 1: Production of 3,5-difluoro-4-(piperazin-1-yl)benzaldehyde>

[0113] 3,4,5-Trifluorobenzaldehyde (4 g, 24.99 mmol), piperazine (6.46 g, 75 mmol), and potassium carbonate (6.91 g, 50 mmol) were diluted in dimethoxyethane (50 mL) and then stirred at an internal temperature of 75-80°C for 20 hours. Once the reaction was complete, the reaction mixture was cooled to 0-5°C and the pH was adjusted to 2 by adding 2N hydrochloric acid aqueous solution. The aqueous layer was washed twice with 50 mL of dichloromethane and then neutralized with 1N caustic soda aqueous solution. After adding 100 mL of dichloromethane to the aqueous layer, the organic layer was extracted, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (4.65 g, 82%) as a yellow solid.

[0114] 1 H-NMR 400 Hz (DMSO-d6): 9.80 (s, 1H), 7.56-7.54 (d, J = 8.2 Hz, 2H), 3.19 (s, 4H), 2.79 (s, 4H). LCMS(ESI, m / z):227.1[M+H + ].

[0115] <Step 2: Preparation of 3,5-difluoro-4-(4(7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)piperazin-1-yl)benzaldehyde>

[0116] 7-Isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (1 g, 3.69 mmol) prepared in step 2 of Example 1 and 3,5-difluoro-4-(piperazin-1-yl)benzaldehyde (0.959 g, 4.24 mmol) prepared in step 1 of Example 2 were diluted in 15 mL of dimethylacetamide, heated to 110-120°C, and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with 75 mL of ethyl acetate and 30 mL of water, and the organic layer was separated and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 5 mL of isopropanol was added to the concentrated residue and stirred at room temperature for 30 minutes. The precipitated crystals were filtered, washed with isopropanol, and then dried under reduced pressure to obtain the title compound as a pale yellow solid (1.25 g, 81%).

[0117] 1 H-NMR 400 Hz(CDCl3):9.81(s, 1H), 7.44-7.36(m, 2H), 5.65-5.55(m, 1H), 4.07(s, 3H), 4.05-4.03(t, J = 5.0 Hz, 4H), 3.43(s, 4H), 1.50-1.48(d, J = 6.2 Hz, 6H). LCMS (ESI, m / z): 418.0 [M+H + ].

[0118] <Step 3: Preparation of 3,5-difluoro-4-(4(7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)piperazin-1-yl)phenol>

[0119] 3,5-difluoro-4-(4-(7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)piperazin-1-yl)benzaldehyde (1 g, 2.4 mmol) prepared in step 2 was diluted in 8 mL of dichloromethane. Then, metachloroperbenzoic acid (1076 mg, 4.8 mmol) was slowly added dropwise at -10 to 0°C, and the mixture was stirred for 2 hours while maintaining an internal temperature of -10 to 10°C. 2N sodium hydroxide aqueous solution (9.6 mL, 19.2 mmol) was added dropwise to the reaction mixture, and the mixture was stirred for 2 hours while gradually raising the temperature to room temperature. Once the reaction was complete, the aqueous layer was separated, and the pH was adjusted to 6 using 1N hydrochloric acid aqueous solution at 0 to 5°C. Then, 50 mL of tert-butyl methyl ether was added and the mixture was stirred for 10 minutes. The organic layer was extracted and washed with 10 mL of sodium bicarbonate aqueous solution. The solution was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 3 mL of isopropanol was added to the residue, and the mixture was stirred at room temperature for 1 hour. The solution was filtered, dried under reduced pressure, and a pale yellow solid of the title compound (388 mg, 40%) was obtained.

[0120] 1 H-NMR 400 Hz (DMSO-d6): 6.44-6.42 (d, J = 11.0 Hz, 2H), 5.57-5.51 (m, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 1.42-1.41 (d, J = 6.2 Hz, 6H). LCMS (ESI, m / z): 406.0 [M+H + ].

[0121] <Step 4: Preparation of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine>

[0122] 3,5-difluoro-4-(4-(7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-yl)piperazin-1-yl)phenol (1 g, 2.5 mmol) prepared in step 3 was diluted in 10 mL of dimethylformamide, and potassium carbonate (1.02 g, 7.4 mmol) was added. The mixture was stirred at 65-70°C for 7 hours. After the reaction was complete, 200 mL of purified water and 550 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 15 minutes. The organic layer was separated, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane and diisopropyl ether were added dropwise to the concentrated residue to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (780 mg, 68%) as a slightly white solid.

[0123] 1 H-NMR 400 Hz(DMSO-d6):6.77-6.69(m, 2H), 5.55(m, 1H), 4.09-4.06(m, 2H), 3.99(s, 3H), 3.93(t, J = 4.8 Hz, 4H), 3.64-3.62(m, 2H), 3.28(s, 3H), 3.09(t, J = 4.8 Hz, 4H), 1.42(d, J = 6.4 Hz, 6H). LCMS (ESI, m / z): 464.1[M+H + ].

[0124] <Step 5: Preparation of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-one>

[0125] 750 mg, 1.62 mmol of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (750 mg, 1.62 mmol) prepared in step 4 was mixed with 4.6 mL of acetic acid and 0.81 mL of sulfuric acid, and the internal temperature was raised to 45-50°C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 11 mL of purified water was added dropwise for 30 minutes while stirring. After the dropwise addition was complete, the internal temperature was cooled to 5-10°C and stirred for 1 hour. The precipitated crystals were filtered and diluted with 7.5 mL of acetone, and the internal temperature was raised to 40-45°C and stirred for 1 hour. The reaction mixture was gradually cooled to 5-10°C and 7.5 mL of purified water was added. The precipitated crystals were stirred for 30 minutes, then filtered and dried under reduced pressure to obtain a slightly white solid of the title compound (575 mg, 84%).

[0126] 1 H-NMR 400 Hz (DMSO-d6): 11.29(brs, 1H), 6.74(d, J = 11.2 Hz, 2H), 4.08(t, J = 4.4 Hz, 2H), 3.92(s, 3H), 3.82-3.76(m, 4H), 3.62(t, J = 4.4 Hz, 2H), 3.29(s, 3H), 3.12-3.06(m, 4H). LCMS(ESI, m / z):422.1[M+H + ].

[0127] Although specific parts of the present invention have been described in detail above, it will be clear to those with ordinary skill in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Therefore, the substantial scope of the invention is defined by the appended claims and their equivalents.

Claims

[Claim 1] (B-1) A first step of producing a compound represented by the following chemical formula 2 from a compound represented by the following chemical formula 1 or a salt thereof by a protective reaction; (B-2) A second step in which a compound represented by the following chemical formula 3 is produced from the compound represented by the chemical formula 2 by an oxidation reaction; (B-3) The third step involves producing a compound represented by the chemical formula 9 from a compound represented by the chemical formula 4 below by an amination reaction; (B-4) The fourth step involves producing a compound represented by the chemical formula 10 from a compound represented by the chemical formula 9 below by an amination reaction; (B-5) The fifth step involves producing a compound represented by the following chemical formula 11 from a compound represented by the following chemical formula 10 by the Dakin reaction; (B-6) A sixth step of producing the compound represented by the chemical formula Ia from the compound represented by the chemical formula 11 below by an alkylation reaction; and (B-7) The seventh step of producing a compound represented by the following chemical formula I from the compound represented by the chemical formula Ia by a deprotection reaction; Method for producing triazolopyrimidinone derivatives, including: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 In the above chemical formula, R is a C1-C6 alkyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, MOM (methoxymethyl acetal), THP (tetrahydropyran), or silyl ether.

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