METHOD FOR PREPARING ARYL 2-TETRAZOLE-2-YL KETONE WITH IMPROVED SELECTIVITY

Abstract

The present description relates to a method for preparing aryl 2-tetrazol-2-yl ketone 1a Formula 1a with improved selectivity.

Description

METHOD FOR PREPARING ARYL 2-TETRAZOLE-2-YL KETONE WITH IMPROVED SELECTIVITY Technical Field The present description relates to a method for preparing aryl 2-tetrazol-2-yl ketone of Formula 1 with improved selectivity: [Formula the] r2 where Ri and R2 are as defined herein. Background Technique The (R)-l-aryl-2-tetrazolyl-ethyl ester of carbamic acid (hereafter also referred to as a carbamate compound) is useful in the treatment of CNS disorders, particularly anxiety, depression, seizures, epilepsy, migraine, manic depression, drug abuse, smoking, attention deficit hyperactivity disorder (ADHD), obesity, sleep disorders, neuropathic pain, stroke, cognitive impairment, neurodegeneration, muscle spasm due to stroke, and the like, in accordance with its anticonvulsant effects. The carbamate compound is prepared from a compound of Formula 1a, which is obtained from a substitution reaction of a compound of Formula 2 and a compound of Formula 3, nir / bnn / zznz / E / Y, as an intermediate. Conventionally, a base is added to the compound of Formula 2, and a tetrazole solution is then added to it to carry out a substitution reaction. However, in this case, the compound of Formula 1b, which is a positional isomer of the same, in addition to the desired compound of Formula 1a, is obtained together as a mixture by the substitution reaction (WO 2011 / 046380). [Formula 2] or r2 [Formula 3] HN, N N [Formula the] r2 [Formula Ib] r2(In the Formulas, Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; and X is a leaving group) Furthermore, when the compound of Formula 2 and the compound of Formula 3 undergo the substitution reaction, the reaction selectivity of nitrogen number 1 of the compound of Formula 3 is better than the reaction selectivity of nitrogen number 2, and thus the compound of Formula Ib is produced with higher selectivity compared to the compound of Formula Ia (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (7), 1157-63; 1986). Therefore, according to the conventional method, less of the compound of Formula Ia used to prepare the carbamate compound is produced than less of the compound of Formula Ib, and thus the yield is low when the carbamate compound is prepared using the compound of Formula 2 and the compound of Formula 3 as starting materials. In this regard, there is an alternative method for selectively preparing only a compound of the same form substituted with nitrogen number 2 by synthesizing a tetrazole ring form (Chem. Pharm. Bull. 30(9) 3450-3452; 1982). However, there may be problems in that it is difficult to use commercially since a diazomethane-based material—which has a risk of explosion during the reaction—is used, and 2 or more equivalents of lithium diisopropylamide are used as a raw material. As such, there is a need to develop a method in which the aryl 2-tetrazol-2-yl ketone of Formula Ia can be prepared from the compound of Formula 2 and the compound of Formula 3 with better selectivity than the aryl 2-tetrazol-l-yl ketone of Formula Ib, and as a result, can be commercialized while obtaining the aryl 2-tetrazol-2-yl ketone of Formula Ia and the carbamate compound in high yield. Description of the Invention Technical Problem The purpose of the present description is to provide a commercially available method capable of improving the productivity of a carbamate compound by more selectively synthesizing aryl 2-tetrazol-2-yl ketone, which is useful as an intermediate of the carbamate compound, on a large scale. Solution to the Problem One aspect of the present description provides a method for preparing a compound of Formula 1, comprising a step of reacting a compound of Formula 2 with a salt of a compound of Formula 3: nir / bnn / zznz / E / Y nir / bnn / zznz / E / Y wherein Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; and X is a leaving group. Another aspect of the present description provides a method for increasing the selectivity of a compound of Formula 1a by using a salt of a compound of Formula 3 in the synthesis of a compound of Formula 1a and a compound of Formula 1b from a compound of Formula 2 and a compound of Formula 3: [Formula the] [Formula Ib] [Formula 3] HN M, Nn-N nir / bnn / zznz / E / Y where Ri R2 and X are the same as defined above. Another aspect of the present description provides a method for preparing a compound of Formula 4, comprising: (1) reacting a compound of Formula 2 with a salt of a compound of Formula 3; (2) separating the compound of Formula 1 from a mixture obtained by the reaction step of step (1); and (3) reducing the compound of Formula 1 separated in step (2) and carbamarizing the reduced compound of Formula 1. nir / bnn / zznz / E / Y [Formula the] r2 [Formula 2J] [Formula 4] where Ri, R2 and X are the same as defined above. Another aspect of the present description provides a method for separating a compound of Formula 1a from a mixture comprising a compound of Formula 1a and a compound of Formula 1b by heat-treating the mixture comprising the compound of chemical formula 1a and the compound of Formula 1b to produce a compound of Formula 5 and removing this compound: [Formula the] r2 [Formula 5] r2en where Ri and Re are the same as defined above. Another aspect of the present description provides a method for preparing a compound of Formula 1, comprising: reacting a compound of Formula 2 with a salt of a compound of Formula 3; and purifying the reaction product of the salt of the compound of Formula 3 and the compound of Formula 2, wherein the purification step comprises a crystallization process or a heat treatment process: [Formula la] nir / bnn / zznz / E / Y r2 [Formula 2J or r2 [Formula 3] where Ri, R2 and X are the same as defined above. Advantageous Effects of the Invention According to the present description, the productivity of carbamate compounds can be significantly improved as a result of more selectively synthesizing aryl 2-tetrazol-2-yl ketone, on a large scale, which is useful as an intermediate of the carbamate compound, through a simple process Brief Description of the Drawings FIG. 1 shows the HPLC results of the ratio for the mixture of compound of Formula la and compound of Formula Ib in the reaction mixture produced nir / bnn / zznz / E / Y in Example 1. FIG. 2 is an ORTEP (Oak Crest Thermal Ellipsoid) image of the 5—(2—chlorophenyl)oxazol-2-amine structure obtained in Example 11. FIG. 3 shows the HPLC ratio results for the compound of Formula 4 transformed from the compound of Formula Ib and the compound of Formula la in the reaction mixture produced in Example 11. Fashion for Invention Then, the present description is described in detail. A method for preparing a compound of Formula 1 according to one aspect of the present description comprises a step of reacting a compound of Formula 2 with a salt of a compound of Formula 3: [Formula 1] [Formula 3] nir / bnn / zznz / E / Y wherein Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms, and more specifically selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, and alkoxy having 1 to 4 carbon atoms; and X is a leaving group, and more specifically selected from halides such as chloride, bromide and the like, and sulfonates such as mesylate, tosylate, 4-nitrophenyl sulfonate and the like. The salt of the Formula 3 compound is obtained by reacting the Formula 3 compound with a base, and the salt can be an inorganic salt or an organic salt. In one embodiment, the inorganic salt of the Formula 3 compound can be a metal salt, more specifically an alkali metal salt, and even more specifically a lithium salt, a sodium salt, a potassium salt, or a cesium salt. In one embodiment, the inorganic salt of the compound in Formula 3 can be obtained by reacting the compound nir / bnn / zznz / E / Y of Formula 3 with an inorganic base. The inorganic base can be, but is not limited to, a metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) or a metal carbonate (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.). In one embodiment, the organic salt of the compound in Formula 3 can be obtained by reacting the compound in Formula 3 with an organic base. The organic base can be an amine compound (e.g., triethylamine, diisopropylethylamine, etc.), but is not limited to them. The reaction between the compound of Formula 3 and the base can be carried out at room temperature, and the reaction solvent can be water, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, lower C1-C4 alcohol (e.g., methanol, ethanol, propanol, butanol), alone or in combination thereof. According to one embodiment, the compound of Formula 3 can be reacted with a base in a reaction solvent, and then the salt of the compound of Formula 3 can be separated from the reaction product of the compound of Formula 3 and the base. According to another embodiment, the salt separated from the compound of Formula 3 can be reacted with the compound of Formula 2. According to another modality, after the reaction of the Formula 3 compound with the base, the Formula 2 compound can be added to the reaction product to react with the salt of the Formula 3 compound. The reaction between the salt of the compound in Formula 3 and the compound in Formula 2 can be carried out at room temperature, and the reaction solvent can be water, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, lower CiC4 alcohol (e.g., methanol, ethanol, propanol, butanol), alone or in combination thereof. The reaction product of the salt of the compound of Formula 3 and the compound of Formula 2 obtained as described above is a mixture that includes the compound of Formula 1a and the compound of Formula 1b: [Formula 1a] r2 [Formula Ib] r2nir / bnn / zznz / E / Y where Ri and R2 are the same as defined above. Therefore, in order to separate the compound of Formula 1a and the compound of Formula 1b from each other in the reaction product, the method for preparing the compound of Formula 1a may further include the purification of the reaction product of the salt of the compound of Formula 3 and the compound of Formula 2. In one modality, the purification stage may include a crystallization process, and more particularly, the crystallization process may include a first crystallization process and a second crystallization process. In one embodiment, the crystallization process can be a process in which a first crystallization solvent (for example, water, C1-C4 lower alcohol, diethyl ether, tert-butyl methyl ether, isopropyl ether, pentane, hexane, cyclohexane, heptane, and a mixture thereof) is added to a reaction product of a salt of a compound of Formula 3 and a compound of Formula 2, the compound of Formula Ib crystallizes, and is then filtered and separated (first crystallization process), a second crystallization solvent (for example, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C1-C4 lower alcohol, or a mixture thereof) is added to the remaining filtrate, and the compound of Formula la is crystallized, filtered and separated (second crystallization process). In one embodiment, a washing and concentrating process can be carried out additionally before the first crystallization solvent is added, if necessary. In one embodiment, the purification stage may include a heat treatment process. Through a heat treatment process, the compound of Formula Ib can be transformed into the compound of Formula 5. In one configuration, the heat treatment process can be carried out at a pressure of approximately 1 atmosphere to 50 atmospheres. The pressure is measured as the internal pressure of the reagent and may depend on the temperature change within the reagent. In one modality, the heat treatment process can be carried out at a reaction temperature of 100°C to 250°C, preferably 150°C to 220°C. In one modality, the heat treatment process can be carried out for 10 minutes to 40 hours, preferably 20 minutes to 24 hours. However, the reaction time can be adjusted appropriately according to the reaction temperature. In one embodiment, the heat treatment process can be a step to heat the reaction product of the nir / bnn / zznz / E / Y salt of the compound of Formula 3 and the compound of Formula 2 to selectively convert only the compound of Formula Ib into the compound of Formula 5 (whereas, because the compound of Formula 1a is thermally stable compared to the compound of Formula Ib, the decomposition or reaction rate of the compound of Formula 1a due to heat treatment is extremely low compared to the compound of Formula Ib). The heating can be carried out in the presence of a solvent (e.g., acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, lower C1-C4 alcohol, or a mixture thereof). After the heat treatment process, a washing process with an acidic aqueous solution can be carried out as an additional step. Through this washing process, the compound of Formula 5, which is transformed from the compound of Formula Ib, is removed. In one embodiment, the acidic aqueous solution can be a solution of a strong acid such as hydrochloric acid or sulfuric acid, or a solution of a weak acid such as acetic acid or citric acid, but is not limited to them. [Formula 5] nir / bnn / zznz / E / Y r2 where Ri and R2 are the same as defined above. According to the present description, when the compound of Formula 3 is prepared as a salt and then reacted with the compound of Formula 2, the compound of Formula 1a can be obtained with increased selectivity compared to a conventional method in which the compound of Formula 2, the compound of Formula 3, and the base are reacted simultaneously. Specifically, the ratio of the compound of Formula 1a to the compound of Formula 1b was 4:6 in the conventional method, but the ratio can be approximately 6:4 according to the method described herein. As the selectivity of the compound in Formula 1 increases according to the method described herein compared to the conventional method described above, the productivities of the compound in Formula 1 and the carbamate compound prepared from it can also be significantly increased. Specifically, their productivities increase by at least approximately 70%, and more specifically, from approximately 70% to approximately 100%. nir / bnn / zznz / E / Y Therefore, another aspect of the present description relates to a method for increasing the selectivity of a compound of Formula 1a by using a salt of a compound of Formula 3 in the synthesis of compounds of Formula 1a and a compound of Formula 1b from a compound of Formula 2 and a compound of Formula 3. Furthermore, yet another aspect of the present description relates to the preparation of a compound of Formula 1, comprising: reacting a compound of Formula 2 with a salt of a compound of Formula 3; and purifying the reaction product of the salt of the compound of Formula 3 and the compound of Formula 2, wherein the purification step comprises a crystallization process or a heat treatment process: [Formula the] r2 [Formula 2] or r2 [Formula 3] nir / bnn / zznz / E / Y Η κΓΝNNN where Ri, R2 and X are the same as defined above. Furthermore, yet another aspect of the present description relates to a method for preparing a compound of Formula 4, comprising: (1) reacting a compound of Formula 2 with a salt of a compound of Formula 3; (2) separating the compound of Formula 1 from a mixture obtained from the reaction of step (1); and (3) reducing the compound of Formula 1 separated in step 2 and carbamarizing the reduced compound of Formula 1: [Formula 4] or XH2N9 N=\ _ 1 < N r2 where Ri and R2 are the same as defined above. The reaction of a compound from Formula 2 and a compound from Formula 3 is the same as described above. The separation of a compound from the formula may include the purification stage described above. In the reduction and carbamate step, the reduction process can be carried out using the enzyme nir / bnn / zznz / E / Y oxidoreductase, which is suspended in a reaction mixture or immobilized in a conventional manner. The enzyme can be used in a fully purified state, a partially purified state, or in a microbial cell state in which it is expressed. The cells themselves can be in a natural state, a permeabilized state, or a lysed state. It will be understood by those of ordinary skill in the art that when the method described herein is carried out using the enzyme in a cellular state, it allows for a significant reduction in costs and is therefore preferable. Even more preferably, the enzyme is expressed in E. coli and used as a natural cell suspension. The enzymatic reduction of the compound of Formula la can be carried out in a reaction mixture comprising the compound of Formula la, an oxidoreductase, NADH or NADPH as a cofactor, a cosubstrate, and a suitable buffer. The oxidoreductase can be used to reduce the compound of Formula la with high conversion and enantiomeric selectivity using polypeptides that have oxidoreductase activity. The enantiomeric excess of the alcohol of configuration R produced in the enantiomeric selective enzymatic reduction is at least approximately 89%, preferably at least approximately 95%, and much more preferably at least approximately 99%. In the reduction and carbamate step, a nir / bnn / zznz / E / Y method for introducing a carbamoyl group, for example, can introduce a carbamoyl group by using an inorganic cyanate-organic acid, isocyanate-water, or a carbonyl compound-ammonia. In the carbamate with inorganic cyanate-organic acid, the alcohol compound of configuration (R) converted from the compound of Formula la by the reduction method can be dissolved in an organic solvent, for example, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and then an inorganic cyanate such as sodium cyanate and an organic acid such as methanesulfonic acid or acetic acid, which are 1 to 4 equivalents, can be added to it, and the reaction can be carried out at a reaction temperature of approximately -10°C to approximately 70°C. In the isocyanate-water utilization method, 1 to 4 equivalents of isocyanate—for example, chlorosulfonyl isocyanate, trichloroacetyl isocyanate, trimethylsilyl isocyanate, or the like—can be added to a solution of an alcohol compound having an (R) configuration obtained by reducing a compound of Formula la in an organic solvent—for example, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, or a mixture thereof—and reacted at a reaction temperature of approximately -50°C to 40°C, and then 1 to 20 equivalents of water can be added sequentially to the same without any purification to carry out the hydrolysis. In the carbonyl-ammonia utilization method, 1 to 4 equivalents of carbonyl compound—for example, 1,1'-carbonyldiimidazole, carbamoyl chloride, N,N'-disuccinimidyl carbonate, phosgene, triphosgene, chloroformate, or the like—are added to the alcohol compound solution in an (R) configuration obtained by reducing a compound of Formula la in an organic solvent—for example, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, or a mixture thereof—and then 1 to 10 equivalents of ammonia are added sequentially without purification at a reaction temperature of approximately 10°C to 70°C. Furthermore, yet another aspect of the present description relates to a method for separating a compound of Formula 1a from a mixture comprising a compound of Formula 1a and a compound of Formula 1b by heat-treating the mixture comprising the compound of chemical formula 1a and the compound of Formula 1b to produce a compound of Formula 5 and by removing this compound. The heat treatment process is the same as described above. nir / bnn / zznz / E / Y nir / bnn / zznz / E / Y In one embodiment, the removal of the compound from Formula 5 can be accomplished by washing with an acidic aqueous solution. The acidic aqueous solution can be a strong acid solution such as hydrochloric acid or sulfuric acid, or a weak acid solution such as acetic acid or citric acid, but is not limited to these. The present invention will then be described specifically with reference to the following examples. However, these are provided solely for a better understanding of the present invention, and the scope of the present invention is not limited to them. Examples Example 1 Tetrazol (0.165 g) was dissolved in methanol (9 mL) and potassium carbonate (0.538 g) was added at room temperature. The reaction product was stirred at room temperature for approximately 15 minutes. After confirming that carbon dioxide gas was no longer produced, n-butyl acetate (9 mL) was added, the methanol was removed by distillation under reduced pressure, and n-butyl acetate was added. After adding 2-bromo-2'-chloroacetophenone (0.50 g) to the reaction solution, the reaction product was stirred at 50°C for 12 hours. After the temperature was adjusted to room temperature, the selectivity of the compound from Formula Ib to Formula Ib was confirmed by HPLC to be 40% and the selectivity of the compound from Formula Ib to Formula Ib to be 60%. The HPLC conditions are as follows and are used in the examples below: The column was a Phenomenex Luna C18, 5 nm, 4.6 x 250 mm, and the column temperature was 35°C. The mobile phase was acetonitrile:water in a 6:4 ratio and contained 0.1% trifluoroacetic acid, and was flowed for 10 minutes at 2.0 mL / min under isocratic conditions. The wavelength was set to 245 nm, and the peak position of the compound was 2.36 minutes for the compound of Formula 1a, 1.94 minutes for the compound of Formula 1b, and 4.01 minutes for 2-bromo-2'-chloroacetophenone. The HPLC results are shown in Figure 1. Example 2 Tetrazol (0.165 g) was dissolved in n-butyl acetate (9 mL) and potassium carbonate (0.538 g) was added at room temperature. The reaction product was stirred at room temperature for approximately 24 hours. After confirming that carbon dioxide gas was no longer produced, 2-bromo-2'-chloroacetophenone (0.50 g) was added to the reaction solution and the reaction product was stirred at 50°C for 12 hours. After the temperature was adjusted to room temperature, the selectivity of the compound of Formula la was confirmed to be 60% by HPLC. nir / bnn / zznz / E / Y nir / bnn / zznz / E / Y Example 3 Tetrazole (1.40 g) and potassium carbonate (1.38 g) were added to water (10 mL) and stirred at 100°C for approximately 1 hour under reflux. The temperature was then cooled to room temperature, the water was distilled, and the resulting material was diluted in 20 mL of ethanol. The mixture was stirred at 80°C for 2 hours, and then the temperature was adjusted to room temperature. Approximately 10 mL of ethanol was removed by distillation under reduced pressure and stirred for 2 hours, then filtered and dried under a nitrogen atmosphere to obtain the potassium salt of tetrazole (1.70 g). The potassium tetrazole salt obtained (0.153 g) was added to n-butyl acetate (1.8 mL), 2-bromo-2'-chloroacetophenone (0.30 g) was added to the same, and the reaction mixture was stirred at 50°C for 12 hours. After the temperature was adjusted to room temperature, the selectivity of the compound of Formula l was confirmed to be 62% by HPLC. Example 4 The potassium salt of tetrazole (0.509 g) obtained in Example 3 was added to 2-methyltetrahydrofuran (6 mL), 2-bromo-2'-chloroacetophenone (1.00 g) was added to the same, and the reaction mixture was stirred at 50°C for 22 hours. After the temperature was adjusted to room temperature, the selectivity of the compound of Formula la was confirmed to be nir / bnn / zznz / E / Y 57% by HPLC. Example 5 Tetrazole (1.40 g) and cesium carbonate (3.26 g) were added to water (10 mL) and stirred at 100°C for approximately 1 hour under reflux. The temperature was then cooled to room temperature, the water was distilled, and the reaction mixture was vacuum-dried to obtain the cesium salt of tetrazole (1.685 g). The obtained cesium salt of tetrazole (0.285 g) was added to n-butyl acetate (1.8 mL), 2-bromo-2'-chloroacetophenone (0.30 g) was added to the same, and the reaction mixture was stirred at 50°C for 12 hours. After the temperature was adjusted to room temperature, the selectivity of the compound of Formula l was confirmed to be 56% by HPLC. Example 6 Tetrazole (1.40 g) and sodium carbonate (0.68 g) were added to water (10 mL) and stirred at 100°C for approximately 1 hour under reflux. The temperature was then cooled to room temperature, the water was distilled, and the reaction mixture was vacuum-dried to obtain tetrazole sodium salt (1.53 g). The obtained tetrazole sodium salt (0.156 g) was added to n-butyl acetate (1.8 mL), to which 2-bromo-2'-chloroacetophenone (0.30 g) was added, and the reaction mixture was stirred at 50°C for 12 hours. After the temperature was adjusted to room temperature, the selectivity of the compound was confirmed to be 63% by HPLC. Comparative Example 1 2-Bromo-2'-chloroacetophenone (86.0 g), potassium carbonate (30.5 g), and 35% tetrazoli DMF solution (81.0 g) were added to ethyl acetate (245 mL) and stirred at 55°C for 2 hours. After the temperature was adjusted to room temperature, the selectivity of the compound of Formula 1 was confirmed to be 42% by HPLC. Example 7 2-Bromo-2'-chloroacetophenone (13.0 g) was reacted with tetrazoi potassium salt (6.62 g) and isopropyl acetate (117 mL), and then washed with dilute hydrochloric acid and brine to remove the secondarily generated potassium bromide. The separated isopropyl acetate layer was thoroughly concentrated, replaced with tert-butyl methyl ether, stirred under reflux for approximately 1 hour, and then slowly cooled to 15 °C. When the compound of Formula Ib had sufficiently precipitated, the resulting material was filtered to obtain the compound of Formula Ib (4.1 g, including the compound of Formula Ia) as a solid. For reference, the filtrate was analyzed by HPLC, and it was confirmed that the filtrate is comprised of 6.0 g of the compound from Formula Ia and 0.74 g of the compound from Formula Ib. nir / bnn / zznz / E / Y nir / bnn / zznz / E / Y Compounds of Formula Ib:1H NMR (CDC13) 8.86 (s, 1H) , 7.77 (d, 1H) , 7. 40-7. 62 (m, 3H) , 5.97 (s, 2H) Example 8 A solution of a mixture of 6.0 g of the compound of Formula 1a and 0.74 g of the compound of Formula 1b obtained as a filtrate in Example 7 was concentrated under reduced pressure to remove as much of the solvent as possible. While being substituted with isopropyl alcohol, the compound of Formula 1a was dissolved in isopropyl alcohol (45 mL), stirred for approximately 1 hour at 60°C, and then slowly cooled to 10°C. The compound of Formula 1a was filtered after sufficient precipitation, washed twice with cooled isopropyl alcohol (13 mL) and once with n-heptane (2.6 mL) to obtain the compound of Formula 1a (5.55 g) as a solid with an HPLC purity of 94.2%. Compounds of the Formula la:1H NMR (CDC13) 8.62 (s, 1H), 7.72 (d, 1H), 7.35-7.55 (m, 3H), 6.17 (s, 2H) Example 9 After reacting 2-bromo-2'-chloroacetophenone (17.1 g) with potassium tetrazole salt (8.71 g) and isopropyl acetate (130 mL), heptane (165 mL) was added to obtain the secondary potassium bromide and the compound of Formula Ib as a solid in one step. After stirring at 60°C for 1 hour, the reaction mixture was slowly cooled to approximately [missing information]. 8.5°C. When the potassium bromide and the compound of Formula Ib had sufficiently precipitated, they were filtered to obtain potassium bromide and the compound of Formula Ib (total of 14 g) as solids. For reference, the filtrate was analyzed by HPLC, and it was confirmed that the filtrate comprises 9.5 g of the compound of Formula Ia and 1.4 g of the compound of Formula Ib. Example 10 A solution of a mixture of 9.5 g of the compound of Formula 1a and 1.4 g of the compound of Formula 1b—obtained as a filtrate in Example 9—was concentrated under reduced pressure to remove as much of the solvent as possible and replaced with isopropyl alcohol. The compound of Formula 1a was stirred for approximately 1 hour at 60°C to dissolve in isopropyl alcohol (96 mL) and then cooled slowly to 10°C. When the compound of Formula 1a had sufficiently precipitated, the solid was filtered and washed twice with cold isopropyl alcohol (17 mL) and once with heptane (34 mL). The compound of Formula 1a (7.6 g) was obtained as a solid. Example 11 A mixture in which 2'-chlorophenyl 2-tetrazol-2-yl ketone (0.3 g) and 2'-chlorophenyl 2-tetrazol-l-yl ketone (0.2 g) were dissolved in isopropyl acetate (3 mL), was heated at 150°C for 24 hours, the temperature was adjusted to room temperature, and a pyrolysis ratio was confirmed by nir / bnn / zznz / E / Y HPLC confirmed that 99.9% of 2'-chlorophenyl 2-tetrazol-1-yl decomposed and was transformed into 5-(2-chlorophenyl)oxazol-2-amine, while 88.2% of 2'-chlorophenyl 2-tetrazol-2-yl remained undecomposed by HPLC. The 5-(2-chlorophenyl)oxazol-2-amine produced was washed with 1 N HCl to remove this compound. The column was a Phenomenex Luna C18, 5 μm, 4.6 x 250 mm, and the column temperature was 35°C. The mobile phase was acetonitrile:water in a 6:4 ratio and contained 0.1% trifluoroacetic acid, and was flowed for 10 minutes at 2.0 mL / min under isocratic conditions. The wavelength was set to 245 nm, and the peak time position of the compound was 2.36 minutes for the compound of Formula 1a, 1.94 minutes for the compound of Formula 1b, and 1.23 minutes for 5-(2-chlorophenyl)oxazol-2-amine of Formula 5. 5-(2-chlorophenyl)oxazol-2-amine: LC-MS [M+H]=195.0 g / mol The structure of 5-(2-chlorophenyl)oxazol-2-amine was confirmed by ORTEP imaging and is represented in Figure 2. The HPLC results are shown in Figure 3. Example 12 A mixture in which 2'-chlorophenyl 2-tetrazol-2-yl ketone (0.3 g) and 2'-chlorophenyl 2-tetrazol-l-yl ketone (0.2 g) were dissolved in isopropanol (3 mL) was flowed into a continuous tube reactor set at 210°C for 20 minutes, and then the temperature was adjusted to room temperature, and a pyrolysis ratio was confirmed by HPLC. It was confirmed that 99.9% of 2'-chlorophenyl 2-tetrazol-l-yl decomposed and was transformed into 5-(2-chlorophenyl)oxazol-2-amine, and 90% of 2'-chlorophenyl 2-tetrazol-2-yl remained undecomposed.

Claims

1. A method for preparing a compound of Formula 1a, [Formula 1a]r2, characterized in that it comprises: reacting a compound of Formula 2 with a salt of a compound of Formula 3: [Formula 2] or r2 [Formula 3], wherein Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; and X is a leaving group.

2. A method for preparing a compound of Formula 1a, [Formula 1a] r2 characterized in that it comprises: reacting a compound of Formula 2 with a salt of a compound of Formula 3; and purifying the reaction product of the salt of the compound of Formula 3 and the compound of Formula 2, wherein the purification step comprises a crystallization process or a heat treatment process; [Formula 2] or r2 [Formula 3] H íT N NN wherein Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; and X is a leaving group.

3. The method according to claim 1 or 2, characterized in that the salt of the compound of Formula 3 is obtained by reacting the compound of Formula 3 with a base.

4. The method according to claim 3, characterized in that the salt is one or more selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, and a cesium salt.

5. The method according to claim 3, characterized in that the base is an inorganic base or an organic base.

6. The method according to claim 5, characterized in that the inorganic base is a metal hydroxide or a metal carbonate, and the organic base is an amine compound.

7. The method according to claim 6, characterized in that the metal hydroxide is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide; the metal carbonate is selected from lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; and the amine compound is selected from triethylamine and diisopropylethylamine. nir / bnn / zznz / E / Y 8. The method according to claim 3, characterized in that the compound of Formula 3 is reacted with a base in a reaction solvent, and then the salt of the compound of Formula 3 is separated from the reaction product of the compound of Formula 3 and the base.

9. The method according to claim 8, characterized in that the salt separated from the compound of Formula 3 is reacted with the compound of Formula 2.

10. The method according to claim 3, characterized in that after the reaction of the compound of Formula 3 with a base, the compound of Formula 2 is added to the reaction product to react with the salt of the compound of Formula 3.

11. The method according to claim 2, characterized in that the crystallization process comprises a first crystallization process and a second crystallization process.

12. The method according to claim 11, characterized in that a solvent for the first crystallization process is selected from the group consisting of water, C1-C4 lower alcohol, diethyl ether, tert-butyl methyl ether, isopropyl ether, pentane, hexane, cyclohexane, heptane, and a mixture thereof.

13. The method according to claim 11, characterized in that a solvent for the second crystallization process is selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, lower CiC4 alcohol, and a mixture thereof.

14. The method according to claim 1 or 2, characterized in that the leaving group is selected from the group consisting of 4-nitrophenyl chloride, bromide, mesylate, tosylate and sulfonate.

15. A method for separating a compound of Formula 1a from a mixture comprising a compound of Formula 1a and a compound of Formula 1b, characterized in that it comprises a heat treatment process of the mixture comprising the compound of Formula 1a and the compound of Formula 1b: [Formula 1a] nir / bnn / zznz / E / Y r2 [Formula 1b] Rz wherein Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl nir / bnn / zznz / E / Y having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms.

16. The method according to claim 2 or Ib, characterized in that the heat treatment process is a step of transforming the compound of Formula Ib to a compound of Formula 5: [Formula 5] nh2 r2 wherein Ri and R2 are the same as defined in claim 15.

17. The method according to claim 2 or 15, characterized in that the heat treatment process is carried out in the presence of a solvent.

18. The method according to claim 17, characterized in that the solvent is acetone, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C1-C4 lower alcohol or a mixture thereof.

19. The method according to claim 2 or 15, characterized in that the heat treatment process nir / bnn / zznz / E / Y is carried out at a pressure of 1 atmosphere to 50 atmospheres.

20. The method according to claim 2 or 15, characterized in that the heat treatment process is carried out at a reaction temperature of 100°C to 250°C.

21. The method according to claim 2 or 15, characterized in that the heat treatment process is carried out for 10 minutes to 40 hours.

22. The method according to claim 2 or 15, characterized in that it further comprises a washing step in a heat treatment process product with an acidic aqueous solution.

23. The method according to claim 22, characterized in that the acidic aqueous solution is an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid or citric acid.

24. The method according to claim 22, characterized in that the compound of Formula 5 is removed by the washing step with the acidic aqueous solution: [Formula 5] wherein Ri and R2 are the same as defined in claim 15.