Method for preparing aryl 2-tetrazol-2-yl ketone with improved selectivity

Abstract

To provide a method for preparing aryl 2-tetrazol-2-yl-ketone with improved selectivity.SOLUTION: The present invention provides a method for producing a compound of a formula (1a), comprising a step of obtaining a salt of a compound of a formula (3) and reacting the salt with a compound of a formula (2). In the formulae, R1 and R2 are each independently hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, or the like, and X is a leaving group.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for producing an aryl 2 - tetrazol - 2 - yl ketone of formula (1a) with improved selectivity

Chemical formula

Background Art

[0002] (R)-1 - Aryl - 2 - tetrazolyl - ethyl carbamate (hereinafter also referred to as 'carbamate compound') is useful for the treatment of CNS disorders according to its antispasmodic effect, particularly, anxiety, depression, spasm, epilepsy, migraine, bipolar disorder, drug abuse, smoking, attention - deficit hyperactivity disorder (ADHD), obesity, sleep disorder, neuropathic pain, stroke, cognitive impairment, neurodegeneration, muscle spasm due to stroke, etc. The carbamate compound is produced using a compound of formula (1a) obtained from a substitution reaction between a compound of formula (2) and a compound of formula (3) as an intermediate. Conventionally, after adding a base to the compound of formula (2), a tetrazole solution was added to carry out the substitution reaction. However, in this case, in addition to the desired compound of formula (1a), its positional isomer, the compound of formula (1b), is obtained together as a mixture by the said substitution reaction (Patent Document 1).

[0003]

Chemical formula

[0004] Furthermore, when subjecting the compound of formula (2) and the compound of formula (3) to a substitution reaction, since the reaction selectivity of the first nitrogen of the compound of formula (3) is better than that of the second nitrogen, the compound of formula (1b) is produced with excellent selectivity compared to the compound of formula (1a) (Non-Patent Document 1). Therefore, according to the conventional method, the amount of the compound of formula (1a) used in the production of the carbamate compound is less than that of the compound of formula (1b). When producing a carbamate compound using the compounds of formula (2) and formula (3) as starting materials, there is a problem of low yield.

[0005] Regarding this, there is an alternative method for selectively producing only the compound in the same form as that in which the second nitrogen is substituted by synthesizing a tetrazole ring shape (Non-Patent Document 2). However, since it uses a diazomethane-based substance that is dangerous of explosion during the reaction and uses more than 2 equivalents of lithium diisopropylamide as a raw material, there is a problem that it is difficult to use commercially. Therefore, by producing the aryl 2-tetrazol-2-yl ketone of formula (1a) from the compounds of formula (2) and formula (3) with better selectivity than the aryl 2-tetrazol-1-yl ketone of formula (1b), as a result, while obtaining the aryl 2-tetrazol-2-yl ketone of formula (1a) and the carbamate compound in high yield, it is necessary to develop a method that can be commercialized.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Non-Patent Documents

[0007]

Non-Patent Document 1

[0008] An object of the present invention is to provide a commercially available method capable of improving the productivity of a carbamate compound by more selectively and on a large scale synthesizing an aryl 2-tetrazol-2-yl ketone useful as an intermediate of a carbamate compound. [Means for Solving the Problems]

[0009] One aspect of the present invention provides a method for producing a compound of the following formula (1a), which includes a step of reacting a compound of the following formula (2) with a salt of a compound of the following formula (3): [Chemical Formula] (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy, and X is a leaving group.)

[0010] Another aspect of the present invention provides a method for increasing the selectivity of a compound of formula (1a) by using a salt of a compound of formula (3) when synthesizing a compound of formula (1a) and a compound of formula (1b) from a compound of formula (2) and a compound of formula (3): [Chemical Formula] (In the formula, R1, R2 and X are as defined above.)

[0011] Another aspect of the present invention provides a method for producing a compound of the following formula (4), comprising: (1) reacting a compound of the following formula (2) with a salt of a compound of the following formula (3); (2) separating a compound of the following formula (1a) from the mixture obtained by the reaction of step (1); and (3) reducing the compound of formula (1a) separated in step (2) and carbamoylating the reduced compound of formula (1a):

Chemical formula

[0012] Another aspect of the present invention provides a method for separating a compound of formula (1a) from a mixture containing a compound of formula (1a) and a compound of formula (1b), comprising heat-treating a mixture containing a compound of formula (1a) and a compound of formula (1b) to provide a compound of formula (5), and removing this compound:

Chemical formula

[0013] Another aspect of the present invention provides a method for producing a compound of the following formula (1a), comprising: reacting a compound of the following formula (2) with a salt of a compound of the following 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 includes a crystallization step or a heat treatment step:

Chemical formula

Advantages of the Invention

[0014] According to the present invention, the productivity of carbamate compounds can be significantly improved by more selectively synthesizing aryl 2-tetrazol-2-yl ketone, which is useful as an intermediate for carbamate compounds, on a large scale in a simple process.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0016] Hereinafter, the present invention will be described in detail. The method for producing the compound of formula (1a) according to one aspect of the present invention includes a step of reacting the compound of formula (2) with a salt of the compound of formula (3):

Chemical formula

[0017] The salt of the compound of formula (3) is obtained by reacting the compound of formula (3) with a base, wherein the salt may be an inorganic salt or an organic salt. In one embodiment, the inorganic salt of the compound of formula (3) may 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.

[0018] In one embodiment, the inorganic salt of the compound of formula (3) can be obtained by reacting the compound of formula (3) with an inorganic base. The inorganic base may be 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.), but is not limited thereto.

[0019] In one embodiment, the organic salt of the compound of formula (3) can be obtained by reacting the compound of formula (3) with an organic base. The organic base may be an amine compound (e.g., triethylamine, diisopropylethylamine, etc.), but is not limited thereto.

[0020] 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, C1-C4 lower alcohols (e.g., methanol, ethanol, propanol, butanol), etc., which can be used alone or in combination.

[0021] According to one embodiment, after reacting the compound of formula (3) with a base in a reaction solvent, 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 separated salt of the compound of formula (3) can be reacted with the compound of formula (2).

[0022] According to another embodiment, after reacting the compound of formula (3) with a base, the compound of formula (2) can be added to the reaction product to react with the salt of the compound of formula (3).

[0023] According to another embodiment, the reaction between the salt of the compound of formula (3) and the compound of 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, C1-C4 lower alcohols (e.g., methanol, ethanol, propanol, butanol), etc., which can be used alone or in combination.

[0024] 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 containing the compound of the following formula (1a) and the compound of the following formula (1b):

Chemical formula

[0025] 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 producing the compound of formula (1a) can further include a step of purifying the reaction product of the salt of the compound of formula (3) and the compound of formula (2). In one embodiment, the purification step includes a crystallization step, and more specifically, the crystallization step can include a first crystallization step and a second crystallization step.

[0026] In one embodiment, in the crystallization step, a first crystallization solvent (e.g., water, C1-C4 lower alcohol, diethyl ether, tert-butyl methyl ether, isopropyl ether, pentane, hexane, cyclohexane, heptane, and mixtures thereof) is added to the reaction product of the salt of the compound of formula (3) and the compound of formula (2) to crystallize the compound of formula (1b), followed by filtration and separation ("first crystallization step"). Then, a second crystallization solvent (e.g., acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C1-C4 lower alcohol, or mixtures thereof) is added to the remaining filtrate to crystallize, filter, and separate the compound of formula (1a) ("second crystallization step").

[0027] In one embodiment, if necessary, before adding the first crystallization solvent, a washing and concentration step can be further performed. In one embodiment, the purification step can include a heat treatment step. By the heat treatment step, the compound of formula (1b) can be converted into the compound of formula (5). In one embodiment, the heat treatment step can be carried out at a pressure of about 1 atm to 50 atm. The pressure is measured for the internal pressure of the reactor and may depend on the temperature change in the reactor.

[0028] In one embodiment, the heat treatment step can be carried out at a reaction temperature of 100°C to 250°C, preferably 150°C to 220°C. In one embodiment, the heat treatment step can be carried out for 10 minutes to 40 hours, preferably 20 minutes to 24 hours. However, the reaction time can be appropriately adjusted according to the reaction temperature.

[0029] In one embodiment, the heat treatment step may be a step of heating the reaction product of the salt of the compound of formula (3) and the compound of formula (2) to selectively convert only the compound of formula (1b) into the compound of formula (5) (wherein the compound of formula (1a) is thermally more stable than the compound of formula (1b), and the decomposition or reaction ratio of the compound of formula (1a) by heat treatment is very low compared to the compound of formula (1b)). The heating can be carried out in the presence of a solvent (for example, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C1-C4 lower alcohols or a mixture thereof).

[0030] After the heat treatment step, a step of washing with an acidic aqueous solution can be further carried out. Through the washing step, the compound of formula (5) converted from the compound of formula (1b) is removed. In one embodiment, the acidic aqueous solution may be, but is not limited to, 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.

[0031]

Chemical formula

[0032] According to the present invention, after producing the compound of formula (3) as a salt and reacting it with the compound of formula (2), the compound of formula (1a) can be obtained with high selectivity as compared with the conventional method of simultaneously reacting the compound of formula (2), the compound of formula (3) and a base. Specifically, the ratio of the compound of formula (1a) to the compound of formula (1b) was 4:6 in the conventional method, but according to the method of the present invention, it may be 6:4.

[0033] According to the method of the present invention, the selectivity of the compound of formula (1a), as well as the productivity of the compound of formula (1a) of the present invention and the carbamate compound produced therefrom, can be significantly increased as compared with the above-mentioned conventional methods. Specifically, these productivities increase by at least about 70%, more specifically from about 70% to about 100%.

[0034] Therefore, another aspect of the present invention relates to a method for increasing the selectivity of the compound of formula (1a) by using a salt of the compound of formula (3) when synthesizing the compound of formula (1a) and the compound of formula (1b) from the compound of formula (2) and the compound of formula (3).

[0035] Furthermore, still another aspect of the present invention relates to a method for producing a compound of the following formula (1a), comprising a step of reacting a compound of the following formula (2) with a salt of a compound of the following formula (3); and a step of purifying the reaction product of the salt of the compound of formula (3) and the compound of formula (2), wherein the purification step includes a crystallization step or a heat treatment step:

Chemical formula

[0036] Furthermore, still another aspect of the present invention relates to a method for producing a compound of the following formula (4), comprising: (1) a step of reacting a compound of formula (2) with a salt of a compound of formula (3); (2) a step of separating the compound of formula (1a) from the mixture obtained from the reaction of step (1); and (3) a step of reducing the compound of formula (1a) separated in step 2 and carbamoylating the reduced compound of formula (1a):

Chemical formula

[0037] The reaction between the compound of formula (2) and the compound of formula (3) is the same as described above. The separation of the compound of formula (1a) can include the above-mentioned purification step.

[0038] In the reduction and carbamation steps, the reduction step can be carried out by using a redox enzyme suspended or immobilized in the reaction mixture by a conventional method. The enzyme can be used in a completely purified state, a partially purified state, or even in the state of microbial cells in which it is expressed. The cells themselves may be in a natural state, a permeabilized state, or a lysed state. Those skilled in the art will understand that when the method of the present invention is carried out by using the enzyme in the cell state, it can significantly reduce the cost as preferred. Most preferably, the enzyme is expressed in Escherichia coli (E. coli) and used as a natural cell suspension.

[0039] The enzymatic reduction of the compound of formula (1a) can be carried out in a reaction mixture containing the compound of formula (1a), a redox enzyme, NADH or NADPH as a cofactor, a cosubstrate, and a suitable buffer. The redox enzyme can be used to reduce the compound of formula (1a) with high conversion rate and enantioselectivity by using a polypeptide having redox enzyme activity. The enantiomeric excess of the R-configuration alcohol produced by enantioselective enzymatic reduction is at least about 89%, preferably at least about 95%, and most preferably at least about 99%.

[0040] In the steps of reduction and carbamation, a carbamoyl group can be introduced, for example, using an inorganic cyanate - organic acid, an isocyanate - water, or a carbonyl compound - ammonia.

[0041] In the carbamation using an inorganic cyanate - organic acid, after dissolving the (R)-configuration alcohol compound converted from the compound of formula (1a) by a reduction method in an organic solvent such as diethyl ether, tetrahydrofuran, 1,4 - dioxane, acetonitrile, dichloromethane, chloroform, or a mixture thereof, an inorganic cyanate such as 1 - 4 equivalents of sodium cyanate and an organic acid such as methanesulfonic acid or acetic acid are added, and the reaction can be carried out at a reaction temperature of about - 10°C to about 70°C.

[0042] In the method of using isocyanate-water, the compound of formula (1a) is reduced with an organic solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and 1 to 4 equivalents of isocyanate such as chlorosulfonyl isocyanate, trichloroacetyl isocyanate, trimethylsilyl isocyanate, etc. are added to the obtained (R)-coordinated alcohol compound solution, and after reacting at a reaction temperature of about -50°C to 40°C, 1 to 20 equivalents of water can be sequentially added without purification to carry out hydrolysis.

[0043] In the method of using carbonyl compound-ammonia, the compound of formula (1a) is reduced with an organic solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and 1 to 4 equivalents of carbonyl compound such as 1,1'-carbonyldiimidazole, carbamoyl chloride, N,N'-disuccinimidyl carbonate, phosgene, triphosgene, chloroformate, etc. are added to the obtained (R)-coordinated alcohol compound solution, and 1 to 10 equivalents of ammonia are sequentially added at a reaction temperature of about -10°C to 70°C without purification.

[0044] Furthermore, another aspect of the present invention relates to a method for separating the compound of formula (1a) from a mixture containing the compound of formula (1a) and the compound of formula (1b) by heat-treating a mixture containing the compound of formula (1a) and the compound of formula (1b) to produce the compound of formula (5) and removing this compound. The heat treatment step is the same as described above.

[0045] In one embodiment, the removal of the compound of formula (5) can be carried out by washing with an acidic aqueous solution. The acidic aqueous solution may 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 thereto.

[0046] Hereinafter, the present invention will be specifically described with reference to the following examples. However, these are provided only for better understanding of the present invention, and the scope of the present invention is not limited thereto.

[0047] Example Example 1 Tetrazole (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 about 15 minutes. After confirming that carbon dioxide gas no longer evolved, n-butyl acetate (9 mL) was added, and 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 adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1b) corresponding to formula (1b) was 40%, and the selectivity of the compound of formula (1a) corresponding to formula (1a) was 60%. The HPLC conditions are as follows and are the same as those used in the following examples. The column was Phenomenex Luna C18, 5 μm, 4.6×250 mm, and the column temperature was 35 °C. The mobile phase contained acetonitrile: water in a ratio of 6:4 and contained 0.1% trifluoroacetic acid, and was flowed at 2.0 mL / min for 10 minutes under isocratic conditions. The wavelength was fixed at 245 nm, and the peak time positions of the compounds were 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.

[0048] Example 2 Tetrazole (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 about 24 hours. After confirming that carbon dioxide gas no longer evolved, 2-bromo-2'-chloroacetophenone (0.50 g) was added to the reaction solution. The reaction product was stirred at 50 °C for 12 hours. After adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1a) was 60%.

[0049] Example 3 Tetrazole (1.40 g) and potassium carbonate (1.38 g) were added to water (10 mL), and the mixture was stirred at 100 °C for about 1 hour under reflux conditions. The temperature was lowered to room temperature, water was distilled off, and the resulting product was diluted with 20 mL of ethanol. The mixture was stirred at 80 °C for 2 hours, then the temperature was adjusted to room temperature. It was distilled under reduced pressure to remove about 10 mL of ethanol, stirred for 2 hours, filtered, and dried under a nitrogen atmosphere to obtain potassium tetrazole salt (1.70 g). The obtained potassium tetrazole salt (0.153 g) was added to n-butyl acetate (1.8 mL), 2-bromo-2'-chloroacetophenone (0.30 g) was added, and the reaction mixture was stirred at 50 °C for 12 hours. After adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1a) was 62%.

[0050] Example 4 The potassium tetrazole salt (0.509 g) obtained in Example 3 was added to 2-methyltetrahydrofuran (6 mL), 2-bromo-2'-chloroacetophenone (1.00 g) was added, and the reaction mixture was stirred at 50 °C for 22 hours. After adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1a) was 57%.

[0051] Example 5 Tetrazole (1.40 g) and cesium carbonate (3.26 g) were added to water (10 mL), and the mixture was stirred at 100 °C for about 1 hour under reflux conditions. The temperature was lowered to room temperature, water was distilled off, and the reaction mixture was dried under vacuum to obtain cesium tetrazole salt (1.685 g). The obtained cesium tetrazole salt (0.285 g) was added to n-butyl acetate (1.8 mL), 2-bromo-2'-chloroacetophenone (0.30 g) was added, and the reaction mixture was stirred at 50 °C for 12 hours. After adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1a) was 56%.

[0052] Example 6 Tetrazole (1.40 g) and sodium carbonate (0.68 g) were added to water (10 mL), and the mixture was stirred at 100 °C for about 1 hour under reflux conditions. After the temperature was lowered to room temperature and the water was distilled off, the reaction mixture was dried under vacuum to obtain sodium tetrazole salt (1.53 g). The obtained sodium tetrazole salt (0.156 g) was added to n-butyl acetate (1.8 mL), and after adding 2-bromo-2'-chloroacetophenone (0.30 g), the reaction mixture was stirred at 50 °C for 12 hours. After adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1a) was 63%.

[0053] Comparative Example 1 2-Bromo-2'-chloroacetophenone (86.0 g), potassium carbonate (30.5 g) and 35% tetrazole DMF solution (81.0 g) were added to ethyl acetate (245 mL), and the mixture was stirred at 55 °C for 2 hours. After adjusting the temperature to room temperature, it was confirmed by HPLC that the selectivity of the compound of formula (1a) was 42%.

[0054] Example 7 2-Bromo-2'-chloroacetophenone (13.0 g) was reacted with potassium tetrazole salt (6.62 g) and isopropyl acetate (117 mL), and then washed with dilute hydrochloric acid and brine to remove secondary potassium bromide formed. The separated isopropyl acetate layer was completely concentrated, replaced with tert-butyl methyl ether, stirred under reflux conditions for about 1 hour, and then slowly cooled to 15 °C. When the compound of formula (1b) was sufficiently precipitated, the product was filtered to obtain the compound of formula (1b) (4.1 g, including the compound of formula (1a)) as a solid. For reference, the filtrate was analyzed by HPLC, and it was confirmed that the filtrate consisted of 6.0 g of the compound of formula (1a) and 0.74 g of the compound of formula (1b). Compound of formula (1b): 1 H NMR (CDCl3) 8.86 (s, 1H), 7.77 (d, 1H), 7. 40-7. 62 (m, 3H), 5.97 (s, 2H)

[0055] Example 8 A mixture solution of 6.0 g of the compound of formula (1a) and 0.74 g of the compound of formula (1b) obtained as the filtrate in Example 7 was concentrated under reduced pressure to remove the solvent as much as possible and then replaced with isopropyl alcohol. The compound of formula (1a) was dissolved in isopropyl alcohol (45 mL), stirred at 60 °C for about 1 hour, and then slowly cooled to 10 °C. After the compound of formula (1a) was sufficiently precipitated, it was filtered and washed twice with cold isopropyl alcohol (13 mL) and once with n-heptane (26 mL) to obtain the compound of formula (1a) (5.55 g) as a solid with an HPLC purity of 94.2%. Compound of formula (1a): 1 H NMR (CDCl3) 8.62 (s, 1H), 7.72 (d, 1H), 7. 35-7. 55 (m, 3H), 6.17 (s, 2H)

[0056] Example 9 2-Bromo-2'-chloroacetophenone (17.1 g) was reacted with potassium tetrazole salt (8.71 g) and isopropyl acetate (130 mL), and then heptane (165 mL) was added to obtain the secondary potassium bromide and the compound of formula (1b) as a solid at once. After stirring at 60 °C for 1 hour, the reaction mixture was slowly cooled to about 8.5 °C. When potassium bromide and the compound of formula (1b) were sufficiently precipitated, they were filtered to obtain potassium bromide and the compound of formula (1b) (total 14 g) as a solid. For reference, the filtrate was analyzed by HPLC to confirm that the filtrate consisted of 9.5 g of the compound of formula (1a) and 1.4 g of the compound of formula (1b).

[0057] Example 10 A mixture solution of 9.5 g of the compound of formula (1a) and 1.4 g of the compound of formula (1b) obtained as the filtrate in Example 9 was concentrated under reduced pressure to remove the solvent as much as possible and then replaced with isopropyl alcohol. The compound of formula (1a) was stirred at 60 °C for about 1 hour to dissolve it in isopropyl alcohol (96 mL), and then slowly cooled to 10 °C. When the compound of formula (1a) was 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.

[0058] Example 11 A mixture in which 2'-chlorophenyl 2-tetrazol-2-yl ketone (0.3 g) and 2'-chlorophenyl 2-tetrazol-1-yl ketone (0.2 g) were dissolved in isopropyl acetate (3 mL) was heated at 150 °C for 24 hours. After adjusting the temperature to room temperature, the thermal decomposition rate was confirmed by HPLC. It was confirmed by HPLC that 99.9% of 2'-chlorophenyl 2-tetrazol-1-yl was decomposed and converted to 5-(2-chlorophenyl)oxazol-2-amine, and 88.2% of 2'-chlorophenyl 2-tetrazol-2-yl remained undecomposed. The generated 5-(2-chlorophenyl)oxazol-2-amine was washed with 1N HCl to remove this compound. The column was Phenomenex Luna C18, 5 μm, 4.6×250 mm, and the column temperature was 35 °C. The mobile phase was a ratio of acetonitrile:water of 6:4, containing 0.1% trifluoroacetic acid, and was flowed at 2.0 mL / min for 10 minutes under isocratic conditions. The wavelength was fixed at 245 nm, and the peak time positions of the compounds were 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 an ORTEP image and is shown in Figure 2. The HPLC results are shown in Figure 3.

[0059] Example 12 A mixture of 2'-chlorophenyl 2-tetrazol-2-yl ketone (0.3 g) and 2'-chlorophenyl 2-tetrazol-1-yl ketone (0.2 g) dissolved in isopropanol (3 mL) was flowed into a tube-type continuous reactor set at 210 °C for 20 minutes. Then, the temperature was adjusted to room temperature, and the thermal decomposition rate was confirmed by HPLC. It was confirmed that 99.9% of 2'-chlorophenyl 2-tetrazol-1-yl was decomposed and converted to 5-(2-chlorophenyl)oxazole-2-amine, and 90% of 2'-chlorophenyl 2-tetrazol-2-yl remained undecomposed.

Claims

1. A process for producing a compound of formula (1a), comprising reacting a compound of formula (2) with a salt of a compound of formula (3), wherein 【Chemical 1】 (wherein, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy, and X is a leaving group) is the method.

2. A step of reacting a compound of formula (2) with a salt of a compound of formula (3); and A process for producing a compound of formula (1a), comprising a step of purifying a reaction product of a salt of a compound of formula (3) and a compound of formula (2), wherein the purification step includes a crystallization step or a heat treatment step, 【Chemical 2】 (In the formula, R 1 and R 2 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) is the method.

3. The method according to claim 1 or 2, wherein 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, wherein the salt is one or more selected from the group consisting of lithium salts, sodium salts, potassium salts, and cesium salts.

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

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

7. 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, The method according to claim 6, wherein the amine compound is selected from triethylamine and diisopropylethylamine.

8. The method according to claim 3, wherein after reacting the compound of formula (3) with a base in a reaction solvent, 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, wherein the separated salt of the compound of formula (3) is reacted with the compound of formula (2).

10. The method according to claim 3, wherein after reacting 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, wherein the crystallization step includes a first crystallization step and a second crystallization step.

12. The solvent in the first crystallization step is water, C 1 -C 4 The method according to claim 11, wherein the solvent is selected from the group consisting of lower alcohols, diethyl ether, tert-butyl methyl ether, isopropyl ether, pentane, hexane, cyclohexane, heptane, and mixtures thereof.

13. The solvent in the second crystallization step is selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C 1 -C 4 The method according to claim 11, wherein the solvent is selected from the group consisting of lower alcohols and mixtures thereof.

14. The method according to claim 1 or 2, wherein the leaving group is selected from the group consisting of chloride, bromide, mesylate, tosylate, and 4-nitrophenylsulfonate.

15. A method for separating a compound of formula (1a) from a mixture containing the compound of formula (1a) and the compound of formula (1b), comprising a step of heat-treating a mixture containing the compound of formula (1a) and the compound of formula (1b), 【Chemical Formula 3】 (wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy) is the method.

16. The method according to claim 2 or 15, wherein the heat treatment step converts the compound of formula (1b) into the compound of the following formula (5): 【Chemical Formula 4】 (wherein R 1 and R 2 are as defined in claim 15).

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

18. The solvent is acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C 1 -C 4 The method according to claim 17, wherein the solvent is a lower alcohol or a mixture thereof.

19. The method according to claim 2 or 15, wherein the heat treatment step is carried out at a pressure of 1 atm to 50 atm.

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

21. The method according to claim 2 or 15, wherein the heat treatment step is carried out for 10 minutes to 40 hours.

22. The method according to claim 2 or 15, further comprising a step of washing the product of the heat treatment step with an acidic aqueous solution.

23. The method according to claim 22, wherein 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, wherein the compound of formula (5) is removed by the step of washing with an acidic aqueous solution: [Chemical Formula 5] (wherein R 1 and R 2 have the same meaning as defined in claim 15).

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