Method for preparing novel compound

Abstract

The present invention relates to a method for preparing 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine, which is a novel candidate material for NF2 treatment. Through an optimal preparation method, it is possible to prepare a compound with low impurities and high purity even at low manufacturing costs and within a short manufacturing time, and the compound prepared thereby can be used as a novel therapeutic agent for type 2 neurofibromatosis (NF2).

Description

Method for preparing a novel compound

[0001] The present invention provides a method for preparing a novel compound, and more specifically, provides a method for preparing 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine.

[0002] Neurofibromatosis (NF) is a genetic disorder that affects the bones, soft tissues, skin, and nervous system. It is classified into neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). Type 2 neurofibromatosis is a benign tumor that develops in the eighth cranial nerve, causing symptoms such as hearing loss, tinnitus, and balance problems. Because it develops within the schwann cells of the central nervous system, it is also called vestibular schwannomas. The average age of onset of type 2 neurofibromatosis is 18 to 24 years, and by the age of 30, almost all patients have developed bilateral vestibular schwannomas. Additionally, neurofibromatosis can progress to other types of schwannomas, including cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas.

[0003] Neurofibromatosis type 2 is caused by mutations in the NF2 gene, located on the long arm of chromosome 22 (22q12.2). The NF2 gene is responsible for making a protein called merlin, which is produced in the nerve sheath cells that surround nerve cells in the brain and spinal cord within the nervous system.

[0004] Meanwhile, Korean Patent Publication No. 10-2022-0128710 discovered a novel compound for the treatment of neurofibromatosis type 2 (NF2), and research is ongoing on the optimal manufacturing method for the compound.

[0005] The purpose of the present invention is to provide an optimal method for preparing 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine.

[0006] In order to achieve the above object, the present invention comprises the steps of: a) synthesizing an intermediate by dissolving 4-MBC (4-methoxybenzyl chloride) in DMF (dimethylformamide), adding NaN3 (Sodium azide), and reacting for 1 to 3 hours; b-1) synthesizing an intermediate by dissolving 4-HPA (4-hydroxyphenylacetonitrile) in THF (tetrahydrofuran), reacting, adding DEAECl.HCl (2-Diehtylaminoethylchloride hydrochloride) and water, and cooling to 5 to 20°C; b-2) synthesizing an intermediate by adding the reactant of step b-1) to an aqueous NaOH solution, and reacting for 2 to 4 hours; c) a step of dissolving the intermediate of step a) and the intermediate of step b-2) in DMSO, adding KTB (Potassium tert-Butoxide (Potassium tert-Butoxide; t-BuOK) and reacting at 20 to 40° C. for 1 to 3 hours; and d) a step of dissolving the reactant of step c) in CH2Cl2 (dichloromethane), adding activated carbon, stirring at 15 to 40° C. for 30 to 100 minutes, filtering, and washing; a method for preparing 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine is provided.

[0007] The present invention relates to a method for producing a novel compound for treating NF2, and through an optimal manufacturing method, a compound can be produced with low impurities and high purity and yield, even with low manufacturing cost and manufacturing time.

[0008] Figure 1 shows a schematic diagram of the synthesis of 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine [4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine; hereinafter referred to as PRG-N-01].

[0009] Hereinafter, the present invention will be described in more detail.

[0010]

[0011] The present invention comprises the steps of: a) dissolving 4-MBC (4-methoxybenzyl chloride) in DMF (dimethylformamide), adding NaN3 (sodium azide) and reacting for 1 to 3 hours to synthesize an intermediate; b-1) dissolving 4-HPA (4-hydroxyphenylacetonitrile) in THF (tetrahydrofuran), reacting, adding DEAECl.HCl (2-Diehtylaminoethylchloride hydrochloride) and water and cooling to 5 to 20°C; b-2) adding the reactant of step b-1) to an aqueous NaOH solution and reacting for 2 to 4 hours to synthesize an intermediate; c) a step of dissolving the intermediate of step a) and the intermediate of step b-2) in DMSO, adding KTB (Potassium tert-Butoxide (Potassium tert-Butoxide; t-BuOK) and reacting at 20 to 40° C. for 1 to 3 hours; and d) a step of dissolving the reactant of step c) in CH2Cl2 (dichloromethane), adding activated carbon, stirring at 15 to 40° C. for 30 to 100 minutes, filtering, and washing; a method for preparing 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine is provided.

[0012] The reaction of step a) above can be carried out at 15 to 60°C, preferably 25 to 30°C.

[0013] The equivalent amount of NaN3 used in step a) above may be 1.0 to 3.0 eq, preferably 1.1 to 2.2 eq, and more preferably 1.5 eq.

[0014] The equivalent amount of DEAECl.HCl used in the above step b-1) may be 1.0 to 1.5 eq, and preferably 1.2 eq.

[0015] The reaction of step b-2) above can be carried out at 40 to 70°C, and preferably 60 to 65°C.

[0016] The equivalent amount of NaOH used in the above step b-2) may be 2.5 to 4 eq, and preferably 3.0 eq.

[0017] The NaOH aqueous solution of step b-2) may be a 20 to 50% (w / v) NaOH aqueous solution, preferably 22 to 45% (w / v), and more preferably 22.5% (w / v).

[0018] The equivalent amount of KTB used in step c) above may be 1.0 to 3.0 eq, and preferably 2.0 eq.

[0019] In the above step d), the volume ratio of the reactants of the above step c) and CH2Cl2 (dichloromethane) may be 1:1.5 to 4.0, and preferably 1:3.

[0020] Hereinafter, to aid understanding of the present invention, examples and other embodiments will be described in detail. However, the following examples and other embodiments merely illustrate the content of the present invention and are not intended to limit the scope of the present invention. The examples and other embodiments of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0021]

[0022] [Manufacturing Example] Synthesis of PRG-N-01 compound

[0023]

[0024] (1) Step 1: Synthesis of intermediate-1 (Azide)

[0025] 4-MBC (4-methoxybenzyl chloride; 638.5 mmol, 100 g) was placed in a round-bottomed flask and dissolved in DMF (dimethylformamide) (1,000 mL). When the reactant was well dissolved, NaN3 (957.8 mmol, 62.3 g) was added and the reaction was carried out at 25 to 30 °C for 2 hours. After cooling the reaction solution to 5 to 10 °C, purified water (2,500 mL) was slowly added. After transferring to a separatory funnel, it was extracted with IPE (isopropyl ether; 2,500 mL), and the residual moisture was removed with anhydrous magnesium sulfate. It was concentrated under reduced pressure and used in the next reaction without any additional purification.

[0026] HPLC analysis result: 98.5 area%

[0027]

[0028] (2) Step 2: Synthesis of intermediate-2 (Cyanide)

[0029] 4-HPA (4-hydroxyphenylacetonitrile) (851.2 mmol, 113.3 g) was placed in a round-bottomed flask and dissolved in THF (Tetrahydrofuran; 1,133 mL). When the reactant was well dissolved, DEAECl.HCl (2-Diehtylaminoethylchloride hydrochloride; 1,021.4 mmol, 175.8 g) and purified water (226 mL) were added and the reactant was cooled to 10–20°C. A solution of NaOH (2,553.5 mmol, 102.1 g) dissolved in purified water (453 mL) was slowly added to the reaction solution, and the temperature of the reaction solution was increased to 60–65°C and reacted for 3 hours. After the reaction solution was cooled to 20–30°C, the reactant was transferred to a separatory funnel, the organic layer was collected, and the residual moisture was removed with anhydrous magnesium sulfate. It was concentrated under reduced pressure and used in the next reaction without any additional purification.

[0030] HPLC analysis result: 99.2 area%

[0031]

[0032] (3) Step 3: Synthesis of crude PRG-N-01

[0033] In a round-bottomed flask, intermediate-1 (Azide, 625.8 mmol, 102.1 g) and intermediate-2 (Cyano, 817.1 mmol, 189.8 g) were placed and dissolved in DMSO (706.3 mL). After the reaction mixture was cooled to 10 to 15 °C, KTB (potassium tert-butoxide; 1,251.5 mmol, 140.4 g) was slowly added, and the reaction mixture temperature was raised to 20 to 30 °C and reacted for 2 hours. After the reaction solution was cooled again to 10 to 15 °C, purified water (1,020 mL) was slowly added. After transferring to a separatory funnel, it was extracted with CH2Cl2 (1,020 mL) and washed with 20% brine (280 mL). The remaining moisture was removed with anhydrous magnesium sulfate. After concentration under reduced pressure, crystallization was performed using CH2Cl2 (150 mL) and IPE (Isopropyl ether; 2,040 mL).

[0034] HPLC analysis results: 99.1 area%

[0035] Yield: 80% total, off-white solid

[0036]

[0037] (4) Step 4: Synthesis of PRG-N-01

[0038] The crude PRG-N-01 (500.6 mmol, 200 g) was placed in a round-bottomed flask and dissolved in CH2Cl2 (600 mL). When the reactant was well dissolved, activated carbon (10 wt%, 20 g) was added and stirred at 20 to 30 °C for 1 hour. The reactant was filtered through a celite pad and washed thoroughly with CH2Cl2, and the organic layer was collected. After concentration under reduced pressure, crystallization was performed using CH2Cl2 (600 mL) and IPE (Isopropyl ether; 2,400 mL).

[0039] HPLC analysis result: 99.8 area%

[0040] Yield: 90%, white solid

[0041] 1 H-NMR (400MHz, DMSO-d6)δ: 7.62(d, 2H), 7.23(d, 2H), 6.95(d, 2H), 6.91(d, 2H), 5.65(s, 2H), 5.36(s, 2H), 4.02(t, 2H), 3.72(s, 3H), 2.77(t, 2H), 2.55(q, 4H), 0.97(t, 6H)

[0042]

[0043] [Experimental Example 1] Optimization Study on the Synthesis of Intermediate-1 (Azide)

[0044]

[0045] Intermediate-1 (Azide) synthesis was performed using the same method as step 1 of the above example, and the results were analyzed by HPLC. The operating conditions and specifications of the HPLC are as follows.

[0046]

[0047] Detector: UV absorption spectrometer (measurement wavelength: 226 nm)

[0048] Column: Agilent eclipse plus C8 (4.6 mm × 250 mm, 5 μm)

[0049] Column temperature: maintained constant at around 40 ℃

[0050] Mobile phase-A: 20mM Sodium octane sulfonate in Water

[0051] Mobile phase B: 0.01% TFA in Acetonitrile

[0052] Time (min)Mobile Phase A (%)Mobile Phase B (%)06535565357604020604035208043208043.16565483535

[0053] Flow rate: 0.8 mL / min Analysis time: 48 minutes

[0054] Dilution: 100% methanol

[0055] Sample concentration: Place 100 mg of the sample in a 100 mL volumetric flask, add diluent, dissolve, and mark.

[0056] Injection volume: 5 μL

[0057]

[0058] (1) Effect of reaction solvent on the induction of intermediate-1 (azide) synthesis

[0059] Solvent reaction temperatureHPLC analysis (area%)4-MBCunknownAzideDMF20~30 ℃tracetrace100 %ACN20~30 ℃55.0914.5530.36ACT20~30 ℃62.6619.6717.67THF20~30 ℃41.4534.1524.40

[0060] The reaction was carried out using DMF, acetonitrile (ACN), acetone (ACT), and tetrahydrofuran (THF) in the same manner as step 1 of the above example. Unknown peaks were generated when acetonitrile, acetone, and tetrahydrofuran solvents were used for the reaction, whereas no unknown peaks were observed when DMF solvent was used for the reaction, and it was confirmed that the reaction was completed in 2 hours.

[0061] (2) Effect of reaction temperature on the induction of intermediate-1 (azide) synthesis

[0062] Reaction temperature SolventHPLC analysis (area%)4-MBCunknownAzide5~10 ℃DMF6.571.9189.0515~20 ℃DMF0.122.1195.1525~30 ℃DMF0.082.0595.5635~40 ℃DMF0.082.0095.4645~50 ℃DMF0.092.0795.4155~60 ℃DMF0.082.0595.42

[0063] As a result of carrying out the reaction in the reaction temperature range of 5 to 65 ℃ in the same manner as step 1 of the above example, it was confirmed that the starting material (4-MBC) remained, and in other temperature ranges, the reaction was completed in 2 hours, and it was confirmed that there was no significant difference in purity. Therefore, the reaction temperature was set to 25 to 30 ℃, which is an appropriate reaction condition.

[0064] (3) Effect of induction of intermediate-1 (azide) synthesis according to the equivalent amount of NaN3 used

[0065] NaN3 equivalent (eq.) reaction temperature SolventHPLC analysis (area%) 4-MBCunknownAzide1.125~30 ℃DMF0.082.0795.571.225~30 ℃DMF0.072.0695.551.325~30 ℃DMF0.072.0795.521.525~30 ℃DMF0.072.0795.682.225~30 ℃DMF0.072.0695.65

[0066] As a result of conducting an equivalent experiment using NaN3 for the synthesis of intermediate-1 (Azide) in the same manner as step 1 of the above example, it was confirmed that the reaction was completed in 2 hours in all cases where 1.1 to 3.0 eq was used. Theoretically, NaN3 and 4-MBC (4-methoxybenzyl chloride) react 1:1, and there is no problem even when an excess of 3 eq of NaN3 is used, but the amount of NaN3 used was set to 1.5 eq, which is in the middle range.

[0067] [Experimental Example 2] Optimization Study on the Synthesis of Intermediate-2 (Cyano)

[0068]

[0069] Intermediate-2 (Cyano) synthesis was performed in the same manner as step 2 of the above example, and the results were analyzed by HPLC.

[0070]

[0071] (1) Effect of reaction temperature on the induction of intermediate-2 (Cyano) synthesis

[0072] Reaction temperatureDEAECl.HCl equivalent amount used (eq.)HPLC analysis (area%)ID4-HPACyanoUK-240 ~ 45 ℃1.2rxn 2h0.1998.770.23rxn 3hTrace98.710.28rxn 4hTrace98.520.3050 ~ 55 ℃1.2rxn 2hTrace98.240.32rxn 3hTrace98.040.35rxn 4hTrace98.100.3060 ~ 65 ℃1.2rxn 2hTrace98.150.14rxn 3hTrace98.030.12rxn 8htrace97.590.20

[0073] In the same manner as in step 2 of the above example, it was confirmed that the reaction was completed in 2 to 3 hours at a temperature of 40 to 65°C. In the reaction at 60 to 65°C, it was confirmed that the reaction rate at which the starting material (4-HPA) was converted to cyano was fast and that relatively little Unknown Imputiry-2 (hereinafter referred to as UK-2) was generated. Therefore, it was confirmed that the reaction temperature was advantageous for completing the reaction in a short time.

[0074] (2) Effect of intermediate-2 (Cyano) synthesis induction according to the type of inorganic base

[0075] Equivalent weight of inorganic base used (eq.) Reaction temperature HPLC analysis (area%) 4-HPACyanoUK-2K2CO34.760 ~ 65 ℃trace97.001.39K2CO34.060 ~ 65 ℃1.2594.872.67K2CO33.060 ~ 65 ℃trace98.770.43K2CO32.8560 ~ 65 ℃0.9596.56traceKOH1.560 ~ 65 ℃83.9811.874.16KOH2.560 ~ 65 ℃40.5756.213.22NaOH1.560 ~ 65 ℃62.2132.145.65NaOH2.560 ~ 65 ℃2.9996.130.8845%(w / v) NaOH solution3.060 ~ 65 ℃Trace98.260.6622.5%(w / v) NaOH solution3.060 ~ 65 ℃trace99.27trace

[0076] In the same manner as in step 2 of the above example, if more than 2.85 equivalents of K2CO3 are used, there is no problem with the reaction, but there is a disadvantage in that the amount of inorganic base to be injected is large. In the case of NaOH, the reaction proceeded best with 3 equivalents, and the reaction proceeded easily because the molecular weight was relatively small. In particular, when a 22.5% (w / v) NaOH solution was injected, it was confirmed that the generation of impurities was minimized at RT 12 minutes, so the inorganic base was set to be injected as a NaOH solution.

[0077] (3) Effect of induction of intermediate-2 (Cyano) synthesis according to the equivalent amount of DEAECl.HCl (2-Diehtylaminoethylchloride hydrochloride) used

[0078] DEAECl.HClEquivalent (eq.)Reaction temperatureReaction timeHPLC analysis (area%)4-HPACyanoUK-21.560 ~ 65 ℃1.5Trace98.260.661.260 ~ 65 ℃1.5Trace98.930.101.260 ~ 65 ℃3.0trace99.27trace1.140 ~ 45 ℃1.51.1998.220.091.140 ~ 45 ℃3.01.1098.330.131.160 ~ 65 ℃1.50.4598.980.111.160 ~ 65 ℃3.00.3199.080.09

[0079] As in step 2 of the above example, the amount of DEADCl.HCl used was varied from 1.1 to 1.5 equivalents, and it was confirmed that 1.1 equivalents was only suitable for the reaction at 65°C. Therefore, it was confirmed that the amount of DEAECl.HCl used to convert all 4-HPA to cyano and minimize the production of UK-2 impurities was 1.2 equivalents.

[0080] [Experimental Example 3] Optimization Study on the Synthesis of Crude PRG-N-01

[0081]

[0082] Crude PRG-N-01 synthesis was performed in the same manner as step 3 of the above example, and the results were analyzed by HPLC.

[0083]

[0084] (1) Effect of reaction solvent on the synthesis of crude PRG-N-01

[0085] Solvent reaction temperatureHPLC analysis (area%)CyanoPRG-N-01UK-3AzideTHF20 ~ 30 ℃1.9971.891.32traceDMSO20 ~ 30 ℃0.5688.404.53traceDMF20 ~ 30 ℃0.4878.394.961.59IPE-THF20 ~ 30 ℃0.1286.045.560.16

[0086] In the same manner as in Step 3 of the Example, the reaction was carried out using THF, DMSO, DMSO, and IPE-THF-DMSO solvents, using THF used in the cyano reaction. When tetrahydrofuran (THF) was used as the reaction solvent, it was confirmed that the purity of the product was low due to the generation of a large amount of unknown impurities, and there was a problem of showing thick brown crystals after crystallization. When DMF was used as the reaction solvent, it was confirmed that the purity of the product overall was lowered due to an increase in Unknown Imputiry-3 (hereinafter referred to as UK-3). When DMSO was used as the reaction solvent, the purity of the product during the synthesis was the best, and since most of the generated impurities were removed during the work-up process, DMSO was set as the reaction solvent.

[0087] (2) Effect of crude PRG-N-01 synthesis induction according to the type of inorganic base

[0088] Solvent Reaction time HPLC analysis (area%) CyanoPRG-N-01UK-3AzideKTB2 hours 0.0586.566.010.27NaOH2 hours 9.1384.422.21 traceNaOEt2 hours 8.3283.852.560.72KOH2 hours 51.054.500.1542.31DBU2 hours 53.92 tracetrace44.77

[0089] An experiment to set the inorganic salt for the synthesis of crude PRG-N-01 was conducted in the same manner as in step 3 of the above example. As a result, the reactivity was significantly reduced in the case of KOH, and the reaction did not proceed with DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene). When the reaction was performed using NaOH and NaOEt, results at a standard level were confirmed, but the reaction mixture became thick and difficult to stir. Therefore, the inorganic salt for the synthesis of crude-PRG-N-01 was set to KTB.

[0090] (3) Effect of induction of crude PRG-N-01 synthesis according to the equivalent amount of KTB (potassium tert-butoxide; t-BuOK) used

[0091] KTB used equivalent (eq.) Reaction time HPLC analysis (area%) CyanoPRG-N-01UK-3Azide 1.52 hours 1.0588.414.400.142.02 hours 0.0586.566.010.272.52 hours trace 88.285.15 trace 3.02 hours trace 85.006.38 trace

[0092] As a result of conducting an experiment on the equivalent amount of KTB used for the synthesis of crude PRG-N-01 using the same method as in step 3 of the above example, it was confirmed that all cases using the range of 1.5 to 3.0 eq were at a level suitable for the standard. In addition, in the case of UK-3, since it was completely removed after crystallization, it was thought that there would be no problem with the purity, and therefore the equivalent amount of KTB used was set to 2.0 eq.

[0093] (4) Effect of crude PRG-N-01 synthesis induction according to the order of raw material input

[0094] EntryInput orderHPLC analysis (area%)PRG-N-01Unknown1Azide, Cyano > KTB99.7-2Cyano > KTB > Azide99.2-3Azide > KTB > Cyano0.475.1

[0095] As a result of proceeding in the same manner as Step 3 of the above example, in the case of Entry-3 in Table 11, it was confirmed that an unknown side reaction occurred when proceeding in the order of Azide > KTB > Cyano addition. In the case of Entry-2 in Table 11, where KTB was added to the cyano reactant and the Azide in DMSO solution was slowly added, heat generation control was possible, but continuous heat generation was observed during the Azide in DMSO addition process and the final product appearance was confirmed to be yellow.

[0096] Even when KTB was added to the Azide and Cyano reactants as in Table 11 Entry-1, exotherm of approximately 25°C was observed. However, when KTB was added in small portions (1% of the total amount added) to control the initial exotherm, no further exotherm was observed. Therefore, the order of adding KTB to the Azide and Cyano reactants was set.

[0097]

[0098] [Experimental Example 4] Optimization Study for PRG-N-01 Synthesis

[0099]

[0100] PRG-N-01 synthesis was performed using the same method as step 4 of the above example, and the results were analyzed by HPLC.

[0101]

[0102] (1) Effect of PRG-N-01 purification induction according to the amount of CH2Cl2 used

[0103] CH2Cl2Amount usedHPLC analysis(area%)Yield(%)Appearance9.7811.0012.3812.8915.5616.961.5 vol*0.1799.300.220.100.090.1396.0Light yellow3.0 vol0.2299.410.190.070.030.0590.5White4.0 vol0.2799.490.160.030.010.0383.8White5.0 vol0.1599.720.090.020.010.0175.5White7.0 vol0.0999.810.060.020.010.0168.3White

[0104] * vol: This means measuring the amount equivalent to XX times the input weight of PRG-N-01 by volume. Example) PRG-N-01 1kg tablet -> 1.5 vol CH2Cl2 = 1.5L

[0105] An experiment was conducted to confirm the purification effect according to the amount of CH2Cl2 used in the same manner as step 4 of the above example. As a result, it was confirmed that the more CH2Cl2 used, the better the color removal was when IPE was added after dissolving the reactant to induce crystal formation. When IPE was added after dissolving in 1.5 vol, an excessive amount of solid was precipitated at once, whereas when IPE was added after dissolving in CH2Cl2, the solid was precipitated slowly, which was more effective in improving purity and appearance. When reflux was performed, the purity improved, but the drawback was that the yield was greatly reduced. Therefore, when purifying Crude PRG-N-01, the amount of CH2Cl2 used was set to 3 vol, which is in the middle range of 1.5 to 4 vol.

[0106]

[0107] (2) Effect of PRG-N-01 purification induction according to activated carbon type

[0108] Activated carbon type HPLC analysis (area%) Properties 9.78 11.00 12.38 12.89 15.56 16.96 Crude (solution) 0.1098.6 20.39 0.19 0.34 0.29 - Shinki carbon (reaction solution) 0.0999.03 0.12 0.04 0.32 0.30 - Shinki carbon solid 0.1099.6 10.11 trace 0.05 0.08 White neutral carbon (reaction solution) 0.1099.04 0.12 0.05 0.34 0.29 - Neutral carbon solid 0.0999.54 0.13 trace 0.05 0.10 White SA-20 (reaction solution) 0.1098.9 10.16 0.11 0.34 0.29 - SA-20 solid0.0999.530.16trace0.040.10white

[0109] As a result of conducting an experiment to confirm the purification effect according to the type of activated carbon in the same manner as step 4 of the above embodiment, it was confirmed that all of Shinki Carbon (Shinki Chemical Industry; Korea), Neutral Carbon (Norit; Japan), and SA-20 (MEADWESTVACO; USA) were removed by impurity carbon treatment at RT 12.38 minutes. Among these, it was confirmed that the purity after Shinki Carbon treatment was the best, so it was set to be purified using Shinki Carbon.

[0110] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will readily appreciate that modifications to other specific embodiments can be made without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0111] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. a) A step of synthesizing an intermediate by dissolving 4-MBC (4-methoxybenzyl chloride) in DMF (dimethylformamide), adding NaN3 (sodium azide), and reacting for 1 to 3 hours; b-1) A step of reacting 4-HPA (4-hydroxyphenylacetonitrile) by dissolving it in THF (tetrahydrofuran), then adding DEAECl.HCl (2-Diehtylaminoethylchloride hydrochloride) and water and cooling to 5 to 20°C; b-2) A step of adding the reactant of step b-1) to an aqueous NaOH solution and reacting for 2 to 4 hours to synthesize an intermediate; c) a step of dissolving the intermediate of step a) and the intermediate of step b-2) in DMSO, adding KTB (potassium tert-Butoxide; t-BuOK) and reacting at 20 to 40°C for 1 to 3 hours; and d) A method for producing 4-(4-(2-(diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-amine, comprising: dissolving the reactant of step c in CH2Cl2 (dichloromethane), adding activated carbon, stirring at 15 to 40° C. for 30 to 100 minutes, and filtering and washing.

2. A manufacturing method according to claim 1, characterized in that the reaction in step a) is carried out at a temperature of 15 to 60°C.

3. A manufacturing method according to claim 1, characterized in that the equivalent amount of NaN3 used in step a) is 1.0 to 3.0 eq.

4. A manufacturing method according to claim 1, characterized in that the equivalent amount of DEAECl.HCl used in step b-1) is 1.0 to 1.5 eq.

5. A manufacturing method according to claim 1, characterized in that the reaction in step b-2) is carried out at a temperature of 40 to 70°C.

6. A manufacturing method according to claim 1, characterized in that the equivalent amount of NaOH used in step b-2) is 2.5 to 4 eq.

7. A manufacturing method according to claim 1, characterized in that the NaOH aqueous solution in step b-2) is a 20 to 50% (w / v) NaOH aqueous solution.

8. A manufacturing method according to claim 1, characterized in that the amount of KTB used in step c) is 1.0 to 3.0 eq.

9. A manufacturing method according to claim 1, characterized in that the volume ratio of the reactants of step c) and CH2Cl2 (dichloromethane) in step d) is 1:1.5 to 4.0.

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