INTERMEDIATE USEFUL FOR SYNTHESIS OF SGLT INHIBITOR AND METHOD FOR PREPARING SGLT INHIBITOR USING SAME

Abstract

An intermediate useful for the synthesis of an SGLT inhibitor and a method for preparing an SGLT inhibitor are provided. By employing an intermediate having Chemical Formula 5, the difficulty of purification with existing processes can be solved, the quality requirements for related substances can be achieved with only one purification step, and the quality control problem in each step can be solved by performing several steps in situ. A method for synthesizing a compound of Chemical Formula 1 by using a compound of Chemical Formula 5 enables purification in an earlier step, thereby solving the problems of existing synthesis processes, in which the quality requirements for related substances were difficult to control step-by-step due to a continuous process, thereby minimizing the amount of related substances in the final product. In addition, the yield of a diphenylmethane derivative according to Chemical Formula 1 is increased.

Claims

1. A compound of the following Chemical Formula 5: ##STR00025## wherein n is 1 or 2, X is a halogen, B is ##STR00026## wherein Ra, Rb, Rc, and Rd are each independently hydrogen, a halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, a C1-7 alkyl, a C1-7 alkylthio, a C2-7 alkenyl, a C2-7 alkynyl, a C1-7 alkoxy, a C1-7 alkoxy-C1-7 alkyl, a C2-7 alkenyl-C1-7 alkyloxy, a C2-7 alkynyl-C1-7 alkyloxy, a C3-10 cycloalkyl, a C3-7 cycloalkylthio, a C5-10 cycloalkenyl, a C3-10 cycloalkyloxy, a C3-10 cycloalkyloxy-C1-7 alkoxy, a phenyl-C1-7 alkyl, a C1-7 alkylthio-phenyl, a phenyl-C1-7 alkoxy, a mono- or di-C1-7 alkylamino, a mono- or di-C1-7 alkylamino-C1-7 alkyl, a C1-7 alkanoyl, a C1-7 alkanoylamino, a C1-7 alkylcarbonyl, a C1-7 alkoxycarbonyl, carbamoyl, a mono- or di-C1-7 alkylcarbamoyl, a C1-7 alkylsulfonylamino, phenylsulfonylamino, a C1-7 alkylsulfinyl, a C6-14 arylsulfanyl, a C6-14 arylsulfonyl, a C6-14 aryl, a 5- to 13-membered heteroaryl, a 5- to 10-membered heterocycloalkyl, a 5- to 10-membered heterocycloalkyl-C1-7 alkyl, or a 5- to 10-membered heterocycloalkyl-C1-7 alkoxy; the ring C is a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5- to 13-membered heteroaryl, or a 5- to 10-membered heterocycloalkyl; the alkyl, the alkenyl, the alkynyl, and the alkoxy are each independently unsubstituted, or have one or more substituents selected from the group consisting of a halogen, hydroxy, cyano, nitro, amino, mercapto, a C1-7 alkyl, and a C2-7 alkynyl; the cycloalkyl, the cycloalkenyl, the aryl, the heteroaryl, and the heterocycloalkyl are each independently unsubstituted, or have one or more substituents selected from the group consisting of a halogen, hydroxy, cyano, nitro, amino, mercapto, a C1-4 alkyl, and a C1-4 alkoxy; and the heteroaryl and the heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

2. A method for preparing a compound of the following Chemical Formula 5, comprising: subjecting a compound of the following Chemical Formula 4 to deprotection and ring-opening reactions under an acidic condition in the presence of water to obtain the compound of Chemical Formula 5: ##STR00027## wherein n is 1 or 2, X is a halogen, PG is a protecting group, B is ##STR00028## wherein Ra, Rb, Rc, and Rd are each independently hydrogen, a halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, a C1-7 alkyl, a C1-7 alkylthio, a C2-7 alkenyl, a C2-7 alkynyl, a C1-7 alkoxy, a C1-7 alkoxy-C1-7 alkyl, a C2-7 alkenyl-C1-7 alkyloxy, a C2-7 alkynyl-C1-7 alkyloxy, a C3-10 cycloalkyl, a C3-7 cycloalkylthio, a C5-10 cycloalkenyl, a C3-10 cycloalkyloxy, a C3-10 cycloalkyloxy-C1-7 alkoxy, a phenyl-C1-7 alkyl, a C1-7 alkylthio-phenyl, a phenyl-C1-7 alkoxy, a mono- or di-C1-7 alkylamino, a mono- or di-C1-7 alkylamino-C1-7 alkyl, a C1-7 alkanoyl, a C1-7 alkanoylamino, a C1-7 alkylcarbonyl, a C1-7 alkoxycarbonyl, carbamoyl, a mono- or di-C1-7 alkylcarbamoyl, a C1-7 alkylsulfonylamino, phenylsulfonylamino, a C1-7 alkylsulfinyl, a C6-14 arylsulfanyl, a C6-14 arylsulfonyl, a C6-14 aryl, a 5- to 13-membered heteroaryl, a 5- to 10-membered heterocycloalkyl, a 5- to 10-membered heterocycloalkyl-C1-7 alkyl, or a 5- to 10-membered heterocycloalkyl-C1-7 alkoxy; the ring C is a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5- to 13-membered heteroaryl, or a 5- to 10-membered heterocycloalkyl; the alkyl, the alkenyl, the alkynyl, and the alkoxy are each independently unsubstituted, or have one or more substituents selected from the group consisting of a halogen, hydroxy, cyano, nitro, amino, mercapto, a C1-7 alkyl, and a C2-7 alkynyl; the cycloalkyl, the cycloalkenyl, the aryl, the heteroaryl, and the heterocycloalkyl are each independently unsubstituted, or have one or more substituents selected from the group consisting of a halogen, hydroxy, cyano, nitro, amino, mercapto, a C1-4 alkyl, and a C1-4 alkoxy; and the heteroaryl and the heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

3. The method of claim 2, further comprising crystallizing the reaction product, which is obtained by subjecting the compound of Chemical Formula 4 to the deprotection and ring-opening reactions under an acidic condition in the presence of water, to obtain the compound of Chemical Formula 5.

4. The method of claim 3, wherein the crystallization is performed by the treatment with a crystallization solvent capable of dissolving the compound of Chemical Formula 5 and the recrystallization of the compound of Chemical Formula 5.

5. A method for preparing a compound of Chemical Formula 1, comprising: cyclizing and methoxylating a compound of Chemical Formula 5 under an acidic condition in the presence of a reaction solvent to obtain a compound of Chemical Formula 6; and obtaining the compound of Chemical Formula 1 from the compound of Chemical Formula 6: ##STR00029## wherein n is 1 or 2, X is a halogen, B is ##STR00030## wherein Ra, Rb, Rc, and Rd are each independently hydrogen, a halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, a C1-7 alkyl, a C1-7 alkylthio, a C2-7 alkenyl, a C2-7 alkynyl, a C1-7 alkoxy, a C1-7 alkoxy-C1-7 alkyl, a C2-7 alkenyl-C1-7 alkyloxy, a C2-7 alkynyl-C1-7 alkyloxy, a C3-10 cycloalkyl, a C3-7 cycloalkylthio, a C5-10 cycloalkenyl, a C3-10 cycloalkyloxy, a C3-10 cycloalkyloxy-C1-7 alkoxy, a phenyl-C1-7 alkyl, a C1-7 alkylthio-phenyl, a phenyl-C1-7 alkoxy, a mono- or di-C1-7 alkylamino, a mono- or di-C1-7 alkylamino-C1-7 alkyl, a C1-7 alkanoyl, a C1-7 alkanoylamino, a C1-7 alkylcarbonyl, a C1-7 alkoxycarbonyl, carbamoyl, a mono- or di-C1-7 alkylcarbamoyl, a C1-7 alkylsulfonylamino, phenylsulfonylamino, a C1-7 alkylsulfinyl, a C6-14 arylsulfanyl, a C6-14 arylsulfonyl, a C6-14 aryl, a 5- to 13-membered heteroaryl, a 5- to 10-membered heterocycloalkyl, a 5- to 10-membered heterocycloalkyl-C1-7 alkyl, or a 5- to 10-membered heterocycloalkyl-C1-7 alkoxy; the ring C is a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5- to 13-membered heteroaryl, or a 5- to 10-membered heterocycloalkyl; the alkyl, the alkenyl, the alkynyl, and the alkoxy are each independently unsubstituted, or have one or more substituents selected from the group consisting of a halogen, hydroxy, cyano, nitro, amino, mercapto, a C1-7 alkyl, and a C2-7 alkynyl; the cycloalkyl, the cycloalkenyl, the aryl, the heteroaryl, and the heterocycloalkyl are each independently unsubstituted, or have one or more substituents selected from the group consisting of a halogen, hydroxy, cyano, nitro, amino, mercapto, a C1-4 alkyl, and a C1-4 alkoxy; and the heteroaryl and the heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

6. The method of claim 5, wherein the obtaining of the compound of Chemical Formula 1 from the compound of Chemical Formula 6 comprises: reducing the compound of Chemical Formula 6 to obtain a compound of the following Chemical Formula 7; and introducing a protecting group into the compound of Chemical Formula 7 and recrystallizing and deprotecting the protecting group-introduced compound to obtain the compound of Chemical Formula 1: ##STR00031## wherein n, B, and X are as defined in claim 5.

7. The method of claim 5, wherein the obtaining of the compound of Chemical Formula 1 from the compound of Chemical Formula 6 is performed by the following steps: reducing the compound of Chemical Formula 6 to obtain a compound of the following Chemical Formula 7; introducing a protecting group into the compound of Chemical Formula 7 and recrystallizing the protecting group-introduced compound to separate a compound of Chemical Formula 8; and deprotecting the compound of Chemical Formula 8 to obtain the compound of Chemical Formula 1, wherein the compound of Chemical formula 1 is a compound of Chemical formula 1a: ##STR00032## wherein PG is a protecting group; and n, B, and X are as defined in claim 5.

8. A crystalline form of Chemical Formula A, which is characterized by an X-ray powder diffraction pattern having 6 or more diffraction peaks at a 2[θ] value selected from 7.8±0.2, 8.9±0.2, 15.1±0.2, 16.6±0.2, 17.9±0.2, 19.4±0.2, 20.2±0.2, 21.1±0.2, 22.5±0.2, 22.9±0.2, 24.5±0.2, 26.0±0.2, and 28.7±0.2: ##STR00033##

9. The crystalline form of claim 8, wherein the X-ray powder diffraction pattern has diffraction peaks at a 2[θ] value selected from 7.8±0.2, 8.9±0.2, 15.1±0.2, 16.6±0.2, 17.9±0.2, and 19.4±0.2.

10. The crystalline form of claim 8, wherein the crystalline form of Chemical Formula A is characterized by a differential scanning calorimetry trace measured at a heating rate of 1° C. per minute which shows a maximum endothermic peak at a temperature of 190° C. to 200° C.

Description

DESCRIPTION OF DRAWINGS

[0085] FIG. 1 shows the results of infrared spectroscopic measurements indicating that the crystal obtained in Step 1 of Example 1 is compound 4.

[0086] FIG. 2 shows the results of powder X-ray diffraction analysis of a compound of Chemical Formula A.

[0087] FIG. 3 shows the differential scanning calorie (DSC) of a certain compound of Chemical Formula A using a differential scanning calorimeter.

BEST MODE

Example 1: Preparation of Target Compound

[0088] ##STR00018## ##STR00019##

Step 1: (2R,3S,4R,5R)-1-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-y)-2,3,4,5,6-pentahydroxyhexan-1-one (compound 4)

[0089] ##STR00020##

[0090] Compound 1 (10.0 g, 1.0 eq) and compound 2 (24.4 g, 1.9 eq) were added to anhydrous THF (80 mL) at room temperature under a nitrogen atmosphere, dissolved, and then cooled to −78° C. An n-BuLi 2.5 M solution (23 mL, 2.1 eq) was slowly added dropwise to the solution in which compound 1 and compound 2 were dissolved over 20 minutes while being maintained at −60° C. or lower. After the dropwise addition was completed, the resulting reaction solution was stirred for 5 minutes. Thereafter, a solution prepared by adding c-HCl (10.2 mL, 4.2 eq) to water (100 mL) was added to the reaction solution. The reaction solution was slowly warmed to room temperature, and stirred for 3 hours. After the completion of the reaction was confirmed by TLC, a saturated NaHCO.sub.3 solution was added to the reaction solution (pH 6-8) to terminate the reaction, and the reaction solution was extracted twice with toluene (30 mL). The organic layer was extracted twice with water (30 mL), and toluene (100 mL) was additionally added to the resulting organic layer, and crystallized while stirring at 40 to 50° C. for 12 hours. The resulting crystal was filtered and dried to obtain compound 4 (11.1 g, 87.4%) as a white solid.

[0091] .sup.1H NMR (500 MHz, DMSO): δ 7.02-7.06 (m, 3H), 6.92-6.94 (m, 2H), 6.27 (d, 1H), 4.84 (d, 1H). 4.66 (d, 1H), 4.47-4.52 (m, 3H), 4.36 (m, 1H), 3.90-3.98 (m, 2H), 3.62-3.65 (m, 2H), 3.50-3.56 (m, 3H), 3.32-3.35 (m, 1H), 3.22-3.27 (m, 1H), 3.08-3.11 (m, 1H), 1.82 (m, 1H), 0.86-0.88 (m, 2H), 0.57-0.59 (m, 2H); LC-MS: [M−H]− 461, mp 195° C.

Step 2: (3R,4S,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (compound 5)

[0092] ##STR00021##

[0093] Compound 4 (5.0 g, 1.0 eq) was added to MeOH (40 mL), dissolved, and then cooled to 0° C. Thereafter, c-HCl (0.5 mL, 0.5 eq) was added thereto, and then stirred at room temperature for 3 hours. After the completion of the reaction was confirmed by TLC, a 3% NaHCO.sub.3 solution was added to the reaction solution to terminate the reaction, and the reaction solution was condensed under vacuum to remove MeOH, and extracted with ethyl acetate. The organic layer obtained by extraction was dried over anhydrous magnesium sulfate, filtered, and then condensed under vacuum to obtain compound 5 (5.2 g, 100%).

[0094] The product was directly used in the next step without any purification.

Step 3: (3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 6)

[0095] ##STR00022##

[0096] Et.sub.3SiH (4.0 mL, 3.0 eq) and BF.sub.3OEt.sub.2 (5.2 mL, 3.0 eq) were sequentially added to a solution of (3R,4S,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (compound 5) (5.2 g, 1.0 eq) in a mixture of dichloromethane (50 mL) and acetonitrile (50 mL) at −50° C. The reaction mixture was stirred at −50 to −10° C. for 2 hours, and stirred at −10 to 0° C. for 3 hours. After the completion of the reaction was confirmed by TLC, an aqueous saturated NaHCO.sub.3 solution (100 mL) was added to the reaction solution to terminate the reaction, and the reaction solution was extracted with ethyl acetate. The organic layer obtained by extraction was dried over anhydrous magnesium sulfate, filtered, and then condensed under vacuum to obtain compound 6 (4.9 g, 100%). The product was directly used in the next step without any purification.

Step 4: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound 7)

[0097] ##STR00023##

[0098] Compound 6 (4.9 g, 1.0 eq) was added to dichloromethane (75 mL) and dissolved therein. Then, DMAP (1.6 g, 1.2 eq) and an acetic anhydride (8.3 mL, 8.0 eq) were added thereto at room temperature under a nitrogen atmosphere, and the resulting mixture was stirred for 2 hours. The completion of the reaction was confirmed by TLC, 1 N HCl (50 mL) was added to terminate the reaction, and the reaction solution was extracted with dichloromethane. The organic layer obtained by extraction was dried with anhydrous magnesium sulfate and filtered, and methanol (10 mL) was added thereto. Then, the resulting reaction solution was condensed under vacuum. The condensed residue was added to methanol (50 mL), and crystallized while stirring for an hour. The resulting crystal was filtered and dried to obtain compound 7 (4.5 g, 67.2%) as a white solid.

[0099] .sup.1H NMR (500 MHz, CDCl3): δ .sup.1H NMR (400 MHz, CDCl3) δ 7.04-7.02 (m, 2H), 6.98-6.95 (m, 2H), 6.53 (s, 2H), 5.29-5.24 (m, 1H), 5.18-5.12 (m, 2H), 4.71-4.65 (m, 2H), 4.31-4.26 (m, 1H), 4.25-4.22 (m, 1H), 4.15-4.11 (m, 1H), 4.15-4.11 (m, 1H), 4.05-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.40-3.35 (m, 2H), 2.60 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.66 (s, 3H), 0.94-0.89 (m, 2H), 0.66-0.61 (m, 2H); [M+Na]+ 637.

Step 5: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 8)

[0100] ##STR00024##

[0101] THF (17.5 mL) and methanol (17.5 mL) were added to Compound 7 (3.5 g, 1.0 eq). A 4 N—NaOH solution (7.1 mL, 5.0 eq) was added to the solution in a slurry state at room temperature, and the resulting mixture was stirred at 30 to 35° C. for 2 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was cooled to 0° C. and adjusted to pH 6.8 by adding 1 N HCl. THF and MeOH used in the reaction were removed by concentration, and the reaction solution was extracted with ethyl acetate. The organic layer obtained by extraction was dried over anhydrous magnesium sulfate, filtered, and then condensed under vacuum. The condensed residue was added to ethyl acetate (40 mL), completely dissolved at 70° C., cooled to 33° C., and then stirred at 33° C. for an hour. Then, IPE (65 mL) was added dropwise for 30 minutes, and the resulting mixture was cooled to 0° C., stirred at 0° C. for an hour, and then kept for an hour. The resulting crystal was filtered and dried to obtain compound 8 (2.4 g, 94.5%) as a white solid.

[0102] .sup.1H NMR (500 MHz, CDCl3): δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.11 (d, J=9.2 Hz, 1H), 3.96 (ABq, ΔvAB=19.0 Hz, JAB=15.2 Hz, 2H), 3.87-3.84 (m, 1H), 3.67-3.63 (m, 1H), 3.47-3.37 (m, 3H), 3.35-3.33 (m, 3H), 1.85-1.79 (m, 1H), 0.91-0.86 (m, 2H), 0.61-0.57 (m, 2H); [M+Na]+ 469

Experimental Example 1: Confirmation of Crystallization of Compound of Chemical Formula 5

[0103] As described above, the compound of Chemical Formula 5 has an open-chain shape as in the c4 compound of Scheme 1 used in the related art. In the process of obtaining the compound of Chemical Formula 5 from the compound of Chemical Formula 4, a reaction product in which the compound of Chemical Formula 5 and a compound of the following Chemical Formula 5R are present in an equilibrium state due to the ring-chain tautomerism was obtained.

[0104] In Step 1 of Example 1, it was confirmed through the infrared spectroscopic measurements that only compound 4 was crystallized in an equilibrium state of the c4 compound (corresponding to the compound of Chemical Formula 5R) and compound 4 (corresponding to the compound of Chemical Formula 5) in Scheme 1.

[0105] The crystal precipitated through the crystallization was measured by IR. As a result, as shown in FIG. 1, it can be seen that the precipitated crystal was the compound of Chemical Formula 5 having an open-chain shape containing a carbonyl group in the molecule because a characteristic peak corresponding to the carbonyl peak was strongly observed at 1,672 cm-1.

Experimental Example 2: Preparation and Analysis of Crystalline Form

[0106] After the compound prepared by the method of the present invention, specifically, unpurified (2R,3S,4R,5R)-1-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-2,3,4,5,6-pentahydroxyhexan-1-one (compound 4) was obtained according to Step 1 of Example 1, and crystals were prepared through crystallization using various solvents and then analyzed.

[0107] The XRD spectrum was obtained by irradiating the crystals with Cu-Kα radiation (wavelength (λ)=1.54056 Å) according to a conventional method using an X-ray diffraction analyzer to determine X-ray powder diffraction. The differential scanning calorie (DSC) was measured at a rate of +1° C./min using a differential scanning calorimeter.

[0108] (1) Preparation of Crystal Using Toluene Solvent

[0109] The crystallization using toluene is as described in the end of the procedure of Step 1 in Example 1. Specifically, compound 4 in a solution state was additionally added to toluene (a 10-fold weight of compound 4), and the mixture was crystallized by heating at 40 to 50° C. for 12 hours. The resulting crystal was filtered, washed with toluene (a 2-fold volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white crystal (yield: 87.4%).

[0110] The XRD spectrum of the prepared crystal shows a crystalline form (crystalline form A) as shown in FIG. 2, and the diffraction angles (20), interplanar spacings (d) and relative intensities (I/Io×100) of the characteristic peaks are summarized in Table 1 below.

TABLE-US-00001 TABLE 1 2θ (±0.2°) d (Å) I/I.sub.0 (%) 2θ (±0.2°) d (Å) I/I.sub.0 (%) 7.8 11.4 37.0 20.2 4.4 7.3 8.9 9.9 89.4 21.1 4.2 14.3 15.1 5.9 38.6 22.5 4.0 10.1 16.6 5.3 100.0 22.9 3.9 10.3 17.9 5.0 45.0 24.5 3.6 8.1 19.4 4.6 44.7 26.0 3.4 11.5 28.7 3.1 9.3

[0111] As shown in FIG. 3, it can be seen that melt endothermic peaks of the corresponding crystals were observed on the DSC spectrum.

[0112] (2) Preparation of Crystal Using Dichloromethane Solvent

[0113] The unpurified compound 4 was additionally added to dichloromethane (a 10-fold weight of compound 4), and the mixture was crystallized by heating at 40 to 50° C. for 12 hours. The resulting crystal was filtered, washed with dichloromethane (a 2-fold volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white crystal (yield: 88.1%).

[0114] The XRD spectrum analysis results of the prepared crystals show that the white crystal had the same crystalline form (crystalline form A) as (1) of Experimental Example 2.

Experimental Example 3: Analysis of Content of Related Substances

[0115] The method for preparing a diphenylmethane derivative as disclosed in Korean Patent Laid-Open Publication No. 2017-0142904 proceeds in a four-step continuous process consisting of the important reaction steps c3-c7 as shown in Scheme 1 above, and the purification of the related substances is performed at c7.

[0116] The purity and impurity content of c7 obtained through the 1.sup.st to 3.sup.rd purifications at the step c7 as shown in Scheme 1 in Korean Patent Laid-Open Publication No. 2017-0142904 were compared to the purity and impurity content of c7 (corresponding to compound 7 in Scheme 2) obtained through a single purification at the step c4 (corresponding to compound 4 in Scheme 2) and another single purification at the step c7 (corresponding to compound 7 in Scheme 2) in Scheme 2 of the present invention. The results are listed in Table 2 below.

TABLE-US-00002 TABLE 2 Purity (%) Impurity C (%) [Standard: ≥ [Standard: ≤ 98.0] 0.10] Existing 1.sup.st purification 98.5 0.15 process 2.sup.nd purification 99.7 0.10 3.sup.rd purification 99.9 0.07 Modified 1.sup.st purification 99.0 0.06 process

[0117] As shown in Table 2, according to the preparation method of the present invention, a purification process may be performed during the synthesis of the compound of Chemical Formula 5. Therefore, even without performing a purification process three times in one step as disclosed in Korean Patent Laid-Open Publication No. 2017-0142904, the amount of related substances in the final product may be minimized.