Method for preparing intermediates for synthesizing sphingosine-1-phosphate receptor agonists

Abstract

The present invention relates to a novel method for producing an intermediate represented by Chemical Formula 6, which can be effectively used to synthesize a sphingosine-1-phosphate receptor agonist.

Description

Technical Field

[0001] The present invention relates to a method for preparing a key intermediate for synthesizing sphingosine-1-phosphate receptor agonists. More specifically, the present invention relates to a novel preparation method capable of large-scale production of the intermediate compound of the following formula 6 in high yield using a simple process under mild conditions:

[0002] [Formula 6]

[0003]

[0004] in,

[0005] X is C or N;

[0006] R1 and R2 are each independently hydrogen, alkyl, halogen, haloalkyl or alkoxyalkyl;

[0007] R4 is hydrogen or alkyl;

[0008] R5 is hydrogen, alkyl, halogen, CN, CF3 or COCF3. Background Art

[0009] Sphingosine-1-phosphate (S1P) is produced by the intracellular ceramide pathway, with ceramide as the starting material. Ceramide is produced by two pathways, the first of which is a de novo biosynthetic pathway. Ceramide is also produced by degradation of the cell membrane component sphingomyelin in cells. The S1P level in each tissue is controlled by two biosynthetic sphingosine kinases (SphK) and two biodegradable S1P phosphatases (S1P lysing enzyme and lysophospholipid phosphatase). It is known that S1P produced by the phosphorylation of sphingosine by sphingosine kinase mediates various cellular responses, such as cell proliferation, cytoskeleton organization and migration, adhesion and tight junction assembly, and morphogenesis. S1P is present in plasma at high levels (100-1000nM) in combination with plasma proteins (including albumin), while it is present in tissues at low levels.

[0010] S1P binds to the G protein-coupled receptor S1P receptor to exhibit various biological functions. S1P receptor subtypes known to date include S1P1 to S1P5, designated as endothelial differentiation gene (EDG) receptors 1, 5, 3, 6, and 8, respectively. S1P receptors are known to be involved in a variety of biological functions, such as leukocyte recycling, neuronal proliferation, morphological changes, migration, endothelial function, vascular regulation, and cardiovascular development.

[0011] In recent years, numerous studies have revealed that S1P signaling through these receptors plays a crucial role in a range of reactions associated with multiple sclerosis, including inflammation and repair processes. Consequently, non-selective S1P1 agonists have been approved as therapeutic agents for multiple sclerosis. S1P receptors are widely expressed in many cells implicated in the development of multiple sclerosis. In particular, S1P1 receptors play a key role in the immune system. S1P1 receptors are primarily expressed on the surfaces of lymphocytes, such as T and B cells, and respond to S1P, thereby participating in lymphocyte recirculation. Under normal conditions, S1P concentrations in body fluids are higher than in lymphoid tissues. This differential S1P concentration causes lymphocytes to leave lymphoid tissues and circulate after exiting the lymphatic circulation. However, if S1P1 receptors in lymphocytes are downregulated by S1P1 agonists, lymphocyte egress from lymphoid tissues is prevented, thereby reducing the infiltration of autoinvasive lymphocytes and the resulting inflammation and tissue damage in the central nervous system (CNS). Consequently, a therapeutic effect is achieved for multiple sclerosis. Fingolimod, a non-selective S1P1 agonist, has been approved as an oral drug for the treatment of multiple sclerosis. Unexpectedly, when it binds to the S1P1 receptor to be activated, the receptor is degraded or internalized from the lymphocyte surface, thus exerting a functional S1P1 antagonistic effect.

[0012] Regarding such S1P receptors, Korean Patent Application Publication No. 10-2014-0104376 discloses a novel compound of the following formula 1, which is a potent S1P receptor agonist:

[0013] [Formula 1]

[0014]

[0015] in,

[0016] X represents C or N,

[0017] R1 represents H or an optionally substituted alkyl group,

[0018] R2 represents H, optionally substituted alkyl, halogen, CN, CF3 or COCF3,

[0019] W represents C, N, C-alkoxy, C-halogen or C-CN,

[0020] Q represents CH2O or S is selected from the following residues:

[0021]

[0022] in

[0023] m and n independently represent 0, 1, 2 or 3,

[0024] R3 to R10 independently represent H, alkyl, halogen, halogenated alkyl or alkoxyalkyl, R11 represents H, R12 represents OH, NH2,

[0025] In a specific example of the above document, the preparation of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-ylmethyl]-piperidine-4-carboxylic acid according to the following reaction scheme 1 is disclosed ("SG35" in reaction scheme 1 refers to "1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde").

[0026] [Reaction Scheme 1]

[0027]

[0028] The steps for preparing 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde in Reaction Scheme 1 can be described in detail as follows:

[0029] (1) Synthesis of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol

[0030] Methyl 1H-indazole-5-carboxylate was dissolved in dimethylformamide, and iodoisopropyl and sodium hydride were slowly added dropwise at 0°C, followed by stirring at 50°C for 8 hours. 1N hydrochloric acid solution was added, followed by extraction with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the filtrate was distilled under reduced pressure. The resulting product was separated by column chromatography to obtain methyl 1-isopropyl-1H-indazole-5-carboxylate.

[0031] The resulting 1-isopropyl-1H-indazole-5-methyl carboxylate was dissolved in dimethylformamide, to which N-chlorosuccinimide was added dropwise, and the mixture was then stirred at room temperature for 18 hours. Water was added, and the reaction mixture was extracted with ethyl acetate. After washing with salt water and drying over anhydrous magnesium sulfate, the filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain 3-chloro-1-isopropyl-1H-indazole-5-methyl carboxylate.

[0032] The resulting 3-chloro-1-isopropyl-1H-indazole-5-methyl carboxylate was dissolved in tetrahydrofuran, and lithium aluminum borohydride was added dropwise. After stirring at room temperature for 1 hour, water, 6N aqueous sodium hydroxide solution, and water were added in sequence. Celite was added dropwise, and the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol.

[0033] (2) Synthesis of 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carboxaldehyde

[0034] First, N,N-dimethylformamide (DMF) and phosphorus oxychloride (POCl3) were added dropwise to a solution of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one dissolved in toluene at 0°C, followed by stirring at 70°C for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with brine, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1 to 10:1) to obtain 1-chloro-6-methoxy-3,4-dihydro-2-naphthaldehyde.

[0035] Next, aluminum chloride (AlCl3) was added to a solution of 1-chloro-6-methoxy-3,4-dihydro-2-naphthaldehyde in dichloromethane at 0°C, followed by stirring at 50°C for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried and concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:tetrahydrofuran = 5:1 to 3:1) to obtain 1-chloro-6-hydroxy-3,4-dihydro-2-naphthaldehyde.

[0036] (3) Synthesis of 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde

[0037] The resulting (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol and 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carboxaldehyde were dissolved in toluene, and tributylphosphine (PBu3) and 1,1'-(azodicarbonyl)dipiperidine (ADD) were added dropwise. After stirring at room temperature for 18 hours, an excess of hexane was added. After filtration and distillation under reduced pressure, the residue was purified by column chromatography to obtain 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde.

[0038] However, the above reaction may have the following problems when preparing clinical active pharmaceutical ingredients (API).

[0039] First, in the process of synthesizing methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate, there may be problems corresponding to the production ratio of the N2 isomer. In addition, lithium aluminum hydride (LAH) used to synthesize (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol cannot be used on a large scale due to its very limited stability and has the disadvantage of being easily decomposed by water.

[0040] Furthermore, the Vilsmeier-Haack reaction to obtain 1-chloro-6-methoxy-3,4-dihydro-2-naphthaldehyde can pose exothermic issues due to the high temperature of 70°C. Furthermore, the use of AlCl₃ in the reaction to obtain 1-chloro-6-hydroxy-3,4-dihydro-2-naphthaldehyde can lead to reactor contamination and safety concerns due to the use of hazardous reagents. The use of AlCl₃ can also lead to stability issues due to batch failures caused by reaction termination or the progression of side reactions, and the overall yield is 70%, necessitating an improvement in yield.

[0041] Furthermore, in the case where 1,1′-(azodicarbonyl)dipiperidine (ADD) is used for the coupling reaction of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol and 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde, it is not preferred in terms of low yield and cost. Summary of the Invention

[0042] Technical issues

[0043] Therefore, the technical problem of the present invention is to provide a method suitable for large-scale production of the compound of formula 6 with high yield through a simpler process, wherein the compound of formula 6 is a key intermediate for synthesizing excellent sphingosine-1-phosphate receptor agonists.

[0044] Technical Solution

[0045] In order to solve the above technical problems, the present invention provides a method for preparing an intermediate compound of the following formula 6, comprising the following steps:

[0046] i) a step of preparing a compound of formula 3 by dealkylation of a compound of formula 2, ii) a step of preparing a compound of formula 5 by coupling reaction of the compound of formula 3 with a compound of formula 4, and

[0047] iii) a step of preparing a compound of formula 6 by reacting the compound of formula 5 with phosphorus oxychloride (POCl3) and dimethylformamide:

[0048] [Formula 2]

[0049]

[0050] [Formula 3]

[0051]

[0052] [Formula 4]

[0053]

[0054] [Formula 5]

[0055]

[0056] [Formula 6]

[0057]

[0058] in,

[0059] R1 and R2 are each independently hydrogen, alkyl, halogen, haloalkyl or alkoxyalkyl;

[0060] R3 is an alkyl group;

[0061] R4 is hydrogen or alkyl;

[0062] R5 is hydrogen, alkyl, halogen, CN, CF3 or COCF3;

[0063] X is C or N;

[0064] L is a leaving group.

[0065] The present invention is described in detail below.

[0066] According to one aspect of the present invention, in the above formula, R1 and R2 are each independently hydrogen, C1-C6 alkyl, halogen, halo-C1-C6 alkyl or C1-C6 alkoxy-C1-C6 alkyl; R3 is C1-C6 alkyl; R4 is hydrogen or C1-C6 alkyl; R5 is hydrogen, C1-C6 alkyl, halogen, CN, CF3 or COCF3; X is C or N; and L is a leaving group.

[0067] According to another aspect of the present invention, in the above formula, R1 and R2 are each independently hydrogen or C1-C4 alkyl; R3 is C1-C4 alkyl; R4 is C1-C4 alkyl; R5 is halogen; X is N; L is a leaving group selected from chlorine (Cl), bromine (Br), iodine (I), methanesulfonate (OMs), p-toluenesulfonate (OTs) and trifluoromethanesulfonate (OTf).

[0068] In the preparation method of the present invention, in step (i), the compound of formula 3 is prepared by dealkylation of the compound of formula 2.

[0069] In the preparation method of the present invention, the compound of formula 3 can be prepared in high yield even in large-scale production by performing a dealkylation reaction on the stable compound of formula 2 without the problem of decomposing the compound.

[0070] In one embodiment according to the present invention, the dealkylation reaction of step (i) may be performed by using one selected from, for example, hydrogen bromide (HBr), aluminum chloride (AlCl 3 ), and iron (III) chloride (FeCl 3 ).

[0071] In the preparation method of the present invention, in step (ii), the compound of formula 5 is prepared by coupling reaction of the compound of formula 3 and the compound of formula 4.

[0072] In another embodiment according to the present invention, the coupling reaction of the compound of Formula 3 and the compound of Formula 4 can be easily performed by using K 2 CO 3 in a dimethylformamide (DMF) solvent.

[0073] In another embodiment of the present invention, the compound of Formula 5 can be obtained with high purity by crystallization after the coupling reaction of the compound of Formula 3 and the compound of Formula 4.

[0074] In the preparation method of the present invention, in step (iii), the compound of formula 6 is prepared by reacting the compound of formula 5 with phosphorus oxychloride (POCl 3 ) and dimethylformamide.

[0075] In another embodiment according to the present invention, the reaction of the compound of formula 5 with phosphorus oxychloride (POCl 3 ) and dimethylformamide may be carried out at a temperature below 60° C., more preferably below 55° C.

[0076] According to another aspect of the present invention, the compound of formula 4 is prepared by the following steps:

[0077] 1) a step of preparing a compound of formula 8 by introducing R4 and R5 substituents into a compound of formula 7, 2) a step of preparing a compound of formula 9 by reacting the compound of formula 8 with a reducing agent, and

[0078] 3) a step of preparing the compound of formula 4 by introducing a leaving group into the alcohol group of the compound of formula 9:

[0079] [Formula 4]

[0080]

[0081] [Formula 7]

[0082]

[0083] [Formula 8]

[0084]

[0085] [Formula 9]

[0086]

[0087] in,

[0088] R4, R5, X and L are the same as defined above.

[0089] According to another aspect of the present invention, in the above formula, R4 is a C1-C4 alkyl group; R5 is a halogen; X is N; and L is a leaving group selected from chlorine (Cl), bromine (Br), iodine (I), methanesulfonate (OMs), p-toluenesulfonate (OTs) and trifluoromethanesulfonate (OTf).

[0090] In the preparation method of the present invention, in step (1), the compound of formula 8 is prepared by introducing R4 and R5 substituents into the compound of formula 7.

[0091] In another embodiment according to the present invention, R5 is introduced into the compound of Formula 7 before R4. In the case of introducing a bulky group R5 into the compound of Formula 7, for example, when X is N and the bulky group R5 is introduced at the 3-position of indazole, the generation of the N2 isomer can be suppressed and the yield can be improved.

[0092] In the preparation method of the present invention, in step (2), the compound of formula 9 is prepared by reacting the compound of formula 8 with a reducing agent.

[0093] In another embodiment of the present invention, the reducing agent in step (2) may be one or more selected from sodium borohydride (NaBH4), lithium borohydride (LiBH4), borane (BH3) and diisobutylaluminum hydride (DIBAH).

[0094] In the preparation method of the present invention, in step (3), a leaving group is introduced into the alcohol group of the compound of formula 9 to prepare the compound of formula 4.

[0095] In another embodiment of the present invention, in step (3), for example, by introducing a leaving group such as Br, the yield of the coupling reaction of the compound of Formula 3 and the compound of Formula 4 can be improved.

[0096] Effects of the present invention

[0097] The preparation method of the present invention can produce the intermediate of Formula 6 on a large scale with high yield under mild conditions by performing the reaction with a simpler process while ensuring safety and stability. DETAILED DESCRIPTION

[0098] The present invention will be described in more detail below using the following examples. However, it must be understood that the scope of protection of the present invention is not limited to the examples.

[0099] Example 1-1: Synthesis of methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate

[0100] 1H-indazole-5-carboxylic acid methyl ester (200g, 1.14mol), N-chlorosuccinimide (NCS, 182g, 1.36mol) and dimethylformamide (DMF, 800ml, 4 times) were added to the reactor, and the internal temperature of the reaction mixture was raised to 70°C, followed by stirring for 150 minutes. Ion pair chromatography (IPC) was performed by HPLC to complete the reaction (1%> 1H-indazole-5-carboxylic acid methyl ester). The external temperature was set to 0°C and cooled for 30 minutes. While maintaining the internal temperature of the reactor at 50°C, K2CO3 (345g, 2.5mol) was added, followed by isopropyl iodide (313g, 1.71mol), and the alkylation reaction was carried out at 60°C for 360 minutes. Since 3-chloro-1H-indazole-5-carboxylic acid methyl ester remained after ion pair chromatography (IPC) by HPLC, isopropyl iodide (31g) was added twice to complete the reaction. The reaction mixture was cooled to 0°C, water (1.6 L) was slowly added and the resulting crystals were filtered off. The filtered crystals were washed twice with 800 mL of water and 400 mL of water and then dried with nitrogen to give the title compound (292 g, net yield: 79.3%).

[0101] 1 H NMR(400MHz, CDCl3):1.58(d,6H),3.96(s,3H),4.81(m,1H),7.42(d,1H),8.06(dd,1H),8.44(s,1H)

[0102] Example 1-2: Synthesis of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol

[0103] Tetrahydrofuran (THF, 1.37 L) and 3-chloro-1-isopropyl-1H-indazole-5-methyl carboxylate (227.47 g, 0.9 mol) were added to the reactor and the internal temperature was raised to 60°C. NaBH4 (51.1 g, 1.35 mol) was added to the reaction mixture and methanol (MeOH, 227 mL) was slowly added dropwise over 40 minutes and then reacted for 30 minutes. IPC was performed using HPLC. Approximately 70% of (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol remained, so additional NaBH4 and MeOH were added at 30-minute intervals until the reaction was complete (1%>3-chloro-1-isopropyl-1H-indazole-5-methyl carboxylate). The internal temperature of the reactor was cooled to 0°C, and 3N HCl was slowly added over 60 minutes to maintain the pH of the reaction solution at 2.0 to remove the B-complex (a complex produced by NaBH4 in which boron is conjugated to the alcohol of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol) and residual NaBH4. The resulting product was extracted twice with dichloromethane (DCM, 1 L) and distilled under reduced pressure to obtain the title compound (173 g, net yield: 86%).

[0104] 1 H NMR (400MHz, CDCl3): 1.5~1.7(m,6H),1.82(m,1H),3.72(m,1H),4.70~5.10(m,2H),7.30~7.50(m,2H),7.62(s,1H)

[0105] Example 1-3: Synthesis of 5-bromomethyl-3-chloro-1-isopropyl-1H-indazole

[0106] DCM (173 mL), methyl tert-butyl ether (MTBE, 692 mL) and (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol (173 g, 0.77 mol) were added to the reactor and the internal temperature was cooled to 0°C. PBr (146 g, 0.54 mol) was slowly added to the reaction mixture over a period of 70 minutes and allowed to react for 80 minutes. IPC was performed using HPLC to complete the reaction (3%> (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol). 1.5 N NaOH (13.6 L) was slowly added over 120 minutes to terminate the reaction. DCM (865 mL) was added to the reaction mixture and stirred for 30 minutes, then the layers were separated to remove the aqueous layer. The organic layer was washed twice with water (865 mL) and distilled under reduced pressure to give the title compound (228.2 g, net yield: 90.8%).

[0107] 1 H NMR (400 MHz, CDCl3): 1.53 (d, 6H), 4.7 (s, 2H), 4.88 (m, 1H), 7.51-7.6 (m, 2H), 7.68 (s, 1H). HPLC (126 method): 19.57 mts

[0108] Example 1-4: Synthesis of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one

[0109] HBr (HBr / H2O, 1.5 L) and 6-methoxy-3,4-dihydro-2H-naphthalen-1-one dissolved in water were added to the reactor and refluxed at an external temperature of 120°C for 52 hours. The reaction was completed by IPC using HPLC (3%> 6-methoxy-3,4-dihydro-2H-naphthalen-1-one). After the internal temperature was cooled to 10°C, the resulting solid was filtered out. The filtered solid was washed twice with water (750 mL) and dried with nitrogen to give the title compound (123 g, net yield: 89.1%).

[0110] 1H NMR (400MHz, CDCl3): 2.05(m,2H),2.60(t,2H),2.85(t,2H),6.68(s,1H),6.80(d,1H),7.90(d,1H)

[0111] Example 1-5: 6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one synthesis

[0112] 5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole (187.4 g, 0.65 mol), 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (96.1 g, 0.59 mol), K2CO3 (122.8 g, 2.88 mol), and DMF (480 mL) were added to a reactor and reacted at an internal temperature of 25°C for 3 hours. IPC was performed using HPLC. 5% of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one remained, so 5-bromomethyl-3-chloro-1-isopropyl-1H-indazole (13 g) was added to complete the reaction (1% > 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one). Water (960 mL) was added to the reactor, the internal temperature was cooled to 0°C, and the resulting solid was filtered. The filtered solid was washed twice with water (750 mL) and twice with MTBE (500 mL), and then dried with nitrogen to give the title compound (178 g, net yield: 79.9%).

[0113] 1 H NMR(400MHz, CDCl3):1.56(d,6H),2.09(m,2H),2.60(t,2H),2.95(m,2H),4.80(m ,1H),5.20(s,2H),6.84-6.94(m,2H),7.42-7.48(m,2H),7.71(s,1H),8.05(d,1H)

[0114] Example 1-6: 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxylic acid Synthesis of aldehydes

[0115] Phosphorus oxychloride (POCl3, 411.5g, 2.68mol) was added to the reactor, and the internal temperature was cooled to 0°C. DMF (327g, 4.47mol) was slowly added dropwise and stirred at an internal temperature of 50°C for 2 hours. 6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one (165g, 0.45mol) was added thereto and reacted at an internal temperature of 50°C for 3 hours. Because excess HCl gas was generated during the reaction, a NaOH trap was installed and a ventilation tube was connected for neutralization. IPC was performed using HPLC to complete the reaction and the internal temperature was cooled to 0°C. Cold water (1.6L), hexane (HEX, 330mL) and MTBE (500mL) were added to another reactor, and the above reaction mixture was slowly added dropwise thereto for 90 minutes to form crystals. The obtained solid was filtered, washed twice with water (800 mL) and twice with a 3% MTBE / HEX mixed solvent (330 mL), and dried to give the title compound (111.7 g, net yield: 60.1%).

[0116] 1 H NMR(500MHz, CDCl3):1.57(d,6H),2.62(m,2H),2.80(t,2H),4.79(m,1H),5.19(s, 2H),6.82-6.93(m,2H),7.42-7.50(m,2H),7.71(s,1H),7.80(d,1H),10.33(s,1H).

Claims

1. A method for preparing an intermediate compound of the following formula 6, comprising the following steps: i) a step of preparing a compound of formula 3 by dealkylation of a compound of formula 2, ii) a step of preparing a compound of formula 5 by coupling reaction of the compound of formula 3 with a compound of formula 4, and iii) a step of preparing a compound of formula 6 by reacting the compound of formula 5 with phosphorus oxychloride and dimethylformamide: [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] in, R1 and R2 are each independently hydrogen, C1-C6 alkyl, halogen, halo-C1-C6 alkyl or C1-C6 alkoxy-C1-C6 alkyl; R3 is a C1-C6 alkyl group; R4 is hydrogen or C1-C6 alkyl; R5 is hydrogen, C1-C6 alkyl, halogen, CN, CF3 or COCF3; X is C or N; L is a leaving group.

2. The method according to claim 1, wherein R1 and R2 are each independently hydrogen or C1-C4 alkyl; R3 is a C1-C4 alkyl group; R4 is a C1-C4 alkyl group; R5 is halogen; X is N; L is a leaving group selected from chloro, bromo, iodo, mesylate, p-toluenesulfonate, and trifluoromethanesulfonate.

3. The method according to claim 1, wherein the compound of formula 4 is prepared by the following steps: 1) a step of preparing a compound of formula 8 by introducing R4 and R5 substituents into a compound of formula 7, 2) a step of preparing a compound of formula 9 by reacting the compound of formula 8 with a reducing agent, and 3) a step of preparing the compound of formula 4 by introducing a leaving group into the alcohol group of the compound of formula 9: [Formula 4] [Formula 7] [Formula 8] [Formula 9] in, R4, R5, X and L are the same as defined in claim 1.

4. The method according to claim 1, wherein the dealkylation reaction of step i) is performed by using one selected from the group consisting of HBr, AlCl 3 and FeCl 3 .

5. The method according to claim 1, wherein the coupling reaction of step ii) is carried out by using K2CO3 in dimethylformamide solvent. The method according to claim 1 , wherein the step iii) is performed at a temperature below 60° C. .

7. The method according to claim 3, wherein R4 is a C1-C4 alkyl group; R5 is halogen; X is N; L is a leaving group selected from chloro, bromo, iodo, mesylate, toluenesulfonate, and trifluoromethanesulfonate.

8. The method according to claim 3, wherein in step 1), R5 is introduced before R4.

9. The method according to claim 3, wherein the reducing agent in step 2) is selected from NaBH4, LiBH4, BH3 and diisobutylaluminum hydride.

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