New processes for the preparation of sphingosine-1-phosphate receptor agonists

Abstract

The present invention relates to a novel process for preparing a compound of formula 7 or a salt thereof, as disclosed in the specification, which can be effectively used as a sphingosine-1-phosphate receptor agonist.

Description

Technical Field

[0001] Cross-references to related applications

[0002] This application claims priority based on Korean Patent Application No. 10-2021-0048768, filed on April 14, 2021, the entire disclosure of which is incorporated herein by reference. Technical Field

[0004] This invention relates to a novel method for preparing a synthetic sphingosine-1-phosphate receptor agonist. Background Technology

[0005] Sphingosine-1-phosphate (S1P) is produced via the intracellular ceramide pathway, in which ceramide is the starting material. Ceramide is produced through two pathways, the first of which is a de novo biosynthetic pathway. Ceramide is also produced by the degradation of sphingomyelin, a cell membrane component. S1P levels in various tissues are controlled by two biosynthetic sphingosine kinases (SphK) and two biodegradable S1P phosphatases (S1P lysophosphatase and lysophospholipid phosphatase). S1P, produced by phosphorylation of sphingosine via sphingosine kinase, is known to mediate various cellular responses, such as cell proliferation, cytoskeleton organization and migration, adhesion and tight junction assembly, and morphogenesis. S1P exists in plasma at high levels (100–1000 nM) in combination with other plasma proteins (including albumin), while it exists at low levels in tissues.

[0006] S1P binds to the G protein-coupled receptor S1P to exhibit various biological functions. As S1P receptor subtypes, S1P1 through S1P5 are known to date, designated as endothelial differentiation gene (EDG) receptors 1, 5, 3, 6, and 8, respectively. S1P receptors are known to participate in a variety of biological functions, such as leukocyte recirculation, nerve cell proliferation, morphological changes, migration, endothelial function, vascular regulation, and cardiovascular development.

[0007] In recent years, numerous studies have revealed the crucial role of S1P signaling processes via these receptors in a range of responses (including inflammatory responses) and repair processes associated with multiple sclerosis (MS). In fact, non-selective S1P1 agonists have recently been approved as therapeutic agents for MS. S1P receptors are widely expressed in many cells associated with MS. In particular, S1P1 receptors play a vital role in the immune system. S1P1 receptors are primarily expressed on the surface of lymphocytes such as T cells and B cells and respond to S1P, thereby participating in lymphocyte recirculation. Under normal conditions, the concentration of S1P in body fluids is higher than in lymphoid tissues; therefore, this concentration difference leads to lymphocytes leaving the lymphoid tissues and circulating along the efferent lymphatic system. However, when S1P1 receptors in lymphocytes are downregulated by S1P1 agonists, lymphocyte outflow from lymphoid tissues is prevented, thereby reducing the infiltration of self-invasive lymphocytes that cause inflammation and tissue damage in the central nervous system (CNS). This has resulted in therapeutic effects against MS. Fingolimod, a nonselective S1P1 agonist, has been approved as an oral medication for the treatment of multiple sclerosis. When it binds to and is activated by the S1P1 receptor, the receptor is either degraded or internalized from the surface of lymphocytes. Thus, anomalously, fingolimod acts as a functional S1P1 antagonist.

[0008] Regarding such S1P receptor agonists, Korean Unexamined Publication No. 10-2014-0104376 discloses a novel compound of Formula 1, which is effective as an S1P receptor agonist:

[0009] [Formula 1]

[0010]

[0011] in

[0012] X is C or N.

[0013] R1 is H or a substituted alkyl group.

[0014] R2 can be H, a substituted alkyl group, a halogen, CN, CF3, or COCF3.

[0015] W represents C, N, C-alkoxy, C-halogen, or C-CN, and Q represents CH2O or S is selected from the following:

[0016]

[0017] In the above structural formula,

[0018] m and n are 0, 1, 2, or 3.

[0019] R3 to R10 are each H, alkyl, halogen, haloalkyl, or alkoxyalkyl.

[0020] R11 is H, and

[0021] R12 is OH or NH2.

[0022] 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-naphth-2-ylmethyl]-piperidine-4-carboxylic acid according to Scheme 1 below (in Scheme 1, "SG35" refers to "1-chloro-6-hydroxy-3,4-dihydro-naphth-2-carboxaldehyde").

[0023] [Option 1]

[0024]

[0025] In Scheme 1 above, the preparation steps of 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde are described in more detail below.

[0026] Synthesis of (1-1))(3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol

[0027] Methyl 1H-indazole-5-carboxylate was dissolved in dimethylformamide, and iodoisopropane 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, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure. Separation was performed by column chromatography to obtain methyl 1-isopropyl-1H-indazole-5-carboxylate.

[0028] The methyl 1-isopropyl-1H-indazole-5-carboxylate obtained above was dissolved in dimethylformamide, and N-chlorosuccinimide (NCS) was added dropwise, followed by stirring at room temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure. The residue was separated by column chromatography to give methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate.

[0029] The methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate obtained above was dissolved in tetrahydrofuran, and lithium aluminum borohydride was added dropwise. After stirring at room temperature for 1 hour, water, 6N sodium hydroxide aqueous solution, and water were added sequentially. Diatomaceous earth was added dropwise, and the filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol.

[0030] (1-2) Synthesis of 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carboxaldehyde

[0031] First, N,N-dimethylformamide (DMF) and phosphoryl chloride (phosphorus oxychloride, POCl3) were added dropwise to a solution of 6-methoxy-3,4-dihydronaphthyl-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 residue was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1 to 10:1) to give 1-chloro-6-methoxy-3,4-dihydro-2-naphthaldehyde.

[0032] Next, aluminum chloride (AlCl3) was added to a solution of 1-chloro-6-methoxy-3,4-dihydro-2-naphthaldehyde dissolved in dichloromethane at 0°C, and the mixture was stirred at 50°C for 6 hours. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:tetrahydrofuran = 5:1 to 3:1) to give 1-chloro-6-hydroxy-3,4-dihydro-2-naphthaldehyde.

[0033] (1-3) 1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde become

[0034] The (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol and 1-chloro-6-hydroxy-3,4-dihydro-2-naphthaldehyde obtained above were dissolved in toluene, and then tributylphosphine (PBu3) and 1,1'-(azodicarbonyl)piperidine (ADD) were added dropwise. After stirring at room temperature for 18 hours, excess hexane was added. After filtration and vacuum distillation, the residue was purified by column chromatography to give 1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthaldehyde.

[0035] However, the above reactions may present the following problems when producing clinical APIs:

[0036] First, problems may arise in the synthesis of methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate due to the N2 isomer production ratio. Lithium aluminum hydride (LAH) used for the synthesis of (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol has the following drawbacks: it has very limited stability when used in large-scale synthesis and is easily decomposed by water.

[0037] Furthermore, the Vilsmeier-Haack reaction aimed at yielding 1-chloro-6-methoxy-3,4-dihydro-2-naphthaldehyde may present exothermic issues due to the high temperature of 70°C. Additionally, the reaction aimed at yielding 1-chloro-6-hydroxy-3,4-dihydro-2-naphthaldehyde may present reactor contamination issues due to the use of AlCl3 or stability issues due to the use of hazardous reagents. When using AlCl3, stability issues arise due to batch failures caused by reaction termination or side reaction progression, and the overall yield is 70%, thus requiring an increase in yield.

[0038] Furthermore, 1,1'-(azodicarbonyl)piperidine (ADD) for the coupling of (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol with 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carboxaldehyde is not preferred in terms of low yield and cost.

[0039] Furthermore, there is a problem that API reprocessing is necessary due to N2 isomer impurities. The synthesis method is linear, and the yield decreases with each subsequent process. Additionally, the synthesis method suffers from difficulty in identifying and resolving problems in intermediate processes. For example, if impurities are not removed during recrystallization, the first step of the process must be restarted.

[0040] Specifically, in Scheme 1 above, in the step of preparing 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthyl-2-carboxaldehyde from 1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthyl-2-methyl]piperidine-4-carboxylic acid, the intermediate product "ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthyl-2-methyl]piperidine-4-carboxylic acid" has viscous oil properties. Therefore, after the reaction is completed, subsequent processes are carried out in the crude material state without a separate purification step.

[0041] However, to improve the reaction purity and the purity of the final API in subsequent API processes, the intermediate ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate needs to be purified. In particular, purification of the intermediate is absolutely necessary because impurities, such as the N2 isomer, are difficult to remove.

[0042] Therefore, there is still a need to develop a new synthetic method that can transform conventional linear methods into efficient aggregate synthesis methods while simultaneously improving the purity and yield of the products. Summary of the Invention

[0043] Technical issues

[0044] Therefore, one aspect of the present invention provides a method suitable for producing a compound of formula 7 or a salt thereof in high yield and high purity, said compound or salt being usable as an excellent sphingosine-1-phosphate receptor agonist:

[0045] [Formula 7]

[0046]

[0047] in

[0048] R1 is hydrogen or a substituted or unsubstituted alkyl group.

[0049] R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF3, or COCF3.

[0050] R3 and R4 are each hydrogen, substituted or unsubstituted alkyl groups, or halogens.

[0051] R5 is hydrogen, a substituted or unsubstituted alkyl group, or a halogen.

[0052] X is C or N.

[0053] Y is N, O, or S, and

[0054] m and n are each 0, 1, 2 or 3, and m + n > 0.

[0055] Technical solution

[0056] According to one aspect of the present invention, a method for preparing a compound of formula 7 or a salt thereof is provided, the method comprising:

[0057] 1) The step of preparing compound 4 by coupling compound 2 with compound 3 in the presence of dimethylacetamide (DMA) solvent;

[0058] 2) The step of reacting compound of formula 4 with compound of formula 5 under reducing conditions to prepare compound of formula 6 or a salt thereof; and

[0059] 3) The step of converting the ester group of the compound of formula 6 or its salt into a carboxylic acid group to prepare the compound of formula 7 or its salt:

[0060] [Equation 2]

[0061]

[0062] [Formula 3]

[0063]

[0064] [Formula 4]

[0065]

[0066] [Formula 5]

[0067]

[0068] [Formula 6]

[0069]

[0070] [Formula 7]

[0071]

[0072] in

[0073] R1 is hydrogen or a substituted or unsubstituted alkyl group.

[0074] R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF3, or COCF3.

[0075] R3 and R4 are each hydrogen, substituted or unsubstituted alkyl groups, or halogens.

[0076] R5 is hydrogen, a substituted or unsubstituted alkyl group, or a halogen.

[0077] R6 is a substituted or unsubstituted alkyl group.

[0078] X is C or N.

[0079] Y is N, O, or S.

[0080] L is a leaving group, and

[0081] m and n are each 0, 1, 2 or 3, and m + n > 0.

[0082] When the 'alkyl' is substituted, there may be one or more substituents, each of which can be independently selected from halogen, cyano, hydroxy, alkoxy, ketone, unsubstituted sulfonyl, and alkyl-substituted sulfonyl.

[0083] According to one embodiment of the present invention, R1 in the above formulas can be hydrogen or a C1-C6 substituted or unsubstituted alkyl group, and R2 can be hydrogen, a C1-C6 substituted or unsubstituted alkyl group, a halogen, CN, CF3, or COCF3. R3 and R4 can each be hydrogen or a C1-C6 substituted or unsubstituted alkyl group. R5 can be F, Cl, Br, or I. Furthermore, R6 can be a C1-C4 substituted or unsubstituted alkyl group.

[0084] According to another embodiment of the invention, R1 can be a C1-C4 substituted or unsubstituted alkyl group, and R2 can be a halogen (F, Cl, Br or I). R3 and R4 can each be hydrogen. R5 can be Cl. In addition, R6 can be ethyl.

[0085] According to one embodiment of the present invention, the leaving group (L) is a reactive group that provides a substitution position for the compound of formula 2 when the compound of formula 2 undergoes a substitution reaction with an alcohol compound such as formula 3, and may be, but is not limited to, selected from chlorine (Cl), bromine (Br), iodine (I), methanesulfonate (Oms), p-toluenesulfonate (OTs) and trifluoromethanesulfonate (OTf).

[0086] According to another embodiment of the present invention, L can be Br.

[0087] According to one embodiment of the present invention, Y can be N or O, and can be m>0, n>0, m+n=3 or 4.

[0088] According to another embodiment of the present invention, Y can be N, and m and n can each be 2.

[0089] In this invention, when referring to 'a compound or a salt thereof', the term 'a salt thereof' means a pharmaceutically acceptable salt of said compound.

[0090] The pharmaceutically acceptable salts include acid addition salts formed from the following acids: inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic acids, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid; or sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid, wherein the acids form non-toxic acid addition salts containing pharmaceutically acceptable anions. In particular, preferred acid addition salts are formed from sulfuric acid, methanesulfonic acid, or hydrohalic acid.

[0091] In one embodiment of the present invention, the salt of the compound of formula 6 and the salt of the compound of formula 7 may be the hydrochloride salt of the compound of formula 6 and the hydrochloride salt of the compound of formula 7, respectively.

[0092] The invention will be described in more detail below.

[0093] In this invention, in step 1), compound 4 is prepared by coupling compound 2 with compound 3 in the presence of dimethylacetamide (DMA) solvent.

[0094] In one embodiment, according to the present invention, the coupling of compound 2 and compound 3 can be readily carried out using K2CO3 in a DMA solvent.

[0095] In coupling reactions, when the reaction solvent is unstable and decomposes, the decomposition products may react with the reactants in the synthesis reaction to generate impurities, thereby reducing the purity of the reaction products. In this regard, since the synthesis reaction using dimethylformamide as the reaction solvent has a higher maximum temperature and adiabatic temperature rise than the synthesis reaction using dimethylacetamide as the reaction solvent, dimethylacetamide may be preferred as the reaction solvent for the synthesis reaction.

[0096] In another embodiment, according to the present invention, after coupling the compound of formula 2 with the compound of formula 3, a high-purity compound of formula 4 can be obtained by crystallizing the compound of formula 4.

[0097] In one embodiment of the invention, depending on the solvent used for crystallizing the compound of formula 4, there may be a problem that crystallization does not continue, and it may be preferable that the crystallization solvent for the compound of formula 4 includes an alcohol solvent. For example, when water or methyl tert-butyl ether (MTBE) is used alone during the crystallization of the compound of formula 4, crystallization may not continue.

[0098] In one embodiment, according to the invention, the crystallization solvent can be a mixture of an alcohol solvent, an ester solvent, a nonpolar solvent, and water. Using a mixture of an alcohol solvent, an ester solvent, a nonpolar solvent, and water as the crystallization solvent allows the compound of formula 4 to crystallize and enables the compound of formula 4 to be obtained in a high yield.

[0099] For example, the 'alcohol solvent' used to crystallize the compound of formula 4 can be, but is not limited to, one or more solvents selected from methanol, ethanol, isopropanol and butanol.

[0100] For example, the 'ester solvent' used to crystallize the compound of formula 4 can be, but is not limited to, one or more solvents selected from methyl acetate, ethyl acetate and isopropyl acetate.

[0101] For example, the 'nonpolar solvent' used to crystallize the compound of formula 4 can be, but is not limited to, one or more solvents selected from pentane, hexane and heptane.

[0102] In another embodiment, according to the present invention, the crystallization solvent may be a mixture of ethanol, isopropyl acetate, heptane and water.

[0103] In this invention, in step 2), compound 6 or its salt is prepared by reacting compound 4 with compound 5 under reducing conditions.

[0104] When compound 4 and compound 5 are mixed under reducing conditions, a bond is formed at the carbonyl (C=O) functional group of compound 4 with a heteroatom represented by Y in compound 5, and the carbonyl functional group is reduced, thereby preparing compound 6. However, the mechanism of the present invention is not limited thereto.

[0105] In one embodiment of the invention, compound 6 is prepared by reacting compound 4 with compound 5 in the presence of a reducing agent.

[0106] For example, the reducing agent may be, but is not limited to, at least one selected from sodium triacetoxyborohydride (NaBH(OAc)3), sodium borohydride (NaBH4), and sodium cyanoborohydride (NaBH3CN).

[0107] In another embodiment of the invention, the compound of Formula 4 and the reducing agent can be used in an equivalent ratio of 1:5 to 5:1, with regard to reaction efficiency. For example, the compound of Formula 4 and the reducing agent can be used in an equivalent ratio of 1:4 to 4:1, 1:3 to 3:1, or 1:2 to 2:1.

[0108] In one embodiment of the invention, a pharmaceutically acceptable salt of Formula 6 can be obtained according to the conditions used in step 2) to obtain the compound of Formula 6.

[0109] In another embodiment of the invention, the hydrochloride salt of compound 6 can be prepared by crystallization after the reaction between compound 4 and compound 5 in step 2).

[0110] In one embodiment of the present invention, the crude product of compound 6 prepared by the reaction between compound 4 and compound 5 in step 2) exhibits viscous oil properties. Therefore, after the reaction is completed, a crystallization step can be further performed to obtain compound 6 or its salt.

[0111] In one embodiment of the present invention, the crude product of compound 6 can be crystallized under acidic conditions.

[0112] The acidic conditions can be, for example, conditions below pH 3.0. Specifically, crystallization can be achieved by adding an acidic compound to make the pH of the solution containing the compound of formula 6 between 1.0 and 3.0.

[0113] Regarding the acid compounds used to produce acidic conditions, known acid compounds can be used within the range that do not damage the structure and physical properties of the compound of formula 6, and there are no restrictions on the type of acid compound.

[0114] According to one embodiment of the present invention, crystallization can be carried out by adding hydrochloric acid (HCl) to the crude reaction product containing the compound of formula 6.

[0115] According to another embodiment of the invention, hydrochloric acid can be used at a concentration of 1N to 8N. Preferably, hydrochloric acid can be used at a concentration of 3N to 6N. If the concentration of hydrochloric acid is too high, the amount of water used in the crystallization process will be insufficient, resulting in a poor removal rate of the B complex and potentially causing the filtration process to stop.

[0116] According to one embodiment of the present invention, crystallization can be carried out at a temperature below 25°C, for example, at a temperature between 0°C and 25°C, but the crystallization temperature is not limited to this.

[0117] According to another embodiment of the invention, crystallization can be carried out at a temperature of 0°C to 20°C, for example, 10°C.

[0118] According to one embodiment of the present invention, crystallization can be carried out using an antisolvent method.

[0119] The crystallization solvent according to the antisolvent method can be one or more solvents selected from the following: water; polar organic solvents, such as methyl tert-butyl ether (MTBE), ethyl acetate (EA), dichloromethane (DCM), etc.; and non-polar organic solvents, such as n-hexane, etc.

[0120] According to another embodiment of the present invention, the crystallization solvent may be a single ether solvent.

[0121] In this invention, 'single solvent' refers to the addition of only one solvent used to crystallize the compound of formula 6. It will be apparent to those skilled in the art that 'single solvent' does not preclude the possibility of crystallizing after the reaction used to prepare the compound of formula 6 without distilling the reaction solvent to retain it in the reactor, and then adding a crystallization solvent.

[0122] Furthermore, the use of a single solvent does not preclude the inclusion of trace amounts of heterogeneous solvents at levels that substantially do not affect the crystallization yield when a solvent is added. For example, a heterogeneous solvent comprising less than 5 vol%, less than 4 vol%, less than 3 vol%, less than 2 vol%, less than 1 vol%, less than 0.5 vol%, or 0 vol% (i.e., excluding) of a content based on the total volume of solvent added for crystallization may be referred to as using a single solvent.

[0123] Examples of ether solvents include, but are not limited to, dialkyl ether solvents such as diethyl ether, dipropyl ether, dibutyl ether, diisopentyl ether, ethyl methyl ether, methyl propyl ether, methyl butyl ether and ethyl propyl ether; arylalkyl ether solvents such as diphenyl ether and anisole; or cyclic ether solvents such as tetrahydrofuran and tetrahydropyran; and so on.

[0124] According to one embodiment of the present invention, the ether-based single solvent may be methyl tert-butyl ether (MTBE).

[0125] According to one embodiment of the present invention, a crystallization solvent can be added in the amount required for crystallization to carry out crystallization, and there is no particular limitation on the amount of solvent used.

[0126] According to another embodiment of the present invention, the amount of crystallization solvent can be 4 to 10 times the amount of crystallization solution.

[0127] According to another embodiment of the invention, crystallization can be carried out by adding 4 to 8 times, specifically 6 times, MTBE to the crude reaction product containing the compound of formula 6.

[0128] In this invention, in step 3), compound 7 or its salt is prepared by converting the ester group of the compound of formula 6 or its salt obtained above into a carboxylic acid group.

[0129] Regarding the compound of formula 6 in step 3), the crude reaction product obtained by completing the reaction in step 2) without purification and crystallization can be used as is, or the reaction product obtained by completing the reaction in step 2) with purification and / or crystallization can be used. However, the compound of formula 6 in step 3) is not limited to these.

[0130] In one embodiment of the invention, a pharmaceutically acceptable salt of the compound of formula 6 obtained by crystallization in step 2), such as the hydrochloride salt of the compound of formula 6, can be used as a reactant in step 2).

[0131] In one embodiment of the invention, an ester group can be converted into a carboxylic acid group by reacting a compound of formula 6 or a salt thereof with water, a polar solvent or a mixture thereof in the presence of a base.

[0132] Examples of polar solvents that can be used for carboxylic acid group conversion include, but are not limited to, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol; and polar non-alcohol solvents such as chloromethane and dichloromethane.

[0133] In one embodiment of the invention, when methanol is used to convert to a carboxyl group, residual methanol in the subsequent API process may generate methyl ester-type impurities. Therefore, ethanol can be used to prepare the compound of formula 7 or its salt.

[0134] In another embodiment of the invention, ethanol, water, dichloromethane, or a mixture thereof can be used as the reaction solvent to convert to carboxyl groups.

[0135] In one embodiment of the present invention, the base that can be used for carboxyl group conversion may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.

[0136] In another embodiment of the invention, the alkali can be used in an aqueous solution or in a solid state. Using a solid alkali offers superior advantages in terms of ease of storage and use of the raw materials.

[0137] In another embodiment of the invention, the compound of formula 6 or its salt can be mixed with ethanol in the presence of NaOH, and the compound of formula 7 or its salt can be prepared at a temperature of 40°C to 60°C.

[0138] In one embodiment of the invention, the reaction can be carried out using 3 to 5 equivalents of base and 5 to 7 equivalents of solvent, in terms of the purity of the product.

[0139] In this invention, the method may further include step 4) recrystallizing the compound of formula 7 or its salt obtained in step 3) under acidic conditions.

[0140] The recrystallization in step 4) can result in the recrystallized product containing the compound of formula 7 or its salt having a dichloromethane (DCM) solvent content of less than 600 ppm, such as in the fraction containing the compound of formula 7 or its salt. However, the purpose of this invention is not limited thereto.

[0141] In one embodiment of the invention, the content of DCM solvent in the fraction obtained after recrystallization can be measured, for example, by HPLC.

[0142] In this invention, crystallization of the compound of formula 7 or its salts can be carried out under acidic conditions. Acidic conditions can be, for example, conditions below pH 3. Specifically, crystallization can be carried out by adding an acidic compound to make the pH of the solution containing the compound of formula 7 between 1 and 3.

[0143] Regarding the acid compounds used to produce acidic conditions, known acid compounds can be used within the range that do not damage the structure and physical properties of the compound of formula 7 or its salts, and there are no restrictions on the type of acid compound.

[0144] According to one embodiment of the present invention, crystallization can be carried out by adding hydrochloric acid (HCl) to the reaction product containing the compound of formula 7 or its salt.

[0145] Examples of recrystallization solvents may include, but are not limited to, one or more solvents selected from the following: water; ester solvents, such as methyl acetate (MeOAc), ethyl acetate (EtOAc), and isopropyl acetate (IPOAc); alcohol solvents, such as methanol (MeOH), ethanol (EtOH), and isopropanol (IPA); and polar organic solvents, such as methyl tert-butyl ether (MTBE), dichloromethane (DCM), and tetrahydrofuran (THF); and nonpolar organic solvents, such as n-hexane and xylene.

[0146] In one embodiment of the present invention, a recrystallization step can be carried out using a mixed solvent of water, ethyl acetate and ethanol.

[0147] In another embodiment of the invention, a recrystallization step can be carried out using a mixed solvent of water, isopropyl acetate, and ethanol.

[0148] In another embodiment of the invention, the recrystallization step can be carried out using a mixed solvent of 4 to 6 times water, 1 to 3 times isopropyl acetate, and 1 to 3 times ethanol compared to the recrystallization compound.

[0149] In another embodiment of the invention, the recrystallization step can be carried out using a mixed solvent of 5 times water, 2 times isopropyl acetate, and 2 times ethanol compared to the recrystallization compound.

[0150] In another embodiment of the invention, the recrystallization step can be performed using a solvent of the same kind as the solvent remaining in step 3).

[0151] In one embodiment of the present invention, the recrystallization step may include adding an acid compound at a temperature of 0-25°C.

[0152] In another embodiment of the invention, the recrystallization step may include adding an acid compound at a temperature of 20-25°C.

[0153] In one embodiment of the invention, the recrystallization step can be carried out with or without stirring.

[0154] In another embodiment of the invention, the recrystallization step can be carried out, for example, while stirring at a speed of 100 to 500 rpm after the addition of the acid compound.

[0155] In another embodiment of the invention, the recrystallization step can be carried out while stirring at a speed of 400 to 500 rpm after the addition of the acid compound.

[0156] In one embodiment of the invention, the recrystallization step can be performed, for example, while the acid compound is being added dropwise for 100 minutes.

[0157] In another embodiment of the invention, the recrystallization step can be carried out simultaneously with the addition of the acid compound over 10 to 60 minutes.

[0158] The recrystallization step can be performed once or multiple times to greatly improve the yield and purity of the product.

[0159] When the recrystallization step is carried out under the same conditions as described above, a high yield and high purity product can be obtained by recrystallizing the compound of Formula 7 or its salt only once.

[0160] According to another aspect of the invention, compounds of formula 3 can be prepared from compounds of formula 8.

[0161] [Formula 3]

[0162]

[0163] [Formula 8]

[0164]

[0165] Specifically, compound 3 can be obtained by introducing an aldehyde into compound 8.

[0166] In one embodiment, according to the invention, the reaction of introducing an aldehyde into a compound of formula 8 can be carried out using reagents used in the Wilsmayer-Hacker reaction.

[0167] In another embodiment, according to the invention, the reaction of introducing an aldehyde into a compound of formula 8 can cause the compound of formula 8 to react with phosphoryl chloride (POCl3) and dimethylformamide (DMF) to prepare a compound of formula 3.

[0168] In one embodiment, according to the invention, the reaction of introducing an aldehyde into a compound of formula 8 can be carried out at a temperature below 30°C, thereby stabilizing the exothermic problem caused by the Wilsmayer-Hacker reaction.

[0169] In another embodiment, according to the invention, the reaction of introducing an aldehyde into a compound of formula 8 can be carried out at a temperature of 0°C to 25°C.

[0170] In another embodiment of the invention, the reaction of introducing an aldehyde into the compound of formula 8 can consist of the following:

[0171] 1) The step of preparing compound 9 by blocking the alcohol group of compound 8.

[0172] 2) The steps for preparing compound 10 by introducing an aldehyde into compound 9, and

[0173] 8) The step of preparing compound 3 by restoring alcohol groups from compound 10.

[0174] [Formula 8]

[0175]

[0176] [Formula 9]

[0177]

[0178] [Formula 10]

[0179]

[0180] Where Y is an alcohol protecting group.

[0181] In this invention, an aldehyde is introduced without blocking the alcohol group of compound formula 8, and compound formula 3 can be prepared by simplifying the process. However, in terms of the yield of compound formula 3, the aldehyde introduction reaction can be carried out after blocking the alcohol group of compound formula 8 with an alcohol protecting group.

[0182] The alcohol group in the blocking formula 8 compound can be blocked by known alcohol blocking methods, and there are no particular limitations on the method.

[0183] Therefore, there are no particular restrictions on the alcohol protecting group (Y) introduced into the compound of formula 8, as long as it is a known alcohol protecting group. Examples include, but are not limited to, acetyl groups (-Ac), trimethylsilyl groups (-TMS), tert-butyldimethylsilyl groups (-TBDMS), etc.

[0184] The procedure for preparing compound 10 by introducing an aldehyde into a compound of formula 9 in which the alcohol group has been blocked can be performed in the same manner as the procedure for introducing an aldehyde into a compound of formula 5 in which the alcohol group has not been blocked.

[0185] Next, after preparing compound 10 by introducing an aldehyde into compound 9, the alcohol group can be restored by using a suitable alcoholysis inhibitor depending on the alcohol protecting group to prepare compound 3.

[0186] According to one embodiment of the present invention, a known basic substance can be used as the alcoholysis inhibitor. Examples of known basic substances include, but are not limited to, K₂CO₃, NaHCO₃, NaOH, etc.

[0187] In this invention, the reaction solvent can be appropriately selected depending on the type of deblocking agent used in the alcohol recovery reaction.

[0188] According to one embodiment of the present invention, when alkaline substances such as K2CO3, NaHCO3 and NaOH are used as alcoholysis inhibitors, the reaction solvent can be an alcohol solvent, such as methanol, ethanol or a mixture thereof.

[0189] According to another embodiment of the present invention, when at least one of K2CO3 and NaHCO3 is used as an alcoholysis inhibitor and methanol is used as the reaction solvent, excellent effects can be observed in terms of reaction time and alcohol recovery reaction yield.

[0190] According to one embodiment of the present invention, compound 3 can be prepared by using acetyl chloride (AcCl) to block the alcohol group in compound 8, using POCl3 and DMF to introduce the aldehyde group, and then using an alcohol solvent containing K2CO3.

[0191] According to another embodiment of the present invention, compound 3 can be prepared by using acetyl chloride (AcCl) to block the alcohol group in compound 8, using POCl3 and DMF to introduce the aldehyde group, and then using a methanol solvent containing K2CO3.

[0192] In this invention, high-purity compound 3 can be obtained by crystallizing the compound of formula 3 prepared as described above.

[0193] According to one embodiment of the present invention, the compound of formula 3 is prepared by a series of steps without purification processes between the steps, and therefore the purity can be improved by crystallization.

[0194] In this invention, the crystallization of compound 3 can be carried out under acidic conditions. Acidic conditions can be, for example, conditions with a pH below 4.0. Specifically, crystallization can be carried out by adding an acidic compound to make the pH of the solution containing compound 3 between 3.0 and 4.0.

[0195] Regarding the acid compounds used to produce acidic conditions, known acid compounds can be used within the range that do not damage the structure and physical properties of the compound of formula 3, and there are no restrictions on the type of acid compound.

[0196] According to one embodiment of the present invention, crystallization can be carried out by adding hydrochloric acid (HCl) to the reaction product containing the compound of formula 3.

[0197] According to another embodiment of the present invention, crystallization can be carried out by simultaneously or sequentially adding water (H2O) and hydrochloric acid (HCl) to the reaction product containing the compound of formula 3.

[0198] According to another embodiment of the present invention, crystallization can be carried out by adding water to the reaction product containing the compound of formula 3 and then adding hydrochloric acid (HCl).

[0199] According to one embodiment of the present invention, the crystallization of compound 3 can be carried out after terminating the reaction to restore the alcohol group and then distilling off the reaction solvent such as methanol.

[0200] According to another embodiment of the invention, crystallization of compound 3 can be carried out after terminating the reaction to restore the alcohol group and then without distilling off the reaction solvent, such as methanol. Crystallization without the reaction solvent from the alcohol group restoration step reduces the loss of compound 3, thereby increasing the yield.

[0201] According to one embodiment of the present invention, the crystallization of compound 3 can be carried out at a reaction temperature below 10°C.

[0202] According to another embodiment of the invention, during the crystallization of the compound of formula 3, the reaction temperature can be below 10°C, and the addition of hydrochloric acid can be carried out for less than 2 hours, for example, 1 hour, 30 minutes, 20 minutes, or 10 minutes or less.

[0203] In another embodiment of the invention, compound 8 can be prepared by dealkylation of compound 11:

[0204] [Equation 11]

[0205]

[0206] R3 and R4 are as defined above, and R7 is a substituted or unsubstituted alkyl group.

[0207] In one embodiment of the present invention, R7 may be an unsubstituted C1-C4 alkyl group.

[0208] In another embodiment of the invention, R7 may be a methyl group.

[0209] Compound 3 can be prepared by introducing an aldehyde into compound 11 using the same method as introducing an aldehyde into compound 8 or 9. However, in one embodiment of the invention, preparing compound 8 by dealkylating compound 11 and preparing compound 3 by introducing an aldehyde into compound 8 or 9 improves the decomposition problem of compound 11 and allows for the preparation of intermediate compounds in high yield even in large-scale production.

[0210] The dealkylation of compound 11 can be carried out using the known method for preparing compound 8 by replacing the alkyl group of R7 with an alcohol group, with no particular restrictions on the method and type of reagent used.

[0211] In one embodiment of the invention, for example, hydrogen bromide (HBr), aluminum chloride (AlCl3), and ferric chloride (III) (FeCl3) can be used to dealkylate the compound of formula 11. However, the invention is not limited thereto.

[0212] The compounds prepared according to the present invention, or their salts, can be used as sphingosine-1-phosphate receptor agonists, but the compounds prepared according to the present invention can be used for purposes other than as sphingosine-1-phosphate receptor agonists. The uses of the present invention are not limited to sphingosine-1-phosphate receptor agonists.

[0213] Beneficial effects

[0214] The preparation method of the present invention can be used to produce compound 7 in large quantities with high yield and high purity. Attached Figure Description

[0215] Figure 1 The image shows an SEM image of the crystals formed when the hydrochloric acid addition time was changed according to Experiment Example 2.

[0216] Figure 2 These are SEM images of crystals generated during the crystallization process when the stirring speed was changed, based on Experiment Example 2. Detailed Implementation

[0217] In the following description, to aid in understanding the invention, embodiments will be presented in more detail. However, embodiments of the invention can be modified in various other ways, and the scope of the invention should not be considered limited to the following embodiments. The embodiments of the invention are provided to fully explain the invention to those skilled in the art to which this invention pertains.

[0218] Example 1. (1-Chloro-6-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthyl-2-methyl) Synthesis of aldehydes

[0219]

[0220] 5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole (16.54 g, 57.5 mol), 1-chloro-6-hydroxy-3,4-dihydronaphthyl-2-carboxaldehyde (10 g, 47.9 mmol), K2CO3 (3.62 kg, 26.2 mol), and dimethylacetamide (DMA, 50 mL, 5 times) were placed in a reactor and reacted at an internal temperature of 25 °C for 16 hours.

[0221] The reaction (1-chloro-6-hydroxy-3,4-dihydronaphthyl-2-carboxaldehyde: N / D) was completed by HPLC IPC. DCM (100 ml, 10x) and water (100 ml, 10x) were added and stirred for 30 minutes for the first chromatographic separation. Water (50 ml, 5x) was added to the reaction mixture and stirred for 10 minutes for the second chromatographic separation. Finally, water (50 ml, 5x) was added and stirred for 10 minutes to allow for layer separation.

[0222] The reaction mixture was distilled under reduced pressure. A mixture of EtOH (10 ml, 1x), IPOAc (10 ml, 1x), and heptane (60 ml, 6x) was added to the reaction mixture containing the crude title compound obtained after DCM distillation. The internal temperature was then set to 60°C, and the mixture was stirred for 1 hour, followed by cooling to room temperature. After the internal temperature reached 20°C, the crystals were aged for 1 hour and then filtered. The filtered solid was washed twice with water (60 ml, 6x) and dried under nitrogen to synthesize the title compound (20.3 g, net yield 85%).

[0223] 1H 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).

[0224] Example 2.1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-yl] Synthesis of ethyl methyl[[]-piperidine-4-carboxylate] hydrochloride

[0225]

[0226] Add 1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde (339.44 g, 0.82 mol), triethylamine (TEA, 83 g, 0.82 mol), DCM (1.36 L, 4 times), MTBE (678 mL, 2 times), and ethyl isoperidolate (160.61 g, 1.02 mol) to the reactor. After stirring for 30 minutes, add NaBH(OAc)3 (268.5 g, 1.27 mol) and allow the reaction to proceed for 2 hours.

[0227] The reaction (1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde: N / D) was carried out by HPLC. After cooling to an internal temperature of 10°C, 1.09 L of 3N HCl (4 equivalents) was added dropwise, followed by the addition of 2.04 L of MTBE (6 times the amount of 1-chloro-6-chloro-1 ...

[0228] 1H NMR(500MHz, CDCl3):1.25(t,3H),1.61(d,6H),1.78(m,2H),1.91(m,2H),2.12(t,2H),2.29-2.35(m,1H),2.52(t,2H),2.82(t, 2H),2.89-2.92(m,2H),3.3(s,2H),4.16(q,2H),4.8-4.87(m,1H),5.2(s,2H),6.83-6.9(m,2H),7.46-7.60(m,3H),7.76(s,1H).

[0229] Example 3.1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-yl] Synthesis of methyl[]-piperidine-4-carboxylate

[0230]

[0231] Ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate (462.8 g, 0.78 mol), EtOH (1.40 L, 3 times), water (0.92 L, 2 times), DCM (0.09 L, 0.2 times), and NaOH (116 g, 2.90 mol) were placed in a reactor. The reaction was carried out at an internal temperature of 60 °C for 2 hours and 20 minutes. The reaction was completed (1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate: N / D) as a result of the reaction IPC by HPLC. Therefore, the reactor was cooled to an internal temperature of 20 °C.

[0232] DCM (0.60 L, 1.3 times) was added to the reaction mixture, followed by slow dropwise addition of 6N HCl (0.50 L, 3.37 mol) over 1 hour and 45 minutes to acidify the solution to pH 0.98. MTBE (4.60 L, 10 times) was then added to induce crystallization. The mixture was cooled to an internal temperature of 5°C, aged for 45 minutes, filtered, washed twice with water (2.06 L, 5 times), washed once with MTBE (1.24 L, 3 times), and dried under nitrogen to synthesize the title compound (435.6 g, net yield 99%).

[0233] 1H NMR(400MHz,DMSO):1.56(d,6H),2.2(d,2H),2.59(t,2H),2.72(bs,1H),2.93(t,2H),3.25(bs,2H),3. 59(bs,2H),4.18(s,2H),4.95(m,1H),5.26(s,2H),6.95-6.99(m,2H),7.55-7.66(m,3H),7.72(s,1H).

[0234] Example 4.

[0235] 1-[1-Chloro-6-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperazine Crystallization of pyridine-4-carboxylate

[0236]

[0237] In Example 3, 5.10 kg (9.0 mol), EtOH (0.77 L, 2x), water (1.92 L, 5x), IPOAc (0.77 L, 2x), and NaOH (54.4 g, 1.36 mol) were placed in a reactor. The mixture was heated at an internal temperature of 45°C for 1 hour, then cooled to an internal temperature of 20°C. 6N HCl (290 ml) was added dropwise to the reaction mixture over 1 hour and 50 minutes to acidify the solution to pH 1.05. The mixture was then aged for 50 minutes and filtered. The filtered solid was washed twice with water (1.92 L, 5x) and once with MTBE (1.15 L, 3x), then dried under nitrogen to synthesize the title compound (368 g, 79% yield in GMP step).

[0238] 1 H NMR(400MHz,CD3OD):1.56(d,6H),2.2(d,2H),2.59(t,2H),2.72(bs,1H),2.93(t,2H),3.25(bs,2H),3 .59(bs,2H),4.18(s,2H),4.95(m,1H),5.26(s,2H),6.95-6.99(m,2H),7.55-7.66(m,3H),7.72(s,1H).

[0239] Experimental Example 1. Yield assessment of the reaction solvent in the synthesis of 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde

[0240] In the synthesis reaction of Example 1, the yield and purity of the reaction product were evaluated depending on the reaction solvent. The evaluation results are shown in Tables 1 and 2, respectively.

[0241] In Tables 1 and 2, “SG40” refers to “1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde”.

[0242] [Table 1]

[0243]

[0244] [Table 2]

[0245]

[0246] As shown in Table 1, it was confirmed that the impurity content increased from 2.6% to 5.3% in the synthesis reaction in DMF, while the impurity content was 0.4% in the synthesis reaction in DMA, thus inhibiting impurity formation.

[0247] Furthermore, as shown in Table 2, it has been confirmed that the purity of the products obtained by using DMA solvent in the synthetic reaction can also be improved.

[0248] Meanwhile, the evaluation results of the degree of impurity removal achieved by washing after the synthesis reaction in the above-mentioned DMF reaction solvent are shown in Table 3 below.

[0249] [Table 3]

[0250]

[0251] As shown in Table 3, when the synthesis reaction was carried out in DMF solvent, even after three washes of the reaction product, the impurity content only decreased from 4.91% to 4.58%. Therefore, it is confirmed that impurities cannot be easily removed by washing.

[0252] Therefore, it has been confirmed that DMA is the preferred reaction solvent in the synthesis reaction in terms of product yield and purity.

[0253] Evaluation of crystallization conditions for Example 2.1 - [1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate

[0254] To reduce the impurities in the final prepared 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate salt to below 0.10% and to restrict the residual amount of DMC solvent to 600 ppm, crystallization conditions were evaluated.

[0255] [Evaluation of Crystallization Solvents]

[0256] When the amount of DCM used in the crystallization process was increased from 0.1 times to 0.5 times, the product yield and purity were evaluated, and the results are shown in Table 4 below. The measurement results of the residual solvent in the product are shown in Table 5.

[0257] In Tables 4 and 5 below, “SG50” refers to “1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate salt”.

[0258] [Table 4]

[0259]

[0260] [Table 5]

[0261]

[0262] As shown in Table 4, it is confirmed that similar levels of yield and purity can be obtained when the amount of DCM is increased. As shown in Table 5, it is confirmed that when using 0.1 times the amount of DCM, it has a residual level of 400 ppm, while when using 0.2 times the amount of DCM, it has a residual level of 800 ppm.

[0263] Therefore, DCM concentrations of 0.1 times or less should be used. However, Table 4 shows no significant difference in purity when DCM is not used, thus confirming that crystallization may be preferred when DCM is not used.

[0264] [Assessment of the time required for adding hydrochloric acid]

[0265] It was confirmed that the particle shape depends on the timing of hydrochloric acid addition during crystallization. Crystals produced by adding hydrochloric acid over periods ranging from 10 to 60 minutes were compared. In Easymax, it was confirmed that adding hydrochloric acid dropwise over 30 minutes at a stirring speed of 500 rpm resulted in a uniform particle shape. Figure 1 ).

[0266] [Evaluation of hydrochloric acid addition temperature]

[0267] The purity and yield of the reaction product and the remaining solvent were evaluated by varying the temperature at which hydrochloric acid was added. The results are shown in Tables 6 and 7 below.

[0268] In Table 6, “SG70” refers to “1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate crystals”.

[0269] [Table 6]

[0270]

[0271] [Table 7]

[0272]

[0273] The above results confirm that, in terms of product purity and yield, the internal temperature of the reactor is preferably 20-25°C when hydrochloric acid is added dropwise.

[0274] [Evaluation of stirring speed]

[0275] The effect of stirring speed during crystallization was determined. Stirring speeds from 100 to 500 rpm were compared in Easymax. At lower stirring speeds, the resulting crystals precipitated at the bottom of the crystallizer. This confirms that lower stirring speeds, and consequently less smooth agitation, lead to the formation of non-uniform crystals. Figure 2 ).

Claims

1. A method of preparing a compound of the following formula 7, or a salt thereof, comprising: 1) a step of preparing a compound of formula 4 by coupling a compound of formula 2 with a compound of formula 3 in the presence of a dimethylacetamide solvent; 2) a step of preparing a compound of formula 6, or a salt thereof, by reacting a compound of formula 4 with a compound of formula 5 under reducing conditions; and 3) a step of converting an ester group of the compound of formula 6, or a salt thereof, to a carboxylic acid group to prepare a compound of formula 7, or a salt thereof: [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] [Formula 7] wherein R1 is hydrogen or substituted or unsubstituted alkyl, R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF3 or COCF3, R3 and R4 are each hydrogen, substituted or unsubstituted alkyl, or halogen, R5 is hydrogen, substituted or unsubstituted alkyl, or halogen, R6 is substituted or unsubstituted alkyl, X is N, Y is N, O or S, L is a leaving group, and m and n are each 0, 1, 2 or 3, and m + n > 0, wherein the substituted alkyl is an alkyl substituted with at least one selected from the group consisting of halogen, cyano, hydroxy, alkoxy, keto, unsubstituted sulfonyl and alkyl substituted sulfonyl.

2. The method according to claim 1, wherein R1 is C1-C4 substituted or unsubstituted alkyl, R2 is halogen, R3 and R4 are each hydrogen or C1-C4 substituted or unsubstituted alkyl, R5 is halogen, R6 is C1-C4 substituted or unsubstituted alkyl, X is N, Y is N, and L is a leaving group selected from the group consisting of chloro, bromo, iodo, mesylate, tosylate and triflate, wherein the substituted alkyl is an alkyl substituted with at least one selected from the group consisting of halogen, cyano, hydroxy, alkoxy, keto, unsubstituted sulfonyl and alkyl substituted sulfonyl.

3. The method according to claim 1, further comprising 4) a step of recrystallizing the compound of formula 7, or a salt thereof, under acidic conditions.

4. The method according to claim 3, wherein the content of dichloromethane solvent in a fraction containing the recrystallized compound of formula 7, or a salt thereof, is 600 ppm or less.

5. The method according to claim 3, wherein the recrystallization solvent comprises water, an ester solvent, an alcohol solvent or a mixed solvent thereof.

6. The method according to claim 5, wherein the recrystallization solvent comprises water, isopropyl acetate and ethanol.

7. The method according to claim 3, wherein the recrystallization step comprises adding an acid compound at a temperature of 0-25°C.

8. The method according to claim 3, wherein the recrystallization step comprises stirring at 100 to 500 rpm.

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