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

Abstract

The present invention relates to a novel process for preparing a compound represented by Formula 5 or a salt thereof as described in the specification, wherein the compound or salt can be used as a sphingosine-1-phosphate receptor agonist.

Description

Technical Field

[0001] Cross-reference to related applications

[0002] This application claims priority based on Korean Patent Application No. 10-2021-0048766, filed on April 14, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This invention relates to a novel method for synthesizing sphingosine-1-phosphate receptor agonists. Background Technology

[0005] Sphingosine-1-phosphate (S1P) is produced via the intracellular ceramide pathway, the initiating substance of which is generated through two pathways: de novo biosynthesis and 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-lysozyme and lysophospholipid phosphatase). S1P, produced by sphingosine phosphorylation induced by 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 high concentrations (100–1000 nM) in plasma in combination with other plasma proteins (including albumin), but in low concentrations in tissues.

[0006] S1P binds to the G protein-coupled receptor S1P and exhibits different biological functions. To date, five S1P receptor subtypes have been identified, namely S1P1 to S1P5, which are named endothelial differentiation gene (EDG) receptors 1, 5, 3, 6, and 8. These 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 associated with multiple sclerosis (MS), including inflammatory responses and repair processes. 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, if S1P1 receptors in lymphocytes are downregulated by S1P1 agonists, lymphocyte outflow from lymphoid tissues is prevented, thus reducing the infiltration of self-invasive lymphocytes that cause inflammation and tissue damage in the central nervous system (CNS). This leads to 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 S1P receptor agonists, Korean Patent Publication No. 10-2014-0104376 discloses a novel compound of Formula 1 as an effective S1P receptor agonist.

[0009] [Formula 1]

[0010]

[0011] In Equation 1,

[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 can be C, N, C-alkoxy, C-halogen, or C-CN.

[0016] Q is CH2O or

[0017] S is selected from the following residues:

[0018]

[0019] In the above structure,

[0020] m and n are 0, 1, 2, or 3.

[0021] R3 to R10 are each H, alkyl, halogen, haloalkyl, or alkoxyalkyl.

[0022] R11 is H,

[0023] R12 is OH or NH2.

[0024] In one specific embodiment of the 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 by the following reaction 1 (in reaction 1, "SG35" refers to "1-chloro-6-hydroxy-3,4-dihydro-naphth-2-carboxaldehyde").

[0025] [Reaction 1]

[0026]

[0027] In reaction 1, during the preparation of 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" had a viscous oil appearance and was carried out in subsequent processes as a crude substance after the reaction was completed without a separate purification process.

[0028] 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. Specifically, the removal of impurities such as the N2 isomer is not easy, therefore the purification of the intermediate is absolutely necessary. Summary of the Invention

[0029] Technical issues

[0030] Therefore, an object of the present invention is to provide a novel method suitable for producing Formula 5 compounds or salts thereof in high yield and high purity, said compounds or salts being usable as sphingosine-1-phosphate receptor agonists.

[0031] [Formula 5]

[0032]

[0033] In Equation 5,

[0034] R1 is hydrogen, or a substituted or unsubstituted alkyl group.

[0035] R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF3, or COCF3.

[0036] R3 and R4 are each hydrogen, substituted or unsubstituted alkyl groups, or halogens.

[0037] R5 is hydrogen, a substituted or unsubstituted alkyl group, or a halogen.

[0038] X is C or N.

[0039] Y is N, O, or S.

[0040] m and n are each 0, 1, 2 or 3, and m + n > 0.

[0041] Technical solution

[0042] In order to achieve the above goals,

[0043] One aspect of the present invention provides a method for preparing a compound of formula 5 or a salt thereof, the method comprising the following steps:

[0044] 1) The step of reacting compound 2 with compound 3 under reducing conditions to prepare compound 4 or a salt thereof; and

[0045] 2) The step of converting the ester group of the compound of formula 4 or its salt into a carboxylic acid group to prepare the compound of formula 5 or its salt:

[0046] [Equation 2]

[0047]

[0048] [Formula 3]

[0049]

[0050] [Formula 4]

[0051]

[0052] [Formula 5]

[0053]

[0054] In equations 2 to 5,

[0055] R1 is hydrogen or a substituted or unsubstituted alkyl group.

[0056] R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF3, or COCF3.

[0057] R3 and R4 are each hydrogen, substituted or unsubstituted alkyl groups, or halogens.

[0058] R5 is hydrogen, a substituted or unsubstituted alkyl group, or a halogen.

[0059] R6 is a substituted or unsubstituted alkyl group.

[0060] X is C or N.

[0061] Y is N, O, or S.

[0062] m and n are each 0, 1, 2 or 3, and m + n > 0.

[0063] When 'alkyl' is a substituted alkyl group, it may have one or more substituents, and each substituent may be independently selected from halogen, cyano, hydroxy, alkoxy, ketone, unsubstituted sulfonyl, and alkyl-substituted sulfonyl.

[0064] According to one embodiment of the present invention, R1 in the above formula can be hydrogen or a C1-C6 substituted or unsubstituted alkyl group, 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, and R5 can be F, Cl, Br, or I. Furthermore, R6 can be a C1-C4 substituted or unsubstituted alkyl group.

[0065] 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, and R5 can be Cl. In addition, R6 can be an ethyl group.

[0066] According to one embodiment of the present invention, Y can be N or O, and can satisfy m>0, n>0, and m+n=3 or 4.

[0067] According to another embodiment of the present invention, Y can be N, and m and n can each be 2.

[0068] In this invention, when referring to "a compound or a salt thereof", the term "salt thereof" refers to a pharmaceutically acceptable salt of the compound.

[0069] 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 included from sulfuric acid, methanesulfonic acid, or hydrohalic acids.

[0070] In one embodiment of the present invention, the salt of the compound of formula 4 and the salt of the compound of formula 5 may be the hydrochloride salt of the compound of formula 4 and the hydrochloride salt of the compound of formula 5, respectively.

[0071] The invention will be described in more detail below.

[0072] In this invention, in step 1), the compound of formula 4 or its salt is prepared by reacting the compound of formula 2 with the compound of formula 3 under reducing conditions.

[0073] When the compound of Formula 2 is mixed with the compound of Formula 3 under reducing conditions, a bond is formed with the heteroatom represented by Y of the compound of Formula 3 at the carbonyl (C=O) functional group of Formula 2, and the carbonyl functional group is reduced to prepare the compound of Formula 4, but the mechanism of the present invention is not limited thereto.

[0074] In one embodiment of the invention, the compound of formula 4 is prepared by reacting the compound of formula 2 with the compound of formula 3 in the presence of a reducing agent.

[0075] The reducing agent may be, for example, but not limited to, at least one or more selected from sodium triacetoxyborohydride (NaBH(OAc)3), sodium borohydride (NaBH4), and sodium cyanoborohydride (NaBH3CN).

[0076] In another embodiment of the invention, the compound of Formula 3 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 equivalent ratio can be 1:4 to 4:1, 1:3 to 3:1, or 1:2 to 2:1.

[0077] In another embodiment of the invention, the compound of formula 3 and NaBH(OAc)3 can be used in an equivalent ratio of 1.5-1.8:1.5-1.8.

[0078] In one embodiment of the invention, a pharmaceutically acceptable salt of the compound of formula 4 can be obtained according to the conditions used in step 1) to obtain the compound of formula 4.

[0079] In another embodiment of the invention, the hydrochloride salt of the compound of formula 4 can be prepared by crystallization after the reaction between the compound of formula 2 and the compound of formula 3 is completed in step 1).

[0080] In one embodiment of the present invention, the crude product of compound 4 prepared by the reaction between compound 2 and compound 3 in step 1) can exhibit a viscous oily appearance. Therefore, after the reaction is completed, a crystallization step can be further performed to obtain compound 4 or its salt.

[0081] In one embodiment of the present invention, the crude product of Formula 4 compound can be crystallized under acidic conditions.

[0082] The acidic conditions can be, for example, conditions below pH 3.0. Specifically, the crystallization can be carried out by adding an acidic compound to change the pH of the solution containing the compound of formula 4 to 1.0 to 3.0.

[0083] As the acid compound used to form acidic conditions, any known acid compound can be used, as long as it does not damage the structure and physical properties of the compound of formula 4, and the type of acid compound is not limited.

[0084] According to one embodiment of the invention, the crystallization can be carried out by injecting hydrochloric acid (HCl) into a crude reaction product containing a compound of formula 4.

[0085] According to another embodiment of the invention, hydrochloric acid with a concentration of 1N to 8N can be used. Preferably, hydrochloric acid with a concentration of 3N to 6N can be used. If the concentration of hydrochloric acid is too high, there may be problems such as insufficient water usage, poor removal rate of B complex, and inability to filter.

[0086] According to another embodiment of the invention, the acid compound can be added in multiple portions to the crude reaction product containing the compound of formula 4. The acid compound required for crystallization can be added dropwise all at once for crystallization, but a portion of the acid compound required for crystallization can be added dropwise to induce preliminary crystal growth within a certain time, and then the remaining acid compound can be added dropwise to show the effect of improving the yield, purity and filterability of the obtained compound of formula 4.

[0087] According to another embodiment of the invention, 3 equivalents of hydrochloric acid can be injected into the crude reaction product containing the compound of formula 4 to induce preliminary crystal growth, and then an additional 1 equivalent of hydrochloric acid can be injected, and the mixture can be filtered to obtain hydrochloride crystals of the compound of formula 4.

[0088] According to one embodiment of the invention, crystallization can be carried out at a temperature below 30°C, for example, at a temperature between 0°C and 30°C, in terms of the purity, yield and filterability of the resulting crystals, but the crystallization temperature is not limited thereto.

[0089] According to another embodiment of the invention, the crystallization can be carried out at a temperature of 20°C to 30°C.

[0090] According to one embodiment of the present invention, the crystallization can be carried out using an antisolvent method.

[0091] 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) and dichloromethane (DCM); and non-polar organic solvents, such as n-hexane.

[0092] According to another embodiment of the present invention, the crystallization solvent can be a single ether solvent.

[0093] In this invention, "single solvent" means adding only one type of solvent for crystallizing the compound of formula 4. It will be apparent to those skilled in the art that "single solvent" does not preclude crystallization after the reaction for preparing the compound of formula 4 without distilling the reaction solvent to leave it in the reactor, and the addition of a single solvent for crystallization.

[0094] 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 of a certain type is added. For example, heterogeneous solvents 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., not included at all) of the total solvent volume added for crystallization can be considered as a single solvent being used.

[0095] 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.

[0096] According to one embodiment of the present invention, the ether-based single solvent may be methyl tert-butyl ether (MTBE).

[0097] 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 said solvent.

[0098] According to another embodiment of the invention, the amount of crystallization solvent used can be 4 to 10 times that of the target solution in terms of crystallization yield, process time, and process cost.

[0099] According to another embodiment of the invention, the crystallization can be carried out by adding 6 to 8 times, specifically 8 times, MTBE to the crude reaction product containing the compound of formula 4.

[0100] In this invention, in step 2), the compound of formula 5 or its salt is prepared by converting the ester group of the compound of formula 4 or its salt obtained above into a carboxylic acid group.

[0101] For the compound of formula 4 in step 2), the crude reaction product obtained as is by completing the reaction in step 1) without purification and crystallization, or the reaction product that has been purified and / or crystallized, can be used, but is not limited to.

[0102] In one embodiment of the invention, a pharmaceutically acceptable salt of the compound of formula 4 obtained by crystallization in step 1), such as the hydrochloride salt of the compound of formula 4, can be used as a reactant in step 2).

[0103] In one embodiment of the present invention, the ester group can be converted into a carboxylic acid group by reacting a compound of formula 4 or its salt with water, an alcohol solvent or a mixture thereof in the presence of a base.

[0104] Examples of alcohol solvents that can be used for carboxylic acid group conversion may include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.

[0105] In one embodiment of the present invention, when methanol is used for the conversion reaction of carboxyl groups, methyl ester-type impurities may be generated by the remaining methanol in the subsequent API process. Therefore, ethanol can be used to prepare compound 5 or its salt.

[0106] In another embodiment of the invention, if ethanol is used as the reaction solvent for carboxyl group conversion, ethanol can be used alone. Therefore, THF, which is used in the case of methanol, is not used together, and the THF removal step can be omitted, thereby achieving the advantage of simplified process.

[0107] In one embodiment of the present invention, the base that can be used for the conversion reaction of the carboxyl group can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.

[0108] 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.

[0109] In another embodiment of the invention, the compound of formula 4 or its salt can be mixed with ethanol in the presence of NaOH, and the compound of formula 5 or its salt can be prepared at a temperature of 40°C to 60°C.

[0110] 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.

[0111] In this invention, the method may further include the step of recrystallizing the compound of formula 5 or its salt obtained in step 2).

[0112] The recrystallization step can be performed once or multiple times to greatly improve the yield and purity of the product.

[0113] In one embodiment of the present invention, if the recrystallization step is repeated more than three times, there may be an increase in impurities during mass production. It is preferable to perform the recrystallization step once or twice.

[0114] In another embodiment of the invention, the recrystallization step can be performed twice, and the first recrystallization and the second recrystallization can use the same solvent.

[0115] The solvent added for recrystallization can be, but is not limited to, one or more of the following: water; polar organic solvents such as methyl tert-butyl ether (MTBE), methanol (MeOH), ethanol (EtOH), isopropanol (IPA), ethyl acetate (EA), dichloromethane (DCM), and tetrahydrofuran (THF); and nonpolar organic solvents such as n-hexane and xylene.

[0116] In one embodiment of the invention, the recrystallization step may be performed once or twice using a mixed solvent of DCM and EtOAc.

[0117] In another embodiment of the invention, the recrystallization step may be performed twice using xylene, THF / H2O, DCM / IPA, or DCM-MTBE (antisolvent).

[0118] The compounds prepared according to the present invention or their salts can be used as sphingosine-1-phosphate receptor agonists, but in addition to sphingosine-1-phosphate receptor agonists, the compounds prepared according to the present invention can also be used for other purposes, and the uses of the present invention are not limited to sphingosine-1-phosphate receptor agonists.

[0119] Beneficial effects

[0120] By using the preparation method of the present invention, it is possible to achieve the effect of producing compound 5 or its salts in large quantities with high yield and purity. Detailed Implementation

[0121] The embodiments described below in more detail with reference to examples are provided to aid in understanding the invention. However, embodiments of the invention may be implemented in different forms and should not be considered as limiting oneself to the embodiments described herein. These embodiments of the invention are provided to provide a more complete explanation of the invention to those skilled in the art.

[0122] Preparation Example 1 - Synthesis of methyl 1,3-chloro-1-isopropyl-1H-indazole-5-carboxylate

[0123]

[0124] Methyl 1H-indazole-5-carboxylate (6.2 kg, 35.19 mol), N-chlorosuccinimide (NCS, 5.64 kg, 42.2 mol), and dimethylformamide (DMF, 31.0 ml, 5 times) were injected into the reactor to raise the internal temperature of the reaction mixture to 75 °C, and then reacted for 1.5 hours.

[0125] The reaction was performed by ion-pair chromatography (IPC) by HPLC. After the reaction (methyl 1H-indazole-5-carboxylate: N / D) was completed, the external temperature was set to 0°C and cooled for 60 minutes. While maintaining the internal temperature of the reactor at 50°C, K₂CO₃ (10.7 kg, 77.4 mol) and 2-iodopropane (8.98 kg, 52.8 mol) were added, and alkylation was carried out at 60°C for 120 minutes.

[0126] As a result of the IPC reaction by HPLC, the remaining 19.3% of methyl 3-chloro-1H-indazole-5-carboxylate was further injected twice with K₂CO₃ (2.14 kg, 15.5 mol) and 2-iodopropane (1.80 kg, 10.6 mol). The remaining 2.4% of methyl 3-chloro-1H-indazole-5-carboxylate was further injected with K₂CO₃ (1.08 kg, 7.75 mol) and 2-iodopropane (0.9 kg, 5.3 mol), terminating the reaction (1% > methyl 3-chloro-1H-indazole-5-carboxylate).

[0127] The reaction mixture was cooled to 30°C, and water (43.4 L) and EtOAc (43.4 L) were added, followed by stirring for 30 minutes. Layer separation was performed, and the aqueous layer was removed. Water (31.0 L) was added, and the organic layer was washed separately. EtOAc was removed by vacuum distillation, and EtOH (24.8 L) was added, raising the temperature to 40°C. The product was heated until a clear solution was obtained. The reactor was cooled, and the internal temperature was maintained at 20°C. Water (24.8 L) was then slowly added dropwise to produce crystals. The solid thus formed was aged for 30 minutes, then filtered, washed twice with water (31.0 L), and dried under nitrogen to give the title compound (6.56 kg, net yield 64.9%).

[0128] 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).

[0129] Preparation Examples 1-2. Synthesis of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol

[0130]

[0131] THF (34.2 L, 6-fold) and methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate (Example 1-1, 5.7 kg, 22.6 mol) were injected into the reactor to raise the internal temperature to 60 °C. NaBH4 (1.68 kg, 44.4 mol) was added to the reaction mixture, and MeOH (5.7 L, 1-fold) was slowly added dropwise over 80 minutes, followed by a 30-minute reaction. At 90-minute intervals, NaBH4 (0.44 kg, 11.6 mol) was added, and MeOH (1.69 L, 0.3-fold) was injected twice, with each injection lasting 30 minutes. IPC was performed using HPLC.

[0132] The remaining 14.3% of methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate was added, with the additional addition of NaBH4 (0.22 kg, 5.8 mol), and the reaction was carried out for 120 minutes. The remaining 2.5% of methyl 3-chloro-1-isopropyl-1H-indazole-5-carboxylate was added, the reaction was terminated, and the result was cooled to an internal temperature of 10 °C.

[0133] To remove the B-complex (generated by the combination of NaBH4 and boron with alcohol (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol) and the remaining NaBH4, 3N HCl (39.3 kg) was slowly injected over 60 minutes to maintain the pH of the reaction solution at 3.0, and the solvent was removed by vacuum distillation.

[0134] DCM (28.5 L) and water (57.0 L) were injected into the residue for layer separation. The aqueous layer was removed, and the residue was washed with water (42.8 L) and subjected to vacuum distillation to give the title compound (4.32 kg, net yield 85%).

[0135] 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).

[0136] Preparation Example 1 - Synthesis of 3,5-bromomethyl-3-chloro-1-isopropyl-1H-indazole

[0137]

[0138] MTBE (43.3 L, 8 times) and (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol (Examples 1-2, 4.32 kg, 19.3 mol) were injected into the reactor, and the internal temperature was cooled to 0 °C. PBr3 (3.64 kg, 13.5 mol) was slowly injected into the reaction mixture over 90 minutes, and the reaction proceeded for 180 minutes.

[0139] The reaction was completed using IPC by HPLC (Examples 1-2: N / D). 1.5N NaOH (34.7 L) was slowly injected over 60 minutes, followed by stirring for 30 minutes to terminate the reaction. Water (21.7 L) was added to the reaction mixture, and the mixture was stirred for 10 minutes and subjected to layer separation. The aqueous layer was removed, and the mixture was washed with an additional 17.3 L of water. The organic layer was then distilled under reduced pressure to synthesize the title compound (4.97 g, net yield 90.0%).

[0140] 1 H NMR (400MHz, CDCl3): 1.53 (d, 6H), 4.7 (s, 2H), 4.88 (m, 1H), 7.51-7.6 (m, 2H), 7.68 (s, 1H).

[0141] Preparation Example 1 - Synthesis of 4,6-hydroxy-3,4-dihydro-2H-naphth-1-one

[0142]

[0143] An aqueous solution of HBr (HBr in H2O) (47.2 L, 10 times) and 6-methoxy-3,4-dihydro-2H-naphth-1-one (4.72 kg, 26.8 mol) were injected into the reactor and refluxed at an external temperature of 100 °C for 16.5 hours.

[0144] The reaction (6-methoxy-3,4-dihydro-2H-naphth-1-one: 0.72%) was completed by IPC using HPLC. The internal temperature was cooled to 10°C, and the resulting solid was filtered off. The title compound (4.22 kg, net yield 92.9%) was synthesized by washing twice with water (23.6 L) and drying under nitrogen.

[0145] 1 H NMR (400MHz, DMSO): 1.94-1.98(m,2H),2.48(m,2H),2.81(t,2H),6.62(d,1H),6.68-6.70(m,1H),7.72(d,1H).

[0146] Preparation Examples 1-5. Synthesis of 5-keto-5,6,7,8-tetrahydronaphthalene-2-yl acetate

[0147]

[0148] 6-Hydroxy-3,4-dihydro-2H-naphth-1-one (4.22 kg, 26.0 mol) and DCM (20.2 L, 5 times) were injected into the reactor, and the internal temperature was cooled to 0 °C. AcCl (2.14 kg, 27.3 mol) was added dropwise over 15 minutes at below 10 °C. After the injection was complete, TEA (3.02 kg, 29.8 mol) was added dropwise at below 10 °C, and the reaction proceeded.

[0149] The internal temperature was raised to 20°C, and the reaction was carried out for 1 hour. Then, the reaction was completed by IPC (6-hydroxy-3,4-dihydro-2H-naphth-1-one: 0.6%) using HPLC. Water (20.2 L) was added to the reaction product, the mixture was stirred for 10 minutes, and layer separation was performed. The aqueous layer was removed, and the mixture was washed with an additional 20.2 L of water. After vacuum distillation, the title compound was synthesized (4.56 kg, net yield 90.0%).

[0150] 1 H NMR (400MHz, CDCl3): 2.10 (m, 2H), 2.30 (s, 3H), 2.60 (t, 2H), 2.95 (t, 2H), 7.00 (s, 1H), 7.05 (d, 1H), 8.05 (d, 1H).

[0151] Preparation Examples 1-6. Synthesis of 5-chloro-6-formyl-7,8-dihydronaphthalene-2-yl ester of acetate

[0152] POCl3 (10.26 kg, 66.9 mol) was injected into the reactor, and the internal temperature was cooled to 0°C. DMF (8.16 kg, 111.6 mol) was slowly added dropwise below 25°C, followed by stirring for 60 minutes. 5-Keto-5,6,7,8-Tetrahydronaphthalene-2-yl acetate (4.56 kg, 22.3 mol) diluted in DMF (1.64 kg, 22.4 mol) was then slowly added dropwise to the reactor below 30°C. After the addition was complete, the reaction proceeded for 4 hours.

[0153] The reaction (5-keto-5,6,7,8-tetrahydronaphthalene-2-yl acetate: 0.4%) was completed by IPC using HPLC, and the reaction was terminated. Water (45.6 L, 10 times) was injected into another reactor, and the internal temperature was cooled to 0 °C. The reaction mixture was diluted in EtOAc (31.0 L, 7 times) by slow dropwise addition, ensuring that the temperature did not rise above 25 °C to decompose the remaining POCl3, thereby quenching the reaction.

[0154] Layer separation was performed, and the organic layer was collected in another reactor. The aqueous layer was then extracted with EtOAc (13.7 L, 3-fold), the aqueous layer was removed, and the remaining layer was injected into the reactor containing the separated first organic layer. The collected organic layer was washed with water (22.8 L, 5-fold), distilled under reduced pressure, and the title compound was synthesized (4.74 kg, net yield 85.0%).

[0155] 1 H NMR (500MHz, CDCl3): 2.30 (s, 3H), 2.65 (t, 2H), 2.85 (t, 2H), 7.00 (s, 1H), 7.05 (m, 1H), 7.90 (d, 1H), 10.40 (s, 1H).

[0156] Preparation Examples 1-7: Synthesis of 1-chloro-6-hydroxy-3,4-dihydronaphthalene-2-carboxaldehyde

[0157]

[0158] MeOH (22.8 L, 5 times) and K₂CO₃ (2.52 kg, 18.2 mol) were injected into the reactor, and the reaction was carried out at an internal temperature below 30 °C for 2 hours. IPC was performed by HPLC. Since there was a remainder of 5-chloro-6-formyl-7,8-dihydronaphthyl-2-yl acetate (5-chloro-6-formyl-7,8-dihydronaphthyl-2-yl acetate: 2.7%), the reaction was carried out for an additional hour.

[0159] The reaction was completed by IPC analysis using HPLC (5-chloro-6-formyl-7,8-dihydronaphthyl-2-yl acetate: 0.75%). The internal temperature was cooled to 5°C, and 3N HCl (18.9 L, 56.7 mol) and water (23.7 L, 5 times) were added dropwise to induce crystallization. The resulting crystals were aged for 60 minutes, filtered, washed with water (23.7 L, 5 times), and dried under nitrogen to synthesize SG35 (4.98 kg, net yield of 81.3% over 4 steps).

[0160] 1 H NMR (400MHz, DMSO): 2.48-2.52(m,4H),6.71(s,1H),6.77(d,1H),7.66(d,1H),10.20(s,1H),10.28(s,1H).

[0161] Example 1. 1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde Synthesis

[0162]

[0163] 5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole (Preparation Examples 1-3, 4.96 kg, 17.2 mol), 1-chloro-6-hydroxy-3,4-dihydronaphthyl-2-carboxaldehyde (Preparation Examples 1-7, 3.56 kg, 17.1 mol), K2CO3 (3.62 kg, 26.2 mol), and DMF (13.1 L, 4 times) were injected into the reactor, and the reaction was carried out at an internal temperature of 30 °C for 4 hours and 50 minutes.

[0164] After IPC was performed by HPLC and the reaction (1-chloro-6-hydroxy-3,4-dihydronaphthalene-2-carboxaldehyde: 0.06%) was completed, the internal temperature was cooled to 10°C. A mixture of EtOH (13.1 L, 4-fold) and water (32.6 L, 10-fold) was slowly injected into the reaction mixture to induce crystallization. After injection, the internal temperature was cooled to 0°C, aged for 1 hour, and the resulting solid was filtered off. The filtered solid was washed with water (16.4 L) and n-hexane (16.3 L) and dried under nitrogen. After drying, the residual moisture content was determined using a K / F analyzer (moisture content: 0.20%). Finally, the title compound was synthesized (6.36 kg, net yield 89.7%).

[0165] 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).

[0166] 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

[0167]

[0168] 1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde (4.9 kg, 11.8 mol), triethylamine (TEA, 1.2 kg, 11.8 mol), DCM (19.6 L, 4 times), MTBE (9.8 L, 2 times), and ethyl isoperidolate (2.3 kg, 14.8 mol) were injected into the reactor. After stirring for 30 minutes, NaBH(OAc)3 (3.90 kg, 18.4 mol) was added, and the reaction was allowed to proceed for 2 hours.

[0169] The reaction was carried out by HPLC using IPC (1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde: 0.08%). After cooling the internal temperature to 10°C, 12.3 kg of 3 N HCl (3 equivalents) was added dropwise, and the mixture was stirred for 30 minutes. Then, another 4.1 kg of 3 N HCl (1 equivalent) was added to proceed with crystallization.

[0170] MTBE (29.5 L, 6 times) was injected into the reaction mixture, the internal temperature was cooled to 0 °C, and the mixture was aged for 1 hour, followed by filtration. The filtered solid was washed once with water (24.5 L, 5 times), once with water (14.7 L, 3 times), once with MTBE (24.5 L, 5 times), and once with MTBE (14.7 L, 3 times). The solid was then dried under nitrogen to synthesize the title compound (7.80 kg, net yield 90.0%).

[0171] 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).

[0172] 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

[0173]

[0174] Ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate (6.3 kg, 10.6 mol), EtOH (31.6 L, 5 times), water (6.3 L, 1 times), and NaOH (1.6 kg, 40.0 mol) were introduced into the reactor. The reaction was carried out at an internal temperature of 40 °C for 5 hours and 20 minutes. The reaction was completed (ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate: 0.05%) as a result of IPC analysis by HPLC, and the internal temperature was cooled to 20 °C.

[0175] DCM (6.3 L, 1x) was injected into the reaction mixture, and 6N HCl (7.75 kg, 4 equivalents) was slowly added dropwise over 30 minutes to acidify the solution to pH 2.5. Then MTBE (63.0 L, 10x) was injected to proceed with crystallization.

[0176] The internal temperature was cooled to 5°C, aged for 1 hour, aged and filtered, washed twice with water (31.5L, 5 times), washed once with MTBE (18.9L, 3 times), and dried with nitrogen to synthesize the title compound (5.10 kg, yield 85.0%).

[0177] 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).

[0178] Example 4.

[0179] 1-[1-Chloro-6-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperazine First recrystallization of pyridine-4-carboxylate

[0180]

[0181] Add 5.10 kg (9.0 mol), EtOH (25.5 L, 5 times), water (12.75 L, 2.5 times), and NaOH (0.70 kg, 18.0 mol) from Example 3 to the reactor. Heat at an internal temperature of 40°C for 30 minutes, then cool to 20°C. Inject DCM (5.1 L, 1 times) and EtOAc (5.1 L, 1 times) into the reaction mixture, check for clarity, and microfilter for transfer to another reactor. Add 6N HCl (4.1 kg, 2.5 times) dropwise to the reaction mixture over 90 minutes to acidify the solution to pH 2.5, cool to an internal temperature of 0°C, and then crystallize. Aging for approximately 1 hour and then filtering. The product was washed twice with water (25.5 L, 5 times) and once with MTBE (15.3 L, 3 times), and then dried with nitrogen to synthesize the title compound (4.13 kg, yield 81.0%).

[0182] 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).

[0183] Example 5.

[0184] 1-[1-Chloro-6-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperazine Second recrystallization of pyridine-4-carboxylate

[0185]

[0186] The reactor was charged with 4.13 kg (7.3 mol), EtOH (21.7 L, 5 times), water (10.9 L, 2.5 times), and NaOH (0.65 kg, 16.3 mol) from Example 4. The mixture was heated at an internal temperature of 40°C for 30 minutes, then cooled to 20°C. DCM (4.4 L, 1 times) and EtOAc (4.4 L, 1 times) were added to the reaction mixture, the mixture was checked for clarity, and microfiltered for transfer to another reactor. 6N HCl (3.5 kg, 2.5 equivalents) was slowly added dropwise to the reaction mixture over 30 minutes to acidify the solution to pH 2.1. The solution was then cooled to 0°C, and crystallization was carried out. After aging for about 1 hour, the mixture was filtered, washed twice with water (21.7 L, 5 times) and once with MTBE (13.0 L, 3 times), and dried with nitrogen to synthesize the title compound (2.2 kg, yield: 43.1% from Example 3).

[0187] 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).

[0188] Experimental Example 1.

[0189] Yield assessment based on crystallization conditions of ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]piperidine-4-carboxylate hydrochloride

[0190] It was confirmed that during the synthesis of Example 2, after the reduction synthesis reaction between 1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde and ethyl isoperidolate, and during crystallization under acidic conditions using 3N HCl and a mixed solvent of MTBE and DCM, the removal rate of impurities such as N2 isomers caused by self-reduction in the reaction mixture was less than 0.3%.

[0191] [Based on the assessment of hydrochloric acid concentration]

[0192] Therefore, during the crystallization process under acidic conditions, the purity and yield of the product were evaluated based on the acid concentration, crystallization temperature, and crystallization solvent. The results are shown in Tables 1 and 2 below.

[0193] First, the crystallization yield based on the amount of MTBE was measured under acidic conditions using 6N hydrochloric acid, and the results are shown in Table 1 below.

[0194] [Table 1]

[0195]

[0196] As shown in Table 1 above, after acidification with 6N HCl and treatment with MTBE as the antisolvent, the purity decreased with increasing MTBE dosage. Furthermore, the filtration performance was generally poor, and these results are believed to be due to insufficient water usage caused by the use of 6N HCl, resulting in ineffective removal of the borane complex.

[0197] [Based on the assessment of solvent usage]

[0198] Next, the crystallization yield based on the amount of MTBE was measured under acidic conditions using 3N HCl, and the results are shown in Table 2 below.

[0199] In Table 2, “SG50” means “ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylic acid hydrochloride”.

[0200] [Table 2]

[0201]

[0202] Table 2 above shows that when crystallization was first examined based on the amount of 3N HCl used, crystallization increased with increasing dosage. Using 5 equivalents, the remaining ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthyl-2-ylmethyl]-piperidine-4-carboxylate hydrochloride (SG50) in the mother liquor was at a level of 4%, and most of it had crystallized (entry 3). Furthermore, using amounts exceeding 5 equivalents showed little change, confirming the effectiveness of using 5 equivalents of 3N HCl. Additionally, based on experimental results regarding MTBE dosage, using 10 times the amount showed optimal results (entry 3). Hexane, heptane, etc., were also used as co-solvents for crystallization.

[0203] [Based on the assessment of the added evaporation process and solvent composition]

[0204] [Table 3]

[0205]

[0206] As shown in Table 3 above, adding an evaporation step after acidification to reduce the amount of crystallization solvent and improve filterability proved to be ineffective, with no significant advantage in terms of yield (items 2, 3). This is believed to be due to the various salts (including borane complexes) present in the post-reaction mixture inhibiting filtration. Crystallization following layer separation of the acidified DCM layer (items 4, 5, 6) improved filterability, but a problem of product (SG50) loss into the aqueous layer was discovered, confirming the effectiveness of applying a method of layer separation followed by acidification. This reduced loss into the aqueous layer and allowed crystallization at a yield of 85%, similar to conventional yields.

[0207] [Evaluation based on crystallization method - 1]

[0208] Based on solvent screening of ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate hydrochloride, it was confirmed that both MeOH and DCM exhibited high solubility. Therefore, after the synthesis of ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate, in order to remove the N2 isomer of ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate hydrochloride using MeOH and DCM solvents, crystallization was performed after purification with EtOAc, and the results are shown in Table 4 below.

[0209] In Table 4 below, "SG20" represents "5-bromomethyl-3-chloro-1-isopropyl-1H-indazole".

[0210] [Table 4]

[0211]

[0212]

[0213] As shown in Table 4, crystallization was examined by dissolving DCM, which showed good solubility as a test result, followed by acidification and injection of an antisolvent. In most cases, a removal efficiency of 50% of the N2 isomer was observed, but aggregation was prone to occur, and problems with particle coating on the reactor walls were observed. As a result of confirming the removal efficiency using MeOH instead of DCM (Entry 8) or using a mixture of THF, MeOH, or acetonitrile as a cosolvent (Entries 9, 11, 12), higher removal efficiency was observed when using acetonitrile as a cosolvent, but losses due to the formation of micronized products (SG50) (Entry 12) were confirmed.

[0214] Based on the results, the crystallization process of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride was carried out without purification.

[0215] [Evaluation based on crystallization method - 2]

[0216] Based on the results, the yield of the solvent was evaluated when crystallization was carried out without purification, and the results are shown in Table 5 below.

[0217] In Table 5 below, “SG40” means “1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carboxaldehyde”.

[0218] [Table 5]

[0219]

[0220] As shown in Table 5, to verify the removal effect of crystallization on N2 isomers, the optimal type and amount of solvent were selected by comparing the HPLC purity and net yield of the crystallized N2 isomers with those of the initial N2 isomers. Under the same conditions, it was confirmed that if MTBE was used as the antisolvent, the net yield increased with increasing antisolvent dosage (items 2, 3, 4). Furthermore, it was confirmed that if the antisolvent dosage was increased by 8 times, the high removal efficiency of N2 isomers reached 60%, and a high yield of over 90% was achieved (item 2).

[0221] Furthermore, when MTBE and n-hexane or water are used as co-solvents (items 5, 7), or when EtOH, EtOAc, n-hexane, etc. are mixed and used as antisolvents, poor filterability and reduced net yield have been demonstrated, or no significant advantage has been shown in the removal of N2 isomers (items 8, 9, 10, 11).

[0222] The above experiments confirmed that using 8 times the amount of MTBE as a single solvent is effective during the crystallization process (Item 2).

[0223] [Based on the assessment of acid concentration and dosage]

[0224] After confirming the crystallization properties after injecting 3 equivalents of 3N HCl, the confirmed results regarding the tendency of the HCl solution used for acidification, such as concentration and amount, temperature, etc., are shown in Table 6 below.

[0225] [Table 6]

[0226]

[0227]

[0228] As shown in Table 6, purity and filterability tend to increase with decreasing HCl dosage (items 1, 2, 3) and concentration (items 4, 5, 6), but the differences are not significant. Meanwhile, at the crystallization temperature, it can be observed that filterability is improved when acidification is performed at room temperature or 30°C compared to acidification at lower temperatures (items 7, 8, 9). Therefore, it is believed that injecting HCl at low temperatures to suppress heating during solution acidification may worsen filterability.

[0229] Furthermore, it was confirmed that stopping the addition of HCl after the initial crystals were produced and then injecting the remaining equivalent to allow the crystals to grow sufficiently was effective in improving filterability (Item 12). Based on experimental results obtained by acidifying only at a scale of 5 g at room temperature to confirm reproducibility, the effect on improving filterability decreased. Therefore, it was confirmed that the method of providing initial crystals for growth time while simultaneously acidifying at room temperature, as an additional application, can improve purity while reproducing the improvement in filterability very well.

[0230] Experimental Example 2. Evaluation of the yield based on the amount of reactants and reducing agent used in the synthesis of ethyl 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate.

[0231] In the synthesis of ethyl isopiridine-4-carboxylate, the yield was evaluated based on the mixing ratio of ethyl isopiridine to reducing agent (NaBH(OAc)3), and the results are shown in Table 7 below.

[0232] In Table 7, "amine" refers to "ethyl isoperidolate".

[0233] [Table 7]

[0234]

[0235] As shown in Table 7, it can be confirmed that as the equivalent of ethyl isoperidolate increases, the impurities generated by self-reduction decrease, and as the equivalent of NaBH(OAc)3 decreases, the total purity of the reaction product (SG50) tends to increase. A series of experiments confirmed that excellent yields were achieved when the amount of TEA was 1-3 equivalents, the amount of ethyl isoperidolate was 1.23-1.5 equivalents, and the amount of NaBH(OAc)3 was 1.5-1.8 equivalents.

[0236] Experimental Example 3. Evaluation of yield based on recrystallization of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate salt

[0237] The recrystallization yields of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate salts obtained by different methods were evaluated, and the results are shown in Table 8 below.

[0238] In Table 8, “SG65” means “1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylate salt before recrystallization (Example 3)”.

[0239] [Table 8]

[0240]

[0241] As shown in Table 8, it was confirmed that the purity of the product could be improved by repeated recrystallization, with a total recovery rate of over 70%, demonstrating excellent yield. As mentioned above, it was confirmed that impurities could be removed to a level below 0.15% by repeating recrystallization twice under the same conditions.

Claims

1. A method for preparing the hydrochloride salt of compound formula 5, the method comprising the following steps: 1) The step of reacting compound 2 with compound 3 under reducing conditions to prepare the hydrochloride salt of compound 4; as well as 2) The step of converting the ester group of the hydrochloride salt of compound 4 into a carboxylic acid group to prepare the hydrochloride salt of compound 5: The product obtained by crystallizing the crude product of the compound of formula 4 prepared in step 1) under hydrochloric acid conditions at a temperature of 20°C to 30°C is used as the reactant in step 2). [Equation 2] [Formula 3] [Formula 4] [Formula 5] In equations 2 to 5, R1 is hydrogen, or a substituted or unsubstituted alkyl group. R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF3, or COCF3. R3 and R4 are each hydrogen, substituted or unsubstituted alkyl groups, or halogens. R5 is hydrogen, a substituted or unsubstituted alkyl group, or a halogen. R6 is a substituted or unsubstituted alkyl group. X is C or N. Y is N, O, or S. m and n are each 0, 1, or 2, and m + n > 0. The substituents are independently selected from halogen, cyano, hydroxy, alkoxy, ketone, unsubstituted sulfonyl, and alkyl-substituted sulfonyl groups. Step 2) involves reacting the hydrochloride salt of compound 4 with water, an alcohol solvent, or a mixture thereof to convert the ester group into a carboxylic acid group. The alcohol solvents mentioned are selected from ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.

2. The method according to claim 1, wherein R1 is a C1-C4 substituted or unsubstituted alkyl group. R2 is a halogen. R3 and R4 are each hydrogen, or C1-C4 substituted or unsubstituted alkyl groups. R5 is a halogen. R6 is a C1-C4 substituted or unsubstituted alkyl group. X is N, Y is N, m>0, n>0, and m+n=3 or 4.

3. The method according to claim 1, wherein In step 1), the hydrochloride salt of compound 4 is obtained, and In step 2), the hydrochloride salt of compound 5 is obtained, thereby preparing the hydrochloride salt of compound 5.

4. The method according to claim 3, wherein the reducing agent used for the reduction conditions in step 1) is at least one or more selected from sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride.

5. The method according to claim 4, wherein the compound of formula 3 and the reducing agent are used in step 1) in an equivalent ratio of 1:2 to 2:

1.

6. The method of claim 1, wherein step 1) is performed without the use of evaporation.

7. The method according to claim 1, wherein the product obtained by crystallizing the crude product of the compound of formula 4 prepared in step 1) with a single ether solvent is used as the reactant in step 2).

8. The method according to claim 1, further comprising step 3) recrystallizing the hydrochloride salt of the compound of formula 5 once or multiple times.

9. The method of claim 8, wherein the recrystallization step is performed twice using the same solvent.

10. The method according to claim 1, wherein the alcohol solvent is ethanol.

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