Method for preparing high-purity 1-(1-(2-benzylphenoxy)prop-2-yl)-2-methylpiperidine single isomer

Abstract

The present invention relates to a method for preparing a high-purity 1-(1-(2-benzylphenoxy)propyl-2-yl)-2-methylpiperidine single isomer.

Description

[Technical field]

[0001] The present invention relates to a method for preparing a high-purity single isomer of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine. [Background Technology]

[0002] Metastasis of cancer cells is the most life-threatening factor of cancer. Although surgery is a common method of treating cancer, cancer cells spread from the primary cancer site to many different parts of the body, so full recovery can only be expected if surgery is performed at an early stage.

[0003] At the same time, cancer metastasis, like cancer occurrence, is caused by the complex interaction of various genes and factors involved in cancer cell migration and invasion.

[0004] The migration of cancer cells plays an important role in cancer metastasis. For example, metastasis is related to the migration of cancer cells from the initial primary cancer site to blood vessels through the extracellular matrix (ECM) or the migration of cancer cells from blood vessels to secondary metastatic tissues, and metastasis involves the migration of vascular endothelial cells from new blood vessels. The polarity of migrating cells is induced by signal receptors activated by cell migration inducers. In addition, the cell membrane at the front of the cell expands forward through the polymerization of actin, and the cell is attached to the extracellular matrix through integrins. At this time, a strong contractile force is generated between the actin polymers by myosin bound to the actin polymer, so that the entire cell generates a strong contractile force. Therefore, the direction of cell migration is determined by the difference in adhesion between the front and rear of the cell, so that the cell migrates in the direction. Therefore, cell migration inhibitors inhibit the migration of cancer cells to prevent metastasis and spread, and when cell migration is inhibited, anticancer substances that induce apoptosis of cancer cells can be administered. It is considered to be a realistic method to prolong the life of cancer patients.

[0005] Meanwhile, benproperine has been used as an antitussive expectorant, and its ability to effectively prevent cancer metastasis by inhibiting the migration and neovascularization of cancer cells has been confirmed (Korean Patent No. 10-1323728 and U.S. Patent No. 8,716,288). In addition, by synthesizing various derivatives of benproperine and verifying their activities, it has been confirmed that CG-609, particularly the (S,R) form of (R)-1-((S)-1-(2-benzylphenoxy)prop-2-yl)-2-methylpiperidinyl, has superior activity.

[0006] However, when (R)-propylene oxide having a low boiling point of 34°C is used as a reactant to selectively synthesize the (S,R) form of CG-609, it is difficult to handle due to the risk of explosion and fire, and there are various legal restrictions on handling due to safety issues. Also, since other reactants (R)-2-methylpiperidine or (S)-2-methylpiperidine used together are very expensive and difficult to obtain, large-scale production is limited. Specifically, in order to synthesize pure CG-609, column chromatography purification is required, so large-scale production is difficult.

[0007] [Disclosure]

[0008] [Technical issues]

[0009] In an effort to develop a method for preparing a certain high-purity isomer, such as the (S,R) form of CG-609, (R)-1-((S)-1-(2-benzylphenoxy)prop-2-yl)-2-methylpiperidine, by using inexpensive, easy-to-handle substitutes as reactants, the inventors have found that the desired isomer CG-609, i.e., (R)-1-((S)-1-(2-benzylphenoxy)prop-2-yl)-2-methylpiperidine, can be provided as a single isomer having a purity of 99% or higher, and further a purity of 99.9% or higher, by using (R)-propylene carbonate instead of (R)-propylene oxide as a synthetic intermediate, using racemic 2-methylpiperidine instead of (R)-2-methylpiperidine to obtain a mixture mainly comprising the (S,R) form and the (S,S) form, treating the mixture with hydrochloric acid, and completing the substitution with a phosphate, thereby completing the present invention.

[0010] [Beneficial Effects]

[0011] According to the preparation method of the present invention, by treating a crude product including all 4 isomers that are difficult to separate although their ratios are small with hydrochloric acid and replacing the obtained product with phosphate without conducting additional recrystallization, a desired single isomer such as (S,R) form of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine phosphate can be obtained with a purity of 99% or more, and further with a purity of 99.9% or more. [Brief Description of the Figures]

[0013] Figure 1 The chiral HPLC result of (R)-1-(2-benzylphenoxy)propan-2-yl methanesulfonate ((R)-Ben-OMs), which is an intermediate synthesized according to Preparation Example 3, is shown.

[0014] Figure 2 The chiral HPLC results of the crude product obtained according to Method 1-1 of Example 1 are shown.

[0015] Figure 3 The C18 HPLC result of the crude product obtained according to Method 1-1 of Example 1 is shown.

[0016] Figure 4 Chiral HPLC results are shown for compositions including isolated (R,R), (S,S), (R,S), and (S,R) isomers of CG-609, either alone or in combination, of high purity.

[0017] Figure 5 C18 HPLC results showing compositions including isolated (R,R), (S,S), (R,S) and (S,R) isomers of CG-609, either alone or in combination, of high purity.

[0018] Figure 6-10 Showing the intermediates and isolated products according to the preparation method of the present invention 1 H NMR results.

[0019] Figure 11-15 MS results for intermediates and isolated products according to the preparation method of the present invention are shown.

[0020] [Best Way]

[0021] The present invention will be described in detail. Meanwhile, each description and embodiment disclosed by the present invention can be applied to this article to describe different descriptions and embodiments. In other words, all combinations of various components disclosed by the present invention are included within the scope of the present invention. In addition, the scope of the present invention should not be limited by the detailed description provided below.

[0022] Moreover, those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention. Such equivalents are intended to be encompassed by the following claims.

[0023] Throughout the specification, “comprising” or “including” an element does not exclude other elements but further includes the elements unless otherwise stated.

[0024] Hereinafter, the present invention will be described in more detail.

[0025] The present invention aims to provide a highly pure (S,R) form isomer having excellent activity and optimized reaction conditions which can effectively mass-produce 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine (CG-609), which is known to have activity in inhibiting tumor metastasis. The present invention originates from the following facts: i) even if one or two types of (R)- or (S)-isomers are used in combination as reactants to selectively provide a desired isomer, a mixture of a total of 4 isomers is formed, which includes theoretically unexpected isomers, although in different ratios, and ii) a conventional recrystallization method using a chiral reagent for isomer separation cannot be applied to a mixture containing all of the above 4 isomers.

[0026] Therefore, the present inventors have found that the desired compound can be obtained as a single isomer in a purity of 99% or more, and further in a purity of 99.9% or more, by reacting the (R)- or (S)-isomer of one reagent with a racemic mixture of another reagent or reacting the (R)- or (S)-isomers of two reagents as reactants, solidifying the crude product by treating it with hydrochloric acid and / or optionally with hydrobromic acid, and replacing the hydrochloride and / or hydrobromide with phosphate, to obtain a crude product comprising more than 80% of diastereomers of the (S,R) form and the (S,S) form or the (R,S) form and the (R,R) form.

[0027] One aspect of the present invention provides a method for preparing a single isomer as a phosphate having a purity of 99% or more from a mixture of two or more of four isomers of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine containing two chiral centers.

[0028] Specifically, the method comprises: step 1, preparing a mixture of two or more isomers of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine by reacting (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol in which a hydroxyl group is activated with a racemic mixture of 2-methylpiperidine, wherein the isomers include an isomer of interest; step 2, treating a solution obtained by dissolving a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidines in acetone with hydrogen chloric acid to obtain 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine hydrochloride in solid form; optional step 2-a, when the isomer of interest is the (S,S) form or the (R,R) form, by recrystallizing the filtrate recovered from step 2 once or more with hydrobromic acid to obtain the hydrobromide of the compound, and step 3, by adding phosphoric acid to a solution of the hydrochloride or hydrobromide of the compound dissolved in ethanol, replacing the hydrochloride or hydrobromide of the compound obtained in the previous step with the phosphate of the compound.

[0029] The present invention is characterized in that it discloses that an optimized preparation method with significantly improved quality and high final product yield can be provided by completing step 2 and step 2-a in an acetone solution and completing step 3 in an ethanol solution.

[0030] For example, when a solvent other than acetone is used in step 2 and step 2-a, the selectivity is significantly reduced, making it difficult to separate a single isomer of interest in high purity. In addition, when a solvent other than ethanol is used in step 3, the selectivity is also reduced, resulting in reduced yield and deteriorated product quality.

[0031] For example, the filtrate recovered from step 2 may be a solution of a crude product dissolved in acetone, the crude product being obtained by neutralizing the acidic solution of step 2 obtained by removing the hydrochloride of the compound therefrom and extracting with an organic solvent. The neutralization of the solution may be performed using sodium hydroxide, but is not limited thereto. Meanwhile, the extraction may be performed using water and dichloromethane, but is not limited thereto.

[0032] For example, (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol in which the hydroxyl group is activated may be activated with a mesyl or tosyl group, but is not limited thereto. For example, compounds substituted with halogen (instead of the hydroxyl group) may be used, but are not limited thereto.

[0033] For example, (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol in which the hydroxyl group is activated can be prepared by reacting (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol with a chloride of an activating group in an organic solvent in the presence of triethylamine (TEA) as a base and dimethylaminopyridine (DMAP) as a catalyst, but is not limited thereto. Alternatively, any commercially available compound can be purchased and used, or any compound synthesized by appropriately utilizing reactions known in the art can be used.

[0034] For example, (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol can be prepared by reacting 2-benzylphenol with (R)- or (S)-propylene carbonate in the presence of TBAF·3H2O as a catalyst at a temperature of 170°C or above, but is not limited thereto. Alternatively, any commercially available compound can be purchased and used, or any compound synthesized by appropriately utilizing a reaction known in the art can be used. Korean Patent Publication No. 10-2259291 discloses an example of synthesis using (R)-propylene oxide.

[0035] Hereinafter, a method for preparing each of the (S,R) form, (S,S) form, (R,S) form and (R,R) form of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine with a purity of 99% or more will be described.

[0036] Specifically, the present invention can provide a method for preparing (R)-1-((S)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine, the method comprising: step 1', preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers, including an isomer of interest, by reacting (R)-1-(2-benzylphenoxy)propan-2-ol in which a hydroxyl group is activated with a racemic mixture of 2-methylpiperidine; Step 2', by treating a solution obtained by dissolving a mixture of two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidines in acetone with hydrochloric acid to obtain the hydrochloride of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine in solid form; and step 3', by adding phosphoric acid to a solution obtained by dissolving the hydrochloride or hydrobromide of the compound in ethanol, replacing the hydrochloride or hydrobromide of the compound obtained in the previous step with the phosphate of the compound.

[0037] Specifically, the present invention can provide a method for preparing (S)-1-((S)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine, the method comprising: step 1', preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers by reacting (R)-1-(2-benzylphenoxy)propan-2-ol in which the hydroxyl group is activated with a racemic mixture of 2-methylpiperidine, wherein the isomers include the isomer of interest; step 2', preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers by treating the mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers with hydrochloric acid; and step 2', preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers by treating the mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers with hydrochloric acid. -(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine in acetone to obtain a solution of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine hydrochloride in solid form; step 2'-a, obtaining the hydrobromide of the compound by recrystallizing the filtrate recovered from step 2 once or more than once with hydrobromic acid; and step 3', replacing the hydrochloride or hydrobromide of the compound obtained in the previous step with the phosphate of the compound by adding phosphoric acid to a solution of the hydrochloride or hydrobromide of the compound dissolved in ethanol.

[0038] Specifically, the present invention can provide a method for preparing (S)-1-((R)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine, the method comprising: step 1″, preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers including an isomer of interest by reacting (S)-1-(2-benzylphenoxy)propan-2-ol in which a hydroxyl group is activated with a racemic mixture of 2-methylpiperidine; Step 2", by treating a solution obtained by dissolving a mixture of two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidines in acetone with hydrochloric acid to obtain the hydrochloride of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine in solid form; and step 3", by adding phosphoric acid to a solution obtained by dissolving the hydrochloride or hydrobromide of the compound in ethanol, replacing the hydrochloride or hydrobromide of the compound obtained in the previous step with the phosphate of the compound.

[0039] Specifically, the present invention can provide a method for preparing (R)-1-((R)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine, the method comprising: step 1″, preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers by reacting (S)-1-(2-benzylphenoxy)propan-2-ol in which the hydroxyl group is activated with a racemic mixture of 2-methylpiperidine, wherein the isomers include the isomer of interest; step 2″, preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers by treating the racemic mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine with hydrochloric acid; and step 2″, preparing a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers by treating the racemic mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine with hydrochloric acid. -(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine in acetone to obtain a solution of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine hydrochloride in solid form; step 2"-a, obtaining the hydrobromide of the compound by recrystallizing the filtrate recovered from step 2 once or more with hydrobromic acid; and step 3", replacing the hydrochloride or hydrobromide of the compound obtained in the previous step with the phosphate of the compound by adding phosphoric acid to a solution of the hydrochloride or hydrobromide of the compound dissolved in ethanol.

[0040] For example, the method may further include step 2-1: recrystallizing the hydrochloride of the compound obtained in step 2, step 2' or step 2" with hydrochloric acid, which is performed once or more than once, but is not limited thereto.

[0041] In this regard, step 2-1 may be performed in a solution obtained by dissolving the hydrochloride of the compound in a polar organic solvent of ketone or lower alcohol (especially ethanol), but is not limited thereto.

[0042] For example, a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers used as a reactant in the preparation method of the present invention may be a mixture in which the sum of the amounts of the (S,R) form and the (S,S) form is 80% or more, but is not limited thereto.

[0043] Alternatively, the mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers used as a reactant in the preparation method of the present invention may be a mixture in which the sum of the amounts of the (R,S) form and the (R,R) form is 80% or more, but is not limited thereto.

[0044] [Invention Mode]

[0045] Hereinafter, the present invention will be described in more detail based on the following examples and experimental examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0046] Experimental Example 1: Identification of isomers

[0047] In view of the fact that the object of the present invention is to separate the desired isomer from an isomer mixture in high yield, it is important to establish a method capable of separating and / or identifying each isomer contained in the product. Therefore, a single isomer or isomer mixture of the compound 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine of the present invention was analyzed by HPLC using chirality and a C18 column.

[0048] The operating conditions for C18 HPLC and chiral HPLC throughout the present invention are as follows.

[0049] [C18 HPLC conditions]

[0050] Column: Aegispak C18 150mm×4.6mm, 5μm

[0051] Eluent: Isocratic, A:B = 50:50

[0052] (Solvent A: methanol and solvent B: 0.1 mol ammonium acetate)

[0053] Detector: 270nm

[0054] Column temperature: 40°C

[0055] Flow rate: 1.0mL / min

[0056] Injection volume: 5 μL

[0057] Total running time: 80 minutes

[0058] Sample preparation method: Dissolve 100 mg of sample in 10 mL of methanol.

[0059] [Chiral HPLC conditions]

[0060] Column: IB-N5 250mm×4.6mm, 5μm

[0061] Eluent: Isocratic, A:B = 90:10

[0062] (Solvent A: Hexane containing 0.15% trifluoroacetic acid (TFA) & 0.05% diethylamine (DEA): ethanol = 99:1 and solvent B: ethanol containing 0.1% trifluoroacetic acid (TFA) & 0.1% diethylamine (DEA))

[0063] Detector: 270nm

[0064] Column temperature: 25°C

[0065] Flow rate: 1.2mL / min

[0066] Injection volume: 5 μL

[0067] Total running time: 40 minutes

[0068] Sample preparation method: 100 mg of sample was dissolved in 10 mL of a mixed solvent of methanol, ethanol and hexane (mixed in a ratio of 1:1:1).

[0069] In addition, the HPLC results using a chiral column and a C18 column are shown in Figure 2 and Figure 3 In. Figure 2 As shown, when separated by a chiral column, it was confirmed that not only the (S, R) form and the (S, S) form were included, but also a small amount of the (R, S) form and the (R, R) form were included. These four isomers were present in a ratio of 3.5% (R, R), 50% (S, S), 4.6% (R, S) and 42% (S, R).

[0070] At the same time, Figure 3 In the separation results using a C18 column, only two peaks are shown in a ratio of approximately 50:50, and the peaks correspond to a mixture of the (R,R) form and the (S,S) form, and a mixture of the (R,S) form and the (S,R) form, respectively, indicating that HPLC using a C18 column can be used to separate diastereomers but not enantiomers.

[0071] To support the results, high purity isolated (R,R), (S,S), (R,S) and (S,R) isomers of CG-609 were analyzed using either chiral HPLC or C18 HPLC alone or in combination, and the results are shown in Figure 4 and Figure 5 In. Figure 4 and Figure 5 As shown, although the four types of isomers showed independent peaks in chiral HPLC, it was possible to separate the (R,S) form and / or the (S,R) form from the (R,R) form and / or the (S,S) form, but in C18 HPLC, the separation of the (S,S) form from the (R,R) form and the separation of the (S,R) form from the (R,S) form was impossible.

[0072] Preparation Example 1: Preparation of (R)-1-(2-benzylphenoxy)propan-2-ol ((R)-Ben-OH)

[0073] Method 1-1: Using (R)-propylene oxide as a reactant

[0074]

[0075] K2CO3 (1.2 g, 8.68 mmol, 4 eq) was added to N,N-dimethylformamide (DMF, 0.85 M, 5 mL, 12 eq) and stirred. After 5 minutes, 400 mg of 2-benzylphenol (2.17 mmol, 1 eq) was added thereto at room temperature. After 30 minutes, (R)-propylene oxide (13.91 mmol, 0.9 mL, 6 eq) was quickly added with a syringe, followed by reaction in a 120°C oil bath for 17 hours. The mixture was cooled to room temperature, and the reaction was terminated by adding water thereto, followed by extraction with ethyl acetate and water three times. Thereafter, the organic layer was washed three times with water and then once with brine. The product was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA: Hex = 1: 9) to give the title compound (970 mg, 92.4%, bright yellow oil).

[0076] Since the boiling point of (R)-propylene oxide used in excess during the reaction is 34°C, the internal reaction temperature is about 70°C in the initial stage of the reaction even if 120°C heating is applied thereto from the outside. The reaction is not completed at this temperature. When the internal reaction temperature gradually increases over time and reaches a final temperature of 120°C, the reaction is completed.

[0077] It is believed that during the reaction, when high temperature heating is provided from the outside, the reaction temperature increases with time because (R)-propylene oxide with a low boiling point evaporates. Therefore, when the amount of (R)-propylene oxide is reduced from 6 eq to 3 eq, the reaction is completed within 6 hours, but when the amount is equal to or less than 3 eq, the reaction is not completed.

[0078] Meanwhile, attempts have been made to develop a substitute due to the low boiling point of (R)-propylene oxide used as a reactant, the risk of explosion and fire, and handling difficulties such as having to keep even small amounts of the reagent refrigerated.

[0079] Method 1-2: Using (R)-propylene carbonate as a reactant

[0080]

[0081] According to the method introduced by Shih Chieh Kao et al. (Adv. Synth. Catal., 2019, 361: 1–7), (R)-propylene carbonate was used instead of (R)-propylene oxide as a reactant to synthesize (R)-1-(2-benzylphenoxy)propan-2-ol. Specifically, since the synthesis was completed by reacting 1.0 eq to 1.3 eq of (R)-propylene carbonate as a raw material with 1 eq of 2-benzylphenol, the reaction was completed when 1.2 eq of (R)-propylene carbonate was used. In addition, since (R)-propylene carbonate is a high-boiling liquid, DMF solvent was used according to the minimum amount disclosed in the literature, and the amount of TBAF·3H2O as a catalyst was also minimized. An experiment to reduce the reaction temperature was conducted, and the reaction was not completed at a temperature of 150°C or below, but the reaction was completed within 4 to 6 hours when the temperature was maintained at 170°C or above. In order to confirm the reaction, process control (IPC) was performed using HPLC. Therefore, it was confirmed that almost no starting material existed and about 5% to 10% of reaction by-products were produced before the title compound was formed.

[0082] Although the solid target substance is isolated by treating the reaction product with water and an organic solvent to separate the title compound from the reaction product, the isolation of the solid requires an additional procedure and the yield is reduced to 60% or less.

[0083] Meanwhile, considering that the amount of the title compound contained in the crude product after the reaction is 90% or more, the crude oily product is used in the reaction without a separation procedure, and it is confirmed that the crystals of the desired product are obtained in high yield and high purity. Therefore, the crude product is used for the reaction of the subsequent step without a separate separation and purification procedure.

[0084] Specifically, 1500g benzylphenol is dissolved in 825mL DMF placed in a 5000mL reactor. In the reaction solution, 997.5g (R)-(+)-propylene carbonate and 25.7g TBAF 3H2O are added, and the temperature is raised to 170°C, followed by reaction for 4 hours. After the reaction is completed, the product is cooled to 20°C to 30°C, and the organic layer is recovered therefrom by adding 7500mL ethyl acetate and 7500mL water. The recovered organic layer is dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated (R)-Ben-OH of the entire amount is used in subsequent reactions.

[0085] Preparation Example 2: Preparation of (S)-1-(2-benzylphenoxy)propan-2-ol ((S)-Ben-OH)

[0086] (S)-Ben-OH was obtained by carrying out the reaction in the same manner as in Method 1-2 of Preparation Example 1, except that (S)-(-)-propylene carbonate was used instead of (R)-(+)-propylene carbonate.

[0087] Preparation Example 3: Preparation of Intermediate Methanesulfonic Acid 1-(2-Benzylphenoxy)propan-2-yl Ester (Ben-OMs) Method 3-1: Preparation of Methanesulfonic Acid (R)-1-(2-Benzylphenoxy)propan-2-yl Ester ((R)-Ben-OMs)

[0088]

[0089] In the presence of a base, the crude product including (R)-Ben-OH obtained in step 1 is reacted with methanesulfonyl chloride (MsCl) to obtain the title compound. Specifically, 1.5 equivalents of triethylamine as a base and 0.1 equivalents of dimethylaminopyridine (DMAP) as a catalyst are added to ethyl acetate as a reaction solvent, and reacted with 1.1 equivalents of MsCl. After the reaction is completed, IPC is performed using HPLC to identify the product. The results confirm that the reaction byproducts observed in the crude product of step 1 disappear, and the title compound (R)-Ben-OMs is synthesized with a yield of 70% to 80%.

[0090] In view of the fact that the object of the present invention is to produce a high-purity chiral compound, the optical purity of the synthesized (R)-Ben-OMs was analyzed using a chiral HPLC column, and as a result, the compound was synthesized with an optical purity of 99.9% or more and a chemical purity of 99.9%. The obtained product was identified using chiral HPLC, and the results are shown in Figure 1 middle.

[0091] Specifically, the concentrated residue of (R)-Ben-OH prepared according to method 1-2 of Preparation Example 1 was added to a 20L reactor, and 9.84L of ethyl acetate was added thereto to dissolve (R)-Ben-OH. 1235.8g of TEA and 99.5g of DMAP were added thereto, and the mixture was cooled to a temperature of 10°C or lower. After 1026.0g of MsCl was slowly added dropwise, the temperature was raised to room temperature, followed by stirring for 1 hour. After the reaction was completed, 7891mL of water was added thereto, and 418.7g of concentrated hydrochloric acid was slowly added dropwise thereto. After the addition was completed, the mixture was further stirred for 30 minutes, and the organic layer was recovered therefrom, treated with 5% NaHCO3 solution, dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. 5918mL of methanol was added to the concentrated residue to dissolve. When crystals were formed, the solution was filtered, and the crystals were dried to obtain (R)-Ben-OMs (2107g, 80.8%). The obtained product was purified by 1 H NMR and MS identification, and the results are shown in Figure 6 and Fig.11 middle.

[0092] Figure 3-2 :Preparation of (S)-1-(2-benzylphenoxy)propan-2-yl methanesulfonate ((S)-Ben-OMs)

[0093]

[0094] (S)-Ben-OMs (2090 g, 80.1%) was obtained by completing the reaction in the same manner as Method 3-1, except that (S)-Ben-OH prepared according to Preparation Example 2 was used instead of (R)-Ben-OH.

[0095] Example 1: Preparation of (R)-1-((S)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine

[0096] Method 1-1: Using racemic 2-methylpiperidine as a reactant

[0097]

[0098] One equivalent of (R)-Ben-OMs was dissolved in 3 equivalents of racemic 2-methylpiperidine, followed by reflux at 120°C for 6 hours. After the reaction was completed, the product was treated with dichloromethane (MC) and water, and an organic layer was recovered therefrom. The recovered organic layer was concentrated under reduced pressure to obtain a crude product.

[0099] Method 1-2: Using (R)-2-methylpiperidine ((R)-2-MP) as a reactant

[0100]

[0101] The reaction was carried out in the same manner as in Example 1, Method 1-1, except that (R)-2-methylpiperidine was used as a reactant instead of racemic 2-methylpiperidine, to obtain a crude product.

[0102] In order to more specifically identify the components of the products obtained from Methods 1-1 and 1-2 of Example 1, chiral HPLC analysis was performed, and the results are shown in Table 1 below.

[0103] Table 1

[0104]

[0105] As shown in Table 1, the product obtained according to method 1-2 is expected to produce only a single isomer in the form of (S, R), but in fact it also includes all 4 isomers, although the (S, R) form ratio is the highest, and the total amount of by-product (R, R) form, (S, S) form and (R, S) form exceeds 20%. Therefore, it is confirmed that even if the synthetic method according to method 1-2 of embodiment 1 is used, additional separation / purification procedures are required to obtain the title compound of high purity. The results show that for mass production of the title compound, it can be more effective to replace the method of (R)-2-methylpiperidine with racemic 2-methylpiperidine, which is difficult to obtain commercially and is expensive. Therefore, it is attempted to develop a method for separating specific isomers from an isomer mixture with 90% or higher purity, and further 99% or higher purity.

[0106] Comparative Example 1: Separation and purification using chiral reagents

[0107] Experiments to separate the pure (S,R) form from the crude product were accomplished using chiral reagents (D)- or (L)-mandelic acid; (D)- or (L)-tartaric acid; or (R)- or (S)-camphorsulfonic acid, which are widely used to separate optically active substances.

[0108] Specifically, after the crude product is dissolved in methanol, an equivalent amount of (D)- or (L)-mandelic acid; (D)- or (L)-tartaric acid; or (R)- or (S)-camphorsulfonic acid is added thereto. After the reaction, the methanol is concentrated under reduced pressure to observe whether crystals are formed. However, after concentration, the sample according to the present invention including 4 isomers did not form crystals, and about 10 available organic solvents were used alone or in combination to further recrystallize the concentrated residue, but all attempts failed. This result shows that separation by recrystallization using a chiral reagent can be used to separate one type from a mixture of two enantiomers, but is difficult to apply to the separation of a crude product including all 4 isomers. Therefore, the inventors attempted to remove relatively small amounts of 2 isomers from a crude product including 4 isomers by recrystallization to obtain a relatively pure mixture of 2 isomers, and then separated the target compound by recrystallization using a chiral reagent.

[0109] Example 2: Isolation and purification of the (S, R) form using strong acid

[0110] In order to prepare a relatively pure mixture of two isomers by recrystallization proposed in Comparative Example 1, the crude oil obtained in Method 1-1 of Example 1 was dissolved in acetone, and an equal amount of various acids such as HCl, HBr, phosphoric acid (H3PO4) and sulfuric acid (H2SO4) were added thereto. The solid formed therein was obtained by filtration and analyzed by a chiral column. The results are shown in Table 2 below.

[0111] Table 2

[0112]

[0113] As shown in Table 2, the purity of the (S, R) form of the compound of interest increased from 41.5% to a significantly high level of 97.6% in the HCl salt compared to other acids, indicating a significantly high selectivity. However, no significantly high selectivity for a specific isomer was observed in the HBr salt and the H3PO4 salt, and no salt was formed in the case of adding sulfuric acid. Therefore, in the case of precipitation using HCl, no additional recrystallization using a chiral reagent is required. At the same time, when recrystallization is performed in the same manner using a solvent other than acetone, the formed HCl salt exhibits a significantly reduced selectivity compared to the case of using acetone, and therefore, a high-purity (S, R) form cannot be prepared.

[0114] As shown in the table above, recrystallization was performed using ethanol to obtain a high purity compound of interest from the HCl salt, and the HCl salt was finally converted to a phosphate salt to obtain a 99.92% high purity (S, R) form. The chiral purity of the salt calculated in each step is shown in Table 3 below.

[0115] Table 3

[0116]

[0117]

[0118] As shown in Table 3, although the yield of the final product of interest was 26.5%, considering that the ratio of the (S,R) form in the crude product was 41.5%, the theoretical yield was 63.9%, thus confirming that a high yield was obtained.

[0119] Example 3: Isolation and purification of the (S,S) form as a byproduct of the (S,R) form

[0120] As described above, when racemic 2-methylpiperidine is used as a reactant according to method 1-1 of Example 1, the (S,R) form of the compound of interest is generated, and a large amount of (S,S) diastereomer is also generated. Therefore, the present inventors attempted to separate and purify the (S,S) form with high purity.

[0121] As shown above, in Table 3, based on the following logic: in the case where the ratio of the (S, S) form in the crude product is 48.6%, and the (S, R) form of the HCl salt is theoretically separated at 63.9%, the content of the (S, S) form in the filtrate should be relatively high, and the filtrate obtained after the primary separation of the (S, R) form of the HCl salt was analyzed. As a result, the ratio of the (S, S) form increased from 48.6% to 76.3%, while the ratio of the (S, R) form decreased from 41.5% to 9.4%. Therefore, after separating the (S, R) form using a strong acid, similar to separating the (S, R) form from the crude product, the inventors attempted to separate the (S, S) form from the filtrate.

[0122] Therefore, after the strongly acidic filtrate obtained by removing the HCl salt of the (S,R) form was neutralized with sodium hydroxide in a water and dichloromethane solution, the organic layer was recovered and concentrated to obtain a crude product in the form of an oil containing a large amount of the (S,S) form.

[0123] The obtained crude product is dissolved in acetone, and similar to Example 2, an equivalent amount of acid such as HCl, HBr, phosphoric acid (H3PO4) is added thereto to neutralize sulfuric acid (H2SO4). As a result, solid salts are formed only when HBr is added, and no salts are formed in other acids. This shows that the (S, S) form has a significant high selectivity for the use of HBr. In addition, although solvents other than acetone are used, high selectivity is observed only in the case of acetone, as observed in Example 2, but in the case of using other solvents, the compound of interest cannot be prepared in high purity. Subsequently, additional recrystallization is carried out in the same manner in Example 2 to increase the purity, and the phosphate of the compound of interest (S, S) form is finally obtained with a high purity of 99.96%. The purity calculated for each step is shown in Table 4 below.

[0124] Table 4

[0125]

[0126]

[0127] As shown in Table 4, although the yield of the (S,S) form was 23.2%, considering that the ratio of the (S,S) form in the crude product was 48.6%, the theoretical yield was 47.8%, thereby confirming that a high yield was obtained.

[0128] Example 4: Separation and purification of (R,S) form and (R,R) form using strong acid

[0129] The reaction was completed in the same manner as in method 1-1 of Example 1 except that (S)-Ben-OMs was used instead of (R)-Ben-OMs to obtain a crude product mainly including the (R,S) form and the (R,R) form. Similar to Examples 2 and 3, the salt was formed twice using HCl and replaced with phosphate. In the same manner as in Examples 2 and 3, a high-purity (R,S) form phosphate was optionally obtained by crystallizing an acetone solution of the crude product using HCl and replacing the crystals with phosphoric acid. A crude product including a large amount of the (R,R) form was obtained from the filtrate after the crystallization of the HCl salt. An acetone solution of the crude product was crystallized using HBr and the crystals were replaced with phosphate to optionally obtain a high-purity (R,R) form phosphate. The purity of each step was calculated and is shown in Tables 5 and 6 below.

[0130] Table 5

[0131]

[0132] Table 6

[0133]

[0134]

[0135] As shown in Tables 5 and 6, the (R,S) form and the (R,R) form were purified with a high purity of 99.9%, and their final yields were 20.5% (theoretical yield was 50.6%) and 21.2% (theoretical yield was 45.4%), respectively.

[0136] Example 5: Preparation of high purity (R)-1-((S)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidinium phosphate

[0137] Step 1

[0138] 20.0g (1eq) dry (R)-Ben-OMs and 18.6g (3eq) 2-methyl piperidine are added in a 200mL reactor, and the temperature is raised, and the mixture is refluxed and stirred for 6 hours. After the reaction is completed, the mixture is cooled, and 100mL MC and 100mL water are added thereto and stirred. After slowly dripping 14g (2eq) c-HCl thereto, the organic layer is reclaimed. After adding 66mL water in the recovered organic layer, the solution is neutralized with a NaOH solution, and the organic layer is then reclaimed.

[0139] Step 2

[0140] The recovered organic layer was concentrated under reduced pressure, and the concentrated residue was dissolved in 100 mL of acetone, to which 5.7 g of c-HCl was then added. When a precipitate was formed, the solution was heated under reflux for 30 minutes and cooled, followed by filtration to obtain a precipitate. In this case, the obtained precipitate was defined as the HCl salt of the crude CG-609 (S, R) form. The filtrate was recovered and stored separately for separation of the (S, S) form.

[0141] The crude HCl salt of CG-609 (S, R) form was added to 100 mL of ethanol, and the solution was heated under reflux for 30 minutes and cooled, followed by filtration to obtain a precipitate formed therein. In this case, the precipitate was defined as the purified HCl salt of CG-609 (S, R) form.

[0142] Step 3

[0143] The purified HCl salt of CG-609 (S, R) was added to a mixed solvent of 100 mL of MC and 100 mL of water, and neutralized with a NaOH solution, and then an organic layer was recovered therefrom. The recovered organic layer was concentrated under reduced pressure, and the concentrate was dissolved in 100 mL of ethanol, and then 2.16 g of 85% phosphoric acid was added thereto. When a precipitate was formed, the solution was filtered to obtain a precipitate, and the precipitate was dried to obtain 6.7 g (26.5%) of purified CG-609 (S, R) phosphate. 1 The products were analyzed by H NMR and MS, and the results are shown in Fig.10 and Fig.15 In addition, the purity of each step was analyzed by chiral HPLC, and the results were the same as those in Table 3.

[0144] [α] 25 D :-24.6 (C=1, MeOH).

[0145] Example 6: Preparation of high purity (S)-1-((S)-1-(2-benzylphenoxy)prop-2-yl)-2-methylpiperidinium phosphate

[0146] Step 2-a

[0147] The storage filtrate obtained after the (S, R) form separation in step 2 of Example 5 is concentrated under reduced pressure. The concentrate is dissolved in 100mL MC and 100mL water, neutralized with NaOH, and the organic layer is recovered therefrom. The recovered organic layer is concentrated under reduced pressure, and the concentrate is dissolved in 100mL acetone, and then 8.9g 48% HBr solution is added thereto. When a precipitate is formed, the mixture is further heated to reflux for 30 minutes and then filtered to obtain a precipitate. In this case, the precipitate is defined as a crude (S, S) form of HBr salt. The crude (S, S) form of HBr salt is added to 100mL ethanol, heated to reflux for 30 minutes, and cooled, and then filtered to obtain the formed precipitate. In this case, the formed precipitate is defined as a purified (S, S) form of HBr salt.

[0148] Step 3

[0149] The purified (S,S) form of HBr salt was added to a mixed solvent of 100 mL of MC and 100 mL of water, and neutralized with a NaOH solution, and then an organic layer was recovered therefrom. The recovered organic layer was concentrated under reduced pressure, and the concentrate was dissolved in 100 mL of ethanol, and then 2.16 g of 85% phosphoric acid was added thereto. When a precipitate was formed, the solution was filtered, and the precipitate was dried to obtain 6.1 g (23.2%) of purified (S,S) form of phosphate. 1 The products were analyzed by H NMR and MS, and the results are shown in Figure 8 and Fig.13 The purity of each step was analyzed by chiral HPLC, and the results are shown in Table 4.

[0150] [α] 25 D :-18.9 (C=1, MeOH).

[0151] Example 7: Purification of high purity (S)-1-((R)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidinium phosphate

[0152] By carrying out synthesis, separation and purification in the same manner as in Example 5 except that (S)-Ben-OMs was used instead of (R)-Ben-OMs, 5.4 g (20.5%) of (R,S)-form phosphate was obtained. 1 The products were analyzed by H NMR and MS, and the results are shown in Fig. 9and Fig.14 In addition, the purity of each step was analyzed by chiral HPLC, and the results were the same as those in Table 5.

[0153] [α] 25 D :+24.2(C=1,MeOH).

[0154] Example 8: Purification of High Purity (R)-1-((R)-1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidinium phosphate

[0155] By performing separation and purification in the same manner as in Example 6, except that the filtrate obtained after separation of the (R,S) form was used instead of the filtrate obtained after separation of the (S,R) form, 5.6 g (21.2%) of the (R,R) form of phosphate was obtained. 1 The products were analyzed by H NMR and MS, and the results are shown in Figure 7 and Fig.12 In addition, the purity of each step was analyzed by chiral HPLC, and the results were the same as those in Table 5.

[0156] [α] 25 D :+19.0(C=1,MeOH).

[0157] The above description of the present invention is provided for the purpose of explanation, and it should be understood by those skilled in the art that various changes and modifications may be made without changing the technical concept and essential features of the present invention. Therefore, it is clear that the above embodiments are illustrative in all aspects and do not limit the present invention. Therefore, the scope of the present disclosure is not defined by the detailed description, but by the claims and their equivalents, and all variations within the scope of the claims and their equivalents are understood to be included in the present disclosure.

Claims

1. A method for preparing a single isomer from a mixture of two or more of the four isomers of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine containing two chiral centers, wherein the single isomer is a phosphate having a purity of 99% or more, the method comprising: Step 1, preparing a mixture comprising two or more isomers of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine, including an isomer of interest, by reacting (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol in which a hydroxyl group is activated with a racemic mixture of 2-methylpiperidine; Step 2, treating a solution obtained by dissolving a mixture containing two or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidines in acetone with hydrochloric acid to obtain 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine hydrochloride in a solid form; Optional step 2-a, when the isomer of interest is the (S,S) form or the (R,R) form, obtaining a hydrobromide salt of the compound by recrystallizing the filtrate recovered from step 2 once or more with hydrobromic acid; and Step 3, by adding phosphoric acid to a solution of the hydrochloride or hydrobromide of the compound dissolved in ethanol, the hydrochloride or hydrobromide of the compound obtained in the previous step is replaced by the phosphate of the compound.

2. The method according to claim 1, wherein the filtrate recovered from step 2 is a solution obtained by dissolving a crude product obtained by neutralizing the acidic solution of step 2 from which the hydrochloride of the compound is removed and extracting with an organic solvent in acetone.

3. The method according to claim 1, wherein the (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol in which the hydroxyl group is activated is (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol activated with a methanesulfonyl group or a toluenesulfonyl group.

4. The method according to claim 1, wherein the hydroxyl-activated (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol is prepared by reacting (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol with a chloride of an activating group in an organic solvent in the presence of triethylamine (TEA) as a base and dimethylaminopyridine (DMAP) as a catalyst.

5. The method according to claim 4, wherein 2-benzylphenol is reacted with (R)- or (S)-propylene carbonate in the presence of TBAF·3H2O as a catalyst at a temperature of 170°C or above to prepare (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol.

6. The method according to claim 1, further comprising step 2-1: recrystallizing the hydrochloride of the compound obtained in step 2 with hydrochloric acid, one or more times.

7. The method according to claim 6, wherein step 2-1 is carried out in a solution obtained by dissolving the hydrochloride of the compound in a polar organic solvent such as ketone or lower alcohol.

8. The method according to claim 1, wherein the mixture containing 2 or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers is a mixture in which the sum of the amounts of the (S,R) form and the (S,S) form is 80% or more.

9. The method according to claim 1, wherein the mixture containing 2 or more 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine isomers is a mixture in which the sum of the contents of the (R,S) form and the (R,R) form is 80% or more.

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