Method for producing (2r, 3s) -2 - (benzo [d] imidazolylpropyl) piperidin-3-ol derivative

Abstract

To provide a method for producing a (2R, 3S) - 2 - (benzo [d] imidazolylpropyl) piperidin-3-ol derivative in high yield even by a shortened process.SOLUTION: To provide a method for producing (2R, 3S) -2 - (3 - (4, 5-dichloro - 1H - benzo [d] imidazol-1-yl) propyl) piperidin-3-ol monohydrochloride which is a (2R, 3S) -2 - (benzo [d] imidazolylpropyl) piperidin-3-ol derivative. In addition, the present invention provides a method for preparing the compound represented by Chemical Formula 1-1, which is a starting material in the method for preparing the (2R, 3S) -2 - (benzo [d] imidazolylpropyl) piperidin-3-ol derivative. Further, the present invention provides a method for preparing an intermediate compound for preparing the compound represented by Chemical Formula 1-1.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol derivative. [Background technology]

[0002] Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase (ARS) family of enzymes that activate amino acids for protein synthesis. After forming aminoacyl adenylate (AA-AMP), ARS performs the translational function of transferring the activated amino acid to the 3′ terminus of the corresponding tRNA. Because ARS plays a crucial role in protein synthesis, ARS inhibition suppresses the growth and development of all cells. Therefore, ARS is recognized as a promising target for antibiotics and therapeutic agents for diseases that require the suppression of cellular overexpression (Nature, 2013, 494:121-125).

[0003] PRS exists and functions in the form of EPRS (Glutamyl-Prolyl-tRNA Synthetase) in the multisynthetase complex (MSC). In particular, EPRS functions as a translational silencer that suppresses the production of VEGF A (vascular endothelial growth factor A), a key factor in angiogenesis, among various MSCs. It has also been reported to be closely associated with various solid cancers (Nat. Rev. Cancer, 2011, 11, 708-718).

[0004] The only known PRS inhibitor is halofuginone. Halofuginone is a derivative of the natural product febrifugine and has antimalarial and various anti-inflammatory effects. It is also used as an animal feed additive. It has also been reported that halofuginone inhibits PRS enzymes, increasing the phosphorylation of GCN2 kinase and inducing the expression of ATF4 and CHOP, thereby promoting cell death (Nat. Chem. Biol. 2012, 8, 311-317). It is currently undergoing clinical research as a therapeutic agent for anti-cancer, anti-inflammatory (J Immunol, 2014, 192(5), 2167-76), autoimmune diseases (Arthritis Rheumatol, 2014, 66(5), 1195-207), and fibrotic diseases (World J Gastroenterol, 2014, 20(40), 14778-14786) (Bioorg. Med. Chem. 2014, 22, 1993-2004).

[0005] However, it has been reported that halofuginone acts on multiple targets, is highly toxic, and even poses the risk of genotoxicity (The EFSA Journal, 2003, 8:1-45). Therefore, discovering a PRS inhibitor that is safer for the human body from among substances that can inhibit PRS, such as halofuginone, is significant in terms of developing antifibrotic agents, anti-inflammatory agents, autoimmune therapeutic agents, or next-generation anticancer agents that can be used alone or in combination with existing targeted anticancer agents.

[0006] Therefore, the present inventors have confirmed that a (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol derivative, which has a chemical structure different from that of PRS enzyme inhibitors reported to date, can exhibit excellent PRS activity inhibitory effects. Therefore, the present inventors have conducted extensive research into a method for commercially producing the (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol derivative. As a result, they have confirmed that the method described below allows for commercial mass production and also improves the overall yield, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides a method for producing (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol monohydrochloride, a (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol derivative, which is a compound represented by Chemical Formula 1 below.

[0008] The present invention also provides a method for producing a compound represented by Chemical Formula 1-1 described below, which is a starting material in the method for producing the (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol derivative.

[0009] Furthermore, the present invention provides a method for producing a compound represented by the below-mentioned Chemical Formula 2, which is an intermediate compound for producing a compound represented by the below-mentioned Chemical Formula 1-1. [Means for solving the problem]

[0010] In order to solve the above problems, a method for preparing (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol 1HCl, which is a compound represented by the following chemical formula 1, is provided. More specifically, the method includes the following steps: 1) reacting a compound represented by the following formula 1-1 with a compound represented by the following formula 1-2 in the presence of a base to prepare a compound represented by the following formula 1-3: 2) reacting a compound represented by the following formula 1-3 in the presence of a sulfur-containing reducing agent to prepare a compound represented by the following formula 1-4: 3) reacting a compound represented by the following formula 1-4 with an orthoformate compound to prepare a compound represented by the following formula 1-5: 4) reacting a compound represented by the following formula 1-5 with hydrochloric acid in the presence of water and acetone to prepare a compound represented by the following formula 1: [Chemical formula 1] JPEG2026004468000001.jpg20167[Chemical formula 1-1] JPEG2026004468000002.jpg28168[Chemical formula 1-2] JPEG2026004468000003.jpg20168[Chemical formula 1-3] JPEG2026004468000004.jpg30170[Chemical formula 1-4] JPEG2026004468000005.jpg29170[Chemical formula 1-5] JPEG2026004468000006.jpg28170In the chemical formulas 1-1 to 1-5, P1 and P2 each independently represent a protecting group.

[0011] In addition, there is provided a method for producing the compound represented by Chemical Formula 1-1, which is a starting material used in the method for producing the compound represented by Chemical Formula 1. More specifically, there is provided a method for producing the compound represented by Chemical Formula 1-1, which includes the following steps: 1) reacting a compound represented by the following formula 1A with pyrrolidine to prepare a compound represented by the following formula 1B: 2) reacting a compound represented by the following formula 1B with 3-bromo-1-propene to prepare a compound represented by the following formula 1C: 3) reducing a compound represented by the following formula 1C in the presence of a ketoreductase enzyme to prepare a compound represented by the following formula 1D: 4) reacting a compound represented by the following formula 1D with a compound represented by the following formula 1d to prepare a compound represented by the following formula 1E: 5) reacting a compound represented by the following formula 1E with (1) a borane compound, and then with (2) an oxidizing agent to prepare a compound represented by the following formula 1F: 6) reacting a compound represented by the following formula 1F with methanesulfonyl chloride in the presence of a base to prepare a compound represented by the following formula 1G: 7) reacting a compound represented by the following formula 1G with an azidation reagent to prepare a compound represented by the following formula 1H; and 8) reacting a compound represented by the following formula 1H in the presence of a base to prepare a compound represented by the following formula 1-1: [Chemical formula 1-1] JPEG2026004468000007.jpg28170[Chemical formula 1A] JPEG2026004468000008.jpg22170[Chemical formula 1B] JPEG2026004468000009.jpg27170[Chemical formula 1C] JPEG2026004468000010.jpg21170[Chemical formula 1D] JPEG2026004468000011.jpg22169[Chemical formula 1d] JPEG2026004468000012.jpg8170[Chemical formula 1E] JPEG2026004468000013.jpg29170[Chemical formula 1F] JPEG2026004468000014.jpg28170[Chemical formula 1G] JPEG2026004468000015.jpg27170[Chemical formula 1H] JPEG2026004468000016.jpg29169In the above chemical formulas 1-1, 1A to 1H and 1d, X is a halogen; Ms is methanesulfonyl; P1 and P2 each independently represent a protecting group.

[0012] Furthermore, there is provided a method for producing a compound represented by the following Chemical Formula 2, which is an intermediate for producing the compound represented by Chemical Formula 1-1. More specifically, there is provided a production method comprising the following steps: 1) reacting a compound represented by the following formula 2-1 with propane-1,3-diol to prepare a compound represented by the following formula 2-2: 2) oxidizing a compound represented by the following Formula 2-2 to prepare a compound represented by the following Formula 2-3: 3) The compound represented by the following chemical formula 2-3 is (1) dibenzyl azodicarboxylate or di(C 1-4 (2) reacting the resulting compound with an alkyl azodicarboxylate and then with an allyl halide to prepare a compound represented by the following formula 2-4: 4) subjecting a compound represented by the following Formula 2-4 to a cyclization reaction to prepare a compound represented by the following Formula 2-5: 5) Aryl carbamate or di(C 1-4 removing the alkyl) carbamate to prepare a compound represented by the following formula 2-6: 6) preparing a compound represented by the following formula 2-7 by subjecting the compound represented by the following formula 2-6 to a boronation-oxidation reaction; 7) preparing a compound represented by the following formula 2-8 by subjecting the compound represented by the following formula 2-7 to a cyclization reaction: 8) reacting a compound represented by the following formula 2-8 in the presence of a base to prepare a compound represented by the following formula 2-9: 9) introducing a protecting group into a compound represented by the following formula 2-9 to prepare a compound represented by the following formula 2-10; 10) reacting a compound represented by the following formula 2-10 in the presence of an acid to prepare a compound represented by the following formula 2-11: 11) introducing a protecting group into a compound represented by the following formula 2-11 to prepare a compound represented by the following formula 2-12; and 12) reacting a compound represented by the following formula 2-12 in the presence of an acid to prepare a compound represented by the following formula 2: [Chemical formula 2] JPEG2026004468000017.jpg29170[Chemical formula 2-1] JPEG2026004468000018.jpg15170[Chemical formula 2-2] JPEG2026004468000019.jpg14170[Chemical formula 2-3] JPEG2026004468000020.jpg14169[Chemical formula 2-4] JPEG2026004468000021.jpg27170[Chemical formula 2-5] JPEG2026004468000022.jpg32170[Chemical formula 2-6] JPEG2026004468000023.jpg26170[Chemical formula 2-7] JPEG2026004468000024.jpg27170[Chemical formula 2-8] JPEG2026004468000025.jpg29169[Chemical formula 2-9] JPEG2026004468000026.jpg29169[Chemical formula 2-10] JPEG2026004468000027.jpg30168[Chemical formula 2-11] JPEG2026004468000028.jpg22169[Chemical formula 2-12] JPEG2026004468000029.jpg22170In the above chemical formulas 2 and 2-1 to 2-12, R1 is benzyl or C 1-4 is alkyl, P1 and P2 each independently represent a protecting group.

[0013] The production methods for each compound will be described in detail below.

[0014] (Method for producing the compound represented by the above chemical formula 1) Meanwhile, the compound represented by Chemical Formula 1 can be prepared according to the following Reaction Scheme 1: [Reaction Scheme 1] JPEG2026004468000030.jpg61166In the above reaction scheme 1, P1 and P2 each independently represent a protecting group.

[0015] More specifically, P1 may be any one protecting group selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), para-methoxybenzylcarbonyl (Moz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), and para-methoxybenzyl (PMB).

[0016] Alternatively, P2 may be any one protecting group selected from the group consisting of tert-butyldimethylsilyl (TBS), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), para-methoxybenzyl (PMB) ether, methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl, Tr), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS) ether, and ethoxyethyl ether (EE).

[0017] In this case, from the viewpoint of ease of production and yield, it is preferable that P1 is tert-butyloxycarbonyl (Boc) and P2 is tert-butyldimethylsilyl (TBS).

[0018] Stage 1) Step 1 is a step of preparing a compound represented by Chemical Formula 1-3 by reacting a compound represented by Chemical Formula 1-1 with a compound represented by Chemical Formula 1-2, and the reaction is an amine substitution reaction carried out in the presence of a base.

[0019] In this step, the compound represented by Chemical Formula 1-1 and the compound represented by Chemical Formula 1-2 can be used in an equivalent ratio of 1:0.5 to 1:1.5. Specifically, the compound represented by Chemical Formula 1-1 and the compound represented by Chemical Formula 1-2 can be used in an equivalent ratio of 1:0.7 to 1:1.3, 1:0.9 to 1:1.1, or 1:1.

[0020] In addition, in this step, the base may be one or more selected from the group consisting of N,N-diisopropylethylamine (DIPEA), diisopropylamine, triethylamine (TEA), pyridine, potassium carbonate (K2CO3), and sodium carbonate (Na2CO3). Among these, it is advantageous to use diisopropylethylamine or potassium carbonate as the base in terms of reaction rate and yield. In particular, it is most preferable to use potassium carbonate.

[0021] The base can be used in an amount of 1 to 4 equivalents relative to 1 equivalent of the compound represented by Formula 1-1. If the base is used in an excessively low amount, the reaction time may be prolonged, but if the base is used in an excessively large amount, there is no difference in the reaction time, so it is preferable to use the base in the above range.

[0022] The reaction is carried out in one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, acetonitrile (ACN), and dimethylformamide (N,N-dimethylformamide (DMF).

[0023] When N,N-dimethylformamide (DMF) is used as a solvent in the reaction, not only is the solvent not completely removed even after work-up, but the residual amount of solvent varies from batch to batch. Furthermore, if the residual amount of solvent is not constant, the crystallization yield and reproducibility of the final compound may vary depending on the residual amount, which is undesirable.

[0024] However, when tetrahydrofuran (THF) or 1,4-dioxane is used as the solvent for the reaction, it has the advantage of being completely removable after the reaction is completed. In particular, tetrahydrofuran (THF) is preferred because it has a fast reaction rate and produces fewer impurities.

[0025] The organic solvent can be used in an amount (mL / g) that is 5 to 30 times the weight of the compound represented by Chemical Formula 1-1, more specifically, in an amount (mL / g) that is 5 to 15 times the weight of the compound represented by Chemical Formula 1-1.

[0026] The reaction is carried out at the reflux temperature of the organic solvent. Specifically, the reaction is carried out at a temperature of 60 to 120°C for 3 to 10 hours. If the reaction is carried out at a temperature lower than the above range and / or for a shorter reaction time, the reaction will not proceed sufficiently, resulting in a lower production yield. Furthermore, if the reaction is carried out at a temperature higher than the above range and / or for a longer reaction time, the production yield will not increase substantially, which is undesirable in terms of process costs. For example, when tetrahydrofuran is used as the organic solvent, the reaction is carried out at the reflux temperature of tetrahydrofuran, 80 to 100°C, for 4 to 7 hours.

[0027] The above steps may further include crystallizing the reaction product from a solvent to purify the compound represented by Formula 1-3. Unlike purification using a silica column, crystallizing the reaction product from a solvent is industrially applicable and advantageous for industrial mass production.

[0028] Meanwhile, after the reaction is completed, the reaction product may be crystallized using ethanol and water, if necessary. Preferably, the crystallization is carried out in two steps, specifically, a primary crystallization using ethanol, which is the most suitable method for crystallization, and a secondary crystallization using purified water. This two-step crystallization prevents crystals from sticking to the wall as they are formed, thereby preventing a decrease in yield, and allows uncrystallized products to be crystallized in the second additional crystallization step.

[0029] In this case, ethanol can be used in a volume (mL / g) that is 3 to 5 times the weight of the compound represented by Chemical Formula 1-1. The volume ratio of ethanol to water may be 1:0.5 to 1:1.5, preferably 1:1.

[0030] Stage 2) Step 2 is a step of preparing a compound represented by the following Formula 1-4 by reduction of a compound represented by the following Formula 1-3, and the reduction reaction is carried out in the presence of a sulfur-containing reducing agent.

[0031] As mentioned above, the reduction of a nitro group to an amino group has generally been carried out using hydrogen gas in the presence of a catalyst, but this has posed safety concerns due to the toxicity of the catalyst and the explosive nature of hydrogen gas. In particular, reduction using metal catalysts such as Raney nickel or palladium on carbon (Pd / C) and hydrogen gas has been unsuitable for industrial applications due to the highly toxic and fire-prone nickel or palladium metal catalysts and the highly explosive hydrogen gas. However, the sulfur-containing reducing agent is inexpensive and non-explosive, making it suitable for industrial applications.

[0032] Specifically, the sulfur-containing reducing agent may be one or more selected from the group consisting of sodium hydrosulfite (sodium dithionite; NaSO), sodium bisulfite, sodium metabisulfite, and sodium sulfide, but is not limited thereto.

[0033] The sulfur-containing reducing agent can be used in an amount of 1 to 10 equivalents relative to 1 equivalent of the compound represented by Formula 1-3. When the sulfur-containing reducing agent is used in the above range, the residue yield is high and the agent is suitable for use. For example, the sulfur-containing reducing agent can be used in an amount of 1 equivalent or more, 2 equivalents or more, 3 equivalents or more, or 4 equivalents or more, and 10 equivalents or less, 9 equivalents or less, 8 equivalents or less, or 7 equivalents or less relative to 1 equivalent of the compound represented by Formula 1-3.

[0034] Furthermore, in order to prevent the production of by-products, the reduction reaction in this step is carried out in the presence of one or more bases selected from the group consisting of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium methylate, and potassium butyrate, but the reduction reaction in this step can also be carried out without a base.

[0035] The reaction solvent used in this step may be at least one selected from the group consisting of ethanol, methanol, isopropanol, butanol, tetrahydrofuran, acetone, dimethylformamide, methyl sulfoxide, and acetonitrile. Such a solvent may be used in an amount of 5 to 30 times (mL / g) the volume of the compound represented by Formula 1-3, more specifically, in an amount of 5 to 15 times (mL / g).

[0036] Preferably, step 2 comprises: 2-a) dissolving the compound represented by Formula 1-3 in the reaction solvent; 2-b) adding the base to the solution prepared in step 2-a); and 2-c) The sulfur-containing reducing agent is added to carry out a reduction reaction.

[0037] This reduction reaction is carried out at 20 to 60°C for 1 to 2 hours. When the reaction is carried out within the above temperature range, there is little color change in the product, and within the above reaction time range, there is no significant increase in impurities, and the impurities that are produced can be completely removed by the work-up process.

[0038] Meanwhile, after the reaction is completed, the steps up to Step 3 described below are carried out in situ in the same reaction vessel without the need for purification or separation of the compound represented by Formula 1-4. As such, since Step 2 does not require purification or a separate separation process for the compound, the method for producing the compound represented by Formula 1 including Step 2 may be advantageous in terms of industrial mass production of the compound.

[0039] Stage 3) Step 3 is a step of reacting the compound represented by Formula 1-4 with an orthoformate compound to produce a compound represented by Formula 1-5 below. The reaction is preferably carried out in the presence of an acid.

[0040] The orthoformate may be trimethyl orthoformate (TMOF), triethyl orthoformate, or diethyl phenyl orthoformate.

[0041] The orthoformate compound can be used in an amount of 1 to 2 equivalents relative to 1 equivalent of the compound represented by Chemical Formula 1-4. Using less than 1 equivalent of the orthoformate compound relative to 1 equivalent of the compound represented by Chemical Formula 1-4 is undesirable because the reaction may not be completed. Using more than 2 equivalents of the orthoformate compound relative to 1 equivalent of the compound represented by Chemical Formula 1-4 does not substantially increase the production yield. For example, the orthoformate compound can be used in an amount of 1 equivalent or more, 1.1 equivalents or more, or 1.2 equivalents or more, but less than 2 equivalents, 1.8 equivalents, 1.6 equivalents, or 1.5 equivalents relative to 1 equivalent of the compound represented by Chemical Formula 1-4. Preferably, the orthoformate compound can be used in an amount of 1.3 equivalents relative to 1 equivalent of the compound represented by Chemical Formula 1-4.

[0042] In addition, it is advantageous in terms of yield to carry out the reaction in the above step in the presence of one or more acid catalysts selected from the group consisting of paratoluenesulfonic acid, methanesulfonic acid (MSA), and camphorsulfonic acid.

[0043] The reaction is carried out at 40 to 60° C. for 0.5 to 3 hours. If the reaction is carried out at a temperature lower than the above temperature, the reaction rate is slow, whereas if the reaction is carried out at a temperature higher than the above reaction temperature, 70 to 80° C., the reaction rate increases but there is a risk of impurities being produced.

[0044] Meanwhile, after the reaction is completed, the method may further include a step of crystallizing the reaction product using a non-polar organic solvent to purify the compound represented by Formula 1-5. For the crystallization, it is preferable to use a non-polar organic solvent, taking into consideration the solubility of the compound represented by Formula 1-5. Unlike purification using a silica column, crystallization of the reaction product using a solvent is industrially applicable and may be advantageous in terms of industrial mass production.

[0045] Specifically, n-hexane can be used as the non-polar organic solvent, which can increase the reaction yield and is less hazardous. The non-polar organic solvent can be used in a volume (mL / g) that is 2 to 5 times the weight of the compound represented by Formula 1-4. The crystallization is carried out at a temperature of about 0 to 10°C with stirring for 2 to 4 hours. It is preferable to proceed with the crystallization in the above temperature range for the above reaction time, since this increases the yield while minimizing the amount of product remaining in the filtrate.

[0046] Stage 4) Step 4 is a step of reacting the compound represented by Formula 1-5 with hydrochloric acid in the presence of water and acetone to prepare the compound represented by Formula 1. Here, before reacting the compound represented by Formula 1-5 with hydrochloric acid in the presence of water and acetone, a deprotection reaction is carried out in the presence of acid. Thereafter, the deprotected compound is crystallized in the presence of water and acetone, and HCl is introduced into the deprotected compound, thereby preparing the final compound, the compound represented by Formula 1.

[0047] The compound represented by Formula 1-5 contains two protecting groups, P1 and P2, and deprotection of these two protecting groups is required to produce the final compound. In KR Patent Registration No. 10-2084772, this deprotection reaction is carried out by using an excess of 4N hydrogen chloride dioxane solution in tetrahydrofuran solvent and stirring at room temperature for 12 hours. Furthermore, the compound is produced in the form of dihydrochloride (2HCl) through this deprotection reaction. However, this method is expensive and dangerous, and is not suitable for mass production because it requires the use of an excess of 4N hydrogen chloride dioxane solution, the concentration of which varies depending on storage conditions. Furthermore, the dihydrochloride (2HCl) form has problems such as hygroscopicity, so production of the monohydrochloride (1HCl) form was required.

[0048] However, if 1) the deprotection reaction is carried out using inexpensive hydrochloric acid together with an organic solvent, and then 2) 1HCl is introduced in the presence of hydrochloric acid, water, and acetone, not only can the raw material cost be significantly reduced and the reaction time be shortened, but the compound in the dihydrochloride (2HCl) form can be directly converted to the monohydrochloride (1HCl) form without having to be converted back to the monohydrochloride (1HCl) form, making it applicable to industrial processes.

[0049] Here, concentrated hydrochloric acid (c-HCl) can be used as the hydrochloric acid. For example, concentrated hydrochloric acid with a concentration of about 30 to 40% can be used for both the deprotection reaction and the monoHCl introduction reaction.

[0050] Specifically, before reacting the compound represented by Formula 1-5 with hydrochloric acid in the presence of water and acetone, a deprotection reaction is carried out in the presence of hydrochloric acid in one or more organic solvents selected from the group consisting of ethyl acetate, dichloromethane, diethyl ether, and tetrahydrofuran, of which ethyl acetate is preferred as the organic solvent in terms of cost and ease of operation.

[0051] The deprotection reaction is carried out at 0 to 10° C. for 30 minutes to 2 hours. If the reaction temperature is higher than 10° C., it is undesirable because unknown impurities increase, and the reaction is completed within 2 hours, so the above reaction time is preferred.

[0052] Furthermore, after the deprotection reaction, the method may further include a step of washing the reaction product with the same organic solvent as that used in the deprotection reaction, thereby effectively removing impurities and significantly improving the purity of the final compound.

[0053] The monoHCl introduction reaction is a step of crystallizing (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol produced in the deprotection reaction as monohydrochloride. Both water and acetone can be used as the crystallization solvent. Acetone is preferred because it is less expensive than other solvents such as methanol, ethanol, and tetrahydrofuran, and it allows the final compound to be obtained in high quality and yield. However, if acetone is used alone, there is a risk of the monoHCl salt crystals clumping together during the crystallization process.

[0054] In this case, the water and acetone can be used in a volume ratio of 1:10 to 1:40, or 1:15 to 1:25, which can maintain the quality of the product and increase the yield of the product.

[0055] Additionally, the hydrochloric acid used with the water and acetone can be more than 0.5 equivalents and less than 2.0 equivalents relative to 1 equivalent of the compound represented by Chemical Formula 1-5. If the hydrochloric acid is used in an amount less than 0.5 equivalents relative to 1 equivalent of the compound represented by Chemical Formula 1-5, only about 50% salt crystals may be formed. If the hydrochloric acid is used in an amount more than 2.0 equivalents relative to 1 equivalent of the compound represented by Chemical Formula 1-5, a diHCl compound may be formed and dissolve in water. Therefore, the hydrochloric acid used with the water and acetone is preferably used in an amount of 0.9 to 1.1 equivalents, or 1 equivalent, relative to 1 equivalent of the compound represented by Chemical Formula 1-5.

[0056] The crystallization is carried out at 0 to 10° C. for 30 minutes to 4 hours. Within the above range, the amount of residual product from this step is minimized and the crystallization is carried out effectively.

[0057] Step 5) Meanwhile, after step 4), the method may further include a step of purifying the compound represented by Formula 1 with purified water at a temperature of 70 to 80° C. This step effectively removes impurities and residual solvents, thereby increasing the purity of the final product.

[0058] In this step, when purified water is used instead of other organic solvents, the quality and yield of the product can be improved by the high-temperature slurry method. In this case, the purified water can be used in an amount (mL / g) of 1 to 3 times the weight of the compound represented by Formula 1.

[0059] In order to effectively purify the compound represented by Chemical Formula 1, the compound represented by Chemical Formula 1 can be stirred in purified water at a temperature of 70 to 80° C. for 30 minutes to 2 hours, and then further stirred at 0 to 5° C. for 1 to 6 hours. If the reaction temperature is lower than 70° C., impurities and residual solvents are removed less, while if it is higher than 80° C., unknown impurities increase, which is not preferable.

[0060] As can be seen from the examples and comparative examples below, the method for preparing the compound represented by Chemical Formula 1 according to the above method not only reduces the number of process steps but also significantly improves the overall yield compared to the method described in KR Patent No. 10-2084772. Furthermore, by applying a solvent crystallization purification method instead of a column purification method at each step and replacing hazardous or expensive raw materials with low-cost, safe raw materials, the method enabled mass production of the compound represented by Chemical Formula 1.

[0061] (Method for producing the compound represented by the above chemical formula 1-1) Meanwhile, the compound represented by Chemical Formula 1-1, which is a starting material used in the method for producing the compound represented by Chemical Formula 1, is prepared according to the following Reaction Scheme 2: [Reaction Scheme 2] JPEG2026004468000031.jpg113170In the above reaction formula 2, X is halogen, Ms is methanesulfonyl, and P1 and P2 each independently represent a protecting group, where P1 and P2 are as described above, and X is preferably chloro or bromo.

[0062] Stage 1) Step 1 is a step of reacting the compound represented by Formula 1A with pyrrolidine to prepare the compound represented by Formula 1B.

[0063] In this step, the compound represented by Formula 1A and pyrrolidine can be used in an equivalent ratio of 1:0.8 to 1:2. Specifically, the compound represented by Formula 1A and pyrrolidine can be used in an equivalent ratio of 1:1.0 to 1:1.5, or 1:1.2.

[0064] The reaction is carried out in an organic solvent such as toluene, dichloromethane, chloroform, dimethylformamide, dioxane, or tetrahydrofuran, where the organic solvent can be used in an amount of 1 to 10 times (L / kg), more specifically, 2 to 4 times (L / kg), the weight of the compound represented by Formula 1A.

[0065] The reaction is carried out for 8 to 16 hours at 80 to 150° C. The above-mentioned range is preferable in terms of reaction rate and production yield.

[0066] Meanwhile, after the reaction is completed, the steps up to Step 2 described below are carried out in situ in the same reaction vessel without purifying or separating the compound represented by Formula 1B.

[0067] Stage 2) Step 2 is a step of reacting the compound represented by Formula 1B with 3-bromo-1-propene to prepare the compound represented by Formula 1C, and by this step, substituents are introduced at positions 2 and 3 of the piperidine ring.

[0068] In this step, the compound represented by Formula 1B and 3-bromo-1-propene can be used in an equivalent ratio of 1:0.7 to 1:2. Specifically, the compound represented by Formula 1B and 3-bromo-1-propene can be used in an equivalent ratio of 1:0.7 to 1:1.3, 1:0.9 to 1:1.1, or 1:1.

[0069] The reaction is carried out in a polar organic solvent. Examples of the polar organic solvent include acetonitrile, methanol, tetrahydrofuran, acetone, dioxane, diethyl ether, dichloromethane, and dimethylformamide. The polar organic solvent can be used in an amount of 1 to 10 times (L / kg) the volume of the compound represented by Formula 1B, more specifically, in an amount of 2 to 4 times (L / kg).

[0070] The reaction is carried out for 8 to 16 hours at 30 to 60° C. or 40 to 45° C. The above ranges are preferable in terms of reaction rate and production yield.

[0071] Stage 3) Step 3 is a step of reducing the compound represented by Formula 1C to produce the compound represented by Formula 1D, and the reduction reaction is carried out in the presence of a ketoreductase enzyme. Therefore, this step involves enzymatic asymmetric reduction of the ketone in the compound represented by Formula 1C, which may result in the carbons at positions 2 and 3 of the piperidine ring becoming chiral centers. Specifically, the carbon at position 2 of the piperidine ring in the compound represented by Formula 1D exhibits (R) chirality, and the carbon at position 3 exhibits (S) chirality.

[0072] On the other hand, as the ketoreductase, Ketoreductase TJ-K066 available from Enzyme Works can be used.

[0073] The ketoreductase can be used in an amount of 0.01 to 0.2 times, more specifically 0.05 to 0.15 times by weight relative to the weight of the compound represented by Chemical Formula 1C.

[0074] The ketoreductase can be dissolved in a buffer solution. The buffer solution can be NaHPO hydroxide, NaHPO hydroxide, KHPO hydroxide, or KHPO hydroxide. For example, NaHPO·2H2O, NaHPO·12H2O, or a mixture thereof can be used. A pH value of 6.5 to 7.5 is preferred for the reaction. The buffer solution can be used in a volume (L / kg) that is 5 to 20 times the weight of the compound represented by Formula 1C.

[0075] And the reduction is One or more enzymes selected from the group consisting of glutamate dehydrogenase (GDH) and glucose; and The reaction is carried out in the presence of one or more cofactors selected from the group consisting of nicotinamide adenine dinucleotide phosphate (NADP) and nicotinamide adenine dinucleotide (NAD).

[0076] In this case, in terms of yield and quality, it is preferable to use a nicotinamide adenine dinucleotide phosphate (NADP) cofactor together with glutamate dehydrogenase (GDH) / glucose for the reduction reaction.

[0077] The reaction is carried out under an inert gas atmosphere at 20 to 40° C. or 25 to 30° C. for 2 to 20 hours.

[0078] Meanwhile, after the reaction is completed, the steps up to Step 4 described below are carried out in situ in the same reaction vessel without purifying or separating the compound represented by Formula 1D.

[0079] Stage 4) Step 4 is a step of preparing a compound represented by Chemical Formula 1E by reacting a compound represented by Chemical Formula 1D with a compound represented by Chemical Formula 1d, and a protecting group is introduced into the hydroxy group of the piperidine ring by this step.

[0080] In this step, the compound represented by Formula 1D and the compound represented by Formula 1d can be used in an equivalent ratio of 1:1 to 1:2. Specifically, the compound represented by Formula 1D and the compound represented by Formula 1d can be used in an equivalent ratio of 1:1.2 to 1:2, 1:1.5 to 1:2, or 1:1.8.

[0081] Here, the compound represented by Chemical Formula 1d may be, but is not limited to, tert-butyldimethylsilyl chloride, 2-methoxyethoxymethyl ether chloride, or methoxymethyl ether chloride in a solution.

[0082] The reaction is carried out in an organic solvent such as dichloromethane, toluene, chloroform, dimethylformamide, dioxane, or tetrahydrofuran. The organic solvent can be used in an amount of 1 to 10 times (L / kg), more specifically, 2 to 6 times (L / kg), based on the weight of the compound represented by Formula 1D. The reaction is carried out at 0 to 25°C for 10 to 20 hours.

[0083] Step 5) Step 5 is a step of introducing a hydroxy group into the propenyl group at position 2 of the compound represented by Chemical Formula 1E to prepare the compound represented by Chemical Formula 1F, and is carried out by (1) reacting the compound represented by Chemical Formula 1E with a borane compound, and (2) reacting the prepared reactant with an oxidizing agent.

[0084] First, the compound represented by Chemical Formula 1E and the borane compound can be used in an equivalent ratio of 1:0.5 to 1:1.0. Specifically, the compound represented by Chemical Formula 1E and the borane compound can be used in an equivalent ratio of 1:0.5 to 1:1.0, or 1:0.7.

[0085] Here, a borane compound is used as a reducing agent to carry out the hydrogenation reaction of the compound represented by Formula 1E in this step. The borane compound may be, but is not limited to, borane dimethylsulfide (BH3-Me2S, BMS) or borane tetrahydrofuran.

[0086] In addition, the borane compound may be used in an amount of more than 0.5 equivalents and less than 1.0 equivalents relative to 1 equivalent of the compound represented by Formula 1E.

[0087] The reaction of the compound represented by Formula 1E with the borane compound is carried out in an organic solvent such as tetrahydrofuran, dichloromethane, toluene, chloroform, dimethylformamide, or dioxane. The organic solvent can be used in an amount of 1 to 10 times (L / kg), more specifically, 2 to 6 times (L / kg), the weight of the compound represented by Formula 1E. The reaction is carried out at 5 to 10°C for 2 to 8 hours.

[0088] Next, the reaction product of the compound represented by Formula 1E and the borane compound is oxidized in the presence of an oxidizing agent, which can be at least one selected from the group consisting of hydrogen peroxide, Dess-Martin periodinane, and oxalyl chloride. The oxidation reaction is carried out at 5 to 10°C for 10 to 20 hours.

[0089] Step 6) Step 6 is a step of reacting the compound represented by Formula 1F with methanesulfonyl chloride to prepare a compound represented by Formula 1G below, and the reaction is carried out in the presence of a base to introduce a protecting group into the hydroxy group.

[0090] In this step, the compound represented by Formula 1F and methanesulfonyl chloride can be used in an equivalent ratio of 1:0.7 to 1:1.5. Specifically, the compound represented by Formula 1F and methanesulfonyl chloride can be used in an equivalent ratio of 1:0.9 to 1:1.5, or 1:1.2.

[0091] The base may be one or more selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, dimethylaniline, dimethylaminopyridine, and sodium hydroxide, and may be used in an amount of 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of the compound represented by Chemical Formula 1F.

[0092] The reaction is carried out in an organic solvent such as tetrahydrofuran, dichloromethane, toluene, chloroform, dimethylformamide, or dioxane. The organic solvent can be used in an amount of 1 to 10 times (L / kg), more specifically, 2 to 6 times (L / kg), based on the weight of the compound represented by Formula 1F. The reaction is carried out at 0 to 5°C for 1 to 6 hours.

[0093] Meanwhile, after the reaction is completed, the steps up to Step 7 described below are carried out in situ in the same reaction vessel without purifying or separating the compound represented by Formula 1G.

[0094] Step 7) Step 7 is a step of reacting the compound represented by Formula 1G with an azidation reagent to prepare the compound represented by Formula 1H, and the methanesulfonyl group of the compound represented by Formula 1G is substituted with an azide group through the reaction.

[0095] The azidation reagent may be one or more selected from the group consisting of sodium azide, potassium azide, and trimethylsilyl azide, and may be used in an amount of 1 to 1.5 equivalents, preferably 1 to 1.3 equivalents, relative to 1 equivalent of the compound represented by Formula 1G.

[0096] The reaction is carried out in an organic solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, toluene, chloroform, or dioxane. The organic solvent can be used in an amount of 1 to 10 times (L / kg), more specifically, 2 to 6 times (L / kg), the weight of the compound represented by Formula 1G. The reaction is carried out in the presence of an inert gas such as nitrogen at 20 to 80°C for 8 to 16 hours.

[0097] Meanwhile, after the reaction is completed, the compound represented by Formula 1H is produced without any purification or separation process, and steps 7 and the following step 8 are carried out in situ in the same reaction vessel. In this way, the four steps of steps 1, 3, 6, and 7 are carried out in situ, and no additional separation process is required at each step, which may be advantageous for industrial mass production of the compound.

[0098] Step 8) Step 8 is a step of preparing a compound represented by Chemical Formula 1-1 by reacting the compound represented by Chemical Formula 1H in the presence of a base, and the azide group of the compound represented by Chemical Formula 1H is substituted with an amide group through the reaction.

[0099] The base may be one or more selected from the group consisting of triphenylphosphine, sodium borohydride, lithium aluminum hydride, and sodium hydride, and can be used in an amount of 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to 1 equivalent of the compound represented by Formula 1H.

[0100] The reaction is carried out in an ether-based organic solvent such as 2-methyltetrahydrofuran (2-MeTHF), diisopropyl ether, dioxane, or 1,2-dimethoxyethane. The organic solvent can be used in an amount of 1 to 10 times (L / kg), more specifically, 4 to 8 times (L / kg), based on the weight of the compound represented by Formula 1H. The reaction is carried out at 5 to 25°C for 12 to 16 hours.

[0101] Meanwhile, after the reaction is completed, the method may further include a step of crystallizing the reaction product using acetonitrile to purify the compound represented by Formula 1-1. Crystallizing the reaction product using a solvent in this manner is industrially applicable, unlike purification using a silica column, and may be advantageous in terms of industrial mass production.

[0102] As can be seen from the examples and comparative examples below, the method for preparing the compound represented by formula 1-1 according to the above method can significantly reduce the process time by shortening the process steps compared to the method described in KR Patent No. 10-2084772, and can also significantly improve the overall yield. Furthermore, since a solvent crystallization purification method is used instead of a column purification method at each step, the method allows for mass production of the compound represented by formula 1-1.

[0103] (Method of producing the compound represented by chemical formula 2) Meanwhile, the compound represented by Chemical Formula 2, which can be used as an intermediate for preparing the compound represented by Chemical Formula 1-1, can be prepared by the following Reaction Scheme 3: [Reaction Scheme 3] JPEG2026004468000032.jpg147165In the above reaction formula 3, R1 is benzyl or C 1-4 alkyl (straight or branched chain alkyl having 1 to 4 carbon atoms); P1 and P2 each independently represent a protecting group.

[0104] More specifically, P1 and P2 are as defined in Reaction Scheme 1. In terms of ease of production and yield, it is preferable that P1 is tert-butyloxycarbonyl (Boc) and P2 is tert-butyldimethylsilyl (TBS).

[0105] Stage 1) Step 1 is a step of reacting the compound represented by Formula 2-1 with propane-1,3-diol to produce the compound represented by Formula 2-2, and the reaction is an etherification reaction carried out in the presence of an acid.

[0106] In this step, the compound represented by Formula 2-1 and propane-1,3-diol can be used in an equivalent ratio of 1:0.5 to 1:2. Specifically, the compound represented by Formula 2-1 and propane-1,3-diol can be used in an equivalent ratio of 1:0.7 to 1:2, 1:1 to 1:1.8, or 1:1.5.

[0107] The acid used as a catalyst in this step may be a solid-phase strong acid catalyst, specifically a strong acid cation exchange resin, and commercially available examples of such acid catalysts include Amberlyst® 15, Amberlite® IRC120H, Amberlyst® 16, and Dowex® 50W.

[0108] Stage 2) Step 2 is a step of oxidizing the compound represented by Formula 2-2 to prepare the compound represented by Formula 2-3, and the reaction is carried out in the presence of an alcohol oxidizing agent.

[0109] The oxidation is carried out in the presence of one or more oxidizing agents selected from the group consisting of pyridinium chlorochromate (PCC) and pyridinium dichlorochromate (PDC); or by SWERN oxidation. Among these, pyridinium chlorochromate is preferred in terms of reaction rate. The compound represented by Formula 2-3 can be prepared by SWERN oxidation by reacting the compound represented by Formula 2-2 with oxalyl chloride and dimethyl sulfoxide, followed by the introduction of an organic base such as triethylamine.

[0110] The reaction is carried out in an organic solvent such as dichloromethane (DCM), toluene, chloroform, dimethylformamide, dioxane, or tetrahydrofuran, at room temperature for 2 to 6 hours.

[0111] Stage 3) Step 3 is a step of converting the compound represented by Formula 2-3 into a dibenzyl azodicarboxylate or di(C 1-4 (2) reacting the compound with an alkyl azodicarboxylate and then with an allyl halide to prepare the compound represented by the formula 2-4.

[0112] First, the compound represented by the formula 2-3 is converted into dibenzyl azodicarboxylate or di(C 1-4 alkyl)azodicarboxylate to create a dibenzylhydrazinedicarboxylate group or di(C 1-4 In this step, the compound represented by Formula 2-3 and dibenzyl azodicarboxylate or di(C 1-4 The alkyl azodicarboxylate can be used in an equivalent ratio of 1:0.5 to 1:2.

[0113] wherein the dibenzyl azodicarboxylate or di(C 1-4 The alkyl azodicarboxylate can be selected from dibenzyl azodicarboxylate (DBAD), diethyl azodicarboxylate (DEAD), dibutyl azodicarboxylate, and di-tert-butyl azodicarboxylate. Of these, dibenzyl azodicarboxylate is preferred for more stereoselective reaction.

[0114] In addition, the reaction is carried out in the presence of a proline catalyst to increase the efficiency of the reaction between the compound represented by Formula 2-3 and the azodicarboxylate compound and to increase the stereoselectivity of the reaction product.

[0115] The reaction is carried out in an organic solvent such as acetonitrile, methanol, tetrahydrofuran, acetone, dioxane, diethyl ether, dichloromethane, or dimethylformamide at −20 to 20° C., preferably −5 to 5° C., and more preferably 0° C., for 1 to 5 hours.

[0116] Next, the dibenzylhydrazinedicarboxylate group or di(C 1-4 The intermediate containing the (alkyl)hydrazinedicarboxylate group is reacted with an allyl halide in the presence of a metal catalyst. Allyl bromide, alkyl chloride, or the like can be used as the allyl halide. This reaction is carried out in the presence of a metal catalyst such as a zinc catalyst or an indium catalyst at a temperature of -20 to 20°C, preferably -5 to 5°C, and more preferably 0°C, for 30 minutes to 5 hours.

[0117] Stage 4) Step 4 is a step of preparing a compound represented by Formula 2-5 by subjecting the compound represented by Formula 2-4 to a cyclization reaction in the presence of an oxidizing agent.

[0118] The cyclization reaction is carried out in the presence of one or more oxidizing agents selected from the group consisting of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), FeCl3, and MoCl5.

[0119] The reaction is carried out in an organic solvent such as dichloromethane (DCM), toluene, chloroform, dimethylformamide, dioxane, or tetrahydrofuran at −30 to 0° C. for 4 to 10 hours. A molecular sieve can be used to prevent moisture from entering during the reaction.

[0120] Step 5) Step 5 is to obtain benzyl carbamate or C from the compound represented by Formula 2-5. 1-4 Alkyl carbamate (C 1-4 This step is carried out in the presence of a base to prepare a compound represented by Formula 2-6 by removing the benzyl carbamate or C 1-4 The alkyl carbamate may be the dibenzylhydrazine dicarboxylate group or the di(C 1-4 (alkyl)hydrazinedicarboxylate group.

[0121] The base may be at least one selected from the group consisting of cesium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, sodium methylate, and potassium butyrate.

[0122] The reaction is carried out in an organic solvent such as acetonitrile (ACN), tetrahydrofuran (THF), 1,4-dioxane, or N,N-dimethylformamide (DMF) at 50 to 100°C for 20 to 30 hours.

[0123] Step 6) Step 6 is a step of producing the compound represented by Formula 2-7 by boronation-oxidation of the compound represented by Formula 2-6. Here, the boronation-oxidation reaction is a two-step hydration reaction that converts an alkene into an alcohol, and through this reaction, the alkene in the compound represented by Formula 2-6 is converted into an alcohol.

[0124] First, the boronation reaction is carried out using a boronation reagent such as borane, borane dimethyl sulfide, etc., and the compound represented by Formula 2-6 and the boronation reagent can be used in an equivalent ratio of 1:1 to 1:1.5. The reaction is carried out in an organic solvent such as tetrahydrofuran, dioxane, diethyl ether, dichloromethane, or dimethylformamide at 0 to 25°C for 1 to 5 hours.

[0125] Next, an oxidation reaction is carried out in the presence of an oxidizing agent such as hydrogen peroxide, sodium perborate, or 4-methylmorpholine N-oxide, etc. The oxidation reaction is carried out at 0 to 25° C. for 1 to 5 hours.

[0126] Step 7) Step 7 is a step of preparing a compound represented by Formula 2-8 by cyclization of the compound represented by Formula 2-7. The cyclization is carried out by reacting the compound represented by Formula 2-7 with methanesulfonyl chloride (MsCl) and then with a strong base.

[0127] First, the reaction of the compound represented by Chemical Formula 2-7 with methanesulfonyl chloride (MsCl) is carried out in the presence of one or more bases selected from the group consisting of triethylamine, pyridine, potassium carbonate, and sodium carbonate at 0 to 25°C for 1 to 4 hours.

[0128] Next, a cyclization reaction is carried out in the presence of a strong base such as sodium hydride, potassium tartrate bromide, or sodium borohydride at −10 to 25° C. for 1 to 4 hours to produce the compound represented by the above chemical formula 2-8.

[0129] Step 8) Step 8 is a step of reacting the compound represented by Formula 2-8 in the presence of a base to prepare the compound represented by Formula 2-9, which can remove the carboxylate group in the carbamate moiety.

[0130] The base may be one or more strong bases selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide, and the reaction is carried out in the presence of such a strong base for 3 to 10 hours.

[0131] Step 9) Step 9 is a step of introducing a protecting group into the compound represented by Formula 2-9 to prepare the compound represented by Formula 2-10. The reaction is carried out in the presence of a base, thereby introducing a protecting group onto the nitrogen atom of the amino group.

[0132] The compound represented by Chemical Formula 2-9 and a reagent capable of introducing a protecting group can be used in an equivalent ratio of 1:0.7 to 1:2. Specifically, the compound represented by Chemical Formula 2-9 and a reagent capable of introducing a protecting group can be used in an equivalent ratio of 1:0.9 to 1:1.8, or 1:1.5.

[0133] The base may be one or more selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, dimethylaniline, dimethylaminopyridine, and sodium hydroxide, and may be used in an amount of 1 to 2.5 equivalents, preferably 1.5 to 2.0 equivalents, relative to 1 equivalent of the compound represented by Chemical Formula 2-9.

[0134] Step 10) Step 10 is a step of preparing a compound represented by Formula 2-11 by reacting the compound represented by Formula 2-10 in the presence of an acid, and the para-methoxybenzyl group in the compound can be removed by this step.

[0135] The acid may be one or more strong acids selected from the group consisting of camphorsulfonic acid (CSA) and p-toluene-4-sulfonic acid, and the reaction is carried out in the presence of such a strong acid for 20 to 40 hours.

[0136] Step 11) Step 11 is a step of introducing a protecting group into the compound represented by Formula 2-11 to prepare the compound represented by Formula 2-12. The reaction is carried out in the presence of a base, thereby introducing a protecting group into the hydroxy group.

[0137] The compound represented by Chemical Formula 2-11 and a reagent capable of introducing a protecting group can be used in an equivalent ratio of 1:1.5 to 1:3.5. Specifically, the compound represented by Chemical Formula 2-11 and a reagent capable of introducing a protecting group can be used in an equivalent ratio of 1:2 to 1:3, or 1:2.5.

[0138] The base may be one or more selected from the group consisting of imidazole, methylaminopyridine, and triethylamine, and can be used in an amount of 2 to 4 equivalents, preferably 2.5 to 3.5 equivalents, relative to 1 equivalent of the compound represented by Chemical Formula 2-11.

[0139] Step 12) Step 12 is a step of preparing a compound represented by Formula 2 by reacting a compound represented by Formula 2-12 in the presence of an acid, and some of the protecting groups in the compound can be removed by this step.

[0140] The acid may be one or more strong acids selected from the group consisting of camphorsulfonic acid (CSA) and p-toluene-4-sulfonic acid, and the reaction is carried out in the presence of such a strong acid for 1 to 4 hours.

[0141] The compound represented by Formula 2 prepared by the above steps can be used as an intermediate for preparing the compound represented by Formula 1-1. For example, the compound represented by Formula 1-1 can be prepared using the compound represented by Formula 2 according to the following Reaction Scheme 4: [Reaction Scheme 4] JPEG2026004468000033.jpg119166In Reaction Scheme 4, P1 and P2 each independently represent a protecting group, more specifically as defined in Reaction Scheme 1. Meanwhile, each step in Reaction Scheme 4 can be more specifically explained with reference to Steps 13 to 19 in Comparative Example 2 described below. [Effects of the Invention]

[0142] As described above, the production method according to the present invention has the advantage that it can produce a (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol derivative and its starting material in high yield even with a shortened process. DETAILED DESCRIPTION OF THE INVENTION

[0143] The present invention will be described in more detail with reference to the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0144] Example 1-1: Preparation of the compound represented by Chemical Formula 1 JPEG2026004468000034.jpg53167

[0145] Step 1) Preparation of Compounds 1-3 Compound 1-1, tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (100.0 g, 0.27 mol, 1.0 eq) was dissolved in 1000 mL of tetrahydrofuran. Compound 1-2, 1,2-dichloro-4-fluoro-3-nitrobenzene (56.4 g, 0.27 mol, 1.0 eq) and N,N-diisopropylethylamine (DIPEA, 93.5 mL, 0.54 mol, 2.0 eq) were added, and the mixture was stirred under reflux conditions (80-100 °C) in tetrahydrofuran for 4-7 hours. Upon completion of the reaction, 1000 mL of purified water was added to extract the organic layer, followed by re-extraction with 1000 mL of ethyl acetate. After vacuum concentration, 100 mL of ethanol was added to the concentrated residue, and the residue was re-concentrated. The concentrated residue was added with 400 mL of ethanol and crystallized. After crystals were formed, 400 mL of purified water was added and crystallization was allowed to proceed at 0-5°C for 2 hours. The crystals were filtered under reduced pressure using a filter and washed with a mixture of 100 mL of EtOH and 100 mL of purified water cooled to 0-5°C. The crystals were dried under vacuum at 45-55°C for 12 hours to obtain compound 1-3, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-((3,4-dichloro-2-nitrophenyl)amino)propyl)piperidine-1-carboxylate (131.5 g, yield: 87%), as an orange or red solid.

[0146] 1 H NMR (500 MHz, MeOD): δ 7.43 (d, 1H), 6.89 (d, 1H), 4.08 (s, 1H), 3.94 (s, 1H), 3.76 (s, 1H), 3.24 (m, 2H), 2.76 (s, 1H), 1.86 (m, 1H), 1.74 (m, 2H), 1.58 (m, 3H), 1.48 (s, 10H), 1.45 (s, 1H), 0.90 (s, 9H), 0.07 (d, 6H)

[0147] Step 2) Preparation of Compounds 1-4 Compound 1-3 (120.0 g, 0.21 mol, 1.0 eq) obtained in Step 1 was dissolved in 1200 mL of ethanol, followed by the addition of potassium carbonate (176.9 g, 1.28 mol, 6.0 eq) and 1400 mL of aqueous sodium hydrosulfite solution (NaSO content in the aqueous solution: 222.8 g, 1.28 mol, 6.0 eq). The mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the ethanol was concentrated under reduced pressure, followed by extraction with 600 mL of purified water and 1200 mL of ethyl acetate. Another 600 mL of ethyl acetate was added for further extraction. The organic layer was washed with 1200 mL of brine. Sodium sulfate was added for drying to remove excess water. The mixture was concentrated under reduced pressure to give compound 1-4, tert-butyl (2R,3S)-2-(3-((2-amino-3,4-dichlorophenyl)amino)propyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (113.6 g, yield: 100%), as a brown liquid. The obtained compound was used in the next step without purification.

[0148] Step 3) Preparation of Compounds 1-5 Compound 1-4 (113.6 g, 0.21 mol, 1.0 eq) obtained in Step 2 was dissolved in 1136 mL of toluene, followed by the addition of trimethyl orthoformate (TMOF, 30.3 mL, 0.28 mol, 1.3 eq) and paratoluenesulfonic acid (0.4 g, 0.02 mol, 0.1 eq). The mixture was stirred at 50-60°C for 1-2 hours. Upon completion of the reaction, the 1136 mL of toluene used in the reaction was removed by concentration under reduced pressure. Extraction was performed by adding 122 mL of aqueous sodium bicarbonate solution, 1136 mL of ethyl acetate, and 1136 mL of purified water; the layers were easily separated. The aqueous layer was then re-extracted with 568 mL of EA. Activated carbon (11.4 g, 0.1 eq) was added to the organic layer to remove color and stirred for 15 minutes. Sodium sulfate was added to remove water and stirred for 15 minutes, then the mixture was filtered through a Celite pad. After the filtrate was concentrated under reduced pressure, 227 mL of n-hexane was added to the concentrated residue. After concentration under reduced pressure, 340 mL of n-hexane was added and refluxed and stirred for 30 minutes to dissolve the crystals. The mixture was then cooled to 0-5°C and stirred at the same temperature for 4 hours. The mixture was filtered under reduced pressure using a filter and washed with 113 mL of n-hexane cooled to 0-5°C. The mixture was dried under vacuum at 45-55°C for 12 hours to obtain compound 1-5, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidine-1-carboxylate (100 g, yield: 86%), as a white solid. The filtrate was concentrated and the crystallization process was carried out in the same manner to obtain additional white solid compound 1-5 (8.0 g, yield: 8%), and finally compound 1-5 (108 g, yield: 94%).

[0149] 1H NMR (500 MHz, MeOD): δ 8.30 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.30 (m, 2H), 4.17 (s, 1H), 4.05 (s, 1H), 3.91 (d, 1H), 3.73 (s, 1H), 2.68 (s, 1H), 1.87 (s, 3H), 1.70 (t, 2H), 1.55 (d, 1H), 1.45 (m, 10H), 1.42 (s, 1H), 0.90 (s, 9H), 0.07 (d, 6H)

[0150] Step 4) Preparation of the compound represented by formula 1 Compound 1-5 (90.0 g, 0.17 mol, 1.0 eq) obtained in Step 3 was dissolved in 540 mL of ethyl acetate and cooled to 0-10°C. Concentrated hydrochloric acid (146.4 mL, 10.0 eq) was added and stirred for 1-2 hours. After the reaction was completed, 540 mL of purified water was added and extracted at room temperature (the product was present in the aqueous layer under acidic conditions). 540 mL of ethyl acetate was added to the aqueous layer again and re-extracted (impurities were removed with EA). The organic layer was discarded, and 8N aqueous sodium hydroxide solution was slowly added to adjust the pH to 12.5 or higher. 900 mL of dichloromethane was added and extraction was performed (the product was present in the MC layer under basic conditions). 450 mL of dichloromethane was added and re-extraction was performed. After completion of concentration under reduced pressure, the concentrated residue, freebase (salt-free) (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, was dissolved in 1100 mL of acetone and 54 mL of purified water. One equivalent of concentrated hydrochloric acid was added dropwise in three portions, and the resulting crystals were stirred at 0-5°C for 4 hours to allow crystallization to proceed. The crystals were filtered under reduced pressure using a filter and washed with 109 mL of acetone cooled to 0-5°C. The crystals were dried under vacuum at 45-55°C for 12 hours to obtain a white solid, (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol 1HCl (58.5 g, yield: 97%), which is the compound represented by Chemical Formula 1.

[0151] 1H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0152] Step 5) Additional refining process The compound represented by Formula 1 (55 g, 0.15 mol, 1.0 eq) obtained in Step 4 was added to 110 mL of purified water and stirred at 70-75°C for 1 hour, then cooled to 0-5°C and stirred at the same temperature for 4 hours. The mixture was filtered under reduced pressure using a filter and washed with 55 mL of acetone cooled to 0-5°C. The mixture was dried in vacuo at 45-55°C for 12 hours to obtain the purified compound represented by Formula 1 (52.0 g, yield: 94%) as a white solid.

[0153] 1 H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0154] Example 1-2: Preparation of the compound represented by Chemical Formula 1 JPEG2026004468000035.jpg55167

[0155] Step 1) Preparation of Compounds 1-3 Compound 1-1, tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (100.0 g, 0.27 mol, 1.0 eq) was dissolved in 1000 mL of tetrahydrofuran. Compound 1-2, 1,2-dichloro-4-fluoro-3-nitrobenzene (56.4 g, 0.27 mol, 1.0 eq) and potassium carbonate (K2CO3, 74.2 g, 0.54 mol, 2.0 eq) were added, and the mixture was stirred under reflux conditions (80-100 °C) in tetrahydrofuran for 1-3 hours. Upon completion of the reaction, 1000 mL of purified water was added to extract the organic layer, followed by re-extraction with 1000 mL of ethyl acetate. After vacuum concentration, 100 mL of ethanol was added to the concentrated residue, and the residue was re-concentrated. The concentrated residue was dissolved in 400 mL of ethanol and crystallized. After crystals were formed, 400 mL of purified water was added and crystallization was allowed to proceed at 0-5°C for 2 hours. The crystals were filtered under reduced pressure using a filter and washed with a mixture of 100 mL of EtOH and 100 mL of purified water cooled to 0-5°C. The resulting mixture was dried under vacuum at 45-55°C for 12 hours to obtain compound 1-3, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-((3,4-dichloro-2-nitrophenyl)amino)propyl)piperidine-1-carboxylate (143.0 g, yield: 95%), as an orange or red solid.

[0156] 1 H NMR (500 MHz, MeOD): δ 7.43 (d, 1H), 6.89 (d, 1H), 4.08 (s, 1H), 3.94 (s, 1H), 3.76 (s, 1H), 3.24 (m, 2H), 2.76 (s, 1H), 1.86 (m, 1H), 1.74 (m, 2H), 1.58 (m, 3H), 1.48 (s, 10H), 1.45 (s, 1H), 0.90 (s, 9H), 0.07 (d, 6H)

[0157] Stages 2) to 4) Thereafter, steps 2) to 4) were carried out in the same manner as in Example 1-1 to obtain (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol 1HCl (58.5 g, yield: 97%), which is a compound represented by Chemical Formula 1.

[0158] 1 H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0159] Step 5) Additional refining process The compound represented by Formula 1 (55 g, 0.15 mol, 1.0 eq) obtained in Step 4 was added to 110 mL of purified water and stirred at 70-75°C for 1 hour, then cooled to 0-5°C and stirred at the same temperature for 4 hours. The mixture was filtered under reduced pressure using a filter and washed with 55 mL of acetone cooled to 0-5°C. The mixture was dried in vacuo at 45-55°C for 12 hours to obtain the purified compound represented by Formula 1 (52.0 g, yield: 94%) as a white solid.

[0160] 1 H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0161] Comparative Example 1: Preparation of Compound Represented by Formula 1 JPEG2026004468000036.jpg54167

[0162] Step 1) Preparation of Compounds 1-3 Compound 1-1, tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (1.0 g, 2.7 mmol), was dissolved in N,N-dimethylformamide (25 mL, 0.67 M). Compound 1-2, 1,2-dichloro-4-fluoro-3-nitrobenzene (629.97 mg, 3.0 mmol) and N,N-diisopropylethylamine (0.93 mL, 5.4 mmol), were added and heated and stirred at 60 °C for 2 hours. Upon completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate = 5:1) to give compound 1-3 (1.2 g, 81% yield).

[0163] 1 H NMR (500 MHz, MeOD): δ 7.43 (d, 1H), 6.89 (d, 1H), 4.08 (s, 1H), 3.94 (s, 1H), 3.76 (s, 1H), 3.24 (m, 2H), 2.76 (s, 1H), 1.86 (m, 1H), 1.74 (m, 2H), 1.58 (m, 3H), 1.48 (s, 10H), 1.45 (s, 1H), 0.90 (s, 9H), 0.07 (d, 6H)

[0164] Step 2) Preparation of Compounds 1-4 Compound 1-3 (2.6 mg, 4.9 mmol) obtained in step 1 was dissolved in methanol (25 mL, 0.2 M), and then an appropriate amount of Raney nickel was added. A hydrogen balloon was connected, and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the reaction solution was filtered through Celite and concentrated under reduced pressure to obtain compound 1-4. The resulting compound was used in the next step without purification.

[0165] Step 3) Preparation of Compounds 1-5 Compound 1-4 obtained in Step 2 was dissolved in toluene (30 mL, 0.16 M), and then trimethyl orthoformate (1.6 mL, 14.6 mmol) and paratoluenesulfonic acid (168 mg, 0.98 mmol) were added. The mixture was heated and stirred at 50°C for 6 hours. Upon completion of the reaction, the solvent was removed, the mixture was diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain compound 1-5 (1.8 g, 74% yield).

[0166] 1 H NMR (500 MHz, MeOD): δ 8.30 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 4.30 (m, 2H), 4.17 (s, 1H), 4.05 (s, 1H), 3.91 (d, 1H), 3.73 (s, 1H), 2.68 (s, 1H), 1.87 (s, 3H), 1.70 (t, 2H), 1.55 (d, 1H), 1.45 (m, 10H), 1.42 (s, 1H), 0.90 (s, 9H), 0.07 (d, 6H)

[0167] Step 4) Preparation of Compounds 1-6 Compound 1-5 (1.8 g, 3.6 mmol) obtained in Step 3 was dissolved in a small amount of tetrahydrofuran, and then 4N hydrogen chloride dioxane solution (30 mL, 0.12 M) was added and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the mixture was dissolved in a small amount of methanol and crystallized from diethyl ether to obtain compound 1-6, (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol diHCl (26 mg, 81% yield).

[0168] 1H NMR (500 MHz, MeOD): δ 9.67 (s, 1H). 8.02 (d, 1H), 7.82 (d, 1H), 4.62 (m, 2H), 3.60 (m, 1H), 3.28 (m, 1H), 2.99 (m, 2H), 2.25 (m, 2H), 2.08 (m, 2H), 1.99 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H)

[0169] Step 5) Preparation of the compound represented by formula 1 Compound 1-6 (17.3 g, 0.04 mol, 1.0 eq) obtained in Step 4 was dissolved in 86.5 mL of an aqueous solution of sodium hydroxide (NaOH, 6.9 g, 0.16 mol, 4.0 eq). This was added to 346 mL of dichloromethane for extraction, and the aqueous layer was re-extracted with 173 mL of dichloromethane. Sodium sulfate was added to dry the mixture and remove excess water. After concentration under reduced pressure, the mixture was dissolved in 346 mL of acetone and 17.3 mL of purified water. One equivalent of concentrated hydrochloric acid (pH 6.5-7) was added and stirred at room temperature for 2 hours. This was filtered under reduced pressure using a filter to obtain a white solid. 16 mL of purified water was added and stirred at 75°C for 1 hour, followed by stirring at 5°C for 1 hour. This was filtered under reduced pressure using a filter to obtain the title compound (11.1 g, 71% yield) represented by Formula 1 as a purified white solid.

[0170] 1 H NMR (500 MHz, DMSO): δ 8.45 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 5.40 (d, 1H), 4.32 (m, 2H), 3.41 (m, 1H), 3.08 (d, 1H), 2.75 (m, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H)

[0171] Comparison of Example 1-1, Example 1-2 and Comparative Example 1 In order to compare the compound represented by Chemical Formula 1 produced by the production methods of Examples 1-1 and 1-2 with the compound produced by Comparative Example 1, the yields of each production method are summarized in Table 1 below.

[0172] [Table 1]

[0173] As shown in Table 1, the manufacturing method of the Example can produce the compound represented by Chemical Formula 1 in an improved yield while reducing the number of process steps compared to the manufacturing method of Comparative Example 1.

[0174] Furthermore, the manufacturing method of the above example does not use hazardous or expensive raw materials in each process step, and does not use a column purification method that is difficult to apply industrially, and it has been confirmed that the manufacturing method of the above example is suitable for mass production of the compound represented by Chemical Formula 1.

[0175] Example 2: Preparation of Compound 1-1 (tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate) JPEG2026004468000038.jpg87166

[0176] Step 1) Preparation of Compound 1B To a solution of compound 1A (180 kg, 903.4 mol, 1.00 eq) in toluene (540 L), pyrrolidine (77.1 kg, 1.08 kmol, 90.5 L, 1.20 eq) was added at 15-25°C. The resulting mixture was stirred at 110°C for 12 hours using a Dean-Stark trap. TLC (petroleum ether / ethyl acetate = 2 / 1, Rf = 0.56) confirmed that compound 1A had been completely consumed and a new spot had formed. The resulting reaction mixture was concentrated in vacuo to give compound 1B (228.0 kg, crude) as a black oil. The resulting compound was used in the next step without purification.

[0177] Step 2) Preparation of Compound 1C To a solution of compound 1B (228 kg, 903 mol, 1.00 eq) obtained in Step 1 dissolved in MeCN (680 L), 3-bromo-1-propene (109.2 kg, 903 mol, 1.00 eq) was added dropwise at 40-45°C over 5 hours. The resulting mixture was stirred at 40-45°C for 12 hours. Complete consumption of compound 1B was confirmed by TLC (petroleum ether / ethyl acetate = 2 / 1, Rf = 0.13). The resulting mixture was cooled to 15-20°C. The resulting mixture was then poured into HCl (750 L, 0.5 N) and extracted with methyl tertiary-butyl ether (MTBE, 500 L, 200 L). The combined organic phase was washed with water (200 L) and brine (200 L), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (1 m × 2 m column, eluent: petroleum ether / ethyl acetate = 4 / 1). The wet product was characterized by gas chromatography (GC) and high-performance liquid chromatography (HPLC). Compound 1C (150 kg, 600 mol, 66.41% yield, 95.4% purity) was obtained in the form of a yellow oil, which was 1 Confirmed by 1 H NMR.

[0178] 1 H NMR (400 MHz CDCl3): 5.65-5.75 (m, 1H), 5.01-5.06 (m, 2H), 4.50-4.51 (m, 1H), 3.10-3.11 (m, 1H), 2.39-2.47 (m, 4H), 1.90-1.94 (m, 2H), 1.41(s, 9H)

[0179] Step 3) Preparation of Compound 1D Compound 1C (150 kg, 627 mol, 1.00 eq) obtained in Step 2, nicotinamide adenine dinucleotide phosphate (NADP, 900 g), glutamate dehydrogenase (GDH, 7.5 kg), glucose (225 kg, 1.14 kmol, 1.81 eq), enzyme (Enzyme Works Ketoreductase TJ-K066, 15 kg) in buffer (NaHPO·12HO, 33.3 kg; NaHPO·2HO, 8.88 kg in water (1500 L), pH = 7.0, 1500 L), and MeOH (150 L) were mixed, and the resulting mixture was stirred at 25-30°C under a N atmosphere for 3 hours. The pH of the mixture was adjusted to 6.0-6.5 using 1 N NaOH. The reaction was confirmed by Chiral GC (product: RT = 34.7 min, recatant: RT = 35.7 min), revealing that 42.1% of the product had formed and 49.6% of the starting material remained. The reaction mixture was heated to 60 °C for 1 hour, filtered, and the filter cake was washed with HO (100 L). The reaction mixture was filtered, and the aqueous phase was extracted with MTBE (600 L, 300 L, 200 L). The organic phase was washed with brine (200 L), dried over anhydrous NaSO, filtered, and concentrated under vacuum. The resulting product, Compound 1D (124 kg, crude) in the form of a yellow oil, was used directly in the next step. Purity was confirmed by Chiral GC, HPLC, and supercritical fluid chromatography (SFC).

[0180] Step 4) Preparation of Compound 1E To a solution of compound 1D (124 kg, 235 mol, 1.00 eq) obtained in Step 3 and imidazole (35.2 kg, 516 mol, 2.2 eq) dissolved in DCM (500 L) was added tert-butyldimethylsilyl chloride (TBDMSCl, 63.7 kg, 423 mol, 1.80 eq) at 0°C. The resulting mixture was stirred at 0-25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 2 / 1, Rf = 0.8) confirmed that compound 1D had been completely consumed and a new major spot was detected. The resulting reaction mixture was washed with water (200 L). The organic layer was then dried and concentrated under reduced pressure to obtain a black oil. This black oil was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 150 / 1 to 1 / 1) to obtain Compound 1E (96.5 kg, 52.8% yield, crude) in the form of a yellow oil.

[0181] 1 H NMR (400 MHz CDCl3): δ 5.66-5.76 (m, 1H), 4.94-5.04 (m, 2H), 3.71-4.10 (m, 2H), 2.70-2.74 (m, 1H), 2.25-2.29 (m, 2H), 1.90 (m, 1H), 1.59-1.63 (m, 2H), 1.41 (s, 9H), 1.27-1.30 (m, 2H), 0.86 (s, 9H), 0.01 (d, J = 4.0 Hz, 6H)

[0182] Step 5) Preparation of Compound 1F The following reactions were carried out in parallel in 24 batches (4 kg x 23, 3 kg x 1).

[0183] To a solution of compound 1E (4.00 kg, 11.3 mol, 1.00 eq) obtained in Step 5 in THF (16 L) was added BH3-Me2S (10 M, 787 mL, 0.7 eq). The resulting mixture was stirred at 5-10 °C for 4 hours. EtOH (3.00 L) and NaOH (3 M, 11.3 L, 3.00 eq) were then added to the mixture at 5-10 °C. H2O2 (5.10 kg, 45.0 mol, 4.32 L, 30% purity, 4.00 eq) was added at 5-10 °C for 16 hours. The reaction was analyzed by HPLC, and TLC (petroleum ether / ethyl acetate = 2 / 1, Rf = 0.25) confirmed that compound 1E had been completely consumed, with many new spots detected. The reaction mixture was separated, and the aqueous phase was extracted with MTBE (3.00 L, 2.00 L). The combined organic phase was washed with saturated NaHSO (5.0 L, 500 g). The mixture was then separated, and the organic phase was dried and concentrated under reduced pressure to give a yellow oil.

[0184] The products of 24 completed batches were combined and purified by column chromatography (petroleum ether / ethyl acetate = 300 / 1 to 1 / 2) to obtain a yellow oil. Finally, compound 1F (41 kg, yield: 42.4%) was obtained.

[0185] 1 H NMR (400 MHz CDCl3): δ 4.05-4.12 (m, 2H), 3.61-3.67 (m, 3H), 2.66-2.72 (m, 1H), 1.87-1.90 (m, 1H), 1.51-1.63 (m, 6H), 1.41 (s, 9H), 1.23-1.25 (m, 2H), 0.85 (s, 9H), 0.01-0.03(d, J = 4.0 Hz, 6H)

[0186] Step 6) Preparation of Compound 1G The following reactions were carried out in parallel in nine batches:

[0187] To a solution of compound 1F (4.50 kg, 12.0 mol, 1.00 eq) obtained in Step 5 in THF (18.0 L) was added triethylamine (TEA, 1.83 kg, 18.1 mol, 2.60 L, 1.50 eq) and methanesulfonyl chloride (MSCl, 1.66 kg, 14.5 mol, 1.15 L, 1.20 eq) at 0°C for 1 hour. The resulting mixture was stirred at 0-5°C for 2 hours. Complete consumption of compound 1F was confirmed by TLC (petroleum ether / ethyl acetate = 2 / 1, Rf = 0.5). The reaction mixture was clean by TLC. The mixture was filtered, and the filter cake was washed with MTBE (20 L).

[0188] The reaction filtrates from the nine batches were combined and concentrated to give compound 1G in the form of a yellow solution, which was used in the next step without further purification.

[0189] 1 H NMR (400 MHz CDCl3): δ 4.16 - 4.30 (m, 2H), 3.97 - 4.14 (m, 2H), 3.65 (br d, J = 1.2 Hz, 1H), 2.98 (s, 3H), 2.66 (br t, J = 12.4 Hz, 1H), 1.85 - 1.94 (m, 1H), 1.50 - 1.77 (m, 6H), 1.41 (s, 10H), 1.28-1.32 (m, 1H), 0.85 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H)

[0190] Step 7) Preparation of Compound 1H The following reactions were carried out in parallel in 12 batches:

[0191] To a solution of compound 1G (4.00 kg, 8.86 mol, 1.00 eq) obtained in Step 6 dissolved in DMF (16.0 L) was added NaN3 (650 g, 10.0 mol, 1.13 eq) at 25°C. The resulting mixture was stirred at 50°C for 10 hours under N2. Complete consumption of compound 1G and the formation of a new spot were confirmed by TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.9).

[0192] The reaction mixture in 12 batches was combined and worked up. The mixture was poured into ice water (200 kg) with stirring. It was extracted with 2-MeTHF (100 L, 70 L, 50 L), and the combined organic layer was washed with brine (40 L x 2). The organic layer was used directly in the next step. Specifically, the crude product compound 1H (crude, final theoretical amount: 42.4 kg) in 2-MeTHF (220 L) in the form of an orange solution was used in the next step without further purification.

[0193] Step 8) Preparation of Compound 1-1 To a solution of the compound represented by Formula 1H (42.36 kg, 106 mol, 1.00 eq) obtained in Step 7 in 2-MeTHF (220 L) and HO (100 L), PPh3 (27.9 kg, 106 mol, 1.20 eq) was added in portions over 1 hour at 5 °C under N2. The resulting mixture was stirred at 25 °C for 14 hours. Complete consumption of Formula 1H was confirmed by TLC (DCM / MeOH = 20 / 1, Rf = 0.02). NaCl (10 kg) and MTBE (200 L) were added to the resulting mixture, which was then separated. The combined aqueous phase of the reaction was extracted with MTBE (200 L, 100 L). The combined organic layer was washed with brine (200 L), dried over Na2SO4, filtered, and concentrated to obtain a residue. The residue was suspended in n-heptane (150 L) and stirred at 25 °C for 30 minutes. The resulting mixture was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was dissolved in CHCN (300 L), and a solution of benzoic acid (1.0 eq) in CHCN (150 L) was added dropwise at 5 °C. The mixture was stirred at 15 °C for 1 hour. The resulting solid was recrystallized from CHCN (350 L) at 70 °C for 2 hours, cooled to 15-25 °C, and filtered four times. The resulting solid was suspended in H2O (100 L), and the pH of the mixture was adjusted to 10 with NaOH (1 M). The mixture was extracted with MTBE (200 L, 100 L). The combined organic layers were washed with water (200 L) and brine (200 L), dried over NaSO, filtered, and concentrated to give the product Compound 1-1 (12.3 kg, 32.8 mol, 30.9% yield, 99.4% purity) in the form of a yellow oil.

[0194] 1H NMR (400 MHz CDCl3): δ 4.06 (br s, 2H), 3.69 (br s, 1H), 2.65 - 2.82 (m, 3H), 2.20 (br s, 3H), 1.83-1.96 (m, 1H), 1.53 - 1.71 (m, 3H), 1.47-1.52 (m, 2H), 1.45 (s, 9H), 1.24 - 1.41 (m, 2H), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H)

[0195] Example 3: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate JPEG2026004468000039.jpg156168

[0196] Step 1) Preparation of 3-((4-methoxybenzyl)oxy)propan-1-ol The starting materials (4-methoxyphenyl)methanol (10 g), propane-1,3-diol (8 g, 1.5 eq), and Amberlyst® 15 (1.5 g) were refluxed in dichloromethane (DCM) (50 mL) and stirred. After stirring overnight, the starting material was confirmed to be gone, and the mixture was cooled to room temperature. After filtering, the solvent was removed, and silica column purification (EA:Hx=1:2) afforded the title compound 3-((4-methoxybenzyl)oxy)propan-1-ol (13.4 g, 95%) as a colorless oil.

[0197] 1H NMR (400MHz, CDCl3) δ 1.85 (m, 2H), 2.38 (br s, 1H), 3.63 (t, 2H), 3.76 (m, 2H), 3.80 (s, 3H), 4.44 (s, 2H), 6.88 (d, 2H), 7.26 (d, 2H)

[0198] Step 2) Preparation of 3-((4-methoxybenzyl)oxy)propanal 3-((4-methoxybenzyl)oxy)propan-1-ol (13.4 g) obtained in Step 1 was dissolved in DCM (200 mL). Celite (50 g) was added to the solution. PCC (22.2 g, 1.5 eq) was added portionwise in an ice bath, and the mixture was allowed to react at room temperature for approximately 4 hours. After filtration, the solvent was removed, and the product was purified on a silica column (EA:Hx=1:4) to obtain the title compound 3-((4-methoxybenzyl)oxy)propanal (10 g, 74%) as a colorless oil.

[0199] 1H NMR (400MHz, CDCl3) δ 2.68 (t, 2H), 3.79 (m, 5H), 4.46 (s, 2H), 6.88 (d, 2H), 7.25 (d, 2H), 9.78 (s, 1H)

[0200] Step 3) Preparation of dibenzyl 1-((2R,3S)-3-hydroxy-1-((4-methoxybenzyl)oxy)hex-5-en-2-yl)hydrazine-1,2-dicarboxylate 3-((4-Methoxybenzyl)oxy)propanal (1 g, 1.0 eq) obtained in Step 2 was dissolved in ACN (15 mL). L-Proline (593 mg, 1.0 eq) was added. DBAD (986 mg, 1.1 eq) was slowly added at 0°C. After stirring at 0°C for 3 hours, sat'd NH4Cl solution (3.5 mL) was added. Next, Zn (673 mg, 2.0 eq) and allyl bromide (0.873 mL, 2.0 eq) were added. After stirring at 0°C for 1 hour, the reaction mixture was extracted with EA and water. The organic layer was treated with MgSO4, filtered, and the solvent was removed. Silica column purification (EA:pet.ether=1:4) gave the title compound dibenzyl 1-((2R,3S)-3-hydroxy-1-((4-methoxybenzyl)oxy)hex-5-en-2-yl)hydrazine-1,2-dicarboxylate (1.2 g, 57%) as a white solid.

[0201] 1H NMR (400MHz, CDCl3) δ 1.26 (t, 6H), 2.28 (br s, 2H), 3.50-3.76 (m, 3H), 3.81 (s, 3H), 3.96-4.24 (m, 5H), 4,46 (m, 2H), 5.13 (m, 2H), 5.85 (br s, 1H), 6.47 (m, 1H), 6.84 (d, 2H), 7.21 (d, 2H)

[0202] Step 4) Preparation of dibenzyl 1-((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)hydrazine-1,2-dicarboxylate A 4Å molecular sieve (4 g) and DDQ (1.2 g, 1.1 eq) were dispersed in DCM (25 mL) and stirred for approximately 1 hour. At 0 °C, dibenzyl 1-((2R,3S)-3-hydroxy-1-((4-methoxybenzyl)oxy)hex-5-en-2-yl)hydrazine-1,2-dicarboxylate (2 g) obtained in Step 3 was dissolved in DCM (20 mL) and slowly added. After stirring at 0 °C for approximately 6 hours, when the starting material was consumed, saturated sodium sulfate solution was added. After filtering through Celite, the filtered solution was washed with saturated NaHCO3, water, and brine. The organic layer was treated with MgSO4, filtered, and the solvent was removed. Silica column purification (EA:pet.ether=3:7) gave the title compound dibenzyl 1-((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)hydrazine-1,2-dicarboxylate (1.29 g, 65%).

[0203] 1H NMR (400MHz, CDCl3) δ 1.30 (t, 6H), 2.40 (br s, 1H), 2.60 (br s, 1H), 3.78 (s, 3H), 3.86-3.97 (m, 2H), 4.15-4.25 (m, 6H), 5.15 (m, 2H), 5.42 (s, 1H), 5.85 (m, 1H), 6.20 (m, 1H), 6.87 (d, 2H), 7.44 (d, 2H)

[0204] Step 5) Preparation of benzyl ((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)carbamate Dibenzyl 1-((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)hydrazine-1,2-dicarboxylate (6 g) obtained in Step 4 was dissolved in dry ACN (110 mL). CsCO (14.36 g, 3.0 eq) and ethyl bromoacetate (2.44 mL, 1.5 eq) were added. The mixture was stirred at 50 °C for 2 hours and then stirred overnight with reflux. The temperature was lowered to room temperature, and saturated NHCl solution was added to the reaction mixture, followed by extraction with EA. The organic layer was treated with MgSO, filtered, and the solvent was removed. Silica column purification (EA:pet.ether=1:3) gave the title compound benzyl ((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)carbamate (3.4 g, 72%) as a white solid.

[0205] 1 H NMR (400MHz, CDCl3) δ 1.25 (t, 3H), 2.40-2.60 (m, 2H), 3.50 (m, 2H), 3.80 (s, 3H), 4.15 (m, 2H), 4.28-4.36 (m, 2H), 5.15 (m, 2H), 5.41 (s, 1H), 5.86 (m, 1H), 6.89 (d, 2H), 7.44 (d, 2H)

[0206] Step 6) Preparation of benzyl ((4S,5R)-4-(3-hydroxypropyl)-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)carbamate Benzyl ((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)carbamate (1 g) obtained in Step 5 was dissolved in dry THF (10 mL). BH3·SMe2 (2 M in THF, 1.85 mL, 1.2 eq) was slowly added at 0 °C. The mixture was stirred overnight while gradually warming to room temperature. Water (2.5 mL), 3 N NaOH (2.5 mL), and H2O2 (2.5 mL) were added at 0 °C, and the mixture was stirred for approximately 2 hours. The reaction mixture was extracted with EA and brine. The organic layer was treated with MgSO4, filtered, and the solvent was removed. Silica column purification (EA:DCM=1:1) gave the title compound benzyl ((4S,5R)-4-(3-hydroxypropyl)-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)carbamate (700 mg, 66%).

[0207] 1 H NMR (400MHz, CDCl3) δ 1.23 (t, 3H), 1.65-1.72 (m, 2H), 1.85-1.95 (m, 2H), 3.50-3.69 (m, 4H), 3.79 (s, 3H), 4.17 (m, 2H), 4.28 (m, 1H), 4.41 (m, 1H), 5.43 (s, 1H), 6.89 (d, 2H), 7.42 (d, 2H)

[0208] Step 7) Preparation of benzyl (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-5H-[1,3]dioxino[5,4-β]pyridine-5-carboxylate Benzyl ((4S,5R)-4-allyl-2-(4-methoxyphenyl)-1,3-dioxan-5-yl)carbamate (700 mg) obtained in Step 6 was dissolved in DCM (20 mL). TEA (0.58 mL, 2.0 eq) was added. At 0 °C, MsCl (0.16 mL, 1.0 eq) was slowly added. After stirring at 0 °C for 2 h, the starting material was consumed. The reaction mixture was quenched with saturated NH4Cl solution and extracted with water and DCM. The organic layer was washed once more with brine, treated with MgSO4, filtered, and the solvent removed. The crude compound was dissolved in DMF (15 mL). At 0 °C, NaH (55% in mineral oil, 90 mg, 1.0 eq) was slowly added. After stirring at 0°C for 2 hours, the starting material was consumed. The reaction mixture was quenched with saturated NH₄Cl solution and then extracted with water and EA. The organic layer was washed once more with brine, treated with MgSO₄, and filtered to remove the solvent. Silica column purification (EA:PET:ether = 4:6) afforded the title compound, benzyl (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-5H-[1,3]dioxino[5,4-β]pyridine-5-carboxylate (600 mg, 90%).

[0209] 1 H NMR (400MHz, CDCl3) δ 1.23 (t, 3H), 1.60 (m, 2H), 1.79 (m, 1H), 2.15 (m, 1H), 2.79 (m, 1H), 3.21 (m, 1H), 3.68 (m, 1H), 3.80 (s, 3H), 4.18 (m, 3H), 4.42 (m, 1H), 4.79 (m, 1H), 5.47 (s, 1H), 6.89 (d, 2H), 7.42 (d, 2H)

[0210] Step 8) Preparation of (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-4H-[1,3]dioxino[5,4-β]pyridine Benzyl (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-5H-[1,3]dioxino[5,4-β]pyridine-5-carboxylate (600 mg) obtained in Step 7 was dispersed in MeOH / HO (5 mL / 5 mL). KOH (5 g) was added and the mixture was stirred for 5 hours while refluxing. The temperature was lowered to room temperature to remove the MeOH from the reaction solution, and EA and water were added for extraction. The organic layer was treated with MgSO4, filtered, and the solvent was removed to yield the title compound (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-4H-[1,3]dioxino[5,4-β]pyridine (450 mg, 96%) as a white solid.

[0211] 1 H NMR (400MHz, CDCl3) δ 1.60 (m, 2H), 1.81 (m, 1H), 2.10 (m, 1H), 2.72 (m, 2H), 3.15 (m, 1H), 3.49 (m, 1H), 3.65 (m, 1H), 3.79 (s, 3H), 4.15 (m, 1H), 5.54 (s, 1H), 6.89 (d, 2H), 7.41 (d, 2H) ESI mass [M+H] + : 250.2

[0212] Step 9) Preparation of tert-butyl (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-5H-[1,3]dioxino[5,4-β]pyridine-5-carboxylate (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-4H-[1,3]dioxino[5,4-β]pyridine (450 mg) obtained in Step 9 was dissolved in DCM (20 mL). TEA (0.50 mL, 2.0 eq) and BocO (590 mg, 1.5 eq) were added under ice bath, and the mixture was stirred for approximately 2 hours. When the starting material was consumed, the reaction mixture was extracted with water and DCM. The organic layer was washed once more with brine, treated with MgSO4, and filtered. The solvent was removed, and the residue was purified on a silica column (EA:PET / ether = 1:4) to give the title compound, tert-butyl (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-5H-[1,3]dioxino[5,4-β]pyridine-5-carboxylate (470 mg, 75%).

[0213] 1 H NMR (400MHz, CDCl3) δ 1.45 (s, 9H), 1.58 (m, 2H), 1.73 (m, 1H), 2.12 (m, 1H), 2.75 (m, 1H), 3.17 (m, 1H), 3.62 (m, 1H), 3.80 (s, 3H), 4.12 (m, 1H), 4.41 (t, 1H), 4.72 (m, 1H), 5.53 (s, 1H), 6.89 (d, 2H), 7.41 (d, 2H)

[0214] Step 10) Preparation of tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate Tert-butyl (4αR,8αS)-2-(4-methoxyphenyl)hexahydro-5H-[1,3]dioxino[5,4-β]pyridine-5-carboxylate (470 mg) obtained in Step 9 was dissolved in MeOH (20 mL). CSA (156 mg, 0.5 eq) was added under ice bath, and the mixture was stirred overnight. When the starting material was consumed, the solvent was removed, and the title compound, tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate (180 mg, 58%), was obtained by silica column purification (EA).

[0215] 1 H NMR (400MHz, CDCl3) δ 1.43 (s, 9H), 1.71 (m, 2H), 1.82 (m,1H), 1.95 (m, 1H), 3.03 (m, 1H), 3.75 (m, 3H), 3.94 (m, 1H), 4.09 (m, 1H)

[0216] Step 11) Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate Tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate (180 mg) obtained in Step 10 was dissolved in DMF (3 mL). Imidazole (159 mg, 3.0 eq) and TBSCl (293 mg, 2.5 eq) were added under ice bath, and the mixture was stirred overnight. When the starting material was consumed, the reaction mixture was extracted with water and EA. The organic layer was washed once more with brine, treated with MgSO4, and filtered. The solvent was removed, and the mixture was purified on a silica column (EA:PET / ether = 1:9) to give the title compound, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (250 mg, 70%).

[0217] 1 H NMR (400MHz, CDCl3) δ 0.02 (m, 12H), 0.85 (m, 18H), 1.35 (m, 1H), 1.45 (s, 9H), 1.63 (m, 2H), 1.85 (m, 1H), 2.61 (m, 1H), 3.57 (m, 1H), 3.65 (t, 1H), 4.01 (m, 3H)

[0218] Step 12) Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (130 mg) obtained in Step 11 was dissolved in MeOH (3 mL). CSA (33 mg, 0.5 eq) was added in an ice bath, and the mixture was stirred for about 2 hours. When the starting material was consumed, solid NaHCO3 was added for quenching, and the solvent was removed. The title compound, compound 2, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate (95 mg, 99%) was obtained by silica column purification (EA:PET / ether = 2:3).

[0219] 1 H NMR (400MHz, CDCl3) δ 0.05 (s, 3H), 0.09 (s, 3H), 0.85 (s, 9H), 1.38 (m, 1H), 1.45 (s, 9H), 1.59 (m, 2H), 1.85 (m, 1H), 2.81 (t, 1H), 3.62 (m, 2H), 3.86 (m, 1H), 3.96 (m, 1H), 4.17(m, 1H); ESI mass [M+H] + : 368.3

[0220] Comparative Example 2: Preparation of Compound 1-1 (tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate) JPEG2026004468000040.jpg234168

[0221] Stages 1) to 12) Steps 1) to 12) were carried out in the same manner as in Example 3 to obtain compound 2, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate.

[0222] 1H NMR (400MHz, CDCl3) δ 0.05 (s, 3H), 0.09 (s, 3H), 0.85 (s, 9H), 1.38 (m, 1H), 1.45 (s, 9H), 1.59 (m, 2H), 1.85 (m, 1H), 2.81 (t, 1H), 3.62 (m, 2H), 3.86 (m, 1H), 3.96 (m, 1H), 4.17(m, 1H); ESI mass [M+H] + : 368.3

[0223] Step 13) Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate Dichloromethane (47 mL, 0.12 M) and oxalyl chloride (1.0 mL, 11.6 mmol) were added to a nitrogen-filled flask, and the reaction mixture was cooled to -78 °C. N,N-dimethyl sulfoxide (1.7 mL, 23.2 mmol) was then added at the same temperature and stirred for 30 minutes. Then, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 5.8 mmol), compound 2 obtained in step 12, was dissolved in a small amount of dichloromethane and slowly added. After stirring at the same temperature for 1 hour, triethylamine (3.3 mL, 23.2 mmol) was added, and the temperature of the reaction mixture was raised from -78 °C to room temperature. Upon completion of the reaction, the solvent was removed, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The mixture was then dissolved in dichloromethane (47 mL, 0.12 M) and stirred at room temperature with (carbethoxymethylene)triphenylphosphorane (4.0 g, 11.6 mmol) for 2 hours. Upon completion of the reaction, the solvent was removed, the mixture was diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by column chromatography (hexane:ethyl acetate = 4:1) to give the title compound (2.1 g, 89% yield).

[0224] Step 14) Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-ethoxy-3-oxopropyl)piperidine-1-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate (3.2 g, 7.7 mmol) obtained in Step 13 was dissolved in tetrahydrofuran (50 mL, 0.15 M). Palladium hydroxide (104 mg, 0.77 mmol) was added, and the mixture was stirred at room temperature for 5 hours after connecting a hydrogen balloon. Upon completion of the reaction, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound. The resulting compound was used in the next reaction without further purification.

[0225] Step 15) Preparation of 3-((2R,3S)-1-(tert-butoxycarbonyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-2-yl)propenoic acid Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-ethoxy-3-oxopropyl)piperidine-1-carboxylate (3.0 g, 7.2 mmol) obtained in Step 14 was dissolved in methanol (20 mL, 0.36 M), and then 2N aqueous sodium hydroxide solution (10 mL) was added and stirred at room temperature for 3 hours. Upon completion of the reaction, the mixture was neutralized with 1N aqueous hydrochloric acid, acidified, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound. The resulting compound was used in the next reaction without further purification.

[0226] Step 16) Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-hydroxypropyl)piperidine-1-carboxylate 3-((2R,3S)-1-(tert-butoxycarbonyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-2-yl)propenoic acid (1.6 g, 4.0 mmol) obtained in Step 15 was dissolved in tetrahydrofuran (50 mL, 0.08 M), and the reaction solution was cooled to 0°C. Lithium aluminum hydride solution (1.6 mL, 4.0 mmol) was then slowly added and reacted at the same temperature for 30 minutes, followed by stirring at room temperature for 2 hours. A small amount of water was added to complete the reaction, and the mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (1.3 g, 85% yield).

[0227] Step 17) Preparation of tert-butyl (2R,3S)-2-(3-bromopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-hydroxypropyl)piperidine-1-carboxylate (5.1 g, 13.8 mmol) obtained in Step 16 was added to dichloromethane (100 mL, 0.14 M). The reaction mixture was cooled to 0°C, and triphenylphosphine (4.3 g, 16.5 mmol) and tetrabromomethane (5.5 g, 16.5 mmol) were added sequentially at the same temperature. The mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the solvent was removed, the mixture was diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate = 5:1) to give the title compound (4.6 g, 76% yield).

[0228] Step 18) Preparation of tert-butyl (2R,3S)-2-(3-azidopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate Tert-butyl (2R,3S)-2-(3-bromopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (7.4 g, 17.0 mmol) obtained in Step 17 was dissolved in N,N-dimethylformamide (25 mL, 0.67 M), and sodium azide (3.3 g, 17.0 mmol) was added and stirred at room temperature for 4 hours. Upon completion of the reaction, the solvent was removed, the mixture was diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=7:1) to give the title compound (5.8 g, 85% yield).

[0229] Step 19) Preparation of tert-butyl (2R,3S)-2-(3-aminopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate Tert-butyl (2R,3S)-2-(3-azidopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (5.5 g, 13.8 mmol) obtained in Step 18 was dissolved in tetrahydrofuran (24 mL, 0.57 M). Triphenylphosphine (4.3 g, 16.5 mmol) was added and stirred at room temperature for 30 minutes. Water (24 mL, 0.57 M) was then added and stirred at room temperature for 1 hour. Upon completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by column chromatography (dichloromethane:methanol = 10:1 + triethylamine 2%) to obtain the title compound, Compound 1-1 (4.0 g, 78% yield).

[0230] 1H NMR (400 MHz CDCl3): δ 4.06 (br s, 2H), 3.69 (br s, 1H), 2.65 - 2.82 (m, 3H), 2.20 (br s, 3H), 1.83-1.96 (m, 1H), 1.53 - 1.71 (m, 3H), 1.47-1.52 (m, 2H), 1.45 (s, 9H), 1.24 - 1.41 (m, 2H), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H)

[0231] Comparison of Example 2 and Comparative Example 2 In order to compare the yields of Compound 1-1, the starting material of Example 1, produced by the production method of Example 2 and the production method of Comparative Example 2, the yields of each production method are summarized in Table 2 below.

[0232] [Table 2]

[0233] As shown in Table 2, the preparation method of Example 2 significantly reduces the number of process steps compared to the preparation method of Comparative Example 2, while at the same time producing Compound 1-1 with an improved yield.

[0234] Furthermore, the preparation method of Example 2 does not use expensive reagents and minimizes column purification, unlike the preparation method of Comparative Example 2, demonstrating that compound 1-1 can be prepared at an industrial level of 10 kg or more. Therefore, compound 1-1 prepared in this example can be mass-produced and supplied for the preparation of the final compound, the compound represented by Chemical Formula 1.

Claims

1. 1) reacting a compound represented by the following formula 2-1 with propane-1,3-diol to prepare a compound represented by the following formula 2-2: 2) oxidizing a compound represented by the following formula 2-2 to prepare a compound represented by the following formula 2-3: 3) The compound represented by the following chemical formula 2-3 is (1) dibenzyl azodicarboxylate or di(C １－４ (2) reacting the resulting compound with an allyl halide to prepare a compound represented by the following formula 2-4: 4) subjecting a compound represented by the following Formula 2-4 to a cyclization reaction to prepare a compound represented by the following Formula 2-5: 5) Benzyl carbamate or C from the compound represented by the following chemical formula 2-5 １－４ removing the alkyl carbamate to prepare a compound represented by the following formula 2-6: 6) subjecting a compound represented by the following formula 2-6 to a boronation-oxidation reaction to prepare a compound represented by the following formula 2-7: 7) subjecting a compound represented by the following formula 2-7 to a cyclization reaction to prepare a compound represented by the following formula 2-8: 8) reacting a compound represented by the following formula 2-8 in the presence of a base to prepare a compound represented by the following formula 2-9: 9) introducing a protecting group into a compound represented by the following formula 2-9 to prepare a compound represented by the following formula 2-10; 10) reacting a compound represented by the following formula 2-10 in the presence of an acid to prepare a compound represented by the following formula 2-11: 11) introducing a protecting group into a compound represented by the following formula 2-11 to prepare a compound represented by the following formula 2-12; and 12) reacting a compound represented by the following chemical formula 2-12 in the presence of an acid to prepare a compound represented by the following chemical formula 2: A method for producing a compound represented by the following chemical formula 2, which is an intermediate for producing a compound represented by the following chemical formula 1-1: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 In the above chemical formulas 1-1, 2 and 2-1 to 2-12, R １ is benzyl or C １－４ is alkyl, P １ and P ２ each independently represents a protecting group.

2. In the step 1), the compound represented by the formula 2-1 and propane-1,3-diol are used in an equivalent ratio of 1:0.5 to 1:

2. The method of claim 1.

3. In step 2), the oxidation is carried out in the presence of one or more oxidizing agents selected from the group consisting of pyridinium chlorochromate (PCC) and pyridinium dichlorochromate (PDC); or carried out by the Swern oxidation reaction, The method of claim 1.

4. In step 3, the compound represented by Formula 2-3 and dibenzyl azodicarboxylate or di(C １－４ alkyl) azodicarboxylate is used in an equivalent ratio of 1:0.5 to 1:2; The method of claim 1.

5. In step 3), the dibenzyl azodicarboxylate or di(C １－４ alkyl) azodicarboxylate is selected from dibenzyl azodicarboxylate, diethyl azodicarboxylate, dibutyl azodicarboxylate and di-tert-butyl azodicarboxylate; The method of claim 1.

6. In step 4), the cyclization reaction is carried out using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), FeCl ３ and MoCl ５ In the presence of one or more oxidizing agents selected from the group consisting of The method of claim 1.

7. Step 5) is carried out in the presence of a base, and the base is at least one selected from the group consisting of cesium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium methylate, and potassium butyrate. The method of claim 1.

8. In step 6), the boronation reaction is carried out with borane or borane dimethyl sulfide; The method of claim 1.

9. In step 6), the oxidation reaction proceeds in the presence of hydrogen peroxide, sodium perborate, or 4-methylmorpholine N-oxide. The method of claim 1.

10. In step 7), the cyclization reaction is carried out by reacting the compound represented by formula 2-7 with (1) methanesulfonyl chloride and then (2) a strong base. The method of claim 1.

11. The strong base is sodium hydride, potassium tartrate, or sodium borohydride. The method of claim 10.

12. In step 8), the base is one or more strong bases selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide. The method of claim 1.

13. Step 9) is carried out in the presence of a base, and the base is at least one selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, dimethylaniline, dimethylaminopyridine, and sodium hydroxide. The method of claim 1.

14. In steps 10) and 12), the acid is one or more strong acids selected from the group consisting of camphorsulfonic acid (CSA) and p-toluenesulfonic acid (toluene-4-sulfonic acid). The method of claim 1.

15. Step 11) is carried out in the presence of a base, and the base is one or more selected from the group consisting of imidazole, methylaminopyridine, and triethylamine. The method of claim 1.

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