Preparation method of cyclic quaternary ammonium salt

Abstract

The invention discloses a method for preparing a compound shown in a formula III. The method comprises the following steps: performing a first nucleophilic substitution reaction on a compound as shown in a formula I and a compound as shown in a formula II to obtain a compound as shown in a formula III; wherein X is selected from oxygen, sulfur,-CH2-or-NH-; r1, R2, R3, R4 and R5 are respectively and independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl and C3-6 cycloalkyl; x, R1, R2, R3, R4 and R5 in the compound shown in the formula I are the same as X, R1, R2, R3, R4 and R5 in the compound shown in the formula II. According to the method, the initial raw materials are easy to obtain, the preparation steps are simple, the reaction conditions are mild, the production cost can be reduced, the yield of the prepared compound shown in the formula III is high, especially the yield can reach 50% or above, and the method is more suitable for industrial production and has wide application prospects.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceutical technology, specifically relating to a method for preparing cyclic quaternary ammonium salt compounds. Background Technology

[0002] Local anesthetics block the influx of sodium ions, temporarily, completely, and reversibly blocking the generation and conduction of nerve impulses. By infiltrating the desired area with local anesthetic, pain signals cannot be transmitted to the brain center, thus achieving an anesthetic effect. Clinically commonly used local anesthetics are mainly divided into esters and amides, such as procaine, lidocaine, bupivacaine, and ropivacaine.

[0003] WO2023 / 221952A1 discloses a series of cyclic quaternary ammonium salt compounds with long-acting anesthetic effects. This patent uses levobupivacaine as the active pharmaceutical ingredient, undergoes nucleophilic substitution to obtain an intermediate compound, and then uses electrophilic substitution to prepare and isolate the target compound. The specific synthetic steps are as follows:

[0004]

[0005] While the above-mentioned synthetic methods for cyclic quaternary ammonium salts use inexpensive and readily available starting materials, the process of separating and purifying intermediates using silica gel column chromatography, along with distillation and other operations, is cumbersome and complex, making it unsuitable for industrial production. Furthermore, the product processing requires preparative separation methods, which have low yields, hindering large-scale production.

[0006] Therefore, a new synthetic method needs to be developed to reduce the difficulty of preparing the target compound and increase the overall yield of the target product, thereby effectively solving the problem of high process difficulty in the existing technology. Summary of the Invention

[0007] This application aims to at least partially address one of the technical problems existing in the prior art. To this end, this application provides a method for preparing cyclic quaternary ammonium salt compounds, which is simple to operate and can improve the yield of cyclic quaternary ammonium salt compounds.

[0008] In one aspect of this application, a method for preparing the compound shown in Formula III is provided. According to an embodiment of this application, the method includes: subjecting the compound shown in Formula I and the compound shown in Formula II to a first nucleophilic substitution reaction to obtain the compound shown in Formula III;

[0009]

[0010] Where X is selected from oxygen, sulfur, -CH2-, or -NH-;

[0011] R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1～6 Alkyl, C 3～6 cycloalkyl;

[0012] X, R1, R2, R3, R4, and R5 in the compound shown in Formula I are the same as X, R1, R2, R3, R4, and R5 in the compound shown in Formula II.

[0013] The starting materials described above are readily available and inexpensive. The preparation steps are simple, and the reaction conditions are mild, which can reduce production costs. Furthermore, the compound represented by Formula III is obtained in high yield and with high purity. In particular, compared with existing synthetic methods (see WO2023 / 221952A1), the synthetic method of this application avoids the silica gel column chromatography process required to generate intermediate product A in the original route, and the target product can be obtained without preparative separation. This significantly improves the overall yield of the compound represented by Formula III (i.e., the overall yield increases from 11.9% in the prior art to over 50% in this application). Therefore, the preparation method of this application is simple, has a high yield (between 50% and 70%), is more suitable for industrial production, and has broad application prospects.

[0014] The structural formula of intermediate product A is shown below:

[0015]

[0016] Unless otherwise specified herein, "X, R1, R2, R3, R4, R5 in the compound shown in Formula I are the same as X, R1, R2, R3, R4, R5 in the compound shown in Formula II" means that X in the compound shown in Formula I is the same as X in the compound shown in Formula II, R1 in the compound shown in Formula I is the same as R1 in the compound shown in Formula II, R2 in the compound shown in Formula I is the same as R2 in the compound shown in Formula II, R3 in the compound shown in Formula I is the same as R3 in the compound shown in Formula II, R4 in the compound shown in Formula I is the same as R4 in the compound shown in Formula II, and R5 in the compound shown in Formula I is the same as R5 in the compound shown in Formula II. However, R1, R2, R3, R4, R5 in the compound shown in Formula I may be the same or different (i.e., R1, R2, R3, R4, R5 in the compound shown in Formula II may be the same or different), and are not specifically limited, all of which are within the scope of protection of this application.

[0017] According to embodiments of this application, the above preparation method may further include at least one of the following technical features:

[0018] According to embodiments of this application, X is selected from oxygen or -NH-.

[0019] According to an embodiment of this application, X is selected from oxygen.

[0020] According to an embodiment of this application, X is selected from -NH-.

[0021] According to embodiments of this application, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogens, and C. 1～6 alkyl.

[0022] According to embodiments of this application, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogens, and C. 1～3 alkyl.

[0023] According to embodiments of this application, R1 and / or R4 are selected from C. 1～3 alkyl.

[0024] In some optional embodiments of this application, R1 and / or R4 are selected from C. 1～3 The alkyl group, and the remaining groups in R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, and halogen.

[0025] In some optional embodiments of this application, R1 and / or R4 are selected from C. 1～3 The alkyl group, and the remaining groups in R1, R2, R3, R4, and R5 are each independently selected from hydrogen and deuterium.

[0026] In some optional embodiments of this application, R1 is selected from C 1～3 Alkyl groups, R2, R3, R4, and R5 are each independently selected from hydrogen and deuterium.

[0027] In some optional embodiments of this application, R1 is selected from C 1～3 Alkyl groups, R2, R3, R4, and R5 are each independently selected from hydrogen.

[0028] In some optional embodiments of this application, R4 is selected from C 1～3 Alkyl groups, R1, R2, R3, and R5 are each independently selected from hydrogen and deuterium.

[0029] In some optional embodiments of this application, R4 is selected from C 1～3 Alkyl groups, R1, R2, R3, and R5 are each independently selected from hydrogen.

[0030] According to embodiments of this application, R3 is selected from halogens.

[0031] In some optional embodiments of this application, R3 is selected from halogens, and R1, R2, R4, and R5 are each independently selected from hydrogen, deuterium, and C. 1～3 alkyl.

[0032] In some optional embodiments of this application, R3 is selected from halogens, and R1, R2, R4, and R5 are each independently selected from hydrogen and deuterium.

[0033] In some alternative embodiments of this application, R3 is selected from halogens, and R1, R2, R4, and R5 are each independently selected from hydrogen.

[0034] According to embodiments of this application, the compound represented by Formula II has the following structure:

[0035]

[0036] According to embodiments of this application, the compound represented by Formula III has the following structure:

[0037]

[0038] According to embodiments of this application, the molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1.0:(1.0 to 2.0), for example 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, or a range between any two of these ratios, for example 1.0:(1.0 to 1.5).

[0039] According to an embodiment of this application, the temperature of the first nucleophilic substitution reaction is 100°C to 110°C, for example, 100°C, 101°C, 102°C, 103°C, 104°C, 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, or any range between two of these ratios.

[0040] According to an embodiment of this application, the temperature of the first nucleophilic substitution reaction is 100°C to 105°C.

[0041] According to an embodiment of this application, the time for the first nucleophilic substitution reaction is 20h to 60h, for example, 20h, 25h, 30h, 35h, 40h, 45h, 50h, 55h, 60h or any range between two of these ratios.

[0042] According to an embodiment of this application, the time for the first nucleophilic substitution reaction is 20h to 40h.

[0043] According to an embodiment of this application, the time for the first nucleophilic substitution reaction is 25h to 35h.

[0044] According to embodiments of this application, the method further includes: dissolving the first nucleophilic substitution reaction product in an organic solvent; and removing impurities from the dissolved product. This further improves the yield and purity of the compound represented by Formula III, achieving a purity of over 98%.

[0045] According to embodiments of this application, the organic solvent is selected from at least one of methanol, dimethyl sulfoxide, and DMF.

[0046] According to an embodiment of this application, the impurity removal process is selected from extraction impurity removal processes.

[0047] According to embodiments of this application, the extraction and impurity removal process is carried out using at least one of the following solvents: n-heptane, petroleum ether, n-hexane, and cyclohexane.

[0048] According to an embodiment of this application, the method further includes: recrystallizing the impurity removal product.

[0049] According to embodiments of this application, the recrystallization system in the recrystallization process is selected from at least one of the following: acetonitrile and isopropyl acetate system, tetrahydrofuran and methyl tert-butyl ether system, and methanol and isopropyl acetate system.

[0050] According to an embodiment of this application, the method further includes: drying the recrystallized product.

[0051] According to an embodiment of this application, the drying process is selected from vacuum drying.

[0052] According to an embodiment of this application, the compound represented by Formula II is prepared by the following steps: subjecting the compound represented by Formula IIa to a second nucleophilic substitution reaction with 1,4-dibromobutane;

[0053]

[0054] Wherein, X, R1, R2, R3, R4, R5 in the compound shown in Formula IIa are the same as X, R1, R2, R3, R4, R5 in the compound shown in Formula II.

[0055] Unless otherwise specified herein, "X, R1, R2, R3, R4, R5 in the compound shown in Formula IIa are the same as X, R1, R2, R3, R4, R5 in the compound shown in Formula II" means that X in the compound shown in Formula IIa is the same as X in the compound shown in Formula II, R1 in the compound shown in Formula IIa is the same as R1 in the compound shown in Formula II, R2 in the compound shown in Formula IIa is the same as R2 in the compound shown in Formula II, R3 in the compound shown in Formula IIa is the same as R3 in the compound shown in Formula II, R4 in the compound shown in Formula IIa is the same as R4 in the compound shown in Formula II, and R5 in the compound shown in Formula IIa is the same as R5 in the compound shown in Formula II. However, R1, R2, R3, R4, R5 in the compound shown in Formula IIa may be the same or different (i.e., R1, R2, R3, R4, R5 in the compound shown in Formula II may be the same or different), and are not specifically limited, all of which are within the scope of protection of this application.

[0056] According to an embodiment of this application, the second nucleophilic substitution reaction is carried out in an alkaline solution.

[0057] According to embodiments of this application, the alkaline solution is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.

[0058] In another aspect of this application, the use of the compound of formula III prepared according to the above method in the preparation of a medicament for local anesthesia or analgesia is provided.

[0059] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0060] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0061] Figure 1 The HPLC chromatogram of the compound of formula III-1 prepared by the method described in Example 1 of this application is shown (main peak retention time is 28.943 min, and relative peak area is 99.15%).

[0062] Figure 2 This is a blank control chromatogram for the HPLC method of this application.

[0063] Figure 3 The HPLC chromatogram of the compound of formula III-1 prepared in the comparative example is shown (main peak retention time is 28.397 min, and relative peak area is 97.04%). Detailed Implementation

[0064] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0065] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0066] Definitions and General Terms

[0067] This document also includes isotopically labeled compounds of the present invention that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Exemplary isotopes that may also be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0068] Compounds of the present invention comprising other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted (i.e., 3 H), and carbon-14 (i.e. 14 C), with particular preference for isotopes. Additionally, heavier isotopes, such as deuterium (i.e.,...), are used. 2 H-substitution can provide some therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0069] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0070] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0071] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each…independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0072] In this paper, the minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes, for example, prefix C. a～b This refers to a carbon atom, which is "a" to "b". For example, "C 1～n "C" refers to a saturated / unsaturated carbon chain, either straight or branched, containing 1, 2, 3, 4, 5, ..., or n carbon atoms; further understanding, "C" 1～n "Should be interpreted as any subranges included, such as C" 1～6 In, containing C 1～5 C 1～4 C 1～3 C 1～2 C 2～5 C 2～4 C 2～3 C 3～5 C 3～4 C 4～5 .

[0073] It should be noted that the term "C" is used in this article. 1～6 For example, in "C" 1～6 In the context of the definition of "alkyl", it refers to an alkyl group having a finite number of carbon atoms, from 1 to 6, that is, 1, 2, 3, 4, 5, or 6 carbon atoms. Further understanding, the term "C"... 1～6 "Should be interpreted as any subranges included, such as C" 1～6 C 2～5 C 3～4 C 1～2 C 1～3 C 1～4 C 1～5 Especially C 1～2 C 1～3 C 1～4 C 1～5 C 1～6 Especially C 1～3 .

[0074] In this invention, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 1～6 A monovalent hydrocarbon group that is straight-chain or branched, and saturated. For example, "C 1～6 "Alkyl" should be understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2, or 3 carbon atoms ("C"). 1～3 Alkyl), such as methyl, methylene, ethyl, n-propyl or isopropyl.

[0075] In this invention, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0076] In this invention, the term "cycloalkyl" refers to a substance having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 3～6 It is a cyclic, saturated monovalent hydrocarbon group. The cycloalkyl group may optionally be further substituted with any substituents.

[0077] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0078] In embodiments of the present invention, unless otherwise stated, the determination conditions for high performance liquid chromatography (HPLC) are as follows:

[0079] Instrument model: Dionex U3000;

[0080] Detector: UV detector;

[0081] Column: Octadecylsilane-bonded silica gel column (Agela Technologies Venusil MP C18, 4.0 mm × 250 mm, 5 μm or equivalent column recommended), with a trapping column added before injection;

[0082] Mobile phase: 0.02 mol / L potassium dihydrogen phosphate solution (pH 3.0) - acetonitrile (90:10);

[0083] Column temperature: 30℃;

[0084] Wavelength: 210nm

[0085] Injection volume: 10 μL;

[0086] Flow rate: 1.0 mL / min.

[0087] Example 1: Synthesis of (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(m-toluenemethoxy)butyl)piperidine bromide

[0088]

[0089] 1. Synthesis of Compound I: (S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (21.5 mmol, 5.0 g), DMF (12.5 mL), and sodium carbonate (2.89 g) were sequentially added to a three-necked flask. The mixture was stirred and heated to 85℃±5℃. Once the temperature was reached, bromobutane (23.3 mmol, 3.2 g) was added dropwise. The temperature rise was significant during the process, and the dropping rate was controlled. After the addition was complete, the mixture was refluxed at 85℃±5℃ for 2 hours. Purified water was added to the flask with stirring, and the mixture was stirred overnight. The mixture was then filtered, and the filter cake was washed twice with purified water. The product was discharged and dried in a vacuum oven at 60℃ for 8 hours to obtain 5.98 g of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide (Compound I), with a yield of 96.3%. HPLC purity > 99%.

[0090] Synthesis of compound II-1: m-cresol (37 mmol, 4.0 g) and 1,4-dibromobutane (370 mmol, 79.89 g) were added to a reaction flask, followed by 8 mL of methanol. The mixture was heated and stirred. At 40 °C, a solution prepared from 8 mL of methanol and 2.28 g of potassium hydroxide was added dropwise to the reaction flask. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 2 hours. The m-cresol concentration was controlled to be less than 1.0% in HPLC. 8 mL of purified water was added to the reaction flask and stirred until dissolved. 16 mL of n-heptane was added for extraction twice. The organic layer was then extracted and separated by adding a solution prepared from 0.15 g of sodium hydroxide and 5 mL of purified water. The organic layer was then extracted again with 8 mL of purified water. After the organic layer was concentrated to dryness under reduced pressure at 50°C, the resulting oily substance was distilled in a column, and the fore fraction was distilled off at 120°C to give 7.28 g of (4-bromobutoxy)-1-toluene (i.e., compound of formula II-1), with a yield of 80.9% and HPLC purity > 97.0%.

[0091] Synthesis of the compound shown in Formula II-1: 3.0 g of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide (0.01 mol, 1.0 eq) and 2.98 g of the compound of Formula II-1 (0.012 mol, 1.2 eq) were weighed and added sequentially into a three-necked flask. The mixture was heated to 100–105 °C under nitrogen protection and reacted for 25–35 hours. The conversion rate was controlled by HPLC. The mixture was cooled to approximately 60°C, dissolved in 9 mL of methanol, and then extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried by rotary evaporation, dissolved in acetonitrile, and then crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.51 g of a white solid ((2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(m-toluenemethoxy)butyl)piperidine bromide, i.e., compound III-1), with a yield of 81.5% and an HPLC purity of 99.2%.

[0092] The overall yield of the obtained compound of formula III-1 was 63.5%, and its HPLC chromatogram is shown in [reference needed]. Figure 1 The blank control chromatogram of the HPLC method is shown below. Figure 2 As shown.

[0093] 2. The synthesis methods for compounds of formula I and formula II-1 are described in step 1 of this embodiment.

[0094] Weigh 3.0 g (0.01 mol, 1.0 eq) of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide and 2.98 g (0.012 mol, 1.2 eq) of compound II-1, and add them sequentially to a three-necked flask. Under nitrogen protection, heat to 100–105 °C and react for 25–35 hours. HPLC analysis was performed until the conversion rate was acceptable. The mixture was then cooled to approximately 60 °C, dissolved in 9 mL of methanol, and extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried, dissolved in tetrahydrofuran, and then crystallized twice with methyl tert-butyl ether. After drying, the mixture was slurried with purified water at room temperature for 10 hours, then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.35 g of a white solid (compound III-1), with a yield of 78.7% and an HPLC purity of 98.9%. The overall yield of the obtained compound of formula III-1 was 61.3%.

[0095] 3. The synthesis methods of compounds of formula I and formula II-1 are described in step 1 of this embodiment.

[0096] Weigh 3.0 g (0.01 mol, 1.0 eq) of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide and 2.98 g (0.012 mol, 1.2 eq) of compound II-1, and add them sequentially to a three-necked flask. Under nitrogen protection, heat to 100–105 °C and react for 25–35 hours. HPLC analysis was performed to control the conversion rate. The mixture was then cooled to approximately 60 °C, dissolved in 9 mL of DMF, and extracted nine times with 81 mL of petroleum ether to remove impurities. After separation, the DMF layer was transferred to a rotary evaporator, dried, dissolved in methanol, and crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours, then filtered. The filter cake was dried to constant weight in a vacuum drying oven to obtain 4.41 g of a white solid (compound III-1), with a yield of 79.8% and an HPLC purity of 99.1%. The overall yield of compound III-1 was 62.2%.

[0097] 4. The synthesis methods for compounds of formula I and formula II-1 are described in step 1 of this embodiment.

[0098] Weigh 3.0 g (0.01 mol, 1.0 eq) of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide and 2.98 g (0.012 mol, 1.2 eq) of compound II-1, and add them sequentially to a three-necked flask. Under nitrogen protection, heat to 100–105 °C and react for 25–35 hours. HPLC analysis was performed until the conversion rate was acceptable. The mixture was then cooled to approximately 60 °C, dissolved in 9 mL of dimethyl sulfoxide, and extracted nine times with 81 mL of n-hexane to remove impurities. After separation, the dimethyl sulfoxide layer was transferred to a rotary evaporator, dried, dissolved in tetrahydrofuran, and then crystallized twice with methyl tert-butyl ether. After drying, the mixture was slurried with purified water at room temperature for 10 hours, and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.0 g of a white solid (compound III-1), with a yield of 72.5% and an HPLC purity of 98.7%. The overall yield of the obtained compound of formula III-1 was 56.5%.

[0099] Example 2: Synthesis of (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(phenoxy)butyl)piperidine bromide

[0100]

[0101] The method for synthesizing compound I is described in step 1 of Example 1.

[0102] Phenol (37 mmol, 3.48 g) and 1,4-dibromobutane (370 mmol, 79.89 g) were added to a reaction flask, followed by approximately 8 mL of methanol. The mixture was heated and stirred. At 60 °C, a solution prepared from approximately 8 mL of methanol and 2.28 g of potassium hydroxide was added dropwise. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 3 hours. The phenol concentration was controlled to be less than 1.0% by HPLC. 8 mL of purified water was added to the reaction flask and stirred until dissolved. 16 mL of n-heptane was added for two extractions. The organic layer was then extracted and separated by adding a solution prepared from 0.15 g of sodium hydroxide and 5 mL of purified water. The organic layer was then extracted again with 8 mL of purified water. The organic layer was concentrated to dryness under reduced pressure at 50 °C. The resulting oily substance was then distilled in a column, and the foremilk fraction was removed at 120 °C to obtain 6.10 g of (4-bromobutoxy)benzene (i.e., compound II-2), with a yield of 71.95% and an HPLC purity of 99.2%.

[0103] 1-Butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide (3.0 g, 0.01 mol, 1.0 eq) and compound II-2 (2.75 g, 0.012 mol, 1.2 eq) were added sequentially to a three-necked flask. The mixture was heated to 100–105 °C under nitrogen protection and reacted for 25–35 hours. The conversion rate was controlled by HPLC. The mixture was cooled to approximately 60°C, dissolved in 9 mL of methanol, and then extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried by rotary evaporation, dissolved in acetonitrile, and then crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.08 g of a white solid (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(phenoxy)butyl)piperidine bromide (i.e., compound III-2), with a yield of 75.8% and an HPLC purity of 98.9%. The overall yield of compound III-2 was 52.5%.

[0104] Example 3: Synthesis of (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(phenylamino)pentyl)piperidine bromide

[0105]

[0106] The method for synthesizing compound I is described in step 1 of Example 1.

[0107] Aniline (37 mmol, 3.45 g) and 1,4-dibromobutane (370 mmol, 79.89 g) were added to a reaction flask, followed by approximately 8 mL of methanol. The mixture was heated and stirred. At 60°C, a solution prepared from approximately 8 mL of methanol and 2.28 g of potassium hydroxide was added dropwise. After the addition was complete, the temperature was raised to 60°C and the reaction proceeded for 3 hours. HPLC analysis showed that the aniline content was less than 1.0%. 8 mL of purified water was added to the reaction flask and stirred until dissolved. 16 mL of n-heptane was added for two extractions. The organic layer was then extracted with a solution prepared from 0.15 g of sodium hydroxide and 5 mL of purified water to separate the layers. The organic layer was then extracted again with 8 mL of purified water. The organic layer was concentrated to dryness under reduced pressure at 50°C. The resulting oily substance was then distilled in a column, and the foremilk fraction was removed at 120°C to obtain 5.82 g of N-(4-bromobutyl)aniline (i.e., compound II-3), with a yield of 68.95% and an HPLC purity of 98.8%.

[0108] Weigh 3.0 g of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide (0.01 mol, 1.0 eq) and compound II-3 (2.74 g, 0.012 mol, 1.2 eq) and add them sequentially to a three-necked flask. Under nitrogen protection, heat to 100–105 °C and react for 25–35 hours. Take samples and control the conversion rate by HPLC until it meets the requirements. The mixture was cooled to approximately 60°C, dissolved in 9 mL of methanol, and then extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried, dissolved in acetonitrile, and then crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.1 g of a white solid (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(phenylamino)pentyl)piperidine bromide (i.e., compound III-3), with a yield of 76.3% and an HPLC purity of 99.2%. The overall yield of compound III-3 was 50.7%.

[0109] Example 4: Synthesis of (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(fluorophenoxy)butyl)piperidine bromide

[0110]

[0111] The method for synthesizing compound I is described in step 1 of Example 1.

[0112] p-Fluorophenol (37 mmol, 4.15 g) and 1,4-dibromobutane (370 mmol, 79.89 g) were added to a reaction flask, followed by approximately 8 mL of methanol. The mixture was heated and stirred. At 60°C, a solution prepared from approximately 8 mL of methanol and 2.28 g of potassium hydroxide was added dropwise. After the addition was complete, the temperature was raised to 60°C and the reaction proceeded for 3 hours. The p-fluorophenol concentration was controlled to be less than 1.0% by HPLC. 8 mL of purified water was added to the reaction flask and stirred until dissolved. 16 mL of n-heptane was added for two extractions. The organic layer was then extracted and separated by adding a solution prepared from 0.15 g of sodium hydroxide and 5 mL of purified water. The organic layer was then extracted again with 8 mL of purified water. The organic layer was concentrated to dryness under reduced pressure at 50°C. The resulting oily substance was then distilled in a column, and the foremilk fraction was removed at 120°C to yield 6.51 g of 1-(4-bromobutoxy)-4-fluorobenzene (i.e., compound II-4), with a yield of 71.2% and an HPLC purity of 98.6%.

[0113] Weigh 3.0 g of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide (0.01 mol, 1.0 eq) and compound II-4 (2.97 g, 0.012 mol, 1.2 eq) and add them sequentially to a three-necked flask. Under nitrogen protection, heat the mixture to 100–105 °C and react for 25–35 hours. Take samples and control the conversion rate by HPLC until it meets the requirements. The mixture was cooled to approximately 60°C, dissolved in 9 mL of methanol, and then extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried, dissolved in acetonitrile, and then crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.41 g of a white solid (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(fluorophenoxy)butyl)piperidine bromide (i.e., compound III-4), with a yield of 79.2% and an HPLC purity of 99.1%. The overall yield of compound III-4 was 54.3%.

[0114] Example 5: Synthesis of (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(p-fluorophenylamino)butyl)piperidine bromide

[0115]

[0116] The method for synthesizing compound I is described in step 1 of Example 1.

[0117] p-Fluoroaniline (37 mmol, 4.11 g) and 1,4-dibromobutane (370 mmol, 79.89 g) were added to a reaction flask, followed by approximately 8 mL of methanol. The mixture was heated and stirred. At 60°C, a solution prepared from approximately 8 mL of methanol and 2.28 g of potassium hydroxide was added dropwise. After the addition was complete, the temperature was raised to 60°C and the reaction proceeded for 3 hours. The p-fluoroaniline concentration was controlled to be less than 1.0% by HPLC. 8 mL of purified water was added to the reaction flask and stirred until dissolved. 16 mL of n-heptane was added for two extractions. The organic layer was then extracted and separated by adding a solution prepared from 0.15 g of sodium hydroxide and 5 mL of purified water. The organic layer was then extracted again with 8 mL of purified water. The organic layer was concentrated to dryness under reduced pressure at 50°C. The resulting oily substance was then distilled in a column, and the foremilk fraction was removed at 120°C to obtain 6.27 g of N-(4-bromobutyl)-4-fluoroaniline, with a yield of 68.85% and an HPLC purity of 99.0%.

[0118] Weigh 3.0 g of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide (0.01 mol, 1.0 eq) and compound II-5 (2.95 g, 0.012 mol, 1.2 eq) and add them sequentially to a three-necked flask. Under nitrogen protection, heat to 100–105 °C and react for 25–35 hours. Take a sample and control the conversion rate by HPLC until it meets the requirements. The mixture was cooled to approximately 60°C, dissolved in 9 mL of methanol, and then extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried, dissolved in acetonitrile, and then crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 4.35 g of a white solid (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(p-fluorophenylamino)butyl)piperidine bromide (i.e., compound III-5), with a yield of 78.2% and an HPLC purity of 99.4%. The overall yield of compound III-1 was 51.8%.

[0119] Example 6: Synthesis of (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(o-tolylamino)butyl)piperidine bromide

[0120]

[0121] The method for synthesizing compound I is described in step 1 of Example 1.

[0122] Add 37 mmol (4.0 g) of o-phenol and 370 mmol (79.89 g) of 1,4-dibromobutane to a reaction flask, followed by approximately 8 mL of methanol. Heat and stir. At 60 °C, add dropwise a solution prepared from approximately 8 mL of methanol and 2.28 g of potassium hydroxide. After the addition is complete, raise the temperature to 60 °C and react for 3 hours. HPLC analysis showed that the o-phenol concentration was less than 1.0%. Add 8 mL of purified water to the reaction flask and stir until dissolved. Add 16 mL of n-heptane for two extractions. Then, extract the organic layer with a solution prepared from 0.15 g of sodium hydroxide and 5 mL of purified water. Extract the organic layer again with 8 mL of purified water. Concentrate the organic layer to dryness under reduced pressure at 50 °C. Distill the resulting oily substance into a column. Distill off the foremilk fraction at 120 °C to obtain 6.55 g of 1-(4-bromobutoxy)-2-toluene (compound II-6), with a yield of 72.8% and an HPLC purity of 98.7%.

[0123] Weigh 3.0 g (0.01 mol, 1.0 eq) of 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide and 2.98 g (0.012 mol, 1.2 eq) of compound II-6, and add them sequentially into a three-necked flask. Under nitrogen protection, heat the mixture to 100–105 °C and react for 25–35 hours. Take a sample and control the conversion rate by HPLC until it meets the requirements. The mixture was cooled to approximately 60°C, dissolved in 9 mL of methanol, and then extracted nine times with 81 mL of n-heptane to remove impurities. After separation, the methanol layer was transferred to a rotary evaporator, dried, dissolved in acetonitrile, and then crystallized twice with isopropyl acetate. After drying, the mixture was slurried with purified water at room temperature for 10 hours and then filtered. The filter cake was dried to constant weight using a vacuum drying oven to obtain 3.99 g of a white solid (2S)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(o-toluidine)butyl)piperidine bromide (i.e., compound III-6), with a yield of 72.2% and an HPLC purity of 99.2%. The overall yield of compound III-1 was 50.6%.

[0124] Comparative Example

[0125] The compound of formula III-1 was synthesized according to the process route described in Example 5 of patent PCT / CN2023 / 094390. The HPLC chromatogram of the obtained compound of formula III-1 is shown below. Figure 3 The overall yield was 11.9% (Patent PCT / CN2023 / 09439). The results showed that, compared to the synthetic route in the comparative example, the compound of formula III-1 obtained in Example 1 had a high yield (56.5%–63.5%), high purity, and was easy to handle and industrially synthesized.

[0126] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0127] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A method for preparing the compound of formula III, characterized in that, include: The compound shown in Formula I and the compound shown in Formula II were subjected to a first nucleophilic substitution reaction to obtain the compound shown in Formula III; Where X is selected from oxygen, sulfur, -CH2-, or -NH-; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1～6 Alkyl, C 3～6 cycloalkyl; X, R1, R2, R3, R4, and R5 in the compound shown in Formula I are the same as X, R1, R2, R3, R4, and R5 in the compound shown in Formula II.

2. The method according to claim 1, characterized in that, X is selected from oxygen or -NH-; And / or, X is selected from oxygen; And / or, X is selected from -NH-; And / or, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogens, and C. 1～6 alkyl; And / or, R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, halogens, and C. 1～3 alkyl; And / or, R1 and / or R4 are selected from C 1～3 alkyl; And / or, R3 is selected from halogens.

3. The method according to claim 1, characterized in that, The compound represented by Formula II has the following structure: And / or, the compound represented by Formula III has the following structure:

4. The method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1.0:(1.0 to 2.0), preferably 1.0:1.2; And / or, the temperature of the first nucleophilic substitution reaction is 100℃~110℃; And / or, the temperature of the first nucleophilic substitution reaction is 100℃~105℃; And / or, the time for the first nucleophilic substitution reaction is 20 h to 60 h; And / or, the time for the first nucleophilic substitution reaction is 20 h to 40 h; And / or, the time for the first nucleophilic substitution reaction is 25h to 35h.

5. The method according to claim 1, characterized in that, Further includes: The product of the first nucleophilic substitution reaction was dissolved using an organic solvent; The dissolved product is then subjected to impurity removal treatment.

6. The method according to claim 5, characterized in that, The organic solvent is selected from at least one of methanol, dimethyl sulfoxide, and DMF; And / or, the impurity removal treatment is selected from extraction impurity removal treatment; Optionally, the extraction and impurity removal process is carried out using at least one of the following solvents: n-Heptane, petroleum ether, n-hexane, cyclohexane.

7. The method according to claim 5, characterized in that, Further includes: The product after impurity removal is recrystallized. Optionally, the recrystallization system in the recrystallization treatment is selected from at least one of the following: acetonitrile and isopropyl acetate system, tetrahydrofuran and methyl tert-butyl ether system, and methanol and isopropyl acetate system.

8. The method according to claim 7, characterized in that, Further includes: The recrystallization product is dried. Optionally, the drying process is selected from vacuum drying.

9. The method according to claim 1, characterized in that, The compound represented by Formula II was prepared by the following steps: The compound shown in formula IIa was subjected to a second nucleophilic substitution reaction with 1,4-dibromobutane; Wherein, X, R1, R2, R3, R4, and R5 in the compound shown in Formula IIa are the same as X, R1, R2, R3, R4, and R5 in the compound shown in Formula II; Optionally, the second nucleophilic substitution reaction is carried out in an alkaline solution; Optionally, the alkaline solution is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.

10. Use of the compound of formula III prepared by the method according to any one of claims 1 to 9 in the preparation of a medicament for local anesthesia or analgesia.

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