A process for the preparation of (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride

Abstract

This invention provides a method for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride, comprising: using 1,4-butanediol as the initial raw material, and proceeding through specific steps (1) to (8) to finally obtain the target product (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride. This product can be used as a key chiral intermediate in the synthesis of inhibitory G protein-coupled receptors. The preparation method provided by this invention uses readily available raw materials, has a simple and easy-to-operate process, mild reaction conditions, and can achieve mass production of the product.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical material synthesis technology, specifically relating to a method for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride. Background Technology

[0002] Publicly available information shows that the kappa / κ-opioid receptor (KOR) is an inhibitory G protein-coupled receptor (GPCR) widely distributed in the central nervous system and peripheral tissues, participating in important physiological activities such as pain, itching, neuroendocrine function, emotional behavior, and cognition. Aticaprant (formerly JNJ-67953964; LY-2456302; CERC501), a potent, orally administered, selective, centrally penetrating, short-acting KOR antagonist, is intended for development in the treatment of depression or anhedonia, particularly as a combination therapy for adult patients with moderate to severe anhedonia. Aticaprant has an affinity (Ki value) of 0.807 nM for KOR, and affinity for μ-opioid receptor (MOR) and δ-opioid receptor (DOR) of 24.0 nM and 155 nM, respectively. Its specific structural formula is as follows (Compound 1):

[0003]

[0004] (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride, a key intermediate in the synthesis of aticaprant, has the following chemical formula:

[0005]

[0006] Its chiral structure and reactivity have a decisive influence on the selectivity and potency of drugs. As a key chiral building block in the synthetic pathway, it participates in the construction of the phenyl-pyrrolidine skeleton in drug molecules, providing reaction sites for the subsequent introduction of fluorobenzamide groups. However, the existing synthetic process of (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride still has problems such as harsh reaction conditions and high purification costs of raw materials and intermediates, which urgently need to be solved. Summary of the Invention

[0007] In view of this, the present invention provides a method for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride, which, compared with the prior art, can achieve the effects of low preparation cost, high optical purity of the product, and simplified subsequent separation process, while having the advantages of readily available raw materials, mild process conditions, and suitability for large-scale production.

[0008] To achieve the above effects, the present invention provides a method for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride, comprising the following steps:

[0009]

[0010] Step (1): Under nitrogen protection, 1,4-butanediol was dissolved in an organic solvent, cooled to 0°C, and imidazole was added; tert-butyldimethylchlorosilane was added under controlled temperature of 0°C. After the addition was complete, the temperature was raised to room temperature, and the reaction was stirred thoroughly. After the reaction was completed, the crude product of compound 4 was obtained by quenching, extraction, drying, and concentration. Step (2): Compound 4 was dissolved in an organic solvent, cooled to 0°C, and DESS-MARTIN oxidizing agent was added in portions under controlled temperature of 0°C. After the addition was complete, the temperature was raised to room temperature, and the reaction was stirred thoroughly. The crude product of compound 5 was obtained by quenching, extraction, drying and concentration. Step (3): Compound 5 was dissolved in an organic solvent, R-tert-butylsulfinamide and anhydrous copper sulfate were added and heated to 40°C. After the reaction was fully stirred, the crude product of compound 6 was obtained by filtration, washing, drying and concentration. Then, the pure product of compound 6 was obtained by purification. Step (4): 3,5-dimethylbromobenzene was dissolved in an organic solvent under nitrogen protection, cooled to -78°C, and butyllithium / n-hexane solution was added. The temperature was controlled at -78°C. The reaction was stirred and an organic solution containing compound 6 was added dropwise. After the reaction was completed, the crude product of compound 7 was obtained by quenching, extraction, drying, and concentration. Then, the crude product of compound 7 was obtained by purification. Step (5): Compound 7 was dissolved in an organic solvent, TBAF was added and heated to 50°C. After the reaction was stirred, the crude product of compound 7 was obtained by extraction, drying, and concentration. Step (6): Compound 8 was dissolved in an organic solvent, triethylamine was added, the temperature was controlled below 25°C and methanesulfonyl chloride was slowly added dropwise. After the reaction was stirred, the crude product of compound 7 was obtained by quenching, extraction, drying, and concentration. The crude product of compound 9 was obtained by quenching, extraction, drying and concentration; Step (7): under nitrogen protection, compound 9 was dissolved in an organic solvent, cooled to 0°C, and sodium hydride was slowly added in batches. After the reaction was completed by stirring, the crude product of compound 10 was obtained by extraction, drying and concentration, and then purified to obtain the pure product of compound 10; Step (8): compound 10 was put into a reaction vessel and hydrogen chloride / dioxane solution was added to the vessel. After the reaction was completed by stirring at room temperature, the target product compound 2 was obtained by extraction, washing and drying.

[0011] Optionally, the process of quenching, extracting, drying, and concentrating to obtain compound 4 in step (1) specifically includes: quenching the reaction solution after stirring by pouring it into water; adding dichloromethane to the aqueous phase and stirring, then combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 4.

[0012] Optionally, the process of quenching, extracting, drying, and concentrating to obtain compound 5 in step (2) specifically includes: adding a saturated sodium bicarbonate aqueous solution to the solution after the reaction is completed to quench; adding methyl tert-butyl ether for extraction and separation, followed by two further extractions with methyl tert-butyl ether, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 5.

[0013] Optionally, the crude product of compound 6 obtained by filtration, washing, drying and concentration in step (3), and the pure product of compound 6 obtained by purification, specifically includes: filtering the mixture after the reaction, washing the filter cake twice with dichloromethane, and combining the organic phases; drying the product with anhydrous sodium sulfate, concentrating under reduced pressure to obtain the crude product of compound 6; and purifying the crude product of compound 6 by silica gel column chromatography to obtain the pure product of compound 6.

[0014] Optionally, the crude product of compound 7 obtained by quenching, extraction, drying and concentration in step (4), and then the pure product of compound 7 obtained by purification treatment, specifically includes: adding an aqueous phosphoric acid solution to the mixture after the reaction is completed for quenching; adding methyl tert-butyl ether for extraction and separation, and then performing two methyl tert-butyl ether extractions, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 7; and purifying the crude product of compound 7 by silica gel column chromatography to obtain the pure product of compound 7.

[0015] Optionally, the extraction, drying, and concentration process in step (5) to obtain compound 8 specifically includes: adding methyl tert-butyl ether and water to the mixture after the reaction is completed, stirring and separating the layers, then performing two methyl tert-butyl ether re-extractions, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 8.

[0016] Optionally, the process of obtaining the crude product of compound 9 by quenching, drying and concentration in step (6) specifically includes: adding water to the mixture after the reaction is completed to quench the separation; then performing two dichloromethane extractions and combining the organic phases; drying the product with anhydrous sodium sulfate and concentrating it under reduced pressure to obtain the crude product of compound 9.

[0017] Optionally, in step (7), after extraction, drying, and concentration, a crude product of compound 10 is obtained, which is then purified to obtain a pure product of compound 10. Specifically, this includes: adding water to quench the mixture after the reaction is completed; then adding methyl tert-butyl ether for extraction and separation, followed by two more extractions with methyl tert-butyl ether, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of compound 10; and purifying the crude product of compound 10 by silica gel column chromatography to obtain a pure product of compound 10.

[0018] Optionally, the precipitation, washing, and drying process in step (8) to obtain the target product compound 2 specifically includes: adding methyl tert-butyl ether to the mixture after the reaction to precipitate the product; and washing and drying the filter cake obtained by filtration twice with methyl tert-butyl ether to obtain the target product compound 2.

[0019] In another aspect, the present invention provides a (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride material prepared according to the method, said material being used as a key chiral intermediate in the synthesis of an inhibitory G protein-coupled receptor.

[0020] The present invention has at least the following beneficial effects:

[0021] (1) Strictly select raw materials, protecting groups, oxidizing agents, etc. to effectively balance the reaction stability and economy of the materials introduced in each preparation step, so that the reaction conditions are mild and the reaction materials are easy to obtain, which is conducive to both improving production efficiency and controlling production costs, and is suitable for the needs of large-scale industrial synthesis.

[0022] (2) Reasonably set up processes such as quenching, extraction, filtration, and purification, effectively adjust the raw material ratio based on the characteristics of reactants and products in each step, selectively omit high-cost preparation steps, optimize the processing flow, improve the feasibility of the preparation method, and effectively ensure the smooth progress of the reaction process.

[0023] Furthermore, additional advantages, objects, and features of the invention will be set forth in part in the description which follows, and will also become apparent in part to those skilled in the art upon studying the following text, or may be learned by practice of the invention. The objects and other advantages of the invention can be realized and obtained by means of the structures and method steps specifically pointed out in the written description, claims, and drawings.

[0024] Those skilled in the art will understand that the objectives and advantages achievable with the present invention are not limited to those specifically described above, and that the above and other objectives achievable with the present invention will become clearer from the following detailed description. Attached Figure Description

[0025] The accompanying drawings, which are provided to further illustrate the invention and form part of this application, are not intended to limit the scope of the invention.

[0026] Figure 1 The hydrogen NMR spectrum of the product obtained in the embodiments of the present invention;

[0027] Figure 2 This is a high-performance liquid chromatogram of the product obtained in the embodiments of the present invention;

[0028] Figure 3 This is a high-performance liquid chromatogram of the racemic product obtained in the embodiments of the present invention;

[0029] Figure 4 This is a high-performance liquid chromatogram of the pure product obtained in the embodiments of the present invention. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments and accompanying drawings. The illustrative embodiments and descriptions of this invention are used to explain the invention, but are not intended to limit the invention. It should also be noted that, in order to avoid obscuring the invention with unnecessary details, only structures and / or processing steps closely related to the solutions according to the invention are shown in the accompanying drawings, while other details not closely related to the invention are omitted.

[0031] It should be emphasized that the term "including / comprises" as used herein refers to the presence of a feature, element, step, or component, but does not exclude the presence or addition of one or more other features, elements, steps, or components.

[0032] One embodiment of the present invention provides a method for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride, comprising the following steps:

[0033]

[0034] Step (1): Under nitrogen protection, 1,4-butanediol (compound 3) was dissolved in an organic solvent, cooled to 0°C, and imidazole was added; tert-butyldimethylchlorosilane (TBS-CL or TBDMSCL) was added under controlled temperature of 0°C. After the addition was completed, the temperature was raised to room temperature, and after the reaction was fully stirred, the crude product of compound 4 was obtained by quenching, extraction, drying and concentration. Using 1,4-butanediol as the initial raw material is advantageous for several reasons. First, its high efficiency in cyclization reactions is a key factor. The thermodynamically, the molecular structure of its two hydroxyl groups favors efficient cyclization, reducing the likelihood of byproduct formation. Furthermore, the functional group transformation of this raw material is flexible, facilitating the introduction of the S-configuration of the target product through asymmetric catalysis or chiral resolution techniques. Second, 1,4-butanediol is a widely used basic chemical in industry, characterized by its low price and stable supply, making it suitable for large-scale synthesis. Moreover, the reaction byproducts are water or ethanol, resulting in a relatively environmentally friendly process. The crude product obtained from the reaction can meet the requirements of the next process step, saving on purification and other reaction procedures, improving production efficiency, and facilitating cost control. The introduction of imidazole and TBS-CL plays a role in protecting the hydroxyl groups. Compared with common organosilicon protecting groups such as TMS / TES / TPS / TIPS, TBS produces products with higher chemical stability and higher yield, and is also cheaper. Moreover, TBS-protected hydroxyl groups are relatively stable in alkaline environments, avoiding interference from subsequent weakly alkaline oxidation reactions and strongly alkaline organometallic reactions. With appropriate stoichiometry, temperature control, and anhydrous operation, the entire reaction process can be made stable and controllable.

[0035] Step (2): Compound 4 was dissolved in an organic solvent and cooled to 0°C. DESS-MARTIN oxidizing agent (Dess-Martin Periodinane, or DMP) was added in portions under controlled temperature of 0°C. After addition, the temperature was raised to room temperature, and the reaction was thoroughly stirred. The mixture was then quenched, extracted, dried, and concentrated to obtain crude compound 5. The oxidizing agent DESS-MARTIN used in this step exhibits high reaction efficiency, mild reaction conditions, relatively simple operation, environmental friendliness, and high selectivity, making it suitable for the oxidation of complex molecular substrates and particularly advantageous in organic synthesis, especially in alcohol oxidation reactions. Furthermore, the crude product obtained after conventional quenching in this step does not require costly separation and purification, and can still meet the specific needs of the next reaction step, thus simplifying the preparation process.

[0036] Step (3): Compound 5 was dissolved in an organic solvent, R-tert-butylsulfinamide and anhydrous copper sulfate were added, and the mixture was heated to 40°C. After thorough stirring and reaction, the mixture was filtered, washed, dried, and concentrated to obtain crude compound 6. Crude compound 6 was then purified to obtain pure compound 6. R-tert-butylsulfinamide, as a chiral inducing agent, reacts with the carbonyl group in compound 5 to achieve chiral control. Tert-butylsulfinamide, as one of the most efficient chiral inducing agents in recent years, condenses with aldehydes and ketones under mild conditions, generating tert-butylsulfinylimides in high yields. Due to the activation effect of the tert-butylsulfinyl group, the resulting imine is more electrophilic and more readily undergoes electrophilic addition with many different types of nucleophiles, thus inducing products with high diastereoselectivity. Simultaneously, the tert-butylsulfinyl group is also a good protecting group with strong alkali resistance; it is easily removed under acidic conditions to obtain amine products. Anhydrous copper sulfate has strong hygroscopicity, high stability and solubility. It can quickly absorb water and release water of crystallization, accelerating the formation of chiral amine compounds.

[0037] Step (4): Under nitrogen protection, 3,5-dimethylbromobenzene was dissolved in an organic solvent and cooled to -78°C. A butyllithium / n-hexane solution was added. The reaction was stirred at -78°C, and an organic solution containing compound 6 was added dropwise. After the reaction was completed, the mixture was quenched, extracted, dried, and concentrated to obtain crude compound 7. The crude compound 7 was then purified to obtain pure compound 7. Butyllithium, as a potent organometallic base, can undergo lithium-halogen exchange with bromine atoms to form an aryllithium intermediate. This aryllithium intermediate then attacks the electrophilic sites of compound 6 (e.g., carbonyl carbons) to form carbon-carbon bonds. Butyllithium is readily available, more convenient to use than Grignard reagents, and has a higher reaction conversion rate. The above reaction, under precise control of reaction conditions and reagent ratios, ensures high selectivity and yield. The subsequent purification step aims to generate compound 7 with higher purity for more efficient participation in subsequent reactions.

[0038] Step (5): Compound 7 was dissolved in an organic solvent, TBAF (tetrabutylammonium fluoride) was added, and the mixture was heated to 50°C. After the reaction was completed by stirring, the mixture was extracted, dried, and concentrated to obtain compound 8. The addition of TBAF provided fluoride ions, which selectively removed the silicon-based protecting group under heating conditions. This method offers high reaction efficiency and mild reaction conditions, making it advantageous for modifying intermediates with complex molecular structures.

[0039] Step (6): Compound 8 is dissolved in an organic solvent, triethylamine is added, the temperature is controlled below 25°C, and methanesulfonyl chloride (MsCl) is slowly added dropwise. After the reaction is completed by stirring, the mixture is quenched, extracted, dried, and concentrated to obtain the crude product of compound 9. In this step, methanesulfonyl chloride acts as a sulfonating agent, reacting with the hydroxyl group in compound 8 to generate methanesulfonate (-OMs). This setting provides a good leaving group for subsequent substitution reactions. Triethylamine, as a base, can neutralize the HCl generated during the reaction, thereby promoting and ensuring the forward reaction. The triethylamine hydrochloride generated during the reaction can be removed simply by filtration, making post-processing simple and convenient. At the same time, the temperature control (25°C) here serves two purposes: firstly, to avoid significant heat release from the highly reactive methanesulfonyl chloride, which could lead to side reactions; and secondly, to prevent local overheating at the overall reaction level, ensuring the smooth progress of the reaction process during large-scale production.

[0040] Step (7): Under nitrogen protection, compound 9 was dissolved in an organic solvent, cooled to 0°C, and sodium hydride was slowly added in batches. After the reaction was completed by stirring, the crude product of compound 10 was obtained by extraction, drying, and concentration. The crude product of compound 10 was then purified to obtain the pure product of compound 10. Sodium hydride, as an efficient and economical ionic salt compound, is inexpensive, highly active, and the cyclization reaction conditions are mild, which helps to protect other parts of the compound molecule from damage. At the same time, the sodium methanesulfonate produced by the reaction is highly water-soluble and can be easily extracted by simple water washing, making it easy for industrial production.

[0041] Step (8): Compound 10 is added to the reaction vessel, and a hydrogen chloride / dioxane solution is added to the vessel. After stirring at room temperature, the reaction is completed, and the target product compound 2 is obtained by extraction, washing, and drying. Among them, the tert-butyl sulfinyl group is an easy-to-remove leaving group under acidic conditions to obtain amine products. The trifluoroacetic acid / dichloromethane (TFA / DCM) system can also remove the tert-butyl sulfinyl group by acid hydrolysis, but the product is not easy to crystallize into salt, and trifluoroacetic acid is difficult to remove, which increases the difficulty of product purification. Compared with other acid hydrolysants, the hydrogen chloride / dioxane solution can remove the tert-butyl sulfinyl group, and the resulting product hydrochloride crystals can be purified by ether solvents after filtration. It is simple and convenient, and the yield is almost quantitative, which is suitable for industrial production. Hydrogen chloride is a strong acid gas that has a strong irritant effect on the eyes and respiratory mucosa and is not easy to use directly. 1,4-Dioxane is an organic solvent with excellent solubility and stability and good solubility for many organic compounds. Hydrogen chloride / dioxane solution is widely used in scientific research and biomedicine. Compared with other hydrogen chloride solution systems, hydrogen chloride / dioxane solution has a high effective concentration of hydrogen chloride (4M), strong solubility, high boiling point, and can resist the exothermic effect of the reaction.

[0042] Optionally, the organic solvent used to dissolve the above compounds can be any organic solvent that can ensure the effective progress of the relevant reactions, including but not limited to one or more solutions of dichloromethane, anhydrous tetrahydrofuran, dioxane, dimethylformamide, ethyl acetate, n-hexane, etc.

[0043] Optionally, the detection method used to determine whether the above reaction is complete can be any detection method that can ensure accurate detection of reaction completion, including but not limited to one or more of TLC detection, HPLC detection, NMR detection, GC-MS detection, and other optional detection methods.

[0044] Optionally, the process of quenching, extracting, drying, and concentrating to obtain compound 4 in step (1) specifically includes: quenching the reaction solution after stirring by pouring it into water; adding dichloromethane to the aqueous phase and stirring, then combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 4.

[0045] Optionally, the process of quenching, extracting, drying, and concentrating to obtain compound 5 in step (2) specifically includes: adding a saturated sodium bicarbonate aqueous solution to the solution after the reaction is completed to quench; adding methyl tert-butyl ether for extraction and separation, followed by two further extractions with methyl tert-butyl ether, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 5.

[0046] Optionally, the crude product of compound 6 obtained by filtration, washing, drying and concentration in step (3), and the pure product of compound 6 obtained by purification, specifically includes: filtering the mixture after the reaction, washing the filter cake twice with dichloromethane, and combining the organic phases; drying the product with anhydrous sodium sulfate, concentrating under reduced pressure to obtain the crude product of compound 6; and purifying the crude product of compound 6 by silica gel column chromatography to obtain the pure product of compound 6.

[0047] Optionally, the crude product of compound 7 obtained by quenching, extraction, drying and concentration in step (4), and then the pure product of compound 7 obtained by purification treatment, specifically includes: adding an aqueous phosphoric acid solution to the mixture after the reaction is completed for quenching; adding methyl tert-butyl ether for extraction and separation, and then performing two methyl tert-butyl ether extractions, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 7; and purifying the crude product of compound 7 by silica gel column chromatography to obtain the pure product of compound 7.

[0048] Optionally, the extraction, drying, and concentration process in step (5) to obtain compound 8 specifically includes: adding methyl tert-butyl ether and water to the mixture after the reaction is completed, stirring and separating the layers, then performing two methyl tert-butyl ether re-extractions, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product of compound 8.

[0049] Optionally, the process of obtaining the crude product of compound 9 by quenching, drying and concentration in step (6) specifically includes: adding water to the mixture after the reaction is completed to quench the separation; then performing two dichloromethane extractions and combining the organic phases; drying the product with anhydrous sodium sulfate and concentrating it under reduced pressure to obtain the crude product of compound 9.

[0050] Optionally, in step (7), after extraction, drying, and concentration, a crude product of compound 10 is obtained, which is then purified to obtain a pure product of compound 10. Specifically, this includes: adding water to quench the mixture after the reaction is completed; then adding methyl tert-butyl ether for extraction and separation, followed by two more extractions with methyl tert-butyl ether, and combining the organic phases; drying the product with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of compound 10; and purifying the crude product of compound 10 by silica gel column chromatography to obtain a pure product of compound 10.

[0051] Optionally, the precipitation, washing, and drying process in step (8) to obtain the target product compound 2 specifically includes: adding methyl tert-butyl ether to the mixture after the reaction to precipitate the product; and washing and drying the filter cake obtained by filtration twice with methyl tert-butyl ether to obtain the target product compound 2.

[0052] Another aspect of this invention provides a (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride material prepared according to the above method, which is used as a key chiral intermediate in the synthesis of an inhibitory G protein-coupled receptor.

[0053] The present invention will be further described in detail below through specific embodiments. The following embodiments are merely descriptive and not limiting, and should not be used to limit the scope of protection of the present invention.

[0054] In one embodiment, the method for synthesizing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride specifically includes the following steps:

[0055] Step (1) Synthesis of compound 4:

[0056]

[0057] In a clean, dried three-necked flask under nitrogen protection, 90.0 g of 1,4-butanediol (compound 3) was added and dissolved in 450 mL of dichloromethane. The mixture was cooled to 0°C, and 1.05 equivalents of imidazole were added. While maintaining the temperature at 0°C, 1.00 equivalents of tert-butyldimethylchlorosilane were slowly added in portions. After the addition was complete, the mixture was heated to room temperature and stirred for 3-4 hours. The reaction was monitored by TLC to confirm completion. After the reaction was complete, the reaction solution was quenched in 225 mL of water, and the layers separated. 225 mL of dichloromethane was added to the aqueous phase, and the mixture was stirred, resulting in separate layers. The organic phases were combined, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to obtain 200.0 g of crude compound 4, which can be used for the next reaction without further purification.

[0058] Step (2) Synthesis of compound 5:

[0059]

[0060] In a clean, dried three-necked flask, 200.0 g of compound 4 was added and dissolved in 1000 mL of dichloromethane. The mixture was cooled to 0°C, and 1.5 equivalents of Dess-Martin oxidizing agent were added in portions while maintaining the temperature at 0°C. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 3-5 hours. The reaction was monitored by TLC to confirm completion. After the reaction was complete, the mixture was quenched with a saturated sodium bicarbonate solution. 1000 mL of methyl tert-butyl ether was added to separate the layers. The aqueous phase was extracted twice more with 500 mL of methyl tert-butyl ether. The combined organic phases were dried over anhydrous sodium sulfate overnight and concentrated under reduced pressure to obtain 200.0 g of crude compound 5, which can be used for the next reaction without further purification.

[0061] Step (3) Synthesis of compound 6:

[0062]

[0063] In a clean, dried three-necked flask, 200.0 g of compound 5 was added and dissolved in 600 mL of dichloromethane. 1.5 equivalents of R-tert-butylsulfinamide and 2.0 equivalents of anhydrous copper sulfate were added. The mixture was heated to 40°C and stirred for 5–6 hours. After the reaction was complete as detected by TLC, the mixture was filtered. The filter cake was washed twice with 200 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate overnight and concentrated under reduced pressure to give 355.0 g of crude compound 6. Purification was achieved by silica gel column chromatography (200–300 mesh) (ethyl acetate / petroleum ether) to give 300.0 g of pure compound 6.

[0064] Step (4) Synthesis of compound 7:

[0065]

[0066] Under nitrogen protection, 185.0 g of 3,5-dimethylbromobenzene was added to 925 mL of anhydrous tetrahydrofuran. The mixture was cooled to -78 °C, and 1.1 equivalents of butyllithium / n-hexane solution were slowly added. After stirring at -78 °C for 1 hour, 1.1 equivalents of tetrahydrofuran solution of compound 6 (335 g of compound 6 / 600 mL of tetrahydrofuran) were slowly added dropwise. The reaction was maintained at -78 °C for 1-2 hours. After the reaction was completed, 10% phosphoric acid aqueous solution was added to quench the reaction. The mixture was extracted with 1500 mL of methyl tert-butyl ether to separate the layers. The aqueous phase was extracted twice more with 750 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to give 425.0 g of crude mixture of compounds 7 and 11. Purification by silica gel column chromatography (200-300 mesh) (ethyl acetate / petroleum ether) yielded 250.0 G of compound 7 and 116.0 G of compound 11. Compound 11 was isolated and stored as a chiral reference and was not used in subsequent reaction processes.

[0067] Step (5) Synthesis of compound 8:

[0068]

[0069] In a clean, dried three-necked flask, 205.8 g of compound 7 was added and dissolved in 1000 mL of anhydrous tetrahydrofuran. 2.0 equivalents of TBAF were added, and the mixture was heated to 50°C and stirred for 3-5 hours until the reaction was complete. After the reaction was complete, 1000 mL of methyl tert-butyl ether and 500 mL of water were added and the mixture was stirred to separate the layers. The aqueous phase was extracted twice more with 500 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to give 140.0 g of crude compound 8.

[0070] Step (6) Synthesis of compound 9:

[0071]

[0072] In a clean, dried three-necked flask, 99.0 g of compound 8 was added and dissolved in 300 mL of dichloromethane. 1.2 equivalents of triethylamine were then added. 1.05 equivalents of methanesulfonyl chloride were slowly added dropwise, maintaining the temperature below 25°C. After the addition was complete, the mixture was stirred for 1-2 hours to confirm the completion of the reaction. After the reaction was complete, 200 mL of water was added to quench the reaction, and the layers were separated. The aqueous phase was extracted twice more with 200 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate overnight and concentrated under reduced pressure to obtain 120.0 g of crude compound 9.

[0073] Step (7) Synthesis of compound 10:

[0074]

[0075] In a clean, dried three-necked flask under nitrogen protection, 94.0 g of compound 9 was added and dissolved in 400 mL of anhydrous tetrahydrofuran. The mixture was cooled to 0 °C, and 1.2 equivalents of sodium hydride (60%) were slowly added in portions. The mixture was stirred for 24 hours, and the reaction was checked for completion. After the reaction was complete, 200 mL of water was added to quench the reaction, followed by the addition of 500 mL of methyl tert-butyl ether. The layers were separated. The aqueous phase was extracted twice more with 250 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate overnight, and concentrated under reduced pressure to obtain 70.0 g of crude compound 10. The crude compound 10 was purified by silica gel column chromatography (200-300 mesh) (ethyl acetate / petroleum ether) to obtain 60 g of pure compound 10.

[0076] (8) Synthesis of compound 2:

[0077]

[0078] In a clean, dried three-necked flask, 60.0 g of compound 10 was added, followed by 500 mL of 4N hydrogen chloride (HCl) / dioxane solution. The mixture was stirred at room temperature for 3–5 hours, and the reaction was confirmed by HPLC. After the reaction was complete, 1000 mL of methyl tert-butyl ether was added, and the mixture was stirred for 1–2 hours. The mixture was then filtered, and the filter cake was washed twice with 500 mL of methyl tert-butyl ether. After drying, the final product, 40.0 g of compound 2, was obtained, with a chemical purity of 98.8% by HPLC and a chiral purity (EE) of 98.9%.

[0079] It should be clarified that the above examples only provide a verified and feasible specific implementation scheme. Other specific implementation schemes based on the inventive concept are not limited to the specific configurations and processes described above and shown in the figures. For the sake of brevity, detailed descriptions of known methods are omitted here. In the above embodiments, several specific steps are described and shown as examples. However, the method process of the present invention is not limited to the specific steps described and shown. Those skilled in the art can make various changes, modifications, and additions, or change the order of steps, after understanding the spirit of the present invention.

[0080] In this invention, features described and / or illustrated for one embodiment may be used in the same or similar manner in one or more other embodiments, and / or combined with or in place of features of other embodiments.

[0081] The above detailed description further illustrates the purpose, technical solution, and beneficial effects of the invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride, characterized in that, Includes the following steps: Step (1): Under nitrogen protection, 1,4-butanediol was dissolved in an organic solvent, cooled to 0°C, and imidazole was added; tert-butyldimethylchlorosilane was added under controlled temperature of 0°C. After the addition was completed, the temperature was raised to room temperature, and after the reaction was fully stirred, the crude product of compound 4 was obtained by quenching, extraction, drying and concentration. Step (2): Dissolve compound 4 in an organic solvent, cool to 0°C, add DESS-MARTIN oxidizing agent in portions under controlled temperature of 0°C, and after the addition is complete, heat to room temperature. After the reaction is fully stirred, quench, extract, dry and concentrate to obtain crude compound 5. Step (3): Dissolve compound 5 in an organic solvent, add R-tert-butylsulfinamide and anhydrous copper sulfate and heat to 40°C. After the reaction is fully stirred, filter, wash, dry and concentrate to obtain crude compound 6. Then purify to obtain pure compound 6. Step (4): Under nitrogen protection, dissolve 3,5-dimethylbromobenzene in an organic solvent, cool to -78°C, and add butyllithium / n-hexane solution; The reaction was stirred at a controlled temperature of -78℃, and an organic solution containing compound 6 was added dropwise. After the reaction was completed, the crude product of compound 7 was obtained by quenching, extraction, drying and concentration. Then, the crude product of compound 7 was obtained by purification. Step (5): Dissolve compound 7 in an organic solvent, add TBAF and heat to 50°C. After stirring and reacting, extract, dry and concentrate to obtain compound 8. Step (6): Dissolve compound 8 in an organic solvent, add triethylamine, control the temperature below 25°C and slowly add methanesulfonyl chloride, stir the reaction until it is complete, then quench, extract, dry and concentrate to obtain crude compound 9; Step (7): Under nitrogen protection, compound 9 was dissolved in an organic solvent, cooled to 0°C, and sodium hydride was slowly added in batches. After the reaction was completed by stirring, the crude product of compound 10 was obtained by extraction, drying and concentration. Then, the pure product of compound 10 was obtained by purification. Step (8): Compound 10 was added to the reaction vessel, and hydrogen chloride / dioxane solution was added to the vessel. After the reaction was completed by stirring at room temperature, the target product compound 2 was obtained by extraction, washing and drying.

2. The preparation method according to claim 1, characterized in that, The process of quenching, extraction, drying, and concentration in step (1) to obtain compound 4 specifically includes: After the reaction was completed, the reaction solution was poured into water for quenching; dichloromethane was added to the aqueous phase and stirred, and the organic phases were combined; the product was dried using anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 4.

3. The preparation method according to claim 2, characterized in that, The process of quenching, extraction, drying, and concentration in step (2) to obtain compound 5 specifically includes: The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution to the solution after the reaction was completed; the product was extracted and separated by adding methyl tert-butyl ether, and then extracted twice more by methyl tert-butyl ether. The organic phases were combined; the product was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product of compound 5.

4. The preparation method according to claim 3, characterized in that, In step (3), the crude product of compound 6 is obtained through filtration, washing, drying, and concentration. The crude product of compound 6 is then purified to obtain the pure product of compound 6. Specifically, this includes: The mixture after the reaction was completed was filtered, and the filter cake was washed twice with dichloromethane. The organic phases were combined. The product was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 6. The crude compound 6 was purified by silica gel column chromatography to obtain pure compound 6.

5. The method according to claim 4, characterized in that, In step (4), the crude product of compound 7 is obtained through quenching, extraction, drying, and concentration. The crude product of compound 7 is then purified to obtain the pure product. Specifically, this includes: The reaction mixture was quenched by adding an aqueous phosphoric acid solution; methyl tert-butyl ether was added for extraction and separation, followed by two more extractions with methyl tert-butyl ether, and the organic phases were combined; the product was dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude compound 7; the crude compound 7 was purified by silica gel column chromatography to obtain pure compound 7.

6. The method according to claim 5, characterized in that: In step (5), compound 8 is obtained through extraction, drying, and concentration, specifically including: After the reaction was completed, methyl tert-butyl ether and water were added and stirred to separate the layers. Then, the mixture was extracted twice with methyl tert-butyl ether and the organic phases were combined. The product was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 8.

7. The method according to claim 6, characterized in that, The crude product of compound 9 obtained in step (6) through quenching, drying, and concentration specifically includes: Water was added to the mixture after the reaction to quench the separation; then the mixture was extracted twice with dichloromethane, and the organic phases were combined; the product was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 9.

8. The method according to claim 7, characterized in that, Step (7) involves extraction, drying, and concentration to obtain crude compound 10, followed by purification to obtain pure compound 10. Specifically, this includes: Water was added to the mixture after the reaction was completed to quench the reaction; then methyl tert-butyl ether was added for extraction and separation, followed by two more extractions with methyl tert-butyl ether, and the organic phases were combined; the product was dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude compound 10; the crude compound 10 was purified by silica gel column chromatography to obtain pure compound 10.

9. The method according to claim 8, characterized in that, Step (8) involves precipitation, washing, and drying to obtain the target product compound 2, specifically including: Methyl tert-butyl ether was added to the mixture after the reaction to precipitate the product; the filter cake obtained by filtration was washed twice with methyl tert-butyl ether and dried to obtain the target product compound 2.

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