Synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-) butyl-2-yl) carbamate

Abstract

The invention relates to the technical field of material synthesis, and discloses a synthesis process of a medical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxo-pyrrolidone-3-yl) butyl-2-yl) tert-butyl carbamate, which comprises the following steps: by taking N-benzyl-3-hydroxypiperidine as a raw material, reacting at the temperature of 60-80 DEG C for 2-4 hours; the preparation method comprises the following steps: carrying out resolution, alkali dissociation, palladium-carbon hydrogenation debenzylation / tert-butyloxycarboryl protection, sulfonyl chloride acylation, hydrolysis, salification purification and crystal form optimization to obtain the high-purity (more than or equal to 95%) and high-optical-purity target product through multi-step fine reaction and subsequent salification purification and crystal form optimization steps. According to the present invention, the strict requirements on the compound quality in the fields of medicine, material science and the like are met, the reliable material basis is provided for the related applications, and compared with the traditional synthesis method, the reaction steps and conditions are optimized to a certain extent, the reaction efficiency is improved, the production time is shortened from about 10 days to about 7 days, and the production cost is reduced; and the market competitiveness of the product is enhanced.

Description

Technical Field

[0001] The invention relates to the technical field of material synthesis, and in particular to a synthesis process of a pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester (abbreviated as: ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamic acid tert-butyl ester). Background Art

[0002] Tert-butyl ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamate is an advanced intermediate of Leretevir. Leretevir is an antimalarial drug mainly used to treat malaria caused by Plasmodium falciparum. It inhibits the growth and reproduction of Plasmodium by blocking the activity of specific enzymes in the metabolism of Plasmodium, thereby playing a therapeutic role. Leretevir is widely used in clinical practice and has good efficacy and safety. Therefore, the development of this project has broad market prospects.

[0003] Traditional routes usually require multiple reaction steps to construct the complex structure of the target compound. Each step of the reaction requires separation, purification and other operations, which not only increases the complexity and time cost of the experimental operation, but also leads to the loss of the product during multiple separation processes, reducing the overall yield. Moreover, the longer reaction route also increases the risk of introducing impurities, further affecting the quality of the product.

[0004] Due to the many reaction steps and the difficulty in avoiding side reactions, the purity of the products obtained by traditional methods is often not ideal. The presence of impurities may affect the performance and application effect of the product, especially in the field of medicine, where impurities may cause toxic side effects and threaten the safety and effectiveness of drugs. Therefore, complex separation and purification operations are required to improve the purity of the product, but this will further increase costs and time. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a synthesis process for a pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester.

[0006] To achieve the above-mentioned purpose, the present invention provides the following technical scheme: a synthesis process of a pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester, which is prepared by using N-benzyl-3-hydroxypiperidine as a raw material through splitting, alkali freeing, palladium carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection, sulfonyl chloride acylation, hydrolysis, salt formation purification and crystal form optimization; Resolution: using a chiral resolution agent to form diastereomeric salts with N-benzyl-3-hydroxypiperidine, and achieving separation based on the difference in their solubility in a specific solvent, thereby obtaining single chiral N-benzyl-3-hydroxypiperidine; Free base: further ensure that N-benzyl-3-hydroxypiperidine exists completely in the form of free base, avoiding the influence of protonation and other problems on the reaction process in the subsequent reaction, and providing more favorable conditions for the subsequent reaction; Palladium-carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection: Under the action of palladium-carbon catalyst, hydrogen reacts with the benzyl group of N-benzyl-3-hydroxypiperidine to remove the benzyl group. At the same time, di-tert-butyl dicarbonate (Boc2O) reacts with the amino group on the piperidine ring to introduce tert-butyloxycarbonyl (Boc) to protect the amino group and improve the stability of the amino group in subsequent reactions; Sulfonyl chloride acylation: The hydroxyl group of N-Boc-3-hydroxypiperidine is nucleophilic. Under the action of a base such as triethylamine, it undergoes a nucleophilic substitution reaction with sulfonyl chloride to form a sulfonyl ester, introducing a sulfonyl group and providing an active site for subsequent reactions. Hydrolysis: Under alkaline conditions, the sulfonyl ester bond of N-Boc-3-toluenesulfonyloxypiperidine undergoes a hydrolysis reaction to break and form a hydroxyl group, thereby obtaining a precursor of the target product. The precursor then undergoes a condensation reaction with cyclopentylamine in the presence of a condensing agent to further construct the molecular structure of the target product; Salt purification: react the crude product with a suitable acid to form a salt, and use the difference in solubility of the salt in different solvents to further remove impurities and improve the purity of the product; Crystal form optimization: By selecting appropriate solvents and crystallization conditions, the crystal form of the product is optimized to improve the physical properties of the product, such as stability and solubility, which is beneficial to the storage and application of the product.

[0007] Preferably, the specific reaction steps of the splitting are: dissolving N-benzyl-3-hydroxypiperidine (100 g, 0.5 mol) in an appropriate amount of methanol, adding a chiral splitting agent (such as L-tartaric acid, 110 g, 0.73 mol), stirring and heating to 50-60° C. to allow the reaction to proceed fully; After cooling to room temperature, crystals precipitate and are filtered to obtain chiral salt crystals. The crystals are washed with a small amount of cold methanol, and then the chiral salt is dissolved in water and the pH is adjusted to 10-11 with sodium hydroxide solution to free N-benzyl-3-hydroxypiperidine; The mixture was extracted with dichloromethane (3×100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain a single chiral N-benzyl-3-hydroxypiperidine with a yield of about 40% and an ee value (enantiomeric excess) ≥98%.

[0008] Preferably, the specific reaction steps of the base release are: dissolving the single chiral N-benzyl-3-hydroxypiperidine (40 g, 0.2 mol) obtained in the previous step in 200 mL of dichloromethane, adding potassium carbonate (27.6 g, 0.2 mol) and an appropriate amount of water, and stirring the reaction for 2-3 hours; After the reaction was completed, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain N-benzyl-3-hydroxypiperidine in the form of a free base.

[0009] Preferably, the specific reaction steps of palladium carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection are: dissolving N-benzyl-3-hydroxypiperidine (30g, 0.15mol) in the form of a free base in 300mL of methanol, adding 10% palladium carbon catalyst (3g), passing hydrogen, stirring and reacting at room temperature and normal pressure for 6-8 hours. After the reaction is completed, the palladium carbon catalyst is filtered to remove the methanol by distillation under reduced pressure. Di-tert-butyl dicarbonate (Boc2O, 33.6g, 0.155mol) and triethylamine (15.2g, 0.15mol) are added to the residue, and the reaction is stirred at room temperature in dichloromethane (200mL) for 4-5 hours. After the reaction is completed, wash with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to remove the solvent to obtain N-Boc-3-hydroxypiperidine with a yield of about 80%.

[0010] Preferably, the specific reaction steps of the sulfonyl chloride acylation are: dissolving N-Boc-3-hydroxypiperidine (25g, 0.12mol) in 150mL of dichloromethane, adding triethylamine (12.1g, 0.12mol), and slowly dropping a dichloromethane solution (50mL) of p-toluenesulfonyl chloride (24.1g, 0.125mol) under ice bath conditions. After the dropwise addition is completed, the reaction is stirred at room temperature for 3-4 hours. After the reaction is completed, it is washed with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phase is dried with anhydrous sodium sulfate, filtered, and the solvent is removed by distillation under reduced pressure to obtain N-Boc-3-toluenesulfonyloxypiperidine with a yield of about 90%.

[0011] Preferably, the specific reaction steps of the hydrolysis are: dissolving N-Boc-3-toluenesulfonyloxypiperidine (30 g, 0.09 mol) in 200 mL of tetrahydrofuran (THF), adding an aqueous solution (100 mL) of lithium hydroxide (3.8 g, 0.15 mol), and stirring the mixture at room temperature for 8-10 hours; After the reaction was completed, THF was distilled off under reduced pressure, water (100 mL) was added to the residue, and extracted with dichloromethane (3×50 mL), the organic phase was discarded, and the pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid. Solids precipitated and were filtered to obtain the precursor of the target product.

[0012] Preferably, the specific reaction steps of the salt formation purification are: dissolving the crude product of tert-butyl ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamate (10 g) in 100 mL of anhydrous ethanol, adding dropwise anhydrous ethanol solution (50 mL) of oxalic acid (1.5 g) to precipitate, stirring for 1-2 hours, cooling to 0-5°C, standing for 3-4 hours and then filtering, washing the precipitate with cold anhydrous ethanol, dissolving the precipitate in 100 mL of water, adding dropwise 10% sodium hydroxide solution to adjust the pH to 8-9 to free the product, extracting with dichloromethane (3×80 mL), drying with anhydrous sodium sulfate for 3-4 hours, filtering and distilling under reduced pressure to obtain a purified product.

[0013] Preferably, the purified product (8 g) is dissolved in 80 mL of acetone, heated to 50-60° C., 120 mL of n-hexane is slowly added dropwise, crystals precipitate, cooled to room temperature and refrigerated (0-5° C.) for 12-15 hours, filtered, and the crystals are washed 2-3 times with a cold acetone-n-hexane mixed solvent (1:3), and vacuum dried at 40-50° C. for 8-10 hours to obtain a white crystalline powder product with optimized crystal form, and the crystal form is confirmed by X-ray powder diffraction (XRD).

[0014] Compared with the prior art, the present invention provides a synthesis process of a pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester, which has the following beneficial effects: 1. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester can ultimately obtain a target product with high purity (≥95%) and high optical purity through multiple steps of fine reaction and subsequent salt purification and crystal form optimization steps, which meets the strict requirements for compound quality in the fields of medicine and materials science, and provides a reliable material basis for related applications. Compared with traditional synthesis methods, this process optimizes the reaction steps and conditions to a certain extent, improves the reaction efficiency, shortens the production time from about 10 days to about 7 days, reduces the production cost, and enhances the market competitiveness of the product.

[0015] 2. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester uses a chiral resolution agent to resolve racemic N-benzyl-3-hydroxypiperidine into a single chiral isomer, with an ee value (enantiomeric excess) of ≥98%. This lays the foundation for the subsequent construction of a target product with a specific chiral structure, ensuring that the final product has the required optical activity and biological activity. The single chiral raw material enables the subsequent reaction to proceed in the expected chiral direction, reduces the occurrence of side reactions, improves the selectivity of the reaction, and is conducive to improving the purity and yield of the product.

[0016] 3. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester converts the chiral N-benzyl-3-hydroxypiperidine obtained by splitting into a free base form, so that it can participate in the subsequent palladium carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection reaction in a more suitable chemical state, avoiding the reaction process being affected by problems such as protonation. This step further removes possible impurities through simple alkali treatment and separation operations, providing purer raw materials for subsequent reactions, which helps to improve the overall reaction efficiency and product quality.

[0017] 4. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester realizes the hydrogenation removal of the benzyl group under the action of palladium-carbon catalyst, and at the same time introduces tert-butyloxycarbonyl (Boc) to protect the amino group. The debenzylation reaction provides convenience for the subsequent construction of the molecular structure of the target product, and the Boc protecting group can protect the amino group from being oxidized or undergoing other unnecessary reactions in the subsequent reaction, thereby improving the stability of the amino group. The debenzylation and amino protection steps are combined to simplify the synthesis route, reduce the reaction steps and separation operations, reduce the risk of product loss, and improve the overall synthesis efficiency.

[0018] 5. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butan-2-yl)carbamic acid tert-butyl ester, wherein the hydroxyl group of N-Boc-3-hydroxypiperidine undergoes an acylation reaction with sulfonyl chloride to introduce a sulfonyl group, thereby providing an active site for subsequent hydrolysis reaction and condensation reaction with cyclopentylamine, so that the molecule can undergo structural transformation according to the designed route. The reaction is carried out under specific conditions, has high selectivity, can accurately introduce a sulfonyl group at the hydroxyl position, reduces the occurrence of side reactions, and improves the yield and purity of the target product.

[0019] 6. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester, under alkaline conditions, the sulfonyl ester bond of N-Boc-3-toluenesulfonyloxypiperidine undergoes a hydrolysis reaction, breaking to form a hydroxyl group, and obtaining a precursor of the target product. This step of reaction provides a suitable reactant for the subsequent condensation reaction with cyclopentylamine, further constructing the molecular structure of the target product. The hydrolysis reaction not only realizes the transformation of the molecular structure, but also removes possible impurities such as sulfonic acid groups, thereby improving the purity of the product and providing a guarantee for the subsequent condensation reaction and the quality of the final product.

[0020] 7. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamate can more effectively remove impurities in the product by forming a salt with oxalic acid and utilizing the difference in solubility of salts in different solvents, thereby increasing the purity of the product from about 80% to ≥95%, greatly improving the quality of the product. The salt-forming process can improve certain physical properties of the product, such as solubility and crystallization properties, and provide a better basis for the subsequent crystal optimization step, which is conducive to obtaining a purer product with better performance.

[0021] 8. The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester optimizes the crystal form of the product by controlling the solvent and crystallization conditions, so that the product presents a regular crystal form, and the crystal form is single and stable. The optimized crystal form improves various physical properties of the product, such as solubility, stability, melting point range, bulk density and powder fluidity, etc. The improvement of these properties is conducive to the storage, transportation and application of the product, especially in the fields of medicine and materials. The regular crystal form makes the quality of the product more stable and consistent, which is conducive to industrial production and quality control. In large-scale production, the consistency of the crystal form can ensure the performance and quality stability of the product, improve production efficiency and product reliability. DETAILED DESCRIPTION

[0022] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0023] The synthesis process of the pharmaceutical intermediate ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester is prepared by using N-benzyl-3-hydroxypiperidine as a raw material through separation, alkali freeing, palladium carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection, sulfonyl chloride acylation, hydrolysis, salt purification and crystal form optimization; Separation: using a chiral separation agent to form diastereomeric salts with N-benzyl-3-hydroxypiperidine, separation is achieved based on the difference in solubility in a specific solvent, thereby obtaining single chiral N-benzyl-3-hydroxypiperidine; the specific reaction steps are: dissolving N-benzyl-3-hydroxypiperidine (100 g, 0.5 mol) in an appropriate amount of methanol, adding a chiral separation agent (such as L-tartaric acid, 110 g, 0.73 mol), stirring and heating to 50-60°C to allow the reaction to proceed fully; After cooling to room temperature, crystals precipitate and are filtered to obtain chiral salt crystals. The crystals are washed with a small amount of cold methanol, and then the chiral salt is dissolved in water and the pH is adjusted to 10-11 with sodium hydroxide solution to free N-benzyl-3-hydroxypiperidine; The mixture was extracted with dichloromethane (3×100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain a single chiral N-benzyl-3-hydroxypiperidine with a yield of about 40% and an ee value (enantiomeric excess) ≥98%.

[0024] Free base: further ensure that N-benzyl-3-hydroxypiperidine exists completely in the form of free base, avoid protonation and other problems in the subsequent reaction affecting the reaction process, and provide more favorable conditions for the subsequent reaction; the specific reaction steps are: dissolve the single chiral N-benzyl-3-hydroxypiperidine (40g, 0.2mol) obtained in the previous step in 200mL of dichloromethane, add potassium carbonate (27.6g, 0.2mol) and an appropriate amount of water, and stir the reaction for 2-3 hours; After the reaction was completed, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain N-benzyl-3-hydroxypiperidine in the form of a free base.

[0025] Palladium-carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection: Under the action of palladium-carbon catalyst, hydrogen reacts with the benzyl group of N-benzyl-3-hydroxypiperidine to remove the benzyl group, and at the same time, di-tert-butyl dicarbonate (Boc2O) reacts with the amino group on the piperidine ring to introduce tert-butyloxycarbonyl (Boc) to protect the amino group and improve the stability of the amino group in subsequent reactions; the specific reaction steps are: dissolve N-benzyl-3-hydroxypiperidine (30g, 0.15mol) in the form of free base in 300mL methanol, add 10% palladium-carbon catalyst (3g), pass hydrogen, and stir the reaction at room temperature and normal pressure for 6-8 hours. After the reaction is completed, filter to remove the palladium-carbon catalyst, and distill the filtrate under reduced pressure to remove methanol. Di-tert-butyl dicarbonate (Boc2O, 33.6 g, 0.155 mol) and triethylamine (15.2 g, 0.15 mol) were added to the residue, and stirred in dichloromethane (200 mL) at room temperature for 4-5 hours. After the reaction was completed, it was washed with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine in sequence, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain N-Boc-3-hydroxypiperidine with a yield of about 80%.

[0026] Sulfonyl chloride acylation: The hydroxyl group of N-Boc-3-hydroxypiperidine is nucleophilic. Under the action of a base such as triethylamine, it undergoes a nucleophilic substitution reaction with sulfonyl chloride to form a sulfonyl ester, introduces a sulfonyl group, and provides an active site for subsequent reactions; the specific reaction steps are: dissolve N-Boc-3-hydroxypiperidine (25g, 0.12mol) in 150mL of dichloromethane, add triethylamine (12.1g, 0.12mol), and slowly drop a dichloromethane solution (50mL) of p-toluenesulfonyl chloride (24.1g, 0.125mol) under ice bath conditions. After the dropwise addition is completed, stir the reaction at room temperature for 3-4 hours. After the reaction is completed, wash with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and remove the solvent by distillation under reduced pressure to obtain N-Boc-3-p-toluenesulfonyloxypiperidine with a yield of about 90%.

[0027] Hydrolysis: Under alkaline conditions, the sulfonyl ester bond of N-Boc-3-toluenesulfonyloxypiperidine undergoes a hydrolysis reaction, breaking to form a hydroxyl group, and obtaining a precursor of the target product. The precursor then undergoes a condensation reaction with cyclopentylamine under the action of a condensing agent to further construct the molecular structure of the target product; the specific reaction steps are: dissolve N-Boc-3-toluenesulfonyloxypiperidine (30g, 0.09mol) in 200mL tetrahydrofuran (THF), add an aqueous solution (100mL) of lithium hydroxide (3.8g, 0.15mol), and stir the reaction at room temperature for 8-10 hours; After the reaction was completed, THF was distilled off under reduced pressure, water (100 mL) was added to the residue, and extracted with dichloromethane (3×50 mL), the organic phase was discarded, and the pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid. Solids precipitated and were filtered to obtain the precursor of the target product.

[0028] Salt purification: react the crude product with a suitable acid to form a salt, and utilize the difference in solubility of the salt in different solvents to further remove impurities and improve the purity of the product; the specific reaction steps are: dissolve the crude product ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamic acid tert-butyl ester (10 g) in 100 mL of anhydrous ethanol, add dropwise anhydrous ethanol solution (50 mL) of oxalic acid (1.5 g), precipitate, stir for 1-2 hours, cool to 0-5°C, stand for 3-4 hours, filter, wash the precipitate with cold anhydrous ethanol, dissolve the precipitate in 100 mL of water, add dropwise 10% sodium hydroxide solution to adjust the pH to 8-9 to free the product, extract with dichloromethane (3×80 mL), dry with anhydrous sodium sulfate for 3-4 hours, filter and distill under reduced pressure to obtain the purified product.

[0029] Crystal form optimization: By selecting appropriate solvents and crystallization conditions, the crystal form of the product is optimized to improve the physical properties of the product, such as stability and solubility, which is beneficial to the storage and application of the product. The specific reaction steps are: the purified product (8 g) is dissolved in 80 mL of acetone, heated to 50-60 ° C, and 120 mL of n-hexane is slowly added dropwise to precipitate crystals. After cooling to room temperature, it is refrigerated (0-5 ° C) for 12-15 hours, filtered, and the crystals are washed 2-3 times with a cold acetone-n-hexane mixed solvent (1:3). The crystals are vacuum dried at 40-50 ° C for 8-10 hours to obtain a white crystalline powder product with optimized crystal form. The crystal form is confirmed by X-ray powder diffraction (XRD). Comparison table of traditional methods and new synthesis methods Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A process for synthesizing tert-butyl ((2S)-4- (-)-3-hydroxy-4-oxo-1- ((S)-2-(-)butyl-2-yl)carbamate, characterized in that: It is prepared from N-benzyl-3-hydroxypiperidine as the raw material through separation, alkali freeing, palladium carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection, sulfonyl chloride acylation, hydrolysis, salt purification and crystal form optimization. Resolution: using a chiral resolution agent to form diastereomeric salts with N-benzyl-3-hydroxypiperidine, and achieving separation based on the difference in their solubility in a specific solvent, thereby obtaining single chiral N-benzyl-3-hydroxypiperidine; Free base: further ensure that N-benzyl-3-hydroxypiperidine exists completely in the form of free base, avoiding the influence of protonation and other problems on the reaction process in the subsequent reaction, and providing more favorable conditions for the subsequent reaction; Palladium-carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection: Under the action of palladium-carbon catalyst, hydrogen reacts with the benzyl group of N-benzyl-3-hydroxypiperidine to remove the benzyl group. At the same time, di-tert-butyl dicarbonate reacts with the amino group on the piperidine ring to introduce a tert-butyloxycarbonyl group to protect the amino group and improve the stability of the amino group in subsequent reactions; Sulfonyl chloride acylation: The hydroxyl group of N-Boc-3-hydroxypiperidine is nucleophilic. Under the action of a base such as triethylamine, it undergoes a nucleophilic substitution reaction with sulfonyl chloride to form a sulfonyl ester, introducing a sulfonyl group and providing an active site for subsequent reactions. Hydrolysis: Under alkaline conditions, the sulfonyl ester bond of N-Boc-3-toluenesulfonyloxypiperidine undergoes a hydrolysis reaction to break and form a hydroxyl group to obtain a precursor of the target product, which then undergoes a condensation reaction with cyclopentylamine under the action of a condensation agent to further construct the molecular structure of the target product; Salt purification: react the crude product with a suitable acid to form a salt, and use the difference in solubility of the salt in different solvents to further remove impurities and improve the purity of the product; Crystal form optimization: By selecting appropriate solvents and crystallization conditions, the crystal form of the product is optimized to improve the physical properties of the product, such as stability and solubility, which is beneficial to the storage and application of the product.

2. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the splitting are: dissolving N-benzyl-3-hydroxypiperidine (100 g, 0.5 mol) in an appropriate amount of methanol, adding a chiral splitting agent, stirring and heating to 50-60° C. to allow the reaction to proceed fully; After cooling to room temperature, crystals precipitate, which are filtered to obtain chiral salt crystals. The crystals are washed with a small amount of cold methanol, and then the chiral salt is dissolved in water, and the pH is adjusted to 10-11 with sodium hydroxide solution to free N-benzyl-3-hydroxypiperidine; The mixture was extracted with dichloromethane (3×100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain single chiral N-benzyl-3-hydroxypiperidine with a yield of about 40% and an ee value of ≥98%.

3. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the base release are: dissolving the single chiral N-benzyl-3-hydroxypiperidine (40 g, 0.2 mol) obtained in the previous step in 200 mL of dichloromethane, adding potassium carbonate (27.6 g, 0.2 mol) and an appropriate amount of water, and stirring the reaction for 2-3 hours; After the reaction was completed, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain N-benzyl-3-hydroxypiperidine in the form of a free base.

4. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the palladium-carbon hydrogenation debenzylation / tert-butyloxycarbonyl protection are as follows: dissolving N-benzyl-3-hydroxypiperidine (30 g, 0.15 mol) in the form of a free base in 300 mL of methanol, adding 10% palladium-carbon catalyst (3 g), introducing hydrogen, and stirring the reaction at room temperature and normal pressure for 6-8 hours; After the reaction is completed, the palladium carbon catalyst is filtered off, the filtrate is distilled under reduced pressure to remove methanol, di-tert-butyl dicarbonate (Boc2O, 33.6 g, 0.155 mol) and triethylamine (15.2 g, 0.15 mol) are added to the residue, and the mixture is stirred in dichloromethane (200 mL) at room temperature for 4-5 hours; After the reaction, the mixture was washed with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain N-Boc-3-hydroxypiperidine with a yield of about 80%.

5. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the sulfonyl chloride acylation are: dissolving N-Boc-3-hydroxypiperidine (25 g, 0.12 mol) in 150 mL of dichloromethane, adding triethylamine (12.1 g, 0.12 mol), and slowly dropping a dichloromethane solution (50 mL) of p-toluenesulfonyl chloride (24.1 g, 0.125 mol) under ice bath conditions; after the dropwise addition, stirring and reacting at room temperature for 3-4 hours; After the reaction, the mixture was washed with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain N-Boc-3-toluenesulfonyloxypiperidine with a yield of about 90%.

6. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the hydrolysis are: dissolving N-Boc-3-toluenesulfonyloxypiperidine (30 g, 0.09 mol) in 200 mL of tetrahydrofuran, adding an aqueous solution (100 mL) of lithium hydroxide (3.8 g, 0.15 mol), and stirring at room temperature for 8-10 hours; After the reaction was completed, THF was distilled off under reduced pressure, water (100 mL) was added to the residue, and extracted with dichloromethane (3×50 mL), the organic phase was discarded, and the pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid. Solids precipitated and were filtered to obtain the precursor of the target product.

7. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the salt formation purification are: dissolving crude tert-butyl ((2S)-4-(cyclopentylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidone-3-yl)butyl-2-yl)carbamate (10 g) in 100 mL of anhydrous ethanol, adding dropwise anhydrous ethanol solution (50 mL) of oxalic acid (1.5 g) to precipitate, stirring for 1-2 hours, cooling to 0-5° C., standing for 3-4 hours, and then filtering, washing the precipitate with cold anhydrous ethanol, dissolving the precipitate in 100 mL of water, adding dropwise a 10% sodium hydroxide solution to adjust the pH to 8-9 to free the product, extracting with dichloromethane (3×80 mL), drying with anhydrous sodium sulfate for 3-4 hours, filtering, and distilling under reduced pressure to obtain a purified product.

8. The synthesis process of tert-butyl ((2S)-4-(-)-3-hydroxy-4-oxo-1-((S)-2-(-)butyl-2-yl)carbamate according to claim 1, characterized in that: The specific reaction steps of the salt-forming purification are: dissolving the purified product (8 g) in 80 mL of acetone, heating to 50-60° C., slowly dropping 120 mL of n-hexane, causing crystals to precipitate, cooling to room temperature and refrigerating (0-5° C.) for 12-15 hours, filtering, washing the crystals 2-3 times with a cold acetone-n-hexane mixed solvent (1:3), and vacuum drying at 40-50° C. for 8-10 hours to obtain a white crystalline powder product with optimized crystal form, and confirming the crystal form by X-ray powder diffraction.