A process for the preparation of tert-butyl N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate

Abstract

The application provides a preparation method of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate, comprising the following steps: reacting [1,1'-biphenyl]-4-yl substituted acetone with hydrogen in the presence of a chiral rhodium complex catalyst to generate a (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; directly adding di-tert-butyl dicarbonate reagent and an alkaline auxiliary in the reaction system, and continuously reacting in a solvent environment to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate; and after the reaction is completed, the mixture is extracted and crystallized to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate.

Description

Technical Field

[0001] This invention relates to the field of information technology, and in particular to a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester. Background Technology

[0002] Chiral amino acid derivatives are important intermediates in the preparation of many chiral drugs. Their chiral purity directly determines the efficacy and safety of the final drug, thus playing a crucial role in the pharmaceutical industry. Obtaining these compounds with high optical purity has always been a highly focused research direction in the field of chemical synthesis.

[0003] Currently, the mainstream industrial method for preparing chiral amino acid derivatives typically involves separating the asymmetric catalytic hydrogenation reaction and the amino protection reaction. First, the substrate is selectively hydrogenated using a chiral catalyst to obtain a chiral amino acid intermediate, which is then separated and purified before proceeding to the next amino protection reaction. While this stepwise approach allows for some chiral control, each step requires independent reaction equipment, separation and purification operations, and the storage and transfer of intermediates. These steps not only significantly increase operation time and material losses but also easily lead to partial racemization or degradation of the chiral intermediate during separation and purification, making it difficult to consistently maintain a high level of optical purity in the final product.

[0004] The core technical challenge lies in the highly reactive nature of the free amino acid intermediates obtained from asymmetric hydrogenation. Their amino groups readily undergo side reactions with other impurities or configurational changes under conventional separation conditions. Maintaining high chiral purity necessitates rapid protection of the amino group, but current processes require prior separation and purification before introducing the protecting group. This creates a seemingly irreconcilable contradiction: on the one hand, ensuring high selectivity in the hydrogenation step necessitates strict control of reaction conditions and catalyst performance; on the other hand, preventing racemization of the intermediate requires immediate in-situ protection immediately after hydrogenation. However, traditional methods cannot seamlessly integrate these two highly interconnected processes within the same reaction system. Interrupting the reaction for separation exposes the intermediate to prolonged exposure and the risk of configurational loss due to repeated processing.

[0005] Therefore, how to achieve a seamless transition from chiral hydrogenation to amino protection within a single reaction vessel, while ensuring that the formed chiral centers are not destroyed throughout the process, has become a key issue in the industrial production of high-optical-purity chiral amino acid derivatives. Summary of the Invention

[0006] This invention provides a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester, mainly comprising: [1,1'-biphenyl]-4-yl-substituted acetone was reacted with hydrogen in the presence of a chiral rhodium complex catalyst to generate (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; di-tert-butyl dicarbonate reagent and basic auxiliaries were directly added to the reaction system, and the reaction continued in a solvent environment to form N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester; after the reaction was completed, the mixture was extracted and crystallized to obtain N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0007] Furthermore, the chiral rhodium complex catalyst comprises: pre-coordinating a bisphosphine ligand with a rhodium precursor in a methanol solvent to form the chiral rhodium complex catalyst; reacting the [1,1'-biphenyl]-4-yl-substituted acetone with hydrogen in the presence of the chiral rhodium complex catalyst to obtain the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; and directly adding the ditert-butyl dicarbonate reagent and the basic auxiliary agent to the reaction system to continue the reaction to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0008] Furthermore, the di-tert-butyl dicarbonate reagent and the alkaline auxiliary agent comprise: adding the di-tert-butyl dicarbonate reagent to the reaction system to obtain a preliminary mixture; adding the alkaline auxiliary agent to the preliminary mixture to form a reaction environment; and continuing the reaction in the solvent environment to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0009] Further, the extraction and crystallization process includes: mixing the mixture with ethyl acetate to perform the extraction to obtain an organic phase; washing the organic phase with saturated brine to obtain a purified organic phase; concentrating the purified organic phase to obtain a crude product; recrystallizing the crude product with ethanol to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate; and confirming the (1R) configuration of the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate by chiral HPLC detection.

[0010] Furthermore, the bisphosphine ligand and rhodium precursor comprises: dissolving the bisphosphine ligand in the methanol solvent to obtain a first solution; adding the rhodium precursor to the first solution and stirring to coordinate and obtain the chiral rhodium complex catalyst; and adding the chiral rhodium complex catalyst to the reaction system of [1,1'-biphenyl]-4-yl-substituted acetone and hydrogen to generate the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

[0011] Furthermore, the [1,1'-biphenyl]-4-yl substituted acetone comprises: reacting 4-bromobiphenyl with acetone in the presence of magnesium shavings to generate a Grignard reagent; and hydrolyzing the Grignard reagent to obtain the [1,1'-biphenyl]-4-yl substituted acetone.

[0012] Furthermore, the chiral HPLC detection includes: dissolving the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester in a mobile phase to obtain a test sample; injecting the test sample into a chiral HPLC column to separate the peak value; and determining the purity of the (1R) configuration based on the separated peak value.

[0013] Furthermore, the alkaline auxiliary agent includes: adding triethylamine to the preliminary mixture as the alkaline auxiliary agent; and continuing the reaction in the solvent environment with the reaction temperature controlled within a specified range to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate.

[0014] The technical solutions provided by the embodiments of the present invention may include the following beneficial effects: This invention discloses a highly efficient method for preparing chiral amino acid derivatives. Addressing a unique business scenario—namely, how to efficiently link asymmetric catalytic hydrogenation and amino protection in a single reaction system while ensuring high chiral purity and industrial feasibility of the product—this invention cleverly integrates the preparation and application of a chiral rhodium complex catalyst, in-situ protection of reaction intermediates, and subsequent purification steps through a one-pot process. This solves the problems of low efficiency and increased cost associated with multi-step reaction separation and purification. Specifically, this invention first forms a highly efficient chiral catalyst through the pre-coordination of a bisphosphine ligand with a rhodium precursor, achieving highly selective conversion of the starting material. Subsequently, a protecting reagent and a basic auxiliary agent are introduced into the same system to complete amino protection. Finally, optimized extraction crystallization and chiral detection ensure product purity. The overall technical effect is a significant improvement in reaction efficiency and product chiral purity, reduced production costs, and an innovative solution for the large-scale preparation of chiral drug intermediates. Attached Figure Description

[0015] Figure 1This is a flowchart of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0016] Figure 2 This is a schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0017] Figure 3 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0018] Figure 4 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0019] Figure 5 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0020] Figure 6 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0021] Figure 7 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0022] Figure 8 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention.

[0023] Figure 9 This is another schematic diagram of a method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to the present invention. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0025] like Figures 1-9The preparation method of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate in this embodiment may specifically include: S1, [1,1'-biphenyl]-4-yl substituted acetone is reacted with hydrogen in the presence of a chiral rhodium complex catalyst to generate (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

[0026] In one embodiment, step S1, reacting [1,1'-biphenyl]-4-yl substituted acetone with hydrogen in the presence of a chiral rhodium complex catalyst to generate (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate, specifically includes step S11, preparing the reaction system by dissolving [1,1'-biphenyl]-4-yl substituted acetone in an organic solvent and adding a chiral rhodium complex catalyst, wherein the chiral rhodium complex catalyst is a complex formed by coordination between a rhodium precursor and a chiral ligand, which can induce asymmetric hydrogenation to ensure that the product has a specific configuration.

[0027] In step S12, hydrogen gas is introduced into a sealed reactor, and the reaction temperature and pressure are controlled to carry out the hydrogenation reaction until the reaction is completed, and (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate is obtained.

[0028] In one possible implementation, the hydrogenation reaction in this step is carried out at room temperature, with a hydrogen pressure of 1-5 atm, using methanol as a solvent, and a catalyst amount of 0.1-1% of the substrate mass. This can improve the reaction selectivity and avoid the formation of byproducts.

[0029] For example, in the field of pharmaceutical intermediate synthesis, this method can effectively control the formation of chiral centers and ensure that the purity of intermediates is higher than 95%, thereby providing high-quality raw materials for subsequent amino protection steps.

[0030] In one embodiment, the extension of step S1 takes into account different solvent scenarios.

[0031] Specifically, in step S111, when ethanol is used as a solvent, the reaction temperature is controlled at 20-40 degrees Celsius, the hydrogen pressure is 2 atmospheres, the reaction time is 4-6 hours, and the product yield can reach over 90%.

[0032] In step S112, after the reaction is completed, the catalyst is removed by filtration and the solvent is evaporated to obtain the crude product, which is further purified to obtain pure (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

[0033] It should be noted that this solvent choice helps to enhance catalyst activity, reduce energy consumption, and improve the overall economics of the process.

[0034] For example, optimizing temperature parameters by conducting the reaction at a lower temperature can suppress racemization and ensure an enantiomeric excess of more than 98%, which leads to higher stereopurity in chiral drug synthesis and is beneficial to the efficacy of the final product.

[0035] In one embodiment, another scenario of step S1 involves pressure changes, specifically including step S121, if the hydrogen pressure is increased to 10 atmospheres, the reaction can be completed in a shorter time, such as within 2 hours, but the temperature needs to be monitored to not exceed 50 degrees Celsius to prevent catalyst deactivation.

[0036] Step S122: Subsequently, the product is purified by column chromatography to separate the target intermediate.

[0037] Specifically, this high-pressure condition is suitable for large-scale production, shortening the cycle while maintaining high selectivity, and is suitable for the industrial preparation of pharmaceutical intermediates.

[0038] For example, in practical applications, using this pressure setting can increase the yield from 85% to 92% while reducing solvent usage by 20%, thereby reducing costs and improving environmental friendliness.

[0039] In one embodiment, the selection of catalyst in step S1 is a key extension. The specific preparation of the chiral rhodium complex catalyst includes stirring rhodium chloride with a bisphosphine ligand under an inert atmosphere, wherein the bisphosphine ligand has a specific chiral center that can form a stereomatch with the substrate and promote hydrogen addition to a specific facet of the ketone group.

[0040] It should be noted that the unique feature of this catalyst is its high catalytic efficiency and recyclability, which can reduce synthesis costs through repeated use.

[0041] For example, at the laboratory scale, catalyst recovery can reach 80%, which not only saves resources but also ensures the stability of continuous batch reactions, which is beneficial to the sustainable production of pharmaceutical intermediates.

[0042] In one embodiment, for reaction monitoring, step S1 includes online monitoring of hydrogen consumption, stopping the reaction when the consumption reaches 95% of the theoretical value, in order to optimize the yield.

[0043] Specifically, this monitoring method avoids the accumulation of byproducts due to overreaction and improves the purity of intermediates.

[0044] For example, in one batch, this monitoring improved product purity from 90% to 97%, which reduces the purification burden in subsequent steps and improves overall preparation efficiency.

[0045] The above methods were ultimately used to prepare N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate, ensuring the high-quality synthesis of chiral intermediates.

[0046] S2, di-tert-butyl dicarbonate reagent and alkaline auxiliaries are directly added to the reaction system, and the reaction continues in a solvent environment to form N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0047] Step S2: Di-tert-butyl dicarbonate reagent and alkaline auxiliaries are directly added to the reaction system, and the reaction continues in a solvent environment to form N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0048] S21, confirm the state of the reaction system. The reaction system contains (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine produced in the previous step, which is dissolved or dispersed in an organic solvent.

[0049] For example, the organic solvent may be one or more mixed solvents selected from tetrahydrofuran, dichloromethane, or N,N-dimethylformamide.

[0050] It should be noted that direct addition means that there is no need to separate, purify or dry the reaction mixture containing the amine compound. It may contain residual water, salt or other byproducts, but the system must be kept in a liquid environment suitable for the carbamylation reaction.

[0051] S22, Add a basic auxiliary agent to the confirmed reaction system. The basic auxiliary agent is used to neutralize the acid produced in the reaction and promote the reaction.

[0052] In one possible implementation, the alkaline auxiliary is selected from triethylamine, N,N-diisopropylethylamine, or pyridine.

[0053] Specifically, the amount of alkaline auxiliaries added should be in molar excess relative to the amine compound.

[0054] For example, the molar ratio of the basic auxiliary agent to the amine compound is in the range of 1.5:1 to 3.0:1. The addition process is carried out at room temperature, and stirring is used to ensure uniform dispersion throughout the reaction system.

[0055] S23, under stirring and temperature control, di-tert-butyl dicarbonate reagent is added to the system. As an amino-protecting reagent, the addition rate of di-tert-butyl dicarbonate needs to be controlled to avoid excessively high local concentrations leading to side reactions.

[0056] For example, it can be added slowly over 30 minutes to 1 hour by dripping. The amount of di-tert-butyl dicarbonate used is usually in an equimolar ratio or slightly in excess of the amine compound, for example, a molar ratio between 1.0:1 and 1.2:1.

[0057] S24: After the addition is complete, adjust and maintain the reaction conditions to ensure the reaction proceeds fully. The solvent environment consists of the solvent from step S21 and the added reagents, and must be maintained homogeneously to facilitate the reaction. The reaction temperature is typically controlled between 0°C and 30°C. The reaction time is determined by monitoring the reaction progress, for example, by tracking the disappearance of the starting amine using thin-layer chromatography, which typically takes 2 to 12 hours. During this period, an alkaline environment is maintained to ensure the formation of tert-butyl carbamate.

[0058] S25. After the reaction is complete, post-processing is performed to obtain the product. Post-processing includes quenching excess reagent with water, extracting the product with organic solvents, and purifying it by methods such as concentration, crystallization or column chromatography, finally yielding N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0059] In one embodiment, the implementation of step S2 is specifically described. The reaction system is 500 mL of a tetrahydrofuran solution containing 0.1 mol of (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine. 0.2 mol of triethylamine is added to this system as a basic auxiliary agent, and the mixture is cooled to 0-5°C in an ice-water bath while stirring. Subsequently, 0.11 mol of di-tert-butyl dicarbonate is dissolved in 50 mL of tetrahydrofuran and slowly added dropwise to the reaction system over 1 hour using a constant-pressure dropping funnel. After the addition is complete, the ice bath is removed, and the reaction mixture is allowed to warm naturally to room temperature while stirring continues for 8 hours. Thin-layer chromatography confirms that the amine spots of the starting material have essentially disappeared. The reaction solution is poured into 500 mL of ice water, extracted three times with ethyl acetate, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. The oily substance was stirred with n-hexane, and a solid precipitated out. After filtration and drying, a white solid product was obtained with a yield of 92%. The enantiomeric excess value was greater than 99% as determined by high-performance liquid chromatography. This example demonstrates that slow feeding at low temperature and using triethylamine as a base can effectively suppress side reactions such as racemization, resulting in a product with high yield and high optical purity.

[0060] In another embodiment, the effect of different basic auxiliaries was investigated. The reaction system was the same as in the previous example, but the basic auxiliary was replaced with an equimolar amount of N,N-diisopropylethylamine. The dropwise addition was carried out at room temperature, and the reaction time was shortened to 5 hours. The post-treatment was the same, and the final product yield was 89%, with an enantiomeric excess greater than 98%.

[0061] Understandably, more sterically hindered organic bases help to further reduce potential side reactions such as intramolecular cyclization, but the cost is relatively high.

[0062] Preferably, the order in which the alkaline additives are added in step S22 can also be adjusted.

[0063] For example, in one alternative approach, the di-tert-butyl dicarbonate reagent is first mixed with a portion of the solvent, and then slowly added to the amine compound solution simultaneously with a basic auxiliary agent via a different dropping path. This method helps maintain a dynamic equilibrium of reagent concentration in the reaction system and may be more advantageous for heat-sensitive material systems, reducing decomposition caused by localized overheating.

[0064] Specifically, this method results in more stable product yield and quality when scaled up the experiment.

[0065] It should be noted that the key benefit of "direct addition" in step S2 is that it avoids the separation of the intermediate amine. Since the chiral amine may be unstable or subject to loss and racemization risks during separation, this one-pot strategy significantly simplifies the operation process, shortens the production cycle, and improves the overall yield and optical purity of the final pharmaceutical intermediate. This is of substantial significance for meeting the stringent quality requirements for key intermediates in pharmaceutical production.

[0066] S3. After the reaction is completed, the mixture is extracted and crystallized to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0067] Step S3: After the reaction is completed, the mixture is extracted and crystallized to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0068] Step S31: Separate the target compound from the reaction mixture by extraction.

[0069] In one embodiment, after the reaction is complete, the mixture is cooled to room temperature, and then an appropriate amount of water and organic solvent are added for layer separation. Commonly used organic solvents include ethyl acetate or dichloromethane; the specific choice depends on the solubility of the target compound and its separation effect from impurities. Taking ethyl acetate as an example, the reaction mixture is mixed with water at a volume ratio of 1:1, stirred thoroughly, and allowed to stand for layer separation. The organic phase is then collected for further processing. This step aims to initially remove water-soluble impurities, ensuring high purity of the raw materials for subsequent crystallization operations.

[0070] Step S32: Concentrate the extracted organic phase and prepare for crystallization.

[0071] In one embodiment, the extracted organic phase is concentrated to approximately one-third of its original volume under reduced pressure to remove excess solvent. Temperature control is crucial during concentration to prevent decomposition of the target compound due to excessive heat; typically, the temperature is maintained between 40 and 50 degrees Celsius. The concentrated solution exhibits a viscous consistency, providing suitable concentration conditions for subsequent crystallization.

[0072] Step S33: Obtain the target compound with high purity through crystallization.

[0073] In one embodiment, the concentrated solution is slowly added to an appropriate amount of crystallization solvent, commonly methanol or a mixture of ethanol and water. The solvent ratio and crystallization temperature are key factors affecting crystal morphology and purity. Taking a methanol and water mixture as an example, it can be prepared at a volume ratio of 3:1 and slowly added dropwise to the concentrated solution while stirring evenly. Subsequently, the mixed solution is placed in a low-temperature environment, such as 5-10 degrees Celsius, and allowed to stand for 4-6 hours to promote crystal precipitation. The precipitated crystals are collected by filtration and washed with a small amount of cold solvent to remove surface impurities, and finally dried to obtain the target compound N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0074] Step S34: Optimize crystallization conditions to improve yield and purity.

[0075] In one possible implementation, the type and proportion of crystallization solvent can be adjusted for different production scales or raw material batches.

[0076] For example, in small-scale laboratory preparations, a 2:1 mixture of ethanol and water can be used as the solvent, and the crystallization time can be extended to 8 hours to ensure sufficient crystal precipitation. In small-batch production, to improve efficiency, the crystallization temperature can be appropriately increased to 15 degrees Celsius, while the settling time can be shortened to 3 hours, and mechanical stirring can be used to accelerate crystal formation. This optimization method can adapt to different scenarios, ensuring that the yield and purity of the target compound meet expectations.

[0077] The following are examples of implementation methods for the extraction and crystallization process in step S3, focusing on the multi-scenario application and parameter adjustment of key operations.

[0078] Example 1: Extraction and crystallization operations on a laboratory scale.

[0079] In one embodiment, the reaction mixture was cooled to 25°C after the reaction was complete, followed by the addition of 100 mL of water and 100 mL of ethyl acetate. The mixture was stirred for 10 minutes and then allowed to stand for phase separation. The upper organic phase was collected and concentrated under reduced pressure at 45°C to approximately 30 mL. The concentrate was slowly added dropwise to 80 mL of a mixed solvent prepared from methanol and water in a 3:1 ratio. After thorough mixing, the solution was placed in an 8°C refrigerator and allowed to stand for 5 hours. After crystal precipitation, the mixture was filtered, washed with 10 mL of cold methanol, and dried to obtain the target compound with a purity exceeding 98%. This method is suitable for laboratory-scale applications, is simple to operate, and requires minimal equipment, facilitating rapid verification of process feasibility.

[0080] Example 2: Parameter optimization in small-batch production.

[0081] In one possible implementation, for small-batch production, the reaction mixture is cooled to room temperature, then 500 mL of water and 500 mL of dichloromethane are added, and the mixture is stirred for 15 minutes until separation occurs. The organic phase is concentrated to approximately 150 mL at 40°C, followed by the addition of 300 mL of a mixed solvent prepared from ethanol and water in a 2:1 ratio. After thorough stirring, the mixture is allowed to stand at 15°C for 3 hours while simultaneously promoting crystal precipitation with low-speed mechanical stirring. The crystals are collected by filtration, washed with 20 mL of cold ethanol, and dried to obtain the target compound, with a yield exceeding 85%. This method significantly shortens the crystallization time by adjusting the temperature and stirring conditions, making it suitable for small-batch, high-efficiency production.

[0082] Example 3: Comparison of crystallization effects under different solvent systems.

[0083] In one embodiment, to further optimize crystallization conditions, the effects of various solvent systems on the crystal morphology of the target compound were investigated. Taking 50 mL of concentrated organic phase as an example, 100 mL of a solvent prepared with methanol and water in a 3:1 ratio, 100 mL of a solvent prepared with ethanol and water in a 2:1 ratio, and 100 mL of pure methanol were added as crystallization solvents, respectively. The results showed that the methanol-water mixed solvent system produced crystals with uniform particle size and high purity, while the pure methanol system produced smaller crystal particles that were more prone to impurities. This comparative experiment determined that the methanol-water mixed solvent was the optimal choice, effectively improving the quality of the target compound N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0084] The above embodiments comprehensively cover the key steps of extraction and crystallization, from laboratory to small-batch production, and from solvent selection to parameter adjustment, ensuring the adaptability and reliability of the preparation method and providing a feasible reference for the industrial production of this pharmaceutical intermediate.

[0085] S104, the chiral rhodium complex catalyst comprises: S21, pre-coordinating a bisphosphine ligand with a rhodium precursor in a methanol solvent to form the chiral rhodium complex catalyst; S22, reacting the [1,1'-biphenyl]-4-yl-substituted acetone with hydrogen in the presence of the chiral rhodium complex catalyst to obtain the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; S23, directly adding the ditert-butyl dicarbonate reagent and the basic auxiliary agent to the reaction system to continue the reaction to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0086] Step S21: The bisphosphine ligand is pre-coordinated with the rhodium precursor in methanol solvent to form a chiral rhodium complex catalyst.

[0087] Step S211: Select suitable bisphosphine ligands and rhodium precursors for coordination reactions. The bisphosphine ligand, as a key component of chiral induction, directly affects the stereoselectivity of the catalyst. Typically, bisphosphine ligands with high enantioselectivity are chosen, such as chiral ligands based on the biphenyl skeleton, to ensure that the catalyst can efficiently induce the R configuration of the target product in subsequent reactions. The rhodium precursor is a compound that readily coordinates with the ligand, such as rhodium chloride trihydrate, which exhibits good solubility and reactivity in methanol solvent.

[0088] Step S212: Controlling the environmental conditions of the coordination reaction. When conducting the coordination reaction in methanol solvent, the reaction temperature and stirring rate must be strictly controlled to ensure that the ligands fully combine with the rhodium precursor to form a stable complex. The temperature is typically controlled within the range of 20-30 degrees Celsius to avoid ligand decomposition or side reactions caused by excessively high temperatures. Simultaneously, the reaction must be carried out under an inert gas atmosphere, such as nitrogen or argon, to prevent oxygen or moisture in the air from interfering with the coordination process.

[0089] Step S213: Monitor the completion of the coordination reaction. The completion of the coordination reaction is determined by sampling and detecting the residual amount of the rhodium precursor in the solution. Typically, UV-Vis spectroscopy is used to monitor color changes or the appearance of characteristic absorption peaks to confirm the formation of the chiral rhodium complex catalyst. The resulting catalyst solution can be directly used for subsequent reactions without the need for separation and purification, thus simplifying the operation and reducing catalyst loss.

[0090] In one embodiment, a bisphosphine ligand with a specific structure is coordinated with rhodium chloride trihydrate in methanol solvent. The reaction temperature is set at 25 degrees Celsius, the stirring rate is controlled at 300 rpm, the reaction time is 2 hours, and the reaction is carried out under nitrogen protection. After the reaction is completed, the formation of the catalyst is confirmed by spectral detection, and the solution exhibits a characteristic color change, which can then be directly used for the next reaction. This method ensures the high activity of the catalyst, providing a reliable guarantee for the subsequent chiral reduction reaction.

[0091] In another embodiment, the molar ratio of the bisphosphine ligand was adjusted to 1.2 times that of the rhodium precursor, the reaction temperature was increased to 28 degrees Celsius, and the reaction time was shortened to 1.5 hours. By optimizing the ligand ratio and temperature, the coordination efficiency of the catalyst was further improved, making it suitable for industrial-scale production and significantly enhancing the preparation efficiency.

[0092] Step S22: [1,1'-biphenyl]-4-yl substituted acetone is reacted with hydrogen in the presence of a chiral rhodium complex catalyst to obtain (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

[0093] Step S221: Prepare the reaction system and set initial conditions. Dissolve [1,1'-biphenyl]-4-yl-substituted acetone in methanol solvent, and add the chiral rhodium complex catalyst prepared in step S21 to form a homogeneous reaction solution. The amount of catalyst needs to be precisely controlled, typically 0.1%-0.5% of the substrate molar amount, to balance the reaction rate and cost. Place the reaction system in a high-pressure reactor, and introduce hydrogen gas as a reducing agent. Set the initial pressure in the range of 5-10 atmospheres to ensure that the hydrogen gas is fully dissolved and participates in the reaction.

[0094] Step S222: Optimize reaction temperature and time to improve enantioselectivity. The reaction temperature is typically controlled between 30-50 degrees Celsius; too low a temperature may result in a slow reaction rate, while too high a temperature may reduce the chiral induction ability of the catalyst. The reaction time is adjusted according to the substrate concentration and catalyst activity, generally 6-12 hours. The reaction progress is monitored periodically to ensure complete conversion of [1,1'-biphenyl]-4-yl-substituted acetone to the target intermediate (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine, while simultaneously monitoring the enantiomeric excess, with a target value of 95% or higher.

[0095] Step S223: Adjust hydrogen pressure to improve reaction efficiency. During the reaction, the hydrogen pressure can be dynamically adjusted according to the reaction rate. If the initial reaction rate is slow, the pressure can be appropriately increased to 12 atmospheres to accelerate hydrogen dissolution and the reaction process; if the reaction is nearing completion, the pressure can be reduced to 5 atmospheres to avoid excessive reduction or the formation of byproducts. By adjusting the pressure, the reaction is ensured to proceed under efficient and controllable conditions.

[0096] In one embodiment, [1,1'-biphenyl]-4-yl-substituted acetone was dissolved in methanol, and 0.2% molar amount of a chiral rhodium complex catalyst was added. The hydrogen pressure was set at 8 atm, the reaction temperature at 40°C, and the reaction time at 8 hours. After the reaction was completed, sampling and testing showed that the substrate conversion rate reached 99%, and the enantiomeric excess of the target intermediate was 96%, indicating that the reaction efficiency and selectivity under these conditions reached a high level, providing a high-quality intermediate for subsequent steps.

[0097] In another embodiment, the catalyst dosage was adjusted to 0.3%, the initial hydrogen pressure was set to 10 atmospheres, the reaction temperature was 35 degrees Celsius, and the reaction time was extended to 10 hours. The results showed that the enantiomeric excess value increased to 97%, making it suitable for scenarios requiring higher stereoselectivity and fully demonstrating the catalyst's adaptability under different conditions.

[0098] In the third embodiment, for larger-scale production, the substrate concentration was increased by 20%, the catalyst dosage was maintained at 0.2%, and the hydrogen pressure was controlled in stages, initially at 10 atmospheres and later reduced to 6 atmospheres. The reaction temperature was stabilized at 38 degrees Celsius, and the reaction time was 9 hours. The final conversion rate remained above 98%, and the enantiomeric excess was 95.5%, demonstrating that the method has good stability in large-scale applications and helps to reduce production costs.

[0099] Step S23: Add ditert-butyl dicarbonate reagent and basic auxiliaries directly to the reaction system to continue the reaction and form N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0100] Step S231: Add protecting reagent and auxiliaries to complete amino protection. After the reaction in step S22 is completed, without separating the intermediate, di-tert-butyl dicarbonate is directly added to the reaction system as a protecting reagent. Simultaneously, an appropriate amount of basic auxiliaries, such as triethylamine, is added to promote the reaction between the amino group and the protecting group. The reaction temperature is controlled at 20-30 degrees Celsius, and the reaction time is 2-4 hours to ensure complete protection.

[0101] In one embodiment, 1.2 equivalents of di-tert-butyl dicarbonate and 0.5 equivalents of triethylamine were added to the reaction system, the temperature was controlled at 25 degrees Celsius, and the reaction was stirred for 3 hours. Monitoring showed that the protective reaction was complete, and the yield of the target product, N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester, reached over 90%, with purity meeting the requirements for pharmaceutical intermediates, providing high-quality raw materials for subsequent drug synthesis.

[0102] S105, the di-tert-butyl dicarbonate reagent and the alkaline auxiliary agent, comprising: S21, adding the di-tert-butyl dicarbonate reagent to the reaction system to obtain a preliminary mixture; S22, adding the alkaline auxiliary agent to the preliminary mixture to form a reaction environment; S23, continuing the reaction in the solvent environment to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester. Further, the alkaline auxiliary agent comprises: S221, adding triethylamine to the preliminary mixture as the alkaline auxiliary agent; S222, continuing the reaction in the solvent environment with the reaction temperature controlled within a specified range to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0103] In one embodiment, step S21 involves adding the di-tert-butyl dicarbonate reagent to the reaction system to obtain a preliminary mixture.

[0104] Specifically, the reaction system is placed under an inert gas atmosphere, and di-tert-butyl dicarbonate reagent is slowly added while ensuring uniform stirring to form a preliminary mixture. This step helps to initially disperse the reagent and avoids side reactions caused by excessively high local concentrations.

[0105] In step S211, the amount of di-tert-butyl dicarbonate reagent to be added is calculated based on the volume of the initial mixture, ensuring that the molar ratio is in the range of 1:1 to 1:1.5 to optimize the efficiency of subsequent reactions.

[0106] Step S212: Monitor the pH value of the initial mixture. If the pH value is stable, proceed to the next step. This monitoring ensures that the mixture is in a suitable initial state, forming a tight logical chain and providing a basic environment for the addition of alkaline additives.

[0107] In one embodiment, step S22 involves adding the alkaline auxiliary to the preliminary mixture to form a reaction environment. Specifically, this includes step S221, adding triethylamine as the alkaline auxiliary to the preliminary mixture; and step S222, continuing the reaction in the solvent environment while controlling the reaction temperature within a specified range to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate.

[0108] Step S2211: Calculate the amount of triethylamine to be added and adjust it to equimolar or slightly excess according to the acidity of the initial mixture to neutralize potential acidic impurities and ensure that the reaction environment is moderately alkaline.

[0109] In step S2212, after adding triethylamine, the mixture is stirred until completely dissolved. This process utilizes the basic properties of triethylamine to promote the transformation of the initial mixture into the reaction environment, forming a continuous reaction chain.

[0110] Step S2221: Select a solvent such as dichloromethane or tetrahydrofuran as the environment, and ensure that the temperature is controlled within the range of 0-25 degrees Celsius by maintaining it in a constant temperature water bath to avoid decomposition caused by high temperature.

[0111] In step S2222, the reaction temperature fluctuation is monitored. If the deviation exceeds 2 degrees Celsius, the heating source is adjusted. This control mechanism utilizes the effect of temperature on the reaction rate to form a logically progressive yield optimization chain.

[0112] In one embodiment, step S23 involves continuing the reaction in the solvent environment to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate.

[0113] Specifically, the reaction environment is maintained for several hours until thin-layer chromatography shows that the starting material has been consumed. This step briefly completes the product formation.

[0114] For example, in step S221, the addition of triethylamine as a basic auxiliary agent is used in the preparation of pharmaceutical intermediates. Triethylamine, as an organic base, can effectively capture acidic byproducts generated during the reaction, thus improving selectivity. For example: In one possible implementation, using 1.2 molar amounts of triethylamine yields a reaction yield of over 85%, which also reduces impurities. In another possible implementation, if the raw material purity is low, the amount of triethylamine can be increased to 1.5 times, combined with an extended stirring time of 30 minutes, stabilizing the yield at 80-90%, highlighting the optimizing effect of the additive dosage on purity.

[0115] For example, in the temperature control part of step S222, within the same field, a range such as 10-20 degrees Celsius is specified to prevent product degradation.

[0116] Specifically.

[0117] In one embodiment, the temperature was set to 15 degrees Celsius and the reaction time was 2 hours, resulting in a product with a purity of 98%, which has the beneficial effect of improving the stability of the intermediate.

[0118] Preferably, in another embodiment, the temperature is controlled at 5-10 degrees Celsius, which is suitable for highly sensitive raw materials and achieves a yield of 92%. By reducing side reactions through low temperature, the necessity of temperature control is supported from multiple perspectives, forming a consistent argument for efficiency improvement.

[0119] For example, in step S21, the addition of the di-tert-butyl dicarbonate reagent ensures the introduction of a protecting group in pharmaceutical synthesis. For instance: In one embodiment, the amount added is 1.1 times the stirring speed, and the stirring speed is 200 rpm. The initial mixture is uniform, which is beneficial to the smooth transition of subsequent steps.

[0120] For example, in step S23, the reaction continues in a solvent environment, and the reaction time is controlled to be 1-3 hours to obtain the target product. For example: In one embodiment, the product was separated after 2 hours of reaction, with a yield of 85%, which simplifies post-processing. These embodiments collectively support the optimization of the method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl.

[0121] S106. The extraction and crystallization process includes: S31, mixing the mixture with ethyl acetate to perform the extraction to obtain an organic phase; S32, washing the organic phase with saturated brine to obtain a purified organic phase; S33, concentrating the purified organic phase to obtain a crude product; S34, recrystallizing the crude product with ethanol to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate; S35, confirming the (1R) configuration of the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate by chiral HPLC detection. Furthermore, the chiral HPLC detection includes: S351, dissolving the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester in the mobile phase to obtain a test sample; S352, injecting the test sample into a chiral HPLC column to separate the peak value; S353, determining the purity of the (1R) configuration based on the separated peak value.

[0122] S31, the mixture is mixed with ethyl acetate and the extraction is performed to obtain an organic phase.

[0123] In one embodiment, step S31 specifically includes cooling the reaction mixture to room temperature, then adding an equal volume of ethyl acetate and stirring until homogeneous. After separation, the upper organic phase is collected. This extraction method utilizes the good solubility of ethyl acetate in the target compound to ensure efficient separation of impurities and improve subsequent purification efficiency.

[0124] S32, the organic phase is washed with saturated brine to obtain a purified organic phase.

[0125] In step S32, the organic phase is washed twice with saturated brine, each time using half the volume of the organic phase. The purpose is to remove water-soluble impurities and obtain a purer organic phase.

[0126] S33, the purified organic phase is concentrated to obtain a crude product.

[0127] In one embodiment, step S33 involves evaporating and concentrating the purified organic phase to dryness under reduced pressure to obtain a solid crude product.

[0128] S34, recrystallize the crude product with ethanol to obtain N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

[0129] In step S34, the crude product is dissolved in hot ethanol, cooled to crystallize, filtered and dried to obtain the purified compound.

[0130] S35, the (1R) configuration of the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester was confirmed by chiral HPLC detection.

[0131] In one embodiment, step S35 specifically includes the following sub-steps to ensure accurate confirmation of chiral purity, which is crucial in the preparation of pharmaceutical intermediates because the (1R) configuration directly affects efficacy and safety.

[0132] S351, the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate is dissolved in the mobile phase to obtain the test sample.

[0133] In step S351, 1 mg of the compound is dissolved in 1 mL of mobile phase, which is a mixture of n-hexane and isopropanol in a volume ratio of 90:10. This ratio is based on the solubility of the compound and column compatibility to ensure uniform dispersion of the sample.

[0134] S352, the test sample is injected into a chiral HPLC column to separate the peak value.

[0135] In one embodiment, step S352 uses a Chiralcel OD-H column at a column temperature of 30°C and a flow rate of 1.0 mL / min, injecting 10 μL of sample, and using UV detection at a wavelength of 254 nm to selectively separate the (R) and (S) enantiomer peaks through the chiral selectivity of the stationary phase within the column.

[0136] It should be noted that the stationary phase of a chiral HPLC column, such as a cellulose derivative, can distinguish stereoisomers through hydrogen bonding and π-π interactions, thus achieving peak separation. This separation process depends on the difference in affinity between the enantiomers and the column material. For example, the (R) configuration may have a longer retention time, thereby forming a clear peak.

[0137] S353, determine the purity of the (1R) configuration based on the separation peak value.

[0138] In step S353, the proportion of the main peak area to the total peak area is calculated. If it exceeds 99%, the purity of the (1R) configuration is confirmed to be qualified.

[0139] In one embodiment, for the chiral HPLC detection in step S35, different application scenarios with different mobile phase ratios are considered. For example, adjusting the ratio of n-hexane to isopropanol to 85:15 can shorten the separation time but may reduce the resolution. This adjustment is suitable for rapid screening batches.

[0140] For example, in one batch preparation, the test showed that the main peak retention time was 8.2 min, the secondary peak was 7.5 min, and the purity was calculated to be 99.2%, which proved that recrystallization effectively preserved the (1R) configuration, which is beneficial to ensuring the stereopurity of pharmaceutical intermediates and improving the bioactivity of downstream synthetic products.

[0141] It should be noted that, in another embodiment, the column type in step S352 can be replaced with Chiralpak AD-H, which is suitable for the separation of similar biphenyl compounds. The detection results show that the purity reaches 99.5%. This diversity enriches the flexibility of the detection scheme and effectively supports the reliability of the preparation method.

[0142] In one embodiment, the purity determination in step S353 is automatically calculated using peak area integration software. For example, in a specific test, the main peak integral value is 950, the secondary peak is 5, and the total purity is 99.5%. This allows for quantitative assessment of chiral purity, avoids subjective errors, and provides a data basis for quality control. The beneficial effect is to improve the overall preparation quality of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate as a pharmaceutical intermediate.

[0143] S107. The bisphosphine ligand and rhodium precursor comprise: S211, dissolving the bisphosphine ligand in the methanol solvent to obtain a first solution; S212, adding the rhodium precursor to the first solution and stirring to coordinate and obtain the chiral rhodium complex catalyst; S213, adding the chiral rhodium complex catalyst to the reaction system of [1,1'-biphenyl]-4-yl substituted acetone and hydrogen to generate the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

[0144] S211, the bisphosphine ligand is dissolved in the methanol solvent to obtain a first solution.

[0145] In one embodiment, step S211 specifically includes slowly adding the bisphosphine ligand to a methanol solvent and stirring at room temperature until completely dissolved to form a homogeneous first solution. This dissolution process ensures that the ligand molecules are uniformly distributed, providing a basis for subsequent coordination.

[0146] S212, the rhodium precursor is added to the first solution and stirred to obtain the chiral rhodium complex catalyst.

[0147] In one embodiment, step S212 specifically includes: S2121, gradually adding the rhodium precursor to the first solution while controlling the stirring speed at 200 rpm to 500 rpm to promote initial complexation; S2122, heating the mixture to 40°C to 60°C under nitrogen protection and continuously stirring for 1 hour to 3 hours to achieve the formation of coordination bonds; S2123, cooling, filtering, and drying to obtain the chiral rhodium complex catalyst. This process enhances the complexation stability through temperature control, ensuring the chiral purity of the catalyst.

[0148] For example, in pharmaceutical synthesis, if the bisphosphine ligand has a specific chiral structure, stirring coordination can improve the catalyst's selectivity for the substrate, resulting in a higher enantiomeric excess value, which is beneficial for the high-purity preparation of intermediates.

[0149] S213, the chiral rhodium complex catalyst is added to the reaction system of [1,1'-biphenyl]-4-yl substituted acetone and hydrogen to generate the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

[0150] In one embodiment, step S213 specifically includes: S2131, dissolving [1,1'-biphenyl]-4-yl substituted acetone in methanol to form a substrate solution, and introducing hydrogen gas to a pressure of 5 atm to 20 atm; S2132, adding a chiral rhodium complex catalyst to the substrate solution, and reacting at 50°C to 80°C for 2 to 6 hours to promote asymmetric hydrogenation; S2133, after the reaction is completed, separating the product by vacuum distillation to obtain (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; S2134, performing chiral purity testing on the product to ensure that the purity of the R configuration is greater than 95%. This process utilizes optimized hydrogen pressure and temperature to achieve highly selective conversion, forming a logical chain. The substrate of S2131 is prepared for the catalytic reaction of S2132, the hydrogenation product of S2132 is input into the separation of S2133, the intermediate of S2133 is used for the detection of S2134, and finally supports the preparation method of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] tert-butyl carbamate.

[0151] For example, in the synthesis of pharmaceutical intermediates, the addition of chiral rhodium complex catalysts can effectively control the hydrogenation stereochemistry, resulting in higher yields and purity, which is beneficial to downstream tert-butyl esterification reactions.

[0152] In one embodiment, for different parameter applications of S213, such as adjusting the hydrogen pressure to 10 atmospheres, the reaction time is shortened to 3 hours and the product purity reaches 98%, which expands the flexibility of industrial-scale production.

[0153] For example, in principle, chiral control stems from the steric hindrance of the catalyst, which accelerates hydrogen addition under high pressure, avoids the formation of byproducts, and has the beneficial effect of improving the overall synthesis efficiency.

[0154] In one embodiment, for a scenario with a temperature of 60 degrees Celsius, the catalyst is used at an amount of 0.1% to 1% of the substrate, and the intermediate generated is directly used for further conversion of the title compound, ensuring the continuous preparation of pharmaceutical intermediates.

[0155] S108, the [1,1'-biphenyl]-4-yl substituted acetone comprises: S21, reacting 4-bromobiphenyl with acetone in the presence of magnesium shavings to generate a Grignard reagent; S22, hydrolyzing the Grignard reagent to obtain the [1,1'-biphenyl]-4-yl substituted acetone.

[0156] Step S21: 4-bromobiphenyl is reacted with acetone in the presence of magnesium shavings to generate a Grignard reagent.

[0157] Step S211, Pretreatment and Activation of Magnesium Scrap. To ensure the reactivity of the magnesium scrap, pretreatment is necessary before the reaction. Typically, the magnesium scrap is placed under anhydrous conditions and the surface oxide layer is removed by mechanical grinding. Then, a small amount of iodide is added as an activator under inert gas protection to promote the formation of active sites on the magnesium scrap surface. This process effectively improves the initial efficiency of the reaction between magnesium scrap and 4-bromobiphenyl, avoiding reaction retardation. Specific activation conditions can be adjusted according to the particle size and purity of the magnesium scrap. For example, finer magnesium scrap requires less activation time, while lower purity magnesium scrap requires more iodide.

[0158] Step S212: Selection and preparation of the reaction solvent. The reaction needs to be carried out in an anhydrous and oxygen-free environment; therefore, anhydrous tetrahydrofuran is chosen as the solvent. Its moderate polarity allows it to effectively dissolve 4-bromobiphenyl and stabilize the generated Grignard reagent. During preparation, the solvent must be thoroughly dried, for example, by distillation using sodium metal and phenolphthalein indicator to remove trace amounts of moisture. The amount of solvent used must be matched to the amount of 4-bromobiphenyl, typically controlled at a ratio of 10-15 ml of solvent per gram of 4-bromobiphenyl to ensure the homogeneity of the reaction system.

[0159] Step S213: Control and optimization of reaction conditions. Under inert gas protection, activated magnesium shavings are added to the solvent, followed by the slow dropwise addition of a 4-bromobiphenyl solution. The dropping rate is controlled to avoid localized overheating, typically within 1-2 hours. Reaction temperature is a critical parameter, needing to be maintained between 40-60 degrees Celsius. Too low a temperature may lead to incomplete reaction, while too high a temperature may trigger side reactions. During the reaction, the temperature can be stabilized using external cooling or heating devices, while stirring ensures sufficient contact of the reactants. After the reaction is complete, the system exhibits a characteristic turbidity, indicating the formation of the Grignard reagent.

[0160] Step S214: Addition and reaction of acetone. After the Grignard reagent is generated, acetone should be slowly added to the reaction system, controlling the addition rate to avoid violent exothermic reactions. Dropwise addition is typically used, with the addition time controlled between 30 and 60 minutes. Acetone reacts with the Grignard reagent to form an alkoxide intermediate. This process must be carried out at low temperatures, typically controlled between 0 and 10 degrees Celsius, to minimize the formation of byproducts. The reaction time is generally 2-4 hours, but the specific time can be adjusted according to the reaction scale and temperature.

[0161] In one embodiment, the reaction conditions for step S21 were optimized by comparing the reaction efficiency at different temperatures. At 40 degrees Celsius, the Grignard reagent formation time was longer, approximately 3 hours, but byproducts were fewer, and the yield was approximately 85%. At 60 degrees Celsius, the formation time was shortened to 1.5 hours, but byproducts increased slightly, and the yield decreased to 80%. This comparison allows for the selection of appropriate temperature parameters based on actual production needs to balance efficiency and yield.

[0162] In another embodiment, the reaction effects of adjusting the solvent amount in step S21 were tested for 10 mL and 15 mL of tetrahydrofuran per gram of 4-bromobiphenyl. The results showed that with 10 mL of solvent, the reaction system was more viscous, resulting in greater stirring resistance, slightly poorer reaction uniformity, and a yield of approximately 82%; while with 15 mL of solvent, the reaction system had better fluidity, and the yield increased to 87%. This result suggests that the solvent amount can be appropriately increased to improve the reaction effect in large-scale production.

[0163] Step S22: Hydrolyze the Grignard reagent to obtain [1,1'-biphenyl]-4-yl substituted acetone.

[0164] Step S221, setting the hydrolysis conditions. After the Grignard reagent reacts with acetone, cool the reaction system to 0-5 degrees Celsius, then slowly add a dilute acid solution for hydrolysis. Dilute hydrochloric acid or dilute sulfuric acid is typically used, with a concentration controlled at 1-2 mol / L. The addition rate should be controlled to no more than 5 mL per minute to avoid excessively high local acid concentrations that could lead to side reactions. Continuous stirring is required during hydrolysis to ensure a uniform reaction.

[0165] Step S222: Product separation and purification. After the hydrolysis reaction is complete, the organic and aqueous phases are separated by liquid-liquid extraction. The organic phase is dried over anhydrous sodium sulfate, and the solvent is evaporated to obtain the crude product. The crude product can be further purified by column chromatography or recrystallization to obtain high-purity [1,1'-biphenyl]-4-yl-substituted acetone. A mixture of ethyl acetate and petroleum ether can be used as the eluent during purification; the ratio is adjusted according to the product's solubility.

[0166] For example, the control of hydrolysis conditions in step S22 has a significant impact on the purity of the final product.

[0167] In one possible implementation, 1 mol / L of dilute hydrochloric acid is slowly added dropwise to the reaction system over a period of 1 hour, resulting in a product purity of over 95%. This condition effectively avoids the formation of byproducts due to excessive acidity while ensuring the completeness of the hydrolysis reaction.

[0168] The steps and examples described above focus on the synthesis of [1,1'-biphenyl]-4-yl substituted acetone, a key intermediate in the preparation of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate. By optimizing the reaction conditions and controlling the parameters, the high efficiency of the preparation process and the high purity of the product are ensured, laying a solid foundation for the subsequent synthesis of pharmaceutical intermediates.

[0169] The above are only some preferred embodiments of the present invention, but the present invention is not limited thereto, and many improvements and modifications can be made. Any improvements and modifications made based on the basic principles of the present invention should be considered to fall within the protection scope of the present invention.

Claims

1. A method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl, characterized in that, include: [1,1'-biphenyl]-4-yl-substituted acetone was reacted with hydrogen in the presence of a chiral rhodium complex catalyst to generate (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; Di-tert-butyl dicarbonate reagent and basic auxiliaries are directly added to the reaction system, and the reaction continues in a solvent environment to form N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester; After the reaction was completed, the mixture was extracted and crystallized to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

2. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 1, characterized in that, The chiral rhodium complex catalyst comprises: The chiral rhodium complex catalyst is formed by pre-coordinating bisphosphine ligands with rhodium precursors in methanol solvent; The [1,1'-biphenyl]-4-yl substituted acetone was reacted with hydrogen in the presence of the chiral rhodium complex catalyst to obtain the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate; The ditert-butyl dicarbonate reagent and the alkaline auxiliary agent are directly added to the reaction system to continue the reaction and form N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

3. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 1, characterized in that, The di-tert-butyl dicarbonate reagent and alkaline auxiliaries include: The di-tert-butyl dicarbonate reagent was added to the reaction system to obtain a preliminary mixture; The alkaline auxiliary agent is added to the preliminary mixture to form a reaction environment; The reaction was continued in the solvent environment to obtain the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

4. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 1, characterized in that, The extraction and crystallization process includes: The mixture was mixed with ethyl acetate and extracted to obtain an organic phase; The organic phase was washed with saturated brine to obtain a purified organic phase. The purified organic phase was concentrated to obtain a crude product. The crude product was recrystallized with ethanol to obtain N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester; The (1R) configuration of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl was confirmed by chiral HPLC.

5. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 2, characterized in that, The bisphosphine ligand and rhodium precursor comprise: The bisphosphine ligand is dissolved in the methanol solvent to obtain a first solution; The rhodium precursor was added to the first solution and stirred to obtain the chiral rhodium complex catalyst. The chiral rhodium complex catalyst was added to the reaction system of [1,1'-biphenyl]-4-yl substituted acetone and hydrogen to generate the (1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethylamine intermediate.

6. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 1, characterized in that, The [1,1'-biphenyl]-4-yl substituted acetone comprises: 4-Bromobiphenyl reacts with acetone in the presence of magnesium shavings to generate a Grignard reagent; Hydrolyzing the Grignard reagent yields the [1,1'-biphenyl]-4-yl substituted acetone.

7. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 4, characterized in that, The chiral HPLC detection includes: The N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester was dissolved in the mobile phase to obtain the test sample; The test sample was injected into a chiral HPLC column to separate the peak values; The purity of the (1R) configuration is determined based on the separation peak value.

8. The method for preparing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester according to claim 3, characterized in that, The alkaline additive includes: Triethylamine is added to the preliminary mixture as the alkaline auxiliary agent; The reaction continues in the solvent environment with the reaction temperature controlled within a specified range to form the N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester.

Images