L-10BPA impurity compound as well as preparation method and application thereof
The method for preparing L-10BPA impurity compounds solves the problem of the lack of detection methods in the existing technology, realizes the preparation and quality control of high-purity impurities, and ensures the purity and safety of drugs.
Patent Information
- Application Number
- CN202511185421.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-22
- Publication Date
- 2025-11-14
AI Technical Summary
The lack of research on L-10BPA impurities in the current technology leads to a lack of appropriate detection methods and judgment criteria, which affects drug production and medication safety.
A method for preparing an L-10BPA impurity compound is provided, comprising silanizing protection of N-Boc-4-halo-L-phenylalanine, reacting isopropyl magnesium chloride-lithium chloride and borate alkyl ester compounds using Turbo Grignard reagent, subsequently synthesizing N-Boc-4-boronic acid-L-phenylalanine in the presence of a base and a catalyst, and obtaining the target impurity compound by deBoc reaction.
This method enables the preparation of high-purity impurity compounds, provides a basis for quality control, improves the purity and safety of drugs, simplifies subsequent purification processes, and ensures the efficacy and safety of drugs.
Smart Images
Figure CN120943747A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically providing an L- 10 BPA impurity compounds, their preparation methods and applications. Background Technology
[0002] 4-( 10 B) Dihydroxyboryl-L-phenylalanine (L- 10 Boron neutron capture therapy (BNCT) is an important boron-containing drug currently known for its application in cancer treatment. Drug impurities refer to substances present in a drug that have no therapeutic effect, affect its stability or efficacy, or are even harmful to human health. In drug research, production, storage, and clinical application, it is essential to ensure drug purity and reduce impurities to guarantee efficacy and safety. Drug purity is typically evaluated as a whole, considering factors such as structure, appearance, physicochemical constants, impurity testing, and content determination. Impurities are a major factor affecting drug purity. If impurities exceed limits, they can alter physicochemical constants, change appearance, and affect drug stability. Increased impurities also inevitably lead to lower drug content, reduced activity, and significantly increased toxic side effects. Therefore, impurity testing is a crucial step in controlling drug purity and improving drug quality.
[0003] L- 10 BPA can generate impurities during preparation and storage, which may then remain in L- 10 In BPA raw materials, thus affecting L- 10 BPA product quality and medication safety. Therefore, in order to improve L- 10 To ensure the quality and safety of BPA and the efficacy of medications, it is necessary to thoroughly study and control L-. 10 Impurities generated during the BPA process and storage.
[0004] However, in the existing technology for L- 10 There is a lack of research on impurities in BPA, and L- is missing. 10 Provide appropriate testing methods and judgment criteria for the production and safe use of BPA.
[0005] Accordingly, a new technical solution is needed in this field to solve the above-mentioned technical problems. Summary of the Invention
[0006] The present invention aims to solve the above-mentioned technical problems, namely, to solve the problems of L- in the prior art. 10 There is a lack of research on impurities in BPA, and L- is missing. 10The issue of providing appropriate testing methods and judgment criteria for the production and safe use of BPA raises concerns.
[0007] In a first aspect, the present invention provides an L- structure as shown in Formula 7. 10 BPA impurity compounds,
[0008] In a second aspect, the present invention provides the L- 10 A method for preparing BPA impurity compounds, wherein the preparation method comprises:
[0009] Compound 6 was subjected to a Boc removal reaction to obtain compound 7;
[0010] In the preferred embodiment of the above preparation method, the preparation method of the compound of formula 6 is as follows:
[0011] In the presence of base A, compound 4 and compound 1 are reacted with a catalyst to obtain compound 6.
[0012] In formula I, X is either I or Br.
[0013] In the preferred embodiment of the above preparation method, the mass ratio of the compound of formula 4, the compound of formula 1, base A and catalyst is 1:(0.8-1.5):(0.5-2.5):(0.2-0.8);
[0014] And / or, the temperature of the reaction is 55–105°C;
[0015] And / or, the reaction time is 10 to 24 hours.
[0016] In the preferred embodiment of the above preparation method, the preparation method of the compound of formula 4 includes:
[0017] S1. The carboxyl group of compound 1 is subjected to a silicon-protecting reaction to obtain compound 2;
[0018] In Equation 2, R is a silicon-based protective group;
[0019] S2. The compound of formula 2 is reacted with isopropyl magnesium chloride-lithium chloride and borate alkyl ester compounds, and the reaction solution is post-treated to obtain the compound of formula 4.
[0020] In the preferred embodiment of the above preparation method, in step S1, the reaction of the silicon-based protecting group is as follows: silicon-based protecting group reagent and base B are added sequentially to the organic solvent solution of compound I, and the reaction is carried out to obtain compound 2.
[0021] In the preferred embodiment of the above preparation method, when adding the silicon-based protecting group reagent, the system temperature is controlled to be room temperature.
[0022] And / or, when adding alkali B, control the system temperature T1 to be no higher than 50°C, preferably 15-30°C.
[0023] And / or, the reaction is carried out at room temperature for 30 to 60 minutes.
[0024] In the preferred embodiment of the above preparation method, the equivalent ratio of the compound of Formula 1 and the silicon-based protecting group reagent is 1:(1.0~3.0);
[0025] And / or, the equivalent ratio of the compound of Formula 1 to base B is 1:(1.0 to 3.0);
[0026] In the preferred embodiment of the above preparation method, step S2 is:
[0027] First, add isopropyl magnesium chloride-lithium chloride solution dropwise to the organic solvent solution of compound 2. After the addition is complete, the reaction is allowed to proceed for a preset time t1. Then, add borate alkyl ester compound dropwise. After the addition is complete, the reaction is allowed to proceed for a preset time t2. Then, the reaction solution is post-treated to obtain compound 4.
[0028] In the preferred embodiment of the above preparation method, when the borate alkyl ester compound is added dropwise, the system temperature T4 is controlled to be no higher than -10℃, preferably -15℃ to -35℃; the preset reaction time t2 after the dropwise addition is completed is 0.5 to 3 hours.
[0029] In the preferred embodiment of the above preparation method, when the isopropyl magnesium chloride-lithium chloride solution is added dropwise, the system temperature T2 is controlled to be no higher than -10℃; preferably -25℃ to -45℃; after the dropwise addition is completed, the reaction is carried out at a system temperature T3 no higher than -15℃, and the preset reaction time t1 is 0.5 to 3h.
[0030] In a third aspect, the present invention provides the L- 10 BPA impurity compounds or impurity compounds prepared by the aforementioned method are used as impurity reference standards in L- 10 Application of BPA in quality control.
[0031] The technical solution of the present invention has the following technical effects:
[0032] 1. The present invention provides the L- structure shown in Formula 7. 10BPA impurity compounds, to further eliminate L- 10 BPA effectively protects against impurities, improves drug purity, and ensures drug efficacy and safety.
[0033] 2. The method of this invention can prepare high-purity L-type polymorphs with the structure shown in Formula 7. 10 BPA impurities are beneficial for studying key process impurities, filling a gap in the research on impurities in this process, and providing a basis for L- 10 BPA provides a basis for quality control;
[0034] 3. The method of the present invention has mild reaction conditions, high reaction purity, short reaction time, simple subsequent purification process, and high product purity after recrystallization purification. Attached Figure Description
[0035] The preferred embodiments of the present invention are described below with reference to the accompanying drawings, in which:
[0036] Figure 1 The 1H-NMR spectrum of compound 7 is shown.
[0037] Figure 2 The image shows the C-NMR spectrum of compound 7;
[0038] Figure 3 The image shows the MS spectrum of compound formula 7. Detailed Implementation
[0039] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings. Those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.
[0040] In this application, the term "and / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, or B existing alone. A and B can be singular or plural. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.
[0041] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or multiple items. For example, "at least one of a, b, or c", or "at least one of a, b, and c", can both mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, and c can be single or multiple.
[0042] It should be understood that in the various embodiments of this application, the order of the above processes does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.
[0043] The terminology used in the embodiments of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of this application. The singular forms “a,” “the,” and “the” used in the embodiments of this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise.
[0044] The weights of the relevant components mentioned in the embodiments of this application can refer not only to the specific content of each component, but also to the proportional relationship between the weights of the components. Therefore, any scaling up or down of the content of the relevant components according to the embodiments of this application is within the scope disclosed in the embodiments of this application. Specifically, the mass described in the embodiments of this application can be a mass unit known in the chemical industry, such as μg, mg, g, or kg.
[0045] The terms "first" and "second" are used for descriptive purposes only, to distinguish objects, such as substances, from one another, and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. For example, without departing from the scope of the embodiments of this application, "first XX" may also be referred to as "second XX," and similarly, "second XX" may also be referred to as "first XX." Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of that feature.
[0046] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used in the following examples are commercially available unless otherwise specified.
[0047] Based on the prior art as pointed out in the background section, regarding L- 10 There is a lack of research on impurities in BPA, and L- is missing. 10 This invention addresses the issue of providing appropriate testing methods and judgment criteria for the production and safe use of BPA. It provides an L- 10 This study, which describes BPA impurity compounds, their preparation methods, and applications, fills a gap in research on impurities in this process and provides a basis for L- 10 BPA provides a basis for quality control.
[0048] In a first aspect, the present invention provides an L- structure as shown in Formula 7. 10 BPA impurity compounds,
[0049] This invention has discovered L- through research. 10 During preparation and storage, BPA can self-couple to produce impurities as shown in Formula 7 above. These impurities have been identified as compounds of Formula 7, with the chemical name L-4,4'-diphenylalanine. This impurity poses a risk of derivation into the finished product, thereby affecting product quality and medication safety.
[0050] In drug research, based on the principle of risk control, it is essential to analyze and study drug impurities, systematically investigate potential impurities, and strictly control their content to ensure drug quality and safety. Appropriate impurity reference standards are required during impurity research and quality control. Without impurity reference standards, it is impossible to develop and validate analytical methods specifically, and it is impossible to guarantee the effective detection and control of the corresponding impurities.
[0051] This invention provides the above-mentioned L- 10 BPA impurity compounds fill the gap in impurity research for this process, providing L- 10 BPA provides a basis for quality control.
[0052] The invention provides the L- in a second aspect. 10 A method for preparing BPA impurity compounds, wherein the preparation method comprises:
[0053] Compound 6 was subjected to a Boc removal reaction to obtain compound 7;
[0054] It should be noted that the Boc removal reaction described in this invention is a method commonly used in the art. No specific Boc removal reaction method is limited in this invention.
[0055] For example, in some specific embodiments, the deBoc reaction can be:
[0056] Compound 6 was reacted in the presence of an acid to give compound 7.
[0057] In some specific embodiments, the equivalence ratio of the compound of Formula 6 to the acid is 1:(2 to 4). For example, it can be 1:2, 1:2.5, 1:3, 1:3.5, 1:4, or any value within the range of the equivalence ratio.
[0058] In some specific embodiments, the acid is one of concentrated hydrochloric acid, hydrochloric acid / dioxane, hydrochloric acid / ethyl acetate, hydrochloric acid / methanol, and hydrochloric acid / methyl tert-butyl ether.
[0059] In some preferred embodiments, the acid is concentrated hydrochloric acid.
[0060] In some specific embodiments, the reaction temperature is 35–105°C. For example, it can be 35°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 105°C, or any value within the temperature range.
[0061] In some preferred embodiments, the reaction temperature is 55°C.
[0062] In some specific embodiments, the reaction time is 1 to 6 hours. For example, it can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or any value within the time range.
[0063] In some specific embodiments, the reaction is carried out in solvent A.
[0064] Specifically, solvent A is one of tetrahydrofuran, 1,4-dioxane, acetone, and dichloromethane.
[0065] In some preferred embodiments, after the reaction is complete, the following purification step is further included:
[0066] The reaction solution was concentrated under reduced pressure to obtain a crude product; the crude product was then pulped with glacial acetic acid and filtered to obtain compound of formula 7.
[0067] In some specific embodiments, the preparation method of the compound of formula 6 is as follows:
[0068] In the presence of base A, the compounds of formula 4 and formula 1 are reacted in the presence of a catalyst to obtain the compound of formula 6.
[0069] In formula I, X is either I or Br.
[0070] In some specific embodiments, the mass ratio of the compound of formula 4, the compound of formula 1, base A, and the catalyst is 1:(0.8–1.5):(0.5–2.5):(0.2–0.8). For example, it can be 1:0.8:0.5:0.2, 1:1:1:0.5, 1:1.2:1.5:0.8, or any value within the range of the mass ratio.
[0071] In some specific embodiments, the base A is an organic base or an inorganic base.
[0072] In some specific embodiments, the organic base is 1,8-diazabicyclo[5,4,0]undec-7-ene, triethylamine, N,N-diisopropylethylamine, or pyridine.
[0073] In some specific embodiments, the inorganic base is potassium carbonate, sodium carbonate, or sodium bicarbonate.
[0074] In some specific embodiments, the catalyst is tetraphenylphosphine palladium.
[0075] In some specific embodiments, the reaction temperature is 55–105°C. For example, it can be 55°C, 75°C, 80°C, 90°C, 100°C, 105°C, or any value within the temperature range.
[0076] In some preferred embodiments, the reaction temperature is 60°C.
[0077] In some specific embodiments, the reaction time is 10 to 24 hours. For example, it can be 10 hours, 15 hours, 20 hours, 24 hours, or any value within the time range.
[0078] In some specific embodiments, the reaction is carried out in solvent B.
[0079] In some specific embodiments, solvent B is one of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, ethyl acetate, and water.
[0080] In some preferred embodiments, after the reaction is complete, the following purification step is further included:
[0081] The reaction solution was cooled to room temperature, and water and ethyl acetate were added for extraction. The aqueous phase was collected, and the pH was adjusted with 18% citric acid. The aqueous phase was then extracted with ethyl acetate, and the organic phase was collected. The organic phase was concentrated under reduced pressure and eluted by column chromatography to obtain compound of formula 6.
[0082] It should be noted that, in this invention, the compound of formula 4 is N-Boc-4-boronic acid-L-phenylalanine, which can be prepared using existing methods. However, as a preferred embodiment, the compound of formula 4, N-Boc-4-boronic acid-L-phenylalanine, is prepared using the following method.
[0083] Specifically, the preparation method of the compound of formula 4 includes:
[0084] S1. The carboxyl group of compound 1 is subjected to a silicon-protecting reaction to obtain compound 2;
[0085] In Equation 2, R is a silicon-based protective group;
[0086] S2. The compound of formula 2 is reacted with isopropyl magnesium chloride-lithium chloride and borate alkyl ester compounds, and the reaction solution is post-treated to obtain the compound of formula 4.
[0087] In existing technologies, N-Boc-4-iodo-L-phenylalanine is typically prepared by directly reacting it with isopropyl magnesium chloride-lithium chloride solution and borate alkyl esters. However, this method suffers from incomplete reaction due to the presence of active hydrogen on the unprotected carboxyl group, leading to the deactivation of a large amount of Grignard reagents. This increases production costs and hinders industrial scale-up.
[0088] In the above-described preparation method of compound 4 (N-Boc-4-boronic acid-L-phenylalanine) provided by this invention, compound 1 (N-Boc-4-halo-L-phenylalanine) is used as the starting material. A silicon-based protecting agent is selected to protect the highly reactive carboxyl group, yielding compound 2 (N-Boc-4-halo-L-phenylalanine silyl ester). Then, it is reacted with Turbo Grignard reagents (isopropylmagnesium chloride-lithium chloride and borate alkyl esters). The reaction solution is post-treated to obtain compound 4 (N-Boc-4-boronic acid-L-phenylalanine). This method significantly shortens the reaction time, provides milder reaction conditions, and achieves a more thorough reaction, improving the reaction yield and product purity. The subsequent purification process is simple; the silicon-based protecting group on the carboxyl group is completely removed during post-treatment, eliminating the need for a separate deprotection step. The product after recrystallization purification has high purity, better ensuring the quality of the final drug product.
[0089] Therefore, the present invention preferably uses the above method to prepare compound 4.
[0090] In some specific embodiments, in step S1, the reaction of the silicon-based protecting group is as follows: silicon-based protecting group reagent and base B are added sequentially to the organic solvent solution of compound I, and the reaction is carried out to obtain compound 2.
[0091] In some specific embodiments, when adding the silicon-based protecting group reagent, the system temperature is controlled to be room temperature;
[0092] In some specific embodiments, when alkali B is added, the system temperature T1 is controlled to be no higher than 50°C, preferably 15-30°C.
[0093] In some specific embodiments, the silicon-based protecting group reagent is one of tert-butyldimethylchlorosilane (TBSCl), triethylchlorosilane (TESCl), triisopropylchlorosilane (TIPSCL), and trimethylchlorosilane (TMCS).
[0094] In some specific embodiments, the equivalence ratio of the compound of Formula 1 to the silicon-based protecting group reagent is 1:(1.0 to 3.0). For example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, or any value within the range of the equivalence ratio.
[0095] In some specific embodiments, the equivalent ratio of the compound of Formula 1 to base B is 1:(1.0 to 3.0). For example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, or any value within the range of the equivalent ratio.
[0096] In some specific embodiments, the base B is one of triethylamine, imidazole, or N-methylmorpholine.
[0097] In some specific embodiments, step S2 is:
[0098] First, add isopropyl magnesium chloride-lithium chloride solution dropwise to the organic solvent solution of compound 2. After the addition is complete, the reaction is allowed to proceed for a preset time t1. Then, add borate alkyl ester compound dropwise. After the addition is complete, the reaction is allowed to proceed for a preset time t2. Then, the reaction solution is post-treated to obtain compound 4.
[0099] In some specific embodiments, when the borate alkyl ester compound is added dropwise, the system temperature T4 is controlled to be no higher than -10°C, preferably -15°C to -35°C; the preset reaction time t2 after the addition is completed is 0.5 to 3 hours. For example, the system temperature T4 can be -25°C, -30°C, -35°C, or any value within the temperature range; the preset reaction time t2 after the addition is completed can be 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or any value within the time range.
[0100] In some specific embodiments, the reaction is carried out under stirring after the addition of borate alkyl ester compounds.
[0101] In some specific embodiments, the equivalence ratio of the compound of Formula 2 to the alkyl borate compound is 1:(1.0 to 3.0). For example, it can be 1:1, 1:1.5, 1:2, 1:3, or any value within the range of the equivalence ratio.
[0102] In this invention, the borate alkyl ester compounds include one or more of the following: tributyl borate, trimethyl borate, triethyl borate, triisopropyl borate, tri-n-propyl borate, and tri-tert-butyl borate.
[0103] In some specific embodiments, when the isopropyl magnesium chloride-lithium chloride solution is added dropwise, the system temperature T2 is controlled to be no higher than -10°C; preferably -25°C to -45°C; after the addition is completed, the reaction is carried out at a system temperature T3 no higher than -15°C, and the preset reaction time t1 is 0.5 to 3 hours. For example, the system temperature T2 can be -25°C, -30°C, -35°C, or any value within the temperature range; the preset reaction time t2 after the addition is completed can be 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or any value within the time range; the system temperature T3 during the reaction can be -25°C, -20°C, -22°C, or any value within the temperature range.
[0104] In some specific embodiments, the reaction is carried out under stirring after the addition of isopropyl magnesium chloride-lithium chloride solution.
[0105] In some specific embodiments, the equivalence ratio of the compound of Formula 2 and isopropyl magnesium chloride-lithium chloride is 1:(4 to 8). For example, it can be 1:4, 1:5, 1:6, 1:7, 1:8, or any value within the range of the equivalence ratio.
[0106] In some specific embodiments, the organic solvents mentioned in steps S1 and S2 are tetrahydrofuran and dimethyltetrahydrofuran.
[0107] In some preferred embodiments, the L- structure shown in Formula 7 provided by the present invention 10 The preparation method of BPA impurity compounds includes the following steps:
[0108] I. Preparation of Compound 4
[0109] The reaction route is shown below:
[0110] In Equation 1, X is I or Br;
[0111] In Equation 2, R is a silicon-based protective base.
[0112] Specifically, the steps include the following:
[0113] S1. Add a silicon-based protecting group reagent and base B sequentially to the organic solvent solution of compound I, and react to obtain compound 2.
[0114] S2. First, add isopropyl magnesium chloride-lithium chloride solution dropwise to the organic solvent solution of compound S2. After the addition is complete, the reaction is allowed to proceed for a preset time t1. Then, add borate alkyl ester compound dropwise. After the addition is complete, the reaction is allowed to proceed for a preset time t2. Then, the reaction solution is post-treated to obtain compound S4.
[0115] II. Preparation of Compound 6
[0116] The reaction route is shown below:
[0117] The specific steps are as follows:
[0118] In the presence of base A, the compounds of formula 4 and formula 1 are reacted with a catalyst to obtain the compound of formula 6.
[0119] III. Preparation of Compound 7
[0120] The reaction route is shown below:
[0121] The specific steps are as follows:
[0122] Compound 6 was reacted in the presence of an acid to give compound 7.
[0123] The method for preparing L-4,4'-diphenylalanine (compound 7) provided by this invention uses N-Boc-4-halo-L-phenylalanine (compound 1) as the starting material. A silicon-based protecting agent is used to protect the highly reactive carboxyl group to obtain N-Boc-4-halo-L-phenylalanine silyl ester (compound 2). Then, it is reacted with Turbo Grignard reagent isopropyl magnesium chloride-lithium chloride and borate alkyl esters. The reaction solution is post-treated to obtain N-Boc-4-boronic acid-L-phenylalanine (compound 4). Then, it is reacted with N-Boc-4-iodo-L-phenylalanine (compound 1) under the catalysis of base A and a catalyst to obtain compound 6. Finally, compound 6 is debonded under the action of concentrated hydrochloric acid to obtain the target product (compound 7).
[0124] The method of this invention has mild reaction conditions, high reaction purity, short reaction time, and simple subsequent purification process. The silicon-protecting group on the carboxyl group can be completely removed during the post-processing without the need for a separate deprotection step. The product has high purity after recrystallization and purification.
[0125] The L- of this application will be described in detail below through several specific embodiments. 10 Preparation method of BPA impurity compounds.
[0126] Example 1-1 Preparation of Compound Formula 4
[0127] This embodiment provides the preparation of compound 4, specifically including the following steps:
[0128] S1. At room temperature, add 600 mL of organic solvent (tetrahydrofuran) and 58.5 g of silane protecting agent (tert-butyldimethylchlorosilane, TBSCl) to 150.0 g of compound 1-1, and stir until dissolved. Maintain the temperature ≤30℃ (system temperature T1), and add 39.0 g of base B (triethylamine) dropwise. After the addition is complete, react at room temperature with stirring for 30 minutes (reaction time). Filter, wash the filter cake with 150 mL of tetrahydrofuran, and collect the filtrate, which is the reaction solution containing compound 2-1. The reaction formula is shown below:
[0129] S2. Under nitrogen protection, at a temperature ≤ -20℃ (system temperature T2), 1500 mL of isopropyl magnesium chloride-lithium chloride was added dropwise to the filtrate. After the addition was complete, the reaction was carried out at a temperature ≤ -25℃ (system temperature T3) with stirring for 1 h (preset time t1), and the reaction was confirmed to be complete by HPLC. Under nitrogen protection, at a temperature ≤ -20℃ (system temperature T4), 105.2 g of a borate ester compound (tributyl borate) was added dropwise. After the addition was complete, the reaction was continued with stirring for 0.5 h (preset time t2), and the reaction was confirmed to be complete by HPLC. The reaction solution was post-processed to obtain compound of formula 4. The reaction formula is as follows:
[0130] The post-processing is as follows:
[0131] The reaction was quenched with 1200 mL of water, and the pH was adjusted to 1-2 by adding concentrated hydrochloric acid dropwise. The mixture was separated, and the organic phase was collected. The organic phase was washed with saturated sodium chloride aqueous solution and then concentrated under reduced pressure until no liquid dripped. n-Butanol and water were added to the concentrate and stirred. The pH was adjusted to 12-13 by slowly adding 20% sodium hydroxide aqueous solution. The mixture was separated, and the aqueous phase was collected. The aqueous phase was washed with n-butanol and n-heptane, respectively. Concentrated hydrochloric acid was added to the aqueous phase and the pH was adjusted to 1-3. Crystallization was carried out at ≤20℃ for 2 hours. The mixture was filtered, and the filter cake was rinsed with water. The filter cake was collected, slurried with water, filtered, rinsed with water, and dried in a vacuum drying oven at 50℃. The crude product of compound formula 4 was obtained. It was added to tetrahydrofuran, heated to 50℃, stirred until dissolved, and n-heptane was added dropwise. After the addition was complete, the temperature was controlled at 0-10℃ and kept at this temperature for 4 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with n-heptane. The filter cake was collected and dried in a vacuum drying oven at 50℃ to obtain 106.8 g of compound 4, with a yield of 94%.
[0132] Example 2-1 Preparation of Compound Formula 6
[0133] This embodiment provides the preparation of compound 6, and the specific process is as follows:
[0134] At room temperature, 5 g of compound 4 and 4 g of compound 1-1 were added to 40 mL of solvent B (a mixture of tetrahydrofuran and water, tetrahydrofuran:water = 7:1) and stirred until dissolved. 5.5 g of base A (sodium carbonate) was added, and 1.6 g of catalyst (tetraphenylphosphine palladium) was added under nitrogen protection. The mixture was heated to 60 °C and reacted for 16 h. The mixture was filtered, and the filtrate was washed with ethyl acetate, collecting the aqueous phase. The pH of the aqueous phase was adjusted to 3-4 with 18% citric acid aqueous solution, and then extracted with ethyl acetate, collecting the organic phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent:dichloromethane:methanol = 50:1) to obtain 6.1 g of compound 6, with a yield of 90.3%. The reaction formula is shown below:
[0135] Example 3-1 Preparation of Compound Formula 7
[0136] This embodiment provides the preparation of compound 7, and the specific process is as follows:
[0137] At room temperature, 5 g of compound 6 was added to 20 mL of solvent A (acetone) and stirred. Then, 5 mL of water was added, and 2.9 g of concentrated hydrochloric acid was added dropwise. The mixture was heated to 55 °C and reacted for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with glacial acetic acid and filtered to obtain 3 g of compound 7, with a yield of 96.7% and a purity of 98.6%. The reaction formula is shown below:
[0138] The structure of compound 7 was confirmed as follows:
[0139] MS[M+1] = 329;
[0140] 1 HNMR (400MHz, D2O / CF3COOD: δ:1.34-1.40(m,2H,CH2),1.57-1.62(m,2H,CH2),2 .50-2.54(m,2H,2CH-NH2),5.49-5.51(d,4H,4H-Ar),5.75-5.77(d,4H,4H-Ar);
[0141] 12 C-NMR (100MHz, D2O / CF3COO: δ: 33.88, 53.02, 126.15, 128.42, 131.38, 138.61, 169.67).
[0142] Examples 1-2 to 1-6 below describe the preparation of compounds of Formula 4. The specific process is the same as in Example 1-1, except that there are some differences in the selection of substances, the amount used, and the process parameters, as shown in Table 1.
[0143] Table 1, Preparation of Compounds of Formula 4
[0144] Examples 2-2 to 2-6 below describe the preparation of compounds of Formula 6. The specific process is the same as in Example 2-1, except that there are some differences in the selection of substances, the amount used, and the process parameters, as shown in Table 2.
[0145] Table 2, Preparation of Compounds of Formula 6
[0146] Examples 3-2 to 3-6 below describe the preparation of compounds of formula 7. The specific process is the same as in Example 3-1, except that there are some differences in the selection of substances, the amount used, and the process parameters, as shown in Table 3.
[0147] Preparation of compounds of formula 7 (Table 3)
[0148] The technical solution of the present invention has been described above with reference to the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after such changes or substitutions will all fall within the scope of protection of the present invention.
Claims
1. An L- structure as shown in Formula 7 below 10 BPA impurity compounds, 2. The L- as described in claim 1 10 The method for preparing BPA impurity compounds is characterized by, The preparation method is as follows: Compound 6 was subjected to a Boc removal reaction to obtain compound 7; 3. The preparation method according to claim 2, characterized in that, The preparation method of the compound of Formula 6 is as follows: In the presence of base A, compound 4 and compound 1 are reacted with a catalyst to obtain compound 6. In formula I, X is either I or Br.
4. The preparation method according to claim 3, characterized in that, The mass ratio of the compound of formula 4, the compound of formula 1, base A, and catalyst is 1:(0.8-1.5):(0.5-2.5):(0.2-0.8); And / or, the temperature of the reaction is 55–105°C; And / or, the reaction time is 10 to 24 hours.
5. The preparation method according to claim 3 or 4, characterized in that, The preparation method of the compound of formula 4 includes: S1. The carboxyl group of compound 1 is subjected to a silicon-protecting reaction to obtain compound 2; In Equation 2, R is a silicon-based protective group; S2. The compound of formula 2 is reacted with isopropyl magnesium chloride-lithium chloride and borate alkyl ester compounds, and the reaction solution is post-treated to obtain the compound of formula 4.
6. The preparation method according to claim 5, characterized in that, In step S1, the silicon-based protecting group reaction is as follows: silicon-based protecting group reagent and base B are added sequentially to the organic solvent solution of compound I, and the reaction is carried out to obtain compound 2.
7. The preparation method according to claim 6, characterized in that, When adding silicon-based protecting agents, the system temperature should be controlled at room temperature; And / or, when adding alkali B, the system temperature T1 should be controlled to be no higher than 50°C, preferably 15-30°C; And / or, the reaction is carried out at room temperature for 30 to 60 minutes.
8. The preparation method according to claim 7, characterized in that, The equivalent ratio of the compound of Formula 1 to the silicon-based protecting group reagent is 1:(1.0 to 3.0); And / or, the equivalent ratio of the compound of Formula 1 to base B is 1:(1.0 to 3.0).
9. The preparation method according to claim 5, characterized in that, Step S2 is as follows: First, add isopropyl magnesium chloride-lithium chloride solution dropwise to the organic solvent solution of compound 2. After the addition is complete, the reaction is allowed to proceed for a preset time t1. Then, add borate alkyl ester compound dropwise. After the addition is complete, the reaction is allowed to proceed for a preset time t2. Then, the reaction solution is post-treated to obtain compound 4.
10. The preparation method according to claim 9, characterized in that, When adding the borate alkyl ester compound, the system temperature T4 is controlled to be no higher than -10℃, preferably -15℃ to -35℃; the preset reaction time t2 after the addition is completed is 0.5 to 3 hours.
11. The preparation method according to claim 9, characterized in that, When adding the isopropyl magnesium chloride-lithium chloride solution, the system temperature T2 is controlled to be no higher than -10℃; preferably -25℃ to -45℃; after the addition is completed, the reaction is carried out at a system temperature T3 no higher than -15℃, and the preset reaction time t1 is 0.5 to 3 hours.
12. The L- as described in claim 1 10 BPA impurity compounds or impurity compounds prepared by the method according to any one of claims 2-11 are used as impurity reference standards in L- 10 Application of BPA in quality control.