Preparation method of gadobutrol derivative A

Abstract

The invention discloses a preparation method of a gadobutrol derivative A. The invention aims to solve the problems of long preparation route, low total yield, difficulty in reaction monitoring, complicated post-treatment and the like of the gadobutrol derivative A in the prior art. The method provided by the invention comprises the following steps: reacting cycleanine with a raw material 2 to obtain an intermediate 1; reacting the intermediate 1 with a raw material 3 to obtain an intermediate 2; and carrying out alkaline hydrolysis and acidification on the intermediate 2 to obtain the gadobutrol derivative A. The method disclosed by the invention has the advantages of short reaction route, high yield, convenience in ultraviolet detection and monitoring and the like, only simple recrystallization or extraction is needed in post-treatment, the operation is simple and convenient, the requirement on production equipment is reduced, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing a drug derivative, and more particularly to a method for preparing a gadobutrol derivative A. Background Technology

[0002] Gadobutrol, as a second-generation macrocyclic nonionic paramagnetic contrast agent for magnetic resonance imaging (MRI), plays a crucial role in clinical diagnostics. Its chemical structure is based on the gadolinium(III) ion, formed through a chelate with the macrocyclic ligand "gadobutrol"—this unique structure not only endows gadobutrol with excellent relaxation efficiency but also gives it high biocompatibility, enabling its widespread application in the detection and auxiliary diagnosis of lesions in various tissues and organs throughout the body. However, during industrial production and long-term storage, gadobutrol inevitably generates various structure-related impurities. Among them, the structure of gadobutrol derivative A is as follows:

[0003]

[0004] Gadobutol derivative A is a critical impurity that is subject to strict control by both the United States Pharmacopeia (USP) and the European Pharmacopeia (EP), with a limit of no more than 0.05%. Therefore, preparing a certain amount of high-purity gadobutol derivative A and conducting systematic research on it to understand its characteristics is a core step in ensuring the quality control of gadobutol drugs and strengthening the safety of clinical drug use.

[0005] Currently, synthetic methods for this type of gadobutrol derivative A have been reported, with a representative technical solution appearing in Chinese patent CN119080708A. This patent discloses a preparation method using cyclotrenin as a starting material, the core idea of ​​which is to employ a "protection-deprotection" chemical strategy. Specifically, this route first uses benzyl chloroformate (CbzCl) to selectively protect the para-nitrogen atom on the cyclotrenin ring, followed by a nucleophilic substitution reaction to introduce a side chain, then removes the Cbz protecting group via palladium-catalyzed hydrogenation, and finally obtains the target product through multiple steps of ring-opening, hydrolysis, and complexation.

[0006] Although this method can produce the target product, it has several inherent drawbacks in industrial applications, limiting its economic viability and operability. First, the synthetic route is lengthy, consisting of six steps including independent protection and deprotection steps. This not only makes the process lengthy and complex but also results in an overall yield of only about 28%, leading to low economic efficiency. Second, several key intermediates in this route lack effective UV chromogenic groups, making it impossible to effectively monitor the reaction progress using a UV detector in high-performance liquid chromatography (HPLC), significantly increasing the difficulty of process control. Third, the deprotection step uses palladium on carbon (Pd / C) as a catalyst for hydrogenation. This catalyst is expensive, and hydrogen is a flammable and explosive gas, imposing stringent requirements on production equipment and operational safety, posing a high safety risk. Finally, the purification process for several intermediates in this patent relies on column chromatography, a cumbersome and solvent-intensive method that is difficult to meet the needs of large-scale industrial production.

[0007] In summary, developing a novel preparation method for gadobutrol derivative A with a shorter route, higher selectivity, lower cost, milder reaction conditions, and simpler post-processing to overcome the shortcomings of existing technologies has become an urgent technical challenge in this field. Summary of the Invention

[0008] To solve the above-mentioned technical problems, this invention prepares a certain amount of high-purity gadobutrol derivative A for scientific research, which can also be used to detect gadobutrol and its products, control their quality, and use the high-purity gadobutrol derivative A as a reference standard in the detection process.

[0009] Therefore, this invention provides a method for preparing gadobutrol derivative A. The method uses cyclotrenin and an epoxy side chain protected with benzophenone as starting materials. Utilizing the large steric hindrance effect of the epoxy side chain, it can be directly and selectively introduced into the N1 and N7 positions of cyclotrenin to obtain the key trans-disubstituted cyclotrenin intermediate. Subsequent substitution and hydrolysis reactions yield derivative A.

[0010] The method for preparing gadobutrol derivative A of the present invention includes the following steps:

[0011]

[0012] Where X = I, R1 = Me, or X = Cl, R1 = t-Bu;

[0013] Its synthesis steps are as follows

[0014] (1) Reacting cyclohexane with raw material 2 to obtain intermediate 1;

[0015] (2) The intermediate 1 is reacted with the raw material 3 to obtain intermediate 2;

[0016] (3) The intermediate 2 is prepared by alkaline hydrolysis and acidification to obtain gadobutrol derivative A.

[0017] Specifically, in step (1), the molar ratio of raw material 2 to the lunhuan tening is greater than 2:1.

[0018] Specifically, the reaction in step (1) is carried out in a polar aprotic solvent selected from the group consisting of sulfolane, dimethyl sulfoxide, N-methylpyrrolidone and N,N-dimethylformamide.

[0019] Specifically, the reaction temperature in step (1) is 75°C to 125°C.

[0020] Specifically, in step (2), in the raw material 3, X is selected from Cl, Br or I; and R1 is selected from C1-C5 alkyl or benzyl groups.

[0021] Specifically, raw material 3 is methyl iodoacetate or tert-butyl chloroacetate.

[0022] Specifically, the reaction in step (2) is carried out in the presence of potassium carbonate for a period of 12 to 36 hours.

[0023] Specifically, step (3) includes:

[0024] The intermediate 2 is reacted with an inorganic base to hydrolyze the ester group;

[0025] And the product of hydrolyzing the ester group is reacted with acid to remove the benzophenone protecting group.

[0026] Specifically, the inorganic base is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0027] Specifically, step (3) includes reacting the intermediate 2 with trifluoroacetic acid to simultaneously remove the tert-butyl and benzophenone protecting groups.

[0028] The preferred technical solution of the present invention is shown in Embodiment 1 of the present invention.

[0029] Technical effects of the present invention

[0030] 1. The reaction route is relatively short (3 steps), and there is no need for protection / deprotection steps, with an overall yield of 42%;

[0031] 2. By introducing chromophores, each step of the reaction can be detected by ultraviolet light, solving the problem of difficult reaction monitoring;

[0032] 3. The post-processing of the reaction is relatively simple. Only simple recrystallization or extraction operations are needed to obtain the corresponding intermediates and finished products, and the requirements for production instruments and equipment are low. Attached Figure Description

[0033] Figure 1 This is the 1H NMR spectrum of intermediate 1 obtained in Example 1 of the technical solution of this application. The spectrum shows that the compound has 20 aromatic hydrogens and 28 aliphatic hydrogens, which is consistent with the structure of intermediate 1 (the solvent is deuterated methanol).

[0034] Figure 2 This is the 1H NMR spectrum of intermediate 2 obtained in Example 1 of the technical solution of this application. The spectrum shows that the compound has 20 aromatic hydrogens and 50 aliphatic hydrogens, which is consistent with the structure of intermediate 2 (the solvent is deuterated DMSO).

[0035] Figure 3 This is the 1H NMR spectrum of gadobutrol derivative A obtained in Example 1 of the technical solution of this application. The spectrum shows that the compound has no aromatic hydrogens and 32 aliphatic hydrogens, which is consistent with the structure of gadobutrol derivative A (the solvent is deuterated water).

[0036] Figure 4 This is the liquid phase spectrum of intermediate 1 obtained in Example 1 of the technical solution of this application. Intermediate 1 has a strong absorption peak at a wavelength of 225 nm.

[0037] Figure 5 This is the liquid phase spectrum of intermediate 2 obtained in Example 1 of the technical solution of this application. Intermediate 2 has a strong absorption peak at a wavelength of 200 nm. Detailed Implementation

[0038] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. It should be understood that the specific embodiments are only used to explain the present invention, but the embodiments are not intended to limit the present invention.

[0039] In this invention, unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0040] In this invention, unless otherwise stated, the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0041] In this invention, unless otherwise specified, the experimental methods used in the embodiments of this invention are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0042] Example 1, Preparation of gadobutrol derivative A

[0043] Step 1: Add 10 g (58 mmol) of cyclohexanetin and sulfolane (100 ml) to a reaction flask, stir until dissolved, and then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 120 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 33 g of intermediate 1 (yield: 82%).

[0044] Step 2: Intermediate 1 (30.0 g, 42 mmol), potassium carbonate (14.6 g, 106 mmol), and acetonitrile (700 ml) were added to a reaction flask. Starting material 3 (135 mmol) was added with stirring. The reaction was carried out at 50 ± 5 °C for 24 h. The reaction was stopped after intermediate 1 disappeared as monitored by TLC. The mixture was cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure to obtain a concentrated solution. Methyl tert-butyl ether (350 ml) was added, and the mixture was stirred at room temperature for 0.5 h. After filtration, the filtrate was concentrated to ~100 ml. Heptane (350 ml) was added at room temperature, and the mixture was stirred to induce crystallization. The crystals were filtered, and the filter cake was dried to obtain intermediate 2 (yield: 75-90%).

[0045] Step 3: Add intermediate 2 (20 mmol), methanol (200 ml), and drinking water (40 ml) to a reaction flask. After stirring until dissolved, add lithium hydroxide monohydrate (8.4 g, 200 mmol). React at 50 ± 5 °C for 24 h. Stop the reaction after intermediate 2 disappears as monitored by TLC. Cool to room temperature, filter, and wash the filter cake with methyl tert-butyl ether (200 ml) to obtain a white solid.

[0046] Add the solid and drinking water (100 ml) to a reaction flask, slowly add 35% hydrochloric acid to adjust the pH to 1, and react at 50 ± 5 °C for 16 h. Stop the reaction after the starting material disappears as monitored by TLC. Add methyl tert-butyl ether (200 ml) to extract impurities, concentrate the aqueous phase under reduced pressure, add anhydrous ethanol (50 ml) to the concentrate, and concentrate to dryness under reduced pressure. Add methanol (100 ml) to the residue, stir and slurry at room temperature for 1 h, filter, wash the filter cake with methanol (10 ml), and dry the filter cake to obtain derivative A (yield: 46~54%).

[0047] Example 2, Screening of preparation methods for intermediate 1

[0048] Step 1: Add 10 g (58 mmol) of cyclohexane and 100 ml of ethanol to a reaction flask, stir until dissolved, then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 80 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 27 g of intermediate 1 (yield: 67%).

[0049] Additionally, 1.3 g of compound IB was obtained, and the structural diagram of compound IB is shown below:

[0050] .

[0051] The inventors discovered that compound IB competes with intermediate 1 in the preparation of intermediate 1. Therefore, the inventors conducted a screening study on the reaction conditions of intermediate 1, and the screening process is as follows:

[0052] Example 3

[0053] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of ethanol to a reaction flask, stir until dissolved, and then add starting material 2 (10 g, 37 mmol). After purging with nitrogen three times, maintain the temperature at 80 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 0 g of intermediate 1 (yield: 0%) and 9 g of compound IB.

[0054] Example 4

[0055] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of ethanol to a three-necked flask, stir until dissolved, and then add raw material 2 (10 g, 37 mmol). Incubate at 80 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 0 g of intermediate 1 (yield: 0%) and 8.5 g of compound I-B.

[0056] Example 5

[0057] Step 1: Add 10 g (58 mmol) of cyclohexanetin and sulfolane (100 ml) to a reaction flask, stir until dissolved, then add starting material 2 (10 g, 37 mmol). After purging with nitrogen three times, maintain the temperature at 120 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 0 g of intermediate 1 (yield: 0%) and 3.3 g of compound I-B1.

[0058] Example 6

[0059] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of ethanol to a reaction flask, stir until dissolved, and then add starting material 2 (46 g, 175 mmol). Incubate at 80 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 25 g of intermediate 1 (yield: 61%) and 2 g of compound I-B.

[0060] Example 7

[0061] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of methanol to a reaction flask, stir until dissolved, and then add starting material 2 (10 g, 37 mmol). After purging with nitrogen three times, maintain the temperature at 80 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 0 g of intermediate 1 (yield: 0%) and 9.6 g of compound I-B.

[0062] Example 8

[0063] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of DMSO to a reaction flask, stir until dissolved, then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 120 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 32 g of intermediate 1 (yield: 79%) and 1.2 g of compound I-B.

[0064] Example 9

[0065] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of NMP to a reaction flask, stir until dissolved, and then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 120 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 30 g of intermediate 1 (yield: 73%) and 0.9 g of compound I-B.

[0066] Example 10

[0067] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of DMF to a reaction flask, stir until dissolved, and then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 120 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 33 g of intermediate 1 (yield: 81%) and 1.4 g of compound I-B.

[0068] Example 11

[0069] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of NFM to a reaction flask, stir until dissolved, then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 120 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 27 g of intermediate 1 (yield: 66%) and 1.1 g of compound I-B.

[0070] Example 12

[0071] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of acetonitrile to a reaction flask, stir until dissolved, and then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 90 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 29 g of intermediate 1 (yield: 71%) and 1.7 g of compound I-B.

[0072] Example 13

[0073] Step 1: Add 10 g (58 mmol) of cyclohexanetin and 100 ml of isopropanol to a reaction flask, stir until dissolved, and then add starting material 2 (46 g, 175 mmol). After purging with nitrogen three times, maintain the temperature at 90 ± 5 °C for 24 h, and then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 26 g of intermediate 1 (yield: 63%) and 1.5 g of compound I-B.

[0074] Example 14

[0075] Step 1: Add 40 g (232 mmol) of cyclohexanetin and 400 ml of tert-butanol to a reaction flask, stir until dissolved, then add starting material 2 (186 g, 700 mmol). After purging with nitrogen three times, maintain the temperature at 90 ± 5 °C for 24 h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 28 g of intermediate 1 (yield: 68%) and 1.3 g of compound I-B.

[0076] In the process of screening the preparation method of intermediate 1, the inventors investigated the variables of process parameters such as solvent type, raw material molar ratio, reaction temperature and reaction atmosphere through Examples 2-15. The specific analysis is as follows:

[0077] When polar aprotic solvents such as sulfolane (Example 1, yield 82%), dimethyl sulfoxide (DMSO, Example 8, yield 79%), N-methylpyrrolidone (NMP, Example 9, yield 73%), and N,N-dimethylformamide (DMF, Example 10, yield 81%) are used, the yield of intermediate 1 remains above 73%. However, when protic solvents such as ethanol (Example 2, yield 67%; Example 6, yield 61%), isopropanol (Example 13, yield 63%), and tert-butanol (Example 14, yield 68%) are used, the yield generally decreases by 5%-10%, and the amount of byproduct compound IB generated increases (e.g., 1.3g of compound IB is generated in Example 2). The reason is speculated to be that polar aprotic solvents can stabilize the amino nucleophilic sites of cyclopentadiene through solvation, promoting the selective occurrence of nucleophilic ring-opening reactions of epoxy side chains (raw material 2), while protic solvents are prone to forming hydrogen bonds with amino groups, weakening their nucleophilic activity, leading to incomplete reactions and increased side reactions.

[0078] The comparison between Examples 1, 2, 8-10 (molar ratio ≈ 3:1) and Examples 3-5, 7 (molar ratio ≈ 0.64:1) shows that the excess amount of raw material 2 is a key prerequisite for ensuring the formation of intermediate 1: when the molar ratio of raw material 2 to cyclotamine is greater than 2:1, the di-substitution reaction of cyclotamine at the N1 and N7 positions can be achieved, successfully generating the target intermediate 1; however, when the molar ratio is less than 2:1, there is insufficient raw material 2 in the reaction system, and cyclotamine can only undergo mono-substitution or not participate in the reaction, resulting in no intermediate 1 being generated, and mainly being converted into the byproduct compound IB (e.g., 9g of compound IB is generated in Example 3 and 13.3g of compound IB is generated in Example 5). This result confirms that raw material 2 needs to meet the stoichiometric requirements for the di-substitution of cyclotamine, and that excess feed can compensate for the trace loss of raw material 2 during the reaction process, further ensuring the completeness of the di-substitution reaction at the N1 and N7 positions.

[0079] Correlation analysis of process parameters and yields in Examples 1, 8-10 (reaction temperature 120±5℃) and Examples 2, 6, 12-13 (reaction temperatures 80±5℃ or 90±5℃) shows that within the process range of 75-125℃, increasing the reaction temperature significantly improves the yield of intermediate 1: at 120±5℃, the yield of intermediate 1 reaches a maximum of 82% (Example 1) and a minimum of 73% (Example 9); while at 80±5℃ or 90±5℃, the yield is only a maximum of 71% (Example 12) and a minimum of 61% (Example 6). The core reason is that the nucleophilic ring-opening reaction between cyclotamine and raw material 2 requires overcoming a certain activation energy. Higher temperatures can increase the molecular kinetic energy of the reaction system, accelerate the reaction rate, shorten the time to reach equilibrium, and reduce the side reaction pathways of the intermediate at low temperatures; while at low temperatures, the reaction kinetic rate is insufficient, which easily leads to raw material retention and reduces the efficiency of target product formation.

[0080] The comparison results of Example 2 (with nitrogen purging, yield 67%) with Example 6 (without nitrogen purging, yield 61%) and Example 4 (without nitrogen purging, yield 0%) show that although nitrogen purging is not the core factor determining the formation of intermediate 1, it can slightly increase the yield (by about 6 percentage points) by removing oxygen from the reaction system and reducing the oxidation side reactions of cyclopentanamine or epoxy groups of raw material 2. Without nitrogen purging, oxygen may cause the oxidation and degradation of raw materials or intermediates, exacerbating the formation of by-products, especially in the case of insufficient feed of raw material 2 (such as in Example 4), which is more likely to lead to complete reaction failure.

[0081] Example 15: Preparation of intermediate 2 and screening of substituents in raw material 3

[0082] Step 2: Add intermediate 1 (30.0 g, 42 mmol), potassium carbonate (14.6 g, 106 mmol), and acetonitrile (700 ml) to a reaction flask. Add starting material 3 (135 mmol) while stirring. React at 50 ± 5 °C for 24 h. Stop the reaction after intermediate 1 disappears as monitored by TLC. Cool to room temperature, filter, and distill the filtrate under reduced pressure to obtain a concentrated solution. Add methyl tert-butyl ether (350 ml), stir at room temperature for 0.5 h, filter, concentrate the filtrate to ~100 ml, add n-heptane (350 ml) at room temperature, stir to precipitate crystals, filter, and dry the filter cake to obtain intermediate 2.

[0083]

[0084] Examples 15-20 investigated the effects of structural differences on the reactivity and selectivity of nucleophilic substitution reactions by changing the combination of halogen atoms X (Cl, Br, I) and alkyl / benzyl substituents R1 (Me, Et, t-Bu, Bn) in starting material 3.

[0085] Comparing the experimental groups where X was Cl, Br, and I (Example 15: Br / Me, yield 85%; Example 16: I / Me, yield 90%; Example 17: Cl / Et, yield 77%), it can be seen that as the electronegativity of the halogen atom decreases and the ionic radius increases, the leaving group ability increases sequentially (I⁻>Br⁻>Cl⁻), and the nucleophilic substitution reaction rate is significantly improved, corresponding to a gradient increase in the yield of intermediate 2. Among them, the highest yield (90%) was achieved when X was I, and the HPLC purity reached 97.2%, indicating that when the iodide is used as raw material 3, efficient substitution of the amino site of intermediate 1 can be achieved at a lower reaction energy barrier, reducing the occurrence of side reactions.

[0086] When R1 is a C1-C5 alkyl group (Me, Et, t-Bu), the yield of intermediate 2 generally remains between 77% and 90%, with the highest HPLC purity reaching 99.4% (Example 17: Cl / Et). However, when R1 is benzyl (Bn) (Example 20: Br / Bn), the yield drops to 75%, and although the purity reaches 97.8%, the yield is significantly lower than that of the alkyl-substituted group. This difference stems from the steric hindrance effect of the benzyl benzene ring structure, and its conjugated system may weaken the stability of the ester group in the starting material 3 through electron delocalization, leading to an increase in local side reactions (such as ester bond hydrolysis) during the reaction and reducing the efficiency of target product formation. Furthermore, when R1 is tert-butyl (t-Bu) (Example 18: Cl / t-Bu, yield 88%; Example 19: Br / t-Bu, yield 87%), although the steric hindrance is slightly higher than that of methyl (Me), the yield remains at a high level, and the purity is excellent (99.1%-96.4%). This indicates that the electron donor characteristics of C1-C5 alkyl groups can offset some of the steric hindrance and ensure the selectivity of the reaction.

[0087] In summary, the optimal structure of raw material 3 is methyl iodoacetate (X=I, R1=Me, Example 16) or tert-butyl chloroacetate (X=Cl, R1=t-Bu, Example 18), which have both strong leaving groups and strong electronic effects, and can achieve high yields (90% and 88%) and high purity (97.2% and 99.1%) of intermediate 2.

[0088] Example 21 Preparation of Intermediate 2

[0089] Step 2: Intermediate 1 (30.0 g, 42 mmol), potassium carbonate (14.6 g, 106 mmol), and acetonitrile (700 ml) were added to a reaction flask. Tert-butyl chloroacetate (20.2 g, 135 mmol) was added under stirring, and the reaction was carried out at 50 ± 5 °C for 3 h. The mixture was cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure to obtain a concentrated solution. Methyl tert-butyl ether (350 ml) was added, and the mixture was stirred at room temperature for 0.5 h. The mixture was then filtered, and the filtrate was concentrated to ~100 ml. Heptane (350 ml) was added at room temperature, and the mixture was stirred to induce crystallization. The crystals were filtered, and the filter cake was dried to obtain intermediate 2 (yield: 35%).

[0090] Preparation of Intermediate 2 in Example 22

[0091] Step 2: Intermediate 1 (30.0 g, 42 mmol), potassium carbonate (14.6 g, 106 mmol), and acetonitrile (700 ml) were added to a reaction flask. Tert-butyl chloroacetate (20.2 g, 135 mmol) was added with stirring, and the reaction was carried out at 50 ± 5 °C for 12 h. The mixture was cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure to obtain a concentrated solution. Methyl tert-butyl ether (350 ml) was added, and the mixture was stirred at room temperature for 0.5 h. The solution was filtered, and the filtrate was concentrated to ~100 ml. Heptane (350 ml) was added at room temperature, and the mixture was stirred to induce crystallization. The crystals were filtered, and the filter cake was dried to obtain intermediate 2 (yield: 76%).

[0092] Preparation of Intermediate 2 in Example 23

[0093] Step 2: Intermediate 1 (30.0 g, 42 mmol), potassium carbonate (14.6 g, 106 mmol), and acetonitrile (700 ml) were added to a reaction flask. Tert-butyl chloroacetate (20.2 g, 135 mmol) was added with stirring, and the reaction was carried out at 50 ± 5 °C for 36 h. The mixture was cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure to obtain a concentrated solution. Methyl tert-butyl ether (350 ml) was added, and the mixture was stirred at room temperature for 0.5 h. The mixture was then filtered, and the filtrate was concentrated to ~100 ml. Heptane (350 ml) was added at room temperature, and the mixture was stirred to induce crystallization. The crystals were filtered, and the filter cake was dried to obtain intermediate 2 (yield: 81%).

[0094] Examples 21-23 used tert-butyl chloroacetate (X=Cl, R1=t-Bu) as raw material 3, and fixed the reaction temperature (50±5℃) and the amount of potassium carbonate, to investigate the effect of reaction time (3h, 12h, 36h) on the yield of intermediate 2:

[0095] When the reaction time was 3 hours (Example 21), the yield of intermediate 2 was only 35%. It is speculated that because the nucleophilic substitution reaction did not reach kinetic equilibrium, intermediate 1 did not react completely with the starting material 3, resulting in a large amount of starting material remaining in the system and thus insufficient production of the target product. When the reaction time was extended to 12 hours (Example 22), the yield increased significantly to 76%, indicating that this time point could meet the requirements for complete reaction, the conversion rate of the starting material was significantly improved, and the side reactions were not significantly aggravated. When the reaction time was further extended to 36 hours (Example 23), the yield increased by only 5 percentage points (to 81%), indicating that the reaction was close to thermodynamic equilibrium at this point, and further extending the time would have limited effect on the yield gain.

[0096] Example 24 Preparation of Gadolinol Derivative A

[0097] Step 3: Add intermediate 2 (16 g, 20 mmol), methanol (200 ml), and drinking water (40 ml) to a reaction flask. After stirring until dissolved, add lithium hydroxide monohydrate (8.4 g, 200 mmol). React at 50 ± 5 °C for 24 h. Stop the reaction after intermediate 2 disappears as monitored by TLC. Cool to room temperature, filter, and wash the filter cake with methyl tert-butyl ether (200 ml) to obtain a white solid.

[0098] Add the solid and drinking water (100 ml) to a reaction flask, slowly add 35% hydrochloric acid to adjust the pH to 1, and react at 50 ± 5 °C for 16 h. Stop the reaction after the starting material disappears as monitored by TLC. Add methyl tert-butyl ether (200 ml) to extract impurities, concentrate the aqueous phase under reduced pressure, add anhydrous ethanol (50 ml) to the concentrate, and concentrate to dryness under reduced pressure. Add methanol (100 ml) to the residue, stir and slurry at room temperature for 1 h, filter, wash the filter cake with methanol (10 ml), and dry the filter cake to obtain derivative A (yield: 54%).

[0099] Example 25 Preparation of Gadolinol Derivative A

[0100] Step 3: Add intermediate 2 (16 g, 20 mmol), methanol (200 ml), and drinking water (40 ml) to a reaction flask. After stirring until dissolved, add sodium hydroxide (8 g, 200 mmol). React at room temperature for 24 h. Stop the reaction after intermediate 2 disappears as monitored by TLC. Cool to room temperature, filter, and wash the filter cake with methyl tert-butyl ether (200 ml) to obtain a white solid.

[0101] The solid and drinking water (100 ml) were added to a reaction flask, and the pH was adjusted to 1 by slowly adding 35% hydrochloric acid. The reaction was carried out at room temperature for 16 h. The reaction was stopped after the starting material disappeared as monitored by TLC. Methyl tert-butyl ether (200 ml) was added to extract impurities, and the aqueous phase was concentrated under reduced pressure. Anhydrous ethanol (50 ml) was added to the concentrate, and the concentrate was concentrated to dryness under reduced pressure. The residue was added to methanol (100 ml), stirred and slurried at room temperature for 1 h, filtered, and the filter cake was washed with methanol (10 ml). The filter cake was dried to obtain derivative A (yield: 51%).

[0102] Example 26 Preparation of Gadolinol Derivative A

[0103] Step 3: Add intermediate 2 (20 mmol), methanol (200 ml), and drinking water (40 ml) to a reaction flask, stir until dissolved, then add potassium hydroxide (11 g, 200 mmol). React at room temperature for 24 h. Stop the reaction after intermediate 2 disappears as monitored by TLC. Cool to room temperature, filter, and wash the filter cake with methyl tert-butyl ether (200 ml) to obtain a white solid.

[0104] The solid and drinking water (100 ml) were added to a reaction flask, and the pH was adjusted to 1 by slowly adding 35% hydrochloric acid. The reaction was carried out at room temperature for 16 h. The reaction was stopped after the starting material disappeared as monitored by TLC. Methyl tert-butyl ether (200 ml) was added to extract impurities, and the aqueous phase was concentrated under reduced pressure. Anhydrous ethanol (50 ml) was added to the concentrate, and the concentrate was concentrated to dryness under reduced pressure. The residue was added to methanol (100 ml), stirred and slurried at room temperature for 1 h, filtered, and the filter cake was washed with methanol (10 ml). The filter cake was dried to obtain derivative A (yield: 52%).

[0105] Example 27 Preparation of Gadolinol Derivative A

[0106] Step 3: Add intermediate 2 (18g, 21.8mmol), dichloromethane (30mL), and trifluoroacetic acid (60mL) to a 500mL three-necked flask, react at room temperature for 18h, evaporate the filtrate to dryness, add toluene to remove trifluoroacetic acid three times, add ethanol (50mL), stir for 2.5h, filter, and dry to obtain 5g of off-white derivative A, with a yield of 46%.

[0107] Summarize:

[0108] In Example 1, step 3 used lithium hydroxide monohydrate as the hydrolysis reagent, and the reaction temperature was controlled at 50±5℃. After 24 hours of hydrolysis, intermediate 2 was completely converted (TLC monitoring), and the final target product yield was 46-54%. Example 24 completely replicated this hydrolysis system (lithium hydroxide monohydrate + 50±5℃), achieving a target product yield of 54%, the highest among all step-by-step processes. In Examples 25 and 26, sodium hydroxide and potassium hydroxide were used as hydrolysis reagents, respectively, and the hydrolysis temperature was lowered to room temperature. Although TLC monitoring still showed complete conversion of intermediate 2, the target product yields decreased to 51% and 52%, respectively, a reduction of 2-3 percentage points compared to steps 3 and 24 of Example 1. The above results indicate that the alkalinity of lithium hydroxide is highly compatible with the ester hydrolysis requirements of intermediate 2. Its alkalinity, weaker than that of sodium hydroxide and potassium hydroxide, avoids local ring-opening side reactions of the macrocyclic skeleton during ester hydrolysis. Simultaneously, the moderate temperature environment of 50±5℃ significantly enhances the kinetic rate of ester hydrolysis, shortens the time to reach equilibrium, and reduces the retention and degradation of the intermediate in the system. At room temperature, even strongly alkaline sodium hydroxide and potassium hydroxide cannot compensate for the temperature-induced reduction in reaction rate, and the strongly alkaline environment may trigger minor side reactions, ultimately leading to a slight decrease in yield. Example 27 uses a process of "one-step reaction of trifluoroacetic acid → dissolution in dichloromethane → removal of trifluoroacetic acid in toluene → slurrying with ethanol," eliminating the steps of "filtration and washing after alkaline hydrolysis." Although this system significantly shortens the operation cycle (reducing the operation time by about 50% compared to the stepwise system), the process of removing trifluoroacetic acid from toluene in the post-processing requires strict control of the rotary evaporation temperature, and the ethanol slurry is slightly less effective than methanol in removing salt impurities. The final yield (46%) is lower than the lower limit of the yield range (46~54%) in step 3 of Example 1.

[0109] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing gadobutrol derivative A, characterized in that, Includes the following steps: Where X = I, R1 = Me, or X = Cl, R1 = t-Bu; (1) Reacting cyclohexane with raw material 2 to obtain intermediate 1; (2) The intermediate 1 is reacted with the raw material 3 to obtain intermediate 2; (3) The intermediate 2 is prepared by alkaline hydrolysis and acidification to obtain gadobutrol derivative A.

2. The method according to claim 1, characterized in that, The molar ratio of raw material 2 to the cyclohexane in step (1) is greater than 2:

1.

3. The method according to any one of claims 1 or 2, characterized in that, The reaction in step (1) is carried out in a polar aprotic solvent selected from the group consisting of sulfolane, dimethyl sulfoxide, N-methylpyrrolidone and N,N-dimethylformamide.

4. The method according to any one of claims 1 to 3, characterized in that, The reaction temperature in step (1) is 75°C to 125°C.

5. The method according to claim 1, characterized in that, In step (2), in the raw material 3, X is selected from Cl, Br or I; and R1 is selected from C1-C5 alkyl or benzyl groups.

6. The method according to claim 5, characterized in that, The raw material 3 is methyl iodoacetate or tert-butyl chloroacetate.

7. The method according to any one of claims 1 to 6, characterized in that, The reaction in step (2) is carried out in the presence of potassium carbonate and the reaction time is 12 to 36 hours.

8. The method according to any one of claims 1 to 7, characterized in that, Step (3) includes: The intermediate 2 is reacted with an inorganic base to hydrolyze the ester group; and the product of the hydrolyzed ester group is reacted with an acid to remove the benzophenone protecting group, wherein the inorganic base is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.

9. The method according to any one of claims 1 to 7, characterized in that, Step (3) involves reacting the intermediate 2 with trifluoroacetic acid to simultaneously remove the tert-butyl and benzophenone protecting groups.

10. The method according to claim 1, characterized in that, The method comprises the following steps: Step 1: Add 10g (58mmol) of cyclohexanetin and sulfolane (100ml) to a reaction flask, stir until dissolved, then add raw material 2 (46g, 175mmol); after purging with nitrogen three times, maintain the temperature at 120±5℃ for 24h, then stop the reaction. Concentrate the reaction solution under reduced pressure to obtain 33g of intermediate 1; Step 2: Add intermediate 1 (30.0 g, 42 mmol), potassium carbonate (14.6 g, 106 mmol), and acetonitrile (700 ml) to a reaction flask, add starting material 3 (135 mmol) while stirring, and react at 50 ± 5 °C for 24 h. Stop the reaction after intermediate 1 disappears as monitored by TLC. Cool to room temperature, filter, and distill the filtrate under reduced pressure to obtain a concentrated solution. Add methyl tert-butyl ether (350 ml), stir at room temperature for 0.5 h, filter, concentrate the filtrate to ~100 ml, add n-heptane (350 ml) at room temperature, stir to precipitate crystals, filter, and dry the filter cake to obtain intermediate 2. Step 3: Add intermediate 2 (20 mmol), methanol (200 ml), and drinking water (40 ml) to a reaction flask, stir until dissolved, then add lithium hydroxide monohydrate (8.4 g, 200 mmol), and react at 50 ± 5 °C for 24 h. Stop the reaction after intermediate 2 disappears as monitored by TLC, cool to room temperature, filter, and wash the filter cake with methyl tert-butyl ether (200 ml) to obtain a white solid. Add the solid and drinking water (100 ml) to a reaction flask, slowly add 35% hydrochloric acid to adjust the pH to 1, and react at 50 ± 5 °C for 16 h. Stop the reaction after the starting material disappears as monitored by TLC, add methyl tert-butyl ether (200 ml) to extract impurities, concentrate the aqueous phase under reduced pressure, add anhydrous ethanol (50 ml) to the concentrate, concentrate to dryness under reduced pressure, add methanol (100 ml) to the residue, stir and slurry at room temperature for 1 h, filter, wash the filter cake with methanol (10 ml), and dry the filter cake to obtain derivative A.

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