Preparation method of gadotetrol isomer

Abstract

The invention discloses a preparation method of a gadotetrol isomer, which comprises the following steps: by taking cycleanine as an initial raw material, firstly reacting with halogenated acetate to obtain a tri-substituted intermediate, and then reacting with 2-halogenated tert-butyl propionate to construct a tetra-substituted intermediate containing two different ester protecting groups; selectively removing tert-butyl ester by using an acidic reagent to obtain a monocarboxylic acid intermediate, and reducing carboxyl by using a borane reducing agent to obtain an alcohol intermediate containing a hydroxypropyl side chain; and finally, removing residual protecting groups through alkaline hydrolysis, and carrying out chelation reaction with a gadolinium source to obtain the gadotetrol isomer. According to the preparation method, two different protecting groups are selected and matched with a step-by-step deprotection and reduction process, so that the preparation of the gadotetrol isomer is realized.

Description

Technical Field

[0001] This invention relates to a method for preparing pharmaceutical impurities, and more particularly to a method for preparing gadoterol isomers. Background Technology

[0002] Gadoteridol is a non-ionic macrocyclic gadolinium chelate widely used clinically as a contrast agent in magnetic resonance imaging (MRI). Due to its unique three-dimensional structure, gadoteridol exhibits extremely high thermodynamic stability and kinetic inertness, effectively reducing the risk of releasing free gadolinium ions in vivo, and is widely used in neurological and whole-body imaging.

[0003] During the synthesis and storage of gadolinium ethanol, a specific positional isomer impurity is easily generated due to the difference in substitution sites on macrocyclic amines, as shown in the following formula:

[0004] .

[0005] This isomer is listed and clearly defined in the United States Pharmacopeia (USP) and is a key related substance that must be strictly monitored in the quality control of gadoterol raw materials and preparations. Therefore, the targeted synthesis and acquisition of high-purity gadoterol isomer reference standards are of vital importance for establishing accurate quality analysis methods, conducting in-depth research on impurity profiles, and ensuring the safety of clinical medication.

[0006] Currently, there are a few literature reports on the synthesis of this gadolinium isomer, but existing preparation processes generally suffer from significant technical defects and industrialization bottlenecks. For example, the method reported in early literature (such as J. Chem. Soc. Perkin Trans. 1, 1991, 3329) adopts a full protection + full deprotection strategy: starting with cyclopentadiene, benzyl protecting groups are first introduced onto three nitrogen atoms, followed by the introduction of isomer side chains, then high-pressure hydrogenation to remove all benzyl groups, and finally the introduction of acetic acid side chains. This route involves more than six steps, which is not only cumbersome but also involves multiple introductions and removals of protecting groups, resulting in poor atom economy and extremely low overall yields (usually below 20%). In the above-mentioned literature methods, chloroacetic acid is typically used as an alkylating agent when introducing the carboxymethyl side chain. Chloroacetic acid is a highly toxic and corrosive substance, posing a serious threat to operators and the environment; furthermore, the debenzylation step usually requires a high-pressure hydrogenation reactor, which carries high operational risks and does not meet the environmental and safety requirements of modern green pharmaceutical manufacturing.

[0007] Existing techniques attempt to introduce the crucial 1-hydroxy-propyl-2-yl structure by directly reducing the ethyl ester side chain using metal hydrides (such as lithium borohydride). However, experimental studies have shown that due to the steric hindrance and electronic effects of the macrocyclic polyamine skeleton, the ethyl ester group attached to the macrocycle exhibits low reductive activity and lacks chemoselectivity. This reaction is often accompanied by severe side reactions (such as incomplete or excessive reduction), resulting in an extremely complex impurity profile in the reaction solution. This not only significantly reduces the yield but also makes it difficult to purify the crude product through conventional crystallization, often requiring expensive preparative liquid chromatography separation, leading to extremely high preparation costs.

[0008] In summary, existing technologies lack a simple route, mild reaction conditions, high selectivity, and efficient method for preparing gadolinium isomers that avoids highly toxic reagents. Therefore, developing a novel synthetic process that utilizes a novel protection strategy to precisely control reaction sites, improve overall yield, and obtain high-purity products is a pressing technical challenge in this field. Summary of the Invention

[0009] To solve the above-mentioned technical problems, this invention prepares a certain amount of high-purity gadoterol isomers for scientific research, which can also be used to detect gadoterol and its products, control their quality, and use the high-purity gadoterol isomers as a reference standard in the detection process.

[0010] Therefore, the present invention provides a method for preparing gadoterol isomers, the method of the present invention specifically includes the following steps:

[0011] Step 1: In the presence of a first basic reagent, cyclohexanetin is reacted with compound A in an N-alkylation reaction to obtain intermediate 1;

[0012] The general structural formula of compound A is: ;

[0013] Step 2: In the presence of a second basic reagent, intermediate 1 is subjected to an N-alkylation reaction with compound B to obtain intermediate 2;

[0014] The general structural formula of compound B is: ;

[0015] Wherein, X is selected from halogens; R1 is an acid-stable carboxyl protecting group; R2 is an acid-sensitive carboxyl protecting group, and R1 and R2 are different;

[0016] Step 3: React intermediate 2 with an acidic reagent to selectively remove group R2, obtaining intermediate 3;

[0017] Step 4: React intermediate 3 with a borane-based reducing agent to selectively reduce the carboxyl group, thereby obtaining intermediate 4;

[0018] Step 5: The intermediate 4 is hydrolyzed under alkaline conditions to remove the R1 group, and then chelated with a gadolinium source to obtain the gadoterol isomer.

[0019] Specifically, in compounds A and B:

[0020] X is selected from chlorine, bromine, or iodine;

[0021] R1 is selected from C1-C4 straight-chain alkyl groups;

[0022] R2 is selected from tert-butyl, diphenylmethyl, or triphenylmethyl.

[0023] The preferred method is shown in the following formula:

[0024] .

[0025] In this compound, compound A (raw material 2) is methyl bromoacetate, and compound B (raw material 3) is tert-butyl 2-bromopropionate. In the intermediates 1, 2, 3, and 4 obtained, R1 is methyl and R2 is tert-butyl.

[0026] Specifically, the first alkaline reagent in step one is selected from sodium acetate, potassium acetate, or ammonium acetate; the reaction solvent in step one is N,N-dimethylformamide.

[0027] Specifically, the second alkaline reagent in step two is selected from potassium carbonate or cesium carbonate; the reaction solvent in step two is acetonitrile.

[0028] Specifically, the acidic reagent mentioned in step three is trifluoroacetic acid (TFA); the reaction is carried out in dichloromethane solvent.

[0029] Specifically, the borane reducing agent mentioned in step four is a borane-tetrahydrofuran complex (BH3·THF); the temperature control of the reduction reaction is as follows: the reducing agent is first added dropwise at -15℃ to -5℃, and then the reaction is maintained at 10℃ to 20℃.

[0030] Specifically, the gadolinium source mentioned in step five is selected from gadolinium oxide or gadolinium chloride; the purification method of the gadolinium isomer is as follows: after the reaction solution is concentrated, a mixed solvent of isopropanol and water is added for recrystallization.

[0031] Specifically, intermediate 3: 1,4,7-tris(methoxycarbonylmethyl)-10-(1-carboxyethyl)-1,4,7,10-tetraazacyclododecane; intermediate 4: 1,4,7-tris(methoxycarbonylmethyl)-10-(1-hydroxy-propyl-2-yl)-1,4,7,10-tetraazacyclododecane.

[0032] An embodiment of the present invention for preparing a gadoterol isomer includes the following steps:

[0033] Step 1: Mix cyclohexane with sodium acetate in DMF, add methyl bromoacetate dropwise, and react at 20~40℃. After the reaction is complete, add sodium bicarbonate solution dropwise to crystallize and obtain intermediate 1.

[0034] Step 2: Mix intermediate 1 with potassium carbonate in acetonitrile, add tert-butyl 2-bromopropionate, react at 75~85℃, and then perform post-treatment to obtain intermediate 2;

[0035] Step 3: Intermediate 2 is reacted with trifluoroacetic acid in dichloromethane to remove tert-butyl ester, yielding intermediate 3;

[0036] Step 4: Add borane-tetrahydrofuran complex dropwise to intermediate 3 in tetrahydrofuran at -10±5℃. After the addition is complete, react at 15±5℃ to obtain intermediate 4.

[0037] Step 5: Hydrolyze intermediate 4 in an alkaline aqueous solution to remove methyl ester, adjust the pH to acidic, add gadolinium oxide for chelation reaction, adjust the pH to neutral after the reaction is complete, concentrate and recrystallize from isopropanol to obtain the gadoterol isomer.

[0038] Technical effects of the present invention

[0039] 1. This invention utilizes the difference between the sensitivity of tert-butyl ester under acidic conditions (TFA) and the stability of methyl ester to achieve precise deprotection of specific sites (99% yield). Then, in conjunction with a low-temperature reduction system of borane, the carboxyl group is successfully reduced to an alcohol without affecting the remaining methyl ester groups, thus avoiding the selectivity problem of direct reduction method. This is the core breakthrough for achieving efficient synthesis of this isomer.

[0040] 2. Compared to the existing literature-reported "tribenzyl protection + high-pressure hydrogenation" route (with an overall yield of only about 14.7%), this invention significantly reduces side reactions by shortening the synthetic route and optimizing reaction conditions (such as using tert-butyl 2-bromopropionate and a potassium carbonate / acetonitrile system). Experimental data show that the overall yield of gadolinium isomers prepared by this invention can reach about 45% (92% in the first step of the preferred embodiment, with high cumulative conversion rates in subsequent steps), achieving a doubling of the yield and greatly reducing production costs.

[0041] 3. This invention avoids the use of highly hazardous reagents (such as highly toxic and corrosive chloroacetic acid) and harsh operating conditions (such as high-pressure hydrogenation reactors) found in existing technologies. The reagents used in this invention (such as brominated esters, potassium carbonate, and trifluoroacetic acid) are all conventional chemicals, and the main reactions are carried out under normal pressure and within a mild temperature range of -10°C to 80°C. The operation is simple, the EHS (environmental, health, and safety) risks are low, and it is more in line with the requirements of green chemistry and industrial production. Attached Figure Description

[0042] Figure 1 The image shows the hydrogen nuclear magnetic resonance spectrum of intermediate 3 prepared in Example 1.

[0043] Figure 2 The image shows the 1H NMR spectrum of intermediate 5 prepared in Example 1. Detailed Implementation

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] Example 1: Preparation of Gadolinol Isomers

[0049]

[0050] Where X is bromine and R1 is methyl.

[0051] Step 1: Add 20g (116mmol) of cyclohexanetin and 100ml of DMF to a reaction flask, stir until dissolved, then add sodium acetate (33.3g, 407mmol), stir for 10min, and then add starting material 2 (407mmol) dropwise. Maintain the reaction temperature at 30±10℃ for 24h, then stop the reaction. Control the temperature at 10±10℃, add 43% sodium bicarbonate solution (400ml) dropwise, and maintain the temperature for crystallization for 2-6h. Filter, wash the filter cake with drinking water (400ml), and dry the filter cake to obtain intermediate 1 (X=Br, R1=Me, yield: 92%).

[0052] Step 2: Add intermediate 1 (100 mmol), potassium carbonate (27.6 g, 200 mmol), and acetonitrile (200 ml) to a reaction flask. Add starting material 3 (150 mmol) while stirring. Incubate at 80 ± 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. Column chromatography of the concentrated solution yields intermediate 2 (X = Br, yield: 62%).

[0053] The column chromatography method is as follows: using 200~300 mesh silica gel as packing material, the concentrated solution is wet-loaded and then eluted with eluent (dichloromethane / methanol = 100 / 1 → 40 / 1), and the corresponding fractions are collected and distilled under reduced pressure.

[0054] Step 3: Add intermediate 2 (50 mmol), dichloromethane (100 ml), and trifluoroacetic acid (25 ml) to a reaction flask and react at room temperature for 16 h. Stop the reaction after intermediate 2 disappears as monitored by TLC. Distill under reduced pressure to obtain intermediate 3 (yield: 99%).

[0055] Please refer to Figure 1 The 1H-NMR spectrum (DMSO-d6) of intermediate 3 shows that the compound contains one active hydrogen (carboxyl hydrogen) and 35 aliphatic hydrogens (including 16 H on the ring ring, 9 H on the three methyl ester groups, and 10 H on the side chain methylene and methine groups). The integral ratio is completely consistent with the theoretical structure of intermediate 3, confirming that tert-butyl ester has been successfully removed while the methyl ester group is retained.

[0056] Step 4: Add intermediate 3 (30 mmol) and tetrahydrofuran (100 ml) to a three-necked flask, stir until dissolved, purge with nitrogen three times, maintain temperature at -10 ± 5 °C, and add dropwise 1 M borohydride tetrahydrofuran solution (33 ml, 33 mmol). After addition, maintain temperature at 15 ± 5 °C for 16 h. Maintain temperature at 0 ± 5 °C, quench with methanol (10 ml), and distill under reduced pressure. Column chromatography of the concentrated solution yields intermediate 4 (yield: 81%).

[0057] The column chromatography method is as follows: using 200~300 mesh silica gel as packing material, the concentrated solution is wet-loaded and then eluted with eluent (dichloromethane / methanol=20 / 1), and the corresponding fractions are collected and distilled under reduced pressure.

[0058] Step 5: Add intermediate 4 (20 mmol), methanol (60 ml), and drinking water (40 ml) to the reaction flask, stir, then add alkali (120 mmol), and keep the mixture at 25 ± 5 °C for 16 h before stopping the reaction. Slowly add hydrochloric acid to adjust the pH to ~3 to obtain intermediate 5 solution.

[0059] Take a small amount of intermediate 5 solution, dry it, and then perform NMR detection. For example... Figure 2As shown, the 1H-NMR spectrum (MeOD) of intermediate 5 shows that the compound contains 28 aliphatic hydrogens (including 16H on the ring ring, 6H on the three acetic acid side chains, and 6H on the isomer side chain). The characteristic peak of the methyl ester group (about 3.6-3.7 ppm) has completely disappeared, and the integral data is consistent with the theoretical structure of intermediate 5 (completely hydrolyzed product).

[0060] At a controlled temperature of 25±5℃, gadolinium oxide (3.6 g, 10 mmol) was added, and the reaction was maintained at 95±5℃ for 8 h. The reaction was stopped when the content of intermediate 5 was <2% as monitored by HPLC. The mixture was cooled to room temperature, and the pH was adjusted to 7.0-7.5 by adding 10% sodium hydroxide solution dropwise. The mixture was filtered, and the filtrate was distilled to dryness under reduced pressure. The residue was added to purified water (10 ml) and isopropanol (10 ml), and the mixture was kept at 75±5℃ with stirring until dissolved. Isopropanol (100 ml) was added dropwise, and stirring was continued for 1 h after the addition was complete. The temperature was then slowly lowered to 25±5℃, and stirring was continued for 2 h. The mixture was filtered, and the filter cake was washed with isopropanol (20 ml). The filter cake was dried to obtain the isomer (2-step yield: 77%).

[0061] Acid-stable carboxyl protecting groups (R1): These are ester protecting groups that maintain chemical stability under acidic deprotection conditions (especially the trifluoroacetic acid / dichloromethane system, reaction at room temperature) and do not undergo hydrolysis or deprotection reactions. In this invention, such protecting groups are mainly used to construct the trisubstituted skeleton of cyclotrenine. Typical acid-stable carboxyl protecting groups include, but are not limited to: C1-C4 straight-chain alkyl groups (such as methyl, ethyl, n-propyl, n-butyl).

[0062] Acid-sensitive carboxyl protecting groups (R2): These are ester protecting groups that are unstable under the aforementioned acidic deprotection conditions and can break down to expose a free carboxyl group. In this invention, such protecting groups are used to introduce key side chains into isomers. Typical acid-sensitive carboxyl protecting groups include, but are not limited to: tert-butyl (t-Bu), diphenylmethyl (Dpm), triphenylmethyl (Trt), p-methoxybenzyl (PMB), or 2,4-dimethoxybenzyl (DMB).

[0063] Comparative Example 1

[0064] Step 1a: Preparation of 1,4,7-tribenzyl-1,4,7,10-tetraazacyclododecane

[0065] In a 2L reaction flask equipped with a mechanical stirrer, dropping funnel, and reflux condenser, 1,4,7,10-tetraazacyclododecane (86.1 g, 0.5 mol) and anhydrous acetonitrile (1 L) were added. Anhydrous potassium carbonate (414 g, 3.0 mol) was added with stirring. The mixture was heated to reflux. Freshly distilled benzyl bromide (256.5 g, 1.5 mol) was slowly added dropwise. After the addition was complete, the mixture was kept under reflux for 48 hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the mixture was cooled to room temperature and filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure. The residue was a viscous oil containing the target product as well as unreacted starting materials, dibenzylated and tetrabenzylated byproducts. This mixture had similar polarities, making separation difficult. Purification was performed by macroporous silica gel column chromatography (eluting with a gradient of dichloromethane / methanol) to obtain 1,4,7-tribenzyl-1,4,7,10-tetraazacyclododecane (114.2 g), with a yield of 51.6%. This separation and purification process is time-consuming and labor-intensive, and requires a large amount of solvent, making it unsuitable for industrial production.

[0066] Step 1b: Alkylation reaction to introduce ethyl ester side chains

[0067] The 1,4,7-tribenzyl-1,4,7,10-tetraazacyclododecane (59.7 g, 0.135 mol) obtained in step 1a was dissolved in acetonitrile (700 mL), and anhydrous sodium carbonate (17.6 g, 0.166 mol) was added. An acetonitrile solution of ethyl-2-(trifluoromethanesulfonyloxy)propionate (41.5 g, 0.166 mol) was slowly added dropwise. The mixture was stirred and reacted at room temperature for 16 hours. After the reaction was complete, the inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give the corresponding ethyl ester intermediate (82.2 g), with a yield of 90.6%. This step requires the use of a special reagent that is not commercially available and requires multiple steps, increasing the complexity and cost of the process.

[0068] Step 1c: Selective reduction of ethyl ester groups

[0069] The ethyl ester intermediate (81.8 g, 0.12 mol) obtained in step 1b was dissolved in anhydrous tetrahydrofuran (THF, 800 mL). A THF solution of lithium borohydride (LiBH4) (2 M, 84 mL, 0.168 mol) and 9-OMe-BBN as a catalyst (9-Borabicyclo[3.3.1]nonane) were added, and the mixture was heated under reflux for 16 hours. After the reaction was completed, the mixture was cooled and carefully quenched with sodium hydroxide solution. After extraction, concentration, and column chromatography purification, the target product 1,4,7-tribenzyl-10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane (64.5 g) was obtained in 85% yield.

[0070] Step 1d: Catalytic debenzylation of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane

[0071] The product obtained in step 1c (63.3 g, 0.1 mol) was dissolved in ethanol (1 L). A 10% palladium on carbon (Pd / C) catalyst (6.3 g, 10 wt%) was added. The reaction system was transferred to a high-pressure reactor, and the air was purged three times with nitrogen, followed by three purgings with hydrogen. The reaction was carried out at 60 °C with stirring for 72 hours under a hydrogen pressure of 50 atm. After the reaction was complete, the pressure inside the reactor was carefully released, and the reactor was purged with nitrogen. The catalyst was removed by diatomaceous earth filtration, and the filtrate was concentrated under reduced pressure to obtain the target product (22.0 g), with a yield of 95.5%. This step requires a high-pressure hydrogenation device, which has high equipment requirements, high operational risks, and expensive catalysts.

[0072] Step 1e: Carboxylation of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (replace bromoacetic acid with chloroacetic acid in the original text).

[0073] The product obtained in step 1 (21.9 g, 0.095 mol) was dissolved in deionized water (250 mL). Under ice bath cooling, the pH was adjusted to 11-12 using a 30% sodium hydroxide aqueous solution. Chloroacetic acid (32.1 g, 0.34 mol) was added in portions. During the addition, the pH was continuously maintained between 11-12 using sodium hydroxide solution. After the addition was complete, the reaction mixture was stirred at 60°C for 24 hours. After the reaction was complete, the pH was adjusted to 2-3 using concentrated hydrochloric acid, resulting in the precipitation of a large amount of salt. The mixture was purified using an ion exchange resin. First, inorganic salts were removed by elution with dilute hydrochloric acid, followed by elution with ammonia to obtain the target product solution. The eluent was concentrated to obtain the target ligand (29.1 g), with a yield of 76.2%. The chloroacetic acid used in this step is a highly toxic and corrosive chemical, posing a serious threat to operators and the environment, and does not meet the production requirements of modern green chemistry.

[0074] Step 1f: Chelation reaction

[0075] The ligand obtained in step 1e (29.0 g, 0.072 mol) was dissolved in deionized water (300 mL), and gadolinium(III) oxide (13.0 g, 0.036 mol) was added. The mixture was heated to 95 °C and reacted at this temperature for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and decolorized by activated carbon. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from isopropanol to give the final product (20.3 g), with a yield of 50.5%.

[0076] The comparative example 1's technical route, involving six reaction steps, resulted in an extremely lengthy process with an overall yield of only 14.7%. Furthermore, its technical defects included: poor selectivity in the selective tribenzylation reaction of step 1a, leading to a complex mixture of products that were difficult to separate and purify; reliance on a non-commercially available special reagent for the alkylation reaction of step 1b; the catalytic hydrogenation deprotection reaction of step 1d requiring expensive and potentially dangerous high-pressure hydrogenation equipment; and the use of highly toxic chloroacetic acid in the carboxymethylation reaction of step 1e, posing serious safety hazards to operators and the environment. Moreover, from a process chemistry perspective, this method introduced three benzyl protecting groups to achieve selective reactions, only to remove them all in subsequent steps. This "introduction-removal" strategy generated a large amount of chemical waste, resulting in unsatisfactory atom economy and process quality intensity (PMI) and other key green chemistry indicators.

[0077] Comparative Example 2

[0078] Step 2a: Preparation of 1,4,7-tris(tert-butoxycarbonylmethyl)-10-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

[0079] Following the method in step two of Example 1, intermediate 1 (R1 = tert-butyl, 100 mmol) was reacted with ethyl bromoacetate (150 mmol) in acetonitrile (200 mL) in the presence of potassium carbonate (200 mmol) at 80 °C for 24 hours. After the reaction was completed, the compound was post-processed and purified by column chromatography to obtain the title compound as a white solid in 60% yield.

[0080]

[0081] Step 2b: Selective reduction

[0082] The product obtained in step 2a (50 g, 0.0813 mol) was dissolved in anhydrous tetrahydrofuran (300 mL). After adjusting the reaction temperature, a reducing agent was slowly added dropwise. The reaction was continued at this temperature for 48 hours. After the reaction was complete, 50 mL of methanol was added to quench the reaction. Water (400 mL) and ethyl acetate (200 mL) were added to the reaction mixture for extraction. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was directly analyzed by high-performance liquid chromatography (HPLC), and the results are shown in the table below.

[0083]

[0084] Example 2

[0085] Step 1: Add 20g (116mmol) of cyclohexanetin and 100ml of DMF to a reaction flask, stir until dissolved, then add sodium acetate (33.3g, 407mmol), stir for 10min, and then add starting material 2 (407mmol) dropwise. Maintain the reaction temperature at 30±10℃ for 24h, then stop the reaction. Control the temperature at 10±10℃, add 43% sodium bicarbonate solution (400ml) dropwise, and maintain the temperature for crystallization for 2-6h. Filter, wash the filter cake with drinking water (400ml), and dry the filter cake to obtain intermediate 1.

[0086] The inventors screened raw material 2 and found that using raw material 2 with different substituents as reactants resulted in significant differences in yield and purity.

[0087]

[0088] The results showed that the chlorinated derivatives were not as effective as the brominated derivatives, and the iodinated derivatives were too reactive, which led to the easy formation of 4-substituted impurities; indicating that the X=Br and R1=Me values ​​used in raw material 2 were the most effective.

[0089] Example 3

[0090] Step 2: Add intermediate 1 (100 mmol), potassium carbonate (27.6 g, 200 mmol), and acetonitrile (200 ml) to a reaction flask, and add starting material 3 (150 mmol) while stirring. Incubate at 80 ± 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. Column chromatography of the concentrated solution yields intermediate 2.

[0091] The inventors screened raw material 3 and found that using raw material 3 with different substituents as reactants and using different basic substances resulted in significant differences in yield and purity.

[0092]

[0093] Chlorinated derivatives are not as good as brominated derivatives, and iodinated derivatives are too reactive, which easily leads to the formation of quaternary ammonium salt impurities. X=Br is the best choice for raw material 3.

[0094] Example 4

[0095] Step 2: Add intermediate 1 (100 mmol), potassium carbonate (27.6 g, 200 mmol), and DMF (200 ml) to a reaction flask. Add starting material 3 (X = Br, 150 mmol) while stirring. Incubate at 80 ± 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. Column chromatography of the concentrated solution yields intermediate 2 (yield: 57%).

[0096] Example 5

[0097] Step 2: Add intermediate 1 (100 mmol), potassium carbonate (27.6 g, 200 mmol), and acetonitrile (200 ml) to a reaction flask. Add starting material 3 (X = Br, 150 mmol) while stirring. Incubate at 100 ± 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. Column chromatography of the concentrated solution yields intermediate 2 (yield: 58%).

[0098] Preparation of intermediate 3 in Example 6

[0099] Step 3: Add intermediate 2 (50 mmol) and dichloromethane (100 ml) to a reaction flask, cool to 0°C, slowly add 50 ml (200 mmol) of 4M hydrogen chloride solution of 1,4-dioxane, and then raise the temperature to room temperature and react for 16 h. Stop the reaction after TLC monitoring shows the disappearance of intermediate 2. Distill under reduced pressure to obtain intermediate 3 (yield: 65%).

[0100] Example 7

[0101] Step 3: Add intermediate 2 (50 mmol), dichloromethane (100 ml), and trifluoroacetic acid (25 ml) to a reaction flask and react at 0 ± 5 °C for 24 h. Stop the reaction after intermediate 2 disappears as monitored by TLC. Distill under reduced pressure to obtain intermediate 3 (yield: 72%).

[0102] Example 8

[0103] Step 4: Add intermediate 3 (30 mmol) and tetrahydrofuran (100 ml) to a three-necked flask, stir until dissolved, purge with nitrogen three times, maintain the temperature at -10 ± 5 °C, and add dropwise a 2 M solution of the boron dimethyl sulfide complex in tetrahydrofuran (16.5 ml, 33 mmol). After addition, maintain the temperature at 15 ± 5 °C for 16 h. Maintain the temperature at 0 ± 5 °C, quench the reaction with methanol (10 ml), and distill the reaction solution under reduced pressure. Column chromatography of the concentrated solution yields intermediate 4 (yield: 66%).

[0104] Example 9

[0105] Step 4: Add intermediate 3 (30 mmol) and tetrahydrofuran (100 ml) to a three-necked flask, stir until dissolved, purge with nitrogen three times, maintain temperature at -10 ± 5 °C, and add dropwise 1 M borohydride tetrahydrofuran solution (33 ml, 33 mmol). After addition is complete, raise the temperature to room temperature and react for 12 h. Maintain temperature at 0 ± 5 °C, quench with dropwise methanol (10 ml), and distill under reduced pressure. Column chromatography of the concentrated solution yields intermediate 4 (yield: 54%).

[0106] Example 10

[0107] Step 5: Add intermediate 4 (20 mmol), methanol (60 ml), and drinking water (40 ml) to the reaction flask, stir, then add sodium hydroxide (120 mmol), and keep the mixture at 25 ± 5 °C for 16 h before stopping the reaction. Slowly add hydrochloric acid to adjust the pH to ~3 to obtain intermediate 5 solution.

[0108] At a controlled temperature of 25±5℃, gadolinium oxide (3.6 g, 10 mmol) was added, and the reaction was maintained at 95±5℃ for 8 h. The reaction was stopped when the content of intermediate 5 was <2% as monitored by HPLC. The mixture was cooled to room temperature, and the pH was adjusted to 7.0-7.5 by adding 10% sodium hydroxide solution dropwise. The mixture was filtered, and the filtrate was distilled to dryness under reduced pressure. The residue was added to purified water (10 ml) and isopropanol (10 ml), and the mixture was kept at 75±5℃ with stirring until dissolved. Isopropanol (100 ml) was added dropwise, and stirring was continued for 1 h after the addition was complete. The temperature was then slowly lowered to 25±5℃, and stirring was continued for 2 h. The mixture was filtered, and the filter cake was washed with isopropanol (20 ml). The filter cake was dried to obtain the isomer (2-step yield: 77%).

[0109] Example 11

[0110] Step 5: Add intermediate 4 (20 mmol), methanol (60 ml), and drinking water (40 ml) to the reaction flask, stir, then add potassium hydroxide (120 mmol), and keep the mixture at 25 ± 5 °C for 16 h before stopping the reaction. Slowly add hydrochloric acid to adjust the pH to ~3 to obtain intermediate 5 solution.

[0111] At a controlled temperature of 25±5℃, gadolinium oxide (3.6 g, 10 mmol) was added, and the reaction was maintained at 95±5℃ for 8 h. The reaction was stopped when the content of intermediate 5 was <2% as monitored by HPLC. The mixture was cooled to room temperature, and the pH was adjusted to 7.0-7.5 by adding 10% sodium hydroxide solution dropwise. The mixture was filtered, and the filtrate was distilled to dryness under reduced pressure. The residue was added to purified water (10 ml) and isopropanol (10 ml), and the mixture was kept at 75±5℃ with stirring until dissolved. Isopropanol (100 ml) was added dropwise, and stirring was continued for 1 h after the addition was complete. The temperature was then slowly lowered to 25±5℃, and stirring was continued for 2 h. The mixture was filtered, and the filter cake was washed with isopropanol (20 ml). The filter cake was dried to obtain the isomer (2-step yield: 75%).

[0112] Example 12

[0113] Step 5: Add intermediate 4 (20 mmol), methanol (60 ml), and drinking water (40 ml) to the reaction flask, stir, then add sodium hydroxide (120 mmol), and keep the mixture at 25 ± 5 °C for 16 h before stopping the reaction. Slowly add hydrochloric acid to adjust the pH to ~3 to obtain intermediate 5 solution.

[0114] At a controlled temperature of 25±5℃, gadolinium chloride (7.4 g, 20 mmol) was added, and the reaction was maintained at 95±5℃ for 8 h. The reaction was stopped when the content of intermediate 5 was <2% as monitored by HPLC. The mixture was cooled to room temperature, and the pH was adjusted to 7.0-7.5 by adding 10% sodium hydroxide solution dropwise. The mixture was filtered, and the filtrate was distilled to dryness under reduced pressure. The residue was added to purified water (10 ml) and isopropanol (10 ml), and the mixture was kept at 75±5℃ with stirring until dissolved. Isopropanol (100 ml) was added dropwise, and stirring was continued for 1 h after the addition was complete. The temperature was then slowly lowered to 25±5℃, and stirring was continued for 2 h. The mixture was filtered, and the filter cake was washed with isopropanol (20 ml). The filter cake was dried to obtain the isomer (2-step yield: 72%).

[0115] Combining the results of Examples 1, 2, and 3, it can be seen that this invention, using a ring-shaped alkylene skeleton as the starting material, achieves precise introduction of side chains through rationally designed alkylation conditions. Comparison of experimental results with different haloalkyl groups shows that the yield and purity of the target product are significantly better when using brominated alkyl groups than when using chloroalkyl or iodoalkyl groups. Chloroalkyl groups, due to their high C-Cl bond energy, have insufficient reactivity, leading to incomplete reactions or low yields; while iodoalkyl groups, although possessing high reactivity, are prone to initiating side reactions such as "over-alkylation" in this system (e.g., generating tetrasubstituted quaternary ammonium salts), severely affecting the selectivity and purity of the target product. Therefore, brominated alkyl groups exhibit the best balance between reactivity and selectivity, making them the preferred embodiment of this invention.

[0116] Further analysis of the screening results from Example 2 revealed that the ester substituents introduced in the alkylating reagent have a significant impact on the reaction results. When smaller substituents such as methyl ester (R1=Me) are used, the nucleophilic substitution reaction proceeds more easily, yielding a higher yield of the target product (92%). However, when larger substituents such as tert-butyl ester or benzyl ester are used, they create significant steric hindrance on the reaction sites on the crowded ring-tengin ring, thereby reducing the reaction rate and increasing the likelihood of byproduct formation. This confirms the necessity of using small-volume substituents (methyl ester) to construct the skeleton in step one.

[0117] Combining the results of Examples 1 and 3, and Examples 4-5, it can be seen that in the key transformation of step two, the reaction process is stable and reproducible when potassium carbonate is used as the base and acetonitrile as the solvent, and the post-processing is the simplest. In contrast, the reaction is incomplete when sodium carbonate is used due to its weak alkalinity; although the reaction can proceed when DMF is used as a solvent, its high boiling point makes it difficult to remove completely in the post-processing, and the residual solvent affects the subsequent crystallization and purification of the product, resulting in a decrease in yield. Therefore, the potassium carbonate / acetonitrile combination is the preferred reaction condition of this invention.

[0118] Combining the results of Examples 1 and 6-7, it can be seen that using trifluoroacetic acid (TFA) as the deprotecting agent can specifically remove tert-butyl ester under mild conditions at room temperature, while retaining the methyl ester group. The resulting intermediate 3 has a yield as high as 99% and extremely high purity. In contrast, when using hydrochloric acid, the lack of selectivity in the strong acid aqueous solution leads to hydrolysis of some methyl ester groups, resulting in a significantly lower yield (65%) and the easy introduction of inorganic salt impurities. Therefore, trifluoroacetic acid is an indispensable reagent for realizing the specific synthetic route of this invention.

[0119] Analysis of the experimental results from Examples 1, 8-9, and Comparative Example 2 revealed that the selective reduction step in step four is highly sensitive to the type of reducing agent. Conventional metal hydrides (such as LiBH4, NaBH4, etc., see Comparative Example 2) could not effectively reduce the side-chain ester / carboxyl groups in this system, and the target product was not observed. In contrast, borane reducing agents exhibited unique advantages. Specifically, the use of a borane-tetrahydrofuran complex under low-temperature (-10~15℃) control enabled effective reduction of the carboxyl group while avoiding over-reduction of the methyl ester group, resulting in a high yield of the target product (81%). This demonstrates the special applicability of this reduction system in the structure of this invention.

[0120] The results from Examples 1 and 10-12 show that, after completing the aforementioned intermediate transformation, the target gadolinium complex can be successfully obtained by introducing a gadolinium source under alkaline conditions for chelation. Comparison of the results from different gadolinium sources reveals that both gadolinium oxide and gadolinium chloride can achieve effective chelation. Specifically, gadolinium oxide produces only water as a byproduct, with no inorganic salt residue, exhibiting a slightly higher overall yield (77%) in the examples and being more advantageous for controlling downstream chloride ion and other impurity levels. These results demonstrate that the chelation conditions employed in this invention have good adaptability and operability.

[0121] Based on the experimental results of the above embodiments and comparative examples, it can be confirmed that the present invention significantly improves the overall yield (from approximately 14.7% in the prior art to approximately 45%) while ensuring high reaction selectivity. Compared with the prior art (Comparative Example 1), the present invention avoids the cumbersome full protection-full deprotection steps and high-pressure hydrogenation operation, and also overcomes the chemical selectivity problem that cannot be achieved by the simple route (Comparative Example 2), demonstrating obvious process improvement effects and good prospects for industrial application.

[0122] 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 a gadoterol isomer, characterized in that, Includes the following steps: Step 1: In the presence of a first basic reagent, cyclohexanetin is reacted with compound A in an N-alkylation reaction to obtain intermediate 1; The general structural formula of compound A is: ; Step 2: In the presence of a second basic reagent, intermediate 1 is subjected to an N-alkylation reaction with compound B to obtain intermediate 2; The general structural formula of compound B is: ; Wherein, X is selected from halogens; R1 is an acid-stable carboxyl protecting group; R2 is an acid-sensitive carboxyl protecting group, and R1 and R2 are different; Step 3: React intermediate 2 with an acidic reagent to selectively remove group R2, obtaining intermediate 3; Step 4: React intermediate 3 with a borane-based reducing agent to selectively reduce the carboxyl group, thereby obtaining intermediate 4; Step 5: The intermediate 4 is hydrolyzed under alkaline conditions to remove the R1 group, and then chelated with a gadolinium source to obtain the gadoterol isomer shown in the following formula. 。 2. The method according to claim 1, characterized in that, In compounds A and B: X is selected from chlorine, bromine, or iodine; R1 is selected from C1-C4 straight-chain alkyl groups; R2 is selected from tert-butyl, diphenylmethyl, or triphenylmethyl.

3. The method according to claim 2, characterized in that, Compound A is methyl bromoacetate, and compound B is tert-butyl 2-bromopropionate.

4. The method according to claim 1, characterized in that, The first alkaline reagent mentioned in step one is selected from sodium acetate, potassium acetate, or ammonium acetate; the reaction solvent in step one is N,N-dimethylformamide.

5. The method according to claim 1, characterized in that, The second alkaline reagent mentioned in step two is selected from potassium carbonate or cesium carbonate; the reaction solvent in step two is acetonitrile.

6. The method according to claim 1, characterized in that, The acidic reagent mentioned in step three is trifluoroacetic acid (TFA); the reaction is carried out in dichloromethane solvent.

7. The method according to claim 1, characterized in that, The borane reducing agent mentioned in step four is a borane-tetrahydrofuran complex (BH3·THF); the temperature control of the reduction reaction is as follows: the reducing agent is first added dropwise at -15℃ to -5℃, and then the reaction is maintained at 10℃ to 20℃.

8. The method according to claim 1, characterized in that, The gadolinium source mentioned in step five is selected from gadolinium oxide or gadolinium chloride; the purification method of the gadolinium alcohol isomer is as follows: after the reaction solution is concentrated, a mixed solvent of isopropanol and water is added for recrystallization.

9. The method according to claim 1, characterized in that, Intermediate 3 and intermediate 4 are respectively: Intermediate 3: 1,4,7-tris(methoxycarbonylmethyl)-10-(1-carboxyethyl)-1,4,7,10-tetraazacyclododecane; Intermediate 4: 1,4,7-tris(methoxycarbonylmethyl)-10-(1-hydroxy-propyl-2-yl)-1,4,7,10-tetraazacyclododecane.

10. A method for preparing the gadolinium isomer according to claim 1, characterized in that, The synthesis route is as follows: Wherein, compound A (raw material 2) is methyl bromoacetate, compound B (raw material 3) is tert-butyl 2-bromopropionate, and in intermediates 1, 2, 3, and 4, R1 is methyl and R2 is tert-butyl. The operation steps are as follows: Step 1: Mix cyclohexane with sodium acetate in DMF, add methyl bromoacetate dropwise, and react at 20~40℃. After the reaction is complete, add sodium bicarbonate solution dropwise to crystallize and obtain intermediate 1. Step 2: Mix intermediate 1 with potassium carbonate in acetonitrile, add tert-butyl 2-bromopropionate, react at 75~85℃, and then perform post-treatment to obtain intermediate 2; Step 3: Intermediate 2 is reacted with trifluoroacetic acid in dichloromethane to remove tert-butyl ester, yielding intermediate 3; Step 4: Add borane-tetrahydrofuran complex dropwise to intermediate 3 in tetrahydrofuran at -10±5℃. After the addition is complete, react at 15±5℃ to obtain intermediate 4. Step 5: Hydrolyze intermediate 4 in an alkaline aqueous solution to remove methyl ester, adjust the pH to acidic, add gadolinium oxide for chelation reaction, adjust the pH to neutral after the reaction is complete, concentrate and recrystallize from isopropanol to obtain the gadoterol isomer.

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