Method for preparing gadobutrol
The steps of reacting diethanolamine with acetyl chloride to form an ester group and combining diethylenetriamine and gadolinium oxide solve the problem of high synthesis cost and many impurities, and achieve low-cost and efficient preparation of gadolinium butrol, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510811397.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-18
- Publication Date
- 2025-08-08
AI Technical Summary
The existing gadobutrol synthesis method has high cost, many side reactions, many impurities, and complex post-reaction treatment, making it difficult to achieve industrial production.
Diethanolamine is used as the starting material to form an ester group by reacting with acetyl chloride, and then reacting with diethylene triamine under strong acid conditions. After steps such as substitution, hydrolysis, ring opening, and deprotection, gadobutrol is finally reacted with gadolinium oxide to prepare.
It realizes low-cost and efficient gadobutrol synthesis, simplifies post-reaction treatment, reduces impurity generation, and is suitable for industrial production.
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Figure CN120441499A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing a pharmaceutical compound, and in particular to a method for efficiently preparing gadobutrol. Background Art
[0002] Gadobutrol is a hydrophilic, macrocyclic, neutral compound based on gadolinium. It is commonly used as a diagnostic drug, and its solution (gadobutrol injection) is used as a contrast agent for contrast-enhanced magnetic resonance imaging.
[0003] The chemical formula of gadobutrol: C 18 H 31 GdN4O9 is soluble in water. Its aqueous solution is a colorless, clear liquid with a density of 1.3 g / mL (at 37°C). Its molecular weight is 604.7. Its chemical name is 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid. Its chemical structure is:
[0004]
[0005] The main defects of the existing technology are:
[0006] 1. Using cyclopentane as raw material is costly and requires excessive cyclopentane, resulting in many side reactions and impurities.
[0007] 2. Diethylenetriamine is protected by p-toluenesulfonic acid and then reacted with diethanolamine. It is difficult to remove p-toluenesulfonic acid and the post-reaction treatment is complicated.
[0008] 3. The boron-directed preparation of the cyclopentane boron complex uses flammable sodium hydride, which is not conducive to industrial production.
[0009] In order to overcome the shortcomings of the existing synthesis of gadobutrol, the present invention discloses a simple and efficient new synthesis method. Summary of the Invention
[0010] The present invention uses diethanolamine as a starting material, which first reacts with acetyl chloride to obtain an ester group. The ester group undergoes an oxidation reaction under strong acid conditions to deesterify and simultaneously reacts with diethylenetriamine to obtain a key acetylcyclamenine intermediate. The acetylcyclamenine subsequently undergoes a substitution reaction, a hydrolysis reaction, a ring-opening reaction, a deprotection reaction, and a complexation reaction to obtain the gadobutrol finished product.
[0011] The synthetic route of the present invention is as follows:
[0012]
[0013] The preparation method of the present invention comprises the following steps:
[0014] 1) Diethanolamine 1 is added with acetyl chloride to obtain intermediate 2;
[0015] 2) Add toluene, hydrochloric acid, and diethylenetriamine to intermediate 2 to obtain intermediate 3;
[0016] 3) Acetonitrile, potassium carbonate, and tert-butyl chloroacetate were added to intermediate 3 to obtain intermediate 4;
[0017] 4) Add water and NaOH to intermediate 4 to obtain intermediate 5;
[0018] 5) adding anhydrous ethanol to intermediate 5 to epoxide side chain to obtain intermediate 6;
[0019] 6) Add water, hydrochloric acid and gadolinium oxide to intermediate 6 to obtain gadobutrol I.
[0020] Preferably, the preparation method of the present invention comprises the following steps:
[0021] 1) Using methanol as solvent, diethanolamine was dissolved, and acetyl chloride was added dropwise to obtain intermediate 2;
[0022] 2) Intermediate 2 was treated with toluene as solvent, hydrochloric acid and diethylenetriamine were added, the temperature was raised to react, and the reaction was followed by extraction with water to obtain intermediate 3;
[0023] 3) Acetonitrile was used as solvent to treat intermediate 3, potassium carbonate was added, and tert-butyl chloroacetate was added dropwise to react. After the reaction, ether was added and the mixture was filtered to obtain intermediate 4;
[0024] 4) Intermediate 4 was treated with water as solvent, and NaOH was added to react, followed by dropwise addition of hydrochloric acid and filtration to obtain Intermediate 5;
[0025] 5) Intermediate 5 was treated with anhydrous ethanol as solvent, and epoxy side chain reaction was added. After the reaction, ether was added and filtered to obtain intermediate 6;
[0026] 6) Add water and hydrochloric acid to the intermediate 6, then add gadolinium oxide to react, add anhydrous ethanol after the reaction, filter and dry to obtain gadobutrol I.
[0027] More preferably, the preparation method of the present invention,
[0028] In step 1), the molar ratio of diethanolamine to acetyl chloride is 1:2-4. After the reaction, the temperature is lowered to 0-5° C. and filtered to obtain intermediate 2.
[0029] In step 2), the molar ratio of intermediate 2 to diethylenetriamine is 1:1, the reaction temperature is 70-90° C., the reaction is stopped, extracted with water, and concentrated to dryness to obtain intermediate 3.
[0030] In step 3), the molar ratio of intermediate 3 to tert-butyl chloroacetate is 1:2-4, the reaction temperature is 40-50° C., and tert-butyl chloroacetate is added dropwise.
[0031] In step 4), when NaOH is added to the intermediate 4, the temperature is controlled at 40-50°C.
[0032] In step 5), the intermediate 5 and the epoxy side chain are in equimolar amounts, and the reaction temperature is controlled at 60-70°C.
[0033] The molar ratio of intermediate 6 to gadolinium oxide in step 6) is 1:1. The temperature is controlled at 40-50°C when water and hydrochloric acid are added to the reaction, and at 60-70°C when gadolinium oxide is added.
[0034] The present invention discovered that during the preparation of acetylcycline intermediate 3, the carboxyl and hydroxyl groups are protonated during a strong acid-catalyzed oxidation reaction, forming an ionic intermediate with poor stability. The less stable ester group readily leaves and reacts with diethylenetriamine to form intermediate 3. The present invention discovered that the amino group attacks the carboxyl and hydroxyl groups of the ionic intermediate, easily breaking the CO bond and forming the corresponding product.
[0035] The present invention further found that the selection of temperature is very important for the preparation of the acetylcycline intermediate reaction. If the reaction temperature is too high, it will lead to a large number of reaction by-products, affecting the quality of the acetylcycline intermediate. If the reaction temperature is too low, the reaction activity will be affected, and the raw materials will hardly react completely. By screening the temperature, 70-90°C was determined to be the optimal temperature.
[0036] The present invention further found that in the hydrolysis reaction step, due to the large number of reaction sites, three ester groups and one amide need to be hydrolyzed, and the amount of base used is particularly important. If the amount of base used is small, the reaction rate is slow and the hydrolysis is likely to be incomplete. If the amount of base used is large, more by-products are produced, which affects the quality of the intermediate. By screening the type and amount of base, 4 equivalents of NaOH were determined to be the optimal condition.
[0037] Advantages of the technical solution of the present invention
[0038] 1. Using diethanolamine as the starting material, the raw material is easily available, cheap, and the cost is low;
[0039] 2. The post-processing method of the reaction is relatively simple. Only simple recrystallization or extraction operations are required to obtain the corresponding intermediates and finished products, and the requirements for production equipment are relatively low.
[0040] 3. Reaction impurities are lower than existing methods. The reaction route of the present invention involves the reaction of intermediate 3 with three molecules of tert-butyl chloroacetate, followed by hydrolysis to produce intermediate 5, which then reacts with the epoxy side chain. Therefore, compared to existing methods, no byproducts from the reaction with two molecules of epoxy side chains are generated. BRIEF DESCRIPTION OF THE DRAWINGS
[0041] Figure 1 Example 1 HPLC spectrum of gadobutrol. DETAILED DESCRIPTION
[0042] The present invention is further illustrated by the following examples, but is not intended to limit the present invention.
[0043] To this end, the inventors screened parameters such as the type, dosage, and addition method of the oxidation reaction acid, and ultimately obtained the present invention.
[0044] Example 1
[0045] 1) Add 50 ml of methanol to a 100 ml three-necked flask, then add 10.5 g (0.1 mol) of diethanolamine. Stir until completely dissolved. Control the temperature at 25°C and dropwise add 23.3 g (0.3 mol) of acetyl chloride. Stop the reaction when the diethanolamine concentration is ≤1%. Cool to 0-5°C and filter to obtain 18.9 g of intermediate 2.
[0046] 2) 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, along with 50 ml of toluene, 10 g of hydrochloric acid, and 8.2 g of diethylenetriamine. The reaction was heated to 80° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 20.3 g of intermediate 3 with an HPLC purity of 94.56%.
[0047] 3) 20.0 g (0.09 mol) of intermediate 3 was added to a 250 ml three-necked flask, along with 100 ml of acetonitrile and 18 g of potassium carbonate. The temperature was controlled at 45°C, and 36.0 g (0.27 mol) of tert-butyl chloroacetate was added dropwise. When the concentration of intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, the mixture was filtered, and the mixture was dried at 50°C to obtain 32.4 g of intermediate 4 with an HPLC purity of 95.88%.
[0048] 4) 30.0 g (0.06 mol) of intermediate 4 was added to a 250 ml three-necked flask, and 100 ml of water and 8 g of NaOH were added. The temperature was controlled at 45°C. When the concentration of intermediate 4 was ≤ 0.2%, the reaction was stopped, 20 mL of hydrochloric acid was slowly added dropwise, and 15.8 g of intermediate 5 was obtained by filtration.
[0049] 5) 15.0 g (0.05 mol) of intermediate 5 was added to a 250 ml three-necked flask, along with 60 ml of anhydrous ethanol and 13.4 g of epoxy side chain (0.05 mol). The temperature was controlled at 65°C. When the epoxy side chain concentration was ≤1%, the reaction was stopped, 150 ml of ether was added, and the mixture was filtered to obtain 22.8 g of intermediate 6.
[0050] 6) 22.0 g (0.04 mol) of intermediate 6 was added to a 250 ml three-necked flask, followed by 60 ml of water and 5.0 g of hydrochloric acid. The temperature was controlled at 45°C. When the concentration of intermediate 6 was ≤ 0.5%, the reaction was stopped. 14.5 g of gadolinium oxide was added and the temperature was controlled at 65°C. When the concentration of intermediate 7 was ≤ 0.1%, the temperature was lowered and 100 mL of anhydrous ethanol was added. The mixture was filtered and dried at 45°C to yield 12.8 g of gadobutrol with an HPLC purity of 100.00%.
[0051] Example 2
[0052] 1) Add 50 ml of methanol to a 100 ml three-necked flask, then add 10.5 g (0.1 mol) of diethanolamine. Stir until completely dissolved. Control the temperature at 25°C and dropwise add 23.3 g (0.3 mol) of acetyl chloride. Stop the reaction when the diethanolamine concentration is ≤1%. Cool to 0-5°C and filter to obtain 18.9 g of intermediate 2.
[0053] 2) 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, along with 50 ml of toluene, 10 g of sulfuric acid, and 8.2 g of diethylenetriamine. The reaction was heated to 80° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 12.5 g of intermediate 3 with an HPLC purity of 92.13%.
[0054] 3) 10.0 g (0.045 mol) of Intermediate 3 was added to a 100 ml three-necked flask, along with 50 ml of acetonitrile and 9 g of potassium carbonate. The temperature was maintained at 45°C, and 18.0 g (0.135 mol) of tert-butyl chloroacetate was added dropwise. When the concentration of Intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, the mixture was filtered, and the mixture was dried at 50°C to yield 20.2 g of Intermediate 4 with an HPLC purity of 90.24%.
[0055] 4) 15.0 g (0.03 mol) of intermediate 4 was added to a 100 ml three-necked flask, and 50 ml of water and 2 g of NaOH were added. The temperature was controlled at 45°C. When the concentration of intermediate 4 was ≤ 0.2%, the reaction was stopped, 20 mL of hydrochloric acid was slowly added dropwise, and 6.5 g of intermediate 5 was obtained by filtration.
[0056] 5) 6.0 g (0.02 mol) of intermediate 5 was added to a 100 ml three-necked flask, along with 24 ml of anhydrous ethanol and 5.4 g of epoxy side chain (0.02 mol). The temperature was controlled at 65°C. When the epoxy side chain concentration was ≤1%, the reaction was stopped, 60 ml of ether was added, and the mixture was filtered to obtain 9.2 g of intermediate 6.
[0057] 6) 9.0 g (0.017 mol) of intermediate 6 was added to a 100 ml three-necked flask, along with 25 ml of water and 2.1 g of hydrochloric acid. The temperature was controlled at 45°C. When the concentration of intermediate 6 was ≤ 0.5%, the reaction was stopped. 6.0 g of gadolinium oxide was added and the temperature was controlled at 65°C. When the concentration of intermediate 7 was ≤ 0.1%, the temperature was lowered and 42 mL of anhydrous ethanol was added. The mixture was filtered and dried at 45°C to yield 5.3 g of gadobutrol with an HPLC purity of 98.82%.
[0058] Example 3
[0059] 1) Add 50 ml of methanol to a 100 ml three-necked flask, then add 10.5 g (0.1 mol) of diethanolamine. Stir until completely dissolved. Control the temperature at 25°C and dropwise add 23.3 g (0.3 mol) of acetyl chloride. Stop the reaction when the diethanolamine concentration is ≤1%. Cool to 0-5°C and filter to obtain 18.9 g of intermediate 2.
[0060] 2) 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, along with 50 ml of toluene, 20 g of hydrochloric acid, and 8.2 g of diethylenetriamine. The reaction was heated to 80° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 13.8 g of intermediate 3 with an HPLC purity of 93.56%.
[0061] 3) 10.0 g (0.045 mol) of intermediate 3 was added to a 100 ml three-necked flask, along with 50 ml of acetonitrile and 9 g of potassium carbonate. The temperature was maintained at 45°C, and 18.0 g (0.135 mol) of tert-butyl chloroacetate was added dropwise. When the concentration of intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, the mixture was filtered, and the mixture was dried at 50°C to yield 20.2 g of intermediate 4 with an HPLC purity of 91.88%.
[0062] 4) 15.0 g (0.03 mol) of intermediate 4 was added to a 100 ml three-necked flask, and 50 ml of water and 12 g of NaOH were added. The temperature was controlled at 45°C. When the concentration of intermediate 4 was ≤ 0.2%, the reaction was stopped, 20 mL of hydrochloric acid was slowly added dropwise, and 8.2 g of intermediate 5 was obtained by filtration.
[0063] 5) 6.0 g (0.02 mol) of intermediate 5 was added to a 100 ml three-necked flask, along with 24 ml of anhydrous ethanol and 5.4 g of epoxy side chain (0.02 mol). The temperature was controlled at 65°C. When the epoxy side chain concentration was ≤1%, the reaction was stopped, 60 ml of ether was added, and the mixture was filtered to obtain 9.2 g of intermediate 6.
[0064] 6) 9.0 g (0.017 mol) of intermediate 6 was added to a 100 ml three-necked flask, along with 25 ml of water and 2.1 g of hydrochloric acid. The temperature was controlled at 45°C. When the concentration of intermediate 6 was ≤ 0.5%, the reaction was stopped. 6.0 g of gadolinium oxide was added and the temperature was controlled at 65°C. When the concentration of intermediate 7 was ≤ 0.1%, the temperature was lowered and 42 mL of anhydrous ethanol was added. The mixture was filtered and dried at 45°C to yield 5.6 g of gadobutrol with an HPLC purity of 98.75%.
[0065] Example 4
[0066] 1) Add 50 ml of methanol to a 100 ml three-necked flask, then add 10.5 g (0.1 mol) of diethanolamine. Stir until completely dissolved. Control the temperature at 25°C and dropwise add 23.3 g (0.3 mol) of acetyl chloride. Stop the reaction when the diethanolamine concentration is ≤1%. Cool to 0-5°C and filter to obtain 18.9 g of intermediate 2.
[0067] 2) 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, along with 50 ml of toluene, 10 g of hydrochloric acid, and 8.2 g of diethylenetriamine. The reaction was heated to 80° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 20.3 g of intermediate 3 with an HPLC purity of 94.56%.
[0068] 3) 20.0 g (0.09 mol) of intermediate 3 was added to a 250 ml three-necked flask, along with 100 ml of acetonitrile and 18 g of potassium carbonate. The temperature was controlled at 45°C, and 36.0 g (0.27 mol) of tert-butyl chloroacetate was added dropwise. When the concentration of intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, the mixture was filtered, and the mixture was dried at 50°C to obtain 32.4 g of intermediate 4 with an HPLC purity of 95.88%.
[0069] 4) 30.0 g (0.06 mol) of intermediate 4 was added to a 250 ml three-necked flask, and 100 ml of water and 14 g of KOH were added. The temperature was controlled at 45°C. When the concentration of intermediate 4 was ≤ 0.2%, the reaction was stopped, 20 mL of hydrochloric acid was slowly added dropwise, and the mixture was filtered to obtain 10.2 g of intermediate 5.
[0070] 5) 6.0 g (0.02 mol) of intermediate 5 was added to a 100 ml three-necked flask, along with 24 ml of anhydrous ethanol and 5.4 g of epoxy side chain (0.02 mol). The temperature was controlled at 65°C. When the epoxy side chain concentration was ≤1%, the reaction was stopped, 60 ml of ether was added, and the mixture was filtered to obtain 9.2 g of intermediate 6.
[0071] 6) 9.0 g (0.017 mol) of intermediate 6 was added to a 100 ml three-necked flask, along with 25 ml of water and 2.1 g of hydrochloric acid. The temperature was controlled at 45°C. When the concentration of intermediate 6 was ≤ 0.5%, the reaction was stopped. 6.0 g of gadolinium oxide was added and the temperature was controlled at 65°C. When the concentration of intermediate 7 was ≤ 0.1%, the temperature was lowered and 42 mL of anhydrous ethanol was added. The mixture was filtered and dried at 45°C to yield 5.0 g of gadobutrol with an HPLC purity of 99.11%.
[0072] Example 5
[0073] 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, and 50 ml of toluene, 5.2 g of trifluoroacetic acid, and 8.2 g of diethylenetriamine were added. The temperature was raised to 80° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 15.6 g of intermediate 3 with an HPLC purity of 84.31%.
[0074] Example 6
[0075] 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, and 50 ml of toluene, 5.8 g of acetic acid, and 8.2 g of diethylenetriamine were added. The temperature was raised to 80° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 16.8 g of intermediate 3 with an HPLC purity of 85.61%.
[0076] Example 7
[0077] 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, and 50 ml of toluene, 10 g of hydrochloric acid, and 8.2 g of diethylenetriamine were added. The temperature was raised to 60° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 15.1 g of intermediate 3 with an HPLC purity of 92.12%.
[0078] Example 8
[0079] 18.0 g (0.08 mol) of intermediate 2 was added to a 100 ml three-necked flask, and 50 ml of toluene, 10 g of hydrochloric acid, and 8.2 g of diethylenetriamine were added. The temperature was raised to 120° C. When the concentration of intermediate 2 was ≤ 0.5%, the reaction was stopped. 50 mL of water was added for extraction, and the mixture was concentrated to dryness to obtain 16.2 g of intermediate 3 with an HPLC purity of 70.52%.
[0080] Example 9
[0081] 30.0 g (0.06 mol) of intermediate 4 was added to a 250 ml three-necked flask, and 100 ml of water and 8 g of KOH were added. The temperature was controlled at 45°C. When the concentration of intermediate 4 was ≤ 0.2%, the reaction was stopped. 20 mL of hydrochloric acid was slowly added dropwise and filtered to obtain 12.6 g of intermediate 5.
[0082] Example 10
[0083] 20.0 g (0.09 mol) of Intermediate 3 was added to a 250 ml three-necked flask, along with 100 ml of acetonitrile and 18 g of potassium carbonate. The temperature was maintained at 45°C, and 52.7 g (0.27 mol) of tert-butyl bromoacetate was added dropwise. When the concentration of Intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, and the mixture was filtered and dried at 50°C to obtain 32.4 g of Intermediate 4 with an HPLC purity of 92.63%.
[0084] Example 11
[0085] 20.0 g (0.09 mol) of intermediate 3 was added to a 250 ml three-necked flask, along with 100 ml of acetonitrile and 18 g of potassium carbonate. The temperature was maintained at 45°C, and 25.5 g (0.27 mol) of chloroacetic acid was added dropwise. When the concentration of intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, and the mixture was filtered and dried at 50°C to obtain 10.6 g of intermediate 5 with an HPLC purity of 75.29%.
[0086] Example 12
[0087] 20.0 g (0.09 mol) of Intermediate 3 was added to a 250 ml three-necked flask, along with 100 ml of acetonitrile and 18 g of potassium carbonate. The temperature was maintained at 45°C, and 37.5 g (0.27 mol) of bromoacetic acid was added dropwise. When the concentration of Intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, and the mixture was filtered and dried at 50°C to obtain 9.56 g of Intermediate 5 with an HPLC purity of 75.88%.
[0088] Example 13
[0089] 20.0 g (0.09 mol) of intermediate 3 was added to a 250 ml three-necked flask, along with 100 ml of acetonitrile and 18 g of potassium carbonate. The temperature was controlled at 45°C, and 33.1 g (0.27 mol) of ethyl chloroacetate (CAS: 105-39-5) was added dropwise. When the concentration of intermediate 3 was ≤ 0.2%, the reaction was stopped, ether was added, the mixture was filtered, and the product was dried at 50°C to obtain 22.6 g of the product with an HPLC purity of 91.63%.
[0090] Example 14
[0091] Add 50 ml of methanol to a 100 ml three-necked flask, and add 10.5 g (0.1 mol) of diethanolamine. Stir until completely dissolved, control the temperature to 25°C, add 66.5 g (0.35 mol) of p-toluenesulfonyl chloride, and stop the reaction when the diethanolamine concentration is ≤1%. Cool to 0-5°C and filter to obtain 30.5 g of product. Add 17.0 g (0.05 mol) of the product to a 100 ml three-necked flask, add 50 ml of toluene, 10 g of hydrochloric acid, and 5.1 g of diethylenetriamine, heat to 80°C, stop the reaction when the starting material concentration is ≤0.5%, add 50 mL of water for extraction, and concentrate to dryness to obtain 5.6 g of intermediate 3 with an HPLC purity of 80.53%.
[0092] Example 15
[0093] 6.0 g (0.02 mol) of intermediate 5 was added to a 100 ml three-necked flask, followed by 24 ml of anhydrous ethanol and 2.9 g of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (0.02 mol). The temperature was controlled at 65°C. When the concentration of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane was ≤1%, the reaction was stopped, 60 ml of ether was added, and the product (5.1 g) was obtained by filtration with a yield of 52%.
[0094] 4.9 g (0.01 mol) of the above product was added to a 250 ml three-necked flask, followed by 30 ml of water and 2.5 g of hydrochloric acid. The reaction was controlled at 45°C. When the product concentration was ≤ 0.5%, the reaction was stopped. 7.25 g of gadolinium oxide was added and the temperature was controlled at 65°C. When the concentration of intermediate 7 was ≤ 0.1%, the temperature was lowered and 50 mL of anhydrous ethanol was added. The mixture was filtered and dried at 45°C to yield 2.56 g of gadobutrol with an HPLC purity of 98.69%.
Claims
1. A method for preparing gadobutrol, wherein the synthetic route is as follows:
2. The method according to claim 1, comprising the steps of: 1) Diethanolamine 1 is added with acetyl chloride to obtain intermediate 2; 2) Add toluene, hydrochloric acid, and diethylenetriamine to intermediate 2 to obtain intermediate 3; 3) Acetonitrile, potassium carbonate, and tert-butyl chloroacetate were added to intermediate 3 to obtain intermediate 4; 4) Add water and NaOH to intermediate 4 to obtain intermediate 5; 5) adding anhydrous ethanol to intermediate 5 to epoxide side chain to obtain intermediate 6; 6) Add water, hydrochloric acid and gadolinium oxide to intermediate 6 to obtain gadobutrol I.
3. The method according to claim 2, comprising the steps of: 1) Using methanol as solvent, diethanolamine was dissolved, and acetyl chloride was added dropwise to obtain intermediate 2; 2) Intermediate 2 was treated with toluene as solvent, hydrochloric acid and diethylenetriamine were added, the temperature was raised to react, and the reaction was followed by extraction with water to obtain intermediate 3; 3) Acetonitrile was used as solvent to treat intermediate 3, potassium carbonate was added, and tert-butyl chloroacetate was added dropwise to react. After the reaction, ether was added and the mixture was filtered to obtain intermediate 4; 4) Intermediate 4 was treated with water as solvent, and NaOH was added to react, followed by dropwise addition of hydrochloric acid and filtration to obtain Intermediate 5; 5) Intermediate 5 was treated with anhydrous ethanol as solvent, and epoxy side chain reaction was added. After the reaction, ether was added and filtered to obtain intermediate 6; 6) Add water and hydrochloric acid to the intermediate 6, then add gadolinium oxide to react, add anhydrous ethanol after the reaction, filter and dry to obtain gadobutrol I.
4. The method according to claim 3, wherein in step 1), the molar ratio of diethanolamine to acetyl chloride is 1:2-4, and after the reaction, the temperature is lowered to 0-5°C and filtered to obtain intermediate 2.
5. The method according to claim 3, wherein in step 2), the molar ratio of intermediate 2 to diethylenetriamine is 1:1, the reaction temperature is 70-90°C, and after stopping the reaction, the mixture is extracted with water and concentrated to dryness to obtain intermediate 3.
6. The method according to claim 3, wherein in step 3), the molar ratio of intermediate 3 to tert-butyl chloroacetate is 1:2-4, the reaction temperature is 40-50°C, and tert-butyl chloroacetate is added dropwise.
7. The method according to claim 3, wherein in step 4) when NaOH is added to the intermediate 4, the temperature is controlled at 40-50°C.
8. The method according to claim 3, wherein in step 5) the intermediate 5 and the epoxy side chain are equimolar, and the reaction temperature is controlled at 60-70°C.
9. The method according to claim 3, wherein the molar ratio of intermediate 6 to gadolinium oxide in step 6) is 1:
1. The temperature is controlled at 40-50°C when water and hydrochloric acid are added to the reaction, and at 60-70°C when gadolinium oxide is added.