Preparation method of imatinib dimer

Abstract

The invention provides a preparation method of an imatinib dimer. The method comprises the following steps: taking imatinib amine as a raw material, reacting the imatinib amine with a raw material 2 under an alkaline condition, and then reacting the imatinib amine with anhydrous piperazine under the alkaline condition to obtain the imatinib dimer. The preparation method has the advantages of short synthetic route, few types of used reagents, mild reaction conditions, simplicity and convenience in operation, and extremely simple treatment steps after the reaction is finished. The product obtained by the preparation method disclosed by the invention is high in purity and high in yield, and can meet the actual requirements of large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing an imatinib dimer. Background Art

[0002] Imatinib mesylate (trade name: Gleevec) is a first-in-class small molecule drug developed by Novartis Pharmaceuticals. It is a KIT inhibitor, PDGFR inhibitor and Bcr-Abl inhibitor. It was selected into the list of national essential medicines in 2002 and has a strong application market for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. High-purity impurity reference substances are crucial to the detection and supervision of drug safety and quality. In order to ensure the safety and quality of imatinib, in-depth research on its related impurities is required.

[0003] Imatinib dimer (CAS: 1365802-18-1), namely 4,4'-(piperazine-1,4-diylbis(methylene))bis(N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide), is one of the imatinib impurities in the EP standard, with the molecular formula C 52 H 48 N 12 O 2 , molecular weight is 873.02, and its chemical structure is as follows:

[0004] This impurity is a process impurity generated during the synthesis of imatinib. It has a complex molecular structure and is difficult to synthesize. Currently, two main methods for synthesizing this impurity have been reported.

[0005] Route 1:

[0006] This method (Wu Lihong, He Yuan, Zhang Yanqiao, et al. Synthesis of related substances of imatinib mesylate [J]. Chinese Journal of Pharmaceutical Industry, 2011, 42(10):4.) uses imatinib as a raw material, reacts with 4-chloromethylbenzoyl chloride under alkaline conditions to obtain intermediate 1, which is then reacted with piperazine to obtain intermediate 2. Then, under the action of anhydrous potassium carbonate, impurities 1 and 2 are reacted to obtain imatinib dimer. This method has a long process, low synthesis efficiency, and low product purity, which cannot meet the quantitative requirements of standard substances.

[0007] Route 2:

[0008] This method (CN105017222) uses methyl 4-chloromethylbenzoate as the starting material and prepares the key intermediate 1,4-bis(4-carboxybenzyl)piperazine (4) through a two-step reaction. The key intermediate 1,4-bis(4-carboxybenzyl)piperazine (4) is reacted with imatinib in the presence of N,N-diisopropylcarbodiimide, 1-hydroxybenzotriazole and N,N-diisopropylethylamine to obtain imatinib dimer. This method has a long route and a low yield (72.6% to 79.6%). The large number of reagents involved in the reaction is not conducive to post-processing and purification.

[0009] Therefore, the present invention provides a new preparation method, which has a short synthesis route, uses fewer types of reagents, has higher purity and yield of the obtained product, and is suitable for large-scale production. Summary of the invention

[0010] In order to overcome the deficiencies of the prior art, the present invention provides a method for preparing an imatinib dimer.

[0011] The invention provides a method for preparing an imatinib dimer. The method comprises taking imatinib as a raw material, firstly reacting with a raw material 2 under alkaline conditions to synthesize an intermediate 1, and then reacting with anhydrous piperazine under alkaline conditions to obtain the imatinib dimer.

[0012] The synthetic route is as follows:

[0013] in, R 1 Selected from: halogen, -O(C 1 -C 6 Alkyl), -OC(O)(C 1 -C 6 alkyl); R 2 For the leaving group.

[0014] In some embodiments of the present invention, R 1 It is a halogen, such as Cl, Br.

[0015] In some embodiments of the present invention, R 2 It is a halogen, such as F, Cl, Br, I.

[0016] Specifically, the preparation method comprises the following steps: 1) Imamidine is dissolved, and raw material 2 and an alkaline reagent are added to react to obtain intermediate 1; 2) The intermediate 1 is dissolved, and anhydrous piperazine and an alkaline reagent are added to react to obtain imatinib dimer.

[0017] Specifically, the raw material 2 is selected from: one or more of 4-chloromethylbenzoyl chloride, 4-bromomethylbenzoyl bromide, 4-bromomethylbenzoyl chloride, 4-fluorobenzoyl bromide, 4-fluorobenzoyl chloride, 4-iodomethylbenzoyl chloride or 4-iodomethylbenzoyl bromide.

[0018] Preferably, the reagent required for dissolving imamine is one or a combination of two or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethyltetrahydrofuran, and N-methylpyrrolidone.

[0019] Preferably, the alkaline reagent is selected from one or a combination of two or more of N,N-diisopropylethylamine, triethylamine, pyridine, tetramethylethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, and cesium acetate.

[0020] Preferably, the molar ratio of imamine to raw material 2 is 1:(1.1-2.0) (e.g., 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.0, etc.), and more preferably 1:(1.1-1.5).

[0021] Preferably, the reaction time of step 1) is 1 to 12 h (e.g., 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h or 12 h, etc.), more preferably 1 to 6 h.

[0022] Specifically, the step 1) is carried out in an ice bath, and the reaction temperature is 0-15°C (eg, 0°C, 3°C, 5°C, 7°C, 10°C, 13°C or 15°C, etc.).

[0023] Specifically, the step 1) further includes a post-processing step, and the post-processing step includes: crystallization, filtration, pulping, and drying.

[0024] Preferably, the reagent required to dissolve the intermediate 1 is one or a combination of two or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, and water, and dimethyl sulfoxide is more preferred.

[0025] Preferably, the molar ratio of intermediate 1 to anhydrous piperazine is 1.9 to 2.2:1, such as 1.9:1, 2.0:1, 2.1:1 or 2.2:1, and more preferably 2.0:1.

[0026] Preferably, the molar ratio of intermediate 1 to the alkaline agent is 0.3-2.0:1, for example, 0.3:1, 0.5:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2.0:1, and more preferably 0.5-1.5:1.

[0027] Specifically, the order of adding materials in step 2) is to first add the intermediate 1, then add the alkaline reagent, and then add anhydrous piperazine.

[0028] Preferably, the reaction temperature in step 2) is 20-100°C (e.g., 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C), more preferably 40-70°C, and even more preferably 50-60°C.

[0029] Preferably, the reaction time of step 2) is 2 to 48 h (e.g., 2 h, 4 h, 5 h, 7 h, 9 h, 11 h, 13 h, 15 h, 18 h, 20 h, 24 h, 28 h, 32 h, 36 h, 40 h, 44 h or 48 h, etc.), more preferably 3 to 24 h, and even more preferably 4 to 16 h.

[0030] Specifically, the step 2) further includes a post-processing step, and the post-processing step includes: crystallization, filtration, pulping, and drying.

[0031] Specifically, the crystallization operation is: pouring the reaction system into ice water to precipitate solids to obtain a crude solid product of imatinib dimer.

[0032] In one embodiment of the present invention, the preparation method is: 1) Using imamidine as a raw material, reacting with 4-chloromethylbenzoyl chloride under alkaline conditions, crystallizing, and beating to obtain intermediate 1; 2) Intermediate 1 reacts with anhydrous piperazine under alkaline conditions. After the reaction is completed, the reaction solution is poured into crushed ice to precipitate solids, which are then slurried with methanol, filtered and dried to obtain imatinib dimer.

[0033] The beneficial effects of the present invention are as follows: the preparation method of the present invention has a short synthetic route, few types of reagents used, extremely high atom economy, and greatly improved resource utilization efficiency. The reaction conditions are mild, the operation process is simple, and the processing steps after the reaction are also extremely simple, abandoning the cumbersome column purification operation in the traditional process, which not only shortens the time cost, but also avoids the product loss that may be caused by the complex purification process. The product obtained by the preparation method of the present invention has high purity and high yield, which is very consistent with the needs of amplified production and can meet the actual requirements of large-scale industrial production. The synthesized imatinib dimer can provide a material basis for the qualitative and quantitative analysis of impurities in imatinib to improve the drug safety and quality control of imatinib. DETAILED DESCRIPTION

[0034] In the present invention, the CAS of imatinib dimer is 1365802-18-1, and its chemical structure is as follows: , sometimes also referred to as imatinib impurity E.

[0035] In the present invention, the CAS number of imamide is 152460-10-1, and its chemical structure is as follows: .

[0036] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophilic reagent, for example, see Smith, March Advanced Organic Chemistry 6th edition. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br or I), alkanesulfonyloxy, arylsulfonyloxy, etc.

[0037] As used herein, "treating" means slowing, interrupting, preventing, controlling, stopping, alleviating, or reversing the progression or severity of a sign, symptom, disorder, condition, or disease after the disease has begun to develop, but does not necessarily involve the complete elimination of all disease-related signs, symptoms, conditions, or disorders.

[0038] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only some embodiments of the present invention, not all. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] Reagents used in the examples: imamide (source: Beijing Coupling Technology Co., Ltd.), 4-chloromethylbenzoyl chloride (source: Beijing Coupling Technology Co., Ltd.), anhydrous piperazine (source: Beijing Coupling Technology Co., Ltd.).

[0040] The instruments used in the examples are as follows: the mass spectrometer is a ThermoExacive Plus (ESI) high-resolution liquid-mass spectrometer, and the nuclear magnetic resonance is a Bruker AVANCE NEO 600 nuclear magnetic resonance spectrometer.

[0041] The method for preparing the imatinib dimer of the present invention has the following synthetic route:

[0042] Example 1

[0043] Step 1

[0044] 4-(Chloromethyl)-N-(4-methyl-3-)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide

[0045] 30 g of imamidine was dissolved in 300 mL of tetrahydrofuran, and 30 mL of triethylamine was added under stirring in an ice-water bath. After mixing and stirring for 15 minutes, 25 g of 4-chloromethylbenzoyl chloride in tetrahydrofuran (50 mL) solution (raw material 2) was added dropwise to the reaction flask. After the addition was completed, the mixture was stirred for 3 hours at room temperature, and then 600 mL of water was added to the reaction system to precipitate solids, which were filtered and dried to obtain a crude intermediate 1'. The crude product was refluxed with ethyl acetate, cooled to room temperature, and filtered and dried to obtain 45.8 g of a light yellow solid intermediate 1' with a molar yield of 98.5%. The next step reaction was directly carried out without further purification.

[0046] Example 2

[0047] Step 2 4,4'-(piperazine-1,4-diylbis(methylene))bis(N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide) Solution 1 8.6 g of intermediate 1' and 0.86 g of anhydrous piperazine were dissolved in 100 mL of dimethyl sulfoxide, 2.1 mL of triethylamine was added under stirring at room temperature, the temperature was raised to 60°C for reaction for 24 hours, cooled to room temperature, the reaction solution was poured into crushed ice to precipitate solids, and filtered and dried to obtain crude imatinib dimer. The crude product was slurried with methanol, filtered and dried to obtain 7.4 g of imatinib dimer (purity: 98.6%), with a molar yield of 84.8%.

[0048] Solution 2 8.6g of intermediate 1' and 0.86g of anhydrous piperazine were dissolved in 100mL of dimethyl sulfoxide, and 2.6mL of N,N-diisopropylethylamine was added under stirring at room temperature, and the temperature was raised to 50°C for reaction for 5 hours, and then cooled to room temperature. The reaction solution was poured into crushed ice to precipitate solids, which were filtered and dried to obtain crude imatinib dimer. The crude product was slurried with methanol, filtered and dried to obtain 7.7g of imatinib dimer (purity: 98.2%), with a molar yield of 88.2%. Its structure was identified, and the specific results are as follows: HR-MS(ESI)Calcd. For : C 52 H 49 N 12 O 2 :[M+H] + , 873.4023. Found: m / z 873.4057. 1 H NMR (600 MHz, DMSO) δ 10.16 (s, 2H), 9.27 (dd, J=0.6, 2.4, 2H), 8.97 (s, 2H), 8.68 (dd, J=1.8, 4.8, 2H), 8.50 (d, J=5.4, 2H), 8.47 (m, 2H),8.08 (d, J=2.4, 2H), 7.90 (d, J=8.4, 4H), 7.52-7.50 (m, 2H), 7.48-7.46 (dd, J=2.4, 8.4, 2H), 7.43-7.41 (m, 6H), 7.20 (d, J=8.4, 2H), 3.54 (s, 4H), 2.48-2.32 (m, 8H), 2.22 (s, 6H). 13 C NMR (151 MHz, DMSO) δ 165.31, 161.63, 161.21, 159.51, 151.41,148.22, 142.06, 137.82, 137.22, 134.46, 133.80, 132.24, 130.07, 128.66,127.64, 127.61, 123.83, 117.24, 116.77, 107.55, 61.62, 52.66, 17.69.

[0049] Comparative Example 1 Step 1 Adjustment of the equivalent of raw material 2 Dissolve 30g of imamamine in 300mL of tetrahydrofuran, add 30mL of triethylamine under stirring in an ice-water bath, mix and stir for 15 minutes, then drop 20g of 4-chloromethylbenzoyl chloride (raw material 2) in tetrahydrofuran (50mL) into the reaction flask, and stir for 4 hours after the addition, then add 600mL of water to the reaction system to precipitate solids, filter and dry to obtain a crude intermediate 1'. Due to the high content of impurities in the crude product, the crude product was separated and purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:30→1:10) to obtain 29.8g of off-white solid intermediate 1', with a molar yield of 64.2%.

[0050] During the reaction, when the amount of 4-chloromethylbenzoyl chloride used in the reaction is 0.98 eq, imamine cannot fully react, resulting in the generation of a large amount of impurities. The obtained product needs to be purified by column chromatography to obtain an intermediate that meets the purity requirements for subsequent reactions. Column chromatography not only increases economic and time costs, but is also not conducive to the research and development of subsequent reaction scale-up production.

[0051] Comparative Example 2 Step 2 Adjustment of the order of adding materials 8.6 g of intermediate 1' and 3.0 mL of triethylamine were added to 100 mL of N,N-dimethylformamide, heated to 50°C and stirred to dissolve, then 0.86 g of anhydrous piperazine was added, and the mixture was stirred and reacted for 24 hours at a temperature of 100°C. The mixture was cooled to room temperature, and the reaction solution was poured into crushed ice to precipitate solids, which were filtered and dried to obtain crude imatinib dimer. The crude product was slurried with methanol, filtered and dried to obtain 6.3 g of imatinib dimer (purity: 92.2%), with a molar yield of 72.7%.

[0052] Comparative Example 3 Step 2 Adjustment of anhydrous piperazine equivalent 8.6 g of intermediate 1' and 0.95 g of anhydrous piperazine were dissolved in 100 mL of dimethyl sulfoxide, 2.1 mL of triethylamine was added under stirring at room temperature, the temperature was raised to 60°C for reaction for 24 hours, cooled to room temperature, the reaction solution was poured into crushed ice to precipitate solids, and the solids were filtered and dried to obtain crude imatinib dimer. The crude product was slurried with methanol, filtered and dried to obtain 8.4 g of imatinib dimer (purity: 82.7%).

[0053] In summary, when the molar ratio of intermediate 1' to piperazine is 1.8:1, even after separation and purification, the purity of the obtained product is poor; in addition, the change of the order of adding piperazine will also affect the reaction, thereby reducing the purity and yield of the product.

[0054] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0055] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing an imatinib dimer, characterized in that: The preparation method uses imatinib as a raw material, first reacts with raw material 2 under alkaline conditions to synthesize intermediate 1, and then reacts with anhydrous piperazine under alkaline conditions to obtain imatinib dimer; The synthetic route is as follows: in, R1 is selected from: halogen, -O(C1-C6 alkyl), -OC(O)(C1-C6 alkyl); R2 is a leaving group; The molar ratio of the imamine to the raw material 2 is 1:(1.1-2.0); The molar ratio of the intermediate 1 to anhydrous piperazine is 1.9-2.2:

1.

2. The preparation method according to claim 1, characterized in that: The raw material 2 is selected from: one or more of 4-chloromethylbenzoyl chloride, 4-bromomethylbenzoyl bromide, 4-bromomethylbenzoyl chloride, 4-fluorobenzoyl bromide, 4-fluorobenzoyl chloride, 4-iodomethylbenzoyl chloride or 4-iodomethylbenzoyl bromide.

3. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: 1) Imamidine is dissolved, and raw material 2 and an alkaline reagent are added to react to obtain intermediate 1; 2) The intermediate 1 is dissolved, and anhydrous piperazine and an alkaline reagent are added to react to obtain imatinib dimer.

4. The preparation method according to claim 3, characterized in that: The alkaline reagent is selected from one or a combination of two or more of N,N-diisopropylethylamine, triethylamine, pyridine, tetramethylethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, and cesium acetate.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the imamine to the raw material 2 is 1:(1.1-1.5).

6. The preparation method according to claim 3, characterized in that: The reaction time of step 1) is 1-12 hours, the reaction of step 1) is carried out in an ice bath, and the reaction temperature is 0-15°C.

7. The preparation method according to claim 3, characterized in that: The reagents required for dissolving the intermediate 1 are one or a combination of two or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, and water.

8. The preparation method according to claim 1, characterized in that: The molar ratio of the intermediate 1 to anhydrous piperazine is 2.0:

1.

9. The preparation method according to claim 3, characterized in that: The reaction temperature of step 2) is 20-100°C, and the reaction time of step 2) is 2-48h.

10. The preparation method according to claim 3, characterized in that: The order of adding materials in step 2) is to first add intermediate 1, then add the alkaline reagent, and then add anhydrous piperazine.

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