Preparation method of ibrutinib and intermediate thereof
Through the new ibrutinib intermediate preparation method, the reaction of Compound II, ester solvent, malonitrile and alkaline substances is used to form Compound III that can be directly used for the next reaction, solving the yield in the prior art Low and complex steps problems achieve efficient irbutinib intermediate synthesis and simplified production processes.
Patent Information
- Application Number
- CN202411226791.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-03
- Publication Date
- 2024-12-10
AI Technical Summary
The yield of existing ibrutinib synthesis intermediates is low, resulting in the inability to effectively improve the total pyrutinib synthesis yield of the total product ibrutinib, and the synthesis steps are complex and require complex filtration and purification treatment.
Using the new ibrutinib intermediate preparation method, the reaction solution of compound III is formed by mixing compound II, ester solvent, malonitrile and alkaline substances, and reacting with dimethyl sulfate under specific conditions. Direct synthesis of ibrutinib intermediates simplifies the synthesis steps and avoids complex purification treatments.
The yield of ibrutinib intermediates is greatly improved, the synthesis steps are simplified, production costs are saved, and the high yield and purity of the product is ensured through specific conditions and the selection of reactants.
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Figure CN119100947A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of compound preparation, and in particular to a method for preparing ibrutinib and its intermediates. Background Art
[0002] Ibrutinib is a small molecule BTK (Bruton's tyrosine kinase) inhibitor. Ibrutinib forms a covalent bond with the cysteine residue in the active site of BTK, thereby inhibiting the enzymatic activity of BTK. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. BTK activates pathways necessary for B cell migration, chemotaxis, and adhesion through B cell surface receptor signaling. Nonclinical study results showed that ibrutinib inhibited the proliferation and survival of malignant B cells in vivo, as well as cell migration and substrate adhesion in vitro.
[0003] In the prior art, ibrutinib is generally synthesized chemically, and the intermediate shown in the following structural formula is an important compound for synthesizing ibrutinib:
[0004] The synthesis yield of the compound in the prior art is low, which results in that the total synthesis yield of the total product ibrutinib cannot be effectively improved.
[0005] In view of this, the present invention is proposed. Summary of the invention
[0006] The object of the present invention is to provide a method for preparing ibrutinib and its intermediates. The embodiment of the present invention provides a new method for preparing an ibrutinib intermediate, which greatly improves the yield of the intermediate, and the reaction solution of the formed compound III can be directly used in the next step of reaction to directly synthesize the intermediate without the need for complex filtering, purification and other steps, thereby simplifying the synthesis steps of the intermediate.
[0007] The present invention is achieved in that:
[0008] In a first aspect, the present invention provides a method for preparing an ibrutinib intermediate, comprising: mixing compound II, an ester solvent, malononitrile and an alkaline substance for reaction;
[0009] After the reaction is completed, the reaction system containing compound III is mixed with an ester solvent, dimethyl sulfate and an alkaline material to react to form an ibrutinib intermediate;
[0010] Wherein, the alkaline material is selected from carbonate or bicarbonate, and the alkaline material and the alkaline substance adopt different bases;
[0011] The structural formula of the compound II is The structural formula of the compound III is: The structural formula of the ibrutinib intermediate is
[0012] In an optional embodiment, the step of forming compound II comprises: mixing compound I with an acyl chloride compound for reaction, wherein the structural formula of compound I is:
[0013] In an optional embodiment, the method comprises: mixing the compound II, the ester solvent and the malononitrile to form a reaction solution 1;
[0014] The alkaline substance is mixed with the ester solvent, and cooled to form a reaction solution 2,
[0015] The reaction solution 2 is added to the reaction solution 1, and the mixture is reacted at 15-30° C. for 1.5-2 hours.
[0016] In an optional embodiment, after the reaction is completed, the reaction system containing compound III is subjected to a simple post-treatment;
[0017] Preferably, the simple post-treatment comprises: washing the reaction system with an acid solution, and then drying.
[0018] In an optional embodiment, the molar ratio of the malononitrile to the compound I is 1-1.2:0.93;
[0019] The molar ratio of the alkaline substance to the compound I is 2-5:0.93;
[0020] Preferably, the alkaline substance is selected from amine substances or hydroxides.
[0021] In an optional embodiment, under an inert gas atmosphere, a reaction system containing compound III, the alkaline material and an ester solvent are mixed at 40-60° C., dimethyl sulfate is added, and the mixture is reacted at 55-80° C. for 5-6 hours.
[0022] In an optional embodiment, the molar ratio of the alkaline material to the compound I is 2-6:0.93;
[0023] The molar ratio of the dimethyl sulfate to the compound I is 1.5-2:0.93.
[0024] In an optional embodiment, the ester solvent is selected from an ethyl ester solvent or a propyl ester solvent;
[0025] Any one of ethyl acetate, ethyl formate, ethyl propionate and isopropyl acetate is preferred.
[0026] In an optional embodiment, the reaction system for forming the ibrutinib intermediate is post-treated;
[0027] The post-treatment includes: cooling the reaction solution after the reaction is completed, adjusting the pH, separating the liquids, extracting the aqueous phase and collecting the organic phase, and then drying and concentrating, and crystallizing the concentrate using isopropanol.
[0028] In a second aspect, the present invention provides a method for preparing ibrutinib, which comprises the method for preparing the ibrutinib intermediate described in any one of the aforementioned embodiments.
[0029] The present invention has the following beneficial effects: the embodiment of the present invention can greatly improve the yield of the ibrutinib intermediate by adopting a synthetic route and specific synthetic conditions. At the same time, the reaction system of compound III formed by the synthetic method does not need to be subjected to complicated post-processing purification, and can directly react with dimethyl sulfate to form the ibrutinib intermediate, thereby simplifying the synthesis steps of the ibrutinib intermediate and saving production costs. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.
[0031] Figure 1 The high-liquid spectrogram of compound III provided in Example 1;
[0032] Figure 2 The high-liquid spectrogram of compound IV provided in Example 1;
[0033] Figure 3 This is the high liquid spectrum of the concentrate of Comparative Example 3;
[0034] Figure 4 This is the high liquid spectrum of the concentrate of Comparative Example 4;
[0035] Figure 5 This is the high liquid spectrum of the concentrate of Comparative Example 5;
[0036] Figure 6 The high-liquid spectrogram of compound III provided in Comparative Example 7;
[0037] Figure 7 This is the high-liquid spectra of compound IV provided in Comparative Example 8. DETAILED DESCRIPTION
[0038] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.
[0039] The preparation method of the ibrutinib intermediate is as follows, and the synthesis is performed according to the following synthesis route:
[0040]
[0041] The prior art is that 4-phenoxybenzoic acid (I) reacts with thionyl chloride to obtain 4-phenoxybenzoyl chloride (II).
[0042] Then, compound II is reacted with malononitrile using toluene / tetrahydrofuran or acetone / water as solvent, and pure compound III is obtained through separation and purification.
[0043] Compound III is subjected to the next methylation reaction with dioxane / water as solvent to obtain compound IV. The yield of the product compound IV obtained by this synthesis method, i.e., the intermediate of Ibrutinib, is low. When compound III is formed, it must be subjected to complex purification before it can be used to synthesize compound IV. Therefore, it needs to be improved. Therefore, an embodiment of the present invention provides a new method for preparing an intermediate of Ibrutinib.
[0044] Specifically, S1, synthesizing compound II;
[0045] Compound I is mixed with an acyl chloride compound for reaction, wherein the structural formula of compound I is: Specifically, compound I4-phenoxybenzoic acid is mixed with a solvent (such as toluene) and an acyl chloride compound (such as thionyl chloride) and stirred for reaction at 70-80°C. After the reaction is completed, the acyl chloride compound and the solvent are removed by concentration under reduced pressure to obtain an oily compound II.
[0046] S2, synthesis of compound III;
[0047] The oily compound II, the ester solvent, malononitrile and the alkaline substance are mixed to react; specifically, the compound II, the ester solvent and the malononitrile are mixed to form a reaction solution 1,
[0048] The alkaline substance is mixed with the ester solvent, and cooled to form a reaction solution 2,
[0049] Then, the reaction solution 2 is added into the reaction solution 1, and the mixture is reacted at 15-30° C. for 1.5-2 hours.
[0050] The molar ratio of malononitrile to the compound I is 1-1.2:0.93; the molar ratio of the alkaline substance to the compound I is 2-5:0.93. The alkaline substance is selected from amine substances or hydroxides, such as but not limited to N, N-diisopropylethylamine, triethylamine and sodium hydroxide.
[0051] After the reaction is completed, the reaction system containing compound III is subjected to simple post-treatment; for example, the reaction system is washed with an acid solution (such as an aqueous sulfuric acid solution), and then the organic phase (pH = 1-1.5) is mixed and dried with a desiccant (such as anhydrous sodium sulfate), and then the desiccant is filtered, and the obtained filtrate can be directly used in the next reaction.
[0052] The present invention adopts the above reaction steps, and after the reaction is completed, it can basically be directly used for the next synthesis reaction without the need for complex purification treatment.
[0053] S3, synthesizing the intermediate of ibrutinib, namely compound IV;
[0054] The reaction system containing the compound III is mixed with an ester solvent, dimethyl sulfate and an alkaline material for reaction. Specifically, an alkaline material and an ester solvent are added to a reaction bottle, and the temperature is raised to 40-60° C. under the protection of an inert gas (such as nitrogen), and the reaction system containing the compound III is added to the reaction bottle under temperature control, and after the addition is complete, dimethyl sulfate is added (for example, dimethyl sulfate is added at 60-70° C.), and then the reaction is carried out at 55-80° C. for 5-6 hours.
[0055] The alkaline material is selected from carbonate or bicarbonate. If the alkaline material is changed, the yield and purity of the final product compound IV may be significantly reduced, and the reaction may not proceed. However, the use of the alkaline material can ensure the yield and purity of the final product.
[0056] Furthermore, the molar ratio of the alkaline material to the compound I is 2-6:0.93; the molar ratio of the dimethyl sulfate to the compound I is 1.5-2:0.93. The ester solvent is selected from ethyl ester solvents or propyl ester solvents; preferably any one of ethyl acetate, ethyl formate, ethyl propionate and isopropyl acetate.
[0057] After the reaction is completed, post-treatment is performed. Specifically, the post-treatment includes: cooling the reaction solution to 30-40°C, adding water, continuing to cool to below 30°C, and controlling the temperature to below 30°C, then dropping an acid solution to adjust the pH to 6.0-7.0, standing for separation, and collecting the aqueous phase. The aqueous phase is extracted with an ester solvent (such as ethyl acetate), the organic phase is collected, and then mixed and dried with a desiccant, the desiccant is removed, and the solvent in the organic phase is removed by reduced pressure concentration to form a concentrate. The concentrate is mixed with isopropanol, heated and dissolved, and then cooled for crystallization, filtered, and the filter cake is dried to obtain the final product.
[0058] The embodiment of the present invention adopts isopropanol for crystallization purification, which can further improve the yield and purity of the product.
[0059] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.
[0060] Example 1
[0061] An embodiment of the present invention provides a method for preparing an ibrutinib intermediate, comprising:
[0062] The synthesis was carried out according to the following synthesis route:
[0063]
[0064] S1, synthesis of compound II;
[0065] 4-Phenoxybenzoic acid (200 g, 0.93 mol) was suspended in toluene (800 ml), and then thionyl chloride (167 g, 1.4 mol) was added and the suspension was stirred at 70-80° C. The thionyl chloride and toluene were removed by concentration under reduced pressure to obtain an oily compound II, which was directly used for the next step reaction.
[0066] S2, synthetic compound III;
[0067] Add 600 ml of ethyl acetate and 68 g (1.03 mol) of malononitrile to the reaction bottle of the oily compound II, dissolve to form reaction solution 1, and set aside. Add 301.7 g (2.33 mol) of N, N-diisopropylethylamine (DIPEA) and 400 ml of ethyl acetate to the reaction bottle, cool to 10°C to form reaction solution 2, add reaction solution 1 dropwise to reaction solution 2 at 10-20°C, heat to 25°C after addition, and react for 1.5 hours, and the reaction is complete.
[0068] Wash with 2*100ml 14.7% (m / m) sulfuric acid aqueous solution, dry the organic phase (pH=1-1.5) with anhydrous sodium sulfate, filter to remove the desiccant, and rinse the filter cake with ethyl acetate. The filtrate obtained is an ethyl acetate solution containing compound III, with a liquid phase purity of 98% (excluding solvent), and is directly used in the next step of reaction. Its high-performance liquid chromatography is shown in Figure 1 .
[0069] S3, synthesis of compound IV;
[0070] Add 350g (4.2mol) of sodium bicarbonate and 360ml of ethyl acetate to the reaction flask, raise the temperature to 50°C under nitrogen protection, and add the above-mentioned ethyl acetate solution containing compound III to the reaction flask at a temperature of 50°C. After the addition is completed, continue to raise the temperature to 65°C, and add 235.5g (1.87mol) of dimethyl sulfate at a temperature of 65°C. After the addition is completed, raise the temperature to 75°C and react for 5 hours. The reaction is completed.
[0071] The reaction solution was cooled to 30°C, 800ml of water was added, and the temperature was further cooled to below 30°C. 18% hydrochloric acid solution was added dropwise to the reaction solution at a temperature below 30°C, and the pH was adjusted to 6.0. The solution was allowed to stand for separation, and the aqueous phase was extracted once with 360ml of ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate for 2 hours. The solution was filtered and the filtrate was concentrated to dryness under reduced pressure. 950ml of isopropanol was added to the concentrate, the temperature was raised to 45°C and stirred until all dissolved. The temperature was lowered to 5°C and the stirring was continued for 1 hour. The filter cake was dried at 40°C to obtain 226g of brown-yellow solid, with a yield of 87.9% (based on 4-phenoxybenzoic acid) and a HPLC purity of 100%. The HPLC spectrum is shown in Figure 2 .
[0072] The characterization data of compound IV are as follows: 1 H-NMR (400MHz, DMSO-d6) δ: 3.93 (s, 3H), 7.12-7.17 (m, 4H), 7.24-7.29 (m, 1H), 7.45-7.50 (m, 2H), 7.68-7.72 (m, 2H).
[0073] Embodiment 2-8
[0074] Examples 2-8 all provide a method for preparing an ibrutinib intermediate, which is basically the same as the method for preparing an ibrutinib intermediate provided in Example 1, except that the base in step S2 is different. The specific conditions are as follows:
[0075] Alkali Feeding amount / mol Reaction temperature Reaction time Yield (IV) purity(%) Example 2 DIPEA 180g / 1.39mol 25℃ 2h 211g / 82.1 100 Example 3 DIPEA 480g / 3.7mol 25℃ 2h 223.2g / 86.8 100 Example 4 DIPEA 600g / 4.6mol 25℃ 2h 221g / 86.0 100 Example 5 DIPEA 301.7g / 2.33mol 15℃ 2h 221g / 86.0 100 Example 6 DIPEA 301.7g / 2.33mol 35℃ 1.5h 218.9g / 85.2 100 Example 7 Triethylamine 235g / 2.33mol 25℃ 2h 223.8g / 87.1 100 Example 8 Sodium hydroxide 93.2g / 2.33mol 25℃ 2h 223.2g / 86.8 100
[0076] Examples 9-14 and Comparative Examples 1-5
[0077] Examples 9-14 and Comparative Examples 1-5 all provide a method for preparing an ibrutinib intermediate, which is basically the same as the method for preparing an ibrutinib intermediate provided in Example 1, except that the base in step S3 is different, and the specific conditions are as follows:
[0078]
[0079]
[0080] Explanation of the above table a: Sodium tert-butoxide, sodium hydroxide or potassium hydroxide is used as a base, the filtrate is concentrated to dryness under reduced pressure, 950 ml of isopropanol is added to the concentrate, the temperature is raised to 45-50°C and stirred until all dissolved, the temperature is lowered to 0-10°C and stirred for 1 hour, no solid is precipitated, and the concentrate is concentrated to dryness, and still no solid is precipitated. The liquid phase diagram of the obtained concentrate is shown in Figures 3 to 5 ,in, Figure 3 This is the high liquid spectrum of the concentrate of Comparative Example 3; Figure 4 This is the high liquid spectrum of the concentrate of Comparative Example 4; Figure 5 This is the high-liquid spectrum of the concentrate of Comparative Example 5.
[0081] It can be seen that changing the selection of the alkaline material may result in a decrease in the yield or purity of the product, or even may cause the reaction to fail.
[0082] Comparative Example 6
[0083] This comparative example provides a method for preparing compound III, comprising:
[0084] According to Example 1, compound II was synthesized. 500 ml of toluene, 90 ml of tetrahydrofuran and 68 g (1.03 mol) of malononitrile were added to a reaction bottle containing 0.93 mol of oily compound II to dissolve and form reaction solution 1 for standby use. 301.7 g (2.33 mol) of N,N-diisopropylethylamine (DIPEA) and 350 ml of toluene were added to the reaction bottle, and the temperature was lowered to 10-20°C to form reaction solution 2. The reaction solution 1 was added dropwise to the reaction solution 2 at 10-20°C. After the addition was completed, the temperature was raised to 20-30°C and the reaction was carried out for 1.5-2 hours. The reaction was completed.
[0085] The amine salt was removed by filtration, and the filtrate was concentrated under reduced pressure. 800 ml of ethyl acetate was added to the residue, and the mixture was washed with 2*100 ml of 14.7% (m / m) aqueous sulfuric acid solution. The organic phase was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The mixture was concentrated under reduced pressure and refrigerated for crystallization to obtain 210.9 g of solid with a yield of 86.1% and a purity of 99.6%.
[0086] Comparative Example 7
[0087] This comparative example provides a method for preparing compound III, comprising:
[0088] Add 500 ml of acetone and 68 g (1.03 mol) of malononitrile to a reaction bottle containing 0.93 mol of oily compound II, stir and dissolve at 10°C, drop 200 ml of 40% sodium hydroxide aqueous solution into the reaction bottle, heat to 20-30°C and react for 1.5-2 hours after the addition is complete. Pour the reaction mixture into water and adjust the pH to 1.5 with 10-12% hydrochloric acid to form a precipitate, filter and obtain 206 g of solid, with a yield of 84.2% and a purity of 97.03%. See the high-performance liquid chromatography for details. Figure 6 .
[0089] According to Comparative Examples 6 and 7, the yield of compound III obtained by using toluene or acetone as solvent is not much different, and the intermediate obtained by using acetone as solvent has poor purity.
[0090] Therefore, the compound III obtained in Comparative Example 6 was used for the reaction of Comparative Example 8 below.
[0091] Comparative Example 8
[0092] 70ml of dioxane, 11ml of water, 11g (0.04mol) of intermediate (Compound III, prepared in Comparative Example 6) and 28g (0.33mol) of sodium bicarbonate were put into a reaction bottle, 38g (0.3mol) of dimethyl sulfate was added dropwise under vigorous stirring, and the reaction was carried out under reflux for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 15ml of water was added, and 3*50ml of ethyl acetate was used for extraction, and the solution was dried over anhydrous magnesium sulfate for 2 hours. Filter, and the filtrate was concentrated under reduced pressure. The concentrate was recrystallized from ethanol to obtain 6.3g of brown-yellow solid, with a final yield of 54.3% (based on 4-phenoxybenzoic acid) and a purity of 99.21%. Its high-liquid spectrum can be found at Figure 7 .
[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing an ibrutinib intermediate, characterized in that: The method comprises: mixing compound II, an ester solvent, malononitrile and an alkaline substance to react; After the reaction is completed, the reaction system containing compound III is mixed with an ester solvent, dimethyl sulfate and an alkaline material to react to form an ibrutinib intermediate; Wherein, the alkaline material is selected from carbonate or bicarbonate, The structural formula of the compound II is The structural formula of the compound III is: The structural formula of the ibrutinib intermediate is 2. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: The step of forming compound II comprises: mixing compound I with an acyl chloride compound for reaction, wherein the structural formula of compound I is:
3. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: include: The compound II, the ester solvent and the malononitrile are mixed to form a reaction solution 1, The alkaline substance is mixed with the ester solvent, and cooled to form a reaction solution 2, The reaction solution 2 is added to the reaction solution 1, and the mixture is reacted at 15-30° C. for 1.5-2 hours.
4. The method for preparing an ibrutinib intermediate according to claim 3, characterized in that: After the reaction is completed, the reaction system containing compound III is subjected to simple post-treatment; Preferably, the simple post-treatment comprises: washing the reaction system with an acid solution, and then drying.
5. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: The molar ratio of the malononitrile to the compound I is 1-1.2:0.93; The molar ratio of the alkaline substance to the compound I is 2-5:0.93; Preferably, the alkaline substance is selected from amine substances or hydroxides.
6. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: Under an inert gas atmosphere, the reaction system containing compound III, the alkaline material and the ester solvent are mixed at 40-60° C., dimethyl sulfate is added, and the mixture is reacted at 55-80° C. for 5-6 hours.
7. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: The molar ratio of the alkaline material to the compound I is 2-6:0.93; The molar ratio of the dimethyl sulfate to the compound I is 1.5-2:0.
93.
8. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: The ester solvent is selected from ethyl ester solvents or propyl ester solvents; Any one of ethyl acetate, ethyl formate, ethyl propionate and isopropyl acetate is preferred.
9. The method for preparing an ibrutinib intermediate according to claim 1, characterized in that: post-treating the reaction system for forming the ibrutinib intermediate; The post-treatment includes: cooling the reaction solution after the reaction is completed, adjusting the pH, separating the liquids, extracting the aqueous phase and collecting the organic phase, and then drying and concentrating, and crystallizing the concentrate using isopropanol.
10. A method for preparing ibrutinib, characterized in that: It comprises the method for preparing the ibrutinib intermediate according to any one of claims 1 to 9.