Preparation method and application of apalutamide impurity
By improving the preparation method of apaluamide impurities, compound II is mixed with an organic solvent and a hydrophobic agent and then added a polar solution of compound III dropwise, and an organic base is added at a high temperature to react. After purification, a high yield and high purity apaluamide impurity compound I was obtained, which solved the problems of low yield and difficult detection in the prior art, and improved the purity of apaluamide raw material.
Patent Information
- Application Number
- CN202410011486.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-01-04
- Publication Date
- 2025-07-04
AI Technical Summary
In the prior art, the yield of apaluamide impurities is low, and it cannot be used as a reference for testing related substances, which increases the difficulty of detection of apaluamide impurities and affects the purity of the raw materials.
After mixing Compound II with an organic solvent and a hydrophobic agent, a polar solution of Compound III was added dropwise, and an organic base was added to react at 90-100°C, followed by purification to obtain apaluamide impurity compound I, which increased its yield and purity.
The high yield and high purity of apaluamide impurity compound I have been achieved, and the purity of apaluamide raw materials or preparations can be used as a reference product, solving the problem of difficult detection and low purity in the prior art.
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Figure CN120247869A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method and application of an apalutamide impurity. Background Art
[0002] Apalutamide is an androgen receptor (AR) inhibitor that acts by blocking the action of androgens on tumors, can inhibit the proliferation of tumor cells, promote their apoptosis, and thus reduce the volume of tumors. It was developed by Janssen Pharmaceutical Companies of Johnson & Johnson and was approved by the US Food and Drug Administration on February 14, 2018, for the treatment of patients with non-metastatic castration-resistant prostate cancer.
[0003] The Chinese chemical name of apalutamide is 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide, and its chemical structure is shown as follows:
[0004]
[0005] There are various synthesis methods for apalutamide. Using compound 1 as a raw material, it is condensed with cyclobutanone and sodium cyanide to obtain a benzamide intermediate 2; using compound 3 as a raw material, it is reacted with thiophosgene to obtain a thioisocyanato-pyridine intermediate 4; finally, the two intermediates are used to prepare apalutamide under microwave promotion. This route requires the use of sodium cyanide and thiophosgene under acidic conditions, and the final cyclization reaction uses microwave, but it is relatively difficult to produce industrially.
[0006]
[0007] To facilitate the industrial production of apalutamide, an N-methyl-2-fluoro-4-halo-benzamide compound and cyclobutylamine hydrochloride are used as starting materials, and are condensed through an Ullmann reaction to obtain an intermediate compound, then esterified to obtain intermediate compound one, then reacted with a thiocyanate to cyclize to obtain intermediate compound two, and finally the two are coupled to obtain apalutamide. This route avoids the use of highly toxic cyanides and heavy metal catalysts, but by-products, apalutamide impurities, will be generated during the synthesis process. Since the yield of apalutamide impurities is relatively low, the apalutamide impurities cannot be used as reference substances for related substance detection, which increases the difficulty of detecting apalutamide impurities and affects the purity of apalutamide raw materials. Summary of the Invention
[0008] The present application provides a preparation method and application of apalutamide impurities, aiming to solve the problems in the prior art that the yield of apalutamide impurities is relatively low, the apalutamide impurities cannot be used as reference substances for related substance detection, resulting in an increase in the difficulty of detecting apalutamide impurities and affecting the purity of apalutamide raw materials.
[0009] On the one hand, the present application provides a preparation method of apalutamide impurities, including:
[0010]
[0011] Adding compound II into an organic solvent and a hydrophobic agent, and then dropping a polar solution of compound III;
[0012] After the dropping is completed, an organic base is added at 90 - 100 °C for reaction to obtain a crude product, and after purification, compound I is obtained.
[0013] Through the improvement of the synthesis process, after adding a hydrophobic agent and an organic solvent to 4-[(1-cyanocyclobutyl)amino]-N-methylbenzamide (compound II), a polar solution of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (compound III) is dropped, and an organic base is added after reacting at an elevated temperature for a period of time to generate apalutamide Formula-A (compound I), and the yield is relatively high; the compound I prepared in the present application can be used as a reference substance for apalutamide impurities, and the purity of apalutamide raw materials or preparations can be controlled through the apalutamide reference substance, solving the problems in the prior art that in the process of preparing apalutamide, the apalutamide impurities cannot be used as reference substances for related substance detection, resulting in an increase in the difficulty of detecting apalutamide impurities and affecting the purity of apalutamide raw materials.
[0014] In a possible implementation manner, the protic solvent includes one or a combination of more of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.
[0015] In a possible implementation manner, the hydrophobic agent is one or a combination of more of polytetrafluoroethylene, perfluoropropylene, trimethylchlorosilane, epoxy silane, and silicone resin.
[0016] In a possible implementation manner, the organic base is one of 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine.
[0017] In a possible implementation manner, the polar solvent in the polar solution of compound III is dichloromethane or toluene.
[0018] In a possible implementation manner, after dropping the polar solution of compound III, keep the reaction at a constant temperature for 16 - 20 h, and the reaction temperature is 90 - 100 °C.
[0019] In a possible implementation manner, the reaction time for adding the organic base is 4 to 6 h.
[0020] In a possible implementation manner, the purification step includes: after subjecting the crude product to column chromatography separation, adding organic alcohol for recrystallization to obtain Compound I.
[0021] In a possible implementation manner, the organic alcohol is one of isopropanol, n-propanol, isobutanol, and n-butanol.
[0022] In a possible implementation manner, the temperature of the recrystallization is 55 to 60 °C.
[0023] In a second aspect, the present application further provides an application of the apalutamide impurity obtained by the method according to the first aspect in the preparation of an impurity reference substance for apalutamide raw material drug or its preparation.
[0024] The present application provides a preparation method and application of an apalutamide impurity. The method includes: mixing 4-[(1-cyanocyclobutyl)amino]-N-methylbenzamide (Compound II) with an organic solvent, adding a hydrophobic agent, and then dropping a polar solution of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (Compound III); after the dropping is completed, adding an organic base at 90 to 100 °C for reaction to obtain a crude product, and obtaining the apalutamide impurity (Compound I) after purification. The apalutamide impurity with the structural formula as shown in Formula I prepared by the present application can be used as an apalutamide impurity reference substance to control the purity of the raw material or preparation; the conversion rate and yield of the apalutamide impurity provided by the present application are relatively high, solving the problem in the prior art that the yield of the apalutamide impurity is relatively low and the apalutamide impurity cannot be used as a reference substance for related substance detection, and improving the purity of the apalutamide raw material drug. Description of the Drawings
[0025] In order to more clearly illustrate the technical solutions of the present application, the drawings required for use in the embodiments will be briefly introduced below. Obviously, for those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.
[0026] Figure 1 It is the liquid phase purity spectrum of the apalutamide impurity prepared in Example 1 provided by the present application;
[0027] Figure 2 It is the nuclear magnetic spectrum of the apalutamide impurity prepared in Example 1 provided by the present application. Detailed Embodiments
[0028] Embodiments will be described in detail below, and examples are shown in the accompanying drawings. When the following description refers to the accompanying drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. The embodiments described in the following examples do not represent all embodiments consistent with the present application. They are merely examples of systems and methods consistent with some aspects of the present application detailed in the claims.
[0029] Apalutamide is an androgen receptor (AR) inhibitor that exerts a therapeutic effect by blocking the action of androgens on tumors. It can inhibit the proliferation of tumor cells, induce their apoptosis, and thereby reduce the volume of tumors. It was developed by Janssen Pharmaceuticals, Inc. and was approved by the U.S. Food and Drug Administration on February 14, 2018, for the treatment of patients with non-metastatic castration-resistant prostate cancer.
[0030] The Chinese chemical name of apalutamide is 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thia-5,7-diazaspiro[3.4]octane-5-yl)-2-fluoro-N-methylbenzamide, and its chemical structure is shown in the following structural formula:
[0031]
[0032] There are various synthesis methods for apalutamide. Using compound 1 as the raw material, it is condensed with cyclobutanone and sodium cyanide to obtain the benzamide intermediate 2; using compound 3 as the raw material, it reacts with thiophosgene to obtain the thiocyanato-pyridine intermediate 4; finally, the two intermediates are used to prepare apalutamide under microwave promotion. This route requires the use of sodium cyanide and thiophosgene under acidic conditions, and the final cyclization reaction uses microwave, but it is relatively difficult to industrialize this method.
[0033] To facilitate the industrial production of apalutamide, in related technologies, N-methyl-2-fluoro-4-halo-benzamide compound 1 and cyclobutylamine hydrochloride 2 are used as starting materials, and they are condensed through the Ullmann reaction to obtain the intermediate compound 3, then esterified to obtain the intermediate compound 4, then reacted with thiocyanate to cyclize to obtain compound 5, and finally compound 5 is coupled with compound 6 to obtain apalutamide. This route avoids the use of highly toxic cyanides and heavy metal catalysts, but by-products of apalutamide impurities will be generated during the synthesis process. In order to control the purity of apalutamide raw materials or preparations, it is necessary to detect the impurities in the crude apalutamide synthesized. Therefore, it is necessary to prepare apalutamide impurities and use apalutamide impurities as reference substances for the detection of related substances.
[0034] In the related art, the synthesis process of apalutamide impurity is as follows: 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile is mixed with dimethylformamide, and isopropyl acetate and 4-[(1-cyanocyclobutyl)amino]-N-methylbenzamide are added thereto and mixed at 25-30 °C. And hydrothermal reaction is carried out at 65-70 °C. After cooling to room temperature, an aqueous sodium hydroxide solution is added to the reaction mixture, and two organic aqueous layers are separated. The organic layer is washed with an aqueous sodium hydroxide solution and then with an aqueous hydrochloric acid solution. The solvent is completely distilled off, and the mixture is cooled to 25-30 °C. Hydrochloric acid and an aqueous methanol solution are added to the obtained mixture at 25-30 °C, heated to 85-90 °C and stirred. The reaction mixture is cooled to 25-30 °C and stirred. The solid is filtered and washed with water. Dichloromethane is added to the obtained compound at 25-30 °C, filtered and washed with dichloromethane. The dichloromethane layer is washed with an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution. The solvent is distilled off and co-distilled with isopropanol. Added to the obtained compound mixture of isopropanol and cyclohexane at 25-30 °C, heated to 65-70 °C and stirred. The reactant is cooled to 25-30 °C and stirred. The solid is filtered, washed with isopropanol and dried, and finally apalutamide impurity Formula-A (Compound I) is prepared. Apalutamide impurity Formula-A (Compound I) is synthesized by a method of high-temperature enrichment of two synthetic raw materials, and the yield is 12%, and the yield is relatively low.
[0035] Since the yield of apalutamide impurity Formula-A (Compound I) in the related art is relatively low, Compound I cannot be used as a reference substance for the detection of related substances, which increases the difficulty of detecting apalutamide impurities and affects the purity of apalutamide raw materials.
[0036] Therefore, the present application provides a preparation method of apalutamide impurity to improve the yield of apalutamide impurity (Compound I), reduce the difficulty of detecting apalutamide impurity, and improve the purity of apalutamide raw material; the preparation method of apalutamide impurity includes:
[0037]
[0038] Compound II is added to an organic solvent and a water repellent, and then a polar solution of Compound III is added dropwise;
[0039] After the addition dropwise is completed, an organic base is added at 90-100 °C to react to obtain a crude product, and after purification, Compound I is obtained.
[0040] Through the improvement of the synthesis process, after adding a water repellent and an organic solvent to 4-[(1-cyanocyclobutyl)amino]-N-methylbenzamide (Compound II), a polar solution of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile is then added dropwise, and an organic base is added after heating and reacting for a period of time to produce apalutamide Formula-A (Compound I) with a relatively high yield; the Compound I prepared in this application can be used as an apalutamide impurity reference substance, and the apalutamide reference substance can be used to control the purity of apalutamide raw materials or preparations, solving the problem that in the prior art during the preparation of apalutamide, the apalutamide impurities cannot be used as reference substances for related substance detection, resulting in an increase in the difficulty of apalutamide impurity detection and affecting the purity of apalutamide raw materials.
[0041] In some embodiments, the organic solvent includes one or more combinations of N,N-dimethylformamide DMF, dimethyl sulfoxide DMSO, and N-methylpyrrolidone NMP.
[0042] Among them, the chemical reagents DMF, DMSO, or NMP increase the solubility of Compound II in the water repellent, and adding 1,8-diazabicyclo[5.4.0]undec-7-ene DBU or triethylamine can make it easier for Compound II and Compound III to generate apalutamide impurities (Compound I) rather than apalutamide raw materials during the reaction.
[0043] Among them, in order to avoid the interference of moisture in the organic solvent on the reaction, a water repellent needs to be added to remove the moisture in the solvent. In some embodiments, the water repellent is one or more combinations of polytetrafluoroethylene, perfluoropropylene, trimethylchlorosilane, epoxy silane, and silicone resin.
[0044] In some embodiments, the polar solvent in the polar solution of Compound III is dichloromethane or toluene.
[0045] In some embodiments, after adding the polar solution of Compound III dropwise, the reaction is kept warm for 16 - 20 h, and the reaction temperature is 90 - 100 °C.
[0046] Among them, setting the temperature to 90 - 100 °C can make the reaction solution react more fully and also make it easier for apalutamide impurities (Compound I) to precipitate.
[0047] In some embodiments, before adding the water repellent, the temperature of the solution obtained by mixing Compound II and the organic solvent is controlled at 20 - 30 °C.
[0048] In some embodiments, after adding the polar solution of Compound III dropwise, the reaction is kept warm for 16 - 20 h, and the reaction temperature is 90 - 100 °C.
[0049] Among them, after adding the polar solution of Compound III and reacting for 16 to 20 h, it is to make Compound II and Compound III uniformly mixed so that the subsequent reaction can be complete.
[0050] In some embodiments, the organic base is one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine. The reaction time after adding the organic base is 4 to 6 h to enable the full reaction of Compound II, Compound III, and the organic base, thereby increasing the yield of Compound I.
[0051] In order to enable the apalutamide impurity (Compound I) to be used in the impurity detection of the preparation of apalutamide bulk drug or its preparations, the purity of the apalutamide impurity (Compound I) needs to be defined. After the apalutamide impurity (Compound I) is prepared, its purity is detected. When the apalutamide impurity (Compound I) is lower than the purity threshold, it can be purified by recrystallization reaction. Adding an organic alcohol to the apalutamide impurity (Compound I) for recrystallization is specifically as follows:
[0052] After column chromatography separation of the crude product, Compound I is mixed with an organic alcohol and stirred at room temperature. After drying under reduced pressure at 55 - 60 °C for 15 - 20 h, the purified apalutamide impurity is obtained; the organic alcohol is one of isopropanol, n-propanol, isobutanol, and n-butanol.
[0053] Among them, in order to increase the yield of the apalutamide impurity (Compound I), by adding isopropanol, n-propanol, isobutanol, or n-butanol, the solubility of the apalutamide impurity in the solution can be reduced, enabling the apalutamide impurity (Compound I) to precipitate more easily.
[0054] Since during the purification process of Compound I, the organic alcohol may combine with Compound I to form a complex, in some embodiments, toluene can be used to wash Compound I to remove some of the combined organic alcohol.
[0055] Example 1
[0056] Put Compound II (20 g), N-methylpyrrolidone (20 mL), and trimethylchlorosilane (13.18 g) into a 1.0 L reaction flask and stir evenly;
[0057] Control the temperature at 90 - 100 °C and drip the dichloromethane solution of Compound III (46.34 g). After the dripping is completed, keep the temperature at 90 - 100 °C and react for 16 h. Then quickly add triethylamine (94.9 g). After the dripping is completed, keep the temperature for reaction for 4 h. Cool down to 20 - 30 °C. After the organic phase is concentrated to dryness, add silica gel to make sand and pass through a column. The eluent is PE:EA = 3:1 to obtain a brown oily substance. Add isopropanol (60.0 g) for recrystallization and stir at room temperature to obtain a large amount of yellow solid. Filter by suction and dry to obtain Compound I.
[0058] Compound I was added to a 100 ml reaction flask, 60.0 g of toluene was added, the temperature was raised to 55 - 60 °C, and it was kept warm and stirred for 4 h. Then the temperature was lowered to room temperature. After suction filtration, liquid phase analysis was carried out. The results of the liquid phase analysis are as Figure 1 shown. Among them, Table 1 shows the analysis results of each component of the liquid phase analysis. As Figure 1 known from Table 1, the related substances of Compound I meet the standards;
[0059] Table 1
[0060]
[0061]
[0062] Nuclear magnetic resonance analysis was carried out on the apalutamide impurity (Compound I), that is, 1H NMR (DMSO, 400 MHz). As Figure 2 shown, δ, m / z [M + H]+: 493.5. It can be confirmed that Compound I is apalutamide impurity Formula-A. Among them, the attribution of the nuclear magnetic resonance spectrum: 1H at ppm 8.85 is the hydrogen of the pyridine ring; 1H at ppm 9.23 is the hydrogen of the pyridine ring; 4H at ppm 2.79 - 2.64, 1H at ppm 2.05, 1H at ppm 1.57 are the hydrogens on the four-membered ring, 1H at ppm 7.47, 1H at ppm 7.86, 1H at ppm 7.56 are the hydrogens of the benzene ring, 1H at ppm 8.5 is the amide hydrogen, 1H at ppm 2.82 is the methyl hydrogen; the yield of Compound I was calculated, and the yield was 99%.
[0063] Example 2
[0064] Compound II (22 g), N-methylpyrrolidone (22 mL), and trimethylchlorosilane (14.49 g) were added to a 1.0 L reaction flask and stirred evenly;
[0065] The temperature was controlled at 90 - 100 °C, and a toluene solution of Compound III (101.94 g) was added dropwise. After the addition was completed, it was kept warm at 90 - 100 °C and reacted for 20 h. Then triethylamine (104.39 g) was quickly added. After the addition was completed, it was kept warm and reacted for 5 h. The temperature was lowered to 20 - 30 °C. After the organic phase was concentrated to dryness, it was added to silica gel to make sand and passed through a column. The eluent was PE:EA = 3:1 to obtain a brown oily substance. Isopropanol (66.0 g) was added for recrystallization, and it was stirred at room temperature to obtain a large amount of yellow solid. After suction filtration and drying, Compound I was obtained.
[0066] Example 3
[0067] Compound II (16 g), N-methylpyrrolidone (16 mL), and trimethylchlorosilane (10.54 g) were added to a 1.0 L reaction flask and stirred evenly;
[0068] Control the temperature at 90-100 °C, and add a dichloromethane solution of compound III (37.07 g) dropwise. After the addition is completed, keep the temperature at 90-100 °C and react for 17 h. Then quickly add triethylamine (75.92 g). After the addition is completed, keep the temperature and react for 6 h. Cool down to 20-30 °C. After the organic phase is concentrated to dryness, add silica gel to make sand and pass through a column. The eluent is PE:EA = 3:1 to obtain a brown oil. Add isopropanol (48.0 g) for recrystallization, stir at room temperature to obtain a large amount of yellow solid, filter by suction and dry to obtain compound I.
[0069] As can be seen from the above examples, the present application provides a method for preparing and applying an apalutamide impurity. The method includes: mixing a benzamide intermediate (compound II) with an organic solvent, adding a hydrophobic agent, and then dropwise adding a polar solution of a thiocyanatopyridine intermediate (compound III); after the addition is completed, adding an organic base at 90-100 °C to react to obtain a crude product, and purifying to obtain an apalutamide impurity (compound I). The apalutamide impurity with the structure shown in formula I prepared in the present application can be used as a reference substance for apalutamide impurities to control the purity of raw materials or preparations; the conversion rate and yield of the apalutamide impurity provided by the present application are relatively high, solving the problem that the yield of apalutamide impurities in the prior art is low and the apalutamide impurities cannot be used as reference substances for related substance detection, and improving the purity of apalutamide raw materials.
[0070] For the similar parts between the embodiments provided in the present application, reference can be made to each other. The specific embodiments provided above are only several examples under the general concept of the present application and do not constitute a limitation on the protection scope of the present application. For those skilled in the art, any other embodiments extended based on the solution of the present application without creative efforts belong to the protection scope of the present application.
Claims
1. A method for preparing apalutamide impurities, characterized in that, Comprising: Adding Compound II into an organic solvent and a hydrophobic agent, and then dropping a polar solution of Compound III; After the dropping is completed, adding an organic base and reacting at 90 - 100 °C to obtain a crude product, and obtaining Compound I after purification.
2. The preparation method of the apalutamide impurity according to claim 1, wherein, The organic solvent is one or a combination of more of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.
3. The preparation method of the apalutamide impurity according to claim 1, wherein, The hydrophobic agent is one or a combination of more of polytetrafluoroethylene, perfluoropropylene, trimethylchlorosilane, epoxy silane, and silicone resin.
4. The preparation method of the apalutamide impurity according to claim 1, wherein The polar solvent in the polar solution of Compound III is dichloromethane or toluene.
5. The preparation method of apalutamide impurities according to claim 1, characterized in that, After dropping the polar solution of Compound III, keep the reaction warm for 16 - 20 h, wherein the reaction temperature is 90 - 100 °C.
6. The preparation method of apalutamide impurities according to claim 1, characterized in that, The reaction time for adding the organic base is 4 - 6 h.
7. The preparation method of apalutamide impurities according to claim 1, wherein, The organic base is one of 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine.
8. The preparation method of the apalutamide impurity according to claim 1, wherein, The purification step comprises: After subjecting the crude product to column chromatography separation, adding an organic alcohol for recrystallization to obtain Compound I; the temperature of the recrystallization is 55 - 60 °C.
9. The preparation method of the apalutamide impurity according to claim 7, characterized in that, The organic alcohol is one of isopropyl alcohol, n-propyl alcohol, isobutyl alcohol, and n-butyl alcohol.
10. Use of the apalutamide impurity obtained by the method according to claim 1 in the preparation of an impurity reference substance for apalutamide bulk drug or its preparation.