Efficient preparation method of aprepitant I crystal form
By using specific solvent ratios and simplifying operating steps, the high cost and multiple waste problems in the preparation of aprepitant I crystal form are solved, and the feasibility of efficient preparation and large-scale production is achieved.
Patent Information
- Application Number
- CN202510535281.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-27
- Publication Date
- 2025-08-08
AI Technical Summary
The prior art is difficult to efficiently prepare the aprepitant I crystal form, and there are problems such as high reaction costs and high three-waste generation.
Aprepitant I crystal form is prepared by heating, cooling, filtration and drying steps, simplifying the operation process and reducing the use of organic solvents and purified water.
It realizes efficient preparation of aprepitant I crystal form, reduces reaction costs, reduces the generation of three wastes, and is suitable for large-scale industrial production.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of medicinal chemistry, and in particular to a method for efficiently preparing aprepitant I crystal form. Background Art
[0002] Aprepitant (chemical name: 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one) is the first NK-1 receptor antagonist developed by Merck for antiemetic purposes. It binds highly selectively to NK-1 receptors in the brain, antagonizing the binding of substance P to these receptors, thereby achieving an antiemetic effect. Aprepitant is indicated for use in combination with other antiemetic drugs to prevent acute and delayed nausea and vomiting during initial and repeat treatment with highly emetogenic anticancer chemotherapy.
[0003]
[0004] Different crystalline forms of the same drug can result in differences in their physicochemical properties, which can affect drug application and, in turn, their bioavailability and clinical efficacy. The original developer of aprepitant has reported Form I and Form II. Form I is anhydrous and non-hygroscopic, thermodynamically more stable, and is the crystalline form of the original marketed product. Other reported crystalline forms of this drug include Form III, Form IV, amorphous form, and mixed crystals of different crystalline forms. Summary of the Invention
[0005] One aspect of the present invention is to provide an efficient preparation method of aprepitant Form I, comprising the following steps: adding aprepitant to a good solvent, heating to dissolve, dropwise adding a poor solvent, cooling, filtering, and drying to obtain Form I.
[0006] In a preferred embodiment of the present invention, the good solvent is any one selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, tetrahydrofuran, and DMSO, preferably methanol.
[0007] In a preferred embodiment of the present invention, the poor solvent is any one selected from water, n-hexane, n-heptane, and petroleum ether, preferably water.
[0008] In a preferred embodiment of the present invention, the weight ratio of aprepitant to the good solvent and the poor solvent is 1:6-10:3-7, preferably 1:8:5.
[0009] In a preferred embodiment of the present invention, aprepitant is added to a good solvent and then heated under reflux to dissolve.
[0010] In a preferred embodiment of the present invention, the temperature is cooled to 0-25°C, preferably to 0-10°C.
[0011] In a preferred embodiment of the present invention, the drying temperature is 50-80°C, preferably 60-70°C.
[0012] In a preferred embodiment of the present invention, the drying method is selected from any one of vacuum drying, spray drying, blast drying, and boiling drying, preferably vacuum drying.
[0013] In a preferred embodiment of the present invention, the crystalline form of aprepitant added to the good solvent is any non-crystalline form I selected from crystalline form II, crystalline form III, crystalline form IV, amorphous form, or mixed crystals of different crystalline forms.
[0014] In a preferred embodiment of the present invention, aprepitant added to a good solvent is prepared by the following method: adding crude aprepitant and n-butyl acetate to a reaction vessel, heating the system and stirring while maintaining the temperature, cooling, filtering, and drying to obtain refined aprepitant.
[0015] In a preferred embodiment of the present invention, the weight ratio of crude aprepitant to n-butyl acetate is 1:1.5-5.5, preferably 1:2.5-4.
[0016] In a preferred embodiment of the present invention, the system is heated to 60-90°C, preferably 70-80°C.
[0017] In a preferred embodiment of the present invention, the system is heated and then stirred for 1.5-5 hours, preferably 2.5-4 hours.
[0018] In a preferred embodiment of the present invention, the temperature is lowered to 0-30°C, preferably to 0-20°C.
[0019] In a preferred embodiment of the present invention, after cooling, the mixture is kept warm and stirred for 0.5-3 hours, preferably for 0.5-2 hours.
[0020] In a preferred embodiment of the present invention, the drying is carried out at 50-80° C. for 8-16 hours, preferably at 60-70° C. for 10-14 hours.
[0021] In a preferred embodiment of the present invention, the purity of the refined aprepitant is >99.9%, preferably >99.95%.
[0022] In a preferred embodiment of the present invention, the content of impurity A in the refined aprepitant is less than 0.05%, preferably less than 0.03%.
[0023] In a preferred embodiment of the present invention, the method for preparing the crude aprepitant comprises the following steps: adding a solvent, compound 3 and a base to a reaction vessel, adding compound 4, stirring at room temperature until the reaction is complete, adding water, collecting the filter cake and drying it to obtain a crude product.
[0024] In a preferred embodiment of the present invention, the solvent is selected from any one of DMF, DMSO, ethyl acetate, acetonitrile and acetone, and the preferred solvent is DMF.
[0025] In a preferred embodiment of the present invention, the weight ratio of the compound 3 to the solvent is 1:3-6.
[0026] In a preferred embodiment of the present invention, the base is selected from any one of DIPEA, DBU, DBN, and triethylamine, and preferably the base is DIPEA.
[0027] In a preferred embodiment of the present invention, the molar ratio of the compound 3 to the base is 1:1.5-3.5.
[0028] In a preferred embodiment of the present invention, the molar ratio of compound 3 to compound 4 is 1:1-1.5.
[0029] In a preferred embodiment of the present invention, the temperature of the heat preservation and stirring is 10-40° C., preferably 20-30° C., and the heat preservation and stirring time is 2-4 hours, preferably 2.5-3.5 hours.
[0030] In a preferred embodiment of the present invention, the weight ratio of the solvent to the added water is 1:0.8-1.5, preferably 1:1-1.2.
[0031] In a preferred embodiment of the present invention, the filter cake is collected by centrifugation.
[0032] In a preferred embodiment of the present invention, the filter cake is dried at 50-80°C for 18-30 hours, preferably at 60-70°C for 22-26 hours.
[0033] In a preferred embodiment of the present invention, the preparation method of compound 3 comprises the following steps: ① reacting compound 1 with compound 2; ② preparing p-toluenesulfonic acid monohydrate with solvent 1 to prepare a reserve solution A, adding solvent 1 to the reaction solution obtained in step ①, then adding the reserve solution A, adding palladium carbon, and catalytic hydrogenation until the reaction is completed; ③ filtering the reaction solution in step ② to obtain a filtrate, concentrating under reduced pressure, adding water and ethyl acetate, stirring and standing, separating the organic layer, concentrating under reduced pressure, adding solvent 2 and stirring, crystallizing, filtering, and drying to obtain compound 3.
[0034] In a preferred embodiment of the present invention, the molar ratio of compound 1 to compound 2 in step ① is 1:1.2-1.6.
[0035] In a preferred embodiment of the present invention, the reaction solvent in step ① is selected from any one of tetrahydrofuran, dioxane, ethyl acetate, and methyltetrahydrofuran, preferably tetrahydrofuran.
[0036] In a preferred embodiment of the present invention, the solvent 1 in step ② is selected from any one of methanol, ethanol, isopropanol, and ethyl acetate, preferably methanol.
[0037] In a preferred embodiment of the present invention, the hydrogenation reaction temperature in step ② is 15-35°C, preferably 20-30°C, and the reaction time is 3-5 hours.
[0038] In a preferred embodiment of the present invention, the solvent 2 in step ③ is 4-methyl-2-pentanone.
[0039] In a preferred embodiment of the present invention, the weight ratio of the solvent 2 in step ③ to the compound 1 in step ① is 2-3:1.
[0040] In a preferred embodiment of the present invention, in step ③, after adding solvent 2, stirring is carried out at 60-90°C, preferably 70-80°C.
[0041] Another object of the present invention is to provide aprepitant crystalline form I prepared by the method of the present invention.
[0042] The XRPD (X-ray powder diffraction) pattern of aprepitant Form I has characteristic peaks at approximately 12.0°, 15.3°, 16.6°, 17.0°, 17.6°, 19.4°, 20.0°, 21.9°, 23.6°, 23.8°, and 24.8° 2θ ( Figure 1 ), the XRPD pattern of Form II has characteristic peaks at about 12.6°, 16.7°, 17.1°, 17.2°, 18.0°, 20.1°, 20.6°, 21.1°, 22.8°, 23.9° and 24.8° 2θ ( Figure 2 ).
[0043] Unless otherwise indicated, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage (ml / g); when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage (g / ml); and the rest are weight / weight percentages.
[0044] Compared with the prior art, the present invention has the following beneficial effects:
[0045] The method of the present invention is simple to operate and does not require repeated heating, cooling, and solvent / water addition steps. The method utilizes less organic solvent and purified water, significantly reducing reaction costs and the generation of the three wastes while also significantly shortening reaction time. The method of the present invention ensures efficient preparation of aprepitant Form I by simply adjusting the method for adding the poor solvent. The method of the present invention is particularly suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0046] Figure 1 is the XRPD pattern of aprepitant Form I;
[0047] Figure 2 is the XRPD pattern of the crystal form of Aprepitant II;
[0048] Figure 3 This is the XRPD pattern of the refined aprepitant obtained in Example 1;
[0049] Figure 4 The XRPD pattern of aprepitant Form I prepared in Example 2; DETAILED DESCRIPTION
[0050] To make the purpose, technical solutions and advantages of the present invention more clearly understood, the embodiments of the present invention will be described in detail below with reference to the accompanying drawings. It should be noted that the embodiments of the present invention and the features therein can be combined with each other in any manner without conflict.
[0051] Example 1 Synthesis of Aprepitant
[0052]
[0053] (1) Synthesis of compound 3
[0054] 71.4 kg of tetrahydrofuran was added to a 500 L reactor, and 80 kg of compound 1 was added under stirring. After complete dissolution, 250 kg of a tetrahydrofuran solution of compound 2 (containing 50 kg of compound 2) was added and stirred for 1 hour.
[0055] 71.45 kg of p-toluenesulfonic acid monohydrate was added to a 500 L reactor and dissolved in 170 kg of methanol to prepare reserve solution A. The reaction solution from the previous step was cooled to -5-0°C and 33 kg of methanol was added dropwise, controlling the internal temperature not to exceed 30°C. After the dropwise addition was completed, the liquid was cooled to -5-0°C and transferred to a 1000 L hydrogenation reactor. Reserve solution A was transferred to the reactor and wet palladium carbon (2.0 kg dry weight, 10%) was added. The hydrogenation temperature was controlled at 20-30°C and the pressure was controlled at 0.5-1.0 MPa. Catalytic hydrogenation was carried out for 4 hours. The reaction liquid from the hydrogenation kettle was filtered and transferred to a 1000L reactor. The filter cake was rinsed with 200kg of methanol and concentrated under reduced pressure to dryness. 600kg of water and 300kg of ethyl acetate were added, stirred for 30min, and allowed to stand to separate the organic layer. The organic layer was washed once with an aqueous sodium carbonate solution (prepared by dissolving 36kg of sodium carbonate in 324kg of water), and concentrated under reduced pressure in a 500L reactor. 180kg of 4-methyl-2-pentanone was added and stirred at 70-80°C for 3 hours. The mixture was cooled and stirred to crystallize at 10-30°C, filtered, rinsed with 20kg of 4-methyl-2-pentanone, and dried with air at 50-70°C for 12 hours to obtain 78.8kg of compound 3 in a yield of 93%.
[0056] (2) Synthesis of Aprepitant
[0057] To a reactor, 325 kg of N,N-dimethylformamide, 67 kg of compound 3, and 45 kg of N,N-diisopropylethylamine were added, and 22.8 kg of compound 4 was added dropwise. The mixture was stirred at 20-30°C for 3 hours. After completion of the reaction by TLC, 325 kg of water was added to the reactor. The reaction solution was centrifuged and the filter cake was collected to obtain a crude wet aprepitant product. The product was then dried at 60-70°C for 24 hours to obtain 74.9 kg of a crude product with a yield of 99.2%. The purity was 99.39% as determined by HPLC, and the impurity A content was 0.38%.
[0058] (3) Refining of Aprepitant
[0059] 259 kg of n-butyl acetate and 74.06 kg of crude aprepitant were added to the reactor, the system was heated to 70-80 ° C, stirred at this temperature for 3 hours, the system was slowly cooled to 0-20 ° C, stirred at this temperature for 1 hour, filtered to obtain a wet product, and dried with air at 60-70 ° C for 12 hours to obtain 73.24 kg of refined product with a yield of 98.9%. The purity was 99.98% by HPLC, the impurity A content was 0.01%, and XRPD detection was aprepitant mixed crystal ( Figure 3 ).
[0060] Example 2
[0061] 65 kg of refined aprepitant was added to a 1000 L reactor, 520 kg of methanol was added and heated under reflux to dissolve, 325 kg of purified water was added dropwise to the reactor, cooled to 0-10 ° C, filtered, and vacuum dried at 60-70 ° C for 24 hours to obtain 61.75 kg of white crystalline solid with a yield of 95%. XRPD analysis showed that it was aprepitant Form I ( Figure 4 ).
[0062] Example 3
[0063] 5 g of the refined aprepitant was added to 40 g of methanol and heated under reflux to dissolve. 25 g of purified water was added dropwise, and the mixture was cooled to 0-10° C., filtered, and dried under vacuum at 60-70° C. to obtain a white crystalline solid. XRPD analysis showed that the solid was aprepitant Form I.
[0064] Comparative Example 1
[0065] 5 g of the refined aprepitant was added to 40 g of methanol and heated under reflux to dissolve, 25 g of purified water was added, the mixture was cooled to 0-10° C., filtered, and dried under vacuum at 60-70° C. to obtain aprepitant mixed crystals.
[0066] Comparative Example 2
[0067] 5 g of refined aprepitant was added to 40 g of methanol, heated at 40-50° C. to dissolve, 25 g of purified water was added dropwise, the mixture was cooled to 0-10° C., filtered, and dried in vacuo at 60-70° C. to obtain aprepitant mixed crystals.
[0068] Comparative Example 3
[0069] 5 g of refined aprepitant was added to 40 g of methanol and heated under reflux to dissolve, then slowly cooled to room temperature, 25 g of purified water was added dropwise, filtered, and dried under vacuum at 60-70° C. to obtain aprepitant mixed crystals.
[0070] Although the embodiments disclosed herein are described above, the contents are merely embodiments for facilitating understanding of the present invention and are not intended to limit the present invention. Any person skilled in the art may make any modifications and changes in the form and details of the embodiments without departing from the spirit and scope of the present invention. However, the scope of patent protection of the present invention shall still be subject to the scope defined by the appended claims.
Claims
1. An efficient preparation method of aprepitant crystalline form I, comprising the following steps: Aprepitant is added to a good solvent, heated to dissolve, a poor solvent is added dropwise thereto, the mixture is cooled, filtered, and dried to obtain Form I.
2. The preparation method according to claim 1, characterized in that The preparation method satisfies at least one of the following conditions (1)-(3): (1) The good solvent is any one selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, tetrahydrofuran, and DMSO, preferably methanol; the poor solvent is any one selected from water, n-hexane, n-heptane, and petroleum ether, preferably water; the weight ratio of aprepitant to the good solvent and the poor solvent is 1:6-10:3-7, preferably 1:8:5; (2) Aprepitant is added to a good solvent and heated under reflux to dissolve. (3) Cooling to 0-25°C, preferably cooling to 0-10°C, drying at 50-80°C, preferably 60-70°C, and drying by vacuum drying, spray drying, blast drying, or boiling drying, preferably vacuum drying.
3. The preparation method according to any one of claims 1 to 2, characterized in that The crystalline form of aprepitant added to the good solvent is any non-crystalline form I selected from crystalline form II, crystalline form III, crystalline form IV, amorphous form or mixed crystals of different crystalline forms.
4. The preparation method according to any one of claims 1 to 3, characterized in that Aprepitant added to a good solvent is prepared by the following method: adding crude aprepitant and n-butyl acetate to a reaction container, heating the system and stirring while keeping the temperature, cooling, filtering, and drying to obtain refined aprepitant.
5. The preparation method according to claim 4, characterized in that The preparation method satisfies at least one of the following conditions (1)-(4): (1) The weight ratio of crude aprepitant to n-butyl acetate is 1:1.5-5.5, preferably 1:2.5-4, (2) heating the system to 60-90°C, preferably 70-80°C, and stirring the system for 1.5-5 hours, preferably 2.5-4 hours. (3) cooling to 0-30°C, preferably to 0-20°C, and then stirring for 0.5-3 hours, preferably for 0.5-2 hours. (4) drying at 50-80°C for 8-16 hours, preferably at 60-70°C for 10-14 hours.
6. The preparation method according to any one of claims 4 to 5, characterized in that The purity of the refined aprepitant is >99.9%, preferably >99.95%. The content of impurity A in the refined aprepitant is <0.05%, preferably <0.03%.
7. The preparation method according to any one of claims 4 to 6, characterized in that The preparation method of the crude aprepitant comprises the following steps: adding a solvent, compound 3 and a base into a reaction container, adding compound 4, keeping warm and stirring until the reaction is completed, adding water, collecting the filter cake and drying it to obtain a crude product.
8. The preparation method according to claim 7, characterized in that The method for preparing the crude aprepitant satisfies at least one of the following conditions (1)-(7): (1) The solvent is selected from any one of DMF, DMSO, ethyl acetate, acetonitrile, and acetone, preferably DMF. (2) The weight ratio of the compound 3 to the solvent is 1:3-6, (3) The base is selected from any one of DIPEA, DBU, DBN, and triethylamine, preferably DIPEA, and the molar ratio of the compound 3 to the base is 1:1.5-3.
5. (4) The molar ratio of compound 3 to compound 4 is 1:1-1.5, (5) The temperature of the heat preservation and stirring is 10-40°C, preferably 20-30°C, and the heat preservation and stirring time is 2-4 hours, preferably 2.5-3.5 hours. (6) The weight ratio of the solvent to the added water is 1:0.8-1.5, preferably 1:1-1.2, (7) Collect the filter cake by centrifugation.
9. The preparation method according to any one of claims 7-8, characterized in that The preparation method of compound 3 comprises the following steps: ① reacting compound 1 with compound 2; ② preparing p-toluenesulfonic acid monohydrate with solvent 1 to prepare a reserve solution A, adding solvent 1 to the reaction solution obtained in step ①, then adding the reserve solution A, adding palladium carbon, and catalytic hydrogenation until the reaction is completed; ③ filtering the reaction solution in step ② to obtain a filtrate, concentrating under reduced pressure, adding water and ethyl acetate, stirring and standing, separating the organic layer, concentrating under reduced pressure, adding solvent 2 and stirring, crystallizing, filtering, and drying to obtain compound 3.
10. The preparation method according to claim 9, characterized in that The preparation method of the compound 3 satisfies at least one of the following conditions (1)-(6): (1) In step ①, the molar ratio of compound 1 to compound 2 is 1:1.2-1.6, (2) The reaction solvent of step ① is selected from any one of tetrahydrofuran, dioxane, ethyl acetate, and methyltetrahydrofuran, preferably tetrahydrofuran. (3) The solvent 1 in step ② is selected from any one of methanol, ethanol, isopropanol, and ethyl acetate, preferably methanol. (4) The hydrogenation reaction temperature in step ② is 15-35°C, preferably 20-30°C, and the reaction time is 3-5 hours. (5) The solvent 2 in step ③ is 4-methyl-2-pentanone, and the weight ratio of the solvent 2 in step ③ to the compound 1 in step ① is 2-3:
1. (6) After adding solvent 2 in step ③, stir at 60-90°C, preferably 70-80°C.