Crystal form of edoxaban intermediate and preparation method thereof
By preparing crystal forms A and B of edoxaban intermediates, the problems of complex processes and high costs in the existing technology are solved, the synthesis process of edoxaban is simplified, the reaction yield and product quality are improved, and the purification cost is reduced.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- INNER MONGOLIA JINGDONG PHARM CO LTD
- Filing Date
- 2025-12-24
- Publication Date
- 2026-04-14
AI Technical Summary
In the existing synthetic routes for edoxaban, compounds of formula II exhibit excellent crystallization properties but have complex processes that increase costs. Therefore, simplifying the synthetic process of edoxaban has become an urgent problem to be solved.
Two crystal forms (crystal form A and crystal form B) of edoxaban intermediates are provided, which are prepared by specific solvent systems and distillation methods, simplifying the synthetic route of edoxaban. The crystal form of compound I can be directly stored and used as an intermediate, reducing the occurrence of side reactions.
This approach simplifies the synthetic route of edoxaban, improves reaction yield and selectivity, ensures product quality, reduces purification costs, and guarantees crystal stability.
Smart Images
Figure CN121850902A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of medicinal chemistry, and in particular to a crystal form of an edoxaban intermediate and a method for its preparation. Background Technology
[0002] Edoxaban p-toluenesulfonate monohydrate (hereinafter referred to as "edoxaban") is a selective factor Xa inhibitor developed by Daiichi Sankyo Co., Ltd. of Japan for the prevention of venous thromboembolism after major orthopedic surgery. Its structural formula is: .
[0003] The main reaction route for the synthesis of edoxaban is shown below: .
[0004] In existing synthetic routes, compound I is usually obtained by first dissociating compound II, and then compound I undergoes a series of subsequent reactions to finally obtain edoxaban.
[0005] Although the synthetic route for preparing edoxaban uses compound of formula I, the intermediate is usually provided and stored in the form of compound of formula II on the market, and then converted back to compound of formula I before use. This is mainly because compound of formula II has superior crystallization properties, making it easier to purify and store. However, this process increases the complexity and cost of the process. Therefore, how to simplify the process steps for the synthesis of edoxaban is an urgent problem to be solved in the synthesis of edoxaban. Summary of the Invention
[0006] The purpose of this application is to provide a crystal form of edoxaban intermediate and a method for preparing the same, in order to solve the above-mentioned problems.
[0007] To achieve the above objectives, this application adopts the following technical solution: This application provides a crystal form of an edoxaban intermediate, the structural formula of which is shown in Formula I: ; The crystalline forms of the edoxaban intermediate include crystalline form A, crystalline form B, or a mixture of crystalline form A and crystalline form B in any proportion; The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 11.20°, 17.66°, 18.61°, 19.29°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 7.99°, 10.82°, 13.33°, 18.22°, 18.48°, 19.34°, and 20.02°. According to an embodiment of this application, the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 11.20°, 17.46°, 17.66°, 18.61°, 19.29°, 24.35°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 7.99°, 10.82°, 11.15°, 13.08°, 13.33°, 15.84°, 16.80°, 17.97°, 18.22°, 18.48°, 19.34°, 20.02°, and 27.37°. According to an embodiment of this application, the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 9.67°, 11.20°, 17.46°, 17.66°, 18.61°, 19.29°, 20.53°, 24.35°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 7.99°, 9.09°, 10.82°, 11.15°, 13.08°, 13.33°, 15.08°, 15.84°, 16.80°, 16.91°, 17.97°, 18.22°, 18.48°, 19.34°, 20.02°, 21.92°, and 27.37°. According to an embodiment of this application, the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate is as follows: Figure 3 As shown; The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate is as follows: Figure 1 As shown.
[0008] This application also provides a method for preparing the crystal form of the edoxaban intermediate as described above, wherein the method for preparing the crystal form of the edoxaban intermediate includes at least one of the following methods: (1) Provide an organic phase containing a compound of formula I, wherein the organic phase contains a compound of formula I and a good solvent; distill the organic phase to remove part of the good solvent in the organic phase until the mass ratio of the remaining good solvent to compound I is 1.5-1.8:1 and stop distillation to obtain a remaining solution; under reflux, add a poor solvent dropwise to the remaining solution to obtain a mixed system; after the dropwise addition is completed, heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain crystal form A of compound of formula I; (2) Provide an organic phase containing a compound of formula I, the organic phase comprising a compound of formula I and a good solvent; add a bad solvent to the organic phase to obtain a mixed solution, and distill the mixed solution to remove part of the good solvent in the mixed solution until the mass ratio of the remaining good solvent to compound I is 1.5-1.8:1, and stop distillation to obtain a mixed system; heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain crystal form A of compound of formula I; (3) Add a poor solvent to the compound of formula I, and then add a good solvent dropwise to form a mixed system; heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain the crystal form B of the compound of formula I.
[0009] According to an embodiment of this application, in method (1), during the step of obtaining the mixed system, the mass ratio of the poor solvent to the mass of the good solvent in the remaining solvent is 4.4-4.8:1; In method (2), in the step of obtaining the mixed solution, the mass ratio of the poor solvent to the good solvent in the organic phase is 1:1-1.6; In method (3), the mass ratio of the compound of formula I to the undesirable solvent is 1:7.8-8.2; In method (3), the mass ratio of the poor solvent to the good solvent is 4.4-4.8:1.
[0010] According to embodiments of this application, the benign solvent is dichloromethane, and the undesirable solvent is n-heptane.
[0011] According to an embodiment of this application, the reflux time is 4-6 hours; And / or, the cooling includes stirring at a temperature of 0-5°C for 2-3 hours.
[0012] According to embodiments of this application, the method for preparing the compound containing formula I includes: Compound II was reacted with a base in water to obtain an aqueous phase containing compound I; A benign solvent is added to the aqueous phase containing the compound of formula I, and extraction is performed to obtain an organic phase containing the compound of formula I, wherein the organic phase comprises the compound of formula I and the benign solvent; The structural formula of compound II is as follows: .
[0013] According to embodiments of this application, the mass ratio of the benign solvent used for extraction to compound II is 2.3-2.9:1, and the number of extractions is greater than or equal to 2. And / or, after the extraction is completed, the method further includes: drying the organic phase with anhydrous magnesium sulfate, followed by filtration to remove the anhydrous magnesium sulfate.
[0014] Compared with the prior art, the beneficial effects of this application include: This application successfully obtains two stable crystalline forms of the compound of Formula I: crystalline form A and crystalline form B. The crystalline forms of the compound of Formula I can be directly stored and used as intermediates, simplifying the synthetic route of edoxaban. Using the crystalline forms of the compound of Formula I as starting materials for subsequent synthesis of edoxaban can effectively reduce side reactions, improve reaction yield and selectivity, thereby ensuring the quality of the edoxaban product and reducing purification costs.
[0015] Moreover, both crystal form A and crystal form B of this application have excellent stability, ensuring stable quality during storage. Attached Figure Description
[0016] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation on the scope of this application.
[0017] Figure 1 X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate in Example 1; Figure 2 The ¹H NMR spectrum of crystal form B of the edoxaban intermediate in Example 1; Figure 3 X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate in Example 2; Figure 4 The ¹H NMR spectrum of crystal form A of the edoxaban intermediate in Example 2 is shown. Detailed Implementation
[0018] As used in this article: "Prepared from" is synonymous with "comprising". The terms "comprising", "including", "having", "containing", or any other variations thereof as used herein are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.
[0019] The conjunction "composed of..." excludes any unspecified elements, steps, or components. If used in a claim, this phrase makes the claim closed, excluding materials other than those described, except for associated conventional impurities. When the phrase "composed of..." appears in a clause of the body of a claim rather than immediately following it, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.
[0020] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.
[0021] In these embodiments, unless otherwise specified, the portions and percentages are all by weight.
[0022] "Parts by mass" refers to the basic unit of measurement that expresses the mass ratio of multiple components. One part can represent any unit mass, such as 1g or 2.689g. If we say that component A has "a" parts by mass and component B has "b" parts by mass, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it can mean that the mass of component A is aK and the mass of component B is bK (where K is any number representing a multiplier). It is important to understand that, unlike parts by mass, the sum of the mass parts of all components is not limited to 100 parts.
[0023] "And / or" is used to indicate that one or both of the described situations may occur, for example, A and / or B includes (A and B) and (A or B).
[0024] This application provides a crystal form of an edoxaban intermediate, the structural formula of which is shown in Formula I: ; The crystalline forms of the edoxaban intermediate include crystalline form A, crystalline form B, or a mixture of crystalline form A and crystalline form B in any proportion; The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 11.20°, 17.66°, 18.61°, 19.29°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 7.99°, 10.82°, 13.33°, 18.22°, 18.48°, 19.34°, and 20.02°. According to an embodiment of this application, the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 11.20°, 17.46°, 17.66°, 18.61°, 19.29°, 24.35°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 7.99°, 10.82°, 11.15°, 13.08°, 13.33°, 15.84°, 16.80°, 17.97°, 18.22°, 18.48°, 19.34°, 20.02°, and 27.37°. According to an embodiment of this application, the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 9.67°, 11.20°, 17.46°, 17.66°, 18.61°, 19.29°, 20.53°, 24.35°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 7.99°, 9.09°, 10.82°, 11.15°, 13.08°, 13.33°, 15.08°, 15.84°, 16.80°, 16.91°, 17.97°, 18.22°, 18.48°, 19.34°, 20.02°, 21.92°, and 27.37°. According to an embodiment of this application, the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate is as follows: Figure 3 As shown; The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate is as follows: Figure 1 As shown.
[0025] This application also provides a method for preparing the crystal form of the edoxaban intermediate as described above, wherein the method for preparing the crystal form of the edoxaban intermediate includes at least one of the following methods: (1) Provide an organic phase containing a compound of formula I, the organic phase comprising a compound of formula I and a good solvent; distill the organic phase to remove part of the good solvent in the organic phase until the mass ratio of the remaining good solvent to compound I is 1.5-1.8:1 (e.g., 1.5:1, 1.6:1, 1.7:1, 1.8:1 or any value between 1.5-1.8:1) and stop distillation to obtain a remaining solution; under reflux, add a poor solvent dropwise to the remaining solution to obtain a mixed system; after the dropwise addition is complete, heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain crystal form A of compound of formula I; (2) Provide an organic phase containing a compound of formula I, the organic phase comprising a compound of formula I and a good solvent; add a bad solvent to the organic phase to obtain a mixed solution, and distill the mixed solution to remove part of the good solvent in the mixed solution until the mass ratio of the remaining good solvent to compound I is 1.5-1.8:1 (e.g., 1.5:1, 1.6:1, 1.7:1, 1.8:1 or any value between 1.5-1.8:1) and stop distillation to obtain a mixed system; heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain crystal form A of compound of formula I; (3) Add a poor solvent to the compound of formula I, and then add a good solvent dropwise to form a mixed system; heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain the crystal form B of the compound of formula I.
[0026] According to an embodiment of this application, in method (1), in the step of obtaining the mixed system, the mass ratio of the poor solvent to the good solvent in the remaining solvent is 4.4-4.8:1; for example, the mass ratio of the poor solvent to the good solvent in the remaining solvent is any value between 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1 or 4.4-4.8:1.
[0027] In method (2), in the step of obtaining the mixed solution, the mass ratio of the undesirable solvent to the good solvent in the organic phase is 1:1-1.6; for example, the mass ratio of the undesirable solvent to the good solvent in the organic phase is any value between 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6 or 1:1-1.6.
[0028] In method (3), the mass ratio of the compound of formula I to the undesirable solvent is 1:7.8-8.2; for example, the mass ratio of the compound of formula I to the undesirable solvent is any value between 1:7.8, 1:7.9, 1:8, 1:8.1, 1:8.2 or 1:7.8-8.2.
[0029] In method (3), the mass ratio of the poor solvent to the good solvent is 4.4-4.8:1. For example, the mass ratio of the poor solvent to the good solvent is 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1 or any value between 4.4 and 4.8:1.
[0030] In some embodiments, the compound of formula I in method (3) is prepared by heating an organic phase containing the compound of formula I to remove the organic phase, thereby obtaining the compound of formula I.
[0031] According to embodiments of this application, the benign solvent is dichloromethane, and the undesirable solvent is n-heptane.
[0032] According to an embodiment of this application, the reflow time is 4-6 hours; for example, the reflow time is any value between 4 hours, 5 hours, 6 hours, or 4-6 hours.
[0033] And / or, the cooling includes stirring at a temperature of 0-5°C for 2-3 hours. For example, the cooling temperature includes any value between 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, or 0-5°C, and the cooling time includes any value between 2 hours, 3 hours, or 2-3 hours.
[0034] According to embodiments of this application, the method for preparing the compound containing formula I includes: Compound II was reacted with a base in water to obtain an aqueous phase containing compound I; A benign solvent is added to the aqueous phase containing the compound of formula I, and extraction is performed to obtain an organic phase containing the compound of formula I, wherein the organic phase comprises the compound of formula I and the benign solvent; The structural formula of compound II is as follows: .
[0035] In some embodiments, the base comprises sodium hydroxide, and the mass ratio of compound II to the base is 10:0.2-0.3, for example, 10:0.21, 10:0.22, 10:0.23, 10:0.24, 10:0.25, 10:0.26, 10:0.27, 10:0.28, 10:0.29, 10:0.3, or any value between 10:0.2-0.3.
[0036] The reaction time of compound II with the base is 0.8-1.2 h, for example, 0.8 h, 0.9 h, 1 h, 1.1 h, 1.2 h or any value between 0.8-1.2 h.
[0037] According to embodiments of this application, the mass ratio of the benign solvent used for extraction to compound II is 2.3-2.9:1, and the number of extractions is greater than or equal to 2; for example, the mass ratio of the benign solvent used for extraction to compound II is 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1 or any value between 2.3 and 2.9:1, and the number of extractions is 2, 3, 4 or any value within the range of 2 or greater.
[0038] And / or, after the extraction is completed, the method further includes: drying the organic phase with anhydrous magnesium sulfate, followed by filtration to remove the anhydrous magnesium sulfate.
[0039] The implementation schemes of this application will be described in detail below with reference to specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating this application and should not be regarded as limiting the scope of this application. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.
[0040] Example 1: Preparation of crystal form B Preparation of sodium hydroxide aqueous solution: Add 20g of drinking water to a 50ml reaction flask, add 0.54g of sodium hydroxide while stirring, stir until dissolved, and set aside.
[0041] Add 80g of drinking water to a 250ml reaction flask, then add 20g of compound II, stir to dissolve, and then add the prepared sodium hydroxide aqueous solution dropwise. After the addition is complete, stir for 1 hour, filter, discard the filter cake, transfer the filtrate to a 250ml reaction flask, add 52g of dichloromethane, stir for 10 minutes, allow to stand and separate, extract the aqueous phase twice with 52g of dichloromethane, combine the organic phases, and dry with anhydrous magnesium sulfate for 1 hour. Filter, transfer the filtrate to a 250ml single-necked flask, concentrate under reduced pressure at 35-40℃ in a water bath to obtain 14.9g, add 120g of n-heptane, add 26g of dichloromethane dropwise while stirring, heat to reflux for 5 hours, then cool to 0℃ and maintain the temperature for 2 hours. Filter, dry under vacuum, collect the filter cake, dry at 40℃ to constant weight, and obtain 13.2g of white powdery solid (relatively loose, bulk density approximately 0.35).
[0042] The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate prepared in Example 1 is shown below. Figure 1 As shown in Table 1, the 2θ angle and peak intensity of the X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate are shown.
[0043] Table 1. 2θ angle and peak intensity in the X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate in Example 1.
[0044] The ¹H NMR spectrum of crystal form B of the edoxaban intermediate prepared in Example 1 is shown below. Figure 2 As shown. HNMR (DMSO-d6, 400MHz) δ H 6.57 (s, 1H), 3.69 (s, 1H), 2.98 (s, 3H), 2.79-2.84 (m, 4H), 2.65-2.69 (m, 1H), 1.79 (d, J=8.0, 1H), 1.57 (d, J=8.0, 1H), 1.26-1.51 (m, 16H).
[0045] Example 2: Preparation of crystal form A Preparation of sodium hydroxide aqueous solution: Add 20g of drinking water to a 50ml reaction flask, add 0.54g of sodium hydroxide while stirring, stir until dissolved, and set aside.
[0046] Add 80g of drinking water to a 250ml reaction flask, then add 20g of compound II, stir to dissolve, and then add the prepared sodium hydroxide aqueous solution dropwise. After the addition is complete, stir for 1 hour, filter, discard the filter cake, transfer the filtrate to a 250ml reaction flask, add 52g of dichloromethane, stir for 10 minutes, let stand and separate the liquid, extract the aqueous phase twice with 52g of dichloromethane, combine the organic phases, and dry with anhydrous magnesium sulfate for 1 hour. Filter, transfer the filtrate to a 250ml single-necked flask, distill off 130g of dichloromethane at normal pressure, leaving 26g of dichloromethane. Stop distillation when the mass ratio of the remaining dichloromethane to compound I is 1.7:1. Add 120g of n-heptane dropwise under reflux, and the product gradually precipitates. After the addition is complete, reflux for 4 hours, then cool to 1℃ and keep warm for 3 hours. Filter, dry, collect the filter cake and dry it at 40°C with forced air until constant weight, and collect 13.6g of white powdery solid (bulk density about 0.43).
[0047] The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate prepared in Example 2 is shown below. Figure 3 As shown in Table 2, the 2θ angle and peak intensity of the X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate prepared in Example 2 are shown in Table 2.
[0048] Table 2. X-ray powder diffraction patterns of crystal form A of edoxaban intermediate in Example 2, showing the 2θ angle and peak intensity.
[0049] The 1H NMR spectrum of crystal form A of the edoxaban intermediate prepared in Example 2 is as follows: Figure 4 As shown. HNMR (DMSO-d6, 400MHz) δ H 6.57 (s, 1H), 3.70 (s, 1H), 2.99 (s, 3H), 2.79-2.84 (m, 4H), 2.67-2.69 (m, 1H), 1.80 (d, J=8.0, 1H), 1.57 (d, J=8.0, 1H), 1.26-1.52 (m, 16H).
[0050] Example 3: Preparation of crystal form A Preparation of sodium hydroxide aqueous solution: Add 20g of drinking water to a 50ml reaction flask, add 0.54g of sodium hydroxide while stirring, stir until dissolved, and set aside.
[0051] Add 80g of drinking water to a 250ml reaction flask, then add 20g of compound II, stir to dissolve, and then add the prepared sodium hydroxide aqueous solution dropwise. After the addition is complete, stir for 1 hour, filter, discard the filter cake, transfer the filtrate to a 250ml reaction flask, add 52g of dichloromethane, stir for 10 minutes, let stand and separate the liquid, extract the aqueous phase twice with 52g of dichloromethane, combine the organic phases, and dry with anhydrous magnesium sulfate for 1 hour. Filter, transfer the filtrate to a 250ml single-necked flask, add 120g of n-heptane at once, distill off 130g of dichloromethane under normal pressure, leaving about 26g of dichloromethane. Stop distillation when the mass ratio of the remaining dichloromethane to compound I is 1.6:1, and the product gradually precipitates out. Reflux for 5 hours, then cool to 2℃ and keep warm for 2 hours. Filter, dry under vacuum, collect the filter cake and dry it at 40℃ to constant weight, obtaining 13.5g of white powdery solid (bulk density about 0.43).
[0052] Stability test Furthermore, accelerated testing was conducted on the crystal forms prepared in Examples 1-3 to determine their stability. The conditions for the accelerated testing were: temperature 40℃ and humidity 75%RH. The test results are shown in Table 3 below.
[0053] Table 3 Comparison of Crystal Form Stability Test Results for Examples 1-3
[0054] As can be seen from Table 1, after 6 months of accelerated testing, the various indicators of the crystal forms in Examples 1-3 showed no significant changes compared with the initial time (0 months), and the purity was greater than 99.8%, indicating that the crystal forms in Examples 1-3 have excellent stability.
[0055] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.
[0056] Furthermore, those skilled in the art will understand that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and form different embodiments. For example, in the foregoing claims, any of the claimed embodiments can be used in any combination. The information disclosed in this background section is intended only to enhance the understanding of the general background of this application and should not be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
Claims
1. A crystal form of an edoxaban intermediate, characterized in that, The structural formula of the edoxaban intermediate is shown in Formula I: ; The crystalline forms of the edoxaban intermediate include crystalline form A, crystalline form B, or a mixture of crystalline form A and crystalline form B in any proportion; The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 11.20°, 17.66°, 18.61°, 19.29°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate has characteristic absorption peaks at 2θ angles of 7.99°, 10.82°, 13.33°, 18.22°, 18.48°, 19.34°, and 20.02°.
2. The crystal form of the edoxaban intermediate according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 11.20°, 17.46°, 17.66°, 18.61°, 19.29°, 24.35°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 7.99°, 10.82°, 11.15°, 13.08°, 13.33°, 15.84°, 16.80°, 17.97°, 18.22°, 18.48°, 19.34°, 20.02°, and 27.37°.
3. The crystal form of the edoxaban intermediate according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 9.67°, 11.20°, 17.46°, 17.66°, 18.61°, 19.29°, 20.53°, 24.35°, and 27.40°. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate shows characteristic absorption peaks at 2θ angles of 7.99°, 9.09°, 10.82°, 11.15°, 13.08°, 13.33°, 15.08°, 15.84°, 16.80°, 16.91°, 17.97°, 18.22°, 18.48°, 19.34°, 20.02°, 21.92°, and 27.37°.
4. The crystal form of the edoxaban intermediate according to any one of claims 1-3, characterized in that, The X-ray powder diffraction pattern of crystal form A of the edoxaban intermediate is shown in Figure 3. The X-ray powder diffraction pattern of crystal form B of the edoxaban intermediate is shown in Figure 1.
5. The method for preparing the crystal form of the edoxaban intermediate according to any one of claims 1-4, characterized in that, The method for preparing the crystal form of the edoxaban intermediate includes at least one of the following methods: (1) Provide an organic phase containing a compound of formula I, wherein the organic phase contains a compound of formula I and a good solvent; distill the organic phase to remove part of the good solvent in the organic phase until the mass ratio of the remaining good solvent to compound I is 1.5-1.8:1 and stop distillation to obtain a remaining solution; under reflux, add a poor solvent dropwise to the remaining solution to obtain a mixed system; after the dropwise addition is completed, heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain crystal form A of compound of formula I; (2) Provide an organic phase containing a compound of formula I, the organic phase comprising a compound of formula I and a good solvent; add a bad solvent to the organic phase to obtain a mixed solution, and distill the mixed solution to remove part of the good solvent in the mixed solution until the mass ratio of the remaining good solvent to compound I is 1.5-1.8:1, and stop distillation to obtain a mixed system; heat the mixed system to reflux, then cool it down, separate the solid and liquid, collect the solid and dry it to obtain crystal form A of compound of formula I; (3) Add a poor solvent to the compound of formula I, and then add a good solvent dropwise to form a mixed system; The mixture was heated to reflux, then cooled, and the solid and liquid were separated. The solid was collected and dried to obtain crystal form B of compound I.
6. The method for preparing the crystal form of the edoxaban intermediate according to claim 5, characterized in that, In method (1), in the step of obtaining the mixed system, the mass ratio of the poor solvent to the good solvent in the remaining solvent is 4.4-4.8:1; In method (2), in the step of obtaining the mixed solution, the mass ratio of the poor solvent to the good solvent in the organic phase is 1:1-1.6; In method (3), the mass ratio of the compound of formula I to the undesirable solvent is 1:7.8-8.2; In method (3), the mass ratio of the poor solvent to the good solvent is 4.4-4.8:
1.
7. The method for preparing the crystal form of the edoxaban intermediate according to claim 5, characterized in that, The benign solvent is dichloromethane, and the undesirable solvent is n-heptane.
8. The method for preparing the crystal form of the edoxaban intermediate according to claim 5, characterized in that, The reflux time is 4-6 hours; And / or, the cooling includes stirring at a temperature of 0-5°C for 2-3 hours.
9. The method for preparing the crystal form of the edoxaban intermediate according to any one of claims 5-8, characterized in that, The preparation method of the compound containing formula I includes: Compound II was reacted with a base in water to obtain an aqueous phase containing compound I; A benign solvent is added to the aqueous phase containing the compound of formula I, and extraction is performed to obtain an organic phase containing the compound of formula I, wherein the organic phase comprises the compound of formula I and the benign solvent; The structural formula of compound II is as follows: .
10. The method for preparing the crystal form of the edoxaban intermediate according to claim 9, characterized in that, The mass ratio of the benign solvent used for extraction to compound II is 2.3-2.9:1, and the number of extractions is greater than or equal to 2. And / or, after the extraction is completed, the method further includes: drying the organic phase with anhydrous magnesium sulfate, followed by filtration to remove the anhydrous magnesium sulfate.