New crystal form of menadione and preparation method thereof

Abstract

The invention discloses a novel crystal form of menadione and a preparation method, and relates to the technical field of organic chemistry. The novel crystal form comprises a crystal form T, and the crystal form T has diffraction peaks when the 2theta value is 9.970 + / -0.2 degrees, 12.250 + / -0.2 degrees, 14.978 + / -0.2 degrees and 19.141 + / -0.2 degrees. The preparation method of the novel crystal form comprises the following steps: dissolving a menadione crude product in a mixed solvent composed of an ester solvent and an alcohol solvent, cooling to 10-20 DEG C, and crystallizing to obtain the menadione crystal form T; the menadione crystal form T obtained through the method is a novel crystal form, the crystal form is good in stability and solubility, a solvent system is environmentally friendly, solvent residues are very small, the risk is low, the medication safety is better guaranteed, the defects of an existing crystal form can be overcome, and high economic benefits and social benefits are achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemistry, and particularly relates to a new crystal form of tetraenyl menadione and a preparation method thereof. BACKGROUND

[0002] Tetraenyl menadione is a high-activity vitamin K2, and is originally researched by Nichi-Iko Pharmaceutical Co., Ltd. It was first approved for marketing in Japan in 1995. It was approved for marketing in China in 2010, and the trade name is: Gukang. It directly acts on osteoblasts to produce bone matrix protein (Gla) gamma-carboxyglutamate residues and enhances bone turnover by promoting bone formation. At the same time, it inhibits bone resorption, improves the imbalance of bone metabolism in osteoporosis, and has the effect of maintaining bone mass. Tetraenyl menadione is a homolog of vitamin K2, and is a coenzyme of gamma-carboxylase, which plays an important role in the formation of gamma-carboxyglutamate. Gamma-carboxyglutamate is essential for osteocalcin to exert normal physiological functions and has the effect of increasing bone mass. After oral administration, the average concentration in the plasma begins to rise after a lag of about 1 hour, and reaches a peak at 6 hours after administration; the absorption rate is lower when administered on an empty stomach than when administered after a meal. Tetraenyl menadione soft capsules are drugs for treating osteoporosis, and are recommended drugs in the “Guidelines for Diagnosis and Treatment of Primary Osteoporosis” and the “Guidelines for Diagnosis and Treatment of Osteoporosis in Combination with Traditional Chinese and Western Medicine”.

[0003] The patent document with the publication number WO2007032378A1 is an original research patent, and provides a method for producing tetraenyl menadione, which adopts acetone and ethanol for recrystallization, but the specific crystal form parameters and XRD data are not reported.

[0004] The patent document with the publication number CN115557835B provides a crystal form of vitamin K2, a preparation method and application thereof, and specifically discloses that: crystal forms A, B and C are included, 9-11 h of reaction is performed under irradiation of a 240-250 nm ultraviolet lamp, the reaction is concentrated to dryness after completion, and menadione disiloxane is obtained; the menadione disiloxane and an acid are added to ethyl acetate, heated, and then geranyl linalool or geranyl geraniol is added dropwise, the reaction liquid is stirred, cooled, filtered, concentrated, and vitamin K2 is obtained; the vitamin K2 is mixed with n-butanol and anhydrous ethanol, heated and dissolved, cooled and crystallized, the cooling temperature range is controlled to be 20-5℃, filtered, and vacuum dried, and vitamin K2 in the crystal form A is obtained. It can be seen that the patent document uses a 240-250 nm ultraviolet lamp for initiation, which is not suitable for industrial production, and the cooling temperature range for crystallization is controlled to be-20--5℃, the crystallization temperature is low, and the energy consumption and cost are high. The patent document with the publication number CN117865787A provides a tetraenyl menadione crystal form I and a preparation method thereof, specifically discloses that tetraenyl menadione crude product is dissolved in a mixed solvent of organic solvent 1 and organic solvent 2, the temperature is controlled to be 40-60 DEG C, stirring is performed until the solution is clear, the obtained mixed solution is cooled to-10-0 DEG C, and crystals are precipitated, the reaction solution is stirred, filtered, and a filter cake is obtained, the filter cake is washed with an organic solvent, and the material is baked under vacuum at 20-25 DEG C for 8 hours to obtain the tetraenyl menadione crystal form I; the organic solvent 1 is one of n-heptane, petroleum ether, n-hexane and n-pentane; and the organic solvent 2 is one of methanol, ethanol, isopropanol and n-butanol. It can be seen that the cooling crystallization temperature of the patent document is-10-0 DEG C, and the problems of low crystallization temperature, high energy consumption and cost still exist.

[0005] In summary, the existing preparation methods of tetraenyl menadione crystal form all have defects, and the crystal form of a drug is directly related to the stability, quality and efficacy of the drug, therefore, it is of great significance and value to develop a new tetraenyl menadione crystal form. SUMMARY

[0006] The present application aims to solve the technical problems of the existing preparation of tetraenyl menadione crystal form, such as the need for ultraviolet light initiation, low crystallization temperature, high energy consumption and cost, and unsuitability for industrial production, and provides a new crystal form of tetraenyl menadione and a preparation method thereof, the obtained tetraenyl menadione crystal form T is a new crystal form, which has good stability, good solubility, a green and environmentally friendly solvent system, small solvent residue, low risk and high drug safety, can make up for the shortcomings of the existing crystal form, and has high economic and social benefits.

[0007] The present application is achieved by the following technical solutions.

[0008] The first object of the present application is to provide a new crystal form of tetraenyl menadione, including crystal form T, which has diffraction peaks at 2 theta values of 9.970°±0.2°, 12.250°±0.2°, 14.978°±0.2° and 19.141°±0.2°.

[0009] The first object of the present application is to provide a preparation method of a new crystal form of tetraenyl menadione, including the following steps: The tetraenyl menadione crude product is dissolved in a mixed solvent composed of an ester solvent and an alcohol solvent, cooled to 10-20 DEG C, and crystallized to obtain tetraenyl menadione crystal form T.

[0010] The prior art uses ester solvent + alcohol solvent or acetone + alcohol solvent, which has the disadvantages of needing an initiator and having a low crystallization temperature, high energy consumption and cost, which limits the industrial production and application of the crystal form. Based on this, the inventors have obtained a new tetraenemenaquinone crystal form through long-term exploration and research, which has the advantages of simple preparation method, high crystallization temperature and low production cost.

[0011] The present application uses ester solvent + alcohol solvent combination for crystallization, which can crystallize the product at a temperature of 10-20 DEG C, is simple to operate, has low energy consumption and cost, is more suitable for industrial production, and the XRD 2 theta value of the crystal form of the present application is different from that of the prior art, which is a new crystal form, named crystal form T. The crystal form has good stability, and the solubility of the crystal form is basically the same as that of the original research crystal form. The solvent system is green and environmentally friendly, the risk of solvent residue is low, and the safety of the drug is more guaranteed. Therefore, the newly prepared tetraenemenaquinone crystal form T of the present application effectively makes up for the problems of the existing crystal form, such as the need for low-temperature crystallization and high energy consumption and cost, has high economic and social benefits, and is suitable for industrial production.

[0012] Further, the ester solvent includes any one or more of ethyl acetate, isopropyl acetate, methyl acetate, ethyl formate and isopropyl formate. The preferred ester solvent is ethyl acetate or isopropyl acetate.

[0013] Further, the alcohol solvent includes any one or more of ethanol, methanol, isopropyl alcohol, n-propanol, n-butanol, isobutyl alcohol and tert-butyl alcohol. The preferred alcohol solvent is ethanol, methanol or isopropyl alcohol.

[0014] Further, the volume ratio of the ester solvent to the tetraenemenaquinone crude product is 0.1-5. For example, the volume ratio of the ester solvent to the tetraenemenaquinone crude product is 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5.

[0015] Further, the volume ratio of the ester solvent to the tetraenemenaquinone crude product is 1-3. For example, the volume ratio of the ester solvent to the tetraenemenaquinone crude product is 1, 1.5, 2, 2.5 or 3.

[0016] Further, the volume ratio of the alcohol solvent to the tetraenemenaquinone crude product is 1-20. For example, the volume ratio of the alcohol solvent to the tetraenemenaquinone crude product is 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20. Further, the volume ratio of the alcohol solvent to the crude menatetrenone is 5-10. For example, the volume ratio of the alcohol solvent to the crude menatetrenone is 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10.

[0017] Further, the crystallization temperature is 15-20 DEG C. For example, the crystallization temperature is 15 DEG C, 16 DEG C, 17 DEG C, 18 DEG C, 19 DEG C, or 20 DEG C.

[0018] Further, a preparation method of a new crystal form of menatetrenone specifically comprises the following steps: The crude menatetrenone is dissolved in a mixed solvent composed of an ester solvent and an alcohol solvent, heated to 30-40 DEG C for dissolution, then cooled to 10-20 DEG C to precipitate a solid, then filtered, the filter cake is washed, and dried to obtain the menatetrenone crystal form T. The filter cake is washed with anhydrous ethanol, and dried under vacuum at 20-25 DEG C.

[0019] Compared with the prior art, the present application has the following advantages and beneficial effects.

[0020] The present application adopts ester solvent + alcohol solvent combination for crystallization, and the product can be precipitated at a temperature of 10-20 DEG C, which is simple to operate, low in energy consumption cost, more suitable for industrial production, and the XRD 2 theta value of the crystal form of the present application is different from that of the prior art, which is a new crystal form, named crystal form T. The crystal form T has good stability, and the solubility of the crystal form T is basically consistent with that of the original research crystal form. The solvent system is green and environmentally friendly, the risk of solvent residue is low, and the safety of the drug is more guaranteed. Therefore, the newly prepared menatetrenone crystal form T of the present application effectively makes up for the problems of the prior art, such as the need for low-temperature crystallization and high energy consumption cost, has high economic and social benefits, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0021] In order to more clearly illustrate the technical solutions of the example embodiments of the present application, the following will briefly introduce the drawings needed to be used in the examples. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be considered as a limitation to the scope. For those skilled in the art, other related drawings can also be obtained without creative labor. In the drawings: Figure 1 X-ray powder diffraction (XRD) pattern of the menatetrenone crystal form T prepared in Example 1 of the present application; Figure 2 Nuclear magnetic resonance hydrogen spectrum of the menatetrenone crystal form T prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0022] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the embodiments and drawings. Obviously, the illustrative embodiments of the present application and their descriptions are only used to explain the present application and not to limit the present application.

[0023] The embodiments of the new crystal form of tetraenemenaquinone and the preparation method of the present application will be described in detail below with reference to the accompanying drawings. However, unnecessary detailed descriptions will be omitted. For example, detailed descriptions of well-known matters and repeated descriptions will be omitted. This is to avoid the following description becoming unnecessarily lengthy and to facilitate understanding by those skilled in the art.

[0024] The ranges disclosed in the present application are defined in the form of lower limit and upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of a particular range. The ranges defined in this way can include or not include the end values, and can be arbitrarily combined, i.e., any lower limit can be combined with any upper limit to form a range.

[0025] If not specifically stated, all embodiments and optional embodiments of the present application can be combined with each other to form new technical solutions.

[0026] If not specifically stated, all technical features and optional technical features of the present application can be combined with each other to form new technical solutions.

[0027] If not specifically stated, the "comprising" and "including" mentioned in the present application means open-ended and can also be closed. For example, the "comprising" and "including" can mean that other substances not listed can also be included or contained, or only the listed substances can be included or contained.

[0028] If not specifically stated, all steps of the present application can be performed in sequence or randomly, and preferably in sequence. For example, the method comprises steps (a) and (b), which means that the method can comprise steps (a) and (b) performed in sequence, or steps (b) and (a) performed in sequence. For example, the method can further comprise step (c), which means that step (c) can be added to the method in any order. For example, the method can comprise steps (a), (b) and (c), or steps (a), (c) and (b), or steps (c), (a) and (b), etc.

[0029] The technical solutions of the present application will be described in further detail below with reference to the embodiments.

[0030] It should be noted that the experimental methods used in the examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used, unless otherwise specified, are conventional materials, reagents, methods and instruments in the art, which can be obtained by commercial channels by those skilled in the art.

[0031] Example 1 A method for preparing a new crystal form of tetraenemenaquinone, comprising the following steps: Take 2g of tetraenemenaquinone crude product in a 100ml glass three-necked flask, add 2mL of ethyl acetate and 10mL of ethanol, heat to 35℃ to completely dissolve, then cool to 15℃ at a rate of 5℃ / h, solid precipitates, continue to crystallize for 3h, filter, wash the filter cake with anhydrous ethanol, then dry at 25℃ under vacuum for 10h to obtain a light yellow crystalline powder, which is tetraenemenaquinone crystal form T.

[0032] The X-ray powder diffraction (XRD) pattern of the crystal form T obtained in this example is shown in Figure 1 It has diffraction peaks at 2θ values of 9.970°±0.2°, 12.250°±0.2°, 14.978°±0.2° and 19.141°±0.2°, which is a new crystal form, and the crystal form is MK-4, and the proton nuclear magnetic resonance spectrum is shown in Figure 2 .

[0033] Example 2 A method for preparing a new crystal form of tetraenemenaquinone, comprising the following steps: Take 2g of tetraenemenaquinone crude product in a 100ml glass three-necked flask, add 2mL of ethyl acetate and 10mL of ethanol, heat to 35℃ to completely dissolve, then cool to 15℃ at a rate of 5℃ / h, solid precipitates, continue to crystallize for 3h, filter, wash the filter cake with anhydrous ethanol, then dry at 25℃ under vacuum for 10h to obtain a light yellow crystalline powder, which is tetraenemenaquinone crystal form T.

[0034] Example 3 A method for preparing a new crystal form of tetraenemenaquinone, comprising the following steps: Take 2g of tetraenemenaquinone crude product in a 100ml glass three-necked flask, add 2mL of ethyl acetate and 10mL of ethanol, heat to 35℃ to completely dissolve, then cool to 15℃ at a rate of 5℃ / h, solid precipitates, continue to crystallize for 3h, filter, wash the filter cake with anhydrous ethanol, then dry at 25℃ under vacuum for 10h to obtain a light yellow crystalline powder, which is tetraenemenaquinone crystal form T.

[0035] Example 4 Take tetraenyl menadione crude 2 g in 100 ml glass three opening bottle, add 2 mL ethyl acetate, 10 mL isopropyl alcohol, heat 35℃ completely dissolved, cooling to 20℃, cooling speed is 5℃ / h, solid precipitate, continue to crystallize 3h, filter, filter cake with anhydrous ethanol, then in 23℃ vacuum drying 10h, get light yellow crystalline powder, get tetraenyl menadione crystal form T.

[0036] Example 5 Take tetraenyl menadione crude 2 g in 100 ml glass three opening bottle, add 2 mL ethyl acetate, 10 mL isopropyl alcohol, heat 35℃ completely dissolved, cooling to 20℃, cooling speed is 5℃ / h, solid precipitate, continue to crystallize 3h, filter, filter cake with anhydrous ethanol, then in 23℃ vacuum drying 10h, get light yellow crystalline powder, get tetraenyl menadione crystal form T.

[0037] Example 6 Take tetraenyl menadione crude 2 g in 100 ml glass three opening bottle, add 2 mL ethyl acetate, 10 mL isopropyl alcohol, heat 35℃ completely dissolved, cooling to 20℃, cooling speed is 5℃ / h, solid precipitate, continue to crystallize 3h, filter, filter cake with anhydrous ethanol, then in 23℃ vacuum drying 10h, get light yellow crystalline powder, get tetraenyl menadione crystal form T.

[0038] Comparative Example 1 The difference between this comparative example and example 1 is that it is cooled to 25℃ naturally, and the rest is unchanged. It is found that solid cannot be precipitated at this temperature.

[0039] Comparative Example 2 The difference between this comparative example and example 1 is that ethyl acetate is replaced by n-heptane, and the rest is unchanged. It is found that solid cannot be precipitated at 15℃ when the ester solvent + alcohol solvent is replaced by the alkane solvent + alcohol solvent.

[0040] Comparative Example 3 The difference between this comparative example and example 1 is that ethyl acetate is replaced by acetone, and the rest is unchanged. It is found that solid cannot be precipitated at 15℃ when the ester solvent + alcohol solvent is replaced by acetone + alcohol solvent.

[0041] The products prepared in the above examples 1-6 are detected for performance, among which the stability is detected by high performance liquid chromatography, and the results are shown in table 1.

[0042] Table 1, performance detection data of products prepared in examples 1-6

[0043] From the crystallization results of the examples and comparative examples, it can be seen that the ester solvent + alcohol solvent combination is used for crystallization in the present application, and solid can be crystallized at a temperature of 10-20℃, while the ester solvent + alcohol solvent or acetone + alcohol solvent cannot crystallize solid at a temperature of 15℃, and if solid is to be crystallized, the temperature needs to be reduced to below 0℃ as shown in the prior art, which will result in a large energy consumption, and the production cost is significantly increased, and the preparation method of the present application is simple to operate, and does not require strict conditions or environment, and is suitable for industrial application and popularization.

[0044] From the data in Table 1, it can be seen that the tetraenemenaquinone crystal form T prepared by the present application has good stability, good solubility, green and environmentally friendly solvent system, small solvent residue, low risk, and higher drug safety, and can greatly reduce the cost of changing the preparation process.

[0045] In summary, the tetraenemenaquinone crystal form T prepared by the present application as a new crystal form can make up for the various shortcomings of the existing crystal form, and has high economic and social benefits.

[0046] Finally, it should be noted that: the above specific examples are only used to explain the purpose, technical solutions and beneficial effects of the present application, and it should be understood that the above description is only a specific embodiment of the present application, and is not used to limit the protection scope of the present application; although the present application has been described in detail with reference to the foregoing specific examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement, improvement, etc. to part or all of the technical features; and these modifications, equivalent replacement, improvement do not make the essence of the corresponding technical solution deviate from the scope of the technical solutions of the embodiments of the present application, and they should be covered in the scope of the claims and the specification of the present application.

Claims

1. A new crystalline form of tetrahydro menadione characterized in that, The crystal form T comprises diffraction peaks at 2θ values of 9.970°±0.2°, 12.250°±0.2°, 14.978°±0.2°, and 19.141°±0.2°.

2. A process for the preparation of a new crystalline form of tetraenemenaquinone according to claim 1, characterized in that, The method comprises the following steps: The tetraenemenaphthoquinone crude product is dissolved in a mixed solvent composed of an ester solvent and an alcohol solvent, and then cooled to 10-20 ℃ to obtain the tetraenemenaphthoquinone crystal form T after crystallization.

3. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 2, characterized in that, The ester solvent comprises any one or more of ethyl acetate, isopropyl acetate, methyl acetate, ethyl formate, and isopropyl formate.

4. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 2, characterized in that, The alcohol solvent comprises any one or more of ethanol, methanol, isopropyl alcohol, n-propanol, n-butanol, isobutyl alcohol, and tert-butyl alcohol.

5. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 2, characterized in that, The volume ratio of the ester solvent to the tetraenemenaphthoquinone crude product is 0.1-5.

6. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 5, characterized in that, The volume ratio of the ester solvent to the tetraenemenaphthoquinone crude product is 1-3.

7. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 2, characterized in that, The volume ratio of the alcohol solvent to the tetraenemenaphthoquinone crude product is 1-20.

8. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 7, characterized in that, The volume ratio of the alcohol solvent to the tetraenemenaphthoquinone crude product is 5-10.

9. A process for the preparation of a new crystalline form of tetrahydro menadione according to claim 2, characterized in that, The crystallization temperature is 15-20 ℃.

10. A process for the preparation of a novel crystalline form of tetrahydro menadione according to claim 2, characterized in that, The method comprises the following steps: The tetraenemenaphthoquinone crude product is dissolved in a mixed solvent composed of an ester solvent and an alcohol solvent, and then heated to 30-40 ℃ for dissolution, and then cooled to 10-20 ℃ to precipitate a solid, and then filtered, washed, and dried to obtain the tetraenemenaphthoquinone crystal form T.

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