Refining method of methyl diene diketone

Abstract

The invention provides a refining method of methyl diene diketone. By utilizing the method, unknown single impurities in methyl diene diketone sold in the market at present can be removed, and high-purity methyl diene diketone is obtained.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field, and in particular relates to a method for refining methyldiene diketone. Background Art

[0002] Methyldiene diketone is a common pharmaceutical intermediate, widely used in organic synthesis, and can be used as a synthetic raw material for ketones. The molecular formula of methyldiene diketone is C 18 H 22 O 2 , molecular weight is 270.366, structure is as follows:

[0003]

[0004] The methyl diethylene diketone currently sold on the market produced by a Hubei merchant contains three impurities above 0.10%, of which the largest single impurity is 0.519%. The three impurities are RT (Retention Time) = 4.315min, RT = 6.560min and RT = 21.453min ( Fig.10 ). There are three impurities above 0.10% in methyl diene diketone produced by a Jiangxi merchant, of which the largest single impurity is 0.379%. The three impurities are RT = 4.319min, RT = 6.675min and RT = 21.807min ( Fig.11 ). Currently, the methyldiene diketone available on the market contains many impurities, a single impurity is relatively large, and the overall purity is relatively low.

[0005] Therefore, there is an urgent need in the art for a purification process to remove impurities in methyldiolefine diketone and improve the purity of methyldiolefine diketone. Summary of the invention

[0006] In view of the problem existing in the prior art, namely, the problem that commercially available methyldiene diketone contains a large number of impurities, the present invention provides a purification method capable of preparing high-purity methyldiene diketone.

[0007] The present invention provides a method for refining methyldiene diketone, the method comprising:

[0008] 1) dissolving methyldiene diketone in a first solvent to obtain a first solvent system;

[0009] 2) adding a second solvent dropwise to the first liquid-solvent system and crystallizing for a first period of time to obtain a first solid-liquid mixed system;

[0010] 3) performing solid-liquid separation on the first solid-liquid mixed system and drying the collected solid to obtain a primary refined product;

[0011] 4) dissolving the primary refined product in a third solvent and crystallizing for a second period of time to obtain a second solid-liquid mixed system;

[0012] 5) subjecting the second solid-liquid mixed system to solid-liquid separation to obtain methyl diene diketone in solid form;

[0013] in,

[0014] The first solvent is C 1 -C 6 Monohydric alcohol;

[0015] The second solvent is water;

[0016] The third solvent is selected from ethyl acetate, n-heptane, or a mixture of ethyl acetate and n-heptane.

[0017] In summary, the present invention provides a method for refining methyldiene diketone using a mixed solvent, which has one or more of the following beneficial effects:

[0018] 1) The purification method has a strong impurity removal ability and a high yield of about 85%-95%, which can effectively improve the purity of methyldiene diketone (up to 99.8%), control the single impurity below 0.10%, improve the usability of methyldiene diketone, and greatly reduce the cost of use;

[0019] 2) The solvent used in the refining method is a conventional solvent, such as methanol, ethanol, isopropanol, ethyl acetate, n-heptane and water, which improves the safety of production;

[0020] 3) The purification method has a stable system, simple operation and is easy to realize industrial production during the treatment process. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the specific implementation manner of the present invention, the drawings in the specific implementation manner are briefly introduced below.

[0022] Figure 1-Figure 2 The HPLC test results of methyldiene diketone obtained by the first purification and the second purification in Example 1 are shown respectively.

[0023] Figure 3-Figure 5 The HPLC detection results of methyldiene diketone obtained by the second purification in Example 2, Example 3 and Example 4 are shown respectively.

[0024] Figure 6-Figure 9 The HPLC test results of methyldiene diketone obtained in Comparative Example 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4 are shown respectively.

[0025] Figure 10-11The HPLC test results of two types of methyldiene diketone currently available on the market are shown. DETAILED DESCRIPTION

[0026] Hereinafter, the present invention will be described in detail. It should be understood that the following description is only used to illustrate the present invention by way of example, and is not intended to limit the scope of the present invention. The scope of protection of the present invention shall be subject to the attached claims. In addition, those skilled in the art will understand that the technical solution of the present invention may be modified without departing from the spirit and purpose of the present invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs. Before describing the present invention in detail, the following definitions are provided for a better understanding of the present invention.

[0028] In the context of the present invention, many embodiments use the expressions "comprising", "including" or "consisting essentially / mainly of..." The expressions "comprising", "including" or "consisting essentially / mainly of..." should be understood as open-ended expressions, indicating that in addition to the elements, components, assemblies, method steps, etc. specifically listed after the expression, other elements, components, assemblies, method steps, etc. are also included. In addition, in this article, the expressions "comprising", "including" or "consisting essentially / mainly of..." may also be understood as closed expressions in some cases, indicating that only the elements, components, assemblies, method steps specifically listed after the expression are included, and no other elements, components, assemblies, method steps are included. At this time, the expression is equivalent to the expression "consisting of..."

[0029] It should be noted that, for the numerical values ​​or numerical ranges mentioned herein, unless the context clearly states otherwise, they are all limited by the term "about". In this article, for a certain numerical value, the term "about" means ±5% of the numerical value, such as ±4%, ±3%, ±2%, or ±1%, and for a certain numerical range, the term "about" means ±5% of the upper and lower limits of the numerical range, such as ±4%, ±3%, ±2%, or ±1%.

[0030] In this document, ordinal numbers such as "first", "second", "third", etc. are sometimes used to modify or qualify elements, components, assemblies, method steps, solutions, solvents, temperatures, systems, etc. It should be noted that, in this document, these expressions are only used to distinguish the elements, components, assemblies, method steps, solutions, solvents, temperatures, systems, etc. that they modify or qualify, and are not intended to limit their order or importance.

[0031] As mentioned above, the present invention aims to solve the problem that the impurities in the current chemical synthesis process of methyldiene diketone are large and unknown impurities are difficult to remove.

[0032] Therefore, the present invention provides a method for refining methyldiene diketone, the method comprising:

[0033] 1) dissolving methyldiene diketone in a first solvent to obtain a first solvent system;

[0034] 2) adding a second solvent dropwise to the first liquid-solvent system and crystallizing for a first period of time to obtain a first solid-liquid mixed system;

[0035] 3) performing solid-liquid separation on the first solid-liquid mixed system and drying the collected solid to obtain a primary refined product;

[0036] 4) dissolving the primary refined product in a third solvent and crystallizing for a second period of time to obtain a second solid-liquid mixed system;

[0037] 5) subjecting the second solid-liquid mixed system to solid-liquid separation to obtain methyl diene diketone in solid form;

[0038] in,

[0039] The first solvent is C 1 -C 6 Alkanol;

[0040] The second solvent is water;

[0041] The third solvent is selected from ethyl acetate, n-heptane, or a mixture of ethyl acetate and n-heptane.

[0042] Compound.

[0043] As mentioned above, the first solvent may be C 1 -C 6 Monohydric alcohols such as methanol, ethanol, 1-propanol, isopropanol (2-propanol), 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, or branched alcohols thereof.

[0044] In a preferred embodiment, the C 1 -C 6 The monohydric alcohol may be methanol, ethanol or isopropanol.

[0045] Each step of the method can be carried out at the same or different temperatures. For example, steps 1) to 5) can be carried out at the same temperature, or, steps 1) and 2) can be carried out at the same temperature, while steps 3), 4) and 5) are carried out at different temperatures, or, steps 1) to 5) can be carried out at different temperatures, and so on. In one embodiment, each step of the method is carried out at room temperature, for example, at 25°C ± 5°C. In a preferred embodiment, each step of the method is carried out at 10°C-35°C. More specifically, the temperature can be 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, or any temperature therebetween. In a more preferred embodiment, the temperature is 25°C-35°C. In the process of implementing the method, the temperature is not limited to a specific value, but can vary within a certain range, for example, 25°C-35°C.

[0046] In one embodiment, the volume mass ratio of the first solvent, the second solvent, the third solvent and the methyldiene diketone is (6-7):(11-16):(1-6):1, wherein the volumes of the first solvent, the second solvent and the third solvent are measured in milliliters, and the mass of the methyldiene diketone is measured in grams. Specifically, for one mass part of methyldiene diketone, the volume of the first solvent can be 6 parts, 6.1 parts, 6.2 parts, 6.3 parts, 6.4 parts, 6.5 parts, 6.6 parts, 6.7 parts, 6.8 parts, 6.9 parts or 7.0 parts or any value therebetween, the volume of the second solvent can be 11 parts, 11.5 parts, 12 parts, 12.5 parts, 13 parts, 13.5 parts, 14 parts, 14.5 parts, 15 parts, 15.5 parts, 16 parts or any value therebetween, the volume of the third solvent can be 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts or any value therebetween. The inventors have found in multiple experiments that when using a volume-to-mass ratio outside the above range, the yield of methyldiene diketone is reduced, and the impurity removal effect is not good, which reduces the purity of methyldiene diketone. In a preferred embodiment, the first solvent is methanol, the third solvent is ethyl acetate, and the volume mass ratio of the first solvent, the second solvent, the third solvent and the methyl diene diketone is 6:(11-12):(1-3):1.

[0047] In one embodiment, the third solvent is a mixture of ethyl acetate and n-heptane, and the mass ratio of ethyl acetate to n-heptane is (0.5-2): 1. In a preferred embodiment, the mass ratio of ethyl acetate to n-heptane is 2: 1. In a more preferred embodiment, the first solvent is ethanol or isopropanol, and the third solvent is a mixture of ethyl acetate and n-heptane, wherein the mass ratio of ethyl acetate to n-heptane is 2: 1, and the volume mass ratio of the first solvent, the second solvent, the third solvent and the methyldiene diketone is 7: 11: (5-6): 1.

[0048] In one embodiment, the first time period and the second time period can be identical or different. In a preferred embodiment, the first time period and the second time period are 2-5 hours, for example 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours or any numerical value therebetween. In an exemplary embodiment, the first time period is 2 hours. In another exemplary embodiment, the second time period is 5 hours.

[0049] In the method, methyldiene diketone is purified (i.e., crystallized) twice in total, and different impurities in methyldiene diketone are removed by each purification. After the two purifications, methyldiene diketone with a high purity is obtained.

[0050] Optionally, the solid form of methyldiene diketone obtained in step 5) may be dried, and there is no particular limitation on the drying method.

[0051] Optionally, the reaction system may be stirred during the crystallization process to ensure better crystal precipitation.

[0052] The inventors conducted multiple methyldiene diketone refining tests using different solvents and different solvent ratios, and finally determined the selection of the above solvents and solvent ratios. The method of the present invention can effectively remove unknown single impurities and larger known single impurities in commercially available methyldiene diketone, obtain high-purity methyldiene diketone, and increase the purity of methyldiene diketone from less than 99% to about 99.8%.

[0053] Example

[0054] The following will clearly and completely describe the concept of the present invention and the technical effects produced in combination with the embodiments and drawings, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0055] Example 1

[0056] Anhydrous methanol (120 mL, 6 v) and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (240 mL, 12 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the mixture was filtered, and the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours. The collected material was weighed to obtain a primary refined product of 19.36 g, with a yield of 96.80%, and the purity of methyldiene diketone was 99.314% ( Figure 1 ); Take another reaction bottle, add ethyl acetate (38.72mL, 2v), the first refined product (19.36g, 1.0eq), and beat at 25℃-35℃ for 5 hours; filter, and place the filter cake in a 40℃ forced air oven to dry for 3 hours to obtain 17.81g of refined product, with a yield of 91.99%, and the purity of methyldiene diketone is 99.799% ( Figure 2 ).

[0057] Example 2

[0058] Anhydrous methanol (120 mL, 6 v) and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (230 mL, 11.5 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours, and the collected material was weighed to obtain a primary refined product. The product was 19.15g, the yield was 95.75%, and the purity of methyldiene diketone was 99.212%; another reaction bottle was added with ethyl acetate (57.45mL, 3v) and the first refined product (19.15g, 1.0eq), and slurried at 25℃-35℃ for 5 hours; filtered, and the filter cake was placed in a 40℃ forced air oven and dried for 3 hours to obtain 17.35g of refined product, with a yield of 90.60%, and the purity of methyldiene diketone was 99.559% ( Figure 3 ).

[0059] Example 3

[0060] Anhydrous ethanol (140 mL, 7 v) and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (220 mL, 11 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours. The collected material was weighed to obtain 19.26 g of a primary refined product. The yield was 96.30%, and the purity of methyldiene diketone was 99.32%; another reaction bottle was added with ethyl acetate (77.04 mL, 4 v) and n-heptane (38.52 mL, 2 v) and a first refined product (19.26 g, 1.0 eq), and slurried at 25°C-35°C for 5 hours; filtered, and the filter cake was placed in a 40°C forced air oven and dried for 3 hours to obtain 17.82 g of a refined product with a yield of 92.52% and a purity of methyldiene diketone of 99.808% ( Figure 4 ).

[0061] Example 4

[0062] Isopropanol (140 mL, 7 v) and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (220 mL, 11 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours. The collected material was weighed to obtain 19.04 g of a primary refined product, and the collected product was The yield was 95.20%, and the purity of methyldiene diketone was 99.22%; another reaction bottle was added with ethyl acetate (76.16mL, 4v) and n-heptane (38.08mL, 2v) and a primary refined product (19.04g, 1.0eq), and slurried at 25°C-35°C for 5 hours; filtered, and the filter cake was placed in a 40°C forced air oven and dried for 3 hours to obtain 17.02g of a refined product with a yield of 89.39% and a purity of methyldiene diketone of 99.813% ( Figure 5 ).

[0063] Comparative Example 1

[0064] Anhydrous methanol (80 mL, 4 v), acetonitrile (20 mL, 1 v), and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (80 mL, 4 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours. The collected material was weighed to obtain 13.78 g of a refined product, with a yield of 68.9%, and the purity of methyldiene diketone was 99.143% ( Figure 6 ).according to Figure 6 It can be seen that the impurities at RT=4.359 min and RT=21.793 min were not removed and the yield of methyl diene diketone was low.

[0065] Comparative Example 2

[0066] Anhydrous methanol (80 mL, 4 v), tetrahydrofuran (25 mL, 1.25 v), and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (60 mL, 3 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours. The collected material was weighed to obtain 14.88 g of a refined product, with a yield of 74.4%, and the purity of methyldiene diketone was 99.109% ( Figure 7 ).according to Figure 7 It can be seen that the impurities at RT=4.359min and RT=21.791min were not removed and the yield of methyldiene diketone was not high.

[0067] Comparative Example 3

[0068] Anhydrous methanol (80 mL, 4 v), ethyl acetate (40 mL, 2 v), and methyldiene diketone (20.0 g, 1.0 eq) were added to the reaction flask, and the methyldiene diketone was dissolved at 25°C-35°C; purified water (100 mL, 5 v) was added to the reaction flask at 25°C-35°C, and the mixture was stirred for crystallization for 2 hours; the filter cake was rinsed with purified water (20 mL, 1.0 v), and the filter cake was placed in a 40°C forced air oven and dried for 4 hours. The collected material was weighed to obtain 12.56 g of a refined product, with a yield of 62.8%, and the purity of methyldiene diketone was 99.100% ( Figure 8 ).according to Figure 8 It can be seen that the impurities at RT = 21.797 min were not removed and the yield of methyl diene diketone was low.

[0069] Comparative Example 4

[0070] Add anhydrous methanol (100 mL, 5 v) and methyldiene diketone (20.0 g, 1.0 eq) to the reaction flask, dissolve the methyldiene diketone at 25°C-35°C; add purified water (240 mL, 12 v) to the reaction flask at 25°C-35°C, stir and crystallize for 2 hours; filter, rinse the filter cake with purified water (20 mL, 1.0 v), dry the filter cake in a 40°C forced air oven for 4 hours, and collect the material. Weighing to obtain 19.33 g of a first refined product with a yield of 96.65%; taking another reaction bottle, adding ethyl acetate (38.66 mL, 2 v) and a first refined product (19.33 g, 1.0 eq), beating at 25°C-35°C for 5 hours; filtering, placing the filter cake in a 40°C forced air oven and drying for 3 hours, to obtain 17.78 g of a refined product with a yield of 91.98%, and the purity of methyldiene diketone is 99.69% ( Fig. 9 ).according to Fig. 9 It can be seen that the impurities at RT = 4.360 min were not removed, which is presumably due to the small volume of anhydrous methanol during the first purification.

[0071] Comparative Example 5

[0072] Add anhydrous methanol (120 mL, 6 v) and methyldiene diketone (20.0 g, 1.0 eq) to the reaction flask, dissolve the methyldiene diketone at 25°C-35°C; add purified water (240 mL, 12 v) to the reaction flask at 25°C-35°C, stir and crystallize for 2 hours; filter, rinse the filter cake with purified water (20 mL, 1.0 v), dry the filter cake in a 40°C forced air oven for 4 hours, and weigh the collected material to obtain a primary refined product. 19.23g, yield 96.15%, methyldiene diketone purity is 99.302%; take another reaction bottle, add ethyl acetate (134.61mL, 7v), a refined product (19.23g, 1.0eq), slurry at 25℃-35℃ for 5 hours; filter, place the filter cake in a 40℃ forced air oven and dry for 3 hours to obtain 10.76g of refined product, yield 55.95%, methyldiene diketone purity is 99.78%. It is speculated that the low yield of the product may be due to the large volume of ethyl acetate.

[0073] Conclusion: Based on the above examples, it can be seen that the method of the present invention can obtain methyldiene diketone with a purity of up to 99.8%. In addition, the present invention also provides comparative examples of refining methyldiene diketone using other methods to compare the yield and purity data. In comparative examples 1-3, the inventors tried to remove impurities in commercially available methyldiene diketone by a single refining; in comparative examples 4-5, the inventors tried to remove impurities in commercially available methyldiene diketone using a reagent volume ratio outside the protection scope of the present invention. It was found that the purity and yield of methyldiene diketone obtained by the single refining method were both low; although the method using the solvent volume outside the protection scope of the present invention can obtain methyldiene diketone with higher purity, its yield is low and it is still not suitable for industrial production.

[0074] The above is a detailed introduction to the method for refining methyldiene diketone provided by the present invention. The principles and implementation methods of the present invention are described in detail using specific examples herein. The description of the above examples is only used to help understand the method of the present invention and its core idea. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation method and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A method for refining methyldiene diketone, characterized in that: The method comprises: 1) dissolving methyldiene diketone in a first solvent to obtain a first solvent system; 2) adding a second solvent dropwise to the first liquid-solvent system and crystallizing for a first period of time to obtain a first solid-liquid mixed system; 3) performing solid-liquid separation on the first solid-liquid mixed system and drying the collected solid to obtain a primary refined product; 4) dissolving the primary refined product in a third solvent and crystallizing for a second period of time to obtain a second solid-liquid mixed system; 5) subjecting the second solid-liquid mixed system to solid-liquid separation to obtain methyldiene diketone in solid form; in, The first solvent is a C1-C6 monohydric alcohol, such as methanol, ethanol or isopropanol; The second solvent is water; The third solvent is selected from ethyl acetate, n-heptane, or a mixture of ethyl acetate and n-heptane.

2. The method according to claim 1, characterized in that The volume mass ratio of the first solvent, the second solvent, the third solvent and the methyldiene diketone is (6-7):(11-16):(1-6):1, wherein the volumes of the first solvent, the second solvent and the third solvent are measured in milliliters, and the mass of the methyldiene diketone is measured in grams.

3. The method according to claim 2, characterized in that The first solvent is methanol, the third solvent is ethyl acetate, and the volume mass ratio of the first solvent, the second solvent, the third solvent and the methyl diene diketone is 6:(11-12):(1-3):

1.

4. The method according to claim 1 or 2, characterized in that: The third solvent is a mixture of ethyl acetate and n-heptane, and the mass ratio of ethyl acetate to n-heptane is (0.5-2):

1.

5. The method according to claim 4, wherein the mass ratio of ethyl acetate to n-heptane is 2:

1.

6. The method according to claim 4 or 5, characterized in that: The first solvent is ethanol or isopropanol, and the volume mass ratio of the first solvent, the second solvent, the third solvent and the methyl diene diketone is 7:11:(5-6):

1.

7. The method according to any one of claims 1 to 6, characterized in that The first time period is the same as or different from the second time period.

8. The method according to any one of claims 1 to 7, characterized in that The first time period and the second time period are 2-5 hours.

9. The method according to any one of claims 1 to 8, characterized in that The first time period is 2 hours.

10. The method according to any one of claims 1 to 9, characterized in that The second time period is 5 hours.

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