Flurbiprofen axetil crystals and preparation method thereof, and flurbiprofen axetil purification method

Abstract

The present invention provides a kind of Flurbiprofen axetil crystal and preparation method thereof and Flurbiprofen axetil purification method.The preparation method of the Flurbiprofen axetil crystal includes: Flurbiprofen axetil liquid crude product is placed in a container, standing at 5~20 DEG C for 36h or more, the crystal separated out is separated from the residual liquid, and the Flurbiprofen axetil crystal is obtained.The crystal preparation method of the present invention not only avoids the use of solvent, simplifies process operation, and obtains the Flurbiprofen axetil crystal of two new crystal forms, and meanwhile, the gained Flurbiprofen axetil crystal can obtain highly purified Flurbiprofen axetil product after being heated and melted.

Description

Technical Field

[0001] The invention belongs to the field of chemistry, and particularly relates to a flurbiprofen axetil crystal, a preparation method thereof, and a flurbiprofen axetil purification method. Background Art

[0002] Flurbiprofen axetil is a prodrug of flurbiprofen. However, flurbiprofen is unstable, so flurbiprofen axetil is commonly used as a medicine. Flurbiprofen axetil is metabolized in the body to produce the active substance flurbiprofen. During the preparation process, the purity of flurbiprofen axetil will affect the quality of the product. Therefore, improving the purity of flurbiprofen axetil is crucial.

[0003] Chinese patent application CN103254075A discloses the purification of flurbiprofen axetil by a method for vacuum distillation, but the temperature of vacuum distillation is too high, the heat transfer efficiency is low, and the sample is exposed to high temperature for a long time and can cause flurbiprofen axetil to decompose. Chinese patent application CN103012144A discloses a method for purifying flurbiprofen axetil through two molecular distillations, but molecular distillation equipment is expensive and has low production capacity, which restricts industrial production; and molecular distillation apparatus must ensure that system pressure reaches high vacuum, has high requirements for material sealing, and the distance between evaporation surface and condensation surface is moderate, equipment processing difficulty is large, and cost is high. Chinese patent applications CN104649906A and CN108558651A disclose a purification method using ordinary silica gel for column chromatography; Chinese patent application CN102381970A discloses a purification method for adsorption by silica gel and activated carbon, but silica gel column chromatography has the disadvantages of long purification cycle, large amount of required solvent, etc., resulting in high product production cost.

[0004] Chinese patent application CN114075109A discloses a method for purifying flurbiprofen axetil, the method comprising: adding an organic solvent to a flurbiprofen axetil crude product, heating to dissolving under stirring, cooling, separating out solid, insulated and stirred crystallizing, temperature-controlled filtering, organic solvent washing, filter cakes drying, and obtaining flurbiprofen axetil white solid crystals. The crystalline form A obtained by the method uses Cu-Ka radiation, the X-ray powder diffraction pattern represented by 2θ angles at 9.6 ± 0.2, 13.8 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, 17.7 ± 0.2, 21.4 ± 0.2, 21.9 ± 0.2, 23.6 ± 0.2, 26.0 ± 0.2 and 30.4 ± 0.2 has characteristic peaks. The method has complex steps, not only requires the use of an organic solvent, but also requires the crude product to be purified to a purity of more than 99.7% and then crystallized, and has higher requirements on the purity of the crude product.

[0005] Chinese patent application CN113527098A discloses a method for purifying flurbiprofen axetil, which comprises: 1) dissolving flurbiprofen axetil in an organic solvent, shaking it to fully dissolve it, and obtaining a flurbiprofen axetil solution, wherein the volume of the organic solvent is 2 to 50 times the mass of the flurbiprofen axetil; 2) stirring or allowing the flurbiprofen axetil solution to stand at -40 to 5°C for 0.5 to 72 hours until crystals precipitate; 3) filtering at a temperature below 25°C, washing the filter cakes with an organic solvent, and vacuum drying to obtain flurbiprofen axetil crystals, which are then stored below 30°C. The crystals obtained by this method have an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles at 9.7, 12.9, 13.9, 16.0, 16.4, 17.3, 17.4, 17.8, 18.8, 19.4, 21.6, 22.0, 22.3, 23.2, 23.4, 23.7, 25.3, 26.1, and 30.6. This method is not only complicated in steps but also requires the use of an organic solvent, which is not conducive to industrial production.

[0006] Chinese patent application CN113173853A discloses a flurbiprofen axetil crystalline form I, which has characteristic peaks at 14.2±0.2, 16.3±0.2, 16.6±0.2, 17.5±0.2, 18.1+0.2, 21.8±0.2, 22.3±0.2, 23.9±0.2, 25.6±0.2, and 26.3:0.2 using Cu-Kα radiation and an X-ray powder diffraction pattern expressed in 2θ angles. The method comprises: adding a flurbiprofen axetil melt or crystal to a first solvent to form a uniform dispersion mixture, adding the flurbiprofen axetil crystalline form I as a seed crystal, crystallizing at -20 to 20°C, and filtering to obtain the flurbiprofen axetil crystalline form I. This method also requires the introduction of a solvent. Summary of the Invention

[0007] In view of the above problems, the object of the present invention is to provide a flurbiprofen axetil crystal and a preparation method thereof, as well as a flurbiprofen axetil purification method. The crystal preparation method not only avoids the use of solvents and simplifies the process operation, but also obtains two new crystal forms of flurbiprofen axetil crystals. At the same time, the obtained flurbiprofen axetil crystals can be heated and melted to obtain a high-purity flurbiprofen axetil product.

[0008] The above object of the present invention is achieved by providing the following technical solutions:

[0009] In a first aspect, the present invention provides a method for preparing flurbiprofen axetil crystals, comprising: placing a crude flurbiprofen axetil liquid product in a container, allowing it to stand at -5 to 20°C for 36 hours or more, separating the precipitated crystals from the residual liquid, and obtaining the flurbiprofen axetil crystals.

[0010] In the present invention, the residual liquid is mainly uncrystallized flurbiprofen axetil. In addition, the present invention is not particularly limited to the source of the flurbiprofen axetil crude liquid product, and the flurbiprofen axetil crude liquid product can be obtained by a conventional method in the art. For example, it is obtained by the following steps:

[0011] Acetone is added to flurbiprofen and potassium bicarbonate with stirring, and 1-bromoethyl acetate is added dropwise. After the reaction is carried out at room temperature, an organic solvent (e.g., ethyl acetate) is poured into the reaction solution to dilute the reaction solution. The organic layer is washed with an alkaline aqueous solution (e.g., a saturated aqueous sodium bicarbonate solution). The organic layer is dried (e.g., dried over anhydrous sodium sulfate) and concentrated to obtain a crude liquid product of flurbiprofen axetil.

[0012] In the present invention, the standing temperature can be selected as -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C or any point value within the range of any two of the above point values.

[0013] Preferably, the purity of the crude flurbiprofen axetil liquid product is greater than or equal to 95%, preferably greater than or equal to 97%.

[0014] Preferably, the standing temperature is 0-10°C.

[0015] Preferably, the standing time is 48 to 72 hours.

[0016] Preferably, the container is not made of plastic.

[0017] More preferably, the container is made of glass or metal.

[0018] Preferably, the glass is borosilicate glass, such as high borosilicate glass, medium borosilicate glass and low borosilicate glass, preferably medium borosilicate glass.

[0019] Preferably, the metal is a metal matrix of stainless steel or aluminum with or without a metal oxide film lining, for example, the stainless steel is 316L stainless steel.

[0020] Preferably, the separation of the precipitated solid from the residual liquid is performed by a method comprising the steps of pouring the liquid and / or filtering the liquid by suction and / or filtering the liquid by pressure.

[0021] In a second aspect, the present invention provides a flurbiprofen axetil crystal prepared by the preparation method according to the first aspect of the present invention, wherein the X-ray powder diffraction pattern thereof using Cu-Kα radiation and expressed in 2θ angles is 9.0±0.1, 9.7±0.1, 10.6±0.1, 11.2±0-1, 13.1±0.1, 13.6±0.1, 14.0±0.1, 14.5±0.1, 16. Characteristic peaks at 1±0.1, 16.5±0.1, 17.5±0.1, 17.8±0.1, 18.9±0.1, 19.3±0.1, 19.9±0.1, 21.1±0.1, 21.7±0.1, 22.1±0.1, 23.8±0.1, 25.4±0.1, 26.2±0.1, 28.1±0.1, 29.3±0.1, and 30.7±0.1.

[0022] In a third aspect, the present invention provides another flurbiprofen axetil crystal prepared by the preparation method according to the first aspect of the present invention, wherein the X-ray powder diffraction pattern thereof using Cu-Kα radiation and expressed in 2θ angles is 9.0±0.1, 9.8±0.1, 10.6±0.1, 11.2±0.1, 13.9±0.1, 14.5±0.1, 15.1±0.1, 16.1±0.1, 16.5±0.1, 17.5±0.1, 17 The characteristic peaks are at .9±0.1, 18.9±0.1, 19.5±0.1, 19.7±0.1, 21.2±0.1, 21.7±0.1, 22.2±0.1, 22.4±0.1, 23.3±0.1, 23.5±0.1, 23.8±0.1, 24.5±0.1, 25.4±0.1, 26.4±0.1, 26.8±0.1, 28.1±0.1, 29.2±0.1, and 30.3±0.1.

[0023] In a fourth aspect, the present invention provides a method for purifying flurbiprofen axetil, comprising the following steps:

[0024] (1) placing a crude flurbiprofen axetil liquid product in a container, allowing it to stand at -5 to 20° C. for 36 hours or longer, and separating the precipitated crystals from the residual liquid to obtain flurbiprofen axetil crystals;

[0025] (2) heating and melting the flurbiprofen axetil crystals to obtain purified flurbiprofen axetil.

[0026] In the present invention, the standing temperature can be selected as -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C or any point value within the range of any two of the above point values.

[0027] Preferably, the standing temperature is 0-10°C.

[0028] Preferably, the standing time is 48 to 72 hours.

[0029] Preferably, the heating and melting is carried out at a temperature of 50°C or above, preferably 50-60°C.

[0030] Preferably, the container is not made of plastic.

[0031] More preferably, the container is made of glass or metal.

[0032] Preferably, the glass is borosilicate glass, such as high borosilicate glass, medium borosilicate glass and low borosilicate glass.

[0033] Preferably, the metal is a metal matrix of stainless steel or aluminum with or without a metal oxide film lining, for example, the stainless steel is 316L stainless steel.

[0034] Preferably, the separation of the precipitated solid from the residual liquid is performed by a method comprising the steps of pouring the liquid and / or filtering the liquid by suction and / or filtering the liquid by pressure.

[0035] Compared with the prior art, the present invention has at least the following beneficial effects:

[0036] 1. The inventors of the present invention unexpectedly discovered that by allowing a crude flurbiprofen axetil product to stand at -5 to 20°C for 36 hours or more, two new crystal forms of flurbiprofen axetil crystals can be obtained, and the two new crystal forms of flurbiprofen axetil crystals can be heated and melted to obtain a high-purity flurbiprofen axetil product.

[0037] 2. The crystal preparation method provided by the present invention not only avoids the use of solvents, simplifies the process operation, reduces costs, reduces the volume of production equipment, and increases product production capacity, but also the crystals after one crystallization can be heated and melted to obtain high-purity flurbiprofen axetil products, which is conducive to industrial production.

[0038] 3. The residual liquid separated in the crystal preparation method provided by the present invention can be collected and reused.

[0039] 4. Compared with Chinese patent application CN114075109A, which requires the crude flurbiprofen axetil to be purified to 99.7% or more (as shown in Example 2 thereof) before crystallization, the crystal preparation method provided by the present invention has a lower requirement on the purity of the crude flurbiprofen axetil. For example, crystallization can be carried out when the purity of the crude flurbiprofen axetil is 98.36%. It can be seen that the crystal preparation method provided by the present invention is more efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which:

[0041] Figure 1 The X-ray powder diffraction pattern of the flurbiprofen axetil crystals obtained in Example 1 of the present invention is shown.

[0042] Figure 2 The DSC thermogram of the flurbiprofen axetil crystals prepared in Example 1 of the present invention is shown.

[0043] Figure 3 The figure is a chromatogram showing the purity of flurbiprofen axetil obtained in Example 1 of the present invention.

[0044] Figure 4 The X-ray powder diffraction pattern of the flurbiprofen axetil crystals obtained in Example 2 of the present invention is shown.

[0045] Figure 5 The DSC thermogram of the flurbiprofen axetil crystals prepared in Example 2 of the present invention is shown.

[0046] Figure 6 The figure is a chromatogram showing the purity of flurbiprofen axetil obtained in Comparative Example 1. DETAILED DESCRIPTION

[0047] The present invention will be further described in detail below in conjunction with specific embodiments. The examples given are only for illustrating the present invention, not for limiting the scope of the present invention.

[0048] In the present invention, unless otherwise specified, all reagents involved can be purchased through commercial channels.

[0049] The crude flurbiprofen axetil used in the following examples and comparative examples was obtained by the following steps:

[0050] To a 5L reaction flask, 244g of flurbiprofen and 160g of potassium bicarbonate were added, 2.2L of acetone was added with stirring, and 268g of 1-bromoethyl acetate was added dropwise. After reacting at room temperature for 5h, 4L of ethyl acetate was poured into the reaction solution, and the reaction solution was diluted. The organic layer was washed with 4L of saturated sodium bicarbonate aqueous solution twice. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude liquid product of flurbiprofen axetil. The purity of the crude liquid product of flurbiprofen axetil was 98.36%, and the remaining components were mainly impurities such as defluorinated flurbiprofen axetil, flurbiprofen, and a small amount of unknown impurities. A small amount of acetone and ethyl acetate may remain in the crude product, but the content of acetone and ethyl acetate does not exceed 0.5%.

[0051] The HPLC detection method of flurbiprofen axetil used in the following examples and comparative examples is described in Example 10 of Chinese patent application 202111345382.8. The specific detection method is as follows:

[0052] Accurately weigh about 20 mg of flurbiprofen axetil, place it in a 200 mL volumetric flask, add acetonitrile to dissolve and dilute it to the mark, shake well, and use it as the test solution.

[0053] Accurately measure 10 μL of the test solution, inject it into the high performance liquid chromatograph, and record the chromatogram.

[0054] HPLC conditions: The chromatographic column was filled with fluorinated octylsilane bonded silica gel; the mobile phase was a mixture of acetonitrile-0.4 potassium phosphate-acetic acid (400:600:1.0, v / v) for 40 min; the column temperature was 35°C; the detection wavelength was 260 nm; and the flow rate was 0.9 mL / min.

[0055] The purity of flurbiprofen axetil used in the following examples and comparative examples was calculated by the area normalization method, and the content of desfluoro flurbiprofen axetil was calculated by the external standard method.

[0056] Example 1

[0057] 100 g of crude flurbiprofen axetil liquid (purity 98.36%) was placed in an aluminum bottle and allowed to stand at 0°C for 72 h. The liquid was then poured out and the remaining liquid was vacuum filtered to obtain white flurbiprofen axetil crystals. Figure 1 The specific peak conditions are shown in Table 1. Its DSC thermal spectrum is shown in Figure 2 The comparison of the crystals obtained in this example and the crystals obtained in Comparative Example 1 is shown in Table 2.

[0058] The flurbiprofen axetil crystals obtained in this example were heated and melted at 50°C to obtain 85.2 g of purified flurbiprofen axetil. The crystals were subjected to HPLC detection, and the detection spectrum was as follows: Figure 3As shown, the peak positions of flurbiprofen axetil are at 24.525 and 25.684, and the peak positions of desfluoro flurbiprofen axetil are at 19.919 and 20.808. After calculation, the purity of the purified flurbiprofen axetil is 99.75%.

[0059] Table 1

[0060] Peak number 1 2 3 4 5 6 7 9 2θ 9 9.7 10.6 11.2 13.1 13.6 14 14.5 Peak number 11 12 14 16 18 19 20 21 2θ 16.1 16.5 17.5 17.8 18.9 19.3 19.9 21.1 Peak number 23 24 28 30 31 34 36 38 2θ 21.7 22.1 23.8 25.4 26.2 28.1 29.3 30.7

[0061] Example 2

[0062] 100 g of crude flurbiprofen axetil liquid (purity 98.36%) was placed in a glass bottle and allowed to stand at 20° C. for 36 h. The liquid was then poured out and the residual liquid was filtered with nitrogen to obtain colorless flurbiprofen axetil crystals. The X-ray powder diffraction pattern of the crystals was as follows: Figure 4 The specific peak conditions are shown in Table 2, and the DSC thermal spectrum is shown in Figure 5 shown.

[0063] The obtained flurbiprofen axetil crystals were heated and melted at 60° C. to obtain 80.3 g of purified flurbiprofen axetil. The purity of the purified flurbiprofen axetil was 99.66% as determined by HPLC.

[0064] Table 2

[0065]

[0066]

[0067] Example 3

[0068] 100 g of crude flurbiprofen axetil liquid (purity: 98.36%) was placed in a stainless steel tank and allowed to stand at -5°C for 48 h. The liquid was then poured out and the remaining liquid was vacuum filtered to obtain white flurbiprofen axetil crystals.

[0069] The obtained flurbiprofen axetil crystals were heated and melted at 80° C. to obtain 83.7 g of purified flurbiprofen axetil. The purity of the purified flurbiprofen axetil was 99.73% as determined by HPLC.

[0070] Example 4

[0071] 100 g of crude flurbiprofen axetil liquid (purity: 98.36%) was placed in a stainless steel tank and allowed to stand at 10° C. for 60 h. The liquid was then poured out and the remaining liquid was vacuum filtered to obtain white flurbiprofen axetil crystals.

[0072] The obtained flurbiprofen axetil crystals were heated and melted at 70° C. to obtain 85.4 g of purified flurbiprofen axetil. The purity of the purified flurbiprofen axetil was 99.69% as determined by HPLC.

[0073] Comparative Example 1

[0074] 100 g of crude flurbiprofen axetil liquid (purity: 98.36%) was purified according to the method of Example 3 in Chinese patent application CN114075109A to obtain 82.87 g of purified flurbiprofen axetil.

[0075] The purified flurbiprofen axetil was detected according to the HPLC detection method used in the present invention, and the detection spectrum was as shown in FIG. Figure 6 As shown, the peak positions of flurbiprofen axetil are at 21.949 and 22.972, and the peak positions of desfluoro flurbiprofen axetil are at 17.89 and 18.681. After calculation, the purity of the purified flurbiprofen axetil is 99.2%.

[0076] In Chinese patent application CN114075109A, the purity of flurbiprofen axetil disclosed in Example 3 is relatively high because its detection method cannot separate flurbiprofen axetil from desfluorinated flurbiprofen axetil, so that the peak area of ​​flurbiprofen axetil also includes the peak area of ​​desfluorinated flurbiprofen axetil, resulting in a higher purity.

[0077] The parameters of the flurbiprofen axetil crystals obtained by the methods of Example 1 and Comparative Example 1 are shown in Table 3. Among them, the flurbiprofen axetil crystals obtained in Example 1 of the present invention have significantly improved purity compared to Comparative Example 1, and the impurity content of defluorinated flurbiprofen axetil is significantly reduced, and no residual organic solvent is detected. That is, the flurbiprofen axetil crystals obtained by the present invention have higher purity, lower impurity content, and higher safety compared to Comparative Example 1.

[0078] Table 3

[0079] Serial number Appearance purity / % Desflurane flurbiprofen axetil / % <![CDATA[Residual organic solvents a > Example 1 White solid 99.75％ 0.18％ None detected Comparative Example 1 White solid 99.22％ 0.31％ n-heptane 0.02%

[0080] a The residual organic solvents were detected by external standard method.

[0081] Examples 5, 6 and Comparative Examples 2, 3

[0082] The crude liquid product of flurbiprofen axetil was purified according to the method of Example 1, except that the crystallization temperatures were -20°C, -5°C, 20°C, and 30°C, respectively. The experimental results are shown in Table 4.

[0083] Table 4

[0084] sample Crystallization temperature / ℃ Flurbiprofen axetil yield / % Flurbiprofen axetil purity / % Comparative Example 2 -20 Unable to form crystals -- Example 5 -5 84.17％ 99.52％ Example 6 20 79.64％ 99.60％ Comparative Example 3 30 50.26％ 99.68％

[0085] Examples 7-9

[0086] The crude liquid product of flurbiprofen axetil was purified according to the method of Example 1, except that the crystallization times were 36 h, 48 h, and 84 h, respectively. The experimental results are shown in Table 5.

[0087] Table 5

[0088] sample Crystallization time / h Flurbiprofen axetil yield / % Flurbiprofen axetil purity / % Example 7 36 78.02％ 99.70％ Example 8 48 83.96％ 99.78％ Example 9 84 86.11％ 99.38％

[0089] Example 10 Accelerated stability test

[0090] The flurbiprofen axetil crystals prepared in Example 1 were placed in a stability test chamber at 40°C and RH 75% for six months. Samples were taken at the end of 1, 2, 3, and 6 months and compared with the results at month 0. Specific experimental data are shown in Table 6.

[0091] Table 6

[0092] Time / month Desflurane flurbiprofen axetil / % purity / % 0 0.18 99.75％ 1 0.18 99.75％ 2 0.18 99.73％ 3 0.19 99.70％ 6 0.18 99.64％

[0093] As can be seen from the above table, the crystals of the present invention have good stability under the conditions of 40° C. and RH 75%, can maintain stable purity within 6 months, and the defluorinated impurity content does not increase.

[0094] The above descriptions are merely exemplary embodiments of the present invention and are not intended to limit the present invention in any way. Although the present invention is disclosed above with reference to preferred embodiments, they are not intended to limit the present invention. Any equivalent or equivalent embodiments obtained by any person skilled in the art, without departing from the scope of the present invention, by making slight changes or modifications to the above-disclosed technical contents, fall within the scope of the present invention.

Claims

1. A flurbiprofen axetil crystal, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG1 .

2. A flurbiprofen axetil crystal, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is shown in FIG4 .

3. A method for preparing the flurbiprofen axetil crystal according to claim 1 or 2, comprising: The crude flurbiprofen axetil liquid product is placed in a container and allowed to stand at -5-20° C. for 36-72 hours, and the precipitated crystals are separated from the residual liquid to obtain the flurbiprofen axetil crystals; wherein, the method does not add a solvent.

4. The method according to claim 3, wherein: The standing temperature is 0-10°C.

5. The method according to claim 3, wherein The standing time is 48-72 h.

6. The method according to claim 3, wherein: The purity of the flurbiprofen axetil liquid crude product is greater than or equal to 95%.

7. The method according to claim 6, wherein: The purity of the flurbiprofen axetil liquid crude product is greater than or equal to 97%.

8. The method according to claim 3, wherein: The material of the container is not plastic.

9. The method according to claim 3, wherein: The container is made of glass or metal.

10. The method according to claim 9, wherein: The glass is borosilicate glass.

11. The method according to claim 9, wherein The metal is a metal substrate of stainless steel or aluminum with or without a metal oxide film lining.

12. The method according to any one of claims 3 to 11, wherein: The separation of the precipitated crystals from the residual liquid is carried out by a method comprising the following steps: pouring the liquid and / or filtering the liquid by suction and / or filtering the liquid by pressure.

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