CN114524746B - Preparation method of lacosamide crystal form - Google Patents
Preparation method of lacosamide crystal form Download PDFInfo
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- CN114524746B CN114524746B CN202210073095.4A CN202210073095A CN114524746B CN 114524746 B CN114524746 B CN 114524746B CN 202210073095 A CN202210073095 A CN 202210073095A CN 114524746 B CN114524746 B CN 114524746B
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
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Abstract
The invention discloses a preparation method of a lacosamide crystal form, which comprises the following steps: heating, refluxing and dissolving the lacosamide crude product in ethyl acetate, cooling to 10-40 ℃ and crystallizing to obtain a crystal form I or a crystal form II of the lacosamide; the cooling speed is 3-15 ℃/h; the crystallization time is 4-20h. The inventor finds that a single crystal form I or a single crystal form II can be obtained by adopting a single solvent of ethyl acetate and combining with the limitation of specific cooling rate, crystallization temperature and crystallization time, the drug requirements of different lacosamide crystal forms under different conditions can be met, and the whole preparation process only adopts ethyl acetate with low toxicity, so that the drug safety of lacosamide is not influenced. In addition, the method is simple to operate, good in reproducibility and easy to industrialize.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of a lacosamide crystal form.
Background
Lacosamide (Lacosamide), also known as Lacosamide, is an anticonvulsant that has been approved for marketing in several countries for the treatment of partial seizures. Compared with other antiepileptic drugs, lacosamide has the activity of regulating a sodium ion channel, and the sodium ion channel has very important functions of regulating the activity of a nervous system and promoting the conduction between nerve cells, and can control the activity of the nerve cells by reducing the overactivity of the sodium ion channel to treat epilepsy.
Lacosamide has three crystal forms: form I, form II and form III. Wherein, the crystal form I is a thermodynamically stable crystal form, but has lower solubility and bioavailability; the crystal form II is a metastable crystal form, has higher solubility and bioavailability, but is unstable to moist heat; form iii is not only unstable but also has low solubility and bioavailability, and therefore, forms I and II are more commonly used than form iii.
The crystal form I is consistent with the originally developed crystal form, but no relevant literature reports about a preparation method of the crystal form I at present. Most of the crystal form II is prepared by dissolving lacosamide crude product in a mixed solvent of ethyl acetate and ethanol, then dripping an anti-solvent ethyl acetate with the temperature lower than 5 ℃, cooling to below 5 ℃ after heat preservation and crystallization, and performing suction filtration at the temperature. The safety of lacosamide medication is seriously influenced if the ethanol adopted in the crystallization process can not be completely removed, and the whole operation after crystallization needs to be carried out at low temperature, so that the method is complicated.
Therefore, the development of a new method for simply and safely preparing the crystal form II and the crystal form I of the lacosamide raw material has important significance on the quality and the medication safety of the lacosamide raw material drug and the preparation thereof.
Disclosure of Invention
In view of this, the invention provides a preparation method of a lacosamide crystal form, which not only has low toxicity of the used solvent and does not influence the safety of the lacosamide medication, but also can obtain a single crystal form I or a single crystal form II; in addition, the method is simple to operate, good in reproducibility and easy to industrialize.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a preparation method of lacosamide crystal form comprises the following steps: heating, refluxing and dissolving the lacosamide crude product in ethyl acetate, cooling to 10-40 ℃ and crystallizing to obtain a crystal form I or a crystal form II of the lacosamide;
the cooling speed is 3-15 ℃/h;
the crystallization time is 4-20h.
The inventor finds that a single crystal form I or a single crystal form II can be obtained by adopting a single solvent of ethyl acetate, combining and limiting specific crystallization temperature, cooling rate and crystallization time and matching parameter steps, so that the drug requirements of different lacosamide crystal forms under different conditions can be met, and the drug safety of the lacosamide is not influenced by only adopting ethyl acetate with low toxicity in the whole preparation process. In addition, the method is simple to operate, good in reproducibility and easy to industrialize.
Optionally, when the cooling speed is 3-5 ℃/h, the crystallization temperature is 20-40 ℃, and the crystallization time is 15-20h, the lacosamide crystal form I is obtained.
Preferably, the temperature of the crystallization is 25-35 ℃.
Preferably, the time for crystallization is 16h.
Optionally, when the cooling speed is 10-15 ℃/h, the crystallization temperature is 10-20 ℃, and the crystallization time is 4-10h, obtaining lacosamide crystal form II.
The inventor finds that by further controlling different cooling rates and different crystallization temperatures and combining crystallization time, a single crystal form I or a single crystal form II can be stably obtained, and the method has good reproducibility and is easy for industrial production. In addition, the crystallization time is further controlled, so that the unicity of the crystal form can be improved, and the phenomenon that the crystallization time is too short or too long, so that the crystallization is incomplete or the target crystal form cannot be obtained is prevented.
When the cooling speed is 5-10 ℃/h but not 5 ℃/h and 10 ℃/h, the crystallization temperature and time can be adjusted in a combined manner, and a single crystal form II of lacosamide or a single crystal form I of lacosamide can be obtained through the mutual cooperation of all parameters.
Optionally, the mass-to-volume ratio of the lacosamide crude product to the ethyl acetate is 1g (8-16) mL.
Preferably, the mass-to-volume ratio of the lacosamide crude product to the ethyl acetate is 1g.
Optionally, when the purity of lacosamide in the lacosamide crude product is not lower than 90%, the crystal form of the obtained lacosamide is single, and related substances and the like meet the related requirements of lacosamide bulk drugs; when the purity of lacosamide in the lacosamide crude product is lower than 90%, the obtained lacosamide is single in crystal form, but related substances and the like cannot meet related requirements of lacosamide raw material medicines.
Optionally, the preparation method of the lacosamide crystal form further comprises the steps of filtering, washing and drying after the crystallization;
the mass volume ratio of the lacosamide crude product to the washed solvent is 1g (1-3) mL, and the washed solvent is ethyl acetate.
Optionally, the drying is vacuum drying;
the drying temperature is 40-60 ℃.
Optionally, the drying time is 6-12h.
Optionally, the preparation method of the crystal form of lacosamide further comprises the steps of heating, refluxing, dissolving, adding activated carbon, stirring, and performing heat filtration before cooling.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
In order to better illustrate the invention, the following examples are given by way of further illustration.
The HPLC purity and ee value of lacosamide in different crystal forms and lacosamide crude products prepared in each example are measured as follows.
HPLC purity detection method
The sample solution was prepared by taking a proper amount of lacosamide of different crystal forms prepared in each example, precisely weighing, adding a solvent (methanol: water =10, volume ratio: 90) to perform ultrasonic dissolution, and diluting to prepare a solution containing about 5mg of lacosamide per 1 mL.
Chromatographic conditions Octylsilane bonded silica gel was used as a filler (Agilent ZORBAX Eclipse XDB-C8.6 mm. Times.150mm, 3.5 μm); elution was carried out with 0.1% trifluoroacetic acid in water (volume percentage) as mobile phase a and trifluoroacetic acid-acetonitrile-methanol (volume ratio 0.3; the detection wavelength is 258nm; the flow rate was 1.2mL per minute; the column temperature is 30 ℃; the injection volume was 20. Mu.L.
| Time min | Mobile phase A% | Mobile phase B% |
| 0 | 89 | 11 |
| 2 | 89 | 11 |
| 14.2 | 69 | 31 |
| 19.5 | 23 | 77 |
| 20 | 0 | 100 |
| 25 | 0 | 100 |
| 25.1 | 89 | 11 |
| 35 | 89 | 11 |
Method for detecting ee value
The test solution is prepared by taking a proper amount of lacosamide with different crystal forms prepared in each example, precisely weighing, adding a mobile phase for dissolving, and quantitatively diluting to prepare a solution containing about 1mg of lacosamide in each 1 mL.
Chromatographic conditions amylose-tris (3, 5-dimethylphenylcarbamate) bonded silica gel was used as a filler (Dacellosolve IA 4.6 mm. Times.250mm, 5 μm); using water-isopropanol-heptane (volume ratio of 3; the flow rate was 1.0mL per minute; the detection wavelength is 215nm; the column temperature is 30 ℃; the injection volume was 20. Mu.L.
The lacosamide crude product prepared by any preparation method of lacosamide in the prior art is suitable for the invention. For comparison, the following crude lacosamide was prepared in each example as follows:
the preparation method comprises the following steps:
d-serine (50g, 0.48mol), acetone (200 mL), purified water (200 mL) and triethylamine (144.4 g, 1.44mol) are added into a reaction flask respectively, then BOC acid anhydride (114.2 g, 0.53mol) is added dropwise, after the addition of the BOC acid anhydride is finished, the reaction solution is concentrated after the reaction is finished at normal temperature for 2-3h, then 100mL of the purified water is added into the concentrate, the solution pH =2-4 is adjusted by 2N hydrochloric acid, after the adjustment of the pH, the solution is extracted by ethyl acetate, the organic phase is collected and dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain INT1 (90.8g, 93.0%).
INT1 (90g, 0.44mol), tetrahydrofuran (450 mL) and 20% sodium hydroxide solution (87.7 g) are respectively added into a reaction bottle, stirring is started, then dimethyl sulfate (221.3 g, 1.76mol) and 50wt% sodium hydroxide solution (157.9 g) are added dropwise, the temperature is controlled to be 0-10 ℃, after the dropwise addition is finished, the normal temperature reaction is recovered for 1.5-2.5h until the reaction is finished, excessive tetrahydrofuran in the reaction liquid is concentrated, 200mL of dichloromethane is added into the concentrated liquid after the concentration is finished, stirring and standing are carried out, liquid separation is carried out, an aqueous phase is retained, an organic phase is abandoned, 2N hydrochloric acid is added into the aqueous phase to adjust the pH =2-4, after the adjustment is finished, the solution is extracted by dichloromethane, the organic phase is collected and dried by anhydrous sodium sulfate, filtering is carried out, and the filtrate is concentrated to obtain INT2 (76.8g, 81.0%).
INT2 (75g, 0.34mol) and tetrahydrofuran (600 mL) are added into a reaction bottle, the temperature is reduced to-20-0 ℃, then N-methylmorpholine (43.3 g, 0.43mol), isobutyl chloroformate (58.5 g, 0.43mol) and benzylamine (45.8g, 0.43mol) are respectively dripped into the reaction liquid, the dripping temperature is controlled to-20-0 ℃, after the dripping is finished, the room temperature is recovered for reaction for 2-3h until the reaction is finished, the filtrate is filtered and concentrated, dichloromethane (600 mL) is added into the concentrated residue, purified water, 3wt% hydrochloric acid, saturated sodium bicarbonate and saturated NaCl are respectively used for washing the organic phase, then the organic phase is dried and concentrated by anhydrous sodium sulfate, dichloromethane (20 mL) and normal hexane (400 mL) are added into the concentrate, the temperature is reduced to 0-5 ℃ by stirring, the temperature is kept for 3h, the filtration is carried out, and the filter cake is collected and dried to obtain INT3 (51.7%, 49.0%).
INT3 (50g, 0.11umol) and dichloromethane (500 mL) are added into a reaction bottle, 36wt% concentrated hydrochloric acid (82.2g, 0.8mol) is added into the reaction bottle, the mixture is reacted at room temperature for 12h until the reaction is finished, 100mL of water is added into the reaction liquid, the mixture is stirred and kept stand, liquid separation is carried out, the water phase is kept, 30wt% sodium hydroxide solution is used for adjusting the pH to be =11-13, dichloromethane is used for extracting the water phase, the organic phase is combined, then the organic phase is added into the reaction bottle, stirring is started, acetic anhydride (16.6g, 0.1umol) is added, the reaction is carried out at room temperature for 1-2h until the reaction is finished, the reaction liquid is respectively washed by purified water, saturated sodium bicarbonate and saturated NaCl, then the organic phase is concentrated to have a large amount of solid, normal hexane (500 mL) is added, the mixture is stirred at room temperature for 2h and then filtered, and a filter cake is dried to obtain a crude lacosamide (28.8g, 71.0%).
The crude lacosamide product had an HPLC purity of 95% and an ee of 99.0%.
The crystal forms of lacosamide prepared in the embodiments are verified by comparing XRD patterns of the crystal forms I and II with those of the crystal forms I and II after powder X-ray diffraction detection.
The powder X-ray diffraction of the crystal form I is characterized in that an XRD pattern is 8.30, 13.00, 16.65, 21.05, 21.27 and 24.95 +/-0.25% 0 2 θ ) One or more peaks are present, and other peaks generally occur at 10.42, 15.62, 17.7, 19.58, 24.27, and 25.39 ± 0.25: (b) 0 2 θ )。
The powder X-ray diffraction of the crystal form II is characterized in that an XRD pattern comprises 5.20, 6.74, 10.42, 10.81, 11.06, 12.64, 15.66, H and 16.25 +/-0.25 ((X-ray diffraction pattern)) 0 2 θ ) One or more peaks are present, and others typically occur at 19.98, 20.80, 21.67, 22.65, 23.27, 23.99, 25.90, and 27.86 ± 0.25: (b) 0 2 θ )。
Example 1
The embodiment provides a preparation method of lacosamide crystal form I, which comprises the following specific steps:
adding 500g of lacosamide crude product into a 20L reaction kettle, then adding 6.0L of ethyl acetate, heating and refluxing, cooling to 25-30 ℃ at a cooling rate of 3-4 ℃/h after the lacosamide crude product is dissolved, then carrying out heat preservation and crystallization for 16h, filtering, washing with 1.0L of ethyl acetate, and carrying out vacuum drying at 50 ℃ for 10h to obtain the lacosamide, wherein the yield is 85.2%.
The purity of the lacosamide by HPLC is 99.98%, the ee value is more than 99.9%, and the crystal form I is detected by powder X-ray diffraction.
XRD of crystal form I shows peaks: 8.36, 10.45, 13.07, 15.71, 16.69, 17.74, 19.65, 21.09, 21.46, 24.33, 25.04, 25.45.
Example 2
The embodiment provides a preparation method of lacosamide crystal form I, which comprises the following specific steps:
adding 500g of lacosamide crude product into a 20L reaction kettle, then adding 5.0L of ethyl acetate, heating and refluxing, cooling to 20-25 ℃ at a cooling rate of 4-5 ℃/h after the lacosamide crude product is dissolved, then carrying out heat preservation and crystallization for 15h, filtering, washing with 0.5L of ethyl acetate, and carrying out vacuum drying at 60 ℃ for 12h to obtain lacosamide, wherein the yield is 70.3%.
The purity of the lacosamide by HPLC is 99.97%, the ee value is more than 99.9%, and the lacosamide is detected as a crystal form I by powder X-ray diffraction.
Example 3
The embodiment provides a preparation method of lacosamide crystal form I, which comprises the following specific steps:
adding 500g of lacosamide crude product into a 20L reaction kettle, then adding 8.0L of ethyl acetate, heating and refluxing, cooling to 35-40 ℃ at a cooling rate of 3-4 ℃/h after the lacosamide crude product is dissolved, then carrying out heat preservation and crystallization for 20h, filtering, washing with 1.5L of ethyl acetate, and carrying out vacuum drying at 40 ℃ for 6h to obtain lacosamide with the yield of 75.6%.
The purity of the lacosamide by HPLC is 99.93%, the ee value is more than 99.9%, and the crystal form I is detected by powder X-ray diffraction.
Example 4
The embodiment provides a preparation method of lacosamide crystal form I, which comprises the following specific steps:
adding 500g of lacosamide crude product into a 20L reaction kettle, then adding 6.0L of ethyl acetate, heating and refluxing, adding 10g of activated carbon after refluxing and clearing, stirring for 10min, performing heat filtration, filtering, cooling to 30-35 ℃ at a cooling rate of 4-5 ℃/h after the lacosamide crude product is dissolved, then performing heat preservation and crystallization for 18h, filtering, washing with 1.0L of ethyl acetate, and performing vacuum drying at 50 ℃ for 10h to obtain lacosamide, wherein the yield is 82.3%.
The purity of the lacosamide by HPLC is 99.98%, the ee value is more than 99.9%, and the crystal form I is detected by powder X-ray diffraction.
Example 5
This example provides a process for preparing lacosamide form ii.
The specific steps of this example are similar to example 1, and the differences are only in the cooling rate, the crystallization temperature (the temperature after cooling) and the time of thermal insulation crystallization, wherein the cooling rate in this example is 10-12 ℃/h, the crystallization temperature is 10-15 ℃, and the time of thermal insulation crystallization is 4h.
The yield of the lacosamide is 72.9%, the HPLC purity is 99.97%, the ee value is more than 99.9%, and the lacosamide is detected as a crystal form II by powder X-ray diffraction.
Form II XRD showed peaks: 5.27, 6.76, 10.45, 10.86, 11.10, 12.67, 15.67, 16.27, 20.76, 21.69, 22.65, 23.34, 23.99, 25.95, 27.85.
Example 6
The present example provides a method for preparing lacosamide crystal form ii.
The specific steps of this example are similar to example 2, and the differences are only in the cooling rate, the crystallization temperature (the temperature after cooling) and the time of thermal insulation crystallization, wherein the cooling rate in this example is 14-15 ℃/h, the crystallization temperature is 12-17 ℃, and the time of thermal insulation crystallization is 6h.
The yield of the lacosamide is 78.5%, the HPLC purity is 99.92%, the ee value is more than 99.9%, and the crystal form II is detected by powder X-ray diffraction.
Example 7
The present example provides a method for preparing lacosamide crystal form ii.
The specific steps of this example are similar to those of example 3, and the differences are only in the cooling rate, the crystallization temperature (the temperature after cooling) and the time of thermal insulation crystallization, wherein the cooling rate is 12-14 ℃/h, the crystallization temperature is 10-15 ℃, and the time of thermal insulation crystallization is 8h.
The yield of the lacosamide is 76.8%, the HPLC purity is 99.91%, the ee value is more than 99.9%, and the lacosamide is detected as a crystal form II by powder X-ray diffraction.
Example 8
This example provides a process for preparing lacosamide form ii.
The specific steps of this example are similar to example 4, and the differences are only in the cooling rate, the crystallization temperature (temperature after cooling) and the time for thermal insulation crystallization, wherein the cooling rate is 11-12 ℃/h, the crystallization temperature is 15-20 ℃, and the time for thermal insulation crystallization is 10h.
The yield of the lacosamide is 80.3%, the HPLC purity is 99.95%, the ee value is more than 99.9%, and the crystal form II is detected by powder X-ray diffraction.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A preparation method of lacosamide crystal form is characterized by comprising the following steps: heating, refluxing and dissolving the lacosamide crude product in ethyl acetate, cooling to 20-40 ℃ at the speed of 3-5 ℃/h, and crystallizing for 15-20h to obtain a crystal form I of lacosamide;
the powder X-ray diffraction characteristics of the crystal form I of the lacosamide are that the XRD pattern is 8.30, 13.00, 16.65, 21.05, 21.27 and 24.95 +/-0.25 (X-ray diffraction pattern) 0 2 θ ) With characteristic diffraction peaks.
2. The method for preparing a crystalline form of lacosamide according to claim 1, wherein the temperature of crystallization is from 25 ℃ to 35 ℃.
3. The process for preparing a crystalline form of lacosamide according to claim 2, wherein the time for crystallization is 16h.
4. A preparation method of a lacosamide crystal form is characterized in that a lacosamide crude product is heated, refluxed and dissolved in ethyl acetate, and then cooled to 10-20 ℃ at the speed of 10-15 ℃/h for crystallization for 4-10h to obtain a lacosamide crystal form II;
the crystal form II of the lacosamide is 5.20, 6.74, 10.42, 10.81, 11.06, 12.64, 15.66 and 16.25 +/-0.25 (II) 0 2 θ ) Having characteristic diffraction peaks.
5. The preparation method of the crystalline form of lacosamide as claimed in any of claims 1-4, wherein the mass volume ratio of the crude lacosamide to the ethyl acetate is 1g (8-16) mL.
6. The method for preparing the crystalline form of lacosamide according to claim 5, wherein the mass-to-volume ratio of the crude lacosamide to the ethyl acetate is 1g.
7. The method for preparing lacosamide crystal form according to claim 1 or 4, further comprising the steps of filtering, washing and drying after the crystallization;
the mass-volume ratio of the lacosamide crude product to the washed solvent is 1g (1-3) mL, and the washed solvent is ethyl acetate.
8. The method for preparing a crystalline form of lacosamide as claimed in claim 7, wherein the drying is vacuum drying; the drying temperature is 40-60 ℃.
9. The process for preparing a crystalline form of lacosamide according to claim 8, wherein the drying time is from 6 to 12 hours.
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| WO2017082396A1 (en) * | 2015-11-13 | 2017-05-18 | 株式会社エーピーアイ コーポレーション | Method for producing lacosamide and intermediate thereof |
| CN105523957A (en) * | 2016-01-15 | 2016-04-27 | 齐鲁天和惠世制药有限公司 | Method for preparing Lacosamide by one-pot method |
| CN105646284A (en) * | 2016-01-15 | 2016-06-08 | 齐鲁天和惠世制药有限公司 | Lacosamide synthesis method |
| CN111559968A (en) * | 2020-06-03 | 2020-08-21 | 上海上药第一生化药业有限公司 | Preparation method of lacosamide crystal form II |
| CN112574058A (en) * | 2020-12-31 | 2021-03-30 | 珠海润都制药股份有限公司 | Synthetic route of lacosamide |
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