CN110498788B - Preparation method of high-purity thalidomide alpha crystal form - Google Patents

Preparation method of high-purity thalidomide alpha crystal form Download PDF

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CN110498788B
CN110498788B CN201810468365.5A CN201810468365A CN110498788B CN 110498788 B CN110498788 B CN 110498788B CN 201810468365 A CN201810468365 A CN 201810468365A CN 110498788 B CN110498788 B CN 110498788B
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thalidomide
tetrahydrofuran
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water
crystal form
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CN110498788A (en
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文勇
王果
仇波
肖飞
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Suzhou Changzheng Xinkai Pharmaceutical Co ltd
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Cinkate Pharm Tech (shanghai) Co ltd
Cinkate Pharmaceutical Intermediates Co ltd
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention relates to a preparation method of a high-purity thalidomide alpha crystal form. Specifically, the high-purity alpha crystal form thalidomide prepared by the method is high in purity. The organic solvent used in the method can be recycled by simple distillation, the crystallization yield is more than 95%, the operation is simple, the method is environment-friendly, and the method has high economic and social values. The process used by the method of the invention is easy to realize industrial mass production.

Description

Preparation method of high-purity thalidomide alpha crystal form
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a high-purity thalidomide alpha crystal form.
Background
Thalidomide (detaval) is a synthetic glutamic acid derivative, alternative name: thalidomide, and its structural formula:
Figure GDA0001682477240000011
the research on the crystal form of thalidomide in J.CHEM.SOC.PERKIN TRANSNS.21994 (2063-2067) discovers that two crystal forms of thalidomide exist, namely an alpha crystal form and a beta crystal form, and the Differential Scanning Calorimetry (DSC) detection shows that the alpha crystal form has an endothermic peak at 271.5-273.0 ℃ and the beta crystal form has an endothermic peak only at 275.0-276.5 ℃, and the research shows that the alpha crystal form can be partially or completely converted into the beta crystal form in the DSC detection process, so that the endothermic peak of the beta crystal form is also generated. An X-ray diffraction pattern (XRPD) of the crystalline form α comprising characteristic peaks at about 11.33, 14.32, 19.20, 22.77, 26.12, 30.36; an X-ray diffraction pattern (XRPD) of the beta crystalline form comprises characteristic peaks at about 11.78, 12.96, 13.75, 17.06, 19.26, 24.06, 25.73, 29.05, 29.29.
The traditional crystallization method of thalidomide uses polar solvents such as pyridine, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidine as benign solvents, and uses solvents such as water, methanol, ethanol, propanol, butanol and acetone as poor solvents to carry out crystallization. Patent CN103068812A describes the preparation of alpha-crystalline thalidomide by recrystallization using dimethylformamide, dimethylacetamide as the first solvent and acetone, methanol and water as the second solvent. Patent CN102924432A describes a method for preparing high-purity thalidomide by dissolving a crude thalidomide product in hot dimethyl sulfoxide or a mixed solvent of hot dimethyl sulfoxide and fatty alcohol, dehydrating with activated carbon, filtering while hot, and cooling and crystallizing a filtrate, but no DSC, XRPD and other crystal form detection data exist. Patent CN102260241A describes a method for preparing thalidomide in alpha crystal form by crystallization using polar solvent and alcohol. The above methods all need high boiling point polar solvents, and solvents such as ketones and alcohols, and the crystallized mother liquor is very difficult to recycle, and has high social cost and economic cost.
Therefore, a better method for preparing the thalidomide alpha crystal form needs to be developed, and a better scheme is provided for the subsequent industrial production of the drug.
Disclosure of Invention
The invention aims to provide a method for preparing the alpha crystal form of thalidomide, which has the advantages of low cost, simple and convenient operation, safety, environmental protection, cyclic application and suitability for industrial mass production.
In a first aspect of the invention, a method for industrially preparing thalidomide alpha crystal form is provided, which comprises the steps of:
(1) providing a first solution, wherein the first solution comprises a mixed solvent and thalidomide dissolved in the mixed solvent, and the mixed solvent is a mixed solvent of tetrahydrofuran and water;
(2) selectively distilling the first solution to obtain a first distillate and a distilled first mixture, wherein the first mixture comprises residual mixed solvent, thalidomide dissolved in the mixed solvent and precipitated crystalline form alpha of thalidomide, and wherein the selective distillation allows tetrahydrofuran to be distilled off while water is not substantially distilled off;
(3) isolating said crystalline form α of thalidomide from said first mixture; and
(4) washing and drying the separated thalidomide alpha crystal form to obtain a dried thalidomide alpha crystal form.
In another preferred embodiment, the first distillate (mainly tetrahydrofuran) obtained in step (2) is recycled.
In another preferred embodiment, the recovered first distillate is used to prepare the first solution.
In another preferred embodiment, in the first distillate, the ratio of tetrahydrofuran: the weight ratio of water is more than or equal to 10:1, preferably more than or equal to 20: 1, more preferably not less than 50: 1.
in another preferred embodiment, the phrase "water does not substantially distill" means that in the first distillate, the ratio of tetrahydrofuran: the weight ratio of water is more than or equal to 10:1, preferably more than or equal to 20: 1, more preferably not less than 50: 1.
in another preferred embodiment, in the first mixture, the ratio of tetrahydrofuran: the weight ratio of the water is less than or equal to 1/10, preferably less than or equal to 1/20, and more preferably less than or equal to 1/100.
In another preferred embodiment, in the first solution, the ratio of tetrahydrofuran: the weight ratio of water is 100:1-1:10, preferably 10:1-1:5, more preferably 3:1-1: 1.
In another preferred embodiment, the mixed solvent further contains a small amount of pyridine, preferably the mass ratio of pyridine to tetrahydrofuran is 1:500-1:5, preferably 1:100-1: 10.
In another preferred example, the mass ratio of the thalidomide to the tetrahydrofuran in the mixed solvent is 1: 0.5-300, preferably 1:1-100, more preferably 1:1-50, more preferably 1:3-30, more preferably 1: 1-10.
In another preferred embodiment, the mass ratio of the thalidomide to water in the mixed solvent is 1:1-50, preferably 1:3-50, more preferably 1:3-10, and still more preferably 1: 1-3.
In another preferred example, the method further comprises: and (0) a step (0) of mixing the crude thalidomide with water and tetrahydrofuran, thereby obtaining a first solution, which is located before the step (1).
In another preferred example, the method further comprises: the recovered distillate was used in step (0).
In another preferred example, in the method, the steps (0) to (2) are performed cyclically and continuously.
In another preferred embodiment, the number of process cycles is from 1 to 1000, preferably from 2 to 100.
In another preferred embodiment, the dissolution is room temperature dissolution or heating dissolution. Preferably, the room temperature is 15-40 ℃; the heating is 40-100 ℃.
In another preferred embodiment, the distillation is carried out at a temperature of t1, wherein the t1 is 15-100 ℃, preferably 15-40 ℃ or 40-100 ℃.
In another preferred embodiment, the distillation is vacuum distillation or atmospheric distillation.
In another preferred embodiment, the volume of the first solution is 1 to 5000L, preferably 10 to 500L.
In another preferred embodiment, the separation is filtration or suction filtration.
In another preferred embodiment, the yield of the method is above 95%.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1 shows the DSC profile of the crystalline form α of thalidomide prepared in example 1.
Figure 2A shows an XRPD pattern of crystalline form of thalidomide α prepared in example 1; figure 2B shows X-ray diffraction data for thalidomide form α prepared in example 1.
Figure 3 shows the DSC profile of the crystalline form α of thalidomide prepared in example 2.
Figure 4A shows an XRPD pattern of crystalline form of thalidomide α prepared in example 2; figure 4B shows X-ray diffraction data for thalidomide form α prepared in example 2.
Figure 5 shows the DSC profile of thalidomide form α prepared in example 3.
Figure 6A shows an XRPD pattern of crystalline form of thalidomide α prepared in example 3; figure 6B shows X-ray diffraction data for thalidomide form α prepared in example 3.
Figure 7 shows the DSC profile of thalidomide form α prepared in example 4.
Figure 8A shows an XRPD pattern of crystalline form of thalidomide α prepared in example 4; figure 8B shows X-ray diffraction data for thalidomide form α prepared in example 4.
Figure 9 shows a process flow diagram for preparing thalidomide form α in example 5.
Detailed Description
The inventor researches extensively and deeply to develop a method for preparing thalidomide alpha crystal form, which has the advantages of low cost, simple operation, safety, environmental protection and cyclic use for the first time. The invention adopts a mixed solvent of tetrahydrofuran and water to dissolve thalidomide, and carries out distillation crystallization to obtain the alpha crystal form of thalidomide. The tetrahydrofuran in the preparation method can be recovered by simple distillation, is easy to recycle, has low cost and is environment-friendly. The method adopts tetrahydrofuran with low boiling point, the solvent is easy to remove, the residue is less, the preparation process is simple and efficient, the condition is mild, the repeatability is good, the cost is low, the yield is high (more than or equal to 97 percent), and the method is suitable for large-scale industrial production. The crystal prepared by the method has high purity, high crystallinity and little solvent residue. On the basis of this, the present invention has been completed.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Thalidomide
Thalidomide (detaval) is a synthetic glutamic acid derivative, alternative name: thalidomide, and its structural formula:
Figure GDA0001682477240000051
in the 50's of the 20 th century, this drug was developed by germany primarily for the treatment of epilepsy, but due to lack of effectiveness, it was subsequently used as a sleep aid and was also widely used during pregnancy for antiemetic use in pregnant women. In the early 60's of the 20 th century, the cessation of the response event, the occurrence of a large number of infant deformities caused by thalidomide (such as short limb deformity, long bone defect, auricle loss, cleft lip, heart and gastrointestinal tract deformity, etc.), has been banned by many countries and withdrawn from the medical market, however, scientists have not completely denied thalidomide and continued intensive research on thalidomide, particularly, have enjoyed favorable and encouraging results in the research on the pharmacology of immunity, anti-inflammation, anti-angiogenesis and clinical treatment of some difficult and baffling diseases, thereby leading people to have new knowledge about thalidomide. In the 70 s of the 20 th century, along with the development of research on leprosy, rheumatism and various types of malignant tumors, israel dermatological thalidomide as a sedative was administered to leprosy erythema nodosum patients, and the symptoms rapidly improved. The response of many cases of leprosy erythema nodosum patients is good, and the FDA in the United states of 1998 approves thalidomide to treat leprosy erythema nodosum. In 2004, the annual meeting of the american society for hematology, RaJkumar, meo, usa, reported 2 studies of first-line treatment of multiple myeloma with thalidomide and its analogs, both of which were effective in treating multiple myeloma. In 1998, the FDA in the united states was approved for the treatment of leprosy complications. Us FDA approval for treatment of multiple myeloma 5 months 2006. Thalidomide was approved for marketing in china in 2010, and in addition to treating erythema nodosum leprosum, thalidomide can treat multiple myeloma in the clinical guidelines blood book; thalidomide can be used for treating ankylosing spondylitis and Behcet's disease in clinical practice guideline rheumatism school booklets.
The research on the crystal form of thalidomide in J.CHEM.SOC.PERKIN TRANSNS.21994 (2063-2067) discovers that two crystal forms of thalidomide exist, namely an alpha crystal form and a beta crystal form, and the Differential Scanning Calorimetry (DSC) detection shows that the alpha crystal form has an endothermic peak at 271.5-273.0 ℃ and the beta crystal form has an endothermic peak only at 275.0-276.5 ℃, and the research shows that the alpha crystal form can be partially or completely converted into the beta crystal form in the DSC detection process, so that the endothermic peak of the beta crystal form is also generated. An X-ray diffraction pattern (XRPD) of the crystalline form α comprising characteristic peaks at about 11.33, 14.32, 19.20, 22.77, 26.12, 30.36; an X-ray diffraction pattern (XRPD) of the beta crystalline form comprises characteristic peaks at about 11.78, 12.96, 13.75, 17.06, 19.26, 24.06, 25.73, 29.05, 29.29.
The traditional crystallization method of thalidomide uses polar solvents such as pyridine, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidine as benign solvents, and uses solvents such as water, methanol, ethanol, propanol, butanol and acetone as poor solvents to carry out crystallization. Patent CN103068812A describes the preparation of alpha-crystalline thalidomide by recrystallization using dimethylformamide, dimethylacetamide as the first solvent and acetone, methanol and water as the second solvent. Patent CN102924432A describes a method for preparing high-purity thalidomide by dissolving a crude thalidomide product in hot dimethyl sulfoxide or a mixed solvent of hot dimethyl sulfoxide and fatty alcohol, dehydrating with activated carbon, filtering while hot, and cooling and crystallizing a filtrate, but no DSC, XRPD and other crystal form detection data exist. Patent CN102260241A describes a method for preparing thalidomide in alpha crystal form by crystallization using polar solvent and alcohol. The above methods all need high boiling point polar solvents, and solvents such as ketones and alcohols, and the crystallized mother liquor is very difficult to recycle, and has high social cost and economic cost.
Crystallization of
Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. Such as dissolving the compound of interest in a solvent at elevated temperature followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
In a preferred embodiment of the invention, the thalidomide is dissolved by a mixed solvent of tetrahydrofuran and water, and the alpha-crystal form thalidomide with high purity is obtained by distillation crystallization treatment.
Solvates
In the process of contacting a compound or a drug molecule with a solvent molecule, the solvent molecule and the compound molecule form eutectic crystals and remain in the solid substance due to external condition and internal condition factors, which is difficult to avoid. The material formed after crystallization of the compound with a solvent is called a solvate (solvate). The solvent which is easily solvated with the organic compound may be water, methanol, benzene, ethanol, ether, aromatic hydrocarbon, heterocyclic aromatic hydrocarbon, etc.
Hydrates are a particular solvate. In the pharmaceutical industry, hydrates have separately discussed value for their specificity, whether in the synthesis of drug substances, pharmaceutical formulations, drug storage, and evaluation of drug activity.
Differential scanning calorimetry analysis
Also known as differential thermal scanning analysis (DSC), is a technique for measuring the relationship between the energy difference between a measured substance and a reference substance and the temperature during heating. The position, shape and number of peaks on a DSC spectrum are related to the nature of the substance and can be used qualitatively to identify the substance. The method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, reaction heat and the like of a substance.
In the present invention, Differential Scanning Calorimetry (DSC) measures the temperature initially at 10 deg.C per minute, from 30 deg.C to 260 deg.C, and then at 1 deg.C per minute from 260 deg.C to 285 deg.C.
X-ray powder diffraction (XRD)
The differences in measurements associated with such X-ray powder diffraction analysis results arise from a number of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak position), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors often result in a shift of all peaks in the same direction. When using a flat holder, small differences in sample height will result in large shifts in XRD peak positions. Systematic studies show that sample height differences of 1mm can result in peak shifts of 2 θ up to 1 °. These shifts can be identified from the X-ray diffraction patterns and can be eliminated by compensating for them (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent. In the embodiment of the invention, the X-ray diffraction takes prothioconazole solvate as a measurement object.
The instrument model is as follows: bruker D8ADVANCE, target: cu target, detector: LynxEye, a divergence slit of 1.0mm, a cable-stayed slit of 0.4 degrees, continuous scanning with a step length of 0.02 degrees, a speed of 8 degrees/min, and a scanning range of 3-45 degrees.
Preparation method
The present invention provides a process for the preparation of thalidomide crystals using a process according to the first aspect of the present invention, said process comprising the steps of:
(1) providing a first solution, wherein the first solution comprises a mixed solvent and thalidomide dissolved in the mixed solvent, and the mixed solvent is a mixed solvent of tetrahydrofuran and water;
(2) selectively distilling the first solution to obtain a first distillate and a distilled first mixture, wherein the first mixture comprises residual mixed solvent, thalidomide dissolved in the mixed solvent and precipitated crystalline form alpha of thalidomide, and wherein the selective distillation allows tetrahydrofuran to be distilled off while water is not substantially distilled off;
(3) isolating said crystalline form α of thalidomide from said first mixture; and
(4) washing and drying the separated thalidomide alpha crystal form to obtain a dried thalidomide alpha crystal form.
In a preferred embodiment of the invention, the thalidomide crude product, tetrahydrofuran and water are respectively added into a crystallization kettle, heated, stirred and dissolved until the materials are completely dissolved, then the tetrahydrofuran is distilled and recovered, after the tetrahydrofuran is basically completely recovered, the mixture is cooled to room temperature, filtered, a filter cake is washed with a proper amount of water for three times, and the filter cake is dried to obtain the thalidomide alpha crystal form finished product.
In the research, the thalidomide is found to be extremely slightly soluble in tetrahydrofuran and extremely slightly soluble in water, and is generally considered to be a poor solvent of the thalidomide. But the unexpected discovery is that: the thalidomide can be dissolved in a mixed solvent of tetrahydrofuran and water, and then the boiling point difference of the tetrahydrofuran and the water is compared, so that the mixed solvent of the tetrahydrofuran and the water is tried to be recrystallized, then the tetrahydrofuran is recovered, the thalidomide is separated out in the water, and the alpha-crystal form thalidomide can be obtained. The dosage of the water is 3 times or more than the weight of the crude thalidomide product, and the dosage of the tetrahydrofuran is 1 time to 300 times, preferably 1 time to 50 times, preferably 1 time to 10 times of the crude thalidomide product, so that the requirement of convenient material transfer in the crystallization filtration industrial production is met.
The invention adopts a mixed solvent of tetrahydrofuran and water to dissolve thalidomide, and carries out crystallization treatment (such as distilling and recovering tetrahydrofuran) to obtain the alpha crystal form of thalidomide. The preparation method adopts tetrahydrofuran with low boiling point, the solvent is easy to remove, the residue is less, the preparation process is simple and efficient, the condition is mild, the repeatability is good, the cost is low, the yield is high (more than or equal to 95 percent), and the preparation method is suitable for large-scale industrial production. The crystal prepared by the method has high purity, high crystallinity and little solvent residue. In the preparation process of the method, the solvent is recycled, so that the using amount of the solvent is very small when the equivalent thalidomide crystal is prepared, and the cost is saved.
The main advantages of the invention are:
(1) the preparation method disclosed by the invention has the advantages that the mixed solvent with low boiling point is adopted, the solvent is easy to remove, the residue is less, the operation is simple and convenient, the distillation crystallization can be carried out at a lower temperature, the energy consumption is less, the impurities are less (the purity of the prepared alpha crystal form is high), the process conditions are mild, the simplicity and the high efficiency are realized, the repeatability is good, the solvent can be repeatedly used, the cost is low, the process is stable, the crystallization yield is over 95%, the time consumption is less, and the preparation method is very suitable for large-scale production.
(2) The method does not need to use polar solvents with high boiling point and solvents such as ketones, alcohols and the like, the used tetrahydrofuran solvent can be recovered by simple distillation, is very easy to recycle, can be directly recycled (without separating or removing a small amount of water in the tetrahydrofuran) even if the recovered tetrahydrofuran contains a small amount of water, is environment-friendly, has simple and efficient preparation method, and has higher economic and social values.
(3) The alpha crystal form prepared by the method has high purity, less solvent residue and easy filtration and washing, and can well meet the requirements of subsequent preparations on the properties of raw materials.
(4) In the preparation process of the method, crystal seeds are not required to be added, the solvent is recovered while crystallization is carried out, the operation is simple, and the industrialization is easy.
(5) The solvent in the method is recycled, so that the solvent consumption is very small and the cost is saved when the equivalent thalidomide crystal is prepared. And the special solvent dosage (such as the dosage of water is 3 times or more of the weight of the thalidomide crude product, and the dosage of tetrahydrofuran is 1 time to 50 times of the weight of the thalidomide crude product) and the special weight ratio of tetrahydrofuran to water in the mixed solvent are adopted, so that the requirement of convenient material transfer in crystallization and filtration industrial production is met.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only. The test materials and reagents used in the following examples are commercially available without specific reference. The normal temperature or room temperature is 4-40 deg.C, preferably 15-30 deg.C.
Example 1
50g of thalidomide crude product and 1500g of tetrahydrofuran are sequentially added into a 2L three-neck round bottom flask, mechanical stirring is carried out, oil bath heating is carried out until reflux is carried out, 150g of purified water is added, the solid is completely dissolved, the oil bath temperature is kept at 95-100 ℃, tetrahydrofuran is distilled under normal pressure, the tetrahydrofuran is completely recovered, mother liquor is cooled to room temperature, reduced pressure suction filtration is carried out, and filter cakes are dried in vacuum at 80 ℃ for 4 hours to obtain 48.5g of thalidomide crystal finished product, the recrystallization yield is 97.0%, the purity is 99.8%, and the tetrahydrofuran residual quantity is almost 0%. The DSC results are shown in fig. 1, and the endothermic peaks of DSC are 271.55 ℃ (α crystal form characteristic endothermic peak) and 274.17 ℃, indicating that the obtained thalidomide crystal is α crystal form and has high purity. The X-ray diffraction pattern (XRPD) is shown in FIG. 2A, and the X-ray diffraction data is shown in FIG. 2B. The result shows that the obtained product is the alpha crystal form thalidomide and has high purity.
Example 2
Adding 50g of thalidomide crude product and 150g of tetrahydrofuran into a 500ml three-neck round-bottom flask in sequence, mechanically stirring, heating in an oil bath until reflux, adding 50g of purified water, completely dissolving the solid, cooling to room temperature, carrying out reduced pressure concentration to recover tetrahydrofuran, after the tetrahydrofuran is recovered, carrying out suction filtration on a mother solution, drying a filter cake in vacuum at 80 ℃ for 4 hours to obtain 49.0g of thalidomide crystal finished product, wherein the recrystallization yield is 98.0%, the purity is 99.7%, and the residual quantity of the tetrahydrofuran is almost 0%. The DSC detection result is shown in figure 3, and the DSC detection endothermic peaks are 271.47 ℃ and 274.32 ℃, which shows that the obtained thalidomide crystal is alpha crystal form and has high purity. An X-ray diffraction pattern (XRPD) is shown in FIG. 4A, and X-ray diffraction data is shown in FIG. 4B. The obtained product is also shown to be thalidomide in alpha crystal form and has high purity.
Example 3
50g of thalidomide crude product and 1500g of tetrahydrofuran recovered in example 1 are sequentially added into a 2L three-neck round-bottom flask, the mixture is mechanically stirred, heated in an oil bath to reflux, 150g of purified water is added, the solid is completely dissolved, the mixture is cooled to room temperature, decompressed and concentrated to recover tetrahydrofuran, after the tetrahydrofuran is recovered, mother liquor is filtered, and a filter cake is dried in vacuum at 80 ℃ for 4 hours to obtain 48.8g of thalidomide crystal finished product, wherein the recrystallization yield is 97.6%, the purity is 99.8%, and the residual quantity of tetrahydrofuran is almost 0%. The DSC results are shown in fig. 5, and the endothermic peaks of DSC are 271.31 ℃ (α crystal form characteristic endothermic peak) and 274.23 ℃, indicating that thalidomide is α crystal form and has high purity. An X-ray diffraction pattern (XRPD) is shown in FIG. 6A, and X-ray diffraction data is shown in FIG. 6B. The result shows that the obtained product is the alpha crystal form thalidomide and has high purity.
Example 4
50g of thalidomide crude product and 150g of tetrahydrofuran recovered in example 2 are sequentially added into a 500ml three-neck round-bottom flask, the mixture is mechanically stirred, heated in an oil bath to reflux, 150g of purified water is added, the solid is completely dissolved, the mixture is cooled to room temperature and decompressed and concentrated to recover tetrahydrofuran, after the tetrahydrofuran is recovered, mother liquor is filtered, and a filter cake is dried in vacuum at 80 ℃ for 4 hours to obtain 49.0g of thalidomide crystal finished product, wherein the recrystallization yield is 98.0%, the purity is 99.7%, and the tetrahydrofuran residue is almost 0%. The DSC detection result is shown in figure 7, and the DSC detection endothermic peak is 271.32 ℃, which indicates that the obtained thalidomide crystal is alpha crystal form and has high purity. An X-ray diffraction pattern (XRPD) is shown in FIG. 8A, and X-ray diffraction data is shown in FIG. 8B. The result shows that the obtained product is the alpha crystal form thalidomide and has high purity.
Example 5
As shown in fig. 9, the steps for preparing thalidomide form α are as follows:
(1) adding 50Kg of thalidomide crude product, 150Kg of tetrahydrofuran and 150Kg of water into a 500L crystallization kettle in sequence, heating, stirring and dissolving until the solution is completely dissolved to obtain a first solution;
(2) subjecting the first solution to an atmospheric selective distillation such that tetrahydrofuran is distilled off and water is not substantially distilled off, to obtain a first distillate and a distilled first mixture containing a residual mixed solvent, thalidomide dissolved in the mixed solvent, and precipitated crystalline thalidomide;
(3) cooling the first mixture after distillation to room temperature, and performing suction filtration under reduced pressure;
(4) washing the filter cake with a proper amount of water for three times and drying to obtain 48Kg of a thalidomide alpha crystal form finished product;
(5) recovering the first distillate (mainly containing tetrahydrofuran) obtained in the step (2), adding the first distillate into a crystallization kettle, adding 50Kg of thalidomide crude product and 150Kg of water, heating, stirring and dissolving until the first distillate is completely dissolved to obtain a first solution;
(6) repeating the steps (2) - (5) for 3 times.
The result shows that 192Kg of thalidomide alpha crystal form finished product can be prepared by using 150Kg of tetrahydrofuran and 200Kg of thalidomide crude product, which is equivalent to about 0.78Kg of tetrahydrofuran required by preparing 1Kg of high-purity thalidomide, and the recrystallization yield is 96%, the purity is 99.8%, and the tetrahydrofuran residue is almost 0%. The endothermic peak detected by DSC is similar to that in figure 1, and the characteristic peak of the alpha crystal form has an endothermic peak, which indicates that the prepared alpha crystal form thalidomide with high purity is obtained. Because tetrahydrofuran is recycled for 4 times, 150Kg of tetrahydrofuran and 200Kg of thalidomide crude product are used together, and 192Kg of alpha crystal form finished product is obtained.
Comparative example 1
Adding 50g of thalidomide crude product and 100g of dimethyl sulfoxide into a 1L three-neck round-bottom flask in sequence, mechanically stirring, heating in an oil bath to 90 ℃, then keeping the temperature and stirring until the solution is clear, then cooling to 20-40 ℃, slowly adding 250g of ethanol, carrying out suction filtration, washing a filter cake with a small amount of ethanol, transferring the filter cake to a vacuum drying process at 80 ℃ for 4 hours to obtain 35.0g of thalidomide finished product, wherein the recrystallization yield is 70.0%, an endothermic peak is detected by DSC to be near 274.30 ℃, and no endothermic peak is detected near 271.30 ℃ (a characteristic endothermic peak of an alpha crystal form), which indicates that the obtained thalidomide finished product contains a large amount of beta crystal forms. And the mother liquor after final crystallization is a mixture of dimethyl sulfoxide and ethanol, and the dimethyl sulfoxide is used as a solvent, and the ethanol is used as an anti-solvent, so that the dimethyl sulfoxide cannot be directly recycled, and the dimethyl sulfoxide needs to be separated.
Comparative example 2
Adding 50g of thalidomide crude product and 100g of dimethyl sulfoxide into a 1L three-neck round-bottom flask in sequence, mechanically stirring, heating in an oil bath until the solution is clear, adding 300g of ethanol, cooling to room temperature, carrying out vacuum filtration, and drying a filter cake in vacuum at 80 ℃ for 4 hours to obtain 38g of thalidomide finished product. And no endothermic peak of the alpha crystal form is found by DSC detection.
Comparative example 3
Adding 50g of thalidomide crude product and 100g of dimethyl sulfoxide into a 1L three-neck round-bottom flask in sequence, mechanically stirring, heating in an oil bath to 90 ℃, then keeping the temperature and stirring until the solution is clear, then cooling to 20-40 ℃, slowly adding 250g of purified water, carrying out suction filtration, washing a filter cake with a small amount of purified water, transferring the filter cake to 80 ℃ vacuum drying, and drying for 4 hours to obtain 45.0g of thalidomide finished product, wherein the recrystallization yield is 90.0%, an endothermic peak exists near 274.30 ℃ as detected by DSC, and no endothermic peak exists near 271.30 ℃ (a characteristic endothermic peak of an alpha crystal form). This indicates that the resulting finished thalidomide product contains a significant amount of the beta crystalline form. And the mother liquor after final crystallization is a mixture of dimethyl sulfoxide and water, and the dimethyl sulfoxide is used as a solvent, and the water is used as an anti-solvent, so that the dimethyl sulfoxide cannot be directly recycled, and the dimethyl sulfoxide needs to be separated.
Comparative example 4
And sequentially adding 50g of the thalidomide crude product and 150g of pyridine into a 1L three-neck round-bottom flask, mechanically stirring, heating in an oil bath until the solution is clear, adding 300g of purified water, cooling to room temperature, carrying out vacuum filtration, and drying a filter cake at 80 ℃ in vacuum for 4 hours to obtain 40g of alpha-crystal thalidomide finished product. Pyridine residues in the finished thalidomide product are easy to exceed the standard, and pyridine wastewater is difficult to treat.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (20)

1. A method for industrially preparing thalidomide alpha crystal form, which is characterized by comprising the following steps:
(1) providing a first solution, wherein the first solution comprises a mixed solvent and thalidomide dissolved in the mixed solvent, and the mixed solvent is a mixed solvent of tetrahydrofuran and water;
(2) selectively distilling the first solution to obtain a first distillate and a distilled first mixture, wherein the first mixture comprises residual mixed solvent, thalidomide dissolved in the mixed solvent and precipitated crystalline form alpha of thalidomide, and wherein the selective distillation allows tetrahydrofuran to be distilled off while water is not substantially distilled off;
(3) isolating said crystalline form α of thalidomide from said first mixture; and
(4) washing and drying the separated thalidomide alpha crystal form to obtain a dried thalidomide alpha crystal form.
2. The process according to claim 1, characterized in that the first distillate obtained in step (2) is recycled.
3. The process of claim 2, wherein the recovered first distillate is used to produce the first solution.
4. The method of claim 1, wherein in the first solution, the ratio of tetrahydrofuran: the weight ratio of the water is 100:1-1: 10.
5. The method of claim 1, wherein in the first solution, the ratio of tetrahydrofuran: the weight ratio of the water is 10:1-1: 5.
6. The method of claim 1, wherein in the first solution, the ratio of tetrahydrofuran: the weight ratio of the water is 3:1-1: 1.
7. The method according to claim 1, wherein the mass ratio of the thalidomide to the tetrahydrofuran in the mixed solvent is 1: 0.5-300.
8. The method according to claim 1, wherein the mass ratio of the thalidomide to the tetrahydrofuran in the mixed solvent is from 1:1 to 100.
9. The method according to claim 1, wherein the mass ratio of the thalidomide to the tetrahydrofuran in the mixed solvent is from 1:1 to 50.
10. The method according to claim 1, wherein the mass ratio of the thalidomide to the tetrahydrofuran in the mixed solvent is from 1:3 to 30.
11. The method according to claim 1, wherein the mass ratio of the thalidomide to the tetrahydrofuran in the mixed solvent is from 1:1 to 10.
12. The method of claim 1, wherein the mass ratio of thalidomide to water in the mixed solvent is from 1:1 to 50.
13. The method of claim 1, wherein the mass ratio of thalidomide to water in the mixed solvent is from 1:3 to 50.
14. The method of claim 1, wherein the mass ratio of thalidomide to water in the mixed solvent is from 1:3 to 10.
15. The method of claim 1, wherein the mass ratio of thalidomide to water in the mixed solvent is from 1:1 to 3.
16. The method of claim 1, wherein the method further comprises: and (0) a step (0) of mixing the crude thalidomide with water and tetrahydrofuran, thereby obtaining a first solution, which is located before the step (1).
17. The method of claim 16, wherein the method further comprises: the recovered distillate was used in step (0).
18. The method of claim 17, wherein steps (0) through (2) are performed cyclically and continuously.
19. The method of claim 1, wherein the distillation is carried out at a temperature of t1, wherein the t1 is from 15 ℃ to 100 ℃.
20. The method of claim 1, wherein the distillation is carried out at a temperature of t1, wherein the t1 is 15-40 ℃ or 40-100 ℃.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260241A (en) * 2010-05-26 2011-11-30 重庆医药工业研究院有限责任公司 Industrial preparation method of thalidomide of crystal form alpha
CN102924432A (en) * 2012-11-09 2013-02-13 常州制药厂有限公司 Preparation method of high-purity thalidomide
CN103068812A (en) * 2010-06-09 2013-04-24 基因里克斯(英国)有限公司 Crystalline forms of thalidomide and processes for their preparation
WO2017081701A1 (en) * 2015-11-12 2017-05-18 Natco Pharma Ltd An improved process for the preparation of thalidomide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260241A (en) * 2010-05-26 2011-11-30 重庆医药工业研究院有限责任公司 Industrial preparation method of thalidomide of crystal form alpha
CN103068812A (en) * 2010-06-09 2013-04-24 基因里克斯(英国)有限公司 Crystalline forms of thalidomide and processes for their preparation
CN102924432A (en) * 2012-11-09 2013-02-13 常州制药厂有限公司 Preparation method of high-purity thalidomide
WO2017081701A1 (en) * 2015-11-12 2017-05-18 Natco Pharma Ltd An improved process for the preparation of thalidomide

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