A ritahist morpholine salt and its preparation method and application

Abstract

The present invention relates to the technical field of drug synthesis, and in particular to a ritahist morpholine salt and its preparation method and application. The ritahist morpholine salt provided by the present invention can dissociate and remove morpholine in a trace amount of acidic water to obtain high-purity ritahist, and has high yield and simple operation, and can greatly reduce the generation of waste solvents and wastewater in the ritahist purification process. The preparation method of the ritahist morpholine salt provided by the present invention is easy to implement, and the obtained ritahist morpholine salt has high yield and high purity, and has a good removal effect on chiral isomer impurities. In the ritahist purification process, the crude ritahist is first prepared into the ritahist morpholine salt, and then a simple acid water dissociation is performed, which can greatly simplify the ritahist purification process, reduce the generation of waste solvents and wastewater, have strong reaction consistency, and the process is safe and controllable, and the impurity content in the product is lower.

Description

[0001] This application claims priority to Chinese patent application No. 202210744975.X filed on June 27, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The invention belongs to the technical field of drug synthesis, and particularly relates to a ritahist morpholine salt and a preparation method and application thereof. Background Art

[0003] Litamilast is a lymphocyte function-associated antigen 1 (LFA-1) antagonist drug used to treat dry eye disease.

[0004] The preparation of lifalast involves purification, but there are currently few reports on this topic. There are two main methods. Method 1 involves directly refining lifalast in a solvent, such as acetonitrile or butanone. However, due to lifalast's unique physical and chemical properties, this method easily forms a sticky solid during crystallization, making it unsuitable for industrial production. Using dust separation yields a better solid state, but the purification effect is poor, requiring multiple crystallizations. Method 2 involves purifying lifalast through the formation of a dicyclohexylamine salt. While this salt formation method yields high purity, it also has significant drawbacks. During the dissociation of lifalast dicyclohexylamine salt, since dicyclohexylamine hydrochloride is insoluble in water, the dicyclohexylamine salts of these acids, such as phosphoric acid, sulfuric acid, formic acid, acetic acid, or trifluoroacetic acid, exhibit a certain solubility in the solvent. Consequently, even after multiple, high-dose extractions, residual dicyclohexylamine remains in the resulting product. Hydrolysis of the salt under alkaline conditions requires extensive solvent extraction to remove the dicyclohexylamine, followed by acidification to precipitate lifalast. Consequently, the resulting product exhibits excessive residue on ignition. Therefore, obtaining a drug substance with acceptable residue on ignition, residual dicyclohexylamine, and residual solvent requires extensive post-processing, and the entire process generates significant amounts of waste acid aqueous solution and waste organic solvent, hindering scale-up. In addition, crude ritahistide often contains chiral isomer impurities, and the use of dicyclohexylamine salt to form a salt is not effective in removing chiral isomer impurities. It is necessary to select crude ritahistide with higher chiral purity to prepare ritahistide dicyclohexylamine salt that meets the required standards. Summary of the Invention

[0005] In view of the above technical problems, the present invention provides a lifamide morpholine salt and its preparation method and application. The lifamide morpholine salt can be dissociated into lifamide in a trace amount of acid water, which can greatly reduce the generation of waste solvents and wastewater in the lifamide purification process, and is easy to operate. The preparation method of the lifamide morpholine salt provided by the present invention is easy to implement, not only can the lifamide morpholine salt of high purity be prepared, but also can significantly remove chiral isomer impurities, thereby significantly reducing the content of chiral isomer impurities in lifamide prepared with the lifamide morpholine salt. The lifamide morpholine salt and its preparation method can be used for industrial purification of crude lifamide.

[0006] To achieve the above-mentioned purpose, the embodiment of the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a morphine salt of ritaminast, the structural formula of which is shown in Formula I:

[0008]

[0009] The morpholine salt of ritalista is simple to post-process. Morpholine can be removed and ritalista released in trace amounts of acidic water, eliminating the need for large volumes of organic solvents and making it more suitable for industrial production. In the ritalista purification process, crude ritalista is first converted into the morpholine salt, followed by acid-water dissociation. This significantly simplifies the purification process and yields pharmaceutical-grade, high-purity ritalista.

[0010] In a second aspect, the present invention provides a method for preparing the above-mentioned ritahist morpholine salt, which specifically comprises the following operations: dissolving crude ritahist in a mixed solution of an organic solvent and water or in an organic solvent, adding morpholine, and separating the solid and the liquid after solid precipitation to obtain the ritahist morpholine salt.

[0011] This method is simple to operate, and the resulting crude product of ritaminast morpholine salt has high purity and high yield. Application of this method to the preparation and purification of ritaminast can significantly reduce solvent usage, simplify operations, and shorten production cycles. Furthermore, during the preparation of the ritaminast morpholine salt, not only is common impurities in the crude ritaminast product effectively removed, but chiral isomer impurities are also effectively removed. Therefore, the ritaminast morpholine salt prepared using this method can produce ritaminast with a lower impurity content, particularly a lower chiral isomer impurity content.

[0012] Optionally, a small amount of ritamilast morpholine salt may be added as seed crystals after the addition of morpholine to accelerate the precipitation of ritamilast morpholine salt in the reaction.

[0013] In combination with the second aspect, the solvent includes at least one of isopropyl alcohol, ethanol, methanol, tetrahydrofuran, butanone, methyl butyl ketone, acetone, acetonitrile, isopropyl acetate and N,N-dimethylformamide.

[0014] Preferably, the ratio of the volume of the mixed solution of the organic solvent and water or the volume of the organic solvent to the mass of the crude product of lisdaplast is 4 to 30:1 (ml:g).

[0015] Preferably, in the mixed solution of the organic solvent and water, the mass of the water is no more than 3 times the mass of the crude lisdaplast.

[0016] In combination with the second aspect, the ratio of the molar amount of morpholine to the molar amount of the crude listamilast is 0.5 to 10: 1. The molar amount of the crude listamilast = the mass of the crude listamilast / the molecular weight of listamilast.

[0017] In combination with the second aspect, the preparation method further includes further purifying the product obtained by solid-liquid separation to further improve the purity of the product.

[0018] Preferably, the purification method comprises dissolving the crude product of ritahist morpholine salt in an organic solvent, heating to 55-65° C., stirring and reacting for 30-60 minutes; cooling to room temperature, and filtering to obtain the refined product of ritahist morpholine salt.

[0019] In a third aspect, the present invention provides use of the above-mentioned ritahist morpholine salt or the preparation method thereof in purifying crude ritahist.

[0020] In combination with the third aspect, the application specifically includes the following operations: dissolving the ritahist morpholine salt in water, adding acid to adjust the pH of the solution to 2-6, and separating the solid and the liquid after solid precipitation to obtain the refined ritahist.

[0021] Using the above-mentioned ritahist morpholine salt under the dissociation conditions, a high-purity ritahist refined product can be obtained, especially one with significantly reduced chiral isomer impurity content. The reaction consistency is strong, the process is safe and controllable, and the obtained ritahist refined product has an HPLC purity of ≥99.5% and a chiral isomer impurity of ≤0.1%, meeting pharmaceutical grade requirements, and a high yield of over 80%.

[0022] Optionally, the acid used to adjust the pH of the solution includes at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and formic acid.

[0023] Preferably, the above operation may further include adding an organic solvent before adjusting the pH of the solution. Adding an organic solvent helps to change the solid state of lifalast and reduce the water content in the lifalast product.

[0024] Preferably, the organic solvent is at least one of methanol, ethanol, acetone, butanone and acetonitrile.

[0025] Preferably, the mass ratio of the volume of the organic solvent to the ritaminat morpholine salt is 1 to 5:1 (ml:g).

[0026] In combination with the third aspect, the application may further specifically include the following operations: dissolving the lisdaplast morpholine salt in water, adding dichloromethane and then acid to adjust the pH of the solution to 2-6, stirring and reacting for 10-40 minutes, separating and extracting, discarding the aqueous phase, concentrating the organic layer and adding an organic solvent to dissolve it, adding the resulting solution to water, continuing to stir and react for 20-40 minutes, and performing solid-liquid separation to obtain lisdaplast.

[0027] Optionally, the organic solvent is at least one of methanol, ethanol, acetone, butanone, and acetonitrile, and the amount used depends on the solubility of the solid in the concentrated organic layer, and the solid in the concentrated organic layer can be dissolved.

[0028] In a fourth aspect, the present invention provides use of the above-mentioned ritahist morpholine salt or its preparation method in preparing crude ritahist. In the process of preparing ritahist, the crude ritahist is prepared into ritahist morpholine salt, which is then dissociated to obtain refined ritahist.

[0029] In a fifth aspect, the present invention also provides a type A crystal of lisdaptomycin morpholine salt. In the X-ray powder diffraction spectrum, as a diffraction angle expressed in 2θ, the type A crystal has peaks at 11.22°±0.2°, 14.90°±0.2°, 18.00°±0.2°, 18.50°±0.2°, 18.94°±0.2°, 19.40°±0.2°, 21.08°±0.2°, 21.76°±0.2°, 22.66°±0.2° and 24.94°±0.2°.

[0030] The beneficial effects of the present invention are:

[0031] 1. The method for preparing the above-mentioned ritahist morpholine salt provided by the present invention can produce high-purity ritahist morpholine salt. This purification method can not only effectively remove common impurities in the crude ritahist, but also effectively remove chiral isomer impurities, and is applicable to crude products obtained under any process conditions;

[0032] 2. Compared with the process for producing ritaminast dicyclohexylamine salt, this process has simpler post-processing. No large amounts of solvent are required to extract and wash the free base. The organic base morpholine can be completely removed by directly adding water to adjust the acidity and precipitate it, thereby obtaining a pharmaceutical-grade refined ritaminast.

[0033] 3. Compared with the process for producing cisplatin dicyclohexylamine salt, the yield of this process is as high as over 80%;

[0034] Therefore, compared with the process for preparing lifamide dicyclohexylamine salt, the preparation method of lifamide morpholine salt provided by the present invention is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the neutral morpholine salt of ritaminast in Example 1 of the present invention;

[0036] Figure 2 This is the mass spectrum of the morpholine salt of ritaminast in Example 1 of the present invention;

[0037] Figure 3 This is the HPLC spectrum of the neutral morpholine salt of ritaminast in Example 1 of the present invention;

[0038] Figure 4 This is the X-ray powder diffraction spectrum of the type A crystal of the neutral morpholine salt of Litamistat in Example 19 of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0040] There are currently two main purification processes for lisdaplast: recrystallization in a solvent or purification after preparation as a dicyclohexylamine salt. The former easily forms a sticky solid during the crystallization process, making it unsuitable for industrial production. While the latter can produce a relatively high-purity lisdaplast dicyclohexylamine salt, the post-processing required to dissociate the lisdaplast dicyclohexylamine salt is very complex. To obtain a drug substance with acceptable residue on ignition, residual dicyclohexylamine, and residual solvent, the post-processing is cumbersome, and the entire process generates large amounts of waste acid aqueous solution and waste solvent, hindering scale-up production. Furthermore, the chiral isomer impurities present in crude lisdaplast cannot be effectively removed by preparing the lisdaplast dicyclohexylamine salt. Therefore, the development of a simple, economical, and scale-up-compatible lisdaplast purification method that can more effectively remove impurities is of paramount importance.

[0041] Through extensive experimental research and condition screening, the present invention has developed a crystallization method suitable for lisdaplast. This crystallization method can produce a high-purity lisdaplast morpholine salt (I). This salt dissociates into lisdaplast upon addition of a trace amount of acid water, significantly reducing the generation of waste solvents and wastewater in the lisdaplast purification process. This makes the synthesis of lisdaplast more conducive to industrial production, simplifies the operation, and is more conducive to the preparation of pharmaceutical-grade lisdaplast. Furthermore, experimental studies have found that the crystallization method provided by the present invention can effectively remove chiral isomer impurities in crude lisdaplast, thus being able to be used to obtain lisdaplast of higher purity.

[0042] Example 1

[0043] This embodiment provides a method for preparing ritaminat morpholine salt.

[0044] 5 g of crude ritahistate was added to 50 mL of butanone at room temperature (25±5°C) and stirred to dissolve. 1.4 g of morpholine was then added and stirred for 0.5 h. A small amount of solid precipitated. The reaction was continued at room temperature for 16 h. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with 10 mL of butanone and dried at 50±5°C to obtain 4.7 g of ritahistate morpholine salt. The yield was 82.05%.

[0045] The structure of the obtained ritahstat morpholine salt was analyzed, and the nuclear magnetic resonance 1H spectrum was as follows: Figure 1 As shown, the mass spectrum Figure 2 As shown, its structure can be determined as shown in Formula I.

[0046]

[0047] The HPLC spectrum of the obtained ritahstat morpholine salt is as follows: Figure 3 As shown, its HPLC purity was 99.82%.

[0048] Example 2

[0049] This embodiment provides a method for preparing ritaminat morpholine salt.

[0050] 5 g of crude ritahistate was added to 40 mL of butanone at room temperature (25±5°C) and stirred for dissolution. 3.5 g of morpholine was then added and stirred for 1 h. After that, 0.05 g of seed crystals were added and the reaction was continued overnight at room temperature for 18 h. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with 10 mL of butanone and dried at 50±5°C to obtain 5.0 g of ritahistate morpholine salt. The yield was 87.61% and the HPLC purity was 99.79%.

[0051] Example 3

[0052] This embodiment provides a method for preparing ritaminat morpholine salt.

[0053] 5 g of crude ritahistate was added to 135 mL of isopropanol, heated to 60±5°C, and stirred to dissolve. 2.1 g of morpholine and 15 g of water were then added. After stirring for 1 h, 0.05 g of seed crystals was added. The temperature was lowered to room temperature and the reaction was carried out for 24 h. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with 10 mL of isopropanol and dried at 50±5°C to obtain 5.2 g of ritahistate morpholine salt. The yield was 91.12% and the HPLC purity was 99.27%.

[0054] Example 4

[0055] This embodiment provides a method for preparing ritaminat morpholine salt.

[0056] 5 g of crude ritahistate was added to 120 mL of ethanol and 10 mL of methanol, heated to 60±5°C, and stirred to dissolve. 5 g of morpholine was then added, and the mixture was stirred for 1 h. 0.05 g of seed crystals was added, and the mixture was cooled to room temperature overnight and reacted for 14 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 10 mL of ethanol and dried at 50±5°C to obtain 5.2 g of ritahistate morpholine salt. The yield was 91.12%; the HPLC purity was 98.82%.

[0057] Example 5

[0058] This embodiment provides a method for preparing ritaminat morpholine salt.

[0059] 5 g of crude ritahistate was added to 20 mL of methanol and 40 mL of isopropanol, stirred and dissolved at room temperature (30±5°C). 2.1 g of morpholine was then added, stirred and reacted for 1 h. 0.05 g of seed crystals were then added. The temperature was lowered to 0±5°C overnight and reacted for 16 h. A large amount of solid precipitated. The solid was filtered, and the filter cake was washed with 10 mL of isopropanol and dried at 50±5°C to obtain 4.4 g of ritahistate morpholine salt. The yield was 77.19%; the HPLC purity was 98.92%.

[0060] Example 6

[0061] This embodiment provides a method for preparing ritaminat morpholine salt.

[0062] 5 g of crude ritahistate was added to 50 mL of tetrahydrofuran and stirred at room temperature (30±5°C) to dissolve. 0.5 g of morpholine was then added and stirred for 1 h. 0.05 g of seed crystals were added and the reaction was continued overnight at room temperature for 16 h. A large amount of solid precipitated, which was filtered and the filter cake was washed with 10 mL of tetrahydrofuran and dried at 50±5°C to obtain 4.8 g of ritahistate morpholine salt. The yield was 70.21% and the HPLC purity was 99.74%.

[0063] Example 7

[0064] This embodiment provides a method for preparing ritaminat morpholine salt.

[0065] 5 g of crude ritahistate was added to 60 mL of methyl butyl ketone and acetonitrile, stirred and dissolved at room temperature (30±5°C). 5.6 g of morpholine was then added, and the mixture was stirred and reacted for 1 h. 0.05 g of seed crystals was added, and the reaction was continued overnight at room temperature for 14 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 10 mL of methyl butyl ketone and dried at 50±5°C to obtain 4.5 g of ritahistate morpholine salt. The yield was 78.95%; the HPLC purity was 99.26%.

[0066] Example 8

[0067] This embodiment provides a method for preparing ritaminat morpholine salt.

[0068] 5 g of crude ritahistate was added to 50 mL of acetone at room temperature (30±5°C) and stirred to dissolve. 1.0 g of morpholine was then added and stirred for 1 h. 0.05 g of seed crystals were added and the reaction was continued overnight at room temperature for 16 h. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with 10 mL of acetone and dried at 50±5°C to obtain 5.0 g of ritahistate morpholine salt. The yield was 87.72% and the HPLC purity was 98.72%.

[0069] 5.0 g of the above-mentioned ritahist morpholine salt was dissolved in 50 mL of acetone, heated to 60±5°C, and stirred for 30 min. The mixture was cooled to room temperature and filtered to obtain 4.8 g of ritahist morpholine salt. The yield was 96.00% and the HPLC purity was 99.72%.

[0070] Example 9

[0071] This embodiment provides a method for preparing ritaminat morpholine salt.

[0072] 5 g of crude ritahistate was added to 70 mL of acetonitrile and stirred at room temperature (30±5°C) to dissolve. 1.4 g of morpholine was then added and stirred for 1 h. 0.05 g of seed crystals were added and the reaction was continued overnight at room temperature for 16 h. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with 10 mL of acetonitrile and dried at 50±5°C to obtain 5.3 g of ritahistate morpholine salt. The yield was 92.87% and the HPLC purity was 99.82%.

[0073] Example 10

[0074] This embodiment provides a method for preparing ritaminat morpholine salt.

[0075] 5 g of crude ritaminast was added to 20 mL of N,N-dimethylformamide and butanone at room temperature (30±5°C) and stirred for dissolution. 3.6 g of morpholine was then added and stirred for 1 h. After that, 0.05 g of seed crystals were added and the reaction was continued overnight at room temperature for 18 h. A large amount of solid precipitated, which was filtered and the filter cake was washed with 10 mL of butanone and dried at 50±5°C to obtain 4.8 g of ritaminast morpholine salt. The yield was 84.11% and the HPLC purity was 98.69%.

[0076] Example 11

[0077] This embodiment provides a method for preparing ritaminat morpholine salt.

[0078] 5 g of crude ritahistate was added to 20 mL of acetonitrile and 2 mL of water, stirred and dissolved at room temperature at 30±5°C. 2.1 g of morpholine was then added, and the mixture was stirred and reacted for 1 h. 0.05 g of seed crystals was added, and the reaction was continued at room temperature for 24 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 10 mL of acetonitrile and dried at 50±5°C to obtain 5.1 g of ritahistate morpholine salt. The yield was 89.48%; the HPLC purity was 99.72%.

[0079] Example 12

[0080] This embodiment provides a method for preparing ritaminat morpholine salt.

[0081] 5 g of crude ritahistate was added to 40 mL of butanone and 20 mL of isopropanol, stirred and dissolved at room temperature (30±5°C). 4.2 g of morpholine was then added, and the reaction was stirred for 1 h. After that, 0.05 g of seed crystals were added and the reaction was continued overnight at room temperature for 18 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 8 mL of butanone and 4 mL of isopropanol and dried at 50±5°C to obtain 5.3 g of ritahistate morpholine salt. The yield was 92.87% and the HPLC purity was 99.39%.

[0082] Example 13

[0083] This embodiment provides a method for preparing ritaminat morpholine salt.

[0084] 5 g of crude ritahistate was added to 20 mL of acetonitrile and 80 mL of butanone, stirred and dissolved at room temperature (30±5°C). 2.1 g of morpholine was then added, and the reaction was stirred for 1 h. 0.05 g of seed crystals was added, and the reaction was continued overnight at room temperature for 18 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 10 mL of acetonitrile and dried at 50±5°C to obtain 5.0 g of ritahistate morpholine salt. The yield was 87.62%; the HPLC purity was 99.73%.

[0085] Example 14

[0086] This embodiment provides a method for preparing ritaminat morpholine salt.

[0087] 5 g of crude ritaminast was added to 50 mL of tetrahydrofuran and 10 mL of isopropyl acetate, stirred and dissolved at room temperature (30±5°C). 1.7 g of morpholine was then added, and the reaction was stirred for 1 h. 0.05 g of seed crystals were added, and the reaction was continued overnight at room temperature for 18 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 10 mL of tetrahydrofuran and 2 mL of isopropyl acetate, and dried at 50±5°C to obtain 4.7 g of ritaminast morpholine salt. The yield was 82.46%; the HPLC purity was 99.42%.

[0088] Example 15

[0089] This embodiment provides a method for preparing ritaminat morpholine salt.

[0090] 5 g of crude ritaminast was added to 60 mL of acetonitrile and 5 mL of water, stirred and dissolved at room temperature at 30±5°C. 3.4 g of morpholine was then added, and the mixture was stirred for 1 h. 0.05 g of seed crystals was added and the reaction was continued at room temperature for 48 h. A large amount of solid precipitated, which was filtered and the filter cake was washed with 10 mL of acetonitrile and dried at 50±5°C to obtain 4.9 g of ritaminast morpholine salt. The yield was 85.97% and the HPLC purity was 99.76%.

[0091] Example 16

[0092] This embodiment provides a method for preparing ritaminat morpholine salt.

[0093] 5 g of crude ritahistate was added to 40 mL of acetone and 1 mL of water, stirred and dissolved at room temperature at 30±5°C. 2.6 g of morpholine was then added, and the mixture was stirred and reacted for 1 h. 0.05 g of seed crystals was added, and the reaction was continued at room temperature overnight for 16 h. A large amount of solid precipitated, which was filtered. The filter cake was washed with 10 mL of acetone and dried at 50±5°C to obtain 4.9 g of ritahistate morpholine salt. The yield was 85.70%; the HPLC purity was 99.83%.

[0094] Example 17

[0095] This embodiment provides a method for preparing ritaminat morpholine salt.

[0096] 100 g of crude ritahistate was added to 800 mL of butanone and 50 mL of water at room temperature (30±5°C) and stirred to dissolve. 28.3 g of morpholine was then added and stirred for 4 h. A large amount of solid precipitated, which was filtered and the filter cake was washed with 100 mL of butanone and dried at 50±5°C to obtain 100 g of ritahistate morpholine salt with a yield of 87.77% and an HPLC purity of 99.86%.

[0097] Example 18

[0098] This embodiment provides a method for preparing ritaminat morpholine salt.

[0099] 100 g of crude ritahistate was added to 600 mL of butanone and 100 mL of acetonitrile and stirred at room temperature (30±5°C) for dissolution. 25.7 g of morpholine was then added and stirred for 8 h. A large amount of solid precipitated, which was filtered and the filter cake was washed with 120 mL of butanone and dried at 50±5°C to obtain 106 g of ritahistate morpholine salt with a yield of 92.98% and an HPLC purity of 99.75%.

[0100] Example 19

[0101] 100 g of crude ritaminast (containing 4.2% chiral isomer impurities) was added to 1 L of acetonitrile and 30 mL of water, stirred and dissolved, 30 g of morpholine was slowly added over 10 min, the temperature was raised to 65±5°C, 0.3 g of seed crystals were added, and stirring was continued for 30 min; the temperature was lowered to 45±5°C and stirred for 1 h; the temperature was then lowered to 25±5°C and the reaction was continued for 4 h, filtered, and the filter cake was washed with 300 mL of acetonitrile; and dried at 50±5°C to obtain 105 g of type A crystals of ritaminast morpholine salt; the yield was 92.16%; the HPLC purity was 99.94%, and no chiral impurities were detected.

[0102] The obtained type A crystals of lifamide morpholine salt were subjected to X-ray powder diffraction measurement. In the X-ray powder diffraction spectrum, as a diffraction angle expressed in 2θ, the obtained type A crystals of lifamide morpholine salt showed peaks at 11.22°±0.2°, 14.90°±0.2°, 18.00°±0.2°, 18.50°±0.2°, 18.94°±0.2°, 19.40°±0.2°, 21.08°±0.2°, 21.76°±0.2°, 22.66°±0.2°, and 24.94°±0.2°; the X-ray powder diffraction spectrum is shown in FIG. Figure 4 shown.

[0103] Example 20

[0104] 100 g of crude ritaminast (containing 4.2% chiral isomer impurities) was added to 1 L of acetonitrile and 35 mL of water and stirred at 30±10°C for dissolution. 35 g of morpholine was then added and stirred at room temperature for 1 h. 0.1 g of seed crystals was added and stirred for 1 h until a large amount of solid precipitated. The reaction was continued at 30±10°C for 4 h, filtered, and the filter cake was washed with 300 mL of acetonitrile. The mixture was dried at 50±5°C to obtain 100 g of type A crystals of ritaminast morpholine salt with a yield of 87.77%. The HPLC purity was 99.96%, and the chiral impurity content was 0.02%.

[0105] Example 21

[0106] 100 g of crude ritaminast (containing 4.2% chiral isomer impurities) was added to 1 L of butanone and 10 mL of water, stirred and dissolved, 30 g of morpholine was slowly added over 10 min, the temperature was raised to 65±5°C, 0.3 g of seed crystals were added, and stirring was continued for 30 min; the temperature was lowered to 45±5°C and stirred for 1 h; the temperature was then lowered to 25±5°C and the reaction was continued for 6 h, filtered, and the filter cake was washed with 300 mL of butanone; 285 g of wet ritaminast morpholine salt was obtained, with an HPLC purity of 99.87% and a chiral impurity content of 0.45%;

[0107] The wet product was added with 800 mL of butanone and heated to 65±5°C. The mixture was beaten for 1 hour, cooled to 45±5°C and stirred for 1 hour. The temperature was then cooled to 25±5°C and the reaction was continued for 6 hours. The mixture was filtered and the filter cake was washed with 250 mL of butanone. 98 g of type A crystals of ritaminat morpholine salt were obtained with a yield of 86.01%; the HPLC purity was 99.95%, and the chiral impurity content was 0.01%.

[0108] Example 22

[0109] This embodiment provides a method for preparing ritahist from ritahist morpholine salt.

[0110] 10 g of the morpholine salt of ritaminast obtained in Example 17 was added to 100 mL of water with stirring to dissolve. Dilute hydrochloric acid was slowly added at 20±10°C to adjust the pH to between 4 and 6 (taking 10 min), causing a large amount of solid to precipitate. The reaction was continued with stirring for 30 min. Litaminast was filtered and dried in vacuo at 40°C to obtain 8.3 g of a white solid with a yield of 95.04% and an HPLC purity of 99.89%. The chiral HPLC purity was 100%; the morpholine content was ≤0.1%.

[0111] Example 23

[0112] This embodiment provides a method for preparing ritahist from ritahist morpholine salt.

[0113] 10 g of the morpholine salt of ritaminast obtained in Example 17 was added to 150 mL of water and stirred to dissolve. 30 mL of acetone was then added, and dilute hydrochloric acid was slowly added at 20±10°C to adjust the pH to between 2 and 4 (over 10 min), resulting in the precipitation of a large amount of solid. The reaction was stirred and continued for 30 min. Litaminast was filtered and dried under vacuum at 40°C to obtain 7.9 g of a white solid with a yield of 90.18% and an HPLC purity of 99.88%. The chiral HPLC purity was 100% and the morpholine content was ≤0.1%.

[0114] Example 24

[0115] This embodiment provides a method for preparing ritahist from ritahist morpholine salt.

[0116] 10 g of the morpholine salt of ritaminast obtained in Example 17 was added to 150 mL of water and stirred to dissolve. 30 mL of methanol was then added, and dilute hydrochloric acid was slowly added at 20±10° C. to adjust the pH to between 5 and 6 (over 10 min). A large amount of solid precipitated. The reaction was stirred and continued for 30 min. Litaminast was filtered and dried in vacuo at 40° C. to obtain 7.0 g of a white solid. The yield was 80.00%, the HPLC purity was 99.86%, the chiral HPLC purity was 100%, and the morpholine content was ≤0.1%.

[0117] Example 25

[0118] This embodiment provides a method for preparing ritahist from ritahist morpholine salt.

[0119] 10 g of the morpholine salt of ritaminast obtained in Example 17 was added to 150 mL of water with stirring to dissolve. Dilute sulfuric acid was slowly added at 20±10° C. to adjust the pH to between 3 and 4 (taking 10 min), causing a large amount of solid to precipitate. The reaction was continued with stirring for 30 min. Litaminast was filtered and dried in vacuo at 40° C. to obtain 7.8 g of a white solid with a yield of 89.04% and an HPLC purity of 99.83%. The chiral HPLC purity was 100%; the morpholine content was ≤0.1%.

[0120] Example 26

[0121] This embodiment provides a method for preparing ritahist from ritahist morpholine salt.

[0122] 10 g of the morpholine salt of ritaminast obtained in Example 17 was added to 150 mL of water with stirring to dissolve. Dilute sulfuric acid was slowly added at 20±10° C. to adjust the pH to between 2 and 3 (taking 10 min), causing a large amount of solid to precipitate. The reaction was continued with stirring for 30 min. Litaminast was filtered and dried in vacuo at 40° C. to obtain 8.0 g of a white solid, with a yield of 91.32% and an HPLC purity of 99.86%. The chiral HPLC purity was 100%; the morpholine content was ≤0.1%.

[0123] Example 27

[0124] This embodiment provides a method for preparing ritahist from ritahist morpholine salt.

[0125] 10 g of the morpholine salt of ritaminast obtained in Example 17 was added to 150 mL of water with stirring to dissolve, then extracted with 100 mL of dichloromethane. Dilute hydrochloric acid was slowly added at 20±10° C. to adjust the pH to between 4 and 5 (over 10 min). After the addition was complete, stirring and reacting for 20 min. The mixture was separated and extracted, and the aqueous phase was discarded. The dichloromethane organic layer was concentrated until no obvious liquid flowed out. Concentration was stopped, and 30 mL of methanol was added with stirring to dissolve. The mixture was slowly added to 150 mL of water (over 10 min), resulting in the precipitation of a large amount of solid. The reaction was stirred and reacted for 30 min. Litaminast was filtered and dried in vacuo at 40° C. to obtain 8.1 g of a white solid, with a yield of 93.10% and HPLC purity of 99.89%. The chiral HPLC purity was 100% and the morpholine content was ≤0.1%.

[0126] Comparative Example 1

[0127] This comparative example provides another method for purifying ritalidomide.

[0128] 50g of crude ritaminast (containing 0.4% chiral isomers) was added to 400mL of acetone and 50mL of water and dissolved with stirring at 30±5°C. 22.07g of dicyclohexylamine was slowly added (over 10 minutes) and stirred overnight. A large amount of solid precipitated, which was filtered and the filter cake washed with 100mL of acetone. The mixture was dried at 50±5°C to yield 45g of ritaminast dicyclohexylamine salt (yield: 69.54%); the HPLC purity was 99.68%.

[0129] 10 g of the above-prepared ritaminast dicyclohexylamine salt was added to 100 mL of dichloromethane, followed by 100 mL of water with stirring. The solid dissolved, and 10% aqueous phosphoric acid solution was slowly added under stirring until the pH of the aqueous phase reached between 3 and 5 (10 min). Stirring was continued for 30 min. Extraction and separation were performed, and the aqueous phase was discarded. 100 mL of water was then added to the organic phase, and 10% aqueous phosphoric acid solution was added under stirring until the pH of the aqueous phase reached between 3 and 5. Stirring was continued for 30 min. Extraction and separation were performed, and the aqueous phase was discarded. TLC analysis revealed that free dicyclohexylamine was still present in the dichloromethane layer; the above-described aqueous phosphoric acid extraction was repeated once more; the dichloromethane phase was concentrated, and ethyl acetate was added to displace the residual dichloromethane. Solids precipitated and were filtered. The filter cake was washed with 20 mL of ethyl acetate and dried under vacuum at 40°C to obtain 6.5 g of refined ritalistat, with a yield of 85%; HPLC purity of 99.59%; and chiral HPLC purity of 99.9%. The dicyclohexylamine content was 0.32%, which did not meet pharmaceutical standards.

[0130] Comparative Example 2

[0131] 10 g of the dicyclohexylamine salt of ritaminast obtained in Comparative Example 1 was taken; 100 mL of methyl tert-butyl ether and 150 mL of water were added, and 10% aqueous sodium hydroxide solution was slowly added with stirring until the pH of the aqueous phase reached between 10 and 11 (taking 10 minutes). Stirring was continued for 30 minutes after the solid was completely dissolved. The layers were extracted and the tert-butyl methyl ether phase was discarded. The aqueous phase was washed once with 60 mL of methyl tert-butyl ether. The layers were extracted and the organic phase was discarded. TLC plate showed that the dicyclohexylamine was completely removed. Dilute hydrochloric acid was slowly added to the resulting aqueous phase to adjust the pH to between 3 and 6 (taking 5 minutes), resulting in the precipitation of a large amount of solid. The reaction was stirred for 30 minutes, filtered, and the filter cake was washed with 100 mL of water. It was dried in vacuo at 40°C to obtain 7.0 g of refined ritaminast, with a yield of 90.9%; HPLC purity: 99.61%; chiral HPLC purity: 99.9%; no dicyclohexylamine was detected; and the residue: 0.31%, which did not meet pharmaceutical standards.

[0132] Comparative Example 3

[0133] 10g of crude ritaminast (containing 4.2% chiral isomer impurities) was dissolved in 80mL of acetone and 10mL of water at 30±5°C with stirring. 4.4g of dicyclohexylamine was slowly added (over 10 minutes) and stirred overnight. A large amount of solid precipitated, which was filtered and the filter cake washed with 20mL of acetone. The mixture was dried at 50±5°C to yield 8.76g of ritaminast dicyclohexylamine salt (yield: 67.68%). The HPLC purity was 99.53%, and the chiral HPLC purity was 97.73%.

[0134] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing ritahist from ritahist morpholine salt, characterized in that: Specifically comprising the following steps: dissolving the risdaplast morpholine salt in water, adding dichloromethane and then acidifying the solution to adjust the pH to 4-5, stirring and reacting for 10-40 minutes, performing separation and extraction, discarding the aqueous phase, concentrating the organic layer, adding an organic solvent to dissolve it, adding the resulting solution to water, continuing to stir and react for 20-40 minutes, and performing solid-liquid separation to obtain risdaplast; The preparation method of the ritahist morpholine salt specifically comprises the following operations: dissolving a crude ritahist product in a mixed solution of an organic solvent and water or in an organic solvent, adding morpholine, and performing solid-liquid separation after solid precipitation to obtain the ritahist morpholine salt; the organic solvent is selected from at least one of methanol, ethanol, and isopropanol.

2. The method for preparing ritahist with ritahist morpholine salt according to claim 1, wherein: The ratio of the volume of the mixed solution of the organic solvent and water or the volume of the organic solvent to the mass of the crude product of lisdaplast is 4-30 mL:1 g.

3. The method for preparing ritahist with ritahist morpholine salt according to claim 1, characterized in that: In the mixed solution of the organic solvent and water, the mass of the water is no more than 3 times the mass of the crude lisdaplast.

4. The method for preparing ritahist with ritahist morpholine salt according to any one of claims 1 to 3, characterized in that The molar ratio of the morpholine to the crude ritalistat is 0.5-10:1.

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