Lisdexamphetamine salt single crystal, chiral isomer salt single crystal thereof, preparation method and application of lisdexamphetamine salt single crystal
By salting dextamphetamine with organic acids, single crystals of dextamphetamine salt were prepared, which solved the problem that dextamphetamine was difficult to prepare stable single crystals, and achieved efficient and high-purity single crystal preparation, supporting drug efficacy and quality control.
Patent Information
- Application Number
- CN202311225503.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-21
- Publication Date
- 2025-03-21
AI Technical Summary
It is difficult to prepare stable single crystals during the preparation process of dextamphetamine, which makes it difficult to determine its absolute configuration and affects drug efficacy and quality control.
By salting the free base of dextamphetamine or its chiral isomer with organic acid, forming a salt into a solution, filtering, and culturing away from light, a single crystal of dextamphetamine salt or its chiral isomer salt is prepared.
It realizes the efficient preparation of single crystals of dextamphetamine salt. The single crystal has high purity and good stability. It can be used for X-ray single crystal diffraction detection, determine the absolute configuration of the drug, and supports drug efficacy and quality control.
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Figure CN119661397A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of medical technology, and in particular relates to a lisdexamfetamine salt single crystal and a chiral isomer salt single crystal thereof, a preparation method and uses thereof. Background Art
[0002] Lisdexamfetamine is a prodrug obtained by covalently binding dextroamphetamine to lysine. It is a central nervous system stimulant and sympathomimetic drug. After entering the blood, it is hydrolyzed in the cytoplasm of red blood cells by aminopeptidase. The dextroamphetamine generated by hydrolysis passes through the blood-brain barrier and enters the binding site of the central nervous system, inducing the release of neurotransmitters and increasing neurotransmission. This drug is commonly used in the treatment of attention deficit hyperactivity disorder (ADHD) and binge eating disorder (BED). The commonly used clinical form of lisdexamfetamine is lisdexamfetamine dimesylate.
[0003]
[0004] In the process of preparing lisdexamfetamine, its chiral isomer (its enantiomer, impurity C and impurity D) can be produced.Lisdexamfetamine enantiomer does not have relevant drug efficacy value, and the existence of chiral isomer can make lisdexamfetamine quality decline, affect drug effect.Therefore, structural verification is carried out for lisdexamfetamine, lisdexamfetamine enantiomer, impurity C and impurity D, which is of great significance for lisdexamfetamine quality control and actual production and use.
[0005]
[0006] When the lysoxamfetamine or lysoxamfetamine salt (such as lysoxamfetamine dimesylate) obtained by chemical synthesis are carried out structural confirmation, particularly when determining its absolute configuration, single crystal x-ray diffraction method becomes common method.During the method test, the relevant single crystal of the compound to be tested needs to be prepared for testing.But, because lysoxamfetamine is a long straight-chain compound, this type of molecule is when preparing single crystal, because molecular flexibility is stronger, extremely difficult to prepare single crystal, and current relevant report is seldom and difficult to repeat.Therefore, the sample detected by the single crystal x-ray diffraction of lysoxamfetamine and its chiral isomer is difficult to obtain at present, and its absolute configuration determines that there is difficulty, causes being difficult to carry out quality control to lysoxamfetamine.
[0007] How to prepare stable single crystals of lisdexamfetamine and its chiral isomers to provide reference materials for single crystal X-ray diffraction detection for structural confirmation is an urgent problem to be solved in this field in order to provide support for single crystal pharmaceutical research and development. Summary of the invention
[0008] The present invention aims to provide a lisdexamfetamine salt single crystal and a chiral isomer salt single crystal thereof, a preparation method and uses thereof.
[0009] The present invention provides a lisdexamfetamine salt single crystal, wherein the lisdexamfetamine salt single crystal is a monoclinic crystal system, and its crystal axis The angles between the crystal planes are α / °=90, β / °=91.636(4), γ / °=90; unit lattice area The number of molecules in the unit cell is Z = 4, and the density is 1.145 g / cm 3 .
[0010] The present invention also provides a single crystal of a chiral isomer salt of lisdexamfetamine, wherein the single crystal of a chiral isomer salt of lisdexamfetamine is a single crystal of a lisdexamfetamine enantiomer salt, a single crystal of an impurity C salt, or a single crystal of an impurity D salt;
[0011] The single crystal of the enantiomeric salt of lisdexamfetamine belongs to the monoclinic system, the C2 space group, and its unit cell parameters are: α=90°, β=91.6964(9)°, γ=90°, The single crystal is a DMF solvate crystal form;
[0012] The impurity C salt single crystal belongs to the triclinic system, and its unit cell parameters are: α=94.081(2)°, β=98.366(2)°, γ=107.605(2)°, P1 space group;
[0013] The impurity D salt single crystal belongs to the triclinic system, P1 space group, and its unit cell parameters are: α=94.7650(10)°, β=97.8500(10)°, γ=107.6580(10)°,
[0014] The present invention also provides a method for preparing a lisdexamfetamine salt single crystal or a chiral isomer salt single crystal thereof, which comprises the following steps:
[0015] (1) forming a salt of lisdexamfetamine free base or its chiral isomer free base with an organic acid;
[0016] (2) The salt obtained in step (1) is prepared into a solution and then filtered, the filtrate is sealed in a container, the container is opened and placed in a container filled with a poor solvent and sealed, and cultured in the dark to obtain a single crystal of lisdexamfetamine salt or a single crystal of its chiral isomer salt.
[0017] Furthermore, in step (1), the chiral isomer free base is lisdexamfetamine enantiomer free base, impurity C or impurity D;
[0018] So the structure of impurity C is
[0019] So the structure of impurity D is
[0020] Further, the preparation method of the lisdexamfetamine free base or the lisdexamfetamine enantiomer free base is:
[0021] Releasing lisdexamfetamine dimethanesulfonate or lisdexamfetamine dimethanesulfonate enantiomers under alkaline conditions to obtain lisdexamfetamine free base or lisdexamfetamine enantiomer free base;
[0022] The alkaline condition is to use a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution with a mass concentration of 20%-60%.
[0023] Furthermore, the preparation method of the free base of lisdexamfetamine or the free base of the enantiomer of lisdexamfetamine comprises the following steps:
[0024] The method comprises preparing a lisdexamfetamine dimethanesulfonate solution or a lisdexamfetamine dimethanesulfonate enantiomer solution with water, adjusting the pH value of the lisdexamfetamine dimethanesulfonate solution or the lisdexamfetamine dimethanesulfonate enantiomer solution to 10-14 with a 20%-60% sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution, extracting, drying and concentrating the organic layer to obtain lisdexamfetamine free base or lisdexamfetamine enantiomer free base.
[0025] Further, in step (1), the organic acid is at least one of p-toluenesulfonic acid, 2-phenyl-5-benzimidazolesulfonic acid, 4,4-biphenyldisulfonic acid, diphenylphosphoric acid, 3-pyridinesulfonic acid, isoquinoline-5-sulfonic acid, morpholineethanesulfonic acid, and quinoline-8-sulfonic acid;
[0026] And / or, in step (1), the free base of lisdexamfetamine or the free base of its chiral isomer is dissolved in an organic solvent and then salted with an organic acid; the organic solvent is at least one of dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, n-hexane, and acetone.
[0027] Furthermore, in step (2), the solvent used to prepare the salt obtained in step (1) into a solution is any one or more aqueous solutions of dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, n-hexane, acetone, acetonitrile, and methyl tert-butyl ether;
[0028] And / or, in step (2), the poor solvent is at least one of acetonitrile, acetone, N,N-dimethylformamide, dichloromethane, ethanol, methanol, diethyl ether, methyl tert-butyl ether, n-hexane, and cyclohexane.
[0029] The present invention also provides a lisdexamfetamine salt single crystal pharmaceutical composition, wherein the pharmaceutical composition contains the above-mentioned lisdexamfetamine salt single crystal.
[0030] The present invention also provides the use of the aforementioned lisdexamfetamine salt single crystal or the aforementioned lisdexamfetamine chiral isomer salt single crystal as a detection sample in single crystal X-ray diffraction detection for structural confirmation of lisdexamfetamine salt or lisdexamfetamine chiral isomer salt.
[0031] Compared with the prior art, the present invention has the following beneficial effects:
[0032] The present invention provides lisdexamfetamine salt and chiral isomer (lisdexamfetamine enantiomer, impurity C and impurity D) salt single crystal and preparation method thereof. The present invention prepares lisdexamfetamine salt and chiral isomer (lisdexamfetamine enantiomer, impurity C and impurity D) salt single crystal preparation method is simple and efficient. Meanwhile, the prepared single crystal has high purity, good stability, uniform and regular internal particle distribution, can be used as a test product, for performing X-ray single crystal diffraction detection, determining the absolute configuration of lisdexamfetamine bulk drug or lisdexamfetamine chiral isomer, for lisdexamfetamine quality control. In addition, lisdexamfetamine salt single crystal can be used to prepare lisdexamfetamine pharmaceutical composition. The present invention has potential clinical use value.
[0033] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.
[0034] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Figure 1 The X-ray single crystal diffraction spatial structure diagram of the lisdexamfetamine salt single crystal prepared in Example 1.
[0036] Figure 2 This is the atomic thermal vibration ellipsoid diagram of the lisdexamfetamine enantiomer cation in the asymmetric unit in the single crystal structure model of the salt of lisdexamfetamine enantiomer prepared in Example 6.
[0037] Figure 3 This is the atomic thermal vibration ellipsoid diagram of the first dimethyl sulfonate lisdexamfetil impurity C cation in the asymmetric unit in the impurity C salt single crystal prepared in Example 11.
[0038] Figure 4 This is the atomic thermal vibration ellipsoid diagram of the first dimethyl succinate lysine diphenylpropane impurity D cation in the asymmetric unit in the impurity D salt single crystal prepared in Example 16.
[0039] Figure 5 The stereochemical structure diagram of the salt single crystal of the lisdexamfetamine enantiomer obtained in Example 6.
[0040] Figure 6 The stereochemical structure of the impurity C salt single crystal obtained in Example 11.
[0041] Figure 7 This is the stereochemical structure of the impurity D salt single crystal obtained in Example 16. DETAILED DESCRIPTION
[0042] The compounds or reagents used in the specific embodiments of the present invention can be purchased from commercial sources, or prepared by conventional methods known to those skilled in the art; the experimental instruments used can be purchased from commercial sources.
[0043] Example 1: A method for preparing a single crystal of lisdexamfetamine salt
[0044] S1, weigh 0.5g of lisdexamfetamine dimethanesulfonate, add 5mL of purified water to prepare lisdexamfetamine dimethanesulfonate solution, adjust the pH of lisdexamfetamine dimethanesulfonate solution to 10 with 20% sodium hydroxide solution, extract with 20mL of dichloromethane, dry the organic layer with anhydrous sodium sulfate, and concentrate to remove dichloromethane to obtain lisdexamfetamine free base;
[0045] S2, dissolving the lisdexamfetamine free base in 20 mL of methanol, adding 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to the lisdexamfetamine free base, and continuing to stir until the solution is completely dissolved, and concentrating under reduced pressure to obtain the lisdexamfetamine salt;
[0046] S3. Weigh 2.30 mg of lisdexamfetamine salt into a vial, dissolve in 0.25 mL of N,N-dimethylformamide and 0.15 mL of purified water, filter into another vial, seal with plastic wrap, and open two micropores. Place the vial in a 100 mL weighing bottle, add 10 mL of acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of lisdexamfetamine salt, the purity of the obtained single crystal is more than 95%.
[0047] Example 2: A method for preparing a single crystal of lisdexamfetamine salt
[0048] S1. Weigh 0.5 g of lisdexamfetamine dimethanesulfonate, add 5 mL of purified water to prepare a lisdexamfetamine dimethanesulfonate solution, adjust the pH of the lisdexamfetamine dimethanesulfonate solution to 12 with 40% sodium hydroxide solution, extract with 20 mL of dichloromethane, dry the organic layer with anhydrous sodium sulfate, and concentrate to remove dichloromethane to obtain lisdexamfetamine free base;
[0049] S2, dissolving the lisdexamfetamine free base in 20 mL of methanol, adding 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to the lisdexamfetamine free base, and continuing to stir until the solution is completely dissolved, and concentrating under reduced pressure to obtain the lisdexamfetamine salt;
[0050] S3. Weigh 2.30 mg of lisdexamfetamine salt into a vial, dissolve in 0.25 mL of N,N-dimethylformamide and 0.15 mL of purified water, filter into another vial, seal with plastic wrap, and open two micropores. Place the vial in a 100 mL weighing bottle, add 10 mL of acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of lisdexamfetamine salt, the purity of the obtained single crystal is more than 95%.
[0051] Example 3: A method for preparing a single crystal of lisdexamfetamine salt
[0052] S1, weigh 0.5g of lisdexamfetamine dimethanesulfonate, add 5mL of purified water to prepare lisdexamfetamine dimethanesulfonate solution, adjust the pH of lisdexamfetamine dimethanesulfonate solution to 14 with 60% sodium hydroxide solution, extract with 20mL of dichloromethane, dry the organic layer with anhydrous sodium sulfate, and concentrate to remove dichloromethane to obtain lisdexamfetamine free base;
[0053] S2, dissolving the lisdexamfetamine free base in 20 mL of methanol, adding 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to the lisdexamfetamine free base, and continuing to stir until the solution is completely dissolved, and concentrating under reduced pressure to obtain the lisdexamfetamine salt;
[0054] S3. Weigh 2.30 mg of lisdexamfetamine salt into a vial, dissolve in 0.25 mL of N,N-dimethylformamide and 0.15 mL of purified water, filter into another vial, seal with plastic wrap, and open two micropores. Place the vial in a 100 mL weighing bottle, add 10 mL of acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of lisdexamfetamine salt, the purity of the obtained single crystal is more than 95%.
[0055] Example 4: A method for preparing a single crystal of lisdexamfetamine salt
[0056] S1. Weigh 0.5 g of lisdexamfetamine dimethanesulfonate, add 5 mL of purified water to prepare a lisdexamfetamine dimethanesulfonate solution, adjust the pH of the lisdexamfetamine dimethanesulfonate solution to 14 with 60% potassium hydroxide solution, extract with 20 mL of dichloromethane, dry the organic layer with anhydrous sodium sulfate, and concentrate to remove dichloromethane to obtain lisdexamfetamine free base;
[0057] S2, dissolving the lisdexamfetamine free base in 20 mL of ethanol, adding diphenylphosphoric acid in a molar ratio of 1:1 to the lisdexamfetamine free base, and continuing to stir until the solution is completely dissolved, and concentrating under reduced pressure to obtain lisdexamfetamine salt;
[0058] S3. Weigh 2.30 mg of lisdexamfetamine salt into a vial, dissolve in 0.25 mL of N,N-dimethylformamide and 0.15 mL of purified water, filter into another vial, seal with plastic wrap, and open two micropores. Place the vial in a 100 ml weighing bottle, add 10 ml of N,N-dimethylformamide to the weighing bottle, the N,N-dimethylformamide does not come into contact with the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of lisdexamfetamine salt, the purity of the obtained single crystal is more than 95%.
[0059] Example 5: A method for preparing a single crystal of lisdexamfetamine salt
[0060] S1. Weigh 0.5 g of lisdexamfetamine dimethanesulfonate, add 5 mL of purified water to prepare a lisdexamfetamine dimethanesulfonate solution, adjust the pH of the lisdexamfetamine dimethanesulfonate solution to 14 with 60% potassium hydroxide solution, extract with 20 mL of dichloromethane, dry the organic layer with anhydrous sodium sulfate, and concentrate to remove dichloromethane to obtain lisdexamfetamine free base;
[0061] S2, dissolving the lisdexamfetamine free base in 20 mL of n-hexane, adding morpholineethanesulfonic acid in a molar ratio of 2:1 to the lisdexamfetamine free base, and continuing to stir until the solution is completely dissolved, and concentrating under reduced pressure to obtain lisdexamfetamine salt;
[0062] S3. Weigh 2.30 mg of lisdexamfetamine salt into a vial, dissolve in 0.25 mL of N,N-dimethylformamide and 0.15 mL of purified water, filter into another vial, seal with plastic wrap, and open two micropores. Place the vial in a 100 mL weighing bottle, add 10 mL of acetone to the weighing bottle, the acetone does not come into contact with the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of lisdexamfetamine salt, the purity of the obtained single crystal is more than 95%.
[0063] The single crystal of lisdexamfetamine salt obtained in Example 1 was subjected to X-ray single crystal diffraction test, and the obtained single crystal spatial structure was as follows: Figure 1 . It can be seen that the obtained lisdexamfetamine salt single crystal has obvious crystal characteristics; its base part has various elements of lisdexamfetamine, and the connection order of each atom conforms to the structure of lisdexamfetamine; its base part has two chiral centers, both of which are in S configuration. The single crystal X-ray diffraction results prove that the base part of the lisdexamfetamine salt single crystal is lisdexamfetamine.
[0064] The single crystal is a monoclinic system, and its crystal axis is The angles between the crystal planes are α / °=90, β / °=91.636(4), γ / °=90; unit lattice area The number of molecules in the unit cell is Z = 4, and the density is 1.145 g / cm 3 The single crystal micrograph shows that it is a colorless columnar crystal.
[0065] Example 6: A method for preparing a single crystal of a salt of a lisdexamfetamine enantiomer
[0066] S1. Weigh 0.5 g of dimethoxy lisdexamfetamine enantiomer, add 5 mL of purified water to prepare a dimethoxy lisdexamfetamine enantiomer solution, adjust the pH of the dimethoxy lisdexamfetamine enantiomer solution to 14 with a 40% sodium hydroxide aqueous solution, then add 20 mL of dichloromethane to stir and extract, stand for separation, dry the organic layer with anhydrous sodium sulfate, and then concentrate under reduced pressure to remove the solvent to obtain dimethoxy lisdexamfetamine enantiomer free base;
[0067] S2, to the enantiomer free base of lisdexamfetamine, add 20mL methanol and 0.28g 4,4-biphenyldisulfonic acid (the molar ratio of lisdexamfetamine enantiomer free base to 4,4-biphenyldisulfonic acid is 1:1), warm to 50°C and stir to dissolve completely, then concentrate under reduced pressure to remove methanol to obtain the enantiomer salt of lisdexamfetamine;
[0068] S3, weigh 2.25mg of lisdexamfetamine enantiomeric salt, add 0.35mL N, N-dimethylformamide (DMF), 0.25mL acetonitrile and 0.05mL water, shake to dissolve, filter, inject the filtrate into the injection bottle, seal with plastic wrap and open 1 hole. Then place the injection bottle in a 100ml weighing bottle, and add 10mL acetonitrile to the weighing bottle, acetonitrile does not contact the filtrate in the injection vial, seal and avoid light and let stand for 2 to 3 days to precipitate crystals, which are lisdexamfetamine enantiomeric salt single crystals, and the resulting crystal purity is more than 95%.
[0069] Example 7: A method for preparing a single crystal salt of a lisdexamfetamine enantiomer
[0070] S1. Weigh 0.5 g of dimethoxy lisdexamfetamine enantiomer, add 5 mL of purified water to prepare a dimethoxy lisdexamfetamine enantiomer solution, adjust the pH of the dimethoxy lisdexamfetamine enantiomer solution to 12 with a 60% sodium hydroxide aqueous solution, then add 20 mL of dichloromethane to stir and extract, stand for separation, dry the organic layer with anhydrous sodium sulfate, and then concentrate under reduced pressure to remove the solvent to obtain dimethoxy lisdexamfetamine enantiomer free base;
[0071] S2, to the enantiomer free base of lisdexamfetamine, add 20mL methanol and 0.28g 4,4-biphenyldisulfonic acid (the molar ratio of lisdexamfetamine enantiomer free base to 4,4-biphenyldisulfonic acid is 1:1), warm to 50°C and stir to dissolve completely, then concentrate under reduced pressure to remove methanol to obtain the enantiomer salt of lisdexamfetamine;
[0072] S3, weigh 2.25mg lisdexamfetamine enantiomeric salt, add 0.35mL DMF, 0.25mL acetonitrile and 0.05mL water, vibrate to dissolve, filter, filtrate is injected into injection bottle, 1 hole is opened after sealing with plastic wrap. Again this injection bottle is placed in 100ml weighing bottle, and 10mL acetonitrile is added in weighing bottle, acetonitrile does not contact with the filtrate in the injection vial, seals and keeps away from light and stands for 2~3 days to separate out crystal, is lisdexamfetamine enantiomeric salt single crystal, and gained crystal purity is more than 95%.
[0073] Example 8: A method for preparing a single crystal of a salt of amphetamine enantiomer
[0074] S1. Weigh 0.5 g of dimethoxy lisdexamfetamine enantiomers, add 5 mL of purified water to prepare a dimethoxy lisdexamfetamine enantiomer solution, adjust the pH of the dimethoxy lisdexamfetamine enantiomer solution to 10 with a 20% sodium hydroxide aqueous solution, then add 20 mL of dichloromethane to stir and extract, stand for separation, dry the organic layer with anhydrous sodium sulfate, and then concentrate under reduced pressure to remove the solvent to obtain dimethoxy lisdexamfetamine enantiomer free base;
[0075] S2, to the enantiomer free base of lisdexamfetamine, add 20mL methanol and 0.28g 4,4-biphenyldisulfonic acid (the molar ratio of lisdexamfetamine enantiomer free base to 4,4-biphenyldisulfonic acid is 1:1), warm to 50°C and stir to dissolve completely, then concentrate under reduced pressure to remove methanol to obtain the enantiomer salt of lisdexamfetamine;
[0076] S3, weigh 2.25mg lisdexamfetamine enantiomeric salt, add 0.35mL DMF, 0.25mL acetonitrile and 0.05mL water, vibrate to dissolve, filter, filtrate is injected into injection bottle, 1 hole is opened after sealing with plastic wrap. Again this injection bottle is placed in 100ml weighing bottle, and 10mL acetonitrile is added in weighing bottle, acetonitrile does not contact with the filtrate in the injection vial, seals and keeps away from light and stands for 2~3 days to separate out crystal, is lisdexamfetamine enantiomeric salt single crystal, and gained crystal purity is more than 95%.
[0077] Example 9: A method for preparing a single crystal of a salt of a lisdexamfetamine enantiomer
[0078] S1. Weigh 0.5 g of dimethoxy lisdexamfetamine enantiomers, add 5 mL of purified water to prepare a dimethoxy lisdexamfetamine enantiomer solution, adjust the pH of the dimethoxy lisdexamfetamine enantiomer solution to 10 with a 20% sodium hydroxide aqueous solution, then add 20 mL of dichloromethane to stir and extract, stand for separation, dry the organic layer with anhydrous sodium sulfate, and then concentrate under reduced pressure to remove the solvent to obtain dimethoxy lisdexamfetamine enantiomer free base;
[0079] S2, to the enantiomer free base of lisdexamfetamine, add 20mL of dichloromethane and 0.28g of 4,4-biphenyldisulfonic acid (the molar ratio of the enantiomer free base of lisdexamfetamine to 4,4-biphenyldisulfonic acid is 1:1), warm to 50°C and stir to dissolve completely, then concentrate under reduced pressure to remove dichloromethane to obtain the enantiomer salt of lisdexamfetamine;
[0080] S3, weigh 2.25mg of lisdexamfetamine enantiomeric salt, add 0.35mL DMF, 0.25mL acetonitrile and 0.05mL water, shake to dissolve, filter, inject the filtrate into the injection bottle, seal with plastic wrap and open 1 hole. The injection bottle is then placed in a 100ml weighing bottle, and 10mL methanol is added to the weighing bottle, methanol does not contact the filtrate in the injection vial, seal and avoid light and stand for 2 to 3 days to separate out crystals, which are lisdexamfetamine enantiomeric salt single crystals, and the resulting crystal purity is more than 95%.
[0081] Example 10: A method for preparing a single crystal of a salt of amphetamine enantiomer
[0082] S1. Weigh 0.5 g of dimethoxy lisdexamfetamine enantiomers, add 5 mL of purified water to prepare a dimethoxy lisdexamfetamine enantiomer solution, adjust the pH of the dimethoxy lisdexamfetamine enantiomer solution to 10 with a 20% sodium hydroxide aqueous solution, then add 20 mL of dichloromethane to stir and extract, stand for separation, dry the organic layer with anhydrous sodium sulfate, and then concentrate under reduced pressure to remove the solvent to obtain dimethoxy lisdexamfetamine enantiomer free base;
[0083] S2, to the described right amphetamine enantiomer free base, add 20mL normal hexane and 0.28g 2-phenyl-5-benzimidazole sulfonic acid (the mol ratio of right amphetamine enantiomer free base to 2-phenyl-5-benzimidazole sulfonic acid is 1:2), warming to 50 DEG C of stirring and dissolving completely, then concentrating under reduced pressure to remove normal hexane, obtain 0.41g right amphetamine enantiomer salt;
[0084] S3, weigh 2.25mg lisdexamfetamine enantiomeric salt, add 0.35mLDMF, 0.25mL acetonitrile and 0.05mL water, vibrate to dissolve, filter, filtrate is injected into injection bottle, 1 hole is opened after sealing with plastic wrap. Again this injection bottle is placed in 100ml weighing bottle, and 10mL DMF is added in weighing bottle, DMF does not contact with the filtrate in the injection vial, seals and keeps away from light and stands for 2~3 days to separate out crystal, is lisdexamfetamine enantiomeric salt single crystal, and gained crystal purity is more than 95%.
[0085] Polarized light microscopy (PLM) was used to characterize the crystal obtained in Example 6, which showed that the crystal sample was rod-shaped. Figure 2 The ellipsoid diagram of the atomic thermal vibration of the cation in the single crystal structure model of the salt of lisdexamfetamine enantiomers; Figure 5 The stereochemical structure of a single crystal salt of lisdexamfetamine enantiomers.
[0086] The single crystal X-ray diffraction characterization results show that the crystal belongs to the monoclinic system, C2 space group, and its unit cell parameters are: α=90°, β=91.6964(9)°, γ=90°, Analysis of the single crystal structure showed that the asymmetric unit of the crystal structure was composed of one lisdexamfetamine enantiomer cation, one 4,4-biphenyldisulfonate anion and a DMF solvent molecule, proving that the single crystal was a DMF solvate crystal form, and the absolute configuration of the chiral center in the molecule was {C5(R), C7(R)}.
[0087] Example 11: Preparation method of impurity C salt single crystal
[0088] S1. Weigh 0.3 g of impurity C, add 20 mL of methanol, stir at room temperature to dissolve, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity C, continue stirring to dissolve, and then heat in a water bath to 50°C and concentrate under reduced pressure to remove methanol to obtain impurity C salt;
[0089] S2, weigh 2.31mg of impurity C salt into a vial, dissolve in 0.25mL acetonitrile and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity C salt, the purity of the obtained crystal is more than 95%.
[0090] Example 12: Preparation method of impurity C salt single crystal
[0091] S1. Weigh 0.3 g of impurity C, add 20 mL of ethanol, stir and dissolve at room temperature, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity C, continue stirring and dissolving, and then concentrate under reduced pressure at 50° C. in a water bath to remove ethanol to obtain impurity C salt;
[0092] S2, weigh 2.31mg of impurity C salt into a vial, dissolve in 0.25mL acetonitrile and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity C salt, the purity of the obtained crystal is more than 95%.
[0093] Example 13: Preparation method of impurity C salt single crystal
[0094] S1. Weigh 0.3 g of impurity C, add 20 mL of methanol, stir at room temperature to dissolve, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity C, continue stirring to dissolve, and then heat in a water bath to 50°C and concentrate under reduced pressure to remove methanol to obtain impurity C salt;
[0095] S2, weigh 2.31mg of impurity C salt into a vial, dissolve in 0.25mL DMF and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml DMF to the weighing bottle, DMF does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity C salt, the purity of the obtained crystal is more than 95%.
[0096] Example 14: Preparation method of impurity C salt single crystal
[0097] S1. Weigh 0.3 g of impurity C, add 20 mL of dichloromethane, stir at room temperature to dissolve, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity C, continue stirring to dissolve, and then heat in a water bath to 50°C and concentrate under reduced pressure to remove dichloromethane to obtain impurity C salt;
[0098] S2, weigh 2.31mg of impurity C salt into a vial, dissolve in 0.1mL acetonitrile, 0.15mL acetone and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity C salt, the purity of the obtained crystal is more than 95%.
[0099] Example 15: Preparation method of impurity C salt single crystal
[0100] S1. Weigh 0.3 g of impurity C, add 20 mL of n-hexane, stir at room temperature to dissolve, add 2-phenyl-5-benzimidazole sulfonic acid in a molar ratio of 2:1 to impurity C, continue stirring to dissolve, and then bathe in water at 50° C. under reduced pressure and concentrate to remove n-hexane to obtain impurity C salt;
[0101] S3, weigh 2.31mg of impurity C salt into a vial, dissolve in 0.25mL acetonitrile and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity C salt, the purity of the obtained crystal is more than 95%.
[0102] The single crystal obtained in Example 11 was tested. Figure 6 The chemical stereo structure diagram and microphotographs show that the impurity C salt single crystal is a short block single crystal. The single crystal X-ray diffraction characterization results show that the single crystal belongs to the triclinic system, P1 space group, and its unit cell parameters are: α=94.081(2)°, β=98.366(2)°, γ=107.605(2)°, The asymmetric unit of the crystal structure is composed of two impurity C cations and two 4,4-biphenyldisulfonate anions, and does not contain any organic solvent molecules or crystal water molecules; the absolute configuration of the chiral center in the molecule is {C5(R), C7(S)}.
[0103] Example 16: Preparation method of impurity D salt single crystal
[0104] S1. Weigh 0.3 g of impurity D, add 20 mL of methanol, stir at room temperature to dissolve, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity D, continue stirring to dissolve, and then heat in a water bath to 50°C and concentrate under reduced pressure to remove methanol to obtain impurity D salt;
[0105] S2, weigh 2.31mg of impurity D salt into a vial, dissolve in 0.25mL acetonitrile and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity D salt, the purity of the obtained crystal is more than 95%.
[0106] Example 17: Preparation method of impurity D salt single crystal
[0107] S1. Weigh 0.3 g of impurity D, add 20 mL of ethanol, stir at room temperature to dissolve, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity D, continue stirring to dissolve, and then heat in a water bath to 50° C. and concentrate under reduced pressure to remove ethanol to obtain impurity D salt;
[0108] S2, weigh 2.31mg of impurity D salt into a vial, dissolve in 0.25mL acetonitrile and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity D salt, the purity of the obtained crystal is more than 95%.
[0109] Example 18: Preparation method of impurity D salt single crystal
[0110] S1. Weigh 0.3 g of impurity D, add 20 mL of methanol, stir at room temperature to dissolve, add 4,4-biphenyldisulfonic acid in a molar ratio of 1:1 to impurity D, continue stirring to dissolve, and then heat in a water bath to 50°C and concentrate under reduced pressure to remove methanol to obtain impurity D salt;
[0111] S2, weigh 2.31mg of impurity D salt into a vial, dissolve in 0.1mL acetonitrile, 0.15mL methyl tert-butyl ether and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity D salt, the purity of the obtained crystal is more than 95%.
[0112] Example 19: Preparation method of impurity D salt single crystal
[0113] S1. Weigh 0.3 g of impurity D, add 20 mL of n-hexane, stir at room temperature to dissolve, add morpholineethanesulfonic acid in a molar ratio of 2:1 to impurity D, continue stirring to dissolve, and then bathe in water at 50° C. under reduced pressure to remove n-hexane to obtain impurity D salt;
[0114] S3, weigh 2.31mg of impurity D salt into a vial, dissolve in 0.25mL acetonitrile and 0.15mL purified water, filter into another vial, seal with plastic wrap, and open 1 micropore. Place the vial in a 100ml weighing bottle, add 10ml acetonitrile to the weighing bottle, the acetonitrile does not contact the filtrate in the vial, seal and avoid light, let stand for 2 to 3 days to grow a lens, and obtain a single crystal of impurity D salt, the purity of the obtained crystal is more than 95%.
[0115] The single crystal obtained in Example 16 was tested. Figure 7The chemical stereostructure diagram and single crystal micrograph show that the impurity D salt single crystal is a short block single crystal. The single crystal X-ray diffraction characterization results show that the single crystal belongs to the triclinic system, P1 space group, and its unit cell parameters are: α=94.7650(10)°, β=97.8500(10)°, γ=107.6580(10)°, }.
[0116] Single crystal structure analysis shows that the asymmetric unit of the crystal structure is composed of two impurity D cations and two 4,4-biphenyldisulfonate anions, and does not contain any organic solvent molecules or crystal water molecules; the absolute configuration of the chiral center in the molecule is {C5(S), C7(R)}.
[0117] In summary, the present invention provides lisdexamfetamine salt and chiral isomer (lisdexamfetamine enantiomer, impurity C and impurity D) salt single crystal and preparation method thereof. The present invention prepares lisdexamfetamine salt and chiral isomer (lisdexamfetamine enantiomer, impurity C and impurity D) salt single crystal preparation method is simple, efficient. Meanwhile, the prepared single crystal has high purity, good stability, uniform and regular internal particle distribution, can be used as a test product, for carrying out X-ray single crystal diffraction detection, determine the absolute configuration of lisdexamfetamine bulk drug or lisdexamfetamine chiral isomer, for lisdexamfetamine quality control. In addition, lisdexamfetamine salt single crystal can be used to prepare lisdexamfetamine pharmaceutical composition. The present invention has potential clinical use value.
Claims
1. A monocrystalline lisdexamfetamine salt, characterized in that: The lisdexamfetamine salt single crystal is a monoclinic system, and its crystal axis The angles between the crystal planes are α / °=90, β / °=91.636(4), γ / °=90; unit lattice area The number of molecules in the unit cell is Z = 4, and the density is 1.145 g / cm 3 .
2. A single crystal of a chiral isomer salt of lisdexamfetamine, characterized in that: The chiral isomer salt single crystal of lisdexamfetamine is a single crystal of enantiomeric salt of lisdexamfetamine, a single crystal of impurity C salt or a single crystal of impurity D salt; The single crystal of the enantiomeric salt of lisdexamfetamine belongs to the monoclinic system, the C2 space group, and its unit cell parameters are: α=90°, β=91.6964(9)°, γ=90°, The single crystal is a DMF solvate crystal form; The impurity C salt single crystal belongs to the triclinic system, and its unit cell parameters are: α=94.081(2)°, β=98.366(2)°, γ=107.605(2)°, P1 space group; The impurity D salt single crystal belongs to the triclinic system, P1 space group, and its unit cell parameters are: α=94.7650(10)°, β=97.8500(10)°, γ=107.6580(10)°, 3. A method for preparing a lisdexamfetamine salt single crystal or a chiral isomer salt single crystal thereof, characterized in that: It includes the following steps: (1) forming a salt of lisdexamfetamine free base or its chiral isomer free base with an organic acid; (2) The salt obtained in step (1) is prepared into a solution and then filtered, the filtrate is sealed in a container, the container is opened and placed in a container filled with a poor solvent and sealed, and cultured in the dark to obtain a single crystal of lisdexamfetamine salt or a single crystal of its chiral isomer salt.
4. The preparation method according to claim 3, characterized in that: In step (1), the chiral isomer free base is lisdexamfetamine enantiomer free base, impurity C or impurity D; So the structure of impurity C is So the structure of impurity D is 5. The preparation method according to claim 4, characterized in that: The preparation method of the lisdexamfetamine free base or the lisdexamfetamine enantiomer free base is: Releasing lisdexamfetamine dimethanesulfonate or lisdexamfetamine dimethanesulfonate enantiomers under alkaline conditions to obtain lisdexamfetamine free base or lisdexamfetamine enantiomer free base; The alkaline condition is to use a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution with a mass concentration of 20%-60%.
6. The preparation method according to claim 5, characterized in that: The preparation method of the free base of lisdexamfetamine or the free base of lisdexamfetamine enantiomers comprises the following steps: The method comprises preparing a lisdexamfetamine dimethanesulfonate solution or a lisdexamfetamine dimethanesulfonate enantiomer solution with water, adjusting the pH value of the lisdexamfetamine dimethanesulfonate solution or the lisdexamfetamine dimethanesulfonate enantiomer solution to 10-14 with a 20%-60% sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution, extracting, drying and concentrating the organic layer to obtain lisdexamfetamine free base or lisdexamfetamine enantiomer free base.
7. The preparation method according to claim 3, characterized in that: In step (1), the organic acid is at least one of p-toluenesulfonic acid, 2-phenyl-5-benzimidazolesulfonic acid, 4,4-biphenyldisulfonic acid, diphenylphosphoric acid, 3-pyridinesulfonic acid, isoquinoline-5-sulfonic acid, morpholineethanesulfonic acid, and quinoline-8-sulfonic acid; And / or, in step (1), the free base of lisdexamfetamine or the free base of its chiral isomer is dissolved in an organic solvent and then salted with an organic acid; the organic solvent is at least one of dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, n-hexane, and acetone.
8. The preparation method according to claim 3, characterized in that: In step (2), the solvent used to prepare the solution of the salt obtained in step (1) is any one or more aqueous solutions of dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, n-hexane, acetone, acetonitrile, and methyl tert-butyl ether; And / or, in step (2), the poor solvent is at least one of acetonitrile, acetone, N,N-dimethylformamide, dichloromethane, ethanol, methanol, diethyl ether, methyl tert-butyl ether, n-hexane, and cyclohexane.
9. A lisdexamfetamine salt monocrystalline pharmaceutical composition, characterized in that: The pharmaceutical composition contains the lisdexamfetamine salt single crystal according to claim 1.
10. The lisdexamfetamine salt single crystal of claim 1 or the lisdexamfetamine chiral isomer salt single crystal of claim 2 is used as a test sample in single crystal X-ray diffraction detection for the purpose of confirming the structure of lisdexamfetamine salt or lisdexamfetamine chiral isomer salt.