Dextral amphetamine sulfate single crystal, enantiomer single crystal thereof, preparation method and application
During the drug synthesis process, dexamphetamine sulfate or its enantiomer is dissolved in a mixed solution of good and poor solvents, and then filtered and cultured under light conditions, successfully solving the problems of drug purity and effect, achieving efficient and stable single crystal preparation, which is suitable for drug quality control.
Patent Information
- Application Number
- CN202311225500.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-21
- Publication Date
- 2025-03-28
AI Technical Summary
During drug synthesis, single crystals of dexamphetamine sulfate and its enantiomer are difficult to prepare stably, which affects the purity and effect of the drug.
Stable single crystals were successfully prepared by dissolving dexamphetamine sulfate or its enantiomer in a mixed solution of good and poor solvents, filtering and culturing under light conditions.
This method is simple and efficient, and can prepare single crystals of dexamphetamine sulfate and its enantiomers, with good stability, suitable for single crystal X-ray diffraction detection, confirm its absolute configuration, and be used for quality control.
Smart Images
Figure CN119707708A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of medical technology, and in particular relates to a dextroamphetamine sulfate single crystal and an enantiomer single crystal thereof, a preparation method and uses thereof. Background Art
[0002] Lisdexamfetamine Dimesylate Capsules are a drug produced by Shire (now Takeda) under the trade name Vyvanse. The drug is a sympathomimetic drug for the central nervous system and is used to treat attention deficit hyperactivity disorder (ADHD) and binge eating disorder (BED). The capsules include lisdexamfetamine Dimesylate, excipients and capsules. The active substance lisdexamfetamine Dimesylate is a prodrug. After oral administration, it is converted from a prodrug with no therapeutic effect to d-amphetamine (d-AMP) to produce a drug effect.
[0003] The structure of lisdexamfetamine dimesylate is shown below:
[0004]
[0005] Lysoxamfetamine dimesylate
[0006] The synthetic route of lisdexamfetamine dimesylate is as follows:
[0007]
[0008] The starting material used in the method is D-amphetamine alcohol, and its commercial source is extensive, and process is simple, and production efficiency is high, so the synthetic route is the most commonly used synthetic route in the current industrial production of dimethylsulfonate lysex-amphetamine. In the route, dextroamphetamine sulfate is an indispensable intermediate substance, and it can be seen from the route that the dextroamphetamine skeleton structure of dextroamphetamine sulfate continues to the final product, and its skeleton structure plays a crucial role in the preparation of dimethylsulfonate lysex-amphetamine, therefore, it is necessary to study the structure of dextroamphetamine sulfate and to perform structural confirmation on it, so as not to affect the final product; the levoamphetamine sulfate remaining in dextroamphetamine sulfate, in the process of preparing dimethylsulfonate lysex-amphetamine, can be derived into the chiral impurities of dimethylsulfonate lysex-amphetamine, such as its enantiomer, so as to cause the purity of dimethylsulfonate lysex-amphetamine to be relatively low, affecting the effect of dimethylsulfonate lysex-amphetamine. Therefore, it is of great significance to carry out quality control for dextroamphetamine sulfate.
[0009] The structures of dextroamphetamine sulfate and its enantiomer, levoamphetamine sulfate, are shown below:
[0010]
[0011] In the field of drug synthesis, it is crucial to carry out structural confirmation to intermediate and its impurity, and the quality of the final product can be guaranteed. Single crystal X-ray diffraction is the common method of structural confirmation, and the relevant single crystal of the test compound needs to be prepared for testing during the method test. Therefore, in the formation of the relevant research carried out to the preparation of lisdexamfetamine dimesylate, it is necessary to study its intermediate dextroamphetamine sulfate and its enantiomer (levorotatory amphetamine sulfate), and they are carried out structural confirmation. This just needs to use the single crystal of dextroamphetamine sulfate and l-amfetamine sulfate as sample, and determines its absolute configuration by X-ray single crystal diffraction, and provides strong support for its structural confirmation.
[0012] How to prepare stable single crystals of dextrorotatory amphetamine sulfate and its enantiomers to provide suitable samples for single crystal X-ray diffraction detection for structural confirmation of the substance to be studied is an urgent problem to be solved in this field. Summary of the invention
[0013] The purpose of the present invention is to provide a dextroamphetamine sulfate single crystal and an enantiomer single crystal thereof, a preparation method and use thereof.
[0014] The present invention provides a single crystal of dextroamphetamine sulfate, wherein the single crystal is of a monoclinic system and a P21 space group, and the crystal axis is The angles between the crystal planes are α / °=90, β / °=95.027(6), γ / °=90; unit lattice area The number of molecules in the unit cell is Z = 4, and the density is 1.177 g / cm 3 .
[0015] The present invention also provides a single crystal of dextrorotatory amphetamine sulfate enantiomer, wherein the single crystal is of a monoclinic system and a P21 space group, and its crystal axis is c=31. The angles between the crystal planes are α / °=90, β / °=95.015(11), γ / °=90; the unit lattice area V= The number of molecules in the unit cell is Z = 4, and the density is 1.185 g / cm 3 .
[0016] The present invention also provides a method for preparing a dextroamphetamine sulfate single crystal or an enantiomer single crystal thereof, which comprises the following steps:
[0017] (1) dissolving dextroamphetamine sulfate or the enantiomer of dextroamphetamine sulfate and levoamphetamine sulfate in an organic solvent, filtering the solution, and placing the filtrate in a sealed container;
[0018] (2) a hole is opened in the sealed container of the filtrate, the container is placed in another container containing a poor solvent and sealed, and cultured in the dark to obtain a single crystal of dextrorotatory amphetamine sulfate or a single crystal of an enantiomer of dextrorotatory amphetamine sulfate.
[0019] Furthermore, in step (1), the organic solvent consists of a good solvent and a poor solvent.
[0020] Further,
[0021] In step (1), the good solvent is at least one of water, methanol, N,N-dimethylformamide, and dimethyl sulfoxide;
[0022] And / or, in step (1), the poor solvent is at least one of acetonitrile, acetone, dichloromethane and n-hexane.
[0023] Furthermore, in step (2), the poor solvent is at least one of acetonitrile, acetone, dichloromethane and n-hexane.
[0024] Furthermore, in step (2), the dark-proof culture time is 2 to 3 days.
[0025] Furthermore, the preparation method of the dextroamphetamine sulfate single crystal comprises the following steps:
[0026] (A) dissolving dextroamphetamine sulfate in an organic solvent, filtering, and placing the filtrate into a container and sealing;
[0027] (B) opening a hole in the container for sealing the filtrate, placing the container in another container containing a poor solvent and sealing the container, and culturing the container in the dark to obtain a single crystal of dextroamphetamine sulfate;
[0028] In step (A), the organic solvent consists of a good solvent and a poor solvent, the good solvent is water, and the poor solvent is acetonitrile;
[0029] In step (B), the poor solvent is acetonitrile.
[0030] Furthermore, the method for preparing the dextrorotatory amphetamine sulfate enantiomer single crystal comprises the following steps:
[0031] (a) dissolving the dextrorotatory amphetamine sulfate enantiomer in an organic solvent, filtering, and placing the filtrate into a sealed container;
[0032] (b) opening a hole in the sealed container of the filtrate, placing the container in another container containing a poor solvent and sealing the container, and culturing the container in the dark, thereby obtaining a single crystal of the enantiomer of dextrorotatory amphetamine sulfate;
[0033] In step (a), the organic solvent consists of a good solvent and a poor solvent, the good solvent is methanol, and the poor solvent is acetonitrile;
[0034] In step (b), the poor solvent is acetonitrile.
[0035] The present invention also provides the use of the aforementioned dextrorotatory amphetamine sulfate single crystal or the aforementioned dextrorotatory amphetamine sulfate enantiomer single crystal as a detection sample in single crystal X-ray diffraction detection, which is used for structural confirmation of the dextrorotatory amphetamine sulfate single crystal or the dextrorotatory amphetamine sulfate enantiomer single crystal.
[0036] Compared with the prior art, the present invention has the following beneficial effects:
[0037] The invention provides a preparation method of a dextrorotatory amphetamine sulfate single crystal and an enantiomer thereof (levorotatory amphetamine sulfate) single crystal, the preparation method is simple, efficient, can successfully prepare a dextrorotatory amphetamine sulfate single crystal and an enantiomer thereof single crystal, the obtained dextrorotatory amphetamine sulfate single crystal and an enantiomer thereof single crystal have good stability, and the particles inside the single crystal are evenly distributed. The single crystal prepared by the present invention can be used as a sample, for carrying out X-ray single crystal diffraction detection, determining the absolute configuration of dextrorotatory amphetamine sulfate and an enantiomer thereof single crystal, for dextrorotatory amphetamine sulfate quality control.
[0038] 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.
[0039] 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
[0040] Figure 1 The crystal structure basic unit of the dextroamphetamine sulfate single crystal prepared in Example 1.
[0041] Figure 2 The main molecular structural formula of the dextroamphetamine sulfate single crystal prepared in Example 1.
[0042] Figure 3 The crystal structure basic unit of the single crystal of dextroamphetamine sulfate enantiomer prepared in Example 5;
[0043] Figure 4 The main molecular structural formula of the dextrorotatory amphetamine sulfate enantiomer single crystal prepared in Example 5.
[0044] Figure 5 The fractional atomic coordinates (×10 4 ) and isotropic displacement Parameters of U eq Defined as orthogonalization U IJ 1 / 3 of the tensor trace.
[0045] Figure 6 The fractional atomic coordinates (×10 4 ) and isotropic displacement Parameters of U eq Defined as orthogonalization U IJ 1 / 3 of the tensor trace. DETAILED DESCRIPTION
[0046] 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.
[0047] Example 1. Preparation of dextroamphetamine sulfate single crystal
[0048] S1. Weigh 2.30 mg of dextroamphetamine sulfate into a sample injection bottle, add 0.25 mL of acetonitrile and 0.1 mL of purified water, shake to dissolve, filter, transfer the filtrate to another sample injection vial, and seal with plastic wrap;
[0049] S2, set perforation on preservative film, the sample injection bottle equipped with the filtrate is placed in a 100mL weighing bottle, 10mL acetonitrile is added to the weighing bottle, acetonitrile is not directly mixed with the filtrate, the weighing bottle is sealed and cultured in dark for 2-3 days, and a crystalline body is grown to obtain a dextrorotatory amphetamine sulfate single crystal. The crystal purity is greater than 99%.
[0050] Example 2, preparation of dextroamphetamine sulfate single crystal
[0051] S1. Weigh 2.30 mg of dextroamphetamine sulfate into a sample injection bottle, add 0.25 mL of acetonitrile and 0.1 mL of N,N-dimethylformamide, shake to dissolve, filter, transfer the filtrate to another sample injection vial, and seal with plastic wrap;
[0052] S2, set perforation on preservative film, the sample injection bottle equipped with the filtrate is placed in a 100mL weighing bottle, 10mL acetonitrile is added to the weighing bottle, acetonitrile is not directly mixed with the filtrate, the weighing bottle is sealed and cultured in dark for 2-3 days, and a crystalline body is grown to obtain a dextrorotatory amphetamine sulfate single crystal. The crystal purity is greater than 99%.
[0053] Example 3, Preparation of Dextroamphetamine Sulfate Single Crystal
[0054] S1. Weigh 2.30 mg of dextroamphetamine sulfate into a sample injection bottle, add 0.25 mL of dichloromethane and 0.1 mL of DMSO, shake to dissolve, filter, transfer the filtrate to another sample injection vial, and seal with plastic wrap;
[0055] S2, set a perforation on the preservative film, place the sample injection bottle containing the filtrate in a 100mL weighing bottle, add 10mL of dichloromethane to the weighing bottle, dichloromethane is not directly mixed with the filtrate, the weighing bottle is sealed and cultured in dark for 2-3 days, and a crystalline body grows to obtain a single crystal of dextroamphetamine sulfate. The crystal purity is greater than 99%.
[0056] Example 4, preparation of dextroamphetamine sulfate single crystal
[0057] S1. Weigh 2.30 mg of dextroamphetamine sulfate into a sample injection bottle, add 0.25 mL of acetone and 0.1 mL of methanol, shake to dissolve, filter, transfer the filtrate to another sample injection vial, and seal with plastic wrap;
[0058] S2, set a perforation on the preservative film, place the sample injection bottle containing the filtrate in a 100mL weighing bottle, add 10mL acetone to the weighing bottle, acetone is not directly mixed with the filtrate, the weighing bottle is sealed and cultured in dark for 2-3 days, grow a crystalline body, and obtain a single crystal of dextroamphetamine sulfate. The crystal purity is greater than 99%.
[0059] Single crystal X-ray diffraction test is carried out on the sample obtained in Example 1, and the test result shows that the sample has obvious crystalline characteristics; the sample has each element of dextrorotatory amphetamine sulfate, and the connection order of each atom conforms to the structure of dextrorotatory amphetamine sulfate; the sample has 1 chiral center, in S configuration; the crystal is monoclinic system, P21 space group, and its crystal axis is c=31. The angles between the crystal planes are α / °=90, β / °=95.027(6), γ / °=90; the unit lattice area V= The number of molecules in the unit cell is Z = 4, and the density is 1.177 g / cm 3 It can be seen that the sample is a single crystal of dextroamphetamine sulfate.
[0060] Example 5. Preparation of single crystals of dextroamphetamine sulfate enantiomers
[0061] S1. Weigh 2.34 mg of dextroamphetamine sulfate enantiomer (levoamphetamine sulfate) into a sample injection bottle, add 0.25 mL of acetonitrile and 0.8 mL of methanol, shake to dissolve, filter, and transfer the filtrate to another sample injection vial, which is sealed with plastic wrap;
[0062] S2, set a perforation on the preservative film, place the sample injection bottle containing the filtrate in a 100mL weighing bottle, add 10mL acetonitrile to the weighing bottle, acetonitrile is not directly mixed with the filtrate, the weighing bottle is sealed and cultured in dark for 2-3 days, grow a crystalline body, and obtain a single crystal of dextrorotatory amphetamine sulfate enantiomer. The crystal purity is greater than 99%.
[0063] Example 6. Preparation of single crystals of dextroamphetamine sulfate enantiomers
[0064] S1. Weigh 2.34 mg of dextroamphetamine sulfate enantiomer (levoamphetamine sulfate) into a sample injection bottle, add 0.25 mL of acetone and 0.8 mL of methanol, shake to dissolve, filter, and transfer the filtrate to another sample injection vial, which is sealed with plastic wrap;
[0065] S2, set a perforation on the preservative film, place the sample injection bottle containing the filtrate in a 100mL weighing bottle, add 10mL acetone to the weighing bottle, acetone is not directly mixed with the filtrate, and the weighing bottle is sealed and cultured in dark for 2-3 days to grow a crystalline body, and obtain a single crystal of the enantiomer of dextrorotatory amphetamine sulfate. The crystal purity is greater than 99%.
[0066] Example 7. Preparation of single crystals of dextroamphetamine sulfate enantiomers
[0067] S1. Weigh 2.34 mg of dextroamphetamine sulfate enantiomer (levoamphetamine sulfate) into a sample injection bottle, add 0.25 mL of acetonitrile and 0.8 mL of N,N-dimethylformamide (DMF), shake to dissolve, filter, and transfer the filtrate to another sample injection vial, which is sealed with plastic wrap;
[0068] S2, set a perforation on the preservative film, place the sample injection bottle containing the filtrate in a 100mL weighing bottle, add 10mL acetonitrile to the weighing bottle, acetonitrile is not directly mixed with the filtrate, the weighing bottle is sealed and cultured in dark for 2-3 days, grow a crystalline body, and obtain a single crystal of dextrorotatory amphetamine sulfate enantiomer. The crystal purity is greater than 99%.
[0069] Example 8. Preparation of single crystals of dextroamphetamine sulfate enantiomers
[0070] S1. Weigh 2.34 mg of dextroamphetamine sulfate enantiomer (levoamphetamine sulfate) into a sample injection bottle, add 0.25 mL of n-hexane and 0.8 mL of methanol, shake to dissolve, filter, and transfer the filtrate to another sample injection vial, which is sealed with plastic wrap;
[0071] S2, set a hole on the preservative film, place the sample injection bottle containing the filtrate in a 100mL weighing bottle, add 10mL of n-hexane to the weighing bottle, the n-hexane is not directly mixed with the filtrate, seal the weighing bottle and culture it in dark for 2-3 days, grow a crystalline body, and obtain a single crystal of the enantiomer of dextrorotatory amphetamine sulfate. The crystal purity is greater than 99%.
[0072] The sample obtained in Example 5 was subjected to a single crystal X-ray diffraction test, and the test results showed that the sample had each element of the dextrorotatory amphetamine sulfate enantiomer; and the connection order of each atom conformed to the structure of the dextrorotatory amphetamine sulfate enantiomer; the sample had 1 chiral center, in R configuration; the sample was monoclinic, P21 space group, and its crystal axis was c=31. The angles between the crystal planes are α / °=90, β / °=95.015(11), γ / °=90; the unit lattice area V= The number of molecules in the unit cell is Z = 4, and the density is 1.185 g / cm 3 , therefore, the sample is a single crystal of dextrorotatory amphetamine sulfate enantiomer.
[0073] In summary, the invention provides a preparation method of dextrorotatory amphetamine sulfate single crystal and its enantiomer single crystal, the preparation method is simple, efficient, can successfully prepare dextrorotatory amphetamine sulfate single crystal and its enantiomer single crystal, the dextrorotatory amphetamine sulfate single crystal obtained and its enantiomer single crystal good stability, single crystal internal particle distribution uniform. The single crystal prepared by the present invention can be used as a sample, for carrying out X-ray single crystal diffraction detection, determine the absolute configuration of dextrorotatory amphetamine sulfate and its enantiomer single crystal, for dextrorotatory amphetamine sulfate quality control.
Claims
1. A dextroamphetamine sulfate single crystal, characterized in that: The single crystal is of monoclinic system, P21 space group, and its crystal axis is The angles between the crystal planes are α / °=90, β / °=95.027(6), γ / °=90; unit lattice area The number of molecules in the unit cell is Z = 4, and the density is 1.177 g / cm 3 .
2. A dextrorotatory amphetamine sulfate enantiomer single crystal, characterized in that: The single crystal is of monoclinic system, P21 space group, and its crystal axis is The angles between the crystal planes are α / °=90, β / °=95.015(11), γ / °=90; the unit lattice area V= The number of molecules in the unit cell is Z = 4, and the density is 1.185 g / cm 3 .
3. A method for preparing a dextroamphetamine sulfate single crystal or an enantiomer single crystal thereof, characterized in that: It includes the following steps: (1) dissolving dextroamphetamine sulfate or the enantiomer of dextroamphetamine sulfate and levoamphetamine sulfate in an organic solvent, filtering the solution, and placing the filtrate in a sealed container; (2) a hole is opened in the sealed container of the filtrate, the container is placed in another container containing a poor solvent and sealed, and cultured in the dark to obtain a single crystal of dextrorotatory amphetamine sulfate or a single crystal of an enantiomer of dextrorotatory amphetamine sulfate.
4. The preparation method according to claim 3, characterized in that: In step (1), the organic solvent consists of a good solvent and a poor solvent.
5. The preparation method according to claim 4, characterized in that: In step (1), the good solvent is at least one of water, methanol, N,N-dimethylformamide, and dimethyl sulfoxide; And / or, in step (1), the poor solvent is at least one of acetonitrile, acetone, dichloromethane and n-hexane.
6. The preparation method according to claim 3, characterized in that: In step (2), the poor solvent is at least one of acetonitrile, acetone, dichloromethane and n-hexane.
7. The preparation method according to claim 3, characterized in that: In step (2), the dark-proof culture time is 2 to 3 days.
8. The preparation method according to any one of claims 3 to 7, characterized in that: The preparation method of the dextroamphetamine sulfate single crystal comprises the following steps: (A) dissolving dextroamphetamine sulfate in an organic solvent, filtering, and placing the filtrate into a sealed container; (B) opening a hole in the container for sealing the filtrate, placing the container in another container containing a poor solvent and sealing the container, and culturing the container in the dark to obtain a single crystal of dextroamphetamine sulfate; In step (A), the organic solvent consists of a good solvent and a poor solvent, the good solvent is water, and the poor solvent is acetonitrile; In step (B), the poor solvent is acetonitrile.
9. The preparation method according to any one of claims 3 to 7, characterized in that: The preparation method of the dextrorotatory amphetamine sulfate enantiomer single crystal comprises the following steps: (a) dissolving the dextrorotatory amphetamine sulfate enantiomer in an organic solvent, filtering, and placing the filtrate into a sealed container; (b) opening a hole in the sealed container of the filtrate, placing the container in another container containing a poor solvent and sealing the container, and culturing the container in the dark, thereby obtaining a single crystal of the enantiomer of dextrorotatory amphetamine sulfate; In step (a), the organic solvent consists of a good solvent and a poor solvent, the good solvent is methanol, and the poor solvent is acetonitrile; In step (b), the poor solvent is acetonitrile.
10. The dextrorotatory amphetamine sulfate single crystal according to claim 1 or the dextrorotatory amphetamine sulfate enantiomer single crystal according to claim 2 is used as a test sample in single crystal X-ray diffraction detection, for structural confirmation of the dextrorotatory amphetamine sulfate single crystal or the dextrorotatory amphetamine sulfate enantiomer single crystal.