Oseltamivir phosphate monocrystal and method for preparing the same

Abstract

The present application relates to oseltamivir phosphate single crystal and its preparation method. The present application selects specific mixed solvent to slowly evaporate to obtain needle-like crystal, which is the first successful preparation of oseltamivir phosphate single crystal in the world. The oseltamivir phosphate single crystal prepared by the present application has the chemical formula of C 16 H 31 N2O8P, a molecular weight of 410.40, and a crystal structure belonging to orthorhombic system, a space group of P21212, a=23.9002(6)Å, b=24.4812(6)Å, c=7.4191(2)Å, α=90°, β=90°, γ=90°, V=4340.96(19)Å 3 , Z=8. The preparation and determination of the single crystal have important significance and application value for the structure-activity relationship study of oseltamivir phosphate drug and new drug development.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a single crystal of oseltamivir phosphate and its preparation method. Background Technology

[0002] Oseltamivir phosphate is a highly effective and selective neuraminidase inhibitor. It was approved by the US FDA in 1999 and launched in my country in October 2001. Oseltamivir phosphate, with the chemical structure shown in Formula 1, is marketed as Tamiflu and has become a globally recognized effective antiviral drug for influenza, as well as one of the most effective drugs against avian influenza and H1N1 influenza A (US5866601A; J. Am. Med. Associate, 2009, 301, 1034).

[0003]

[0004] Formula 1

[0005] The chemical name of oseltamivir phosphate is [(3R,4R,5S)-4-acetamido-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-en-carboxylic acid ethyl ester phosphate]. To date, there are no reports on the single-crystal structure of oseltamivir phosphate. Existing reports on the crystal structure of this drug only provide polycrystalline information (CN 101910118A, CN 120349257A, CN120349256A), determined by X-ray powder diffraction, which cannot provide the fine structure of the oseltamivir phosphate molecule. Obtaining single crystals and confirming their structures is of significant theoretical and academic importance for a complete and accurate understanding of the fine structure of this type of drug molecule, as well as for understanding its activity and structure-activity relationship. It also provides important guidance for the development of new drugs.

[0006] Different stereoisomers of chiral drugs can exhibit significant differences in efficacy, metabolism, and toxicology. Developing new drugs based on stereoisomers requires pharmacological and toxicological studies of the chiral drug, necessitating the acquisition of each stereoisomer and conducting comparative studies to determine the next steps for development. Therefore, for generic drug research with a well-defined structure, ensuring that the stereoconfiguration of the produced active pharmaceutical ingredient (API) matches that of the original drug is crucial for its safety and efficacy.

[0007] Oseltamivir phosphate is a typical chiral drug with three chiral centers in its molecule. Determining its absolute configuration using single-crystal X-ray diffraction (XRD) is the most direct method. Analyzing single-crystal compounds using XRD allows for the precise structure of the molecule and the determination of the absolute configuration of each chiral atom. Simultaneously, single-crystal XRD provides quantitative information on the three-dimensional structure of the drug molecule and information on intermolecular interactions. By reconstructing and analyzing the single-crystal diffraction data, the three-dimensional structure of the crystal can be obtained, thereby determining parameters such as composition, unit cell parameters, crystal system and space group, bonding mode, and molecular conformation. Therefore, cultivating single crystals and analyzing their structure using XRD to confirm their absolute configuration and fine structure can compensate for the limitations of current detection methods such as NMR, mass spectrometry, infrared spectroscopy, ultraviolet spectroscopy, elemental analysis, thermogravimetric analysis, and X-ray powder diffraction in determining spatial structure and intermolecular interactions.

[0008] However, oseltamivir phosphate single crystals are difficult to cultivate, and to date, there are no reports on the single crystal structure of oseltamivir phosphate, either domestically or internationally, making it impossible to obtain accurate crystal structure and data. Therefore, developing a mild, simple, and easy-to-operate method for preparing oseltamivir phosphate single crystals is crucial for the development of oseltamivir phosphate-containing drugs. Summary of the Invention

[0009] Therefore, the purpose of this invention is to provide a single crystal of oseltamivir phosphate and a simple preparation method thereof.

[0010] The technical solutions for achieving the above objectives include the following.

[0011] In one aspect, the present invention provides a method for preparing oseltamivir phosphate single crystals, comprising the following steps:

[0012] Oseltamivir phosphate was added to the first solvent, then the second and third solvents were added, and the mixture was stirred until it was fully dissolved to form a clear solution. The solvent was allowed to evaporate by standing, and the oseltamivir phosphate single crystal was obtained.

[0013] The first solvent is selected from one or more dipole aprotic solvents;

[0014] The second solvent is selected from one or more C1-C4 short-chain fatty alcohols;

[0015] The third solvent is selected from one or more of ester solvents, haloalkanes, ketone solvents, ether solvents, and cyanide solvents.

[0016] Secondly, the present invention provides a single crystal of oseltamivir phosphate prepared by the preparation method described herein. In some embodiments, its single crystal structure is as follows:

[0017] The crystal system is orthorhombic.

[0018] The space group is P21212;

[0019] The unit cell volume is 4340.96(19) Å. 3 ;

[0020] The cell parameters are: a = 23.9002(6) Å, b = 24.4812(6) Å, c = 7.4191(2) Å.

[0021] In some embodiments, the crystal structure of oseltamivir phosphate single crystal provided by the present invention is shown in Table 1.

[0022] The present invention has the following beneficial effects:

[0023] This invention successfully prepared a single crystal of oseltamivir phosphate for the first time and provides a simple preparation method. The invention involves first adding oseltamivir phosphate to a first solvent (a dipolar solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamine), then adding a second solvent (alcohol) and a third solvent (ester, haloalkanes, ketones, ethers, or cyanides), stirring to dissolve, and then slowly evaporating the solvent to crystallize and obtain a single crystal of oseltamivir phosphate. This preparation method requires mild conditions, is simple to operate, and produces a single crystal with good crystal structure, facilitating the determination of the structural information of oseltamivir phosphate.

[0024] The fine structure of oseltamivir phosphate molecules was determined by analyzing the structure of single-crystal oseltamivir phosphate using single-crystal X-ray diffraction. This allowed for the detection of whether the absolute configuration of each chiral carbon in the oseltamivir phosphate sample was S- or R-configuration, and the observation of intermolecular interactions. This provides a direct, three-dimensional, and comprehensive determination of the oseltamivir phosphate molecule structure. The preparation and determination of single crystals using this invention are of significant importance and high application value for structure-activity relationship studies of oseltamivir phosphate and for new drug development. Attached Figure Description

[0025] Figure 1 This is a molecular absolute configuration diagram (ball-and-stick model) of oseltamivir phosphate single crystal in Example 1 of the present invention.

[0026] Figure 2 This is a molecular thermal ellipsoid diagram of the oseltamivir phosphate single crystal in Example 1 of the present invention;

[0027] Figure 3 Single crystal Figure 2 The structural formula of the two molecules of oseltamivir phosphate corresponding to 4;

[0028] Figure 4 This is a molecular unit cell packing diagram of the oseltamivir phosphate single crystal in Example 1 of the present invention;

[0029] Figure 5 The unit cell of the oseltamivir phosphate single crystal in Example 1 of this invention is H2PO4. - A diagram of hydrogen bonds formed by anions;

[0030] Figure 6 This is a diagram showing the hydrogen bonding between oseltamivir cations within the single crystal cell of oseltamivir phosphate in Example 1 of the present invention. Detailed Implementation

[0031] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0032] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the examples are commercially available products.

[0033] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0034] Furthermore, as used herein, the term "or" is an inclusive "or" sign and is equivalent to the term "and / or" unless the context clearly specifies otherwise. The term "based on" is not exclusive and allows for basing on other factors not described unless the context clearly specifies otherwise. Additionally, throughout the specification, the meanings of "an," "a," and "the" include plural indicators. The meaning of "in" includes both "in" and "on."

[0035] Through extensive experimentation, the inventors of this invention discovered that only by selecting a suitable mixed solvent can transparent needle-like oseltamivir phosphate single crystals be prepared. Using only a single solvent or an inappropriate mixed solvent can only precipitate small crystals, which cannot grow larger, or result in gel-like or flocculent substances, or even prevent the precipitation of solids. Based on this discovery, this invention systematically studied the types and ratios of solvents, thereby obtaining a very simple method for preparing oseltamivir phosphate single crystals, and successfully preparing oseltamivir phosphate single crystals for the first time.

[0036] In an embodiment of the present invention, the oseltamivir phosphate single crystal provided by the present invention has the following single crystal structure:

[0037] The crystal system is orthorhombic.

[0038] The space group is P21212;

[0039] The unit cell volume is 4340.96(19) Å. 3 ;

[0040] The cell parameters are: a = 23.9002(6) Å, b = 24.4812(6) Å, c = 7.4191(2) Å.

[0041] In some of these embodiments, the number of molecules within a unit cell is 8.

[0042] In some embodiments, the crystal size is 0.19 mm × 0.12 mm × 0.11 mm.

[0043] In some embodiments, the structural information of oseltamivir phosphate single crystals provided by the present invention is shown in Table 1.

[0044] The oseltamivir phosphate single crystal provided by this invention is colorless and transparent needle-shaped. The fine structure of the oseltamivir phosphate molecule can be determined by single-crystal X-ray diffraction analysis, the absolute configuration of each chiral carbon in the oseltamivir phosphate sample can be detected as S-configuration or R-configuration, and the intermolecular interactions can be observed. It can intuitively, three-dimensionally and comprehensively determine the molecular structure of oseltamivir phosphate, and has high application value.

[0045] The present invention provides a method for preparing oseltamivir phosphate single crystals, comprising the following steps:

[0046] Oseltamivir phosphate was added to the first solvent, then the second and third solvents were added, and the mixture was stirred until it was fully dissolved to form a clear solution. The solvent was allowed to evaporate by standing, and the oseltamivir phosphate single crystal was obtained.

[0047] The first solvent is selected from one or more dipole aprotic solvents;

[0048] The second solvent is selected from one or more C1-C4 short-chain fatty alcohols;

[0049] The third solvent is selected from one or more of ester solvents, haloalkanes, ketone solvents, ether solvents, and cyanide solvents.

[0050] It should be noted that the present invention does not require specific preparation of the oseltamivir phosphate sample, which can be prepared using conventional methods in the art.

[0051] In some embodiments, the first solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and hexamethylphosphoramide.

[0052] In some embodiments, the second solvent is selected from one or more of methanol, ethanol, and isopropanol.

[0053] In some embodiments, the ester solvent is selected from one or more of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate.

[0054] In some embodiments, the haloalkane is selected from one or more of dichloromethane, trichloromethane, dichloroethane, and carbon tetrachloride.

[0055] In some embodiments, the ketone solvent is selected from one or more of acetone, butanone, and methyl isobutyl ketone.

[0056] In some embodiments, the ether solvent is selected from one or more of diethyl ether, methyl ethyl ether, butyl ether, methyl tert-butyl ether, and tetrahydrofuran.

[0057] In some embodiments, the cyanide solvent is selected from acetonitrile.

[0058] In some embodiments, the first solvent is N,N-dimethylformamide, the second solvent is methanol, and the third solvent is ethyl acetate.

[0059] In some embodiments, the mass / volume ratio of oseltamivir phosphate to the first solvent is 1 mg: 0.08 mL to 10 mL, preferably 1 mg: 0.1 mL to 10 mL, more preferably 1 mg: 0.1 mL to 0.2 mL, and even more preferably 1 mg: 0.1 mL to 0.12 mL.

[0060] In some embodiments, the volume ratio of the first solvent, the second solvent, and the third solvent is 1:0.01~100:0.01~100, preferably 1:0.1~10:0.1~10, preferably 1:0.4~2.5:0.4~2.5, preferably 1:0.5~2:0.5~2, preferably 1:0.5~1.6:0.5~1.6 (for example, it can be 1:0.5:0.5, 1:1:1, or 1:1.5:1.5, etc.), and more preferably 1:1.5~1.6:1.5~1.6.

[0061] In some embodiments, the volume ratio of the second solvent to the third solvent is 1:0.8-1.2, preferably 1:1.

[0062] In some embodiments, the temperature of the solvent being allowed to evaporate is 0°C to 50°C, preferably 10°C to 40°C, and more preferably 15°C to 30°C.

[0063] In some embodiments, the time for allowing the solvent to evaporate is 3 to 20 days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 days), preferably 5 to 15 days, and more preferably 7 to 12 days.

[0064] The method for preparing oseltamivir phosphate single crystals provided by this invention uses a mixed solvent and grows crystals at an appropriate temperature to obtain oseltamivir phosphate single crystals. The conditions are mild and the operation is simple and easy to perform. The prepared single crystals have good crystal structure, which facilitates the determination of the structural information of oseltamivir phosphate.

[0065] The present invention will be further described in detail below with reference to specific embodiments.

[0066] In the following examples, room temperature refers to an indoor temperature of 15℃-25℃.

[0067] Example 1

[0068] This embodiment provides a method for preparing oseltamivir phosphate single crystals, including the following steps:

[0069] Add 10 mg of oseltamivir phosphate and 1 mL of N,N-dimethylformamide to a 10 mL flask, then add 1.5 mL of methanol and 1.5 mL of ethyl acetate. Stir and dissolve at room temperature, seal with sealing film, make small holes, and place in a fume hood at room temperature to allow the solvent to evaporate. Observe regularly and allow crystals to grow for 7 days. Pour off the supernatant and blow off the solvent remaining on the crystals with nitrogen to obtain colorless transparent needle-like crystals.

[0070] Example 2

[0071] This embodiment provides a method for preparing oseltamivir phosphate single crystals, including the following steps:

[0072] Add 10 mg of oseltamivir phosphate and 1 mL of N,N-dimethylformamide to a 10 mL flask, then add 0.5 mL of methanol and 0.5 mL of dichloromethane. Stir and dissolve at room temperature, seal with sealing film, make small holes, and let stand at 0 °C for 5 days to grow crystals. Pour off the supernatant and use nitrogen to blow away the solvent remaining on the crystals to obtain colorless transparent needle-like crystals.

[0073] Example 3

[0074] This embodiment provides a method for preparing oseltamivir phosphate single crystals, including the following steps:

[0075] Add 5 mg of oseltamivir phosphate and 0.5 mL of dimethyl sulfoxide to the reaction flask, along with 0.5 mL of ethanol and 0.5 mL of chloroform. Stir and dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 10 days to grow crystals. Pour off the supernatant and use nitrogen to blow away the solvent remaining on the crystals to obtain colorless, transparent needle-like crystals.

[0076] Example 4

[0077] This embodiment provides a method for preparing oseltamivir phosphate single crystals, including the following steps:

[0078] Add 5 mg of oseltamivir phosphate and 0.5 mL of hexamethylphosphamide to the reaction flask, along with 0.5 mL of methanol and 0.5 mL of acetone. Stir and dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 9 days to grow crystals. Pour off the supernatant and use nitrogen to blow away the solvent remaining on the crystals to obtain colorless, transparent needle-like crystals.

[0079] Example 5

[0080] This embodiment provides a method for preparing oseltamivir phosphate single crystals, including the following steps:

[0081] Add 5 mg of oseltamivir phosphate sample and 0.5 mL of N,N-dimethylformamide to the reaction flask, then add 0.5 mL of isopropanol and 0.5 mL of diethyl ether. Stir and dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 7 days. Pour off the supernatant and use nitrogen to blow away the solvent remaining on the crystals to obtain colorless transparent needle-like crystals.

[0082] Example 6

[0083] This embodiment provides a method for preparing oseltamivir phosphate single crystals, including the following steps:

[0084] Add 5 mg of oseltamivir phosphate sample and 0.5 mL of N,N-dimethylacetamide to the reaction flask, then add 0.5 mL of isopropanol and 0.5 mL of methyl acetate. Stir and dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 15 days to grow crystals. Pour off the supernatant and use nitrogen to blow away the solvent remaining on the crystals to obtain colorless transparent needle-like crystals.

[0085] Comparative Example 1

[0086] Add 10 mg of oseltamivir phosphate and 2 mL of N,N-dimethylformamide to a 10 mL flask, stir to dissolve, seal with sealing film, make small holes, and let stand at room temperature for 13 days to grow crystals, resulting in a white lumpy solid.

[0087] Comparative Example 2

[0088] Add 10 mg of oseltamivir phosphate and 2 mL of dimethyl sulfoxide to a 10 mL flask, stir to dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 14 days to allow crystals to grow, while still maintaining a clear liquid.

[0089] Comparative Example 3

[0090] Add 10 mg of oseltamivir phosphate and 2 mL of methanol to a 10 mL flask, stir to dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 7 days to grow crystals, and obtain a white gel-like substance.

[0091] Comparative Example 4

[0092] Add 5 mg of oseltamivir phosphate and 0.5 mL of dimethyl sulfoxide to a 10 mL flask, then add 0.5 mL of dichloromethane. Stir and dissolve at room temperature, seal with sealing film, poke small holes, and let stand at room temperature for 9 days to obtain a white flocculent solid.

[0093] Comparative Example 5

[0094] Add 5 mg of oseltamivir phosphate and 0.5 mL of N,N-dimethylformamide to a 10 mL flask, then add 0.5 mL of ethyl acetate. Stir and dissolve at room temperature, seal with sealing film, make small holes, and let stand at room temperature for 12 days to crystallize, obtaining a white flocculent solid.

[0095] Comparative Example 6

[0096] Add 10 mg of oseltamivir phosphate and 1 mL of methanol to a 10 mL flask, then add 1.5 mL of toluene and 1.5 mL of ethyl acetate. Stir to dissolve at room temperature, seal with sealing film, poke a small hole, and let stand for 10 days to form a gel.

[0097] Comparative Example 7

[0098] Add 10 mg of oseltamivir phosphate and 0.5 mL of N,N-dimethylformamide to a 10 mL flask, then add 0.8 mL of methanol and 0.5 mL of ethyl acetate. Stir and dissolve at room temperature, seal with sealing film, poke small holes, and let stand at room temperature for 9 days to form a gel.

[0099] Example 7 Crystal Structure Analysis

[0100] The crystal structure of oseltamivir phosphate single crystal prepared in Example 1 was analyzed. The molecular formula of this compound is C1. 16 H 31 N2O8P, with a molecular weight of 410.40, has the predicted structural formula shown in Formula 1.

[0101]

[0102] Formula 1

[0103] 1) Single crystal testing instruments and methods

[0104] Instrument model: Bruker D8 VENTURE X-ray single crystal diffractometer; Instrument technical parameters: PHOTON-II detector, four-circle Kappa analyzer, Cu target source. Detection parameters: temperature 193 K, Cu target source, wavelength 1.54178 Å. Data analysis software used: Bruker APEX4, SHELXL-2019, OLEX2, Mercury 3.9.

[0105] 2) Basic Structure

[0106] A crystal of suitable size and complete crystal form was selected and placed on a single-crystal X-ray diffractometer for measurement to obtain crystal structure and data. The single-crystal data has been stored in the Cambridge Crystal Data Centre, UK (www.ccdc.cam.ac.uk, Deposition No., CCDC: 2527100). The oseltamivir phosphate single crystal provided by this invention has a crystal size of 0.19 mm × 0.12 mm × 0.11 mm. Its crystal belongs to the orthorhombic crystal system, space group P21212, and cell volume of 4340.96(19) Å. 3 The number of molecules in the unit cell is 8, and the unit cell parameters are: a = 23.9002(6) Å, b = 24.4812(6) Å, c = 7.4191(2) Å.

[0107] The absolute configurations of the chiral carbon atoms in Equation 1 were determined intuitively and accurately using single-crystal structures, namely 3R, 4R, and 5S, which are consistent with results previously confirmed by other methods.

[0108] 3) Single crystal structure analysis

[0109] The single-crystal structure analysis data are shown in Table 1. Table 2 shows the hydrogen bond information of the unit cell. Table 3 shows the atomic coordinates and temperature factor of the target molecule. Tables 4 and 5 show the bond lengths and bond angles. Figure 1 and Figure 2 The basic structure of the compound's single-crystal molecules is presented (ball-and-stick model and thermal ellipsoid diagram). Detailed structural analysis will be explained in categories. For ease of explanation, it will be presented in the following ways: Figure 1 The atoms in the molecular arrangement diagram are designated by their atomic numbers, and all atoms are color-coded according to the following standard: C - gray, N - blue, H - sky blue, O - red, P - purple.

[0110] Depend on Figure 1As can be seen, the structure obtained from the single-crystal structure analysis is completely consistent with the structural formula of the target product. Each asymmetric structural unit contains two oseltamivir phosphate molecules, with one disordered ethyl group distributed at two different positions with occupancy rates of approximately 0.80 and 0.20, respectively. This indicates that the cultivation of the single crystal and the X-ray diffraction experiment were successful. The target molecule crystallizes in the orthorhombic crystal system P21212 space group, with chiral centers C6 and C22 in S configuration and C7, C8, C23, and C24 in R configuration.

[0111] Figure 2 The diagram is an ellipsoidal representation of the molecule. As can be seen from the diagram, the thermal vibrations of each atom are at a reasonable level, and the atom identification is correct.

[0112] Figure 4 This is a unit cell packing diagram of the molecules. From this diagram, we can see that each unit cell contains 2 complete target compound molecules and 20 parts of the target compound molecules, totaling 128 carbon atoms, 248 hydrogen atoms, 16 nitrogen atoms, 64 oxygen atoms, and 8 phosphorus atoms, which is equivalent to 8 target molecules.

[0113] Table 1 Single Crystal Structure Information Table

[0114]

[0115]

[0116]

[0117]

[0118] Table 2. Intracellular hydrogen bond information

[0119]

[0120]

[0121] Table 3. Coordinate parameters and equivalent temperature factor values ​​of non-hydrogen atoms

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] Table 4 Bond Lengths

[0129]

[0130]

[0131]

[0132] Table 5 Bond Angles

[0133]

[0134]

[0135]

[0136]

[0137] 4) Analysis of intermolecular interactions within the crystal

[0138] The non-covalent interactions between molecules within the unit cell were analyzed using Mercury 3.9, and the results are as follows: Figure 5 and Figure 6 As shown, the calculation results indicate that H2PO4 in the target compound molecule - Anions can react with neighboring H2PO4 - The anion and oseltamivir cation form numerous hydrogen bonds, including with H2PO4. - The anions form OH…O hydrogen bonds, with interatomic distances of 2.452(2) Å and 2.513(2) Å, respectively; H2PO4 - The anions mainly form NH…O and OH…O hydrogen bonds with the ammonium ions and amide bonds in the oseltamivir cations. The distance between nitrogen and oxygen atoms ranges from 2.731(2) to 3.142(3) Å, while the distances between oxygen atoms are 2.638(2) and 2.687(2) Å, respectively. Furthermore, the oseltamivir cations can also form CH…O hydrogen bonds with each other, with the distances between carbon and oxygen atoms being 3.282(3) and 3.461(3) Å, respectively. Data on hydrogen bond analysis are listed in Table 2. The calculation results indicate that hydrogen bonding can stabilize the molecule and facilitate molecular crystallization.

[0139] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing oseltamivir phosphate single crystals, characterized in that, Includes the following steps: Oseltamivir phosphate was added to the first solvent, then the second and third solvents were added, and the mixture was stirred until it was fully dissolved to form a clear solution. The solvent was allowed to evaporate by standing, and the oseltamivir phosphate single crystal was obtained. The first solvent is selected from one or more dipole aprotic solvents; The second solvent is selected from one or more C1-C4 short-chain fatty alcohols; The third solvent is selected from one or more of ester solvents, haloalkanes, ketone solvents, ether solvents, and cyanide solvents.

2. The method for preparing oseltamivir phosphate single crystals according to claim 1, characterized in that, The first solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and hexamethylphosphoramide; And / or, the second solvent is selected from one or more of methanol, ethanol and isopropanol; And / or, the ester solvent is selected from one or more of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; And / or, the haloalkane is selected from one or more of dichloromethane, trichloromethane, dichloroethane, and carbon tetrachloride; And / or, the ketone solvent is selected from one or more of acetone, butanone, and methyl isobutyl ketone; And / or, the ether solvent is selected from one or more of diethyl ether, methyl ethyl ether, butyl ether, methyl tert-butyl ether, and tetrahydrofuran; And / or, the cyanide solvent is selected from acetonitrile.

3. The method for preparing oseltamivir phosphate single crystals according to claim 1, characterized in that, The first solvent is N,N-dimethylformamide, the second solvent is methanol, and the third solvent is ethyl acetate.

4. The method for preparing oseltamivir phosphate single crystals according to any one of claims 1-3, characterized in that, The mass / volume ratio of oseltamivir phosphate to the first solvent is 1 mg: 0.08 mL to 10 mL, preferably 1 mg: 0.1 mL to 10 mL, more preferably 1 mg: 0.1 mL to 0.2 mL, and even more preferably 1 mg: 0.1 mL to 0.12 mL.

5. The method for preparing oseltamivir phosphate single crystals according to any one of claims 1-3, characterized in that, The volume ratio of the first solvent, the second solvent, and the third solvent is 1:0.01~100:0.01~100, preferably 1:0.1~10:0.1~10, preferably 1:0.4~2.5:0.4~2.5, preferably 1:0.5~2:0.5~2, preferably 1:0.5~1.6:0.5~1.6, and more preferably 1:1.5~1.6:1.5~1.6; Preferably, the volume ratio of the second solvent to the third solvent is 1:0.8-1.2, and more preferably 1:

1.

6. The method for preparing oseltamivir phosphate single crystals according to any one of claims 1-3, characterized in that, The temperature at which the solvent is allowed to evaporate is 0°C to 50°C, preferably 10°C to 40°C, and more preferably 15°C to 30°C.

7. The method for preparing oseltamivir phosphate single crystals according to any one of claims 1-3, characterized in that, The time for allowing the solvent to evaporate to stand is 3 to 20 days, preferably 5 to 15 days, and more preferably 7 to 12 days.

8. Oseltamivir monophosphate single crystal, characterized in that, It is prepared by the preparation method according to any one of claims 1-7.

9. A single crystal of oseltamivir phosphate, characterized in that, Its single crystal structure is as follows: The crystal system is orthorhombic. The space group is P21212; The unit cell volume is 4340.96(19) Å. 3 ; The cell parameters are: a = 23.9002(6) Å, b = 24.4812(6) Å, c = 7.4191(2) Å.

10. The oseltamivir phosphate single crystal according to claim 9, characterized in that, Its crystal size is 0.19 mm × 0.12 mm × 0.11 mm; and / or, the number of molecules in its unit cell is 8.

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