Preparation method of oseltamivir phosphate crystal form B

Abstract

The invention discloses a preparation method of an oseltamivir phosphate crystal form B. The preparation method comprises the following steps: mixing oseltamivir, phosphoric acid and a first solvent at a first temperature to prepare a first solution; mixing the first solution with a second solvent at a first temperature, cooling to a third temperature, stirring, filtering, taking a filter cake, and drying to prepare an oseltamivir phosphate crystal form B; or mixing oseltamivir phosphate with a third solvent at a second temperature to prepare a second solution; mixing the second solution, a fourth solvent and the seed crystal at a second temperature, cooling to a third temperature, stirring, filtering, taking a filter cake, and drying to prepare an oseltamivir phosphate crystal form B; wherein the first solvent is an alcohol solvent; the second solvent is a ketone solvent; the third solvent is selected from one or more of an alcohol solvent and water; the fourth solvent is selected from one or more of a ketone solvent, an alkane solvent and an ester solvent. The preparation method can obviously improve the yield of the target crystal form, and is simple and convenient to operate.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and particularly relates to a preparation method and application of oseltamivir phosphate polymorph B. Background Art

[0002] Neuraminidase (NA) is an enzyme composed of protein on the surface of influenza virus particles and is the most critical enzyme for virus replication and spread. Viral neuraminidase inhibitors are a new class of anti-influenza drugs with a completely new mechanism of action after amantadine and influenza vaccines. They can selectively inhibit the activity of neuraminidase on the surface of respiratory viruses and prevent the replication and release of progeny virus particles in human cells.

[0003] The phosphate salt of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (Formula I), namely oseltamivir phosphate, is a new type of neuraminidase (NA) inhibitor with high selectivity. It can be used for the treatment and prevention of diseases such as influenza virus infection, bronchitis, pneumonia, and general pain accompanied by infections, and is particularly effective against influenza A and B viruses, with good clinical application prospects. Its structure is shown in Formula (I):

[0004] Formula (I) Traditional technologies have disclosed the synthesis method of Formula (I). Research shows that oseltamivir phosphate has four forms: phosphate polymorph A, polymorph B, polymorph C, and amorphous form. Among them, phosphate polymorph B is obtained by rapidly cooling a supersaturated solution at 50 °C to -40 °C and then slowly stirring overnight at -40 °C. However, this preparation method has problems such as complex process, energy consumption, and time-consuming.

[0005] Polymorphs of the same drug may change its physicochemical properties, such as solubility, and may thus affect the effect of the drug in the human body. Therefore, it is necessary to develop a more excellent, stable, and easy-to-operate polymorph preparation method to provide more and better choices for the development of drugs containing oseltamivir phosphate. Summary of the Invention

[0006] Based on this, the present invention provides a preparation method of oseltamivir phosphate polymorph B, which can significantly improve the yield of the target polymorph, and is easy to operate, with mild conditions and short process steps.

[0007] The present invention is achieved through the following technical solutions.

[0008] A preparation method of oseltamivir phosphate polymorph B, comprising the following steps: Mix oseltamivir, phosphoric acid and a first solvent at a first temperature to prepare a first solution; mix the first solution with a second solvent at the first temperature, then cool to a third temperature, stir, filter, take the filter cake, and dry to prepare oseltamivir phosphate polymorph B; or Mix the phosphate of oseltamivir with a third solvent at a second temperature to prepare a second solution; mix the second solution, a fourth solvent and a seed crystal at the second temperature, then cool to the third temperature, stir, filter, take the filter cake, and dry to prepare oseltamivir phosphate polymorph B; Wherein, the first solvent is an alcohol solvent; the second solvent is a ketone solvent; the third solvent is selected from one or more of an alcohol solvent and water; the fourth solvent is selected from one or more of a ketone solvent, an alkane solvent and an ester solvent.

[0009] In one embodiment, in the first solvent, the alcohol solvent is selected from one or more of methanol and ethanol.

[0010] In one embodiment, in the second solvent, the ketone solvent is selected from one or more of acetone, 2-butanone and methyl isobutyl ketone.

[0011] In one embodiment, in the third solvent, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol.

[0012] In one embodiment, in the fourth solvent, the ketone solvent is selected from one or more of acetone, 2-butanone and methyl isobutyl ketone; and / or the alkane solvent is selected from one or more of n-heptane and n-hexane; and / or the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate and isobutyl acetate.

[0013] In one embodiment, the first temperature is selected from 40°C to 60°C.

[0014] In one embodiment, the second temperature is selected from 40°C to 50°C.

[0015] In one embodiment, the third temperature is selected from 0°C to 10°C.

[0016] The present invention also provides the application of the preparation method of oseltamivir phosphate polymorph B as described above in the preparation of drugs for treating influenza virus infection.

[0017] In one embodiment, the influenza virus is an influenza A virus or an influenza B virus.

[0018] Compared with the prior art, the preparation method of oseltamivir phosphate polymorph B of the present invention has the following beneficial effects: The present invention can improve the yield of oseltamivir phosphate polymorph B to a certain extent by successively mixing a mixture of oseltamivir and phosphoric acid with a solvent and an anti-solvent, or mixing oseltamivir phosphate with a solvent and an anti-solvent, while defining the types of the solvent and the anti-solvent. More importantly, the preparation method of the present invention is easy to operate, has mild conditions, and short process steps, and can significantly improve the preparation method and conditions for obtaining oseltamivir phosphate polymorph B in the traditional technology.

[0019] Therefore, the preparation method of the present invention has advantages in at least one of the aspects of operation, energy consumption, convenience, purification effect, stability, fluidity, processability, safety, etc., provides a new and better choice for the preparation of the pharmaceutical preparation, and has very important significance for drug development. BRIEF DESCRIPTION OF THE DRAWINGS Attached Figure 1 is the structural formula of oseltamivir phosphate polymorph B. EMBODIMENTS

[0020] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below with reference to relevant embodiments. Preferred embodiments of the present invention are given in the embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0021] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

[0022] The solvents used in the present invention are commercially available.

[0023] "Crystal form" or "crystalline form" refers to a solid with a highly regular chemical structure, including but not limited to, single-component or multi-component crystals, and / or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of a compound. The crystalline form of a substance can be obtained by many methods known in the art. Such methods include but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallization anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding, and solvent-drop grinding, etc.

[0024] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, their mixtures, and so on.

[0025] "Anti-solvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Anti-solvents can include cold gases, or fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0026] Crystal forms or amorphous forms can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, single crystal X-ray diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility, and dissolution rate, etc.

[0027] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystal structure state, and is a commonly used means for identifying crystal forms. The peak positions of the XRPD pattern mainly depend on the structure of the crystal form and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to sample preparation and instrument geometry. At the same time, the measurement of 2θ in the XRPD pattern can have experimental errors, and there may be slight differences in the measurement of 2θ in the XRPD patterns between different instruments and different samples. Therefore, the value of 2θ cannot be regarded as absolute. According to the instrument conditions used in the experiments of the present invention, there is an error tolerance of ± 0.2° for the diffraction peaks.

[0028] Solids with the same chemical composition often form polymorphs or variants with different crystal structures under different thermodynamic conditions, and this phenomenon is called polymorphism or polyphasic phenomenon. When the temperature and pressure conditions change, mutual transformation occurs between the variants, and this phenomenon is called crystal form transformation. The crystal form or amorphous form of the compounds of the present invention can undergo crystal form transformation under appropriate conditions.

[0029] In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are all in degrees (°).

[0030] In the present invention, unless otherwise specified, "room temperature" generally refers to a temperature range from 22°C to 28°C.

[0031] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.

[0032] When referring to a spectrum or / and the data shown in the figure, a "peak" refers to a feature that can be recognized by those skilled in the art and does not belong to background noise.

[0033] In the context of the present invention, when the words "about" or "approximately" are used or not used, it means within 10% of the given value or range, preferably within 5%, especially within 1%. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within the acceptable standard error range of the average value. Whenever a number with a value of N is disclosed, any number within the range of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% is clearly disclosed, where "+ / -" means plus or minus.

[0034] The terms "first" and "second" in the present invention are only used for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include at least one of such features. In the description of the invention, "a plurality" means at least two, such as two, three, etc., unless otherwise specifically defined. In the description of the present invention, "several" means at least one, such as one, two, etc., unless otherwise specifically defined.

[0035] The terms "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention.

[0036] When a numerical range is disclosed herein, the above range is considered continuous and includes the minimum and maximum values of the range, as well as every value therebetween. Further, when the range refers to integers, every integer between the minimum and maximum values of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0037] Unless otherwise specified, all percentages, fractions, and ratios are calculated based on the total mass of the composition of the present invention. Unless otherwise specified, all masses of the listed components are given as the content of the active substance, and thus they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percentage content" in this text may be represented by the symbol "%". Unless otherwise specified, all molecular weights herein are weight-average molecular weights expressed in daltons.

[0038] The terms "comprising", "including", "containing", "having", or other variants herein are intended to cover non-closed inclusion, and no distinction is made between these terms. The term "including" means that other steps and components may be added without affecting the final result. The compositions and methods / processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any additional or optional components, ingredients, steps, or limitations described herein. No distinction is made between the terms "efficacy", "performance", "effect", and "function" in this text.

[0039] The weights of the relevant components mentioned in the specification of the embodiments of the present invention not only can refer to the specific contents of each component, but also can represent the proportional relationship of the weights between the components. Therefore, as long as the contents of the relevant components in the specification of the embodiments of the present invention are scaled up or down in proportion, they are within the scope disclosed in the specification of the embodiments of the present invention. Specifically, the weights described in the specification of the embodiments of the present invention can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention pertains. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0041] The present invention provides a method for preparing oseltamivir phosphate polymorph B, comprising the following steps: Mix oseltamivir, phosphoric acid and a first solvent at a first temperature to prepare a first solution; mix the first solution and a second solvent at the first temperature, then cool to a third temperature, stir, filter, take the filter cake, and dry to prepare oseltamivir phosphate polymorph B; or Mix the phosphate of oseltamivir and a third solvent at a second temperature to prepare a second solution; mix the second solution, a fourth solvent and a seed crystal at the second temperature, then cool to the third temperature, stir, filter, take the filter cake, and dry to prepare oseltamivir phosphate polymorph B; Wherein, the first solvent is an alcohol solvent; the second solvent is a ketone solvent; the third solvent is selected from one or more of an alcohol solvent and water; the fourth solvent is selected from one or more of a ketone solvent, an alkane solvent and an ester solvent.

[0042] It can be understood that in the present invention, the seed crystal is a seed crystal of oseltamivir phosphate polymorph B.

[0043] In a specific example, in the first solvent, the alcohol solvent is selected from one or more of methanol and ethanol.

[0044] In a specific example, in the second solvent, the ketone solvent is selected from one or more of acetone, 2-butanone and methyl isobutyl ketone.

[0045] In a specific example, in the third solvent, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol.

[0046] In a specific example, in the fourth solvent, the ketone solvent is selected from one or more of acetone, 2-butanone and methyl isobutyl ketone.

[0047] In a specific example, in the fourth solvent, the alkane solvent is selected from one or more of n-heptane and n-hexane.

[0048] In a specific example, in the fourth solvent, the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate and isobutyl acetate.

[0049] It can be understood that in the present invention, the second solvent and the fourth solvent are antisolvents.

[0050] In a specific example, the first temperature is selected from 40°C to 60°C.

[0051] It can be understood that in the present invention, the first temperature includes but is not limited to 40°C, 42°C, 44°C, 46°C, 48°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C.

[0052] In a specific example, the second temperature is selected from 40°C to 50°C.

[0053] Understandably, in the present invention, the second temperature includes but is not limited to 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, 45 °C, 46 °C, 47 °C, 48 °C, 49 °C, 50 °C.

[0054] In a specific example, the third temperature is selected from 0 °C to 10 °C.

[0055] Understandably, in the present invention, the third temperature includes but is not limited to 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, 5 °C, 6 °C, 7 °C, 8 °C, 9 °C, 10 °C.

[0056] In a specific example, the stirring time is 0 h to 24 h.

[0057] In a specific example, the drying is vacuum drying.

[0058] The present invention also provides the use of the above-mentioned preparation method of oseltamivir phosphate polymorph B in the preparation of drugs for treating influenza virus infection.

[0059] In a specific example, the influenza virus is influenza A virus or influenza B virus. The present application will be described in detail below by way of examples, but this does not mean any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments have also been disclosed. For those skilled in the art, various changes and improvements to the specific embodiments of the present application will be obvious without departing from the spirit and scope of the present application.

[0060] The explanations of the abbreviations used in the present invention are as follows: XRPD: X-ray powder diffraction The X-ray powder diffraction range described in the present invention is collected on a D2 type X-ray powder diffractometer of Bruker. The method parameters of the X-ray powder diffraction described in the present invention are as follows: X-ray source: Cu(Å): 1.54184 Voltage: 30 kilovolts (kV) Current: 10 milliamperes (mA) Scanning range: from 3.0 to 50.0 degrees The phosphate starting material of compound (I) used in the following examples can be prepared according to the prior art. For example, it can be prepared according to the method described in CN101801914B, but the starting crystal form is not a limiting condition for preparing the crystal form of the present invention.

[0061] Example 1: Preparation of oseltamivir phosphate polymorph B This embodiment provides a method for preparing oseltamivir phosphate polymorph B, which is as follows: Under room temperature conditions, weigh 2 g of the free base of the compound of formula (I) and 0.75 g of phosphoric acid (purity > 90%) and place them in a 50 mL three-necked flask. Add 5 mL of methanol solution, and stir to dissolve at 55 °C. Then slowly add 25 mL of acetone to the reaction solution, and then slowly cool down to 10 °C and stir magnetically for 2 hours. Filter and dry in vacuo to obtain oseltamivir phosphate polymorph B, with a yield of 90%. Its X-ray powder diffraction data are 5.3° ± 0.2°, 6.0° ± 0.2°, 7.4° ± 0.2°, 12.7° ± 0.2°, 13.6° ± 0.2°, 16.1° ± 0.2°, 18.6° ± 0.2°, 21.4° ± 0.2°, 23.7° ± 0.2°.

[0062] Example 2: Preparation of oseltamivir phosphate polymorph B This embodiment provides a method for preparing oseltamivir phosphate polymorph B, which is as follows: Under room temperature conditions, weigh 2 g of the phosphate solid of the free base of the compound of formula (I) (purity > 98%) and place it in a 50 mL three-necked flask. Add 5 mL of a water-ethanol mixed solution (volume ratio 1:1), and stir to dissolve at 45 °C. Add 30 mL of acetone and 20 mg of the seed crystal of oseltamivir phosphate polymorph B to the solution. After stirring magnetically for 1 hour, slowly cool down to 10 °C and stir under this condition for 1 hour. Filter and dry in vacuo to obtain oseltamivir phosphate polymorph B, with a yield of 93.6%. Its X-ray powder diffraction data are 5.3° ± 0.2°, 6.0° ± 0.2°, 7.4° ± 0.2°, 12.8° ± 0.2°, 13.6° ± 0.2°, 16.1° ± 0.2°, 18.6° ± 0.2°, 21.4° ± 0.2°, 23.7° ± 0.2°.

[0063] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0064] Although the embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A preparation method of oseltamivir phosphate polymorph B, characterized in that, It includes the following steps: Mix oseltamivir, phosphoric acid and a first solvent at a first temperature to prepare a first solution; mix the first solution with a second solvent at the first temperature, then cool down to a third temperature, stir, filter, take the filter cake, and dry to prepare oseltamivir phosphate polymorph B; or Mix the phosphate salt of oseltamivir with a third solvent at a second temperature to prepare a second solution; mix the second solution, a fourth solvent and a seed crystal at the second temperature, then cool down to the third temperature, stir, filter, take the filter cake, and dry to prepare oseltamivir phosphate polymorph B; Wherein, the first solvent is an alcohol solvent; the second solvent is a ketone solvent; the third solvent is selected from one or more of an alcohol solvent and water; the fourth solvent is selected from one or more of a ketone solvent, an alkane solvent and an ester solvent.

2. The preparation method of oseltamivir phosphate polymorph B according to claim 1, characterized in that, In the first solvent, the alcohol solvent is selected from one or more of methanol and ethanol.

3. The preparation method of oseltamivir phosphate polymorph B according to claim 1, characterized in that, In the second solvent, the ketone solvent is selected from one or more of acetone, 2-butanone and methyl isobutyl ketone.

4. The preparation method of oseltamivir phosphate polymorph B according to claim 1, characterized in that, In the third solvent, the alcohol solvent is selected from one or more of methanol, ethanol and isopropyl alcohol.

5. The preparation method of oseltamivir phosphate polymorph B according to claim 1, characterized in that, In the fourth solvent, the ketone solvent is selected from one or more of acetone, 2-butanone and methyl isobutyl ketone; and / or the alkane solvent is selected from one or more of n-heptane and n-hexane; and / or the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate and isobutyl acetate.

6. The preparation method of oseltamivir phosphate polymorph B according to any one of claims 1 to 5, characterized in that, The first temperature is selected from 40°C to 60°C.

7. The preparation method of oseltamivir phosphate polymorph B according to any one of claims 1 to 5, characterized in that, The second temperature is selected from 40°C to 50°C.

8. The preparation method of oseltamivir phosphate polymorph B according to any one of claims 1 to 5, characterized in that, The third temperature is selected from 0°C to 10°C.

9. Use of the method for preparing oseltamivir phosphate polymorph B according to any one of claims 1 to 8 in the preparation of a medicament for treating influenza virus infection.

10. The application according to claim 9, characterized in that The influenza virus is an influenza A virus or an influenza B virus.

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