CN113307834A - Polymorphic substance of ribonucleoside analogue, preparation method and application thereof - Google Patents
Polymorphic substance of ribonucleoside analogue, preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention provides a polymorphic form of a ribonucleotide analogue, a preparation method and application thereof. Polymorphic form of a ribonucleotide analog (i.e., compound 1): crystal form I, crystal form II, crystal form III;the crystal form provided by the invention has high purity, good stability and storage resistance, and small change, even basically no obvious change, of the impurity content in long-term storage.
Description
Technical Field
The invention belongs to the field of compound crystal forms, and particularly relates to a polymorphic substance of a ribonucleoside analogue, and a preparation method and application thereof.
Background
Molnupiravir (EIDD-2801, CAS number: 2349386-89-4) is a drug developed by Emmeril university drug Innovation, Inc. of Atlanta, Georgia. It is a ribonucleoside analogue, mimicking naturally occurring nucleosides, that generate errors during replication of single-stranded RNA viruses to prevent viral propagation, thereby inhibiting viral replication, and has the following structure:
it has been shown that EIDD-2801 has therapeutic effects on Murine Hepatitis Virus (MHV), severe acute respiratory syndrome coronavirus (SARS-COV), middle east respiratory syndrome coronavirus (MERS-COV), novel coronavirus (2019-nCoV), etc.
How to develop the EIDD-2801 is more suitable for pharmaceutical crystal forms, especially crystal forms with improved stability, hygroscopicity, storage stability and/or drug effect, so as to obtain good effects in the pharmaceutical and pharmaceutical stages, and becomes a technical problem to be solved urgently.
Disclosure of Invention
In order to improve the above technical problems, the present invention provides a polymorph of compound 1 (EIDD-2801):
the invention provides a compound 1 in a crystal form I, wherein the crystal form I has characteristic peaks at 6.45 +/-0.20 degrees, 12.99 +/-0.20 degrees, 16.30 +/-0.20 degrees, 16.95 +/-0.20 degrees, 17.19 +/-0.20 degrees and 21.21 +/-0.20 degrees by X-ray powder diffraction represented by a 2 theta angle by using Cu-Kalpha radiation.
Preferably, the crystal form I has characteristic peaks at 6.45 +/-0.20 degrees, 12.99 +/-0.20 degrees, 16.30 +/-0.20 degrees, 16.95 +/-0.20 degrees, 17.19 +/-0.20 degrees, 21.21 +/-0.20 degrees, 27.96 +/-0.20 degrees and 28.39 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.
Also preferably, the crystal form I has characteristic peaks at 6.45 + -0.20 °, 12.99 + -0.20 °, 16.30 + -0.20 °, 16.95 + -0.20 °, 17.19 + -0.20 °, 19.60 + -0.20 °, 20.53 + -0.20 °, 21.21 + -0.20 °, 27.96 + -0.20 °, 28.39 + -0.20 °, 33.94 + -0.20 ° by X-ray powder diffraction at 2 θ using Cu-Kalpha radiation.
More preferably, the crystal form I has characteristic peaks at 6.48 + -0.20 °, 12.99 + -0.20 °, 16.30 + -0.20 °, 16.95 + -0.20 °, 17.19 + -0.20 °, 18.03 + -0.20 °, 19.35 + -0.20 °, 19.60 + -0.20 °, 20.31 + -0.20 °, 20.53 + -0.20 °, 21.21 + -0.20 °, 27.96 + -0.20 °, 28.39 + -0.20 °, 28.92 + -0.20 °, 31.58 + -0.20 °, 33.94 + -0.20 ° by X-ray powder diffraction at 2 θ using Cu-Kalpha radiation.
According to an embodiment of the present invention, said form I is obtained by X-ray powder diffraction using Cu-ka radiation, expressed in 2 Θ angles, as shown in table 1, with a range of error ± 0.20 °:
table 1 XRPD analysis data for form I
Preferably, the crystalline form I has a powder X-ray diffraction pattern substantially as shown in figure 1.
According to an embodiment of the present invention, said form I has a DSC profile substantially as shown in figure 2.
According to an embodiment of the invention, the crystalline form I has a TGA profile substantially as shown in figure 3.
The invention provides a compound 1 in a crystal form II, which uses Cu-Kalpha radiation, and has characteristic peaks at 3.20 +/-0.20 degrees, 16.94 +/-0.20 degrees, 17.98 +/-0.20 degrees, 20.50 +/-0.20 degrees, 21.24 +/-0.20 degrees and 27.94 +/-0.20 degrees in X-ray powder diffraction represented by 2 theta angles.
Preferably, the crystal form II has characteristic peaks at 3.20 +/-0.20 °, 6.44 +/-0.20 °, 16.94 +/-0.20 °, 17.98 +/-0.20 °, 20.50 +/-0.20 °, 20.28 +/-0.20 °, 21.24 +/-0.20 ° and 27.94 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.
More preferably, the crystal form II has characteristic peaks at 3.20 +/-0.20 °, 6.44 +/-0.20 °, 16.94 +/-0.20 °, 17.98 +/-0.20 °, 19.36 +/-0.20 °, 20.50 +/-0.20 °, 20.28 +/-0.20 °, 21.24 +/-0.20 °, 27.94 +/-0.20 ° and 28.36 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.
According to an embodiment of the present invention, the crystalline form II is obtained by X-ray powder diffraction using Cu-ka radiation at 2 θ angles as shown in table 2 with a tolerance range ± 0.20 °:
table 2 XRPD analysis data for form II
Peak numbering | 2θ[°] | Relative strength% | Peak numbering | 2θ[°] | Relative strength% |
1 | 3.198 | 100.0 | 27 | 33.900 | 8.5 |
2 | 6.440 | 17.0 | 28 | 34.362 | 6.7 |
3 | 9.700 | 2.7 | 29 | 34.956 | 1.8 |
4 | 12.981 | 9.9 | 30 | 35.175 | 1.6 |
5 | 16.297 | 8.8 | 31 | 36.138 | 3.1 |
6 | 16.940 | 80.3 | 32 | 36.579 | 3.2 |
7 | 17.980 | 32.6 | 33 | 37.296 | 2.9 |
8 | 18.299 | 5.8 | 34 | 37.818 | 1.4 |
9 | 19.360 | 16.2 | 35 | 38.684 | 2.2 |
10 | 19.819 | 9.3 | 36 | 39.096 | 2.2 |
11 | 20.278 | 18.5 | 37 | 40.419 | 2.2 |
12 | 20.501 | 34.4 | 38 | 40.863 | 3.6 |
13 | 21.241 | 68.1 | 39 | 42.337 | 2.6 |
14 | 22.519 | 5.0 | 40 | 43.539 | 1.6 |
15 | 23.317 | 8.1 | 41 | 44.177 | 2.8 |
16 | 24.141 | 7.1 | 42 | 45.262 | 1.0 |
17 | 25.696 | 3.3 | 43 | 48.397 | 1.3 |
18 | 26.359 | 4.4 | |||
19 | 27.437 | 4.2 | |||
20 | 27.942 | 51.4 | |||
21 | 28.360 | 14.9 | |||
22 | 28.839 | 10.6 | |||
23 | 30.061 | 12.1 | |||
24 | 30.822 | 2.3 | |||
25 | 31.542 | 11.1 | |||
26 | 33.662 | 6.3 |
. Preferably, the crystalline form II has a powder X-ray diffraction pattern substantially as shown in figure 4.
According to an embodiment of the present invention, the crystalline form II has a DSC profile substantially as shown in figure 5.
According to an embodiment of the invention, the crystalline form II has a TGA profile substantially as shown in figure 6.
The invention provides a compound 1 in a crystal form III, which uses Cu-Kalpha radiation, and has characteristic peaks at 16.71 +/-0.20 degrees, 17.57 +/-0.20 degrees, 18.22 +/-0.20 degrees, 19.90 +/-0.20 degrees and 22.31 +/-0.20 degrees in X-ray powder diffraction represented by 2 theta angles.
Preferably, the crystal form III has characteristic peaks at 14.15 +/-0.20 degrees, 16.71 +/-0.20 degrees, 17.57 +/-0.20 degrees, 18.22 +/-0.20 degrees, 19.90 +/-0.20 degrees, 20.52 +/-0.20 degrees, 22.31 +/-0.20 degrees and 24.39 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.
More preferably, the crystal form III has characteristic peaks at 10.10 +/-0.20 DEG 11.10 +/-0.20 DEG, 14.15 +/-0.20 DEG, 16.71 +/-0.20 DEG, 17.57 +/-0.20 DEG, 18.22 +/-0.20 DEG, 19.90 +/-0.20 DEG, 20.52 +/-0.20 DEG, 22.31 +/-0.20 DEG, 24.13 +/-0.20 DEG, 24.39 +/-0.20 DEG and 25.42 +/-0.20 DEG by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.
According to an embodiment of the present invention, said form III is obtained by X-ray powder diffraction using Cu-ka radiation, expressed in 2 Θ angles, as shown in table 3, with a range of error ± 0.20 °:
table 3 XRPD analysis data for form III
Peak numbering | 2θ[°] | Relative strength% | Peak numbering | 2θ[°] | Relative strength% |
1 | 10.100 | 20.3 | 19 | 28.890 | 16.6 |
2 | 11.101 | 19.6 | 20 | 30.069 | 4.4 |
3 | 13.211 | 13.6 | 21 | 30.940 | 9.3 |
4 | 14.150 | 27.9 | 22 | 31.239 | 4.7 |
5 | 16.710 | 49.8 | 23 | 31.870 | 5.9 |
6 | 17.570 | 88.7 | 24 | 32.390 | 16.3 |
7 | 18.220 | 100.0 | 25 | 33.870 | 6.8 |
8 | 19.900 | 41.8 | 26 | 35.129 | 4.2 |
9 | 20.280 | 17.5 | 27 | 36.698 | 3.5 |
10 | 20.520 | 33.3 | 28 | 37.139 | 5.0 |
11 | 20.870 | 17.0 | 29 | 38.630 | 4.4 |
12 | 22.310 | 42.5 | 30 | 39.060 | 4.5 |
13 | 22.710 | 8.0 | 31 | 40.970 | 3.9 |
14 | 23.399 | 5.1 | 32 | 41.610 | 7.6 |
15 | 24.130 | 20.4 | 33 | 42.591 | 9.0 |
16 | 24.390 | 29.8 | 34 | 45.690 | 2.5 |
17 | 25.421 | 21.0 | 35 | 46.682 | 2.9 |
18 | 27.161 | 13.8 | 36 | 47.479 | 2.9 |
Preferably, the crystalline form III has a powder X-ray diffraction pattern substantially as shown in figure 7.
According to an embodiment of the present invention, the crystalline form III has a DSC profile substantially as shown in figure 8.
According to an embodiment of the invention, the crystalline form III has a TGA profile substantially as shown in figure 9.
According to an embodiment of the invention, the polymorph comprises a non-solvate (anhydrate) as well as a crystalline form of a solvate of compound 1; in some embodiments, the polymorph comprises a hydrate, e.g., is a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate.
The invention also provides a preparation method of the polymorphic substance of the compound 1(EIDD-2801), which comprises the steps of mixing the compound 1 with a solvent, and recrystallizing to prepare the polymorphic substance;
the solvent is selected from organic solvents and/or water.
According to an embodiment of the present invention, the organic solvent is selected from one, two or more of methanol, ethanol, isopropanol, acetone, acetonitrile, toluene, ethyl acetate, butyl acetate, methyl t-butyl ether, tetrahydrofuran, and the like.
According to an embodiment of the present invention, the solvent may be selected from methanol, ethanol, isopropanol, acetone, acetonitrile, toluene, ethyl acetate, butyl acetate, tetrahydrofuran, a mixed solvent of ethyl acetate and methyl t-butyl ether, a mixed solvent of ethanol and water, or a mixed solvent of acetonitrile and water.
According to an embodiment of the invention, the mass to volume ratio of compound 1 to solvent is 1g (2-10) mL, for example 5g:25 mL.
According to an embodiment of the invention, the preparation method comprises: and mixing the compound 1 with a solvent, heating and stirring until the system is clear, cooling, washing and drying to obtain the polymorphic substance.
According to an embodiment of the invention, the process for the preparation of said polymorph may be selected from any one of the following processes:
the method comprises the following steps: mixing the compound 1 and ethyl acetate according to a mass-to-volume ratio of 1g (2-10) mL, heating, stirring and heating to reflux (preferably reflux time is 1-5 hours), slowly cooling to 10-15 ℃, filtering, rinsing with ethyl acetate, and drying (preferably drying temperature is 30-50 ℃) to obtain the polymorphic substance;
the second method comprises the following steps: mixing the compound 1 and ethyl acetate according to a mass-volume ratio of 1g (2-10) mL, heating, stirring, heating to reflux (preferably refluxing for 0.5-2 hours), cooling to 50-55 ℃, and adding (preferably dropwise adding) methyl tert-butyl ether (preferably dropwise adding over 2 min) into the system; continuously cooling to 10-15 deg.C, stirring (preferably stirring for 0.5-1 hr), filtering, washing, and drying to obtain the polymorph; preferably, the volume ratio of the ethyl acetate to the methyl tert-butyl ether is 1 (0.8-1.3);
the third method comprises the following steps: heating, stirring and heating the compound 1, absolute ethyl alcohol and water according to the mass volume ratio of 1g (2-10) mL (0.3-0.8) mL to the system solution, slowly cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method four comprises the following steps: mixing the compound 1 and absolute ethyl alcohol according to a mass volume ratio of 1g (2-10) mL, heating, stirring and heating until the system is dissolved clearly, cooling to 10-15 ℃ in an ice water bath, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method five comprises the following steps: mixing the compound 1 and acetone according to the mass volume ratio of 1g (2-10) mL, heating, refluxing and pulping, then slowly cooling to 0-5 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method six: mixing the compound 1 and methanol according to the mass-volume ratio of 1g (2-10) mL, heating and stirring until the system is clear, then slowly cooling to 0-5 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method comprises the following steps: mixing the compound 1 with water according to a mass-volume ratio of 1g (2-10) mL, heating, stirring and heating to a clear solution (for example, heating to 60 ℃), naturally cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method eight: mixing the compound 1 and tetrahydrofuran according to a mass-volume ratio of 1g (2-10) mL, heating, stirring and heating to a clear solution (for example, heating to 60 ℃), naturally cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method comprises the following steps: heating and stirring the compound 1, water and acetonitrile according to the mass volume ratio of 1g (0.3-0.8) mL (0.8-2) mL until the system is clear, then slowly cooling to 0-5 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method comprises the following steps: heating and stirring the compound 1, water and methanol according to the mass volume of 1g (0.3-0.8) mL (0.8-2) mL until the system is clear, then slowly cooling to 0-5 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method eleven comprises the following steps: mixing the compound 1 and tetrahydrofuran according to a mass volume ratio of 1g (2-10) mL, heating, stirring and heating until the system is clear, naturally cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method twelve: mixing the compound 1 and toluene according to a mass-volume ratio of 1g (2-10) mL, heating, stirring, refluxing, naturally cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method thirteen comprises the following steps: mixing the compound 1 and isopropanol according to a mass-volume ratio of 1g (2-10) mL, heating and stirring until the system is dissolved clearly (for example, heating to 70 ℃), naturally cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
the method is fourteen: mixing the compound 1 and isopropanol according to a mass-volume ratio of 1g (2-10) mL, heating and stirring until the system is clear, then slowly cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorphic substance;
fifteen methods: and (3) mixing the compound 1 and n-propanol according to a mass-volume ratio of 1g (2-10) mL, heating and stirring until the system is clear, then slowly cooling to 10-15 ℃, stirring, filtering, washing and drying to obtain the polymorph.
The invention also provides a pharmaceutical composition containing the polymorphic substance.
According to an embodiment of the present invention, the pharmaceutical composition may further comprise at least one pharmaceutically acceptable excipient.
According to an embodiment of the present invention, the pharmaceutical composition may be a formulation known in the art. Such as oral preparations, capsules, troches, injections, etc.
The invention also provides the application of the polymorphic substance or the pharmaceutical composition in preparing the antiviral drugs. For example, the antiviral drug may be selected from a coronavirus and/or a Murine Hepatitis Virus (MHV), for example the coronavirus may be selected from severe acute respiratory syndrome coronavirus (SARS-COV), middle east respiratory syndrome coronavirus (MERS-COV) and/or a novel coronavirus (2019-nCoV).
Advantageous effects
The crystal form provided by the invention has high purity, good stability and storage resistance, and can be used in accelerated experiments, high temperature (such as 50 +/-2 ℃, 60 +/-2 ℃, 70 +/-2 ℃), high humidity (such as 70 +/-5% RH, 80 +/-5% RH and 90 +/-5% RH), illumination (such as total illumination intensity not less than 1.0 multiplied by 10)6Lux hr), the crystal transformation is not easy to occur, and the content change of impurities (single impurities and/or total impurities) is small, even basically has no obvious change. Is beneficial to further improving the stability and safety, reducing side effects, increasing the bioavailability and the like in the preparation process.
The preparation method of the crystal form has low cost, simple operation and easy control of reaction conditions, and can stably obtain the target crystal form.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of form I;
figure 2 is a DSC profile of form I;
figure 3 is a TGA profile of form I;
FIG. 4 is a powder X-ray diffraction pattern of form II;
figure 5 is a DSC profile of form II;
figure 6 is a TGA profile of form II;
FIG. 7 is a powder X-ray diffraction pattern of form III;
FIG. 8 is a DSC spectrum of form III;
figure 9 is a TGA profile of crystalline form III.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
The powder X-ray diffraction scan range is 4.0-50.0 deg., 0.01/1s, Cu (40kV,100 mA).
Example 1
Weighing 5g of crude EIDD-2081 product into a reaction bottle, adding 25mL of ethyl acetate, heating and stirring, heating to reflux, refluxing for 3 hours, slowly cooling to 10-15 ℃, filtering, and leaching with a small amount of ethyl acetate. Scraping, and drying in a 45 ℃ blast oven for 24h to obtain the product. The product yield is 95%.
And identifying the product of the example to obtain the crystal form I.
Example 2
Weighing 5g of EIDD-2081 crude product into a reaction bottle, adding 25mL of absolute ethyl alcohol and 2.5mL of water, heating and stirring to raise the temperature to 70 ℃, dissolving the solid to be clear, slowly cooling to 10-15 ℃, stirring for 0.5h, filtering, and leaching with a small amount of ethanol. Scraping, and drying in a 50 ℃ forced air oven for 24h to obtain the product. The product yield is 75%.
And identifying the product of the example to obtain the crystal form I.
Example 3
Weighing 5g of EIDD-2081 crude product into a reaction bottle, adding 25mL of absolute ethyl alcohol, heating and stirring to raise the temperature to 70 ℃, dissolving the solid clearly, cooling to 10-15 ℃ in ice water bath, stirring for 0.5h, filtering, and leaching with a small amount of glacial ethyl alcohol. Scraping, and drying in a 50 ℃ forced air oven for 24h to obtain the product. The product yield was 78%.
And identifying the product of the example to obtain the crystal form I.
Example 4
Weighing 5g of EIDD-2081 crude product, adding into a reaction bottle, adding 30ml of acetone, heating, refluxing and pulping for 2h, slowly cooling to 0-5 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of acetone, and drying in a drying oven (T ═ 50 ℃) to obtain 3.52g of white solid. The product yield was 70.4%.
And identifying the product of the example to obtain the crystal form I.
Example 5
Weighing 5g of EIDD-2081 crude product, adding into a reaction bottle, adding 2.5ml of water and 5ml of acetonitrile, heating, dissolving, stirring for 2h, slowly cooling to 0-5 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of acetonitrile, and drying in a drying oven (T ═ 50 ℃) to obtain 2.23g of white solid. The product yield was 44.6%.
And identifying the product of the example to obtain the crystal form I.
Example 6
Weighing 5g of EIDD-2081 crude product, adding 20mL of tetrahydrofuran into a reaction bottle, heating and stirring to raise the temperature to 60 ℃, dissolving the solid to be clear, naturally cooling to 10-15 ℃, stirring for 1h, filtering, leaching a small amount of tetrahydrofuran with ice, scraping, and drying in a 50 ℃ blast oven for 24h to obtain the crystal form II. The yield thereof was found to be 60%.
Example 7
Weighing 5g of EIDD-2081 crude product, adding into a reaction bottle, adding 25ml of ethanol, heating to dissolve, stirring for 2h, slowly cooling under heat preservation condition, separating out solid when the temperature is reduced to 60 ℃, preserving heat for 0.5h at the temperature, and continuously and slowly cooling. Cooling to 5 ℃ every half hour, cooling to 35 ℃, cooling with ice water, continuously cooling to 10-15 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of ethanol, and drying in a drying oven (T is 50 ℃).
Example 8
The polymorph of EIDD-2081 can also be obtained by any of the following methods of preparation.
Weighing 5g of EIDD-2081 crude product into a reaction bottle, adding 20mL of ethyl acetate, heating and stirring, heating to reflux, refluxing for 0.5h, cooling to 50-55 ℃, dropwise adding 20mL of methyl tert-butyl ether, and finishing dropping within 2 min. And continuously cooling to 10-15 ℃, stirring for 0.5h, filtering, and leaching with a small amount of glacial methyl tert-butyl ether. Scraping out, and drying in a forced air oven at 45 ℃ for 24h to obtain the product yield of 95%.
Or weighing 5g of crude EIDD-2081, adding the crude EIDD-2081 into a reaction bottle, adding 10ml of methanol, heating, dissolving, stirring for 2h, slowly cooling to 0-5 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of methanol, and drying in a drying oven (T ═ 50 ℃) to obtain 2.53g of white solid, wherein the yield is 50.6%.
Or weighing 5g of EIDD-2081 crude product, adding 10mL of water into a reaction bottle, heating and stirring to raise the temperature to 60 ℃, dissolving the solid to be clear, naturally cooling to 10-15 ℃, stirring for 1h, filtering, scraping, and drying in a 50 ℃ forced air oven for 24 h. The yield thereof was found to be 76%.
Or weighing 5g of crude EIDD-2081, adding the crude EIDD-2081 into a reaction bottle, adding 2.5ml of water and 5ml of methanol, heating, dissolving, stirring for 2 hours, slowly cooling to 0-5 ℃, stirring for 1 hour, filtering, washing a filter cake with a small amount of methanol, and drying in a drying oven (T ═ 50 ℃) to obtain 2.17g of white solid with the yield of 43.4%.
Or weighing 5g of crude EIDD-2081 product, adding 50mL of butyl acetate into a reaction bottle, heating, stirring, heating to reflux for 1h, naturally cooling to 10-15 ℃, stirring for 1h, filtering, leaching a small amount of butyl glacial acetate, scraping, and drying in a 50 ℃ blast oven for 24 h. The yield thereof was found to be 65%.
Or weighing 5g of crude EIDD-2081 product, adding 50mL of toluene into a reaction bottle, heating, stirring, heating to reflux for 1h, naturally cooling to 10-15 ℃, stirring for 1h, filtering, leaching with a small amount of toluene ice, scraping, and drying in a 50 ℃ blast oven for 24 h. The yield thereof was found to be 70%.
Or weighing 5g of EIDD-2081 crude product into a reaction bottle, adding 50mL of isopropanol, heating and stirring to raise the temperature to 70 ℃, dissolving the solid to be clear, naturally cooling to 10-15 ℃, stirring for 1h, filtering, leaching with a small amount of ice isopropanol, scraping, and drying in a 50 ℃ blast oven for 24h, wherein the yield is 71%.
Or weighing 5g of EIDD-2081 crude product into a reaction bottle, adding 50mL of n-propanol, heating and stirring to raise the temperature to 70 ℃, dissolving the solid to be clear, naturally cooling to 10-15 ℃, stirring for 1h, filtering, leaching with a small amount of ice n-propanol, scraping, and drying in a 50 ℃ blast oven for 24h with the yield of 65%.
Example 9 Crystal form identification test
The XRD spectrum of the crystal form I is shown in figure 1, and the spectrum analysis data is shown in table 1. The DSC spectrum and the TGA spectrum of the crystal form I are respectively shown as figure 2 and figure 3.
The XRD spectrum of the crystal form II is shown in figure 4, and the spectrum analysis data is shown in table 2. The DSC spectrum and the TGA spectrum of the crystal form II are respectively shown in figure 5 and figure 6.
The XRD spectrum of the crystal form III is shown in figure 7, and the spectrum analysis data is shown in Table 3. The DSC and TGA spectra of form III are shown in figures 8 and 9, respectively.
Table 1 XRPD analysis data for form I
Table 2 XRPD analysis data for form II
Table 3 XRPD analysis data for form III
Peak numbering | 2θ[°] | Relative strength% | Peak numbering | 2θ[°] | |
1 | 10.100 | 20.3 | 19 | 28.890 | 16.6 |
2 | 11.101 | 19.6 | 20 | 30.069 | 4.4 |
3 | 13.211 | 13.6 | 21 | 30.940 | 9.3 |
4 | 14.150 | 27.9 | 22 | 31.239 | 4.7 |
5 | 16.710 | 49.8 | 23 | 31.870 | 5.9 |
6 | 17.570 | 88.7 | 24 | 32.390 | 16.3 |
7 | 18.220 | 100.0 | 25 | 33.870 | 6.8 |
8 | 19.900 | 41.8 | 26 | 35.129 | 4.2 |
9 | 20.280 | 17.5 | 27 | 36.698 | 3.5 |
10 | 20.520 | 33.3 | 28 | 37.139 | 5.0 |
11 | 20.870 | 17.0 | 29 | 38.630 | 4.4 |
12 | 22.310 | 42.5 | 30 | 39.060 | 4.5 |
13 | 22.710 | 8.0 | 31 | 40.970 | 3.9 |
14 | 23.399 | 5.1 | 32 | 41.610 | 7.6 |
15 | 24.130 | 20.4 | 33 | 42.591 | 9.0 |
16 | 24.390 | 29.8 | 34 | 45.690 | 2.5 |
17 | 25.421 | 21.0 | 35 | 46.682 | 2.9 |
18 | 27.161 | 13.8 | 36 | 47.479 | 2.9 |
Testing of Crystal Properties
Through experimental tests, the crystal form of the invention has high purity and low impurity content; has good stability and storage stability, and can be used in accelerated test (such as accelerated test for 1 month, 2 months, 3 months, 6 months), high temperature (such as 50 + -2 deg.C, 60 + -2 deg.C, 70 + -2 deg.C), high humidity (such as humidity 70 + -5% RH, 80 + -5% RH, 90 + -5% RH), and illumination (such as total illuminance of not less than 1.0 × 10)6Lux hr), crystal transformation is not easy to occur, the content change of impurities (single impurities and/or total impurities) is small, even no obvious change is generated basically.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
2. the polymorph according to claim 1, characterized in that it is form I having characteristic peaks at 6.45 ± 0.20 °, 12.99 ± 0.20 °, 16.30 ± 0.20 °, 16.95 ± 0.20 °, 17.19 ± 0.20 °, 21.21 ± 0.20 ° by X-ray powder diffraction, expressed in terms of 2 Θ angles, using Cu-ka radiation.
Preferably, the crystal form I has characteristic peaks at 6.45 +/-0.20 degrees, 12.99 +/-0.20 degrees, 16.30 +/-0.20 degrees, 16.95 +/-0.20 degrees, 17.19 +/-0.20 degrees, 21.21 +/-0.20 degrees, 27.96 +/-0.20 degrees and 28.39 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.
Also preferably, the crystal form I has characteristic peaks at 6.45 + -0.20 °, 12.99 + -0.20 °, 16.30 + -0.20 °, 16.95 + -0.20 °, 17.19 + -0.20 °, 19.60 + -0.20 °, 20.53 + -0.20 °, 21.21 + -0.20 °, 27.96 + -0.20 °, 28.39 + -0.20 °, 33.94 + -0.20 ° by X-ray powder diffraction at 2 θ using Cu-Kalpha radiation.
More preferably, the crystal form I has characteristic peaks at 6.48 + -0.20 °, 12.99 + -0.20 °, 16.30 + -0.20 °, 16.95 + -0.20 °, 17.19 + -0.20 °, 18.03 + -0.20 °, 19.35 + -0.20 °, 19.60 + -0.20 °, 20.31 + -0.20 °, 20.53 + -0.20 °, 21.21 + -0.20 °, 27.96 + -0.20 °, 28.39 + -0.20 °, 28.92 + -0.20 °, 31.58 + -0.20 °, 33.94 + -0.20 ° by X-ray powder diffraction at 2 θ using Cu-Kalpha radiation.
3. The polymorph of claim 2, wherein form I has a powder X-ray diffraction pattern substantially as shown in figure 1.
Preferably, said form I has a DSC profile substantially as shown in figure 2.
Preferably, the crystalline form I has a TGA profile substantially as shown in figure 3.
4. The polymorph according to claim 1, characterized in that it is form II having characteristic peaks at 3.20 ± 0.20 °, 16.94 ± 0.20 °, 17.98 ± 0.20 °, 20.50 ± 0.20 °, 21.24 ± 0.20 °, 27.94 ± 0.20 ° by X-ray powder diffraction, expressed in terms of 2 Θ angles, using Cu-ka radiation.
Preferably, the crystal form II has characteristic peaks at 3.20 +/-0.20 °, 6.44 +/-0.20 °, 16.94 +/-0.20 °, 17.98 +/-0.20 °, 20.50 +/-0.20 °, 20.28 +/-0.20 °, 21.24 +/-0.20 ° and 27.94 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.
More preferably, the crystal form II has characteristic peaks at 3.20 +/-0.20 °, 6.44 +/-0.20 °, 16.94 +/-0.20 °, 17.98 +/-0.20 °, 19.36 +/-0.20 °, 20.50 +/-0.20 °, 20.28 +/-0.20 °, 21.24 +/-0.20 °, 27.94 +/-0.20 ° and 28.36 +/-0.20 ° by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.
5. The polymorph of claim 4, wherein the form II has a powder X-ray diffraction pattern substantially as shown in figure 4.
Preferably, said crystalline form II has a DSC profile substantially as shown in figure 5.
Preferably, the crystalline form II has a TGA profile substantially as shown in figure 6.
6. The polymorph according to claim 1, characterized in that it is form III having characteristic peaks in X-ray powder diffraction at 16.71 ± 0.20 °, 17.57 ± 0.20 °, 18.22 ± 0.20 °, 19.90 ± 0.20 °, 22.31 ± 0.20 ° in degrees 2 Θ using Cu-ka radiation.
Preferably, the crystal form III has characteristic peaks at 14.15 +/-0.20 degrees, 16.71 +/-0.20 degrees, 17.57 +/-0.20 degrees, 18.22 +/-0.20 degrees, 19.90 +/-0.20 degrees, 20.52 +/-0.20 degrees, 22.31 +/-0.20 degrees and 24.39 +/-0.20 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.
More preferably, the crystal form III has characteristic peaks at 10.10 +/-0.20 DEG 11.10 +/-0.20 DEG, 14.15 +/-0.20 DEG, 16.71 +/-0.20 DEG, 17.57 +/-0.20 DEG, 18.22 +/-0.20 DEG, 19.90 +/-0.20 DEG, 20.52 +/-0.20 DEG, 22.31 +/-0.20 DEG, 24.13 +/-0.20 DEG, 24.39 +/-0.20 DEG and 25.42 +/-0.20 DEG by X-ray powder diffraction expressed by 2 theta angle by using Cu-Kalpha radiation.
7. The polymorph of claim 6, wherein the form III has a powder X-ray diffraction pattern substantially as shown in figure 7.
Preferably, said form III has a DSC profile substantially as shown in figure 8.
Preferably, the crystalline form III has a TGA profile substantially as shown in figure 9.
8. A process for the preparation of the polymorph of compound 1 according to any one of claims 1 to 7, which comprises mixing said compound 1 with a solvent and preparing said polymorph by recrystallization;
the solvent is selected from organic solvents and/or water.
Preferably, the organic solvent is selected from one, two or more of methanol, ethanol, isopropanol, acetone, acetonitrile, toluene, ethyl acetate, butyl acetate, methyl t-butyl ether, tetrahydrofuran, and the like.
Preferably, the solvent may be selected from methanol, ethanol, isopropanol, acetone, acetonitrile, toluene, ethyl acetate, butyl acetate, tetrahydrofuran, a mixed solvent of ethyl acetate and methyl t-butyl ether, a mixed solvent of ethanol and water, or a mixed solvent of acetonitrile and water.
Preferably, the preparation method comprises: and mixing the compound 1 with a solvent, heating and stirring until the system is clear, cooling, washing and drying to obtain the polymorphic substance.
9. A pharmaceutical composition comprising the polymorph of any one of claims 1 to 7.
Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
Preferably, the pharmaceutical composition is a formulation known in the art, such as an oral agent, a capsule, a lozenge, an injection, and the like.
10. Use of the polymorph of any one of claims 1 to 7 or the pharmaceutical composition of claim 9 in the manufacture of a medicament for the treatment of an antiviral.
Preferably, the antiviral drug is selected from a coronavirus and/or a Murine Hepatitis Virus (MHV), for example the coronavirus may be selected from severe acute respiratory syndrome coronavirus (SARS-COV), middle east respiratory syndrome coronavirus (MERS-COV) and/or a novel coronavirus (2019-nCoV).
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