CN111961064A - Novel crystal form of Barosavir ester and preparation method and application thereof - Google Patents
Novel crystal form of Barosavir ester and preparation method and application thereof Download PDFInfo
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- CN111961064A CN111961064A CN202010865540.1A CN202010865540A CN111961064A CN 111961064 A CN111961064 A CN 111961064A CN 202010865540 A CN202010865540 A CN 202010865540A CN 111961064 A CN111961064 A CN 111961064A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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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
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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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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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
Abstract
The invention belongs to the field of medicines, and particularly relates to a new crystal form of baroxavir ester, and a preparation method and application thereof. The crystal form provided by the invention is easy to prepare, can be stored for a long time under accelerated experiment, high temperature, high humidity and illumination conditions, and has better stability and storage resistance. The nuclear magnetic resonance hydrogen spectrum determination result shows that the crystal form prepared by the invention has high purity and low impurity content. The preparation method of the crystal form has the advantages of low cost, simple operation, mild reaction conditions, easy control and good reproducibility, and can stably obtain the target product crystal form.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a new crystal form of baroxavir ester, and a preparation method and application thereof.
Background
Chemical name of baroxavir ester: ({ (12aR) -12- [ (11S) -7, 8-difluoro-6, 11-dihydrodibenzothiaheptin-11-yl)]-6, 8-dioxo-3, 4,6,8,12,12 a-hexahydro-1H- [1,4]Benzoxazine [3,4-c ]]Pyrido [2,1-f][1,2,4]Triazin-7-yl } oxy) methyl methylcarbonate of formula: c27H23F2N3O7And S. The structure is as follows:
baroswarriol is an innovative CAP-dependent endonuclease inhibitor and is a small number of new drugs which can inhibit the proliferation of influenza viruses in the world. The Baroswarriol can inhibit the Baroswarriol from obtaining a CAP structure at the 5' end of host mRNA from a host cell aiming at the key link of the replication of the influenza virus, thereby inhibiting the transcription of the self mRNA of the influenza virus. Since there is no protease with a similar mechanism in the host cell, this drug theoretically has no effect on the host cell.
There are many factors affecting the crystal form of a drug, and for example, different crystal forms can be obtained by changing the types of solvents, temperature, illumination and the like. Due to the difference of lattice structures, the physical properties of different crystal forms of the same medicament are obviously different, so that the safety and the effectiveness of the medicament are influenced.
The inventor discovers that the compound exists in a new stable crystal form through researching the crystal form of the baroxavir and the baroxavir ester.
Disclosure of Invention
The invention aims to provide a novel crystal form of baroxavir ester, which is an alpha crystal form.
It is another object of the present invention to provide a process for preparing the above-mentioned alpha crystalline form.
It is a further object of the present invention to provide the use of the above-mentioned alpha crystalline form.
The purpose of the invention is realized by the following technical scheme.
An alpha crystal form of Baroswarriol ester has characteristic peaks at 8.77 +/-0.2 degrees, 10.81 +/-0.2 degrees, 24.12 +/-0.2 degrees, 26.48 +/-0.2 degrees and 29.73 +/-0.2 degrees by X-ray powder diffraction expressed by 2 theta angles by using Cu-Kalpha radiation.
Preferably, the crystalline form further has characteristic peaks at 14.20 ± 0.2 °, 20.20 ± 0.2 °, 21.69 ± 0.2 ° by X-ray powder diffraction expressed in terms of 2 θ angle using Cu-K α radiation.
Preferably, the crystalline form further has characteristic peaks at 16.18 ± 0.2 ° and 17.52 ± 0.2 ° in X-ray powder diffraction expressed in terms of 2 θ angle using Cu-K α radiation.
Also preferably, the crystalline form is irradiated with Cu-Ka, the X-ray powder diffraction expressed by the angle of 2 theta also has the characteristic +/-0.1 degrees, 13.14 +/-0.1 degrees, 13.53 +/-0.1 degrees, 13.86 +/-0.1 degrees, 15.75 +/-0.1 degrees, 16.42 +/-0.1 degrees, 18.59 +/-0.1 degrees, 18.86 +/-0.1 degrees, 19.31 +/-0.1 degrees, 20.78 +/-0.1 degrees, 21.95 +/-0.1 degrees, 22.22 +/-0.1 degrees, 23.00 +/-0.1 degrees, 23.89 +/-0.1 degrees, 25.68 +/-0.1 degrees, 27.24 +/-0.1 degrees, 27.59 +/-0.1 degrees, 28.32 +/-0.1 degrees, 28.59 +/-0.1 degrees, 30.22 +/-0.1 degrees, 31.39 +/-0.1 degrees, 32.56 +/-0.1 degree, 32.96 +/-0.1 degrees, 33.25 +/-0.1 degrees, 7 +/-0.1 degree, 34.82 +/-0.1 degree, 350.1 +/-0.1.1 degree, 11 +/-0.1.1 degree, 1 +/-0.1.1 degree, 21 +/-0.26 degrees, 11 +/-0.1.1.1 degree, 11 +/-0.1.1.1 +/-0.1 degree, 21 +/-0.1 degree, 11 +/-0.1.1.1 degree, 11 +/-0.1 degree, 11 +/-0.1.1.1.1.1 degree, 19 +/-0.1 degree, 11 +/-0.1.1.1.1 degree, 19 +/-0.1 degree, 11 +/-0.1 degree, 19 +/-0.1.1.1.1.
Most preferably, the crystalline form has an X-ray powder diffraction pattern substantially as shown in figure 1.
According to the invention, the DSC endotherm of said crystalline form is 227.9 ℃.
Preferably, the crystalline form has a DSC profile substantially as shown in figure 2.
The invention also provides a preparation method of the alpha crystal form, which comprises the following steps: adding the amorphous baroxavir ester into dimethyl sulfoxide, and stirring for dissolving; adding a mixed solution of dimethyl sulfoxide and water, and stirring to obtain the product.
According to the embodiment of the invention, the mass volume ratio of the amorphous baroxavir ester to the dimethyl sulfoxide is 1 g: (1-7) ml, for example 1 g: 4 ml.
According to an embodiment of the present invention, the volume ratio of dimethyl sulfoxide to water in the mixed solution is 3: (3-7).
According to an embodiment of the invention, the temperature of the stirring is 25 ± 5 ℃.
According to the embodiment of the invention, the method also comprises the step of cooling to 0-5 ℃ after stirring, and pulping and washing by using water.
The invention also provides a pharmaceutical composition comprising the alpha crystalline form as described above.
According to an embodiment of the invention, the pharmaceutical composition has an antiviral effect.
According to an embodiment of the invention, the pharmaceutical composition has cap-dependent endonuclease inhibition.
According to an embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient. The adjuvant is an inert, non-toxic excipient, carrier or diluent, for example, the adjuvant is selected from one, two or more of the following: disintegrating agent, glidant, lubricant, filler, binder, colorant, effervescent agent, flavoring agent, preservative, coating material.
According to an embodiment of the present invention, the pharmaceutical composition is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, lemon, spirit, aromatic water, extract, decoction or tincture.
According to an embodiment of the invention, the pharmaceutical composition is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a buccal tablet, a sublingual tablet, a buccal tablet, a chewable tablet, an orally disintegrating tablet, a dry syrup, a soft capsule, a microcapsule or a sustained-release capsule.
According to an embodiment of the invention, the pharmaceutical composition is for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.
According to an embodiment of the present invention, the pharmaceutical composition is an injection, a drip, an eye drop, a nose drop, an ear drop, an aerosol, an inhalant, a lotion, an injectant, a coating, a gargle, an enema, an ointment, a plaster, a gel, a cream, a patch, a paste, a powder for external use, or a suppository.
The present invention also provides the use of the alpha crystalline form as described above for the manufacture of a therapeutic or prophylactic agent for a disease caused by a virus having a cap-dependent endonuclease, or an antiviral drug.
The present invention also provides a method for treating or preventing a disease caused by a virus having a cap-dependent endonuclease, comprising administering the alpha crystalline form as described above or the pharmaceutical composition to a subject in need thereof.
Advantageous effects
The crystal form provided by the invention is easy to prepare, can be stored for a long time under accelerated experiment, high temperature, high humidity and illumination conditions, and has better stability and storage resistance. The nuclear magnetic resonance hydrogen spectrum determination result shows that the crystal form prepared by the invention has high purity and low impurity content. The preparation method of the crystal form has the advantages of low cost, simple operation, mild reaction conditions, easy control and good reproducibility, and can stably obtain the target product crystal form.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of the alpha crystalline form.
Fig. 2 is a differential scanning thermogram (DSC chart) of the α crystal form.
FIG. 3 is an infrared diffraction spectrum of the alpha crystal form.
Fig. 4 is a raman spectrum of the alpha crystal form.
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the alpha crystal form.
FIG. 6 is a high resolution mass spectrum of the alpha crystal form.
Fig. 7 is an X-ray powder diffraction pattern of the form α after standing for 2 months.
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 X-ray powder diffraction is at Mini XRD: (*Detection completed on Mini Flex 600).
Preparation example 1
Taking a 250mL reaction bottle, sequentially adding 12.00g of baloxavir, 6.86g of potassium carbonate, 4.12g of potassium iodide and 60mL of dimethylacetamide, adding 5.87g of chloromethyl methyl carbonate under stirring, heating in an oil bath, raising the temperature to 50 ℃, preserving the temperature for 3 hours, and transferring to a low-temperature constant-temperature water bath to reduce the temperature to 0 ℃. 58g of hydrochloric acid with the concentration of 1mol/L and 50mL of purified water are added, and a white loose flocculent solid is obtained by suction filtration.
Example 1
The preparation process of the alpha crystal form of the baroxavir disoproxil comprises the following steps: adding 10g of the white loose flocculent baloxavir ester synthesized in the preparation example 1 into 40.0ml of dimethyl sulfoxide, and stirring and dissolving at 25 +/-5 ℃; controlling the temperature of the feed liquid to be 25 +/-5 ℃, dropwise adding a mixed solution of 30ml of dimethyl sulfoxide and 50ml of purified water for about 15min, then slowly cooling, controlling the temperature of the feed liquid to be 0-5 ℃, and stirring for 1 h; suction filtering, pulping and washing a filter cake with 15ml of purified water for three times; and (3) drying the wet product at 40 +/-5 ℃ by blowing until the weight is constant to obtain the new crystal form of the baroxavir disoproxil.
The X-ray powder diffraction pattern is shown in FIG. 1.
The differential scanning thermogram (DSC) is shown in figure 2, and as can be seen from figure 2, the initial melting point of the crystal form is 226.4396 ℃, and an endothermic peak is present at 227.9424 ℃, which shows that the sample has a specific melting point and is a crystalline compound. In addition, a DSC test spectrum can confirm that the crystal form sample does not contain a solvent.
The infrared diffraction spectrum is shown in figure 3.
The Raman spectrum is shown in FIG. 4.
The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 5. Specific nuclear magnetic data are as follows:1H NMR(600MHz,DMSO):7.41(t,J＝4.9Hz,2H),7.23(d,J＝7.8Hz,1H),7.15(t,J＝7.6Hz,1H),7.09(d,J＝7.9Hz,1H),7.01(d,J＝7.7Hz,1H),6.85(t,J＝7.4Hz,1H),5.74(dd,J＝7.2,2.8Hz,3H),5.67(d,J＝6.6Hz,1H),5.42(d,J＝14.9Hz,1H),4.45(dd,J＝9.9,2.9Hz,1H),4.40(d,J＝11.9Hz,1H),4.06(d,J＝14.4Hz,1H),4.00(dd,J＝10.8,2.8Hz,1H),3.73(s,3H),3.69(dd,J＝11.5,3.0Hz,1H),3.45(t,J＝10.4Hz,1H),3.29(td,J＝11.6,2.3Hz,1H),2.98–2.91(m,1H).
the high resolution mass spectrum is shown in figure 6. The detection result is as follows: HRMS (ESI) m/z calcd for C27H23F2N3O7S[M+H]+572.1303,found 572.1329。
The influence factor test is carried out on the crystal form alpha of the baroxavir disoproxil, and the test result is shown in the table.
TABLE 1
TABLE 2
The experimental results in table 2 prove that the crystal form of the active ingredient baclovir ester alpha has good stability and storage stability under different experimental conditions, is a stable crystal form and has great application value.
In addition, the α crystal form was also subjected to powder diffraction characterization after being left for 2 months at normal temperature and pressure (fig. 7). As can be seen from FIG. 7, the crystal form is unchanged and has good stability.
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)
1. An alpha crystal form of baroxavir disoproxil, characterized in that, using Cu-Kalpha radiation, X-ray powder diffraction expressed by 2 theta angle has characteristic peaks at 8.77 + -0.2 degrees, 10.81 + -0.2 degrees, 24.12 + -0.2 degrees, 26.48 + -0.2 degrees, 29.73 + -0.2 degrees.
2. The crystalline form α according to claim 1, characterized in that it further has characteristic peaks, expressed in terms of 2 Θ angles, by X-ray powder diffraction using Cu-ka radiation, at 14.20 ± 0.2 °, 20.20 ± 0.2 °, 21.69 ± 0.2 °;
preferably, the alpha crystal form further has characteristic peaks at 16.18 ± 0.2 ° and 17.52 ± 0.2 ° by X-ray powder diffraction expressed in terms of 2 θ using Cu-K alpha radiation.
3. The alpha crystalline form according to claim 2, characterized in that it uses Cu-ka radiation, the X-ray powder diffraction, expressed in 2 Θ angles, is also at 9.86 ± 0.1 °, 13.14 ± 0.1 °, 13.53 ± 0.1 °, 13.86 ± 0.1 °, 15.75 ± 0.1 °, 16.42 ± 0.1 °, 18.59 ± 0.1 °, 18.86 ± 0.1 °, 19.31 ± 0.1 °, 20.78 ± 0.1 °, 21.95 ± 0.1 °, 22.22 ± 0.1 °, 23.00 ± 0.1 °, 23.89 ± 0.1 °, 25.68 ± 0.1 °, 27.24 ± 0.1 °, 27.59 ± 0.1 °, 28.32 ± 0.1 °, 28.59 ± 0.1 °, 30.22 ± 0.1, 31.39 ± 0.1 °, 4830.1 °, 32.56 ± 0.1 °, 32.96 ± 0.1 °, 33 ± 0.1 °, 28.1 °, 28 ± 0.32 ± 0.1 °, 3 ± 0.38 ± 0.1 °, 3 ± 0.38 °, 3 ± 0.1 °, 3 ± 0.1 °, 3 ± 0.1 °, 3 ± 0.1, The peak has characteristic peaks at 46.76 +/-0.1 degrees, 47.45 +/-0.1 degrees and 48.66 +/-0.1 degrees.
4. The crystalline form α of any one of claims 1-3, having an X-ray powder diffraction pattern substantially as shown in figure 1.
5. The form α of claim 4, characterized by a DSC endotherm of 227.9424 ℃.
6. A process for preparing the alpha crystalline form of any one of claims 1 to 5, comprising the steps of: adding the amorphous baroxavir ester into dimethyl sulfoxide, and stirring for dissolving; adding a mixed solution of dimethyl sulfoxide and water, and stirring to obtain the product.
7. A pharmaceutical composition comprising the alpha crystalline form of any one of claims 1-5.
8. Pharmaceutical composition according to claim 7, characterized in that it has an antiviral action.
9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition has cap-dependent endonuclease inhibition;
preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient;
preferably, the adjuvant is an inert, non-toxic excipient, carrier or diluent;
preferably, the adjuvant is selected from one, two or more of the following: disintegrating agent, glidant, lubricant, filler, binder, colorant, effervescent agent, flavoring agent, preservative, coating material.
10. Use of the alpha crystalline form of any one of claims 1-5 for the manufacture of a therapeutic or prophylactic agent for a disease caused by a virus having a cap-dependent endonuclease, or an antiviral medicament.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110494141A (en) * | 2016-08-10 | 2019-11-22 | 盐野义制药株式会社 | Pharmaceutical composition containing substituted polycyclic Pyridione derivatives and its prodrug |
| CN111377944A (en) * | 2018-12-25 | 2020-07-07 | 广东东阳光药业有限公司 | Baloxavir marboxil crystal form and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110494141A (en) * | 2016-08-10 | 2019-11-22 | 盐野义制药株式会社 | Pharmaceutical composition containing substituted polycyclic Pyridione derivatives and its prodrug |
| CN111377944A (en) * | 2018-12-25 | 2020-07-07 | 广东东阳光药业有限公司 | Baloxavir marboxil crystal form and preparation method thereof |
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