CN115093453A - Crystalline form I of zifu pyridine and preparation method thereof - Google Patents
Crystalline form I of zifu pyridine and preparation method thereof Download PDFInfo
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- CN115093453A CN115093453A CN202210912706.XA CN202210912706A CN115093453A CN 115093453 A CN115093453 A CN 115093453A CN 202210912706 A CN202210912706 A CN 202210912706A CN 115093453 A CN115093453 A CN 115093453A
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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
- C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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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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Abstract
The invention discloses a crystal form I of azifodine, wherein an X-ray powder diffraction pattern has diffraction peaks at positions of 2 theta =15.6, 16.0, 16.3, 16.8, 18.8, 25.4 and 30.7, wherein the error range of the 2 theta value is +/-0.2; adding the crystalline form I of the zilfuridine into a single solvent or a plurality of mixed solvents, heating and refluxing, adding seed crystals, cooling, stirring, filtering, collecting crystals, and drying to obtain the crystalline form I product of the zilfuridine. The crystal form I of the zifu pyridine has higher stability than the existing crystal forms of the zifu pyridine on the market, and is beneficial to the processing of medicaments and the use in pharmaceutical compositions.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel crystal form of azifodine and a preparation method thereof.
Background
Azifodine is a known compound with the chemical name 4-amino-1- (4-C-azido-2-deoxy-2-fluoro-BETA-D-arabinofuranosyl) -2(1H) -pyrimidinone and the structural formula is as follows:
the ziefovir is a HIV reverse transcriptase inhibitor, can effectively inhibit the reverse transcription and replication of HIV in vivo, and is a new anti-AIDS drug variety with independent intellectual property rights in China.
The crystal form of the medicine has a direct relation with the quality and the curative effect of the medicine, and for AIDS-resistant medicines, different crystal forms of the Alzifuding have certain difference in the aspect of physicochemical property, and the difference necessarily influences the curative effect and the toxic and side effect of the medicine.
Disclosure of Invention
One of the purposes of the invention is to provide a crystal form I of the ziffidine, so as to solve the problem that the stability of the existing crystal form of the ziffidine is required to be improved to influence the bioavailability.
The technical scheme adopted by the invention for solving the technical problems is as follows: crystalline form i of azifodine having an X-ray powder diffraction pattern with diffraction peaks at 2 Θ =15.6, 16.0, 16.3, 16.8, 18.8, 25.4, 30.7, wherein the 2 Θ value error range is ± 0.2.
The invention also aims to provide a preparation method of the crystalline form I of the zifu pyridine, which comprises the following steps: sequentially adding 20-50 g of crude azifodine and 160-200 mL of single solvent or multiple mixed solvents into a 500-1000 mL three-mouth reaction bottle, heating and refluxing, adding crystal form I seed crystal, slowly cooling to 20-30 ℃, stirring for 2 hours, filtering, and drying a filter cake to obtain 14-38 g of white solid azifodine crystal form I product.
Further, the solvent is one or a mixture of water, methanol, ethanol, isopropanol, acetonitrile, 1, 4-dioxane and ethyl acetate.
Furthermore, the heating is carried out in an oil bath to 60-80 ℃, the mixture is stirred for half an hour, and then the temperature is reduced to 60-65 ℃.
The invention has the beneficial effects that: the crystal form I of the zifu pyridine has higher stability than the existing crystal forms of the zifu pyridine on the market, is beneficial to the processing of the medicine and the use in a pharmaceutical composition, can keep the solubility constant, improves the bioavailability, has better effect on the subsequent preparation of injection, and has important significance for further researching the curative effect of the medicine.
Drawings
Figure 1 is a powder diffraction pattern of crystalline form i of acyclovir.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The inventor conducts experimental research on the crystal form of the zifu pyridine to obtain a stable zifu pyridine crystal form, namely the crystal form I. The X-ray powder diffraction pattern has characteristic peaks at 2 theta =15.6, 16.0, 16.3, 16.8, 18.8, 25.4 and 30.7, wherein the error range of the 2 theta value is +/-0.2.
The X-ray powder diffraction spectrum of the crystalline form I of the invention is shown in figure 1.
Example 2
The preparation method of crystalline form i of azifodine of this example comprises the following steps:
sequentially adding 20g of crude product of the ziefovir dipivoxil and 200mL of purified water into a 500mL three-port reaction bottle, heating to 70-80 ℃ in an oil bath, stirring for half an hour, cooling to about 65 ℃, adding crystal form I seed crystal, slowly cooling to 20-30 ℃, stirring for 2 hours, and filtering. The filter cake was dried to give 14g of crystalline form i product of zifu, yield 70%, as a white solid.
Example 3
The preparation method of crystalline form i of azifodine of this example comprises the following steps:
adding 50g of crude azifodine and 200mL of 1, 4-dioxane into a 1000mL three-mouth reaction bottle in sequence, heating to 70-80 ℃ in an oil bath, stirring for half an hour, cooling to about 60 ℃, adding crystal form I seed crystal, slowly cooling to 20-30 ℃, stirring for 2 hours, and filtering. The filter cake was dried to yield 38g of crystalline form i product of ziefovir, 76% yield, white solid.
Example 4
The preparation method of crystalline form i of azifodine of this example comprises the following steps:
and sequentially adding 20g of crude azifodine, 60mL of methanol and 100mL of water into a 500mL three-mouth reaction bottle, heating to 60-70 ℃ in an oil bath, stirring for half an hour, adding crystal seeds of the crystal form I, slowly cooling to 20-30 ℃, stirring for 2 hours, and filtering. The filter cake was dried to obtain 12g of crystalline form i product of zifu pyridine, yield 60%, white solid.
Example 5
The preparation method of crystalline form i of azidime of this example is different in that the solvent is one or a mixture of ethanol, isopropanol, acetonitrile and ethyl acetate.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (4)
1. Crystalline form i of azifodine characterized in that: the X-ray powder diffraction pattern has diffraction peaks at 2 theta =15.6, 16.0, 16.3, 16.8, 18.8, 25.4, 30.7, wherein the error range of the 2 theta value is +/-0.2.
2. A process for the preparation of crystalline form i of aliskirine according to claim 1, which comprises the steps of: sequentially adding an crude product of the crystalline form I and a solvent into a three-mouth reaction bottle, heating and refluxing, adding crystal seeds of the crystalline form I, slowly cooling to 20-30 ℃, stirring for 2 hours, filtering, and drying a filter cake to obtain a product of the crystalline form I of the crystalline form I of the crystalline form of the.
3. The process for preparing crystalline form i of azidime as claimed in claim 2, wherein said solvent is one or more of water, methanol, ethanol, isopropanol, acetonitrile, 1, 4-dioxane, ethyl acetate.
4. The preparation method of crystalline form i of azidime as claimed in claim 2, wherein the heating is oil bath heating to 60-80 ℃, stirring for half an hour, and then cooling to 60-65 ℃.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110016068A (en) * | 2019-03-15 | 2019-07-16 | 河南真实生物科技有限公司 | The crystal form A and its preparation method and application of 2 '-fluoro- 4 '-substituted nucleosides analog I |
CN111892636A (en) * | 2020-08-07 | 2020-11-06 | 山东大学 | Synthesis method of azvudine |
CN114149475A (en) * | 2021-12-14 | 2022-03-08 | 新乡拓新药业股份有限公司 | Process method for synthesizing azvudine |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110016068A (en) * | 2019-03-15 | 2019-07-16 | 河南真实生物科技有限公司 | The crystal form A and its preparation method and application of 2 '-fluoro- 4 '-substituted nucleosides analog I |
CN111892636A (en) * | 2020-08-07 | 2020-11-06 | 山东大学 | Synthesis method of azvudine |
CN114149475A (en) * | 2021-12-14 | 2022-03-08 | 新乡拓新药业股份有限公司 | Process method for synthesizing azvudine |
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