Crystal form a of 2'-fluoro-4'-substituted nucleoside analog i and its preparation method and application

A technology of nucleoside analogs and crystal forms, which is applied in the field of its new crystal forms and its preparation, 2'-fluoro-4'-substituted nucleoside analogs I, to reduce drug resistance, no static electricity generation, uniformity Improved effect

Active Publication Date: 2021-12-14
HENAN GENUINE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The crystal form of 2'-fluoro-4'-substituted nucleoside analog I has not been reported so far

Method used

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  • Crystal form a of 2'-fluoro-4'-substituted nucleoside analog i and its preparation method and application
  • Crystal form a of 2'-fluoro-4'-substituted nucleoside analog i and its preparation method and application
  • Crystal form a of 2'-fluoro-4'-substituted nucleoside analog i and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1. Preparation of Form B

[0030] 1.1 Suspension experiment

[0031] Dissolve the 2'-fluoro-4'-substituted nucleoside analog I of the present invention in one of the solvents selected below, and prepare the solution with a concentration of 7-20mg / mL. The solvent was evaporated with a rotary evaporator to obtain Form B.

[0032] The solvents used in this experiment are: methanol, ethanol, n-propanol, isopropanol, NN-dimethylformamide (DMF), ethyl acetate, isopropyl acetate, n-hexane, cyclohexane, water, ether , isopropyl ether, methyl tert-butyl ether, 4-methyl-dipentanone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform.

[0033] 1.2 Rapid evaporation method experiment

[0034] Weighed 100 mg of compound I, added excess methanol solution and raised the temperature to dissolve, put it in a vacuum rotary evaporator at 50°C, and obtained a white solid as crystal form B after removing the solvent.

Embodiment 2

[0035] Example 2. Preparation of Form A

[0036] 2.1 Recrystallization experiment

[0037] Weigh a certain amount of 2'-fluoro-4'-substituted nucleoside analog I of the present invention, heat it to reflux with methanol, or ethanol, or n-propanol, or water to prepare its saturated solution, cool and crystallize to obtain crystal form A.

[0038] 2.2 Liquid surface diffusion experiment

[0039]Compound I was dissolved in a soluble solvent at 60°C, and the anti-solvent was slowly dripped into the sample solution along the wall, and cooled until the solid precipitated. The crystal form of the obtained crystal is Form A.

[0040] The easily soluble solvents used here are: methanol, DMF or water.

[0041] The anti-solvents used here are: n-hexane, cyclohexane, isopropyl ether or ethyl acetate

[0042] 2.3 Binary solvent experiments

[0043] Weigh 15 mg of compound I into a sample bottle, add 3 mL of binary mixed solvent, shake at 200 rpm at 50°C for 48 hours, filter, and slowl...

Embodiment 3

[0055] Embodiment 3. Antiviral effect of compound I crystal form A

[0056] The anti-HIV activity of compound I crystal form A was determined according to the literature method (Eur. J. Med. Chem. 2011, 46, 4178).

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Abstract

The present invention discloses a new crystal form A of 2'-fluoro-4'-substituted nucleoside analog I, belonging to the field of medicinal chemistry, which has the following structure: The CuKα-XRPD spectrum of compound I crystal form A of the present invention is shown in the figure 2. Because its crystal form A has good stability, it is easy to mix evenly with auxiliary materials. The compound I of the crystal form A is mixed with the excipients to improve the uniformity in the tablet, which is beneficial to the quality control of the medicine and the guarantee of the efficacy of the medicine. Applying it to the preparation of anti-HBV or anti-HCV or anti-HIV virus drugs or anti-tumor drugs has good application value.

Description

technical field [0001] The present invention relates to 2'-fluoro-4'-substituted nucleoside analog I, in particular to its new crystal form and its preparation method and application, belonging to the field of medicinal chemistry. Background technique [0002] Certain nucleoside analogues have significant antiviral activity, especially anti-AIDS virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and are clinically used to treat viral infection diseases. In addition to antiviral activity, certain nucleosides also possess anticancer activity. At present, these medicines all have certain deficiencies. On the one hand, the efficacy is limited, and on the other hand, long-term use has serious toxic and side effects, and drug resistance will occur. Therefore, the design and synthesis of new nucleoside analogs is still an important research direction for the discovery of new antiviral drugs. In order to find more effective nucleoside antiviral drugs, people have ca...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/06A61P31/14A61P31/20A61P31/18
CPCC07H19/073C07H1/06A61P31/14A61P31/20A61P31/18C07B2200/13A61P31/12A61P35/00C07H19/06
Inventor 常俊标杜锦发弋冬旭
Owner HENAN GENUINE BIOTECH CO LTD
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