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N4-hydroxycytidine monohydrate and crystal form B thereof and preparation method and application thereof

A technology of hydroxycytidine and monohydrate, which is applied in the field of N4-hydroxycytidine hydrate and its crystal form B and preparation, and can solve the related reports on the research on polymorphism, crystal hydrate and its base that have not been found yet, etc. problem, to achieve good medicinal effect

Pending Publication Date: 2022-02-25
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Searching the published research literature on N4-hydroxycytidine has not found any relevant reports related to the study of polymorphs, crystalline hydrates and bases of this compound

Method used

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  • N4-hydroxycytidine monohydrate and crystal form B thereof and preparation method and application thereof
  • N4-hydroxycytidine monohydrate and crystal form B thereof and preparation method and application thereof
  • N4-hydroxycytidine monohydrate and crystal form B thereof and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Add 5.0g of N4-hydroxycytidine and 120g of water to the reaction bottle in turn, start stirring, gradually raise the temperature to 55-65°C until completely dissolved, slowly cool down, the solution appears turbid, continue to cool down to 3-5°C, and fully crystallize for 3~ After 4 hours, filter, wash the filter cake with cold water, and dry under normal pressure at 45-55°C for 6-7 hours to obtain 4.5 g of white solid of N4-hydroxycytidine monohydrate, the molar yield is 84.2%, and the moisture content is 6.7%; X X-ray powder diffraction spectrum (XRPD) as attached figure 1 Shown, differential scanning calorimetry analysis and thermogravimetric analysis curve (DSC-TGA) as attached figure 2 shown.

Embodiment 2

[0057] Add 5.0g of N4-hydroxycytidine, 120g of a mixed solvent of methanol and water (among them: 100g of methanol and 20g of water) into the reaction flask in sequence, start stirring, gradually raise the temperature to 45-55°C until it is completely dissolved, slowly cool down, and the solution When turbidity appears, continue to cool down to 0-5°C, fully crystallize for 3-4 hours, filter, wash the filter cake with cold methanol, and dry at 45-55°C under normal pressure for 4-5 hours to obtain the white color of N4-hydroxycytidine monohydrate Solid 4.2g, molar yield 78.5%, moisture determination 6.5%; X-ray powder diffraction spectrum (XRPD) as attached image 3 shown.

Embodiment 3

[0059] Add 5.0g of N4-hydroxycytidine, 120g of mixed solvent of ethanol and water (among them: 100g of ethanol and 20g of water) into the reaction flask in sequence, start stirring, gradually raise the temperature to 55-65°C until completely dissolved, slowly cool down, and the solution When turbidity appears, continue to cool down to 0-5°C, fully crystallize for 3-4 hours, filter, wash the filter cake with cold ethanol, and dry at 45-55°C under normal pressure for 5-6 hours to obtain the white color of N4-hydroxycytidine monohydrate Solid 4.1g, molar yield 76.7%, moisture determination 6.8%; X-ray powder diffraction spectrum (XRPD) as attached Figure 4 shown.

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Abstract

The invention discloses an N4-hydroxycytidine monohydrate and a crystal form B thereof and a preparation method thereof, the N4-hydroxycytidine monohydrate has the effect of preventing and treating infection of various viruses including novel coronavirus pneumonia and is shown in a formula I. The crystal form B of the N4-hydroxycytidine monohydrate is obtained by dissolving and crystallizing N4-hydroxycytidine in a solvent and then filtering and drying. The N4-hydroxycytidine monohydrate and the crystal form B thereof have better stability and druggability, so that a pharmaceutical composition and a preparation thereof can be formed, and economic and social benefits of the N4-hydroxycytidine monohydrate and the crystal form B thereof in prevention and treatment of novel coronavirus infection are achieved; the invention also discloses a pharmaceutical composition and application of the N4-hydroxycytidine monohydrate and the crystal form B of the N4-hydroxycytidine monohydrate, and is used for preparing medicines for preventing or treating symptoms or diseases caused by respiratory syncytial virus, influenza virus, chikungunya fever virus, Ebola virus, Venezuela equine encephalitis virus, Eastern or western equine encephalitis virus, coronavirus or Zika virus.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to N4-hydroxycytidine hydrate, its crystal form B, its preparation method and application, which can prevent and treat various viral infections including new coronary pneumonia. Background technique [0002] Ribonucleosides and their analogs are common reverse transcriptase inhibitors that have been widely used in the prevention and treatment of HIV, MCV and MBV. Further studies have shown that N4-hydroxyribonucleoside and its derivatives can inhibit the replication of various RNA viruses, for respiratory syncytial virus, influenza virus, chikungunya virus, Ebola virus, Venezuelan equine encephalitis virus and eastern equine encephalitis virus have strong inhibitory ability. At the same time, this type of compound also shows inhibitory activity against coronaviruses including SARS, MERS and SARS-CoV-2. "SCIENCE ADVANCES [Scienceadvances (2020), 6...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/06A61P31/16A61P31/14A61K31/7068
CPCC07H19/067C07H1/06A61P31/16A61P31/14C07B2200/13
Inventor 许学农包志坚薛佳黄栋梁苏健王喆冷秀云刘娟娟顾新禹范红沈贤敏冯钰晔
Owner SUZHOU LIXIN PHARMA
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