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N4-hydroxycytidine monohydrochloride and crystal form C thereof, and preparation method and application of N4-hydroxycytidine monohydrochloride

A technology of hydroxycytidine monohydrochloride and hydroxycytidine, which is applied in the field of medicine and chemical industry, can solve the problems such as the related reports on the research of polymorphism, crystalline hydrate and its salt base that have not been found, and achieve good stability and finished medicine. sexual effect

Pending Publication Date: 2022-01-21
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 monohydrochloride and crystal form C thereof, and preparation method and application of N4-hydroxycytidine monohydrochloride
  • N4-hydroxycytidine monohydrochloride and crystal form C thereof, and preparation method and application of N4-hydroxycytidine monohydrochloride
  • N4-hydroxycytidine monohydrochloride and crystal form C thereof, and preparation method and application of N4-hydroxycytidine monohydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Add N4-hydroxycytidine (5.18g, 20mmol) and 50mL of water in sequence in the reaction flask, start stirring, add 2.0M hydrochloric acid (11mL, 1.1eq) dropwise, react at 20-30°C for 2-4 hours, and depressurize Distill until no droplets are produced. Add 105mL of ethanol to the above reaction bottle, gradually raise the temperature to 45-55°C until it completely dissolves, then slowly cool down to room temperature, the solution becomes turbid, continue to cool down to 0-5°C, fully crystallize for 2-4 hours, filter, and filter the cake with cold water Washed with ethanol and dried in vacuum to obtain 3.55 g of white crystalline powder of N4-hydroxycytidine monohydrochloride, with a molar yield of 60.3%. X-ray powder diffraction (XRPD) as figure 1 Shown; Differential scanning calorimetry and thermogravimetric analysis curve (DSC-TGA) such as figure 2 shown.

Embodiment 2

[0047] Add N4-hydroxycytidine (5.18g, 20mmol) and 50mL of water in sequence in the reaction flask, start stirring, add 2.0M hydrochloric acid (11mL, 1.1eq) dropwise, react at 20-30°C for 2-4 hours, and depressurize Distill until no droplets are produced. Add 105mL of methanol to the above reaction bottle, gradually raise the temperature to 45-55°C until it completely dissolves, slowly cool down to room temperature, the solution appears cloudy, continue to cool down to 0-5°C, fully crystallize for 2-4 hours, filter, and filter the cake with cold water Washing with methanol and drying in vacuo gave 3.25 g of white crystalline powder of N4-hydroxycytidine monohydrochloride with a molar yield of 55.0%. X-ray powder diffraction (XRPD) as image 3 shown.

Embodiment 3

[0049] Add N4-hydroxycytidine (5.18g, 20mmol) and 50mL of water in sequence in the reaction flask, start stirring, add 2.0M hydrochloric acid (11mL, 1.1eq) dropwise, react at 20-30°C for 2-4 hours, and depressurize Distill until no droplets are produced. Add 105mL of isopropanol to the above reaction bottle, gradually raise the temperature to 45-55°C until it completely dissolves, slowly cool down to room temperature, the solution becomes turbid, continue to cool down to 0-5°C, fully crystallize for 2-4 hours, filter, filter cake Wash with cold isopropanol and dry in vacuum to obtain 3.37 g of white crystalline powder of N4-hydroxycytidine monohydrochloride, with a molar yield of 57.0%. X-ray powder diffraction (XRPD) as Figure 4 shown.

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Abstract

The invention discloses N4-hydroxycytidine monohydrochloride, a crystal form C and a preparation method thereof. The N4-hydroxycytidine monohydrochloride has the effect of preventing and treating infection of various viruses including new coronal pneumonia and is shown in a formula I. N-hydroxycytidine and hydrochloric acid are subjected to a salt forming reaction, a crystallization solvent is added after a solvent is removed, and the N4-hydroxycytidine monohydrochloride is prepared through dissolving, crystallizing, filtering and drying. The N4-hydroxycytidine monohydrochloride and the crystal form C thereof have relatively good stability and druggability, can form a pharmaceutical composition and a preparation thereof, and exert economic and social benefits in prevention and treatment of novel coronavirus infection; and the invention also discloses a pharmaceutical composition and application of the N4-hydroxycytidine monohydrochloride and the crystal form C of the N4-hydroxycytidine monohydrochloride. The compound 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 monohydrochloride and its crystal form C, as well as 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 [S...

Claims

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Application Information

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IPC IPC(8): C07H19/067C07H1/00A61P31/12A61P31/14A61P31/16
CPCC07H19/067C07H1/00A61P31/12A61P31/14A61P31/16C07B2200/13
Inventor 许学农包志坚薛佳黄栋梁苏健刘娟娟王喆冷秀云苏爱蓉顾秋琴李青干婧
Owner SUZHOU LIXIN PHARMA
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