Eureka AIR delivers breakthrough ideas for toughest innovation challenges, trusted by R&D personnel around the world.

Crystal form of dihydropyrimidine derivative, preparation method of crystal form and application of crystal form in medicine

A crystal form and drug technology, which is applied in the direction of drug combinations, medical preparations containing active ingredients, antineoplastic drugs, etc., can solve problems affecting drug efficacy, stability and pharmacokinetic properties, and inconvenience in preparation development.

Active Publication Date: 2022-07-05
SOUTH CHINA UNIV OF TECH
View PDF3 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in the preparation of compound (4-((S)-7-(((R)-6-(2-chloro-4-fluorophenyl )-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5-a ]pyrazin-2(3H)-yl)benzoic acid (I) and its tautomer (4-((S)-7-(((R)-6-(2-chloro-4-fluorobenzene Base)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-1,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5- a] During the process of pyrazin-2 (3H)-yl) benzoic acid (Ia), the stability and pharmacokinetic properties of the compound were found to be unsatisfactory, which brought a lot of inconvenience to the later stage formulation development
[0008] As we all know, different crystal forms, salt forms and salt crystal forms of the same drug may have significant differences in their stability, bioavailability, and pharmacokinetic effects. Therefore, it is of great significance to develop new crystal forms of dihydropyrimidine derivatives that are more conducive to drug processing and pharmaceutical compositions.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Crystal form of dihydropyrimidine derivative, preparation method of crystal form and application of crystal form in medicine
  • Crystal form of dihydropyrimidine derivative, preparation method of crystal form and application of crystal form in medicine
  • Crystal form of dihydropyrimidine derivative, preparation method of crystal form and application of crystal form in medicine

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0116] Preparation of compound represented by formula (I)

[0117] Step 1) Synthesis of Compound 1-1

[0118]

[0119] Drop into acetone (3138kg) in the reactor, add 1,4-bis-Boc-2-piperazinecarboxylic acid (198.74kg, 601.6mol) under stirring, after stirring and dissolving completely, add (S)-1-phenylethylamine again (80.0 kg, 660.2 mol). After the addition, the reaction was stirred at 30±5°C for 18h, centrifuged, and the filter cake was washed with acetone (627.8kg), and the filter cake was vacuum-dried at 60±5°C for 16h to obtain a white solid compound 1-1 (85.32kg, 31.4%) . MS(ESI,pos.ion)m / z:329.3[M-H] - .

[0120] Step 2) Synthesis of Compound 1-2

[0121]

[0122] In the reactor, add water (853.8kg), ethyl acetate (923.0kg) and compound 1-1 (85.22kg) successively, the reaction mixture is stirred at 25 ± 5 ° C, and concentrated hydrochloric acid is added dropwise to adjust pH to 3~4, Set aside to layer. The aqueous layer was extracted with ethyl acetate (460.6...

Embodiment 1

[0146] Example 1 is (4-((S)-7-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl) )-3,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)benzoic acid crystal form A-1 , its preparation method is as follows:

[0147] The compound of formula (I) prepared above (6 g, 11.4 mmol) and dichloromethane (100 mL) were successively added to a dry reaction flask, stirred at room temperature to dissolve completely, and the solvent was evaporated under reduced pressure to obtain a foamy solid. Anhydrous methanol (120 mL) was added to the foamy solid, the solid was completely dissolved under stirring, the temperature was raised to reflux, and the system gradually precipitated a solid, kept stirring for 30 min, turned off the heating, cooled to room temperature naturally, then kept stirring for 12 hours, filtered, anhydrous Washed with methanol (20 mL), the solid was dried under vacuum at 50° C. for 8 h to obtain a yellowish solid (5.2 g, 87%).

...

Embodiment 2

[0153] Example 2 is (4-((S)-7-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl) )-3,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)benzoic acid crystal form B-1 , its preparation method is as follows:

[0154] The compound of formula (I) prepared above (0.3 g, 0.5 mmol) and dichloromethane (5 mL) were sequentially added to a dry reaction flask, stirred at room temperature to dissolve completely, and the solvent was evaporated under reduced pressure to obtain a foamy solid. Ethyl acetate (5 mL) was added to the foamy solid, the temperature was raised to 70° C., kept stirring for 30 min, the heating was turned off, and the temperature was naturally cooled to room temperature. Stirring was continued for 12 h, filtered, and the filter cake was washed with ethyl acetate (1.5 mL), and then dried under vacuum at 60° C. for 12 h to obtain a yellowish solid (0.27 g, 90%).

[0155] Result identification:

[0156] (1) LC-MS: MS (ESI, ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a crystal form of a dihydropyrimidine derivative, a preparation method of the crystal form and application of the crystal form in medicines. Specifically, the invention relates to a crystal form A-1 or a crystal form B-1 having a compound represented by a formula (I) or a formula (Ia), a preparation method thereof and an application of the crystal form A-1 or the crystal form B-1 in drugs, and the crystal form A-1 and the crystal form B-1 have high stability under high temperature, high humidity and illumination conditions, and have good pharmacokinetic properties in beagle bodies.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine, and in particular relates to a crystal form of a dihydropyrimidine derivative, a preparation method and its application in medicine. Background technique [0002] Hepatitis B virus belongs to the hepatoviridae family and can cause acute and / or progressive chronic disease. Hepatitis B virus can also cause many other clinical manifestations of pathological morphology - especially chronic inflammation of the liver, cirrhosis and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can adversely affect the development of the disease. [0003] The conventional drugs licensed for the treatment of chronic hepatitis are interferon and lamivudine. However, interferon has only moderate activity and has high toxic side effects; although lamivudine has good activity, its drug resistance increases rapidly during treatment and often occurs after stopping treatment A rebound ef...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D487/04A61K31/506A61P31/20A61P35/00A61P1/16
CPCC07D487/04A61P31/20A61P35/00A61P1/16C07B2200/13
Inventor 张珉刘辛昌时佳佳尹丽华闫兴国
Owner SOUTH CHINA UNIV OF TECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com