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
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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  • 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, ...

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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

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Application Information

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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
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