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Acid addition salt of dihydropyrimidine derivative and application of acid addition salt in medicine

A technology of acid addition salt and hydrobromide, applied in the field of chemical medicine, can solve the problems of stability, solubility and bioavailability differences, unsatisfactory compound stability and pharmacokinetic properties, and inconvenient formulation development.

Active Publication Date: 2022-07-05
SOUTH CHINA UNIV OF TECH
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  • 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), it was found that the stability and pharmacokinetic properties of the compound were not ideal, which brought a lot of inconvenience to the later stage formulation development
[0008] As we all know, different crystal forms, salt forms or salt crystal forms of the same drug may have significant differences in stability, solubility and bioavailability, so that Affect the efficacy of drugs, therefore, it is of great significance to develop crystal forms of salts of dihydropyrimidine derivatives that are more conducive to stability and better pharmacokinetic data

Method used

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  • Acid addition salt of dihydropyrimidine derivative and application of acid addition salt in medicine
  • Acid addition salt of dihydropyrimidine derivative and application of acid addition salt in medicine
  • Acid addition salt of dihydropyrimidine derivative and application of acid addition salt in medicine

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Experimental program
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preparation example Construction

[0145] Preparation of compounds shown as (I)

[0146] Step 1) Synthesis of Compound 1-1

[0147]

[0148] 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] - .

[0149] Step 2) Synthesis of Compound 1-2

[0150]

[0151] 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 kg), the org...

Embodiment 1

[0175] Example 1 is (4-((S)-7-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl) )-1,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)benzoic acid hydrochloride crystal Type A, its preparation method is as follows:

[0176] The compound represented by formula (I) (0.3g, 0.5mmol) and acetone (6mL) were added to the dry reaction flask in turn, the temperature was raised to 50°C, the solid was completely dissolved, and concentrated hydrochloric acid (52mg, 37%) was mixed with water (0.15mL) After dilution, it was added to the reaction system, and after the addition was completed, the system was clarified, and then a large amount of solid was precipitated. Keep stirring for about 30 minutes, turn off the heating, and naturally cool down to room temperature. Stirring was continued at room temperature for 66 h, filtered, washed with acetone (2 mL), and the solid was dried under vacuum at 60° C. for 12 h to obtain a yellow solid (0.3 ...

Embodiment 2

[0187] Example 2 is (4-((S)-7-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl) )-1,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)benzoic acid hydrochloride crystal Form B, its preparation method is as follows:

[0188] The compound represented by formula (I) (0.3 g, 0.5 mmol) and acetone (4.5 mL) were sequentially added to a dry reaction flask, the temperature was raised to 50° C., the solid was completely dissolved, and concentrated hydrochloric acid (52 mg, 37%) was mixed with water (0.45 mL). ) was diluted and added to the reaction system, and after the addition was completed, the system was clarified, and a large amount of solid was subsequently precipitated. Keep stirring for about 30min, turn off the heating, cool down to room temperature naturally, then continue stirring at room temperature for 17h, filter, wash the filter cake with acetone (2mL), and dry the solid under vacuum at 60°C for 12h to obtain a yellow soli...

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Abstract

The invention discloses an acid addition salt of a dihydropyrimidine derivative and application of the acid addition salt in medicines. The invention particularly relates to a hydrochloride crystal form A, a hydrochloride crystal form B, a sulfate crystal form A, a hydrobromide crystal form A, a phosphate crystal form A, a mesylate crystal form A or a mesylate crystal form B of a compound as shown in a formula (I) or a formula (Ia) and application of the hydrochloride crystal form A, the hydrochloride crystal form B, the sulfate crystal form A, the hydrobromide crystal form A, the phosphate crystal form A, the mesylate crystal form A or the mesylate crystal form B in medicines. The salts provided by the invention have better stability under the conditions of high temperature, high humidity and illumination, and have good pharmacokinetic properties in beagle bodies.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine, and particularly relates to an acid addition salt of a dihydropyrimidine derivative and its application in medicine. Background technique [0002] Hepatitis B virus belongs to the Hepatoviridae family. It 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 effect occurs. ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07C309/04A61K31/506A61P31/20A61P1/16
CPCC07D487/04C07C309/04A61P31/20A61P1/16C07B2200/13C07B2200/07Y02A50/30
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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