Crystal forms, salts and complexes of dihydropyrimidine derivatives and their application in medicine

A compound and crystal form technology, which is applied in the directions of drug combinations, medical preparations containing active ingredients, antitumor drugs, etc., can solve the problems of inconvenient development of preparations, unfavorable storage and weighing, and unsatisfactory stability.

Active Publication Date: 2020-02-11
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the preparation of compound 3-((R)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propionic acid (I) and its tautomer (Ia), the compound was found to be a foamy solid flowing Poor, and has a certain degree of hygroscopicity, unsatisfactory stability, not conducive to storage and weighing, and brings a lot of inconvenience to the later development of preparations

Method used

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  • Crystal forms, salts and complexes of dihydropyrimidine derivatives and their application in medicine
  • Crystal forms, salts and complexes of dihydropyrimidine derivatives and their application in medicine
  • Crystal forms, salts and complexes of dihydropyrimidine derivatives and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] 1. Preparation of the crystal form I(A) of the citrate of the compound shown in formula (I) or the citric acid complex

[0154] Add 3-((R)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazole- 2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propionic acid (I) (50g, 86mmol) and ethyl acetate (300mL), after stirring and dissolving completely, The temperature was raised to 45°C, and a solution of citric acid (9.9g, 51.53mmol) prepared in advance in acetone (100mL) was added. After the addition, the residual solution was rinsed with acetone (50mL), and then the temperature was raised to 50°C and kept stirring for 1.5 hours. Heating was stopped, the temperature was naturally cooled to room temperature, and stirring was continued for 24 hours. Solids were precipitated, filtered, and the filter cake was washed with ethyl acetate (250 mL). The filter cake was collected, air dried for 1 hour, then vacuum dried at room temperature for 3 hours, followed by vacu...

Embodiment 2

[0168] 1. Preparation of the mesylate crystal form I(B) of the compound represented by formula (I)

[0169] Add 3-((R)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazole-2 -yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propionic acid (I) (10g, 17.20mmol), dichloromethane (84mL) and ethyl acetate (50mL ), stirred at room temperature until the solution was completely dissolved, and added dropwise a solution of methanesulfonic acid (1.82 g, 18.9 mmol) in ethyl acetate (6 mL). After dropping, the resulting reaction solution was stirred at room temperature for 12 hours, and solids were precipitated, filtered, and the filter cake was washed with ethyl acetate (50 mL). The filter cake was collected and dried under vacuum at room temperature for 6 hours to obtain the product as a yellow solid (8 g, yield 68.64%).

[0170] 1 H NMR (400MHz,D 2 O)δ(ppm):7.86(d,1H),7.77(d,1H),7.42-7.38(m,2H),7.06(td,1H),6.11(s,1H),4.66(d,1H) ,4.43(d,1H),4.16-4.12(m,1H),4.04-3.92(...

Embodiment 3

[0179] 1. Preparation of the mesylate crystal form II of the compound represented by formula (I)

[0180]Add 3-((R)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazole- 2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic acid (I) (50 g, 86.00 mmol), acetone (720 mL) and ethyl acetate (100 mL) , heated to 55°C and stirred until completely dissolved. A solution of methanesulfonic acid (7.85 g, 81.7 mmol) in ethyl acetate (80 mL) was added dropwise thereto. After the dropwise addition was completed, the resulting reaction solution was kept warm and stirred for 1.5 hours. After cooling down to room temperature, the mixture was kept warm and stirred for 12 hours, and solids were gradually precipitated out. After filtration, the filter cake was washed with ethyl acetate (300 mL), collected and vacuum-dried at 70° C. for 8 hours to obtain the product as a yellow solid (51 g, yield 88%).

[0181] 2. Identification of the mesylate crystal form II of the co...

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Abstract

Disclosed are salts of dihydropyrimidine derivative and uses thereof in medicine. Specifically, it relates to citric acid complex, acid addition salt of 3-((R)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic acid or tautomer thereof, or crystalline form thereof, and pharmaceutically compositions thereof.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to compound 3-((R)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazole -2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propionic acid (I) or various solid forms of its tautomer (Ia), such as The compound, acid addition salt, crystal form and pharmaceutical composition thereof, further relates to the use of said solid form and pharmaceutical composition thereof in the preparation of medicaments, especially in the preparation of prevention, treatment, treatment or alleviation of hepatitis B Use in medicine for (HBV) infection. Background technique [0002] Hepatitis B virus belongs to the Hepaviridae family. It can cause acute and / or progressive chronic disease. Hepatitis B virus can also cause many other clinical manifestations in the pathological form - especially chronic inflammation of the liver, cirrhosis and canceration of hepatocellular cells. In addition, co-in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14C07C59/265C07C309/04A61K31/5377A61P1/16A61P35/00A61P31/20
CPCC07B2200/13C07D417/14A61P1/16A61P31/20A61P35/00
Inventor 刘辛昌任青云张英俊S·戈尔德曼
Owner SUNSHINE LAKE PHARM CO LTD
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