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Compound salt and crystal form or amorphous material and preparation methods thereof, pharmaceutical composition containing compound salt and crystal form or amorphous material and application

A crystal form and drug technology, applied in medical preparations containing active ingredients, organic chemistry methods, organic chemistry and other directions, can solve the problem of solution becoming turbid, achieve good aqueous solution stability, avoid unstable absorption, and simple process. Effect

Active Publication Date: 2017-01-04
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solubility of this salt in water is greater than 200 mg / ml, but when its aqueous solution is placed at room temperature for 24 hours, solids will precipitate and the solution will become turbid. According to the HPLC content detection, the precipitated solid is BMS-790052 free base. In view of this phenomenon, BMS -790052 Dihydrochloride not suitable for preparation of sustained release formulations

Method used

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  • Compound salt and crystal form or amorphous material and preparation methods thereof, pharmaceutical composition containing compound salt and crystal form or amorphous material and application
  • Compound salt and crystal form or amorphous material and preparation methods thereof, pharmaceutical composition containing compound salt and crystal form or amorphous material and application
  • Compound salt and crystal form or amorphous material and preparation methods thereof, pharmaceutical composition containing compound salt and crystal form or amorphous material and application

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0135] According to the compound (I) seed crystal preparation method disclosed in the patent document WO2009020828A1, BMS-790052 free base was prepared as a starting material, and the specific operations were as follows:

[0136] 60.0g (105mmol, 1 equivalent) 4,4'-bis(2-((S)-pyrrolidinyl-2-yl)-1H-imidazol-5-yl) biphenyl, 38.7g (221mmol, 1 equivalent ) N-(methoxycarbonyl)-L-valine, 44.5g (232mmol, 2.2 equivalents) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2.89g ( Add 21.4mmol, 0.2eq) of 1-hydroxybenzotriazole to 300mL of acetonitrile, stir to disperse, add 73.3mL (420.3mmol, 4eq) of diisopropylethylamine, and stir at 24-30°C for about 18 hours. Add 60 mL of water and heat to 50°C for about 5 hours. After cooling to room temperature, 320 mL of ethyl acetate and 300 mL of water were added, and the separated organic layer was washed with 300 mL of 10 wt % sodium bicarbonate aqueous solution, 300 mL of water and 200 mL of 10 wt % sodium chloride aqueous solution...

Embodiment 1

[0147] Example 1 Preparation of BMS-790052 di-p-toluenesulfonate

[0148] At room temperature, take 500 mg of the BMS-790052 free base prepared in Preparation Example 1, add 10 mL of acetone and dissolve it ultrasonically, add 256 mg of anhydrous p-toluenesulfonic acid solid to the acetone solution of the BMS-790052 free base, form a slurry and stir for 16 After 1 hour, it was filtered, and the filter cake was vacuum-dried at 40° C. for 16 hours to obtain 521 mg of BMS-790052 di-p-toluenesulfonate, with a yield of 71.1%.

[0149] As determined by HPLC, the actual content of BMS-790052 free base in BMS-790052 di-p-toluenesulfonate is 67.6%, and the theoretical content is 68.3%. The test results show that the free base of BMS-790052 and p-toluenesulfonic acid in the di-p-toluenesulfonate salt of BMS-790052 form a salt with a molar ratio of about 1:2.

Embodiment 2

[0150] Example 2 Preparation of BMS-790052 di-p-toluenesulfonate

[0151]At room temperature, take 50.0 mg of the BMS-790052 free base prepared in Preparation Example 1, add 2.0 mL of isopropanol and ultrasonically dissolve it, add 23.2 mg of anhydrous p-toluenesulfonic acid solid to the isopropanol solution of BMS-790052 free base, A slurry was formed and stirred. After stirring for 8 hours, it was filtered, and the filter cake was vacuum-dried at 40° C. for 16 hours to obtain 51.5 mg of BMS-790052 di-p-toluenesulfonate, with a yield of 70.3%.

[0152] The sample prepared in Example 2 has the same or similar HPLC detection results (not shown) as the sample in Example 1, indicating that the sample in Example 2 and the sample in Example 1 are the same substance.

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Abstract

The invention relates to a solid medicinal ((1s)-1-(((2S)-2-(5-(4'-((2-(2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutyryl)-2-pyrrolidinyl)-1H-imidazole-5-yl)-4-biphenyl)-1H-imidazole-2-yl)-1-pyrrolidinyl)carbonyl)-2-methyl propyl)methyl carbamate salt and a crystal form and amorphous material thereof. Compared with the prior art, the specific compound salt and the crystal form and amorphous material thereof have the slow-release effect and aqueous solution stability which are obviously superior to those of the prior art, are suitable for slow release preparation application, preparation methods of the salt and the crystal form and the amorphous material thereof are simple in technology, conventional operation is conducted under the room temperature condition, and industrialization of products is promoted. The invention further relates to the preparation methods of the compound salt and the crystal form and the amorphous material thereof, a pharmaceutical composition of the compound salt and the crystal form and the amorphous material and application in preparing drugs for treating hepatitis C virus (HCV) infection.

Description

[0001] This application is a patent application "a salt of a compound and its crystal or amorphous form, Its preparation method, its drug combination and its use” is a divisional application. technical field [0002] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a drug for treating hepatitis C ((1S)-1-(((2S)-2-(5-(4'-(2-((2S)-1-(( 2S)-2-((Methoxycarbonyl)amino)-3-methylbutyryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenyl)-1H-imidazole-2 -base)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)salt of methyl carbamate and its crystal form or amorphous substance, the present invention also relates to the preparation method of said compound salt and its crystal form , its pharmaceutical composition and use. Background technique [0003] Daclatasvir, also known as BMS-790052, is a replication inhibitor developed by Bristol-Myers Squibb to treat hepatitis C virus (HCV) infection. The chemical name of the compound is ((1S)-1-(((2S)-2-(...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/4178A61P31/12
CPCC07B2200/13C07D403/14A61P31/12A61P31/14
Inventor 胡晨阳盛晓霞盛晓红
Owner SOLIPHARMA
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