Crystalline form of hepatitis C drug, preparation method thereof, pharmaceutical composition and application thereof
A technology of crystal form and crystallization, which is applied in the direction of drug combination, pharmaceutical formula, organic chemical method, etc., can solve the problems of poor solubility and inability to maintain shape, and achieve the effect of good crystal form stability and chemical stability
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preparation example 1
[0126] TMC435 can be prepared by referring to the preparation method in Example 5 of patent document WO2007014926A1. Specifically: 17-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14 -Dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2.80g, 4.335mmol) and carbonyl biimidazole (1.54g, 9.5mmol ) in anhydrous tetrahydrofuran (50 mL) was stirred at reflux for 2 hours under nitrogen. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (2.00 g, 16.505 mmol) and DBU (1.43 g, 9.405 mmol) were added. The solution was heated at 50 °C for 15 hours, then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane and 1 N (1N) hydrochloric acid, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. Purification by flash chromatography (gradient: ethyl acetate (0-25%) in dichlorometha...
preparation example 2
[0129] Form I of TMC435 can be prepared by referring to the preparation method in Example 3 of patent document WO2008092954A2. Specifically: take TMC4352.1g and reflux in 5mL n-butanol, add 45mL n-butanol to the boiling suspension until a clear solution is obtained. The solution was stirred under reflux for 48 hours and then cooled to room temperature naturally. After filtering, the filter cake was washed with n-butanol, and vacuum-dried overnight at 40°C to obtain TMC435.
[0130] Its XRPD pattern is as follows Figure 15 As shown, it is consistent with the TMC435 crystal form I disclosed in WO2008092954A2.
preparation example 3
[0132] The amorphous sodium salt of TMC435 can be prepared by referring to the preparation method in Example 1 of patent document WO2010097229A2. Specifically: sodium hydroxide solution (24.10 g of sodium hydroxide dissolved in 60.03 g of purified water) was added to 5950.30 g of vigorously stirred dichloromethane. Under stirring conditions, TMC435 (450.09 g) was added, and the gradient was continued with stirring until a clear solution was obtained. Under nitrogen, the resulting clear solution was spray-dried, and the spray-dried product was collected and vacuum-dried at 50° C. to obtain TMC435 sodium salt.
[0133] Its XRPD pattern is as follows Figure 16 As shown, it shows no characteristic peaks and is amorphous.
[0134] FT-IR spectrum such as Figure 17 Shown, FT-IR analysis is TMC435 sodium salt amorphous.
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