Crystal forms of thiazole compounds and their applications
A compound and crystal form technology, which is applied to the crystal form of thiazole compounds and its application field, can solve the problems of damage to host cell DNA replication and decreased therapeutic effect
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Embodiment 1
[0085] Embodiment 1: the preparation of formula (I) compound
[0086]
[0087] Step 1: Synthesis of compound 2
[0088] NBS (57.70 g, 324.22 mmol) and AIBN (5.32 g, 32.42 mmol) were added to a solution of compound 1 (30.00 g, 162.11 mmol) in carbon tetrachloride (400.00 mL), and the system was stirred at 80° C. for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Compound 2 as a colorless oil. 1 H NMR (400MHz, CDCl 3 )δ7.55 (s, 1H), 7.47-7.45 (m, 1H), 7.28-7.25 (m, 1H), 4.62 (s, 1H), 4.60 (s, 2H).
[0089] Step 2: Synthesis of Compound 3
[0090] Sodium hydrogen (9.60g, 240.02mmol, content 60%) was slowly added to a solution of ethanol (144.00mL) and tetrahydrofuran (432.00mL), stirred at room temperature for 5 minutes, and then diethyl malonate (18.22g, 113.75mmol ) and compound 2 (39.00g, 113.75mmol), the system was stirred at room temperature for 30 minutes. After t...
Embodiment 2
[0101] Embodiment 2: Preparation of the A crystal form of the compound of formula (I)
[0102]Weigh about 20 g of the compound of formula (I), add 800 mL of ethanol, and stir overnight with a magnetic stirrer. The mixture was filtered, the filter cake was rinsed with a small amount of ethanol, and the obtained solid was dried under reduced pressure. XRPD detection, the A crystal form of the compound of formula (I) was obtained.
Embodiment 3
[0103] Embodiment 3: Preparation of the B crystal form of the compound of formula (II)
[0104]
[0105] Weigh the compound of formula (I) (56.5g, 131.85mmol) into a 3L round bottom flask, add 2L of anhydrous tetrahydrofuran, and heat to 50-55°C to dissolve it completely. After filtration, methanesulfonic acid (12.67 g, 131.85 mmol) diluted with 50 mL of anhydrous tetrahydrofuran was added dropwise to the filtrate at 55° C., a solid precipitated out, and stirring was continued for 2 hours. After filtering, the filter cake was dried under reduced pressure, and the resulting solid was added to a round bottom flask, and 1 L of absolute ethanol was added, heated to 40°C and stirred for 14 hours. After filtration, the filter cake was vacuum-dried, and detected by XRPD, the crystal form B of the compound of formula (II) was obtained.
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