Bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof
A compound, cycloalkyl technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of marketed, no oral small molecule PAR4 antagonists, etc.
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Embodiment 1
[0066] 8-(4-chloro-6-methoxybenzo[d]thiazol-2-yl)-3-methylquinazolin-4(3H)-one (compound 10)
[0067]
[0068] Compound 10-1 (5 g, 33.98 mmol) and NBS (6.05 g, 33.98 mmol) were dissolved in PEG-200 (20 mL) at room temperature and stirred for 24 h. The reaction was monitored by TLC. If the reaction is not complete, add a small amount of NBS. After the raw material point disappeared, the reaction liquid was poured into ice water, stirred for 30 min, filtered with suction, the filter cake was washed with water, and dried to obtain compound 10-2 (7.68 g) as a red solid with a yield of 100%. Rf = 0.6 (P / E = 1 / 1).
[0069]Compound 10-2 (5g, 22.12mmol) was added to aqueous sodium hydroxide solution (5%W / V, 100mL), heated to 50°C, and aqueous hydrogen peroxide solution (30%, 10mL) was slowly and carefully added dropwise, the red-black solution gradually shallow. After 30 min of reaction, the solution turned into a light yellow suspension. The reaction was monitored by TLC. Af...
Embodiment 2
[0075] 8-(4-Chloro-6-methoxybenzo[d]thiazol-2-yl)-3,6-dimethylquinazolin-4(3H)-one (compound 11)
[0076]
[0077] At room temperature, hydroxylamine hydrochloride (5.9 g, 84.9 mmol) was dissolved in H 2 O (30 mL). 2,2,2-Trichloroacetaldehyde (4.54g, 30.8mmol) was added to H 2 O, add anhydrous sodium sulfate (21g, 148mmol), stir to dissolve, then add compound 11-1 (3.0g, 28.0mmol) and concentrated hydrochloric acid (3mL), stir for 5min, add the above aqueous solution of hydroxylamine hydrochloride dropwise. React at 90°C for 10 min, suction filter the insoluble matter while it is hot, wash the filter cake with water, and dry to obtain compound 11-2 (1.34 g) as a light brown solid with a yield of 27%. Rf = 0.3 (P / E = 2 / 1).
[0078] Concentrated hydrochloric acid (20 mL) was added into a 50 mL round-bottomed flask, raised to 50° C., and compound 11-2 (1.34 g, 7.52 mmol) was slowly added in batches. After the addition was complete, the temperature was raised to 80 °C and s...
Embodiment 3
[0086] 8-(4-Chloro-6-methoxybenzo[d]thiazol-2-yl)-2,3,6-trimethylquinazolin-4(3H)-one (Compound 13)
[0087]
[0088] At room temperature, compound 11-5 (5 g, 21.74 mmol) was added with acetic anhydride (20 mL), and refluxed at 140° C. for 3 h. It is a white suspension at room temperature and dissolves into a colorless solution at 60°C. After the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of white solids precipitated out, which were concentrated to a small volume. The residue was stirred with toluene (50 mL) for 30 min and then concentrated to dryness to obtain 6 g of crude compound 13-1 as a white solid. Yield 100%.
[0089]At room temperature, compound 13-1 (5 g, 19.68 mmol) was added with aqueous ammonia (50 mL), and refluxed at 65° C. for 2 h. During the process of reflux, aqueous ammonia (25 mL) was slowly added in batches. After the reaction was completed, it was cooled to room temperature, the insoluble matter w...
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