Heterocyclic compound and application thereof and pharmaceutical composition containing heterocyclic compound
A technology of heterocyclic compounds and pharmacy, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, antipyretics, etc., can solve the problem of single structure of ATX inhibitors
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[0824] Preparation Example 1 Intermediate synthesis method
[0825]
[0826] Step 1, 2-Amino-4-(3,4-difluorophenyl)thiazole-5-carbonitrile
[0827] To a solution (18 mL) of 3-(3,4-difluorophenyl)-3-oxopropionitrile (1.38 g, 7.63 mmol) in ethanol was added pyridine (0.60 g, 7.63 mmol). The reaction solution was stirred at 70°C for 15 minutes and then cooled to room temperature. Mix thiourea (1.18 g, 215.52 mmol) and iodine (1.96 g, 7.63 mmol) in ethanol (18 mL). This mixture was slowly added dropwise to the above solution and stirred at room temperature for 1 hour. The reaction was quenched by adding cold sodium thiosulfate solution (10 mL) to the reaction solution. Filter and wash the filter cake with water. After the filter cake is dried, 2-amino-4-(3,4-fluorophenyl)thiazole-5-carbonitrile is obtained as an off-white solid (1.50 g, 82.9%). 1H NMR(400MHz,DMSO-d6)δ8.28(s,2H),,7.89–7.83(m,1H),7.82–7.78(m,1H),7.65-7.58(m,1H)
[0828] Step 2. 2-Chloro-4-(3,4-difluorophenyl)thiazole-5...
Example Embodiment
[0845] Example 1S-0021: 2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazine-1- Yl)imidazo[1,2-a]pyrimidin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile
[0846]
[0847] Step 1: 2-Chloro-1-(3-hydroxyazetidin-1-yl)acetyl
[0848] To an aqueous solution (8 mL) of potassium carbonate (3 g, 22 mmol) was added 3-hydroxyazetidine hydrochloride (1.1 g, 10 mmol). The reaction solution was stirred at room temperature for 10 minutes, and then diluted with dichloromethane (8 mL) and the reaction solution was cooled to 0°C, and then 2-chloroacetyl chloride (1.3 g, 12 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours, filtered, and the organic phase was separated. The aqueous phase was extracted with a methanol / ethyl acetate mixture (1 / 1) (20 mL x 6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was resuspended in acetone (50 mL) and stirred vigorou...
Example Embodiment
[0867] Example 2S-0022: 2-((2-ethyl-5-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazine-1- Yl)-7-methyl-2H-indazol-3-yl)(methyl)amine)-4-(4-fluorophenyl)thiazole-5-carbonitrile
[0868]
[0869] Step 1: 5-Bromo-2-fluoro-3-methylbenzonitrile
[0870] Iodine (11.67g, 46.3mmol) was added to the mixture of 5-bromo-2-fluoro-3-methylbenzaldehyde (5g, 23.1mmol) in tetrahydrofuran (20mL) and ammonia (20mL), and the reaction solution was kept at room temperature. Stir for 16 hours. The reaction was quenched by adding sodium bisulfite solution (20 mL) to the reaction solution, and then extracted with ethyl acetate (50×2 mL). The organic phases were combined, washed with saturated brine (10mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 5-bromo-2-fluoro-3-methylbenzonitrile as a white solid (5g, 98%) , Directly used in the next reaction without purification. 1 H NMR(400MHz, CDCl 3 )δ7.55-7.59 (m, 2H), 2.32 (s, 3H).
[0871] Step 2: 5-bromo-2-ethyl-7-meth...
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