Pyrimidocyclic compound and its preparation method and application
A technology of cyclic compounds and compounds, applied in the field of salts and their solvates, and pyrimidocyclic compounds, which can solve the problem of low inhibitory activity of tumor cells
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Embodiment 1
[0211] Example 1: Preparation of intermediate 5-chloro-8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidine (B1)
[0212] Step 1: 2-Chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine
[0213]
[0214] To a dry 2 L flask was added 2,4-dichloro-5-iodopyrimidine (110 g, 400 mmol) followed by 2,2-dimethoxyethylamine (84 g, 800 mmol) and absolute ethanol (1.2 L). Under nitrogen at 0°C, triethylamine (109 mL, 800 mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature to react for 10 hours. After the reaction was completed, concentrated in vacuo, the obtained concentrate was added with 1 L of water, extracted with dichloromethane (3×300 mL), washed with saturated brine, and the organic layers were mixed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain The brown-black solid was washed with absolute ethanol (3×50 mL) to give a brown solid 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine (110 g, yield: 78%).
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Embodiment 2
[0228] Example 2: Preparation of intermediate 5-chloro-8-iodoimidazo[1,2-c]pyrimidine (E1)
[0229]
[0230]Into a dry 250mL single-necked flask were added 8-iodoimidazo[1,2-c]pyrimidin-5-ol (5g, 19.1mmol) and phosphorus oxychloride (50mL) in turn, under the protection of nitrogen, slowly added N , N-diisopropylethylamine (1 mL), after which the mixture was heated to 120°C and stirred for 4 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and concentrated in vacuo, then quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate (3×100 mL), the organic layers were mixed and washed with saturated brine, washed with anhydrous sodium sulfate Dried, filtered and concentrated, and purified by column chromatography to give the resulting residue was purified by silica gel chromatography (0 to 10% gradient of methanol:ethyl acetate) to give 5-chloro-8-iodoimidazo[1,2- c] Pyrimidine El (1.6 g, yield: 29.8%)...
Embodiment 3
[0232] Example 3: Intermediate (R)-2-methyl-N-((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A) preparation
[0233] Step 1: (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester
[0234]
[0235] In a dry 100mL single-necked flask were sequentially added tert-butyl 1-carbonyl-8-azaspiro[4.5]decane-8-carboxylate (2.53g, 10mmol), tetraethoxytitanium (6.84g, 30mmol) and 50 mL of tetrahydrofuran, and the reaction was stirred under reflux for 4 hours. After cooling to room temperature, methanol (10 mL) was added followed by lithium borohydride (0.65 g, 30 mmol). The resulting mixture was stirred at room temperature for 3 hours. Methanol was added slowly to quench excess borohydride, followed by brine. The resulting mixture was stirred for 15 minutes and then filtered through celite. The aqueous mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was MgSO 4 Dry, filter, and remove volatiles under re...
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