CSF1R inhibitor intermediate and preparation method thereof
A technology of inhibitors and intermediates, applied in the field of preparation of intermediates of CSF1R inhibitors
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[0063] Preparation of compound INT-1:
[0064]
[0065] At 0°C, cesium carbonate (241.0g, 0.74mol) and 5-bromo-2-nitropyridine (100.0g, 0.49mol) were sequentially added to a solution of 2-chloro-4-hydroxypyridine (70.2g, 0.54mol) in N,N-dimethylformamide (1.5L) solution. The reaction solution was stirred at 80° C. for 24 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove most of the solvent, and diluted with ethyl acetate (2L); the organic layer was washed with water (2Lx2) and saturated brine (1Lx2) successively, and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain INT-1a (43.5 g, yield: 31.9%) as a yellow oil. 1 H NMR (DMSO-d 6 ,400MHz)δ8.64(s,1H),8.47-8.40(m,2H),8.14–8.02(m,1H),7.39(s,1H),7.25(s,1H); MS:252.0[M+ H]+.
[0066]...
Embodiment 1
[0099] Embodiment 1: the preparation of compound 1
[0100]
[0101] At 0°C, a solution of triphosgene (95 mg, 0.32 mmol) pre-dissolved in tetrahydrofuran (2 mL) was slowly added dropwise to compound INT-1 (107 mg, 0.40 mmol) and triethylamine (222 μL, 1.60 mmol) in tetrahydrofuran (5 mL) solution. The reaction solution was gradually raised to room temperature with stirring, and continued stirring at room temperature for 1 hour. LC / MS showed that the starting material was completely consumed, and the reaction solution was concentrated under reduced pressure, and water (15 mL) and a mixed solution of dichloromethane and methanol (15 mL, v / v=10 / 1) were added. The organic phase was washed with saturated brine (15 mLx2), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain compound 1a, which was directly used in the next step without isolation.
[0102] Sodium hydrogen (60% w / w in kerosene; 80 mg, 2.0 mmol) was added to a solu...
Embodiment 2
[0113] Embodiment 2: the preparation of compound 11
[0114]
[0115] Starting from compound INT-1, following the synthesis of compound 1, a white solid 11a was obtained. 1HNMR (DMSO-d 6,500MHz)δ11.04(s,1H),8.37(d,J=5.7Hz,1H),8.27(d,J=3.0Hz,1H),8.25(s,1H),8.08(d,J=9.0 Hz,1H),7.96(s,1H),7.76(dd,J=9.0,3.0Hz,1H),7.23(d,J=3.0Hz,1H),6.69(dd,J=5.7,3.0Hz,1H ),3.84(s,3H),3.79(t,J=7.1Hz,4H),3.07-2.92(m,2H),2.03(t,J=7.1Hz,2H),1.65-1.53(m,4H) , 1.40 (s, 9H); MS: 548.3 [M+H]+.
[0116] To a solution of compound 11a (350 mg, 0.64 mmol) in dichloromethane (6 mL) was added hydrochloric acid (4Min dioxane, 0.8 mL). After the reaction solution was stirred at room temperature for 4 hours, LC / MS showed that the starting material had been consumed. The reaction solution was concentrated under reduced pressure to obtain 11 as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ11.05(s,1H),8.78(s,1H),8.56(d,J=6.0Hz,1H),8.46(s,1H),8.41(s,1H),8.14(d,J=9.0 Hz, 1H), 7.91(d, J=9.0Hz, 1H), 7.75(s, 1H),...
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