Cyanopyrroloheteroaryl derivatives, their preparation method and their application in medicine
An alkyl, drug technology, applied in the field of TLR7 agonist, can solve problems such as side effects
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Embodiment 1
[0208] 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile
[0209]
[0210] first step
[0211] 2-Butoxy-4,6-dichloropyrimidine-5-carbaldehyde 1b
[0212] Add phosphorus oxychloride (6.24g, 40.70mmol) into 75mL of dichloromethane, cool down to 0°C in an ice bath, slowly add N,N-dimethylformamide (2.98g, 40.70mmol), and stir After reacting for 1 hour, 2-butoxypyrimidine-4,6-diol 1a (6.24 g, 40.70 mmol, prepared by the method disclosed in the patent application "WO201644183") was added, and the reaction was continued to stir at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, 50 mL of phosphorus oxychloride was added to the residue, the temperature was cooled to 0°C in an ice bath, N,N-diisopropylethylamine (6.99 g, 54.20 mmol) was added dropwise, and the temperature was raised to 60°C and stirred React for 2 hours. The reaction solution was cooled to room temperature, concentrated un...
Embodiment 2
[0226] 4-Amino-2-butoxy-7-(4-(morpholinemethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 2
[0227]
[0228]
[0229] first step
[0230] 4-(morpholinomethyl)benzonitrile 2b
[0231] 4-(bromomethyl)benzonitrile 2a (2.0g, 10.20mmol, prepared by a known method "Journal of Organic Chemistry, 2014, 79(1), 223-229") was added to 20mL of acetonitrile, and Potassium carbonate (2.11 g, 15.30 mmol) was added, and morpholine (1.33 g, 15.30 mmol) was added, and the reaction was stirred at room temperature for 2 hours after the addition. The reaction solution was poured into 50 mL of water, extracted with ethyl acetate (40 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product 2b (1...
Embodiment 3
[0255] 4-Amino-2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6- Formaldehyde 3
[0256]
[0257]
[0258] first step
[0259] 4-((4-Methylpiperazin-1-yl)methyl)benzonitrile 3a
[0260] 2a (1.96g, 10.00mmol) was added to 20mL of chloroform, N-methylpiperazine (1.72g, 17.20mmol) was added dropwise, and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3a (1.7 g, yield: 79.0%).
[0261] MS m / z(ESI):216.3[M+1]
[0262] second step
[0263] (4-((4-Methylpiperazin-1-yl)methyl)phenyl)methanamine 3b
[0264] 3a (1.6g, 7.43mmol) was added to 30mL of tetrahydrofuran, cooled with ice water, lithium aluminum hydride (564mg, 14.86mmol) was added in batches, after the addition was completed, it was raised to room temperature and stirred for 3 hours. Ad...
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