Dihydropyrazolopyrimidinone derivatives
A compound and a selected technology, which are applied in the field of medical technology and can solve problems such as no drugs on the market yet
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Embodiment 1
[0182] Example 1: 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(8-methyl-3,8-diazo Preparation of Heterobicyclo[3.2.1]oct-3-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound 1)
[0183] 1. Preparation of 4-(2-allyl-2-(tert-butoxycarbonyl) hydrazine)-2-(methylthio) pyrimidine-5-carboxylic acid ethyl ester
[0184]
[0185] 1-Allylhydrazine-1-carboxylate tert-butyl ester (0.37g, 21.5mmol) was dissolved in ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (0.5g, 21.5mmol) Tetrahydrofuran (100.0 mL) was added with N,N-diisopropylethylamine (0.69 g, 53.8 mmol), the reaction was carried out at 70°C for 16 h, the solvent was spin-dried, and the product was obtained by column chromatography (ethyl acetate / petroleum ether=25%) (0.62 g, 78.5%).
[0186] 2. Preparation of 4-(2-allylhydrazino)-3-(methylthio)-1,2,4-triazine-6-carboxylic acid ethyl ester
[0187]
[0188] Ethyl 4-(2-allyl-2-(tert-butoxycarbonyl)hydrazino)-2-(methylthio)pyrimidin...
Embodiment 2
[0215] Example 2: 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(5-methyl-2,5-diazo Preparation of Heterobicyclo[2.2.2]oct-2-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound 2)
[0216] 1. Preparation of 2-methyl-5-(4-nitrophenyl)-2,5-diazabicyclo[2.2.2]octane
[0217]
[0218] 2-Methyl-2,5-diazabicyclo[2.2.2]octane (100 mg, 0.5 mmol) was dissolved in 10 ml of acetonitrile, 1-fluoro-4-nitrobenzene (141 mg, 1.0 mmol) was added and N,N-diisopropylethylamine (323 mg, 2.5 mmol) was reacted at 60° C. for 16 h. Concentration, silica gel column purification (methanol: dichloromethane = 1:7) to obtain 74 mg of the target compound, yield 60.0%.
[0219] 2. Preparation of 4-(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)aniline
[0220]
[0221] 2-Methyl-5-(4-nitrophenyl)-2,5-diazabicyclo[2.2.2]octane (70 mg, 0.28 mmol) was dissolved in methanol (5 mL), and palladium / carbon ( 40 mg), reacted at 16 °C for 1 hour under a hydrogen atmosphere. Concentr...
Embodiment 3
[0227] Example 3: 2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6-(((4-(6-methyl-2,6-di Preparation of azaspiro[3.3]hept-2-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound 3)
[0228] 1. Preparation of 2-methyl-6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane
[0229]
[0230] 2-Methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (100 mg, 0.54 mmol), p-fluoronitrobenzene (83 mg, 0.59 mmol) and N,N-diisopropyl Ethylamine (349 mg, 2.7 mmol) was dissolved in acetonitrile (20 mL), and reacted at 60 °C for 6 h. The reaction was completed, and saturated sodium bicarbonate (3 mL) solution was added, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol= 10:1) to obtain the product (100 mg, yield 79.1%).
[0231] 2. Preparation of 4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)aniline
[0232]
[0233] 2-Methyl-6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane (30 mg, 0.13 mmol) was dissolved in methanol (10 mL)...
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