Inhibitors of protein kinases
A technology of amino compounds, applied in the treatment of diseases characterized by unnecessary thrombosis, and the field of preparing compounds described in this paper, can solve the problems of Src kinase inactivity and the like
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Embodiment 1
[0800] N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
[0801]
[0802] To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 10.6 mmol) in DCM (32 mL) was added NIS (2.4 g, 10.6 mmol) at room temperature . After stirring for 1 hour, the obtained precipitate was collected by filtration to obtain 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.8 g).
[0803] To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.80 g, 5.73 mmol) in DCM (20 mL) was added TsCl (1.09 g, 5.73 mmol) and TEA (1.60 mL, 11.46 mmol), followed by DMAP (70 mg, 0.573 mmol). After stirring at room temperature for 1 h, the solution was concentrated and the residue was dissolved in EtOAc and H 2 Partition between O, separate the organic phase with 1N HCl, 5% NaHCO 3 Washing, drying and concentration gave 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g).
[0804] To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2...
Embodiment 2
[0809] 1-(4-(4-(4-(methylamino)-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazine -1-yl)ethanone
[0810]
[0811] To 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.044g, 0.11mmol) To a mixture of nBuOH (0.6 mL) was added 1-(4-4-aminophenyl)piperazin-1-yl)ethanone (0.047 g, 0.22 mmol) and TMSCl (0.043 mL, 0.33 mmol). After heating at 115 °C for 48 h, the mixture was purified by preparative HPLC to obtain 1-(4-(4-(4-(methylamino-5-(pyridin-4-yl)-7H-pyrrolo[2,3- d] pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (0.015 g), MS (MH 443.3), λ = 259.4, 302.1.
Embodiment 3
[0813] N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
[0814]
[0815] To 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.175g, 0.38mmol), Pd(PPh 3 ) 2 Cl 2 (0.053g, 0.076mmol) and pyridin-3-ylboronic acid (0.102g, 0.83mmol) in dioxane (2mL) was added Na 2 CO 3 (0.12 g, 1.14 mmol) in water (1 mL). After degassing, the mixture was heated at 100 °C for 1.5 h. The mixture was purified by flash column chromatography (hexane / EtOAc=1:1) to obtain 2-chloro-N-methyl-5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2 , 3-d] Pyrimidin-4-amine (0.084 g).
[0816] To 2-chloro-N-methyl-5-(pyridin-3-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.075g, 0.182mmol) To a mixture of nBuOH (1 mL) was added 6-aminoindazole (0.048 g, 0.36 mmol) and TMSCl (0.06 mL, 0.46 mmol). After heating at 115 °C for 72 h, the mixture was purified by preparative HPLC to obtain N 2 -(1H-indazol-6-yl)-N 4 -Methyl-5-(pyridin-3-yl)-7H-pyrr...
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