Selective inhibitors of janus kinase 1 and pharmaceutical uses thereof
A pharmacy and compound technology, applied in the field of Janus kinase inhibitors, can solve the problem of not providing compounds and so on
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Embodiment 1
[0175] Example 1: (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropionitrile
[0176]
[0177]Add 103 mg (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine to a 10 mL round bottom flask, and then use 4.70 mL normal Butanol dissolves. After adding 0.505 mL of ethyl cyanoacetate to it, the reaction mixture was treated with 0.0360 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and heated at about 80 °C About 24 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent. The resulting residue was subjected to flash column chromatography (MeOH:CH 2 Cl 2 =2:98) purification. The resulting fractions were concentrated under reduced pressure, then further concentrated under vacuum. As a result, 101 mg of (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropane was obtained Nitrile, the yield is about 74.8%.
[0178] 1 H NMR (400MHz, CDC...
Embodiment 2
[0180] Example 2: (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)propionitrile
[0181]
[0182] Add 60 mg of (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine to a 5 mL round bottom flask, then add 1.00 mL of di Chloromethane (CH 2 Cl 2 ) dissolved. After adding 0.0240 mL of 3-bromopropionitrile thereto, the reaction mixture was treated with 0.0720 mL of N,N-diisopropylethylamine, and then stirred at room temperature for about 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to flash column chromatography (MeOH:CH 2 Cl 2 =2:98) purification. The resulting fractions were concentrated under reduced pressure and then further concentrated under vacuum. As a result, 55.3 mg of (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)propionitrile was obtained, yield About 74.7%.
[0183] 1 H NMR (400MHz, CDCl 3 )δ9.65(s,1H),8.30(s,1H),7.05(d,J=3.6Hz,1H...
Embodiment 3
[0185] Example 3: (R)-N-(1-butylpyrrolidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[0186]
[0187] Add 80 mg of (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine to a 5 mL round bottom flask, then add 1.00 mL of di Chloromethane (CH 2 Cl 2 ) dissolved. After adding 0.0420 mL of 1-bromobutane thereto, the reaction mixture was treated with 0.0960 mL of N,N-diisopropylethylamine. After adding 20 drops of N,N-dimethylformamide thereto, the resulting reaction mixture was stirred at room temperature for about 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to flash column chromatography (MeOH:CH 2 Cl 2 =2:98) purification. The resulting fractions were concentrated under reduced pressure and then further concentrated under vacuum. As a result, 90.0 mg (R)-N-(1-butylpyrrolidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained in a yield of about was 83.3%.
[0188] 1 ...
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