(3S)-(+)-1-Benzyl-3-(methylamino)pyrrolidine

131852-53-4

169749-99-9

1. To a 100 mL round bottom flask was added 720 mg of (S)-1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine. 11.5 mL of tetrahydrofuran and 623 mg of lithium aluminum hydride (LiAlH4) were added sequentially and the reaction mixture was refluxed for 4 hours and subsequently cooled to 0°C. 1.16 mL of deionized water was slowly added and stirred for 5 minutes followed by 1.16 mL of 15% aqueous sodium hydroxide. Stirring was continued for 5 minutes and the reaction was terminated by adding 3.80 mL of deionized water. The reaction mixture was filtered through Celite 545, the filtrate was concentrated under reduced pressure and the residue was purified by fast column chromatography (MeOH:CH2Cl2:NH4OH = 5:90:5) to give 440 mg (S)-1-benzyl-N-methylpyrrolidin-3-amine in 89.9% yield. 2. 440 mg of (S)-1-benzyl-N-methylpyrrolidin-3-amine and 9.00 mL of deionized water were added to a 25 mL round-bottom flask, followed by 373 mg of 6-chloro-7-deazapurine and 639 mg of potassium carbonate. The reaction mixture was refluxed for 36 hours, cooled to room temperature and extracted three times with 40.0 mL of dichloromethane. The organic phases were combined, concentrated under reduced pressure and the residue was purified by fast column chromatography (MeOH:CH2Cl2 = 2:98) to afford 544 mg (S)-N-(1-benzylpyrrolidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine in 76.6% yield. 3. 534 mg of (S)-N-(1-benzylpyrrolidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added to a 25 mL round bottom flask and dissolved in 5.00 mL of methanol. 534 mg 10% w/w palladium/carbon (Pd/C) was added, a hydrogen balloon was mounted and stirred vigorously overnight. The reaction mixture was filtered through Celite 545, the filtrate was concentrated under reduced pressure and the residue was purified by fast column chromatography (MeOH:CH2Cl2 = 2:98) to afford 250 mg (S)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine in 66.1% yield. 4. 150 mg of (S)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added to a 5 mL round-bottom flask and dissolved in 2.25 mL of n-butanol. 0.0730 mL of ethyl cyanoacetate and 0.0520 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added and heated at 80°C for 24 hours. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was purified by fast column chromatography (MeOH:CH2Cl2 = 2:98) to afford 140 mg of (S)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile in 71.4% yield. 5. The product was analyzed by 1H NMR. 5. The product was characterized by 1H NMR (400 MHz, CDCl3) and LRMS (ESI). 1H NMR data: δ 10.39 (s, 1H), 8.33 (s, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.60 (s, 1H), 5.89-5.56 (m, 1H), 3.96-3.72 (m, 2H), 3.69-3.72 (m, 2H), 3.69-3.72 (m, 2H). 2H), 3.69-3.49 (m, 2H), 3.46 (t, J = 5.4 Hz, 2H), 3.35 (d, J = 14.9 Hz, 3H), 2.40-2.13 (m, 2H).LRMS (ESI): Calculated (C14H16N6O + H+) 285.2, measured 285.1.