| 100% |
With lithium aluminium tetrahydride; In tetrahydrofuran; for 4.0h;Reflux; |
500 mg of (R)-3-amino-1-benzylpiperidine was added to a 100-mL round-bottomed flask, and then 5.00 mL of deionized water and 5.00 mL of saturated sodium hydrogen carbonate (NaHCO3) were added thereto. After 602 mg of di-tert-butyl dicarbamate (Boc2O) was added thereto, the reaction mixture was vigorously stirred for about 4 hours and then concentrated under reduced pressure. An aqueous phase was extracted with 20.0 mL of ethyl acetate (EtOAc) to obtain an organic phase. The organic phase was washed with 10.0 mL of deionized water and 15.0 mL of saturated brine. The organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 730 mg of <strong>[454713-13-4]tert-butyl (R)-(1-benzylpiperidine-3-yl)carbamate</strong> was obtained with a yield of about 95.7%. (0273) 730 mg of <strong>[454713-13-4]tert-butyl (R)-(1-benzylpiperidine-3-yl)carbamate</strong> was added to a 100-mL round-bottomed flask, and then 12.0 mL of tetrahydrofuran was added thereto. After 601 mg of lithium aluminum hydride (LiAlH4) was added thereto, the reaction mixture was refluxed for about 4 hours and then cooled at room temperature. 1.5 mL of deionized water was slowly added thereto while cooling. After the reaction mixture was stirred for about 5 minutes, 1.5 mL of a 15% sodium hydroxide (NaOH) aqueous solution was added thereto. The reaction mixture was further stirred for about 5 minutes, and then 2.0 mL of deionized water was added thereto to terminate the reaction. The reaction mixture was filtered through a Celite 545 filter agent. The resulting filtrate was distilled under reduced pressure. As a result, 580 mg of (R)-1-benzyl-N-methylpiperidine-3-amine was obtained with a quantitative yield. (0274) 580 mg of (R)-1-benzyl-N-methylpiperidine-3-amine was added to a 100-mL round-bottomed flask, and then 12.0 mL of deionized water was added thereto. After 458 mg of 6-chloro-7-deazapurine and 785 mg of potassium carbonate (K2CO3) were added into the reaction mixture, the reaction mixture was refluxed for about 24 hours and then collected at room temperature. The reaction mixture was extracted three times with 10.0 mL of dichloromethane (CH2Cl2) to collect an organic phase. The collected organic phase was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). As a result, 440 mg of (R)-N-(1-benzylpiperidine-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 48.2%. (0275) 438 mg of (R)-N-(1-benzylpiperidine-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 50-mL round-bottomed flask and then dissolved with 5.00 mL of methanol. After 400 mg of a 10w/w% palladium/ carbon (Pd/C) was added thereto, a hydrogen-containing balloon was installed on the reaction flask. The reaction mixture was vigorously stirred for about 24 hours and then filtered through a Celite 545 filter agent. The resulting filtrate was concentrated under reduced pressure. The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 310 mg of (R)-N-methyl-N-(piperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 98.4%. (0276) 90.0 mg of (R)-N-methyl-N-(piperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask, and then dissolved with 1.70 mL of n-butanol. After 0.414 mL of ethyl cyanoacetate was added into the solution, the reaction mixture was treated with 0.0291 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and then heated at about 80C for about 24 hours. After termination of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 42.0 mg of (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropanenitrile was obtained with a yield of about 36.2%. (0277) 1H NMR (400 MHz, CDCl3) 510.41 (d, J = 84 Hz, 1H), 8.32 (s, 1H), 7.13-7.12 (m, 1H), 6.62-6.59 (m, 1H), 4.79-4.72 (m, 1H), 4.67 (d, J = 11.2 Hz, 1H), 3.91 -3.55 (m, 3H), 3.38 (s, 2H), 3.27 (s, 1H), 3.12 (q, J = 11.2, 13.2 Hz, 1H), 2.65-2.58 (m, 1H), 2.11-2.08 (m, 1H), 2.02-1.69 (m, 3H). (0278) LRMS (ESI) calcd for (C15H18N6O + H+) 299.2, found 299.1. |
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