7H-Pyrrolo[2,3-d]pyriMidin-4-aMine, N-Methyl-N-[(3

Dissolve the compound (3R, 4R)-1-benzyl-N, 4-dimethyl-piperidin-3-amine (4.3 g, 19.7 mmol, 1.0 eq.)In 180 ml of water, the compound 4-chloro-7-(p-toluenesulfonyl)-pyrrolo[2, 3-d]pyrimidine is then added thereto.(12.3 g, 39.2 mmol, 2.0 eq.) and potassium carbonate (16.6 g, 119 mmol, 6.0 eq.). The reaction is performed at 100oC for 16 hoursWhen it is, it is then cooled to room temperature. After adding three times with ethyl acetate (500ml), it is backwashed with water and brine.After drying over sodium sulfate and spin-drying, the resulting crude compound was isolated by column chromatography (ethyl acetate/petroleum ether = 1:1) to give pale yellowThe target compound (8.6 g, yield = 90percent).Add SMA 11.0kg, SMB 12.8kg, DIPEA 19.5kg, DMSO to a 200L reactor50.0 kg, 15.0 kg of purified water, and the temperature was raised to 107°C. After the reaction is complete, add 24.0kg absolute ethanol to room temperature and addWater 30.0kg, stirring and decrystallization 2h, suction filtration, drying at 60±5°C, 17.2kg of white solid. Yield 93.0percent, SMB residue0.3percent, HPLC purity 98.9percent.Example 8; Preparation of [(3R, 4R)-1-benzyl-4-methyl-piperidin-3-yl]-methyl-[7-(4-methyl-benzenesulfonyl)-7H- pyrrolo[2, 3-d]pyrimidin-4-yl]amine:; To a clean, dry, nitrogen-purged reactor were charged 4-chloro-7-(4-methyl-benzenesulfonyl)- 7H-pyrrolo[2, 3-d]pyrimidine (25.12 g, 0.082 mol), bis-(3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)- methylamine di-p-toluoyl-L-tartaric acid (40.31 g, 0.041 mol), potassium carbonate (34.2 g, 0.245 mol), and water (125.6 ml). The mixture was heated to 95-105A mixture of chromium trioxide (49 mg, 0.49 mmol) in sulfuric acid (0.16 mL), acetic acid (0.16 mL) and water (0.11 mL) was added to a stirred solution of 14 (50 mg, 0.24 mmol) in acetone (0.5 mL) at 0 °C. After 2 h at <20 °C the reaction was basified to pH 12 with 33percent aq NH3 at 0 °C and extracted with ether (4*5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (0.17 mL) followed by addition of NH2Me (40percent in MeOH, 0.05 mL, 0.49 mmol) and Ti(OiPr)4 (0.08 mL, 0.27 mmol) at 0 °C. After stirring 30 min at room temperature, the reaction mixture was added sodium borohydride (46.5 g, 1.23 mol) in a small portion in 30 min at °0 C and stirred for an additional hour at the same temperature. The reaction mixture was filtered off to obtain crude amine. The crude amine in water (0.65 mL) was added K2CO3 (65 mg, 0.47 mmol) and 15 (120 mg, 0.39 mmol), and the mixture was refluxed (120 °C) for 16 h under argon. After cooling to rt, the resulting mixture was added CH2Cl2 (5 ml) and sonicated crush the solid. The mixture was extracted with CH2Cl2 (4*5 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes, 1:1) to give trans-16 (8 mg, 7percent) as a white solid and cis-16 (75 mg, 63percent) as a white solid. Rf = 0.4 (trans-16), 0.48 (cis-16) (EtOAc/hexanes, 1:1). trans-16: 1H NMR (400 MHz, CDCl3) δ: 8.35 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 4 Hz, 1H), 7.32–7.18 (m, 7H), 6.53 (br s, 1H), 3.56, 3.45 (ABq, JAB = 12.8 Hz, 2H), 3.08 (s, 3H), 2.90–2.84 (m, 2H), 2.36 (s, 3H), 2.10–1.95 (m, 2H), 1.80–1.65 (m, 3H), 1.50–1.39 (m, 1H), 0.81 (d, J = 6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 158.0, 152.8, 151.7, 145.2, 138.1, 135.1, 129.6, 129.0, 128.2, 127.1, 120.9, 105.6, 104.7, 62.8, 55.4, 53.4, 33.6, 33.4, 21.6, 18.3. cis-16: [a]D28 = +19.3(c 1.0 CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.31 (s, 1H), 8.03 (d, J = 8 Hz, 2H), 7.40 (d, J = 3 Hz, 1H), 7.27–7.17 (m, 7H), 6.63 (d, J = 3.2 Hz, 1H), 5.16 (br s, 1H), 3.56 (s, 3H), 3.47, 3.42 (ABq, JAB = 13.2 Hz, 2H), 2.79–2.76 (m, 1H), 2.75 (br s, 1H), 2.52 (d, J = 10.8, 1H), 2.36 (s, 2H), 2.35–2.22 (m, 1H), 2.10–2.03 (m, 1H), 1.70–1.610 (m, 2H), 0.87 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 189.3, 157.9, 152.5, 151.8, 145.2, 135.1, 129.6, 128.9, 128.2, 128.1, 127.1, 120.6, 106.2, 104.6, 63.5, 55.2 (br), 53.1 (br), 51.6 (br), 35.8 (br), 32.5, 31.2, 21.6, 15.7 (br). HRMS (ESI) calcd for C27H31N5O2S [M+H]+: 490.2277, found: 490.2273.