| 88% |
Stage #1: 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 1.25h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; cyclohexane at -78℃; for 1h; |
1.B
A flask was charged with 4-chloro-l-(triisopropylsilyl)-l//-pyrrolo[2,3-ft]pyridine (25.2 g, 82.0 mmol) in THF (400 mL) and cooled to about -78 °C. sec-BuLi (1.4 M in cyclohexane, 116 mL, 163 mmol) was added drop-wise over about 15 min. The mixture was stirred at -78 °C for about 1 h. To the mixture was added DMF (18.9 mL, 245 mmol) drop-wise and the temperature was maintained at about -78 °C for about 1 h. The mixture was quenched by the slow addition of a solution of HCl (4.0 M in 1,4-dioxane, 20.4 mL, 82.0 mmol) followed by the addition of saturated aqueous NaHCC (100 mL). The mixture was extracted with EtOAc (500 mL). The organic layer was allowed to sit at rt overnight. The precipitate formed was collected by filtration. The filtrate formed more precipitate which was collected by filtration again. The precipitated material from both filtrations was combined to give 4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carbaldehyde (12.9 g, 88%): LC/MS (Table 2, Method a) Rt = 1.85 min; MS m/z 181 (M+H) + |
| 14 kg |
Stage #1: 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine With sec.-butyllithium In tetrahydrofuran; cyclohexane at -75 - -60℃; for 8h; Inert atmosphere; Large scale;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; cyclohexane at -75 - -65℃; for 2h; Large scale; |
2.4 Step 4: Synthesis of 4-chloro-lH-pyrrolo [2, 3-bJ pyridine-5 -carbaldehyde
To a 1000 L cryogenic reactor was charged crude 4-chloro-l -(triisopropylsilyl)- IH- pyrrolo|2.3- Ipyridine (50 Kg, -138 mol) and anhydrous THF (150 Kg). The mixture was cooled to -75 °C, and stirred under N2 as L'-BuLi (1.3 M in cyclohexane, 230 L, 300mol, 2.2 eq.) was added drop-wise over about 6.0 h while maintaining internal temperature below -60 °C. The mixture was stirred at -75 °C for additional 2 h. N, A- Dimethyl formamide (30.4 Kg, 4l6.lmol, 3.0 eq.) was added drop-wise over a period of -3.0 h to control the internal temperature below (0759) -65 °C. After being stirred at -65- 75 °C for 2 h, the mixture was quenched by drop-wise addition of a solution of 20% HC1 in isopropyl alcohol (115 Kg, 635 mol, 4.5eq.)· The mixture was then stirred at room temperature (20-25 °C) overnight. The pH was adjusted to 7-8 by charging saturated NaHCCh. The precipitate formed was collected by filtration. The filter cake was washed with 76 L water to give 4-chloro-l//-pyrrolo [2, 3 -b pyridine-5- carbaldehyde (14 Kg, 58% yield): ^NMR (400 MHz, DMSO-de) d 12.54 (s, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 7.74 (m, 1H), 6.72 (m, 1H). |
| 14 kg |
Stage #1: 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine With sec.-butyllithium In cyclohexane at -75 - -60℃; for 0.8h; Inert atmosphere; Large scale;
Stage #2: N,N-dimethyl-formamide In cyclohexane at -75 - -65℃; for 0.5h; Large scale;
Stage #3: With hydrogenchloride In cyclohexane; water; isopropyl alcohol at 20 - 25℃; Large scale; |
2.4 Step 4:
Synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde
To a 1000 L cryogenic reactor was charged crude 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 Kg, ˜138 mol) and anhydrous THE (150 Kg). The mixture was cooled to -75° C., and stirred under N2 as S-BuLi (1.3 M in cyclohexane, 230 L, 300 mol, 2.2 eq.) was added drop-wise over about 6.0 h while maintaining internal temperature below -60° C. The mixture was stirred at -75° C. for additional 2 h. N, N-Dimethylformamide (30.4 Kg, 416.1 mol, 3.0 eq.) was added drop-wise over a period of ˜3.0 h to control the internal temperature below -65° C. After being stirred at -65˜-75° C. for 2 h, the mixture was quenched by drop-wise addition of a solution of 20% HCl in isopropyl alcohol (115 Kg, 635 mol, 4.5eq.). The mixture was then stirred at room temperature (20-25° C.) overnight. The pH was adjusted to 7-8 by charging saturated NaHCO3. The precipitate formed was collected by filtration. The filter cake was washed with 76 L water to give 4-chloro-1H-pyrrolo[2, 3-b]pyridine-5-carbaldehyde (14 Kg, 58% yield): 1HNMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 7.74 (m, 1H), 6.72 (m, 1H). |
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