| 99% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil for 1h; Cooling with ice;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 20℃; for 24h; |
3 4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
REFERENCE SYNTHETIC EXAMPLE 3 4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.84 g, 18.6 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL), and sodium hydride (55 wt% dispersion in mineral oil, 1.08 g, 27.0 mmol) was added to it at ice bath temperature, and the mixture was stirred for 1 hour. Triisopropylsilyl chloride (6.0 mL, 28 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. The reaction mixture was mixed with water and extracted with hexane twice. The resulting organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (only hexane) to obtain the title compound as a reddish brown oil (5.74 g, yield: 99%). |
| 97% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h;
Stage #2: triisopropylsilyl chloride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; |
1.1 Step 1: synthesis of 4-chloro-1-(triisopropylsilyl)-7-azaindole
4-chloro-7-azaindole (100.00 g, 655.39 mmol) was dissolved in DMF (1.2 L) at room temperature, and cooledto 0° C in an ice bath. NaH (39.47 g, 983.09 mmol) was added in batches and stirred for 1 hour at 0° C after the additionwas complete. Triisopropylchlorosilane (190.80 g, 983.09 mmol, TIPSCl for short) was dropwise added and warmed toroom temperature. The reaction continued for 2 hours. The reaction was poured into 2 L of ice water, and extracted withpetroleum ether (1 L x2). The organic phases were combined, washed with saturated brine (1 L x3), concentrated underreduced pressure to dryness, and subjected to column chromatography (PE:EA=1:0) to obtain 197.50 g of a colorlesstransparent liquid, with a yield of 97%. |
| 93.5% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; hexane at 0℃; for 0.25h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; hexane at 80℃; for 18h; Further stages.; |
|
| 93% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide at 0 - 25℃; for 0.5h; Inert atmosphere;
Stage #2: triisopropylsilyl chloride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; |
1.B.1 Step 1: 4-chloro-l-(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridine
[0156] To a solution of 4-chloro-lH-pyrrolo[2,3-b]pyridine (30 g, 196 mmol) in (0276) dimethylformamide (300 mL) was added sodium hydride (10 g, 255 mmol, 60% purity) at 0 °C under nitrogen. The mixture was stirred at 25 °C for 0.5 hour, then cooled to 0 °C. Triisopropyl- chlorosilane (49 g, 255 mmol) was added to the mixture at 0 °C. The reaction was stirred at room temperature for 0.5 hour. Upon completion, the mixture was quenched with water (500 mL),extracted with ethyl acetate (3x 300 mL). The organic layer was washed by water (200 mL), brine (2x 200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 4-chloro-l-(triisopropylsilyl)-lH- pyrrolo[2,3-b]pyridine (56.8 g, 93% yield) as a colorless oil |
| 93.84% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h;
Stage #2: triisopropylsilyl chloride In N,N-dimethyl-formamide; mineral oil at 0 - 70℃; for 12h; Inert atmosphere; |
5; 68
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (10 g, 65.54 mmol, 1 eq) in DMF (200 mL) was added NaH (3.93 g, 98.31 mmol, 60% purity, 1.5 eq) portionwise at 0°C, the resulting mixture was stirred at 0oC for 30 min. Then TIPSCl (25.27 g, 131.08 mmol, 28.05 mL, 2 eq) was added dropwise at 0°C under N2 atmosphere, and the resulting mixture was heated to 70°C for 12 h. The reaction mixture was quenched by adding saturated aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 10/1) to give (4-chloropyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane (19 g, 61.50 mmol, 93.84% yield) as a yellow oil.1H NMR (CDCl3, 400 MHz) d 8.05 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 5.2 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 1.79-1.73 (m, 3H), 1.03 (d, J = 7.6 Hz, 18Hz) |
| 92% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h;
Stage #2: triisopropylsilyl chloride at 0℃; |
|
| 92% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; mineral oil at 0℃; |
3.4 Synthesis of 4
Synthesis of 4 5 g of NaH (60% on mineral oil) are added in portions to a solution of 16 g of intermediate 3 in 500 ml of THF at 0° C. When the addition is complete, the mixture is left to stir at the temperature indicated for a further 20 min, and 22.3 g of triisopropylsilyl chloride are added dropwise at this temperature. When the reaction is complete, the mixture is worked up using saturated ammonium chloride solution, diluted with water and extracted with petroleum ether. The crude product obtained is chromatographed on silica gel with petroleum ether, giving product 4 in 92% (30 g) yield as colourless liquid; LCMS: (method A) 309.2 (M+H), RT. 7.56 min, 93.4% (max); 1H NMR 400 MHz, DMSO-d6: δ [ppm] 8.18 (d, J=5.16 Hz, 1H), 7.59 (d, J=3.80 Hz, 1H), 7.23 (d, J=5.16 Hz, 1H), 6.67 (d, J=3.52 Hz, 1H), 1.82-1.90 (m, 3H), 1.05 (d, J=7.52 Hz, 18H). |
| 92.6% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; mineral oil at 0℃; |
1.1 Step 1: Preparation of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 2a)
Add NaH (60% in mineral oil, 5g, 0.14mol) to a stirred solution of 1a (16.0g, 0.10mol) in THF (300ml) at 0°C,And stir the mixture for 20 minutes at the same temperature,Then triisopropylsilyl chloride (22.3g, 0.16mol) was added dropwise,Keep the temperature at 0°C. After the reaction was completed, the reaction mixture was quenched with saturated NH 4 Cl solution (10 mL), diluted with water and extracted with ethyl acetate (3×200 ml). The crude compound was purified by column chromatography to obtain 30.0 g of colorless oily liquid 2a with a yield of 92.6%. |
| 92.6% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; mineral oil at 0℃; |
1.1 Step 1: Preparation of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 2a)
Add NaH (60% in mineral oil, 5g, 0.14mol) to a stirred solution of 1 (16.0g, 0.10mol) in THF (300ml) at 0°C, And stir the mixture for 20 minutes at the same temperature, Then triisopropylsilyl chloride (22.3g, 0.16mol) was added dropwise, keeping the temperature at 0°C. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl solution (10 mL), Dilute with water and extract with ethyl acetate (3×200 ml). Purify the crude compound by column chromatography, 230.0 g of a colorless oily liquid was obtained with a yield of 92.6%. |
| 91% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; mineral oil at 20℃; |
1.A
A flask was charged with 4-chloro-l//-pyrrolo[2,3-&]pyridine (6.0 g, 39 mmol, Arkpharm) and THF (100 mL). The mixture was cooled to about 0 °C and 60 wt% NaH (1.89 g, 47.2 mmol) was added portion-wise. The mixture was warmed to rt and after about 45 min. TIPSC1 (12.5 mL, 59.0 mmol) was added drop-wise and mixture was allowed to stir overnight at rt. The mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgS04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of 0 to 10% EtO Ac/heptane to give 4-chloro-l- (triisopropylsilyl)-lH-pyrrolo [2, 3 -b] pyridine (11.0 g, 91%): .H NMR (J-DMSO) δ 8.20 (d, J = 5.17 Hz, 1H), 7.59 (d, J =3.55 Hz, 1H), 7.23(d, J =5.16 Hz, 1H), 6.68 (d, J = 3.50 Hz, 1H), 1.83 (m, 3H), 1.06 (m, 18H). |
| 91% |
With sodium hydride In tetrahydrofuran at 0 - 20℃; |
1.1 Example 1:
step 1: To a three-necked flask was added 4-chloro-7-azaindole (50 g, 329 mmol) and tetrahydrofuran (700 mL)Sodium hydride (60%, 9.5 g, 395 mmol) and triisopropylchlorosilane (94.8 g, 494 mmol) were added successively at 0 ° C and the reaction stirred overnight at room temperature.At 0 ° C, saturated aqueous ammonium chloride solution (200 mL) was added and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate and filtered.The filtrate was spin dried and the crude product was chromatographed on silica gel (petroleum ether) to give a colorless liquid, Compound 1 (92.1 g, 299 mmol, 91%) |
| 90% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; mineral oil at 50℃; Inert atmosphere; |
|
| 79% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide at 5℃; for 1h;
Stage #2: triisopropylsilyl chloride In N,N-dimethyl-formamide for 1h; |
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (7)
To a solution of 3 (25 g, 164 mmol) in DMF (250 mL), 60% NaH (7.9 g, 197 mmol) was added portionwise at 5°C. The mixture was stirred at the same temperature for 1 h, and then TIPSCl (36 mL, 172 mmol) was added. After stirring for additional 1 h, EtOAc and H2O were added to the mixture. The organic layer was separated, washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography with n-hexane to give the title compound (40 g, 79%). 1H-NMR (DMSO-d6) δ: 1.06 (18H, d,J=7.5 Hz), 1.79-1.91 (3H, m), 6.68 (1H, d, J=3.5 Hz), 7.24 (1H,d, J=5.2 Hz), 7.60 (1H, d, J=3.5 Hz), 8.20 (1H, d, J=5.2 Hz). MS (ESI) m/z: 309 (M+H)+. |
| 76% |
With sodium hydride In tetrahydrofuran at 80℃; |
|
| 68% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.75h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran at 20 - 80℃; for 8h; |
2 Preparation of methyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo [2,3-b] pyridine-5-carboxylate (2)
Compound (1) (985 mg, 6.45 mmol) was dissolved in tetrahydrofuran (15 ml) and sodium hydride (308 mg, 60%, 7.74 mmol) was added portionwise at 0 ° C. The mixture was stirred at room temperature for 45 minutes, then TRIISOPROPYLSILYLCHLORIDE (TIPSCl) (2.05 ml, 9.68 mmol) was added dropwise, followed by stirring at room temperature for 8 hours. To this mixture was added water (30 ml) and extracted three times with ethyl acetate (30 ml). Magnesium sulfate (MgSO4) is added to the obtained organic layer to remove remaining water, and then filtered using a filter paper. The mixture was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (hexane: dichloromethane = 7: 1) to give compound (2) in the form of a pale brown oil. (1350 mg, 68% yield): |
| 65.85% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran at 75℃; Inert atmosphere; |
3.I Part I - Synthesis of 4-chloro- 1 - (triisopropylsilyl) pyrrolo[2,3-b] pyridine
[0782] To a stirred solution of 4-chloro- 1H-pyrrolo[2,3-b]pyridine (450.0 g, 2949.0 mmol, 1.0 equiv) in THF (4,500 mL) was added NaH (106.2 g, 4424.0 mmol, 1.5 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for lh at 0 °C under nitrogen atmosphere. Then chlorotris(propan-2-yl)silane (853.0 g, 4424.0 mmol, 1.5 equiv) was added. The resulting mixture was stirred overnight at 75 °C under nitrogen atmosphere. The reaction was quenched by the addition of water/ice (5,000 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 2,000 mL). The combined organic layers were washed with brine (1x1000 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 4-chloro- 1 -(triisopropylsilyl) pyrrolo [2,3 -b]pyridine (600 g, 65.85%) as a light yellow oil. |
| 65.85% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran at 75℃; Inert atmosphere; |
3.I Part I - Synthesis of 4-chloro- 1 - (triisopropylsilyl) pyrrolo[2,3-b] pyridine
[0782] To a stirred solution of 4-chloro- 1H-pyrrolo[2,3-b]pyridine (450.0 g, 2949.0 mmol, 1.0 equiv) in THF (4,500 mL) was added NaH (106.2 g, 4424.0 mmol, 1.5 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for lh at 0 °C under nitrogen atmosphere. Then chlorotris(propan-2-yl)silane (853.0 g, 4424.0 mmol, 1.5 equiv) was added. The resulting mixture was stirred overnight at 75 °C under nitrogen atmosphere. The reaction was quenched by the addition of water/ice (5,000 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 2,000 mL). The combined organic layers were washed with brine (1x1000 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 4-chloro- 1 -(triisopropylsilyl) pyrrolo [2,3 -b]pyridine (600 g, 65.85%) as a light yellow oil. |
| 60.4% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
Stage #2: triisopropylsilyl chloride In N,N-dimethyl-formamide at 0 - 70℃; |
1
00257] NaH (0.177 g, 4.42 mmol) was added to 4-chloro-lH-pyrrolo[2,3-b]pyridine(0.450 g, 2.95 mmol) in dimethylformamide ("DMF"; 5 mL) at 00C. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was then cooled to 00C. Chlorotriisopropylsilane (0.945 mL, 4.42 mmol) was added to the mixture. The reaction mixture was warmed to 700C and stirred for 2 hours. Next, the reaction was poured into water (50 mL) and extracted with DCM (3 X 50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The resulting residue was purified by column chromatography (10: 1 hexanes:DCM) to give 4-chloro-l-(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridine (0.55 g, 60.4% yield). |
| 37% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran at 20℃; |
406.1 Example 406: 4-chloro-1-methyl-1H-pyrrolo[2,3-b] pyridine-5-carboxylic acid (4-isopropylphenyl)amide
To a solution of 4-chloro-1H-pyrrolo[2,3-bjpyridine (2.0 g, 13.3 mmol) in THF (15 mL) was added NaH (60%, 630 mg, 15.76 mmol) at 0 °C in portions. After stirring at room temperature for 1 hr, chlorotriisopropyl-silane (3.3 g, 17.1 mmol) was added and stirred at rt overnight. The reaction was poured into water (50 mL) and extracted with EA (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column (PE/EA = 50/1) to give 4-chloro-1- triisopropylsilanyl-1H-pyrrolo[2,3-bjpyridine (1.5 g, yield: 37%) as a yellow oil.‘HNMR (400 MI-Tz, CDC13): = 8.13 (d, J= 5.2 Hz, 1H), 7.32 (d, J= 3.6 Hz, 1H), 7.05 (d, J 4.8 Hz, 1H), 6.65 (d,J= 3.2 Hz, 1H), 1.88-1.81 (m, 3H), 1.12-1.09 (m, 18H). |
|
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Inert atmosphere;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; mineral oil for 3h; Reflux; |
15.A
Step A: 4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine In a round-bottomed flask under argon, 6 g (39.32 mmol) of 4-chloro-1H-pyrrolo[2,3-b]pyridinc are dissolved in 90 ml of tetrahydrofuran and cooled to 0° C. 1.73 g (43.25 mmol) of sodium hydride (60% in oil) are then added in portions. The mixture is stirred for 15 minutes at 0° C. 8.42 ml (39.32 mmol) of triisopropylsilyl chloride are then added. The reaction mixture is stirred for 3 hours at reflux. It is hydrolyzed with 50 ml of saturated ammonium chloride solution and extracted 3 times with 50 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (pure petroleum ether, then petroleum ether/ethyl acetate: 95/5) to yield the title product in the form of a yellowish oil. MS: m/z=309 [M+H]+35Cl; 311 [M+H]+37Cl. |
|
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran
Stage #2: triisopropylsilyl chloride In tetrahydrofuran at 80℃; for 3h; |
76.1
Step 1. Preparation of 4-chloro-l-(triisopropylsilyl)-lH- pyrrolo [2,3-b]pyridine; Sodium hydride (880 mg, 22 mmol, 1.1 equiv, 60% in mineral oil) was washed with 15 mL of dry hexanes under an argon atmosphere. Most of the hexanes were removed and replaced with 40 mL of THF. 4-Chloro-7-azaindole was added portionwise into the sodium hydride suspension. The suspension was stirred until the gas evolution ceased. Triisopropylchlorosilane (3 g, 20 mmol, 1 equiv) was added via syringe. The reaction was placed in a preheated oil bath at 80 °C and monitored by LC-MS and TLC. After 3 hours, the A-909 - 140 - reaction was cooled to room temperature. The reaction was quenched slowly with saturated NH4CI. The product was extracted with hexanes and EtzO. The organic layers were combined, washed with brine, dried over MgS04, and concentrated. The residue was passed through a plug of silica gel with an aid of hexanes to remove the baseline spots. The filtrate was concentrated to afford 4-chloro-1- (triisopropylsilyl) -1H-pyrrolo[2,3-b]pyridine as a viscous colorless oil. |
|
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran at 25℃; for 20h; |
2.3 Step 3: Synthesis of 4-chloro-l-(triisopropylsilyl)-lH-pyrrolo [2, 3-b]pyridine
A solution of crude 4-chloro-lH-pyrrolo[2,3-b]pyridine (24 Kg, 155.2 mol) in THF (216 L) was stirred 0 °C as NaH (60%, 7.56 Kg, 188.6 mol, 1.3 eq.) was added portion-wise under N2. After addition, the mixture was stirred at rt for 1 h. Triisopropylsilyl chloride (39.6 Kg, 188.6 mol, l .3eq) was added drop-wise while maintaining a temperature below 25 °C. After stirring for 20 h, the mixture was quenched with 144 L water and extracted with 144 L heptane. The water layer was back extracted with 72 L methyl /-butyl ether. The combined organic layers were dried over anhydrous MgSCft and concentrated under vacuum to give crude 4-chloro- l -(triisopropylsilyl)- l //-pyrrolo| 2. 3-b]pyridine as a liquid. The material was used without purification, but its water content was controlled to below 0.1%. |
|
Stage #1: 4-chloro-1H-pyrrolo[2,3-b]pyridine With pyridine; sodium hydride In mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Large scale;
Stage #2: triisopropylsilyl chloride In mineral oil at 20 - 25℃; for 20h; Large scale; |
2.3 Step 3:
Synthesis of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2, 3-b]pyridine
A solution of crude 4-chloro-1H-pyrrolo[2,3-b]pyridine (24 Kg, 155.2 mol) in THE (216 L) was stirred 0° C. as NaH (60%, 7.56 Kg, 188.6 mol, 1.3 eq.) was added portion-wise under N2. After addition, the mixture was stirred at rt for 1 h. Triisopropylsilyl chloride (39.6 Kg, 188.6 mol, 1.3eq) was added drop-wise while maintaining a temperature below 25° C. After stirring for 20 h, the mixture was quenched with 144 L water and extracted with 144 L heptane. The water layer was back extracted with 72 L methyl t-butyl ether. The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to give crude 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2, 3-b]pyridine as a liquid. The material was used without purification, but its water content was controlled to below 0.1%. |
|
With sodium hydride In tetrahydrofuran; mineral oil at 5 - 25℃; Large scale; |
1 Example 1: Preparation of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5- carboxylate hydrochloride (STG-02 HCl Salt) [
To a suspension of NaH (2.01 Kg, 60% oil dispersion, 1.4 eq.) in THF (55.0 L, 10.0 vol.) was added 4-chloro-1H-pyrrolo[2,3-b] pyridine (SM-01, 5.5 Kg, 1.0 eq.) in THF (110.0 L, 20.0 vol.) slowly at 25±5 °C. Reaction mass was cooled to 5±5 °C and Tri- isopropylsilyl chloride (8.33 kg, 1.2 eq.) was added at same temperature. The reaction mass temperature was raised to 25±5 °C and stirred for 1-2 h, progress of the reaction was monitored by TLC. Reaction mass was cooled to -87.5±7.5 °, slowly added Sec-BuLi (23.79 Kg, 1.4M in cyclohexane solution, 1.2 eq.) at -87.5±7.5 °C under nitrogen atmosphere. Stirred the reaction mass at -87.5±7.5 °C for 1h ±15 min under nitrogen atmosphere. A mixture of Ethyl Chlorofomate (5.88 Kg, 1.5 eq.) in THF (5.5 L, 1.0 vol) was added slowly into the reaction mass at -87.5±7.5 °C (addition is exothermic) under nitrogen atmosphere. The reaction mixture was stirred for 1h ±15 min at -87.5±7.5 °C under nitrogen atmosphere. Reaction was monitored by HPLC (Limit NMT 5.0% by HPLC). After completion of reaction, aq. Ammonium chloride solution (8.0 vol.) was slowly added at -87.5 to -40 °C under nitrogen atmosphere. Reaction mass temperature was increased to 25±5 °C and it was extracted with MTBE (2x6.0 vol.) at 30±5 °C. The organic layer was washed with purified water (5.0 vol.) at 30±5 °C followed by washing with aqueous sodium chloride solution (10%, 5.0 vol.). Organic layer was evaporated under reduced pressure to obtain the crude (16.5 Kg). Ethanol (2.0 vol.) was added to the crude compound at 25±5 °C. EtOH.HCl (27.5 L, 5M, 20%, 5.0 vol.) was added slowly at 25±5 °C and stirred for 1-2 h.The resulting solids were filtered, washed with ethanol (1-2 vol.) and dried under vacuum at 45 ± 5 °C to obtain the ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate hydrochloride (STG-01) as an off-white solid (7.25 Kg, 77%). 1H NMR (400 MHz, CDCl3), δ ppm: 13.48 (bs, 1H), 11.60 (bs, 1H), 9.02 (s, 1H), 7.76-7.75 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 4.52-4.47 (q, J = 7.2,7.2,7.2 Hz, 2H), 1.48-1.44 (t, 7.2, 7.2 Hz, 3H). MS(ES) m/z = 225.42 [M+H] |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
