* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8859 - 8874
2
[ 348640-02-8 ]
[ 7546-50-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8859 - 8874
3
[ 271-63-6 ]
[ 98-59-9 ]
[ 348640-02-8 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃;
1-(4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine To a stirred solution of 7-azaindole (6.0 g, 50.0 mmol, 1.0 eq.) in THF (20 mL) was added NaH (60percent dispersion in mineral oil, 2.2 g, 66.0 mmol, 1.3 eq.) at 0° C. The reaction mixture was allowed to warm to rt and stirred for 30 min. After cooling to 0° C., TsCl (11.6 g, 2.1 mmol, 1.2 eq.) was added to the reaction mixture and it was stirred at rt overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (EtOAc gradient in hexane) to give 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 1a) as a white solid (12.8 g; yield: 93percent; UPLC purity: 100percent).
87%
With sodium hydroxide In water at 20℃; for 4 h;
To a mixture of 209-1 (45.0 g, 381.4 mmol), para-toluenesulfonyl chloride (80.1 g, 421.6 mmol) and a catalytic amount of tetrabutyl ammonium bromide (TBABr) in toluene (540 ml) was added aq. NaOH (288.0 g in 900 ml water, 7.2 mol). The biphasic solution was stirred at ambient temperature for 4 h, and then extracted twice with toluene. The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude product was triturated in ethyl acetate/petroleum ether (V:V=1:20) and filtrated to afford the compound 209-2 (90g, 87percent yield). MS-ESI: m/z=273.1 [M+1]+
330 g
With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 20 - 30℃;
Example 1B: 1-tosyl-1H-pyrrolo[2,3-b]pyridine. [0286] A flask was charged with 1H-pyrrolo[2,3-b]pyridine (350.0 g, 2.963 mol) and toluene (2800 mL), followed by 4-toluenesulfonyl chloride (626.9 g, 3.288 mol) and TBAB (9.55 g, 0.0296 mol) in toluene (2800 mL). An aqueous solution of 25percent NaOH (1185.2 g) was added dropwise into the mixture while controlling the temperature between 20 —30 °C. The mixture was stirred at 20 —25 °C overnight. Water (700 ml) and THF (1750 ml) were added to the mixture and aqueous phase was extracted with THF (2 x 1750 ml). The organic phase was washed with brine (2 x 1750 mL) and dried over Mg2SO4. The organic phase was then concentrated to 700 — 850 mL and filtered. The cake was then washed with n-heptane (3 x 350 ml). After drying, 330 g of 1-tosyl-1H-pyrrolo[2,3-b]pyridine was obtained.
Reference：
[1] Patent: US2018/179199, 2018, A1, . Location in patent: Paragraph 0445-0446
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 39, p. 11859 - 11862[3] Angew. Chem., 2016, vol. 128, p. 12038 - 12041,4
[4] Chemistry Letters, 2011, vol. 40, # 6, p. 555 - 557
[5] Patent: US2009/318455, 2009, A1, . Location in patent: Page/Page column 98-99
[6] Chemical Communications, 2016, vol. 52, # 23, p. 4329 - 4332
[7] Patent: US2004/9983, 2004, A1, . Location in patent: Page/Page column 107
[8] Patent: US2009/253679, 2009, A1, . Location in patent: Page/Page column 37
[9] Chemical Biology and Drug Design, 2010, vol. 76, # 2, p. 100 - 106
[10] Patent: WO2015/27005, 2015, A1, . Location in patent: Paragraph 0285; 0286
[11] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7195 - 7216
[12] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8859 - 8874
4
[ 13578-51-3 ]
[ 55052-24-9 ]
[ 348640-02-8 ]
[ 935466-64-1 ]
[ 1219601-43-0 ]
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 8, p. 2722 - 2725
5
[ 348640-02-8 ]
[ 866545-91-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7195 - 7216
[2] Patent: US2018/179199, 2018, A1,
6
[ 348640-02-8 ]
[ 1198416-32-8 ]
Yield
Reaction Conditions
Operation in experiment
58%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.33333 h; Stage #2: With 1,2-dibromo-1,1,2,2-tetrachloroethane In tetrahydrofuran; hexane at -78 - 20℃;
A solution of 209-2 (50.0 g, 183.8 mmol) in dry THF cooled to -78° C. and n-BuLi (81 ml, 2.5 M in hexane) was added over 20 minutes. The resulted solution was maintained at -78° C. for 1 h, and then a solution of BrCl2CCCl2Br (71.0 g, 220.5 mmol) in dry THF was added. The mixture was stirred -78° C. for 30 min and allowed to warm slowly to room temperature. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (5percent ethyl acetate in petroleum ether to 20percent ethyl acetate in petroleum ether as the eluent) to afford 209-3 (37 g, 58percent yield). MS-ESI: m/z=351.0 [M+1]+
1-(4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine To a stirred solution of 7-azaindole (6.0 g, 50.0 mmol, 1.0 eq.) in THF (20 mL) was added NaH (60% dispersion in mineral oil, 2.2 g, 66.0 mmol, 1.3 eq.) at 0 C. The reaction mixture was allowed to warm to rt and stirred for 30 min. After cooling to 0 C., TsCl (11.6 g, 2.1 mmol, 1.2 eq.) was added to the reaction mixture and it was stirred at rt overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (EtOAc gradient in hexane) to give 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 1a) as a white solid (12.8 g; yield: 93%; UPLC purity: 100%).
87%
With sodium hydroxide;tetrabutylammomium bromide; In water; at 20℃; for 4h;
To a mixture of 209-1 (45.0 g, 381.4 mmol), para-toluenesulfonyl chloride (80.1 g, 421.6 mmol) and a catalytic amount of tetrabutyl ammonium bromide (TBABr) in toluene (540 ml) was added aq. NaOH (288.0 g in 900 ml water, 7.2 mol). The biphasic solution was stirred at ambient temperature for 4 h, and then extracted twice with toluene. The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude product was triturated in ethyl acetate/petroleum ether (V:V=1:20) and filtrated to afford the compound 209-2 (90g, 87% yield). MS-ESI: m/z=273.1 [M+1]+
With sodium hydroxide;tetrabutylammonium sulfate; In water; toluene; at 20℃; for 3h;
To a solution of 7-azaindole (25 g), para-toluenesulfonyl chloride (44.5 g) and a catalytic amount of tetrabutylammoniun sulfate in dry toluene (300 mL) was added sodium hydroxide (160 g in 500 mL of water). The biphasic solution was stirred at ambient temperature for 3 hours then extracted twice with toluene (100 mL). The combined extracts were dried over magnesium sulfate then concentrated under vacuo. The resultant solid was triturated with diethyl ether then dried at 60 C. under vacuo to yield the title compound (39.74 g) as a pale yellow solid, m.p. 136-138 C.
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 0 - 20℃; for 4h;Inert atmosphere;
Introduce, i.e. add, 100 mg of N,N,N-tributylbutane-1-ammonium hydrogen sulphate and 8.75 g of 4-methylbenzenesulphonyl chloride to a solution of 4.72 g of 1H-pyrrolo[2,3-b]pyridine in 110 cm3 of toluene. To the mixture cooled to 0 C., add a solution of 20.8 g of sodium hydroxide in 110 cm3 of water. Stir the reaction mixture under argon at a temperature close to 20 C. for four hours then add 100 cm3 of water. Extract the resultant mixture with 200 cm3 then 100 cm3 of ethyl acetate. Wash the combined organic phases with a saturated aqueous solution of sodium chloride, dry over magnesium sulphate, filter and concentrate to dryness at reduced pressure. 10.9 g of 1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a white powder with the following characteristics: Rf TLC silica=0.34 [eluent: heptane/ethyl acetate (70/30 by volume)] Mass spectrum: LC-MS-DAD-ELSD: 273(+)=(M+H)(+) 295(+)=(M+Na)(+)
330 g
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 20 - 30℃;
Example 1B: 1-tosyl-1H-pyrrolo[2,3-b]pyridine. [0286] A flask was charged with 1H-pyrrolo[2,3-b]pyridine (350.0 g, 2.963 mol) and toluene (2800 mL), followed by 4-toluenesulfonyl chloride (626.9 g, 3.288 mol) and TBAB (9.55 g, 0.0296 mol) in toluene (2800 mL). An aqueous solution of 25% NaOH (1185.2 g) was added dropwise into the mixture while controlling the temperature between 20 -30 C. The mixture was stirred at 20 -25 C overnight. Water (700 ml) and THF (1750 ml) were added to the mixture and aqueous phase was extracted with THF (2 x 1750 ml). The organic phase was washed with brine (2 x 1750 mL) and dried over Mg2SO4. The organic phase was then concentrated to 700 - 850 mL and filtered. The cake was then washed with n-heptane (3 x 350 ml). After drying, 330 g of 1-tosyl-1H-pyrrolo[2,3-b]pyridine was obtained.
A solution of <strong>[348640-02-8]1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine</strong> 154.4 g, Reference Example 9(a)] in dry tetrahydrofuran (1200 mL) cooled to -78 C., was treated with a solution of butyllithium in hexanes (2.5M, 92 mL) over a 20 minute period. The solution was maintained at -78 C. for 30 minutes, then a solution of iodine (101 g) in tetrahydrofuran (600 mL) was added until the iodine colour persisted (ca.300 mL). The mixture was allowed to warm slowly to ambient temperature and the solvent removed under vacuo. The residue was partitioned between ethyl acetate (1000 mL) and water (500 mL) and the water re-extracted with ethyl acetate (2*500 mL). The organic extracts were combined, dried over sodium sulfate and removed under reduced pressure to give a yellow solid which was triturated with diethyl ether to give the title compound (79.6 g) as a pale yellow solid. m.p. 105-107 C. MS: 399(MH+).
Cool a solution of 2 g of <strong>[348640-02-8]1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine</strong> in 20 cm3 of tetrahydrofuran to a temperature close to -70 C. using a dry ice/acetone bath. At this temperature and under argon, add dropwise 9.2 cm3 of a 1.6M solution of n-butyllithium in hexane. Stir the reaction medium (or mixture) at this temperature for thirty minutes then add 1.37 cm3 of methyl iodide. Stir the mixture under argon at a temperature close to -70 C. for three hours. After heating the mixture to a temperature close to 0 C., add 20 cm3 of water, then allow the temperature to approach 20 C. and extract with three times 50 cm3 of ethyl acetate. Wash the combined organic phases with a saturated aqueous solution of sodium chloride, dry over magnesium sulphate, filter and concentrate to dryness at reduced pressure. 2.2 g of 2-methyl-<strong>[348640-02-8]1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine</strong> is obtained in the form of a beige powder with the following characteristics: 1H-NMR spectrum at 400 MHz: 2.30 (s: 3H); 2.32 (s: 3H); 2.69 (s broad: 3H); 6.59 (s broad: 1H); 7.15 (s broad: 1H); 7.17 (dd, J=5 and 8 Hz: 1H); 7.26 (d broad, J=8 Hz: 1H); 7.90 (dd, J=2 and 8 Hz: 1H); 7.97 (d, J=8 Hz: 1H); 8.08 (dd, J=2 and 5 Hz: 1H) Mass spectrum: LC-MS-DAD-ELSD: 301(+)=(M+H) (+); 299(-)=(M-H) (-)
A solution of 209-2 (50.0 g, 183.8 mmol) in dry THF cooled to -78 C. and n-BuLi (81 ml, 2.5 M in hexane) was added over 20 minutes. The resulted solution was maintained at -78 C. for 1 h, and then a solution of BrCl2CCCl2Br (71.0 g, 220.5 mmol) in dry THF was added. The mixture was stirred -78 C. for 30 min and allowed to warm slowly to room temperature. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (5% ethyl acetate in petroleum ether to 20% ethyl acetate in petroleum ether as the eluent) to afford 209-3 (37 g, 58% yield). MS-ESI: m/z=351.0 [M+1]+
Stage 1(k): 1-(Toluene-4-sulfonyl)-2-tributylotannanyl-1H-pyrrolo[2,3-b]pyridine, 12 Add n-BuLi (2.5 M, 0.85 mL) dropwise, in the space of 10 min, to a solution of <strong>[348640-02-8]N-tosyl-7-azaindole</strong> (0.5 g, 1.84 nmmol) in THF (20 mL) at -78 C. After stirring the reaction medium for 30 min at -78 C., add Bu3SnCl dropwise (0.575 mL, 2.12 mmol), and leave the reaction to return gradually to room temperature. After 16 h, stop the reaction with H2O and extract with EtOAc, wash with brine, dry (MgSO4) and concentrate, to give a raw oil which is submitted to flash chromatography immediately, on SiO2 pretreated with Et3N/CH2Cl2, which is washed with CH2Cl2. Elution with EtOAc at 5%/heptane gives 12 (0.62 g, 60%) as a colorless oil: 1H NMR (CDCl3) delta 8.27 (d, 1H, J=6 Hz), 7.98 (d, 2H, J=8 Hz), 7.74 (d, 1H, J=9), 7.23 (d, 2H, J=12), 7.07 (dd, 1H, J=4.8, 7.8 Hz), 6.67 (s, 1H), 2.35 (s, 3H), 1.58 (m, 6H), 1.38 (m, 6H), 1.27 (m, 6H), 0.89 (m, 9H). TLC (EtOAc at 10%/heptane) Rf=0.15, m/z obs.=562 (M+1).
2-deuterio-1-tosyl-1H-pyrrolo[2,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[0290]Example 2B: 2-deuterio-1-(tosyl)-1H-pyrrolo [2,3-b] pyridine.[0291] A solution of <strong>[348640-02-8]1-tosyl-1H-pyrrolo[2,3-b]pyridine</strong> (165.0 g, 0.6059 mol) in dry THF (2975 mL) under N2 was cooled to -78 C. A solution of BuLl (484 mL of 2.5 M, 1.2118 mol) was added slowly the flask maintaining the temperature <-70 C. After 2 hours of stirring at -78 C, D20 (182.0 g, 9.0885 mol) was added at -78 C. This mixture was then warmed to 20 -25 C while stirring overnight. A 10% aqueous NaC1 solution (825 mL) was then added. After stirring for 30 minutes, the phases were separated. The aqueous phase was extracted with MTBE (2 x 825 mL). The combined organic phase was washed with brine C (2 x 825 mL) and dried over Mg2SO4. The organic phase was then concentrated to obtain 2-deuterio- 1 -tosyl- 1 H-pyrrolo[2,3 -b]pyridine (>99% deuteratium incorporation by HNMR).
With N-Bromosuccinimide; In dichloromethane; at 0 - 25℃; for 24h;
A solution of 9 (1.84 mmol) in CH2Cl2 (30 mL) was slowly added toNBS (2.02 mmol) at 0 C, The mixture was stirred at 25 C for 24 h. Themixture was diluted with CH2Cl2, and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated.The residue was purified by column chromatography to afford compound10 as a white solid, yield: 89%. 1H NMR (600 MHz, DMSO-d6) delta8.45 (dd, J = 4.8, 1.4 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H),7.96-7.94 (m, 1H), 7.44-7.40 (m, 3H), 2.33 (s, 3H).
With bromine; In chloroform; at 20℃; for 48.75h;
3-bromo-<strong>[348640-02-8]1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine</strong> To a solution of <strong>[348640-02-8]1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine</strong> (Intermediate 1a) (12.8 g, 47.0 mmol, 1.0 eq.) in chloroform (40 mL) bromine (2.7 mL, 52.0 mmol, 1.1 eq.) was added via a dropping funnel over 45 min and the reaction mixture was stirred at rt for 48 h. The reaction mixture was quenched with saturated solution of Na2SO3. The organic layer was dried over Na2SO4 and evaporated to dryness to afford 3-bromo-<strong>[348640-02-8]1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine</strong> (Intermediate 1b) as an off-white solid (15.2 g; yield: 92%; UPLC purity: 87%).
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