| 92% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydroxide; tetrabutylammonium hydrogensulfate In 1,4-dioxane; dichloromethane; water monomer
Stage #2: benzenesulfonyl chloride In 1,4-dioxane; dichloromethane; water monomer at 0℃; for 120h; |
2.a; 3.a
4-Bromo-1 /-/-pyrrolo[2,3-b]pyridine (which may be prepared as described in Org Letts, 2003, 5, 5023) (15.Og, 76mmol) was suspended in DCM (300ml) and 1 ,4-dioxane (100ml) and 50% aq. sodium hydroxide (23ml) was added followed by NaBu4HSO4 solution (7.5ml). The mixture was vigorously stirred and cooled in an ice bath whilst benzene sulfonyl chloride (14.6ml, 1 15mmol) was added dropwise. The reaction mixture was left stirring vigorously for 5 days. It was evaporated to dryness and the resulting solid was washed with water (100ml) followed by methanol (50ml). The yellow solid was dried in vacuo. The title compound was obtained as a pale yellow solid (23.5g, 92%). MH+ 337 / 339, rt= 3.35 min |
| 88% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 16h; Inert atmosphere; |
Step A: 4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine.
To a solution of 4-bromo-1H- pyrrolo[2,3-b]pyridine (8 g, 40.6 mmol) in N,N-dimethylformamide (160 mL) was added sodium hydride (60% in mineral oil, 1.79 g, 44.8 mmol) at 0 °C under argon. The reaction mixture was stirred at 0 °C for 30 min under argon. To the reaction mixture was added benzenesulfonyl chloride (5.7 mL, 44.7 mmol, 1.384 g/mL) dropwise at 0 °C over 10 min under argon. The reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 h under argon. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (9:0 → 9:1) to afford the title compound (12.1 g, 88%) as a white crystalline solid. MS (ESI): mass calcd. for C + 13H9BrN2O2S, 336.0; m/z found, 337.0 [M+H] . |
| 88% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 16h; Inert atmosphere; |
Step A: 4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine.
To a solution of 4-bromo-1H- pyrrolo[2,3-b]pyridine (8 g, 40.6 mmol) in N,N-dimethylformamide (160 mL) was added sodium hydride (60% in mineral oil, 1.79 g, 44.8 mmol) at 0 °C under argon. The reaction mixture was stirred at 0 °C for 30 min under argon. To the reaction mixture was added benzenesulfonyl chloride (5.7 mL, 44.7 mmol, 1.384 g/mL) dropwise at 0 °C over 10 min under argon. The reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 h under argon. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (9:0 → 9:1) to afford the title compound (12.1 g, 88%) as a white crystalline solid. MS (ESI): mass calcd. for C + 13H9BrN2O2S, 336.0; m/z found, 337.0 [M+H] . |
| 86% |
With dmap; triethylamine In dichloromethane at 20℃; |
33.I Part I - Synthesis of 1-(Benzenesulfonyl)-4-bromo-1H-pyrrolo[2,3-b]pyridine
Into a 100 mL round-bottom flask, was placed 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.5 g, 7.61 mmol), dichloromethane (30 mL), triethylamine (1.59 mL, 11.4 mmol), N,N-dimethylpyridin-4-amine (93.0 mg, 0.76 mmol), benzenesulfonyl chloride (1.6 g, 9.14 mmol). The resulting solution was stirred overnight at room temperature. The mixture was concentrated, and applied onto a silica gel column, then eluted with ethyl acetate/petroleum ether (0%-l0%) to yield the title compound (2.2 g, 86%). |
| 84% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; for 3h; |
71.1 Example 71. Synthesis of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 205
To a solution of NaH (1.46 g, 30.4 mmol, 1.2 eq.) in THF under argon and at 0° C. was slowly added a solution of 4-bromo-7-azaindole (5 g, 25.4 mmol, 1.0 eq.) in THF (1 M). The mixture was stirred at room temperature for 30 min. Return to 0° C., benzenesulfonyl chloride (3.5 ml, 27.9 mmol, 1.1 eq.) was added drop by drop. After 3 h stirring at room temperature the mixture was poured into a vial filled with ice. Once the medium back to room temperature, the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was triturated with pentane and vacuum filtered to obtain compound 205 (7.2 g, 84%) as a brown solid. 1H NMR (400 MHz, CDCl3, 20° C.) δ 8.18 (d, J=7.8 Hz, 3H), 7.52 (m, 4H), 7.30 (m, 1H), 7.02 (s, 1H). CAS Number: 889939-25-7. |
| 84% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: benzenesulfonyl chloride In tetrahydrofuran at 20℃; for 1h; |
10.1 Step 1:
Synthesis of Compound 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
Under the protection of nitrogen atmosphere, the compound 4-bromo-1H-pyrrolo[2,3-b]pyridine (3.0 g, 15.23 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (50 mL), then 60% NaH (800 mg, 20 mmol) was added portionwise into the above mixed solution at 0° C. After stirring at this temperature for 30 min, benzenesulfonyl chloride (3.53 g, 20 mmol) was added, the resulting mixture was reacted at RT for 1 h. After the reaction was completed, the reaction mixture was carefully quenched by ice-water at 0° C. and extracted with EA. The organic phase was washed with water, dried with anhydrous Na2SO4 and concentrated to give a crude product, which was separated by column chromatography to give the desired product (4.3 g, yield 84%). |
| 73% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0℃;
Stage #2: benzenesulfonyl chloride In tetrahydrofuran; mineral oil at 0℃; Saturated solution;
Stage #3: With ammonia hydrochloride In ethyl acetate Saturated solution; |
2 Method D: N-Benzene sulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine
Method D: N-Benzene sulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine 4-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 1 Eq.) was dissolved in dry THF and cooled in an ice-bath. NaH (60% dispersion in mineral oil, 305 mg, 1.2 Eq.) was added portionwise. The resultant mixture was stirred at 0° C. for 45 minutes and benzene sulfonyl chloride (1.076 g, 1.2 Eq.) was added slowly dropwise. The resultant mixture was stirred at 0° C. for a further 75 minutes and then the solvent was removed in vacuo. The residue was partitioned in EtOAc/sat. NH4Cl and extracted with EtOAc (3*50 mL). The combined organics were washed with sat. aq. Na2CO3 (1*20 mL), brine (1*20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (20% EtOAc/80% hexanes), followed by recrystallization from EtOAc/hexanes. The product was filtered and then washed with pentane obtaining the title compound as a white powder (1.24 g, 73% yield); 1H NMR (DMSO D6) 6.8 (1H, d), 7.6-7.66 (3H, m), 7.72-7.76 (1H, m), 8.0 (1H, d), 8.1 (2H, m), 8.24-8.26 (1H, m); LC/MS M+1; (obs.) 339.1; LC/MS M-1 (obs.) 337.1. |
| 72% |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.166667h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.2 mmol) in DMF (31 ml) was treated with 60% NaH (410 mg, 1.0 eq) at 0 under nitrogen. After 10 min, benzenesulfonyl chloride (1.8 g, 1.0 eq) was added and the mixture warmed to room temperature and allowed to stir overnight. Methanol (10 ml) was added and the mixture was diluted with ethylacetate (200 ml), washed with water (3 * 75 ml) and brine, then dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified via silica gel chromatography using a gradient (PE:EA, 10:1~8:1 v/v) to afford 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 22 (2.47 g, 72%). MS (ESI) m/z 236.9 [M+H]+. |
| 72% |
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; |
18 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
0.3M 18d (2.0g, 10.2mmol) of DMF solution was cooled to 0 ° C,60% NaH (410 mg, 1.0 eq) was added in portions.Under N2 protection, stir for 10 min, pipette benzenesulfonyl chloride (1.8 g, 1.0 eq), and add dropwise.After the addition was completed, transfer to room temperature and stir overnight.Methanol (7.5 ml) was quenched, EA (200 mL) was extracted and washed with water (50ml×3).Wash with saturated brine and dry with anhydrous Na2SO4.Evaporate the solvent under reduced pressure.Column chromatography separation (PE: EA = 10:1 ~ 8:1v / v) to get 18d(2.47g, 72%). |
|
With benzyl-triethyl-ammonium chloride; sodium hydroxide In dichloromethane at 20℃; Cooling with ice; |
40
Example 40; 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridineTo a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.9 g, prepared according to the method described in Organic Letters, 2003, vol. 5, 5023-5025) and benzyltriethylammonium chloride (210 mg) in methylene chloride (150 mL), sodium hydroxide (4.3 g) and benzenesulfonyl chloride (5.5 mL) were added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and filtered through “Celite” (registered trademark), and the filtrate was concentrated. The resulting residue was purified by a purification system CombiFlash CompanionXL (manufactured by Isco, Co., Ltd., column: RediSep 120 g; hexane:ethyl acetate=95:5→60:40) to obtain the title compound (9.8 g) having the following physical properties.TLC:Rf 0.58 (hexane:ethyl acetate=2:1)1H-NMR (DMSO-D6): δ 6.78, 7.56-7.67, 7.68-7.76, 8.05, 8.08-8.17, 8.21-8.27 |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide; mineral oil for 0.5h; Inert atmosphere; Cooling with ice; |
4-Bromo-1 H-pyrrolo[2,3-b]pyridine (2 g) and sodium hydride (60 % in mineral oil) (0.406 g) were added to DMF (30 ml) with stirring under nitrogen. After 15 min the reaction was cooled in an ice bath and benzenesulfonyl chloride (1 .295 ml) was added. The reaction mixture was stirred in the ice bath for 30 min and then allowed to warm up to RT. Water (30 ml) was added and the precipitate collected by filtration to afford the title compound as an orange solid, 4.8 g.LCMS (Method B) Rt = 1.19 min, MH+ = 339. |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide at 0℃; for 1.5h; |
D224-bromo-l-(phenylsulfonyl)-lH-pyrrol eTo a solution of 4-bromo- lH-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) in DMF (50 mL) stirred at 0 °C was added sodium hydride (0.487 g, 12.18 mmol). After stirring for 30 min at 0 °C, benzenesulfonyl chloride (1.570 mL, 12.18 mmol) was added to the mixture and stirred at 0 °C for 1.5 hour. The reaction was quenched with addition of saturated NH4C1 aq. solution and the mixture was poured into saturated aq. NH4C1 (100 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (100 mL), dried over MgSO/t, filtered and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-25% ethyl acetate in cyclohexane to give the title compound (3.39 g). LCMS (A): m/z (M+H)+ 337/339, C 13H9BrN202S requires 336/338 (acidic). |
|
With potassium-t-butoxide In tetrahydrofuran at 20℃; for 4h; |
|
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide at 20℃; for 16h; |
135A 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (15 g, 76 mmol) in N,N-dimethyformamide (300 mL) was added NaH (95%, 3.96 g, 99 mmol) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. Benzenesulfonyl chloride (11.78 mL, 91 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was quenched with aqueous NaHCO3 solution and was extracted with ethyl acetate (three times with 450 mL). The combined organic layers were washed with water, dried over MgSO4, and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 5% of ethyl acetate in dichloromethane) to provide the title compound. MS (ESI+) m/z 337 (M+1). |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With tetrabutylammonium hydrogensulfate; sodium hydroxide In 1,4-dioxane; dichloromethane; water monomer
Stage #2: benzenesulfonyl chloride In 1,4-dioxane; dichloromethane; water monomer Cooling with ice; |
1 Intermediate A: 5-(2-iodo-1 -(phenylsulfonyl)-l H-pyrrolo[2,3-b]pyridin-4-yl)- 2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile Step 1 :
4-Bromo-1 H-pyrrolo[2,3-b]pyridine (10 g, 51 mmol) was suspended in a mixture of dichloromethane (200 mL) and 1 ,4-dioxane (70 mL) and treated with 50 % w/w aqueous sodium hydroxide solution (15 mL), followed by tetra-n-butylammonium bisulfate. The mixture was vigorously stirred and cooled in an ice-water bath whilst benzenesulfonyl chloride (9.6 mL, 76 mmol) was added dropwise. The reaction mixture was left stirring vigorously overnight. The mixture was evaporated to dryness and the resulting solid was triturated with water (approximately 100 mL), followed by methanol (approximately 50 mL). The solid was dried in a vacuum oven to give the desired product LCMS-ESI+ (m/z): [M+H]+ calcd for C13H9BrN2O2S: 337.0; found: 337.3 |
| 4.8 g |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide; mineral oil at 20℃; Cooling with ice; |
4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 4-Bromo-1H-pyrrolo[2,3-b]pyridine (2 g) and sodium hydride (60% in mineral oil) (0.406 g) were added to DMF (30 ml) with stirring under nitrogen. After 15 min the reaction was cooled in an ice bath and benzenesulfonyl chloride (1.295 ml) was added. The reaction mixture was stirred in the ice bath for 30 min and then allowed to warm up to RT. Water (30 ml) was added and the precipitate collected by filtration to afford the title compound as an orange solid, 4.8 g. LCMS (Method E) R=1.19 mi MH=339. |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran for 0.166667h; Cooling with ice;
Stage #2: benzenesulfonyl chloride In tetrahydrofuran for 0.333333h; Cooling with ice; |
12.1 First step: Preparation of 4-bromo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine
4-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol)Dissolved in anhydrous THF,Keep it in an ice water bath,Add NaH (608.97 mg, 15.23 mmol) in portions,After the addition, stir for 10 minutes.Add benzenesulfonyl chloride (986 mg, 5.58 mmol) slowly.After the addition, continue to stir for 20 minutes.Concentrated under reduced pressure, extracted with water,Collect organic phase,Washing the organic phase with alkaline water,Dry the organic phase, filter,The collected filtrate was evaporated to dryness under reduced pressure.Reusing petroleum ether,The ethyl acetate mixture was washed to give the title compound. |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide for 0.25h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Inert atmosphere; |
31
4-Bromo-1 H-pyrrolo[2,3-b]pyridine (2g, 10.15 mmol) and sodium hydride (0.406 g, 10.15 mmol) were added to N,N-dimethylformamide (30 ml.) with stirring and under nitrogen. After 15 minutes the reaction was cooled in an ice bath and benzenesulfonyl chloride (1.295 ml_, 10.15 mmol) was added. The reaction mixture was stirred in the ice bath for 30 min and then allowed to warm up to room temperature. Water (3OmL) was added and the precipitate collected by filtration to afford the title compound as an orange solid (4.8g). LCMS (Method B) Rt = 1.19 min, MH+= 339 |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide for 0.25h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide for 0.5h; Cooling with ice;
Stage #3: With hydrogenchloride In tetrahydrofuran; water monomer; mineral oil |
119
Intermediate 119 4-Bromo-1 -(phenylsulfonyl)-i H-pyrrolo[2,3-b]pyridine 4-Bromo-1 H-pyrrolo[2,3-b]pyridine (2g, 10.15 mmol) and sodium hydride (0.406 g, 10.15 mmol) were added to N,N-Dimethylformamide (30 mL) with stirring and under nitrogen. After 15 minutes the reaction was cooled in an ice bath and benzenesulfonyl chloride (1.295 mL, 10.15 mmol) was added to the reaction mixture. The reaction was stirred in the ice bath for 30 min and then allowed to warm up to room temperature. Water (3OmL) was added to the reaction mixture and the precipitate was collected by filtration to afford the title compound as an orange solid: mass (4.8g). LCMS (Method D) R1 = 1.19 min, MH+= 338. |
| 18.1 g |
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere;
Stage #2: benzenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; |
a a. 4-Bromo-1 -(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridine
4-Bromo-1H-pyrrolo[2,3-b]pyridine (10.5 g, 53.3 mmol) was dissolved in THF (200 mL) under argon and cooled to 0°C. Sodium hydride (1.41 g, 58.65 mmol) was added portionwise and after 30 minutes benzenesulfonyl chloride (7.5 mL, 58.65 mmol) was added. The reactionmixture was allowed to warm up to room temperature and stirred at room temperature overnight. The mixture was poured into water (1.8 L) and stirred one hour at room temperature. The solid formed was collected by filtration and dried in a vacuum oven at 45°C (18.1 g)1H NMR (400 MHz, DMSO) 8.25 (1H, d, J=5.2 Hz), 8.14- 8.11 (2H, m), 8.07 (1H, d, J=4.1Hz), 7.77 - 7.73 (1 H, m), 7.66 - 7.61 (3H, m), 6.81 (1 H, d, J=4.0 Hz). |
|
Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: benzenesulfonyl chloride In tetrahydrofuran for 0.333333h; |
1.5 General procedure for the synthesis of intermediates 9a-c
General procedure: To a stirred solution of 8a-c (25 mmol, 1 equiv) in THF (150 mL), NaH (75 mmol, 3 equiv) was added sodium hydride in several batches at 0 °C . After stirred for 10 min, benzenesulfonyl chloride (28 mmol, 1.1 equiv) was added. Then, the mixture was stirred for 20 min. Afterwards, the solvent was removed in vacuo, and the residue was extracted with water and EtOAc. The combined organic phase was separated, dried, and filtered. The filtrate was evaporated to dryness under reduced pressure to give target compound 9a-c (yield 95-99%). |
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