| 55% |
With anhydrous potassium acetate; acetic anhydride; isopentyl nitrite In toluene at 90℃; Inert atmosphere; |
9.3 Step 3. 1-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-ethanone
A mixture of N- (5-bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 1 5.28 mmol, 1 .00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv ), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene ( 1 0 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :5) to give in 2 g (55%) of the title compound as a light yellow solid. LC MS (Method I, ESI): RT= 1 .44 min, m z = 240.0; 242.0 [M · H]*. |
| 55% |
With anhydrous potassium acetate; acetic anhydride; isopentyl nitrite In toluene at 90℃; Inert atmosphere; |
9.3 Step 3. 1-(6-Bromo-pyrazolo[4,3-blpyridin-1-yl)-ethanone.
[0202] Step 3. 1-(6-Bromo-pyrazolo[4,3-blpyridin-1-yl)-ethanone. A mixture of N-(5- bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 15.28 mmol, 1.00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene (150 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:5) to give in 2 g (55%) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1.44 mm, m/z = 240.0; 242.0 [M+H]. |
| 55% |
With anhydrous potassium acetate; isopentyl nitrite In toluene at 90℃; Inert atmosphere; |
Step 3. l-(6-Bromo-pyrazolor4,3-blpyridin-l-yl)-ethanone
0210] Step 3. l-(6-Bromo-pyrazolor4,3-blpyridin-l-yl)-ethanone. A mixture of N-(5- bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 15.28 mmol, 1.00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene (150 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:5) to give in 2 g (55%) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1.44 min, m/z = 240.0; 242.0 [M+H]+. |
| 48% |
Stage #1: N-(5-bromo-2-methylpyridin-3-yl)acetamide With anhydrous potassium acetate In toluene at 80℃; for 0.5h; Inert atmosphere;
Stage #2: With 2-Methyl-2-nitropropane; acetic anhydride In toluene at 80℃; for 18h; Inert atmosphere; |
1.3 Synthesis of 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone
A solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (2.8 g, 12 mmol) and potassium acetate (3.59 g, 36.6 mmol) in toluene (50 mL) was heated at 80° C. under nitrogen. After 30 min, 2-methyl-2-nitropropane (3.77 g, 36.6 mmol) and acetic anhydride (3.73 g, 36.6 mmol) were added, and the resulting mixture was stirred at 80° C. for another 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3*60 mL). The collected organic extractions were concentrated in vacuo. Purification by flash column chromatography (5→10% ethyl acetate in petroleum ether) afforded 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 48.% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 2.79 (s, 3H). |
|
With anhydrous potassium acetate; acetic anhydride; glacial acetic acid; isopentyl nitrite In toluene for 3h; Reflux; |
To a solution of T-5 (13.14 g, 57.36 mmol) in toluene (200 mL) is added acetic anhydride (16.50 mL, 174.5 mmol), acetic acid (16.50 mL, 288.2 mmol) and potassium acetate (12.30 g, 125.3 mmol). The mixture is warmed at reflux and isoamyl nitrite (10.0 mL, 71.5 mmol) is added. After 3 hours, the reaction is concentrated to provide without isolation T-6. The residue is diluted with methanol (250 mL) and K2CO3 (32.0 g, 188 mmol) is added and the mixture is warmed at reflux. After 1 hour, the reaction is poured into water and extracted with EtOAc (3 x 150 mL). The combined organic layers are washed with brine (2 x 50 mL), dried over magnesium sulfate, filtered through a pad of silica gel and filter agent and concentrated. The solid is triturated with Et2O to provide T-7. The filtrate is purified on silica gel using a gradient of 25-100% EtOAc in hexanes and then 5% methanol in ethyl acetate. The material from the column is triturated with ether-heptane to provide T-7. |
|
Stage #1: N-(5-bromo-2-methylpyridin-3-yl)acetamide With anhydrous potassium acetate; acetic anhydride; glacial acetic acid In toluene Reflux;
Stage #2: With isopentyl nitrite In toluene for 2h; Reflux; |
172.5 [0005711 Step 5: Synthesis of 1-(6-bromo-1H-pyrazolo [4,3-bi pyridin-1-yl)ethanone (6):
[0005721 To a stirred solution of compoundS (1.35 g,1 eq) in toluene (15 mE), potassiumacetate (1.27 g, 2.2 eq), acetic anhydride (1.67 mL, 3 eq) and acetic acid (1.68 mL, 5 eq) was heated to reflux followed by the addition of isoamyl nitrite (1 mL, 1.25 eq) and refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 X 50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6. LCMS (mlz): 242.15 (M + 2). |
|
With 3-methyl-1-nitrobutane; anhydrous potassium acetate; acetic anhydride; glacial acetic acid In toluene at 90℃; for 5h; |
B [B] 1- (6-Bromo-1H-pyrazolo [4 3-b] pyridin-1-yl) ethanone
[B] 1- (6-Bromo-1H-pyrazolo [4 3-b] pyridin-1-yl) ethanone[0265][0266]To a solution of N- (5-bromo-2-methylpyridin-3-yl) acetamide (14 g 61.1 mmol) in toluene (200 mL) was added Ac2O (21 mL 183 mmol) AcOH (21 mL 300 mmol) and KOAc (11.7 g 120 mmol) . The resulting reaction mixture was warmed up to 90 added CHMe2CH2CH2NO2(110 mL) and stirred at 90 for 5 h. After cooling to room temperature the mixture was poured into water basified with aq. NaHCO3solution and extracted with EtOAc (50 mL x 6) . The combined organic layers were dried over anhy. MgSO4 filtered and concentrated in vacuo to give a crude title compound (6.5 g 44.5yield) as a solid. MS 241.06 [M+H]+. |
| 50 mg |
Stage #1: N-(5-bromo-2-methylpyridin-3-yl)acetamide With anhydrous potassium acetate; acetic anhydride In toluene at 120℃; for 0.333333h; Inert atmosphere;
Stage #2: With isopentyl nitrite In toluene |
11.2 Step 2: 1-(6-bromopyrazolo[4,3-b]pyridin-1-yl)ethanone (C11-3)
Intermediate C11-2 (100 mg, 0.44 mmol), KOAc (94 mg, 0.96 mmol) and Ac2O (265 mg, 1.31 mmol) were dissolved in toluene (10 mL) under N2, and the mixture was refluxed at 120 °C for 20 min. Isopentyl nitrite (64 mg, 0.55 mmol) was added via a syringe. The reaction continued overnight. TLC was used to monitor the reaction and the reaction was incomplete. The mixture was extracted with EtOAc (20 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5:1) to afford the title compound as a yellow solid (50 mg, 48%). NMR (400 MHz, CDCl3) d 8.91 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 2.80 (s, 3H). |
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