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With hydrazine hydrate In 1,2-dimethoxyethane at 75℃; for 16 h;
To a stirred solution of 4,6-dichloronicotinaldehyde (3 x 1.0 g, 1.0 eq) in DME (3 x 14 mL), hydrazine hydrate (3 x 1.14 g, 4.0 eq, 99percent) was added slowly in a vial. The vial was sealed and the contents heated at 75°C for 16 h. After TLC showed completion, the mixture was cooled to rt and diluted with water (3 x 10 mL) and EtOAc (3 x 10 mL). After combining all 3 mixtures, the layers were separated and the organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The resulting crude was purified by flash chromatography (Combiflash® - Redisep, 12 g) using MeOH in DCM as eluent. The desired product was eluted at 1percent MeOH in DCM. The fractions with product were concentrated to obtain pure 6-chloro- lH-pyrazolo[4,3-c]pyridine as yellow solid (1.4 g, 53.43percent, from 3 batches). 1H NMR (400 MHz, DMSO-d6): δ 13.608 (s, 1H), 8.946 (s, 1H), 8.350 (s, 1H), 7.652 (s, 1H). LCMS calculated for (M) 423.15 and found (M+H) 424.23.
41%
With N-ethyl-N,N-diisopropylamine; hydrazine In N,N-dimethyl acetamide at 80℃; for 4 h;
Part III-- Synthesis of 6-chloro-1H-pyrazolo[4,3-c]pyridine [0232] 4,6-Dichloropyridine-3-carbaldehyde (3.7 g, 32 mmol), hydrazine (3.5 mL, 1 10 mmol) and N,N-diisopropylethylamine (20 mL) were combined in DMA (100 mL) and stirred at 80 °C for four hours. Then, the solution was cooled to room temperature, diluted with EtOAc, and washed three times with water and then with brine. The organic solution was concentrated and the resulting mixture was precipitated from dichloromethane to give 6- chloro-lH-pyrazolo[4,3-c]pyridine. Yield 2 g (41percent). LCMS (ESI): calc. C6H4C1N3 = 153; obs. M+H = 154.
38%
With hydrazine In 1,4-dioxane; water at 150℃; for 18 h; Sealed tube
To a reaction vessel containing a mixture of 4,6-dichloronicotinaldehyde (300 g, 1.7 mol) in 1,4- dioxane (1200 mL) was added hydrazine (50percent> in water)(360 mL, 3.6 mol). The reaction vessel was sealed and heated at 150 °C over 18 h. The mixture was cooled to room temperature, concentrated in vacuo, poured over water and filtered. The filter cake was washed with 20percent> EtOAc in hexanes and dried to afford 6-chloro-lH-pyrazolo[4,3-c]pyridine (101.4 g, 38 percent>) as a light-yellow solid. LCMS (ESI) [M+H]+ = 154.
(2) To the compound obtained in the above step (1) (1.4 g) was added phosphorus oxychloride (30 mL) and the mixture was refluxed under heating for 3 hours. The reaction mixture was concentrated and to the residue was added an aqueous saturated sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate and concentrated to give a mixture of 4-chloro-1H-pyrazolo[4,3-c]pyridine and 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.81 g, yield: 51 percent). MS(APCI)m/z; 154/156 [M+H]+
With potassium carbonate; In acetonitrile; at 80℃; for 72h;
A suspension of 6-chloro-lH-pyrazolo[4,3-c]pyridine (712mg, 4.6mmol), 2-cyano-5- fluorobenzyl bromide (l . leq) and potassium carbonate (2.2eq) in acetonitrile (60mL) was heated at 80C for 72h. The resultant mixture was diluted with DCM and washed with H20. The organic phase was collected, dried (hydrophobic frit) and concentrated in vacuo. The resultant residue was purified by column chromatography (petrol:EtOAc) to give 2-((6- chloro-lH-pyrazolo[4,3-c]pyridin-l-yl)methyl)-4-fluorobenzonitrile.
With potassium carbonate; In acetonitrile; at 60℃; for 48h;
Example 3: 6-((l-(2,5-difluorobenzyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)amino A suspension of 6-chloro-lH-pyrazolo[4,3-c]pyridine (lg, 6.54mmol), 2,5-difluorobenzyl bromide (l . leq) and potassium carbonate (2eq) in acetonitrile (20mL) was heated at 60C for 48h. The resultant mixture was filtered, the filtrate diluted with DCM and washed with H20. The organic phase was collected, dried (hydrophobic frit) and concentrated in vacuo. The resultant residue was purified by column chromatography (petrol:EtOAc) to give 6-chloro-l- (2 , 5 -difluorobenzyl)- 1 H-pyrazo lo [4 , 3 -c]pyridine . A suspension of 6-chloro-l-(2,5-difluorobenzyl)-lH-pyrazolo[4,3-c]pyridine (50mg, 0.18mmol), 2-amino-5-cyanopyridine (l . leq), Xantphos (O.leq), Pd2(dba)3 (O.leq) and cesium carbonate (2eq) in dioxane:H20 (5: 1) (5mL) was heated at 150 C for 30min under microwave irradiation. The resultant mixture was diluted with DCM and washed with H20. The organic phase was collected, dried (hydrophobic frit) and concentrated in vacuo. The resultant mixture was purified by prep. HPLC to give the title compound^1 H NMR (d6- DMSO) delta 10.48 (s, 1H), 8.87 (d, 1H), 8.65 (dd, 1H), 8.24 (s, 2H), 8.01 (dd, 1H), 7.47 (dd, 1H), 7.29-7.35 (m, 1H), 7.20-7.27 (m, 1H), 7.10-7.15 (m, 1H), 5.62 (s, 2H); LC-MS method C, (ES+) 363, RT = 8.02 min.
With iodine; potassium carbonate In N,N-dimethyl-formamide for 20h;
1.7 Step 7: 6-Chloro-3-iodo-lH-pyrazolo[4.3-c]pyridine
To a solution of 6-chloro-lH-pyrazolo[4,3-c]pyridine (5.2 g, 34 mmol) in NN-dimethylformamide (75 mL) was added potassium carbonate (5.7 g, 41 mmol) and iodine (4.3 g, 41 mmol). The reaction was stirred at room temperature. After 4 h, additional iodine (4.3 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were added. After 16 h, the reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified via flash chromatography on silica gel (solvent gradient: 0%-100% EtOAc in heptane) to give 6-chloro-3-iodo-lH-pyrazolo[4,3-c]pyridine (7.5 g, 79%). LCMS (ESI) [M+H]+ = 280; lH NMR (400 MHz, DMSO-d6) δ 14.02 (br, 1H), 8.63 (br, 1H), 7.69 (s, 1H).
59%
With iodine; potassium hydroxide In N,N-dimethyl-formamide at 40 - 70℃; for 19h;
1 Step 1: 6-chloro-3 odo-lf/^yrazolo[4^-c]pyridiiie (2a)
Step 1: 6-chloro-3 odo-lf/^yrazolo[4^-c]pyridiiie (2a) A flask was charged with 6-chloro-lH-pyrazolo[4,3-c]pyridine (3 g, 19.54 mmol), iodine (13.11 g, 51.7 mmol), KOH (3.29 g, 58.6 mmol) and DMF (60 mL) (Note: heat generated during adding DMF). The mixture was heated at 40 °C for 16 h and then additional iodine (7.8 g, 30.7 mmol) and KOH (1.6 g, 28.4 mmol) were added. The mixture was heated at 70 °C for 3 h and then quenched with IN Na2S 03 and extracted with EtOAc. The organic phase was washed with water, brine and dried (Na2S04). After evaporation of volatiles DCM was added. A solid precipitated and filtrated off to yield 6-chloro-3-iodo-lH-pyrazolo[4,3- c]pyridine (3.2 g, 11.51 mmol, 59%), which was carried out in the next step without further purification. MS ESI calc'd. for QH4CIIN3 [M+l]+280, found 280.
59%
With iodine; potassium hydroxide In N,N-dimethyl-formamide at 40 - 70℃; for 19h; Inert atmosphere;
59%
With iodine; potassium hydroxide In N,N-dimethyl-formamide at 40 - 70℃; for 19h;
1 Step 1: 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2a)
A flask was charged with 6-chloro-1H-pyrazolo[4,3-c]pyridine (3 g, 19.54 mmol), iodine (13.11 g, 51.7 mmol), KOH (3.29 g, 58.6 mmol) and DMF (60 mL) (Note: heat generated during adding DMF). The mixture was heated at 40 °C for 16 h and then additional iodine (7.8 g, 30.7 mmol) and KOH (1.6 g, 28.4 mmol) were added. The mixture was heated at 70 °C for 3 h and then quenched with 1N Na2S2O3 and extracted with EtOAc. The organic phase was washed with water, brine and dried (Na2SO4). After evaporation of volatiles DCM was added. A solid precipitated and filtrated off to yield 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (3.2 g, 11.51 mmol, 59%), which was carried out in the next step without further purification. MS ESI calc'd. for C6H4ClIN3 [M+1]+280, found 280.
0.5 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 1h;
90.1 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.3 g, 2 mmol) (Frontier Cat. No. Z13659) and N-iodosuccinimide (0.53 g, 2.3 mmol) in N,N-dimethylformamide (2 mL) was stirred at 80° C. for 1 h. After cooling it was concentrated and the residue was treated with methanol. The white solid was collected by filtration to afford the desired product (0.5 g). LCMS (M+H)+=279.9.
With iodine; potassium hydroxide In N,N-dimethyl-formamide at 50℃; for 1.5h;
Synthesis of 6-chloro-3-iodo- 1 H-pyrazolo[4,3-c]pyridine
To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (300 mg, 1.953 mmol) in N,N-dimethylformamide (9.8 mL) was added potassium hydroxide (3.0 eq., 332 mg, 5.861 mmol)followed by iodine (1.8 eq., 892.4 mg, 3.516 nimol). The reaction was heated to 50°C for 1.5 hours. The reaction was then cooled to room temperature and quenched with aqueous sodium thiosulfate until the dark colour disappeared. The solution was diluted with water and extracted 2 times with iPrOAc. The organic layers were combined, dried with sodium sulfate and concentrated to afford 475 mg of a yellow solid as the title compound (87 % yield). The crude material was useddirectly in subsequent reactions.
With iodine; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
2.06g
With iodine; potassium hydroxide In N,N-dimethyl-formamide at 50℃;
35.I Part I- Synthesis of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (3.0 g, 19.5 mmol), DMF (100 mL), potassium hydroxide (3.29 g, 58.6 mmol) and iodine (8.9248 g, 35.163 mmol) was stirred at 50 °C overnight. The mixture was cooled, and quenched with aqueous sodium thiosulfate, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated. The residue was triturated with dichloromethane, filtered, and dried to afford 6-chloro-3-iodo-1H- pyrazolo[4,3-c]pyridine (2.06 g).
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 100℃; for 3h;
To a mixture of <strong>[1152093-60-1]tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate</strong> (2.55 g, 7.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.51 mmol) in 1,4-dioxane (20 mL) was added Cul (494 mg, 2.6 mmol), K2CO3 (3.6 g, 26 mmol), and diamine (460 mg, 5.2 mmol). The mixture was heated at 100 C for 3 hours, which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluting solvents to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (1.6 g, 57%). MS (ESI) m/z: 429 [M+H] +.
With 4-methylbenzene-1-sulfonyl chloride In 1,4-dioxane at 110℃;
76.A 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (11.5 g, 0.075 mol) and 3,4-dihydro-2H-pyran (19 g, 0.225 mol) and Tos-OH (0.13 g 0. 75 mmol) in 1,4-dioxane (175 mL) was heated at 110 °C overnight. The mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether ethylacetate 20:0~20: 1) to afford a mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 6-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-c]pyridine (13.5 g, yield 76 %) MS (ESI) m/z: m/z: 238 [M+1]+.
76%
With toluene-4-sulfonic acid In 1,4-dioxane at 110℃; for 18h;
72%
With toluene-4-sulfonic acid In dichloromethane for 24h; Reflux;
149 Preparation 1496-Chloro-1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazolo[4,3-c]pyridine
Preparation 1496-Chloro-1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazolo[4,3-c]pyridine10684] To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyri- dine (75 g, 488.37 mmol) in DCM (2 L) was added dihydropyran (66.98 mE, 732.56 mmol) followed by para-toluenesulfonic acid (18.58 g, 97.67 mmol) and the reaction was heated to reflux for 18 hours. Further para-toluenesulfonic acid (0.1 eq) and dihydropyran (0.75 eq) were added and the reaction continued heating at reflux for 6 hours. The reaction was cooled and quenched with saturated aqueous sodium bicarbonate solution. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 17% EtOAc in hexanes followed by trituration with ether to afford the title compound as a pale yellow solid (83 g, 72%). ‘H NMR (400 MHz, DMSO-d5): öppm 1.59 (m, 2H), 1.71 (m, 1H), 2.02 (m, 2H), 2.29 (m, 1H), 3.74 (m, 1H), 3.89 (m, 1H), 5.91 (m, 1H), 7.93 (s, 1H), 8.38 (s, 1H), 8.94 (s, 1H).
60%
With toluene-4-sulfonic acid In dichloromethane at 45℃; for 16h;
1 Step 1: 6-(hloro-l -(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo|4,-c|pyridine
[00297] A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine(3 g, 19.54 mmol),DHP (5.4 mL, 58.61 mmol), and TsOH H2O (743 mg, 3.91 mmol) in DCM (40 mL) was stirred at 45 °C for 16 h, allowed to cool to rt, adjusted to pH=7 with sat. aq. NaHCO3, and then extracted with DCM (3 x30 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate=30: 1 to 3 : 1) to give 6-chloro- 1 -(tetrahydro-2H -pyran-2-yl)- l H-pyrazolo[4,3-c]pyridine (2.8 g, 60%) as a yellow solid. 1HNMR(400 MHz, DDDMSO-d δ6): 8.95 (d, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 5.91 (dd, 1H), 3.90-3.87 (m, 1H), 3.79-3.73 (m, 1H), 2.36-2.32 (m, 1H), 2.03-1.95 (m, 2H), 1.73-1.69 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 238.1 [M+H]+.
0.8 g
With methanesulfonic acid In tetrahydrofuran; dichloromethane at 20 - 50℃;
24.1 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine
At r.t. to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.5 g, 3 mmol) (Frontier Cat. No. Z13659) in methylene chloride (3 mL) and THF (1 mL) was added methanesulfonic acid (42 μL, 0.65 mmol), followed by dihydropyran (0.89 mL, 9.8 mmol). The mixture was stirred at r.t. for 2 h., and then at 50° C. overnight. After cooling the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.8 g). LCMS (M+H)+=238.0; LCMS (M-84+H)+=154.0/156.0.
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 100℃; for 20h; Sealed tube; Inert atmosphere;
101.A 1-(5-bromo-6-fluoro-2-pyridyl)-6-chloropyrazolo[4,3-c]pyridine and 6-chloro-1-(6-fluoro-5-iodo-2-pyridyl)pyrazolo[4,3-c]pyridine
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.045 mmol; 314.0 mg), 3-bromo-2-fluoro-6-iodo-pyridine (2.249 mmol; 679.0 mg), N,N’-Dimethylethylenediamine (0.2045 mmol;18.02 mg; 0.0203 mL), copper iodide (2.045 mmol; 393.3 mg), and potassium carbonate (2.249mmol; 314.0 mg) in 1,4-Dioxane (10 mL) was purged with Argon, then sealed and stirred at 100°C for 20 hours. The mixture was cooled to room temperature, and then filtered through Celite. The filtrate was concentrated; the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford a mixture of 1-(5-bromo-6-fluoro-2-pyridyl)-6-chloro-pyrazolo[4,3-c]pyridine (80 mg, 12%) and 6-chloro-1-(6-fluoro-5-iodo-2-pyridyl)pyrazolo[4,3-c]pyridine (163 mg, 21%).
Stage #1: 6-chloro-1H-pyrazolo[4,3-c]pyridine With N-Bromosuccinimide In N,N-dimethyl-formamide at 22 - 32℃; for 1.5h;
Stage #2: With sodium thiosulfate In N,N-dimethyl-formamide at 0 - 20℃;
[00437] Step A: 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 eq) was added to DMF (3v) and the solution was heated to 27 °C (internal temperature should not exceed 35 °C). NBS (1.2 eq) was dissolved in DMF (3v) and added to the reaction over 1.5 h while maintaining the internal temperature at 22-32 °C. After 4 h the reaction was cooled to 0 °C and 10% sodium thiosulfate (1.5v) was added dropwise while keeping the internal temperature below 20 °C. Water (11 v) was added slowly. The solids were filtered and washed with water (5v). The wet cake was suspended in DCM (3v) and slurried at 22 °C for 1 h. The solids were filtered and washed with DCM (2v). The solids were dried in a vacuum oven at 35 °C for 20 h. (1s,4s)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl 4-methylbenzenesulfonate was isolated as a yellow solid (131 g, 87%).
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 4h;
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