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Chemical Structure| 885271-72-7 Chemical Structure| 885271-72-7

Structure of 885271-72-7

Chemical Structure| 885271-72-7

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Product Details of [ 885271-72-7 ]

CAS No. :885271-72-7
Formula : C8H5BrN2O
M.W : 225.04
SMILES Code : O=CC1=NNC2=C1C=CC(Br)=C2
English Name :6-Bromo-1H-indazole-3-carbaldehyde
MDL No. :MFCD06738286
InChI Key :RQQKGUPOPZJRLE-UHFFFAOYSA-N
Pubchem ID :24727999

Safety of [ 885271-72-7 ]

Application In Synthesis of [ 885271-72-7 ]

* 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.

  • Downstream synthetic route of [ 885271-72-7 ]

[ 885271-72-7 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 52415-29-9 ]
  • [ 885271-72-7 ]
YieldReaction ConditionsOperation in experiment
83.6% With hydrogenchloride; water; sodium nitrite In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; 1.3.1 1. Synthesis of Intermediate 1-11: 6-Bromo-1H-indazole-3-carbaldehyde Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75 ml of DMF and 100 ml of water, cooled to 0 degrees, under nitrogen protection, 3N HCl (23 ml, 68.9 mmol) was slowly added dropwise, and the reaction was completed for 10 minutes.At 0°C, a solution of 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowly added dropwise to the reaction solution, the dropwise addition was completed, and the reaction was carried out at room temperature overnight.Extracted with ethyl acetate three times, combined the organic phases, washed with water three times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified with silica gel column to obtain intermediate 1-11 with a yield of 83.6%.
78% With hydrogenchloride; water; sodium nitrite In N,N-dimethyl-formamide at 0 - 50℃; for 5h; Inert atmosphere;
55% With hydrogenchloride; sodium nitrite In water; acetone
450 g With hydrogenchloride; sodium nitrite In water; acetone at 10 - 25℃; 10.a (a) 6-Bromo-1H-indazol-3-yl-carbaldehyde A solution of NaNO2 (704 g, 10.2 mol) in water (1 L) was added dropwise to a solution of 6-bromo-1H-indole (400 g, 2.0 mol) in acetone (7 L) at 10° C. The reaction mixture was stirred at 10° C. for 30 min, aqueous 3M HCl (437 mL) was added slowly with vigorous stirring, keeping the internal temperature between 10 and 25° C. The solution was stirred at 20° C. for 3 h, and concentrated while keeping the temperature below 35° C. The solid was collected by filtration. The filter cake was washed with 1:2 petroleum ether:MTBE (800 mL). The solids were collected by filtration and dried under vacuum to afford the title intermediate (450 g) as a black brown solid. 1H NMR (CH3OD, 400 MHz) δ (ppm) 7.77 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 5.70 (s, 1H).
83.6 % With hydrogenchloride; sodium nitrite In water; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; 1 Synthetic intermediate 1: 6-bromo-1H-indazole-3-carbaldehyde Sodium nitrite (14.00g, 200mmol) was dissolved in 75ml DMF and 100ml water, cooled to 0°C, under nitrogen protection, 3N HCl (23ml, 68.9mmol) was slowly added dropwise, and the reaction was completed for 10 minutes. At 0°C, a solution of 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowly added dropwise to the reaction solution, and after the addition was complete, the reaction was carried out overnight at room temperature. Extracted 3 times with ethyl acetate, combined the organic phases, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain intermediate 1 with a yield of 83.6%.
With hydrogenchloride; water; sodium nitrite In N,N-dimethyl-formamide at 0℃; Inert atmosphere;

  • 2
  • [ 24424-99-5 ]
  • [ 885271-72-7 ]
  • [ 1365803-32-2 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine In dichloromethane at 0 - 20℃; 11 To a solution of the 6- bromo-lH-indazole-3-carbaldehyde (500 mg, 2.22 mmol) in dichloromethane (125 mL) was added triethylamine (0.34 mL, 2.44 mmol), di-tert-butyl dicarbonate (970 mg, 4.444 mmol) and 4-(dimethylamino)pyridine (27 mg, 0.222 mmol) at 0 °C. The mixture was slowly warmed to room temperature and was washed with water and brine, was dried over magnesium sulfate, was filtered and was concentrated in vacuo. The crude material was purified by silica gel column chromatography (eluted with hexanes: ethyl acetate = 3 : 1 , f = 0.7 in hexanes:ethyl acetate= 2: 1) to give tert-butyl 6-bromo-3 -formyl- 1 H-indazole- 1- carboxylate (746 mg, 2.294 mmol, 99% yield) as a colorless solid. XH NMR (400 MHz, CDC13): δ 10.30 (s, 1H), 8.42 (s, 1H), 8.18 (d, 1H), 7.57 (d, 1H), 1.76 (s, 9H), 1.52 (s, 12H).
  • 3
  • [ 885271-72-7 ]
  • [ 124-40-3 ]
  • [ 1226985-39-2 ]
YieldReaction ConditionsOperation in experiment
66% With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran at 25℃; for 12h; Inert atmosphere; A28.A Step A: 1-(6-Bromo-IH-indazol-3-yl)-N,N-dimethylmethanamineNB To a solution of 6-bromo-1H-indazole-3-carbaldehyde (2 g, 8.9 mmol, 1 eq. ) inTHF (8 mL) was added acetic acid (0.8 mL, 13.3 mmol, 1.5 eq.), dimethylamine (8.9 mL, 17.8mmol, 2 eq., 2.0 M in THF), and NaBH(OAc); (1.9 g, 8.9 mmol, 1 eq.). The reaction mixture was stirred at 25 C for 12 hours under N2 atmosphere. The reaction mixture was thenconcentrated and purified by flash column chromatography on silica gel (100-200 mesh silicagel, 0-6% DCM in MeOH) to give 1-(6-bromo-1H-indazol-3-y1)-N.N-dimethylmethanamine(1.5 g, 66% yield) as a brown solid.LC-MS (ESI): mass calcd. for CioH12BrN3, 253.0/255.0; m/z found,254.0/256.0 [M+H]+1H NMR (400 MHZ, DMSO-d6) 12.93 (s. 1H), 7.78 (d. J = 8.5 Hz, IH), 7.70(d, J = 1.1 Hz, 1H), 7.21 (dd, J = 8.6, 1.6 Hz, 1H), 3.73 (s, 2H), 2.17 (s, 6H).
With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran; water at 20℃; for 20h; 6.1 Step 1-Synthesis of 1-(6-bromo-1H-indazol-3-yl)-N,N-dimethylmethanamine Step 1-Synthesis of 1-(6-bromo-1H-indazol-3-yl)-N,N-dimethylmethanamine To a solution of 6-bromo-1H-indazole-3-carbaldehyde (300 mg, 1.33 mmol) in THF (1 mL) was added acetic acid (0.11 mL, 2 mmol), 2M dimethylamine in THF (1.33 mL, 2.66 mmol) and sodium triacetoxyborohydride (283 mg, 1.33 mmol). The reaction was stirred at RT for 2 hr then allowed to stand at RT for 18 hr. The mixture was concentrated in vacuo, then diluted with EtOAc (50 mL) and washed with 1M aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5 mL), followed by water (5 mL). The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a beige solid: 1H NMR (500 MHz, MeOD) δ 2.31 (6H, s), 3.85 (2H, s), 7.27 (1H, dd, J=8.67, 1.58 Hz), 7.68-7.72 (1H, m), 7.77 (1H, d, J=8.67 Hz). LC-MS: m/z=+253.9/255.9 (M+H)+.
  • 4
  • [ 110-87-2 ]
  • [ 885271-72-7 ]
  • [ 1421503-36-7 ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: 3,4-dihydro-2<i>H</i>-pyran; 6-bromo-1H-indazole-3-carbaldehyde With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water 1 Preparation 16-Bromo-1-(tetrahvdro-pyran-2-yl)-1 H-indazole-3-carbaldehyde Preparation 16-Bromo-1-(tetrahvdro-pyran-2-yl)-1 H-indazole-3-carbaldehydeTo a solution of 6-bromo-1 H-indazole-3-carbaldehyde (13.97g, 61.9mmol) in DCM (150ml_) was added p-TsOH (2.36g, 12.4mmol) and the mixture was cooled to 0°C. 3,4-Dihydro-2H-pyran (8.47ml_, 92.8mmol) was added dropwise to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200ml_) and washed with a solution of saturated aqueous sodium hydrogen carbonate (500ml_). The aqueous layer was re- extracted with DCM (500ml_) and the combined organic layers were washed with brine (2 x 1 L), dried over MgS04 and concentrated in vacuo to yield a black oil. The crude material was refluxed in cyclohexane (20ml_) and filtered while hot. The filtrate was concentrated in vacuo and the residue was stirred in heptane for 48 hours. The resulting solid was collected by filtration to give the title compound (13.87g) in a 73% yield.1H NMR (400 MHz, CDCI3) δ ppm 1 .71 -1.80 (m, 3H), 2.10-2.20 (m, 2H), 2.49-2.57 (m, 1 H), 3.76-3.82 (m, 1 H), 3.98-4.03 (m, 1 H), 5.78 (dd, 1 H), 7.46 (dd, 1 H), 7.87 (d, 1 H), 8.16 (d, 1 H), 10.22 (s, 1 H).
73% With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; Inert atmosphere;
65% With methanesulfonic acid In dichloromethane for 0.166667h; Step 1: 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxaldehyde (2-1) The compound 6-bromo-1H-indazole-3-carboxaldehyde (10.00 g, 44.44 mmol) was placed in a 250 mL reaction flask and dissolved in 100 mL of dichloromethane. 3,4-2H-pyran (10.14 mL, 111.09 mmol) was diluted with 20 mL of dichloromethane and added dropwise to the above reaction solution.Then, methanesulfonic acid (0.29 mL, 4.44 mmol) was added dropwise. The reaction rapidly changed from turbid to black, and the reaction was complete after 10 min. The reaction solution was evaporated to dryness, 30 mL of EA was added, and the mixture was stirred for 5 min. The mixture was then filtered, and the filter cake was washed twice with 20 mL of PE. After drying, 2-1 9 g of white solid was obtained, with a yield of 65%.
  • 5
  • [ 885271-72-7 ]
  • [ 74-88-4 ]
  • [ 1781630-54-3 ]
YieldReaction ConditionsOperation in experiment
58% With caesium carbonate In tetrahydrofuran at 25℃; for 16h; Step 1 To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde (503 mg, 2.20 mmol) in THF (8.0 mL) were sequentially added CH3I (381 mg, 167 μL, 2.70 mmol) and Cs2CO3(452 mg, 3.27 mmol) at 25 . The mixture was stirred at that temperature for 16 h before it was quenched with water (20 mL) and then extracted with EtOAc (15 mL × 2) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum (with EtOAc from 1%to 82%) in 25 min to give 6-bromo-1-methyl-indazole-3-carbaldehyde (313 mg, 58%yield) as a white solid. LC-MS: m/z [M+H]+240.0.
58% With caesium carbonate In tetrahydrofuran at 25℃; for 16h; Step 1 To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde (503 mg, 2.20 mmol) in THF (8.0 mL) were sequentially added CH3I (381 mg, 167 μL, 2.70 mmol) and Cs2CO3(452 mg, 3.27 mmol) at 25 . The mixture was stirred at that temperature for 16 h before it was quenched with water (20 mL) and then extracted with EtOAc (15 mL × 2) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum (with EtOAc from 1%to 82%) in 25 min to give 6-bromo-1-methyl-indazole-3-carbaldehyde (313 mg, 58%yield) as a white solid. LC-MS: m/z [M+H]+240.0.
58% With caesium carbonate In tetrahydrofuran at 25℃; for 16h; Step 1 To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde (503 mg, 2.20 mmol) in THF (8.0 mL) were sequentially added CH3I (381 mg, 167 μL, 2.70 mmol) and Cs2CO3(452 mg, 3.27 mmol) at 25 . The mixture was stirred at that temperature for 16 h before it was quenched with water (20 mL) and then extracted with EtOAc (15 mL × 2) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum (with EtOAc from 1%to 82%) in 25 min to give 6-bromo-1-methyl-indazole-3-carbaldehyde (313 mg, 58%yield) as a white solid. LC-MS: m/z [M+H]+240.0.
Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 1h; 36-38.2 Step 2: Synthesis of 6-bromo-1-methyl-1H-indazole-3-carbaldehyde (3): [000264j To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde 2 (2 g, 1 eq) in DMF (15 mL), NaH (0.53 g, 1.5 eq) was added and stirred at room temperature for 10 mm followed by the addition of methyl iodide(1.52 g, 2 eq). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3 X 50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by column chromatography on silica gel 100-200 mesh using 10% EtOAc-hexane to afford the title compound 3. LCMS (mlz): 240.90 (M + 2).
2.1 g With potassium carbonate In tetrahydrofuran at 20 - 25℃; for 12h; Inert atmosphere; 7.2 6-bromo-1-methyl-indazole-3-carbaldehyde To a solution of 6-bromo-1H-indazole-3-carbaldehyde (3 g) in dry THF (30 ml) were added methyl iodide (2.27 g) and K2CO3 (2.76 g) under inert atmosphere. Reaction mixture was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (60 ml) and extracted with Ethyl acetate (80 ml x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 15-20% ethyl ace- tate in heptane as a mobile phase) to afford (2.1 g) of the title compound. HPLC/MS (method 1): Rt: 1.898 min; MS: m/z = 238.2 (M+1).
2.3 g With potassium carbonate In tetrahydrofuran at 20 - 25℃; for 12h; Inert atmosphere; C-5.2 Step 2: Synthesis of 6-bromo-1-methyl-indazole-3-carbaldehyde To the stirring solution of 6-bromo-1 H-indazole-3-carbaldehyde (3.1 g) in dry THF (30 mL), were added Methyl iodide (2.94 g) and Potassium carbonate (3.9 g) at room temperature under inert atmosphere. Thr reaction mixture was continued to stir for 12 h at room temperature. Re- action mixture was diluted with ethyl acetate and washed with water. The mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (2.3 g). 1H NMR (300 MHz, DMSO-d6) d 13.17 (s, 1 H), 8.14 (d, J= 1.5 Hz, 1 H), 7.99 (dd, J= 8.7, 0.7 Hz, 1 H), 7.45 (dd, J= 8.6, 1.6 Hz, 1 H).
65.9 % With caesium carbonate In N,N-dimethyl-formamide at 50℃; S85.1 Step 1: Synthesis of 6-bromo-1-methyl-indazole-3-carbaldehyde To a solution of 6-bromo-1H-indazole-3-carbaldehyde (5.000 g, 22.22 mmol, 1.00 eq) in Dimethyl Formamide (50 mL) was added cesium carbonate (14.480 g, 44.44 mmol, 2.00 eq) and iodomethane (3.780 g, 26.66 mmol, 1.7 mL, 1.20 eq) the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature. The mixture was filtered and the filtrate was added ethyl acetate (100 mL) and water (50 mL) and organic layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). Combined extracts were washed with sat brine (50 mL), dried over magnesium sulfate, filtered and the filtrate were concentrated to give the product. The residue was purified by silica gel column (5~10% ethyl acetate in petroleum ether). The title compound (3.500 g, 14.64 mmol, 65.9% yield) was obtained as a white solid. LCMS: 240.9[M+H]+
65.9 % With caesium carbonate In N,N-dimethyl-formamide at 50℃; S85.1 Step 1: Synthesis of 6-bromo-1-methyl-indazole-3-carbaldehyde To a solution of 6-bromo-1H-indazole-3-carbaldehyde (5.000 g, 22.22 mmol, 1.00 eq) in Dimethyl Formamide (50 mL) was added cesium carbonate (14.480 g, 44.44 mmol, 2.00 eq) and iodomethane (3.780 g, 26.66 mmol, 1.7 mL, 1.20 eq) the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature. The mixture was filtered and the filtrate was added ethyl acetate (100 mL) and water (50 mL) and organic layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). Combined extracts were washed with sat brine (50 mL), dried over magnesium sulfate, filtered and the filtrate were concentrated to give the product. The residue was purified by silica gel column (5~10% ethyl acetate in petroleum ether). The title compound (3.500 g, 14.64 mmol, 65.9% yield) was obtained as a white solid. LCMS: 240.9[M+H]+

  • 6
  • [ 885271-72-7 ]
  • [ 76513-69-4 ]
  • [ 2082789-58-8 ]
YieldReaction ConditionsOperation in experiment
49.2% Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran at 0 - 20℃; 1 Synthesis Intermediate 2: 6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde Dissolve Intermediate 1 (1.56g, 6.93mmol) in dry tetrahydrofuran, cool to 0°C, slowly add sodium hydride (0.33g, 8.32mmol), react at room temperature for 1 hour, cool to 0°C, slowly add 2- (Trimethylsilyl)ethoxymethyl chloride (1.73g, 10.40mmol), after dripping and reacting at room temperature overnight, add water to quench the reaction, extract twice with ethyl acetate, combine the organic phases, and wash with water and saturated brine , Dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain Intermediate 2, with a yield of 49.2%.
49.2% Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran at 0 - 20℃; 1.3.2 2. Synthesis of intermediate 1-12: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde Intermediate 1-11 (1.56g, 6.93mmol) was dissolved in dry tetrahydrofuran, cooled to 0°C, slowly added sodium hydride (0.33g, 8.32mmol), reacted at room temperature for 1 hour, cooled to 0°C, slowly added dropwise 2-(Trimethylsilyl)ethoxymethyl chloride (1.73 g, 10.40 mmol) was added dropwise to react at room temperature overnight, water was added to quench the reaction, extracted twice with ethyl acetate, the organic phases were combined, water and saturated Washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain Intermediate 1-12 with a yield of 49.2%.
22.97 g Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran; mineral oil for 16h; Cooling; Inert atmosphere;
49.2 % Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran at 0 - 20℃; 1 Synthetic intermediate 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde Intermediate 1 (1.56g, 6.93mmol) was dissolved in dry tetrahydrofuran, cooled to 0°C, slowly added sodium hydride (0.33g, 8.32mmol), reacted at room temperature for 1 hour, cooled to 0°C, slowly added dropwise 2-(trimethylsilyl)ethoxymethyl chloride (1.73g, 10.40mmol), add dropwise and react at room temperature overnight, add water to quench the reaction, extract twice with ethyl acetate, combine the organic phases, wash with water and saturated brine , dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain intermediate 2 with a yield of 49.2%.
49.2 % Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran at 20℃; 1 Synthesis of intermediate 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy) methyl) -1H-indazole-3-formaldehyde Intermediate 1 (1.56 g, 6.93 mmol) was dissolved in dry tetrahydrofuran, and then cooled to 0°C. Sodium hydride (0.33 g, 8.32 mmol) was added slowly, the reaction was carried out at room temperature for 1 hour, and then cooled to 0°C. After that, 2-(trimethylsilyl)ethoxymethyl chloride (1.73 g, 10.40 mmol) was added dropwise and the reaction was carried out at room temperature overnight. The reaction was quenched by adding water. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 2, with a yield of 49.2%. (0174) 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.22 (dd, J = 8.0 Hz, J = 4.0 Hz 1H), 7.88 (dd, J = 4.0 Hz, J = 4.0 Hz, 1H), 7.52 (dd, J = 4.0 Hz, J = 4.0 Hz, 1H), 5.81 (s, 2H), 3.63-3.58 (m, 2H), 0.97-0.93 (m, 2H), 0.04 (s, 9H).
49.2 % Stage #1: 6-bromo-1H-indazole-3-carbaldehyde With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran at 20℃; 1 Synthesis of intermediate 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy) methyl) -1H-indazole-3-formaldehyde Intermediate 1 (1.56 g, 6.93 mmol) was dissolved in dry tetrahydrofuran, and then cooled to 0°C. Sodium hydride (0.33 g, 8.32 mmol) was added slowly, the reaction was carried out at room temperature for 1 hour, and then cooled to 0°C. After that, 2-(trimethylsilyl)ethoxymethyl chloride (1.73 g, 10.40 mmol) was added dropwise and the reaction was carried out at room temperature overnight. The reaction was quenched by adding water. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 2, with a yield of 49.2%. (0174) 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.22 (dd, J = 8.0 Hz, J = 4.0 Hz 1H), 7.88 (dd, J = 4.0 Hz, J = 4.0 Hz, 1H), 7.52 (dd, J = 4.0 Hz, J = 4.0 Hz, 1H), 5.81 (s, 2H), 3.63-3.58 (m, 2H), 0.97-0.93 (m, 2H), 0.04 (s, 9H).

  • 7
  • [ 885271-72-7 ]
  • [ 2096999-92-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium hydrogensulfite / N,N-dimethyl-formamide / 6 h / 140 °C 2.1: water; methanol; 2-methyltetrahydrofuran / 1 h / 20 °C / Large scale 2.2: 18 h / 25 °C / Large scale 3.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; 1,4-dioxane / 1.5 h / 130 °C / Inert atmosphere 4.1: 10 wt% Pd(OH)2 on carbon; trifluoroacetic acid; hydrogen / methanol / 16 h / 25 °C / 2585.81 Torr 5.1: sodium tris(acetoxy)borohydride; acetic acid / N,N-dimethyl-formamide / 48 h / 20 °C
Multi-step reaction with 6 steps 1.1: N,N-dimethyl acetamide / 1 h 1.2: 3 h / 135 °C 2.1: sodium hydroxide / water; 2-methyltetrahydrofuran / 1 h / 65 °C / Large scale 3.1: water; methanol; 2-methyltetrahydrofuran / 1 h / 20 °C / Large scale 3.2: 18 h / 25 °C / Large scale 4.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; 1,4-dioxane / 1.5 h / 130 °C / Inert atmosphere 5.1: 10 wt% Pd(OH)2 on carbon; trifluoroacetic acid; hydrogen / methanol / 16 h / 25 °C / 2585.81 Torr 6.1: sodium tris(acetoxy)borohydride; acetic acid / N,N-dimethyl-formamide / 48 h / 20 °C
  • 8
  • [ 885271-72-7 ]
  • [ 2247925-36-4 ]
  • [ 2097002-70-3 ]
YieldReaction ConditionsOperation in experiment
86% Stage #1: 6-bromo-1H-indazol-3-yl-carbaldehyde; 1-benzyl-4-imino-1,4-dihydropyridin-3-amine hydrobromide In N,N-dimethyl acetamide for 1h; Large scale; Stage #2: With sodium hydrogensulfite In N,N-dimethyl acetamide at 135℃; for 3h; Large scale; (a) 5-Benzyl-2-(6-bromo-1H-indazol-3-yl)-5H-imidazo[4,5-c]pyridine A solution of 6-bromo-1H-indazole-3-carbaldehyde (550 g, 2.444 mol), 1-benzyl-4-imino-1,4-dihydropyridin-3-amine HBr (721 g, 2.333 mol) and DMAc (2.65 L) was stirred for 60 min and sodium bisulfite (257 g, 2.468 mol) was added. The reaction mixture was heated to 135 °C. and held for 3 h, and allowed to cool to 20° C. and held at 20 °C. overnight. Acetonitrile (8 L) was added and the reaction mixture was stirred for 4 h at 15 °C. The slurry was filtered on a pressure filter at medium filtration rate. To the reactor was added ACN (1 L) The cake was washed with the ACN reactor wash and dried under nitrogen overnight and then under vacuum at 50 °C. for 24 h to provide the HBr salt of the title compound (1264 g, 2.444 mol, 100 % yield, 94% purity) as a dense wet beige/brown solid. HPLC Method A Retention time 8.77 min. A mixture of the product of the previous step (1264 g, 2.444 mol), MeTHF (6 L) and water (2.75 L) was heated to 65 °C. and sodium hydroxide 50 wt % (254 g, 3.177 mol) was added over 5 min and the reaction mixture was stirred at 65° C. for 1 h, cooled to RT, then to 5 °C. and held for 2 h. The slurry was filtered and the reactor and cake were washed with MeTHF (1L). The resulting beige to yellow solid was dried on the filter under nitrogen for 3 d to provide the title compound (475 g, 1.175 mmol, 48% yield) as a beige/yellow solid. The mother liquor (about 8 L) was concentrated to about 2 L, whereupon solids began to crash out., The slurry was heated to 50 °C., held for 2 h, cooled to 5° C. over 2 h, stirred overnight, and filtered. The cake was washed with MeTHF (100 mL) and dried overnight under vacuum at 40° C. to provide additional title compound (140 g, 0.346 mol, 14% yield). A mixture of the total product of the previous step, combined with the product of a second batch at the same scale (1500 g, 3.710 mol) and MeTHF (4 L) was stirred at 20 °C. for 2 h and filtered. The reactor and cake were washed with MeTHF (1.5 L). The resulting beige to yellow solid was dried under nitrogen for 3 d to provide the title compound as a beige yellow solid (1325 g, 3.184 mol, 86% yield (overall 68% yield), 97% purity). HPLC Method A Retention time 8.77 min.
  • 9
  • [ 52415-29-9 ]
  • [ 68-12-2 ]
  • [ 885271-72-7 ]
YieldReaction ConditionsOperation in experiment
83.6% With hydrogenchloride; sodium nitrite In water at 0 - 20℃; Inert atmosphere; 1 Synthesis Intermediate 1: 6-Bromo 1H-indazole-3-carbaldehyde Sodium nitrite (14.00g, 200mmol) was dissolved in 75ml DMF and 100ml water, cooled to 0°C, and under nitrogen protection, 3N HCl (23ml, 68.9mmol) was slowly added dropwise, and the reaction was completed dropwise for 10 minutes. At 0°C, a solution of 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowly added dropwise to the reaction solution. After the addition, the reaction was carried out at room temperature overnight. Extracted with ethyl acetate 3 times, combined the organic phases, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column.The intermediate 1 was obtained with a yield of 83.6%.
83.6 % Stage #1: N,N-dimethyl-formamide With hydrogenchloride; sodium nitrite In water at 20℃; Inert atmosphere; Stage #2: 6-bromo-1H-indole In water at 0 - 20℃; 1 Synthesis of intermediate 1:6-bromo-1H-indazole-3-formaldehyde Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75ml DMF and 100 ml water, and then cooled to 0°C. Under nitrogen protection, 3N HCl (23 ml, 68.9 mmol) was slowly added dropwise and after addition, the reaction was carried out for 10 minutes. At 0°C, to the reaction solution, 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35ml) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued at room temperature overnight. The resulting mixture was extracted with ethyl acetate 3 times, and then the organic phases were combined, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate 1, with a yield of 83.6%. (0172) 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.52 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H).
83.6 % Stage #1: N,N-dimethyl-formamide With hydrogenchloride; sodium nitrite In water at 20℃; Inert atmosphere; Stage #2: 6-bromo-1H-indole In water at 0 - 20℃; 1 Synthesis of intermediate 1:6-bromo-1H-indazole-3-formaldehyde Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75ml DMF and 100 ml water, and then cooled to 0°C. Under nitrogen protection, 3N HCl (23 ml, 68.9 mmol) was slowly added dropwise and after addition, the reaction was carried out for 10 minutes. At 0°C, to the reaction solution, 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35ml) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued at room temperature overnight. The resulting mixture was extracted with ethyl acetate 3 times, and then the organic phases were combined, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate 1, with a yield of 83.6%. (0172) 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.52 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H).
 

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