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CAS No. : | 261953-36-0 | MDL No. : | MFCD04114695 |
Formula : | C7H5IN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RSGAXJZKQDNFEP-UHFFFAOYSA-N |
M.W : | 244.03 | Pubchem ID : | 12991241 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.81 |
TPSA : | 28.68 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.23 cm/s |
Log Po/w (iLOGP) : | 1.32 |
Log Po/w (XLOGP3) : | 2.2 |
Log Po/w (WLOGP) : | 2.17 |
Log Po/w (MLOGP) : | 2.04 |
Log Po/w (SILICOS-IT) : | 3.04 |
Consensus Log Po/w : | 2.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.41 |
Solubility : | 0.096 mg/ml ; 0.000394 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.44 |
Solubility : | 0.893 mg/ml ; 0.00366 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.87 |
Solubility : | 0.0331 mg/ml ; 0.000136 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With potassium iodide In dichloromethane; water at 0 - 40℃; for 2.16667 h; |
A concentrated hydrochloric acid (35 mL, 420 mmol) and an aqueous solution (30 mL) of sodium nitrite (6.64g, 96 mmol) were added to a suspension prepared by adding water (30 mL) to 6-aminoindazole (10.4 g, 78 mmol) at0°C and stirred at 0°C for 30 minutes. Subsequently, to this solution, an aqueous solution (30 mL) of potassium iodide(15.91 g, 96 mmol) was added at 0°C, stirred at room temperature for 30 minutes, to which dichloromethane (80 mL)was then added, and stirred at 40°C for 2 hours. The reaction mixture was cooled down to 0°C, then adjusted to pH =14 with a 3N sodium hydroxide aqueous solution, and the precipitate was taken by filtration. The resulting precipitatewas washed with 10percent sodium thiosulfate, dissolved in tetrahydrofuran, and then silica gel was added. After stirring atroom temperature for 1 hour, hexane (600 mL) was added and filtered. The residue was washed twice with a THF/hexane(1/3 (v/v)) solution, then the solvent was distilled away under a reduced pressure to obtain the title compound (15.23 g,80percent) as an orange powder.1H NMR (400 MHz, CDCl3) δ 10.24 (1H, br, s), 8.04 (1H, br s), 7.92 (1H, br s), 7.51 (1H, br d, J = 8.4 Hz), 7.46 (1H, dd,J = 8.4, 1.2 Hz). |
48% | With sodium hydroxide; concentrated aqueous HCl; Ki; sodium hydrogencarbonate; sodium nitrite In tetrahydrofuran; hexane; water | (i) To 6-aminoindazole (40.8 g, 0.3065 mol, 1 equiv) in a 2-liter (2-L) round-bottom flask containing a large magnetic stir bar was added ice (256 g), followed by water (128 mL) and the reaction vessel was lowered into an ice bath. To this stirring slurry at 0° C. was added concentrated aqueous HCl (128 mL, 1.53 mol, 5 equiv). Immediately after, a solution of NaNO2 (23.3 g, 0.338 mol, 1.1 equiv) in water (96 mL) was added. After 10 min of stirring at 0° C., KI (61 g, 0.368 mol, 1.2 equiv) was added very slowly at first (~100 mg at a time because the first small bits of KI cause an abrupt evolution of gas) then more rapidly (5 min total time). The cold bath was removed and the reaction mixture was warmed to 40° C. (gas evolved). When the rate of gas evolution decreased (~30 min) the reaction mixture was warmed to 50° C. for 30 min. The mix was then cooled to 23° C., and 3N NaOH (320 mL) was added to neutralize followed by 50percent saturated NaHCO3 (320 mL). The slurry was then filtered through a Buchner funnel to give a dark reddish-brown solid. The solid was taken up in warm THF (800 mL) and silica (600 mL dry) was added with stirring. To this slurry was added hexane (1.2 L) and the mix was vacuum filtered through a pad of silica (300 mL) in a large fritted filter. The silica was further washed with 2 L of 40percent THF in hexane. The filtrates were combined and concentrated under reduced pressure to give a solid. The solid was further triturated with ethyl acetate (~100 mL), filtered and dried under reduced pressure to give 6-iodo-1H-indazole as a light brown solid (36.1 g, 48percent yield): Rf sm 0.12, p 0.48 (Hex-EtOAc 1:1); 1H NMR (300 MHz, CDCl3) 7.9 (s, 1H), 7.8 (s, 1H), 7.42 (d, 1H), 7.33 (d, 1H); MS (ES) [m+H]/z Calc'd 245, Found 245, [m-H]/z Calc'd 243, Found 243. |
0.9 g | Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.166667 h; Stage #2: With potassium iodide In water at 40 - 50℃; for 1.16667 h; |
6-Aminoindazole (1.0 g, 7.5 mmol) was mixed with ice (6 g) and water (3.5 mL). The reaction mixture was cooled to 0°C and concentrated aqueous hydrochloride solution (3.8 mL) was added followed by a solution of sodium nitrite (0.6 g, 8.2 mmol) in water (2.5 mL). After 10 min of stirring at 0°C potassium iodide (1.3 g, 9.0 mmol) was added in few portions. Then the cold bath was removed and reaction mixture was warmed to 40°C, heated for 40 min and next the temperature was increased to 50°C and heated for another 30 min. After cooled to ambient temperature the solution was alkalized with 10percent NaOH. The brown precipitate was collected by filtration and washed with saturated aqueous solution of sodium hydrogen carbonate. The crude product was dissolved in tetrahydrofuran (25 mL) and refluxed with silica gel for 10 min. To this slurry hexane was added and the mixture was vaccum filtered through a silica pad. The silica was washed with solution of tetrahydrofuran in hexane (2:3). The filtrate was concentrated under reduced pressure to give 6-iodoindazole (0.9 g). The 6-iodoindazole (0.9 g, 3.9 mmol) was dissolved in dry dichloromethane (30 mL), cooled to 0°C and N- bromosuccinimide (0.8 g, 4.3 mmol) was added in portions. The reaction mixture was stirred at 0°C for lh. The precipitate was collected by filtration and washed with dichloromethane. The obtained product 3-bromo-6-iodo-lH-indazole was used to the next step without further purification. LC-MS (m/z) 324.8 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: With hydrogenchloride In 1,4-dioxane; water at 70℃; |
To a solution of step-d product (12 g, 0.04 mol) in 1 ,4-dioxane (60 ml, 5 times), 6N HCI (60 ml, 5 times) was added at rt. Reaction mixture was heated to 7O0C and allowed to stir for 2 hrs at the same temperature. Progress of the reaction was monitored by TLC (30percent ethyl acetate/hexane, Rf-0.5). On completion of the reaction, 1 ,4-dioxane was distilled off completely, residue obtained was basified to a pH-12 -13 with sodium hydroxide solution and the compound extracted with ethyl acetate (2 * 75 ml). Combined extract was dried over sodium sulfate and concentrated under reduced pressure to yield the required product (10 g, 78percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | A concentrated hydrochloric acid (35 mL, 420 mmol) and an aqueous solution (30 mL) of sodium nitrite (6.64g, 96 mmol) were added to a suspension prepared by adding water (30 mL) to 6-aminoindazole (10.4 g, 78 mmol) at0C and stirred at 0C for 30 minutes. Subsequently, to this solution, an aqueous solution (30 mL) of potassium iodide(15.91 g, 96 mmol) was added at 0C, stirred at room temperature for 30 minutes, to which dichloromethane (80 mL)was then added, and stirred at 40C for 2 hours. The reaction mixture was cooled down to 0C, then adjusted to pH =14 with a 3N sodium hydroxide aqueous solution, and the precipitate was taken by filtration. The resulting precipitatewas washed with 10% sodium thiosulfate, dissolved in tetrahydrofuran, and then silica gel was added. After stirring atroom temperature for 1 hour, hexane (600 mL) was added and filtered. The residue was washed twice with a THF/hexane(1/3 (v/v)) solution, then the solvent was distilled away under a reduced pressure to obtain the title compound (15.23 g,80%) as an orange powder.1H NMR (400 MHz, CDCl3) delta 10.24 (1H, br, s), 8.04 (1H, br s), 7.92 (1H, br s), 7.51 (1H, br d, J = 8.4 Hz), 7.46 (1H, dd,J = 8.4, 1.2 Hz). | |
48% | With sodium hydroxide; concentrated aqueous HCl; Ki; sodium hydrogencarbonate; sodium nitrite; In tetrahydrofuran; hexane; water; | (i) To 6-aminoindazole (40.8 g, 0.3065 mol, 1 equiv) in a 2-liter (2-L) round-bottom flask containing a large magnetic stir bar was added ice (256 g), followed by water (128 mL) and the reaction vessel was lowered into an ice bath. To this stirring slurry at 0 C. was added concentrated aqueous HCl (128 mL, 1.53 mol, 5 equiv). Immediately after, a solution of NaNO2 (23.3 g, 0.338 mol, 1.1 equiv) in water (96 mL) was added. After 10 min of stirring at 0 C., KI (61 g, 0.368 mol, 1.2 equiv) was added very slowly at first (~100 mg at a time because the first small bits of KI cause an abrupt evolution of gas) then more rapidly (5 min total time). The cold bath was removed and the reaction mixture was warmed to 40 C. (gas evolved). When the rate of gas evolution decreased (~30 min) the reaction mixture was warmed to 50 C. for 30 min. The mix was then cooled to 23 C., and 3N NaOH (320 mL) was added to neutralize followed by 50% saturated NaHCO3 (320 mL). The slurry was then filtered through a Buchner funnel to give a dark reddish-brown solid. The solid was taken up in warm THF (800 mL) and silica (600 mL dry) was added with stirring. To this slurry was added hexane (1.2 L) and the mix was vacuum filtered through a pad of silica (300 mL) in a large fritted filter. The silica was further washed with 2 L of 40% THF in hexane. The filtrates were combined and concentrated under reduced pressure to give a solid. The solid was further triturated with ethyl acetate (~100 mL), filtered and dried under reduced pressure to give 6-iodo-1H-indazole as a light brown solid (36.1 g, 48% yield): Rf sm 0.12, p 0.48 (Hex-EtOAc 1:1); 1H NMR (300 MHz, CDCl3) 7.9 (s, 1H), 7.8 (s, 1H), 7.42 (d, 1H), 7.33 (d, 1H); MS (ES) [m+H]/z Calc'd 245, Found 245, [m-H]/z Calc'd 243, Found 243. |
Example 12 6-Iodo-1H-indazole (compound 20) sodium nitrite (5.87 g, 85 mmol) in water (20 ML) was added dropwise to an ice-cooled solution of 6-aminoindazole (10 g, 75.6 mmol) in DMF (80 ML) and hydrochloric acid (6M, 40 ML).. The mixture was stirred for 30 minutes.. potassium iodide (13.5 g) was then added in small portions (gas evolution occurred) and the mixture stirred for 1 h before warming to room temperature for 16 h.. The reaction was neutralized with aqueous sodium bisulfite, followed by aqueous sodium hydroxide.. The mixture was filtered to remove solids, and the solid was washed with water to remove impurities, and then with ethyl acetate and THF to collect the product.. The organic washes were evaporated and recombined with the aqueous layer for extraction with ethyl acetate (3*250 ML).. The organic layer was washed sequentially with water and brine, dried over sodium sulfate, and the solvent removed in vacuo.. Filtration chromatography on silica gel (35-60% ethyl acetate in hexane) gave a yellow solid which was triturated firstly with 50% ethyl acetate in hexane and then with ethyl acetate to yield the product (4.96 g). |
0.9 g | <strong>[6967-12-0]6-Aminoindazole</strong> (1.0 g, 7.5 mmol) was mixed with ice (6 g) and water (3.5 mL). The reaction mixture was cooled to 0C and concentrated aqueous hydrochloride solution (3.8 mL) was added followed by a solution of sodium nitrite (0.6 g, 8.2 mmol) in water (2.5 mL). After 10 min of stirring at 0C potassium iodide (1.3 g, 9.0 mmol) was added in few portions. Then the cold bath was removed and reaction mixture was warmed to 40C, heated for 40 min and next the temperature was increased to 50C and heated for another 30 min. After cooled to ambient temperature the solution was alkalized with 10% NaOH. The brown precipitate was collected by filtration and washed with saturated aqueous solution of sodium hydrogen carbonate. The crude product was dissolved in tetrahydrofuran (25 mL) and refluxed with silica gel for 10 min. To this slurry hexane was added and the mixture was vaccum filtered through a silica pad. The silica was washed with solution of tetrahydrofuran in hexane (2:3). The filtrate was concentrated under reduced pressure to give 6-iodoindazole (0.9 g). The 6-iodoindazole (0.9 g, 3.9 mmol) was dissolved in dry dichloromethane (30 mL), cooled to 0C and N- bromosuccinimide (0.8 g, 4.3 mmol) was added in portions. The reaction mixture was stirred at 0C for lh. The precipitate was collected by filtration and washed with dichloromethane. The obtained product 3-bromo-6-iodo-lH-indazole was used to the next step without further purification. LC-MS (m/z) 324.8 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 150℃; for 0.5h;Microwave irradiation; | A stirred mixture of 6-iodo-1H-indazole (0.45g), N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 18, 0.54g) tetrakis(triphenylphosphine)palladium(0) (0.05g) and aqueous sodium hydrogen carbonate (1M, 1ml) in isopropanol (10ml) was heated at 150C for 30min in a microwave oven . The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (3x25ml). The extracts w ere w ashed with w ater (25ml) d ried (Na2SO4) a nd oncentrated u nder v acuum. The residual oil was purified by column chromatography on silica (50g) eluting with ether/ ethyl acetate (7:3) to give the title compound as a pale yellow foam (0.25g). LC-MS: Rt 2.7min. | |
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 150℃; for 0.5h; | Intermediate 12: N-Ethyl-3- (1H-indazol-6-yl)-4-methvibenzamide; A stirred mixture of 6-iodo-1 H-indazole (0.45g), N-ethyl-4-methyl-3- (4, 4,5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yi) benzamide (Intermediate 10, 0. 54g) tetrakis (triphenylphosphine) palladium (0) (0.05g) and aqueous sodium hydrogen carbonate (1M, 1ml) in isopropanol (10ml) was heated at 150C for 30min in a microwave oven. The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (3x25ml). The extracts were washed with water (25ml) d ried (Na2SO4) a nd concentrated u nder vacuum. The residual oil was purified by column chromatography on silica (50g) eluting with ether/ ethyl acetate (7: 3) to give the title compound as a pale yellow foam (0.25g). LC-MS: Rt 2.7min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 150℃; for 0.5h;Microwave irradiation; | A stirred mixture of 6-iodo-1H-indazole (0.5g) {5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyljboronic acid (Intermediate 16, 0.56g), tetrakis(triphenylphosphine)palladium(0)25 (0.05g) and aqueous sodium hydrogen carbonate (1M, 1ml) in isopropanol (10ml) was heated at 150C for 30min in a microwave oven. The reaction mixture was poured into water (30ml) and extracted with ethyl acetate (3x20ml). The extracts were dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50g) eluting with ether/ethyl acetate (4:1). The resultant product was triturated with a30 small quantity of dichloromethane to give the title compound as a pale yellow solid (0.15g). LC-MS: Rt 2.96min, MH+ 298. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
An aqueous solution of NaHSO3 was prepared by adding 13.6 g of solid NaHSO3 into 250 mL of Dl water with strong stirring. 6-iodoindazole (30.0 g), followed by DMF (60 mL) were added to a 500 mL three-neck flask that was fitted with a mechanical stirrer, a temperature probe, and a 100 mL dropping funnel. After the stirring had begun, the flask was immersed in an ice/water bath. After 30 mintues, KOH was added in one portion, and the resulting mixture was stirred for an additional 30 minutes. A solution of 54.3g of I2 in 55 mL of DMF (total volume was 71 mL) was added to the dropping funnel and the run-in started. After 30 minutes, 42 mL of the solution had been added to the reaction mixture. The addition was stopped and an aliquot sample was taken and analyzed with HPLC (TFASH method), which indicated that there was still 6-iodoindazole present. After an additional 10 mL of the iodine/DMF solution was added, the second aliquot sample showed that all the starting 6-iodoindazle was consumed. A solution of 13.6g of NaHSO3 in Dl water was added slowly to the reaction mixture. At this stage the dark solution became a yellow suspension. After stirring for one hour, the mixture was filtered and the cake was washed with 200 mL of water and 200 mL of hexanes. The cake was sucked dry and further dried in a vacuum oven (25 inch vacuum/60C) for 18 hours to afford 38.60 g of the final product as a tan solid. 1H NMR 300MHz, DMSO ppm: 7.96 (s, 1H), 7.46 (d, J=8.4 Hz, 1 H), 7.24 (d, J=8.4 Hz, 1H), 3.33 (s, 1 H). | ||
With iodine; potassium hydroxide; In water; N,N-dimethyl-formamide;Cooling with ice; | An aqueous solution of NaHSO 3 was prepared by adding 13.6 g of solid NaHSO 3 into 250 mL of DI water with strong stirring. 6 -iodoindazole (30.0 g), followed by DMF (60 mL) were added to a 500 mL three -neck flask that was fitted with a mechanical stirrer, a temperature probe, and a 100 mL dropping funnel. After the stirring had begun, the flask was immersed in an ice/water bath. After 30 mintues, KOH was added in one portion, and the resulting mixture was stirred for an additio nal 30 minutes. A solution of 54.3g of I 2 in 55 mL of DMF (total volume was 71 mL) was added to the dropping funnel and the run -in started. After 30 minutes, 42 mL of the solution had been added to the reaction mixture. The addition was stopped and an a liquot sample was taken and analyzed with HPLC (TFASH method), which indicated that there was still 6 -iodoindazole present. After an additional 10 mL of the iodine/DMF solution was added, the second aliquot sample showed that all the starting 6 - iodoindazle was consumed. A solution of 13.6g of NaHSO 3 in DI water was added slowly to the reaction mixture. At this stage the dark solution became a yellow suspension. After stirring for one hour, the mixture was filtered and the cake was washed with 200 mL of water and 200 mL of hexanes. The cake was sucked dry and further dried in a vacuum oven (25 inch vacuum/60C) for 18 hours to afford 38.60 g of the final product as a tan solid. 1H NMR 300MHz, DMSO ppm: 7.96 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 3.33 (s, 1H). | |
Example 3 Preparation of 3,6-diodoindazole An aqueous solution of NaHSO3 was prepared by adding 13.6 g of solid NaHSO3 into 250 mL of DI water with strong stirring. 6-iodoindazole (30.0 g), followed by DMF (60 mL) were added to a 500 mL three-neck flask that was fitted with a mechanical stirrer, a temperature probe, and a 100 mL dropping funnel. After the stirring had begun, the flask was immersed in an ice/water bath. After 30 mintues, KOH was added in one portion, and the resulting mixture was stirred for an additional 30 minutes. A solution of 54.3g of 12 in 55 mL of DMF (total volume was 71 mL) was added to the dropping funnel and the run-in started. After 30 minutes, 42 mL of the solution had been added to the reaction mixture. The addition was stopped and an aliquot sample was taken and analyzed with HPLC (TFASH method), which indicated that there was still 6-iodoindazole present. After an additional 10 mL of the iodine/DMF solution was added, the second aliquot sample showed that all the starting 6-iodoindazle was consumed. A solution of 13.6g of NaHSO3 in DI water was added slowly to the reaction mixture. At this stage the dark solution became a yellow suspension. After stirring for one hour, the mixture was filtered and the cake was washed with 200 mL of water and 200 mL of hexanes. The cake was sucked dry and further dried in a vacuum oven (25 inch vacuum/60 C.) for 18 hours to afford 38.60 g of the final productproduct as a tan solid. 1H NMR 300MHz, DMSO ppm: 7.96 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 3.33 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tris-(dibenzylideneacetone)dipalladium(0); cesiumhydroxide monohydrate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 4.5h;Inert atmosphere; | N,N-Dimethylformamide (25 mL) was added to 6-iodo-1H-indazole (5.51 g, 22 mmol), 2-mercapto-N-methylbenzamide(5.16 g, 31 mmol), Pd2(dba)3 (1.02 g, 1.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.46 g,2.5 mmol) and cesium hydroxide monohydrate (5.67 g, 33 mmol) and stirred under an argon atmosphere at 100C for4.5 hours. The solvent was distilled away from the reaction solution under a reduced pressure, the residue was dissolvedin ethyl acetate and washed with water and saturated saline. The organic layer was dried with anhydrous sodium sulfate,and the solvent was distilled away under a reduced pressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate (v/v) = 1/3) to obtain the title compound (6.14 g, 96%) as a pale orange solid.1H NMR (400 MHz, DMSO-d6) δ 13.13 (1H, br s), 8.36 (1H, br q, J = 4.4 Hz), 8.10 (1H, s), 7.78 (1H, br d, J = 8.4 Hz),7.59 (1H, br s), 7.48-7.46 (1H, m), 7.29 (1H, td, J = 7.6, 1.6 Hz), 7.25 (1H, td, J = 7.6, 1.6 Hz), 7.08 (1H, dd, J = 8.4, 1.6Hz), 6.99-6.97 (1H, m), 2.76 (3H, d, J = 4.4 Hz) |
With cesium hydroxide; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1-methyl-pyrrolidin-2-one; water; at 80℃; for 18.5h;Inert atmosphere; | A 5 L three neck flask was equipped with a mechanical stirrer, a temperature probe, and a N2 inlet. The flask was charged with 6 -iodoindazole (200 g) followed by 2 - mercapto-N-methylbenzamide (144 g), Pd2(dba)3(3.75 g), Xantphos (4.74 g), NMP (1.2 L), and 50% aqueous CsOH solution (150 mL) in that order. Stirring was then commenced. The dark reaction mixture was degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was heated to 80 C over a period of half an hour and maintained at the same temperature for 18 hours. The reaction was monitored by HPLC . It was noted that heating may be discontinued when the amount of 6-diiodoindazole is < 3%. The reaction mixture was allowed to cool to room temperature. An aqueous solution of Na HSO3 was prepared by adding 90 g of solid NaHSO3 into 1.5 L of deionized water with strong stirring. This solution was then set aside until the reaction quench step as described below. The reaction mixture in the 5 L flask was chilled in an ice-water bath until an internal temperature of 0.9 C was reached. KOH (183 g) was then charged in a single portion and the resulting mixture was allowed to stir for half an hour in ice-water bath (slight exotherm, highest point 4.0 C). Iodine (417 g) was dissolved in NMP (420 mL) in a separate flask with stirring. Once complete dissolution of iodine was been confirmed, the dark mixture was charged to a 1 L addition funnel. The iodine/NMP solution was then added dropwise over 1 h to the reaction mixture. (Note: the addition is exothermic and the internal reaction temperature must therefore be controlled via external cooling in addition to the controlled addition rate; the internal tempe rature should be kept between 0 C and 16.8C). Upon complete addition the final temperature was 14.5C. The flask was then taken out of the bath and the in ternal temperature reached 21.1C in 70 min. The mixture was allowed to stir at room temperature for three hours, at which time, analysis of an aliquot sample indicated the reacti on was complete (<3% left). Upon confirmation of reaction completion (HPLC), the flask was re -immersed in the icewater bath. The aqueous NaHSO3 solution prepared as described previously was added slowly over 40 minutes from an addition funnel. ( Note: this addition is exothermic and the internal reaction temperature must therefore be controlled via external cooling in addition to the controlled addition rate; the internal temper ature should be kept below15.7 C). Upon complete addition the reaction was a slurry of light yellow solids. The mixture was allowed to stir at ambient temperature overnight. The solid produ ct was collected by filtration. The wet cake was recharged back into the 5 L flask and the funnel was rinsed with 1.5 L of water, and the r inses were also charged into the 5 L flask. The mixture was stirred for one hour and filtered. The wet cake was recharged back to the 5 L flask, and the funnel was rinsed with 1.5 L of methanol, and the rinses were also charged into the 5 L flask. The mixture was heated at 45 C for two hours, then allowed to cool. The mixture was filtered and the cake was washed with 500 mL of MeOH, and sucked dry. The product (cake) was placed in a vacuum oven at 60 C for 18 h to afford 317 g of 2-(3-lodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide. | |
With cesium hydroxide;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1-methyl-pyrrolidin-2-one; water; at 80℃; for 18.5h; | A 5 L three neck flask was equipped with a mechanical stirrer, a temperature probe, and a N2 inlet. The flask was charged with <strong>[261953-36-0]6-iodoindazole</strong> (200 g) followed by 2-mercapto-N-methylbenzamide (144 g), Pd2(dba)3 (3.75 g), Xantphos (4.74 g), NMP (1.2 L), and 50% aqueous CsOH solution (150 mL) in that order. Stirring was then commenced. The dark reaction mixture was degassed three times by alternately connecting to house vacuum and nitrogen. The mixture was heated to 80 C. over a period of half an hour and maintained at the same temperature for 18 hours. The reaction was monitored by HPLC. It was noted that heating may be discontinued when the amount of 6-diiodoindazole is <3%. The reaction mixture was allowed to cool to room temperature. An aqueous solution of NaHSO3 was prepared by adding 90 g of solid NaHSO3 into 1.5 L of deionized water with strong stirring. This solution was then set aside until the reaction quench step as described below. The reaction mixture in the 5 L flask was chilled in an ice-water bath until an internal temperature of 0.9 C. was reached. KOH (183 g) was then charged in a single portion and the resulting mixture was allowed to stir for half an hour in ice-water bath (slight exotherm, highest point 4.0 C.). Iodine (417 g) was dissolved in NMP (420 mL) in a separate flask with stirring. Once complete dissolution of iodine was been confirmed, the dark mixture was charged to a 1 L addition funnel. The iodine/NMP solution was then added dropwise over 1 h to the reaction mixture. (Note: the addition is exothermic and the internal reaction temperature must therefore be controlled via external cooling in addition to the controlled addition rate; the internal temperature should be kept between 0 C. and 16.8 C.). Upon complete addition the final temperature was 14.5 C. The flask was then taken out of the bath and the internal temperature reached 21.1 C. in 70 min. The mixture was allowed to stir at room temperature for three hours, at which time, analysis of an aliquot sample indicated the reaction was complete (<3% left). Upon confirmation of reaction completion (HPLC), the flask was re-immersed in the ice-water bath. The aqueous NaHSO3 solution prepared as described previously was added slowly over 40 minutes from an addition funnel. (Note: this addition is exothermic and the internal reaction temperature must therefore be controlled via external cooling in addition to the controlled addition rate; the internal temperature should be kept below 15.7 C.). Upon complete addition the reaction was a slurry of light yellow solids. The mixture was allowed to stir at ambient temperature overnight. The solid product was collected by filtration. The wet cake was recharged back into the 5 L flask and the funnel was rinsed with 1.5 L of water, and the rinses were also charged into the 5 L flask. The mixture was stirred for one hour and filtered. The wet cake was recharged back to the 5 L flask, and the funnel was rinsed with 1.5 L of methanol, and the rinses were also charged into the 5 L flask. The mixture was heated at 45 C. for two hours, then allowed to cool. The mixture was filtered and the cake was washed with 500 mL of MeOH, and sucked dry. The product (cake) was placed in a vacuum oven at 60 C. for 18 h to afford 317 g of 2-(3-Iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide. |
Yield | Reaction Conditions | Operation in experiment |
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(ff) 6-(3-thienyl)-1H-indazole (237 mg, 71%); from 6-iodo-1H-indazole (403.5 mg, 1.65 mmol) and 3-thiopheneboronic acid (236.5 mg, 1.8 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With ammonium chloride; In tetrahydrofuran; | (ii) To a solution of 6-iodo-1H-indazole (7.35 g, 30.1 mmol, 1 equiv) in THF (100 mL) cooled to 0 C. under argon, was added sodium t-butoxide (2.89 g, 30.1 mmol, 1 equiv). A color change from orange to red was observed. Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) was added in one portion and the ice bath was removed allowing the reaction mixture to warm to 23 C. After 40 min the mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous was extracted a total of 3 times with ethyl acetate. The combined organic material was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as an orange solid (12.8 g, 100% yield, 2:1 mixture). 1H NMR (CDCl3) 8.51 (s, 1H), 7.95 (s, 0.66H, major isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d, 0.33H, J=8.4 Hz), 7.29 (d, 0.33H, J=8.4 Hz), 7.26 (d, 0.66H, J=8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid; sodium nitrite; In water; at 20℃; | Production Example 15-1 6-Iodo-1H-indazole An aqueous solution (4 mL) of sodium nitrite (1.1 g) was dropwise added to an acetic acid solution (360 mL) of (5-iodo-2-methylphenyl)amine, and after the addition, this was stirred overnight at room temperature. The solvent was evaporated off under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 4:1) to obtain the entitled compound (1 g) as an orange powder. |
Yield | Reaction Conditions | Operation in experiment |
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35% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) chloride; In tetrahydrofuran; at 20℃; | Example 159; Synthesis of [5-(lH-Indazol-6-ylethynyl)-lH-benzoimidazol-2-yl]-(2-trifluoromethyl- phenyl)-amineA mixture of 4-bromo-2-nitrophenylamine (2.17 g, 10 mmol), ethynyltrimethyl-silane (2.11 mL, 98%, 15 mmol), dichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.3 mmol) and copper(I) chloride (66.5 mg, 0.35 mmol) in THF (10 mL) and triethyl amine (10 mL) was stirred at room temperature for 3 days. The product, 2-nitro-4- trimethylsilanylethynylphenylamine was purified by silica gel column chromatography. LC-MS m/z: 235 (M+l)+. A mixture of the silyl intermediate from previous above potassium carbonate (2.76 g,20 mmol) and methanol (30 mL) was stirred for two days. Purification by silica gel column chromatography gave 4-ethynyl-2-nitrophenylamine as red solid (1.306 g, 8.05 mmol, yield81% for 2 steps). LC-MS m/z: 163 (M+l)+.A mixture of 4-ethynyl-2-nitro-phenylamine (1.306 g, 8.05 mmol), 6-iodo-lH- indazole (1.965 g, 8.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (122 mg, 0.24 mmol) and copper(I) chloride (54.4 mg, 0.28 mmol) in THF (8 mL) and triethyl amine (8 mL) was stirred at room temperature overnight. Purification by column chromatography on silica <n="86"/>gel gave 4-(lH-indazol-6-ylemynyl)-2-nitrophenylamine as red solid (777 mg, 2.79 ramol, yield 35%). LC-MS m/z: 279 (M+l)+.A mixture of the nitro compound from above (774 mg, 2.78 mmol), iron powder (1.61 g, 97%, 28 mmol) and ammonium chloride (2.25 g, 42 mmol) in ethanol (1.5 mL) and water (1.5 mL) was refluxed for 6 h. Purification by column chromatography on silica gel gave 4- (lH-indazol-6-ylethynyl)-benzene-l,2-diamine as brown solid (284 mg, 1.14 mmol, yield 41%). LC-MS m/z: 249 (M+l)+.The diamine (0.3 mmol) from above was reacted with 1 -isothiocyanato-2- trifluoromethylbenzene (0.3 mmol) followed by cyclization in situ using EDC as described in general procedure B to provide [5-(lH-Indazol-6-ylethynyl)-lH-benzoimidazol-2-yl]-(2- trifluoromethylphenyl)-amine as yellow solid (178 mg, 0.426 mmol, yield 66%). LC-MS m/z: 418 (MH-I)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 20℃; | General Procedure 8a (GP8a): Sonogashira coupling (Conditions A)One equivalent of the halopyrimidine intermediate, CuI (0.2 eq.) and Pd(PPh3J2Cl2 (0.1 eq.) are weighed into a Schlenk flask, set under an atmosphere of argon and dissolved in dry DMF (1 mL per mmol halide). The respective ethynyl(hetero)aryl compound (1.2 eq.) and triethylamine (5-10 eq.) are added sequentially and the resulting mixture is stirred at rt (unless otherwise noted) until TLC or LCMS analysis show complete consumption of the starting halide compound. The reaction mixture is partitioned between DCM and water, the aqueous layer is extracted with DCM (3x) and the combined organic layers are dried and concentrated in vacuo. The target compound is isolated by crystallization and /or flash column chromatography and/or preparative HPLC purification.; 6-lodo-1 H-indazole (1.00 g, 4.10 mmol) was reacted with trimethylsilyl acetylene (0.61 mi_, 4.30 mmol) in analogy to GP8a to give 675 mg (77 %) of pure 6- (trimethylsilyl)ethynyl-IH-indazole.1H-NMR (300 MHz, DMSO): 13.17 (s br, 1 H); 8.07 (s, 1 H); 7.71 (d, 1 H); 7.59 (s, 1 H); 7.08 (d, 1 H); 0.21 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
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Example 13 6-iodo-1-isopropyl-1H-indazole (compound 21) sodium hydride (85 mg, 60%, 2.12 mmol) was added to an ice-cooled solution of 6-iodo-1H-indazole (249.5 mg, 1.02 mmol) in DMF (2.5 ML).. After stirring this mixture for 1 h at 0 C., 2-iodopropane (0.32 ML, 3.2 mmol) was added and the mixture stirred at 100 C. for 16 h.. After the reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo.. Flash chromatography (silica gel, 5-20% ethyl acetate in hexane) yielded two products, the less polar 1-substituted-1H-indazole (105 mg) and the more polar 2-substituted indazolium (107.7 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Production Example 15-2 6-Iodo-1-(2-pyrrolidin-1-ylethyl)-1H-indazole and 6-iodo-2-(2-pyrrolidin-1-ylethyl)-2H-indazole Potassium carbonate was added to a DMF solution (10 mL) of the compound (1 g) obtained in Production Example 15-1, and stirred at room temperature for 30 minutes. N-(2-chloroethyl)pyrrolidine hydrochloride (1.1 g) was added to the reaction liquid, and stirred overnight at 60 C. Water was added to the reaction liquid, and extracted with a mixed solvent of chloroform/methanol (10:1). The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane:ethyl acetate=4:1 to 3:2) to obtain 6-iodo-1-(2-pyrrolidin-2-ylethyl)-1H-indazole (838 mg) and 6-iodo-2-(2-pyrrolidin-1-ylethyl)-2H-indazole (338 mg) successively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h; | To a solution of step-e product (2.5 g, 0.01 mol) in DMF (10 ml, 4 times), potassium carbonate (2.827 g, 0.02 mol, 1.5 eq), benzyl bromide (3.48 g, 0.02 mol, 1.5 eq) were added at rt Reaction mixture was heated to 7O0C and allowed it to stir for 4 hrs at the same temperature Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rf-0.8). On completion of the reaction, reaction contents were poured into ice cold water and the compound extracted with ethyl acetate (2 x 25 ml). Combined extract was dried over sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica gel, 10% ethyl acetate/hexane) to yield the required product as a yellow colored solid (2.2 g, 78% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To a solution of step-d product (12 g, 0.04 mol) in 1 ,4-dioxane (60 ml, 5 times), 6N HCI (60 ml, 5 times) was added at rt. Reaction mixture was heated to 7O0C and allowed to stir for 2 hrs at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rf-0.5). On completion of the reaction, 1 ,4-dioxane was distilled off completely, residue obtained was basified to a pH-12 -13 with sodium hydroxide solution and the compound extracted with ethyl acetate (2 * 75 ml). Combined extract was dried over sodium sulfate and concentrated under reduced pressure to yield the required product (10 g, 78% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1-Synthesis of 5-chloro-4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 32 mg, 0.82 mmol) at 0 C. The mixture was stirred at 0 C. to RT for 10 min before addition of 4,5-dichloropyrimidin-2-amine (134.4 mg, 0.82 mmol). The mixture was stirred at 50 C. for 2 hr, then quenched with water and extracted with DCM (2*). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. LC-MS (Method B) indicated a mixture of title compound [67%, Retention time=2.11 min, m/z=+371.9/373.9 (M+H)+] and an isomeric by-product [10%, Retention time=2.07 min, m/z=+371.9/373.9 (M+H)+]. Purification by flash chromatography (Isolute column, 50% EtOAc in heptane) afforded the title compound: 1H NMR (500 MHz, DMSO) δ 7.31 (2H, br. s.), 7.65 (1H, dd, J=8.51, 1.26 Hz), 7.71 (1H, d, J=8.20 Hz), 8.45-8.48 (1H, m), 8.56-8.71 (1H, m), 8.61 (1H, s); LC-MS: m/z=+371.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; oil; at 0 - 70℃; for 23.1667h; | Step 1-Synthesis of 6-(6-iodoindazol-1-yl)pyrimidin-4-amine To a solution of <strong>[261953-36-0]6-iodoindazole</strong> (500 mg, 2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion, 131.12 mg, 3.28 mmol) at 0 C. The mixture was stirred at 0 C. to RT for 10 minutes before addition of 6-chloropyrimidin-4-amine (477.78 mg, 3.69 mmol) and stirring at 60 C. for 17 hr and then transferred to a pressure tube and heated at 70 C. for a further 6 hr. The reaction mixture was cooled and quenched by the addition of water (10 ml) and EtOAc (a few drops) was added. The resultant precipitate was collected by suction filtration and then thoroughly dried under high vacuum to give the title intermediate (248 mg): LC-MS: m/z=+338.20 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 110℃; for 18.1667h; | Step 2-Synthesis of 6-(6-iodoindazol-1-yl)-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (5 mL) was added NaH (60% oil dispersion, 32.78 mg, 0.82 mmol)) at 0 C. The reaction mixture was stirred at 0 C. for 10 minutes before the addition of 6-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (126.7 mg, 0.55 mmol). The reaction mixture was then stirred at 110 C. for 18 hr. The reaction mixture was then cooled to RT, quenched by the addition of water (2 ml), EtOAc (a few drops) was added and the resultant precipitate was collected by suction filtration and thoroughly dried under high vacuum to give the title compound (120 mg, LC-MS: m/z=+444.90). This compound of 62% purity LC-MS (UV) was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.16667h;Cooling with ice; | Step 1-Synthesis of 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine To a solution of 6-iodo-1H-indazole (537 mg, 2.20 mmol) in DMF (16 mL) was added NaH (60% oil dispersion) (132 mg, 3.30 mmol) at 0 C. Mixture was stirred at RT for 10 min before addition of a portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 500 mg, 1.71 mmol). The mixture was stirred at RT for 20 min. Another portion of NaH (60% oil dispersion) (132 mg, 3.30 mmol) was added at RT. After 10 min, another portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 300 mg, 1.03 mmol) was added. Stirring continued for 30 min. The reaction mixture was cooled in an ice bath before quenching with water. The mixture was acidified by addition of 1 M aq HCl then the pH was adjusted to 8-9 by dropwise addition of saturated aq NaHCO3. The mixture was further diluted with water (20 mL) and extracted with EtOAc (20 mL*3). During the first extraction with EtOAc the insoluble solid was removed by suction filtration. The combined EtOAc layer was washed with water (20 mL), dried over Na2SO4 filtered and concentrated in vacuo to give the crude title compound: LC-MS (Method B): m/z=+382.9 (M+H)+, (purity=45%) This intermediate was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1-Synthesis of 4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1) and 4-(6-iodo-2H-indazol-2-yl)pyrimidin-2-amine (1-a2) To a solution of 6-iodo-1H-indazole (500 mg, 1.95 mmol) in DMF (5 mL) was added NaH (60% oil dispersion) (125 mg, 3.11 mmol) at 0 C. The mixture was stirred at RT for 10 min before addition of 4-chloropyrimidin-2-amine (504 mg, 3.89 mmol). Stirring was continued at RT for 18 hr then the mixture was heated at 50 C. for 2 hr. LCMS showed formation of a (1:1) mixture of (1-a1) and (1-a2). These isomers were separated as follows:The reaction mixture was quenched by addition of water (5 mL). Extraction with EtOAc (3×5 mL) resulted in precipitation. Suction filtration gave 4-(6-iodo-2H-indazol-2-yl)pyrimidin-2-amine (1-a2) as a pale brown solid: 1H NMR (250 MHz, DMSO)S 7.13 (2H, s), 7.28 (1H, d, J=5.33 Hz), 7.39 (1H, d, J=1.37 Hz), 7.67 (1H, dd, J=8.91, 0.69 Hz), 8.21 (1H, d, J=0.91 Hz), 8.46 (1H, d, J=5.18 Hz), 9.12 (1H, d, J=1.07 Hz). LC-MS: m/z=+337.90 (M+H)+.The filtrate was washed with water (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Isolute column, 50% EtOAc in heptanes) to give (6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1) as a pale brown solid: 1H NMR (250 MHz, DMSO) δ 7.08 (1H, d, J=5.48 Hz), 7.11-7.16 (2H, m), 7.69 (2H, dd, J=1.75, 0.99 Hz), 8.30 (1H, d, J=5.63 Hz), 8.47 (1H, d, J=0.76 Hz), 9.31 (1H, d, J=0.91 Hz) LC-MS: m/z=+337.90 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Sodium hydroxide (0.3 g, 6 mmol) was suspended in 10 ml DCM. 5-iodo-lif-indazole (448 mg, 2 mmol) was added, and the mixture was stirred for 30 minutes. A solution of 4-methyl-benzene-l-sulfonyl chloride (456 mg, 2.4 mmol) in 2 mL DCM was added dropwise and the mixture was stirred for several hours. The mixture was partitioned with water. The organic layer was washed with saturated aqueous NaHC03, dried over MgS04, filtered and evaporated. The residue was purified via column chromatography on silica gel using the hexanes/EtOAc as eluent (100/0 to 90/10) to give 358 mg (45%) of the title compound as a gray solid. 6-Iodo-l-tosyl-lii-indazol NMR (600 MHz , CDC13) δ 8.64 (d, J = 0.6 Hz, 1H) , 8.12 (d, J= 0.6 Hz, 1H), 7.89-7.87 (m, 2H) , 7.64- 7.62 (m, 1H), 7.43-7.41 (m, 1H) , 7.29-7.27 (m, 2H) , 2.38 (s, 3H) ; 13C NMR (150 MHz, CDC13) δ 145.73, 141.06, 140.90, 134.34, 133.33, 129.98, 127.68, 125.00, 122.37, 122.18, 95.55, 21.68; HRMS (ESI-TOF) Calcd for C14H12IN202S [M+H]+: 398.9659; found: 398.9662. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | With potassium phosphate; tetrabutylammomium bromide; In water; at 180℃; for 0.333333h;Microwave irradiation; Green chemistry; | General procedure: To a 10 mL glass microwave vial equipped with a magnetic stir bar was charged with a mixture of 1H-indazoles (0.5 mmol, 1 equiv), 2-vinylpyridine or 4-vinylpyridine (1.5 mmol, 3 equiv), Potassium phosphate (1 mmol, 2 equiv) and TBAB (20 mol %, 0.1 mmol) in water (2 mL). The mixture was heated to 180C as fast as possible in microwave oven, and stirred for 20 min at 180C. The resulting solution was cooled to temperature and extracted with EtOAc twice. The combined organic layer was washed with saturated salt water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by gradient elution (PE/AcOEt for starting materials, PE/AcOEt/TEA = 100/50/3 for the pure N1 substituted products and PE/AcOEt/TEA = 20/20/1 for N2 substituted products). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.7%; 32.7% | With potassium phosphate; tetrabutylammomium bromide; In water; at 180℃; for 0.333333h;Microwave irradiation; Green chemistry; | General procedure: To a 10 mL glass microwave vial equipped with a magnetic stir bar was charged with a mixture of 1H-indazoles (0.5 mmol, 1 equiv), 2-vinylpyridine or 4-vinylpyridine (1.5 mmol, 3 equiv), Potassium phosphate (1 mmol, 2 equiv) and TBAB (20 mol %, 0.1 mmol) in water (2 mL). The mixture was heated to 180C as fast as possible in microwave oven, and stirred for 20 min at 180C. The resulting solution was cooled to temperature and extracted with EtOAc twice. The combined organic layer was washed with saturated salt water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by gradient elution (PE/AcOEt for starting materials, PE/AcOEt/TEA = 100/50/3 for the pure N1 substituted products and PE/AcOEt/TEA = 20/20/1 for N2 substituted products). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; at 74℃;Inert atmosphere; | A reaction mixture of 6-iodo-1H-indazole (1 g, 4.10 mmcl), benzyl 4-(4,4,5,5-tetramethyl-1 ,3,2-diox-aborolan-2-yI)-5,6-dihydropyridine-1(2H)-carboxylate (1.41 g, 4.10 mmol),PdCI2(dppf)-CH2CI2 adduct (0.335 g, 0.410 mmol) and sodium carbonate (1.30 g, 12.3 mmol)was bubbled with nitrogen and stirred at 74 C (oil bath) overnight. Then the reactionmixture was filtered, concentrated to remove solvent and diluted with ethyl acetate (180 mL) and water (50 mL). Separated organic part was dried over anhydrous Na2504, fitered and concentrated. Purification via ISCO system (ethyl acetate/petroleum ether) afforded the title product.LC-MS (ESI) [mobile phase: from 95% water (0.05% TFA) and 5% CH3CN to 5% water (0.05%TFA) and 95% CH3CN in 5.0 mm]: m/z 334 [M + H] Rt 3.50 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In dichloromethane; at 0℃; for 1h; | 6-Aminoindazole (1.0 g, 7.5 mmol) was mixed with ice (6 g) and water (3.5 mL). The reaction mixture was cooled to 0C and concentrated aqueous hydrochloride solution (3.8 mL) was added followed by a solution of sodium nitrite (0.6 g, 8.2 mmol) in water (2.5 mL). After 10 min of stirring at 0C potassium iodide (1.3 g, 9.0 mmol) was added in few portions. Then the cold bath was removed and reaction mixture was warmed to 40C, heated for 40 min and next the temperature was increased to 50C and heated for another 30 min. After cooled to ambient temperature the solution was alkalized with 10% NaOH. The brown precipitate was collected by filtration and washed with saturated aqueous solution of sodium hydrogen carbonate. The crude product was dissolved in tetrahydrofuran (25 mL) and refluxed with silica gel for 10 min. To this slurry hexane was added and the mixture was vaccum filtered through a silica pad. The silica was washed with solution of tetrahydrofuran in hexane (2:3). The filtrate was concentrated under reduced pressure to give <strong>[261953-36-0]6-iodoindazole</strong> (0.9 g). The <strong>[261953-36-0]6-iodoindazole</strong> (0.9 g, 3.9 mmol) was dissolved in dry dichloromethane (30 mL), cooled to 0C and N- bromosuccinimide (0.8 g, 4.3 mmol) was added in portions. The reaction mixture was stirred at 0C for lh. The precipitate was collected by filtration and washed with dichloromethane. The obtained product 3-bromo-6-iodo-lH-indazole was used to the next step without further purification. LC-MS (m/z) 324.8 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide; tetra-(n-butyl)ammonium iodide; N,N-dimethylethylenediamine; potassium iodide; In 1,4-dioxane; for 48h;Reflux; | The method of synthesizing the above-described 6-iodo-1H-indazole, comprising the steps of: Weigh 5.0 g of the compound of formula V and 13.38 g of potassium iodide in the reactor.After adding 50 mL of 1,4-dioxane, 0.2 g of tetrabutylammonium iodide was added, based on the compound of formula V.0.51 g of cuprous iodide and 0.47 g of N,N-dimethylethylenediamine (0.2 equiv.) were added to the reactor, the temperature was raised to reflux, and the reaction was refluxed for 48 h.After the reaction was completed, after cooling to room temperature, the reaction solution was filtered, and the filter cake was washed three times with 1,4-dioxane.The filtrate was combined, and the obtained filtrate was concentrated. After the concentrate was dissolved in ethyl acetate, ethyl acetate layer was washed with 13% aqueous ammonia.The organic phase is separated, the organic phase is concentrated, and the concentrate is recrystallized from acetonitrile.To give compound of formula 6-iodo-1H-indazole in 85% yield, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Under nitrogen atmosphere 3 kg of 1 -methyl-2-pyrrolidone is mixed with 4.4 kg of 6- iodo-lH-indazole, 7.3 kg of potassium carbonate and 0.17 kg of Copper (II) acetate hydrate at 20-25C. The mixture is heated to 80C. 3.5 kg of 2-mercapto-N-methylbenzamide is mixed with 1.75 kg of l-methyl-2- pyrrolidone and the mixture is heated to 60C. The solution is added to the previously prepared solution of 6-iodo-lH-indazole at 80C in the course of 15 minutes. The mixture is then stirred at 105C for 90 minutes. Then a solution of 8.2 kg of iodine in 2.8 kg of l-methyl-2-pyrrolidone is added. The mixture is stirred at 105C for 120 minutes. Then it is cooled to 80C. 10.7 kg of acetonitrile is added. A mixture of 5 kg of ascorbic acid in 24 kg of water is added in the course of 120 minutes at 80C. Then 24 kg of water is added in the course of 80 minutes at 80C. The resulting mixture is cooled to 0-5C in the course of 4 hours. The mixture is filtered off. Under nitrogen atmosphere the obtained solid is mixed with 20 kg of acetone and 10 kg of water, the mixture is heated to 55-60C and stirred at this temperature for 1 hour. Then the mixture is cooled to 20 C, filtered and the filtered solid is washed with 3 kg of chilled acetone and dried to provide 2-((3-iodo-lH-indazol-6-yl)thio)-N-methylbenzamide in 65% yield and 99% purity (HPLC ES). |
Tags: 261953-36-0 synthesis path| 261953-36-0 SDS| 261953-36-0 COA| 261953-36-0 purity| 261953-36-0 application| 261953-36-0 NMR| 261953-36-0 COA| 261953-36-0 structure
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H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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