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[ CAS No. 261953-36-0 ] {[proInfo.proName]}

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Chemical Structure| 261953-36-0
Chemical Structure| 261953-36-0
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Product Details of [ 261953-36-0 ]

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 :

Calculated chemistry of [ 261953-36-0 ]      Expand+

Physicochemical Properties

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 ?2

Pharmacokinetics

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

Lipophilicity

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

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

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

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.94

Safety of [ 261953-36-0 ]

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:

Application In Synthesis of [ 261953-36-0 ]

* 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 [ 261953-36-0 ]

[ 261953-36-0 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 6967-12-0 ]
  • [ 261953-36-0 ]
YieldReaction ConditionsOperation 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) 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 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 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 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).

  • 2
  • [ 7597-18-4 ]
  • [ 261953-36-0 ]
  • 3
  • [ 261953-36-0 ]
  • [ 861905-31-9 ]
  • N-ethyl-3-(1H-indazol-6-yl)-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation 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
  • 4
  • [ 261953-36-0 ]
  • [ 861905-39-7 ]
  • [ 861972-64-7 ]
YieldReaction ConditionsOperation 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.
  • 5
  • [ 261953-36-0 ]
  • [ 319472-78-1 ]
YieldReaction ConditionsOperation 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).
  • 6
  • [ 261953-36-0 ]
  • [ 20054-45-9 ]
  • [ 944835-85-2 ]
YieldReaction ConditionsOperation 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.
  • 7
  • [ 261953-36-0 ]
  • [ 6165-69-1 ]
  • [ 281203-98-3 ]
YieldReaction ConditionsOperation in experiment
(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).
  • 8
  • [ 261953-36-0 ]
  • [ 773-64-8 ]
  • [ 319472-76-9 ]
  • [ 319472-53-2 ]
YieldReaction ConditionsOperation 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).
  • 9
  • [ 83863-33-6 ]
  • [ 261953-36-0 ]
YieldReaction ConditionsOperation in experiment
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.
  • 10
  • [ 261953-36-0 ]
  • [ 656798-50-4 ]
  • [ 947311-93-5 ]
YieldReaction ConditionsOperation in experiment
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)+.
  • 11
  • [ 261953-36-0 ]
  • [ 1066-54-2 ]
  • [ 1093847-81-4 ]
YieldReaction ConditionsOperation 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).
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