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CAS No. : | 271-44-3 | MDL No. : | MFCD00005691 |
Formula : | C7H6N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 118.14 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 9 |
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 : | 36.09 |
TPSA : | 28.68 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.44 cm/s |
Log Po/w (iLOGP) : | 0.95 |
Log Po/w (XLOGP3) : | 2.23 |
Log Po/w (WLOGP) : | 1.56 |
Log Po/w (MLOGP) : | 1.12 |
Log Po/w (SILICOS-IT) : | 2.15 |
Consensus Log Po/w : | 1.6 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.72 |
Solubility : | 0.226 mg/ml ; 0.00192 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.47 |
Solubility : | 0.403 mg/ml ; 0.00341 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.86 |
Solubility : | 0.163 mg/ml ; 0.00138 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.17 |
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% | With hydrogenchloride; bromine; sodium hydrogensulfite In sodium hydroxide | A. 3-Bromo-1H-indazole To a suspension of 1H-indazole (3.00 g, 25.4 mmol) in 2.0 M sodium hydroxide solution (70 mL) at ambient temperature was added a solution of bromine (3.00 g, 18.8 mmol) in 2.0 M sodium hydroxide solution (30 mL) dropwise. After stirring for 3 hours, to the reaction mixture was added sodium bisulfite (0.1 g), followed by 2.0 N hydrochloric acid solution (80 mL). The precipitates were filtered and washed with water to provide the title compound (3.98 g, 80percent yield): mp 136° C.; 1H NMR (CDCl3) δ 13.4 (br s, 1H), 7.57 (m, 2H), 7.45 (t, 1H), 7.22 (t, 1H); EI-MS (m/z) 198 [M+2]+, 196 [M]+. |
80% | at 20℃; for 3 h; | Bromine (1.5g, 9.4mmol) in 2M NaOH solution (lOmL) was added drop wise tosuspension of indazole (1.5g, 12.7mmol) in 2M NaOH solution (23mL) at ambient temperature. Stined the reaction mass for 3h at room temperature and added sodium bisulfate (0.05g) followed by the addition of 2N HC1. The solid precipitated was filtered out and washed with water, suction dried followed by in Rotavap under reduced pressure to afford the title compound (2g, 80percent). LCMS: mlz = 197.1 (M+H). |
45% | With bromine; sodium hydrogensulfite In sodium hydroxide | 3-Bromoindazole 4a was prepared using a procedure described by Boulton, B. E. and Coller, A. W (Aust. J Chem., 1974, 27, 2343-2346): A solution of bromine (0.99 g, 6.19 mmol) in 10percent NaOH was slowly added to a suspension of indazole (1 g, 8.50 mmol) in 2 N NaOH (25 mL). The reaction mixture became a thick white slurry. After stirring for 2 hours, a small amount of sodium bisulfite was added and the solution was neutralized with 1 N HCl. The white solid was filtered and washed with water. Recrystallization from water gave 0.76 g (45percent yield) of 3-bromoindazole 4a: 1H NMR (CDCl3) δ 7.22-7.27 (m, 1H), 7.43-7.52 (m, 2H), 7.60-7.67 (m, 1H); IR (KBr, cm-1) 3154, 2944, 2915, 1624, 1479, 1331, 1242, 1026, 901, 770, 735, 639; MS m/e 195 (MH-); Anal. Calcd for C7H5BrN2: C, 42.67; H, 2.56; N, 14.22 Found: C, 42.37; H, 2.55; N, 14.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With sodium hydroxide; iodine In methanol; water at 20℃; for 73 h; Stage #2: With hydrogenchloride; sodium thiosulfate In methanol; water at 0℃; |
58.1 g of iodine (229 mmol) are introduced in portions into a suspension of 25.6 g of indazole (217 mmol) in 625 ml of methanol and 625 ml of 2N sodium hydroxide solution in the course of 1 hour. The mixture is stirred at room temperature for 3 days and 75 ml of concentrated hydrochloric acid is then added, while cooling with ice, the mixture is rendered acid with 2N hydrochloric acid and 20percent strength sodium thiosulphate pentahydrate solution is added until the iodine colour disappears. The precipitate which separates out is filtered off with suction, washed neutral with water and dried in a vacuum drying cabinet at 50° C. For purification, the solid is taken up in methanol. After undissolved constituents are filtered off, the filtrate is concentrated to dryness on a rotary evaporator, the product being obtained as an almost white solid.Yield: 52.6 g (quantitative)Rf value: 0.63 (silica gel; cyclohexane/ethyl acetate 1:1)Melting point: 137° C. |
100% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3 h; | 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole (3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol)in DMF (7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 × 30 mL). The solid was left to dry at 30 °C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100percent; m.p.: 136–138 °C (lit.:[36] 134–136 °C); IR (KBr) ν (cm−1): 3086 (NH); 424 (C-I). 1H-NMR δ (ppm): 13.50 (1H, s, H-1); 7.55(1H, d, J = 8.6 Hz, H-7); 7.45–7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). 13C-NMR δ(ppm): 140.41; 127.22; 126.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C7H5IN2: 243.9497,Found: 243.9499.3-Iodo-1H-indazole (1a). 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole(3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol) in DMF(7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 30 mL). The solid was left to dry at 30 °C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100percent; m.p.: 136–138 °C (lit.: [36] 134–136 °C);IR (KBr) (cm1): 3086 (NH); 424 (C-I). 1H-NMR (ppm): 13.50 (1H, s, H-1); 7.55 (1H, d, J = 8.6 Hz,H-7); 7.45–7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). 13C-NMR (ppm): 140.41; 127.22;126.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C7H5IN2: 243.9497, Found: 243.9499. |
97% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 2 h; | A mixture of 1H-indazole (1.00 g, 8.46 mmol, 1.00 equiv), iodine(4.30 g, 16.94 mmol, 2.00 equiv), and potassium hydroxide (1.19 g, 21.21 mmol, 2.50 equiv) in DMF (49.98 mL) was stirred for 2 hours at room temperature. The resulting solution was diluted with ethyl acetate, washed withwater and sodium thiosulfate pentahydrate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (2 g, 97percent) as an off-white solid. LC-MS (ES, mlz): 245 [M+H]. |
96% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; | Intermediate 14: 3-Iodoindazole; Powdered potassium hydroxide (3.75 eq, 1.78 g, 31.7 mmol) was added to a solution of indazole (1.0 g, 8.46 mmol) and iodine (4.29 g, 16.9 mmol) in DMF (17 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into aqueous sodium thiosulfate solution (10percent, 200 ml) and extracted with toluene (2 x 75 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an off-white solid (2.0 g, 96percent). 1H NMR (250 MHz, CDC13) δ 6.98 - 7.27 (m, 2 H) and 7.32 - 7.59 (m, 2 H). |
95% | With iodine; sodium hydroxide In methanol at 20℃; for 48 h; | 3-lodo-1H-indazole Iodine (5.8 g, 22.9 mmol) was added in portions over approximately 20 min to a solution of indazole (2.5 g, 21.7 mmol) in methanol (63 ml) and 2N sodium hydroxide solution (65 ml). The mixture remained colourless and a white precipitate slowly formed. The mixture was stirred at room temperature 48 h. The mixture was cooled in an ice-bath and 7.5 ml of concentrated hydrochloric acid was slowly added. The mixture was further acidified with 2N hydrochloric acid. 20percent w/v Sodium thiosulfate pentahydrate solution was added until the iodine colour disappeared. The precipitate was filtered, washed with water and dried in the oven at 50 ºC to constant weight. The solid was taken up in methanol, filtered and the filtrated was evaporated under reduced pressure to give 5.0 g (20.6 mmol, 95percent) of the title compound as a white solid. Purity 100percent.1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.43-7.59 (m, 3H), 7.21-7.26 (m, 1H).UPLC/MS (3 min) retention time 1.56 min.LRMS: m/z 245 (M+1). |
95% | With iodine; sodium hydroxide In methanol at 20℃; for 48 h; | Iodine (5.8 g, 22.9 mmol) was added in portions over approximately 20 min to a solution of indazole (2.5 g, 21 .7 mmol) in methanol (63 ml) and 2N sodium hydroxide solution (65 ml). The mixture remained colourless and a white precipitate slowly formed. The mixture was stirred at room temperature 48 h. The mixture was cooled in an ice-bath and 7.5 ml of concentrated hydrochloric acid was slowly added. The mixture was further acidified with 2N hydrochloric acid. 20percent w/v Sodium thiosulfate pentahydrate solution was added until the iodine colour disappeared. The precipitate was filtered, washed with water and dried in the oven at 50 °C to constant weight. The solid was taken up in methanol, filtered and the filtrated was evaporated under reduced pressure to give 5.0 g (20.6 mmol, 95percent) of the title compound as a white solid. Purity 100percent. 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.43-7.59 (m, 3H), 7.21 -7.26 (m, 1 H). UPLC/MS (3 min) retention time 1 .56 min. LRMS: m/z 245 (M+1 ). |
95% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1.25 h; | Step 13 -Io do - 1 H-indazo leIn a 50 mL round-bottomed flask, indazole (0.80 g, 6.8 mmol) was dissolved in DMF (14 mL). Iodine (3.4 g, 13.5 mmol) was added followed by potassium hydroxide (1.47 g, 26.2 mmol). The dark reaction mixture was stirred at room temperature for 1.25 h then was quenched with 10percent aq NaHS03 and extracted with diethyl ether (2x). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 1.65 g (95percent>) of 3-iodo-lH-indazole as a light yellow solid. 1H NMR (CDC13, 300 MHz): ? (ppm) 10.56 (br. s, 1H), 7.47 - 7.57 (m, 3H), 7.23 - 7.30 (m, 1H). |
91% | With iodine; potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 19 h; | 3-iodo-lH-indazole (VII): Indazole (l .Og, 8.47 mmol) and K2C03 (1.71 g, 12.4 mmol) were combined in DMF (5 mL) and chilled to 0 °C. I2 (2.70 g, 1.3 mmol) dissolved in DMF (2 mL) was added dropwise over a one hour time period, then stirred 18 hours at room temperature. The reaction was then poured into a solution of sodiumthiosulfate (2.0 g) and K2C03 (10 mg) in 10 mL water. A white precipitate formed and was stirred at room temperature for 1.5 hours. Product was isolated by filtration and indentified by LCMS yielding (1.87g, 7.68 mmol, 91percent). |
77.5% | With iodine; sodium hydroxide In N,N-dimethyl-formamide at 25℃; for 6 h; | 3-iodo-1 H-indazole [00446] To a mixture of 1H-indazole (5 g, 42.32 mmol) and NaOH (3.4 g, 84.6 mmol) in DMF (50 mL) was added 12 (16.1 g, 63.4 mmol) in one portion at 25 °C and the mixture wasstirred for 6 h. The mixture was concentrated, diluted with water (150 mL,) extracted with EA (100 mLx3), and the combined organic phase was washed with saturated brine (200 mLx2),dried with anhydrous Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography to afford the title compound (8 g, 77.5percent) as a white solid. |
77.5% | With iodine; sodium hydroxide In N,N-dimethyl-formamide at 25℃; for 6 h; | [3881 To a mixture of 11-1-indazole (5 g, 42.32 mrnoi) and NaOFI (3.4 g, 84.6 minol) in DMF(50 mL) was added 12 (16.1 g, 63.4 mnioi) in one portion at 25 °C and the mixture was stirred for6 h. The mixture was concentrated, diluted with water (150 mL,) extracted with EA (100 mL*3),and the combined organic phase was washed with saturated brine (200 mL*2), dried withanhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gelchromatography to afford the title compound (8 g, 77.5percent) as white solid. |
68% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere | Example 10 N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indazol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide (10) N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indazol-3-yl)pyrimidin- 2- amine (Scheme 8, Intermediate R). Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1H- indazole (10 g, 84.65 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), I2 (21.5 g, 84.65 mmol, 1.00 equiv). This was followed by the addition of KOH (19 g, 338.62 mmol, 4.00 equiv) in several batches at 0°C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 200 mL of aqueous Na2S203. The resulting solution was extracted with 3x500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with 1x100 mL of hexane. This resulted in 14 g (68percent) of 3- iodo- lH-indazole as a white solid. |
64.7% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; for 5 h; | 5.5 g (45 mmol) of indazole and 12.69 g (100 mmol) of iodine granules were added to the reaction flask.Dissolved with 100 mL of N,N-dimethylformamide,Stir at 0°C,11.2 g (200 mmol) of potassium hydroxide solids are added in portions.After the addition is completed, it is returned to room temperature and stirred for 5 hours;After the reaction is complete, quench the solution by adding 50 mL of saturated sodium thiosulfate solution to the reaction flask.Then pour the reaction solution into 200mL water,Extract with ethyl acetate (200 mL x 3)Combine organic layers,Wash with saturated brine (200 mL × 3)Drying with anhydrous sodium sulfate,Concentrate under reduced pressure,It was isolated by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give 7.3 g of a white solid (3-iodoindazole).Yield 64.7percent, |
64% | With potassium hydroxide; iodine In N,N-dimethyl-formamide at 20℃; for 0.5 h; | 3. Synthesis of indazole derivatives; A iodine was introduced at 3-positon of an indazole ring (the following scheme). An objective compound, XO-KT30, was prepared by converting the iodine into a cyano group using zinc cyanide, followed by coupling in the usual way, and finally by hydrolysis.; 15) Synthesis of XO-KT30; XO-KT13; Indazole (1.18 g, 10 mmol) was dissolved in dimethylformamide (6 mL), and to the solution were added iodine (2.8 g, 11 mmol) and potassium hydroxide (2.8 g, 50 mmol), and the mixture was allowed to react for 0.5 hour at room temperature. After the reaction, the reaction mixture was extracted with ethyl acetate and water added. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give XO-KT13 (1.55 g, 64percent yield). |
52% | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 4 h; | KOH (31.10g, 0.555mol) was added in portions at 0°C to a solution of 4a (15.80g, 0.134mol) and I2 (85.40g, 0.336mol) in DMF (263.40mL). The mixture was stirred for 4h at room temperature, quenched with saturated Na2S2O3 solution (50mL), diluted with H2O (150mL), and extracted with EtOAc (70mL×3). The organic phase was washed with brine (50mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15:1, v/v) to give an orange solid (16.78g). |
8 g | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; | Synthesis of 3-iodo-1 H-indazole (Intermediate-71):Starting Material-28 (42mmol) in DMF (50m1) was cooJed to 0°C. Then potassium hydroxide(84.6mmol) was added which was followed by the addition of Iodine (42mmol). The reactionmixture was maintained at room temperature for 2 hours. Then the reacUon mixture was diluted with ice cooled water and extracted with ethyl acetate. The organic layer was dried over arihydrous MgSO4, and evaporated to give lntermediate-71 (8g, pale yellow solid). |
8 g | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 2 h; | Synthesis of 3-iodo-1H-indazole (Intermediate-71) Starting Material-28 (42 mmol) in DMF (50 ml) was cooled to 0° C. Then potassium hydroxide (84.6 mmol) was added which was followed by the addition of Iodine (42 mmol). The reaction mixture was maintained at room temperature for 2 hours. Then the reaction mixture was diluted with ice cooled water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, and evaporated to give Intermediate-71 (8 g, pale yellow solid). |
15.3 g | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; Inert atmosphere | Example 1 1. Synthesis of Intermediate 001-2 The intermediate 001-1 (10 g, 84.7 mmol) as the raw material was dissolved in N,N-dimethylformamide (DMF) (500 mL) in a 1000 mL three-necked flask under nitrogen (N2) at room temperature, and then iodine (I2) (21.5 g, 84.8 mmol) and potassium hydroxide (KOH) (19 g, 338.6 mmol) were added sequentially, followed by stirring the reaction overnight at room temperature. After completion of the reaction, 200 mL of 10percent sodium thiosulfate (Na2S2O3) was added to the reaction mixture, and ice water was used to quench the reaction. The mixture was extracted three times with 500 mL of ethyl acetate (EA). The organic phases were combined and washed once with 500 mL of saturated brine (NaCl), and the organic phases were dried over anhydrous sodium sulfate (Na2SO4) and concentrated to give 15.3 g of the intermediate 001-2 (74percent) as an off-white solid. Liquid Chromatography Mass Spectrometry (LCMS): 245.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydroxide; hydroxylamine-O-sulfonic acid In ethanol; water; ethyl acetate | REFERENCE EXAMPLE 12 Synthesis of 1-aminoindazole To a solution of 2.2 g(55 mmol) of sodium hydroxide in 30 ml of water was added 1.33 g(10 mmol) of 1H-indazole and ethanol was slowly added at 50° C. until the reaction mixture was dissolved thoroughly. The resulting mixture was heated to 55° C. and 2.83 g(25 mmol) of hydroxylamine-O-sulfonic acid was slowly added over 30 min with vigorous stirring followed by further stirring for 30 min. After completion of reaction, the resulting precipitate was filtered off, and the filtrate was extracted with dichloromethane(30 ml*2), dried over anhydrous magnesium sulfate and concetrated under the reduced pressure. The concentrate was chromatographed over silica gel using 10percent ethyl acetate/dichloromethane as an eluent. The fractions containing the desired product were concentrated under the reduced pressure and crystallized from benzene/petroleum ether to give 0.63 g of the desired compound(47percent). m.p. =104°~106° C. NMR (DMSO-d6, δ) 5.41 (s, 2H, NH2), 6.85~7.95 (m, 4H) 8.05 (s,1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; | To a solution of the 4-bromo-1H-indazole (500 mg, 2.54 mmol) and bis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was added potassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 mol percent, 0.076 mmol, 62 mg). The mixture was degassed with argon and heated at 80° C. for 40 h. The reaction mixture was allowed to cool and partitioned between water (50 mL) and ether (3.x.50 mL). The combined organic layers were washed with brine (50 mL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30percent-->40percent EtOAc-petrol to give an inseparable 3:1 mixture of the 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (369 mg, 60percent) and indazole (60 mg, 20percent); the title compound (IVa) was isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H NMR (400 MHz, d6-DMSO) 1.41 (12H, s), 7.40 (1H, dd, J=8.4 Hz, 6.9 Hz), 7.59 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=6.9 Hz), 10.00 (1H, br s), 8.45 (1H, s), and indazole: 7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=9.1 Hz), 7.77 (1H, d, J=7.9 Hz), 8.09 (1H, s). Impurity at 1.25. |
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; | The mixture was degassed with argon and heated at 80° C. for 40 h. The reaction mixture was allowed to cool and partitioned between water (50 mL) and ether (3*50 mL). The combined organic layers were washed with brine (50 mL), separated and dried (MgSO4). The crude material was purified by chromatography eluding with 30percent-->40percent EtOAc-petrol to give an inseparable 3:1 mixture of the 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (369 mg, 60percent) and indazole (60 mg, 20percent); this was isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H NMR (400 MHz, d6-DMSO) 1.41 (12H, s), 7.40 (1H, dd, J=8.4 Hz, 6.9 Hz), 7.59 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=6.9 Hz), 10.00 (1H, br s), 8.45 (1H, s), and indazole: 7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=9.1 Hz), 7.77 (1H, d, J=7.9 Hz), 8.09 (1H, s). Impurity at 1.25. |
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; | To a solution of the 4-bromo-lH-indazole B (500 mg, 2.54mmol) and bis(pinacolato)diboron (1.5 eq., 3.81mmol) in DMSO (2OmL) was added potassium acetate (3.0 eq., 7.61mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 molpercent, 0.076mmol, 62 mg). The mixture was degassed with argon and heated at 8O0C for 40 h. The reaction mixture was allowed to cool and partitioned between water (5OmL) and ether (3 x 5OmL). The combined organic layers were washed with brine (5OmL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30percent-40percent EtO Ac-petrol to give an inseparable 3:1 mixture of the 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole 1 (369 mg, 60percent) and indazole (60 mg, 20percent), isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H NMR (400 MHz, J6-DMSO) 1.41 (12H, s), 7.40 (IH, dd, J=8.4Hz, 6.9Hz), 7.59 (IH, d, J=8.4Hz), 7.67 (IH, d, J=6.9Hz), 10.00 (IH, br s), 8.45 (IH, s), and indazole: 7.40 (IH, t), 7.18 (IH, t, J=7.9Hz), 7.50 (IH, d, J=9.1Hz), 7.77 (IH, d, J=7.9Hz), 8.09 (IH, s). Impurity at 1.25. |
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; Inert atmosphere | To a solution of the 4-bromo-lH-indazole B (500 mg, 2.54 mmol) andbis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was added potassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in drying pistol) and PdCi2(dppf)2 (3 molpercent>, 0.076 mmol, 62 mg). The mixture was degassed with argon and heated at 80 °C for 40 h. The reaction mixture was allowed to cool and partitioned between water (50 mL) and ether (3 X 50mL). The combined organic layers were washed with brine (50 mL), separated and dried (MgS04). The crude material was purified by chromatography eluting with 30percent to 40percent EtO Ac-petrol to give an inseparable 3: 1 mixture of the 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole 24 (369 mg, 60percent)) and indazole (60 mg, 20percent>), isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H NMR (400 MHz, d6-DMSO) 1.41 (12H, s), 7.40 (IH, dd, J=8.4Hz, 6.9Hz), 7.59 (IH, d, J=8.4Hz), 7.67 (IH, d, J=6.9Hz), 10.00 (IH, br s), 8.45 (IH, s), and indazole: 7.40 (IH, t), 7.18 (IH, t, J=7.9Hz), 7.50 (IH, d, J=9.1Hz), 7.77 (IH, d, J=7.9Hz), 8.09 (IH, s) |
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; Inert atmosphere | To a solution of the 4-bromo-1H-indazole B (500 mg, 2.54 mmol) and bis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was added potassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 mol percent, 0.076 mmol, 62 mg). The mixture was degassed with argon and heated at 80° C.for 40 h. The reaction mixture was allowed to cool and partitioned between water (50 mL) and ether (3×50mL). The combined organic layers were washed with brine (50 mL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30percent to 40percent EtOAc-petrol to give an inseparable 3:1 mixture of the 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 24 (369 mg, 60percent) and indazole (60 mg, 20percent), isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H NMR (400 MHz, d6-DMSO) 1.41 (12H, s), 7.40 (1H, dd, J=8.4 Hz, 6.9 Hz), 7.59 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=6.9 Hz), 10.00 (1H, br s), 8.45 (1H, s), and indazole: 7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50 (1H ,d, J=9.1 Hz), 7.77 (1H, d, J=7.9 Hz), 8.09 (1H, s); impurity at 1.25. |
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; | To a solution of the 4-bromo-lH-indazole B (500 mg, 2.54mmol) and bis(pinacolato)diboron (1.5 eq., 3.81mrnol) in DMSO (2OmL) was added potassium acetate (3.0 eq., 7.61mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 molpercent, 0.076mmol, 62 mg). The mixture was degassed with argon and heated at 800C for 40 h. The reaction mixture was allowed to cool and partitioned between water (5OmL) and ether (3 x 5OmL). The combined organic layers were washed with brine (5OmL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30percent- 40percent EtO Ac-petrol to give an inseparable 3:1 mixture of the 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH- indazole 7 (369 mg, 60percent) and indazole (60 mg, 20percent), isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H NMR (400 MHz5 c?6-DMSO) 1.41 (12H, s), 7.40 (IH, dd, J=8.4Hz, 6.9Hz), 7.59 (IH, d, J=8.4Hz), 7.67 (IH, d, J=6.9Hz), 10.00 (IH, br s), 8.45 (IH, s), and indazole: 7.40 (IH, t), 7.18 (IH, t, J=7.9Hz), 7.50 (IH, d, J=9.1Hz), 7.77 (IH, d, J=7.9Hz), 8.09 (IH, s). Impurity at 1.25. |
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; Inert atmosphere | To a solution of the 4-bromo-lH-indazole B (500 mg, 2.54 mmol) and bis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was added potassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 molpercent, 0.076 mmol, 62 mg). The mixture was degassed with argon and heated at 80 0C for 40 h. The reaction mixture was allowed to cool and partitioned between water (50 mL) and ether (3 X 5OmL). The combined organic layers were washed with brine (50 mL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30percent to 40percent EtO Ac -petrol to give an inseparable 3: 1 mixture of the 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- lH-indazole 24 (369 mg, 60percent) and indazole (60 mg, 20percent), isolated as a yellow gum which solidified upon standing to furnish as an off-white solid. 1H νMR (400 MHz, d6-DMSO) 1.41 (12H, s), 7.40 (IH, dd, J=8.4Hz, 6.9Hz), 7.59 (IH, d, J=8.4Hz), 7.67 (IH, d, J=6.9Hz), 10.00 (IH, br s), 8.45 (IH, s), and indazole: 7.40 (IH, t), 7.18 (IH, t, J=7.9Hz), 7.50 (IH, d, J=9.1Hz), 7.77 (IH, d, J=7.9Hz), 8.09 (IH, s); impurity at 1.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium acetate In dimethyl sulfoxide at 80℃; for 40 h; | To a solution of 3-bromo-2-methyl aniline (5.0g, 26.9mmol) in chloroform(5OmL) was added potassium acetate (1.05eq.5 28.2mmol, 2.77g). Acetic anhydride (2.0eq., 53.7mmol, 5.07mL) was added with concurrent cooling in ice- water. The mixture was then stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.2eq., 5.37mmol, 1.42g) was then added followed by iso-amyl nitrite (2.2eq., 59.1mmol, 7.94mL) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool, and was partitioned between chloroform (3 x 10OmL) and saturated aqueous sodium hydrogen carbonate (10OmL). The combined organic extracts were washed with brine (10OmL), separated and dried (MgSO4). <n="44"/>The crude product was evaporated onto silica and purified by chromatography eluting with 20percent-->40percent EtO Ac-petrol to give l-(4-bromo-indazol-l-yl)-ethanone (A) (3.14g, 49percent) as an orange solid, and 4-bromo-lH-indazole (B)(2.13g, 40percent) as a pale orange solid. A 1H NMR (400 MHz, CDCl3) 2.80 (3H5 s), 7.41 (IH, t, J=7.8Hz), 7.50 (IH5 d, J=7.8Hz)5 8.15 (IH5 s), 8.40 (IH5 d, J=7.8Hz).B: 1HNMR (400 MHz5 CDCl3) 7.25 (IH51, J=7.3Hz), 7.33 (IH5 d, J=7.3Hz)5 7.46 (IH5 d, J=7.3Hz), 8.11 (IH, s), 10.20 (IH, br s),To a solution of the l-(4-bromo-indazol-l-yl)-ethanone (3.09g, 12.9mmol) in MeOH (5OmL) was added 6N aqueous HCl (3OmL) and the mixture was stirred at room temperature for 7 h. The MeOH was evaporated and the mixture partitioned between EtOAc (2 x 5OmL) and water (5OmL). The combined organic layers were washed with brine (5OmL)5 separated and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to give 4-bromo-lH-indazole (2.36 g, 93percent). To a solution of the 4-bromo-lH-indazole (500 mg5 2.54mmol) and bis(pinacolato)diboron (1.5 eq., 3.81mmol) in DMSO (2OmL) was added potassium acetate (3.0 eq., 7.61mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 molpercent5 0.076mmol, 62 mg). The mixture was degassed with argon and heated at 80°C for 40 h. The reaction mixture was allowed to cool and partitioned between water (5OmL) and ether (3 x 5OmL). The combined organic layers were washed with brine (5OmL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30percent- 40percent EtO Ac-petrol to give an inseparable 3:1 mixture of the 4- (454,5,5-tetramethyl-[l5352]dioxaborolan-2-yl)-lH-indazole (369 mg, 60percent) and indazole (60 mg, 20percent); this was isolated as a yellow gum which solidified upon standing to furnish as an off-white solid.1HNMR (400 MHz5 ^6-DMSO) 1.41 (12H5 s)5 7.40 (IH5 dd, J=8.4Hz, 6.9Hz)5 7.59 (IH5 d, J=8.4Hz)5 7.67 (IH5 d, J=6.9Hz), 10.00 (IH5 br s), 8.45 (IH5 s)5 and indazole: 7.40 (IH5 1), 7.18 (IH5 15 J=7.9Hz)5 7.50 (IH5 d, J=9.1Hz), 7.77 (IH5 d5 J=7.9Hz), 8.09 (IH5 s). Impurity at 1.25. |