* 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.
General procedure: To a suspension of corresponding amine (1 equiv) in H2O/98percent H2SO4 (1:1) was added NaNO2 (1 equiv) slowly at 0 °C. After stirred at 120 °C for 2 h, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to afford the desired products 26 and 27. 6.1.12.1 H-Indazol-6-ol (26) Orange solid (yield: 87percent). 1H NMR (400 MHz, DMSO-d6): δ 12.55 (s, 1H), 9.56 (s, 1H), 7.85 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.75 (s, 1H), 6.62 (dd, J = 8.8, 1.6 Hz, 1H).
87%
Stage #1: With sulfuric acid; sodium nitrite In water at 20℃; for 2 h; Cooling with ice Stage #2: at 120℃; for 2 h;
AB27-1 (80 mg, 0.60 mmol) was dissolved in water / concentrated sulfuric acid (0.6 mL: 0.6 mL) The sodium nitrite (42 mg, 0.60 mmol) was slowly added under ice bath and allowed to react at room temperature for 2 hours. Subsequently, water (10 mL) was added and the temperature was raised to 120 ° C for 2 hours. Add saturated aqueous solution of sodium bicarbonate to adjust pH to 7. Water (30 mL) was added and extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (dichloromethane : Methanol = 20: 1) to give a yellow solid (707mg, 87percent)
55.6%
With sulfuric acid In water at 0 - 110℃; for 2 h;
To a suspension of compound 92-1 (4.5 g, 33.8 mmol) in 20 mL of ice water was added 6 mL of cone, sulfuric acid dropwise at 0 °C. The mixture was stirred at room temperature for 1 h and then heated to 110 °C for another hour. The mixture was cooled and adjusted to pH 6 with 2 M sodium hydride to give a suspension. The suspension was filtered. The solid was collected and dried in vacuo to afford the crude product as a brown solid (2.5 g, yield: 55.6percent). MS (ESI): m/z 135 [M+H]+.
51%
Stage #1: at 170℃; for 1 h; Microwave irradiation Stage #2: With sodium hydroxide In water for 0.166667 h;
Example 38 IV-5 Preparation of 6-[4-(4-(3-(6-fluoro-benzisoxazolyl))-1-piperazinyl)-n-butoxy]-(1H)-indazole 6-aminoindazole (2.66g, 20 mmol) is added to 20percent of dilute sulfuric acid and the reaction is performed under microwave radiation at 170°C for 1 hour using microwave powder of 600 watt, and then terminated. The reaction solution is cooled, adjusted to pH=7 with 5percent NaOH and stirred for 10 minutes to precipitated a deposit, which is recrystallized in water to obtain 1.5g of 6-hydroxyindazole, with a yield of 51 percent. 6-hydroxyindazole and 3-(1-(4-chlorobutyl)-4-piperidinyl)-6-fluoro-benzisoxazole are used as starting materials and react according to step 4 in the method of preparation of IV-1 to obtain 6-[4-(4-(3-(6-fluoro-benzisoxazolyl))-1-piperazinyl)-n-butoxy]-(1H)-indazole, with a yield of 62percent. Element analysis: C23H23FN4O2(calculated valuepercent: C 66.99,H 5.88, N 14.20; found valuepercent: C 66.71, H 5.80, N 13.89) 1HNMR(DMSO-d6): 8.21-6.49,(6H,aromatic ring-H), 4.18-4.19(2H, piperazine-H), 3.87(m,5H, O-CH2,) 3.66-3.75(2H, piperazine-H), 3.25-3.54(m, 6H), 2.79(t, J=8Hz, 2H),2.42(t, J=8Hz, 2H)1.71-1.90(m, 4H) MS : m/z 394
51%
at 170℃; for 1 h; Microwave irradiation
6-aminoindazole (2.66 g, 20 mmol) was added to 20percent diluted sulfuric acid and reacted in a microwave reactor at 170 ° C. for 1 hour, microwave output was 600 W. The reaction is stopped, cooled, adjusted to pH 7 with 5percent NaOH, stirred for 10 minutes, precipitate is precipitated and recrystallized from water to give 1.5 g of 6-hydroxyindazole. Yield is 51percent.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6855 - 6868
[2] Patent: CN104876912, 2017, B, . Location in patent: Paragraph 0047; 0201-0204
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 2324 - 2328
[4] Patent: WO2004/39796, 2004, A1, . Location in patent: Page/Page column 60-61
[5] Patent: WO2013/169964, 2013, A1, . Location in patent: Paragraph 00369; 00370
[6] Patent: EP2322520, 2011, A1, . Location in patent: Page/Page column 25-26
[7] Patent: JP5714152, 2015, B2, . Location in patent: Page/Page column 31
[8] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 4, p. 1966 - 1982
[9] Chemische Berichte, 1890, vol. 23, p. 3642[10] Chemische Berichte, 1892, vol. 25, p. 3152
[11] Justus Liebigs Annalen der Chemie, 1914, vol. 404, p. 84
[12] Journal of the American Chemical Society, 1926, vol. 48, p. 1101
[13] Journal of the Chemical Society, 1955, p. 2412,2419
[14] Bulletin de la Societe Chimique de France, 1950, p. 466,476
[15] Patent: EP2103620, 2009, A1, . Location in patent: Page/Page column 75-76
[16] Patent: US2010/152265, 2010, A1, . Location in patent: Page/Page column 51
[17] Patent: US2010/160256, 2010, A1, . Location in patent: Page/Page column 51
[18] Patent: WO2007/95124, 2007, A2, . Location in patent: Page/Page column 108-109
[19] Patent: EP2484668, 2012, A1,
[20] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6048 - 6057
2
[ 7597-18-4 ]
[ 6967-12-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With hydrogen In methanol
A mixture of 6-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10percent Pd/C (2.0 g) in MeOH was stirred under H2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 1H-indazol-6-ylamine (18.5 g, 94percent yield) as a yellow solid.
92%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
General procedure: To a solution of corresponding nitrobenzene (1 equiv) in methanol (20 mL) was added Pd/C (10percent), and the mixture was stirred at room temperature under H2 overnight. The mixture was filtered,and the filtrate was concentrated to afford the desired products 24 and 25. 6.1.11.1 1H-Indazol-6-amine (24) Yellow solid (yield: 92percent). 1H NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 7.71 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.52-6.43 (m, 2H), 5.21 (s, 2H).
92%
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 12 h;
Β24-1(1.5 g, 9.2 mmol) was dissolved in methanol (20 mL), Pd / C (150 mg) was added under nitrogen, replaced twice with hydrogen, Under normal pressure and pressure under hydrogen protection for 12 hours, diatomaceous earth filter, the filtrate was concentrated under reduced pressure yellow solid (l.lg, 92percent).
90%
With hydrazine In ethanol at 60℃; for 8 h; Inert atmosphere; Sealed tube
General procedure: To a sealed tube containing the nitro compound (0.6 mmol) and 2 mL ethanol were added 2.6–6.0 mmol of NH2NH2 (see Table 2) and Au/TiO2 (100 mg, 1 wt.percent in [Au], 0.8 molpercent). The reaction was heated at 60 °C for an appropriate time (see Table 2) under an inert atmosphere. The reaction was monitored by TLC, and after completion, the slurry was filtered under pressure through a short pad of celite and silica gel to withhold the supported catalyst with the aid of ethanol or methanol (~ 5 mL). The filtrate was evaporated under vacuum to afford the corresponding amines in pure form. The spectroscopic data (1H NMR, 13C NMR) of amines 1a–20a are in agreement with those previously reported [28,30,31], while the majority of them are commercially available substances. The screened catalysts Au/TiO2, Au/Al2O3, and Au/ZnO (~ 1 wt.percent in Au) are commercially available (Strem Chemicals), and have an average gold crystallite size of ~ 2–3 nm.
Reference：
[1] Tetrahedron Letters, 2010, vol. 51, # 5, p. 786 - 789
[2] ChemCatChem, 2014, vol. 6, # 11, p. 3153 - 3159
[3] Tetrahedron, 2008, vol. 64, # 28, p. 6711 - 6723
[4] Patent: WO2006/71940, 2006, A2, . Location in patent: Page/Page column 407
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6855 - 6868
[7] Patent: CN104876912, 2017, B, . Location in patent: Paragraph 0047; 0184-0187
[8] Catalysis Communications, 2013, vol. 36, p. 48 - 51
[9] RSC Advances, 2014, vol. 4, # 43, p. 22567 - 22574
[10] ACS Catalysis, 2014, vol. 4, # 10, p. 3504 - 3511
[11] Synlett, 2006, # 7, p. 1043 - 1046
[12] Chemische Berichte, 1890, vol. 23, p. 3642[13] Chemische Berichte, 1892, vol. 25, p. 3152
[14] Chemische Berichte, 1896, vol. 29, p. 308
[15] Justus Liebigs Annalen der Chemie, 1927, vol. 451, p. 285,302
[16] Journal of the American Chemical Society, 1943, vol. 65, p. 1804,1805
[17] Justus Liebigs Annalen der Chemie, 1927, vol. 454, p. 306
[18] Journal of the American Chemical Society, 1926, vol. 48, p. 1101
[19] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 240 - 249
[20] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000327
[21] Tetrahedron, 2017, vol. 73, # 48, p. 6805 - 6814
3
[ 99-55-8 ]
[ 6967-12-0 ]
Reference：
[1] Chemische Berichte, 1890, vol. 23, p. 3642[2] Chemische Berichte, 1892, vol. 25, p. 3152
[3] Chemische Berichte, 1890, vol. 23, p. 3642[4] Chemische Berichte, 1892, vol. 25, p. 3152
4
[ 64-17-5 ]
[ 7783-06-4 ]
[ 7597-18-4 ]
[ 6967-12-0 ]
Reference：
[1] Chemische Berichte, 1890, vol. 23, p. 3642[2] Chemische Berichte, 1892, vol. 25, p. 3152
5
[ 6967-12-0 ]
[ 348-25-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6048 - 6057
6
[ 6967-12-0 ]
[ 73907-98-9 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 15, p. 3072 - 3077
[2] Tetrahedron Letters, 1980, vol. 21, # 32, p. 3029 - 3032
7
[ 6967-12-0 ]
[ 73907-95-6 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 15, p. 3072 - 3077
[2] Tetrahedron Letters, 1980, vol. 21, # 32, p. 3029 - 3032
8
[ 6967-12-0 ]
[ 79762-54-2 ]
Yield
Reaction Conditions
Operation in experiment
48%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.25 h; Stage #2: With copper(I) bromide In water at 20 - 80℃; for 1.5 h;
6-Aminoindazole (1.33 g, 10 mmol) was dissolved in 48percent hydrobromic acid (5 mL) and water (16 mL). To the resulting solution at 0° C. was added dropwise a solution of sodium nitrite (0.77 g, 11 mmol) in water (9 mL). The mixture was stirred at 0° C. for 15 min. Urea (0.40 g) was added to remove excess nitrous acid. After stirring for 10 min, this solution was added dropwise to a stirred mixture of copper(I) bromide (4.3 g, 30 mmol), 48percent hydrobromic acid (10 mL) and water (24 mL) at room temperature. The reaction mixture was heated at 75-80° C. for 1.5 h, cooled to room temperature, basified with concentrated ammonium hydroxide, and extracted with chloroform (4.x.30 mL). The combined extracts were dried over sodium sulfate and concentrated to provide the bromoindazole (0.96 g, 48percent) as a greenish yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 7.74-7.72 (d, J=8.5 Hz, 1H), 7.25-7.23 (dd, J=8.5, 1.4 Hz, 1H).
With hydrogen bromide; sodium nitrite In hexane; water; ethyl acetate
(i) 6-Bromo-1H-indazole Sodium nitrite (315 mg, 4.56 mmol) was added in 2 portions to an ice-cooled suspension of 6-aminoindazole (500 mg, 3.8 mmol) in water (0.4 mL) and hydrobromic acid (48percent, 1.8 mL). The reaction mixture was stirred for 10 minutes longer than required for the brown gas to disappear. Copper powder (35 mg, 0.55 mmol) was then added and the mixture heated gently until nitrogen evolution began. The reaction mixture was then alternately heated and cooled to control the rate of reaction. When nitrogen evolution ceased, the reaction mixture was heated at 90° C. for 30 minutes, cooled to room temperature, neutralized with aqueous sodium hydroxide and the product extracted into ethyl acetate. The organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash chromatography on silica gel (20-40percent ethyl acetate in hexane) yield the title product (119 mg, 16percent).
Reference：
[1] Patent: US6380242, 2002, B1,
10
[ 6967-12-0 ]
[ 261953-36-0 ]
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).
With sulfuric acid; water; sodium nitrite; at 0 - 120℃;
General procedure: To a suspension of corresponding amine (1 equiv) in H2O/98% H2SO4 (1:1) was added NaNO2 (1 equiv) slowly at 0 C. After stirred at 120 C for 2 h, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to afford the desired products 26 and 27. 6.1.12.1 H-Indazol-6-ol (26) Orange solid (yield: 87%). 1H NMR (400 MHz, DMSO-d6): delta 12.55 (s, 1H), 9.56 (s, 1H), 7.85 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.75 (s, 1H), 6.62 (dd, J = 8.8, 1.6 Hz, 1H).
87%
AB27-1 (80 mg, 0.60 mmol) was dissolved in water / concentrated sulfuric acid (0.6 mL: 0.6 mL) The sodium nitrite (42 mg, 0.60 mmol) was slowly added under ice bath and allowed to react at room temperature for 2 hours. Subsequently, water (10 mL) was added and the temperature was raised to 120 C for 2 hours. Add saturated aqueous solution of sodium bicarbonate to adjust pH to 7. Water (30 mL) was added and extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (dichloromethane : Methanol = 20: 1) to give a yellow solid (707mg, 87%)
55.6%
With sulfuric acid; In water; at 0 - 110℃; for 2h;
To a suspension of compound 92-1 (4.5 g, 33.8 mmol) in 20 mL of ice water was added 6 mL of cone, sulfuric acid dropwise at 0 C. The mixture was stirred at room temperature for 1 h and then heated to 110 C for another hour. The mixture was cooled and adjusted to pH 6 with 2 M sodium hydride to give a suspension. The suspension was filtered. The solid was collected and dried in vacuo to afford the crude product as a brown solid (2.5 g, yield: 55.6%). MS (ESI): m/z 135 [M+H]+.
51%
Example 38 IV-5 Preparation of 6-[4-(4-(3-(6-fluoro-benzisoxazolyl))-1-piperazinyl)-n-butoxy]-(1H)-indazole 6-aminoindazole (2.66g, 20 mmol) is added to 20% of dilute sulfuric acid and the reaction is performed under microwave radiation at 170C for 1 hour using microwave powder of 600 watt, and then terminated. The reaction solution is cooled, adjusted to pH=7 with 5% NaOH and stirred for 10 minutes to precipitated a deposit, which is recrystallized in water to obtain 1.5g of 6-hydroxyindazole, with a yield of 51 %. 6-hydroxyindazole and 3-(1-(4-chlorobutyl)-4-piperidinyl)-6-fluoro-benzisoxazole are used as starting materials and react according to step 4 in the method of preparation of IV-1 to obtain 6-[4-(4-(3-(6-fluoro-benzisoxazolyl))-1-piperazinyl)-n-butoxy]-(1H)-indazole, with a yield of 62%. Element analysis: C23H23FN4O2(calculated value%: C 66.99,H 5.88, N 14.20; found value%: C 66.71, H 5.80, N 13.89) 1HNMR(DMSO-d6): 8.21-6.49,(6H,aromatic ring-H), 4.18-4.19(2H, piperazine-H), 3.87(m,5H, O-CH2,) 3.66-3.75(2H, piperazine-H), 3.25-3.54(m, 6H), 2.79(t, J=8Hz, 2H),2.42(t, J=8Hz, 2H)1.71-1.90(m, 4H) MS : m/z 394
51%
With sulfuric acid; at 170℃; for 1h;Microwave irradiation;
6-aminoindazole (2.66 g, 20 mmol) was added to 20% diluted sulfuric acid and reacted in a microwave reactor at 170 C. for 1 hour, microwave output was 600 W. The reaction is stopped, cooled, adjusted to pH 7 with 5% NaOH, stirred for 10 minutes, precipitate is precipitated and recrystallized from water to give 1.5 g of 6-hydroxyindazole. Yield is 51%.
1H-Indazol-6-amine (10 g) was dissolved in 47% sulfuric acid (40 g) and water (40 mL) with heating, and the solution was cooled to -10C. 47% Sulfuric acid (40 g) and water (40 mL) were added, and a solution of sodium nitrite (5.69 g) in water (16 mL) was added dropwise. Water (5 mL) was added and the mixture was stirred for 10 min and then at room temperature for 30 min. Boric acid (6.96 g) was added, and the mixture was stirred at 110C for 1 hr. Aqueous ammonia was added to the reaction mixture, and the precipitate was collected by filtration. The precipitate was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50?100:0). The object fraction was concentrated under reduced pressure. The residue was filtered with ethyl acetate to give the title compound (2.56 g) as a vermillion powder. 1H-NMR (DMSO-d6) delta: 6.63 (1H, dd, J = 2.1 Hz, 8.6 Hz), 6.74-6.78 (1H, m), 7.52 (1H, d, J = 8.6 Hz), 7.83-7.87 (1H, m), 9.52 (1H, s), 12.55 (1H, br s)
Reference Example 35 Indazol-6-ol Indazol-6-amine (24.33 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) was dissolved in water (100 mL) and 48% by weight of tetrafluoroboric acid solution (242 mL; manufactured by Sigma-Aldrich Co.). After cooling to 0 C., an aqueous solution of sodium nitrite [20 mL (sodium nitrite (13.87 g; manufactured by Kanto Chemical Co., Inc.) was dissolved in water (20 mL) to give the solution] was added dropwise thereto for 10 minutes, followed by stirring at 0 C. for 30 minutes. The precipitate from the reaction solution was filtered and washed with chloroform. Thus-obtained precipitate was dissolved in acetic acid (250 mL) and stirred for 10 minutes at 50 C., 10 minutes at 110 C., and 10 minutes at 130 C. The reaction solution was cooled and added with a saturated aqueous solution of sodium carbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then dried. Thereafter, the solvent was evaporated under reduced pressure. Thus-obtained residue was dissolved in ethanol (240 mL), added with an aqueous solution of 2 mol/L-sodium hydroxide (365 mL), followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 2 mol/L-hydrochloric acid (200 mL), water and a saturated aqueous solution of ammonium chloride were added to the residue to obtain pH 7 approximately, and the extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue, chloroform was added, and then the insoluble matters were filtered, washed with chloroform to obtain the target compound as a crude product (13.5401 g). 1H-NMR (DMSO-d6); delta (ppm) 6.64 (1H, dd, J=1.8, 8.8), 6.78 (1H, dd, J=0.7, 1.8), 7.52 (1H, d, J=8.8), 7.86 (1H, d, J=0.7), 9.54 (1H, s), 12.56 (1H, s) LCMS: 134 [M+H]; retention time; 0.72 minutes:LCMS condition: C
Reference Example 21Indazol-6-ol Indazol-6-amine (24.33 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in water (100 mL) and a 48 wt % aqueous solution of tetrafluoroboric acid (242 mL; manufactured by Sigma-Aldrich Co.), and the solution was cooled to 0 C. Subsequently, an aqueous solution of sodium nitrite (20 mL (sodium nitrite (13.87 g; manufactured by Kanto Chemical Co., Inc.) was dissolved in water (20 mL)) was added dropwise to the solution over 10 minutes, and the resulting mixture was stirred for 30 minutes at 0 C. Precipitates of the reaction solution were filtered, and were washed with chloroform. The obtained precipitates were dissolved in acetic acid (250 mL), and the solution was stirred for 10 minutes at 50 C., for 10 minutes at 110 C., and for 10 minutes at 130 C. The reaction solution was cooled, a saturated aqueous solution of sodium carbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethanol (240 mL). A 2 mol/L aqueous solution of sodium hydroxide (365 mL) was added to the solution, and the mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and 2 mol/L hydrochloric acid (200 mL), water and a saturated aqueous solution of ammonium chloride were added to the residue to adjust the pH to about 7. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and chloroform was added to the residue. Insoluble matters were filtered, and were washed with chloroform. Thus, a crude product (13.5401 g) of the title compound was obtained.1H-NMR (300 MHz, DMSO-d6); delta (ppm) 6.64 (1H, dd, J=1.8, 8.8), 6.78(1H, dd, J=0.7, 1.8), 7.52(1H, d, J=8.8), 7.86(1H, d, J=0.7), 9.54(1H, s), 12.56 (1H, s)LCMS: 134.9 [M+H]; Retention time: 0.72 minutes; LCMS condition: C
Example 211; Synthesis of [6-(lH-indazol-6-yloxy)-lH-benzimidazol-2-yl]-(2-trifluoromethylphenyl)- amineTo a stirred suspension of 6-aminoindazole (20 mmol) in concentrated HCl (6 mL) at 00C was added a solution of NaNtheta2 (22 mmol) in water (12 mL) in portions. During the addition, the temperature of the reaction mixture was maintained at 0-5 0C, and the stirring continued for additional 45 min. The contents were then added into a flask containing 1 % aqueous HCl (200 mL), and heated at 1000C. The reaction mixture was then stirred at 100 0C for 5 h. The contents were cooled to RT, neutralized to pH 7 using 5% aqueous Na2COs, and extracted with EtOAc (2x70 mL). Combined organic layers were washed with brine and dried over anhydrous Na2SO4. Removal of solvent under vacuum provided 6- hydroxyindazole as dark brown solid, which was used for further transformation without any purification.To a stirred solution of 2-chloro-4-fluoro-l -nitrobenzene (3 mmol) in DMF (5 mL) was added 6-hydroxyindazole (3 mmol) and K2CO3 (6 mmol). The contents were heated at900C for 6 h. The reaction mixture was cooled to RT, and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 6-(3-chloro-4-nitrophenoxy)-lH-indazole as a yellow solid, which was used for further transformation without any purification. A stirred solution of the nitro compound (2 mmol) in DMF (4 mL) was added with benzylamine (4 mmol) and contents were heated at 100 0C for 6 h. The reaction mixture was cooled to RT and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo. The residue obtained was purified on silica gel column chromatography using hexane/EtOAC as eluent to provide the product, benzyl-[5-(lH-indazol-6-yloxy)-2-nitrophenyl]-amine as a yellow solid. <n="111"/>The nitroaniline (1 mmol) obtained as above was reduced under hydrogenation conditions as described in general procedure F to 4-(l H-Indazol-6-yloxy)-benzene-l,2- diamine.The diamine (0.3 mmol) from above was reacted with l-isothiocyanato-2- trifluoromethylbenzene (0.3 mmol) followed by cyclization in situ using EDC as described in general procedure B to provide [6-(lH-indazol-6-yloxy)-lH-benzimidazol-2-yl]-(2- trifluorornethylphenyl)-arnine. MS: m/? 40 (M+H)+.
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr;
A mixture of 6-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10% Pd/C (2.0 g) in MeOH was stirred under H2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 1H-indazol-6-ylamine (18.5 g, 94% yield) as a yellow solid.
92%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
General procedure: To a solution of corresponding nitrobenzene (1 equiv) in methanol (20 mL) was added Pd/C (10%), and the mixture was stirred at room temperature under H2 overnight. The mixture was filtered,and the filtrate was concentrated to afford the desired products 24 and 25. 6.1.11.1 1H-Indazol-6-amine (24) Yellow solid (yield: 92%). 1H NMR (400 MHz, DMSO-d6): delta 12.25 (s, 1H), 7.71 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.52-6.43 (m, 2H), 5.21 (s, 2H).
92%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 12h;
Beta24-1(1.5 g, 9.2 mmol) was dissolved in methanol (20 mL), Pd / C (150 mg) was added under nitrogen, replaced twice with hydrogen, Under normal pressure and pressure under hydrogen protection for 12 hours, diatomaceous earth filter, the filtrate was concentrated under reduced pressure yellow solid (l.lg, 92%).
90%
With hydrazine; In ethanol; at 60℃; for 8h;Inert atmosphere; Sealed tube;
General procedure: To a sealed tube containing the nitro compound (0.6 mmol) and 2 mL ethanol were added 2.6-6.0 mmol of NH2NH2 (see Table 2) and Au/TiO2 (100 mg, 1 wt.% in [Au], 0.8 mol%). The reaction was heated at 60 C for an appropriate time (see Table 2) under an inert atmosphere. The reaction was monitored by TLC, and after completion, the slurry was filtered under pressure through a short pad of celite and silica gel to withhold the supported catalyst with the aid of ethanol or methanol (~ 5 mL). The filtrate was evaporated under vacuum to afford the corresponding amines in pure form. The spectroscopic data (1H NMR, 13C NMR) of amines 1a-20a are in agreement with those previously reported [28,30,31], while the majority of them are commercially available substances. The screened catalysts Au/TiO2, Au/Al2O3, and Au/ZnO (~ 1 wt.% in Au) are commercially available (Strem Chemicals), and have an average gold crystallite size of ~ 2-3 nm.
With iron; ammonium chloride; In ethanol; water; for 2h;Reflux;
[000327j To a stirred solution of compound 1 (2 g, 1 eq) in ethanol (20 mL), iron powder (3.4 g, 5 eq), water (10 mL) and ammonium chloride (3.18 g. 5 eq) were added slowly. The reaction mixture was heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 2. LCMS (mlz): 134.05 (M + 1).
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).
To the solution of 0.145g (0.98mmol) of 4-nitrobenzaldehyde in 3 ml of dichloromethane was added 0.31g (1.47mmol) of sodium triacetoxyborohydride, 0.6ml (0.98mmol) of acetic acid and 0.13g (0.98mmol) of 6-aminoindazole. After stirring the mixture overnight at room temperature, the solvent was evaporated. The resulting residue was dissolved in 10 ml of ethanol, 20mg of 10% palladium on carbon was added and stirred under hydrogen atmosphere overnight. The catalyst was filtered off through celite. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 0.2 g (86%) of the title compound.1H-NMR (CDCl3) delta:4.12 (2H,br), 6.50-6.70 (5H, m), 7.52 (1H, d), 7.86-7.94 (2H, m), 8.18 (1H, br), 8.29 (1H, br).
6,7-dimethoxy-4-(1H-indazol-6-ylamino)-quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 2-methoxy-ethanol;
EXAMPLE 102 6,7-Dimethoxy-4-(1H-indazol-6-ylamino)-quinoline-3-carbonitrile A solution of 500 mg (2.00 mM) of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile</strong> and 975 mg (2.61 mM) of 6-aminoindazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100 C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80 C. to yield 738 mg of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 345.9, mp=180-183 C.
A solution of 500 mg (2.00 mM) of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile</strong> and 975 mg (2.61 mM) of 6-aminoindazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100C, then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80C to yield 738 mg of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 345.9, mp = 180-183C.
With pyridine hydrochloride; In 2-methoxy-ethanol; at 120℃; for 2h;Alkaline aqueous solution;
A mixture of 0.50 g (1 equivalent) of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.25 g (1.1 equivalents) of 6-aminoindazole, 0.22 g (1.1 equivalents) of pyridine hydrochloride and 15 ml of 2-methoxyethanol was heated in 120C oil bath for 2 hours. The reaction progress was monitored by thin layer chromatography (acetone/hexane 1:1). After 2 hours, the reaction mixture was cooled to room temperature; a total of 25 ml of 1M sodium bicarbonate was added and the reaction was stirred for 1 hour. The resultant precipitate was collected, washed with water and dried in vacuo at 60C overnight to give 0.645 g (97%) of the desired product. :mass spectrum (electrospray m/e): M+H = 393.9 (M+H)+; Analysis calculated for C20H16ClN5O2 : 2 H2O: Calculated C:55.88; H:4.69; N:16.29 ;Found C:55.63; H:4.78; N:15.24
0.645 g (97%)
With pyridine hydrochloride; sodium hydrogencarbonate; In 2-methoxy-ethanol;
EXAMPLE 166 7-(2-Chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile A mixture of 0.50 g (1 equivalent) of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.25 g (1.1 equivalents) of 6-aminoindazole, 0.22 g (1.1 equivalents) of pyridine hydrochloride and 15 ml of 2-methoxyethanol was heated in 120 C. oil bath for 2 hours. The reaction progress was monitored by thin layer chromatography (acetone/hexane 1:1). After 2 hours, the reaction mixture was cooled to room temperature; a total of 25 ml of 1M sodium bicarbonate was added and the reaction was stirred for 1 hour. The resultant precipitate was collected, washed with water and dried in vacuo at 60 C. overnight to give 0.645 g (97%) of the desired product.:mass spectrum (electrospray m/e): M+H=393.9 (M+H)+; Analysis calculated for C20H16ClN5O2: 2 H2O: Calculated C:55.88; H:4.69; N:16.29; Found C:55.63; H:4.78; N:15.24
4-(1H-6-Indazolylamino)-2-methylthio-5-pyrimidinecarboxylic Acid Ethyl Ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; In methanol; at 20 - 35℃; for 5h;
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 6-aminoindazole (3.15 g) in methanol (70 ml) was added N,N-diisopropylethylamine (4.2 ml), and then the solution was reacted at 30-35 C. for 4 hr. The reaction mixture was cooled, and then stirred at 20 C. for 1 hr. The reaction mixture was filtered, washed with methanol (20 ml) and dried at 40-50 C. in vacuo to obtain the desired compound (5.8 g, 82%). m.p.: 212-214 C. 1H-NMR (DMSO-d6), ppm: delta 1.33(t, 3H), 2.53(s, 3H), 4.33(m, 2H), 7.10(d, 1H), 7.70(d, 1H), 8.00(s, 1H), 8.22(s, 1H), 8.72(s, 1H), 10.40(s, 1H), 13.09(br s, 1H)
PREPARATION EXAMPLE 2 Preparation of 6-chloro-2-(1H-6-indazolylamino)-3-nitropyridine To the solution of 2,6-dichloro-3-nitropyridine (4 g) and 6-aminoindazole (2.8 g) in acetonitrile (50 ml) was added triethylamine (3.2 ml), and then the solution was reacted at 35-40 C. for 12 hr.. The reaction mixture was cooled at room temperature with slowly adding H2O (20 ml), and then reacted at 20-25 C. for 1 hr.. The reaction mixture was filtered, washed with acetonitrile (6 ml) and H2O (15 ml), and then dried at 50 C. in vacuo to obtain the desired compound (4.4 g, 73%). [00061] m.p.: 234 C. (dec.) [00062] 1H-NMR (DMSO-d6), ppm: delta 7.02(d, 1H), 7.20(d, 1H), 7.73(d, 1H), 7.99(d, 2H), 8.55(d, 1H), 10.26(s, 1H), , 13.09(s, 1H)
EXAMPLE 2 Preparation of 2-(1H-6-indazolylamino)-6-methoxy-3-nitropyridine To the solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (5 g) and 6-aminoindazole (3.9 g) in methanol (60 ml) was added triethylamine (4.1 ml), and then the solution was reacted at 55-60 C. for 14 hr.. The reaction mixture was cooled at room temperature, added H2O 30 mi slowly at 25 C., and then stirred for 0.5 hr.. The reaction mixture was filtered, washed with 50% aqueous methanol solution (15 ml) and obtained a solid product.. The solid product was dried at 50 C. in vacuo to obtain the desired compound (6.8 g, 90%). [00067] m.p.: 261264 C. [00068] 1H-NMR (DMSO-d6), ppm: delta 3.94(s, 3H), 6.39(d, 1H), 7.24(m, 1H), 7.71(d, 1H), 8.01(s, 1H), 8.19(s, 1H), 8.44(d, 1H), 10.62(s, 1H), 13.04(br s, 1H)
6-Aminoindazole (1.33 g, 10 mmol) was dissolved in 48% hydrobromic acid (5 mL) and water (16 mL). To the resulting solution at 0 C. was added dropwise a solution of sodium nitrite (0.77 g, 11 mmol) in water (9 mL). The mixture was stirred at 0 C. for 15 min. Urea (0.40 g) was added to remove excess nitrous acid. After stirring for 10 min, this solution was added dropwise to a stirred mixture of copper(I) bromide (4.3 g, 30 mmol), 48% hydrobromic acid (10 mL) and water (24 mL) at room temperature. The reaction mixture was heated at 75-80 C. for 1.5 h, cooled to room temperature, basified with concentrated ammonium hydroxide, and extracted with chloroform (4×30 mL). The combined extracts were dried over sodium sulfate and concentrated to provide the bromoindazole (0.96 g, 48%) as a greenish yellow solid; 1H NMR (500 MHz, DMSO-d6) delta 13.16 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 7.74-7.72 (d, J=8.5 Hz, 1H), 7.25-7.23 (dd, J=8.5, 1.4 Hz, 1H).
2-(1H-6-indazolylamino)-6-methylnicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With pyridine; In methanol; water;
Preparation Example 2 Preparation of 2-(1H-6-Indazolylamino)-6-Methylnicotinic Acid To the solution of <strong>[30529-70-5]2-chloro-6-methylnicotinic acid</strong> 10 g and 6-aminoindazole 8.6 g in methanol 100 ml was added pyridine 9.5 ml, and then the solution was refluxed for 3 days. The reaction mixture was cooled, added H2O 30 ml slowly at 20 C., and then stirred for 2 hr. The reaction mixture was filtered and the obtained solid was washed with methaol 20 ml. The desired compound (13.3 g, yield 85%) was obtained by drying of the solid product at 40~50 C. in vacuo. m.p.: 273~274 C. 1H-NMR (DMSO-d6), ppm: delta 2.49(s, 3H), 6.75(d, 1H), 7.01(d, 1H), 7.65(m, 1H), 7.93(s, 1H), 8.14(m, 1H), 8.53(s, 1H), 10.70(s, 1H), 13.13(br s, 2H)
1-(2,6-dichloro-4-trifluoromethylphenyl)-6-methylthio-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; potassium carbonate; sodium nitrite In water; N,N-dimethyl-formamide
15 (Compound 79 in Table I)
6-indazolamine (4 g, 30 mmol) was dissolved in 30 mL cold water containing 5.4 mL of conc. sulfuric acid. Upon chilling in ice, the solution became a paste and a solution of sodium nitrite (2.2 g) in 10 mL of cold water was added to the paste portionwise with constant agitation. The temperature was maintained below about 4° C. by adjusting the rate of addition of the nitrite solution. The solid paste gradually dissolved giving a reddish-brown solution. This solution was added carefully portionwise to a stirred suspension of freshly prepared cuprous methylmercaptan (35 g) in 200 mL of water at 4° C. Immediately, gas evolution was evident and addition was regulated to prevent frothing out of the container. Subsequently, the tan suspension was stirred until gas evolution ceased. The solution was suction filtered and the tan solid was washed with water and dried to give 0.9 g of intermediate. Preparation of compound 79: the 6-methylthio-1H-indazole (0.9 g, 6 mmol) above was dissolved in anhydrous DMF containing anhydrous potassium carbonate (1.52 g, 11 mmol) and 3,5-dichloro-4-fluorobenzotrifluoride (1.3 g, 6 mmol) and stirred overnight at 60° C. The mixture was poured into cold water and the product extracted into ethyl acetate, which was dried over sodium sulfate and evaporated to give an oily residue. This was separated into two components by silica gel chromatography (5% ethyl acetate/hexane) to give 1.1 g of compound 79 and 0.1 g of the 2-aryl isomer.
N-(4-nitro-3-pyridinyl)-1H-indazol-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 7 N-(4-Nitro-3-pyridinyl)-1H-indazol-6-amine, N6 -oxide To 100 ml of ethanol were added <strong>[769-54-0]3-fluoro-4-nitropyridine-1-oxide</strong> (6.0 g) and 1H-indazol-6-amine (5.5 g) and this mixture was heated to 70 C. and stirred for four hours. The mixture was filtered to yield a solid (9.5 g) which was recrystallized from methanol to yield a solid, 6.0 g, m.p. 247-248 C. (decomposed).
In ethanol;
EXAMPLE 7 N-(4-Nitro-3-pyridinyl)-1H-indazol-6-amine, N6 -oxide To 100 ml of ethanol were added <strong>[769-54-0]3-fluoro-4-nitropyridine-1-oxide</strong> (6.0 g) and 1H-indazol-6-amine (5.5 g) and this mixture was heated to 70 C. and stirred for four hours. The mixture was filtered to yield a solid (9.5 g) which was recrystallized from methanol to yield a solid, 6.0 g, m.p. 247-248 C. (decomposed). ANALYSIS: Calculated for C12 H9 N5 O3: 53.14% C., 3.34% H, 25.82% N. Found: 52.96% C., 3.17% H, 25.72% N.
A mixture of <strong>[934524-10-4]2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (400 mg, 1.17 mmol), 6-aminoindazole (171 mg, 1.29 mmol) and triethylamine (0.400 mL, 2.88 mmol) in n-butyl alcohol (10 mL) was heated at 80 C. overnight. After cooling down, H2O and CH2Cl2 were added. The organic phase was separated, washed with 1N HCl, followed by 5% NaHCO3, before it was dried over Na2SO4 and concentrated in vacuo to give 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (490 mg).
To leta-indazol-6-amine (0.5 g, 3.76 mmol) and (S)-2-(tert- butoxycarbonylamino)-3-phenylpropanoic acid (0.996 g, 3.76 mmol) in pyridine (5 mL) cooled in ice/acetone bath was added POCI3 (0.350 mL, 3.76 mmol). After 1 h, the reaction was quenched with water (15 mL), and dilute 0. IN HCl (15 mL) was added and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with sat'd NaHCO3 (20 mL), brine (20 mL) and dried (MgSO4). Filtration and concentration afforded 57C (1.1 g, 79%) as a foam. LCMS m/z 381.3[M + H]+.
With hydrogen;5% rhodium-on-charcoal; In ethanol; at 120℃; under 51716.2 Torr; for 72h;
Combine 1H-indazol-6-ylamine (12.45 g, 93.6 mmol) and 5% Rh/C (6.13 g) in ethanol (300 mL) and heat at 120 C. for 72 hours under ~1000 psi H2. Cool the reaction and filter through hyflo. Remove the solvent in vacuo and purify the crude product with 10% 2 M NH3 in MeOH in CH2Cl2 and re-purify mixed fractions with 15% 2 M NH3 in MeOH in CH2Cl2 to afford 4.80 g (37%) of the titled product. MS (m/z): 138 (M+1).
With chloro-trimethyl-silane; In butan-1-ol; at 115.0℃; for 8.0h;
To a mixture of <strong>[1192711-88-8]2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine</strong> (0.06 g, 0.353 mmol) in nBuOeta (0.7 mL) was added 6-aminoindazole (0.094 g, 0.70 mmol) and TMSCl (0.023 mL, 0.175 mmol). After heating at 115 C for 8 h, it was cooled and purifed by prep etaPLC to give N2-(lH-indazol-6-yl)- 7H-pyrrolo [2,3-d]pyrimidin-2,4-diamine (0.012 g, MS calcd for C13H1 1N7 265.3, found 266.1; UV 216.9, 308.0 nm).
With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 3.5h;
To a cold (0C) DMF (10mL) solution of DIPEA (1.3mL, 7.5mmol) and Ac2O (0.40g, 3.9mmol) and DMAP (14mg, 0.11mmol) was added 1H-indazol-6-amine (0.50g, 3.7mmol) in one portion. The reaction was stirred at the temperature for 3.5h then aq NaOH (2M, 2mL) was added and stirring was continued at rt for 1h. The solvent was removed under reduced pressure, the residue was taken into DCM, filtered, rinsed with DCM and subsequently with H2O (10mL) to afford N-(1H-indazol-6-yl)acetamide as a white solid (0.56g, 87%); MS ESI 175.8 [M+H]+, calcd for [C9H9N3O+H]+ 176.1.
N-(1H-indazol-6-yl)thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.533333h;
The solution of 1H-indazol-6-amine (266mg, 2mmol), Et3N (0.42mL, 3mmol) in DMF (5mL) was added the solution of thiophene-2-carbonyl chloride (0.21mL, 2mmol) in DMF (1mL) dropwise over 2min at rt. The resulting reaction mixture was stirred at 0C for 30min, quenched with H2O and filtered. The filter cake was rinsed with H2O, collected and dried to give N-(1H-indazol-6-yl)thiophene-2-carboxamide as a yellow solid (460mg, 95%). 1H NMR (400MHz, DMSO-d6) delta ppm 12.96 (s, 1H), 10.32 (s, 1H), 8.17 (s, 1H), 8.06 (d, J=3.8Hz, 1H), 7.98-8.00 (m, 1H), 7.87 (d, J=5.0Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.32-7.37 (m, 1H), 7.23 (dd, J=4.6, 3.9Hz, 1H); MS ESI 244.1 [M+H]+, calcd for [C12H9N3OS+H]+ 244.0.
12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
86%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
11-(2-bromophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-1H-pyrazolo[3,4-a]acridin-10(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With copper(l) iodide; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
3-chloro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 10h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
85%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 10h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-chloro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
83%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 15h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
2-chloro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 10h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-chloro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 15h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-chloro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
3-fluoro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 12h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
82%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
3-fluoro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-fluoro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 15h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
78%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-fluoro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-fluoro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 15h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-methoxy-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 14h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-methoxy-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 18h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2-methoxy-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2,3-dimethoxy-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2,3-dimethoxy-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 18h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
2,3-dimethoxy-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
12,12-dimethyl-2-nitro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 10h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
3-chloro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 10h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-fluoro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With copper(l) iodide; caesium carbonate In dimethyl sulfoxide for 12h; Reflux;
Synthesis of Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one Derivatives 4
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-chloro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 12h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-fluoro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(l) iodide; caesium carbonate In dimethyl sulfoxide for 12h; Reflux;
Synthesis of Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one Derivatives 4
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-fluoro-12-methyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With copper(l) iodide; caesium carbonate In dimethyl sulfoxide for 16h; Reflux;
Synthesis of Pyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one Derivatives 4
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
In neat (no solvent); at 120℃; under 1500.15 Torr; for 0.166667h;Microwave irradiation;
General procedure: A mixture of 4,7-dichloroquinoline (1, 1.2 mmol) and therespective aryl/heteroaryl amino compounds (2a-2g,1.0 mol) was mixed thoroughly with the use of glass rod ina microwave vessel and subjected to microwave irradiation(Biotage microwave oven, 120 C, 2 bar pressure) for10 min. The progress of the reaction was monitored bythin-layer chromatography. After completion of the reaction,the reaction mixture was cooled and washed withaqueous methanol. The crude product obtained was driedand recrystallized from methanol to afford pure 4-arylaminosubstituted quinoline compounds 3a-3g.
7′,9′-bis(4-fluoro-2-nitrophenyl)-3-phenyl-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In ethanol; at 80℃; for 12h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9?13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
(E)-9-(2-bromo-5-chlorophenyl)-8-[(hydroxyimino)(phenyl)methyl]-8,9-dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In ethanol at 80℃; for 11h;
8,9-Dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-ones 5; General Procedure
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (1.0 mmol), 1H-indazol-6-amine (2a; 133 mg, 1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 8-11 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 5 was collected by filtration without further purification.
(E)-9-(2,4-dichlorophenyl)-8-[(hydroxyimino)(phenyl)methyl]-8,9-dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In ethanol at 80℃; for 9h;
8,9-Dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-ones 5; General Procedure
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (1.0 mmol), 1H-indazol-6-amine (2a; 133 mg, 1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 8-11 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 5 was collected by filtration without further purification.
(E)-9-(2-bromo-4-chlorophenyl)-8-[(hydroxyimino)(phenyl)-methyl]-8,9-dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol; at 80℃; for 11h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (1.0 mmol), 1H-indazol-6-amine (2a; 133 mg, 1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 8-11 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 5 was collected by filtration without further purification.
7′,9′-bis(5-fluoro-2-nitrophenyl)-3-phenyl-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In ethanol; at 80℃; for 9h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
7′,9′-bis(4-bromo-2-nitrophenyl)-3-phenyl-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In ethanol; at 80℃; for 13h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
7′,9′-bis(4-chloro-2-nitrophenyl)-3-phenyl-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol; at 80℃; for 12h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
7′,9′-bis(4-bromo-2-nitrophenyl)-3-(4-methoxyphenyl)-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In ethanol; at 80℃; for 10h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
7′,9′-bis(4-chloro-2-nitrophenyl)-3-(4-methoxyphenyl)-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol; at 80℃; for 12h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
N-(1H-indazol-6-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.7%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (70 mg, 0.37 mmol), HATU (209 mg, 0.55 mmol), and DIPEA (0.13 mL, 0.74 mmol) in 1 mL of DMF was added lH-indazol-6-amine (59 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 hours until the reaction was complete. The solid was collected by filtration, washed with 0, DCM and diethyl ether to provide the title compound (51 mg, 63.7%) as a brown solid.XH NMR (400 MHz, DMSO) delta 12.96 (s, 1H), 10.36 (s, 1H), 8.65 (s, 1H), 8.34 (s, 1H), 8.00 (s, 1H), 7.73 (d, J= 8.8 Hz, 1H), 7.19 (s, 1H), 7.12 (d, J= 8.4 Hz, 1H), 2.75 (s, 3H), 2.72 (s, 3H). ES-MS m/z: 307.1 [M+H]+. LC-MS Purity (214 nm): >97 %; tR= 1.45 min.
benzo[g]-1H-indazolo[5,6-b][1,8]naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
In N,N-dimethyl-formamide; at 160 - 180℃; for 2.5h;
General procedure: The 2-chloroquinolines-3-carbaldehyes (2mmol) compound 4(a-d) was taken in 10mL (DMF) and 1H-Indazole-6-amine (2mmol) was added and refluxed for 2-3h 160-180C on a mantle. After the completion of reaction as it indicated by TLC spot change, the reaction mixture was slowly poured in ice water, filtered, dried and chromatographed over silica gel using Ethyl acetate: Methanol (90:10) (v/v) as eluent which pure orange/green colored solid compound 5(a-d). It was recrystallised from absolute methanol. 2.4.1 Benzo[g]-1H-Indazolo[5,6-b][1,8]naphthyridine (5a) Yield: 60%; light orange solid; mp 282-285C. IR (KBr, cm-1): 1563, 2926, 3390. 1H NMR (400MHz, DMSO-d6): delta 7.02 (s, 1H, Ar-H), 7.43 (d, J=7.6Hz, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.59-7.65 (m, 5H, Ar-H), 7.70 (d, J=8.8Hz, 1H, Ar-H), 12.47 (s, 1H, for NH). 13C NMR (100MHz, DMSO-d6): delta 116.98, 117.73, 118.92, 119.94, 125.66, 126.38, 128.47, 128.57, 128.98, 131.29, 132.07, 133.71, 133.94, 137.15, 146.08, 150.51, 158.71, 165.97. ESI-MS (m/z): calcd for [M+H]+ 270.29, found 270.21; Anal. Calcd for C17H10N4: C, 75.54; H, 3.73; N, 20.73 Found: C, 75.58; H, 3.69; N, 20.70.
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzoic acid[ No CAS ]
[ 6967-12-0 ]
4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indazol-6-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.94%
A mixture of 97 (0.30 g, 0.88mmol), HBTU (0.50 g, 1.32mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 6- aminoindazole (0.18 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was filtered by suction filtration to yield a red product. The residue was filtered without further purification to afford 38 (0.13 g, 37.94 %) as a red solid. 1H- NMR (300 MHz, DMSO-d6): delta 5.05 (s, 2H), 7.36 (d, J= 8.4 Hz, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.68 (d, J= 8.7 Hz, 1H), 7.75 (t, J= 6.9 Hz, 1H), 7.83 (t, J= 6.9 Hz, 1H), 7.92 (d, J= 8.1 Hz, 2H), 7.97-7.98 (m, 3H), 8.12 (br, 1H), 8.24 (s, 1H), 10.32 (s, 1H), 12.94 (s, 1H).
37.94%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
General procedure: A mixture of 12 (0.25 g, 0.73 mmol), HBTU (0.42 g, 1.10 mmol), DIPEA (0.29 ml, 1.65 mmol) and DMF (2.0 ml) was stirred for a while then the aniline (0.08 g, 0.88 mmol) was added at room temperature and the mixture was stirred overnight. The residue was filtered and purified by washing with different solvents to afford 10a (0.23 g, 76.33%) as a red solid.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
[00172]A mixture of 97 (0.30 g, 0.88mmol), HBTU (0.50 g, 1.32mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 6-aminoindazole (0.18 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was filtered by suction filtration to yield a red product. The residue was filtered without further purification to afford 38 (0.13 g, 37.94 %) as a red solid.1H-NMR (300 MHz, DMSO-d6): ^5.05 (s, 2H), 7.36 (d, J= 8.4 Hz, 1H), 7.46 (d, J= 8.1 Hz, 2H), 7.68 (d, J= 8.7 Hz, 1H), 7.75 (t, J= 6.9 Hz, 1H), 7.83 (t, J= 6.9 Hz, 1H), 7.92 (d, J= 8.1 Hz, 2H), 7.97-7.98 (m, 3H), 8.12 (br, 1H), 8.24 (s, 1H), 10.32 (s, 1H), 12.94 (s, 1H).
N<SUP>4</SUP>-(2-(1H-indol-3-yl)ethyl)-6-chloro-N<SUP>2</SUP>-(1H-indazol-6-yl)quinazoline-2,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrogenchloride; In ethanol; at 120℃; for 6h;
General procedure: To a vessel charged with N-(2-(1H-indol-3-yl)ethyl)-2-chloroquinazolin-4-amine (8a, 232 mg, 0.72 mmol)was added ethanol (5 mL), hydrochloric acid (10 mL), and 1Hindazol-5-amine (96 mg, 0.72 mmol). The vessel was sealed andstirred for 6 h at 120 C. The resulting mixture was dried underreduced pressure and subjected to silica gel column chromatographyusing dichloromethane/methanol (90:10) as the mobilephase to afford the desired compound 9a as a white solid (184 mg,0.87 mmol, 61% yield).
1-benzyl-N-(1H-indazol-6-yl)pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃; for 3h;
General procedure: To a solution of intermediate 9, 11 or 6 (0.39 mmol) and 5- or 6-aminoindazole (0.47 mmol) in dryDMF (3 mL), EDCI (90 mg, 0.47 mmol) was added at r.t. Afterwards, the mixture was stirred for 7 h at80 C and then the reaction mixture was cooled to room temperature. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel (2%-10% CH3OH inCH2Cl2) to give the target compounds.
(R)-1-benzyl-N-(1H-indazol-6-yl)pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃; for 3h;
General procedure: To a solution of intermediate 9, 11 or 6 (0.39 mmol) and 5- or 6-aminoindazole (0.47 mmol) in dryDMF (3 mL), EDCI (90 mg, 0.47 mmol) was added at r.t. Afterwards, the mixture was stirred for 7 h at80 C and then the reaction mixture was cooled to room temperature. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel (2%-10% CH3OH inCH2Cl2) to give the target compounds.
(S)-1-benzyl-N-(1H-indazol-6-yl)pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃; for 3h;
General procedure: To a solution of intermediate 9, 11 or 6 (0.39 mmol) and 5- or 6-aminoindazole (0.47 mmol) in dryDMF (3 mL), EDCI (90 mg, 0.47 mmol) was added at r.t. Afterwards, the mixture was stirred for 7 h at80 C and then the reaction mixture was cooled to room temperature. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel (2%-10% CH3OH inCH2Cl2) to give the target compounds.
9-phenyl-1,6,8,9-tetrahydro-7H-pyrazolo[3,4-f]quinolin-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tin(II) chloride hydrate; In tetrahydrofuran; at 80℃;
General procedure: Aromatic aldehyde 1 (1 mmol), 6-nitro-1H-indazole 2 or 5-nitrobenzimidazole 7 (1 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione 3 or 1,3-cyclohexanedione or dimedone 5 (1 mmol), SnCl2·2H2O (3 mmol), and THF (6 mL) were put into a 25-mL round-bottom flask. Then, the mixture was stirred at 80 oC about 3-8 h (monitored reactions by TLC). After completion the reaction, the solution was allowed to cool and the pH was made slightly basic (pH 8) by addition of 5% aqueous NaHCO3. The mixture was transferred to a separatory funnel, and was extracted with 3x15 mL of ethyl acetate. Organics were combined and washed thoroughly with saturated NaCl (aq), dried over anhydrous Na2SO4, and filtered through Celite. Following reduction of the solvent in vacuo, the material remaining was purified by crystallization from DMF or EtOH, to give the pure products 4, 6 and 8.
hexa[4-bromo-2-(1H-indazol-6-yl-iminomethyl)phenoxy]cyclotriphosphazene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.5%
With formic acid; In tetrahydrofuran; at 20℃; for 24h;
General procedure: In a 100-mL single-necked flat-bottom flask equipped with magnetic mixing, the compound 2 (0.40 g, 0.375 mmol), THF (30 mL), two drops of formic acid and primary amine derivative (4.50 mmol) were added sequentially. The reaction was continued for 24 h under room conditions. After the solution was reduced to approximately 5 mL under reduced pressure, the solution was dropped into diethyl ether or alcohol for the removal of free primary amine. The precipitate was filtered off and the color solid was dried under room conditions. The compounds 3a-3k were obtained from the compound 3.
hexa[4-chloro-2-(1H-indazol-6-yl-iminomethyl)phenoxy]cyclotriphosphazene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.5%
With formic acid; In tetrahydrofuran; at 20℃; for 24h;
General procedure: In a 100-mL single-necked flat-bottom flask equipped with magnetic mixing, the compound 2 (0.40 g, 0.375 mmol), THF (30 mL), two drops of formic acid and primary amine derivative (4.50 mmol) were added sequentially. The reaction was continued for 24 h under room conditions. After the solution was reduced to approximately 5 mL under reduced pressure, the solution was dropped into diethyl ether or alcohol for the removal of free primary amine. The precipitate was filtered off and the color solid was dried under room conditions. The compounds 2a-2k were obtained from the compound 2.
(5-bromo-2-nitrophenyl)-1H-indazol-6-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With triethylamine; In dimethyl sulfoxide; at 65℃;
2-Fluoro-4-bromonitrobenzene (7 g, 32 mmol) was dissolved in 8 mL of DMSO. <strong>[6967-12-0]6-Aminoindazole</strong> (4.7 g, 35 mmol) was then added, followed by 8 mL of triethylamine. The mixture was warmed to 65 C and allowed to stir overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried using anhydrous Na2SC)4, filtered, and concentrated. The solid was washed with MTBE and used without further purification (8g, 75%). ESI MS [M-H]+ for C'nHxBr^CT, calcd 330.98, found 331.0.
2-chloro-2-fluoro-N-(1H-indazol-6-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 1.5h;
General procedure: To a stirred solution of 5-amino-1-naphthol (126 mg, 0.792 mmol) and <strong>[70395-35-6]sodium chlorofluoroacetate</strong> (159 mg,1.18 mmol) in dichloromethane (8 mL) was added T3P (50 wt%solution in AcOEt, 701 μL, 1.18 mmol) and N,N-diisopropylethylamine(DIPEA) (273 μL, 1.57 mmol) at 0C. Afterstirred at ambient temperature for 1 h, the reaction mixturewas diluted with water and extracted thrice with CHCl3. Thecombined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (hexane/AcOEt = 3 : 1) to afford the title compound (37.2 mg, 18% yield) as a pale purple solid.
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