* 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.
Reference：
[1] Synthetic Communications, 2004, vol. 34, # 3, p. 523 - 531
[2] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 9, p. 3417 - 3427
2
[ 4769-97-5 ]
[ 5192-23-4 ]
Yield
Reaction Conditions
Operation in experiment
89%
With iron; ammonium chloride In water; isopropyl alcohol for 2 h; Reflux; Inert atmosphere
General procedure: Method A. Nitrocompound (1 mmol) was dissolve in a 0.1 M mixture of IPA: H2O(4:1) and iron powder (Fe, 3 mmol), ammonium chloride (NH4Cl,2 mmol) were added and refluxed for two hours. After cooling down to room temperature reaction mixture was filtered through celite, extracted with EtOAc (25 mL x 3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure and purified by column chromatography.
Reference：
[1] Patent: US6255306, 2001, B1,
[2] Chemistry - A European Journal, 2014, vol. 20, # 11, p. 3050 - 3060
[3] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2280 - 2287
[4] RSC Advances, 2014, vol. 4, # 43, p. 22567 - 22574
[5] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
[6] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 13 - 23
[7] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4128 - 4139
[8] Journal of the American Chemical Society, 2017, vol. 139, # 20, p. 7004 - 7011
[9] Patent: WO2009/34581, 2009, A1, . Location in patent: Page/Page column 24
[10] Patent: WO2011/23081, 2011, A1, . Location in patent: Page/Page column 55-56
[11] Patent: WO2012/28106, 2012, A1, . Location in patent: Page/Page column 50
[12] ACS Catalysis, 2014, vol. 4, # 5, p. 1441 - 1450
[13] RSC Advances, 2016, vol. 6, # 63, p. 58805 - 58812
[14] Catalysis Science and Technology, 2018, vol. 8, # 5, p. 1454 - 1467
3
[ 4769-97-5 ]
[ 7439-89-6 ]
[ 5192-23-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
With acetic acid In methanol; ethanol
A. 4-Aminoindole. Iron powder (1.20 g, 21.58 mmol) and acetic acid (2.47 mL, 43.19 mmol) are added to a solution of 4-nitroindole (1.0 g, 6.17 mmol) in ethanol (20 mL). The resulting suspension is heated to reflux for 14 hours. The ethanol is removed by rotary evaporation and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered, and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 1percent methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.815 g of 4-aminoindole as an orange solid (82percent yield).
Reference：
[1] Patent: US6162818, 2000, A,
4
[ 606-20-2 ]
[ 5192-23-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 9, p. 3417 - 3427
[2] Synthetic Communications, 2004, vol. 34, # 3, p. 523 - 531
[3] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 11, p. 3742 - 3744
[4] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
5
[ 52537-01-6 ]
[ 5192-23-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 11, p. 3742 - 3744
6
[ 78283-23-5 ]
[ 5192-23-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
7
[ 75822-01-4 ]
[ 5192-23-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
10
[ 77759-08-1 ]
[ 5192-23-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 11, p. 3742 - 3744
11
[ 118742-89-5 ]
[ 5192-23-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 11, p. 3742 - 3744
12
[ 253-66-7 ]
[ 5192-23-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
13
[ 78311-07-6 ]
[ 5192-23-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
14
[ 16732-64-2 ]
[ 5192-23-4 ]
Reference：
[1] Chemische Berichte, 1955, vol. 88, p. 370,373
15
[ 78283-21-3 ]
[ 5192-23-4 ]
[ 4769-97-5 ]
[ 78283-23-5 ]
[ 78283-24-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
[2] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
[3] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 3, p. 726 - 738
16
[ 98592-11-1 ]
[ 5192-23-4 ]
Reference：
[1] Chemische Berichte, 1955, vol. 88, p. 370,373
With potassium carbonate In isopropyl alcohol at 90℃; for 48 h;
4-aminoindole (2g, 15.2mmol), bis(2-chloroethyl)amine hydrochloride (3.2g, 18.2mmol) and potassium carbonate (4.2g, 30.4mmol) was added to isopropanol (30 mL) after the reaction solution was reacted at 90 °C for 48 hours, and thereto was added dichloromethane (50mL) and methanol (50mL). The reaction mixture was filtered and the filtrate under reduced pressure to spin dry, the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)= 10/1) by to give the title compound as a brown solid (2.78g, 90.8percent).
Reference：
[1] Patent: CN105367472, 2016, A, . Location in patent: Paragraph 0179; 0180; 0181; 0182
[2] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 19-20
19
[ 5192-23-4 ]
[ 84807-09-0 ]
Yield
Reaction Conditions
Operation in experiment
90.8%
With potassium carbonate In isopropyl alcohol at 90℃; for 48 h;
[00190] To 30 mL of i-propanol were added 4-aminoindole (2 g, 15.2 mmol), bis(2-chloroethyl)amine hydrochloride (3.2 g, 18.2 mmol) and potassium carbonate (4.2 g, 30.4 mmol). The mixture was stirred at 90 °C for 48 hours. To the reaction mixture were added dichlormethane (50 mL) and methanol (50 mL), and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography eluted with DCMIMeOH (v/v = 10/1) to give the title compound as a brown solid (2.78 g, 90.8percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 202.1 [M+H] and ‘H NMR (600 MHz, DMSO-d6) (ppm): 11.17 (s, 1H), 7.29-7.25 (m, 1H), 7.09 (d, J= 8.1 Hz, 1H), 6.98 (t, J= 7.8 Hz, 1H), 6.49 (d, J= 7.5 Hz, 1H), 6.46 (s, 1H), 3.32-3.28 (m, 8H).
EXAMPLE 1 General Conversion of 4-Nitroindoles to 1-(Indol-4-yl)piperazines A mixture of the 4-nitroindole (10.0 mmol), 10% palladium on carbon (20% by weight), and absolute ethanol (50 mL) was shaken under a hydrogen atmosphere (3 atm) for 2 hours. The resulting reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to afford the corresponding 4-aminoindole, which was used directly (assumed 100% yield) in the next step below.
89%
With iron; ammonium chloride; In water; isopropyl alcohol; for 2h;Reflux; Inert atmosphere;
General procedure: Method A. Nitrocompound (1 mmol) was dissolve in a 0.1 M mixture of IPA: H2O(4:1) and iron powder (Fe, 3 mmol), ammonium chloride (NH4Cl,2 mmol) were added and refluxed for two hours. After cooling down to room temperature reaction mixture was filtered through celite, extracted with EtOAc (25 mL x 3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure and purified by column chromatography.
A mixture of 4-nitroindole (15 grams, 92.5 mmol), iron powder (25.92 grams, 462.9 mmol), concentrated hydrochloric acid (5 mL) and water (50 mL) in ethanol (150 mL) was refluxed at 90 0C and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction (2 hours), the reaction mixture was filtered through hy-flow bed and the filtrate was concentrated under reduced pressure. The residual mass was diluted with ice water (500 mL), basified with aqueous sodium hydroxide solution to pH 9 - 10 and extracted with ethyl acetate (2.x 250 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product (13.2 grams), thus obtained, was purified by column chromatography using silica-gel (100 - 200 mesh), the eluent system being ethyl acetate and n-hexane (1:9) to obtain 12.13 grams of title product. Melting Range: 101.7 - 106.8 0C; I.R (cm-'): 1109, 1519, 2931, 3325, 3394, 3440;1H-NMR (ppm): 3.92 (2H, bs), 6.40 - 6.42 (IH, m), 6.46 - 6.47 (IH, m), 6.86 - 6.88 (IH; d, J = 8.14 Hz), 6.99 - 7.03 (IH, t, J = 7.8 Hz), 7.11 - 7.12 (IH, t, 2.8 Hz), 8.11 (IH, bs); Mass (m/z): 133.15 (M+H) +
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran;
A round-bottom flask was charged with 4-nitroindole (4.8 g, 30 mmol), Palladium on carbon (10%, 480 mg), and THF (50 mL), and the mixture was stirred under one hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 4-amino- IH- indole, which was used directly in the next step without purification.
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran;
A round-bottom flask was charged with 4-nitroindole (4.8 g, 30 mmol), Palladium on carbon (10%>, 480 mg), and THF (50 mL), and the mixture was stirred under one hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 4-amino-lH-indole (Q-1), which was used directly in the next step without purification.
55%Spectr.
With 6Zr(4+)*C20H12O4(2-)*14O(2-)*3Co(2+); hydrogen; sodium triethylborohydride; In toluene; at 115℃; under 30003.0 Torr; for 72h;Glovebox; Inert atmosphere;
General procedure: Scheme 23 shows the hydrogenation of nitroarenes catalyzed by Zr12-TPDC-Co. In a nitrogen-filled glove box, Zr12-TPDC-CoH (0.50 mg) in 1.0 mL THF was charged into a glass vial. NaBEt3H (10 muL, 1.0 M in THF) was then added to the vial and the mixture was stirred for 1 h. The solid was then centrifuged, washed with THF twice, and transferred to a glass vial in 1.0 mL toluene. The nitroarene substrate was added to the vial, which was placed in a Parr reactor, sealed under nitrogen, and charged with hydrogen to 40 bar. After stirring at 115 C. for 1-2 d, the pressure was released and the MOF catalyst was removed from the reaction mixture via centrifugation. Mesitylene (internal standard) was added to the organic extracts and the yield of the product was determined by integrations of the product and mesitylene peaks in the 1H NMR spectra in CDCl3. Table 20, below summarizes the optimization of conditions for the MOF-CoH catalyzed hydrogenation of nitroarenes using nitrobenzene as an exemplary nitroarene. Table 21 summarizes results of the hydrogenation of various nitroarenes using Zr12-TDPC-CoH.
EXAMPLE 80A 4-isocyanato-1H-indole 4-Aminoindole (0.5 g, 3.78 mmol) in toluene (50 mL) was treated with triphosgene (0.4 g, 1.35 mmol) and heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in diethyl ether, filtered, and the filtrate was concentrated under reduced pressure to provide title compound as yellow oil (0.4 g). 1H NMR (300 MHz, CDCl3-d6) delta 6.62 (m, 1H), 6.84 (d, 1H), 7.1 (t, 1H), 7.23 (m, 2H), 8.3 (s, 1H).
In diethyl ether; toluene;
EXAMPLE 80A 4-isocyanato-1H-indole 4-Aminoindole (0.5 g, 3.78 mmol) in toluene (50 mL) was treated with triphosgene (0.4 g, 1.35 mmol) and heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in diethyl ether, filtered, and the filtrate was concentrated under reduced pressure to provide title compound as yellow oil (0.4 g). 1H NMR (300 MHz, CDCl3-d6) delta 6.62 (m, 1H), 6.84 (d, 1H), 7.1 (t, 1H), 7.23 (m, 2H), 8.3 (s, 1H).
In toluene; for 5h;Heating / reflux;
EXAMPLE 80A 4-isocyanato-1H-indole 4-Aminoindole (0.5 g, 3.78 mmol) in toluene (50 mL) was treated with triphosgene (0.4 g, 1.35 mmol) and heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in diethyl ether, filtered, and the filtrate was concentrated under reduced pressure to provide title compound as yellow oil (0.4 g). 1H NMR (300 MHz, CDCl3-d6) delta 6.62 (m, 1H), 6.84 (d, 1H), 7.1 (t, 1H), 7.23 (m, 2H), 8.3 (s, 1H).
N-(3,4-dichlorobenzyl)-N'-1H-indol-4-ylurea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; hexane;
EXAMPLE 79 N-(3,4-dichlorobenzyl)-N'-1H-indol-4-ylurea 4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0. 25 g of the title compound as a tan solid. mp 201 C.; 1H NMR (300 MHz, DMSO-d6) delta 6.23 (d, 2 H), 6.36 (s, 1H), 6.54 (t, 1H), 7. 0 (dd, 1 H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H 3.68; N, 11.97.
In tetrahydrofuran; hexane;
EXAMPLE 79 N-(3,4-dichlorobenzyl)-N'-1H-indol-4-ylurea 4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N, 11.97.
In tetrahydrofuran; at 20℃; for 3h;
EXAMPLE 79 N-(3,4-dichlorobenzyl)-N'-1H-indol-4-ylurea 4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N, 11.97.
In tetrahydrofuran; hexane;
EXAMPLE 79 N-(3,4-dichlorobenzyl)-N'-1H-indol-4-ylurea 4-Aminoindole (0.13 g, 1 mmol) in THF (3 muL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N, 11.97.
EXAMPLE 78 N-(4-bromobenzyl)-N'-1H-indol-4-ylurea <strong>[5192-23-4]4-aminoindole</strong> (0.13 g, 1 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.23 g, 1.1 mmol) for 3 hours at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.26 g of the title compound as a tan solid. mp 198 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.30 (d, 2H), 6.51 (t, 1H), 6.89 (t, 1H), 6.95 (d, 2H), 7.29 (t, 1H), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H); Anal. Calcd. For C16H14N3BrO: C, 55.83; H, 4.10; N, 12.21. Found: C, 55.71, H 4.12; N, 12.01.
In tetrahydrofuran; hexane;
EXAMPLE 78 N-(4-bromobenzyl)-N'-1H-indol-4-ylurea <strong>[5192-23-4]4-aminoindole</strong> (0.13 g, 1 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.23 g, 1.1 mmol) for 3 hours at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.26 g of the title compound as a tan solid. mp 198 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.30 (d, 2H), 6.51 (t, 1H), 6.89 (t, 1H), 6.95 (d, 2H), 7.29 (t, 1H), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H); Anal. Calcd. For C16H14N3BrO: C, 55.83; H, 4.10; N, 12.21. Found: C, 55.71, H, 4.12; N, 12.01.
In tetrahydrofuran; at 20℃; for 3h;
EXAMPLE 78 N-(4-bromobenzyl)-N'-1H-indol-4-ylurea <strong>[5192-23-4]4-aminoindole</strong> (0.13 g, 1 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.23 g, 1.1 mmol) for 3 hours at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.26 g of the title compound as a tan solid. mp 198 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.30 (d, 2H), 6.51 (t, 1H), 6.89 (t, 1H), 6.95 (d, 2H), 7.29 (t, 1H), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H); Anal. Calcd. For C16H14N3BrO: C, 55.83; H, 4.10; N, 12.21. Found: C, 55.71, H, 4.12; N, 12.01.
In tetrahydrofuran; hexane;
EXAMPLE 78 N-(4-bromobenzyl)-N'-1H-indol-4-ylurea <strong>[5192-23-4]4-aminoindole</strong> (0.13 g, 1 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.23 g, 1.1 mmol) for 3 hours at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.26 g of the title compound as a tan solid. mp 198 C.; 1H NMR (300 MHz, DMSO-d6) delta 4.30 (d, 2H), 6.51 (t, 1H), 6.89 (t, 1H), 6.95 (d, 2H), 7.29 (t, 1H), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H); Anal. Calcd. For C16H14N3BrO: C, 55.83; H, 4.10; N, 12.21. Found: C, 55.71, H, 4.12; N, 12.01.
4-(1H-indol-4-ylamino)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,2-dimethoxyethane; at 90℃; for 2h;
To a stirred solution of 4-chloro-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile (100 mg, 0.313 mmol), <strong>[5192-23-4]4-aminoindole</strong> (62 mg, 0.47 mmol), DavePhos (37 mg, 0.094 mmol), and K3PO4 (99.8 mg, 0.47 mmol) in 4 mL of anhydrous ethylene glycol dimethyl ether was added Pd2(dba)3 (28.7 mg, 0.031 mmol). The mixture was heated to 90 C. for 2 h, then cooled, filtered through celite, concentrated in vacuo, and crystallized by tritration with ether/hexane to yield 42.5 mg (33% yield) of the title compound 153 as a tan solid. MS: 415.1 (M+H), HPLC retention time: 7.70 min(b).
5-[3-(2-chloroethoxy)phenyl]-4-(1H-indol-4-ylamino)-nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,2-dimethoxyethane; at 90℃; for 2h;
To a stirred solution of 4-chloro-5-[3-(2-chloroethoxy)phenyl]-nicotinonitrile (200 mg, 0.68 mmol), <strong>[5192-23-4]4-aminoindole</strong> (135 mg, 1 mmol), DavePhos (80 mg, 0.20 mmol), and K3PO4 (216 mg, 1 mmol) in 4 mL anhydrous ethylene glycol dimethyl ether was added Pd2(dba)3 (62 mg, 0.07 mmol). The mixture was heated at 90 C. for 2 h then cooled, filtered through celite, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 5-50% MeOH in CH2Cl2 to yield 155 mg (59% yield) of 5-[3-(2-chloroethoxy)phenyl]-4-(1H-indol-4-ylamino)-nicotinonitrile 165 as a tan solid. MS: 389.1 (M+H), HPLC retention time: 9.60 min.(a).
4-(1H-indol-4-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine hydrochloride; In 1-ethoxyethanol; for 2h;Heating / reflux; Alkaline aqueous solution;
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.132 g of 4-aminoindole, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust pH to 7. The product was collected, washed with water, and dried to give 0.249 g of 4-(1H-indol-4-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 260C (decomposed); mass spectrum (EI, m/e): M 344.1282.
To a stirred solution of 80 mg (0.278 MMOL) of 5-acetyl-2-ethyl-4-nitro-6- phenylpyridazin-3 (2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997,40, 1417) in 4 ml of ethanol, 55 mg (0.417 MMOL) of <strong>[5192-23-4]4-aminoindole</strong> was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (83 mg, 79.8 % yield).
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 80℃; for 6h;
4,6-Dichloropyrimidine (1.01 g, 6.6 mmol), <strong>[5192-23-4]4-aminoindole</strong> (900 mg, 6.6 mmol) and N,N-diisopropylethylamine (3.14 ml, 18 mmol) were dissolved in N,N-dimethylformamide (20 ml), and the reaction mixture was stirred at 80C for 6 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; and a small amount of methanol was added to the residue to crystallize; and the crystals were filtered off, washed with methanol and ethyl acetate, and dried under aeration to yield the title compound (599 mg, 2.5 mmol, 37%) as pale brown crystals. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 6.49 (1H, brs), 6.75 (1H, brs), 7.10 (1H, m), 7.25 (1H, d, J=8.0 Hz), 7.33-7.40 (2H, m), 8.42 (1H, s), 9.71 (1H, brs), 11.24 (1H, brs).
2-(2-adamantyl)-N-(1H-indol-4-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 60℃; for 2h;
Example 2 2-(2-ADAMANTYL)-N-LH-INDOL-4-YLACETAMIDE To a solution of <strong>[5192-23-4]1H-<strong>[5192-23-4]indol-4-amine</strong></strong> (20 mg) in DIMETHYLFORMAMIDE (5 mL) were added 1- (3- DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE hydrochloride (29 mg), NN-DIMETHYLPYRIDIN-4- amine (18.5 mg) and 2-adamantylacetic acid (29 mg) with continuous stirring. The mixture was heated to 60C for 2 hours under nitrogen. The reaction was subsequently cooled to room temperature and then partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was further extracted with ethyl acetate (2 x 20 mL) and the combined organics were washed with aqueous potassium hydrogen sulphate (2 x 10 mL, 2 M), saturated aqueous sodium bicarbonate (2 X 10 ML) and brine (20 mL). The organics were then dried, filtered and evaporated under vacuum to give the title compound as a white solid (23 mg). 1H NMR (300 MHz, CDC13) 8 7.77-7. 75 (1H, m), 7.22-7. 14 (3H, m), 6.47 (1H, d), 2.60 (2H, d), 2.40 (1H, bt), 1.96-1. 86 (4H, m), 1.76 (2H, s), 1.53 (6H, s). MS: APCI (+ve) 309 (M+H+) MP: 206-208C
With sodium hydroxide; N-ethyl-N,N-diisopropylamine; In chlorobenzene;
Method A A mixture of 500 mg (3.78 mmole) 1H-indol-4-yl-amine, 993 mg (3.78 mmole) N-benzyl-bis(2-chloroethyl)amine hydrochloride, and 1.32 mL (7.6 mmole) diisopropylethylamine in 10 mL chlorobenzene was heated at 130 C. for 24 hours. Another 0.66 mL (3.8 mmole) diisopropylethylamine was added and the mixture was heated at 130 C. for an additional 5 hours. The mixture was partitioned between 25 mL ethyl acetate and 10 mL 5% sodium hydroxide. The organic phase was extracted with 10 mL 3 N hydrochloric acid. The aqueous phase was washed with 15 mL ethyl ether, then made basic with 50% sodium hydroxide. The product was extracted with 25 mL dichloromethane, the organic phase was washed with 10 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. 4-(4-benzyl-piperazin-1-yl)-1H-indole (274 mg) was isolated as the hydrochloride salt from ethyl ether.
A. 4-Aminoindole. Iron powder (1.20 g, 21.58 mmol) and acetic acid (2.47 mL, 43.19 mmol) are added to a solution of 4-nitroindole (1.0 g, 6.17 mmol) in ethanol (20 mL). The resulting suspension is heated to reflux for 14 hours. The ethanol is removed by rotary evaporation and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered, and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 1% methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.815 g of 4-aminoindole as an orange solid (82% yield).
With hydrogenchloride; potassium carbonate; In butan-1-ol;
EXAMPLE 9 1-Azepan-1-yl-4-[4-(1H-indol-4-yl)piperazin-1-yl]-2-phenylbutan-1-one A suspension of 4-aminoindole (2.30 g, 0.017 moles), bischloroethylamine hydrochloride (3.49 g, 0.02 moles) and potassium carbonate (5.41 g, 0.02 moles) in butanol (50 ml) was heated at reflux under argon for 7 h. Further bischloroethylamine hydrochloride (0.70 g, 0.04 moles) and potassium carbonate (1.1 g 0.04 moles) was added, then the suspension was heated at reflux for 18 h. The solvent was evaporated in vacuo to give a brown gummy residue which was taken up into dilute hydrochloric acid (200 ml), washed with ethyl acetate (2*100 ml), made basic with potassium carbonate, extracted into dichloromethane (3*50 ml), dried (MgSO4) then evaporated in vacuo to give a white solid which was triturated with ethyl acetate and dried to give 4-(1-piperazinyl)indole (0.78 g, 0.0038 moles) as white crystals.
4-(1H-indol-4-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; pyridine hydrochloride; sodium carbonate; In water;
EXAMPLE 136 4-(1H-Indol-4-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.132 g of 4-aminoindole, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust pH to 7. The product was collected, washed with water, and dried to give 0.249 g of 4-(1H-indol-4-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 260 C. (decomposed); mass spectrum (EI, m/e): M 344.1282.
4-(1H-indol-4-ylamino)-2-phenylthieno[2,3-b]pyridine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,2-dimethoxyethane; at 120℃; for 3h;
EXAMPLE 5 Preparation of 4-(1H-indol-4-ylamino)-2-phenylthieno[2,3-b]pyridine-5-carbonitrile 115 A mixture of 4-chloro-2-phenylthieno[2,3-b]pyridine-5-carbonitrile 20 (150 mg, 0.55 mmol), <strong>[5192-23-4]4-aminoindole</strong> (123 mg, 0.93 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (92 mg, 0.23 mmol), tris(dibenzylidineacetone)dipalladium (71 mg, 0.078 mmol) and potassium phosphate (245 mg, 1.15 mmol) in 4 mL of DME was heated at 120 C. for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluding with a gradient of 2 to 5% methanol in dichloromethane. Trituration with methanol and dichloromethane provided 35 mg of 4-(1H-indol-4-ylamino)-2-phenylthieno[2,3-b]pyridine-5-carbonitrile 115 as a tan solid, mp>245 C., MS 367.1 (M+H)+.
With triethylamine; In dichloromethane; at 0℃; for 13h;
[00354] To dichloromethane (20 mL) were added <strong>[5192-23-4]4-aminoindole</strong> (2.0 g, 15.1 mmol) and triethylamine (6.0 mL, 43 mmol) at 0 C, then Boc2O (4.5 mL, 20 mmol) was added dropwise. The mixuture was sitirred for 13 hours, then concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a gray solid (998 mg, 28.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 233.2 [M+Hfb; and ?HNIVIR (600 MHz, DMSO-d6) (ppm): 11.01 (s, 1H), 8.95 (s, 1H), 7.34 (d, J= 7.5 Hz, 1H), 7.21 (t, J= 2.8 Hz, 1H), 7.07 (d, J 8.1 Hz, 1H), 6.97 (t, J= 7.9 Hz, 1H), 6.73 (t, J= 2.1 Hz, 1H), 1.50 (s, 9H).
Indole-1,4-diamine, Obtainable from the Following Synthesis Strategy Condensation of 2,6-dinitrotoluene 1 with N,N-dimethylformamide dimethylacetal (DMF-DMA) in the presence of pyrrolidine (Org. Syn. Coll. Vol. VII, 1990, 34) gives the enamine 2. Reductive cyclization of 2 with hydrogen over a palladium catalyst or with Raney nickel or hydrazine gives rise to <strong>[5192-23-4]4-aminoindole</strong> 3. Treatment of 3 with di-tert-butyl-dicarbonate provides compound 4. N-Amination of 4 with O-diphenylphosphinylhydroxylamine (Org. Syn. 1986, 64, 96) affords N-aminoindole 5. Treatment of 5 with 4N-HCl in dioxane gives rise to indole-1,4-diamine 6.
8.34 g
In dichloromethane; at 23℃; for 16h;
Di-7-butyl dicarbonate (9.9 g) is added lH-<strong>[5192-23-4]indol-4-amine</strong> (5 g) in dichloromethane (50 mL). The reaction mixture is stirred at 23 C for 16 hours, washed with water, and then brine, dried over MgSC>4 and evaporated to dryness. The residue is purified by chromatography on silica gel to yield tert-butyl (1H- indol-4-yl)carbamate as a gray solid (8.34 g).
With potassium carbonate; In isopropyl alcohol; at 90℃; for 48.0h;
4-aminoindole (2g, 15.2mmol), bis(2-chloroethyl)amine hydrochloride (3.2g, 18.2mmol) and potassium carbonate (4.2g, 30.4mmol) was added to isopropanol (30 mL) after the reaction solution was reacted at 90 °C for 48 hours, and thereto was added dichloromethane (50mL) and methanol (50mL). The reaction mixture was filtered and the filtrate under reduced pressure to spin dry, the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)= 10/1) by to give the title compound as a brown solid (2.78g, 90.8percent).
With sodium carbonate; In isopropyl alcohol;Heating / reflux;
Into a 1000 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1H-indol-4-ylamine (2.8 g, 21.05 mmol, 1.00 equiv) in i-PrOH (800 mL). To this was added bis(2-chloroethyl)amine hydrochloride (4.5 g, 25.21 mmol, 1.20 equiv). To the mixture was added Na2CO3 (8.9 g, 83.96 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This results in 4.3 g (crude) of 4-piperazin-1-yl-1H-indole as a red oil.
Table LL: Examples of amides prepared from 5-(4-Chloro-phenyl)-isoxazole-3-carboxyIic acid; A 20 mL scintillation vial was charged with 5-(4-chloro-phenyl)-isoxazole-3-carboxylic acid in DMA (1.0 eq, 8.93 mmol, 35.78 mg) followed by a solution of HATU in DMA (1.10 eq, <n="136"/>9.83 mmol). This mixture was shaken briefly followed by the addition of triethylamine in a solution of DMA (2.20 eq, 19.65 mmol). The mixture is shaken again briefly at room temperature. A solution of amine monomer in DMA (1.4 eq, 3.0 mL DMA) was then added and the mixture was placed to shake overnight at room temperature. The solvent was then removed and the crude material was purified by HPLC method (n) and the solvents evaporated.
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 110 mg; 0.40 mmol) in DCM was treated with polymer- supported Mukaiyama reagent (1.1 g) followed by 1 H-<strong>[5192-23-4]indol-4-amine</strong> (Aldrich, 58.2 mg; 0.44 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with <n="217"/>petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (120 mg, 77%).1H NMR (400MHz, DMSO-d6) delta 11.33 (1 H, s), 10.39 (1 H, s), 8.72 (1 H, s), 7.85 (1 H, d, J = 7.6 Hz), 7.44-7.40 (2H, m), 7.29 (1 H, d, J = 8.1 Hz), 7.15 (1 H, t, J = 7.9 Hz), 6.54 (1 H, s), 3.52-3.40 (2H, m), 1.93-1.70 (4H, m), 1.73-1.54 (3H, m), 1.52-1.37 (2H, m), 1.28-1.15 (2H, m), 1.13-0.99 (1 H, m), 0.62- 0.51 (2H, m), 0.45-0.39 (2H, m). MS (APCI+): 390. HPLC (Condition C): Rt 4.80 min (HPLC purity 99.1 %).
A cooled (0 0C) solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4- carboxylic acid (Intermediate 21 , 0.23 g; 0.98 mmol) in DCM (5 ml) was <n="208"/>treated with DMF (1 drop of a 10% solution in DCM) followed by (COCI)2 (0.1 ml; 1.15 mmol). After stirring at 0 0C for 30 minutes, the mixture was treated with 1 H-<strong>[5192-23-4]indol-4-amine</strong> (Aldrich, 146 mg; 1.1 mmol) and diisopropylamine (0.5 ml; 2.9 mmol). After stirring overnight, water was added and the layers separated. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of Et2O to give the title compound as an off-white solid. 1H NMR (400MHz, CDCI3) delta 10.40 (1 H, s), 8.62 (1 H, s), 8.28 (1 H, br s), 8.13-8.08 (1 H, m), 7.42 (1 H, s), 7.28-7.19 (3H, m), 6.77-6.70 (1 H, m), 3.71 - 3.35 (4H, br m), 1.77-1.63 (2H, m), 1.16-1.04 (1 H, m), 0.97 (3H, t, J = 7.33 Hz), 0.62-0.51 (2H, m), 0.35-0.29 (2H, m). MS (APCI+): 350. HPLC (Condition D): Rt 4.04 min (HPLC purity 98.6%).
A mixture of <strong>[5192-23-4]4-aminoindole</strong> (5 grams, 37.8 mmol) (obtained from preparation 1), 1- methyl piperidine-4-one (5.5 mL, 45.4 mmol), sodium triacetoxyborohydride (16.02 grams, 75.6 mmol) and acetic acid (2.15 mL, 37.8 mmol) in ethylene dichloride (100 mL) was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography. After completion of reaction (5 hours), the reaction mixture was diluted with ice water (500 mL), basified with 10% aqueous sodium hydroxide solution and extracted the mass with ethyl acetate (2 x 250 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained crude product (11.32 grams) was purified by column chromatography using silica-gel (100 - 200 mesh), the eluent system being ethyl acetate and triethyl amine (99:1) to obtain 7.6 grams of the title product. Melting Range: 128.3 - 131C; LR (Cm"1): 1109, 1373, 1519, 2931, 3417; 1H-NMR (ppm): 1.55 - 1.64 (2H, m), 2.14 - 2.20 (4H, m), 2.32 (3H, s), 2.83 - 2.86 (2H, m), 3.48 (IH, m), 3.82 (IH, bs), 6.28 - 6.30 (IH; d, J = 7.6), 6.43 - 6.44 (IH, t), 6.79 - 6.81 (IH, d, J = 8.08 Hz), 7.03 - 7.09 (2H, m), 8.19 (IH, bs); Mass (m/z): 230.4 (M+H)+.
EXAMPLE 6:PREPARATION OF 4-(I H-I NDOL^-YLAMI NO)-S-IODO-B-METHYL- NICOTINONITRILEA mixture of 4-chloro-5-iodo-6-methylnicotinonitrile (500 mg, 1.80 mmol) and 4- aminoindole (249 mg, 1.89 mmol) in 9 ml. of ethanol was heated at reflux overnight. Additional <strong>[5192-23-4]4-aminoindole</strong> (25 mg, 0.189 mmol) was added and the mixture was heated for an additional 24 h. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, filtered and washed with water to give 630 mg (94%) of 4-(1 H-indol-4-ylamino)-5-iodo-6-methylnicotinonitrile as a grey solid, mp 192-194oC; MS 375.0 (M+H).
4-chloro-5-(3,4-dimethoxybenzyl)nicotinonitrile[ No CAS ]
[ 1160918-28-4 ]
Yield
Reaction Conditions
Operation in experiment
43%
A stirred solution of 4-chloro-5-(3,4-dimethoxybenzyl)nicotinonitrile (144 mg, 0.50 mmol), 4- aminoindole (99 mg, 0.75 mmol), pyridine hydrochloride ( 58 mg, 0.50 mmol), and 1.5 mL of t- amyl alcohol was heated at reflux for 24 h. The cooled mixture was stirred in dilute NaHCO3 and hexane, and the resulting solid was filtered, washed with water, and dried. Chromatography of the residue on silica gel with DCM-EtOAc-MeOH gave 5-(3,4- dimethoxybenzyl)-4-(1H-indol-4-ylamino)nicotinonitrile as an amber solid (82 mg, 43%); Rf (25:25:1 DCM-EtOAc-MeOH) 0.50; MS 385.1 (M+H).
A mixture of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile (135 mg, 0.56 mmol) and 4- aminoindole (105 mg, 0.79 mmol) in 4 mL of ethanol was heated at reflux overnight. The resulting mixture was cooled slightly and filtered, washing with diethyl ether. The solid was stirred with saturated aqueous sodium bicarbonate for 20 min, then the suspension was extracted with ethyl acetate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was collected by filtration washing with diethyl ether to give 45 mg (23%) of 4-(1H-indol-4-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid; MS 337.2 (M+H); HPLC: 98.8% at 215 nm, rt = 9.7 min [a].
EXAMPLE 19. N-(3-(9H-PURGammaN-6-YL)PYRIDGammaN-2-YL)- 1H-LNDOL-4-AMGammaNE [00165] 6-(2-Fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (115.0 mg, 0.3842 mmol) and lH-<strong>[5192-23-4]indol-4-amine</strong> (Aldrich, St. Louis, MO, 70.7 mg, 0.535 mmol) were suspended in EtOH (1.8 mL) and aqueous hydrochoric acid (5.0 M, 0.090 ml, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100 0C), and the reaction was stirred for 3 hours. Then, the reaction was cooled to room temperature and diluted with DCM, 2 N ammonia in MeOH, EtOH, and MeOH and concentrated. The residue was treated with MeOH and filtered. Neither the filtrate nor the solid contained pure material, so they were combined, concentrated, treated with DMF, and filtered. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN / water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and filtered through a silica gel plug (about 1 inch, 50: 1 DCM / 2 N ammonia in MeOH to 20: 1 DCM / 2 N ammonia in MeOH to 5: 1 DCM / 2 N ammonia in MeOH) to afford N-(3-(9H-purin-6-yl)pyridin-2-yl)-lH-<strong>[5192-23-4]indol-4-amine</strong> (6.9 mg, 5% yield). MS (ESI pos. ion) m/z: 328, (M+H)+. 1H NMR (d6-DMSO, 400 MHz) delta 12.90 (s, IH), 11.16 (s, IH), 9.87 (d, J = 7.82 Hz, IH), 9.24 (s, IH), 8.73 (s, IH), 8.43 (dd, J = 4.69 Hz, 1.96 Hz, IH), 8.28 (dd, J = 4.6 Hz, 3.81 Hz, IH), 7.38 - 7.35 (m, IH), 7.09 (s, IH), 7.08 - 7.06 (m, IH), 7.04 (dd, J = 7.82 Hz, 4.69 Hz, IH), 6.79 - 6.76 (m, IH).
EXAMPLE 71. N-(5-((4-METHOXYBENZYLOXY)METHYL)-3-(2-METHYL-9H-PURIN- 6-YL)PYRIDIN-2-YL)- 1H-INDOL-4-AMINE[00250] 6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (171.2 mg, 0.3694 mmol) and <strong>[5192-23-4]4-aminoindole</strong> (Aldrich, St. Louis, MO, 69.2 mg, 0.524 mmol) were suspended in EtOH (2.0 mL) and hydrochloric acid (J.T. Baker, Phillipsburg, NJ, 5 N, 0.090 mL, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100 0C) and stirred for about 105 minutes. Then, the reaction was cooled to room temperature and diluted with MeOH and 2 N ammonia in MeOH. The reaction was concentrated and treated with DMF and DCM and filtered. The filtrate was filtered again, and the solid was again washed with DCM. This filtrate was concentrated and purified by HPLC (10% to 100% MeCN / water with 0.1% TFA over 30 minutes with a total flow rate of 100 ml/min). The fractions with product were collected, concentrated, and filtered through a silica gel filter (about 1 inch, 10: 1 DCM / 2 N ammonia in MeOH) to give N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9H-purin-6- yl)pyridin-2-yl)-lH-<strong>[5192-23-4]indol-4-amine</strong> (13.1 mg, 7% yield). MS (ESI pos. ion) m/z 492 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) delta 12.49 (s, IH), 11.17 (s, IH), 9.84 (s, IH), 8.64 (s, IH), 8.33 (s, IH), 8.04 (d, J = 6.85 Hz, IH), 7.38 - 7.32 (m, 3H), 7.12 - 7.04 (m, 2H), 6.93 (d, J = 8.80 Hz, 2H), 6.72 (s, IH), 4.53 (s, 2H), 4.51 (s, 2H), 3.75 (s, 3H), 2.92 (s, 3H).
With hydrogenchloride; In 1,4-dioxane; water; at 100℃;
STEP 2. N-(3-(4-AMINO-6-METHYL-1 ,3,5-TRIAZGammaN-2-YL)PYRIDIN-2-YL)-1H-GammaNDOL-4-AMGammaNE[00171 ] 2 N HCl(aq) (0.42 mL, 833 mumol) was added to a stirred mixture of 4-(2- fluoropyridin-3-yl)-6-methyl-l,3,5-triazin-2-amine (171 mg, 833 mumol) and lH-<strong>[5192-23-4]indol-4-amine</strong> (132 mg, 1000 mumol) in 1,4-dioxane (4.00 mL, 46762 mumol) and the brown mixture was heated at 100 0C overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with Sitheta2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) followed by washing the eluent concentrates with EtOAc to give N-(3-(4-amino-6-methyl- l,3,5-triazin-2-yl)pyridin-2-yl)-lH-<strong>[5192-23-4]indol-4-amine</strong> (58 mg, 22%) as a yellow solid. LCMS (API-ES) m/z 318 (M+H)+; 1H NMR (400 MHz, d6-DMSO) delta ppm 12.00 (s, 1 H) 11.15 (br. s., 1 H) 8.77 (dd, J=7.78, 1.76 Hz, 1 H) 8.38 (dd, J=4.52, 1.51 Hz, 1 H) 8.09 (d, J=6.02 Hz, 1 H) 7.53 - 7.81 (m, 2 H) 7.35 (t, J=2.76 Hz, 1 H) 6.99 - 7.19 (m, 2 H) 6.90 (dd, J=7.78, 4.77 Hz, 1 H) 6.66 (br. s., 1 H) 2.55 (s, 3 H).
EXAMPLE 56. N-(3-(2-METHYL-9H-PURGammaN-6-YL)PYRIDIN-2-YL)- 1H-LNDOL-4-AMLNE [00233] 6-(2-Fluoropyridin-3 -yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (270 mg, 0.862 mmol) and 4 aminoindole (159.3 mg, 1.205 mmol) were suspended in EtOH (5.0 mL) and then aqueous hydrochloric acid, (5 N, 0.21 mL, 1.1 mmol) was added. The reaction flask was fit with a reflux condenser, placed in a preheated oil bath (100 0C), and stirred for 3 hours. Then, the reaction was cooled to room temperature, diluted with 2 N ammonia in MeOH (4.0 mL), and allowed to stand overnight. Then, the material was concentrated, treated with DMF and filtered. The solid was washed with DCM, and the filtrate was concentrated and purified on prep HPLC (10% to 100% MeCN / water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and filtered through a silica gel plug (about 1 inch) with 10: 1 DCM / 2 N ammonia in MeOH to give N-(3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-lH-<strong>[5192-23-4]indol-4-amine</strong> (13.7 mg, 5%). MS (ESI pos. ion) m/z 342 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) delta 13.60 (s, IH), 12.44 (s, IH), 11.16 (s, IH), 9.77 (d, J = 7.04 Hz, IH), 8.61 (s, IH), 8.37 (dd, J = 4.69 Hz, 1.76 Hz, IH), 8.05 (dd, J = 6.85 Hz, 1.56 Hz, IH), 7.37 (t, J = 2.64 Hz, IH), 7.11 - 7.04 (m, 2H), 7.01 (dd, J = 7.82 Hz, 4.69 Hz, IH), 6.72 (s, IH), 2.92 (s, 3H).
1
A solution of 5-chloro-2-methoxyphenyl isocyanate (Int-4, 5.5 g, 30 mmol) in DCM (20 mL) was added dropwise to the 4-amino- lH-indole in DCM (30 mL) from Step A, and the resulting mixture was stirred overnight, then filtered to give the crude product l-(5-chloro-2-methoxyphenyl)-3-(lH-indol-4-yl)urea (6.6 g, 70%), which was used directly in the next step without purification.
The appropriate amine (II) was dissolved in z'so-propanol (0.2 g/mL). 1.1 Eq of pyrimidine (III) and 1.2 eq of N,N-diisopropylethylamine (DIPEA) were added and the mixture was stirred at 50-120 C for 1-3 h. The reaction mixture was dissolved in EtOAc/MeOH 5: 1 and washed with saturated aqueous NaHC03, water and brine. The solvent was removed in vacuo and the residue was purified by columnchromatography on silica gel with heptane/EtOAc or EtOAc/MeOH as eluent to give the major intermediate (IV) and the minor intermediate (IV"). The intermediate (IV or IV") was dissolved in ethylene glycol (0.2 g/mL) and 1.1 eq of amine (V) was added. The mixture was then stirred at 100-150 C for 1-3 h. The reaction mixture was dissolved in EtOAc/MeOH 5: 1 and washed with saturated aqueous NaHC03, water and brine. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with heptane/EtOAc or EtOAc/MeOH/TEA as eluent to give the compound of formula I. This procedure is exemplified in Scheme 1.
1-(5-chloro-2-methoxyphenyl)-3-(1H-indol-4-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane
VII
A solution of 5-chloro-2-methoxyphenyl isocyanate (Int-4, 5.5 g, 30 mmol) in DCM (20 mL) was added dropwise to the 4-amino-lH-indole in DCM (30 mL), and the resulting mixture was stirred overnight, then filtered to give the crude product l-(5-chloro-2- methoxyphenyl)-3-(lH-indol-4-yl)urea (lnt-29, 6.6 g, 70%>), which was used directly in the next step without purification.
With triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: Dry triethylamine (0.54 mL, 3.9 mmol) and p-nitrophenylchlorocarbonate (0.786 g, 3.9 mmol) were added to a stirred solution of <strong>[5192-23-4]4-aminoindole</strong> 22 (or 5-aminoindole 23) (0.396 g, 3.0 mmol) in dry CH2Cl2 (30 mL) at room temperature and in argon atmosphere. After 2 h a TLC control (CH2Cl2/EtOAc 99:1) showed the disappearance of the aminoindole and the reaction was quenched by adding water (15 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo affording compound 24 (or 25) as a yellow solid.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In acetonitrile; at 80℃; for 0.5h;Microwave;
N-(lH-indol-4-yl)-2-(3-methoxyphenyl)acetamide (26d) A mixture of 4-Aminoindole (0.150 g, 1.135 mmol), 3-methoxyphenyl acetic acid (260 g, 1.564 mmol), EDC hydrochloride (0.440 g, 2.26 mmol), 4-dimethylaminopyridine (0.050 g, 0.410 mmol) in acetonitrile (4mL) was heated in the Biotage Microwave for 30min at 80C. The solution was then washed with lOmL of IN HCl, extracted with ethyl acetate, and then washed with lOmL of a saturated NaHC03 solution. The organic phase was dried over Na2S04 and filtered. The solution was concentrated under reduced pressure to afford 26d as a dark brown solid (0.312 g, 1.114 mmol, 99%>). The crude material was used in the next step without purification. 1H NMR (400 MHz, CDC13) delta 8.22 (s, 1H), 7.79 (t, J = 4.4 Hz, 1H), 7.47 - 7.29 (m, 1H), 7.17 (d, J = 4.5 Hz, 2H), 7.11 (t, J = 2.9 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.94-6.92 (m, 1H), 5.99 (t, J= 2.2 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 2H).
N-{(S)-1-[(1H-indol-7-ylamino)methyl]propyl}-2,4,6-trimethylbenzenesulfonamide trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With beta?cyclodextrin; In methanol; at 65℃; for 24h;Microwave irradiation;
A mixture of 120 mg (0.47 mmol) of (S)-2-ethyl-l-(2,4,6-trimethylbenzenesulfonyl)- aziridine, 62.6 mg (0.47 mmol) of <strong>[5192-23-4]4-aminoindole</strong>, and 177.4 mg (0.16 mmol) of beta- cyclodextrin hydrate in 1.5 mL of methanol in a sealed tube was warmed at 65C in a microwave. After 24 hours, the mixture was concentrated in vacuo and purified first by chromatography on silica gel eluting with EtOAc-hexanes (0-40% gradient), and second by reversed phase HPLC to afford the title compound as the trifluoroacetic acid salt. LCMS M+ = 386.24.
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere;
General procedure: A solution of 20 (0.1mmol) and the amino (0.12mmol), in dichloromethane (3.0mL) under argon protect was stirred at room temperature for 30min, then NaBH(OAc)3 (0.15mmol)was added and stirred at the same temperature until TLC showed no traces of the starting aldehyde 19. The solvent was removed under reduced pressure, the residue was dispersed in EtOAc (10mL) and the solution was washed with H2O (3×15mL), dried over MgSO4 and concentrated to give a target analog.
In N,N-dimethyl-formamide; at 120℃; for 2h;Green chemistry;
General procedure: The solution of isatin (380 mumol), <strong>[5192-23-4]1H-indole-4-amine</strong> (380 mumol, 1.0 equiv), and Meldrum's acid (380 mumol, 1.0 equiv) in DMF (4.0 ml) was heated to 120 C for 2 h. The reaction mixture was cooled down to room temperature and concentrated to remove the solvents. The crude residue was subjected to reverse phase preparative HPLC to provide pure products.
In N,N-dimethyl-formamide; at 120℃; for 2h;Green chemistry;
General procedure: The solution of isatin (380 mumol), <strong>[5192-23-4]1H-indole-4-amine</strong> (380 mumol, 1.0 equiv), and Meldrum's acid (380 mumol, 1.0 equiv) in DMF (4.0 ml) was heated to 120 C for 2 h. The reaction mixture was cooled down to room temperature and concentrated to remove the solvents. The crude residue was subjected to reverse phase preparative HPLC to provide pure products.
In N,N-dimethyl-formamide; at 120℃; for 2h;Green chemistry;
General procedure: The solution of isatin (380 mumol), <strong>[5192-23-4]1H-indole-4-amine</strong> (380 mumol, 1.0 equiv), and Meldrum's acid (380 mumol, 1.0 equiv) in DMF (4.0 ml) was heated to 120 C for 2 h. The reaction mixture was cooled down to room temperature and concentrated to remove the solvents. The crude residue was subjected to reverse phase preparative HPLC to provide pure products.
In N,N-dimethyl-formamide; at 120℃; for 2h;Green chemistry;
General procedure: The solution of isatin (380 mumol), <strong>[5192-23-4]1H-indole-4-amine</strong> (380 mumol, 1.0 equiv), and Meldrum's acid (380 mumol, 1.0 equiv) in DMF (4.0 ml) was heated to 120 C for 2 h. The reaction mixture was cooled down to room temperature and concentrated to remove the solvents. The crude residue was subjected to reverse phase preparative HPLC to provide pure products.
In N,N-dimethyl-formamide; at 120℃; for 2h;Green chemistry;
General procedure: The solution of isatin (380 mumol), <strong>[5192-23-4]1H-indole-4-amine</strong> (380 mumol, 1.0 equiv), and Meldrum's acid (380 mumol, 1.0 equiv) in DMF (4.0 ml) was heated to 120 C for 2 h. The reaction mixture was cooled down to room temperature and concentrated to remove the solvents. The crude residue was subjected to reverse phase preparative HPLC to provide pure products.
The chloropyrimidine and amino indole (both commercially available) were combined in DMF and heated at 70C overnight. LCMS showed a major peak (89% by ELSD 1.38min) for product mass ion (ES+343). DMF removed in vacuo to give an orange solid. Slurried in hot TBME/water and cooled to room temperature. Filtered off to give the product as a grey solid. LCMS: m/z 343 MH+.
With hydrogenchloride; In water; butan-1-ol; for 2h;Inert atmosphere; Reflux;
General procedure: To a 100-mL round-bottomed flask, flushed with nitrogen, were added 20 (127 mg, 0.7 mmol), the appropriate aniline (1.05 mmol), BuOH (20 mL), and 2-3 drops of conc. HCl. The reaction mixture was heated at reflux with stirring for 2 h until the starting material 20 disappeared (TLC). The reaction solution was allowed to cool to room temperature; the solvent was removed under reduced pressure to dryness, and the residue was purified by column chromatography on silica gel with EtOAc/Hexane (1:10) as the eluent. Fractions containing the product (TLC) were combined and evaporated to afford target compounds.
With potassium carbonate; In isopropyl alcohol; at 90℃; for 48.0h;
[00190] To 30 mL of i-propanol were added 4-aminoindole (2 g, 15.2 mmol), bis(2-chloroethyl)amine hydrochloride (3.2 g, 18.2 mmol) and potassium carbonate (4.2 g, 30.4 mmol). The mixture was stirred at 90 °C for 48 hours. To the reaction mixture were added dichlormethane (50 mL) and methanol (50 mL), and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography eluted with DCMIMeOH (v/v = 10/1) to give the title compound as a brown solid (2.78 g, 90.8percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 202.1 [M+H] and ?H NMR (600 MHz, DMSO-d6) (ppm): 11.17 (s, 1H), 7.29-7.25 (m, 1H), 7.09 (d, J= 8.1 Hz, 1H), 6.98 (t, J= 7.8 Hz, 1H), 6.49 (d, J= 7.5 Hz, 1H), 6.46 (s, 1H), 3.32-3.28 (m, 8H).
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃;
11. To a solution of 3-(2-chlorophenyl)-2-methylbutanal, Compound 11, (500 mg, 2.55 mmol) and Compound 12 (0.336 g, 2.55 mmol) in MeOH (5 mL) were added NaCNBH3 (160 mg, 2.55 mmol). HOAc (290 mg, 2.55 mmol) was added and the mixture was stirred at RT for overnight. The reaction mixture was concentrated and the residue purified by silica gel column and Prep-HPLC to give 24.6 mg of FLS-116. 1HNMR (CDC13, 300 MHz) delta: 1.0-1.2 (m, 3 H), 1.3-1.5 (m, 3H), 2.2 (m, 1H), 3.0-3.5 (m, 3H), 6.2 (m, 1H), 6.4 (s, 1H), 6.9 (t, 1 H), 7.0-7.5 (m, 6H). LC-MS: m/z=313.2 (M+l) +.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
4. To a solution of Compound 4 (500 mg, 2.57 mmol) in DCM (10 mL) were added 4- aminoindole (340 mg, 2.57 mmol), EDCI (1 g, 5.14 mmol) and DMAP (80 mg). The reaction mixture was stirred at RT overnight. TLC indicated reaction completion. The residue was treated with water and extracted with DCM. The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a crude oil. The crude product was purified by silica gel chromatography to afford Example 43 (200 mg, 25.2%). 1HNMR (CDCI3, 300 MHz) delta: 1.3-1.4 (d, 3 H), 2.6-3.0 (m, 2 H), 3.7-3.9 (m, 4 H), 6.8- 7.0 (m, 2 H), 7.2-7.5 (m, 5 H), 7.6-7.8 (m, 1H). 8.2-8.3 (m, 1 H). LC-MS: m/z= 309.3 (M+l) +.
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzoic acid[ No CAS ]
4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indol-4-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.78%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
[00170]A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5ml) was stirred for a while, to which was then added <strong>[5192-23-4]4-aminoindole</strong> (0.17 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was purified by flash column over silica gel (ethyl acetate: n-hexane = 1:1, Rf = 0.45) to afford 36 (0.30 g, 74.78 %) as a red solid. 1H-NMR (300 MHz, DMSO-d6): ^5.04 (s, 2H), 6.56 (s, 1H), 7.04 (t, J= 7.8 Hz, 1H), 7.20 (d, J= 1.5 Hz, 1H), 7.27 (t, J= 3.0 Hz, 1H), 7.35 (d, J= 7.2 Hz, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.72-7.77 (m, 1H), 7.80-7.85 (m, 1H), 7.93-7.99 (m, 4H), 8.11 (br, 1H), 9.99 (s, 1H), 11.10 (s, 1H).
74.78%
A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5ml) was stirred for a while, to which was then added 4- aminoindole (0.17 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was purified by flash column over silica gel (ethyl acetate: n-hexane = 1:1, Rf = 0.45) to afford 36 (0.30 g, 74.78 %) as a red solid.1H-NMR (300 MHz, DMSO-d6): delta 5.04 (s, 2H), 6.56 (s, 1H), 7.04 (t, J= 7.8 Hz, 1H), 7.20 (d, J= 1.5 Hz, 1H), 7.27 (t, J= 3.0 Hz, 1H), 7.35 (d, J= 7.2 Hz, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.72-7.77 (m, 1H), 7.80-7.85 (m, 1H), 7.93- 7.99 (m, 4H), 8.11 (br, 1H), 9.99 (s, 1H), 11.10 (s, 1H).
74.78%
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.
4-bromo-N-(1H-indol-4-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With pyridine; In acetonitrile; at 20℃; for 2h;Inert atmosphere;
General procedure: To a mixture of amine (1 mmol), pyridine (1 mL) and acetonitrile (0.25 mL) was added 4-bromobenzenesulfonyl chloride (1.1 mmol) portion wise,and then was allowed to stir at room temperature for 2 h. The reaction was quenched with water and was acidified with dropwise addition of 3 N HCl. The reaction mixture was then extracted with EtOAc (20 mL 3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc:n-hexane 3: 7).
1-(methyldiphenylsilyl)-1H-indol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With dodecacarbonyl-triangulo-triruthenium; In toluene; at 120℃; for 18h;Schlenk technique; Inert atmosphere;
General procedure: Condition B: A mixture of 33 indole (1) (0.2mmol, 1equiv), hydrosilanes (2) (0.3mmol, 1.5 equiv), 16 Ru3(CO)12 (3.8mg, 0.006mmol, 3.0mol %), were weighted in a Schlenk tube equipped with a stir bar. Dry 11 toluene (2.0mL) was added and the mixture was stirred at 120C for 12-24h under Ar atmosphere. Afterwards, it was diluted with CH2Cl2 and transferred to a 50mL round bottom flask. Silica was added to the flask and solvents were evaporated under reduced pressure. Flash column chromatography on silica gel with EtOAc:petroleum ether=1:100 as eluent afforded the 47 N-silylated indole.
ethyl 1,6-dihydropyrrolo[2,3-e]indole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 18h;Schlenk technique; Molecular sieve;
Take a 25mL Schlenk reaction tube, add <strong>[5192-23-4]1H-indole-4-amine</strong> 53mg, palladium acetate 9mg and molecular sieve 80mg,93 mg of ethyl 2-oxopropionate, 96 mg of acetic acid and 2 mL of dimethyl sulfoxide were injected, followed by a 200 mL oxygen balloon, and stirred at 70 C for 18 hours.After the reaction was completed, 15 mL of ethyl acetate was added to dilute the reaction solution, and the filtrate was washed twice with 10 mL of saline.The organic phase was separated, and the aqueous phase was extracted with ethyl acetate.Column chromatography was carried out to obtain the objective product pure product 14 mg, yield 15%.
4β-NH-(4''-aminoindole)-4-desoxy-podophyllotoxin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
General procedure: Analytical grade chemical reagents were used as purchasedfrom commercial sources (Aladdin, J&K and Sigma-Aldrich).Podophyllotoxin (1 mM, 1 equiv) and KI (1.5 mM, 1.5 equiv) weredissolved in CH3CN (10 mL) at 0 C for 5 min. And then BF3OEt2(3.5 mM, 3.5 equiv) was slowly added dropwise under magneticstirring. The mixture was stirred at room temperature for 1 h andresulted in a brown solution. The reaction mixture was concentratedin vacuo to afford 4b-iodopodophyllotoxin (yield, 85%),respectively, which was unstable intermediates for the next step ofthe synthesis leading to the final products. The indole intermediates(1 mM, 1 equiv) and amino substituted precursors(1 mM, 1 equiv) were dissolved in THF. BaCO3 (5 mM, 5 equiv) wasadded to the mixture as an acid-binding agent. Triethylamine (TEA)was slowly added dropwise under magnetic stirring. The sampleswere filtered with a 0.45 mm micropore filter and transferred to asampling vial for HPLC analysis. HPLC analysis was carried out on aWaters 600 Series HPLC system, equipped with 2487 UV detector.An Akasil C18 column (5 mm, 4.6mm 150 mm) was used. Mobilephase was methanol/water (40:60 v/v) and the pH was adjusted to3.00 with formic acid. The HPLC oven temperature was maintainedat 45 C, and the detection wavelength was 230 nm or 219 nm. Theflow rate was 0.8 mL/min. All 1H and 13C NMR spectra were
With sulfur; copper(l) iodide; In acetonitrile; at 100℃; for 12h;
26.4 mg (0.2 mmol) of <strong>[5192-23-4]4-aminoindole</strong>, 1.9 mg (0.01 mmol) of iodideCopper, 59.2 mg (0.3 mmol) of sodium difluorobromoacetate (1.5 eq.), 51.2 mg (0.2 mmol) of S8 (1.0 eq.), 84.9 mg (0.004 mmol) of potassium phosphate (2% eq.). The reaction was carried out at 100 C for 12 hours, and after the reaction was completed, it was cooled, and the filtrate was filtered to obtain a filtrate. The filtrate was evaporated to give a residue, and the residue was applied to silica gel column eluting with eluent petroleum ether. The effluent was collected, detected by TLC, and the product-containing effluent was combined, and the solvent was distilled off on a rotary evaporator, and dried in vacuo to give 4-isothiocyano-1H-indole 24.7 mg (yield: 71%).
4-chloro-2-(4-fluorophenyl)-5-isopropylpyrimidine[ No CAS ]
N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-indol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.6 g
With sodium hexamethyldisilazane; In tetrahydrofuran; N,N-dimethyl-formamide; at -5℃; for 5h;Inert atmosphere;
To the solution of compound <strong>[5192-23-4]1H-<strong>[5192-23-4]indol-4-amine</strong></strong> (1.04 g, 7.91 mmol, 1.1 eq) in 5 ml DMF cooled at -5 C were added 4-chloro-2-(4-fluorophenyl)-5-isopropylpyrimidine (1.8 g, 7.19 mmol) followed by slow drop wise addition of NaHMDS solution (22.7 ml, 43.14 mmol, 35 % in THF) in two lots, under N2 atmosphere. Reaction mass was continued at same temperature for 5 h. After completion of reaction (TLC monitoring), reaction mass was poured in 500 ml of ice cooled water. Resulting solid product was filtered out, which was further purified by flash column chromatography to give 0.6 g of N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-<strong>[5192-23-4]1H-<strong>[5192-23-4]indol-4-amine</strong></strong> as pale pink solid. LCMS (M+1): 347.3
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
A solution of <strong>[5192-23-4]4-aminoindole</strong> (132 mg, 1 mmol) in DCM (5 mL) and DMF (5 mL) was cooled to 0 oC. To the solution was added acryloyl chloride (109 mg, 1.2 mmol) followed by triethylamine (121 mg, 1.2 mmol). The solution was allowed to warm to room temperature after 26 min and stirred overnight. The solution was washed two times with brine and dried with magnesium sulfate. The crude product was purified via basic alumina chromatography (60% to 75% ethyl acetate in hexanes) to afford the product in 30% yield as a white-grey solid (56 mg).1H NMR (600MHz, MeOD): d 7.51 (d, J = 7.6 Hz, 1H), 7.24-7.22 (m, 2H), 7.08 (t, J = 7.6 Hz, 1H), 6.64 (dd, J = 10.1, 16.7 Hz, 2H), 6.38 (dd, J = 1.7, 16.9 Hz, 1H), 5.78 (dd, J = 1.7, 10.3 Hz, 1H), 4.6 (s, 1H).13C NMR (150MHz, MeOD): d 165.0, 137.2, 131.1, 129.2, 126.0, 123.8, 121.5, 120.9, 112.2, 108.4, 98.5. HRMS (+ESI): Calculated: 187.0866 (C11H11N2O).Observed: 187.0865.
1-(1H-indol-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 H-<strong>[5192-23-4]indol-4-amine</strong> (50 mg, 0.38 mmol) and triphosgene (37 mg, 0.12 mmol) were dispersed in 5 ml DCM and the solution was cooled to 0C. Triethylamine (105 mI, 0.76 mmol) was added and the mixture was stirred at 0C for 1.5 h. A solution of 3-methyl-4-phenoxy- aniline (83 mg, 0.42 mmol) and triethylamine (105 mI, 0.76 mmol) in 0.5 ml DCM was added. The reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction was quenched with H20. NH4CI (aq. sat.) and DCM were added and the phases were separated. The organic phase was concentrated at reduced pressure. The solid was washed with pentane and dried under vacuum at 35C to yield 118 mg of the crude title compound that was used without further purification in the next step. MS(ESI+) m/z 358 (M+H)+
7-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
4-((1H-indol-4-yl)amino)-7-fluoro-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.1%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 90℃; for 0.5h;Microwave irradiation; Inert atmosphere;
4-Bromo-7-fluoro-1H-indole-2-carboxylic acid ethyl ester (100 mg, 0.35 mmol), Pd2 (dba) 3 (32 mg, 0.035 mmol), X-phos (33 mg, 0.07 mmol), Cs2CO3 ( 342mg, 1.05mmol) and <strong>[5192-23-4]4-aminoindole</strong> (139mg, 1.05mmol) were added to the microwave tube, dissolved in 1,4-dioxane (2mL), filled with argon protection, microwave reaction at 90 C for 0.5h The raw material disappears. Cool to room temperature, add EA (10 mL), wash with saturated brine (10 mL × 3), wash with water (10 mL × 2), and column chromatography (P / E = 10: 1) to obtain 85 mg of a pale yellow solid with a yield of 72.1% Melting point: 237-238 C.
72.1%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃;Inert atmosphere; Microwave irradiation;
General procedure: Ethyl 4-bromo-1H-indole-2-carboxylate (1 eq), Pd2(dba)3 (0.1 eq), X-phos(0.2 eq), Cs2CO3 (3 eq) and aryl amine (3 eq) was added to a microwave tube,dissolved in 1,4-dioxane, and filled with argon gas. The microwave reaction wascarried out at 100 C for 0.5-1.5 h, and the starting material disappeared. The mixturewas cooled to room temperature and concentrated. Ethyl acetate was added todissolve the residue, and the mixture was washed with saturated brine and water, driedover anhydrous Na2SO4, and concentrated in vacuo. The crude product was purifiedby column chromatography to afford the target compound. Compounds 8m-8o, 8s,8a-3 ~ 8a-5, 8a-13, 8a-15 ~ 8a-17, 8o-1 ~ 8o-24 were prepared with method 3.
In dichloromethane at 20℃; for 12h; Inert atmosphere;
General Preparation of Bi-substituted Ureas
General procedure: The corresponding isocyanate (0.6 mmol) was added dropwise to a stirred solution of the aryl amine (0.5 mmol) in dichloromethane (15 mL) [38-39] . The reaction mixture was stirred under a dried nitrogen atmo- sphere overnight at ambient temperature. The resulting precipitate was filtered, washed with cold ether, and purified by recrystalliza- tion from ethanol and water.
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