* 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.
Stage #1: at 0℃; for 1 h; Inert atmosphere Stage #2: With methanol In diethyl ether at -70 - 0℃;
A three-necked flask equipped with a magnetic stirrer and two addition funnels was charged with indole (10.1 g, 0.086 mol) and 100 mL of diethyl ether. Oxalyl chloride (7.3 mL, 0.086 mol) was added dropwise to the solution at 0 °C under nitrogen in 0.5 h. Yellow precipitate were formed and the reaction mixture was stirred for another 0.5 h. The reaction mixture was cooled to -70 °C by dry-ice, then sodium methylate (25 percent solution in methanol, 37.3 g, 0.173 mol) was added dropwise to the reaction mixture in 1 h. After that the reaction mixture was warmed to 0 °C and 50 mL of water was added. The precipitate were filtered, washed with water several times, and then dried at 60 °C under vacuum. The product of methyl indolyl-3- glyoxylate was obtained as a yellow powder and used without further purification. Yield 90 percent. A three-necked flask equipped with a magnetic stirrer and an addition funnel was charged with 3-indoleacetamide (8.0 g, 0.046 mol), methyl indolyl-3-glyoxylate (10.0 g, 0.049 mol) and 80 mL of tetrahydrofuran. A solution of potassium tert-butoxide (15.2 g, 0.135 mol) in 130 mL of tetrahydrofuran was added dropwise to the reaction mixture at 0 °C under nitrogen in 1.5 h. Then the reaction mixture was warmed to room temperature and stirred for 3 h. A solution of Hydrochloric acid (35 percent in water, 64 mL) was added dropwise to the reaction mixture in 1 h. Then 200 mL of ethyl acetate and 100 mL of water were added and stirred for dissolving. The organic phase was separated, washed with water several times until neutral, and then washed with brine once, dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the solution was concentrated. The product was crystallized by adding a 1:1 (v/v) mixture of ethyl acetate and n-hexane dropwise to the concentrated solution at 50~60 °C. The pure product of 3,4-bisindolylmaleimide was obtained as a red crystal.
86.3%
Stage #1: at 0 - 5℃; for 1 h; Stage #2: at -25℃; for 0.5 h;
To a three-necked flask was added 3.0 g (0.026 mol) of indole,30 mL of anhydrous ether, stirring dissolved, control the temperature 0-5 oC,A solution of 3.4 g (0.026 mol) of oxalyl chloride in anhydrous ethyl ether (5 mL) was slowly added dropwise, followed by incubation for 1 h and then cooled to about -25 ° C,A solution of 16.3 g of sodium methoxide in methanol (17.5percent, 0.052 mol)After dripping for 30 min, the reaction solution was poured into 100 mL of ice water, filtered, washed with water (3 x 10 mL)Dichloromethane (2 x 10 mL),Dried to give 4.5 g of a pale yellow solid 5a in a yield of 86.3percent
86%
Stage #1: at 0℃; for 0.5 h; Stage #2: at -78 - 20℃;
To a solution of 1H—indole (6.00 g, 51.2 mmol, 1.00 equiv) in Et20(60.0 mL, 0.850 M) was added oxalyl chloride (5.27 mL, 61.4 mmol, 1.20equiv) dropwise at 0 °C. The yellow slurry was stirred at 0 °C for 30mm and then cooled to —78 °C. A solution of NaOMe in MeOH (25percent, 23.0mL) was added to this slurry at the same temperature. The reaction mixture was then allowed to warm up to room temperature, and was quenched by addition of water (40.0 ml) . The precipitate was collected by filtration, washed with water and dried to afford the title compoundas a gray solid (8.96 g, 44.0 mmol, 86percent yield).NMR Spectroscopy: 1H NMR (700 MHz, (CD,)2S0, 25 °C, 5): 12.50 (s, 1H),8.44 (d, J = 3.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.55 (d, J 7.7Hz, 1H), 7.25 — 7.33 (m, 2H), 3.89 (s, 3H) . “C NMR (175 MHz, (CD3)2S0,25 °C, 5): 178.7, 164.0, 138.4, 136.7, 125.5, 123.8, 122.9, 121.1,112.8, 112.4, 52.5. The ‘H NMR data were in good agreement with values reported in the literature (Ye, Q. et al. 2015)
Reference：
[1] Chinese Chemical Letters, 2018, vol. 29, # 3, p. 513 - 516
[2] Journal of Materials Chemistry A, 2018, vol. 6, # 39, p. 18794 - 18798
[3] Archiv der Pharmazie, 2013, vol. 346, # 5, p. 349 - 358
[4] Patent: CN104693198, 2017, B, . Location in patent: Paragraph 0035; 0036
[5] Patent: WO2018/132636, 2018, A1, . Location in patent: Page/Page column 41
[6] Journal of Organic Chemistry, 1999, vol. 64, # 7, p. 2465 - 2470
2
[ 67-56-1 ]
[ 1477-49-2 ]
[ 18372-22-0 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: With oxalyl dichloride In dichloromethane at 0 - 20℃; for 20 h; Stage #2: at 0 - 25℃; for 1 h;
Synthesis of 3-indole glyoxylic acid, methyl ester Commercially available 3-indole glyoxylic acid (9.55 g) was suspended in methylene chloride (300 mL), and cooled on ice. Thereafter, to the suspension was added oxalyl chloride (8.8 mL), followed by stirring at 20°C for 20 hrs. The reaction fluid was cooled on ice, and after adding methanol (190 mL) thereto, the reaction fluid was stirred at 25°C for 1 hour. To the reaction fluid were added water and methylene chloride, and thus deposited crystals were filtrated, followed by washing of the crystals with methylene chloride. The crystals were dried under a reduced pressure to obtain 3-indole glyoxylic acid, methyl ester (7.07 g, 69percent).
Reference：
[1] European Journal of Medicinal Chemistry, 1999, vol. 34, # 2, p. 161 - 165
[2] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6053 - 6058
[3] Patent: EP1645286, 2006, A1, . Location in patent: Page/Page column 26
3
[ 22980-09-2 ]
[ 124-41-4 ]
[ 18372-22-0 ]
Yield
Reaction Conditions
Operation in experiment
2.5 g
at -78 - 20℃;
To a solution of indole (2.0 g, 17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL, 17.2 mmol) dropwise at 0 °C. The yellow slurry was stirred at same temperature for 0.5 h and then cooled to -78 °C. A solution of NaOMe in MeOH (25 wt percent, 7.8 mL, 34.1 mmol) was added to this slurry at same temperature. After addition, the reaction mixture was allowed to warm to ambient temperature, and quenched by addition of H2O (10 mL). The precipitate was collected by filtration, washed with H2O and dried to give 12 (2.5 g, 73percent) as a yellow solid: mp 160 °C (dec.); 1H NMR (DMSO-d6) δ 12.42 (s, 1H), 8.45 (d, J = 3.5 Hz, 1H), 8.16 (dd, J = 1.5, 6.0 Hz, 1H), 7.55 (dd, J = 1.5, 6.0 Hz, 1H), 7.32-7.27 (m, 2H), 3.89 (s, 3H).
2.53 g
at -78 - 20℃;
To a stirred solution of indole (2.0 g, 17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL,17.2 mmol) dropwise at 0 °C. After the resultant yellow slurry was stirred at 0 °C for 0.5 h, it was cooled to -78 °C. A solution of NaOMe in MeOH (25 wt percent, 7.8 mL, 34.1 mmol) was added to this slurry at -78 °C. The reaction mixture was allowed to warm to room temperature and quenched by addition of water (10 mL). The solid was collected by filtration, rinsed with water and dried to give 4a (2.53 g, 73percent) as a yellow solid
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6053 - 6058
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 14, p. 2261 - 2267
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 612 - 620
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 245 - 249
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1649 - 1653
[6] Molecules, 2013, vol. 18, # 5, p. 5498 - 5516
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1179 - 1188
[8] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 287 - 292
4
[ 120-72-9 ]
[ 18372-22-0 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium methylate In diethyl ether; water
Preparation 6 Methyl indolyl-3-glyoxylate A solution of indole (2.0 g, 1.70 mmol) in Et2 O (20 mL) was cooled to 0°-5° C. under N2 and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5° C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65° C. and a 25percent wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at <-58° C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93percent) of the titled compound. NMR. MS (FD) m/z=203 (M+, 100percent). Analytical calculated for C11 H9 NO3 C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03.
93%
With sodium methylate In diethyl ether; water
Preparation 6 Methyl indolyl-3-glyoxylate A solution of indole (2.0 g, 1.70 mmol) in Et2O (20 mL) was cooled to 0°-5°C under N2and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5°C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65°C and a 25percent wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at <-58°C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93percent) of the titled compound. NMR. MS (FD) m/z= 203 (M+, 100percent). Analytical calculated for C11H9NO3C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03.
Reference：
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 1171,1176
[2] Patent: US5948907, 1999, A,
[3] Patent: EP825190, 1998, A1,
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1649 - 1653
[5] Organic and Biomolecular Chemistry, 2012, vol. 10, # 46, p. 9158 - 9164,7
[6] Organic and Biomolecular Chemistry, 2012, vol. 10, # 46, p. 9158 - 9164
[7] Organic and Biomolecular Chemistry, 2013, vol. 11, # 7, p. 1149 - 1166
[8] Molecules, 2013, vol. 18, # 5, p. 5498 - 5516
[9] Chemical Communications, 2014, vol. 50, # 10, p. 1231 - 1233
[10] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1179 - 1188
[11] Chemical Biology and Drug Design, 2015, vol. 86, # 4, p. 746 - 752
[12] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 287 - 292
[13] Green Chemistry, 2017, vol. 19, # 13, p. 2952 - 2956
[14] Archiv der Pharmazie, 2018, vol. 351, # 10,
5
[ 1477-49-2 ]
[ 18372-22-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 0 - 20℃;
A suspension of Compound 1a (10.0 g, 0.053 mole) in dichloromethane : methanol (6: 1 ratio; 350 mL) was stirred and cooled in an ice bath while a solution of TMSCHN2 (79 mL, 2.0 M) in hexane was added dropwise over a 1 hr period. The mixture was allowed to warm to rt and was stirred overnight. The resulting light yellow solid was filtered and washed with ether to yield Compound 1B (7.5 g, 70percent). 1H NMR (DMSO-d6) a 12.5 (s, 1H), 8.45 (d, 1H), 8.2 (d, 1H), 7.55 (d, 1H), 7.3 (m, 2H), 3.95 (s, 3H).
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 2, p. 530 - 535
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1725 - 1728
9
[ 120-72-9 ]
[ 79-37-8 ]
[ 18372-22-0 ]
Reference：
[1] Patent: US2004/102467, 2004, A1,
10
[ 67-56-1 ]
[ 22980-09-2 ]
[ 18372-22-0 ]
Reference：
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 1171,1176
[2] Chemical Communications, 2006, # 44, p. 4638 - 4640
[3] Organic and Biomolecular Chemistry, 2012, vol. 10, # 46, p. 9158 - 9164,7
[4] Organic and Biomolecular Chemistry, 2012, vol. 10, # 46, p. 9158 - 9164
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 7, p. 1149 - 1166
[6] Chemical Communications, 2014, vol. 50, # 10, p. 1231 - 1233
[7] Chemical Biology and Drug Design, 2015, vol. 86, # 4, p. 746 - 752
[8] Green Chemistry, 2017, vol. 19, # 13, p. 2952 - 2956
[9] Archiv der Pharmazie, 2018, vol. 351, # 10,
11
[ 120-72-9 ]
[ 67-56-1 ]
[ 527-31-1 ]
[ 18372-22-0 ]
Reference：
[1] Chemical Communications, 2018, vol. 54, # 38, p. 4798 - 4801
12
[ 18372-22-0 ]
[ 125314-13-8 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 22, p. 4127 - 4140
13
[ 879-37-8 ]
[ 18372-22-0 ]
[ 119139-23-0 ]
Yield
Reaction Conditions
Operation in experiment
80.2%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -10 - 20℃; for 3.75 h; Stage #2: With hydrogenchloride In tetrahydrofuran; ethyl acetate
A. Chemical Examples; Example 1; 3,4-Di-(1 H-indol-3-yl)pyrrole-2,5-dione (Compound 1); Potassium tert-butoxide (0.976 g, 8.7 mmol) was added to a stirred suspension of (1 H-indol-3-yl)acetamide (0.5 g, 2.8 mmol) and methyl 3-indolylglyoxylate (0.650, 3.15 mmol) in anhydrous tetrahydrofuran (15 ml), under argon at -10°C. After 15 minutes the resultant dark red solution was allowed to warm to 20°C over 3.5 hours. Concentrated hydrochloric acid (2ml) was added with cooling, and the orange-red precipitate then dissolved in ethyl acetate by stirring overnight. The organic phase was washed with water and brine, dried (magnesium sulphate) and evaporated to give the title compound as red crystals (0.780 g, 80.2percent yield), mp 234°C. 1H-NMR (DMSO-d6, No./ppm) : 11.6 (br s, 1 H), 10.95 (br s, 1 H), 7.68 (s, 1 H), 7.38 (d, 1 H), 6.98 (t, 1 H), 6.8 (d, 1 H), 6.6 (t, 1 H).
75%
With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 4.5 h; Inert atmosphere
A three-necked flask equipped with a magnetic stirrer and two addition funnels was charged with indole (10.1 g, 0.086 mol) and 100 mL of diethyl ether. Oxalyl chloride (7.3 mL, 0.086 mol) was added dropwise to the solution at 0 °C under nitrogen in 0.5 h. Yellow precipitate were formed and the reaction mixture was stirred for another 0.5 h. The reaction mixture was cooled to -70 °C by dry-ice, then sodium methylate (25 percent solution in methanol, 37.3 g, 0.173 mol) was added dropwise to the reaction mixture in 1 h. After that the reaction mixture was warmed to 0 °C and 50 mL of water was added. The precipitate were filtered, washed with water several times, and then dried at 60 °C under vacuum. The product of methyl indolyl-3- glyoxylate was obtained as a yellow powder and used without further purification. Yield 90 percent. A three-necked flask equipped with a magnetic stirrer and an addition funnel was charged with 3-indoleacetamide (8.0 g, 0.046 mol), methyl indolyl-3-glyoxylate (10.0 g, 0.049 mol) and 80 mL of tetrahydrofuran. A solution of potassium tert-butoxide (15.2 g, 0.135 mol) in 130 mL of tetrahydrofuran was added dropwise to the reaction mixture at 0 °C under nitrogen in 1.5 h. Then the reaction mixture was warmed to room temperature and stirred for 3 h. A solution of Hydrochloric acid (35 percent in water, 64 mL) was added dropwise to the reaction mixture in 1 h. Then 200 mL of ethyl acetate and 100 mL of water were added and stirred for dissolving. The organic phase was separated, washed with water several times until neutral, and then washed with brine once, dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the solution was concentrated. The product was crystallized by adding a 1:1 (v/v) mixture of ethyl acetate and n-hexane dropwise to the concentrated solution at 50~60 °C. The pure product of 3,4-bisindolylmaleimide was obtained as a red crystal.
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6053 - 6058
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 2, p. 326 - 331
[3] Patent: WO2005/107465, 2005, A1, . Location in patent: Page/Page column 20
[4] Chinese Chemical Letters, 2018, vol. 29, # 3, p. 513 - 516
[5] Journal of Materials Chemistry A, 2018, vol. 6, # 39, p. 18794 - 18798
[6] Organic Letters, 2007, vol. 9, # 18, p. 3583 - 3586
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3835 - 3839
[8] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3841 - 3846
[9] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 3049 - 3053
[10] Tetrahedron Letters, 2012, vol. 53, # 50, p. 6861 - 6864
14
[ 18372-22-0 ]
[ 133052-90-1 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6053 - 6058
15
[ 18372-22-0 ]
[ 133052-90-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3841 - 3846
[2] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6053 - 6058
[3] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6053 - 6058
To a solution of methyl 2-(1H-indol-3-yl)-2-oxoacetate (1.04 g, 5.12mmol, 1.00 equiv) in anhydrous DMF (25.0 mL, 0.205 H) was added sodiumhydride (57-63% suspension in mineral oil, 225 mg, 5.63 mmol, 1.10 equiv) at 0 C. The reaction mixture was stirred at 0 C for 30 mm before iodomethane (872 mg, 6.14 mmol, 1.20 equiv) was added. The reaction mixture was stirred overnight at room temperature. Thereaction was quenched with ice water (50.0 mL) and the aqueous layer was extracted with EtOAc (6 x 30.0 mL) . The organic extracts were combined, washed with 5% LiC1(aq) (5.00 mL), and then dried over Na2SO4. After being concentrated in vacuo, the residue was purified by flash chromatography on silica gel (EtCAc:hexanes = 1:1) to affordthe title compound as a white solid (1.01 g, 4.65 mmol, 91% yield) NMR Spectroscopy: H NHR (400 MHz, CDCl, 25 C, 6): 8.40-8.46 (m, lH), 8.29 (s, 1H), 7.31- 7.40 (m, 3H>, 3.95 (5, 3H), 3.84 (s, 3H) . NMR (100 MHz, CDC13, 25 C, 6): 177.0, 163.5, 140.6, 137.5, 127.1, 124.3, 23.7, 122.8, 112.9, 110.1, 52.8, 33.9. The 1H NMR data werein good agreement with values reported in the literature (N. Wang etal. 2011).
76.4%
Add 1.0 g (4.9 mmol) of 5a and 10 mL of anhydrous DMF in a three-necked flask, cool to 0 0C, add 0.17 g (4.9 mmol) of 70% NaH, add to room temperature for 30 min and then cool to 0 (5.3 mmol) of CH3I was added dropwise and the reaction was allowed to proceed to room temperature for 1 h. After the reaction was completed, the reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, Washed with saturated brine (3 x 150 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure,The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 0.81 g of a white solid 6b, yield: 76.4%
33%
Synthesisof2-(1-methylindole-3-yl)-2-oxoacetic acid, methyl ester The 3-indole glyoxylic acid, methyl ester (5.88 g) obtained in the step 1 was dissolved in N,N-dimethylformamide (180 mL), and thereto was added hydrogenated sodium (dispersed in oil at 60%, 1.4 g) in small portions while stirring at 0C. After stirring the reaction mixture for 1 hour, methyl iodide (1.2 mL) was added thereto, and stirred at 20C for 20 hrs. After adding ice-cooled water to the reaction fluid, the pH value was adjusted with 1 mol/L hydrochloric acid to become 5. Thus deposited crystals were filtrated, and washed with water. The crystals were dried under a reduced pressure to obtain 2-(1-methylindole-3-yl)-2-oxoacetic acid, methyl ester (1.96 g, 33%).
A. Chemical Examples; Example 1; 3,4-Di-(1 H-indol-3-yl)pyrrole-2,5-dione (Compound 1); Potassium tert-butoxide (0.976 g, 8.7 mmol) was added to a stirred suspension of (1 H-indol-3-yl)acetamide (0.5 g, 2.8 mmol) and methyl 3-indolylglyoxylate (0.650, 3.15 mmol) in anhydrous tetrahydrofuran (15 ml), under argon at -10C. After 15 minutes the resultant dark red solution was allowed to warm to 20C over 3.5 hours. Concentrated hydrochloric acid (2ml) was added with cooling, and the orange-red precipitate then dissolved in ethyl acetate by stirring overnight. The organic phase was washed with water and brine, dried (magnesium sulphate) and evaporated to give the title compound as red crystals (0.780 g, 80.2% yield), mp 234C. ¹H-NMR (DMSO-d6, No./ppm) : 11.6 (br s, 1 H), 10.95 (br s, 1 H), 7.68 (s, 1 H), 7.38 (d, 1 H), 6.98 (t, 1 H), 6.8 (d, 1 H), 6.6 (t, 1 H).
75%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 4.5h;Inert atmosphere;
A three-necked flask equipped with a magnetic stirrer and two addition funnels was charged with indole (10.1 g, 0.086 mol) and 100 mL of diethyl ether. Oxalyl chloride (7.3 mL, 0.086 mol) was added dropwise to the solution at 0 C under nitrogen in 0.5 h. Yellow precipitate were formed and the reaction mixture was stirred for another 0.5 h. The reaction mixture was cooled to -70 C by dry-ice, then sodium methylate (25 % solution in methanol, 37.3 g, 0.173 mol) was added dropwise to the reaction mixture in 1 h. After that the reaction mixture was warmed to 0 C and 50 mL of water was added. The precipitate were filtered, washed with water several times, and then dried at 60 C under vacuum. The product of methyl indolyl-3- glyoxylate was obtained as a yellow powder and used without further purification. Yield 90 %. A three-necked flask equipped with a magnetic stirrer and an addition funnel was charged with 3-indoleacetamide (8.0 g, 0.046 mol), methyl indolyl-3-glyoxylate (10.0 g, 0.049 mol) and 80 mL of tetrahydrofuran. A solution of potassium tert-butoxide (15.2 g, 0.135 mol) in 130 mL of tetrahydrofuran was added dropwise to the reaction mixture at 0 C under nitrogen in 1.5 h. Then the reaction mixture was warmed to room temperature and stirred for 3 h. A solution of Hydrochloric acid (35 % in water, 64 mL) was added dropwise to the reaction mixture in 1 h. Then 200 mL of ethyl acetate and 100 mL of water were added and stirred for dissolving. The organic phase was separated, washed with water several times until neutral, and then washed with brine once, dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the solution was concentrated. The product was crystallized by adding a 1:1 (v/v) mixture of ethyl acetate and n-hexane dropwise to the concentrated solution at 50~60 C. The pure product of 3,4-bisindolylmaleimide was obtained as a red crystal.
Synthesis of 3-indole glyoxylic acid, methyl ester Commercially available 3-indole glyoxylic acid (9.55 g) was suspended in methylene chloride (300 mL), and cooled on ice. Thereafter, to the suspension was added oxalyl chloride (8.8 mL), followed by stirring at 20C for 20 hrs. The reaction fluid was cooled on ice, and after adding methanol (190 mL) thereto, the reaction fluid was stirred at 25C for 1 hour. To the reaction fluid were added water and methylene chloride, and thus deposited crystals were filtrated, followed by washing of the crystals with methylene chloride. The crystals were dried under a reduced pressure to obtain 3-indole glyoxylic acid, methyl ester (7.07 g, 69%).
To a solution of indole (2.0 g, 17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL, 17.2 mmol) dropwise at 0 C. The yellow slurry was stirred at same temperature for 0.5 h and then cooled to -78 C. A solution of NaOMe in MeOH (25 wt %, 7.8 mL, 34.1 mmol) was added to this slurry at same temperature. After addition, the reaction mixture was allowed to warm to ambient temperature, and quenched by addition of H2O (10 mL). The precipitate was collected by filtration, washed with H2O and dried to give 12 (2.5 g, 73%) as a yellow solid: mp 160 C (dec.); 1H NMR (DMSO-d6) δ 12.42 (s, 1H), 8.45 (d, J = 3.5 Hz, 1H), 8.16 (dd, J = 1.5, 6.0 Hz, 1H), 7.55 (dd, J = 1.5, 6.0 Hz, 1H), 7.32-7.27 (m, 2H), 3.89 (s, 3H).
2.53 g
In methanol; diethyl ether; at -78 - 20℃;
To a stirred solution of indole (2.0 g, 17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL,17.2 mmol) dropwise at 0 C. After the resultant yellow slurry was stirred at 0 C for 0.5 h, it was cooled to -78 C. A solution of NaOMe in MeOH (25 wt %, 7.8 mL, 34.1 mmol) was added to this slurry at -78 C. The reaction mixture was allowed to warm to room temperature and quenched by addition of water (10 mL). The solid was collected by filtration, rinsed with water and dried to give 4a (2.53 g, 73%) as a yellow solid
A three-necked flask equipped with a magnetic stirrer and two addition funnels was charged with indole (10.1 g, 0.086 mol) and 100 mL of diethyl ether. Oxalyl chloride (7.3 mL, 0.086 mol) was added dropwise to the solution at 0 C under nitrogen in 0.5 h. Yellow precipitate were formed and the reaction mixture was stirred for another 0.5 h. The reaction mixture was cooled to -70 C by dry-ice, then sodium methylate (25 % solution in methanol, 37.3 g, 0.173 mol) was added dropwise to the reaction mixture in 1 h. After that the reaction mixture was warmed to 0 C and 50 mL of water was added. The precipitate were filtered, washed with water several times, and then dried at 60 C under vacuum. The product of methyl indolyl-3- glyoxylate was obtained as a yellow powder and used without further purification. Yield 90 %. A three-necked flask equipped with a magnetic stirrer and an addition funnel was charged with 3-indoleacetamide (8.0 g, 0.046 mol), methyl indolyl-3-glyoxylate (10.0 g, 0.049 mol) and 80 mL of tetrahydrofuran. A solution of potassium tert-butoxide (15.2 g, 0.135 mol) in 130 mL of tetrahydrofuran was added dropwise to the reaction mixture at 0 C under nitrogen in 1.5 h. Then the reaction mixture was warmed to room temperature and stirred for 3 h. A solution of Hydrochloric acid (35 % in water, 64 mL) was added dropwise to the reaction mixture in 1 h. Then 200 mL of ethyl acetate and 100 mL of water were added and stirred for dissolving. The organic phase was separated, washed with water several times until neutral, and then washed with brine once, dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the solution was concentrated. The product was crystallized by adding a 1:1 (v/v) mixture of ethyl acetate and n-hexane dropwise to the concentrated solution at 50~60 C. The pure product of 3,4-bisindolylmaleimide was obtained as a red crystal.
86.3%
To a three-necked flask was added 3.0 g (0.026 mol) of indole,30 mL of anhydrous ether, stirring dissolved, control the temperature 0-5 oC,A solution of 3.4 g (0.026 mol) of oxalyl chloride in anhydrous ethyl ether (5 mL) was slowly added dropwise, followed by incubation for 1 h and then cooled to about -25 C,A solution of 16.3 g of sodium methoxide in methanol (17.5%, 0.052 mol)After dripping for 30 min, the reaction solution was poured into 100 mL of ice water, filtered, washed with water (3 x 10 mL)Dichloromethane (2 x 10 mL),Dried to give 4.5 g of a pale yellow solid 5a in a yield of 86.3%
86%
To a solution of 1H-indole (6.00 g, 51.2 mmol, 1.00 equiv) in Et20(60.0 mL, 0.850 M) was added oxalyl chloride (5.27 mL, 61.4 mmol, 1.20equiv) dropwise at 0 C. The yellow slurry was stirred at 0 C for 30mm and then cooled to -78 C. A solution of NaOMe in MeOH (25%, 23.0mL) was added to this slurry at the same temperature. The reaction mixture was then allowed to warm up to room temperature, and was quenched by addition of water (40.0 ml) . The precipitate was collected by filtration, washed with water and dried to afford the title compoundas a gray solid (8.96 g, 44.0 mmol, 86% yield).NMR Spectroscopy: 1H NMR (700 MHz, (CD,)2S0, 25 C, 5): 12.50 (s, 1H),8.44 (d, J = 3.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.55 (d, J 7.7Hz, 1H), 7.25 - 7.33 (m, 2H), 3.89 (s, 3H) . “C NMR (175 MHz, (CD3)2S0,25 C, 5): 178.7, 164.0, 138.4, 136.7, 125.5, 123.8, 122.9, 121.1,112.8, 112.4, 52.5. The ‘H NMR data were in good agreement with values reported in the literature (Ye, Q. et al. 2015)
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 50℃;
Compound 1b (4.0 g, 0.0197 mole) and 1,2-dibromoethane (18.5 g, 0.0985 mole) were combined in anhydrous DMF (80 mL) and treated with cesium carbonate (12.8 g, 0.0394 mole). The mixture was stirred under an argon atmosphere at rt for 1 h, then the temperature was raised to 50 C for 4 h. The mixture was stirred at rt overnight. The resulting white solids were removed by filtration, then partitioned between 600 mL of ether and 300 mL of water. The organic layer was washed with water (3X) and brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the resulting oily residue triturated with hexane to give a crude solid product. The crude solid was RECRYSTALLIZED from ethyl acetate/hexane and flash chromatographed on silica eluted with ethyl acetate/hexane to give Compound 1c (5.5 g, 47%).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 70℃; for 5h;Inert atmosphere;
In a three-necked flask, 47 mL lithium aluminum hydride (4.44 g, 117 mmol, 2.5 mol/L THF solution) was injected under Nitrogen at 0 C. 10.15 g (50 mmol) 1 was dissolved in 36 mL of dry THF. The above solution was added dropwise for a period of 1 h, then heated to 70 C for 4 hours. The reaction was complete and quenched by the Fisher treatment for a suspension. The suspension was filtered and the filter cake washed with ethyl acetate. The combined organic layer was wash with brine, dry over Na2SO4 and concentrated in vacuum. The residue was purified by flash silica gel column chromatography(ethyl acetate / petroleum ether, 25%) to obtain a white solid 2 (6.44 g, 80% yield).
80%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 70℃; for 5h;Inert atmosphere;
In a three-necked flask, under nitrogen protection, inject 47mL lithium aluminum hydride (4.44g, 117mmol, 2.5mol/L THF solution), place it at 0, and dissolve 10.15g (50mmol) yellow solid 1 in 36mL THF , Added dropwise to the above solution for 1 hour, then heated to 70C to keep the reaction for 4 hours, the reaction was complete, the reaction was quenched by Fieser treatment, the resulting suspension was filtered, the filter cake was washed with ethyl acetate, saturated salt The filtrate was washed with water, the organic layer was separated, concentrated, and finally purified by silica gel column chromatography to obtain 6.44 g of white solid 2 with a yield of 80%.
With sodium borohydrid; In isopropyl alcohol;
EXAMPLE 1 3-(2-Hydroxyethyl)indole A vigorously-stirred mixture of isopropanol (3 1), methyl 3- indolylglyoxylate (305 g) and sodium borohydride (125 g) was warmed to 40 - 50 and held at that temperature until the initial exothermic reaction was complete. The mixture was then heated to reflux for 4 hours, cooled and diluted with water (5 l). After acidification with hydrochloric acid the product was extracted into dichloromethane. The separated extract was washed with sodium carbonate solution to remove 3-indolylacetic acid and then with water. Evaporation of the solvent gave the crude product as a brown oil. This was distilled at 0.5 - 1 mm pressure (vapour temperature 160 - 190) and crystallized from toluene (1 l) to give the title compound as white to pale brown crystals m.p. 57 - 59. Yield 170 g. (70% of theory).
1.3 g
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;
To a solution of indole (10.0 mmol, 1.0 equiv) in dry Et2O (50 mL) was added dropwise oxalyl chloride (2.7 mL, 30.0 mmol, 3.0 equiv) at 0 C. Then the ice bath was removed and the resulting yellow slurry was stirred for 6 h at room temperature. The reaction mixture was then cooled to 0 C and quenched with MeOH (2.0 mL, 50.0 mmol, 5.0 equiv). The crude precipitate was collected by filtration and was washed with cold Et2O. The solid 3 was dried under vacuum and useddirectly for the next step without further purification.A solution of compound 3 in THF (20 mL) was added dropwise to a suspension of LiAlH4 (1.5 g, 4.0equiv) in THF (40 mL) at 0 C. The reaction mixture was stirred for 4 h at room temperature and quenched with H2O (1.5 mL), 10% aqueous NaOH (3.0 mL), and H2O (4.5 mL) slowly at 0 C. Thereaction mixture was then filtered and the filtrate was extracted with EtOAc. The combined organic layerswere dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel (petroleum ether:EtOAc, v/v = 1:1) to give tryptophol 5 (1.3 g, 80% for two steps) as a yellow solid. NMR data were in consistent with those reported.15
16.1 (1H-indol-3-yl)-oxo-acetic acid A mixture of 610 mg of methyl indolyl-3-glyoxylate and 3.3 cm3 of 1N soda in 3.3 cm3 of water is heated for 1 h at 80 C., then it is cooled on an ice bath and 3.5 cm3 of 1N hydrochloric acid is added. The mixture is extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 554 mg of (1H-indol-3-yl)-oxo-acetic acid in the form of a yellow solid.
Preparation 6 Methyl indolyl-3-glyoxylate A solution of indole (2.0 g, 1.70 mmol) in Et2 O (20 mL) was cooled to 0-5 C. under N2 and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5 C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65 C. and a 25% wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at <-58 C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93%) of the titled compound. NMR. MS (FD) m/z=203 (M+, 100%). Analytical calculated for C11 H9 NO3 C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03.
3.21 g (93%)
With sodium methylate; In diethyl ether; water;
Preparation 6 Methyl indolyl-3-glyoxylate A solution of indole (2.0 g, 1.70 mmol) in Et2O (20 mL) was cooled to 0-5C under N2and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65C and a 25% wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at <-58C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93%) of the titled compound. NMR. MS (FD) m/z= 203 (M+, 100%). Analytical calculated for C11H9NO3C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 47℃; for 24h;
Compound 1b (1.50 g, 7.4 mm) and 1,3-dibromopropane (3.75 mL, 37.0 mm) were dissolved in dry DMF (30 mL) followed by the addition of cesium carbonate (4.89 g, 15.0 mm). The mixture was stirred at 47 C for 24 hrs, then cooled to rt and filtered. The filtrate was diluted with ethyl acetate, washed with water (4x) and brine (1X), then dried (NA2SO4) and evaporated in vacuo. The crude product was chromatographed (SILICA GEL-10% EtoAc/90% Hex to 20% EtoAC/80% Hex) to afford Compound 5a (0.890 G). HNMR (CDOS) 8 2.39- 2.47 (m, 2H, CH2), 3.33 (t, 2H, CH2), 3.96 (s, 3H, CH3), 4.44 (t, 2H, CH2), 7.35- 7.46 (m, 3H, aromatics), 8.45-8. 47 (m, 2H, aromatics). ES-MS M/Z 324 (MH+).
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 28h;
Compound 1 B (2.50 g, 12.3 mm) was dissolved in dry DMF (50 mL) followed by the addition of 3-dimethylaminopropyl chloride hydrochloride (2.34 g, 14.8 mm) and cesium carbonate (10.00 g, 30.7 mm). The mixture was stirred at 60 C for 24 hrs. Additional 3-dimethylaminopropyl chloride hydrochloride (0.5848 g, 3.7 mm) was added and the reaction was stirred at 60 C C for 4 hrs. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with water (4x) and brine (1X), then dried (NA2SO4) and evaporated in vacuo. The crude product was chromatographed (silica gel 97% DCM/3% MeOH to 95% DCM/5% MeOH) to afford Compound 4c (1.35 G). HNMR (DMSO) 6 1.88- 2.00 (m, 2H, CH2), 2.12 (s, 8H, CH2 and CH3), 3.89 (s, 2H, CH3), 4.34 (t, 2H, CH2), 7.29-7. 38 (m, 2H, H-5 and H-6), 7.67 (d, 1H, H-7), 8.17 (d, 1H, H-4) and 8.49 (s, 1 H, H-2). ES-MS M/Z 289 (MH). Compound 4b (0.060 g, 0.26 mm) and Compound 4c (0.1124 g, 0.39 mm) were dissolved in dry THF (1 mL) followed by the addition of 60% NaH (0.104 g, 2.6 mm). The mixture was stirred at ambient temperature for 3 hrs and then the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (1X15 mL) and brine (1x15 mL), then dried (NA2SO4), and evaporated in vacuo. The crude product was chromatographed (silica gel-97% DCM/ 1% MeOH/2% NH40H) to afford Compound 31 (0.0275 g, 23%). HNMR (CD30D) 8 0.3793-0. 4566 (m, 2H, CH2), 0. 6618 (s, 6H, CH3), 0.759 (t, 2H, CH2), 2.71 (t, 2H, CH2), 4.85-4. 99 (m, 2H, aromatics), 5.42-5. 61 (m, 3H, aromatics), 5.80 (d, 2H, aromatics), 6.19 (d, 1H, aromatics), 6.38 (d, 2H, aromatics). ES-MS M/Z 464 (MH+).
A suspension of Compound 1a (10.0 g, 0.053 mole) in dichloromethane : methanol (6: 1 ratio; 350 mL) was stirred and cooled in an ice bath while a solution of TMSCHN2 (79 mL, 2.0 M) in hexane was added dropwise over a 1 hr period. The mixture was allowed to warm to rt and was stirred overnight. The resulting light yellow solid was filtered and washed with ether to yield Compound 1B (7.5 g, 70%). 1H NMR (DMSO-d6) a 12.5 (s, 1H), 8.45 (d, 1H), 8.2 (d, 1H), 7.55 (d, 1H), 7.3 (m, 2H), 3.95 (s, 3H).
With sodium hydride; In tetrahydrofuran; at 20℃; for 5h;
Potassium carbonate (2.42 g, 17.5 MMOL) and 3-dimethylaminopropyl chloride hydrochloride (1.03 g, 6.51 MMOL) were added to phenol Compound 9a (0.92 g, 4.34 MMOL) in DMF (20 mL) and heated in an oilbath at 60 C for 3 h. The mixture was cooled and partitioned between DCM (75 mL) and water (25 mL); the DCM was washed twice with water and once with brine, then dried (K2CO3) and evaporated in vacuo to an oil Compound 9b (1. 08 G). H NMR (CDCI3) 8 1.95 (m, 2 H), 2.30 (s, 3H), 2.45 (m, 2H), 3.80 (s, 2H), 4.0 (m, 2H), 6.78 (bd d, J = 8. 0 Hz, 1 H), 7.05 (bd s, 1 H), 7.45 (d, J = 8. 0 Hz, 1 H). ES-MS MLZ 297 (MH+). This was dissolved in t-butanol (30 mL) and potassium hydroxide (1.02 g, 17.5 MMOL) was added and the reaction REFLUXED for 45 min. The reaction was cooled and evaporated in vacuo to a brown oil Compound 9c (0.35 g); ES- MS m/z 315 (MH+). A portion of the amide Compound 9c (350 mg, 1.11 MMOL) and the ester Compound 1b (250 mg, 1.22 MMOL) in THF (20 mL) were stirred at rt as 60% NaH (266 mg, 6.66 MMOL) was added. After 5 h, the reaction was quenched with 12 N HCI (4.0 mL, 48 mmol), stirred for 10 min and then partitioned between EA and saturated sodium bicarbonate. The organic layer was washed once with sodium bicarbonate and twice with brine, then dried (NA2SO4) and evaporated in vacuo to give the crude product of Compound 24 (250 mg) as a yellow oil. The product was purified by preparative TLC to give Compound 24. 1H NMR (CDC13) 8 1.90 (m, 2 H), 2.30 (s, 3H), 2.45 (m, 2H), 3.95 (m, 2H), 6.65 (d, J = 8.0 Hz, 1 H), 6.80 (m, 1 H), 6.85 (s, 1 H), 7.10-7. 60 (m, 4H), 8.05 (s, 1 H), 8.80 (s, 1 H) ; ES-MS M/Z 468 (MH+).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 1h;
3-BUTYNYL P-TOSYLATE Compound 2a (0.90 g, 4.0 MMOL) and 2-METHYLAMINOETHANOL (0.30 g, 4.0 mmol) were dissolved in DMF (2 mL) and sodium bicarbonate (0.34 g, 4.0 MMOL) was added. The mixture was heated to 75 C under argon for 2 h then cooled to rt and partitioned between DCM (30 mL) and saturated sodium bicarbonate (15 mL). The organic layer was washed once with sodium bicarbonate (15 mL), once with brine (10 mL), then dried (NA2SO4) and evaporated in vacuo to give Compound 2b as a colorless oil (0.98 g). Compound 2b was added to Compound 1b (0.43 g, 2.1 MMOL) followed by triphenyl phosphine (0.73 g, 2.8 MMOL) in THF (15 mL) and DIETHYLAZODICARBOXYLATE (0.49 g, 2.8 MMOL) and the mixture was stirred at ambient temperature for 1 h. The product was evaporated in vacuo to an oil, which was purified via flash column chromatography (ethyl acetate) to give Compound 2c (0.37 g, 56%) as a tan solid. ES-MS m/z 313 (MH+). A portion of the indole Compound 2c (34 mg, 0.11 MMOL) and 1-naphthalene acetamide (Compound 2d, 18 mg, 0.11 MMOL) in THF (1 mL) were treated with 1 M potassium t-butoxide in THF (0.33 mL, 0.33 MMOL) while being cooled in an ice bath. The mixture was stirred at ambient temperature for 3 h, then treated with 12 N HCI (0.15 mL), stirred for 10 min and evaporated in vacuo to give an oil. The oil was partitioned between chloroform and saturated sodium bicarbonate. The organic layer was washed again with saturated sodium bicarbonate, once with brine, then dried (NA2SO4) and evaporated in vacuo to give a mixture of Compound 17 and Compound 18 (50 mg) as an orange oil. The material was purified by preparative TLC to separate Compound 17 and Compound 18. Compound 17 : H NMR (CDCI3) 5 1.81 (s, 3 H), 2.31 (s, 3H), 2.81 (m, 2H), 3.30 (BD S, 2H), 4.22 (m, 2H), 6.18 (d, J=8. 0HZ, 1H), 6.52 (m, 1 H), 7.0 (m, 1 H), 7.15-8. 0 (m, 8H), 8.07 (s, 1 H) ; ES-MS M/Z 448 (MH+). Compound 18: 1H NMR (CDCI3) 61. 97 (m, 1 H), 2.24 (m, 2H), 2.29 (s, 3H), 2.61 (t, J = 7.3 Hz, 2H), 2.77 (m, 2H), 4.19 (m, 2H), 6.18 (d, J = 8.2 Hz, 1H), 6.51 (m, 1 H), 7.0 (m, 1 H), 7.20-7. 93 (m, 8H), 8.04 (s, 1 H) ; ES-MS M/Z 448 (MH+).
3-[2-amino-5-(4-methyl-piperazin-1-yl)-phenyl]-4-(1H-indol-3-yl)-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 1h;
Example 2: 3-[2-Amino-5-(4-methyl-piperazin-I -yl)-phenyl]-4-(l H-indol-3-yl)-pyrrole-2,5-dione; To a solution of 2-[2-amino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (124 mg, 0.50 mmol) and (1 H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (4.0 mL) is added a solution of 1.0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at 0 C under argon. After stirring for 30 min at 0 C and 30 min at RT, TLC indicates the complete consumption of the acetamide. The dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat. , aqueous NH4CI solution. The aqueous layer is extracted with EtOAc (2 x 25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2S04, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc / AcOH / H20 5.5 : 1 : 1) to afford the title compound as its water soluble acetate salt. Red solid. ¹H NMR (DMSO-d6, 400 MHz): 8 1.70 (s, 9H, CH3COO-), 2.25 (s, 3H), 2.22 - 2.38 (m, 4H), 2.78 - 2.84 (m, 4H), 6.51 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1 H), 6.64 - 6.68 (m, 2H), 6.77 (dd, J = 8.7 Hz, J = 2.8 Hz, 1 H), 6.97 - 7.02 (m, 1 H), 7.35 (d, J = 8.0 Hz, 1H), 7.90 (s, 1 H), 11.91 (bs, 1H). ES+-MS: 402 [M + H]+.
N-[2-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-4-(4-methyl-piperazin-1-yl)-phenyl]-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 18h;
Example 3:; N-[2-[4-(1 H-Indol-3-yl)-2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl]-4-(4-methyl-piperazin-I -yl)- phenyl] -acetamide; To a suspension of 2-[2-Acetylamino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (145 mg, 0.50 mmol) and (1 H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (6.0 m L) is a dded a s olution of f 1 .0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at O under argon. The resulting yellow suspension is stirred for 18 h at RT. The now dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat. , aqueous NH4CI solution. The aqueous layer is extracted with EtOAc (2 x 25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2S04, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/ AcOH / H20 5.5 : 1 : 1) to afford the title compound as its water soluble acetate salt. Orange solid. ¹H NMR (DMSO-d6, 400 MHz) : No. 1.75 (s, 12H, CH3COO-), 2.16 (s, 3H), 2.31 - 2.38 (m, 4H), 2.92 - 2.99 (m, 4H), 6.61 (d, J = 7.8 Hz, 1 H), 6.66 (t, J = 7.4 Hz, 1 H), 6.75 (d, J = 2.5 Hz, 1 H), 6.92 (dd, J = 9.0 Hz, J = 2.7 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.47 (d, J = 8.9 Hz, 1 H), 7.75 (s, 1 H), 8.69 (s, 1 H), 11.86 (bs, 1 H). ES+-MS: 444 [M + H]+.
3-(1H-indol-3-yl)-4-[5-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 1.5h;
Example 1:; 3-(l H-Indol-3-yl)-4-[5-(4-methyl-piperazin-I -yl)-2-nitro-phenyl]-pyrrole-2,5.dione ; To a solution of 2-[5-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-acetamide (278 mg, 1.00 mmol) and (1 H-indol-3-yl) -oxo-acetic acid methyl ester (366 mg, 1.80 mmol) in dry THF (8.0 mL) is added a solution of 1.0 M t-BuOK in THF (4.0 mL, 4.0 mmol) at 0 C under argon. After stirring for 30 min at 0 C and 1 h at RT, TLC indicates the complete consumption of the acetamide. The purple reaction mixture is partitioned between EtOAc (50 mL) and brine (50 mL), the layers are separated, and the aqueous layer is extracted with EtOAc (50 mL). The combined organic layers are dried over Na2S04 and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc / AcOH / H20 7 : 1 : 1) to afford the title compound as its water soluble acetate salt. Orange solid. (at)H NMR (DMSO-d6, 400 MHz) : No. 1.84 (s, 6H, CH3COO-), 1.97 - 2.15 (m, 4 H), 2.03 (s, 3H), 2.95 - 3.21 (m, 4H), 6.51 (d, J = 7.8 Hz, 1 H), 6.54 (d, J = 2.7 Hz, 1 H), 6.73 (t, J = 7.8 Hz, 1 H), 7.01 - 7.07 (m, 2H), 7.41 (d, J = 8.1 Hz, 1 H), 8.00 (s, 1 H), 8.13 (d, J = 9.4 Hz, 1 H), 10.8 - 11.4 (br, 1 H), 11.95 (bs, 1 H). ES+-MS: 431 [M + H]+.
EXAMPLE 19 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-[1-(3-pyridinyl)-1H-indazol-3-yl]-1H-pyrrole-2,5-dione (Compound 59) The indol-3-yl-glyoxylic methyl ester (0.50 g, 2.46 mmol) Compound 2b and 3-dimethylamino propyl chloride hydrochloride (0.44 g, 2.78 mmol) were combined in DMF (5 mL) and cooled to 0 C. as 95% NaH (135 mg, 5.34 mmol) was added. The reaction vessel was placed in an oilbath at 55 C. for 20 h and then cooled to ambient temperature. The solution was diluted with DCM (30 mL), washed with water, 3 times with saturated NaHCO3 and once with brine, then dried (K2CO3) and evaporated in vacuo to give an oil (0.44 g, 62%). The oil was purified via flash column (DCM:MeOH; 10:1) to afford Compound 19a. ES-MS m/z 289 (MH+).
2-[6-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-pyridin-2-yl]-acetamide[ No CAS ]
[ 18372-22-0 ]
3-(1H-indol-3-yl)-4-[6-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-pyridin-2-yl]-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 20 - 50℃; for 1.03333h;
Example 1: 3-(1H-indol-3yl)-4-[6-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-pyridin-2-yl]-pyrrole-2,5-dione 2-[6-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-pyridin-2-yl]-acetamide (60 mg, 0.132 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (40 mg, 0.199 mmol) are azeotroped twice are dry THF and then dissolved in dry THF (2 ml). A solution of 1.0 M KOtBu in THF (0.73 ml) is added dropwise over 2 minutes at RT. The reaction mixture is warmed to 50C for 1 hour, after which TLC analysis indicates complete conversion of starting materials. The reaction is quenched by the addition of water (5 ml). The mixture is diluted with EtOAc and washed twice with saturated aq. NH4Cl. The aqueous layers are backextracted twice with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 800:55:45 to 750:83:68 to 700:110:90 to 600:150:150) to afford the title compound as its acetate salt. After azeotroping with MeOH/toluene, the product is obtained as its acetate-methanol complex. 1H NMR (DMSO, 400 MHz) δ 2.10 (s, 3H), 2.10-2.22 (m, 4H), 3.47-3.52 (m, 4H), 6.58 (d, J = 8.9 Hz, 1H), 6.73-6.76 (m, 1H), 7.02 (d, J = 10.0 Hz, 1H), 7.04-7.08 (m, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 10.0, 1 H), 8.03 (s, 1 H); ES-MS: 456.5 [M+H]+.
2-(5-chloro-2-dimethylaminomethyl-1H-indol-4-yl)-acetamide[ No CAS ]
[ 18372-22-0 ]
4-(5-chloro-2-dimethylaminomethyl-1H-indol-4-yl)-3-hydroxy-3-(1H-indol-3-yl)-pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1.01667h;
Example 29: 3-(5-Chloro-2-dimethylaminomethyl-1H-indol-4-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione 2-(5-chloro-2-dimethylaminomethyl-1H-indol-4-yl)-acetamide (50 mg, 0.19 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (57 mg, 0.28 mmol) are dissolved under an atmosphere of argon in 3 ml of dry THF. Molecular sieves (3Å, 100 mg) are added. A solution of 1.0 M KOtBu in THF (0.57 ml) is added dropwise at RT over a period of 1 minute. After 1 hour, TLC analysis indicates complete consumption of starting materials. The reaction mixture was diluted with EtOAc and washed twice with saturated aq. NH4Cl and once with saturated aq. NaCl. The aqueous layers are backextracted with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent evaporated to give a quantitative yield of crude 4-(5-chloro-2-dimethylaminomethyl-1H-indol-4-yl)-3-hydroxy-3-(1H-indol-3-yl)-pyrrolidine-2,5-dione. This product is dissolved in dry DMF (4 ml) under an atmosphere of argon, and DBU (141 microL, 0.94 mmol) is added at RT. The reaction flask is then immersed in a oil-bath preheated to 120C for 10 minutes. TLC analysis indicates complete conversion of the starting material. The reaction mixture is diluted with EtOAc and washed with saturated aq. NaCl. The organic layer is dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 700:110:90 to afford the title compound as its acetate salt. 1H NMR (DMSO, 400 MHz) δ 1.96 (s, 6H), 3.30-3.42 (m, 2H), 5.86 (s, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.51 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.32 (d, 8.4 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 11.3 (s, 1H), 12.0 (br s, 2H); ES-MS: 419.1 [M+H]+.
With potassium tert-butylate; In tetrahydrofuran; hydrogenchloride; water; ethyl acetate;
Example 2 3-[(1-Methyl)-3-indolyl]-4-(3-indolyl)-1 H -pyrrole-2,5-dione Method 1 : A suspension of 1-methyl-<strong>[879-37-8]indole-3-acetamide</strong> (1.00 g, 5.31 mmol) and methyl indolyl-3-glyoxylate (1.30 g, 6.40 mmole) [or 1.32 g, 63.6 mmol of indole-3-glyoxyl chloride] in THF (10 mL) was cooled in an ice bath under N2and then treated with a 1 molar solution of potassium tert-butoxide in THF (15.9 mL, 15.9 mmol). The resultant dark reaction mixture was stirred 5 minutes in the ice bath and 2.5 hrs. at room temperature and was then treated with concentrated (37%) HCl (8 mL) allowing the reaction to exotherm. The reaction was worked up extractively using EtOAc (150 mL), water (100 mL), brine (25 ml) and the organic layer dried (MgSO4) and the solvent removed in vacuoto give a solid that was purified by flash chromatography using a gradient of 2:1 to 1:1 hexanes:acetone to give 1.66 g (92%) of the titled compound [1.38 g (76%) obtained upon using glyoxyl chloride]. Method 2 : A suspension of <strong>[879-37-8]indole-3-acetamide</strong> (1.00 g, 5.74 mmol) and methyl-(1-methyl-indolyl-3-glyoxylate (1.50 g, 6.91 mmole) in THF (10 mL) was cooled in an ice bath under N2and then treated with a 1 molar solution of potassium tert-butoxide in THF (17.2 mL, 17.2 mmol). The resultant dark reaction mixture was stirred 5 minutes in the ice bath and 2.5 hrs. at room temperature and was then treated with conc. (37%) HCl (8 mL) allowing the reaction to exotherm. The reaction was worked up extractively using EtOAc (150 mL), water (100 mL), brine (25 ml) and the organic layer dried (MgSO4) and the solvent removed in vacuo to give a solid that was purified by flash chromatography using a gradient of 2:1 to 1:1 hexanes:acetone to give 1.71 g (87%) of the titled compound. NMR. MS (FD); m/z= 341 (M+, 100%). Analytical calculated for C21H15N3O2C, 73.89; H, 4.43; N, 12.31. Found C 73.31; H 4.57; N 12.27.
With potassium tert-butylate; In ethyl acetate; N,N-dimethyl-formamide;
3-[4-(1H-imidazol-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indole (19) To a stirred solution of t-BuOK (140 mg, 1.25 mmol) in DMF (2.0 mL) at 0 C. was added a solution of 20 (31.1 mg, 0.249 mmol) and <strong>[18372-22-0]methyl indole-3-glyoxylate</strong> (21) (101.1 mg, 0.498 mmol) in DMF (3.0 mL). The reaction mixture was stirred for 12 h at rt and then heated to 45 C. for 3 h. The reaction mixture was then cooled and treated with saturated aqueous NH4Cl (5 mL) and EtOAc (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2*20 mL). The combined organic extracts were washed with brine (4*10 mL), dried (MgSO4), and concentrated. Flash chromatography (25 g of silica gel, 10:1 then 6:1 CH2Cl2-MeOH) of the crude material afforded 54.5 mg (79%) of 19 as a red solid that exhibited IR (KBr) 3121, 2729, 1767, 1719, 1651, 1495, 1340, 1239, 746 cm-1; 1H NMR (400 MHz) 10.75 (bs, 1H), 10.00 (bs, 1H), 8.03 (d, 1 H, J=3.1 Hz), 7.78 (s, 1H), 7.48 (d, 1H, J=8.2 Hz), 7.29 (s, 1H), 7.11 (dd, 1H, J=8,8 Hz), 7.04 (s, 1H), 6.80 (dd, 1H, J=8,8 Hz), 6.21 (d, 1H, J=7.6 Hz); 13C NMR (100 MHz) 170.4, 168.4, 137.8, 136.4, 131.6, 128.8, 125.8,124.3,124.1, 122.5, 120.6, 120.1, 119.6,112.3,102.3; HREIMS calcd for C15H10N4O2 278.0804, found 278.0804.
With acetic acid; acetyl chloride; In ethanol; for 18h;Heating / reflux;
Example 2 2-Ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-l-carbaldehyde EPO <DP n="53"/>Part AAcetyl chloride (0.7 mL, 9.8 mmol), acetic acid (1 mL), and ethylhydrazine (1.5 g, 9.8 mmol) were added sequentially to a suspension of methyl (l/f-indol-3-yl)gly oxalate (1.0 g, 4.9 mmol) in ethanol (25 mL). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was combined with acetonitrile. A pink solid was isolated by filtration and then purified by automated flash chromatography (Biotage, eluted with a gradient of 0 - 30% CMA in chloroform) to provide a white solid. This material was recrystallized from acetonitrile to provide 360 mg of 2-ethyl-2,5-dihydro-4H- pyrazolo[3,4-c]quinolin-4-one as white crystals, mp >250 0C. MS (APCI) m/z 214 (M + H)+; Anal, calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.52; H, 5.14; N, 19.90.
With sodium methylate; In methanol; diethyl ether;
Intermediate B1: Methyl 3-indoleglyoxylate Oxalyl chloride (1.50 mL; 17.2 mmol) was added dropwise to an ice cold solution of indole, A1, (2.00 g; 17.1 mmol) in anhydrous diethyl ether (20 mL). The resulting solution was allowed to stir on ice for 1 hour after which time a yellow slurry had formed. A freshly prepared solution of sodium methoxide in methanol (780 mg Na metal in 20 mL methanol; 34.1 mmol) was added, the reaction allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with the addition of water (30 mL) and the resulting orange solid isolated by fitration, washed with diethyl ether and recrystallized from methanol. Yield 2.94 g; 85%. mp 226-228 C. 1H NMR (500 MHz, DMSO-d6) 12.40 (br s, 1H), 8.17 (dd, J=1.5, 7.6 Hz, 1H), 7.55 (dd, J=1.5, 7.6 Hz, 1H), 7.29 (dt, J=1.5, 7.6 Hz, 1H), 7.26 (dt, J=1.5, 7.6 Hz, 1H), 3.89 (s, 3H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
A mixture of Compound 1d (10.7 g, 0.052 mol), Compound 1b (7.10 g, 0.069 mol) and cesium carbonate (33.7 g, 0.10 mol) in DMF (40 mL) was stirred at room temperature overnight. The solid was filtered and washed with MeOH. The filtrate was evaporated, and the residue was dissolved in EtOAc. The solution was washed with H2O, brine, and dried (over Na2SO4) and concentrated to give the crude product. Flash chromatography purification (EtOAc/heptane, 1:5) afforded Compound 1e. 1H NMR (CDCl3): δ8.46 (m, 2H), 7.43 (m, 1H), 7.35 (m, 2H), 4.37 (t, J=6.7 Hz, 2H), 3.96 (s, 3H), 2.22 (m, 2H), 2.11 (m, 3H). ES-MS m/z 270 (MH+).
3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-1H-pyrrole-2,5-dione acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.7%
EXAMPLE 1:Preparation of polymorph A2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide (4.7 mg, 16.3 mmol) and 3- indoleglyςxylic acid methyl ester (4.35 mg, 1.3 eq.) are dissolved in THF (55 ml_). To the suspension is added dropwise a 20% solution of t-BuOK in THF (46.5 g, 5.1 eq.) at -5C. The mixture is stirred at 0-50C for 8h and the conversion is checked by a PSC. After the conversion is complete, the reaction mixture is quenched with a mixture of 10% sodium chloride in water (50 ml) and acetic acid (5g). Subsequent the aqueous layer is extracted with ethyl acetate (50 ml). The organic layer is extracted twice with 5% aqueous sodium bicarbonate (2x50ml), followed by concentration to 40 ml residual volume. To the residue ethyl acetate (50 ml) is added and subsequently is distilled off. This procedure is carried out four times. To the distillation residue (40 ml) ethaϖol is added (30 ml). The red solution is heated to 700C over a period of 30 minutes and acetic acid (4g) is added. After seeding the reaction is stirred at 700C for 90 minutes. The mixture is cooled to 300C over a period of 60 minutes and is stirred additionally for 30 minutes before it is cooled to 20C over a period of 90 minutes. After 14h at 200C the suspension is filtered, washed once with TBME (15ml) and once with a mixture TBME (13.5ml) - ethanol (1.5ml). After drying at 5OC under reduced pressure for 2h, the product is obtained in 87.7% yield as an orange crystalline solid. 1H NMR (DMSO, 400 MHz) δ 1.92 (s, 3H), 2.13 (s, 3H), 2.17 (m, 4H), 2.51 (m, 1H), 3.69 (m, 4H), 6.35 (d, J = 8.0 Hz, 1H), 6.64 (dd, J = 7.8, 7.4 Hz, 1 H), 7.02 (dd, J = 7.6, 7.4 Hz1 1H)1 7.10 (dd, J = 7.8, 7.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H)1 7.63-7.73 (m, 2H), 8.13 (s, 1H), 11.29 (br s, 1H), 12.01 (br s, 1H).
To a solution of 2-(5-dimethylaminomethyl-2-trifluoromethyl-1 H-indol-3-yl)-acetamide (59.2 mg, 0.198 mmol) and (1 H-indol-3-yl)-oxo-acetic acid methyl ester (60.3 mg, 0.297 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of f-BuOK in THF (0.989 mL) under an argon atmosphere at 0 0C, followed by the addition of DMF(1.0 mL). The resulting deep red reaction mixture is stirred for 1 h at room temperature, diluted with EtOAc, washed with a saturated aqueous NH4CI solution and washed with brine. The aqueous layer is extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford a red solid. The crude product is dissolved in DMF (1.0 mL), DBU (300 μL) is added, and the thus obtained solution is heated for 5 min. at 100 0C. After cooling, the reaction mixture is diluted with EtOAc and washed with brine. The aqueous layer is extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford a red solid. Purification by flash column chromatography (silica gel, EtOAc / acetic acid / water 8 : 1 : 1) affords the title compound as an orange solid (1 1 mg, 0.024 mmol, 12 %). 1H NMR (400 MHz, DMSO-d6, 298 K): δ = 12.54 (bs, 1 H), 11.78 (bs, 1 H), 11.06 (bs, 1 H), 7.95 (d, J = 2.9 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.25 (d, J = 8.1 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 6.88 (t, J = 8.1 Hz, 1 H), 6.84 (s, 1 H), 6.51 (t, J = 8.1 Hz1 1 H), 6.45 (d, J = 8.4 Hz, 1 H), 3.10 (AB-system: δA = 3.24 (d, JAB <n="31"/>= -12.4 Hz, 1H), δB = 2.97 (d, JAB = -12.4 Hz, 1 H), 1.70 (s, 6H). MS (ES+): 453 (M(C24H19F3N4O2HH)+.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 0.583333h;
To a solution of 2-(5-dimethylaminomethyl-benzofuran-3-yl)-acetamide (91 mg, 0.39 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (119 mg, 0.59 mmol) in anhydrous THF (5.0 ml.) is added dropwise a 1 M solution of t-BuOK in THF (1.6 ml.) under an argon atmosphere at 0 0C. The resulting deep red reaction mixture is stirred for 5 min. at 0 0C and 30 min. at room temperature followed by partitioning between brine and EtOAc. The layers are separated and the aqueous layer is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc / acetic acid / water 7 : 1 : 1) affords the title compound as an orange solid (91.4 mg, 0.237 mmol, 63 %). 1H NMR (400 MHz, DMSO-d6, 298 K): δ = 11.90 (bs, 1 H), 11.06 (bs, 1H), 8.28 (s, 1 H), 7.89 (s, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 6.94 (t, J = 8.2 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 6.63 (d, J = 8.2 Hz, 1 H), 6.60 (s,1 H)1 2.98 (s, 2H), 1.69 (s, 6H). MS (ES+): 386 (M(C23Hi9N3O3)+H)+.
Potassium tert-butoxide (1.0 M in THF, 0.55 ml, 0.55 mmol, 2.7 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-indol-3-yl)-oxo-acetic acid methyl ester (45 mg, 0.22 mmol, 1.1 equiv) and of 2-(6-dimethylaminomethyl- imidazo[1 ,2-a]pyridin-3-yl)-acetamide (50 mg, 0.20 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0 "C. It is then diluted with EtOAc and poured into a saturated aqueous NH4CI solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (5 ml), treated with DBU (0.27 ml, 1.8 mmol, 8.9 equiv) and heated to 110 0C for 10 minutes. After cooling, the reaction mixture is diluted with water and extracted three times with CH2CI2. The combined organic layers are ished with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC affords the title compound (34 mg, 43%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ = 12.11 (s, 1 H), 11.27 (s, 1 H), 9.47 (br s, 1 H), 8.21 (d, J = 2.9 Hz, 1 H), 8.05 (s, 1 H), 7.78 - 7.76 (m, 2H), 7.73 (d, J = 8.0 Hz, 1 H), 7.29 (dd, J = 8.0 / 4.0 Hz, 1 H), 6.94 (t, J = 8.0 Hz, 1 H), 6.49 (t, J = 8.0 Hz, 1 H), 5.95 (d, J = 8.0 Hz, 1 H), 3.48 - 3.40 (m, 2H), 2.16 (s, 6H). MS (ES+): 386 (M+H)+.
Potassium tert-butoxide (1.0 M in THF, 1.90 ml, 1.90 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-lndol-3-yl)-oxo-acetic acid methyl ester (192 mg, 0.93 mmol, 1.5 equiv) and of 2-[6-(tert-butyl-diphenyl- silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyridin-3-yl]-acetamide (300 mg, 0.62 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0 0C, 30 minutes at room temperature and 1 hour at 45 0C. It is then diluted with EtOAc and poured into a saturated aqueous NH4CI solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane / EtOAc 50 : 50 to 20 : 80) affords the title compound (180 mg, 45%). MS (ES+): 611 (M+H)+.
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-l-yl)-propionamide (249 mg, 1.1 mmol) and (lH-indol-3-yl)-oxo-acetic acid methyl ester (244 mg, 1.2 mmol) in anhydrous tetrahydrofuran (10 ml) at 0 0C was added potassium tert-butoxide (4.36 ml, 4.36 mmol; IM in tetrahydrofuran). The mixture was allowed to warm to room temperature for 2 hours. Concentrated hydrochloric acid (4 ml) was added and the mixture stirred at room temperature for a further 30 minutes. The mixture was poured into ethyl acetate (250 ml), washed with water (750 ml) and purified by flash column chromatography (SiO2, 30 to 40% EtOAc in hexanes) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,l- ij]quinolin-l-ylmethyl)-4-(lH-indol-3-yl)-pyrrole-2,5-dione as an orange foam (226 mg). 400 MHz 1H NMR (CDCl3) δ: 8.54 (s, IH), 7.80 (d, J = 8.4 Hz, IH), 7.53 (d, J= 3.2 Hz, IH), 7.42 (m, IH), 7.3-7.25 (m, IH), 7.21-7.17 (m, IH), 7.09(dd, J= 1.6 and 7.2 Hz, IH), 6.92-6.86 (m, 2H), 4.15-4.04 (m, 4H), 2.95 (t, J= 6.4 Hz, 2H), 2.22-2.16 (m, 2H); LCMS: 382 [M+H].
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 5h;Inert atmosphere;
To a suspension of compound 12 (1.17 g, 5.7 mmol) and compound 6 (586.5 mg, 2.9 mmol) in THF (50 mL) was added 1.0 M KOBut in THF (11.5 mL, 11.5 mmol) under nitrogen atmosphere. After stirring at ambient temperature for 5 h, thereaction mixture was quenched with 1 N HCl (50 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed in vacuo, and the crude product waspurified by column chromatography with (2:1 hexanes/acetone) to give 13 (726.0 mg, 71%) as an orange solid: mp 254 - 256 C; 1H NMR (DMSO-d6) δ 12.02 (s, 1H), 11.19 (s, 1H), 8.04 (d, J = 3.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 2.0, 8.5 Hz, 1H), 7.43 (dd, J = 3.0, 8.5 Hz, 2H), 7.09-7.06 (m, 1H), 6.76-6.73 (m, 1H), 6.40(d, J = 8.0 Hz, 1H); HRMS (EI, m/z): calcd for C18H10N2O2Cl2 ([M]+) 356.0114, found 356.0126.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 10℃; for 0.75h;
Compound 38a (0.30 g, 1.3 mmol) and compound 39 (0.41 g, 2.0 mmol) were dissolved in anhydrous THF (8.0 mL).Slowly add potassium tert-butoxide (5.5 mL, 1 M THF solution) at 0 C.The temperature was restored to 10 C and the reaction was continued for 45 minutes. After the reaction was detected by TLC, HCl (5 N) was added to adjust the pH to 6,After distilling off the solvent,Ethyl acetate extraction(2 × 120 mL),Saturated brine for organic phase(2 × 40 mL)The organic phase was collected after washing,Anhydrous Na2SO4 was dried, and concentrated and separated and purified by column chromatography to obtain 0.35 g of a yellow solid with a yield of 66%.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃;
To a stirred suspension of 3 (200 mg, 0.57 mmol) and 4a (168 mg, 0.83 mmol) in THF (5 mL) was added 1.0 M t- BuOK in THF(1.15 mL, 1.15 mmol) at 0 C. The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and 5% NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC plate (100:5 CH2Cl2/MeOH) to afford 5a (194.5 mg, 68%) as an orange solid
With aluminum (III) chloride; In methanol; at 70℃;
General procedure: Appropriate indole of 1.0 equiv, 1.0 equiv of the corresponding aminoheterocycle and 0.5 equiv of AlCl3 were heated in 20 mL of dry methanol at 70 C. When the reaction was completed (TLC control), the solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography.
With aluminum (III) chloride; In methanol; at 70℃;
General procedure: Appropriate indole of 1.0 equiv, 1.0 equiv of the corresponding aminoheterocycle and 0.5 equiv of AlCl3 were heated in 20 mL of dry methanol at 70 C. When the reaction was completed (TLC control), the solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography.
tert-butyl 3-(2-methoxy-2-oxopropanoyl)-1H-indole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.1%
With dmap; In tetrahydrofuran; at 20℃; for 3h;
To a three-necked flask was added 2.0 g (9.8 mmol)5a and 100 mL of anhydrous tetrahydrofuran, stirred and dissolved,2.7 g (12.3 mmol) of Boc anhydride and 0.01 g of DMAP were added,Room temperature reaction 3h. After completion of the reaction, the reaction solution was concentrated under reduced pressure,The residue was recrystallized from petroleum ether / ethyl acetate,To give 2.0 g of white solid 6a, yield: 67.1%
To a three-necked flask was added 3.0 g (14.8 mmol) of 5a,30 ml of anhydrous DMF, stirred and dissolved, the reaction solution was cooled to about 0 0C, 0.51 g (14.8 mmol) of 70% NaH was added in portions,After adding up to room temperature reaction for 30 min,3.14 g (19.2 mmol) of 1- (3-chloropropyl) -1H-imidazole,60 0C reaction overnight, after cooling the reaction solution into the 150 mL of water,Ethyl acetate (3 x 100 mL), combined with organic phase,Saturated brine (3 x 300 mL), dried over anhydrous sodium sulfate,And concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 50: 1) to give 2.43 g of yellow Color solid 6n, yield 52.8%
General procedure: 70% NaH (0.17 g, 4.9 mmol) was added portionwise to a solutionof 5a-i (4.9 mmol) in dry DMF (10 mL) at 0-5 C. The reactionmixture was then warmed to room temperature and stirred for30 min. After that, alkyl halide (5.9 mmol) was added at 0 C andstirred for 1 h at room temperature. The mixture was then pouredinto cold water (100 mL) and extracted with ethyl acetate(3 50 mL). The organic phase was combined, washed with brine(3 150 mL), dried over Na2SO4 and concentrated in vacuo. Theresidue was purified by flash column chromatography on silicagel using petroleum ether/ethyl acetate (3:1, v/v) as eluent toafford 6c-k.
With caesium carbonate; In tetrahydrofuran; at 50℃; for 8h;
A mixture of 5a (0.61 g, 3 mmol), cesium carbonate(1.96 g, 6 mmol), 2-bromopropane (0.74 g, 6 mmol) and dry DMF(20 mL) was stirred at 50 C for 8 h. After cooling, the mixturewas poured into water (200 mL) and extracted with ethyl acetate(3 50 mL). The organic phase was combined, washed with brine(3 100 mL), dried over Na2SO4 and concentrated in vacuum. Theresidue was purified by flash column chromatography on silica gelusing petroleum ether/ethyl acetate (3:1, v/v) as eluent to afford6m (0.55 g, 74.8%) as a light yellow solid
74.8%
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 8h;
To a three-necked flask was added 0.61 g (3 mmol) of 5a, 0.74 g (6 mmol) of 2-bromopropane, 1.96 g (6 Mmol) of cesium carbonate, 20 mL of dry DMF, 50 oC for 8 h. After the reaction, the reaction solution was poured into 200 mL of ice water, Ethyl acetate (3 x 50 mL), combined with organic phase, washed with saturated brine (3 x 100 mL), dried over anhydrous sodium sulfate, The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1, v: v) to give 0.55 as a pale yellow solid6M, Yield: 74.8%
2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)but-2-enedioic acid dimethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With lithium diisopropyl amide; In tetrahydrofuran;
Example 64 Preparation of (±)-Cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl) pyrrolidine-2,5-dione and (±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl) pyrrolidine-2,5-dione (0314) The cis and trans isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl) pyrrolidine-2,5-dione may be prepared beginning with the reaction of (1H-indol-3-yl)-oxo-acetic acid methyl ester and (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetic acid methyl ester in the presence of a base such as LDA (lithium diisopropylamide) in a polar aprotic solvent such as THF to yield 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester. Alternatively, 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester may be prepared by reaction of (1H-indol-3-yl)-acetic acid methyl ester and (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester in the presence of a base (e.g., LDA) in THF. The 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester is reduced by catalytic hydrogenation over a noble metal catalyst (e.g., Pd on charcoal) to give 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-succinic acid dimethyl ester, which is reacted with benzylamine (PhCH2NH2) to yield a mixture of cis and trans 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrolidine-2,5-dione. The mixture of cis and trans isomers may be deprotected by catalytic hydrogenation over Pd on charcoal (Pd-C) to give rise to a mixture of cis and trans 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione. The cis and trans isomers may be separated to give all four cis and trans isomers (e.g., by chromatography as in Examples 4 and 5). The deprotected mixture of cis and trans isomers may be treated with potassium tert-butoxide in tert-butanol (as in Example 3) or a mixture of THF and tert-butanol at 50 C. to yield a mixture with a predominance of the trans isomers. Alternatively, the 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-succinic acid dimethyl ester can be reacted with ammonia in methanol at elevated temperatures to yield predominantly the cis isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, which may be isomerized to yield predominately the trans isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione with potassium tert-butoxide in tert-butanol (as in Example 3) or a mixture of THF and tert-butanol at 50 C.
To a solution of methyl 2-(1H-indol-3-yl)--2-oxoacetaLe (983 mg, 4.84 mmol, 1.00 equiv) in anhydrous DM8’ (20.0 mL, 0.242 M) was added sodium hydride (57-63% suspension in mineral oil, 213 mg, 5.32 mmol, 1.10 equiv) at 0 C. The reaction mixture was stirred at 0 C for 30 mmbefore l-bromo-2-f1uoroethane (737 mg, 5.81 mmol, 1.20 equiv) was added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with ice water (40.0 mL) and the aqueous layer was extracted with EtOAc (6 x 30.0 ml) . The organic extracts were combined, washed with 5% LiC1(aq) (5.00 mL), and then dried overNa2SO. After being concentrated in vacuo, the residue was purified by flash chromatography on silica gel (EtOAc:hexanes = 1:1) to afford the title compound as a white solid (780 mg, 3.13 rnmol, 65% yield) NMR Spectroscopy: ‘H NMR (700 MHz, CDC13, 25 C, 5): 8.46-8.50 (m, 1H), 8.44 (s, 1H), 7.32- 7.42 (m, 3H), 4.80 (td, J = 4.8, 46.8 Hz,2H), 4.49 (td, J 4.8, 26.0 Hz, 2H), 3.97 (s, 3H) . ‘C NMR (175 MHz, CDC13, 25 C, 5): 177.3, 163.3, 140.1, 136.8, 127.3, 124.6, 123.9,123.2, 113.7, 110.0, 81.5 (J = 172 Hz), 53.0, 47.7 (J 21.0 Hz>.
3-(1H-indol-3-yl)-4-(1-(3-(pyridin-4-yl)propyl)-1H-imidazol-4-yl)-1H-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: 1M t-BuOK in THF (5 mL) was added to a mixture ofcompoud 16 (1 equiv.), compound 17 (2 equiv.), and 4 Åmolecular sieve (100 mg) in anhydrous DMF (10 mL) at 0 C under N2 atmosphere, the whole solution was stirred atroom temperatue for 24 h. After the completion of thereaction (monitored by TLC), the resulting solution wasfiltered and concentrated in vacuo. The residue was dissolvedin ethyl acetate and washed twice with saturatedsolution of NH4Cl. The organic layer was dried, concentratedin vacuo, and the residue was purified by columnchromatography on silica gel eluted with DCM/MeOH(25:1-10:1) to give compounds C1-C3.
3-(1-(3-(3,5-dichlorophenyl)propyl)-1H-imidazol-4-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: 1M t-BuOK in THF (5 mL) was added to a mixture ofcompoud 16 (1 equiv.), compound 17 (2 equiv.), and 4 Åmolecular sieve (100 mg) in anhydrous DMF (10 mL) at 0 C under N2 atmosphere, the whole solution was stirred atroom temperatue for 24 h. After the completion of thereaction (monitored by TLC), the resulting solution wasfiltered and concentrated in vacuo. The residue was dissolvedin ethyl acetate and washed twice with saturatedsolution of NH4Cl. The organic layer was dried, concentratedin vacuo, and the residue was purified by columnchromatography on silica gel eluted with DCM/MeOH(25:1-10:1) to give compounds C1-C3.
3-(5-fluoro-2-(nitro)phenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 10℃; for 0.75h;
Compound 38b (0.30 g, 1.5 mmol) and compound 39 (0.45 g, 2.2 mmol) were dissolved in anhydrous THF (15 mL), and potassium tert-butoxide (7.5 mL, 1 M THF solution) was slowly added dropwise at 0 C. The temperature was restored to 10 C and the reaction was stirred for 45 minutes. After the reaction was detected by TLC, HCl (5 N) was added to adjust the pH to 6. After the solvent was distilled off, ethyl acetate was added for extraction (2 × 120 mL). The organic phase was washed with saturated brine (2 × 40 mL) and collected. , Dried over anhydrous Na2SO4, concentrated and separated and purified by column chromatography to obtain 0.30 g of a yellow solid with a yield of 72%.
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