* 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 80 - 90℃; for 3 h; Stage #2: With sodium hydroxide In water at 70 - 80℃; for 3 h;
EXAMPLE 13 (FROM TABLE 3) 3-[4-(2-Carboxy-ethyl)-3-methyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid 2-Oxindole (6.7 g) was added to a stirred suspension of 23 g aluminum chloride in 30 mL dichloroethane in an ice bath. Chloroacetyl chloride (11.3 g) was slowly added and hydrogen chloride gas was evolved. After ten minutes of stirring, the reaction was warmed to 40..50° C. for 1.5 hours. Thin layer chromatography (ethyl acetate, silica gel) showed no remaining starting material. The mixture was cooled to room temperature and poured into ice water. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 10.3 g (98percent) of 5-chloroacetyl-2-oxindole as an off-white solid.
97%
Stage #1: at 80 - 90℃; for 3 h; Stage #2: at 70 - 80℃; for 3 h; Stage #3: With hydrogenchloride In water
A suspension of 93 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80 to 90° C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL ethanol. The solid was dissolved in 90 mL 2.5N sodium hydroxide and stirred at 70 to 80° C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid. After standing overnight the filtrate yielded 2 g of 5-carboxy-2-oxindole as a yellow solid. The crude dark brown product was dissolved in hot methanol, the insoluble material removed by filtration and the filtrate concentrated to give 5.6 g of 5-carboxy-2-oxindole as a brown solid. The combined yield was 97percent.
97%
With pyridine; sodium hydroxide In water at 70 - 90℃; for 6 h;
A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 ML pyridine at 80 to 90° C. for 3 hours then cooled to room temperature.. The precipitate was collected by vacuum filtration and washed with 20 ML ethanol.. The solid was dissolved in 90 ML 2.5N sodium hydroxide and stirred at 70 to 80° C. for 3 hours.. The mixture was cooled to room temperature and acidified to PH 2 with 0.5 N hydrochloric acid.. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.. After standing overnight the filtrate yielded 2 g of 5-carboxy-2-oxindole as a yellow solid.. The crude dark brown product was dissolved in hot methanol, the insoluble material removed by filtration and the filtrate concentrated to give 5.6 g of 5-carboxy-2-oxindole as a brown solid.. The combined yield was 97percent.
Reference：
[1] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 220
[2] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 172
[3] Patent: US6350754, 2002, B2, . Location in patent: Page column 24
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 745 - 750
[5] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, # 6, p. 2253 - 2258
[6] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5120 - 5130
[7] Patent: US2003/69421, 2003, A1,
[8] Patent: US2002/183364, 2002, A1,
[9] Patent: US6395734, 2002, B1,
[10] Patent: US6051593, 2000, A,
[11] Patent: US6486185, 2002, B1,
[12] Patent: US6114371, 2000, A,
[13] Patent: US4737501, 1988, A,
[14] Patent: EP168003, 1991, B1,
[15] Patent: EP2130829, 2009, A1, . Location in patent: Page/Page column 19-20
[16] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3500 - 3511
[17] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 197 - 209
2
[ 199328-10-4 ]
[ 102359-00-2 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride In water at 100℃;
Step 1: A mixture of compound 1 (200 mg, 1.0 mmol) and HC1 (2.0 M in H20, 5 mL) was heated to 100°C for overnight. The mixture was concentrated to get compound 2 (180 mg, 97percent) as light yellow solid.
80%
With sodium hydroxide In methanol; water at 0 - 20℃; for 14 h;
Into a 50-mL round-bottom flask was placed methyl 2-oxo-2,3-dihydro-1H- indole-5-carboxylate (800 mg, 4.18 mmol, 1.00 equiv) and methanol (10 mL). This was followed by the addition of a solution of NaOH (670 mg, 16.75 mmol, 4.00 equiv) in water (10 mL) dropwise with stirring at 0oC. The resulting solution was stirred for 14 h at 20oC. The mixture was then concentrated under vacuum and the residue taken up in 20 mL of H2O. This was washed with 2x5 mL of dichloromethane. The pH was adjusted to 4 with hydrochloric acid (1 N) and extracted with 5x50 mL of ethyl acetate and the organic layers combined. Concentration resulted in 592 mg (80percent) of 2-oxo-2,3-dihydro- 1H-indole-5-carboxylic acid as a yellow solid
78%
With sodium hydroxide In methanol; water
Step 2: Synthesis of 5-Carboxy-2-oxindole. 5-Methoxycarbonyl-2-oxindole (1 g) and 1 g of sodium hydroxide in 20 mL of methanol was refluxed for 3 hours. The reaction mixture was cooled and concentrated to dryness. The residue was dissolved in water and extracted twice with ethyl acetate. The aqueous layer was acidified with 6 N hydrochloric acid and the precipitated solid collected, washed with water, and dried to give 0.7 g (78percent) of the title compound as an off-white solid.
Reference：
[1] Patent: WO2014/121062, 2014, A1, . Location in patent: Page/Page column 30
[2] Patent: KR2017/45749, 2017, A, . Location in patent: Paragraph 0952; 0955-0957
[3] Patent: US6147106, 2000, A,
3
[ 1670-81-1 ]
[ 102359-00-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With bromine; acetic acid; lithium bromide In ethanol; <i>tert</i>-butyl alcohol at 15℃; for 2.25 h; Cooling with ice Stage #2: With zinc In ethanol; <i>tert</i>-butyl alcohol at 20℃; for 16 h;
Oxindole-5-carboxylic acidIndole-5-carboxylic acid 5.00g (31.0 mmol) solution in ethanol 99percent 120mL and tert-butanol 180mL in a 1L RB flask was cooled on ice bath to +5 °C. Meanwhile, a solution of lithium bromide 9.0g (103.6 mmol) in neat acetic acid 60mL was placed into an addition funnel. Neat bromine 5.0 mL (16.0g; 100.1 mmol) was then charged to this LiBr solution and the resulting bromine + LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5 °C over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH (2 x 5 mL) and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15 °C bath for 1 hour and at 15 °C for additional 15 min. The reaction mixture was then diluted with additional acetic acid lOOmL. Zn dust 20g [Aldrich; <10 μΜ] (306 mmol) was added in one portion (gas evolution) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours). The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300mL) and filtered. The extraction with boiling methanol was repeated twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid + LiBr - containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6L and acidified with 6M HC1 to about pH= 1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (-20 °C) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23g (95percent) of a light tan solid. 1H-NMR (d6-DMSO, 400MHz): 12.58 (br s, 1H), 10.72(s, 1H), 7.82 (dd, 8.3Hz, 1.6Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3Hz, 1H), 3.54 (s, 2H)
With pyridine; thionyl chloride; In dichloromethane;
EXAMPLE 45 To a suspension of 1.76 g of 5-carboxyoxindol in 200 ml of methylene chloride was added 2 ml of pyridine. After completion of addition, to the suspension was added dropwise 1.4 g of thionyl chloride with stirring held at 0 to 20 C. After completion of addition, the mixture was stirred at the same temperature for 1 hour, and a solution of 1.74 g of benzylpiperazine in 10 ml of methylene chloride was added dropwise thereto. The mixture was then stirred for 4 hours at room temperature. The reaction mixture was thoroughly washed with an aqueous potassium carbonate solution, then washed with water, and dilute hydrochloric acid, dried over sodium sulfate, and the solvent was distilled off. The residue was isolated and purified by silica-gel column chromatography [silica-gel: WAKO C-200, eluent: chloroform:methanol (V/V)=20:1] followed by recrystallization from isopropyl alcohol to give 298 mg of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol. m.p.: 151-153 C.
With pyridine; sodium hydroxide; In water; at 70 - 90℃; for 6h;
A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 ML pyridine at 80 to 90 C. for 3 hours then cooled to room temperature.. The precipitate was collected by vacuum filtration and washed with 20 ML ethanol.. The solid was dissolved in 90 ML 2.5N sodium hydroxide and stirred at 70 to 80 C. for 3 hours.. The mixture was cooled to room temperature and acidified to PH 2 with 0.5 N hydrochloric acid.. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.. After standing overnight the filtrate yielded 2 g of 5-carboxy-2-oxindole as a yellow solid.. The crude dark brown product was dissolved in hot methanol, the insoluble material removed by filtration and the filtrate concentrated to give 5.6 g of 5-carboxy-2-oxindole as a brown solid.. The combined yield was 97%.
97%
A suspension of 93 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80 to 90 C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL ethanol. The solid was dissolved in 90 mL 2.5N sodium hydroxide and stirred at 70 to 80 C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid. After standing overnight the filtrate yielded 2 g of 5-carboxy-2-oxindole as a yellow solid. The crude dark brown product was dissolved in hot methanol, the insoluble material removed by filtration and the filtrate concentrated to give 5.6 g of 5-carboxy-2-oxindole as a brown solid. The combined yield was 97%.
97%
EXAMPLE 13 (FROM TABLE 3) 3-[4-(2-Carboxy-ethyl)-3-methyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid 2-Oxindole (6.7 g) was added to a stirred suspension of 23 g aluminum chloride in 30 mL dichloroethane in an ice bath. Chloroacetyl chloride (11.3 g) was slowly added and hydrogen chloride gas was evolved. After ten minutes of stirring, the reaction was warmed to 40..50 C. for 1.5 hours. Thin layer chromatography (ethyl acetate, silica gel) showed no remaining starting material. The mixture was cooled to room temperature and poured into ice water. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 10.3 g (98%) of 5-chloroacetyl-2-oxindole as an off-white solid.
In pyridine; sodium hydroxide;
A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80 to 90 C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL ethanol. The solid was dissolved in 90 mL 2.5N sodium hydroxide and stirred at 70 to 80 C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.
In pyridine; sodium hydroxide; ethanol;
A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL of pyridine at 80-90 C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solid was dissolved in 90 mL of 2.5 N sodium hydroxide and stirred at 70-80 C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.
In pyridine; sodium hydroxide; ethanol;
A suspension of 9.3 g 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80-90 C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solid was dissolved in 90 mL of 2.5 N sodium hydroxide and stirred at 70-80 C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.
In pyridine; sodium hydroxide;
A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80 to 90 C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL ethanol. The solid was dissolved in 90 mL 2.5 N sodium hydroxide and stirred at 70 to 80 C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.
In pyridine; sodium hydroxide;
A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80 to 90 C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL ethanol. The solid was dissolved in 90 mL 2.5N sodium hydroxide and stirred at 70 to 80 C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid.
With pyridine; sodium hydroxide; In water;
REFERENCE EXAMPLE 1 5-Chloroacetyloxindol (45 g) was added to 180 ml of pyridine and the mixture was stirred at 80 C. for an hour. After completion of reaction, the mixture was allowed to cool and crystals which precipitated were collected by filtration and washed with acetone. The crystals were then recrystallized from methanol to give 5-alpha-pyridinumacetyloxindolchloride. The compound was added to 600 ml of water containing 12.7 g of sodium hydroxide and stirred at 70-80 C. for 30 minutes. After completion of reaction, the resultant solution was allowed to cool down and acidified with concentrated hydrochloric acid. Crystals which precipitated were collected by filtration and washed with water. The crystals were then recrystallized from a mixture of dimethylformamide (DMF) and water to give 28 g of 5-carboxyoxindol. m.p.: >300 C.
With pyridine; sodium hydroxide; In water;
Reference Example 1 5-Chloroacetyloxindol (45g) was added to 180ml of pyridine and the mixture was stirred at 80C for an hour. After completion of reaction, the mixture was allowed to cool and crystals which precipitated were collected by filtration and washed with acetone. The crystals were then recrystallized from methanol to give 5-alpha-pyridinumacetyloxindolchloride. The compound was added to 600 ml of water containing 12.7 g of sodium hydroxide and stirred at 70-80C for 30 minutes. After completion of reaction, the resultant solution was allowed to cool down and acidified with concentrated hydrochloric acid. Crystals which precipitated were collected by filtration and washed with water. The crystals were then recrystallized from a mixture of dimethylformamide (DMF) and water to give 28 g of 5-carboxyoxindol. m.p.: >300C
[Example 4] (3E)-3-[(5-((E)-(5-carboxy-2-oxoindolin-3-ylidene)methyl)furan-2-yl)methylene]-2-oxoindolin-5-carboxylic acid (4) Under ice-cooling, aluminum chloride (anhydride) (3.5 equivalents) was suspended in methylene chloride, and oxindole (1 equivalent) was added to this solution while stirring. To this solution, chloroacetyl chloride (2 equivalents) was gradually added dropwise, and after generation of hydrogen chloride gas was stopped, the resulting mixture was stirred for about 10 minutes. Thereafter, the reaction mixture was warmed to 40 to 50C and stirred for 2 hours. After cooling, the reaction mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water and dried, whereby 5-chloroacetylindolin-2-one was obtained. 5-chloroacetylindoline was dissolved in pyridine and the resulting mixture was heated and stirred at 80 to 90C for 3 hours. After cooling, the resulting precipitate was collected by filtration, washed with ethanol several times and dissolved in 2.5 N sodium hydroxide, and the resulting solution was stirred at 70 to 75C. After cooling, the reaction mixture was acidified with hydrochloric acid and the resulting precipitate was collected by filtration, washed with water and dried, whereby 5-carboxyindolin-2-one was obtained. From the thus obtained 5-carboxyindolin-2-one and diformylfuran, a target compound was obtained in the same manner as in Example 1. 1H-NMR (d6-DMSO, 400 Mz): 12.30 (s, br, 2H), 11.15 (d, J= 7.84 Hz, 1H), 11.02 (d, J= 3.92 Hz), 10.46 (d, J= 7.84 Hz, 1H), 10.13 (d, J= 7.35 Hz, 1H), 10.04 (s, 1H), 9.98 (d, J= 3.92 Hz, 1H), 9.80 (s, 1H), 9.88-9.73 (m, 2H), 9.53 (t, J= 7.84 Hz, 1H), MS m/z: 442(M)+
2-oxo-3-(4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-1-ylmethylene)-2,3-dihydro-1H-indole-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20 mg (25%)
In methanol; ethanol;
2-Oxo-3-(4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-1-ylmethylene)-2,3-dihydro-1H-indole-5-carboxylic acid A mixture of <strong>[102359-00-2]2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> (44.5 mg, 0.25 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (41 mg, 0.25 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80 C. for 6 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol. The solid was then dissolved in methanol, the insoluble materials were removed and the filtrate was concentrated to give 20 mg (25%) of the title compound as a yellow solid. 1NMR (300 MHz, DMSO-d6) delta 13.59 (s, 1H, NH), 11.10 (br s, 1H, NH), 8.24 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.65 (m, 2H), 7.37 (br s, 1H, NH), 6.78 (d, J=8.1 Hz, 1H), 3.38 (m, CH2), 3.0 (t, 2H, CH2). MS m/z 324 [M++1].
3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
In ethanol;
3-(1H-Indol-2-ylmethylene)-<strong>[102359-00-2]2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> A mixture of <strong>[102359-00-2]5-carboxy-2-oxindole</strong> (88.5 mg) (prepared as described in Compound IN-05), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was heated in a sealed tube at 95 C. for 4 hours. The mixture was cooled to room temperature. The solid was filtered and acidified with 2N hydrochloric acid. The resulting darker solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 60 mg (40% yield) of 3-(1H-indol-2-ylmethylene)-<strong>[102359-00-2]2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> as a mustard-colored solid. 1H NMR (360 MHz, DMSO-d6) 12.8 (s, br, 1H, NH), 12.69 (s, 1H, COOH), 11.35 (s, br, 1H, NH), 8.33 (s, 1H), 8.16 (s, 1H), 7.86 (dd, J=1 and 8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.28 (t, 1H), 7.21 (s, 1H), 7.08 (t, 1H), 6.99 (d, J=8 Hz, 1H). MS m/z 304 [M]+.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane;
1-[5-(Morpholine-4-carbonyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,5,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-4-one PyBOP (3.5 g, 6.72 mmol) was added to a mixture of <strong>[102359-00-2]5-carboxy-2-oxindole</strong> (1 g, 5.6 mmol), morpholine (0.5 mL, 6.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 4 hours, the reaction was diluted with more dichloromethane, washed with saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one. 1NMR (300 MHz, DMSO-d6) delta 10.54 (br s, 1H, NH), 7.24 (m, 2H), 6.83 (d, J=7.6 Hz, 1H), 3.56 (m, 4H, 2*CH2), 3.49 (s, 2H, CH2), 3.47 (m, 4H, 2*CH2). MS APCI neg. m/z 245 [M+-1].
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane;
1-[2-Oxo-5-(pyrrolidine-1-carbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-2,5,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-4-one PyBOP (3.5 g, 6.72 mmol) was added to a mixture of <strong>[102359-00-2]5-carboxy-2-oxindole</strong> (1 g, 5.6 mmol), pyrrolidine (0.5 mL, 6.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 4 hours, the reaction was diluted with more dichloromethane, washed with saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 5-(pyrrolidine-1-carbonyl)-1,3-dihydro-indol-2-one. 1H NMR (300 MHz, DMSO-d6) delta 10.52 (br s, 1H, NH), 7.37 (m, 2H), 6.80 (d, J=8.5 Hz, 1H), 3.49 (s, 2H, CH2), 3.42 (m, 4H, 2xCH2), 1.81 (m, 4H, 2*CH2). MS-El m/z 230 [M+].
With dimethyl amine; triethylamine; In tetrahydrofuran; dichloromethane;
2-Oxo-3-(4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-1-ylmethylene)-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 3.5 g, 6.72 mmol) was added to a mixture of <strong>[102359-00-2]5-carboxy-2-oxindole</strong> (1 g, 5.6 mmol), dimethylamine (5.6 mL of 2.0 M in THF, 11.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 3 hours, the reaction was diluted with more dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 480 mg (42%) of <strong>[102359-00-2]2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> dimethylamide. 1H NMR (300 MHz, DMSO-d6) delta 10.50 (br s, 1H, NH), 7.23 (m, 2H), 6.81 (d, J=6.9 Hz, 1H), 3.49 (s, 2H, CH2), 2.93 (s, 6H, 2xCH3). MS-El m/z 204 [M+].
3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 38 COMPOUND IN-030 3-[5-(2-Morpholin-4-yl-ethoxy)-1H-indol-2-ylmethylene]-<strong>[102359-00-2]2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> <strong>[102359-00-2]2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> was condensed with 5-(2-morpholin-4-yl-ethoxy)-1HH-indole-2-carbaldehyde to give the title compound.
3-[4-(2-Carboxy-ethyl)-3-methyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In methanol;
After standing overnight the filtrate yielded 2 g of <strong>[102359-00-2]5-carboxy-2-oxindole</strong> as a yellow solid. The crude dark brown product was dissolved in hot methanol, the insoluble material removed by filtration and the filtrate concentrated to give 5.6 g of <strong>[102359-00-2]5-carboxy-2-oxindole</strong> as a brown solid. The combined yield was 97%. 1H-NMR (360 MHz, DMSO-d6) delta 12.56 (s, br, 1 H, COOH-5), 10.70 (s, 1 H, NH-1), 7.82 (dd, J=1.57, 7.79 Hz, 1 H, H-6), 7.74 (s, br, 1 H, H-4), 6.87 (d, J=7.79 Hz, 1 H, H-7), and 3.53 (s, 2 H, CH2-3). MS m/z (relative intensity, %) 178 ([M+1]+, 100).
Step 1: A mixture of compound 1 (200 mg, 1.0 mmol) and HC1 (2.0 M in H20, 5 mL) was heated to 100C for overnight. The mixture was concentrated to get compound 2 (180 mg, 97%) as light yellow solid.
80%
With sodium hydroxide; In methanol; water; at 0 - 20℃; for 14h;
Into a 50-mL round-bottom flask was placed methyl 2-oxo-2,3-dihydro-1H- indole-5-carboxylate (800 mg, 4.18 mmol, 1.00 equiv) and methanol (10 mL). This was followed by the addition of a solution of NaOH (670 mg, 16.75 mmol, 4.00 equiv) in water (10 mL) dropwise with stirring at 0oC. The resulting solution was stirred for 14 h at 20oC. The mixture was then concentrated under vacuum and the residue taken up in 20 mL of H2O. This was washed with 2x5 mL of dichloromethane. The pH was adjusted to 4 with hydrochloric acid (1 N) and extracted with 5x50 mL of ethyl acetate and the organic layers combined. Concentration resulted in 592 mg (80%) of 2-oxo-2,3-dihydro- 1H-indole-5-carboxylic acid as a yellow solid
0.7 g (78%)
With sodium hydroxide; In methanol; water;
Step 2: Synthesis of 5-Carboxy-2-oxindole. 5-Methoxycarbonyl-2-oxindole (1 g) and 1 g of sodium hydroxide in 20 mL of methanol was refluxed for 3 hours. The reaction mixture was cooled and concentrated to dryness. The residue was dissolved in water and extracted twice with ethyl acetate. The aqueous layer was acidified with 6 N hydrochloric acid and the precipitated solid collected, washed with water, and dried to give 0.7 g (78%) of the title compound as an off-white solid.
With sodium hydrogencarbonate; trimethylamine; In tetrahydrofuran;
EXAMPLE 43 5-Carboxyoxindol (0.93 g) and 0.8 ml of trimethylamine were suspended in 10 ml of tetrahydrofuran (THF), and a solution of 1.0 g of diethylchlorophosphate in 10 ml of THF was added dropwise thereto at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. To the mixture was added dropwise a solution of 1.1 g of benzylpiperazine in 10 ml of THF and was further stirred for 10 hours at room temperature. After completion of reaction, crystals which precipitated were filtered off and the filtrate was concentrated. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and the mixture was extracted with chloroform. Organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. Recrystallization of the residue from isopropyl alcohol gave 1.01 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol. m.p.: 151-153 C.
EXAMPLE 15 To a solution of 0.88 g of 5-carboxyoxindol in 10 ml of DMF was added under ice-cooling 0.82 ml of triethylamine, and 0.77 ml of isobutyl chloroformate was added thereto subsequently. The mixture was stirred at the same temperature for 1 hour. Then, 1.1 g of 1-benzylpiperazine was added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, DMF was removed under reduced pressure, and to the residue was added an aqueous sodium hydrogencarbonate solution and extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: methylene chloride:methanol=50:1) and recrystallized from isopropyl alcohol to give 0.7 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol. m.p.: 151-153 C.
With triethylamine; In N,N-dimethyl-formamide;
Example 12 To a solution of 0.88g of 5-carboxyoxindol in 10 ml of DMF was added under ice-cooling 0.82 ml of triethylamine, and 0.77 ml of isobutyl chloroformate was added thereto subsequently. The mixture was stirred at the same temperature for 1 hour. Then, 1.1g of 1-benzylpiperazine was added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, DMF was removed under reduced pressure, and to the residue was added an aqueous sodium hydrogencarbonate solution and extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: methylene chloride: methanol = 50:1) and recrystallized from isopropyl alcohol to give 0.7g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol. (Not claimed) m.p.: 151-153C
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine;dmap; In N,N-dimethyl-formamide; acetonitrile;
To a solution of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (0.200 g, 1.12 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.477 g, 2.47 mmol), diisopropylethylamine (0.586 mL, 3.37 mmol) and catalytic amount of N, N- dimethylaminopyridine in N, N-DIMETHYLFORMAMIDE/ACTEONITRILE (1: 1,4 mL) was added 2- methoxybenzylamine (0.295 mL, 2.26 mmol) and the reaction mixture stirred at room temperature for 1 h. The solvent was evaporated and the crude material was purified on a short silica gel column using dichloromethane containing 5% methanol as the eluent. This was followed by triturating from ethyl acetate to give 0.10 g (33% yield) of the yellow title compound : 1H NMR (DMSO-d6,400 MHz) 8 10.60 (br s, 1 H), 8.65 (t, J = 6 Hz, 1 H), 7.79-7. 77 (m, 2 1-1), 7.21 (t, J = 8 Hz, 1 H), 7.15 (d, 7= 8 HZ, 1 H), 6. 98 (d, J = 8 Hz, 1 H), 6.90-6. 84 (m, 2 H), 4.42 (d, J = 6 Hz, 2 H), 3.81 (s, 3 H), 3.53 (s, 2 H) ; MS (ES) m/z 297 (M++1), NILZ 295
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 12.5h;
2-Oxoindoline-5-carboxylic acid (0.214 g, 1.21 mmol), O-(BENZOTRIAZOL-L-YL)-N, N, N, N- TETRAMETHYLURONIUM TETRAFLUOROBORATE (0. 462 G, 1.44 mmol), 1-HYDROXYBENZOTRIAZOLE hydrate (0.194 g, 1.44 mmol) and N, N-diisopropylethylamine (0.3 ML, 1.71 mmol) were suspended in a mixture of acetonitrile (4 mL) and N, N-DIMETHYLFORMAMIDE (1 ML) and stirred at room temperature for 30 min. Benzylamine (0. 155 g, 1.45 mmol) was added and stirring was continued for 12 h. The solvent was removed in vacuo and the residue was separated between chloroform and a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform (3X30 mL). The combined organic layers were dried over sodium sulfate. Filtration and removal of the solvent in vacuo yielded the crude product which was purified on a silica gel column using a gradient chloroform/methanol, (100: 1 to 1: 1), as the eluent to give 0.104 g (30% yield) of the title compound as a solid : 1H NMR (DMSO-D6, 400 MHz) 8 10. 60 (s, 1 H), 8.85 (m, 1 H), 7.77 (m, 2 H), 7.29 (m, 4 H), 7.21 (m, 1 H), 6.85 (d, J = 11 HZ, 1 H), 4.45 (d, J = 6 Hz, 2 H), 3.52 (s, 2 H); MS (ES) TIZZY 267 (M++1).
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 1.58333h;
To A NN-DIMETHYLFORMAMIDE/ACETONITRILE, (2 mL: 10 mL), mixture containing ethyldiisopropylamine (0.52 ML, 3 mmol) was added <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (0.354 g, 2.0 mmol; described in: Sun L. et al. J. MED. Chem. 2000, 43 (14), 2655:), O- (BENZOTRIAZOL-1-YL)-N, N, N, N-TETRAMETHYLURONIUM tetrafluoroborate (0.77 g, 2.4 mmol) and 1-HYDROXYBENZOTRIAZOLE hydrate (0.324 g, 2.4 mmol) and stirred for 5 min at room temperature. Thereafter, 2- (AMINOMETHYL) pyridine (0.562 g, 5.2 mmol) was added and the resulting reaction mixture was stirred for 90 min followed by addition of a saturated aqueous NAHCO3 solution (10 ML). The solvents were removed in vacuo and 0.364 g (68% yield) of the title product was obtained as a white solid after purification on a silica gel column using chloroform/methanol, (9: 1), as the eluent : 1H NMR (DMSO-d6, 400 MHz) 8 10. 66 (s, 1 H), 8.96 (t, 7= 5. 6 HZ, 1 H), 8.55 (d, J = 4.4 Hz, 1 H), 7. 85 (d, J = 8. 0 HZ, I H), 7.83 (s, 1 H), 7. 78 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.29 (t, J= 6. 4 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 4.59 (d, J = 6.0 Hz, 2 H), 3. 58 (s, 2 H); MS (EI) MLZ 268 (M++1).
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 2.5h;
2-Oxoindoline-5-carboxylic acid (0.470 g, 2.66 mmol), O-(benzotriazol-1-yl)-N,N,N',N'- TETRAMETHYLURONIUM TETRAFLUOROBORATE (1. 010 g, 3.15 mmol), 1-hydroxybenzotriazole hydrate (0.417 g, 3.09 mmol) and N, N-diisopropylethylamine (0.7 ML, 4.0 mmol) were suspended in ACETONITRILE/N-DIMETHYLFORMAMIDE, (10 mL: 2 mL), and stirred at room temperature for 30 min. 2-Methoxyethanamine (0.516 g, 6.88 mmol) was added and stirring was continued for 2 h. Saturated aqueous sodium hydrogencarbonate was added (10 mL) and the solvents were removed M vacuo. The residue was purified on a silica gel column using a gradient chloroform/methanol, (100: 1 to 1: 1), as the eluent to give 0.355 g (57% yield) of the title compound as a solid : 1H NMR (DMSO-DE, 400 MHz) 8 10.59 (s, 1 H), 8.31 (m, 1 H), 7.72 (d, J = 7 Hz, 1 H), 7.71 (s, 1 H), 6.83 (d, Y= 8 HZ, 1 H), 3.51 (s, 2 H), 3.42 (m, 2 H), 3.39 (m, 2 H), 3.24 (s, 3 H); MS (ES) TIL/Z 235 (M++1).
The above material was dissolved in methanol (50 mL) and formic acid (5 miL) and hydrogenated over Pd/C (0.40 g) at elevated hydrogen pressure (50 psi) for 16 h. The reaction mixture was filtered through a plug of celite (10 g), the celite was washed with methanol (2X20 ML), the combined filtrates were evaporated to dryness, dissolved in H20 (20 mL), and re-evaporated. The resulting residue was dissolved in N, N-DIMETHYLFORMAMIDE (5 mL), and added in one portion to the previously prepared suspension of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (0.53 g, 3 MMOL), O-(BENZOTRIAZOL-L-YL)-N, N, N, N-TETRAMETHYLURONIUM tetrafluoroborate (1.1 g, 3.6 mmol), 1-HYDROXYBENZOTRIAZOLE (0.486 g, 3.6 mmol) and N,N-diisopropylethylamine (1.7 g, 12 mmol) in acetonitrile (10 ML) and N,N-dimethylformamide (10 mL). The mixture was stirred overnight, the solvents were removed in vacuo, and the residue was purified on a silica gel column using chloroform/methanol, (10: 1), then CHLOROFORM/METHANOL/AQUEOUS ammonia, (100: 10: 1), as the eluent. The semi-solid crude material was again subjected to silica gel chromatography using chloroform/methanol/aqueous ammonia, (150: 10: 1), as the eluent to afford 0.20 g (19% yield) the title compound as yellow foam: MS (ES) M/Z 367 (M++1).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12h;
2-Oxo-2,3-dihydro-lH-indole-5-carboxylic acid (7 g, 39 mmol) is dissolved together with benzylalcohol (4.2 mL, 39 mmol) and 4-lambda/,lambda/-dimethylaminopyridine (1 g, 7.9 mmol) in 70 mL DCM and cooled in the ice bath. Then l-ethyl-3-(3-dimethylaminopropyl)carbo- diimide (8.3 g, 43 mmol) is added and the mixture is heated to RT for 12 h. After evaporation of the solvent the residue is taken up in a little methanol and combined with 1 N hydrochloric acid (200 mL). The precipitate formed is filtered and dried. Yield: 6.9 g (65 %) (A86).
Ethyl chloroformate and TEA were added to a THF solution of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> and stirred. The reaction solution was mixed with N,N-diethylethylenediamine, stirred and then purified to obtain N-[(2-diethylamino)ethyl]-2-oxoindoline-5-carboxamide as a brown solid. F+: 276.
(S)-2-cyclopropylaminomethyl-pyrrolidine-1-tert-butyl carboxylate[ No CAS ]
[ 102359-00-2 ]
(S)-2-[cyclopropyl-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-methyl}-pyrrolidine-1-tert-butyl carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
264 mg (1.1 mmol) of (S)-2-cyclopropylaminomethyl-pyrrolidine-1-tert-butyl carboxylate is added to a solution of 177 mg (1 mmol) of <strong>[102359-00-2]2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid</strong> (prepared according to the following procedure: Li Sun, Ngoc Tran, Congxin Liang, Flora Tang, Audie Rice, Randall Schreck, Kara Waltz, Laura K. Shawver, Gerald McMahon, and Cho Tang, Journal of Medicinal Chemistry, 1999, Vol. 42, 25, 5120), 417 mg (1.1 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium, 646 mg (5 mmol) of diisopropylethylamine and 27 mg (0.1 mmol) of 1-hydroxybenzotriazole in 2 ml of dimethylformamide, then the reaction mixture is stirred at room temperature for 30 minutes. The solvent is evaporated, then the product is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica (ethyl acetate/methanol 95/5 then 9/1) to give 254 mg (64%) of (S)-2-[cyclopropyl-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-methyl}-pyrrolidine-1-tert-butyl carboxylate in the form of a beige solid.
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; for 4h;
An oven-dried round-bottom flask was charged with 2-oxoindoline-5- carboxylic acid (89 mg, 0.500 mmol), TBTU (193 mg, 0.600 mmol), HOBt hydrate (81 mg, 0.600 mmol), DIPEA (0.13 mL, 0.750 mmol) and DMF (3.0 mL) and stirred for 5 minutes. Methyl amine (0.75 mL of a 2.0 M solution in THF) was then <n="102"/>added and reaction was stirred for 4 hours at which time NaHCO3(Sat ) (2mL) was added. Solvents were removed in vacuo and the residue was purified by column chromatography (silica gel, 92:8 CH2Cl2ZMeOH) to give the title compound (11 mg, 12 %). IH NMR (400 MHz, CD3OD) delta ppm 7.69 - 7.75 (m, 2 H), 6.94 (d, J=8.1 Hz, 1 H), 3.58 (s, 2 H), 2.97 (s, 3 H); MS ESI 191.0 [M + H]+, calcd for [C10H10N2O2 + H]+ 191.08.
[Example 6] (3E)-3-((5-((E)-(1-acetyl-2-oxoindolin-3-ylidene)methyl)furan-2-yl)methylene)-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (5) <strong>[102359-00-2]5-carboxyindolin-2-one</strong> (1 equivalent), 3-((5-formylfuran-2-yl)methylene)-N-acetyl-2-oxoindoline (1.2 equivalents) and piperidine (0.2 equivalent) were dissolved in ethanol such that 1 mL of ethanol was used per 1 mumol of the total amount of the compounds, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the resulting precipitate was collected by filtration, washed with cooled ethanol several times and dried, whereby a target compound was obtained. 1H-NMR (d6-DMSO, 400 Mz): 9.41 (s, 1H), 9.39 (s, 1H), 8.42 (d, J= 3.91 Hz, 1H), 8.32 (d, J= 3.91 Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.92 (d, J= 8.05 Hz, 1H), 7.82 (d, J= 8.05 Hz, 1H), 7.60 (s, 1H), 7.55 (dd, J= 8.21 Hz, 1.72 Hz, 1H), 7.36 (d, J= 7.22 Hz, 1H), 7.26 (d, J= 7.22 Hz, 1H), 6.87 (m, 1H), 2.66 (s, 3H), MS m/z: 440(M)+
Oxindole-5-carboxylic acidIndole-5-carboxylic acid 5.00g (31.0 mmol) solution in ethanol 99% 120mL and tert-butanol 180mL in a 1L RB flask was cooled on ice bath to +5 C. Meanwhile, a solution of lithium bromide 9.0g (103.6 mmol) in neat acetic acid 60mL was placed into an addition funnel. Neat bromine 5.0 mL (16.0g; 100.1 mmol) was then charged to this LiBr solution and the resulting bromine + LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5 C over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH (2 x 5 mL) and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15 C bath for 1 hour and at 15 C for additional 15 min. The reaction mixture was then diluted with additional acetic acid lOOmL. Zn dust 20g [Aldrich; <10 muMu] (306 mmol) was added in one portion (gas evolution) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours). The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300mL) and filtered. The extraction with boiling methanol was repeated twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid + LiBr - containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6L and acidified with 6M HC1 to about pH= 1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (-20 C) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23g (95%) of a light tan solid. 1H-NMR (d6-DMSO, 400MHz): 12.58 (br s, 1H), 10.72(s, 1H), 7.82 (dd, 8.3Hz, 1.6Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3Hz, 1H), 3.54 (s, 2H)
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 60℃;
Step 2 : A solution of compound 2 (90 mg, 0.5 mmol), EDCI (192 mg, 1.0 mmol), HOAT (136 mg, 1.0 mmol) and DIPEA (0.5 mL) in DMF (3 mL) was stirred at rt for 10 min, amine (115 mg, 0.5 mmol) was added, then the mixture was heated to 60 oC for overnight. The reaction was quenched with water and the precipitate was collected to afford compound 3 (100 mg, 41 %) as brown solid
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
Reference Example 15 Production of 5-(5-phenyloxazol-2-yl)indolin-2-one To a solution of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (1.3 g, 7.3 mmol) in DMF (50 ml) was added iPr2NEt (3.8 ml, 22 mmol), HOBt (1.2 g, 8.8 mmol), WSCI (1.7 g, 8.8 mmol) and 2-amino-1-phenylethanone hydrochloride (1.3 g, 7.3 mmol). The reaction mixture was stirred for 2 h at room temperature. The mixture was poured into H2O and EtOAc. The resulting precipitate was removed by filtration, and the filtrate was separated. The organic layer was washed with sat. NaHCO3 solution, sat. NH4Cl solution and brine, and then dried over Na2SO4. The solvent was evaporated and the residue (0.73 g) was used for the next reaction without further purification. Sulfuric acid (5 ml) was added to the residue, and the mixture was heated for 2 h at 100 C. Ice was added, and the mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated. The residue was crystallized from EtOH to afford 5-(5-phenyloxazol-2-yl)indolin-2-one (0.27 g, 13%). 1H NMR (300 MHz, DMSO-d6) delta 10.68 (s, 1H), 7.96-7.91 (m, 2H), 7.84-7.80 (m, 2H), 7.77 (s, 1H), 7.52-7.47 (m, 2H), 7.37 (m, 1H), 6.97 (d, 1H, J=8.0 Hz), 3.60 (s, 2H).
(3Z)-1-acetyl-3-(ethoxymethylene)-2-oxoindoline-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
at 100℃; for 8h;
Step A: (3Z)-1-Acetyl-3-(ethoxymethylene)-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> A mixture of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (5.221 g, 29.50 mmol) and triethylorthoformate (13.320 g, 90 mmol) in acetic anhydride (75 mL) were stirred at 100 C for 8 h. The solvent was removed under reduced pressure. The residue was stirred with i-Pr2O (250 mL) for 2 h to give a solid, which was filtered and washed with i-Pr2O to provide (3Z)-1-acetyl-3-(ethoxymethylene)-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (4.8 g, 59%): NMR (300 MHz, DMSO-d6) delta ppm: 12.6 (bs,1H), 8.17 (d,1H), 8.15 (s,1H), 8.05 (d,1H), 7.87 (dd,1H), 4.54 (q,2H), 2.62 (s,3H), 1.41 (t,3H); tR: 3.17 min; MS (ESI): m/z (M+H)+ 276; (M+H)- 274.
59%
at 100℃; for 8h;
Example 5:Step A:(3Z)-1 -Acetyl-3-(ethoxymethylene)-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong>A mixture of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (5.221 g, 29.50 mmol) and triethylorthoformate (13.320 g, 90 mmol) in acetic anhydride (75 ml_) were stirred at 100 C for 8 h. The solvent was removed under reduced pressure. The residue was stirred with i-Pr2O (250 ml_) for 2 h to give a solid, which was filtered and washed with i-Pr2O to provide (3Z)-1 -acetyl-3-(ethoxymethylene)-2-oxoindoline-5- carboxylic acid (4.8 g, 59%): NMR (300 MHz, DMSO-d6) delta ppm: 12.6 (bs,1 H), 8.17 (d,1 H), 8.15 (s,1 H), 8.05 (d,1 H), 7.87 (dd,1 H), 4.54 (q,2H), 2.62 (s,3H), 1 .41 (t,3H); tR: 3.17 min; MS (ESI): m/z (M+H)+ 276; (M+HV 274.
(3Z)-3-[3,5-dimethyl-4-(piperidin-1-ylcarbonyl)-1H-pyrrol-2-yl]methylene}-2-oxoindoline-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.25%
With piperidine; In ethanol; for 8h;Reflux;
Example 1 (3Z)-3-[(4-[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol-2-yl)methylene]-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (1) A mixture of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (0.708 g, 4 mmol), 3,5-dimethyl-4-(piperidin-1-ylcarbonyl)-1H-pyrrole-2-carbaldehyde (1.030 g, 4.4 mmol) and piperidine (0.2 mL) in EtOH (75 mL) was refluxed for 8 h. The mixture was cooled down to room temperature to provide a precipitate which was filtered and washed with EtOH to provide the target compound 1 (0.980 g, 62.25%) NMR (300 MHz, DMSO-d6) delta ppm: 13.52 (s,1H), 12.5 (bs,1H), 11.19 (s,1H), 8.37 (s,1H), 7.78 (s,1H), 7.77 (d,1H), 6.96 (d,1H), 3.43 (m,4H), 2.29 (s,6H), 1.60 (bs,2H), 1.47 (bs,4H); tR: 3.18 min, MS (ESI): m/z (M+H)+ 394; (M+H)-392.
62.25%
With piperidine; In ethanol; for 8h;Reflux;
Example 1 :(3Z)-3-[(4-[2-(diethylamino)ethyl]carbamoyl}-3,5-dimethyl-1H-pyrrol- 2-yl)methylene]-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (1)A mixture of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (0.708 g, 4 mmol), 3,5-dimethyl-4- (piperidin-1 -ylcarbonyl)-1 /-/-pyrrole-2-carbaldehyde (1 .030 g, 4.4 mmol) and piperidine (0.2 ml_) in EtOH (75 ml_) was refluxed for 8 h. The mixture was cooled down to room temperature to provide a precipitate which was filtered and washed with EtOH to provide the target compound 1 (0.980 g, 62.25%).NMR (300 MHz, DMSO-c/6) delta ppm: 13.52 (s,1 H), 12.5 (bs,1 H), 1 1 .19 (s,1 H), 8.37 (s,1 H), 7.78 (s,1 H), 7.77 (d,1 H), 6.96 (d,1 H), 3.43 (m,4H), 2.29 (s,6H), 1 .60 (bs,2H), 1 .47 (bs,4H); tR: 3.18 min, MS (ESI): m/z (M+H)+ 394; (M+HV392.
N-{3-[(4-fluorophenyl)amino]pyridin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 60℃; for 2h;
INTERMEDIATE 8 N-{3-[(4-Fluorophenyl)amino]pyridin-4-yl}-2-oxo-2,3-dihydro-1 H-indole-5- carboxamide2-Oxo-2, 3-dihydro-1 H-indole-5-carboxylic acid (200mg, 1.13mmol), Intermediate 5 (241 mg, 1.19mmol), HATU (644mg, 1.69mmol) and NEt^ (392uL, 2.82mmol) were dissolved in DMF (7.0ml_) and the reaction mixture heated at 60C for 2h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (50ml_), washed with water (40ml_). Brine (40ml_) was added to the organic phase and the biphasic mixture was filtered to give the title compound (409mg, 100%) as a brown solid. LCMS (ES+): 363.1 [MH]+. HPLC: Rt 4.23min, 79.8% purity.
1-cyclopropyl-4-methylpyrrolidin-3-amine[ No CAS ]
[ 102359-00-2 ]
(±)-trans-N-(1-cyclopropyl-4-methylpyrrolidin-3-yl)-2-oxoindoline-5-carboxamide[ No CAS ]
(±)-cis-N-(1-cyclopropyl-4-methylpyrrolidin-3-yl)-2-oxoindoline-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (200 mg, 1.12 mmol) in DMF (3 mL) was added HATU (644 mg, 1.69 mmol) and the reaction mixture was stirred for 30 min at room temperature. After being cooled to 0 C 1-cyclopropyl-4-methylpyrrolidin- 3-amine (174 mg, 1.24 mmol) and DIPEA (0.29 mL, 1.69 mmol) were added successively to the reaction mixture. The reaction was further stirred at room temperature for 2 hrs. Completion of the reaction was confirmed by TLC. After completion, water (30 mL) was added to reaction mixture and product was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with brine, and dried over sodium sulfate and concentrated under vacuum to get crude product which was purified by column chromatography. The desire compound started eluting at 4% methanol in DCM. Evaporation of the fractions afforded 70 mg of pure racemic compound as a mixture of cis : trans isomer. The cis and trans isomers were separated out using reverse-phase prep. HPLC using 0.1% TFA in ACN and 0.1% TFA in water as mobile phase. Lyophilization of pure fractions afforded the pure title compounds. The yields of the isomers were (18 mg (5.33%) and 23 mg (6.81%) a and LCMS of the isomers were: 1H NMR (400 MHz, MeOD): 7.7 97-6.95 (m, 1H), 4.15 (dd, J = 6 Hz, 1H), 3.60-3.58 (m, 1H), 3.51 (m , 1H), 3.18 (dd, J = 6 Hz, 1H), 2.82- 2.78 (m, 1H), 2.40-2.36 (t, J = 8.4 Hz, 1H), 2.25 2.21 (m, 1H), 1.21-1.20 (m, 3H), 0.53- 0.49 (m, 4H). LCMS (m/z): 300.25 [M+H]+. 1H NMR (400 MHz, MeOD): 7.78-7.76 (m, 2H), 6.98-6.96 (m, 1H), 4.68 (dd, J=5.2 Hz, 1H), 3.61-3.59 (m, 1H), 3.24 (dd, J=5.2 Hz, 1H), 3.12 (dd, J=7.6 Hz, 1H), 2.72 (dd, J=6.4 Hz, 1H), 2.59-2.55 (m, 1H), 2.45 (t, J= 9.2 Hz, 1H), 1.86-1.84 (m, 1H), 0.97-0.95 (m, 3H), 0.54-0.48 (m, 4H). LCMS (m/z): 300.25 [M+H]+.
(3Z)-1-acetyl-3-[ethoxy(phenyl)methylene]-2-oxoindoline-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
at 100℃; for 8h;
A mixture of 2-oxoindoline-5-carboxilic acid (5.221 g, 29.50 mmol) and triethylorthobenzoate (20.16 g, 90 mmol)in acetic anhydride (75 ml) were stirred at 100 C for 8 h.The solvent was removed under reduced pressure. The residuewas stirred with i-Pr2O (250 ml) for 2 h to give a solid which was filtered and washed with i-Pr2O to provide (3Z)-1-acetyl-3-[ethoxy(phenyl)methylene]-<strong>[102359-00-2]2-oxoindoline-5-carboxylic acid</strong> (3.5 g, 33 %) 1H-NMR in DMSO-d6 12.3(bs,1H);8.61(d,1H); 8.22(d,1H); 7.90(dd,1H); 7.54(m,5H); 3.99(q,2H); 2.45(s,3H); 1.35(t,3H). tR: 3.82 min, MS(ESI):m/z(M+H)+352, (M+H)- 350.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
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