* 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: With hydrogen In ethanol for 2 h; Stage #2: Heating / reflux
2,4-dinitrophenylacetic acid (10 g; 44 mmol) was dissolved in ethanol (200 mL) and purged with N2. 10percent Pd/C (400 mg) was added and the reaction hydrogenated at 45 psi for 2 hours. The reacton was then transferred to a RBF and p-toluenesulfonic acid (150 mg) was added and the reaction heated at reflux overnight. The reaction was then filtered through celite to remove catalyst and concentrated. The product crashed out and was filtered as tan crystals 4.68 g (72percent yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.20 (s, 2H), 4.97 (br s, 2H), 6.07 (m, 2H), 6.76 (d, J=8.7 Hz; 1H), 10.05 (s, 1H); HPLC ret. time: 2.123 min. LRMS (M+) 148.7.
71%
With hydrogen; acetic acid In methanol
A solution of 2-(2,4-dinitrophenyl)acetic acid (1.0 g, 4.42 mmol), AcOH (10 mL), and MeOH (5 mL) was purged with Ar for 15 minutes at which time 10wt. percent Pd/C (lOOmg) was added. The mixture was then purged briefly with H2 and then stirred under latm of H2 overnight. The mixture was filtered through a pad of celite, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 90:10 CH2Cl2/Me0H) to give 462 mg, 71 percent of a brown solid. 1H NMR (400 MHz, CD3OD) δ 6.95 (d, J = 7.7 Hz, IH), 6.37 (d, J = 7.8 Hz, IH), 6.34 (s, IH), 3.38 (s, 2H); MS ESI 149.0 [M + H]+, calcd for [C8H8N2O + H]+ 149.07.
Reference：
[1] Patent: US2005/256125, 2005, A1, . Location in patent: Page/Page column 29
[2] Patent: WO2009/79767, 2009, A1, . Location in patent: Page/Page column 87
[3] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 10939 - 10954
[4] ChemMedChem, 2012, vol. 7, # 5, p. 777 - 791
[5] Chemische Berichte, 1881, vol. 14, p. 830
[6] Helvetica Chimica Acta, 1948, vol. 31, p. 1392,1395
[7] Helvetica Chimica Acta, 1937, vol. 20, p. 373,383
[8] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 234
[9] Patent: US2013/281451, 2013, A1,
[10] European Journal of Medicinal Chemistry, 2014, vol. 85, p. 268 - 288
[11] Patent: WO2008/115369, 2008, A2, . Location in patent: Page/Page column 113-114
With trimethylaluminum In toluene at 60℃; for 1 h;
18.8 g (104 mmol) of 2,4-diaminophenylacetic acid methyl ester in 500 ml of absolute toluene is mixed at 4° C. with 52 ml of 2-molar solution of trimethyl aluminum in toluene, and then it is heated for 60 minutes to 60° C. After cooling, it is set at pH 7 with 2N sodium hydroxide solution, filtered on diatomaceous earth and extracted from ethyl acetate. The organic phase is washed, dried, filtered and concentrated by evaporation. 8.7 g (55percent of theory) of 6-amino-1,3-dihydro-indol-2-one is obtained.
To <strong>[150544-04-0]6-aminoindolin-2-one</strong> (30 mg, 0.202 mmol) in THF (1 mL) was added acetic anhydride (19 uL, 0.202 mmol). After 2 hrs the product was precipitated with ether, filtered and dried to give 25 mg, 66percent of a white solid. 1H NMR (400 MHz, CD3OD) delta 7.41 (s, IH), 7.16 (d, J = 7.0 Hz, IH), 7.00 (d, J = 8.0 Hz, IH), 3.49 (s, 2H), 2.12 (s, 3H); MS ESI 191.0 [M + H]+, calcd for [C10H10N2O2 + H]+ 191.08.
2,4-dinitrophenylacetic acid (10 g; 44 mmol) was dissolved in ethanol (200 mL) and purged with N2. 10percent Pd/C (400 mg) was added and the reaction hydrogenated at 45 psi for 2 hours. The reacton was then transferred to a RBF and p-toluenesulfonic acid (150 mg) was added and the reaction heated at reflux overnight. The reaction was then filtered through celite to remove catalyst and concentrated. The product crashed out and was filtered as tan crystals 4.68 g (72percent yield). 1H NMR (DMSO-d6, 400 MHz) delta 3.20 (s, 2H), 4.97 (br s, 2H), 6.07 (m, 2H), 6.76 (d, J=8.7 Hz; 1H), 10.05 (s, 1H); HPLC ret. time: 2.123 min. LRMS (M+) 148.7.
71%
With hydrogen; acetic acid;palladium on activated charcoal; In methanol; under 760.051 Torr;
A solution of 2-(2,4-dinitrophenyl)acetic acid (1.0 g, 4.42 mmol), AcOH (10 mL), and MeOH (5 mL) was purged with Ar for 15 minutes at which time 10wt. percent Pd/C (lOOmg) was added. The mixture was then purged briefly with H2 and then stirred under latm of H2 overnight. The mixture was filtered through a pad of celite, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 90:10 CH2Cl2/Me0H) to give 462 mg, 71 percent of a brown solid. 1H NMR (400 MHz, CD3OD) delta 6.95 (d, J = 7.7 Hz, IH), 6.37 (d, J = 7.8 Hz, IH), 6.34 (s, IH), 3.38 (s, 2H); MS ESI 149.0 [M + H]+, calcd for [C8H8N2O + H]+ 149.07.
With tin chloride; In ethanol; at 90℃; for 10h;
EXAMPLE 38 (FROM TABLE 3) 3-[2,4-Dimethyl-5-(6-Morpholin-4-Yl-2-Oxo-1,2-Dihydroindol-3-Ylidenemethyl)-1H-Pyrrol-3-Yl]-Propionic Acid Tin chloride dihydrate (225 g) was added to a solution of 2,4-dinitrophenylacetic acid (22.6 g) in ethanol (450 mL). The mixture was heated at 90° C. for 10 hours. The reaction mixture was cooled and basified to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 mL). The insolubles were filtered and washed with ethanol (5*60 mL). The combined ethanol washes were evaporated and dried under vacuum to give 15 g of 6-amino-2-oxindole as a brown powder. 1H-NMR (360 MHz, DMSO-d6): delta 10.03 (s, br, NH), 6.78 (d, J=8.55 Hz, 1H, H-4), 6.09-6.11 (m, 2H), 4.95 (s, br, 2H, NH2), 3.22 (s, 2H, H-3); MS (+APCI) m/z (relative intensity, percent) 147 ([M-1]+, 100).
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; ethanol; at 20 - 50℃; for 36h;
Example 73; 5-FIuoro-N-methyl-2-f2-(2-oxoindolin-6-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)benzamide; 6-Aminooxindole; Methanol (15 mL) and 1.25 M HCl in EtOH (10 ml) was added to 2,4- dinitrophenylacetic acid (837 mg, 3.7 mmol) and Pd/C (10percent; 205 mg) under Argon. The argon balloon was replaced with a hydrogen balloon and it was stirred at RT for <n="115"/>12 h and at 50 °C for 24 h. It was cooled to RT and filtered through celite. The solvent was removed and the residue was purified by silica gel chromatography (DCM/methanol gradient) to give the title compound as a red solid.
A mixture of 2,4-dinitrophenylacetic acid (10 g) and H2SO4 (0.1 eq) in EtOH (300 ml) was refluxed overnight. The solvent was evaporated, and EtOAc (150 ml) and H2O (200 ml) were added. The solution was extracted three times with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated to give ethyl 2-(2,4-dinitrophenyl)acetate for next step without further purification. The above compound (5 g) was mixed with Pd-C (10percent, 500 mg) in EtOH (200 ml) and hydrogenated under H2 atmosphere overnight. The reaction was filtered through Celite and evaporated. The residue was washed with EtOAc and filtered to give 6-aminoindolin-2-one.
Following the procedure of Example 2, but substituting ethyl (2,4-dinitrophenyl)acetate for methyl (5-fluoro-2,4-dinitrophenyl)acetate gives 6-amino-2-indolinone as a tan solid, mp 194°-195 C.
With sodium carbonate; acetic acid; In ethanol; hexane; water;
6-(Morpholin-4-yl)-2-oxindole 6-Amino-2-oxindole (2.2 g), 4.0 g 2,2'-dibromoethyl ether and 7.9 g sodium carbonate were refluxed in 20 ml ethanol overnight, concentrated and diluted with 50 ml of water. The mixture was extracted three times with 50 ml of ethyl acetate and the organic extracts combined, washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to dryness. The solid was chromatographed on a column of silica gel (ethyl acetate:hexane (1:1) containing 0.7percent acetic acid) to give 1.2 g (37percent yield) of the title compound as a beige solid.
37%
With sodium carbonate; acetic acid; In ethanol; hexane; water;
6-(Morpholin-4-yl)-2-oxindole 6-Amino-2-oxindole (2.2 g), 4.0 g 2,2'-dibromoethyl ether and 7.9 g sodium carbonate were refluxed in 20 ml ethanol overnight, concentrated and diluted with 50 ml of water. The mixture was extracted three times with 50 ml of ethyl acetate and the organic extracts combined, washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to dryness. The solid was chromatographed on a column of silica gel (ethyl acetate:hexane (1:1) containing 0.7percent acetic acid) to give 1.2 g (37percent yield) of the title compound as a beige solid.
37%
With sodium carbonate; In ethanol;Heating / reflux;
6-(Morpholin-4-yl)-2-oxindole 6-Amino-2-oxindole (2.2 g), 4.0 g 2,2'-dibromoethyl ether and 7.9 g sodium carbonate were refluxed in 20 ml ethanol overnight, concentrated and diluted with 50 ml of water.. The mixture was extracted three times with 50 ml of ethyl acetate and the organic extracts combined, washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to dryness.. The solid was chromatographed on a column of silica gel (ethyl acetate:hexane (1:1) containing 0.7percent acetic acid) to give 1.2 g (37percent yield) of the title compound as a beige solid.
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃;
An EtOH solution of (2,4-dinitro-phenyl)-acetic acid methylester was treated with H2 balloon and catalyzed with Pd/c(10percent, 500 mg) at RT. The resulting mixture was filteredthrough a layer of Celite.(R). and concentrated in vacuum toafford the desired compound.
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃;
An EtOH solution of (2,4-dinitro-phenyl)-acetic acid methyl ester was treated with H2 balloon and catalyzed with Pd/C (10percent, 500 mg) at RT. The resulting mixture was filtered through a layer of Celite.(R). and concentrated in vacuum to afford the desired compound.
A mixture of above compound (2 g) and ethyl 1,3-dioxobenzo[c]azolidine-2-carboxylate (1.1 eq) in THF was refluxed overnight. The reaction was cooled and the precipitate was filtered. The gray solid (2 g) was heated with acetic anhydride (2 eq) in acetic acid (40 ml) at 115° C. overnight. The solvent was evaporated and the product was triturated with 50percent EtOAc/Hexane and filtered to give 1-acetyl-6-(1,3-dioxobenzo[c]-azolidin-2-yl)-2-oxoindoline as a dark gray solid.
With trimethylaluminum; In toluene; at 60℃; for 1h;
18.8 g (104 mmol) of 2,4-diaminophenylacetic acid methyl ester in 500 ml of absolute toluene is mixed at 4° C. with 52 ml of 2-molar solution of trimethyl aluminum in toluene, and then it is heated for 60 minutes to 60° C. After cooling, it is set at pH 7 with 2N sodium hydroxide solution, filtered on diatomaceous earth and extracted from ethyl acetate. The organic phase is washed, dried, filtered and concentrated by evaporation. 8.7 g (55percent of theory) of 6-amino-1,3-dihydro-indol-2-one is obtained.
6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With triethylamine;zinc(II) chloride; In tetrahydrofuran; diethyl ether; at 20℃;
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (3.51 g; 16.2 mmol) in THF (100 mL) was added a solution of ZnCl2 (1M in ether; 16.2 mL). After 15 minutes 6-aminooxindole (2 g; 13.5 mmol) was added in small portions, followed by the dropwise addition of Et3N (1.63 g; 16.2 mmol) in 10 mL of THF. The reaction was then stirred at RT overnight. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 2.2 g (50percent yield). 1H NMR (DMSO-d6, 400 MHz) delta 3.40 (s, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.9 Hz; 1H), 7.27 (br s, 1H), 8.75 (s, 1H), 10.41 (s, 1H), 10.62 (s, 1H); HPLC ret. time: 5.933 min. LRMS (M+) 329.1, 331.0.
With triethylamine; In 1,4-dioxane; dichloromethane; at 20℃; for 2h;
[00108] To a solution of 6-amino-l ,3-dihydro-indol-2-one (0.15 g, 1.0 mmol) in2:1 CH2Cl2- 1,4-dioxane mixture (30 ml) is added triethylamine (0.30 g, 3.0 mmol) and benzoyl chloride (0.14 g, 1.0 mmol). The reaction is stirred for 2 hours at room temperature, and then a saturated aqueous solution OfNH4Cl is added. The precipitate is collected and washed with water to give crude N-(2-oxo-2,3-dihydro-lH-indol-6-yl)- benzamide. To a solution of this benzamide (20 mg, 0.079 mmol) and lH-rhoyrrole-2- carbaldehyde (7.6 mg, 0.079 mmol) in ethanol (2 ml) is added 2 drops of piperidine. It is EPO <DP n="37"/>stirred at 8O0C for 4 hours and then cooled to room, temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol and purified by HPLC (Ci8 column, eluted with CH3CN-H2O containing 0.05percent TFA) to give the desired compound as an orange solid: 1H NMR (DMSOd6) delta 6.34(s, IH)5 6.80 (s, IH), 7.33 (s, IH), 7.39 (d, IH, J = 8.4 Hz), 7.53 (t, 2H, J = 7.8 Hz), 7.57 (s, IH), 7.59 (s, IH), 7.61 (s, IH), 7.64 (s, IH), 7.96 (d, 2H, J = 7.8 Hz), 10.29 (s, IH), 10.94 (s, IH), 13.23 (s, IH); LC-MS: 330.1 (MH+).
Intermediate 4b and 2,5-dimethoxytetrahydrofuran (525mul) are added to acetic acid (17mL) and heated to 110°C for 3 hours. The mixture is then cooled to room temperature, diluted with water and the pH is adjusted to 10 using 2M NaOH. The reaction mixture is extracted using ethyl acetate (4 times). The organic phase is washed with water and saturated brine solution and dried over Na2SO4. The solvent is removed under reduced pressure. The residue is dissolved again in ethyl acetate and the resulting solid particles are removed by filtration. The solvent is again removed under reduced pressure to yield the desired intermediate 4c (790mg).
With triethylamine; In tetrahydrofuran; at 20℃; for 1h;
[00110] To a solution of 6-amino-l ,3-dihydro-indol-2-one (0.15g, 1.0 mmol) and triethylamine (0.30 g, 3.0 mmol) in THF (10 ml) is added l-isocyanato-3-nitro-benzene (0.16 g, 1.0 mmol). The reaction is stirred at room temperature for 1 hour and the precipitate is collected by vacuum filtration and washed with ethanol to give the desired compound as a light yellow solid. LC-MS: 313.1 (MH+).
EXAMPLE 38 3-[2,4-Dimethyl-5-(6-morpholin-4-yl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid Tin chloride dihydrate (225 g) was added to a solution of 2,4-dinitrophenylacetic acid (22.6 g) in ethanol (450 mL). The mixture was heated at 90° C. for 10 hours. The reaction mixture was cooled and basified to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 mL). The insolubles were filtered and washed with ethanol (5*60 mL). The combined ethanol washes were evaporated and dried under vacuum to give 15 g of 6-amino-2-oxindole as a brown powder. 1H-NMR (360 MHz, DMSO-d6): delta 10.03 (s, br, NH), 6.78 (d, J=8.55 Hz, 1H, H-4), 6.09-6.11 (m, 2H), 4.95 (s, br, 2H, NH2), 3.22 (s, 2H, H-3); MS (+APCI) m/z (relative intensity, percent) 147 ([M-1]+, 100).
25
[ 150544-04-0 ]
2'-dibromoethyl ether[ No CAS ]
[ 1026261-28-8 ]
Yield
Reaction Conditions
Operation in experiment
37%
With sodium carbonate; acetic acid; In ethanol; water;
6-Amino-2-oxindole (2.2 g), 4.0 g 2, 2'-dibromoethyl ether and 7.9 g sodium carbonate were refluxed overnight in 20 ml of ethanol, concentrated and diluted with 50 ml of water. The mixture was extracted three times with 50 ml ethyl acetate, the organic extracts were combined, washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to dryness. The solid was chromatographed on a column of silica gel eluding with ethyl acetate:hexane 1:1 containing 0.7percent acetic acid to give 1.2 g (37percent yield) of 6-(morpholin-4-yl)-2-oxindole as a beige solid. 1H-NMR (360 MHz, DMSO-d6): delta 10.2 (s, br, 1H, NH-1), 7.02 (d, J=7.87 Hz, 1H, H-4), 6.47 (dd, J=2.11, 7.87 Hz, 1H, H-5), 6.37 (d, J=2.11 Hz, 1H, H-7), 3.69-3.72 (m, 4H), 3.32 (s, 2H, CH2), 3.01-3.04 (m, 4H); MS m/z (relative intensity, percent) 219 ([M+1]+, 100).
N-(2-oxo-6-indolinyl)-1-cyclohexene-1,2-dicarboximide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Following the procedure of Example 3, but substituting <strong>[150544-04-0]6-amino-2-indolinone</strong> for 6-amino-5-fluoro-2-indolinone gives N-(2-oxo-6-indolinyl)-1-cyclohexene-1,2-dicarboximide as a green solid, mp 225°-226° C.
With sodium carbonate; In ethanol;Heating / reflux;
6-Morpholin-4-yl)-2-oxindole 6-Amino-2-oxindole (2.2 g), 4.0 g, 2,2'-dibromoethyl ether and 7.9 g sodium carbonate were refluxed in 20 ml ethanol overnight, concentrated and diluted with 50 ml of water. The mixture was extracted three times with 50 ml of ethyl acetate and the organic extracts combined, washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to dryness. The solid was chromatographed on a column of silica gel (ethyl acetate:hexane (1:1) containing 0.7percent acetic acid) to give 1.2 g (37percent yield) of the title compound as a beige solid.
A THF (2.5 mL) solution of <strong>[150544-04-0]6-aminoindolin-2-one</strong> (100 mg, 0.675 mmol) and di-t- butyl dicarbonate (155 mg, 0.709 mmol) at rt under N2, was treated with Et3N (0.28 mL, 2.03 mmol). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, CH2Cl2/Me0H, 98:2 to 95:5) to give 76 mg,45percent of a tan solid. 1U NMR (400 MHz, CDCl3) delta 7.21 (s, IH), 7.10 (d, J = 8.08 Hz,IH), 6.88 (d, J = 7.58 Hz, IH), 3.45 (s, 2H), 1.51 (s, 9H); MS ESI 249.0 [M + H]+, calcd for [C13Hi6N2O3+ H]+ 249.12.
To 2,4-dimtrophenylacetic acid (1.2 gm) in methanol (60 mE), added Pd/C (80 mg, 10 wt percent). H2 gas environment was maintained with pressure using hydrogen gas balloon and solution stirred for 6 hours at RT. The catalyst was removed by filtration, over celite. The filtrate was concentrated in vacuo to give 2,4-diaminophenylacetic acid without further purification, immediately refluxed with 16 ml of iN HC1 for 6 hrs. Reaction was monitored with TEC. The solution was neutralized with 1percent sodium hydroxide, extracted with three portions of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate or magnesium sulfate, evaporated in vacuo to get the title compoundD4: YD: 67.85percent: mp: 193-195° C.; R1 0.358 (EA:Hx : 7.0:3.0). ?H NMR (DMSO-d6) 200 MHz, delta 3.227 (s, 2H), 5.004 (s, 2H) -NH2, 6.094 (dd, J=2.2 & 6.2 Hz, 1H), 6.098 (d, J=2.0 Hz, 1H), 6.786 (d, J=8.4 Hz, 1H), 10.088 (s, 1H). MS (ESI): mlz 146.8 [M-H]-.
(4-amino-2-nitro-phenyl)-acetic acid methyl ester[ No CAS ]
[ 150544-04-0 ]
Yield
Reaction Conditions
Operation in experiment
<Step 4> 6-aminoindolin-2-one[380] Palladium/charcoal (108 mg, 10 wtpercent) was added to a solution of methyl 2-(4-amino-2-nitrophenyl)acetate (885.9 mg, 4.22 mmol) prepared in Step 3 in methanol (20 ml). The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight and then filtered through a celite pad. The resulting filtrate was concentrated under reduced pressure. The resulting residue was mixed with a 10 percent hydrochloric acid solution (5 ml) and then refluxed under stirring for 3 hours. The reaction mixture was cooled to room temperature, controlled to pH 5 with a 2N sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate = 1/1) to give 330 mg of the titled compound as a yellow solid.[381] 1H-NMR(400MHz, CDCl3) delta 7.39(brs, NH), 6.98(d, 1H), 6.31(d, 1H), 6.22(s, 1H), 3.69(brs, NH), 3.43(s, 2H)
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; for 3h;
6-Aminoindolin-2-one (148.0 mg, 1.0 mmol) was made to react to D72 (197.0 mg, 1.0 mmol) in the presence of TBTU (487.0 mg, 1.5 mmol) and TEA (0.42 mL, 3.0 mmol) in a mixture of dry DMF and acetonitrile (1:3, 6 mL) under rt for 3 h. Resultant solid was collected, washed by water and dried to give the title compound. YD: 65percent; mp: 221° C. (Charring). 1H-NMR (400 MHz, DMSO-d6) delta: 3.39 (s, 2H, CH2), 3.43 (s, 2H, CH2), 7.01 (d, J=8.4 Hz, 1H, ArH), 7.10 (d, J=8.4 Hz, 1H, ArH), 7.17-7.12 (m, 2H, ArH), 7.35 (s, 1H, ArH), 7.63-7.59 (m, 2H, ArH), 10.11 (s, 1H, NH), 10.20 (s, 1H, NH), 10.35 (s, 1H, NH). Anal. (C17H14FN3O3.1H2O) C, H, N. MS (ESI) 325.9 (M-H)-.
213 mg
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
bis(trichloromethyl)carbonate in tetrahydrofuran was added dropwise within 1 hour to the compound D78 in tetrahydrofuran in such a way that the internal temperature was kept at 55-60° C. The mixture was stirred for 5 h at this temperature. The formation of 3-methyl-2-oxoimidazolidine-1-carbonyl chloride was confirmed by TLC. The <strong>[150544-04-0]6-aminoindolin-2-one</strong> (D4) was added to the mixture in situ and the mixture was relluxed for 4 h. The completion of reaction was monitored using TLC. The residue obtained after workup using saturated sodium carbonate was further purified using flash chromatography on silica gel to afford the title compound D79.
With toluene-4-sulfonic acid; In tetrahydrofuran; N,N-dimethyl-formamide; at 60℃; for 22h;
To a solution of 1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3- yn-2-yl)-1-(p-tolyl)-1 H-pyrazol-5-yl)urea (see Example 2(H) above; 254 mg, 0.473 mmol) in DMF (4 ml_) and THF (2 ml_) was added p-TSA monohydrate (90 mg, 0.473 mmol) followed by <strong>[150544-04-0]6-aminoindolin-2-one</strong> (140 mg, 0.946 mmol) and the reaction heated at 60 °C for 22 h. The reaction mixture was partitioned between ethyl acetate (20 ml_) and sat. aqueous sodium bicarbonate (10 ml_). The organic layer was taken, dried over MgS04, filtered and concentrated under reduced pressure to afford 150 mg of a brown solid. The MgS04 was washed with 10percent MeOH/DCM (50 ml_) and the washings concentrated under reduced pressure to afford a pale yellow powder which was purified by chromatography on the Companion (12 g column, 0-10percent MeOH in DCM) to afford the title compound (50 mg) as a pale yellow powder. 1 H NMR (400 MHz; DMSO-d6) delta: 10.19 (s, 1 H), 9.49 (s, 1 H), 9.16 (s, 1 H), 8.82 (s, 1 H), 8.37 (d, 1 H), 8.07 (d, 1 H), 7.93 (d, 1 H), 7.82 (dd, 1 H), 7.63 (ddd, 1 H), 7.56 (ddd, 1 H), 7.50-7.46 (m, 2H), 7.43-7.38 (m, 3H), 7.14 (br.s, 1 H), 6.95 (br.dd, 1 H), 6.79 (br.dd, 1 H), 6.56 (s, 1 H), 6.49 (d, 1 H), 3.30 (s, 2H), 3.10 (s, 1 H), 2.41 (s, 3H), 6.17 (s, 6H). LCMS m/z 649 (M+H)+ (ES+); 647 (M-H)" (ES")
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
N-(4-fluorophenyl)-N-(2-oxoindolin-6-yl)cyclopropane-1,1-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
N-(4-methoxyphenyl)-N-(2-oxoindolin-6-yl)cyclopropane-1,1-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
(Z)-5-(4-fluorophenyl)-N-(3-((4-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide[ No CAS ]
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 3h;
General procedure: Appropriate aminoindolin-2-one (1equiv) was added to a mixture of appropriate 3-amino-3-oxopropanoic acid/2-pyridone acid/4-pyridone acid (1equiv), TBTU (1.5equiv) and TEA (3equiv) in DMF/acetonitrile (1:3, 0.16M). The resulting reaction mixture was stirred at room temperature for 3h. Reaction mixture was then concentrated in vacuo. Title compound was collected as solid by filtration and dried.
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