* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 716 - 719[2] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 940 - 943
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 716 - 719[4] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 940 - 943
With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; for 0.0833333 h; Inert atmosphere
General procedure: TiCl4 (0.7 mL, 6 mmol)was added to a stirred suspension of Zn powder (0.78 g, 12 mmol) in freshlydistilled anhydrous THF (15 mL) at room temperature (rt) under a dry N2atmosphere. After completion of the addition, the mixture was refluxed for 2 h.The suspension of the low-valent titanium reagent thus-formed was cooled tort. A solution of isatin or its derivatives 1 or 3 (2 mmol) in THF (10 mL) wasadded dropwise. The mixture was stirred at room temperature for about 5 minunder N2. After this period, the thin layer chromatography (TLC) analysis of themixture showed the reaction completed. The reaction mixture was quenchedwith 3percent HCl (15 mL) and extracted with CHCl3 (3 50 mL). The combinedextracts were washed with water (3 50 mL) and dried over anhydrousNa2SO4. After evaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography (petroleum ether/ethylacetate = 5:1) to give the pure products 2 or 4.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 14, p. 2238 - 2242
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 2033 - 2042
[3] Patent: US4658037, 1987, A,
[4] Patent: US4652658, 1987, A,
[5] Patent: US4730004, 1988, A,
[6] Patent: US4721712, 1988, A,
[7] Patent: US4725616, 1988, A,
[8] Patent: US4556672, 1985, A,
[9] Patent: US4569942, 1986, A,
[10] Patent: US4690943, 1987, A,
[11] Patent: EP208510, 1991, B1,
[12] Tetrahedron, 2011, vol. 67, # 5, p. 982 - 989
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[14] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6371 - 6379
[15] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1071 - 1082
4
[ 147124-32-1 ]
[ 56341-37-8 ]
Yield
Reaction Conditions
Operation in experiment
75%
With iron; acetic acid In 5,5-dimethyl-1,3-cyclohexadiene at 25 - 105℃; Large scale
Example- 4: Preparation of 6-chloro 2-oxindole (iron as reductant) 3.5L acetic acid is charged with 1 kg of dimethyl ester of 2- nitrophenylmalonate, 4.5L xylene under stirring at 25-30°C. 0.573 kg iron powder is added in lots keeping the temperature at 25-30°C. Stirring is continued when temperature reaches at 45-50°C. Reaction mass is then heated to reach at 100-105 °Ctill HPLC showed cyclized monoester to be less than lpercent.Reaction mass is gradually cooled to reach at 30-35°C and 10L water is added slowly under stirring followed by addition of 6L of con HC1 keeping the temperature below 40°C. Contents are cooled to 10- 15°C and 6-choloro 2-oxindole is collected by filtration, washed with water till free from free acid. Crude weight: 0.7kg, areapercent= 96percent, assay=93percent Crude is purified from ethyl acetate. Dry weight: 0.43kg, yield=75percent areapercent=99.91percent, assay 99.82percent , sulphated ash:0.04percent
75%
Stage #1: With hydrogenchloride; water In methanol at 20 - 95℃; Large scale Stage #2: With tin In methanol at 45 - 95℃; Large scale
Example- 4: Preparation of 6-chloro 2-oxindole (Tin as reductant metal): 8.8 L methanol is charged with 1.1 kg dimethyl ester of 2- nitrophenylmalonate under stirring at ambient temperature followed by the addition of 4.8 L concentrated hydrochloric acid keeping the temperature in the range of 30-40°C. Contents are heated to reach at 75- 80°C till clear solution is obtained. Methanol is distilled off at 90-95°C reaction mass is compensated with 4Lwater and the reaction mass is maintained at 90-95 °C till HPLC showed malonate to be less than 2percent. Reaction mass is cooled to 45-50°C and 4L methanol is added followed by adding 0.975g tin in lots keeping the temperature in the range of 45- 50°C. Temperature is brought to 75-80°C by gradual heating and maintained for 2-3 hours. Methanol is distilled off at 90-95 °C with compensating the mass with (6.8L) 5N HC1 under stirring at 92-95 °C with HPLC monitoring for content of nitro phenyl acetic acid and nitro phenyl methyl acetate to be less than 1percent. Contents were cooled to 15- 20°C and product is filtered of, washed with water till free from acidity. Wt of crude =0.7kg, Areapercent = 96, HPLC assay= 86percent The crude mass is further purified from ethyl acetate. Dry weight = 0.5kg, yield 75percent, area: 98percent, HPLC assay 97.98percent, , sulphated ash 0.08percent
Reference：
[1] Patent: WO2013/93928, 2013, A1, . Location in patent: Page/Page column 49; 50
[2] Patent: WO2013/93928, 2013, A1, . Location in patent: Page/Page column 49
[3] Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1828 - 1834
[4] Synthesis, 1993, # 1, p. 51 - 53
[5] Patent: WO2012/20424, 2012, A1, . Location in patent: Page/Page column 13
[6] Patent: CN105753765, 2016, A,
[7] Patent: CN105753765, 2016, A,
5
[ 37777-71-2 ]
[ 28230-26-4 ]
[ 56341-37-8 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With 1,10-Phenanthroline; platinum on carbon; hydrogen In ethanol at 20℃; Flow reactor; Green chemistry Stage #2: With acetic acid In ethanol at 20℃; Green chemistry
General procedure: Ethanol (30 mL) wasadded to 2-nitrophenylacetic acid (300 mg, 1.66 mmol) and 1,10-phenanthroline (33 mg, 0.23 mmol) in a reaction flask. The resultant solutionwas pumped through the H-Cube Mini (5percent Pt/C, 20 C, flowrate 1.5 mL min1,H2 inlet pressure 610 bar) to near dryness. Then the reaction flask was rinsedwith ethanol (3 5 mL). The product eluant from the H-Cube was collected andconcentrated in vacuo to 1 mL, then diluted to 6 mL with ethanol. Glacialacetic acid (0.21 mL, 36.7 mmol) was added and the reaction mixture stirredovernight at room temperature. The reaction mixture was concentrated invacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with saturatedaqueous NaHCO3 (5 5 mL). The combined aqueous extracts were treated withconc. H2SO4 to pH 1 to precipitate the hydroxamic acid, which was filteredand washed with cold deionized water (10 mL).
Reference：
[1] Patent: WO2003/99198, 2003, A2, . Location in patent: Page 12-13
[2] Patent: CN105753765, 2016, A,
7
[ 588-07-8 ]
[ 623-48-3 ]
[ 56341-37-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
at 120℃; for 24 h; Sealed tube; Inert atmosphere; Schlenk technique
General procedure: A seal-tube (15 mL) initially fitted with a septum containing anilide 1 (0.5 mmol), Pd(OAc)2 (11.3 mg, 0.05 mmol, 10 molpercent), and AgOAc (83.5 mg, 0.5 mmol) was evacuated and purged with N2 three times. TFA (4.0 mL), and ethyl 2-iodoacetate (2a; 160 mg, 0.75 mmol) were added to the system and the reaction mixture was stirred at 120 °C for 24 h. The mixture was cooled to r.t. and filtered through a short Celite pad and washed with CH2Cl2 several times. The filtrate was concentrated under vacuum and purified on a silica gel column using hexane/EtOAc as eluent to give the corresponding pure oxindole product 3.
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 716 - 719[2] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 940 - 943
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[4] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6371 - 6379
[5] Synthesis (Germany), 2016, vol. 48, # 12, p. 1872 - 1879
13
[ 879-32-3 ]
[ 56341-37-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 2033 - 2042
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6371 - 6379
14
[ 17122-55-3 ]
[ 56341-37-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6371 - 6379
15
[ 1261152-95-7 ]
[ 56341-37-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
16
[ 2564-05-8 ]
[ 20870-77-3 ]
[ 56341-37-8 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 716 - 719[2] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 940 - 943
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 716 - 719[4] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 940 - 943
17
[ 56341-37-8 ]
[ 118289-55-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 143 - 148
[2] Patent: WO2012/20424, 2012, A1,
[3] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1142 - 1145
18
[ 56341-37-8 ]
[ 884305-06-0 ]
[ 118289-55-7 ]
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1142 - 1145
19
[ 56341-37-8 ]
[ 884305-06-0 ]
[ 118289-55-7 ]
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1142 - 1145
20
[ 56341-37-8 ]
[ 1156390-49-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3500 - 3511
With sodium hydroxide In water Heating; Yield given;
With sodium hydroxide In water at 100℃; for 1.66667h;
1.1
EXAMPLE 1; Compound No. 16; 7-chloro-N,N,9-trimethyl-2-pyridin-3-yl-9H-pyrimido[4,5-b]indole-4-carboxamide; 1.1. 6-chloro-1-methyl-1,3-dihydro-2H-indol-2-one; 20 g (0.119 mol) of 6-chloro-1,3-dihydro-2H-indol-2-one were introduced into 600 ml of water. Next, 17 ml (0.180 mol) of dimethyl sulfate and 7.2 g (0.180 mol) of sodium hydroxide pellets were added. The mixture was heated at 100° C. for 20 min. The hot mixture was filtered. The insoluble part containing the starting oxindole was kept. The filtrate was cooled with an ice bath, then it was filtered. A white solid was recovered that was rinsed with water. The insoluble part obtained in the first filtration was added to the filtrate, then 17 ml (0.180 mol) of dimethyl sulfate and 7.2 g (0.180 mol) of sodium hydroxide pellets were added. The mixture was brought to 100° C. for 20 min. The hot mixture was filtered. The insoluble part was kept. The filtrate was cooled with an ice bath, then it was filtered. A white solid was recovered that was rinsed with water. This cycle was then repeated 3 times. At the end, the solids obtained from the various filtrations were combined and they were dried under vacuum in the presence of phosphorus pentoxide. The solid was purified by chromatography on a column of neutral alumina gel with a mixture of solvents (petroleum ether/dichloromethane: 20/80).9.8 g of 6-chloro-1-methyl-1,3-dihydro-2H-indol-2-one were isolated in the form of a white solid.M.P.: 116-117° C.
6-CHLOROOXINDOLE (2.5 g, 14.9 MMOL) was suspended in 50 ml 4 M aqueous NAOH and the mixture was REFLUXED for 6 hours. The reaction mixture was allowed to cool and the product precipitated and filtered off with suction. The solid was dissolved in water (100 ml) and precipitated with 4 M aqueous HCI at 0C. The solid was then filtered with suction and dried under vacuum to yield 2.0 g (72%) of white crystalline solid. (2-Amino-4-chloro-phenyl)-acetic acid (700 mg, 3.8 MMOL) was then dissolved in 25 ML pyridine and 1-bromo-3-isocyanato-benzene (811 mg, 4.1 MMOL) was added drop-wise and the solution was stirred for 90 minutes. The reaction mixture was diluted with 150 ml ethyl acetate and washed twice with 1 M aqueous HCI. The organic phase was reduced under vacuum and the product recrystallised from ethyl ACETATE/HEPTANE to yield 680 mg of white crystalline solid (47%) (m. p. 195-196C)
Stage #1: 4-chloro-2-nitro-phenylacetic acid With iron; acetic acid In methanol at 50 - 75℃; for 1h;
Stage #2: With hydrogenchloride In methanol; water at 20 - 25℃;
3 Example 3; Preparation of 6-chloro-oxindole.
Preparation of 6-chloro-oxindole. 4 chloro-2-nitrophenylacetic acid (l00 mg) is mixed with acetic acid (250ml) and methanol (250 ml.) At 25-30°C. The reaction mixture is then heated to 50-55°C and iron powder (64.7 gm) is then added to it. The temperature is raised to about 75°C and the reaction mixture is heated with stirring for an hour. The reaction mixture is then cooled to 40-45°C and chilled water (5 liters) is added to it, followed by concentrated hydrochloric acid (0.5 liters). The temperature is maintained at 20-25°C. The 6-chloro-oxindole thus obtained is filtered, washed with water till the mother liquor shows a pH of 4.5-5.5, and dried at 70°C under vacuum.
Multi-step reaction with 2 steps
1: sodium dithionite / ethanol / 4 h / 40 - 45 °C
2: hydrogenchloride / ethanol / 2 h / 70 - 75 °C / pH 2 - 2.5
N-[3,5-Bis(trifluoromethyl)phenyl]-6-chloro-2-hydroxyindole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.7%
With triethylamine In tetrahydrofuran at 20℃; for 4h;
77
A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added to a solution of 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) in tetrahydrofuran(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6):δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%
With triethylamine In tetrahydrofuran at 20℃; for 4h;
77
A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added to a solution of 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) in tetrahydrofuran(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6):δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%
With triethylamine In tetrahydrofuran at 20℃; for 4h;
77
A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added to a solution of 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) in tetrahydrofuran(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6):δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%
With triethylamine In tetrahydrofuran at 20℃; for 4h;
28
Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) was dissolved in tetrahydrofuran(5mL). A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%
With triethylamine In tetrahydrofuran at 20℃; for 4h;
28
Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) was dissolved in tetrahydrofuran(5mL). A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%
With triethylamine In tetrahydrofuran at 20℃; for 4h;
28
Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) was dissolved in tetrahydrofuran(5mL). A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
30a E/Z-6-Chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one
EXAMPLE 30a E/Z-6-Chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 hours. After cooling to 4° C., the resulting precipitate was collected and dried to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. (Yield 25.2 g, 95%).
95%
With pyrrolidine In methanol at 70℃; for 3h;
1.a Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one
EXAMPLE 1a Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 25.2 g, 95%).
95%
With pyrrolidine In methanol at 70℃; for 3h;
61 Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one
To the mixture of 6-chloro-2-oxindole (16.2 g, 92 mmol) (Crescent) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 25.2 g, 95%).
94.4%
With pyrrolidine In methanol at 70℃; for 3h;
1 Preparation of intermediate E/Z-6-chloro-3-[1-(3-chlorophenyl)-methylidene]-1,3-dihydro-indol-2-one
EXAMPLE 1Preparation of intermediate E/Z-6-chloro-3-[1-(3-chlorophenyl)-methylidene]-1,3-dihydro-indol-2-one To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 25.2 g, 94.4%).
With piperidine In ethanol Reflux; Inert atmosphere;
4.1.1. General procedure for the synthesis of 2-indolinones
General procedure: A reaction mixture of the proper substituted indolin-2-ones 6,aldehyde (1.2 eq.), and piperidine (0.1 eq.) in ethanol (1 mL/0.5 mmol oxindole) was refluxed for 3-5 h, under nitrogen atmosphere. After, the mixture was cooled and put on ice, where the product precipitated. The product was filtered in vacuum with cold ethanol [10,14-17]. Finally, the product was placed in the vacuum desiccators to give the expected compound. The indolin-2-ones 3e was generated through substituted isatin in the presence of hydrazine monohydrate and ethylene glycerol, under reflux [18].
With pyrrolidine In methanol at 70℃; for 3h;
1a
EXAMPLE 1a Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one To the mixture of 6-chlorooxindole (16.7 g, 0.1 mol) (Crescent) and 3-chlorobenzaldehyde (14.1 g, 0.1 mol) (Aldrich) in methanol (100 mL) was added pyrrolidine (7.1 g, 0.1 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 20 g of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.
With piperidine In methanol at 70℃; for 5h;
1 Example 1
Compound 1 (62 mmol) and Compound 2 (60 mmol) were dissolved in 200 mL of methanol.After the dissolution was sufficient, piperidine (12 mmol) was added, and the mixture was refluxed at 70 °C.After 5 hours, it was cooled to room temperature and stirred overnight.After the reaction is completed, the suspension is filtered.The obtained solid was washed three times with methanol and dried to give a yellow solid.Compound 3 data:
With piperidine In ethanol Inert atmosphere; Reflux;
2.1 Preparation of the Alkylidene Oxindoles:
General procedure: To the oxindole (A, 1.49 mmol, 1 eq.) and aldehyde (B, 2.24 mmol, 1.5 eq.) in ethanol (3 mL) was added piperidine (0.15 mmol, 0.1 eq.) and the reaction mixture was stirred under reflux overnight. The solution was diluted with ethyl acetate and washed twice with brine. The organic layers were dried over Na2SO4 and evaporated under reduced pressure. The product (1) was isolated as a yellow solid after silica gel column chromatographic purification (cHex/EtOAc 85:15 → EtOAc → ethanol) as a dark yellow solid.
54d
EXAMPLE 54d; Preparation of intermediate E/Z-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-acetonitrile; To the mixture of 6-chlorooxindole (18.4 g, 0.110 mol) and (4-chloro-2-formyl-phenoxy)-acetonitrile (21.5 g, 0.110 mol) in methanol (200 mL) was added pyrrolidine (8.60 g, 0.121 mol) dropwise. Then the mixture was heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered. The precipitate was collected and dried to give the title compound as a yellow solid (8.5 g).
6-chloroindolin-2-one (8.35 g, 50 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (8.295 g, 52.5 mmol) were stirred at reflux for 6 hours in the presence of piperidine (1 ml). Then filter the reaction suspension, The collected solid was washed with methanol and dried to give (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indol-2-one product (14.63 g, 47.5) as a yellow solid. Mmol), yield 95%.
95%
With piperidine; for 6h;Reflux;
6-Chloroindolin-2-one (8.35 g, 50 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (8.295 g, 52.5 mmol) were stirred at reflux in the presence of piperidine (1 ml) for 6 hours. The reaction suspension was then filtered, and the solid obtained was washed with methanol and dried to give a yellow solid product, (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indol2-one (14.63g, 47.5mmol). Yield: 95%. 1H NMR (400MHz, DMSO): delta 10.85 (s, 1 H), 7.70 (q, J=7.3Hz 2 H), 7.54 (s, 1 H), 7.36 (t, J=8Hz 1 H), 7.16 (d, J=8Hz 1 H), 6.92-6.86 (m, 2 H); MS: Calcd for C15H9Cl2FNO ([M+H]+): 308, found: 308.0.
84%
With piperidine; In methanol; at 50℃; for 3h;
General procedure: To the mixture of optionally substituted 6-chlorooxindole (5.0 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was addedpiperidine (Aldrich) (1.7 g, 20 mmol) dropwise. The mixture was then heated at 50 Cfor 3 h. After cooled to 4 C, the mixture was filtered and resulting precipitate wascollected, washed with cold methanol, dried to give the desired product.(E)-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one 13.1 (R3a = H,R3b = H, R3c = H): a yellow solid (Yield, 84%); 1H NMR (300 MHz, DMSO-d6) 10.88 (br.s., 1H), 7.73 (q, J = 7.41 Hz, 2H), 7.56 (s, 1H), 7.34 - 7.43 (m, 1H), 7.17 (d, J = 8.10 Hz,1H), 6.87 - 6.97 (m, 2H) ppm.
With piperidine; In methanol;
3-Chloro-2-fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6-chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3) as a green solid.
To the mixture of 6-chloro-2-oxindole (5.3 g, 32 mmol) (Crescent) and <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (5 g, 32 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.7 g, 32 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 8 g, 82%).
To the mixture of 6-chloro-2-oxindole (4.4 g, 26 mmol) (Crescent) and <strong>[90390-49-1]3-chloro-5-fluorobenzaldehyde</strong> (4.2 g, 26 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.3 g, 26 mmol) (Aldrich) dropwise.The mixture was then heated at 80° C. for 2 h.After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.5 g, 92percent).
To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).
Stage #1: 6-chloro-2-oxindole; azulene With trifluoromethylsulfonic anhydride In dichloromethane at 20℃; for 2.5h;
Stage #2: With potassium carbonate In dichloromethane; water
A typical procedure: Tf2O (203 mg, 0.72 mmol) in CH2Cl2 (5 mL) were added at room temperature to a solution of azulene (1) (67 mg, 0.52 mmol) and 2-indolinone (101 mg, 0.76 mmol) in CH2Cl2 (15 mL). The resulting solution was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into a 2 M K2CO3 solution, extracted with AcOEt, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel with hexane/AcOEt (10:1) as an eluent to give 1-(indol-2-yl)azulene (2) (113 mg, 89%) as green crystals.
With hydrogenchloride; In ethanol; at 70 - 75℃; for 2.0h;pH 2 - 2.5;
(5) The pH of the reaction system was adjusted to 2.0-2.5 with concentrated hydrochloric acid, the reaction was carried out in water bath at 70-75 C for 2 hours and the disappearance of TLC (chloroform: methanol = 10: 1) Stirring at room temperature for 2 hours or more, filtering to get wet product; 50 ± 10 C under reduced pressure drying, 6-chloro-2-indolone 157.2g, 75% yield.
Stage #1: 4-chloro-2-nitro-phenylacetic acid With 1,10-Phenanthroline; platinum on carbon; hydrogen In ethanol at 20℃; Flow reactor; Green chemistry;
Stage #2: With acetic acid In ethanol at 20℃; Green chemistry;
Representative continuous-flow hydrogenation procedure
General procedure: Ethanol (30 mL) wasadded to 2-nitrophenylacetic acid (300 mg, 1.66 mmol) and 1,10-phenanthroline (33 mg, 0.23 mmol) in a reaction flask. The resultant solutionwas pumped through the H-Cube Mini (5% Pt/C, 20 C, flowrate 1.5 mL min1,H2 inlet pressure 610 bar) to near dryness. Then the reaction flask was rinsedwith ethanol (3 5 mL). The product eluant from the H-Cube was collected andconcentrated in vacuo to 1 mL, then diluted to 6 mL with ethanol. Glacialacetic acid (0.21 mL, 36.7 mmol) was added and the reaction mixture stirredovernight at room temperature. The reaction mixture was concentrated invacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with saturatedaqueous NaHCO3 (5 5 mL). The combined aqueous extracts were treated withconc. H2SO4 to pH 1 to precipitate the hydroxamic acid, which was filteredand washed with cold deionized water (10 mL).
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