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[ CAS No. 59-48-3 ] {[proInfo.proName]}

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Chemical Structure| 59-48-3
Chemical Structure| 59-48-3
Structure of 59-48-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 59-48-3 ]

CAS No. :59-48-3 MDL No. :MFCD00005711
Formula : C8H7NO Boiling Point : -
Linear Structure Formula :- InChI Key :JYGFTBXVXVMTGB-UHFFFAOYSA-N
M.W : 133.15 Pubchem ID :321710
Synonyms :
2-Indolinone;NSC 274863;Indolin-2-one;2-Oxindole;2-indolone

Calculated chemistry of [ 59-48-3 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.73
TPSA : 29.1 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.29 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.42
Log Po/w (XLOGP3) : 1.16
Log Po/w (WLOGP) : 0.61
Log Po/w (MLOGP) : 1.13
Log Po/w (SILICOS-IT) : 1.91
Consensus Log Po/w : 1.25

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.84
Solubility : 1.92 mg/ml ; 0.0144 mol/l
Class : Very soluble
Log S (Ali) : -1.37
Solubility : 5.73 mg/ml ; 0.043 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.85
Solubility : 0.186 mg/ml ; 0.0014 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.18

Safety of [ 59-48-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 59-48-3 ]

* 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.

  • Upstream synthesis route of [ 59-48-3 ]
  • Downstream synthetic route of [ 59-48-3 ]

[ 59-48-3 ] Synthesis Path-Upstream   1~50

  • 1
  • [ 59-48-3 ]
  • [ 2058-74-4 ]
  • [ 97207-47-1 ]
YieldReaction ConditionsOperation in experiment
86% With zirconium(IV) chloride In ethanolReflux General procedure: A mixture of isatins (1, 1.0 mmol), indolin-2-ones (2, 1.0 mmol) and ZrCl4 (23 mg, 0.1 mmol) was heated in anhydrous ethanol (5 mL) under reflux. After the disappearance of the reactants (8–12 h, monitored by TLC), the mixture was slowly cooled to room temperature. The red solids precipitated and were collected by filtration, then washed by a small amount of anhydrous ethanol to deliver pure compounds 3.
Reference: [1] Tetrahedron Letters, 2016, vol. 57, # 52, p. 5856 - 5858
[2] Bulletin de la Societe Chimique de France, 1914, vol. <4> 15, p. 335[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1913, vol. 156, p. 1385
  • 2
  • [ 59-48-3 ]
  • [ 61-70-1 ]
  • [ 97207-47-1 ]
Reference: [1] Chemical Communications, 2018, vol. 54, # 59, p. 8265 - 8268
  • 3
  • [ 59-48-3 ]
  • [ 74-88-4 ]
  • [ 19155-24-9 ]
YieldReaction ConditionsOperation in experiment
48.3%
Stage #1: With n-butyllithium; lithium chloride In tetrahydrofuran at -78℃; for 0.333333 h;
Stage #2: at 25℃;
To a solution of indolin-2-one (5 g, 37.55 mmol) and LiCl (5.6 g, 131.4 mmol) in THF (100 mL) was added w-BuLi (2.5 M, 30 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min, followed by the addition of Mel (4.8 mL, 75.1 mmol). The reaction was stirred at 25 °C overnight, then quenched with saturated aqueous NH4C1 (100 mL) and diluted with EtOAc (100 mL x 3). The organic phase was washed with H20 (100 mL) followed by brine (100 mL), dried over anhydrous a2S04, filtered and concentrated in vacuo. The residue was purified by a silca gel column chromatography (PE/EtOAc (v/v) = 8/1) to give the title compound as a white solid (2.92 g, 48.3percent). MS (ESI, pos. ion) m/z: 162 [M + H]+; NMR (CDCI3) δ (ppm): 9.23 (s, 1H), 7.21-7.18 (m, 2H), 7.04 (t, 1H), 6.96 (d, 1H), 1.41 (s, 6H).
41%
Stage #1: With n-butyllithium; lithium chloride In tetrahydrofuran; hexanes at -78℃; for 0.333333 h;
Stage #2: at -78 - 25℃;
Step 1
Oxindole (20.0 g; 0.15 mol) and lithium chloride (21.0 g; 0.49 mol) were suspended in tetrahydrofuran (400 mL) and the mixture cooled to -78° C. n-Butyllithium (120.0 mL; 0.30 mol, 2.5M in hexanes) was added slowly and the mixture was stirred for 20 minutes, then iodomethane (18.7 mL; 0.30 mol) was added.
The mixture was warmed to 25° C., stirred overnight and then quenched with saturated aqueous ammonium chloride and diluted with diethyl ether.
The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
Purification by flash chromatography (0-20percent ethyl acetate-hexane) afforded 10.0 g (41percent) of 3,3-dimethyl-1,3-dihydro-indol-2-one as a yellow solid. MS (ESI) m/z 162 ([M+H]+).
Reference: [1] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0202
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 4929 - 4931
[3] Patent: US2007/72897, 2007, A1, . Location in patent: Page/Page column 66
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 419 - 430
[5] ChemMedChem, 2016, vol. 11, # 5, p. 497 - 508
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 23, p. 3487 - 3490
  • 4
  • [ 59-48-3 ]
  • [ 77-78-1 ]
  • [ 61-70-1 ]
YieldReaction ConditionsOperation in experiment
67% With sodium hydroxide In water at 40 - 100℃; for 0.5 h; Heating / reflux To 5 L 4-neck flask (equipped with a mechanical stirrer, condenser and N2 inlet) was charged with 2 L water and 50percent sodium hydroxide (NAOH) (2.52 mol, 201.6 g, 2.25 equiv) followed by oxindol (1.12 mol, 150 g, 1 equiv) and the reaction mixture was heated TO-40° C. Dimethylsulfate (1.68 mol, 211.7 g (159 mL), 1.5 equiv) was added slowly via syringe. The addition was slightly exothermic with temperature rising to 53° C. When addition was complete, the reaction mixture was heated to- 100° C and held for 15 minutes (min). The reaction mixture was cooled TO-600 C, and a second portion of dimethylsulfate (0.476 mol, 60 g (45 mL), 0.425 equiv) was added. The reaction mixture was heated TO ~ 100° C and held 15 min. TLC (heptane/ethyl acetate (EtOAc), 1: 1) show methylation was essentially complete. The reaction mixture was cooled TO-50° C and the pH adjusted to-7 with concentrated HCI. The reaction mixture was seeded, cooled to room temperature and allowed to stand overnight. The solids were collected, wash with water (4X) and dried overnight in a vacuum over AT-40° C to give 110.7 g (67percent) of 1-methyl-1, 3-dihydroindol-2-one as a pink solid, mp 84-86° C.
67.3%
Stage #1: With sodium hydride In xylene for 1.5 h; Heating / reflux
Stage #2: for 2 h; Heating / reflux
A stirred mixture of sodium hydride (60percent, 31g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. l,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hrs. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hrs. After cooling to room temperature, the reaction mixture was washed with water, dried over Na2SC>4, and concentrated under reduced pressure to afford l-methyl-l,3-dihydro-indol-2-one 16b (74 g, 67.3percent). .HNMR (300 MHz, CDC13) 5 7.23-7.31 (m, 2 H), 7.04 (t, J= 7.5 Hz, 1 H), 6.82 (d, J= 7.8 Hz, 1 H), 3.52 (s, 2 H), 3.21 (s, 3 H).[0270] A suspension of NaH (60percent, 70 g, 0.48 mol) in THF (300 mL) was stirred for 10 min at 0 °C. Then a solution of l-methyl-l,3-dihydro-indol-2-one 16b (70 g, 2.88 mol) in THF (200 mL) was added at 0 °C, and the mixture was stirred for 1 h at room temperature. Benzyl-bis-(2-chloro-ethyl)-amine (129 g, 0.48 mol) was added in portions at 0 °C. The mixture was stirred overnight at room temperature, and then was poured into ice-water, extracted with EtOAc. The combined organic layers were dried over IS^SO^ and concentrated under reduced pressure. The residue was purified by column on silica gel (P.E./E.A. 2:1) to give compound 16c (24 g, 16.3percent). lH NMR (300 MHz, CDCI3) 5 7.25-7.42 (m, 7 H), 7.02-7.07 (m, 1 H), 6.83 (d, J= 7.5, 1 H), 3.68 (s, 2 H), 3.19 (s, 3 H), 2.74-2.99 (m, 2 H), 2.66-2.72 (m, 2 H), 1.93-2.01 (m, 2 H), 1.79-1.85 (m, 2 H).[0271] To a solution of compound 16c (12 g, 39.2 mmol) in MeOH (100 mL) was added Pd(OH)2/C (1.5 g, 20percent>) under N2. The suspension was hydrogenated under H2 (50 psi) at room temperature for 4.5 hrs. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the deprotected spiroindolone product 16d (8 g, 94.5percent). ]H NMR (400 MHz, DMSO-rf6) 5 7.46 (d, J= 7.2,1 H), 7.23-7.27 (m, 1 H), 6.96-7.03 (m, 2 H), 3.04-3.14 (m, 5 H), 2.83-2.89 (m, 2 H), 1.61-1.67 (m, 2 H), 1.45-1.51 (m, 2 H). MS (ESI) m/z 217.1 [M+H]+ [0272] 1.0 eq of deprotected spiroindolone 16d (22 mg, 0.10 mmol) was dissolved in anhydrous l,2-dichloroethane:l,2-dimethoxyethane (1.0 mL, 1:1 v/v) and treated with 1.5 N-Carbethoxy-4-tropinone (30 mg, 0.15 mmol), followed by titanium tetraisopropoxide (88 /xL, 85 mg, 0.30mmol). The vial was flushed with nitrogen and stirred at room temperature ~70 h. The reactionwas then diluted with methanol (1.0 mL), cooled in an ice-BbO bath and treated with sodiumborohydride (8 mg, 0.20 mmol). After warming to room temperature and stirring for 90 min, thereaction was further diluted with methanol (2.0 mL), quenched with 1.0 N NaOH (500 juL) andstirred vigorously at room temperature for 10 min. The suspension obtained was centrifuged(3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residueobtained was dissolved in MeOH:acetonitrile (1250 fiL, 1:1 v/v), filtered, and purified byreverse-phase HPLC (2-40percent CH3CN/0.1percent TFA gradient over 10 min) to yield productcompound no. 149. LC/MS (10-99percent) m/z [M+H]+398.2, retention time 1.93 min.
Reference: [1] Organic Letters, 2012, vol. 14, # 10, p. 2544 - 2547
[2] Tetrahedron Letters, 2015, vol. 56, # 26, p. 3992 - 3995
[3] Chemistry - An Asian Journal, 2017, vol. 12, # 7, p. 734 - 743
[4] Journal of Organic Chemistry, 2010, vol. 75, # 4, p. 1047 - 1060
[5] Tetrahedron Letters, 2001, vol. 42, # 41, p. 7315 - 7317
[6] Patent: WO2004/37820, 2004, A1, . Location in patent: Page 25; 36-37
[7] Patent: WO2006/23852, 2006, A2, . Location in patent: Page/Page column 107; 108
[8] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7568 - 7573
[9] Itsuu Kenkyusho Nempo, 1956, # 7, p. 7,10; engl. Ref. S. 44, 48[10] Chem.Abstr., 1957, p. 2823
[11] Journal of Organic Chemistry, 1991, vol. 56, # 13, p. 4218 - 4223
[12] Chemistry - A European Journal, 2016, vol. 22, # 8, p. 2595 - 2598
  • 5
  • [ 67-56-1 ]
  • [ 59-48-3 ]
  • [ 61-70-1 ]
YieldReaction ConditionsOperation in experiment
59.1% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 25℃; Add diethyl azodicarboxylate (DEAD, 8.0 g, 44.9 mmol) dropwise to a solution of indolin-2-one (4.0 g, 30.0 mmol), methanol (1.4 g, 44.9 mmol) and triphenylphosphine (12.0 g, 44.9 mmol) in THF (40 mL) at 0° C., stir the reaction at room temperature overnight.
Concentrate under reduced pressure, purify the resulting residue with flash chromatography (silica gel, EtOAc:PE=1:3) to afford the title compound (2.6 g, 59.1percent). MS: (M+1): 148.2.
Reference: [1] Patent: US2015/197511, 2015, A1, . Location in patent: Paragraph 0298; 0299
  • 6
  • [ 59-48-3 ]
  • [ 74-88-4 ]
  • [ 61-70-1 ]
Reference: [1] Patent: US2008/15179, 2008, A1, . Location in patent: Page/Page column 136-137
  • 7
  • [ 59-48-3 ]
  • [ 61-70-1 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 33, p. 7244 - 7248
  • 8
  • [ 59-48-3 ]
  • [ 77-78-1 ]
  • [ 166883-22-3 ]
  • [ 61-70-1 ]
Reference: [1] Patent: US5478842, 1995, A,
  • 9
  • [ 59-48-3 ]
  • [ 20876-36-2 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 3, p. 563 - 567
[2] Zhurnal Obshchei Khimii, 1956, vol. 26, p. 2019,2023, 2024; engl. Ausg. S. 2251, 2254, 2255
[3] MedChemComm, 2014, vol. 5, # 5, p. 655 - 658
[4] Archiv der Pharmazie, 2015, vol. 348, # 10, p. 715 - 729
  • 10
  • [ 59-48-3 ]
  • [ 3416-18-0 ]
YieldReaction ConditionsOperation in experiment
70% With trifluoroacetic acid; bis-[(trifluoroacetoxy)iodo]benzene In dichloromethane at 20℃; Compound 1 was prepared as described in Itoh et al. [22]: 799 mg (6.0 mmol) of oxindole were dissolved at room temperature in 40 mL of waterefree dichloromethane 3.1 g (7.2 mmol) of phenyliodine(III)-bis(trifluoroacetate) PIFA was added in portions, followed by 4.6 mL of trifluoroacetic acid. The mixture was stirred at RT overnight and the dichloromethane was evaporated. 60 mL of 5percent sodium bicarbonate solution and 50 mL of ethyl acetate were added to the residue and the organic layer was separated by a separatory funnel. The aqueous layer was extracted with ethyl acetate (5 50 mL) the combined organic layer was dried with Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol ¼ 9:1 (v/v)) and afforded 627mg (70percent) of 1 as light brown crystals. Mp: 266e268 C (lit: 260e263 C), 1H NMR (d, ppm, DMSO-d6): 3.36 (s, 2H, H-3); 6.55 (d, 1H, 2J ¼ 8.6 Hz, H-6); 6.60 (d, 1H, 2J ¼ 8.7 Hz, H-7); 6.66 (s, 1-H, H-4); 8.93 (s, 1H, OH); 10.47 (s, 1H, NH); ESI-MS (ES-): m/z ¼ 148 [M H].
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7424 - 7428
[2] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 272 - 280
[3] Organic Letters, 2012, vol. 14, # 10, p. 2544 - 2547
[4] ChemMedChem, 2016, vol. 11, # 1, p. 72 - 80
  • 11
  • [ 59-48-3 ]
  • [ 109-94-4 ]
  • [ 78610-70-5 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1924, vol. 436, p. 117
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 797,798
  • 12
  • [ 59-48-3 ]
  • [ 60-29-7 ]
  • [ 64-17-5 ]
  • [ 917-58-8 ]
  • [ 109-94-4 ]
  • [ 78610-70-5 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1924, vol. 436, p. 117
  • 13
  • [ 59-48-3 ]
  • [ 20870-79-5 ]
YieldReaction ConditionsOperation in experiment
98% at -15℃; for 0.5 h; Preparation of 5-nitro-oxindole
To a solution of oxindole (26 g) in 100 mL of concentrated sulfuric acid at -15° C. was added fuming nitric acid (8.4 mL) dropwise.
Careful attention was paid to maintain the reaction temperature at -15° C.
After the addition was complete, the reaction was stirred for 30 minutes and then poured into ice water.
A yellow precipitate was formed which was isolated by filtration to provide 34 grams (98percent) of 5-nitro oxindole.
98% at -15℃; for 0.5 h; To a solution of oxindole (26 g) in 100 mL of concentrated sulfuric acid at -15° C. was added fuming nitric acid (8.4 mL) dropwise. Careful attention was paid to maintain the reaction temperature at -15° C. After the addition was complete, the reaction was stirred for 30 minutes and then poured into ice water. A yellow precipitate was formed which was isolated by filtration to provide 34 grams (98percent) of 5-nitro oxindole.
92.4% With sulfuric acid; nitric acid In water at 0℃; for 1 h; Step 1
5-Nitro-indol-2-one
1,3-Dihydro-indol-2-one 30a (20.0 g, 150 mmol) was dissolved in sulfuric acid (100 ml, 98percent) in an ice-water bath under stirring, and added dropwise with nitric acid (10 ml, 65percent-68percent) while maintaining the temperature below 0° C.
Upon completion of the addition, the mixture was stirred for 1 hour at 0° C.
After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ice and filtered after ice-out.
The filter cake was washed with water (20 ml*3), and the resulting solid was recrystallized to obtain the title compound 5-nitro-indol-2-one 30b (25.3 g, yield 92.4percent) as an orange solid.
92.4% With sulfuric acid; nitric acid In sulfuric acid at 0℃; 1,3-Dihydro-indol-2-one 30a (20.0 g, 150 mmol) was dissolved in sulfuric acid (100 ml, 98percent) in an ice-water bath under stirring, and added dropwise with nitric acid (10 ml, 65percent-68percent) while maintaining the temperature below 0°C. Upon completion of the addition, the mixture was stirred for 1 hour at 0°C. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ice and filtered after ice-out. The filter cake was washed with water (20 ml.x.")), and the resulting solid was recrystallized to obtain the title compound 5-nitro -indol-2-one 30b (25.3 g, yield 92.4percent) as an orange solid. MS m/z (ESI): 177.3[M-1]
70% at -15 - 0℃; for 0.5 h; 5-Nitro-2-oxindole
2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at -10 to -15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid.
The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-vitro-2-oxindole.
70% at -15 - -10℃; for 0.5 h; 5-Nitro-2-oxindole
2-Oxindole (6.5 g) was dissolved in 25 ML concentrated sulfuric acid and the mixture maintained at -10 to -15° C. while 2.1 ML of fuming nitric acid was added dropwise..
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water..
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid..
The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-oxindole.
69% at 0℃; for 2 h; Concentrated nitric acid (9.31 g, 0.096 mol) was added in drops over 60 min and at 0° C. to a solution of indolin-2-one (13.3 g, 0.100 mol) in concentrated sulfuric acid (67 mL), and the resultant dark-brown solution was then stirred at this temperature for 1 h.
The reaction mixture was then poured over ice and sucked away.
The residue was washed again with water and dried, then recrystallized from isopropanol.
5-nitroindolin-2-one in the form of golden, shiny sheets was obtained (12.28 g, 69percent).
fp: >300° C.
1HNMR (300 MHz, d6-DMSO): δ=3.61 (s, 2H, H2), 6.97 (d, 1H, H7), 8.05 (d, 1H, H6), 8.05 (s, 1H, H4), 8.15 (d, 1H, H6), 11.03 (bs, 1H, NH).
13C NMR (100 MHz, DMSO): 35.9 (C2), 109.2 (C7), 120.3 (C4), 125.1 (C6), 127.2 (C9), 142.0 (C5), 150.6 (C8), 177.0 (C2)
48% With nitric acid In sulfuric acid; acetic acid The starting material was prepared as follows:
Fuming nitric acid (1.58 ml, 39.4 mmol) was added dropwise to a solution of oxindole (5 g, 37.5 mmol) in concentrated sulphuric acid (25 ml) cooled by an ice bath and maintained below 5° C.
The mixture was stirred for 30 minutes at 0° C. and then poured into water.
The precipitate was collected by filtration and thoroughly washed with water.
The solid was suspended in 50percent acetic acid (100 ml) and heated at 90° C. for 1 hour.
The mixture was allowed to cool, the solid product was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide at 40° C. to give 5-nitrooxindole (3.2 g, 48percent).
1H NMR Spectrum: (CDCl3, CD3CO2D) 3.68(s, 2H); 7.05(d, 1H); 8.16(s, 1H); 8.22(s, 1H)
MS-EI: 178 [M]+
48% at -15℃; for 0.5 h; Step-a: 5-nitroindolin-2-one: To a stirred solution of oxindole (20 g, 150.21 mmol) in 100 mL of concentrated H2S04 at -15°C was added fuming HN03 (9.47 g, 150.206 mmol) dropwise and maintained the reaction temperature at -15°C. After completion of addition, the mixture was stirred for 30 min and then poured into ice water. A yellow precipitate was formed which was isolated by filtration (13 g, 48percent). -NMR (300 MHz, DMSO-ito): δ 11 (s, 1H), 8.2 (d, 1H), 8.1 (s, 1H), 7.0 (d, 1H), 3.6 (s, 2H).
48% at -15℃; for 0.5 h; To a stined solution of oxindole (20 g, 150 mmol) in 100 mL of Conc. H2S04 at -15 °Cwas added fuming HNO3 (9.47 g, 150 mmol) drop wise. The reaction mixture was allowed tomaintain the temperature at -15 °C for 0.5h. After completion of the reaction, the reaction mixture was poured into crushed ice. The yellow solid precipitate out which was isolated by filtration and dried under vacuum (13 g, 48percent). ‘H-NMR (300 MHz, DMSO-d6) ö ii (s, 1H), 8.20-8.10 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 3.6 (s, 2H).LC-MS: mlz 177 (M-H).
70% With nitric acid In sulfuric acid 5-Nitro-2-Oxindole
2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at -10 to -15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid.
The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-oxindole.
70% With nitric acid In sulfuric acid 5-Amino-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one
2-Oxindole (6.5 g) was dissolved in 25 mL of concentrated sulfuric acid and the mixture maintained at -10-15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hour and poured into ice-water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid.
The final crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-oxindole.
70% With nitric acid; acetic acid In sulfuric acid Preparation of 5-Nitro-2-indolinone
The 2-indolinone (6.5 g) was dissolved in 25 mL of concentrated sulfuric acid and the mixture maintained at -10-15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water.
The precipitate was collected by filtration,.
washed with water and crystallized from 50percent of acetic acid.
The final crystal was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-indolinone.
70% With nitric acid In sulfuric acid 5-Nitro-2-oxindole
2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at -10 to -15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid.
The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-oxindole.
70% With nitric acid In sulfuric acid 5-Nitro-2-oxindole
2-Oxindole (6.5 g) was dissolved in 25 mL concentrated sulfuric acid and the mixture maintained at -10 to -15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid.
The crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-oxindole.
70% With nitric acid; acetic acid In sulfuric acid (b)
Preparation of 5-Nitro-2-oxindole.
The 2-oxindole (6.5 g) was dissolved in 25 mL of concentrated sulfuric acid and the mixture maintained at -10-15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent of the acetic acid.
The final crystal was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-2-oxindole.
70% With nitric acid In sulfuric acid 2.
5-Amino-3-(3,5-diethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one
2-Oxindole (6.5 g) was dissolved in 25 mL of concentrated sulfuric acid and the mixture maintained at -10-15° C. while 2.1 mL of fuming nitric acid was added dropwise.
After the addition of the nitric acid, the reaction mixture was stirred at 0° C. for 0.5 hr and poured into ice-water.
The precipitate was collected by filtration, washed with water and crystallized from 50percent acetic acid.
The final crystalline product was then filtered, washed with water and dried under vacuum to give 6.3 g (70percent) of 5-nitro-1,3-dihydro-indol-2-one.

Reference: [1] Patent: US2005/256145, 2005, A1, . Location in patent: Page/Page column 43
[2] Patent: US2005/256144, 2005, A1, . Location in patent: Page/Page column 19
[3] Patent: US2010/75952, 2010, A1, . Location in patent: Page/Page column 64
[4] Patent: EP2157093, 2010, A1, . Location in patent: Page/Page column 61-62
[5] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 169
[6] Patent: US6350754, 2002, B2, . Location in patent: Page column 20
[7] Patent: US2017/165166, 2017, A1, . Location in patent: Paragraph 0224; 0225; 0226; 0227; 0228; 0229
[8] Synthetic Communications, 2008, vol. 38, # 17, p. 3017 - 3022
[9] Letters in Organic Chemistry, 2011, vol. 8, # 7, p. 526 - 530
[10] Patent: US6265411, 2001, B1,
[11] Patent: WO2015/92118, 2015, A1, . Location in patent: Page/Page column 26
[12] Patent: WO2018/109650, 2018, A1, . Location in patent: Page/Page column 27
[13] Archiv der Pharmazie, 2015, vol. 348, # 10, p. 715 - 729
[14] Zhurnal Obshchei Khimii, 1956, vol. 26, p. 2019,2023, 2024; engl. Ausg. S. 2251, 2254, 2255
[15] Journal of the American Chemical Society, 1945, vol. 67, p. 500
[16] Patent: US2003/100555, 2003, A1,
[17] Patent: US2002/183364, 2002, A1,
[18] Patent: US6316635, 2001, B1,
[19] Patent: US2003/69421, 2003, A1,
[20] Patent: US2003/216410, 2003, A1,
[21] Patent: US6051593, 2000, A,
[22] Patent: US2002/156292, 2002, A1,
[23] Patent: US6486185, 2002, B1,
[24] Patent: US6114371, 2000, A,
[25] Patent: US6147106, 2000, A,
[26] Patent: US6846839, 2005, B1,
[27] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[28] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4979 - 4985
[29] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7440 - 7443
[30] MedChemComm, 2014, vol. 5, # 5, p. 655 - 658
[31] Patent: US4118561, 1978, A,
  • 14
  • [ 59-48-3 ]
  • [ 20870-79-5 ]
YieldReaction ConditionsOperation in experiment
25% With NaNO3 In sulfuric acid Example 159a
5-nitro-1,3-dihydro-indol-2-one
A solution of 5 g (37.6 mmol) of oxindole in 75 ml of conc. H2SO4 was chilled to -5° C. in an ice/EtOH bath.
A solution of 3.83 g (45.1 mmol) of NaNO3 in 25 ml of conc. H2SO4 was added dropwise over 30 min.
The mixture was stirred at -5° C. for 1 hr.
The ice bath was then removed and the mixture was allowed to slowly warm to ambient temperature.
The mixture was poured onto 500 g of crushed ice.
The solid was collected by vacuum filtration and air-dried.
The solid was stirred in warm methanol and collected by vacuum filtration to yield 5-nitro-1,3-dihydro-indol-2-one (1.7 g, 25percent): 1H NMR (DMSO-d6): δ3.6 (s, 2H), 6.95 (d, J=8.5 Hz, 1H), 8.1 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 11.01 (s, 1H). APCI-MS: m/z 177 (m-H)-.
Reference: [1] Patent: US6268391, 2001, B1,
  • 15
  • [ 59-48-3 ]
  • [ 30490-21-2 ]
  • [ 20870-79-5 ]
  • [ 186250-44-2 ]
  • [ 64030-97-3 ]
Reference: [1] Tetrahedron Letters, 1996, vol. 37, # 51, p. 9263 - 9266
  • 16
  • [ 15307-79-6 ]
  • [ 59-48-3 ]
  • [ 87-65-0 ]
  • [ 15362-40-0 ]
  • [ 69220-40-2 ]
  • [ 601-88-7 ]
  • [ 15307-93-4 ]
  • [ 10113-35-6 ]
  • [ 6697-95-6 ]
  • [ 39920-37-1 ]
  • [ 13603-93-5 ]
  • [ 608-31-1 ]
Reference: [1] Revue Roumaine de Chimie, 2014, vol. 59, # 11-12, p. 1021 - 1027
  • 17
  • [ 59-48-3 ]
  • [ 612-54-4 ]
  • [ 479-41-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 821 - 828
  • 18
  • [ 59-48-3 ]
  • [ 7135-31-1 ]
YieldReaction ConditionsOperation in experiment
93% With N,N-diethylaniline; trichlorophosphate In toluene at 20℃; for 3 h; Heating / reflux At room temperature, POCI3 (1 ml, 10.82 mmol, 2 eq) is added to a well stirred suspension of N,N-diethylaniline (1 ml, 5.41 mmol, 1 eq) and 1 ,3-dihydro-2H-indol-2-one x159 (0.72 g, 5.41 mmol, 1 eq) in dry toluene (15 ml). The mixture is heated at reflux during 3 hours. After cooling, water (15 ml) is carefully added and the organic layer is washed with water (3 x 25 ml). The organic layer is dried on anhydrous MgSOφ filtered EPO <DP n="127"/>off and concentrated under reduced pressure to obtain 0.76 g of 2-chloro-1 H-indole x160 as an orange solid (0.76 g, 93percent).Yield: 93 percent.LC-MS (MH-): 150/152.
Reference: [1] Patent: WO2006/128692, 2006, A2, . Location in patent: Page/Page column 125; 126
  • 19
  • [ 59-48-3 ]
  • [ 459-57-4 ]
  • [ 3476-86-6 ]
YieldReaction ConditionsOperation in experiment
85% With piperidine In ethanol at 90℃; Inert atmosphere General procedure: The appropriate aldehyde (1 equiv) was added to EtOH (3 mL/0.2 mmol) and the mixture was stirred until complete solution. Theoxindole (1 equiv) and piperidine (0.1 equiv) were added, and themixture was heated to 90°C for 3-7 h, and cooled. The resultingprecipitatewas filtered, washed with cold ethanol and dried to givethe pure compound. If necessary, additional recrystallization inethanol was applied to obtain the pure product.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 286 - 307
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 5, p. 2077 - 2090
[3] Journal of Chemical Research, 2018, vol. 42, # 5, p. 244 - 246
  • 20
  • [ 59-48-3 ]
  • [ 459-57-4 ]
  • [ 3476-86-6 ]
  • [ 90828-17-4 ]
YieldReaction ConditionsOperation in experiment
25% With piperidine In ethanol for 3 h; Reflux General procedure: The preparation of compounds 3-25 was carried out by refluxing oxindole with different aromatic aldehydes in ethanol in the presence of a catalytic amount of piperidine were refluxed for 3 h. After cooling reaction mixture was concentrated at reduced pressure to obtain solid of 3-oxindole derivatives, then washed with 1:1 mixture of hexane-ethyl acetate (25 mL) and dried to afford titles compoundsin good yields (Table 1). Only in two cases (10 and21), both E and Z isomers were obtained, these isomers wereseparated by column chromatography using 1:9 ethyl acetate: hexane as eluent. The structures of synthetic compounds 3-25 were elucidated by 1H NMR and EI MS. Elemental analysis results were also found to be satisfactory.
Reference: [1] Medicinal Chemistry, 2013, vol. 9, # 5, p. 681 - 688
  • 21
  • [ 59-48-3 ]
  • [ 496-15-1 ]
  • [ 5339-85-5 ]
Reference: [1] Chemical Science, 2016, vol. 7, # 5, p. 3432 - 3442
  • 22
  • [ 15307-79-6 ]
  • [ 59-48-3 ]
  • [ 87-65-0 ]
  • [ 15362-40-0 ]
  • [ 69220-40-2 ]
  • [ 601-88-7 ]
  • [ 15307-93-4 ]
  • [ 10113-35-6 ]
  • [ 6697-95-6 ]
  • [ 39920-37-1 ]
  • [ 13603-93-5 ]
  • [ 608-31-1 ]
Reference: [1] Revue Roumaine de Chimie, 2014, vol. 59, # 11-12, p. 1021 - 1027
  • 23
  • [ 15307-79-6 ]
  • [ 59-48-3 ]
  • [ 87-65-0 ]
  • [ 15362-40-0 ]
  • [ 69220-40-2 ]
  • [ 601-88-7 ]
  • [ 15307-93-4 ]
  • [ 10113-35-6 ]
  • [ 6697-95-6 ]
  • [ 39920-37-1 ]
  • [ 13603-93-5 ]
  • [ 608-31-1 ]
Reference: [1] Revue Roumaine de Chimie, 2014, vol. 59, # 11-12, p. 1021 - 1027
  • 24
  • [ 30095-98-8 ]
  • [ 59-48-3 ]
  • [ 35613-44-6 ]
Reference: [1] Liebigs Annalen der Chemie, 1985, vol. 1985, # 7, p. 1398 - 1412
[2] Organic Letters, 2009, vol. 11, # 6, p. 1345 - 1348
  • 25
  • [ 59-48-3 ]
  • [ 3342-78-7 ]
Reference: [1] Patent: WO2012/28100, 2012, A1, . Location in patent: Page/Page column 27
  • 26
  • [ 56-23-5 ]
  • [ 59-48-3 ]
  • [ 7732-18-5 ]
  • [ 3342-78-7 ]
Reference: [1] Annali di Chimica (Rome, Italy), 1957, vol. 47, p. 1238,1240
  • 27
  • [ 59-48-3 ]
  • [ 79-04-9 ]
  • [ 65435-04-3 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride; aluminum (III) chloride In 1,1-dichloroethane at 0 - 50℃; for 1.66667 h; 5-Carboxy-2-oxindole
2-Oxindole (6.7 g) was added to a stirred suspension of 23 g of aluminum chloride in 30 mL of 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 at 40 to 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.
98% With hydrogenchloride; aluminum (III) chloride In 1,1-dichloroethane at 40 - 50℃; for 1.5 h; 5-Carboxy-2-oxindole
2-Oxindole (6.7 g) was added to a stirred suspension of 23 g of aluminum chloride in 30 ML of 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 at 40 to 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.
90% With carbon disulfide In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water Step 1:
Synthesis of 5-Chloroacetyl-2-oxindole.
Aluminum chloride (30.8 g) and 2-oxindole (5.0 g) were added to 200 ml of carbon disulfide at room temperature and the mixture stirred.
Chloroacetyl chloride (3.8 mL) was added and the stirring continued for 1 hour.
The mixture was heated to reflux for 3 hours, cooled and the solvent decanted.
The residue was stirred in ice water until it became a solid suspension.
The solid was collected by vacuum filtration, washed in water, and dried to give 7.0 g (90percent yield) of the title compound.
90% With aluminum (III) chloride In dichloromethane for 3 h; Cooling with ice; Reflux Step 1: (0378) Indolin-2-one 15-a (2 g, 15.03 mmol) was dissolved in dichloromethane (10 ml), aluminum trichloride (7 g, 52.60 mmol) was added, then chloroacetyl chloride (2.26 ml, 30.06 mmol) dissolved in dichloromethane (10 ml) was slowly added dropwise under ice bath, the mixture was stirred at this temperature for 1 hour and at reflux for 2 hours. The mixture was cooled, poured into ice water, the aqueous layer was adjusted to be strongly acidic, the precipitated solid was filtered and dried to give a light gray white solid (2.811 g, yield: 90percent).
77%
Stage #1: With aluminum (III) chloride In 1,2-dichloro-ethane at 0℃; for 1 h;
Stage #2: at 0 - 45℃; for 5 h;
00222] Synthesis of 5-(2-chloroacetyl)indolin-2-one [00223] 5-(2-Chloroacetyl)indolin-2-one was synthesized according to the procedure described below and as shown in the following scheme: [00224] To a 0 °C round bottom flask containing a suspension of 7.53 g A1C13 (56.3 mmol) in 7 mL 1,2-dichloroethane, 3.6 mL (45.1 mmol) chloroacetyl chloride was added dropwise, resulting in a color change from yellow to dark red. The reaction was allowed to run for 1 hour after which a solution of 3.00 g oxindole (22.5 mmol) in 16 mL 1,2-dichloroethane was added. The reaction was allowed to run for an additional 2 hours at 0 °C, and thereafter for another 3 hours at 45°C. The reaction was stopped by pouring into ice cold water, in which a tan precipitate formed immediately. The precipitate was filtered to provide 0.788 g (77percent) of product as a beige solid.
53% for 3.5 h; Heating / reflux Example 43; 5- (Chloroacetyl)-1, 3-dihydro-2H-indol-2-one; To a mixture of aluminum trichloride (17 gram, 128 mmol) and chloroacethyl chloride (3 gram, 2.65 mmol) in carbon disulfide (40 mL) was oxindole (2.73 gram, 20.5 mmol) added and the mixture was stirred at reflux for 3.5 h. The mixture was cooled to room temperature and carefully quenched with cooled water (50 mL). The quenched reaction mixture was stirred for 2 h and the formed precipitate was filtered and washed two times with water. The solid was dried to give 2.3 gram (53percent yield) of the title compound :'H NMR (DMSO-d6,300 MHz) 8 10.82 (br s, 1 H), 7.87 (d, J = 8 Hz, 1 H), 7.82 (s, 1 H), 6.92 (d, J = 8 Hz, 1 H), 5.08 (s, 2 H), 3.57 (s, 2 H).
31% With aluminum (III) chloride In carbon disulfide at 20 - 50℃; for 1.25 h; Heating / reflux [0150] To a solution OfAlCl3 (6.28g , 47.1 mmol) in 20 mL of dry carbon disulfide was added chloroacetylchloride (800μL, 10.0 mmol) at room temperature. Oxindole (1.02g, 7.7 mmol) in 10 mL dry carbon disulfide was added portionwise via a syringe for 5 minutes. The reaction mixture was stirred at RT for an additional 10 min, then refluxed (40-50 0C) for 1 EPO <DP n="52"/>hour. The reaction was cooled, added to ice and the beige precipitate filtered, washed with cold water and dried in a vacuum desiccator to afford 501 mg (31 percent) of the desired compound. 1H NMR (400 MHz, DMSO-tfd) δ: 10.82 (s, IH), 7.89 (dd, J= 1.8 Hz, 8.2 Hz, IH), 7.83 (s, IH)3 6.93 (d, J= 8.2 Hz, IH), 5.08 (s, 2H), 3.32 (s, 2H). ESI-MS 232 (M+Na)+, 234 (M+2+Na)+

Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1860 - 1866
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5120 - 5130
[3] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 172; 219
[4] Patent: US6350754, 2002, B2, . Location in patent: Page column 23-24
[5] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 6, p. 1525 - 1532
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4133 - 4146
[7] Patent: US6147106, 2000, A,
[8] Patent: US6255322, 2001, B1,
[9] Patent: US2017/158680, 2017, A1, . Location in patent: Paragraph 0376; 0377; 0378
[10] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, # 6, p. 2253 - 2258
[11] Patent: WO2014/70983, 2014, A1, . Location in patent: Paragraph 00221-00224
[12] Patent: WO2003/82853, 2003, A1, . Location in patent: Page/Page column 55
[13] Patent: WO2007/38613, 2007, A2, . Location in patent: Page/Page column 49-50
[14] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 143 - 148
[15] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 3, p. 223 - 226
[16] Patent: US2002/4504, 2002, A1,
[17] Patent: US2002/183364, 2002, A1,
[18] Patent: US6395734, 2002, B1,
[19] Patent: US2003/69421, 2003, A1,
[20] Patent: US6051593, 2000, A,
[21] Patent: US6486185, 2002, B1,
[22] Patent: US6114371, 2000, A,
[23] Patent: US4737501, 1988, A,
[24] Patent: US4831031, 1989, A,
[25] Patent: EP281309, 1991, B1,
[26] Patent: EP168003, 1991, B1,
[27] Patent: US6245766, 2001, B1,
[28] Patent: US6127373, 2000, A,
[29] Patent: EP901789, 1999, A1,
[30] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 745 - 750
[31] Patent: EP2130829, 2009, A1, . Location in patent: Page/Page column 19-20
[32] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3500 - 3511
[33] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 197 - 209
[34] Patent: EP281309, 1988, A1,
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[2] European Journal of Medicinal Chemistry, 1992, vol. 27, # 8, p. 779 - 789
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Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5120 - 5130
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3500 - 3511
[3] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 197 - 209
  • 31
  • [ 2199-58-8 ]
  • [ 59-48-3 ]
  • [ 194413-58-6 ]
YieldReaction ConditionsOperation in experiment
86% With piperidine In methanolReflux General procedure: To a solution of indolin-2-one (compound 1) (200 mg, 1eq.) in MeOH (5 mL), piperidine (1.5 eq.), and correspondingaldehydes (2a–2k) (1.2 eq.) were added. Thereaction mixture was heated to reflux and stirred for 1–4 h,then cooled to room temperature. The mixture was filtered,and the filter cake was washed with MeOH three times, thenthe filter cake was collected and dried under vacuum toremove MeOH to give the desired compounds 3a–3k.
Reference: [1] Journal of Antibiotics, 2018, vol. 71, # 10, p. 887 - 897
[2] Tetrahedron, 2009, vol. 65, # 25, p. 4894 - 4903
[3] ChemMedChem, 2016, vol. 11, # 1, p. 72 - 80
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2588 - 2603
[5] Synthetic Communications, 2008, vol. 38, # 17, p. 3017 - 3022
  • 32
  • [ 110-89-4 ]
  • [ 2199-58-8 ]
  • [ 59-48-3 ]
  • [ 194413-58-6 ]
Reference: [1] Patent: US5834504, 1998, A,
[2] Patent: US5883116, 1999, A,
[3] Patent: US5883113, 1999, A,
[4] Patent: US6846839, 2005, B1,
  • 33
  • [ 59-48-3 ]
  • [ 199328-31-9 ]
YieldReaction ConditionsOperation in experiment
98% at 20 - 68℃; for 2.5 h; Chlorosulfonic acid (27 mL, 408 mmoli) was slowly added dropwise to indolin-2-one 23 (13.3 g, 100 mmol).
The reaction temperature was maintained below 30 °C during the addition.
Later the reaction mixture was stirred at rt for 1.5 h, and then at 68 °C for 1 h, cooled, and poured carefully into water.
The precipitate formed was collected by vacuum filtration, washed with H2O and dried in a vacuum oven to give compound 23, which was used without further purification (3.02 g, 13.03 mmol, 98percent yield): mp 180-185 °C. 1H NMR: δ 3.46 (s, 2H, CH2); 6.74 (d, 1H, J = 7.7 Hz, Ar); 7.42-7.46 (m, 2H, Ar); 10.48 (br s, 1H) ppm. 13C NMR: δ 175.89, 143.68, 139.71, 124.55, 121.32, 107.39; 35.16 ppm. Anal. (C8H6ClNO3S) Calcpercent: C 41.48, H 2.61, N 6.05, S 13.84; Foundpercent: C 41.57, H 2.72, N 6.14, S 13.92.
98.3% at 0 - 70℃; for 1.5 h; In a round bottle vessel was added chlorosulfonic acid (3mL) dropwise to compound 1 (500 mg) at 0 °C. The mixturewas stirred for 30 min then was heated to 70 °C andreacted for 1 h and cooled to room temperature. Theresulting mixture was added dropwise into ice water andthen filtered, the filter cake was washed with water for threetimes and dried to give intermediate 7 as a pink solid (yield98.3percent)
97.1% at 0 - 70℃; for 2.5 h; 186.43 g (1.6 mol, 8 eq) of chlorosulfonic acid was placed in an ice salt bath until the internal temperature dropped to 0 ° C, 26.6 g (0.2 mol) of 2-indolone was added to it with stirring, Exothermic There is a small amount of white smoke, After stirring for 30 min, the mixture was stirred at room temperature for 1 h, The oil bath was stirred at 70 ° C for 1 h, Stop the reaction. Cold to room temperature, Which will slowly drop into the ice water with a constant pressure dropping funnel, The alkaline exhaust gas absorption device, The original brown reaction solution encountered ice water after the formation of pink solid, Reaction is intense, Have bubbles. Drop finished, Standing for a moment to filter, Dry, 45 g of a red solid, The yield was 97.1percent. To give 2-indolone-5-sulfonyl chloride, Compound code M2.
95% at 70℃; for 1.58333 h; Cooliing with ice Preparation of synthetic precursorsCertain reagents are commercially available or can be prepared using no more than routine experimentation by one of ordinary skill in the art based on known procedures. Certain synthetic precursors were prepared as described herein. -mere aptooxindoleChloro sulfonic acid 115 mL (1.73 mol) in a 1L wide-mouth round flask (with a 45/50 joint, equipped with a gas outlet tube) was cooled on ice bath and solid oxindole 25.60g (192.2 mmol) was gradually spooned in with vigorous stirring and cooling on ice, over a 20 min period. After the complete addition, the flask was removed from the cooling bath and the mixture was stirred for additional 15 min. The flask was then placed on a 70 °C oil bath and the mixture was stirred at 70 °C for 2 hours. The resulting dark reaction mix was cooled on ice, then very cautiously poured in a thin stream onto crushed ice 1.4kg that was pre-chilled in a freezer, in a 3L beaker, with stirring. The quenched mixture was stirred until all ice melted, the precipitated solid was collected by filtration on a very large glass Buchner funnel, washed with 0.05 M HC1, semi-dried by filtration and then thoroughly dried under high vacuum ("highvac") over a 60 hour period. Y=42.23g (95percent th) of a tan solid.
88% at 30 - 70℃; for 2.5 h; Oxindole (5.5 g, 41.30 mmol) was added portionwise to chlorosulfonic acid (50 ml) maintaining the temperature below 30 "C during the addition. After the addition the reaction mixture was stirred at room temperature for 1.5 h and then at 70 "C for 1 h. After cooling to <n="61"/>room temperature, the reaction mixture was poured into ice-water (200 ml) and the pink precipitate was filtered, washed with water (50 ml) and dried, to give pure rpm277 (8.4 g, 36.36 mmol, 88 percent), mp 280-282 "C. 1H NMR (400 MHz, CD3CN) δ 3.59 (2H, s), 7.10 (IH, d, J8.7 Hz), 7.92 (IH, s), 7.95 (IH, dd, J2.2, 8.7 Hz), 8.95 (IH, s, NH).
86% at 0 - 50℃; Oxindole (2.0 g, 15 mmol) is added slowly to 5.0 mL (75 mmol) of chlorosulfonic acid at 0 °C. The mixture is stirred at 0 °C until gas evolution slows. The mixture is warmed first to rt, then to 50 9C until the gas evolution stops (40 min). The mixture is cooled to rt, then poured over chipped ice. The resulting precipitate is filtered and washed with cold water and hexanes, and then dried to provide 3.0 g (86percent) of 1-003.
82% at 0 - 50℃; for 2.33333 h; [0211] 2-Oxo-2,3-dihydro-lH-indole-5-sulfonyl chlorideTo a solution of chlorosulfonic acid (25 mL, 37.5 mmol) at 0 0C was slowly added oxindole over 40 min. The resulting solution was stirred at RT for 1.5 h and then heated to 50 0C for 10 min until gas evolution ceased. After cooling to RT, the reaction mixture was carefully poured onto ice. A white precipitate was formed which was filtered, washed with ice-water and dried under HV. Yield: 14.35 g (82percent). LC/MS (10-99percent): M/Z: M+(ObS) = 232; tR= 2.24 min.
72% at 30 - 70℃; for 3 h; Chlorosulfonic acid (9.5 g, 80 mmol) was cooled in a water bath and 2.7 g (20 mmol) of 2-oxindole was added in portions keeping the temperature below 30° C. After 1 hour the reaction was slowly raised to 70° C. and stirred for 2 hours. The mixture was cooled and poured into 50 mL of ice and water. The precipitate was washed with water and dried under vacuum. The crude product was refluxed in 250 mL of ethyl acetate and dried under vacuum to give 3.3 g (72percent yield) of 5-chlorosulfonyl-2-oxindole.
70% at 20 - 68℃; for 3 h; 2-Oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 141
1,3-Dihydro-indol-2-one 13 (4.43 g, 33.3 mmol) was added slowly to cold chlorosulfonic acid (9 ml, 135 mmol).
The reaction temperature was maintained below 30° C. during the addition.
After the addition, the reaction mixture was stirred for 2 h at room temperature, then heated to 68° C. for 1 h, cooled and poured into ice water.
The precipitate was washed with water and dried under vacuum to give 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 14 (5.4 g, 70percent). MS m/z 229 [MH]+. 1H NMR, CD3CN 8.91 (S, 1H), 7.90-7.95 (m, 2H), 7.04 (d, J=0.11, 1H), 3.57 (S,1H).
70% at 20 - 68℃; 1,3-Dihydro-indol-2-one (4.43 g, 33.3 mmol) was added slowly to cold chlorosulfonic acid (9.0 ml, 135 mmol). The reaction temperature was maintained below 30 °C during the addition. After the addition, the reaction mixture was stirred for 2 h at room temperature, then heated to 68 °C for 1 h, cooled and poured into ice water. The precipitate was washed with water and dried under vacuum to give 2,3-Dihydro-2- oxo-1H-indole-5-sulfonyl chloride 6 (5.4 g, 70percent). MS m/z 232.2 (MH)+, 1H NMR, (CD3CN) 8.91 (br s, 1H), 7.90-7.95 (m, 2H), 7.04 (d, J = 8.4, 1H), 3.54 (s, 2H).
65% With chlorosulfonic acid In water at 68℃; Cooling 1,3-Dihydro-indol-2-one 64a (13.3 g, 100 mmol) was added slowly with chlorosulfuric acid (26.6 ml, 400 mmol) in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred for 1 hour in an ice-water bath, for another 1 hour at room temperature, and heated to 68°C for 1 hour. The reaction mixture was cooled down to room temperature, added slowly with water (400 ml), stirred and yellow precipitates were formed. After standing for 1 hour at room temperature, the filter cake was washed with water (20 ml.x.4) and dried to obtain the title compound 5-chlorosufonyl-indol-2-one 64b (15.0 g, yield 65percent) as a yellow solid. Reference: Acta Pharmacol Sin,; 2007, 28(1), 140-152.
59% at 20 - 68℃; for 3 h; Oxindole (1.33g, 10 mmol) was slowly added to cooled clorosulfonic acide (2.7 ML). The mixture was slowly allowed to warm to room temperature and stirred 1H at this temperature before heated to 68°C for 2h. After cooling to 0°C the reaction mixture was poured on ice to quench and the product was filtered of and washed with cold water. After drying 1.24 g (59percent) of the title compound was OBTAINED. H NMR (DMSO-d6): 8 3.61, (2H, s), 6.75 (1H, s), 7.50 (2H, d) 10.61 (1H, s, NH). 13C NMR (DMSO-d6): 8 36.1, 108.2, 122.3, 125.3, 125.4, 141.7, 144.3, 176.9. MS (ECI) nz/z 232 (M+1).
50% at 20 - 68℃; for 2.5 h; 5-Aminosulfonyl-2-oxindole
To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole.
The reaction temperature was maintained below 30° C. during the addition.
After the addition, the reaction mixture was stirred at room temperature for 1.5 hr, heated to 68° C. for 1 hr, cooled, and poured into water.
The precipitate was washed with water and dried in a vacuum oven to give 11.0 g of 5-chlorosulphonyl-2-oxindole (50percent yield) which was used without further purification.
50% at 30 - 68℃; for 2.5 h; 5-Aminosulfonyl-2-oxindole
To a 100 ML flask charged with 27 ML of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole..
The reaction temperature was maintained below 30° C. during the addition..
After the addition, the reaction mixture was stirred at room temperature for 1.5 hr, heated to 68° C. for I hr, cooled, and poured into water..
The precipitate was washed with water and dried in a vacuum oven to give 11.0 g of 5-chlorosulfonyl-2-oxindole (50percent yield) which was used without further purification.
50% at 20 - 68℃; for 2.5 h; To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole. The reaction temperature was maintained below 30° C. during the addition. After the addition the reaction mixture was stirred at room temperature for 1.5 hour, heated to 68° C. for 1 hour, cooled, and poured into water. The precipitate was washed with water and dried in a vacuum oven to give 11.0 g (50percent yield) of 5-chlorosulfonyl-2-oxindole which was used without further purification.
50% at 20 - 68℃; for 2.5 h; [0297] To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole. The reaction temperature was maintained below 30° C. during the addition. After the addition the reaction mixture was stirred at room temperature for 1.5 hour, heated to 68° C. for 1 hour, cooled, and poured into water. The precipitate was washed with water and dried in a vacuum oven to give 11.0 g (50percent yield) of 5-chlorosulfonyl-2-oxindole which was used without further purification.

Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 105, p. 274 - 288
[2] Journal of Antibiotics, 2018, vol. 71, # 10, p. 887 - 897
[3] Patent: CN104211632, 2016, B, . Location in patent: Paragraph 0081; 0082
[4] Patent: WO2011/119777, 2011, A2, . Location in patent: Page/Page column 26
[5] European Journal of Medicinal Chemistry, 2008, vol. 43, # 4, p. 755 - 762
[6] Patent: WO2007/117699, 2007, A2, . Location in patent: Page/Page column 59-60
[7] Patent: WO2009/126675, 2009, A1, . Location in patent: Page/Page column 123
[8] Patent: WO2006/10008, 2006, A1, . Location in patent: Page/Page column 190
[9] Patent: US6265411, 2001, B1,
[10] Patent: US2004/186160, 2004, A1, . Location in patent: Page/Page column 21
[11] Patent: US2009/42876, 2009, A1, . Location in patent: Page/Page column 8
[12] Patent: US2005/209301, 2005, A1, . Location in patent: Page/Page column 19
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5078 - 5083
[14] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 419 - 430
[15] Patent: EP2157093, 2010, A1, . Location in patent: Page/Page column 90-91
[16] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 807 - 812
[17] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7546 - 7559,14
[18] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7546 - 7559
[19] Patent: WO2004/99190, 2004, A1, . Location in patent: Page 18
[20] Patent: US2003/100555, 2003, A1,
[21] Patent: US2002/183364, 2002, A1,
[22] Patent: US6395734, 2002, B1,
[23] Patent: US6486185, 2002, B1,
[24] Patent: US2003/69421, 2003, A1,
[25] Patent: US2003/216410, 2003, A1,
[26] Patent: US6051593, 2000, A,
[27] Patent: US2002/156292, 2002, A1,
[28] Patent: US6114371, 2000, A,
[29] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 170; 220
[30] Patent: US6350754, 2002, B2, . Location in patent: Page column 21-22
[31] Patent: US2004/204407, 2004, A1, . Location in patent: Page/Page column 28
[32] Patent: US2004/266843, 2004, A1, . Location in patent: Page 24
[33] Patent: WO2014/70983, 2014, A1, . Location in patent: Paragraph 00233-00236
[34] Journal of Medicinal Chemistry, 1999, vol. 42, # 23, p. 4890 - 4908
[35] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 3111 - 3114
[36] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 187 - 190
[37] Patent: US6316635, 2001, B1,
[38] Patent: WO2007/122219, 2007, A1, . Location in patent: Page/Page column 10
[39] Patent: WO2012/61597, 2012, A1, . Location in patent: Page/Page column 30
[40] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4979 - 4985
[41] Marine Drugs, 2015, vol. 13, # 2, p. 806 - 823
[42] RSC Advances, 2015, vol. 5, # 111, p. 91795 - 91801
[43] Marine Drugs, 2017, vol. 15, # 11,
[44] Patent: CN105481751, 2016, A, . Location in patent: Paragraph 0028; 0038
  • 34
  • [ 7790-94-5 ]
  • [ 59-48-3 ]
  • [ 199328-31-9 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: at 50 - 60℃; for 12 h;
A mixture of 46 ml chlorosulfonic acid and lOg of 1, 3-dihydro-indol-2-one (a-1) was heated to [50°C] during 12 hours. After cooling down to room temperature, the mixture was poured on ice and water and extracted with dichloromethane. The organic layer was separated, dried over [MgS04] and the solvent was evaporated to yield 16.33 g (94percent) of intermediate a-2 (2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride).
Reference: [1] Patent: WO2004/16619, 2004, A1, . Location in patent: Page 25
[2] Patent: US2005/32871, 2005, A1, . Location in patent: Page/Page column 30
  • 35
  • [ 59-48-3 ]
  • [ 1133-96-6 ]
  • [ 210644-62-5 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With sodium hydroxide In water at 50℃; for 4 h;
Stage #2: With acetic acid In ethanol for 0.25 h; Heating / reflux
Alternatively, a mixture of 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 51 mmol), 2-oxindole (6.5 g, 49 mmol) and sodium hydroxide (40 g, 58 mmol) dissolved in 50 ml of water was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate acidified with to pH 3 with 12 N hydrochloric acid. The solid which precipitated was collected by vacuum filtration, washed with 10 ml of water and dried under vacuum overnight. The crude solid slurry washed with hot ethanol twice. The solid was then collected by vacuum filtration, washed with 10 ml of ethanol and dried under vacuum to give 13.8 g (91percent) of 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid.1HNMR (360 MHz, DMSO-d6): δ 13.38 (s, br, 1H, NH-1'), 12.05 (s, br, 1H, COOH), 10.70 (s, br, 1H, NH-1), 7.69 (d, J=7.39 Hz, 1H, H-4), 7.53 (s, 1H, H-vinyl), 7.06 (t, J=7.39 Hz, 1H, H-6), 6.95 (t, J=7.39 Hz, 1H, H-5), 6.85 (d, J=7.39 Hz, 1H, H-7), 2.63 (t, J=7.45 Hz, 2H, CH2CH2COOH), 2.34 (t, J=7.45 Hz, 2H, CH2CH2COOH), 2.28 (s, 3H, CH3), 2.24 (s, 3H, CH3); MS m/2 (relative intensity, percent) 311 ([M+1]+, 100).
88%
Stage #1: With pyrrolidine In ethanol for 2 h; Heating / reflux
Stage #2: With acetic acid In ethanol for 0.25 h; Heating / reflux
3-(2-Carboxyethyl)-2,4-dimethyl-5-dormylpyrrole-(18.2 g) and 11.7 g 2-oxindole were dissolved in 100 mL of ethanol by heating in a 250 mL round bottom flask equipped with a magnetic stirrer and a reflux condenser in an oil bath. Pyrrolidine (7.0 g) was added and the reaction mixture refluxed for 2 hours at which time a large quantity of brown-black solid was present. Thin layer chromatography (ethyl acetate:ethanol:acetic acid 96:2:2, silica gel) showed the absence of oxindole starting material. Eight mL of acetic acid was added and the mixture refluxed for 15 minutes. The thick mixture was diluted with 50 mL of ethanol and cooled to 10° C. The solid was collected by vacuum filtration and washed with 50 mL of ethanol. The solid was stirred in 125 ml of ethanol at reflux for 10 minutes, cooled to 10° C., collected by vacuum filtration and washed with 50 mL of ethanol. The product was dried overnight at 45° C. under vacuum to give 25.5 g (88percent yield) of 3-[2,4-dimethyl-3-(2-carboxyethyl) pyrrol-5-methylidenyl]-2-indolinone as an orange solid.
91% With hydrogenchloride; sodium hydroxide In ethanol; water Alternatively, a mixture of 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 51 mmol), 2-oxindole (6.5 g, 49 mmol) and sodium hydroxide (40 g, 58 mmol) dissolved in 50 ml of water was stirred at 50° C. for 4 hours.
The reaction mixture was cooled to room temperature, filtered and the filtrate acidified with to pH 3 with 12 N hydrochloric acid.
The solid which precipitated was collected by vacuum filtration, washed with 10 ml of water and dried under vacuum overnight.
The crude solid slurry washed with hot ethanol twice.
The solid was then collected by vacuum filtration, washed with 10 ml of ethanol and dried under vacuum to give 13.8 g (91percent) of 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid.
1H-NMR (360 MHz, DMSO-d6): δ 13.38 (s, br, 1 H, NH-1'), 12.05 (s, br, 1 H, COOH), 10.70 (s, br, 1 H, NH-1), 7.69 (d, J=7.39 Hz, 1 H, H-4), 7.53 (s, 1 H, H-vinyl), 7.06 (t, J=7.39 Hz, 1 H, H-6), 6.95 (t, J=7.39 Hz, 1 H, H-5), 6.85 (d, J=7.39 Hz, 1 H, H-7), 2.63 (t, J=7.45 Hz, 2 H, CH2CH2COOH), 2.34 (t, J=7.45 Hz, 2 H, CH2CH2COOH), 2.28 (s, 3 H, CH3), 2.24 (s, 3 H, CH3); MS m/z (relative intensity, percent) 311 ([M+1]+, 100).
Reference: [1] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 215
[2] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 215
[3] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 1, p. 181 - 185
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5120 - 5130
[5] Patent: US6395734, 2002, B1,
  • 36
  • [ 123-75-1 ]
  • [ 59-48-3 ]
  • [ 1133-96-6 ]
  • [ 210644-62-5 ]
Reference: [1] Patent: US6846839, 2005, B1,
  • 37
  • [ 2199-58-8 ]
  • [ 59-48-3 ]
  • [ 204005-46-9 ]
YieldReaction ConditionsOperation in experiment
10.4 g With piperidine In methanol at 65℃; To a solution of 2-formyl-3,5-dimethylpyrrole (compound 27, 7.17 g) and indolin-2-one (5.0 g) in methanol (100 mL) was added piperidine (1.0 mL). The mixture was stirred at 65 °C overnight. After cooling down to room temperature, the resulting solid gave desired compound 29 (10.4 g) as a yellow solid.
Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 10, p. 3086 - 3095
  • 38
  • [ 59-48-3 ]
  • [ 252882-61-4 ]
Reference: [1] Patent: US6172076, 2001, B2,
[2] Patent: WO2008/144266, 2008, A1,
[3] Patent: US2008/306102, 2008, A1,
  • 39
  • [ 59-48-3 ]
  • [ 118753-70-1 ]
  • [ 252882-60-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 2945 - 2959
[2] Patent: US6172076, 2001, B2,
[3] Patent: WO2008/144266, 2008, A1, . Location in patent: Page/Page column 25-26
  • 40
  • [ 59-48-3 ]
  • [ 75-36-5 ]
  • [ 64483-69-8 ]
YieldReaction ConditionsOperation in experiment
86.3% at 0 - 20℃; EXAMPLE I
5-acetyl-2-indolinone
171 g (1.28 mol) of aluminium chloride are cooled in 500 ml of 1,2-dichloroethane in the ice bath.
Then 78 g (1.1 mol) acetyl chloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is kept at 10-12° C.
The reaction mixture is allowed to come up to ambient temperature slowly overnight.
Then the solution is slowly added to 1 kg of ice with vigorous stirring.
The slurry is with diluted 1 l water and stirred for another 30 min.
Then the precipitate is suction filtered.
Yield: 80.9 g (86.3percent of theory)
Rf=0.36 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
C10H9NO2 (MG=175.19)
Mass spectrum: m/z=174 (M-H)-
86.3%
Stage #1: at 0 - 10℃; for 1 h;
Stage #2: at 10 - 20℃;
Stage #3: at 0℃; for 0.5 h;
EXAMPLE I
5-acetyl-2-indolinone
171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath.
Then 78 g (1.1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h, 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is kept at 10-12° C.
The reaction mixture is left overnight to warm up slowly to ambient temperature.
Then the solution is slowly added to 1 kg ice with vigorous stirring.
The slurry is diluted with 1 l water and stirred for another 30 min.
Then the precipitate is suction filtered.
Yield: 80.9 g (86.3percent of theory) Rf=0.36 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2) C10HgNO2 (MG=175.19) Mass spectrum: m/z=174 (M-H)-
73% at 50℃; for 5 h; 5-Acetyl-2-oxindole
2-Oxindole (3 g) was suspended in 1,2-dichloroethane and 3.2 mL acetyl chloride were slowly added.
The resulting suspension was heated to 50° C. for 5 hours, cooled, and poured into water.
The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73percent yield) of the title compound as a brown solid.
73% at 50℃; for 5 h; 5-Acetyl-2-oxindole
2-Oxindole (3 g) was suspended in 1,2-dichloroethane and 3.2 ML acetyl chloride were slowly added..
The resulting suspension was heated to 50° C. for 5 hours, cooled, and poured into water..
The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73percent yield) of the title compound as a brown solid.

Reference: [1] Patent: US2005/203104, 2005, A1, . Location in patent: Page/Page column 8
[2] Patent: WO2005/87726, 2005, A1, . Location in patent: Page/Page column 22
[3] Patent: US2005/234120, 2005, A1, . Location in patent: Page/Page column 7
[4] Patent: US2009/42876, 2009, A1, . Location in patent: Page/Page column 25
[5] Patent: US6395734, 2002, B1,
[6] Patent: US6486185, 2002, B1,
[7] Patent: US6486185, 2002, B1,
[8] Patent: US6114371, 2000, A,
[9] Patent: US6114371, 2000, A,
[10] Patent: US2003/69421, 2003, A1,
[11] Patent: US6051593, 2000, A,
[12] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 177; 222
[13] Patent: US6350754, 2002, B2, . Location in patent: Page column 29
[14] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 9, p. 2609 - 2616
[15] Patent: US4652658, 1987, A,
[16] Patent: US4658037, 1987, A,
[17] Patent: US4721712, 1988, A,
[18] Patent: US4678802, 1987, A,
[19] Patent: US4556672, 1985, A,
[20] Patent: US4569942, 1986, A,
[21] Patent: US4690943, 1987, A,
[22] Patent: US6291523, 2001, B1,
[23] New Journal of Chemistry, 2017, vol. 41, # 21, p. 12604 - 12610
  • 41
  • [ 59-48-3 ]
  • [ 64483-69-8 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 10℃; for 1 h;
Stage #2: at 10 - 12℃;
EXAMPLE I
5-acetyl-2-indolinone
171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath.
Then 78 g (1,1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is maintained at 10-12° C.
The reaction mixture is left overnight to come up slowly to ambient temperature.
Then the solution is slowly added to 1 kg ice with vigorous stirring.
The slurry is diluted with 1 l water and stirred for another 30 min.
Then the precipitate is suction filtered.
Yield: 80.9 g (86.3percent of theory)
Rf=0.36 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
C10H9NO2 (MW=175.19)
Mass spectrum: m/z=174 (M-H)-
Reference: [1] Patent: WO2005/87727, 2005, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2005/87761, 2005, A1, . Location in patent: Page/Page column 22
[3] Patent: US2005/209302, 2005, A1, . Location in patent: Page/Page column 8-9
  • 42
  • [ 59-48-3 ]
  • [ 75-36-5 ]
  • [ 64483-69-8 ]
Reference: [1] Patent: US2002/183364, 2002, A1,
  • 43
  • [ 59-48-3 ]
  • [ 118753-70-1 ]
  • [ 752234-64-3 ]
Reference: [1] Patent: WO2004/69256, 2004, A1, . Location in patent: Page/Page column 46
  • 44
  • [ 59-48-3 ]
  • [ 79099-07-3 ]
  • [ 400797-94-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6773 - 6776
  • 45
  • [ 59-48-3 ]
  • [ 830-79-5 ]
  • [ 186611-52-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2958 - 2963
  • 46
  • [ 59-48-3 ]
  • [ 34270-90-1 ]
  • [ 304876-29-7 ]
Reference: [1] Patent: WO2006/31610, 2006, A2, . Location in patent: Page/Page column 69
  • 47
  • [ 5414-19-7 ]
  • [ 59-48-3 ]
  • [ 304876-29-7 ]
YieldReaction ConditionsOperation in experiment
17%
Stage #1: at -78℃; for 1 h;
Stage #2: at -50 - 25℃; for 18 h;
Oxindole la (CAS number: 59-48-3, 40 g, 264.659 mmol) was added to a solution of LiHMDS (800 ml, 800 mmol) at -78°C. The mixture was stirred 1 hour at -78°C.Bis(2-bromomethyl)ether (CAS number: 5414-19-7, 61.378 g, 264.659 mmol) was then added, maintaining the internal temperature <-5 0°C. The reaction was warmed to ambient temperature. After 18 hours the reaction was quenched with H20 and the mixture was partitioned between EtOAc and H20. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, dried overNa2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of petroleum ether: ethyl acetate = 3:1 to give 10.187 g (17percent) of 2’,3’,5’,6’-tetrahydrospiro[indoline-3 ,4’-pyran]-2-one lb.
Reference: [1] Patent: WO2014/60411, 2014, A1, . Location in patent: Page/Page column 36
  • 48
  • [ 59-48-3 ]
  • [ 304876-29-7 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 2, p. 94 - 97
  • 49
  • [ 59-48-3 ]
  • [ 873779-30-7 ]
Reference: [1] Patent: WO2008/144266, 2008, A1,
  • 50
  • [ 59-48-3 ]
  • [ 135-02-4 ]
  • [ 186611-04-1 ]
Reference: [1] Organic Letters, 2009, vol. 11, # 17, p. 3874 - 3877
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Indolines

Chemical Structure| 13220-46-7

[ 13220-46-7 ]

4-Methylindolin-2-one

Similarity: 0.98

Chemical Structure| 150544-04-0

[ 150544-04-0 ]

6-Aminoindolin-2-one

Similarity: 0.98

Chemical Structure| 120266-80-0

[ 120266-80-0 ]

5-Aminoindolin-2-one hydrochloride

Similarity: 0.98

Chemical Structure| 729598-50-9

[ 729598-50-9 ]

5,7-Dimethylindolin-2-one

Similarity: 0.96

Chemical Structure| 139122-19-3

[ 139122-19-3 ]

4-(2-Hydroxyethyl)indolin-2-one

Similarity: 0.91