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CAS No. : | 20870-78-4 | MDL No. : | MFCD00456998 |
Formula : | C8H6BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 212.04 | Pubchem ID : | - |
Synonyms : |
5-Bromooxindole
|
Num. heavy atoms : | 11 |
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 : | 49.43 |
TPSA : | 29.1 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.28 cm/s |
Log Po/w (iLOGP) : | 1.74 |
Log Po/w (XLOGP3) : | 1.85 |
Log Po/w (WLOGP) : | 1.37 |
Log Po/w (MLOGP) : | 1.87 |
Log Po/w (SILICOS-IT) : | 2.53 |
Consensus Log Po/w : | 1.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.72 |
Solubility : | 0.401 mg/ml ; 0.00189 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.08 |
Solubility : | 1.76 mg/ml ; 0.00828 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.75 |
Solubility : | 0.0379 mg/ml ; 0.000179 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.54 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H317-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | Stage #1: With hydrogen bromide; sodium nitrite In water at -5 - 0℃; for 0.0025 h; Stage #2: With hydrogen bromide; copper(I) bromide; copper(ll) bromide In water at 0.5 - 25℃; for 1.5 h; |
The 5-bromofluorenone 670.7 g obtained in the previous step,Add 1320ml of water and cool to -5-0 °C in an ice bath.Then add 1100g of hydrogen bromide (48percent) aqueous solution and stir.Most of the raw materials are dissolved, and the temperature is controlled within the range of -5-0 °C.Add 143 g of sodium nitrite to a solution of 286 ml of water.During the period, the control temperature does not exceed 0 °C, about 15 minutes,The incubation reaction was continued for 1 h, and a large amount of brown granular solid (diazonium salt) was precipitated in the reaction solution for use.In another 10000ml four-necked flask, 297g of cuprous bromide, 22g of copper bromide, 13200ml of water, hydrogen bromide(48percent) 1100g of aqueous solution, stirred, the reaction solution was dark red, heated to 20-25 ° C, the diazonium salt obtained in the previous step was added dropwise.After the completion of the dropwise addition, the reaction was continued for 1 h, the temperature was lowered to about 5 ° C, the temperature was kept for 0.5 h, and the filter cake was washed with cold water until the washing liquid was colorless. drying,The solid 2,5-dibromophenylacetic acid 746 g was obtained in a yield of 80.5percent, and the HPLC purity was 98.8percent. |
322.5 g | Stage #1: With hydrogen bromide; sodium nitrite In water at -5 - 0℃; for 1 h; Stage #2: With copper(l) iodide; hydrogen bromide; copper(I) bromide In water at 20 - 25℃; for 1 h; |
300.0 g of bromoindolinone (Formula II) prepared in the previous step was put into a reaction flask, 600 ml of water was added, and the temperature was lowered to -5 to 0 ° C in an ice bath,Then 493.5g of hydrogen bromide (48percent) aqueous solution was added and stirred. Most of the raw materials were dissolved and the temperature was controlled at -5-0 ° C. A solution of 65.0g of sodium nitrite dissolved in 130ml of water was added dropwise,During the temperature does not exceed 0 , about 15min plus Bi, continue to heat the reaction 1h,The reaction liquid has a large number of brown granular solid precipitation, stand-by. In another reaction flask, 135.0 g of cuprous bromide, 10.0 g of cupric bromide, 600 ml of water and 500 g of a hydrogen bromide (48percent) aqueous solution were added and the mixture was stirred. The reaction mixture was dark red,The temperature was raised to 20-25 ° C., the diazonium salt obtained from the previous step was added dropwise and the reaction was continued for 1 h after the completion of the incubation.Cool to about 5 , incubated 0.5h, filtered, the filter cake washed with cold water to wash colorless.Drying afforded 322.5g of solid, HPLC purity 99.1percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-Bromosuccinimide; In dichloromethane; at 42℃; for 1h; | Obtained in the previous step indolinone was added 3600 g of methylene chloride,Control the reaction temperature not to exceed 42 C,Add NBS613g to the reaction system within half an hour.After the addition, the reaction was kept for another half an hour, and when the content of the anthrone was less than 0.5% by HPLC analysis, the reaction was completed.Cool to below 10 C, filter, filter cake with a small amount of dichloromethane,The mixture was dried to obtain 670.7 g of 5-bromofluorenone, the yield was 95%, and the purity was 98.5%. |
93% | With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 3h;Inert atmosphere; | To a stirred suspension of indolin-2-one (LIII, 4.0 g, 27.0 mmol) in acetonitrile (160 mL), N-bromosuccinimide (6.24 g, 35.1 mmol) was added portion-wise at 0C under nitrogen atmosphere and then stirredfor 3 h at 15-20 C. The reaction mixture was quenchedwith ice-water (100 mL) to afford solid. The resultant solid was filteredthrough sintered funnel, washed with water and dried to afford the title compound as a solid (LIV, 6.0 g, 93%). LC-MS m/z calcd for C8H6BrNO, 210.9; found 212.0. [M+H]+. |
90% | With N-Bromosuccinimide; In acetonitrile; | 5-Bromo-2-Oxindole 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to -10 C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. |
90% | With N-Bromosuccinimide; In acetonitrile; | 5-Bromo-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one 2-Oxindole (1.3 g) in 20 mL of acetonitrile was cooled to -10 C. and 2.0 g of N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of 5-bromo-2-oxindole. 1H NMR (360 MHz, DMSO-d6) delta10.44 (s, br, 1H, NH-1), 7.32-7.36 (m, 2H), 6.76 (d, J=8.5 Hz, 1H, H-7), 3.5 (s, 2H, CH2). MS m/z 212.1 and 214.1 [M and M+2]+. |
90% | With N-Bromosuccinimide; In acetonitrile; | Preparation of 5-Bromo-2-indolinone 2-indolinone (1.3 g) in 20 mL of acetonitrile was collected to -10 C. and 2.0 g of N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at 10 C. and 2 hours at 0. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. |
90% | With N-Bromosuccinimide; In acetonitrile; | 5-Bromo-2-oxindole 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to -10 C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. |
90% | With N-Bromosuccinimide; In acetonitrile; | (e) Preparation of 5-Bromo-2-oxindole. 2-Oxindole (1.3 g) in 20 mL of acetonitrile was cooled to -10 C. and 2.0 g of N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. |
90% | With N-Bromosuccinimide; In acetonitrile; | 5-Bromo-2-oxindole 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to -10 C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. |
90% | With N-Bromosuccinimide; In acetonitrile; at -10 - 0℃; for 3h; | 5-Bromo-2-oxindole 2-Oxindole (1.3 g) in 20 ML acetonitrile was cooled to -10 C. and 2.0 g N-bromosuccinimide was slowly added with stirring.. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. |
88% | With N-Bromosuccinimide; In acetonitrile; at 0℃; for 3h; | To a solution of 1,3-Dihydro-indol-2-one (20 g, 133.15 mmol) in acetonitrile (300 ml) at 0 C. was added NBS (30.76 gm, 173.8 mmol) in several portions and the solution stirred at this temperature for 3 h. Water was added to the reaction mixture, upon which a white solid precipitated. The solid was collected by filtration, washed with hot water and dried under vacuum to obtain compound 5-Bromo-1,3-dihydro-indol-2-one (28 g, 88%). |
88 - 90% | With N-Bromosuccinimide; In acetonitrile; at -10℃; for 1h; | 5-Bromo-2-oxindole 2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to -10 C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at -10 C. and 2 hours at 0 C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound. 2-Oxindole (53.3 g) was suspended in 640 mL acetonitrile and the mixture cooled to 7 C. in an ice bath with mechanical stirring. Solid N-bromosuccinimide (74.8 g) was added in portions over 20 minutes. After about one-third of the N-bromosuccinimide had been added (over 5 minutes), the temperature had increased to 12 C. The addition was halted until the temperature of the mixture had dropped to 10 C. The addition was resumed keeping the temperature below 12 C. After the addition was complete, the mixture was stirred for 1 hour at 10 C. and then for 1 additional hour during which the mixture was allowed to warm to ambient temperature. The precipitate was collected by vacuum filtration, washed with 80 mL of ethanol and sucked dry for 20 minutes in the filtration funnel to give product containing 6.4% of 2-oxindole by HPLC. The solid was suspended in 1440 mL of denatured ethanol and slurry-washed by stirring and refluxing for 5 minutes at which time most of the solid had dissolved. The mixture was cooled in an ice bath to 13 C. The solid product was collected by vacuum filtration, washed with 80 mL of ethanol and dried under vacuum to give 57.7 g (68.0%) of 5-bromo-2-oxindole containing 1.13% 2-oxindole by HPLC. Slurry-washing with 30% less ethanol gave a better yield (88%) but contained more 2-oxindole (1.76%). |
87% | With N-Bromosuccinimide; In acetonitrile; | EXAMPLE 483A 5-bromo-1,3-dihydro-2H-indol-2-one A suspension of 1,3-dihydro-indol-2-one (1.3 g, 9.76 mmol) in acetonitrile (20 mL) at -5 C. was treated with N-bromosuccinimide, warmed to room temperature, stirred overnight and filtered to give 1.8 g (87% yield) of the desired product. MS (ESI(+)) m/e 209.9, 211.9 (M-H)-. |
82% | With N-Bromosuccinimide; In acetonitrile; at -10 - 10℃; for 3h; | Oxindole (1.30 g, 0.010 mmol) was suspended in dry acetonitrile (22.0 mL) under N2 and cooled to -10 C. To this stirred mixture was added recrystallized NBS (2.00 g, 0.011 mol) portionwise. The resulting suspension was stirred at -10 to 10 C. for 3 h. The precipitated solid was collected by filtration, washed with H2O and dried to give the intermediate title compound as an off white solid 1.75 g (82%). Electrospray mass spectrum (M-1)=210, (M-1)=211 |
68% | With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 2h; | 2-Oxindole (5.3 g, 0.04 mol) was suspended in 64 mL of acetonitrile cooled in a ice bath. N-Bromosuccinimide (7.5 g, 0.042 mol) was slowly added with vigorous stirring keeping the temperature below 12 C. The mixture was stirred for 1 hour at 10 C. and then for 1 hour while warming to room temperature. The precipitate was collected by vacuum filtration, washed with 8 mL of ethanol and slurry-washed in 140 mL of refluxing ethanol to give 5.8 g (68% yield) of the title compound. |
67.8% | With potassium bromide; In water; for 0.0833333h;Heating; | Oxindole (2.50g, 19mmol, 1eq.) was dissolved in 80mL of boiling water. Bromine (3 g,19mmol, 1eq.) and potassium bromide (4.50g, 38mmol, 2eq.) were dissolved in 10mL ofwater and then added dropwise to a warm, stired solution of oxindole in 5 min. A whiteprepcipitate appeared. The mixture was stored for 20min in refrigerator. The precipitate wasfiltered, extensively washed with water and dried in vacuum at elevated temperature to give2.70g of 5-bromo-oxindole as a colorless solid. |
64.4% | With N-Bromosuccinimide; In acetonitrile; at -10 - 0℃; for 3h; | To the solution of 28a (500mg, 3.76mmol) in acetonitrile (8mL) cooled to - 100C, was slowly added N-bromosuccinimide (770mg, 4.33mmol) with stirring. After the addition was complete, the mixture was stirred for Ih at -1O0C, then warmed to O0C for 2h. The resulting precipitate was collected by filtration, washed with water and dried under vacuo to give 28b (513mg, 64.4%). |
63% | With N-Bromosuccinimide; acetic acid; In water; at 0 - 23℃; for 1h; | 1,3-Dihydro-2H-indol-2-one (5.25 g, 39.43 mmol) (Aldrich) was treated with a 1:1 solution of glacial acetic acid and distilled water (246 mL). The resulting reaction mixture was cooled to 0 C and then slowly treated with N-bromosuccinimide (14.03 g, 78.85 mmol) (J.T. Baker). After the complete addition of N-bromosuccinimide, the cooling bath was removed, and the reaction mixture was stirred at 23 C for 1 h. Upon stirring at 23 C, the reaction mixture became viscous and a white solid precipitated. The reaction mixture was poured into 500 mL distilled water and filtered to provide a crude white solid. Recrystallization from methanol provided pure 5-bromo-1,3-dihydro-2H-indol-2-one as a light pink solid. (Yield 5.28 g, 63%; mp 219 - 220 C). |
43% | With N-Bromosuccinimide; In acetonitrile; at -10 - 0℃; | Preparation of 5-Bromo-1,3-dihydro-indol-2-one. 5-Bromo-1,3-dihydro-indol-2-one can be prepared following the procedure described by Sun et al., J. Med. Chem., 41, 2588-2603 (1998).For example, to a stirred suspension of oxindole(1.30 g, 10 mmol) in dry acetonitrile(22.0 ML) at -10 C. was added portionwise recrystallized NBS (2.00 g, 11.0 mmol) and the resulting suspension was stirred at -10 to 0 C. for 3 hours.The suspension was allowed to warm to ambient temperature and the mixture was filtered to give a white solid which was recrystallized (EtOH) to provide the intermediate title compound (1.47, 43%) as a slightly pink solid; mp 212-214 C. |
With bromine; sodium acetate; In chloroform; | 5-(Bromo)-1,3-dihydro-indol-2-one A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1 g, 25.5 mmol) in CHCl3 (20 cm3) was treated with bromine (2.4 g, 15.0 mmol) in CHCl3 (10 cm3). After 30 min. the mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with EtOAc (500 cm3) and poured into water. The aqueous layer was extracted with EtOAc (*2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, brine, dried (MgSO4), and evaporated to give the title compound (3.1 g, 14.6 mmol, 96 %) as an off-white solid which was used without further purification: mp. 221-223 C.; 1H NMR (DMSO-d6) delta3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33(dd, 1H, J=8.1, 1.7 Hz), 7.37 (s, 1H), 10.49 (br s, 1H); 13C NMR (DMSO-d6) delta36.10 (t), 111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s), 176.24 (s); MS (EI) m/z 211, 213 (M)+. | |
With bromine; sodium acetate; In chloroform; | 5-(Bromo)-1,3-dihydro-indol-2-one. A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1 g, 25.5 mmol) in CHCl3 (20 cm3) was treated with bromine (2.4 g, 15.0 mmol) in CHCl3 (10 cm3). After 30 min. the mixture was allowed to warm to room temperature (RT) and stirred for 1 hour. The reaction mixture was diluted with EtOAc (500 cm3) and poured into water. The aqueous layer was extracted with EtOAc (*2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, brine, dried (MgSO4), and evaporated to give the title compound (3.1 g, 14.6 mmol, 96%) as an off-white solid which was used without further purification: mp. 221-223 C.; 1H NMR (DMSO-d6) delta 3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33(dd, 1H, J=8.1, 1.7 Hz), 7.37 (s, 1H), 10.49 (br s, 1H); 13C NMR (DMSO-d6) delta 36.10 (t), 111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s), 176.24 (s); MS (EI) m/z 211, 213 (M)+. | |
With N-Bromosuccinimide; In water; acetic acid; | Starting Material 6: 5-Bromo-1,3-dihydro-2H-indol-2-one 1,3-Dihydro-2H-indol-2-one (5.25 g, 39.43 mmol) (Aldrich) was treated with a 1:1 solution of glacial acetic acid and distilled water (246 mL). The resulting reaction mixture was cooled to 0 C. and then slowly treated with N-bromosuccinimide (14.03 g, 78.85 mmol) (J. T. Baker). After the complete addition of N-bromosuccinimide, the cooling bath was removed, and the reaction mixture was stirred at 23 C. for 1 h. Upon stirring at 23 C., the reaction mixture became viscous and a white solid precipitated. The reaction mixture was poured into 500 mL distilled water and filtered to provide a crude white solid. Recrystallization from methanol provided pure 5-bromo-1,3-dihydro-2H-indol-2-one as a light pink solid. (Yield 5.28 g, 63%; mp 219-220 C.). | |
In acetonitrile; | Preparation of 5-Bromo-oxindole Oxindole (1.30 g, 0.010 mmol) was suspended in dry acetonitrile (22.0 mL) under N2 and cooled to -10 C. To this stirred mixture was added recrystallized NBS (2.00 g, 0.011 mol) portionwise. The resulting suspension was stirred at -10 to 10 C. for 3 h. The precipitated solid was collected by filtration, washed with H2O and dried to give the intermediate title compound as an off white solid 1.75 g (82%). Electrospray mass spectrum (M-1)=210, (M-1)=211 | |
With N-Bromosuccinimide; In acetonitrile; at 0℃; for 4h; | To a 50 ml single-flask containing 30 ml of acetonitrile was cooled to 0C. Indole-2-one (0.023 mol) and N-bromosuccinimide (0.023 mol) was added, and then stirred at 0C for 4 hours. The primrose precipitate was collected by vacuum filtration, washed with water, and dried under in the air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With tetraethylammonium chloride;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile;Heating / reflux; | Example 37; 5-Pyridin-3-yl-1, 3-dihydro-2H-indol-2-one; A mixture of 5-bromooxindole (0.95 g, 4.48 mmol), 3-(tri-n-butylstannyl) pyridine (1.65 g, 4.48 mmol), tetraethyl ammonium chloride (2.23 g, 13.4 mmol) and bis (triphenylphospine palladium (II) chloride (0.16 g, 0.22 mmol) in acetonitrile (20 mL) was heated at reflux over night. After cooling to ambient temperature the mixture was diluted with chloroform (100 mL) and a potassium fluoride solution (10%, 250 mL) was added. The mixture was filtered through Celite and the layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified on a silica gel column using chloroform/ethanol, (50: 1), as the eluent affording 165 mg (18% yield) of the title compound as a white solid :'H NMR (DMSO-d6,400 MHz) 8 9.64 (br s, 1 H), 7.97 (d, J = 2 Hz, 1 H), 7.66 (dd, J = 5,1 Hz, 1 H), 7.21-7. 10 (m, 1 H), 6.73 (s, 1 H), 6. 73-6.65 (m, 1 H), 6.65-6. 54 (m, 1 H), 6.08 (d, J = 8 Hz, 1 H), 2.69 (s, 2 H); MS (ES) n2/z 211 (M+ +1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 5-bromo-2-indolin-2-one With potassium <i>tert</i>-butylate In tetrahydrofuran at -15℃; for 0.5h; Stage #2: 1,5-dibromo-pentane In tetrahydrofuran at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With titanium tetrachloride; zinc; In tetrahydrofuran; at 20℃; for 0.1h;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 3% 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. |
75% | With hydrazine hydrate; for 5h;Reflux; | General procedure: The suspension of isatin 1a-c in hydrazine hydrate was refluxed for 5h until clear solution formation. After reaction completion the mixture was cooled down to room temperature and poured into cold water. Then pH value of the mixture was adjusted to 1-2 via concentrated hydrochloride acid addition. The reaction mixture was left at room temperature for 2-3days, the precipitate formed was filtered, washed with water and dried on air and was used without additional purification. The following compounds were obtained according to this general procedure: |
72% | General procedure: Isatins (1a-j, 3.0 g), hydrazine hydrate (80%, 13 mL) and water (13 mL) were added to a flask equipped with a thermometer with vigorous stirring. The reaction mixture was kept at 140 C in an oil bath for 6 h before being cooled to r.t., when hydrochloric acid (2.0 mol L-1) was added to bring the pH to pH 2. The reaction mixture was stirred at r.t. for 12 h. Compounds 2a-j were obtained by filtering under vacuum and recrystallisation from absolute ethanol. |
37% | With hydrazine hydrate; potassium hydroxide; In ethylene glycol; at 80℃; for 4h; | Step 90a: 5-Bromoindolin-2-one (Compound 0601-194)To a mixture of 5-bromoindole-2,3-dione (2.25 g, 10 mmol), ethyleneglycol (45 mL) and hydrazine hydrate (1.06 g, 21.10 mmol) was added KOH (1.68 g, 30 mmol). The reaction mixture was stirred at 80C for 4 hours. The mixture was cooled to room temperature and poured into ice cold water and the mixture was adjusted to pH 1-2 with 12N hydrochloric acid and stirred at room temperature for 12 hours. The mixture was filtered and solid was washed with water (5 mL) and dried to get the crude product which was purified by column chromatography on silica gel (methanol in dichloromethane, 0.5% v/v) to give 0601-194 (785 mg, 37%) as a yellow solid. LCMS: 214 [M+l]+. 1H-NMR (400 MHz. OMSO-de) delta 3.51 (s, 2H), 6.76 (d, J= 8.0 Hz, 1H), 7.34 (dd, J= 8.0, 2.0 Hz, 1H), 7.38 (m, 1H), 10.49 (s, 1H). |
37% | Step 90a: 5-Bromoindolin-2-one (Compound 0601-194)[0597]To a mixture of 5-bromoindole-2,3-dione (2.25 g, 10 mmol), ethyleneglycol (45 mL) and hydrazine hydrate (1.06 g, 21.10 mmol) was added KOH (1.68 g, 30 mmol). The reaction mixture was stirred at 80 C. for 4 hours. The mixture was cooled to room temperature and poured into ice cold water and the mixture was adjusted to pH 1-2 with 12N hydrochloric acid and stirred at room temperature for 12 hours. The mixture was filtered and solid was washed with water (5 mL) and dried to get the crude product which was purified by column chromatography on silica gel (methanol in dichloromethane, 0.5% v/v) to give 0601-194 (785 mg, 37%) as a yellow solid. LCMS: 214 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) delta 3.51 (s, 2H), 6.76 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 2.0 Hz, 1H), 7.38 (m, 1H), 10.49 (s, 1H). | |
37% | With hydrazine hydrate; In ethylene glycol; at 80℃; for 4h; | 5-bromo-indole-2,3-dione (2.25g, 10mmol), ethylene glycol (45 mL) and heatIt was added KOH (1.68g, 30mmol) in a mixture of hydrazine hydrate (1.06g, 21.10mmol). The reaction mixture was stirred for 4 hours at 80 C.. The mixture was cooled to room temperature, poured into ice-cold water, with 12N hydrochloric acid was adjusted to pH 1 ~ 2, and stirred at room temperature for 12 hours. The mixture was filtered solid was washed with water (5 mL), and dried to give the crude product which was purified juice dim over a column chromatography (methanol in dichloromethane, 0.5% v / v), 0601 -194 as a yellow solid (785mg, 37%). |
General procedure: The preparation was divided into two steps. Firstly, substituent indoline-2,3-dione (1 equiv) was dissolved in ethanol (10 mL), hydrazine hydrate (2 mL) was added. The reaction mixture was refluxed with magnetic stirring for 3 h and cooled to 0 C, then sodium hydroxide (3 equiv) was added, refluxed for 0.5 h and cooled to room temperature, then 150 mL water was added. The mixture was acidified by adding 2 N hydrochloric acid to pH 2, and extracted twice with dichloromethane. The organic filtrate was washed twice with brine, dried (Na2SO4), and then concentrated to give corresponding indolin-2-one by high-vacuum drying. Secondly, a mixture of the corresponding indolin-2-one (1 equiv) and furan-2-carbaldehyde (1 equiv) in ethanol was added two drops of piperidine and refluxed with magnetic stirring for 5 h. After the mixture cooled, the precipitate was filtered, washed with cold ethanol, dried, and recrystallized from methanol to afford the terminal product. | ||
With hydrazine hydrate; potassium hydroxide; In ethylene glycol; at 110 - 130℃; | General procedure: To a mixture of isatin (6a-e, 1.0 g) and hydrazine-hydrate (5 mL,~30 mmol) in ethylene glycol, potassium hydroxide (10 equiv.) was added and the resulting reaction mixturewas stirred at 110-130 C for 2-3 h (reaction monitored by TLC). The reaction mixture wascooled to room temperature, poured into ice-cold water (50 mL), acidified to pH 2 with 6N hydrochloric acid and extracted with ethylacetate (3 30 mL). The organic extracts were combined, washed with brine (15 mL), dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane as eluents to furnish 7a-e in moderate yields. | |
With hydrazine hydrate; potassium hydroxide; In ethylene glycol; at 110 - 130℃; | General procedure: To a mixture of isatin (7a-e, 1.0 g) and hydrazine-hydrate (5 mL, ~30 mmol) in ethylene glycol,potassium hydroxide (10 equiv.) was added and the resulting reaction mixture was stirred at110-130 C for 2-3 h (monitored by TLC). The reaction mixture was cooled to roomtemperature, poured into ice-cold water (50 mL), acidified to pH 2 with 6N hydrochloric acidand extracted with ethyl acetate (3 x 30 mL). The organic extracts were combined, washed withbrine (15 mL), dried over sodium sulfate and concentrated in vacuo. The obtained residue waspurified by column chromatography using ethyl acetate-hexane as eluents to furnish 8a-e inmoderate yields. | |
With titanium tetrachloride; zinc; In tetrahydrofuran; at 20℃; for 0.0833333h;Inert atmosphere; | General procedure: TiCl4 (0.7 mL, 6 mmol) wasadded to a stirred suspension of Zn powder (0.78 g, 12 mmol) infreshly distilled anhydrous THF (15 mL) at room temperature (r.t.)under a dry N2 atmosphere. After completion of the addition, themixture was refluxed for 2 h. The suspension of the low-valent titaniumreagent formed was cooled to r.t. A solution of isatin derivatives(2 mmol) in THF (10 mL)was added dropwise. The mixturewas stirred at room temperature for about 5 min under N2. Afterthis period, the thin layer chromatography (TLC) analysis of themixture showed the reaction completed. The reaction mixture wasquenched with 5% HCl (15 mL) and extracted with CH2Cl2(3 x 50 mL). The combined extracts were washed with water (350 mL) and dried over anhydrous Na2SO4. After evaporation of thesolvent under reduced pressure, the crude product was purified bycolumn chromatography (petroleum ether/EtOAc = 5:1) to give thepure products 9a-d. | |
402.4 g | In a 5L four-necked flask, add 5-bromoisatin 250.0g,1000ml absolute ethanol, stirring, and then slowly add hydrationHydrazine (80%) 81.4g, heated to reflux (80 C)Reaction 2h,Sampling HPLC test, no raw material remaining, the reaction liquid coolingTo about 15 , crystallization 15min, filtered, the filter cake was washed with a small amount of cold ethanol or mother liquor,Then at 50 oven drying 12h, get hydrazone crude. In a 5L four-necked flask, put the crude hydrazide obtained above,Ethylene glycol 1000ml, stirring, adding sodium hydroxide 32.5g,Heated to reflux,Reflux temperature gradually increased from 95 to 115 , the reaction 7h,Sample HPLC test, no raw material remaining, stop heating, cooling to below 30 , the reaction solution was transferred to a 10L bottle, add water 1500ml, with concentrated hydrochloric acid to adjust PH = 2.5 or so, adding methylene chloride 1500ml, The floc was precipitated, filtered, and the layers were separated. The aqueous layer was further extracted with 500 ml of dichloromethane, and the organic layers were combined.The solvent was distilled off under reduced pressure to give 402.4 g of bromoindolinone (Formula II). |
Yield | Reaction Conditions | Operation in experiment |
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95% | With piperidine; In isopropyl alcohol; for 20h;Heating / reflux; | A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (3.10 g, 14.62 mmol) (Starting Material 6) and pyrrole-2-carboxaldehyde (1.46 g, 15.35 mmol) (Aldrich) in 2-propanol (73 mL) was treated with 10-12 drops of piperidne. The reaction mixture was heated at reflux for 20 h and then allowed to cool to 23 C, at which time, the reaction mixture was filtered. The resulting solid was washed well with hexanes, followed by petroleum ether, and then allowed to air dry to provide pure (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid which was used without further purification. (Yield 4.01 g, 95%; mp 267 - 268 C). |
In isopropyl alcohol; Petroleum ether; | Starting Material 7: (Z)-5-Bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (3.10 g, 14.62 mmol) (Starting Material 6) and pyrrole-2-carboxaldehyde (1.46 g, 15.35 mmol) (Aldrich) in 2-propanol (73 mL) was treated with 10-12 drops of piperidne. The reaction mixture was heated at reflux for 20 h and then allowed to cool to 23 C., at which time, the reaction mixture was filtered. The resulting solid was washed well with hexanes, followed by petroleum ether, and then allowed to air dry to provide pure (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid which was used without further purification. (Yield 4.01 g, 95%; mp 267-268 C.). | |
piperidine; In ethanol; at 20 - 150℃; for 0.5h;Microwave irradiation; Sealed vessel; | Description 3:(Z)-3-{(1H-Pyrrol-2-yl)methylene)-5-bromoindolin-2-oneIn a 35 ml microwave tube were placed 5-bromo-1,3-dihydro-2H-indol-2-one (1 mmol), pyrrole-2-carbaldehyde (1.2 mmol), piperidine (2 drops), ethanol (10 ml) and a magnetic stir bar. The vessel was sealed with a septum and placed in the microwave cavity. Initial microwave irradiation of 200 W was used, the temperature being ramped from RT to 150 C. Once 150 C was reached the reaction vessel was held at this temperature for 30 min by moderation of the initial microwave power. After cooling, solvent was removed in vacuo and ethyl acetate was added to the reaction mixture. The precipitate was collected by filtration and washed with ethyl acetate (2x 10 ml) to afford a yellow-brown solid. The results set out below identify the product as the title compound D3. |
Yield | Reaction Conditions | Operation in experiment |
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65% | With n-butyllithium; N,N,N,N,-tetramethylethylenediamine at 25℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
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93.8% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 85℃; for 15h; | EXAMPLE 58A 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one Under N2, 5-Bromoindolin-2-one (Aldrich, 2.11 g, 10.0 mmol) was coupled with bis(pinacolato)dibon (Frontier Scientific, 3.05 g, 12 mmol) in the presence of KOAc (Aldrich, 1.50 g, 15.0 mmol) under the catalysis of PdCl2(dppf).CH2Cl2 (Aldrich, 163 mg, 0.2 mmol) in anhydrous dioxane (Aldrich, 50 mL) at 85 C. for 15 hours. After the reaction was completed, it was cooled down to ambient temperature and diluted with EtOAc (100 mL). The mixture was then washed with brine (2*10 mL) and concentrated. The residue was purified with chromatography on silica gel (EtOAc/hexanes, v. 1:1, Rf=0.5) to provide the title compound (2.43 g, yield, 93.8%). 1H NMR (300 MHz, CD3OD) delta 1.24 (s, 12H), 3.51 (s, 2H), 6.88 (d, J=8.5 Hz, 1H), 7.52-7.75 (m, 2H) ppm. MS (DCI/NH3): m/z 260 (M+H)+. |
82% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90℃; for 12h; | To a solution of 5-Bromo-1,3-dihydro-indol-2-one (318 mg, 1.5 mmol) and Bis(pinacolato)diboron (420 mg, 1,65 mmol) in dioxane (15 mL) was added KOAc (516 mg, 5.25 mmol). The resulting mixture was degassed, treated with [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium methylene choloride complex (62 mg, 0.075 mmol), heated at 90 C. for 12 h and concentrated. The residue was dissolved in CH2Cl2 (100 mL), washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel eluding with 30% ethyl acetate/hexanes to afford 320 mg of Example 133a (82%). 1H NMR (300 MHz, DMSO-D6) delta ppm 1.27 (s, 12H) 3.46 (s, 2H) 6.81 (d, J=7.72 Hz, 1H) 7.49 (m, 2H) 10.51 (s, 1H)) MS (ESI) m/z 260.2 (M+H)+, 276.8 (M+NH4)+ |
75% | A mixture of 28b (513mg, 2.42mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl (l,3,2-dioxaborolan-2-yl))-l ,3,2-dioxaborolane (716mg, 2.82mmol) and KOAc (878mg, 8.95mmol) in dioxane (2OmL) was purged with nitrogen for lOmin, then added Pd(dppf)Cl2. CH2Cl2 (108mg, 0.13mmol). The resulting mixture was stirred at 800C overnight and evaporated. The residue was dissolved in ethyl acetate and filtrated. The filtrate was washed with brine (15mLchi2), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EA: PE =4:1) to afford 28c (470mg, 75%). |
74% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 10h; | 5-Bromo-1,3-dihydro-indol-2-one (Aldrich, 1.06 g, 5 mmol) was coupled with bis(pinacolato)diboron (Aldrich, 1.52 g, 6 mmol) catalyzed by PdCl2(dppf)2.CH2Cl2 (Aldrich, 82 mg, 0.1 mmol) using KOAc (Aldrich, 0.98 g, 10 mmol) as base in dioxane (anhydrous, Aldrich, 50 mL) at 80 C. for 10 h. After being cooled down to ambient temperature, the mixture was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was then concentrated under vacuum. The title compound was purified by chromatography (SiO2, hexane:EtOAc, 70:30, Rf. 0.5) as a solid (0.96 g, yield, 74%). 1H NMR (300 MHz, CDCl3) delta 1.24 (s, 3 H), 1.28 (s, 3 H), 1.34 (s, 6 H), 3.69 (s, 2 H), 6.86 (d, J=7.8 Hz, 1 H), 7.57-7.78 (m, 2H) ppm. MS (DCl/NH3): 260 (M+H)+. |
74% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 10h; | 5-Bromo-1 ,3-dihydro-indol-2-one (Aldrich, 1.06 g, 5 mmol) was coupled with bis(pinacolato)diboron (Aldrich, 1.52 g, 6 mmol) catalyzed by PdCI2(dppf)2-CH2CI2 (Aldrich, 82 mg, 0.1 mmol) using KOAc (Aldrich, 0.98 g, 10 mmol) as base in dioxane (anhydrous, Aldrich, 50 ml_) at 8O0C for 10h. After being cooled down to ambient temperature, the mixture was diluted with EtOAc (50 ml_) and washed with brine (2 x 10 ml_). The organic solution was then concentrated under vacuum. The title compound was purified by chromatography (SiO2, hexane : EtOAc, 70:30, Rf. 0.5) as a solid (0.96 g, yield, 74%). 1H NMR (300 MHz, CDCI 3) delta 1.24 (s, 3 H), 1.28 EPO <DP n="81"/>(s, 3 H), 1.34 (s, 6 H), 3.69 (s, 2 H), 6.86 (d, J=7.8 Hz, 1 H), 7.57 - 7.78 (m, 2 H) ppm. MS (DCI/NH3): 260 (M+H)+. |
64% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 16h;Product distribution / selectivity; | To a solution of 5-Bromo-1,3-dihydro-indol-2-one (10 g, 47.1 mmol) in dioxane (120 ml) was added bispinacolato diborane (26.25 gm, 103.7 mmol); the reaction was purged with nitrogen for 30 min followed by addition of potassium acetate (13.86 g, 141 mmol) and Pd(dppf)Cl2 (1.92 g 2.3 mmol). The reaction mixture was warmed to 100 C. and stirred at this temperature for 16 h. After the completion of the reaction it was filtered through Celite and the filtrate was diluted with water, extracted with EtOAc. The combine organic layer ware washed with brine, dried over Na2SO4, concentrated and purified by column chromatography to obtain 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, (7.8 g, 64%). |
14% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dichloromethane; dimethyl sulfoxide; | A. 5-(4,4,5,5-Tetramethyl-l ,3>2-dioxaborolan-2-yl)indolin-2-one. Bis(pinacolato)diboron (1.31 g, 4.71 mmol), dichloro[l,l'-bis(diphenylphosphino) ferrocenejpalladium (II) dichloro-methane (385 mg, 0.47 mmol) and potassium acetate (1.38 g, 14.1 mmol) were successively added to a solution of <strong>[20870-78-4]5-bromooxindole</strong> (1.0 g, 4.71 mmol) in methylene chloride (25 mL), followed by DMSO (15 mL). The crude mixture was diluted with water, extracted with methylene chloride (3x). the combined organic fractions were washed with water, brine, dried over magnesium sulfate, filtered, and the volatiles were removed under reduced pressure. The crude product was triturated with diethyl ether, sonicated, and the precipitate was collected by filtration to afford the title compound (165 mg, 14%). MS (ESI) m/z 260.3 [M+l]+. |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 3h; | 5-(4,4,5,5-Tetramethyl-l,3,2-dioxaboroIan-2-yl)-l,3-dihydroindol-2-one; A mixture of 5-bromo-2,3-dihydroindol-2-one (500 mg), bis(pinacolato)diboron (899 mg) and potassium acetate (695 mg) in DMF (20 mL) was degassed for 5 minutes. 1,1'- 5 Bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct (78 mg) was added to the mixture and the reaction was heated to 8O0C and left to stir for 3 hours. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was suspended in water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organics were dried (MgSO4), filtered and concentrated in vacuo to give the desired 0 material as a brown solid. (611 mg). Mass Spectrum; M+H+MeCN+ 301.NMR Spectrum: 1H NMR (DMSOd6) deltal.28 (12H, s), 3.47 (2H, s), 6.82 - 6.84 (IH, d), 7.51 (2H, m), 10.52 (IH, s) | |
15 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere; | To a solution of 5-bromo-2-oxindole (21 g, 100 mmol) in 1 ,4-dioxane (150 mL) was added bis(pinacolato)diboron (38 g, 150 mmol), l , l-bis(diphenylphosphino) ferrocene-palladium(II) dichloride dichloromethane complex (8.2 g, 10 mmol), and potassium acetate (20 g, 200 mmol). The resulting mixture was degassed and then stirred overnight at 80 C under an Ar atmosphere. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water (500 mL) and then extracted with EtOAc. The combined organic layers were washed with water and brine, and then dried. The solvent was concentrated and the residue was purified by column chromatography (EtOAc / Pet = 2: 1) to give oxindole-5-boronic acid pinacol ester (15 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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77% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 12h; | 5-Phenyloxindole 5-Bromo-2-oxindole (5 g, 23.5 mmol) was dissolved in 110 mL toluene and 110 mL ethanol with stirring and a little heat. Tetrakis(triphenylphosphine)palladium(0) (1.9 g, 1.6 mmol) was added followed by 40 mL (80 mmol) 2M aqueous sodium carbonate. To this mixture was added benzene boronic acid (3.7 g, 30.6 mmol) and the mixture was heated in a 100 C. oil bath for 12 hours. The reaction was cooled, diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate (200 mL), water (200 mL), 1N HCl (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate and concentrated to afford a brown solid. Trituration with dichloromethane afforded 3.8 g (77%) of 5-phenyl-2-oxindole as a tan solid. 1H NMR (360 MHz, DMSO-d6) delta 10.4 (br s, 1H, NH), 7.57 (dd, J=1.8 and 7.2 Hz, 1H), 7.5 to 7.35 (m, 5H), 7.29 (m, 1H), 6.89 (d, J=8.2 Hz, 1H), 3.51 (s, 2H, CH2CO). MS m/z 209 [M+]. |
63% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 18h;Heating / reflux; | 5-Bromo-2-oxindole (10 g, 47 mmol), 7.4 g (61 mmol) of benzeneboronic acid, 4.0 g (3.5 mmol) of tetrakis(triphenylphosphine)palladium(0), 17 g (160 mmol) of anhydrous sodium carbonate, 100 mL of toluene and 100 mL of ethanol were refluxed for 18 hours. The mixture was vacuum filtered hot to remove insolubles. The organic layer of the filtrate was separated while hot and concentrated. The solids were collected by vacuum filtration and washed with 5 mL of ethanol. The solids were triturated with 1 N hydrochloric acid, collected by vacuum filtration, washed with water and dried under vacuum. The crude solids were triturated with dichloromethane and dried under vacuum to give 8.3 g (63% yield) of the title compound. 1H-NMR (dimethylsulfoxide-d6) delta10.00 (s, 1H), 7.20-6.80 (multiplets, 9H), 3.50 (s, 3H). |
51% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 100℃; for 12h;Reflux; | 5-Bromo-2-oxindole 16 (150 mg, 0.71 mmol), benzeneboronic acid (113 mg, 0.92 mmol), tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.05 mmol) and Natrium carbonate (250 mg, 2.41 mmol) were suspended in toluene (1.5 mL) and ethanol (1.5 mL) and refluxed for 12 h at 100 C. Water was added and extracted 3 times with ethyl acetate. The combined organic layers were wash with 1N hydrochloric acid, brine, dried over MgSO4, filtered and concentrated in vacuum to give 75 mg (51%) as a light brown solid and was used for the next step without further structure determination. |
[0409] A mixture of an appropriately substituted oxindole, an appropriately substituted aldehyde (1 equivalent) and piperidine (excess) in ethanol (0.2M) was stirred at between room temperature to 100 C. After completion, the mixture was concentrated and then triturated with dil. HCl solution. The resulted precipitate was collected by vacuum filtration, washed with water and dried to give the desired product 5-Phenyloxindole (synthesised from <strong>[20870-78-4]5-bromooxindole</strong> and phenyl boronic acid [Aldrich] via Suzuki coupling) was condensed with 3-(4-benzensulfonyl-2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (prepared as described above in the synthesis of aldehyde 2) and piperidine in ethanol to give the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
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96% | With piperidine; In ethanol; at 90℃; for 6h; | To a solution of commercial available 5-bromoindoline-2-one 2b (425 mg, 2 mmol) and pyrrole 3 (636 mg, 2.4 mmol) in ethanol (4.0 mL) six drops of piperidine were added and the mixture was heated for six hours under reflux. After cooling on ice the precipitate was filtered off, washed with ethanol and dried under vacuum to give 5 (886 mg) as an orange solid in 96% yield, mp: 245-247C, HNMR (d, ppm, DMSO-d): 0.97 (t, 6H, N(CH2CH3)2); 2.43 (s, 3H, CH3); 2.44 (s, 3H, CH3); 2.50 (m, 6H, 3xCH2); 3.29 (m, 2H, NH-CH2); 6.82 (d, 1H, 7-H); 7.25 (d, 1H, 6-H); 7.42 (s, 1H, 4-H); 7.77 (s, 1H, NH-CH2); 8.10 (s, 1H, Hvinyl); 10.99 (s, 1H, NHindole); 13.62 (s, 1H, NHpyrrole); ESI-MS (ES+): m/z=461 (M+H)+ |
0.09 g (26%) | Example 51 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-diethylamino-ethyl)amide 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J=1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J=5.5 Hz, 1H, CONHCH2), 7.24 (dd, J=1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J=8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3*NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J=7.2 Hz, 6H, 2*NCH2CH3). MS-EI m/z 458 and 460 [M+-1 and M++1]. | |
0.09 g (26%) | Example 51 5-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J=1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J=5.5 Hz, 1H, CONHCH2), 7.24 (dd, J=1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J=8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3*NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J=7.2 Hz, 6H, 2*NCH2CH3). MS-EI m/z 458 and 460 [M+-1 and M++1]. |
368 mg | With piperidine; In ethanol; at 80℃; for 1h; | Reference Example 27 Production of (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide To the solution of 5-bromoindolin-2-one (262 mg, 1.24 mmol) in EtOH (5 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (298 mg, 1.12 mmol) and piperidine (112 muL, 1.13 mmol). The mixture was stirred at 80 C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (368 mg) as orange solid. MS m/z 459.4/461.4 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
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0.09 g (26%) | Example 19 Synthesis of 5-(5-Bromo-2-oxo-1,2-Dihydroindol-3-Ylidenemethyl)-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic Acid (2-Diethylamino-Ethyl) Amide 5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with <strong>[356068-86-5]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide</strong> (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid. 1H-NMR (360 MHz, DMSO-d6) delta 13.61 (s, br, 1H, NH), 10.98 (, br, 1H, NH), 8.09 (d, J=1.7 Hz, 1H, H-4), 7.76 (s, 1H, H-vinyl), 7.42 (t, J=5.5 Hz, 1H, CONHCH2), 7.24 (dd, J=1.7 & 8.0 Hz, 1H, H-6), 6.82 (d, J=8.0 Hz, 1H, H-7), 3.23-3.32 (m, 2H, NCH2), 2.46-2.55 (m, 6H, 3*NCH2), 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3), 0.96 (t, J=7.2 Hz, 6H, 2*NCH2CH3). MS-EI m/z 458 and 460 [M+-1 and M++1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol | 5-Bromo-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one 5-Bromo-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one A mixture of 5-bromo-2-oxindole (212 mg) (prepared as described in Compound IN-014), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 5-bromo-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one. 1H NMR (360 MHz, DMSO-d6) δ12.96 (s, br, 1H, NH), 11.09 (s, br, 1H, NH), 8.21 (d, J=2 Hz, 1H), 8.02 (s, 1H, H-vinyl), 7.63 (d, J=8 Hz, 1H), 7.5 (d, J=8 Hz, 1H), 7.33 (dd, J=2, 8 Hz, 1H), 7.29 (dt, J=1, 7 Hz, 1H), 7.07 (dt, J=1, 7 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 2.62 (s, 3H, CH3). MS El 352 and 354. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 15h; | 47 To a 250 mL round-bottom flask, was added 5-bromoindolin-2-one (2 g, 9 mmol), N,N'-tetramethylethylenediamine (4 mL, 28 mmol) and 70 mL of THF. The reaction mixture was cooled to -78° C. 2.5 M n-butyllithium in hexanes (8.4 mL, 21 mmol) was then added slowly to the reaction mixture. The reaction mixture was stirred for 15 hours, 5 mL of saturated NH4Cl solution was added to the reaction mixture, and then the reaction mixture was extracted twice with 30 mL of EtOAc. The combined organic layers were concentrated and purified with silica gel column chromatography, eluting with 0-40% EtOAc/hexane to give 5-bromo-3-methylindolin-2-one (0.37 g, 17% yield). MS m/z: 227 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 - 84% | With lithium hydride; In 1-methyl-pyrrolidin-2-one; at 120℃; for 12 - 14h;Product distribution / selectivity; | Example 1;To a solution of 5-bromooxindole (4Og, 188.6mmol) in iV-methylpyrrolidinone (34OmL) at room temperature was added lithium hydride (3.0Og, 377.3mmol) and (6-chloro-pyridin-3- yl)-morpholin-4-yl methanone (85.5g, 377.3mmol). The resulting solution was heated to 12O0C for 14 h. The reaction mixture was then cooled to an inner temperature of 5O0C and divided into two portions. Portion 1: Saturated aqueous ammonium chloride (591 mL) was added over 1 h at 50C. The resulting orange coloured slurry was stirred at 5O0C for 1 h then cooled to 50C over 3 h. The solid was filtered off, washed with water (4x80mL), methanol (2x30mL) and toluene (3OmL). Vacuum drying gave 27.54g, 73% yield of [6-(5- <n="21"/>bromo-2-hydxoxyl-lH-indol-3-yl)-pyridin-3-yl]-morpholin-4-yl-niethanone having a purity of at least 90% according to HPLC. Portion 2: Aqueous ammonium chloride (400 mL, 5% w/v) was added over 1 h at 5O0C. The resulting orange coloured slurry was stirred at 5O0C for 1 h then cooled to 50C over 3 h. The solid was filtered off, washed with water (4x80mL), methanol (2x30mL) and toluene (3OmL). Vacuum drying gave 33.6g, 88% yield of [6-(5-bromo-2-hydroxyl-lH-indol-3-yl)-pyridin-3-yl]-morpholin-4-yl-methanone (combined yield of 80%) having a purity of at least 90% according to HPLC 1H NMR (d- DMSO5 400 MHz) delta 14.9 (br s, 1 H), 10.62 (s, 1 H), 8.31 (d, J = 1.4Hz, 1 H), 7.76 (m, 2 H), 7.64 (d, J= 1.56, IH), 7.05 (dd, J = 1.84, 8.20 Hz, 1 H), 6.84 (d, J = 8.16 Hz, 1 H), 3.6 o (dd, J= 4.68, 8.8 Hz, 8 H), 3.31 (br m, 2 H) ppm; 13C NMR (d6-OMSO, 400MHz) delta 168.6, 148.4, 141.7, 135.8, 132.9, 126.9, 121.8, 121.6, 118.0, 117.9, 112.1, 109.9, 85.0, 66.3, 66.1, 58.4, 52.8, 40.1, 39.9, 39.7, 39.3, 39.1, 38.8 ppm; MS (ES) m/z [M++l]+ 404.Example 2 5 |"6-f5-Bromo-2-hvdroxyl-lH-indol-3-yl)-pyridin-3-yll-morpholin-4-yl-methanone. To a solution of 5-bromooxindole (4.0 kg, 18.86 mol) iniV-methylpyrrolidinone (68L) under nitrogen was added lithium hydride (30Og, 37.73 mol) and (6-chloro-pyridin-3-yl)- morpholin-4-yl methanone (8.54 kg, 37.73 mol). The resulting suspension was heated to an internal temperature of 12O0C and kept there for 12 h. The reaction mixture was cooled to o 5O0C and saturated aqueous ammonium chloride solution (119L) was added over 2 h at such a rate that the internal temperature was kept in the range of 5O0C. The resulting suspension was stirred for 1 h at 5O0C and then cooled down to an inner temperature of 150C over 4 h and held there for 5 h. The solid was filtered and the filter cake washed with water (3x16 L), then with cooled (50C) methanol (2 x 6L) and washed with cooled (5C) 5 TBME (6 L). Vacuum drying at 450C for 24 h gave 6.387 kg, 84% yield of [6-(5-bromo-2- hydroxyl-lH-indol-3-yl)-pyridin-3-yl]-mophiholin-4-yl-methanone having a purity of at least 90 %. 1H NMR (dtf-DMSO, 400 MHz) delta 14.85 (br s, 1 H), 10.50 (s, 1 H), 8.05 (s, 1 H), 7.75 (dd, J= 1.84, 9.08Hz, IH), 7.65 (br d, J= 9.0, IH), 7.58 (d, J = 1.44Hz, 1 H), 7.00 (dd, J = 1.88, 8.16 Hz, 1 H), 6.82 (d, J= 8.20Hz), 3.57 (d, J= 2.80Hz, 4 H), 3.35 (s, 2 H), o 2.37 (s, 4H) ppm; 13C NMR (Jd-DMSO, 400MHz) delta 168.6, 148.4, 141.7, 135.8, 132.9, <n="22"/>126.9, 121.8, 121.6, 118.0, 117.9, 112.1, 109.9, 99.5, 84.9, 79.1, 67.0, 58.4, 52.8, 40.1, 39.9, 39.7, 39.5, 39.3, 39.1, 38.8 ppm; MS (ES) m/z [M++lf 404. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 15.0h;Sealed; | Step 1 3-Methyl-4-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile To a pressure flask was added; 5-bromoindolin-2-one (10.0 g, 47.2 mmol), <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (9.11 g, 56.6 mmol) were combined with DMF (370 ml) to give a light brown solution, a solution of sodium carbonate in water (37 ml) was added, while the mixture was degassed with nitrogen, a catalytic amount of Pd(dppf)Cl2*CH2Cl2 was added, and the flask sealed. The reaction mixture was heated to 90 C. for 15 h., water was added, the dark solid was collected, the solid was washed with water, MeOH and 20% EtOAc/hexanes to give 3-methyl-4-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile as a dark purple solid (12.1 g, 103%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 5-bromo-2-indolin-2-one With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: mechlorethamine hydrochloride In tetrahydrofuran at -78 - 20℃; for 48.5h; | 4.1.1. Synthesis of 10 To a solution of 5-bromo-1,3-dihydro-2H-indole-2-one (1.272 g, 6 mmol) in THF(15 ml) was added a solution of NaN(SiMe3)2 in THF (30 ml, 30 mmol). The reaction mixture was cooled to -78 °C and stirring was continued at the same temperature for 0.5 h. The 2-chloro-N-(2-chloroethyl)-N-methyl ethylamine hydrochloride (1.155 g, 6 mmol) was added to the mixture, continued to stir at -78 °C for 0.5 h, then stirred for 2 d at room temperature (TLC control). 4 M HCl (10 ml) was added, the mixture was adjusted pH to 10 with concentrated ammonia and extracted with CH2Cl2 (3 × 20 ml). The combined organic layer was dried (3 g of Na2SO4) and concentrated to afford the crude product, which was purified by FC with MeOH/CH2Cl2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a stirred solution of 5-bromoindolin-2-one (LIV, 7.25 g, 34.36 mmol) in tetrahydrofuran (70 mL) under nitrogen atmosphere, was added sodium hydride (5.9 g, 137.0 mmol) portion-wise at 0 C. After addition of sodium hydride, the reaction was stirred at room temperature for 30 min, then cooledto 0 C. methyl iodide (8.5 mL, 137.0 mmol) was added, and then allowed to stir at room temperature for 2h. The reaction mass was cooled to 0 C and carefully quenched with ice-water. Then the reaction mixture was diluted with water (150 mL) and ethylacetate (150 mL). The organic layer was separated, washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the titled product as brown colour solid (LV, 7.4 g, 85%). LC-MS m/z calcd for CnHi2BrNO, 253.0; found 254.0 [M+H]+. | |
79% | NaH (60 % in mineral oil; 5.66 g, 141.48 mmol) was added portionwise to a mixture of 5-bromo-l,3-dihydro-2H-Indol-2-one (10.0 g, 47.16 mmol) in THF (100 ml) at 0 C.The mixture was stirred for 30 min, and then CH3I (21.42 g, 150.91 mmol) was added.The r.m. was stirred at 0 C for 30 min. Subsequently, H20 (2 ml) was added dropwise.The solvent was removed in vacuo. The residue was dissolved in H20 (q.s.) and extracted with EtOAc. The separated organic layer was washed with brine, dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by column chromatography (eluent: PE/EtOAc 20/1). The desired fractions were collected and the solvent was evaporated. Yield: 9.5 g of intermediate 3 (79 % yield). | |
Under argon, 2.64 g (66 mmol) of sodium hydride (60% in mineral oil) were suspended in 25 ml of THF and cooled to 0 C. A solution of 4.00 g (18.86 mmol) of 5-bromo-1,3-dihydro-2H-indol-2-one in 25 ml of DMF was added dropwise and the mixture was stirred at 0 C. for 30 min. Subsequently, 4.11 ml (66 mmol) of methyl iodide were slowly added dropwise thereto, then the reaction mixture was warmed to RT and stirring continued at this temperature overnight. For workup, the mixture was poured onto 200 ml of 1M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with water, then a saturated sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue was dissolved in 200 ml of acetonitrile and the mineral oil was extracted with n-pentane. The acetonitrile phase removed was concentrated on a rotary evaporator and the remaining brownish solid was dried under HV. This gave 4.45 g (84% of theory) of the title compound in 91% purity. LC-MS (Method 3): Rt=1.18 min; m/z=254, 256 (M+H)+. 1H NMR (400 MHz, DMSO-d6): delta [ppm]=1.27 (s, 6H), 3.12 (s, 3H), 6.99 (d, 1H), 7.45 (dd, 1H), 7.60 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine In ethanol for 5h; Reflux; | 1 4.1.2. Method A: General procedure for the preparation of compounds 3a-o The preparation was divided into two steps. Firstly, substituent indoline-2,3-dione (1 equiv) was dissolved in ethanol (10 mL), hydrazine hydrate (2 mL) was added. The reaction mixture was refluxed with magnetic stirring for 3 h and cooled to 0 °C, then sodium hydroxide (3 equiv) was added, refluxed for 0.5 h and cooled to room temperature, then 150 mL water was added. The mixture was acidified by adding 2 N hydrochloric acid to pH 2, and extracted twice with dichloromethane. The organic filtrate was washed twice with brine, dried (Na2SO4), and then concentrated to give corresponding indolin-2-one by high-vacuum drying. Secondly, a mixture of the corresponding indolin-2-one (1 equiv) and furan-2-carbaldehyde (1 equiv) in ethanol was added two drops of piperidine and refluxed with magnetic stirring for 5 h. After the mixture cooled, the precipitate was filtered, washed with cold ethanol, dried, and recrystallized from methanol to afford the terminal product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In ethanol; for 5h;Reflux; | The preparation was divided into two steps. Firstly, substituent indoline-2,3-dione (1 equiv) was dissolved in ethanol (10 mL), hydrazine hydrate (2 mL) was added. The reaction mixture was refluxed with magnetic stirring for 3 h and cooled to 0 C, then sodium hydroxide (3 equiv) was added, refluxed for 0.5 h and cooled to room temperature, then 150 mL water was added. The mixture was acidified by adding 2 N hydrochloric acid to pH 2, and extracted twice with dichloromethane. The organic filtrate was washed twice with brine, dried (Na2SO4), and then concentrated to give corresponding indolin-2-one by high-vacuum drying. Secondly, a mixture of the corresponding indolin-2-one (1 equiv) and furan-2-carbaldehyde (1 equiv) in ethanol was added two drops of piperidine and refluxed with magnetic stirring for 5 h. After the mixture cooled, the precipitate was filtered, washed with cold ethanol, dried, and recrystallized from methanol to afford the terminal product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.45% | With piperidine; In ethanol; for 6h;Reflux; | General procedure: In a 100 mL round bottom flask5-[4-(diphenylamino) phenyl] thiophene-2-carbaldehyde (2) (12 mmol) was treated with the appropriateoxindole (1a-d) (10 mmol) and piperidine (1 mmol) in 20 mL of ethanol. After the reaction mixturewas refluxed for 6 h, it was cooled and the resulting precipitate was filtered, washed with cold ethanol,and dried to give the target compounds (70-90% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hydrogencarbonate; In tetrahydrofuran; for 3h;Reflux; | 5-bromoindolin-2-one (1.50 g; 6.93 mmol; 1.00 eq) was dissolved in THF (45.00 ml) then di-ferf-butyl dicarbonate (2.29 g; 10.40 mmol; 1.50 eq) and NaHC03 (5.24 g; 62.41 mmol; 9.00 eq) were added. The mixture was stirred 3h under reflux. Solids were filtered and the filtrate was concentrated. The residue was purified by chromatography (gradient from 100% n-heptane to 80/20 n-heptane / EtOAc) to give tert-butyl 5-bromo-2-oxo-indoline-1-carboxylate (1.52 g; 71 %) as a white solid. |
54% | With sodium hydrogencarbonate; In tetrahydrofuran; at 66℃; | 4 mmol of 5-bromo-2-fluorenone (IX) was dissolved in 20 ml of tetrahydrofuran solution, 4.8 mmol of sodium hydrogencarbonate was added, and then 8 mmol of di-tert-butyl dicarbonate was added, and the reaction system was stirred at 66 C. The reaction was quenched by TLC until the material disappeared, and then the mixture was evaporated to ethyl ether.Hexane:Separation and purification of ethyl acetate = 5:1 as eluent gave 670 mg of white solid. The yield was 54%. |
3.1 g | With sodium carbonate; In tetrahydrofuran; at 60℃; for 12h; | Compound 43a (5 g, 23.7 mmol) was dissolved in 150 mL THF.Sodium carbonate (25 g, 23.5 mmol) and di-tert-butyl dicarbonate (12.8 g, 58.6 mmol) were added in that order.Reaction at 60 C for 12 h,After completion of the reaction, the mixture was filtered and purified by silica gel column chromatography to afford compound 43b (3.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: Ca. 47 %Chromat. 2: Ca. 44 %Chromat. 3: 3.7 %Chromat. 4: 2.9 %Chromat. 5: Ca. 2 %Chromat. 6: 0.6 %Chromat. | With ferric WT dehaloperoxidase hemoglobin B; dihydrogen peroxide In methanol; aq. phosphate buffer at 25℃; for 0.0833333h; Inert atmosphere; Glovebox; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-bromo-2-indolin-2-one With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran; hexane at -78 - -20℃; for 1h; | 1 Method 1: S nthesis of Intermediate A & B To a solution of A-1 (3.0 g, 14.1 mmol) in THF (90 mL) is added A-2 (4.93 g, 42.4 mmol), and the resulting solution is cooled to -78°C. BuLi (2.5 M in hexane, 12.4 mL, 31.1 mmol) is added dropwisely and the resulting solution is stirred for 30min at -78°C. A-3 ( 1.06 mL, 16.9 mmol) is added dropwisely and the solution is slowly warmed up to -20 °C and stirred for lh. The reaction is quenched with saturated aqueous NH4C1 (20 mL) and extracted with EtOAc (50 mL). Phases are separated, and organic layer is washed with water (20 mL) and brine (20 mL). Organic layer is seperated and dried over anhydrous Na2S04, filtered and concentrated. The residue is purified by column chromatography on silica gel (3-40% EtOAc/Heptane) to yield A MS (ES+): m/z 227.4 [M+H]+ and B MS (ES+): m z 241.2 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tert.-butylnitrite; oxygen; In tetrahydrofuran; at 50℃; under 760.051 Torr; for 24h;Schlenk technique; Inert atmosphere; | General procedure: To a Schlenk tube were added oxindole 1 (0.3 mmol), t-BuONO (0.6 mmol), andTHF (2 mL). Then the tube was stirred at 50 C under 1 atm of O2 for the indicatedtime until complete consumption of starting material monitored by TLC analysis.After the reaction was finished, the reaction mixture was washed with brine. The aqueous phase was re-extracted with ethyl acetate. The combined organic extractswere dried over Na2SO4, removal of the solvent under vacuum afforded the crudeproduct, which was purified further by column chromatography using hexane-ethylacetate. |
76% | With tert.-butylnitrite; In tetrahydrofuran; at 25℃; under 1520.1 Torr; | To 10 ml schlenk bottle by adding 5 - bromo -2 - indolone (1 a, 0.3 mmol), tert-butyl nitrite (t - BuONO, 2 a, 0.6 mmol) and THF (2 ml), then oxygen atmosphere (1 atm) next, the reactor is placed 25 C stirring under the conditions of reaction, monitoring the reaction by TLC or GC process, to the reaction raw material 5 - bromo -2 - indolone reaction is complete, to stop the reaction, the reaction the fluid uses full and salt water washing, recovering the organic phase, the aqueous phase is extracted with ethyl acetate, the combined organic phase; organic phase was dried with anhydrous sodium sulfate, filtered, distilled under reduced pressure, the residue by column chromatography (petroleum ether/ethyl acetate) separation to obtain the target product 5 - [...], I - 6, the isolation yield is 76% |
70% | With tert.-butylhydroperoxide; In 1,2-dichloro-ethane; at 85℃; for 24h;Schlenk technique; | General procedure: To a Schlenk tube were added indolin-2-one 1 (0.3 mmol), t-BuOOH (0.6 mmol), and DCE (2 mL). Then the tube was stirred at 85 oC under air for the indicated time until complete consumption of starting material monitored by TLC analysis. After the reaction was finished, the reaction mixture was washed with brine. The aqueous phase was re-extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, removal of the solvent under vacuum afforded the crude product, which was purified further by column chromatography using hexane-ethyl acetate (10:1). |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; oxygen; In acetonitrile; at 20℃; for 24h; | General procedure: An oven-dried flask was charged with stir bar, oxindole (0.5 mmol), PIDA (0.25 mmol) in dry acetonitrile (4.0 mL). Then to the reaction mixture TEMPO (0.5 mmol) was added in presence of air and the mixture was stirred at room temperature until complete conversion takes place as indicated by TLC analysis. The resulting reaction mixture was extracted with ethyl acetate (3 10 mL). The combined organics were dried with Na2SO4 and dried under vacuum to afford crude solid. Then the crude product was purified by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0) In N,N-dimethyl-formamide at 140℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 5-bromo-2-indolin-2-one With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: methyl halide In tetrahydrofuran; hexane at -78 - 20℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With piperidine In ethanol for 6h; Reflux; | Synthesis of (E)-3-(benzothiazol-2-ylmethylene)indolin-2-ones (6a-j); general procedure General procedure: A mixture of 2a-j (1.50 mmol) and 5 (1.50 mmol) in ethanol (10 mL) was treated with a catalytic amount of piperidine. The reaction mixture was stirred under reflux until complete consumption of the substituted indolin-2-ones was observed by TLC. After cooling, the precipitate was filtered, recrystallised from absolute ethanol and dried in air to furnish pure (E)-3-(benzothiazol-2-ylmethylene)indolin-2-ones 6a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | The 5-bromofluorenone 670.7 g obtained in the previous step,Add 1320ml of water and cool to -5-0 C in an ice bath.Then add 1100g of hydrogen bromide (48%) aqueous solution and stir.Most of the raw materials are dissolved, and the temperature is controlled within the range of -5-0 C.Add 143 g of sodium nitrite to a solution of 286 ml of water.During the period, the control temperature does not exceed 0 C, about 15 minutes,The incubation reaction was continued for 1 h, and a large amount of brown granular solid (diazonium salt) was precipitated in the reaction solution for use.In another 10000ml four-necked flask, 297g of cuprous bromide, 22g of copper bromide, 13200ml of water, hydrogen bromide(48%) 1100g of aqueous solution, stirred, the reaction solution was dark red, heated to 20-25 C, the diazonium salt obtained in the previous step was added dropwise.After the completion of the dropwise addition, the reaction was continued for 1 h, the temperature was lowered to about 5 C, the temperature was kept for 0.5 h, and the filter cake was washed with cold water until the washing liquid was colorless. drying,The solid 2,5-dibromophenylacetic acid 746 g was obtained in a yield of 80.5%, and the HPLC purity was 98.8%. | |
322.5 g | 300.0 g of bromoindolinone (Formula II) prepared in the previous step was put into a reaction flask, 600 ml of water was added, and the temperature was lowered to -5 to 0 C in an ice bath,Then 493.5g of hydrogen bromide (48%) aqueous solution was added and stirred. Most of the raw materials were dissolved and the temperature was controlled at -5-0 C. A solution of 65.0g of sodium nitrite dissolved in 130ml of water was added dropwise,During the temperature does not exceed 0 , about 15min plus Bi, continue to heat the reaction 1h,The reaction liquid has a large number of brown granular solid precipitation, stand-by. In another reaction flask, 135.0 g of cuprous bromide, 10.0 g of cupric bromide, 600 ml of water and 500 g of a hydrogen bromide (48%) aqueous solution were added and the mixture was stirred. The reaction mixture was dark red,The temperature was raised to 20-25 C., the diazonium salt obtained from the previous step was added dropwise and the reaction was continued for 1 h after the completion of the incubation.Cool to about 5 , incubated 0.5h, filtered, the filter cake washed with cold water to wash colorless.Drying afforded 322.5g of solid, HPLC purity 99.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane at 20℃; for 18h; Inert atmosphere; | 3.2.1. General Procedure for the Synthesis of 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-oneDerivatives (Table 2, 3a-d). General procedure: Appel’s salt (Scheme 2, 1; 4,5-dichloro-1,2,3-dithiazolium chloride; 15.76 mmol) was added to asolution of each appropriate 2-oxindole derivative (Scheme 2, 2a-d; 14.33 mmol) in CH2Cl2 (20 mL).After a few minutes, the uncolored mixture turned to a dark red color, and was stirred at roomtemperature for 18 h. The solvent was evaporated under reduced pressure, and the crude productwas dissolved with acetone (a minimum of 30 mL), and then precipitated with water (300 mL).The heterogeneous mixture was filtered in a vacuum, and the red solid was washed three times withwater (25 mL). This solid was finally dried over phosphorus pentoxide in a vacuum in a desiccator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With trimethylamine-N-oxide; tricarbonyl(η4-1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-inden-2-one)iron; potassium carbonate at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 5-bromo-2-indolin-2-one; (2-bromoethyl)(diphenyl)sulfonium trifluoromethanesulfonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: With triethylamine In N,N-dimethyl-formamide at 20℃; for 6h; | General procedure for cyclopropanation of compound 10 General procedure: To a 25 mL round bottomed flask was added different substituted oxindoles 8 (0.2 mmol, 1.0 equiv.) and bromoethylsulfonium salt 9 (132.99 mg, 0.3 mmol, 1.5 equiv.), DMF (2 mL). The mixture was stirred at room temperature for 5min and Et3N (61.88 mg, 0.6 mmol, 3.0 equiv.) was added into reaction system. The mixture was stirred for 6h at room temperature until the reaction completed, quenched with saturated ammonium chloride solution (5 mL), and was extracted with EtOAc (3×30 mL). The combined organic layer washed with H2O (2×10 mL), dried with anhydrous sodium sulfate. After concentration, product was purified using column chromatography on silica gel with suitable eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With piperidine; In ethanol; at 80℃; for 16h;Inert atmosphere; | General procedure: Piperidine (8.7 muL, 0.088 mmol), 3,5-difluoro-4-hydroxybenzaldehyde (69.5 mg, 0.44 mmol) and S3 (100.0 mg, 0.44 mmol) were dissolved in EtOH (2.0 mL). The mixture was heated to 80 oC for 16 h. The orange solid was filtered and washed with 1N HCl and Et2O to afford 3 (114.0 mg, 70percent, mixture of E/Z isomers). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: 5-bromo-2-indolin-2-one With n-butyllithium In tetrahydrofuran; hexane at -30℃; for 0.5h; Inert atmosphere; Stage #2: ethylene dibromide In tetrahydrofuran; hexane at 20℃; for 18h; Inert atmosphere; | 3.1 Step 1) 5-Bromospiro[cyclopropyl-1,3-indoline]-2-one 3b Under the protection of nitrogen at -30, add a solution of n-butyl lithium in n-hexane (6.0 mL, 15 mmol, 2.5 mol/L) dropwise to 5-bromoindolin-2-one 3a (1.0 g, 4.7 mmol) in tetrahydrofuran ( 15 mL) white suspension solution, the reaction solution was moved to an ice bath to react for 0.5 hours, and then 1,2-dibromoethane (1.2 mL, 14 mmol) in tetrahydrofuran (2 mL) was added dropwise, followed by reaction at room temperature for 18 hours. The reaction was quenched by adding water (20mL), extracted with ethyl acetate (20mL×3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated by suction. The residue obtained was passed on silica gel Purification by column chromatography [petroleum ether/ethyl acetate (v/v)=2/1] gave the title compound 3b (0.54 g, yield 48%) as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In lithium hydroxide monohydrate; toluene at 100℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / 0 °C 1.2: 3 h / 0 - 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 16 h / 0 - 50 °C |
[ 14548-51-7 ]
7-Bromo-3,4-dihydroquinolin-2(1H)-one
Similarity: 0.92
[ 14548-51-7 ]
7-Bromo-3,4-dihydroquinolin-2(1H)-one
Similarity: 0.92
[ 1351240-72-6 ]
(E)-6,6'-Dibromo-[3,3'-biindolinylidene]-2,2'-dione
Similarity: 0.91
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
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Prevention | |
Code | Phrase |
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P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
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P243 | Take precautionary measures against static discharge. |
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P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
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P311 | Call a POISON CENTER or doctor/physician. |
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P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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