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CAS No. : | 6326-79-0 | MDL No. : | MFCD01631138 |
Formula : | C8H4BrNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HVPQMLZLINVIHW-UHFFFAOYSA-N |
M.W : | 226.03 | Pubchem ID : | 95716 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 49.86 |
TPSA : | 46.17 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) : | -6.73 cm/s |
Log Po/w (iLOGP) : | 1.14 |
Log Po/w (XLOGP3) : | 1.33 |
Log Po/w (WLOGP) : | 1.01 |
Log Po/w (MLOGP) : | 0.91 |
Log Po/w (SILICOS-IT) : | 2.19 |
Consensus Log Po/w : | 1.32 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.45 |
Solubility : | 0.803 mg/ml ; 0.00355 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.9 |
Solubility : | 2.84 mg/ml ; 0.0126 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.64 |
Solubility : | 0.0521 mg/ml ; 0.000231 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.7 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | 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 |
---|---|---|
98% | at 90℃; for 3 h; | Step 2: 6-Bromo-lH-indole-2,3-dioneTo the concentrated sulfuric acid (275 mL) at 50 °C was added N-(3-Bromo- phenyl)-2-hydroxyimino-acetamide (55 g, 0.2272 mol). The temperature was raised to 90 °C and maintained for 3 h. The reaction mixture was added to ice cold water to get yellow precipitate. The precipitate was filtered and dried to get the title compound as a yellow solid [50 g, 98percent]. This material was taken to the next step without any further purification |
32% | Stage #1: at 65 - 80℃; for 0.75 h; Stage #2: With sodium hydroxide In water at 60℃; |
6-bromo-1 /-/-indole-2,3-dioneTo sulfuric acid (2.3 L) at 60°C was added A/-(3-bromophenyl)-2- (hydroxyimino)ethanamide (1 10 g, 456.43 mmol) portionwise over 30 minutes such that the temperature of the reaction mixture did not exceed 65°C. The mixture was heated to 80°C for 15 minutes, cooled to 70°C, and poured onto crushed ice. The ice mixture was allowed to stand for 1 h. Solids were collected by filtration, washed with water, and dried. The crude material was dissolved in a solution of NaOH (58 g) in water at 60°C and acidified with acetic acid. After standing for 0.5 h, the mixture was cooled to 35°C. Solids were collected by filtration and washed with a minimal amount of water. The filter cake was set aside. The filtrate was acidified with concentrated HCI and allowed to stand for 2 h at 5°C. Solids were collected by filtration and washed with water. The combined filter cakes were dried in vacuo to afford 6-bromo-1 H-indole-2,3-dione (33 g, 32percent yield). 1H NMR (400 MHz, DMSO-d6) δ 1 1 .14 (s, 1 H), 7.41 - 7.47 (m, 1 H), 7.24 - 7.28 (m, 1 H), 7.06 - 7.09 (m, 1 H). |
50 g | at 90℃; for 3 h; | To concentrated sulfuric acid (275 mL) at 50° C. was added N-(3-bromo-phenyl)-2-hydroxyimino-acetamide (55 g, 0.2272 mol). The temperature was raised to 90° C. and maintained for 3 hours. The reaction mixture was added to ice cold water to provide a yellow precipitate. The precipitate was filtered and dried to provide the title compound as a yellow solid (50 g, 98percent). This material was taken for next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: at 50 - 80℃; for 0.333333 h; Stage #2: at 0℃; for 1 h; |
Example 59; Preparation of A33; Synthesis of 4-Bromoisatin (K-98) and 6-Bromoisatin (K-99); To a solution chloral hydride (50.0 g, 0.247 mol) in water (237mL) were successively added Na2SO4 (69.Og, 0.486mol), 3-bromoaniline (40.Og, 0.233mol) in a mixture of 37percent HCl (25ml, 0.302mol) and water (632ml) with vigorous stirring. After the addition was completed, the resulting reaction mixture was heated to reflux for 10 min, and allowed to cool to room temperature. The precipitate formed was collected by filtration, washed with water (3 x 100 ml) and dried in vacuo to yield the crude isonitrosoacetanilide. This product was added portion-wise to rapidly stirred concentrated H2SO4 (790ml) at a rate to keep the reaction temperature between 50 and 7O0C. The reaction mixture was heated to 80 0C for 20 min and allowed to cool to room temperature. The cooled mixture was poured into crushed ice (ca.3200g). The mixture was allowed to stand for Ih. The orange precipitate was collected by a filtration, washed with water and dried to yield a mixture of 4-bromoisatin (K-98) and 6-bromoisatin (K-99) (4Og, 83percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | at 60 - 80℃; for 0.75 h; | Sulfuric acid (1 L) was heated in a 3 L beaker on a hot plate to 60 °C and then removed. The dry isonitrosoacetanilide 2a-f was added in portion with stirring over 30 min so that the temperature did not exceed 65 °C. The mixture was then heated to 80 °C for 15 min, allowed to cool to 70 °C and cooled on ice. The solution was poured onto crushed ice (5 L) and left to stand for 1 h before filtering the orange-red precipitate. The product was washed by stirring with water (400 mL) and filtered to give a mixture of 3a-f and 4a-f. The crude product was dissolved in a solution of NaOH (20 g) in water (200 mL) at 60 °C, and then acidified with acetic acid (60 mL). After standing 0.5 h and cooling to 35 °C, the 4a-4f precipitate was filtered and washed with water (50 mL). The combined filtrate and washings were acidified with conc. HCL (60mL) and, after standing for 2 h at 5 °C, the 3a-f precipitate was filtered off and washed with water (50 mL). Yields: 3a: 27percent, 3b: 14percent, 3c : 29percent, 3d: 22percent, 3e: 33percent, 3f : 31percent, 4a: 56percent, 4b: 64percent, 4c: 53percent, 4d: 59percent, 4e: 49percent, 4f : 51percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.4% | Stage #1: With hydrogenchloride; hydroxylamine hydrochloride; sodium sulfate In water at 20℃; for 0.0833333 h; Stage #2: at 20 - 90℃; for 2.25 h; Stage #3: at 50 - 65℃; for 0.5 h; |
10.00 g (58.13 mmol) of 3-bromoaniline was placed in a 1000 mL round bottom flask, 500 mL of water was added,(45.343 mmol) of anhydrous sodium sulfate and 13.33 g (191.84 mmol) of hydrochloric acid light were added under stirring. Then, 10 mL of a 2 mol / L hydrochloric acid solution was added and stirred at room temperature for 5 min.Finally, 10.58 g (63.95 mmol) of chloral hydrate was added. The reaction mixture was stirred at room temperature for 15 min, then heated at 90 ° C under reflux reaction 2KTLC detection of raw materials disappeared,Then cooled to room temperature, filtered and vacuum dried to give 12.90 g of a pale yellow solid. 0 mL of concentrated sulfuric acid was added to a 100 mL round bottom flask and 12.90 g of a yellow solid was slowly added to concentrated sulfuric acid at 50 ° C and reacted at 65 ° C for 30 min after complete addition.After the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was poured into an ice-water mixture and stirred for 30 minutes. The solid was filtered by suction filtration and dried in a vacuum oven. Petroleum ether: ethyl acetate = To give 4.12 g of 6-bromoindolinedione in a yield of 31.4percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: at 50 - 80℃; for 0.333333 h; Stage #2: at 0℃; for 1 h; |
Example 59; Preparation of A33; Synthesis of 4-Bromoisatin (K-98) and 6-Bromoisatin (K-99); To a solution chloral hydride (50.0 g, 0.247 mol) in water (237mL) were successively added Na2SO4 (69.Og, 0.486mol), 3-bromoaniline (40.Og, 0.233mol) in a mixture of 37percent HCl (25ml, 0.302mol) and water (632ml) with vigorous stirring. After the addition was completed, the resulting reaction mixture was heated to reflux for 10 min, and allowed to cool to room temperature. The precipitate formed was collected by filtration, washed with water (3 x 100 ml) and dried in vacuo to yield the crude isonitrosoacetanilide. This product was added portion-wise to rapidly stirred concentrated H2SO4 (790ml) at a rate to keep the reaction temperature between 50 and 7O0C. The reaction mixture was heated to 80 0C for 20 min and allowed to cool to room temperature. The cooled mixture was poured into crushed ice (ca.3200g). The mixture was allowed to stand for Ih. The orange precipitate was collected by a filtration, washed with water and dried to yield a mixture of 4-bromoisatin (K-98) and 6-bromoisatin (K-99) (4Og, 83percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | at 60 - 80℃; for 0.75 h; | Sulfuric acid (1 L) was heated in a 3 L beaker on a hot plate to 60 °C and then removed. The dry isonitrosoacetanilide 2a-f was added in portion with stirring over 30 min so that the temperature did not exceed 65 °C. The mixture was then heated to 80 °C for 15 min, allowed to cool to 70 °C and cooled on ice. The solution was poured onto crushed ice (5 L) and left to stand for 1 h before filtering the orange-red precipitate. The product was washed by stirring with water (400 mL) and filtered to give a mixture of 3a-f and 4a-f. The crude product was dissolved in a solution of NaOH (20 g) in water (200 mL) at 60 °C, and then acidified with acetic acid (60 mL). After standing 0.5 h and cooling to 35 °C, the 4a-4f precipitate was filtered and washed with water (50 mL). The combined filtrate and washings were acidified with conc. HCL (60mL) and, after standing for 2 h at 5 °C, the 3a-f precipitate was filtered off and washed with water (50 mL). Yields: 3a: 27percent, 3b: 14percent, 3c : 29percent, 3d: 22percent, 3e: 33percent, 3f : 31percent, 4a: 56percent, 4b: 64percent, 4c: 53percent, 4d: 59percent, 4e: 49percent, 4f : 51percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With bromine In acetic acid for 48 h; Reflux | To a mixture of 6-bromoisatin (0.88 mmol) in AcOH (9 ml), Br2 (0.88 mmol) was added and the mixture was stirred for 48 h at reflux. After this time the reaction was cooled at 0 °C, and the solid residue was paper filtered off, washed with AcOH and dried in the oven. The crude product was then recrystallized from AcOH to give the pure orange coloured product 1, 57percent; mp >270 °C with decomposition. 1H NMR, 300 MHz, DMSO-d6 δ = 7.23 (1H, s, H7); 7.82 (1H, s, C4), 11.22 (1H, brs, NH). 13C NMR, 75 MHz, DMSO-d6 δ = 117.40, 117.64, 119.61, 129.33, 133.81, 150.67, 159.83, 183.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.7% | Stage #1: at 20℃; for 0.5 h; Stage #2: at 20℃; for 1 h; Cooling with ice |
20 mL of 5percent NaH was taken into a 100 mL round bottom flask,Then slowly add 4.0ml 6-bromoindole dione, stirring at room temperature for 30min,8 mL of H2O2 solution was added under ice-cooling,Remove the ice room temperature reaction lh JLC detection reaction is complete,The precipitate was collected by filtration and dried in vacuo to give 3.20 g of 2-amino-4-bromobenzoic acid in a yield of 83.7percent. |
21% | Stage #1: With dihydrogen peroxide; sodium hydroxide In water at 0℃; for 2 h; Stage #2: With hydrogenchloride In water at 0℃; |
Step 3: 2-Amino-4-bromo-benzoic acidTo a 500 mL round bottom flask, 6-bromo-lH-indole-2,3-dione (50 g, 0.2192 mol) and NaOH (20 g in 250 mL water) were added and cooled the reaction vessel to 0 °C. To this reaction mixture 30percent> hydrogen peroxide (50 mL) was slowly added. The reaction mixture was stirred at 0 °C for 2 h. Subsequently, the reaction mixture was acidified with 2N HC1 [pH-6] at 0 °C to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound [10 g, 21percent]. 1H NMR (300 MHz, DMSO-de): δ 7.59 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.7 Hz, J" = 1.8 Hz, 1H) |
10 g | With dihydrogen peroxide; sodium hydroxide In water at 0℃; for 2 h; | To a 500 mL round bottom flask, 6-bromo-1H-indole-2,3-dione (50 g, 0.2192 mol) and NaOH (20 g in 250 mL water) were added and the reaction vessel was cooled to 0° C. To this reaction mixture, 30percent hydrogen peroxide (50 mL) was slowly added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was then acidified with 2N HCl (pH 6) at 0° C. to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound (10 g, 21percent). 1H NMR (300 MHz, DMSO-d6): δ 7.59 (d, J=8.7 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.65 (dd, f=8.7 Hz, f′=1.8 Hz, 1H) LC-MS (ESI): Calculated mass: 215.0; Observed mass [M+H]+: 217.9. (RT: 0.83 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With sodium hydroxide In water at 20 - 50℃; for 1.5 h; Stage #2: With sulfuric acid; sodium nitrite In water at 0℃; for 0.75 h; Stage #3: With hydrogenchloride; tin(ll) chloride In water at 0℃; for 1.16667 h; |
The conversion of the substituted isatins to the corresponding indazole-3-carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H. R., et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50° C. for 30 min. The burgundy solution was allowed to cool to rt and was maintained for 1 h. The reaction mixture was cooled to 0° C. and was treated with a 0° C. solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0° C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0° C.) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the reaction mixture was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. This material was of sufficient purity (1H NMR and LC/MS) to use in the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to provide pure material. The following acids were prepared using this method: 6-Bromo-1H-indazole-3-acid. 5-Methoxy-1H-indazole-3-acid. 6-Methoxy-1H-indazole-3-acid. |
1.1 g | Stage #1: at 50℃; for 1 h; Stage #2: With sulfuric acid; sodium nitrite In water at 0℃; for 0.5 h; |
To a round bottom flask containing 6-bromoindoline-2,3-dione (1 g, 4.42 mrnol) was added NaOH (4.9 mL, 4.87 mmol) and stirred at 50 °C for I h. The reaction mixture is then brought to ii and cooled to 0°C before adding a solution of NaNO2 (0.31 g, 4.42 mmol) in 1-120 (1 1 mL) dropwise over a period of 15 mins, The above mixture was then added to a solution of H20 (9 mL) and H2S04 (46 mL) thai is precooled to 0 °C dropwise over a period of 15 mins. The crude mixture was then added to a mix of cone. HCI (4 mL)and SnC1?.2H20 (2.5 g, 11.06 rnmoi) at ii and continued to stir at rt for I h. The solids are then filtered and dried to give the crude product 6-hromo-IH-indazoie-3-carhoxyiic acid (Intermediate I 12A) (1.1 g, 93percent) as a tan solid. The crude product was taken to the next step without further purification. |
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