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CAS No. : | 7342-82-7 | MDL No. : | MFCD00023009 |
Formula : | C8H5BrS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SRWDQSRTOOMPMO-UHFFFAOYSA-N |
M.W : | 213.09 | Pubchem ID : | 123250 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 49.53 |
TPSA : | 28.24 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.91 cm/s |
Log Po/w (iLOGP) : | 2.38 |
Log Po/w (XLOGP3) : | 3.79 |
Log Po/w (WLOGP) : | 3.66 |
Log Po/w (MLOGP) : | 3.38 |
Log Po/w (SILICOS-IT) : | 4.37 |
Consensus Log Po/w : | 3.52 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.21 |
Solubility : | 0.013 mg/ml ; 0.000061 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.08 |
Solubility : | 0.0178 mg/ml ; 0.0000837 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.2 |
Solubility : | 0.0134 mg/ml ; 0.000063 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.19 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-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 |
---|---|---|
85% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 25℃; Inert atmosphere | General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 molpercent), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide; acetic acid In chloroform at 0 - 20℃; for 52 h; | To a solution of benzo[b]thiophene (10 g, 74.5 16 mmol) in chloroform (75 mL) and acetic acid (75 mL), was stepwise added NBS (16.6 g, 93.268 mmol) for 4 hr at 0°C and the mixture allowed to stir at room temperature for 48 hr. The progress of the reaction was monitored by TLC and, after completion of reaction, the reaction mass was diluted with chloroform (200 mL) and the resulting mixture was successively washed with a saturated solution of sodium thiosulfate (200 mL), sodium carbonate (200 mL) and brine (150 mL). The extracted organic layer was then dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting red liquid was then filtered of a pad of silica gel, eluting with hexane to afford 3-bromo-1-benzothiophene (15.87 g, 74.474 mmol, 100percent) as yellow oil. The ‘H NMR and mass was confirmed by reported literature. |
95% | With N-Bromosuccinimide; acetic acid In chloroform for 3 h; Reflux | Benzo [b] thiophene 30 g (0.224 mol)225 mL of CHCl3 and 225 mL of AcOH were added at room temperature. 43.8 g (0.246 mol) of N-Bromosuccinimide was added to the reaction solution, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to 0 [deg.] C and neutralized with a saturated aqueous solution of NaHCO3 to terminate the reaction. The organic layer was separated with 500 mL of CH3Cl and washed with distilled water and brine. The obtained organic layer was dried over anhydrous MgSO4, distilled under reduced pressure, and then purified by silica gel column chromatography to obtain the aimed compound (45.3 g, yield 95percent). |
94% | With bromine In acetic acid at 0 - 20℃; for 16 h; | Benzothiophene (2.68 g, 20.0 mmol) was dissolved in glacial acetic acid (100 mL) and cooled to 0° C. The resulting solution was treated by dropwise addition of bromine (1.08 mL, 21.0 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The crude mixture was concentrated to an oil. The residue was purified by silica gel chromatography eluting with hexane to obtain 4.02 g (94percent) 3-bromobenzothiophene. |
90% | With N-Bromosuccinimide In tetrachloromethane at 20℃; for 2 h; Irradiation | Weigh benzothiophene (1.34 g, 10 mmol),N-bromosuccinimide (1.78 g, 10 mmol) was added to a three-necked flask and 20 mL of carbon tetrachloride was added.Irradiate with a 200w incandescent bulb and react at room temperature for 2 hours.The white solid was filtered off and the liquid was concentrated.1.9 g (90percent) of a colorless transparent liquid were obtained. |
88% | With bromine; sodium acetate In dichloromethane at 0℃; for 4 h; | A 2 L round bottom flask was charged with benzo[b]thiophene (50 g, 373.13 mmol), CH2Cl2 (800 mL), and NaOAc (62 g, 756.10 mmol). To this was added a solution of Br2 (34 g, 212.50 mmol) and CH2Cl2 (700 mL), dropwise at 0° C. over 3 hours. The resulting solution was stirred for 1 hour while the temperature was maintained at 0° C. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:100). Work up: the resulting mixture was washed three times with saturated NaHSO3(200 mL). The organic layers were combined, dried over MgSO4, concentrated, and purified by flash chromatography with a 1:1000 EtOAc/petroleum ether. This resulted in 70 g (88percent) of product as a colorless oil. |
84% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 25℃; for 9 h; Inert atmosphere | To a solution of benzo[b]thiophene (6.91 g, 51.5 mmol) in DMF (100 mL) was addedN-bromosuccinimide (8.71 g, 48.9 mmol) at 0 °C, and the mixture was allowed to warm up to25 °C and stirred for 9 h. Into the reaction mixture was added saturated aq. Na2SO3 (50 mL).The resulting mixture was extracted with hexane (3 × 100 mL) and the combined organic phasewas washed with water (3 × 100 mL) and brine (100 mL). The organic phase was dried overMgSO4, filtered, and concentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (hexane) to afford the title compound as colorless liquid(9.23 g, 43.3 mmol, 84percent). |
83.3% | With N-Bromosuccinimide; acetic acid In chloroform at 20℃; | Benzo[b]-thiophene (10 g, 74.5 mmol) was dissolved in AcOH/CHCl3 (100 mL/100 mL), and then NBS (14.6 g, 82.0 mmol) was added in portions with 2 h at room temperature, the resulting solution was stirred overnight. The reaction was quenched by the addition of brine (200 mL) and extracted with hexane (100 mL × 3). The combined organic fraction was washed with brine (100 mL × 3), dried over anhydrous Na2SO4, and filtered. Removing the solvent under vacuum, the residue was purified by column chromatography over silica gel using (DCM/hexane) as the eluent, yielding 1 as colorless oil (13.2 g, 83.3percent). 1H NMR (400 MHz, CDCl3) d: 7.87-7.84 (m, 2H), 7.48 (td, J = 7.2 Hz, J = 1.0 Hz, 1H), 7.45-7.39 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 138.6, 137.5, 125.3, 125.0, 123.5, 123.1, 122.7, 107.7. |
63.4% | With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃; for 13 h; | Benzo on L reactor thiophene 35 g (261 mmol), was stirred into 350 mL of tetrahydrofuran. 0 And cooled to ° C, were introduced into N-bromo-succinimide 55.7 g (313 mmol) and stirred for 1 hour. After the temperature was raised to roomtemperature and stirred for 12 hours, into a sodium sulfite aqueous solution and then Imohsel using ethyl acetate and distilled water and the organic layer was extracted. Theorganic layer was concentrated under reduced pressure to give the intermediate 14-b43 g (yield: 63.4percent). |
48% | With bromine; sodium thiosulfate In tetrachloromethane | EXAMPLE 5 4-[(Benzo[b ]thiophene-3-yl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester STR13 Dissolve benzo[b]thiophene (23 g, 0,170 mmol) in carbon tetrachloride (80 mL). Add, by dropwise addition, a solution of bromine (26.85 g, 0,168 mmol) in carbon tetrachloride (30 mL) and stir at room temperature for 2 days. Quench with a 1M solution of sodium thiosulfate and separate the organic phase. Extract the aqueous phase with carbon tetrachloride, combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33 g, 48percent); bp 64°-72° C. at; 0.02 mm Hg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: With potassium iodide; N,N`-dimethylethylenediamine In toluene at 110℃; for 24 h; Stage #2: With ammonia In water; ethyl acetate; toluene at 25℃; for 0.166667 h; |
An oven dried screw cap test tube was charged with [NACN] (60 mg, [1.] 225 mmol), dried KI (34 mg, 0.205 mmol, 20 molpercent) and Cul (20 mg, 0.105 mmol, 10 molpercent), evacuated and backfilled with argon three times. 3-Bromo-benzo [b] thiophene [(135, UL,] 1.032 mmol), N, N'-dimethylethylenediamine (110 [VLL,] 1.033 mmol) and anhydrous toluene (700 [RL)] were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at [110 °C] for 24 h. The resulting suspension was cooled to room temperature, 2 mL of ethyl acetate, [1] mL of ammonium hydroxide (30percent) and 1 mL of water were added. The mixture was stirred at [25 °C] for 10 min, then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3 x 2 mL). The combined organic layers were washed with 5 [ML] of water and dried over [MGS04.] The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2 x 15 cm; hexane/ethyl acetate 10: 1) provided 122 mg (74percent yield) of the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Stage #1: With tert.-butyl lithium In diethyl ether; hexane at -78℃; for 0.5 h; Stage #2: at -30 - 20℃; for 1 h; Stage #3: With bromine In diethyl ether; hexane at -78 - 0℃; for 2 h; |
EXAMPLE 4-5Preparation of Compound 4-L [0551j To a solution of 3-bromobenzo[b]thiophene (4-K) (4 g, 18.7 mmol) in Et20 (20 mL), t-BuLi (15.6 mL, 1.3M in hexane) was added at —78°C. The solution was stirred for 30 mins at —78°C and DMF (1.5 g, 20.6 mmol) was then added. The cooling bath was removed and the mixture was stirred for another 30 mins at rt. The mixture was cooled to —30°C. Another portion of t-BuLi (15.6 mL, 1.3 M in hexane) was added at —30°C. The cooling bath was removed and the mixture was stirred for another 30 mins at rt. The mixture was cooled to —78°C. And a solution of bromine (3.9 g, 24.4 mmol) in hexane was in one portion. The temperature was allowed to gradually rise to 0°C (2 h). The solution was diluted with 1 M HC1 and extracted with EA. The organic phase was concentrated and the residue was purified by chromatography with silica gel to afford the 2-bromobenzo[b]thiophene-3- carboxaldehyde (4-L) (0.3 g, 7 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1 h; Inert atmosphere Stage #2: for 1 h; Inert atmosphere |
Under a nitrogen atmosphere, 100 ml of THF was added to 10 g (47 mmol) of 3-bromobenzothiophene and cooled to - 60°C, 36 ml of a hexane solution of n-butyllithium (1.57 mol/l was added dropwise, and the mixture was stirred for 1 hour. Then, 13.3 g (71 mmol) of triiospropyl borate was added and the stirring was continued for 1 hour. The reaction solution was returned to room temperature and 50 ml of a saturated aqueous solution of ammonium chloride and 100 ml of toluene were added. The organic layer was washed with distilled water (3×100 ml) and dried over anhydrous magnesium sulfate, the magnesium sulfate was separated by filtration, the solvent was distilled off under reduced pressure, and Intermediate B-1 weighing 6.9 g (39 mmol, 83percent yield) was obtained |
83% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1 h; Inert atmosphere Stage #2: at -60℃; for 1 h; |
Under a nitrogen atmosphere, 10 g (47 mmol) of 3-bromobenzothiophene and 100 ml of THF were loaded, and then the mixture was cooled to -60°C. 36 Milliliters (1.57 mol/l) of a solution of n-butyllithium in hexane were dropped to the mixture and then the whole was stirred for 1 hour. 13.3 Grams (71 mmol) of triisopropyl borate were added to the resultant and then the mixture was stirred for 1 hour. The temperature of the reaction solution was returned to room temperature, and then 50 ml of a saturated aqueous solution of ammonium chloride and 100 ml of toluene were added to the solution. An organic layer was washed with distilled water (3×100 ml). After the organic layer had been dried with anhydrous magnesium sulfate, magnesium sulfate was separated by filtration and then the solvent was distilled off under reduced pressure to provide 6.9 g (39 mmol, 83percent yield) of an intermediate B-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1 h; Inert atmosphere Stage #2: at -60 - 20℃; for 2 h; Inert atmosphere |
To a solution of 3-bromo-benzo[b]thiophene (2.13 g, 10.00 mmol) in THF(22 mL) in a 100 mL round bottom flask at -60°C, was added dropwise n-BuLi 2.5 M in hexane (4.81 mL, 12.00mmol) and the resulting mixture was stirred for 1h at -60°C. Then, trimethylborate(1.72 mL, 15.00 mmol) was added to the reaction mixture which was stirred 1h at-60°C and 1h while letting gradually warm up to room temperature. The reactionmixture was then quenched with NH4Cl (11 mL) and toluene was added(22 mL). The mixture was washed with water (325 mL) and the combined organicphases were finally dried with MgSO4, filtered and the solvents wereremoved under reduced pressure. The crude product was purified by flashchromatography (CH2Cl2/MeOH 95:5) to give compound 11a (1.02 g, 59percent) as a white solid. 1H NMR (300 MHz, CDCl3): δ = 7.41-7.49(m, 2H), 7.85-7.90 (m, 2H), 8.0 (dd, J = 6.9-2.4, 2H), 8.34 (s, 1H). |