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CAS No. : | 30186-18-6 | MDL No. : | MFCD03428533 |
Formula : | C8H7BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LQCMMXGKEGWUIM-UHFFFAOYSA-N |
M.W : | 215.04 | Pubchem ID : | 10727403 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 46.36 |
TPSA : | 37.3 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) : | -5.69 cm/s |
Log Po/w (iLOGP) : | 2.08 |
Log Po/w (XLOGP3) : | 2.7 |
Log Po/w (WLOGP) : | 2.36 |
Log Po/w (MLOGP) : | 1.86 |
Log Po/w (SILICOS-IT) : | 2.35 |
Consensus Log Po/w : | 2.27 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.21 |
Solubility : | 0.132 mg/ml ; 0.000614 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.14 |
Solubility : | 0.157 mg/ml ; 0.000731 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.02 |
Solubility : | 0.207 mg/ml ; 0.000962 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-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 |
---|---|---|
94% | Stage #1: at 120 - 165℃; for 2 h; Stage #2: With water In dichloromethane at 0℃; |
Intermediate 9B:; [00217] Aluminum chloride (36 g, 270 mmol) was added to Intermediate 9A(32.0 g, 149 mmol) in a round bottom flask fitted with a reflux condenser, nitrogen gas inlet, and sodium hydroxide solution to scrub the HCl(g) effluent. The reaction flask was place in a 120 0C oil bath. The reaction mixture become fluid, then was warmed to 165 0C over 1 h. The temperature was maintained at this temperature for 1 <n="99"/>h, then was allowed to cool to rt. To the solid reaction mixture was added dichloromethane (~ 200 mL) to form a slurry. The slurry was added to ice. This process was repeated multiple times to process the entire reaction mixture. The dichloromethane/water mixture was stirred until both phases were fairly clear, then the phase were separated. The organic phase was washed with brine, dried (MgSO4) and then concentrated in vacuo to obtain Intermediate 9B (30.14 g, 140 mmol, 94 percent yield) as a dark red oil. MS (ESI) m/z 213, 215.3 (M+H)+. -90percent pure. |
90% | at 170℃; for 3 h; Inert atmosphere | Commercially available 3-bromophenol (1, 50 g, 0.289 mol) was added to a mixture of Ac2O (187.5 mL, 1.987 mol) and anhyd NaOAc (50 g,0.6095 mol) in a round-bottom flask. The mixture was refluxed and stirred for 2.5 h. The mixture was poured into ice-water (400 mL).The organic phase was separated, washed with water (200 mL) and sat. aq NaHCO3 solution (100 mL). The combined aqueous phases were extracted with CH2Cl2(3 × 80 mL), the combined organic phaseswere dried (MgSO4), then filtered. The solvent was evaporated in vacuo to give the pure 3-bromophenyl acetate17(50.4 g, 81percent) as pale yellow oil; Rf= 0.62 (toluene/EtOAc, 4:1). 3-Bromophenyl acetate was transferred into a three-neck flask and AlCl3(103 g, 0.7724 mol) was added in small portions. The mixture was heated and stirred at 170 °Cfor 3 h. The mixture was cooled to approx. 60 °C, and then ice (200 g)and 10percent HCl solution (100 mL) were added and the mixture was stirred and distilled using steam. From the distillate white crystals were filtered off to give product 219(45 g, 90percent); Rf= 0.55 (toluene);mp 39–40 °C. Its spectral data are identical with the literature.20IR (KBr): 3082, 3039, 3010, 1636, 1610, 1462, 1348, 1315, 1232, 1201,967, 890, 735, 626, 497 cm–1.1H NMR (360 MHz, CDCl3): δ= 2.61 (s, 3 H, Me), 7.04 (dd, J= 2.5, 8.5Hz, 1 H, 5′-H), 7.18 (d, J= 2.5 Hz, 1 H, 3′-H), 7.58 (d, J= 8.5 Hz, 1 H, 6′-H), 12.34 (s, 1 H, OH). |
76% | at 160℃; for 3 h; | Compound 15-2 (0413) To a stirred suspensions of compound 15-1 (46 g, 0.0.21 mol) and anhydrous aluminum chloride power (57 g, 0.42 mol) was heated to 160° C. for 3 h. The mixture reaction was cooled to room temperature and ice (200 g) and water (800 mL) was poured and purified with hydrochloric acid at pH 7. the reaction was extracted with ethyl acetate (500 mL×3) and the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtrated, concentrated and purified by column chromatography (PE:EA=60:1) to afford compound 15-2 as a light green solid (35.1 g, 76percent). |
70% | for 8 h; Heating / reflux | Fries migration of the same was carried out by heating with anhydrous aluminum chloride in o-dichlorobenzene for 8 hours to obtain the product in 70percent yield, which was condensed with N-bocpiperidone in methanol in the presence of pyrrolidine, and desired product Vb was obtained in 65percent yield. |
70% | for 8 h; | 2. 2-hydroxy-4-bromoacetophenone was synthesized through the schematic pathway shown below. 3-Bromophenol was acylated with acetic anhydride in the presence of catalytic quantity of sulfuric acid to get the acylated product in quantitative yield. Fries migration of the same was carried out by heating with anhydrous aluminium chloride in o-dichlorobenzene for 8 h to get the product in 70 percent yield, which is condensed with N- bocpiperidone in methanol in the presence of pyrrolidine and desired product Vb was obtained in 65 percent yield. |
70% | at 160℃; for 2 h; | In a 250 mL round bottom flask (8) (5.49 g, 26 mmol) and anhydrous AlCl3 (6.92 g, 51 mmol) was mixed thoroughly on oil bath at 160 °C for 2 h. Reaction mixture was poured into ice water and concentrated hydrochloric acid solution was added to break complex formed during reaction. The mixture was taken in AcOEt (50 mL * 3). The organic layer was combined and washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 30:1) gave (9) (3.85 g, 70 percent) as white solid. Mp: 36-38 °C, MS (EI) [M]+: m/z = 213, 1H NMR (400 MHz, CDCl3) δ ppm: 7.60 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 2.63 (s, 3H). |
4.74 g | at 160℃; for 3 h; | 3-Bromophenol (5) (10.0 g, 58 mmol) was dissolved in pyridine(30 mL) under ice-bath and was stirred for 30 min. Acetic anhydride (8.3 mL, 88 mmol) was added dropwise into above mixture at the same temperature. The ice-bath was removed after dropping and the mixture was stirred for 2 h. Concentrated HCl and ice-water (300 mL) was added to neutralize pH to 7. The mixture was extracted with AcOEt (100 mL 3). The organic layer was collected and washed with brine and dried over Na2SO4. Filtration and concentration in vacuo afforded yellow oil. In a 250 mL round bottom flask, the obtained yellow oil (6.45 g, 30 mmol) and anhydrous AlCl3 (12.02 g, 90 mmol) was mixed at 160 °C for three hours. Reaction mixture was poured into ice water and concentrated hydrochloric acid solution was added to break complex formed during reaction.The mixture was taken in AcOEt (50 mL 3). The organic layer was combined and washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt 30:1) give (6) (4.74 g, 73.5percent) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.9% | Stage #1: at 0 - 20℃; for 15 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water; toluene at 0℃; for 2 h; Heating / reflux |
To a stirred solution of 4-Bromo-2-hydroxy-benzonitrile (3. 6 g, 18. 2MMOL) in anhydrous THF solution (20 mL) was added methylmagnesium bromide (1. 4 M in THF/toluene, 39.0 mL, 54. 6MMOL, 3 eq) at 0 °C under argon. The reaction mixture was slowly warm up to rt and stirred for 15 h. The mixture was cooled to 0 °C and quenched by the addition of water (5 mL) followed by concentrated HCI (10 mL). The resulting solution was refluxed for 2 h before cooled down to rt. The reaction mixture was then poured into EtOAc (100 mL) and water (100 mL). The layer was separated and the organic layer was washed with water (2 x 50 mL), dried over NA2SO4, filtrated, and concentrated under reduced pressure. The residue was then subjected to silica gel chromatography (20percent EtOAc/Hexane) to provide 1- (4-BROMO-2-HYDROXY-PHENYL)- ethanone (2.81 g, 71.9percent) as yellow OIL. 1H-NMR (CDCI3) : 8 12.32 (s, 1H, OH), 7.57 (d, J = 8. 7HZ, 1H), 7.17 (d, J = 1,9 Hz, 1H), 7.03 (dd, J = 1.9, 8.7 Hz, 1H), 2.62 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: at 20℃; Stage #2: With aluminum (III) chloride In ethyl acetate at 140℃; for 2 h; |
Intermediate 2: (E)-3-{4-Oxo-spiro[chromane-2,4'-piperidine]-7-yl}-acrylic acid methyl ester [Show Image] STEP A 3-Bromo-phenol (10.0 g, 57.8 mmol) was dissolved in 10 ml of pyridine and 10 ml of acetic anhydride and stirred overnight at RT. The mixture was than poured into water, and 1 M HCl was added until reaching a neutral pH value. Extraction with AcOEt furnished a crude product, which was treated with AlCl3 (13.25 g, 100 mmol) at 140°C. After 2 h, the mixture was poured into water and extracted with diethyl ether. The crude residue was purified by column chromatography (eluent: hexane/AcOEt 70:30) to give 1-(4-bromo-2-hydroxy-phenyl)-ethanone (10.1 g) as a red solid. Y=81percent LC-MS: Method B, rt=1.95 min; (ES+) MH+:215 1H-NMR (CDCl3) δ (ppm): 12.34 (s, 1H), 7.58 (d, J=8 Hz, 1H), 7.18 (d, J=2 Hz, 1H), 7.04 (dd, J=8, 2 Hz, 1H), 2.61 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With aluminum (III) chloride In 1,1-dichloroethane for 4 h; Heating / reflux | A dichloroethane solution (250 ml) of 1-bromo-3-methoxybenzene (30 g), acetyl chloride (15.5 g) and aluminum chloride (25.6 g) was refluxed for 4 hours. The reaction mixture was poured into ice water, and the organic layer was separated. The organic layer was washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, and the title compound was obtained as a colorless oil (14.4 g, yield 42percent) from the diethyl ether-hexane (1:10) eluate. 1H-NMR (200MHz, CDCl3) δ: 2.61 (3H, s), 7.04 (1H, dd, J=1.9, 8.5Hz), 7.18 (1H, d, J=1.8Hz), 7.58 (1H, d, J=8.4Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: With aluminum (III) chloride In 1,2-dichloro-ethane for 2 h; Heating / reflux Stage #2: With hydrogenchloride; water In 1,2-dichloro-ethane |
Reference Example 101 4'-bromo-2'-hydroxyacetophenone Aluminum chloride (5.78 g, 43.35 mmol) was added to a solution of 3-bromophenol (5.0 g, 28.90 mmol), and then acetyl chloride (2.27 g, 28.90 mmol) in 1,2-dichloroethane (25 mL) was added. The resulting mixture was refluxed for 2 hours. After cooling, the reaction mixture was added to 1N hydrochloric acid (100 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluding solution: ethyl acetate/hexane = 1/10) to give the title compound (2.2 g, 35percent) as a colorless liquid. 1H-NMR (300MHz, CDCl3) δ: 2.61 (3H, s), 7.04 (1H, dd, J = 8.4, 1.8 Hz), 7.18 (1H, d, J = 1.8 Hz), 7.59 (1H, d, J = 8.4 Hz), 12.30 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With ammonia In N,N-dimethyl-formamide at 60℃; for 9 h; Inert atmosphere | 2-Acetyl-5-bromophenol (322 mg, 1.5 mmol) was dissolved in N, N-dimethylformamide (3 mL)Ammonia (1.7 mL, 45 mmol) was added dropwise thereto, reacted at 60 ° C under nitrogen for 9 hours, and allowed to cool to room temperature. The reaction solution was poured into 16 mL of water and extracted with dichloromethane (3 x 5 mL). The organic phase was washed with saturated brine (2 x 5 mL), dried over anhydrous sodium sulfate, filtered, sonicated and purified by flash column chromatography The product was dichloromethane: methanol = 50: 1 V / V)2-acetyl-5-bromoaniline as a yellow oil in a yield of 56percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Compound 15-3 (0414) To a suspensions of compound 15-2 (25 g, 0.12 mol) and potassium carbonate (24 g, 0.18 mol) in anhydrous DMF (20 mL) was added to MeI (22.6 mL, 0.23 mol) and the mixture reaction was stirred at room temperature overnight. LCMS showed that the reaction was complete. Then water (300 mL) was poured and the mixture was extracted with ethyl acetate and the organic phase was (200 mL×3) and the organic phase was washed saturated sodium chloride, dried over anhydrous sodium sulfate, filtrated, concentrated to afford compound 15-3 as a colorless solid (26.1 g, 98percent). |
94% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 16 h; Inert atmosphere | To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)ethan-1-one 1 (1 g, 4.65 mmol) in DMF (10 mL) were added K2C03 (963 mg, 6.98 mmol) and Mel (0.6 mL, 9.3 mmol) drop wise at 0 °C under Ar. The reaction mixture was stirred at RT for 16 h then diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2 SO4, filtered and concentrated in vacuo to afford compound 2 (1 g, 94percent) as an off white solid. ‘H NMR (400MHz, CDC13): 7.62 (d, J= 8.2 Hz, 1H), 7.17-7.11 (m, 2H), 3.92 (s, 3H), 2.59 (s, 3H); LC-MS (ESI): m/z 230.8 (M+2). |
92% | at 0 - 20℃; for 3 h; | Intermediate 9C:; [00218] Iodomethane (10.5 mL, 168 mmol) was added dropwise over 30 min to a solution of Intermediate 9B (30.14 g, 140 mmol) in DMF (100 mL) at 0 0C. After 30 min, the reaction was warmed to rt for 2.5 h. Water (250 mL) was added and the resulting tan precipitate was filtered and washed with water to give Intermediate 9C(29.64 g, 129 mmol, 92 percent yield). MS (ESI) m/z 229. 231 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.12 g | Stage #1: With potassium carbonate In acetone at 50℃; for 0.5 h; Stage #2: at 50℃; |
A mixture of (9) (2.14 g, 10 mmol), potassium carbonate (4.14 g, 30 mmol), and acetone (100 mL) was stirred at 50 °C for 30 min. Dimethyl sulfate (1.1 mL,12 mmol) was added dropwise into the above mixture at 50 °C. After completion of reaction, the solid was filtered off and the solvent was evaporated. The solid obtained was dried to give (10) (2.12 g, 75percent) as yellow solid. Mp: 60-61 °C, MS (EI) [M]+: m/z = 229, 1H NMR (400 MHz, CDCl3) δ ppm: 7.65 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J = 4.0 Hz, 1H), 3.94 (s, 3H), 2.61 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyrrolidine In methanol at 60 - 65℃; for 3 h; | EXAMPLE 1; Reaction of 5-bromo-2-hydroxy acetophenone with N-Boc-4-piperidone; In a 500 ml 3-necked flask, fitted with a reflux condenser, a CaCl2 gaurd tube and a magnetic needle, 0.1 mole of N-Boc-4-piperidone (19.5 g) and 0.116 mole of pyrrolidine (8.95 g), dissolved in 100 ml of anhydrous MeOH at ambient temperature were added to 0.0837 mole 5-bromo-2-hydroxyacetophenone (18 g). The reaction mixture was stirred under reflux at 60-65° C. for about 3 hours. The reaction mixture was transferred to a rotary flask, and MeOH was distilled off to obtain an orange viscous liquid. 75 ml of water was added, and the product was extracted four times with 100 ml portions of ethyl acetate. The aqueous layer was discarded, and the organic layer was dried over anhydrous Na2SO4. Ethyl acetate was distilled off, and an orange viscous oil was obtained that was thoroughly dried in vacuo. Further purification by column chromatography with ethyl acetate/petrolether 10/90 yielded 28,7 g (87percent) of a pale yellow crystalline solid. Melting Point: 140-143° C. |
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