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CAS No. : | 4072-67-7 | MDL No. : | MFCD00017877 |
Formula : | C16H12Br2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RTSLQVZQORGDQQ-UHFFFAOYSA-N |
M.W : | 396.07 | Pubchem ID : | 77689 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 88.01 |
TPSA : | 34.14 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.52 cm/s |
Log Po/w (iLOGP) : | 2.52 |
Log Po/w (XLOGP3) : | 4.5 |
Log Po/w (WLOGP) : | 4.51 |
Log Po/w (MLOGP) : | 3.47 |
Log Po/w (SILICOS-IT) : | 5.37 |
Consensus Log Po/w : | 4.07 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.24 |
Solubility : | 0.00225 mg/ml ; 0.00000569 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.94 |
Solubility : | 0.00457 mg/ml ; 0.0000115 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.25 |
Solubility : | 0.0000223 mg/ml ; 0.0000000562 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.11 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P260-P270-P264-P280-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405 | UN#: | 3261 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
84.9% | Stage #1: With aluminum (III) chloride In dichloromethane at 0 - 10℃; Stage #2: at 0℃; Reflux |
138.8 g (1.04 mol, 2.9 eq) of aluminum trichloride was added to the reaction flask.Add 700ml of dichloromethane,The system is cooled to 0 to 10 ° C for stirring.174.6 g (0.87 mol, 2.4 eq) of bromoacetyl bromide was added dropwise to the upper system.The dropping process controls the temperature at 0 to 10 ° C.After the dropwise addition, the mixture is stirred for 10 to 30 minutes.150 ml of a dichloromethane solution containing 55.8 g of biphenyl (0.36 mol, 1.0 eq) was added dropwise.After the addition is complete, stir to room temperature and stir.At the same time, 200 ml of n-heptane was added to the system, and the temperature was raised to reflux.The reaction was kept for 4 to 5 hours, and the basic reaction was completed, and the product was largely precipitated.The mixture was stirred at room temperature for 3 to 5 hours, and suction filtered to obtain crude 4,4'-bis(2-bromoacetyl)biphenyl. The crude product I was suspended in 500 ml of water.Beating at room temperature for 1 to 2 hours, suction filtration,4,4'-bis(2-bromoacetyl)biphenyl crude II,The crude product II was beaten in 300 ml of dichloromethane at room temperature for 1 to 2 hours.Filtering to obtain 4,4'-bis(2-bromoacetyl)biphenyl,Dry at 70 ° C under vacuum,Get 121.3g solid,The purity was 99.4percent, and the yield was 84.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | at 20 - 50℃; for 24 h; | 2-Bromo-1-[4'-(2-bromo-acetyl)-biphenyl-4-yl]ethanone A solution of bromine (13.4 g, 4.32 mL, 83.9 mmol) in glacial acetic acid (30 mL) was added drop wise to a mixture of 1,1-(biphenyl-4-4-diyl)diethanone (10.0 g, 42.0 mmol) in glacial acetic acid (100 mL) at 50 C. After addition was complete, the mixture was stirred at room temperature for 24 hours. The solid was filtered and washed with chloroform to afford 1,1-(biphenyl-4,4-diyl)-bis(2-bromoethanone as white solid, (15.9 g, 96percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.98 (s, 4H) 7.85-8.25 (m, 8H). |
92% | Stage #1: With trimethylsilyl trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25 h; Stage #2: With N-Bromosuccinimide In dichloromethane at 0℃; for 2 h; |
Taking 4.4-diacetyl biphenyl (40g, 0.17mol) and DIPEA (49g, 0.38mol) is dissolved in 1000 ml of methylene chloride, 0 °C dropwise TMSOTf (0.39mol), the drop finishes stirring 15 minutes, dropping NBS (73g, 0.41mol) in dichloromethane (200 ml) solution, the drop finishes 0 °C stirring reaction 2h, the reaction is complete, system is poured into 500 ml water, layered, dry anhydrous sodium sulfate, filtered, concentrated to remove dichloromethane, produced intermediate 1 crude, toluene crystallization get 62g solid, yield 92percent; |
86% | With bromine In dichloromethane at 20℃; for 6.75 h; Cooling with ice | A solution of Br2 (2.7 g, 17 mmol) in CH2Cl2 (10 mL) was added dropwise over 5 min to an ice water cooled solution of 1,1'-([1,1'-biphenyl]-4,4'-diyl)diethanone 1 (2.0 g, 8.4 mmol) in CH2Cl2 (40 mL). The cooling bath was removed 40 min later, and stirring was continued at ambient temperature for 6 h. The cake of solid that formed was filtered, washed with CH2Cl2 and dried in vacuo to aord 2 (2.86 g, 86 percent) as off-white solid. |
82% | With bromine In dichloromethane at 20℃; for 20 h; | EXAMPLES; Preparation of Compound (3); A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1'-(biphenyl-4,4'-diyl)diethanone, 200 mL CH2Cl2 and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL CH2Cl2 and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into tetrahydrofuran (THF) to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 hour and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH2Cl2. The product was dried under vacuum at 60° C. to yield 27.4 g (69.2 mmol, 82percent) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H13Br2O2 (M+H; DCI+): 394.9282. Found: 394.9292. mp 224-226° C. |
82% | With bromine In dichloromethane at 20℃; for 20 h; Inert atmosphere | A l L, 3 -neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple was charged with 20 g (83.9 mmol, 1 equiv) l,l'-(biphenyl-4,4'- diyl)diethanone, 200 mL CH2Cl2 and 8.7 mL (27. Ig, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 2Oh under ambient conditions. The resulting slurry was charged with 200 mL CH2Cl2 and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25 0C over Ih and allowed to stir at 20-25 0C for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH2Cl2. The product was dried under vacuum at 60 0C to provide 27.4 g (69.2 mmol, 82percent) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (ss 4H); 13C NMR (100 MHz, CDCl3) δ 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr9 cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H13Br2O2 (M + H; DCI+): 394.9282. Found: 394.9292. mp 224-226 0C. |
82% | With bromine In dichloromethane at 20℃; for 20 h; Inert atmosphere | In a 1 L 3-neck round bottom flask equipped with a nitrogen line, overhead stirrer and thermocouple 20 g (83.9 mmol, 1 equivalent) of 1,1 '- (biphenyl-4,4'-diyl) diethanone, 200 mL CH2Cl2 and 8.7 mL (27.1 g, 169.3 mmol, 2.02 equivalents) bromine. The mixture was stirred under nitrogen for about 20 hours under ambient conditions. To the resulting slurry was added 200 mL CH2Cl2 and concentrated to about 150 mL by vacuum distillation. The slurry was then solvent exchanged to a target volume of 200 mL with THF via vacuum distillation. The slurry was cooled to 20-25 [deg.] C over 1 hour and stirred at 20-25 [deg.] C for an additional hour. The off-white crystalline solid was filtered off and washed with 150 mL CH2Cl2. The product was dried under vacuum at 60 & lt; 0 & gt; C to give 27.4 g (69.2 mmol, 82percent) of the desired product: |
81% | With bromine In dichloromethane | Intermediate 5: 1 , 1 '-(biphenyl-4,4'-diyl)bis(2-bromoethanone); Br2 (21.6 mL, 420 mmol) in DCM (60 mL) was added dropwise to a suspension of 1,1'- (biphenyl-4,4'-diyl)diethanone (50 g, 210 mmol) in DCM (500 mL). The mixture was stirred overnight, slurry filtered of washed with DCM to give intermediate 5 (67.4 g, yield: 81percent) as a off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.11 (d, J= 8.4 Hz, 4H), 7.76 (d, J= 8.4 Hz, 4H), 4.49 (s, 4H). |
77.5% | With bromine In acetic acid at 20 - 50℃; | Example 43 Compound 47 A solution of bromine (1.3 mL, 25.0 mmol) in glacial acetic acid (15 mL) was added drop-wise to a solution of 4,4'-diacetylbiphenyl (3.0 g, 12.5 mmol) in acetic acid (40 mL) at 50° C. After the addition, the reaction mixture was stirred at room temperature overnight. The precipitate was filtered and re-crystallized from chloroform to give 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethanone) 47 (3.84 g, 77.5percent) as a white solid. LC/MS (ESI): [M+1]+: 397. |
77.5% | With bromine In acetic acid at 20 - 50℃; | A solution of bromine (1.3 mL, 25.0 mmol) in 15 mL glacial acetic acid was added drop-wise to a solution of 4-4'-diacetylbiphenyl (3.0 g, 12.5 mmol) in 40 mL acetic acid at 50° C. Upon completion of addition the mixture was stirred at room temperature overnight. The precipitated product was filtered off and re-crystallized from chloroform to give 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethanone) (3.84 g, 77.5percent) as a white solid.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.09 (4 H, d, J=7.93 Hz) 7.75 (4 H, d, J=8.24 Hz) 4.47 (4 H, s)Nominal/LRMS-Anal. Calcd. for 369.07 found; (M+H)+ -397.33, (M-H)- 395.14 |
77.5% | With bromine In acetic acid at 20 - 50℃; | A solution of bromine (1.3 mL, 25.0 mmol) in 15 mL glacial acetic acid was added drop-wise to a solution of 4-4'-diacetylbiphenyl (3.0 g, 12.5 mmol) in 40 mL acetic acid at 50° C. Upon completion of addition the mixture was stirred at room temperature overnight. The precipitated product was filtered off and re-crystallized from chloroform to give 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethanone) (3.84 g, 77.5percent) as a white solid.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.09 (4 H, d, J=7.93 Hz) 7.75 (4 H, d, J=8.24 Hz) 4.47 (4 H, s)Nominal/LRMS-Anal. Calcd. for 369.07 found; (M+H)+-397.33, (M-H)--395.14 |
77.5% | With bromine In dichloromethane at 20 - 50℃; for 20 h; | A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple was charged with 20 g (83.9 mmol, 1 equiv) 1,1'-(biphenyl-4,4'-diyl)diethanone, 200 mL CH2Cl2 and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 h under ambient conditions. The resulting slurry was charged with 200 mL CH2Cl2 and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 h and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH2Cl2. The product was dried under vacuum at 60° C. to provide 27.4 g (69.2 mmol, 82percent) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H13Br2O2 (M+H; DCI+): 394.9282. Found: 394.9292. mp 224-226° C.; A solution of bromine (1.3 mL, 25.0 mmol) in 15 mL glacial acetic acid was added drop-wise to a solution of 4-4'-diacetylbiphenyl (3.0 g, 12.5 mmol) in 40 mL acetic acid at 50° C. Upon completion of addition the mixture was stirred at room temperature overnight. The precipitated product was filtered off and re-crystallized from chloroform to give 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethanone) (3.84 g, 77.5percent) as a white solid.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.09 (4H, d, J=7.93 Hz) 7.75 (4H, d, J=8.24 Hz) 4.47 (4H, s)Nominal/LRMS-Anal. Calcd. for 369.07 found; (M+H)+ -397.33, (M-H)- -395.14 |
75.6% | at 30 - 35℃; for 16 h; Large scale | 20 kg of 4,4'-diacetylbiphenyl was suspended in 400 kg of acetic acid,The temperature was raised to 30 ° C. Then 27.2 kg of bromine was added and reacted at 30-35 ° C for 16 h.After the reaction was monitored by HPLC, the filter was filtered and the filter cake was rinsed with 6 kg of chloroform,A white powder of 31 kg.The resulting crude product was recrystallized from 130 kg of tetrahydrofuran. |
93 kg | With bromine In acetic acid at 10℃; for 12 h; Large scale | 2) 62kg of 4,4-diacetylbiphenyl was added to 400kg of acetic acid, and the temperature was lowered to 10 ° C, 120kg of bromine was added dropwise, and the reaction was incubated at 10 ° C for 12 hours. 3) After the completion of the reaction, the product was filtered, concentrated, crystallized and dried to obtain 93 kg of 4,4'-bis (2-bromoacetyl) biphenyl. After testing: Purity: 99.5percent (GC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.0 g | Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 15 - 25℃; Stage #2: With ammonium acetate In toluene at 95 - 105℃; |
4,4’-Bis(2-bromoacetyl)biphenyl bOg was added to methylene dichloride (l000ml) andstirred to get solution. Boc-L-Proline (120g) was added to it. Diisopropylethylamine68.5g was added to the reaction mass at 15-25°C. The reaction mass was stirred for about4 to 5h. The reaction mass was quenched by adding water. The aqueous layer was separated and organic layer was washed with aqueous acetic acid solution (Conc HC1 also can be used instead of acetic acid) till pH of aqueous layer was between 4-6. Theorganic layer was washed with water and distilled under vacuum to get a residue. The residue was dissolved in toluene and toluene solution was used further. Ammonium acetate 390g was added to the toluene solution and the reaction mass was stirred. The reaction mass heated to 95-105°C and maintained till completion of reaction. After completion of the reaction, the reaction mass was cooled to 50-60°C, methanol wasadded and the reaction mass cooled to 20-30°C and stirred for 2 to 3 hours. The solid was filtered and washed with toluene. Purity of crude:- 93.92percent.Crude wet cake was stirred in mixture of toluene, methanol and acetic acid and the reaction mass was heated to 60- 70°C, water was added to reaction mass at 60-70°C and the reaction mass cooled to 20-30°C and stirred. The solid obtained was filtered and washed with toluene and then withwater. Wet solid was dried. Purity - 97.04percent. The above purification was repeated to obtain 60.Og of the title compound in a purity of 98.97percent. |