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Structure of 2-Bromo-4′-chloroacetophenone
CAS No.: 536-38-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 536-38-9 |
Formula : | C8H6BrClO |
M.W : | 233.49 |
SMILES Code : | C1=C(C=CC(=C1)Cl)C(CBr)=O |
MDL No. : | MFCD00000625 |
InChI Key : | FLAYZKKEOIAALB-UHFFFAOYSA-N |
Pubchem ID : | 68303 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.52 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.96 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.82 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.92 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.82 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.33 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.77 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.34 |
Solubility | 0.108 mg/ml ; 0.000461 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.84 |
Solubility | 0.341 mg/ml ; 0.00146 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.23 |
Solubility | 0.0139 mg/ml ; 0.0000594 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.72 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.55 |
* 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 |
---|---|---|
General procedure: A stirred mixture of <strong>[90008-50-7]3-amino-6-propoxypyridazine</strong> 3 (4.50g, 29.4mmol), 2-bromo-1-[4-(2-methoxyethoxy)phenyl]ethanone 11 (8.03g, 29.4mmol) and EtOH (280mL) was heated at reflux for 2.5 hours. The mixture was cooled and NaHCO3 (2.50g, 30mmol) was added. The mixture was stirred at room temperature for 15 hours, heated at reflux for 1 hour, then cooled and evaporated. The residue was extracted with CHCl3 (150mL) and the extract washed with saturated, aqueous NaCl solution (50mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography over silica gel. Elution with 1-2% MeOH in CH2Cl2 afforded a green/brown solid. Treatment with decolourising charcoal and recrystallization from cyclohexane gave 6f (3.95g, 41%) as pale green crystals, m.p. 82.5-84C. 1H NMR (CDCl3) ? 1.06 (3H, t, J=7.2Hz), 1.75-1.94 (2H, m), 3.47 (3H, s), 3.74-3.81 (2H, m), 4.14-4.21 (2H, m), 4.27 (2H, t, J=6.6Hz), 6.68 (1H, d, J=9.3Hz), 7.00 (2H, d, J=8.8Hz), 7.76-7.88 (3H, m), 7.94 (1H, s). MS (APCI+) m/z 328 (M+H, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; | 6.1. 2-(4-Chlorophenyl)-6-methoxyimidazo[1,2-a]pyridine A mixture of 1.3 g (10.5 mmol) of 5-methoxy-2-pyridinamine, 2.44 g (1eq) of alpha-bromo-4-chloroacetophenone and 1.76 g (2eq) of sodium bicarbonate in 20 ml of 95percent strength alcohol is heated under reflux for 4 h 30 min. under argon. The mixture is evaporated to dryness and the residue taken up between CH2 Cl2 and H2 O, followed by washing, drying and evaporation. The product is purified by chromatography and then crystallized in ether. M.p. 148°-9° C. 5-Methoxy-2-pyridinamine was obtained according to a process described in the literature: G. J. Clark and L. W. Deady, Aust. J. Chem. 34, 927 (1981). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;silica gel; In water; N,N-dimethyl-formamide; toluene; | EXAMPLE 2 Preparation of 1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one 5,6,7,8-Tetrahydroquinolin-5-one (35 g) was dissolved in 80 ml of toluene. To this solution was added 4-chlorophenacyl bromide (55.6 g) gradually and refluxed for 18 hours. The reaction mixture was cooled to room temperature, and depositing crystals were collected by filtration (78 g). These solids were dissolved in 700 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (30 g) and triethylamine (34 ml), then the reaction mixture was heated at 100 C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. To the residue was added 300 ml of water, and extracted with 200 ml of methylene chloride three times. This methylene chloride solution was washed with 100 ml of brine and dried over anhydrous sodium sulfate. The dark brown solution that obtained after removing drying agent by filtration was concentrated under reduced pressure, the resultant dark brown residue was purified by alumina column chromatography. The title compound was obtained as dark red crystals (29 g). m.p.: 153.4-157.2 C. IR: 2360, 1683, 1535, 1514, 1471, 1448, 1400, 1384, 1271 264, 1229, 1089, 8365 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; for 72h;Reflux; | EXAMPLE 104; Methyl 6-(4-chlorophenyl)-5-(hydroxymethyl)imidazo[2,l-b][l,3]thiazole-2- carboxylate; A solution of methyl-2-aminothiazole-5-carboxylate (1.0 g, 7.8 mmol) and 2-bromo-4'- chloroacetophenone (1.8 g, 7.8 mmol) in acetone (200 mL) was heated at reflux for 72 h. The remaining intermediate was filtered off and the filtrate was collected. The solvent was removed under reduced pressure to afford the intermediate compound methyl 6-(4- chlorophenyl)imidazo[2,l-b][l,3]thiazole-2-carboxylate as a yellow solid (1.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 4; 6-(4-Chlorophenyl)-5-(hydroxymethyl)imidazo [2, 1-b] [ 1 ,3] thiazoIe-2-carbaldehyde; A solution of <strong>[1003-61-8]2-aminothiazole-5-carboxaldehyde</strong> (1.0 g, 7.8 mmol) and 2-bromo-4'- chloroacetophenone (1.8 g, 7.8 mmol) in acetone (5 mL) was heated at reflux for 5 h. The solvent was evaporated and the crude material purified by preparative HPLC (Xterra Cl 8, 50 mM NH4HCO3 (pH 10) - CH3CN) to give the intermediate compound 6-(4- chlorophenyl)imidazo[2,l-b][l,3]thiazole-2-carbaldehyde as a yellow solid (176 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20℃; for 2h; | Preparation Example 2 To a mixture of tert-butyl 4-(aminocarbonothionyl)piperidine-1-carboxylate (500 mg) and DMF (5 mL) was added 2-bromo-1-(4-chlorophenyl)ethanone (573 mg), followed by stirring at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. To the residue were added water and ethyl acetate, and the organic phase was separated. The organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure. To the residue were added DCM (6 mL), and under ice-cooling, 4 M hydrogen chloride/dioxane (6 mL), followed by warming to room temperature and then stirring for 4 hours. The solvent was evaporated under reduced pressure, diisopropyl ether and a small amount of methanol were added to the residue, and the resulting solid was collected by filtration. The solid was washed with diisopropyl ether and then dried under reduced pressure to obtain 4-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]piperidine hydrochloride (437 mg). | |
In ethanol;Reflux; | General procedure: 4-chlorobromoacetophenone (A) and N-Boc-piperidine 4-thioamide (B) in a protic solvent ethanol to form a thiazole ring intermediate (C);Then, the Boc group is removed under strong acid TFA conditions to obtain a compound (D) and a reductive amination reaction with 5-nitrofurfural (C) to obtain a final product F. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In toluene; at 130℃;Product distribution / selectivity; | Example 23; Synthesis of (4S)-trans-,cis-2-(4-chlorophenyl)-2-bromomethyl-4-chloromethyl-1,3-dioxolane suppressing halogen exchange between substrates A mixture of 2-bromo-4'-chloroacetophenone (4.94 g, 2-chloro-4'-chloroacetophenone content=0.09%), p-toluenesulfonic acid monohydrate (0.20 g, 0.05 equivalent) and toluene (100 mL) was refluxed at 130C using an azeotropic distillation device with a Dean-Stark tube, and (S)-monochlorohydrin (2.59 g, 1.1 equivalents, >99%ee) was added dropwise under reflux such that the amount of the (S)-monochlorohydrin present in the reaction solution would be not more than 0.1 equivalent (not more than 2.1 mmol) relative to the amount of 2-bromo-4'-chloroacetophenone to be used (21.2 mmol), while analyzing the progress of the reaction by GC. After confirmation of the completion of the azeotropic distillation, the reaction mixture was cooled and washed with 10% aqueous sodium hydrogen carbonate solution and 10% brine. The solvent was evaporated under reduced pressure to give (4S)-trans-,cis-2-(4-chlorophenyl)-2-bromomethyl-4-chloromethyl-1,3-dioxolane (6.56 g, >99%ee). Here, the content percentage of (4S)-trans-,cis-2-(4-chlorophenyl)-2-chloromethyl-4-chloromethyl-1,3-dioxolane halogen-exchanged with a chlorine atom was 0.09%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To <strong>[89226-13-1]tert-butyl 2-amino-2-thioxoethylcarbamate</strong> (1.0 g, 5.3 mmol) and 4-chlorophenacylbromide (1.2 g, 5.3 mmol) was added ethanol (8 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 4 mol/L hydrochloric acid/1,4-dioxane solution (10 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration, washed with a small amount of 1,4-dioxane, and dried under reduced pressure to give the title compound as a white powder (1.4 g, 5.3 mmol, 100%). 1H NMR (400 MHz, DMSO) delta 8.56 (s, 3H), 8.27 (s, 1H), 8.04 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 4.51 (s, 2H). MS (ESI) m/z 225 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 80℃; for 0.5h;Microwave irradiation; | General procedure: 2-Aminothiazole derivatives 1-37 were prepared by Hantzsch thiazole synthesis: The cyclic condensation of an α-bromoketone (1 equiv) and N-substituted thiourea (1 equiv) in anhydrous ethanol, stirring under microwave irradiation at 80 C for 30 min. The precipitating hydrobromide salts were collected and washed with H2O and cold ethanol. If needed, further purification was done after neutralization with saturated NH4OH solution, stirring at room temperature, filtration of the precipitate and washing with cold ethanol. Colum chromatography on silica gel (eluent: hexane/ethylacetate 2:1 or dichloromethane/methanol 9:1) afforded the title compound.30 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of thiochroman-4-one 1 (1 mmol), benzaldehyde 2(1 mmol), thiourea 3 (1 mmol) was stirred in presence of ionic liquid,[Bmim]HSO4 (1 mL) at 80 C for 20 min followed by the additionof 3-bromo-1-phenylpropan-1-one 4 (1 mmol) and theresulting mixture was further stirred at 80 C for 40-70 min. Theprogress of reaction was monitored by TLC. After completion ofthe reaction, the mixture was diluted with 20 mL of water,2 20 mL of EtOAc was added and shaken vigorously. The organiclayer was separated from the solution. The aqueous layer wasevaporated, the ionic liquid was dried at 60-70 C under vacuumand then reused. The results have shown that the [Bmim]HSO4ionic liquid could be reused at least for four times. The productwas purified by column chromatography on neutral alumina(100-200 mesh), eluted with a solvent system of ethyl acetate-hexane to afford the title compounds 5a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: A mixture of thiochroman-4-one 1 (1 mmol), benzaldehyde 2(1 mmol), thiourea 3 (1 mmol) was stirred in presence of ionic liquid,[Bmim]HSO4 (1 mL) at 80 C for 20 min followed by the additionof 3-bromo-1-phenylpropan-1-one 4 (1 mmol) and theresulting mixture was further stirred at 80 C for 40-70 min. Theprogress of reaction was monitored by TLC. After completion ofthe reaction, the mixture was diluted with 20 mL of water,2 20 mL of EtOAc was added and shaken vigorously. The organiclayer was separated from the solution. The aqueous layer wasevaporated, the ionic liquid was dried at 60-70 C under vacuumand then reused. The results have shown that the [Bmim]HSO4ionic liquid could be reused at least for four times. The productwas purified by column chromatography on neutral alumina(100-200 mesh), eluted with a solvent system of ethyl acetate-hexane to afford the title compounds 5a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With polyethylene glycol (PEG-400); In water; for 0.133333h;Microwave irradiation; Green chemistry; | To stirred solution of polyethylene glycol (PEG-400) (2 mL) in water (2 mL) were added 1-(2-amino-4-methylthiazol-5-yl)ethanone (2 mmol)/ethyl 2-amino-4-methylthiazole-5-carboxylate (2 mmol) and α-bromo aralkyl ketones (phenacyl bromides) (2 mmol), and the mixture was heated at 90 C or subject to microwave irradiation at 300 W, until reaction completion as indicated by TLC. After reaction completion, the reaction mixture was cooled at room temperature, and the solid product formed was collected by filtration, washed with water, and recrystallized from ethanol to give pure product. The recovered PEG with water was reused for five further cycles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With polyethylene glycol (PEG-400); In water; for 0.116667h;Microwave irradiation; Green chemistry; | To stirred solution of polyethylene glycol (PEG-400) (2 mL) in water (2 mL) were added 1-(2-amino-4-methylthiazol-5-yl)ethanone (2 mmol)/ethyl 2-amino-4-methylthiazole-5-carboxylate (2 mmol) and α-bromo aralkyl ketones (phenacyl bromides) (2 mmol), and the mixture was heated at 90 C or subject to microwave irradiation at 300 W, until reaction completion as indicated by TLC. After reaction completion, the reaction mixture was cooled at room temperature, and the solid product formed was collected by filtration, washed with water, and recrystallized from ethanol to give pure product. The recovered PEG with water was reused for five further cycles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium phosphate; In acetonitrile; at 70℃;Molecular sieve; | General procedure: A mixture of 3,4-dihydro-isoquinoline imine 1 (0.2 mmol), arylacyl bromides 2 (0.24 mmol), K3PO4 (0.24 mmol), 4Å molecular sieves (powder, 50 mg) and MeCN (0.5 mL) was stirred at 70C for 1.5-3h. Upon the consumption of imine 1 (monitored by TLC), the reaction was cooled to room temperature, filtered, concentrated and purified by a silica gel flash chromatography (PE/EtOAc) to afford compound 3. |
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