Structure of 42860-10-6
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CAS No. : | 42860-10-6 |
Formula : | C7H4BrClO2 |
M.W : | 235.46 |
SMILES Code : | BrC1=C(C=CC(=C1)C(=O)O)Cl |
MDL No. : | MFCD00079706 |
Boiling Point : | No data available |
InChI Key : | NLEPZGNUPNMRGF-UHFFFAOYSA-N |
Pubchem ID : | 2735544 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 46.11 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.52 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.8 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.94 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.54 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.69 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.86 |
Solubility | 0.0329 mg/ml ; 0.00014 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.99 |
Solubility | 0.0243 mg/ml ; 0.000103 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.25 |
Solubility | 0.134 mg/ml ; 0.000568 mol/l |
Class? Solubility class: Log S scale |
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) |
No |
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 |
-5.24 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 |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.41 |
* 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 |
---|---|---|
With thionyl chloride;N,N-dimethyl-formamide; at 80℃; for 2h; | Example 4; (Method C) <n="51"/>Example 4aSynthesis of 3-Bromo-4-chlorobenzamideTo a mixture of S-bromo^-chlorobenzoic acid (5.07 g, 22 mmol, Alfa Aesar) and thionyl chloride (15 ml, 206 mmol) was added 1 drop of DMF and the reaction was heated at 80 0C. After 2 h the excess SOCl2 was removed in vacuo and the residue was azeotroped with toluene (2x). The residue was dissolved in 40 mL OfCH2Cl2 and cooled to 0 0C. Ammonia was bubbled into the reaction for 30 min. The mixture was diluted with 200 mL Of CH2Cl2 and washed with saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 (3x) and the combined organic layers were washed with H2O and dried over Na2SO4 to give 3.81 g (75percent) of a white amorphous solid. MS- m/z: 233.9, 235.9 [M+l]. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20 - 40℃; for 1h; | Step 1. To a solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> 71 (5.30 g, 23 mmol) in DCM (10 mL) at room temperature was added DMF (5 drops) and oxalyl dichloride (3.0 mL, 34 mmol). The reaction mixture was heated to 40° C. for 1 h. The solvent and excess oxalyl chloride were removed under a stream of nitrogen followed by high vacuum. The acid chloride was dissolved in DCM (100 mL), cooled to 0° C., and then pyridine (2.8 mL, 34 mmol) was added followed by (R)-1-phenylethanamine (3.8 mL, 30 mmol). The reaction mixture was stirred at 0° C. for 1 h and concentrated under reduced pressure. The crude amide was dissolved in EtOAc, washed with 1 M HCl (2*), brine (1*), dried over MgSO4, filtered, and concentrated to give (R)-3-bromo-4-chloro-N-(1-phenylethyl)benzamide 72 (8.15 g, 71percent yield) as a white solid which was used without further purification. Mass spectrum: calculated for C15H13BrClNO 337.0; found 338.0 (M++1). | |
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | Step 1. A solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> 104 (2.354 g, 10.0 mmol) in 30 mL of CH2Cl2 was chilled to 0° C. in an ice bath. To this solution was added a solution of thionyl chloride (2.2 mL, 30 mmol) in CH2Cl2 and then a few drops of DMF. The reaction was warmed to room temperature and stirred under N2 for 2 h. The reaction mixture was concentrated in vacuo. The crude acid chloride was re-dissolved in CH2Cl2 and it was chilled to 0° C. Triethylamine (2.8 mL, 20 mmol) was slowly added to the reaction via syringe. The reaction was warmed to room temperature and stirred for 2 h under N2. The reaction mixture was concentrated and then diluted with EtOAc. The solution was extracted with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by ISCO flash chromatography using a 5percent to 60percent gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give 3-bromo-4-chloro-N-methoxy-N-methylbenzamide 105 (2.43 g, 87percent yield) as a colorless oil. |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; | Example 77 3-Bromo-4-chlorobenzamide 3-Bromo-4-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 muL). Gas evolution began, and the mixture was stirred until gas evolution ceased. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for 30 min. The phases were separated and the organic washed 1* with brine dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.54 min (ret time); mp 146-147° C.; analytical HPLC shows 100percent purity, (ret time: 11.835 min). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere; | Example 94 3-Bromo-4-chlorobenzamide 3-Bromo-4-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 muL). Gas evolution began, and the mixture was stirred until gas evolution ceased. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for thirty min. The phases were separated and the organic washed 1* with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.54 min (ret time); mp 146-147° C.; analytical HPLC shows 100percent purity, (ret time 11.835 min). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere; | Example 77 3-Bromo-4-chlorobenzamide3-Bromo-4-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (SO mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 muL). Gas evolution began, and the mixture was stirred until gas evolution ceased. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for 30 min. The phases were separated and the organic washed IX with brine dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.54 min (ret time); mp 146-147 0C; analytical HPLC shows 100percent purity, (ret time: 11.835 min). | |
With thionyl chloride; sodium chloride; In ethyl acetate; for 5h;Reflux; Inert atmosphere; | To a stirred suspension of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (0.5 g) in EtOAc (10 mL) NaCl was added followed by the addition of 0.77 mL of thionyl chloride. This heterogeneous reaction mixture was then refluxed. After 5 hours, the reaction was cooled to room temperature and the volatiles were removed under reduced pressure. Excess solvent was removed and the residue was taken up in THF (10 mL) and cooled in an ice bath. Solid sodium cyanamide (0.272 g) was added to this stirred solution portionwise and the reaction was allowed to stir for twelve hours. Then THF was removed under reduced pressure and 15 mL of water was added to the residue. The solid was filtered off and the filtrate was acidified with IN aq. HC1. The precipitated white solid was isolated, filtered, and dried. Compound S3 was carried forward without additional purification. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 1h; | To <strong>[42860-10-6]3-bromo-4-chloro-benzoic acid</strong> (9.4 g, 40 mmol ) in dry DCM (100 mL), was added DMF (0.5 ml.) followed by addition of oxalyl chloride (22.5 ml_, 55 mmol, 2M in DCM ) slowly. The mixture was stirred for 1 hr, then concentrated to yield 3-bromo-4-chloro-benzoyl chloride as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; for 24h;Heating / reflux; | Example 9A. 3-Bromo-4-chlorobenzoic acid ethyl ester.To a solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (5.0 g, 21 mmol) in 150 mL absolute ethanol was added 15 mL of 4N HCl/dioxane. The mixture was heated to reflux for 24 hours then cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and H2O, and the separated organic phase was washed sequentially with saturated NaHCpsi3 solution, brine, dried (Na2SO-O, filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-ddelta) delta 8.22 (d, IH), 7.94 (dd, IH), 7.80 (d, IH), 4.33 (q, 2H), 1.33 (t, 3H); MS (DCI4) m/z 263 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | A. (3-Bromo-4-chloro-phenyl)-methanolTo a mixture of <strong>[42860-10-6]3-bromo-4-chloro-benzoic acid</strong> (10.0 g, 42.5 mmol) in THF (50 mL) under nitrogen at 0 °C is added 1 .0 M solution of borane.THF (55.3 mL, 55.3 mmol). After stirring at ambient temperature overnight the reaction is poured into a mixture of NaHCO3/H2O/ice and extracted with EtOAc. The organic layer is washed with saturated aqueous NaCI, dried over MgSO4, filtered and concentrated in vacuo to provide the desired product (9.4 g, 100percent) as a clear, colorless oil.1 H NMR (300 MHz, CDCI3) delta 7.61 (s, 1 H), 7.41 (d, J = 5.1 Hz, 1 H), 7.21 (d, J = 5.1 Hz, 1 H), 4.63 (s, 2H), 2.12 (br s, 1 H). |
92% | With dimethylsulfide borane complex; In tetrahydrofuran; at 20℃; | General procedure: <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (34.2 g, 145.25 mmol) was dissolved in THF (250 ml)and cooled to 0 °C, to this was added borane-methyl sulfide complex (153 ml,305.02 mmol) and the reaction was warmed to room temperature and stirred overthe weekend. The reaction was very carefully quenched with saturated Na2CO3 (100mL), extracted with EtOAc (3 x 100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a colourless liquid. The crude product was purifiedby distillation at 0.2 mBar, collecting fractions that distilled at 100 °C to afford (3-bromo-4-chlorophenyl)methanol (29.5 g, 92 percent) as a colourless liquid. |
90% | With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 80℃; for 1.5h;Reflux; | Example 6, Step 1To a solution of 3-bromo-4-benzoic acid 6-1 (4.0 g, 17.0 mmol) in anhydrous TI{F (18 mL) was slowly added BH3.DMS (1.6 g, 20.4 mmol) at 0°C then the reaction was refluxed at 80°C for 90 mm. The mixture was cooled and concentrated in vacuo, diluted with water and extracted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate solution then brine, dried over Na2SO4 and concentrated in vacuo. The residue waspurified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 0:100) to afford 3.4 g (90percent) of intermediate 6-2. |
Example 12 4-Aminomethyl-cyclohexanecarboxylic acid {1-[3-(3-amino-1H-indazol-6-yl)-4-chloro-phenyl]-2-phenyl-ethyl}-amide 12A. 3-Bromo-4-chloro-benzaldehyde: To a cooled (0° C.), clear, colorless solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (1.0 g, 4.25 mmol) in THF (43 mL) was added dropwise a 1.0 M borane-THF complex (12.7 mL, 12.7 mmol). After 15 min, the reaction was warmed to rt and then to reflux. After 2 h, the reaction was cooled to rt, then to 0° C., and then quenched with MeOH (10 mL). The reaction was warmed to rt and after 15 min., the reaction was concentrated. The residue was dissolved in EtOAc and washed with 1.0 N HCl, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give a clear, colorless liquid. The liquid was dissolved in CH2Cl2 (17 mL) and cooled to 0° C. Next Dess-Martin periodinane (2.16 g, 5.10 mmol) was added. The resulting cloudy pale orange suspension was stirred for 30 min. and then diluted with Et2O (50 mL). The reaction was filtered through a plug of silica gel and the filtrate was concentrated to give an off-white solid. Column chromatography on silica gel (gradient elution 0-25percent EtOAc in Hex) gave 0.815 g (87percent) of the aldehyde as a white solid. 1H NMR (400 MHz, CDCl3) delta: 9.94 (s, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.1, 2.0 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H). | ||
With borane; In tetrahydrofuran; at 65℃; for 12h; | A solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (3.53 g, 15 mmol) was dissolved in anhydrous THF (20 [ML)] and cooled to 0 C prior to addition of borane [(1M] soln in [THF,] 20 mL, 20 mmol). The solution was then heated at 65 C for 12 hours then cooled to 0 C and methanol was added dropwise to quench excess borane. The solvent was evaporated under reduced pressure, the residue was redissolved in ethyl acetate and washed with saturated NH4Cl then brine, dried over sodium sulphate. The solvent was removed in vacuo to afford 3.23 g of title compound. [ <P>C7H6BRC10] Mass (calculated): [221], [MH NOT] found. NMR (400 MHz, CDC13) : 4.6 (2H, s, CH20H); 7.15 [(1H,] dd, [J=] 1 and 8 Hz, aryl- H); 7.35 [(1H,] d, [J =] 8 Hz, aryl-H); 7.55 [(1H,] d, [J = 1 HZ,] aryl-H). | |
Step 1:199.0 g (0.845 mol) of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> were dissolved in 2.5 litres of THF, the mixture was cooled to -10° C. and 1.69 litres (1.69 mol) of a 1 M solution of borane in THF were added at this temperature. The reaction mixture was warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. After the addition of water, the mixture was extracted twice with ethyl acetate and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 206 g of (3-bromo-4-chlorophenyl)methanol which were used in the subsequent step without further purification. | ||
Example 28A2-Bromo-4-(bromomethyl)-1-chlorobenzene Step 1:199.0 g (0.845 mol) of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> were dissolved in 2.5 litres of THF, the mixture was cooled to -10° C. and 1.69 litres (1.69 mol) of a 1 M solution of borane in THF were added at this temperature. The reaction mixture was warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. After addition of water, the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave 206 g of (3-bromo-4-chlorophenyl)methanol as a crude product which was reacted without further purification. | ||
With borane-THF; In tetrahydrofuran; at -10 - 20℃; | Step 1: [0430] 199.0 g (0.845 mol) of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> were dissolved in 2.5 litres of THF, the solution was cooled to ?10° C. and 1.69 litres (1.69 mol) of a 1 M solution of borane in THF were added at this temperature. The reaction mixture was warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. After addition of water, the mixture was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 206 g of (3-bromo-4-chlorophenyl)methanol which were used without further purification for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With caesium carbonate; In hexane; ethyl acetate; acetonitrile; | a. Ethyl <strong>[42860-10-6]3-bromo-4-chlorobenzoate</strong>. To a solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (3.00 g, 12.74 mmol) and cesium carbonate (6.23 g, 19.11 mmol) in acetonitrile (70 mL) was added iodoethane (5.1 mL, 63.7 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Choromatography on silica gel (biotage, 5percent EtOAc in hexane) afforded 3.5 g of ethyl <strong>[42860-10-6]3-bromo-4-chlorobenzoate</strong> (97percent). 1H NMR (300 MHz; CDCl3) delta1.40 (t, 3H); 4.37 (q, 2H); 7.52 (d, J=8.1 Hz, 1H); 7.91 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H); 8.28 (d, J=1.8 Hz, 1H). |
97% | With caesium carbonate; In hexane; ethyl acetate; acetonitrile; | a. Ethyl <strong>[42860-10-6]3-bromo-4-chlorobenzoate</strong> To a solution of <strong>[42860-10-6]3-bromo-4-chlorobenzoic acid</strong> (3.00 g, 12.74 mmol) and cesium carbonate (6.23 g, 19.11 mmol) in acetonitrile (70 mL) was added iodoethane (5.1 mL, 63.7 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Choromatography on silica gel (biotage, 5percent EtOAc in hexane) afforded 3.5 g of ethyl <strong>[42860-10-6]3-bromo-4-chlorobenzoate</strong> (97percent). 1H NMR (300 MHz; CDCl3) 1.40 (t, 3H); 4.37 (q, 2H); 7.52 (d, J=8.1 Hz, 1H); 7.91 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H); 8.28 (d, J=1.8 Hz, 1H). |
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