Structure of 103724-99-8
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CAS No. : | 103724-99-8 |
Formula : | C8H8BrCl |
M.W : | 219.51 |
SMILES Code : | CC1=CC(Cl)=CC(C)=C1Br |
MDL No. : | MFCD07780649 |
InChI Key : | CFMPIQSLDJXNPD-UHFFFAOYSA-N |
Pubchem ID : | 5324738 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.65 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.73 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.72 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.06 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.88 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.62 |
Solubility | 0.00521 mg/ml ; 0.0000237 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.46 |
Solubility | 0.00762 mg/ml ; 0.0000347 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.65 |
Solubility | 0.00495 mg/ml ; 0.0000225 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
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 |
-4.28 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
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 |
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) |
1.42 |
* 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 n-butyllithium; In tetrahydrofuran; N,N-dimethyl-formamide; | B. 4-Chloro-2,6-dimethyl benzaldehyde Dissolve <strong>[103724-99-8]4-bromo-3,5-dimethyl chlorobenzene</strong> (6.5 g) in 50 mL anhydrous THF and cool to -78 C. (dry ice/acetone) under N2. Dropwise over 5 minutes add a solution of butyllithium (12.50 mL, 2.5M in hexanes) to the stirring solution of aryl bromide at -78 C. After 2 hours, dropwise add anhydrous DMF (5.0 mL) to the orange/red reaction solution and allow to warn to ambient temperature overnight while stirring under N2. Evaporate the yellow solution down to a yellow oil and partition between H2O (100 mL) and CH2Cl2 (100 mL). Extract the aqueous layer once with CH2Cl2, then pool the organic layers and dry over Na2SO4, filter and evaporate down to 5.0 g of yellow oil. Use without further purification. LCMS=169.6 (MH+) | |
With n-butyllithium; In tetrahydrofuran; N,N-dimethyl-formamide; | B. 4-Chloro-2,6-dimethyl benzaldehyde Dissolve <strong>[103724-99-8]4-bromo-3,5-dimethyl chlorobenzene</strong> (6.5 g) in 50 mL anhydrous THF and cool to -78 C. (dry ice/acetone) under N2. Dropwise over 5 min add a solution of butyllithium (12.50 mL, 2.5M in hexanes) to the stirring solution of aryl bromide at -78 C. After 2 h, dropwise add anhydrous DMF (5.0 mL) to the orange/red reaction solution and allow to warn to ambient temperature overnight while stirring under N2. Evaporate the yellow solution down to a yellow oil and partition between H2O (100 mL) and CH2Cl2 (100 mL). Extract the aqueous layer once with CH2Cl2, then pool the organic layers and dry over Na2SO4, filter and evaporate down to 5.0 g of yellow oil. Use without further purification. LCMS=169.6 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | A. 4-Bromo-3,5-dimethyl chlorobenzene Slurry 2,6-dimethyl-4chloroaniline hydrochloride (23g, 193.11 g/mol) in CH2Cl2 (100 ml) and wash with saturated NaHCO3 to generate the free base. Dry over Na2SO4, filter and evaporate down to a violet oil. Slurry up in 120 mL 6.0 N H2SO4 and stir vigorously at ambient temperature to break up larger pieces of solid. | |
In dichloromethane; | A. 4-Bromo-3,5-dimethyl chlorobenzene Slurry 2,6-dimethyl-4-chloroaniline hydrochloride (23 g, 193.11 g/mol) in CH2Cl2 (100 ml) and wash with saturated NaHCO3 to generate the free base. Dry over Na2SO4, filter and evaporate down to a violet oil. Slurry up in 120 mL 6.0 N H2SO4 and stir vigorously at ambient temperature to break up larger pieces of solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | EXAMPLE 34-Chloro-2,6-dimethylbromobenzene; The procedure is as in Example 1, except that only 6.95 g [0.025 mol] of FeSO4×7H2O are used. This gives 20.7 g of an oil which, according to GC, contains 97.1% 4-chloro-2,6-dimethylbromobenzene (91% of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 18h;Inert atmosphere; Sealed tube; | In a microwave vial equipped with a magnetic stirring bar and nitrogen flow at room temperature was placed <strong>[103724-99-8]2-bromo-5-chloro-1,3-dimethylbenzene</strong> (250 mg, 1.14 mmol), pinacol diborane (347 mg, 1.37 mmol), KOAc (335 mg, 3.42 mmol), and the catalyst PdCl2(dppf) (83 mg, 0.11 mmol). Nitrogen gas was bubbled through a solution of dioxane (5.7 mL) and then the solution was added to the reaction mixture. The vial was capped and placed in an oil bath at 85 C for 18 h. The reaction mixture was and filtered on a pad of Celite and washed with dioxane.The solvent was evaporated under vacuum and the crude product was purified by flash chromatography on silica gel using a solution of EtOAc in hexanes (1 to 2 % gradient) and afforded the title compound (94 mg, 0.35 mmol, 31%) as white solid. |
31% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 20 - 85℃; for 18h;Inert atmosphere; Sealed tube; | In a microwave vial equipped with a magnetic stirring bar and nitrogen flow at room temperature was placed <strong>[103724-99-8]2-bromo-5-chloro-1,3-dimethylbenzene</strong> (250 mg, 1.14 mmol), pinacol diborane (347 mg, 1.37 mmol), KOAc (335 mg, 3.42 mmol), and the catalyst Pd012(dppf) (83 mg, 0.11 mmol). Nitrogen gas was bubbled through a solution of dioxane (5.7 mL) and then the solution was added to the reaction mixture. The vial was capped and placed in an oil bath at 85 00 for 18 h. The reaction mixture was and filtered on a pad of Celite and washed with dioxane.The solvent was evaporated under vacuum and the crude product was purified by flash chromatography on silica gel using a solution of EtOAc in hexanes (ito 2 % gradient) and afforded the title compound (94 mg, 0.35 mmol, 31%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 400 mL vessel equipped with a mechanical stirrer, thermometer, distillation head and dropping funnel, solid sodium hydroxide (10.9 g, 0.27 mol, microprills with 0.5 - 1 mm diameter) is charged under an inert atmosphere.1-Methyl-2-pyrrolidone (NMP, 137 g) is added to the vessel in one portion through the dropping funnel and the reaction mixture cooled to 10 - 15 C while stirring. A solution of malononitrile (NEC-CH2-CEN) (6.6 g, 0.10 mol) in NMP (8.9 g) is added through the dropping funnel over 10 - 15 minutes maintaining the temperature at 10 - 15 C. The reaction mixture is then heated to 100 C and a vacuum (30 mbar) applied, upon which solvent (40 g) is distilled off.2-Bromo-5-chloro-1 ,3-dimethyl-benzene (20 g, 0.089 mol) is then added through the dropping funnel over 5- 10 minutes, whilst maintaining the temperature at 100- 110 CC. A mixture containingpalladium (II) chloride (0.19 g, solution in conc. hydrochloric acid, assay 20% Pd, 0.36 mmol), triphenylphosphine (0.45 g, 1.6 mmol) and NMP (18 g) is then added through the dropping funnel over a 5 - 10 minute period. The temperature is allowed to rise to 124 C and the reaction mixture stirred at this temperature for 2 - 3 hours. Conversion is monitored by pulling samples and subsequent HPLC analysis.When conversion is complete, a vacuum (20-40 mbar) is applied and solvent (90 g) is distilled off. The resulting residue is cooled below 100 C and water (95 g) is added. After cooling to room temperature, the resulting mixture is filtered through hyflo (Hyflo SuperCel diatomaceous earth, ca. 10 g) and the filter cake washed with water (20 g). To the combined filtrates, hydrochloric acid (20.6 g, assay 32%, 0.18 mol) is added to adjust the pH from 13.3 to 2.7.The resulting mixture is extracted with tert-butyl-methyl ether (2 x 110 g). The organic phases are washed with water (2 x 50g) and the combined organic phases evaporated to dryness. The resulting solid residue is recrystallized from iso-propanol (63 g) and the resulting crystals filtered, washed with cold iso-propanol (5 g) and dried under vacuum to yield 2-(4-chloro-2,6-dimethyl-phenyl)propanedinitrile (melting point (m.p.) 145 - 147 C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-50 C. from 10 mmol of <strong>[103724-99-8]4-chloro-2,6-dimethylbromobenzene</strong> and 11.1 mmol of magnesium in 10 ml of tetrahydrofuran, were metered in 8.8 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (22 mmol, calculated for a concentration of 2.5 M) at 50 C. over the course of 30 minutes. After 3 hours at 50 C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was 87:13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of bromo(4-chloro-2,6-dimethylphenyl)magnesium, prepared at 30-35 C. from 50 mmol of <strong>[103724-99-8]4-chloro-2,6-dimethylbromobenzene</strong>, 1 mmol of bromo(4-chloro-2,6-dimethylphenyl)magnesium (to start the Grignard synthesis) and 55.5 mmol of magnesium in 50 ml of tetrahydrofuran, were added 5 mmol of copper(I) iodide. Then, 48 ml of a 2.5-3.3 molar solution of ethylene oxide in tetrahydrofuran (120 mmol, calculated for a concentration of 2.5 M) were metered in at 20 C. over the course of 30 minutes. After 16 hours at 20 C., the reaction mixture was placed on 100 g of ice and adjusted to pH 1 with sulphuric acid. After triple extraction with in each case 50 ml of methylene chloride, the combined organic phases were extracted once by shaking with 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator. There remained an oil, in which, according to GC/MS analysis, the ratio of 2-(4-chloro-2,6-dimethylphenyl)ethanol to 1-(4-chloro-2,6-dimethylphenyl)ethanol was >99:1. GC/MS: m/e=184 (M+ (35Cl), 25%), 153 (35Cl, 100%). 1H-NMR (600 MHz, d-DSMO): delta=2.28 (s, 6H), 2.75 (m, 2H), 3.45 (m, 2H), 4.74 (m, 1H), 7.0 (s, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Under an argon atmosphere, to a 200 ml three-neck flask, 96 ml of an anhydrous THF solution of 10.54 g (48.0 mmol) of <strong>[103724-99-8]2-bromo-5-chloro-1,3-dimethylbenzene</strong> was added and then, stirred at about -78 C. 30.0 ml (48.0 mmol) of a 1.6 M n-butyllithium hexane solution was added thereto dropwise, followed by stirring for about 1 hour. The solution thus obtained was added to a solution obtained by the first reaction dropwise, followed by heating and stirring at about 80 C. for about 2 hours for performing reaction. After cooling in the air, water was added, an organic layer was separately taken, and solvents were evaporated under a reduced pressure. The crude product thus obtained was separated by silica gel column chromatography to obtain 5.99 g (yield 27%) of Compound H as a white solid. The molecular weight of Compound H measured by FAB-MS was 459. |
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