Structure of 1010422-51-1
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CAS No. : | 1010422-51-1 |
Formula : | C7H5BrF3N |
M.W : | 240.02 |
SMILES Code : | CC1=CC(=NC=C1Br)C(F)(F)F |
MDL No. : | MFCD18257679 |
InChI Key : | MIJYRALTRQVVAF-UHFFFAOYSA-N |
Pubchem ID : | 68471500 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.29 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 41.9 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.14 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.83 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.32 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.64 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.48 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.08 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.42 |
Solubility | 0.0923 mg/ml ; 0.000385 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.76 |
Solubility | 0.418 mg/ml ; 0.00174 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.16 |
Solubility | 0.0167 mg/ml ; 0.0000697 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 |
-5.75 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 |
0.0 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) |
1.69 |
* 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 |
---|---|---|
14% | In a dried 250 mL 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (16 mL, Aldrich, inhibitor free) followed by N, N-diisopropylamine (0.895 g, 8.85 mmol, Aldrich, redistilled 99.95% pure). After cooling the stirred solution to -70 0C, n-butyl lithium (3.54 mL of a 2.5M solution in hexanes, 8.85 mmol) was added dropwise, keeping the reaction temperature less than -60 0C. The resulting solution was stirred at -70 0C for a further 10 min, then warmed to -20 0C, before immediately cooling to -90 0C. A solution of 5-bromo-2-(trifluoromethyl)pyridine (2 g, 8.85 mmol) in anhydrous THF (8 mL, Aldrich, inhibitor free) was added dropwise, keeping the reaction temperature less than -85 0C. The resulting orange solution was stirred at -90 0C for 40 min.In a separate dried 250 mL 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (5 mL, <n="47"/>Aldrich, inhibitor free) followed by methyl iodide (5 mL, 80 mmol). The solution was cooled to -90 0C. To this was added (via cannula) the solution of the pre-formed lithiated pyridine, controlling the rate so as to keep the reaction temperature of the receiving flask less than -80 0C. The resulting dark solution was stirred at -90 0C for a further 15 min (LCMS indicated reaction complete). The reaction was quenched with sat aq. NH4CI solution (50 mL), then allowed to slowly warm to room temperature. Organics were extracted with EtOAc (2 x 50 mL), then the combined organic layers washed with water (50 mL), then brine (50 mL), separated, dried over MgSO4, and then filtered. Concentration in vacuo gave 1.68 g of a brown oil which was purified via short-path vacuum distillation (45-46 0C, ca. 5 mmHg) to give 5-bromo-4-methyl-2- (trifluoromethyl)pyridine 1-2 (0.289 g, 14%) as a yellow oil (>97% pure). MS (M + H)+: 241.8, tR = 2.458 min (method 1 ); 1H NMR (CDCI3) delta 8.74 (1 H, s), 7.56 (1 H, s), 2.50 (3H, s). | |
14% | In a dried 250 mL 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (16 mL, Aldrich, inhibitor free) followed by N, N-diisopropylamine (0.895 g, 8.85 mmol, Aldrich, redistilled 99.95% pure). After cooling the stirred solution to -70 0C, n-butyl lithium (3.54 mL of a 2.5M solution in hexanes, 8.85 mmol) was added dropwise, keeping the reaction temperature less than -60 0C. The resulting solution was stirred at -70 0C for a further 10 min, then warmed to -20 0C, before immediately cooling to -90 0C. A solution of 5-bromo-2-(trifluoromethyl)pyridine (2 g, 8.85 mmol) in anhydrous THF (8 <n="39"/>ml_, Aldrich, inhibitor free) was added dropwise, keeping the reaction temperature less than -85 0C. The resulting orange solution was stirred at -90 0C for 40 min.In a separate dried 250 ml_ 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (5 ml_, Aldrich, inhibitor free) followed by methyl iodide (5 ml_, 80 mmol). The solution was cooled to -90 0C. To this was added (via cannula) the solution of the pre-formed lithiated pyridine, controlling the rate so as to keep the reaction temperature of the receiving flask less than -80 0C. The resulting dark solution was stirred at -90 0C for a further 15 min (LCMS indicated reaction complete). The reaction was quenched with sat aq. NH4CI solution (50 mL), then allowed to slowly warm to rt. Organics were extracted with EtOAc (2 x 50 mL), then the combined organic layers washed with water (50 mL), then brine (50 mL), separated, dried over MgSO4, and then filtered. Concentration in vacuo gave 1.68 g of a brown oil which was purified via short-path vacuum distillation (45-46 0C, ca. 5 mmHg) to give 5-bromo-4-methyl-2- (trifluoromethyl)pyridine 1-2 (0.289 g, 14%) as a yellow oil (>97% pure). MS (M + H)+: 241.8, tR = 2.458 min (method 1); 1H NMR (CDCI3) delta 8.74 (1H, s), 7.56 (1H, s), 2.50 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With potassium fluoride; copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 60℃;Inert atmosphere; | To a suspension of 5-bromo-2-iodo-4-methylpyridine(1g, 3.36 mmol) in NMP (6mL) with an inert atmosphere of argon, KF (0.585 g, 10.07 mmol), Cul (1.92 g, 10.08 mmol) and CF3SiMe3 (2.49 mL, 15.07 mmol) were added. The resulting solution was stirred overnight at 60C. After cooling, the mixture was poured into 12% aqueous ammonia, and then extracted with Et2O. The organic solutions were combined, dried over MgSO4, filtered and concentrated. Purification of the crude residue by normal phase chromatography (0% to 100%, hexane - diethyl ether) afforded the desired product (23% yield) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 110℃;Schlenk technique; Inert atmosphere; | General procedure: An oven dried resealable Schlenk tube was charged with 5-bromo-2-chloro-1H-pyrrolo[2,3-b]pyridine (Preparation 1c, 0.5 g, 2.07 mmol), (6-methoxy-4-methylpyridin-3-yl)boronic acid (Preparation 2, 0.35 g, 2.08 mmol), cesium carbonate (2.027 g, 6.22 mmol), 5.5 ml dioxane and 5.5 ml water. The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.085 g, 0.10 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 100 C. After 6h, the mixture was cooled and the solvent was removed in vacuo. Water was added and product was extracted with dichloromethane and organic layer was dried (Na2SO4). The residue was purified by flash chromatography (10%, dichloromethane-methanol) to give the title compound (0.353 g, 62% yield) as a solid. <strong>[1010422-51-1]5-bromo-4-methyl-2-(trifluoromethyl)pyridine</strong> (Preparation 63a, 0.27mg, 1.13 mmol) was treated with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.57 mg, 2.27 mmol),1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (56 mg, 0.07 mmol), potassium acetate (0.33 mg, 3.4 mmol) and dioxane (3 mL) as a solvent. The reaction was heated at 110C overnight according to the method described in Preparation 3a under standard conditions. The crude was purified by flash chromatography (10%, dichloromethane-methanol) to give the title compound (0.325 g, 93% yield) as a brown solid. LRMS (m/z): 288 (M+1)+ |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; | A mixture of <strong>[1010422-51-1]5-bromo-4-methyl-2-(trifluoromethyl)pyridine</strong> (150 mg, 625 mumol), bis(pinacolato)diboron (189 mg, 729 mumol), Pd(dppf)Cl2 (89 mg, 106 mumol) and potassium acetate (120 mg, 1.25 mmol) in dioxane (1 mL) was stirred under N2 at 90 C. overnight. Aqueous NH4Cl was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired compound which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere; | [0338] Cs2CO3 (2g, 6.45 immol) was added to an argon purged solution of CIS- 1 -(cyclobutylmethyl)-8- (dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (1.1 g, 3.225 mmol, 1 equiv.), Xantphos (279 mg, 0.483 mmol, 0.15 equiv.), Pd2(dba)3 (295 mg, 0.322 mmol, 0.1 equiv.) and <strong>[1010422-51-1]5-bromo-4-methyl-2-(trifluoromethyl)pyridine</strong> (774 mg, 3.225 mmol, 1 equiv.) in 1 ,4-dioxane (55 mL). The mixture was purged again with argon for 15 mm. The reaction mixture was stirred at 90C for 18 h, then cooled down to RT, filtered through Celite and washed with EtOAc (80 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (neutral alumina, 0-3% methanol in DCM) to afford 0.6 g (37%) of CIS- 1 -(cyclobutylmethyl)-8-(dimethylamino)-3 -(4-methyl-6-(trifluoromethyl)pyridin-3 -yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one (SC 3103) as an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.5). ?H NMR (DMSO-d6): 5 8.56 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m, 5H), 3.71 (s, 2H), 3.17 (d, 2H), 2.70-2.56 (m, 3H), 2.31 (s, 3H), 2.17-2.11 (m, 2H), 2.03-2.00 (m, 8H), 1.82-1.73 (m, 4H), 1.54-1.41 (m, 4H). Mass: mlz 501.3 (M+H). |
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