Structure of 445303-69-5
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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. : | 445303-69-5 |
Formula : | C7H4BrF3 |
M.W : | 225.01 |
SMILES Code : | FC(F)C1=C(F)C=CC(Br)=C1 |
MDL No. : | MFCD06411633 |
InChI Key : | YHQZVEGLXIBPRA-UHFFFAOYSA-N |
Pubchem ID : | 2761161 |
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 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 39.17 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.11 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.46 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.37 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.79 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.61 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.67 |
Solubility | 0.048 mg/ml ; 0.000214 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.01 |
Solubility | 0.222 mg/ml ; 0.000985 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.14 |
Solubility | 0.0162 mg/ml ; 0.0000719 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 |
No |
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 |
-5.31 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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.61 |
* 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 |
---|---|---|
70% | With diethylamino-sulfur trifluoride; In dichloromethane;Heating / reflux; | 5-Bromo-2-fluorobenzaldehyde (2 g, 9.8 mmol) in CH2Cl2 (50 ml) was treated at 0C. with (diethylamino)sulfur trifluoride (2 ml, 14.8 mmol). The reaction mixture was refluxed overnight and then quenched with saturated solution of NaHCO3. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethyl acetate 99 : 01) to provide 4-bromo-2-difluoromethyl-1-fluoro-benzene (1.55 g, 70%) as a colorless oil, MS: m/e=226.0 (M+H+). |
61% | With diethylamino-sulfur trifluoride; In dichloromethane; at 20.0℃; for 18.0h;Inert atmosphere; | [143] To a solution of 5-bromo-2-fluoro-benzaldehyde (4.06 g, 20 mmol) in DCM (50 mL) was added DAST (diethylaminosulfur trifluoride) (4.03 g, 25 mmol) and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture was quenched into ice-water and extracted with DCM. The organic layer was dried and concentrated. Yield: 2.74 g (61 %) |
With diethylamino-sulfur trifluoride; In dichloromethane; at 20.0℃; for 1.0h; | Preparation 3:4-BROMO-2-(DIFLUOROMETHYL)-l-FLUOROBENZENE5-bromo-2-fluorobenzaldehyde (2.0 g, 9.85 mmol) and diethylaminosulfur trifluo?de (2.2 ml) was stirred at ambient temperature for 1 hour. Methylene chloride (100 ml) was added and the solution was cooled to 0 0C. Aqueous sodium bicarbonate (10%, 50 ml) was added slowly and the phases were separated. The organic phase was washed with water (50 ml), dried (MgSO4), filtered and evaporated to dryness to yield the crude product (1.79 g). MS m/z (rel. intensity, 70 eV) 226 (M+, 98), 224 (M+, bp), 207 (17), 145 (79), 125 (22). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With diethylaminosulfur trifluoride; In dichloromethane; | 4-Bromo-2-difluoromethyl-1-fluoro-benzene 5-Bromo-2-fluorobenzaldehyde (2 g, 9.85 mmol) was dissolved in CH2Cl2 (50 ml). The reaction mixture was put under an argon atmosphere and cooled to 0 C. Diethylaminosulfur trifluoride (2.04 ml, 14.78 mmol) was added dropwise. The mixture was allowed to warm up to room temperature and stirred overnight. It was then quenched with a saturated aqueous NaHCO3 solution. The layers were separated and the aqueous one was extracted with CH2Cl2. The combined organic phases were dried with Na2SO4 and the solvent evaporated. The brown oil was chromatographed (silica, elution hexane/AcOEt) to afford the title compound (1.55 g, 70%) as a colorless oil. MS: m/e=226.0 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | 2-(3-Difluoromethyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane The title compound was obtained according to example 342 as a colorless oil (54% yield) using <strong>[445303-69-5]4-bromo-2-difluoromethyl-1-fluoro-benzene</strong> and bis(pinacolato)diboron as the starting materials. MS: m/e=272 (M+). | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90.0℃; for 21.0h;Inert atmosphere; | A stirred mixture of 4-bromo-2-(difluoromethyl)-l-fluorobenzene (0.53 g, 2.3 mmol), bis(pinacolato)diboron (0.72 g, 2.8 mmol), l,l'-bis(diphenylphosphino)- ferrocene-palladium dichloride (0.2 g, 0.24 mmol), and potassium acetate (0.7 g, 7.09 mmol) in dry 1,4-dioxane (7.0 mL) was purged three times with argon and placed under vacuum three times. The mixture was heated to 90 C and monitored with LC-MS and TLC. After 21 h, the reactions were cooled to rt then filtered through celite. The organic solvent was removed under reduced pressure, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield a yellow liquid as 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane. .H NMR (500 MHz,CDCl3) delta ppm 8.22 (1 H, d, J=7.6 Hz), 8.12(1 H, m), 7.29 (1 H, ddd, J=9.8, 8.8, 0.7 Hz), 7.05 (1 H, t), 1.52 (12 H, s). Mass Spectrum (pos.) m/e: 273.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 16.0h;Heating / reflux; | Preparation 4:4-[3-(DIFLUOROMETHYL)-4-FLUOROPHENYL]PYRIDINETo a mixture of 4-bromo-2-(diotafluoromethyl)-l-fluorobenzene (0.5 g, 2.24 mmol), 1- pyriotadyl-4-boroniotac acid (0.33 g, 2.69 mmol) and sodium carbonate (0.64 g, 5.6 mmol) in toluene/ethanol (1 : 1, 20 ml) under nitrogen, was added palladium tetrakis (0.13 g , 5 mol%). The mixture was heated at reflux for 16 h, cooled to ambient temperature and <n="30"/>diluted with water (50 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (2x50 ml). The combined organic phases was evaporated to dryness and dissolved in aqueous hydrochloric acid (10%, 50 ml). The solution was washed with diethyl ether (2x40 ml), basified with aqueous sodium hydroxide (2M) and extracted with ethyl acetate (2x50 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give the crude product. Purification by flash column chromatography (ethyl acetate/isooctane 2: 1) gave the title compound (0.34 g). MS m/z (rel. intensity, 70 eV) 223 (M+, bp), 222 (12), 204 (7), 172 (12), 145 (8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In 1,2-dimethoxyethane; at 130.0℃; for 0.25h;Microwave irradiation; Sealed tube; | To a 10 mL microwave vial was added 4-(4-fluorophenyl)-l-(l-methyl-lH-imidazol-4- ylsulfonyl)pyrrolidin-3 -amine hydrochloride (100 mg, 0.277 mmol) and premixed tris(dibenzylidene- acetone)dipalladium(0)/sodium tert-butoxide/ 2,2'-bis(diphenylphosphino)-l ,1 '-binaphthyl (100 mg, 0.05:0.15:2), aldrich 715530). The solids were suspended in 1 ,2-dimethoxyethane, and 4-bromo-2- (difluoromethyl)-l -fluorobenzene (74.8 mg, 0.333 mmol) was added. The reaction vessel was capped and the reaction mixture was heated in a microwave (Biotage Initiator, maximum 400 Watts) for 15 min at 130C. The mixture was filtered through celite, concentrated, dissolved in 2 ml 50% methanol/dimethylsulfoxide, and purified by HPLC to provide the title compound. MS (ESI) m/z 469 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90.0℃;Inert atmosphere; | A solution of 4-bromo-2-(difluoromethyl)-l-fluorobenzene (1.2 g, 5.33 mmol), bis(pinacolato)diboron (1.490 g, 5.87 mmol) and potassium acetate (1.570 g, 16.00 mmol) in 1 ,4-dioxane (20 mL) was flushed with nitrogen. PdCl2(dppf)-CH2Cl2 adduct (0.218 g, 0.267 mmol) was added and the reaction mixture was heated at 90 C overnight. The reaction mixture was then filtered through diatomaceous earth (Celite) and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (0-25% EtOAc in hexanes) to afford (3-(difluoromethyl)-4- fluorophenyl)boronic acid (1.2 g, 4.17 mmol, 78% yield). NMR (400 MHz, CDCh): delta 8.04 (m, 1H), 7.90 (m, 1H), 7.1 1 (m, 1H), 6.87 (t, J = 15.2 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90.0℃; for 4.0h;Inert atmosphere; | A solution of (2-methoxypyridin-4-yl)boronic acid (75 mg, 0.490 mmol), 4- bromo-2-(difluoromethyl)-l-fluorobenzene (121 mg, 0.539 mmol), potassium phosphate tribasic (312 mg, 1.471 mmol) and PdCl2(dppf)-CH2Cl2 adduct (20.02 mg, 0.025 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was purged with nitrogen and heated to 90 C for 4 h. The reaction mixture was diluted with ethyl acetate (10 mL). The black suspension was filtered through diatomaceous earth (Celite) and the bed was washed with ethyl acetate (10 mL). The residue was purified via silica gel chromatography (15% pet ether: ethyl acetate) to afford 4-(3-(difluoromethyl)-4- fluorophenyl)-2-methoxypyridine (100 mg, 0.363 mmol, 74% yield) as a brown solid. LCMS (ESI) m/e 254.0 [(M+H)+, calcd for C13H11F3NO 254.1]; LC/MS retention time (Method C): tR = 1.02 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; dichloromethane; at 20.0℃; for 48.0h; | General procedure: To a solution of 4-bromo-2-methoxybenzaldehyde (1.0 g, 4.6 mmol) in anhydrous dichloromethane (4.7 mL) was added N-ethyl-N-(trifluoromethylsulfanyl)ethanamine (1.84 mL, 13.91 mmol) and anhydrous ethanol (500 muL) and the reaction mixture was stirred at room temperature for 48 h. The reaction was quenched with 2M aqueous sodium hydroxide (4.5 mL) at 0 C. The mixture was extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane to afford the title compound (529 mg, 2.24 mmol, 48%) as a colorless oil. (0584) LCMS Method F: 100%, tR=2.348 min, no ion 1H NMR (300 MHz, Chloroform-d) d 7.44 (d, J = 8.1 Hz, 1H), 7.31- 7.14 (m, 1H), 7.13- 7.09 (m, 1H), 6.80 (t, J = 55.5 Hz, 1H), 4.11- 3.64 (m, 3H). |