Structure of 954235-83-7
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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. : | 954235-83-7 |
Formula : | C7H4BrF3O |
M.W : | 241.01 |
SMILES Code : | FC1=CC=C(Br)C(OC(F)F)=C1 |
MDL No. : | MFCD11036070 |
Boiling Point : | No data available |
InChI Key : | BZXMUSAMMGLTMI-UHFFFAOYSA-N |
Pubchem ID : | 45158711 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H227-H302-H319-H412 |
Precautionary Statements: | P210-P273-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 40.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.21 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.63 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.45 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.3 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.35 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.39 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.86 |
Solubility | 0.0333 mg/ml ; 0.000138 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.51 |
Solubility | 0.0742 mg/ml ; 0.000308 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.88 |
Solubility | 0.0316 mg/ml ; 0.000131 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) |
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 |
-5.19 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<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.82 |
* 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 |
---|---|---|
58% | With caesium carbonate; In N,N-dimethyl-formamide; at 100.0℃; for 15.0h; | itermediteExthp1eI5. ?sulfOnamide ?,?a) .To a solutiOn of 2-brotho-5-fludrophenol (3g. 15.7 mmol) in DMF (5 ml) was added cesium carbonate (7.7 g, 23.56 mmol, 1.5 eq) and sodium chlorodifluoroacetate(6 g, 39.26 nimol;2:5 eq) and the reaction mixture was heated at 100C for 15 h. Thereaction mixture was then exttacted with Water and ethyl acetate (3 x 50 mI) Thecombined Organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica ge110% ethyl acetate in hexane) in 58 % yield (2.2 g). |
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100.0℃; for 15.0h; | Preparation Example 3 A mixture of 2-bromo-5-fluorophenol (3 g), sodium chlorodifluoroacetate (6 g), cesium carbonate (7.7 g), water (3 mL) and DMF (30 mL) was stirred under heating at an oil temperature of 100C for 15 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide solution, further washed with water, dried and concentrated under reduced pressure to obtain 1-bromo-2-(difluoromethoxy)-4-fluorobenzene (2.77 g). | |
With water; caesium carbonate; In N,N-dimethyl-formamide; at 100.0℃; for 2.0h; | Intermediate Example Int 17.11 -Bromo-2-(dif luoromethoxy)-4-f luorobenzeneTo a stirred solution of 2-bromo-5-fluorophenol (21 .0 g) in DMF (600 mL) was added cesium carbonate (107.5 g), sodium chlorodifluoroacetate (52.3 g) and water (29.4 mL). The mixture was stirred at 100 C for 2 h. The mixture was filtrated and the resulting solution was extracted with pentane (4 x 400 mL). The combined organic layers were washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 7.14 g of the title compound as a crude product. Silica gel chromatography afforded 3.2 g of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm] = 7.10 - 7.16 (m, 1 H), 7.34 (t, 1 H), 7.33 - 7.36 (m, 1 H), 7.79 (dd, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 60.0℃; for 1.0h; | Intermediate Example Int 17.41 -bromo-2-(dif luoromethoxy)-4-(ethy Isu Ifany l)benzene To a stirred solution of Int 17.1 (500 mg) in DMF (4.75 mL) was added sodium ethanethiolate (276 mg). The mixture was stirred for 1 h at 60 C. The mixture was cooled to r.t., water (150 mL) was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 302 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 60.0℃; for 1.0h; | Intermediate Example Int 17.21 -bromo-2-(dif luoromethoxy)-4-(methy Isu Ifany l)benzene To a stirred solution of Int 17.1 (1 .0 g) in DMF (9.5 mL) was added sodium methanethiolate (460 mg). The mixture was stirred for 1 h at 60 C. The mixture was cooled to r.t., water (150 mL) was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 850 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16 mg | A mixture of l -bromo-2-(difluoromethoxy)-4-fluorobenzene (intennediate 176a, 75 mg), (6-(2- (4-(ethylsulfonyl)phenyl)acetamido)-2-methylpyridin-3-yl)boronic acid (intermediate 178a, 310 mg), PdCl2(dppf)-CH2Cl2 adduct (20.33 mg) and Na2COj (39.6 mg) in acetonitrile (2.4 mL)/water (0.8 mL) was sealed in a vessel and heated in the microwave at 100C for 45 mins. The mixture was filtered through celite and silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by MDAP to afford N-(5-(2-(difIuoromethoxy)-4-fluorophenyl)-6-methylpyridin-2-yl)-2-(4- (ethyIsulfonyl)phenyi)acetarnide, trifluoroacetic acid salt (16 mg) as a white solid. ?-NMR (400 MHz, DMSO-i¾) delta ppm 1.10 (t, J= 7.2 Hz, 3H), 2.21 (s, 3H), 3.27 (q, J= 7.2 Hz, 2H), 3.89 (s, 2H), 7.22 (t, J= 72 Hz, 1H), 7.24 (m, 2H), 7.40 (m, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.63 (d, 7= 8.4 Hz, 2H), 7.85 (d, 8.4 Hz, 2H), 7.94 (d, J= 8.4 Hz, 1H), 10.92 (s, 1H); 19F-NMR (376 MHz, DMSO- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
133 mg | With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; at 100.0℃; for 0.75h;Microwave irradiation; Sealed tube; | A mixture of l-bromo-2-(difluoromethoxy)-4-fluorobenzene (intermediate 176a, 150 mg), (4-(2- (4-(ethylsulfonyI)phenyl)acetamido)-2,6-difluorophenyl)boronic acid (intermediate 122a, 404 mg), tri-ierf-butylphosphine, tetrafluoroboric acid salt (217 mg), Pd2(dba)j (171 mg) and sodium carbonate solution (2 M, 1.245 mL) in 1,4-dioxane (4.5 mL) was sealed in a vessel and heated in the microwave at 100C for 45 mins. The reaction mixture was filtered through celite and silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by MDAP to afford N-(2'- (difluoromethoxy) -2,4',6-trifiuoro-[ 1 , 1 '-biphenyl] -4-yl) -2-(4-(ethylsulfonyl)phenyl) acetamide ( 133 mg) as a yellow solid. ?-NMR (400 MHz, DMSO-<¾) 5 ppm 1.10 (t, J= 7.2 Hz, 3H), 3.28 (q, J= 7.2 Hz, 2H), 3.86 (s, 2H), 7.25 (t, J= 73.2 Hz, 1H), 7.27 (m, 2H), 7.43 (m, 2H), 7.50 (m, 1H), 7.62 (d, J = 8.4 Hz, 2H),7.86 (d, J= 8.4 Hz, 2H), 10.74 (s, 1H); WF-NMR (376 MHz, DMSO-tf6) delta ppm -82.88, -109.41 , -111.99; MSfES^ m/z 500 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; acetonitrile; at 100.0℃; for 0.75h;Microwave irradiation; Sealed tube; | A mixture of l-bromo-2-(difluoromethoxy)-4-fIuorobenzene (intermediate 176a, 70 mg), N-[3- chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-2-[4-(ethylsulfonyl)phenyl]acetamide (intermediate 6b, 148 mg), PdCl2(dppi)-CH2CI2 adduct (18.98 mg) and Cs2C03 (114 mg) in acetonitrile (1.5 mL)/water (0.5 mL) was sealed in a vessel and heated in (lie microwave at 100C for 45 mins. The reaction mixture was filtered through celite and silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by MDAP to afford N-(2-chloro-2'- (difluoromethoxy)-4'-fluoro-[l, -biphenyl]-4-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (22 mg) as a white solid. ?-NMR (400 MHz, DMSO-<¾ delta ppm 1.10 (t, /= 7.2 Hz, 3H), 3.28 (q, J= 7.2 Hz, 2H), 3.84 (s; 2H), 7.21 (t, J= 73.2 Hz, 1H), 7.21 (m, 2H)} 7.28 (d, J - 8.4 Hz, 1H), 7.37 (m, 1H), 7.53 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.62 (d, J= 8.0 Hz, 2H), 7.86 (d, J= 8.4 Hz, 2H), 7.91 (d, J= 2.0 Hz, 1H), 10.55 (s, 1H); 19F-NMR (376 MHz, DMSO-rf6) delta ppm -82.43, -110.64; MSiES4) m/? 498 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 110.0℃; for 4.0h;Inert atmosphere; | b) 2,6-Dichloro-4-(2-(difluoromethoxy)-4-fluorophenyl)pyridineA Slutin of the? cpomid of termediate Example 15() (2.2 g; 9 13 mmOl)in 1,2-dimethoxyethane (50 ml) was degassed by N2 bubbling for 5 mm. 2,6-Dichloro-4- (4,4,5,5.-tetramethyl- 1 ,3,2-diOxaboroian-2-yl)pyridine (2.75 g, 10;04 mnioI, 1.1 eq) wasadded and the mixture ?was degassed fOr anOther 5 mm. Pd(dppC1 (074 0.9 mmdl,0?1 eq)nd aqueous sodiumCarbonate (2.9 g, 27.3 nmo1, 2.5q) weEe added?sequentially using the procedure of Intermediate Example 1 and then heated at 110 C for 4 h. The reaction mixture was then quenched and extracted as in IntermediateExample 1. The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) to affordthe title product in 43 % yield (1.2 g). LC-MS (ESI): Calculated mass: 306.98; Observedmass: 307.85 [M+H] (rt: 2.0 mm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 90.0℃; | Compound 15 (80 g, 0.42 mol) was dissolved in DMF (800 mL), and sodium carbonate (266 g, 2.5 mol) wasadded. The temperature was increased to 90 C. Chlorodifluoroacetic acid (191 g, 1.46 mol) was added dropwise. Afterthe completion of addition, temperature was maintained at 90 C to react overnight. The reaction solution is cooled toroom temperature, poured slowly into ice water, and extracted twice with ethyl acetate. The organic phases were combined,washed once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 95 g of crudeproduct, which was used directly in the next reaction. 1H NMR (400 MHz, CDCl3): delta 7.62-7.58 (m, 1H), 7.04-7.01 (m,1H), 6.93-6.88 (m, 1H), 6.57 (t, J = 72.8 Hz, 1H); MS (ESI) (m/z): [M+H]+ 240.9. |
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