Structure of 81971-39-3
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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. : | 81971-39-3 |
Formula : | C6H6BrNO |
M.W : | 188.02 |
SMILES Code : | CN1C=C(Br)C=CC1=O |
MDL No. : | MFCD09972188 |
InChI Key : | HHVFVHIUOMMWRN-UHFFFAOYSA-N |
Pubchem ID : | 13024027 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 39.66 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.91 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.8 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.15 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.37 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.0 |
Solubility | 1.87 mg/ml ; 0.00993 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.84 |
Solubility | 27.0 mg/ml ; 0.143 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.35 |
Solubility | 0.844 mg/ml ; 0.00449 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 |
-6.88 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) |
1.52 |
* 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 |
---|---|---|
23.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 2h;Microwave irradiation; | A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100° C. for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL*3). The combined organics were dried over Na2SO4, filtered and concentrated to give the crude title compound (59.0 mg, 23.6percent). LCMS (M+H)+ 236. |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 0.5h; | To a solution of 5-bromo-1-methylpyridin-2(1H)-one (800 mg) in DMSO (21 ml) was added bis(pinacolato)diboron (1620 mg), potassium acetate (1253 mg) and 1,1'-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (213 mg). The reaction mixture was stirred at 80°C for 30 min. The reaction was diluted with water (20 ml) and extracted with EtOAc (3 x 30 ml). The organic layer was dried with Na2SO4 and solvents were reduced under reduced pressure. The crude product was purified by flash chromatography. | |
With sodium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 120 - 130℃; for 8.5h; | 5-Bromo-l-methylpyridin-2 (IH) -one (0.100 g, 0.532 mmol) was suspended in dioxane (2 mL) then added 4,4,5,5- tetramethyl-2- (4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - 1, 3, 2-dioxaborolane (0.203 g, 0.798 mmol), PdC12 (dppf) - CH2C12Adduct (0.0217 g, 0.0266 mmol) and sodium acetate (0.109 g, 1.33 mmol) . The reaction mixture was heated at 120 0C for 5.5 hours then at 130 0C for 3 hours. The reaction mixture was <n="119"/>filtered through a pad of Celite, washing with MeOH. The filtrate was concentrated under vacuum. The remaining black residue was then dissolved in dichloromethane and filtered through another pad of Celite, washing well with dichloromethane. The filtrate was concentrated under vacuum and the remaining black residue was further dried under high vacuum to afford l-methyl-5- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyridin-2 (IH) -one as a black solid. MS (ESI pos. ion) m/z: 236.1 (MH+). |
With potassium acetate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In dichloromethane; N,N-dimethyl-formamide; at 80℃; for 10h; | Example 9N-(3-fluoro-4-(l-methyl-6-oxo-l,6-dihvdropyridin-3-yl)benzyl)-4-(pyrazin-2-yl)benzamideCompound 21[0174] Step 1: A mixture of 5-bromo-l-methylpyridin-2(lH)-one 21-1 (350 mg, 1.87 mmol), (4,4',4',5,5,5',5'-heptamethyl-[2,2'-bi(l,3,2-dioxaborolan)]-4-yl)methylium 21-2 (617 mg, 2.43 mmol), potassium acetate (550 mg, 5.61 mmol) and Pd(dppf)2Cl2 dichloromethane complex (82 mg, 0.1 mmol) in DMF (10 mL) was stirred at 80 °C for 10 hours. After cooling to room temperature, the mixture was filtered through celite, concentrated by evaporation under reduced pressure and then redistributed between ethyl acetate and water. The organic phase was dried over Na2S04 and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography with 1: 1 ethyl acetate/hexanes as eluent to give l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one 21-3. | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃;Inert atmosphere; Reflux; | Preparation of Compound 2222a 22b To a dry flask was added 5-bromo-l-methylpyridin-2(lH)-one 22a (1.0 g, 5.32 mmol), potassium acetate (1.57 g, 15.96 mmol, 3.0 equiv), bis(pinacolato)diboron (1.49 g, 5.85 mmol, LI equiv) and 1,4-dioxane (25 mL). Nitrogen was bubbled through the solution for 10 minutes, at which time dichloro[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (217 mg 0.27 mmol, 0.05 equiv) was added. The reaction mixture was refluxed at 115 °C overnight under nitrogen. After cooling to room temperature, EtOAc (30 mL) was added and the resulting slurry was sonicated and filtered. Additional EtOAc (20 mL) was used to wash the solids. The combined organic extracts was concentrated and purified by flash chromatography (90percent EtOAc/ hexanes) to yield 22b (520 mg).Compound 22 was prepared analogous to the preparation of 2 but using compound 22b. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 110℃; for 0.5h; | General procedure: A mixture of 3-bromo-1-methylpyridin-2(1H)-one (Step 1 of Example 25, 770 mg, 4.1 mmol),bis(pinacolato)diboron (1248 mg, 4.91 mmol), PdCI2(dppf)CH2CI2 complex (401 mg, 0.491mmol) and potassium acetate (1206 mg, 12.29 mmol) in dioxane (16 mL) was stirred for 2 h at 110 00. The reaction mixture was diluted with toluene, sonicated for 30 mm at 40°C and filtered (the filter cake was rinsed with hot toluene). The filtrate was concentrated to afford the title compound (1.7 g, purity 40percent) as a brown oil. The title compound was prepared using an analogous procedure to that described in Step 2 of Example 25 using 5-bromo-1-methylpyridin-2(1H)-one (ABCR, 1.05 g, 5.58 mmol) and stirringthe reaction mixture for 30 mm at 110°C. The title compound (2.75 g, purity 30percent) was used without purification. Rt: 0.83 mm (LC-MS 1); MS m/z: 236.2 [M+H] (boronic acid) (LC-MS 1). | |
160 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In ethylene glycol; at 80℃; for 3h; | To a stirred suspension of 5-bromo-l-methylpyridin-2(lH)-one (470 mg, 2.49 mmol), potassium acetate (736 mg, 7.49 mmol) and bis(pinacolato)diboron (952 mg, 3.74 mmol) in degassed polyethylene glycol-400 (15 mL) was added [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (204 mg, 0.24 mmol) at RT. The resultant suspension was stirred for 3 h at 80 °C. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (100 mL). The organic layer was concentrated and the residue obtained purified by flash column chromatography to afford 160 mg of the titled product; 1H NMR (300 MHz, CDC13) delta 1.30 (s, 12H), 3.54 (s, 3H), 6.53 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H); APCI- MS (m/z) 236 (M+H)+. |
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