Structure of 144100-07-2
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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. : | 144100-07-2 |
Formula : | C5H3BrFN |
M.W : | 175.99 |
SMILES Code : | C1=CC=C(F)N=C1Br |
MDL No. : | MFCD03095258 |
InChI Key : | ZIDIKYIZXMYHAW-UHFFFAOYSA-N |
Pubchem ID : | 639438 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 31.9 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.75 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.4 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.68 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.54 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.03 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.59 |
Solubility | 0.447 mg/ml ; 0.00254 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.65 |
Solubility | 3.96 mg/ml ; 0.0225 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.15 |
Solubility | 0.124 mg/ml ; 0.000703 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 |
-6.12 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 |
2.0 |
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 |
1.0 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) |
1.9 |
* 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 |
---|---|---|
76% | With (dppf)2PdCl2.HCl; potassium acetate; In 1,4-dioxane; at 20 - 115℃; for 1h;Inert atmosphere; | 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Pd(dppf)2Cl2.HCl (102 mg, 0.14 mmol) was added to a degassed mixture of 2-bromo-6-fluoropyridine (410 mg, 2.33 mmol), bis(pinacolato)diboron (828 mg, 3.26 mmol) and KOAc (685 mg, 6.99 mmol) in dioxane (6 mL) at room temperature. The mixture was heated at 115 C. for 1 h. The solid material was then filtered off the solvent evaporated and the crude compound purified by chromatography (silica, MeOH in DCM 0:100 to 10:90). The desired fractions were collected to obtain the title compound (400 mg, 76%). 1H NMR (400 MHz, CDCl3) 7.78 (td, J=8.1, 7.2 Hz, 1H), 7.70 (ddd, J=6.9, 2.8, 0.9 Hz, 1H), 6.98 (ddd, J=8.1, 2.7, 0.9 Hz, 1H), 1.38 (s, 12H), |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 3h; | 2-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 2-bromo-6-fluoropyridine (200 mg, 1.136 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (317 mg, 1.250 mmol), potassium acetate (335 mg, 3.41 mmol), PdCl2(dppf) (83 mg, 0.114 mmol) were collected in a vial, deareated, and then suspended in DMSO (10 ml) under nitrogen atmosphere. The resulting mixture was stirred at 80 C. for 3 hours, diluted with DCM (500 ml) and washed with water (5*100 ml). The resulting organic phase was concentrated under vacuum to give 250 mg of a crude residue which was used in the next step without any further purification. UPLC-MS: 0.38 min, 142 [M-C6H10+H]+ | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 18h; | A mixture of 2-bromo-6-fluoropyridine (1.056 g, 6 mmol), 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.60 g, 6.30 mmol), PdCI2(dppf) CH2CI2 adduct (0.294 g, 0.360 mmol) and potassium acetate (1.767 g, 18.00 mmol) in dioxane (12 mL) was stirred at 100 C for 18 hrs. The reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), filtered and concentrated under reduced pressure. The crude material of 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine was directly used in the next step without further purification. LCMS (m/z): 142.0 [MS fragment]; Rt = 0.35 min. [Note: LCMS shows only boronic acid fragment.] |
With Nonafluorobutanesulfonyl fluoride;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 18h; | A mixture of 2-bromo-6-fluoropyridine (1 .056 g, 6 mmol), 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1 .60 g, 6.30 mmol), PdCI2(dppf) CH2CI2 adduct(0.294 g, 0.360 mmol) and potassium acetate (1 .767 g, 18.00 mmol) in dioxane (12 mL) was stirred at 100 C for 18 hrs. The reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), filtered and concentrated under reduced pressure. The crude material of 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine was directly used in the next step without further purification. LCMS (m/z): 142.0 [MS fragment]; Rt = 0.35 min. [Note: LCMS shows only boronic acid fragment.] | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 10h;Inert atmosphere; | To a solution of 2-bromo-6-fluoropyridine (5.0 g, 28.4 mmol) in 1,4-dioxane (150 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (8.6 g, 34.1 mmol), and potassium acetate (5.6 g, 56.8 mmol) followed by [l,l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.2 g, 1.4 mmol) and the mixture was degassed with nitrogen. The mixture was heated at 1 10C for 10 hours, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated and purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to afford the title compound. LCMS: 224 (M+H)+. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere; | To a solution of 2-bromo-6-fluoropyridine (5.32 g,30.23 mmol), potassium acetate (9.02 g, 90.70 mmol) andbis(pinacolato)diboron(8.11 g, 31.75 mmol) in 1,4-dioxane was added[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (7.89 g, 1.81 mmol), followed by stirring at 80Covernight under a nitrogen atmosphere. After cooling, the reaction mixture wasdiluted with ethyl acetate (40 mL), then filtered through pad of Celite. Thefiltrate was concentrated under reduced pressure to afford 25.65 g of 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,which was used directly without further purification. To a solution of thiscrude compound (7.08 g), compound 7 (4.00g, 8.34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (0.72 g, 0.88 mmol) in 1,2-dimethoxyethane(80 mL) was added sodium bicarbonate (2.0 M in water, 22.5 mL, 45.0 mmol),followed by stirring at 95C for 1 hour under a nitrogen atmosphere. Aftercooling, the mixture was diluted with chloroform, and washed with saturatedaqueous brine solution. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (75:25 to 50:50 hexane/ethyl acetate) togive 4.34 g (quant) of compound 8a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 100℃; for 16h; | A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.8 mmol), tert-butyl 1,4-diazepane-1-carboxylate (568 mg, 2.8 mmol) in DIPEA (1.83 g, 14.2 mmol) in ethanol (10 mL) was heated at 100 C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL). The solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (500 mg, 50%). MS (ESI) m/z: 356 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 1h;Inert atmosphere; | Potassium carbonate (213.62 mg, 1.55 mmol), CuI (213.30 mg, 1.12 mmol, 1.00 eq) and N,N-dimethylethylenediamine (110.58 mg, 1.25 mmol, 134.85 muL) were added into compound I1 (250.00 mg, 1.12 mmol) and 2-bromo-6-fluoropyridine (203.02 mg, 1.15 mmol) in dioxane (8.00 mL) solution. The reaction mixture was stirred under nitrogen atmosphere at 95C for 1 hour. The reaction mixture was cooled down and then ammonia (30 mL) was added, extracted by EtOAc (50 mL×3), the organic phases were combined, the organic phase was washed by saturated brine (50 mL) once, dried over anhydrous sodium sulfate, then filtered, the filtrate was evaporated to give the compound 27-A. MS m/z : 318.0 [M+H]+ |
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