Structure of 881402-22-8
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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. : | 881402-22-8 |
Formula : | C7H5BF4O3 |
M.W : | 223.92 |
SMILES Code : | FC(F)(F)OC1=CC=C(F)C(B(O)O)=C1 |
MDL No. : | MFCD09027234 |
InChI Key : | NGTLLTDDJHXHQE-UHFFFAOYSA-N |
Pubchem ID : | 44717610 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 42.91 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.69 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.11 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.08 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.92 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.34 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.09 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.66 |
Solubility | 0.495 mg/ml ; 0.00221 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.78 |
Solubility | 0.368 mg/ml ; 0.00164 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.2 |
Solubility | 1.41 mg/ml ; 0.00628 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) |
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 |
-6.17 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 |
0.0 |
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) |
2.38 |
* 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 |
---|---|---|
With sodium hydroxide; water; In diethyl ether; | Boron trifluoride etherate (0.453 ml, 3.89 mmol) and trimethyl borate (0.867 ml, 7.77 mmol) were stirred in anhydrous tetrahydrofuran (THF, 10 ml) for 10 minutes to form dimethoxyfluoroborane in situ.To a solution of the 4-fluoro(trifluoromethoxy)benzene (2.0 g, 11.1 mmol) in dry THF (30 ml) at -780C, was added ethylenediaminetetraacetic acid (EDTA, 1.36 g, 11.7 mmol) followed by a 1.4 M solution of sec-butyllithium in cyclohexane (8.33 ml, 11.7 mmol) and the reaction stirred for 2 hours under nitrogen. To this reaction mixture at - 780C, was then added dropwise the preformed dimethoxyfluoroborane mixture. The reaction was stirred at -780C for 30 minutes, warmed to room temperature for 30 minutes, and then quenched with water (10 ml). The volume of the reaction mixture was reduced in vacuo, then the residue dissolved in diethyl ether (10 ml) and washed with an aqueous solution of 10percent NaOH (50 ml). The aqueous layer was acidified and extracted with ethyl acetate (3 x 40 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a single regioisomer (1.51 g).LCMS Rt = 1.38 minMS m/z 223 [M]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 160℃; for 0.166667h;Microwave irradiation; | l-[(6-Chloro-3-pyridinyl)methyl]-2-hydroxy-3-iodo-4-oxo-4H-pyrido[l,2- alphajpyrimidinium inner salt (i.e. the product of Step C) (206 mg, 0.5 mmol), 2-fluoro-5- (trifluoromethoxy)benzeneboronic acid (224 mg, 1 mmol) and bis(triphenylphosphino)- palladium dichloride (35 mg, 0.005 mmol) were dissolved in dioxane (2 mL). Aqueous sodium carbonate solution (2 N, 1 mL) was added, and the reaction mixture was heated in a microwave reactor for 10 min at 160 0C. The cooled reaction mixture was poured directly onto a silica gel column and eluted successively with hexanes, 30percent ethyl acetate in hexanes, 50percent ethyl acetate in hexanes, and finally ethyl acetate to yield the title compound (compound number 58), a compound of this invention, as a solid (20 mg). 1H NMR (CDCl3) 5 9.53 (d, IH), 8.49 (s, IH), 8.11 (dd, IH), 7.69 (d, IH), 7.50 (d, IH), 7.41 (m, 2H), 7.34 (d, IH), 7.16 (d, 2H), 7.58 (br s, 2H). | |
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 160℃; for 0.166667h;Microwave irradiation; | Step D: Preparation of l-[(6-chloro-3-pyridinyl)methyl]-3-[2-fluoro-5-(trifluoromethoxy)phenyl]-2-hydroxy-4-oxo-4H-pyrido[l,2-alpha]pyrimidinium inner saltl-[(6-Chloro-3-pyridinyl)methyl]-2-hydroxy-3-iodo-4-oxo-4H-pyrido[l,2- alpha]pyrimidinium inner salt (i.e. the product of Step C) (206 mg, 0.5 mmol), 2-fluoro-5- (trifluoromethoxy)benzeneboronic acid (224 mg, 1 mmol) and dichlorobis(triphenyl- phosphine)palladium(II) (35 mg, 0.005 mmol) were dissolved in dioxane (2 mL). Aqueous sodium carbonate solution (2 N, 1 mL) was added, and the reaction mixture was heated in a microwave reactor for 10 min at 160 0C. The cooled reaction mixture was poured directly onto a silica gel column and eluted successively with hexanes, 30percent ethyl acetate in hexanes, 50percent ethyl acetate in hexanes, and finally ethyl acetate to yield the title compound as a solid (20 mg).1H NMR (CDCl3) delta 9.53 (d, IH), 8.49 (s, IH), 8.11 (dd, IH), 7.69 (d, IH), 7.50 (d, IH), 7.41 (m, 2H), 7.34 (d, IH), 7.16 (d, 2H), 7.58 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
250 mg | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 3.0h;Inert atmosphere; | A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (800 mg, 4.26 mmol [4-fluoro-3-(trifluoromethoxy)phenyl]boronic acid (606 mg, 3.1 mmol) and sodium carbonate (1.3 g, 12.8 mmol) in a mixture of DME (5 mL) and water (2.5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh3)2.Cl2 (147 mg, 0.21 mmol) and again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100 C for 3h. The reaction was monitored by LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and extracted with EtOAc (2x50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography to obtain 4-chloro-2-[2-fluoro-5- (trifluoromethoxy)phenyl]-5-isopropenyl-pyridine (250 mg) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide; In ethanol; at 0 - 5℃; for 3.0h; | To a stirred soln. of(2-fluoro-5-(trifiuoro- methoxy)phenvi)boronic acid (1340 g, 60 mmoi) in anhyd. EtOH (20 mL) was added dropise 30percent H202 (10.2 inL, 90 minol) at 0-5 °C, and the reaction mixture was stirred for 3 h. The reaction was quenched with a satd, soin. of Na2S2O3, and concentrated in vueno. The resulting residue was dissolved in DCM (30 mL), and the soin. was washed with brine (10 mLx2). Theorganic layer was concentrated in vacu.o to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.78 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16.0h;Inert atmosphere; | A mixture of A-1 (150.00 mg, 673.98 mmol), <strong>[881402-22-8][2-fluoro-5-(trifluoromethoxy)phenyl]boronic acid</strong> (150.92 mg, 673.98 mmol) and Cs2C03 (439.19 mg, 1.35 mmol) in dioxane (3 mL) and H20 (300 __) was added Pd(dppf)Cl2.CH2Ci2 (82.56 mg, 101.10 mmol) was stirred at 90 C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated to give a residue that was purified by prep-TLC (silica gel, EtOAc:PE = 1:2) to afford Compound 18 (22.78 mg, 62.21 mmol) as a solid. 1H NMR (400MHz, CDC13) _ = 8.34 (d, 1H), 7.85 - 7.79 (m, 2H), 7.50 - 7.43 (m, 1H), 7.37 - 7.31 (t, 1H). LCMS R, = 1.19 min using Method A, MS ESI calcd. for C13H6F7N40 [M+H]+ 367.0, found 367.2. |
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