Structure of 16075-42-6
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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. : | 16075-42-6 |
Formula : | C5H4F3N3 |
M.W : | 163.10 |
SMILES Code : | NC1=NC=CC(=N1)C(F)(F)F |
MDL No. : | MFCD00828624 |
InChI Key : | NKOTXYPTXKUCDL-UHFFFAOYSA-N |
Pubchem ID : | 595915 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 31.44 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.8 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.77 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.51 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.25 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.17 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.67 |
Solubility | 3.46 mg/ml ; 0.0212 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.44 |
Solubility | 5.95 mg/ml ; 0.0365 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.17 |
Solubility | 1.1 mg/ml ; 0.00676 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 |
-6.75 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) |
1.57 |
* 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 |
---|---|---|
85% | With N-Bromosuccinimide In acetonitrile at 20℃; for 4.5 h; Darkness | To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (800 mL) was added dropwise (over 2.5 hours) NBS (34.8 g, 0.195 mol) dissolved in 200 mL of CH3CN in the dark. The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated. The residue was dissolved in EtOAc and H2O and the binary mixture was transferred into a separating funnel. The aqueous layer was separated and extracted with EtOAc. The organic layers were washed with H2O and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane/EtOAc 9:1 to 3:2. The combined pure fractions were evaporated and the residue suspended in 40 mL hexane, stirred for 10 min., filtered and washed with 2*20 mL of hexane to give the title product as a beige solid (31.2 g, 85percent). tR: 0.82 min (LC-MS 1). |
85% | With N-Bromosuccinimide In acetonitrile for 7 h; Darkness | To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (600 mL) was added in the dark a solution of N-bromosuccinimide (34.8 g, 195 mmol) in acetonitrile (200 mL) over a period of 2.5 h. The reaction mixture was stirred for 4.5 h at RT and then concentrated. The residue was dissolved in EtOAc and H2O, the organic solvents were separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 10percent to 40percent to provide the title compound as a beige solid (31.2 g, 85percent). LC-MS: Rt 0.82 min; (LCMS method 2). |
82% | With N-Bromosuccinimide In chloroform for 20 h; | Method 9; Synthesis of 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine; [0249] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g,22.5 mmol) was added. After stirring for an additional 4 hours the solution was added toCH2Cl2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine:LCMS (m/z): 242/244 (MH+); 1H NMR (CDCl3): δ 8.52 (s, IH), 5.38 (bs, 2H). |
82% | Stage #1: With N-Bromosuccinimide In chloroform for 20 h; Stage #2: With sodium hydroxide In dichloromethane; chloroform; water |
[0250] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2CI2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and <n="97"/>the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS (m/z): 242/244 (MH+). 1H NMR (CDCl3): δ 8.52 (s, IH), 5.38 (bs, 2H). |
82% | Stage #1: With N-Bromosuccinimide In chloroform for 20 h; Darkness Stage #2: With sodium hydroxide In dichloromethane; chloroform |
[0092] Synthesis -bromo-4-(trifluoromethyl)pyrimidin-2-amine[0093] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2C12 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2S04, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS im/z): 242/244 (MH ). 3/4 NMR (CDC13): δ 8.52 (s, 1H), 5.38 (bs, 2H). |
75% | With N-Bromosuccinimide In chloroform at 20 - 50℃; for 20 h; | 4-(Trifluoromethyl)pyrimidin-2-ylamine (2 g, 12.3 mmol) was suspended in chloroform (70 ml) followed by the addition of N-bromosuccinimide (3.3 g, 18.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours and then at room temperature for 15 hours. A mixture of methylene chloride (50 ml) and 1 M sodium hydroxide (50 ml) was added, the resulting mixture was stirred, and then the organic layer was fractionated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.2 g, 75percent) as a pale orange solid.1H-NMR (CDCl3) δ: 5.37 (2H, brs), 8.52 (1H, s). |
73% | With N-Bromosuccinimide In dichloromethane at 25℃; for 48 h; Darkness | To a solution of compound 31(500mg, 3.06 mmol) in DCM (60 mL) was added NBS (1.66g, 9.32 mmol). The solution was stirred in the dark for 2d at rt. Then the reaction was quenched with iN NaOH (50 mL) and extracted with DCM (50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound 32 as a white solid (530 mg, 73percent yield), which was used directly in the next step without further purification. ‘H NIVIR (CDC13): 8.52(s, 1H), 5.29(bs, 2H). |
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