Structure of 1221171-96-5
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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. : | 1221171-96-5 |
Formula : | C6H2ClF3INO |
M.W : | 323.44 |
SMILES Code : | FC(F)(F)OC1=CC(I)=CC(Cl)=N1 |
MDL No. : | MFCD22571776 |
InChI Key : | GBLAONUGHUCGKN-UHFFFAOYSA-N |
Pubchem ID : | 49871804 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 48.65 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.42 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.5 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.59 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.4 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.56 |
Solubility | 0.00886 mg/ml ; 0.0000274 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.15 |
Solubility | 0.0231 mg/ml ; 0.0000715 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.2 |
Solubility | 0.0206 mg/ml ; 0.0000638 mol/l |
Class? Solubility class: Log S scale |
Moderately 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 |
-5.45 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 |
2.0 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) |
2.29 |
* 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 |
---|---|---|
71% | 2-Chloro-6-trifluoromethoxy isonicotinic acid (43); At 0 0C, butyllithium (1.56 M in hexane, 4.0 mL, 6.2 mmol, 0.67 eq) was added dropwise to a solution of butylmagnesium chloride (2M in THF, 1.5 mL, 3.0 mmol, 0.33 eq) in THF (8 mL), followed after 10 min by a solution of 2-chloro-4-iodo-6- trifluoro?iepsilonthoxypyridinepsilon (42, 3.0 g, 9.3 mmol, 1 eq) in THF (5 mL). After 10 min the reaction mixture was poured onto an excess of freshly crushed dry ice before being treated with an aqueous solution of sodium hydroxide (5%, 15 mL). The resulting aqueous layer was collected, washed with diethylether (10 mL) and acidified to pH 4 by dropwise addition of hydrochloric acid (6 N, 5 mL). After extraction with ethyl acetate (3 x 10 mL), the combined organic layers were dried over sodium sulfate before being evaporated to afford pure 2-chloro-6-trifluoromethoxy isonicotinic acid (43, 1.6 g, 6.6 mmol, 71%) as a white powder; m.p. 65-68 0C.1H NMR (CDCl3, 300 MHz): delta = 10.12 (br s, 1 H), 7.88 (d, J = 0.9 Hz, 1 H), 7.56 (d, J = 0.9 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -57.3 - 13C NMR (CDCl3, 75 MHz): delta = 167.6, 156.3, 150.4, 143.0, 122.5, 120.2 (q, J = 260 Hz), 113.5. - C7H3ClF3NO3 (241): calcd. (%) C 34.81, H 1.25, N 5.80; found C 34.64, H 1.55, N 5.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 2-ChIoro-4-iodo-6-trifluoromethoxy pyridine (42); At 0 0C, diisopropylamine (1.4 g, 1.9 mL, 13.6 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 9.0 mL, 13.6 mmol, 1.1 eq) in THF (20 mL). At -78 0C, a solution of 2-chloro-5-iodo-6-trifluoromethoxypyridine (41, 4.0 g, 12.4 mmol, 1 eq) in THF (10 mL) was added dropwise and the reaction mixture was stirred for 1 h at this temperature. It was then neutralized with a solution of hydrochloric acid (2N, 10 mL), treated with a saturated aqueous solution sodium hydrogencarbonate (30 mL) and extracted with diethylether (3 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude dark oil was distilled under vacuum (b.p. 104-107 0C / 16 mbar) to afford pure 2-chloro-4-iodo-6- trifluoromethoxypyridine (42, 3.2 g, 10.9 mmol, 80%) as a colorless oil; 1H NMR(CDCl3, 300 MHz): delta = 7.66 (d, J= 1.0 Hz, 1 H), 7.34 (d, J= 1.0 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -57.1 - 13C NMR (CDCl3, 75 MHz): delta = 155.1, 149.4, 130.7, 120.3, 119.1 (q, J= 262 Hz), 108.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Amino-2-chloro-6-trifluoromethoxypyridine (45); At -78 0C, butyllithium (1.56 M in hexane, 2.2 mL, 3.4 mmol, 1.1 eq) was added dropwise to a solution of <strong>[1221171-96-5]2-chloro-4-iodo-6-trifluoromethoxypyridine</strong> (42, 1.0 g, 3.1 mmol) in THF (8 mL) followed after 10 min by benzenesulfonyl azide (0.6 g, 3.4 mmol, 1.1 eq). The reaction mixture was was allowed to reach 25 0C before being treated with a saturated aqueous solution of ammonium chloride (10 mL) and extracted with diethylehter (3 x 8 mL). The combined organic layers were dried over sodium sulfate and evaporated to afford a crude red oil of 4-azido-2-chloro-6- trifluoromethoxypyridine. It was then dissolved in anhydrous diethylether (25 mL) and added dropwise to a suspension of lithium aluminium hydride (130 mg, 3.4 mmol, 1.1 eq) in diehtylether (25 mL). The reaction mixture was heated under reflux for 5 h before being treated with water (10 mL) and extracted with diethylether (3 x 10 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate/cyclohexane (1:9) as eluent which afforded pure 4-amino-2-chloro-6- trifluoromethoxypyridine (45, 0.3 g, 1.4 mmol, 46%) as a yellow oil.1H NMR (CDCl3, 300 MHz): delta = 6.41 (d, J = 1.6 Hz, 1 H), 6.07 (d, J = 1.6 Hz, 1 H),4.30 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -56.8 - 13C NMR (CDCl3, 75 MHz): delta = 157.4, 156.7, 149.7, 119.9 (q, J = 260 Hz), 107.6, 96.0. - C6H4ClF3N2O (212): calcd. (%) C 33.90, H 1.90, N 13.18; found C 33.56, H 2.01, N 12.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(tri-t-butylphosphine)palladium(0); In tetrahydrofuran; at 65℃; for 3.0h;Inert atmosphere; | A 0.36 M solution of intermediate 6a in THF (42 mL, 15.12 mmol) was added to a stirred mixture of 4-bromo-2-methoxy-6-methylpyridine (CAS: 1083169-00-9; 2.98 g, 14.75 mmol) and Pd(/-Bu3P)2 (0.22 g, 0.31 mmol) at rt under N2. The mixture was stirred at reflux for 16 h. After cooling to rt a (1 : 1) mixture of a 32% solution of NFl·, (0369) (50 mL) and a saturated solution of NELCl (50 mL) was added. The mixture was extracted with EtOAc (200 mL). The organic layer was separated, dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in heptane, gradient from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate 7b as a colorless oil (4.34 g, 91%). |
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