Structure of 1221171-88-5
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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. : | 1221171-88-5 |
Formula : | C6H5F3N2O |
M.W : | 178.11 |
SMILES Code : | NC1=NC=C(OC(F)(F)F)C=C1 |
MDL No. : | MFCD19690149 |
InChI Key : | HCYQWUCBICRJGO-UHFFFAOYSA-N |
Pubchem ID : | 49871146 |
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 | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 35.32 |
TPSA ? Topological Polar Surface Area: Calculated from |
48.14 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.39 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.69 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.83 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.45 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.22 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.52 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.25 |
Solubility | 1.01 mg/ml ; 0.00566 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.32 |
Solubility | 0.861 mg/ml ; 0.00483 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.29 |
Solubility | 0.911 mg/ml ; 0.00512 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 |
-6.19 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) |
1.9 |
* 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 |
---|---|---|
2-Amino-5-trifluoromethoxy pyridine (34); 2-Chloro-5-trifluoromethoxypyridine (6, 1.0 g, 5.0 mmol), benzophenone imine (1.09 g, 6.0 mmol, 1.2 eq), NaOtBu (0.72 g, 7.5 mmol, 1.5 eq), DPEphos (0.03 g, 0.05mmol, 0.01 eq), Pd2dba3 (0.07 g, 0.1 mmol, 0.02 eq) were introduced in dry toluene (15 mL) and the reaction mixture was heated at 80 0C and vigorously stirred for 2 h. GC monitoring indicated 100% conversion. The mixture was allowed to cool to ambient temperature before being filtrated on celite and washed with ethyl acetate. The filtrate was poured onto a 10% aqueous solution of citric acid (30 mL) and the reaction mixture was then vigorously stirred for 16 h at room temperature. GC of the organic phase indicated disappearance of starting reagent and formation of diphenylketone. The aqueous phase was adjusted to pH 9-10 with 5% sodium hydroxide (40 mL) and extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated to afford a crude yellow powder. Crystallization in hexane provided pure 2-amino-5-trifluoromethoxy pyridine (34, 0.36 g, 2.0 mmol, 40%) as colorless needles; m.p. 71 -73 0C.1H NMR (CDCl3, 300 MHz): delta = 7.91 (d, J = 2.7 Hz, 1 H), 7.23 (dd, J = 2.7, 8.9 Hz, 1 H), 6.39 (d, J= 8.9 Hz, 1 H), 4.49 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.9 - 13C NMR (CDCl3, 75 MHz): delta = 157.1, 141.4, 138.7, 131.6, 120.6 (q, J = 256 Hz), 108.7. - C6H5F3N2O (178): calcd. (%) C 40.46, H 2.83, N 15.73; found C 40.46, H 2.90, N 16.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In water; trifluoroacetic acid; at 100℃; for 0.5h;Microwave irradiation; | A mixture of N-(4-methoxybenzyl)-5-(trifluoromethoxy)pyridin-2-amine (Intermediate 16; 1.2 g, 4 mmol), TEA (12 mL) and H20 (1.2 mL) was stirred at 100 oC (microwave) for 0.5 hrs. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and H20 (25 mL). The organic layer was separated (phase separating cartridge) and the solvent was removed under reduced pressure. The crude product was purified by SPE (Isolute SCX-2 10 g column, 0 to 100% 7 M NH3 in MeOHDCM) to give the title compound as an off-white solid (0.46 g, 70%).1H NMR (ppm)(400 MHz, CDCI3): 4.52 - 4.51 (2H, m), 6.49 (1 H, d, J=9.6 Hz), 7.33 - 7.30 (1 H, m), 8.01 (IH, d, J=2.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Benzophenone imine; tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; sodium t-butanolate; In toluene; at 80℃; for 2h;Inert atmosphere; | 2-Chloro-5-(trifluoromethoxy)pyridine (int-80) (1.0 g, 5.06 mmol), sodium tertbutoxide (0.97 g, 10.12 mmol) and benzophenone imine (int-81) (1.10 g, 6.07 mmol) were dissolved in toluene (15 mL). Then Pd2(dba)3 (92.60 mg, 0.10 mmol) and DPEPhos (109.0 mg, 0.20 mmol) were added under nitrogen atmosphere. The mixture was heated at 80 C for 2 h. Then it was filtered and washed with EtOAc (20 mL). The filtrate was treated with 3 M HC1 (50 mL) at 50 C for 4 h. The phases were separated and the aq. phase was basified with 10% NaOH to pH 10. The aq. phase was extracted with EtOAc (3 x 50 mL). The combined organic layers was dried over anhydrous Na2SO4 and concentrated in vacuo. Crude 5-(trifluoromethoxy)pyridin-2-amine (int-82) (400 mg, 44%) was used directly in the next step without further purification. MS (ESI): mlz 178.9 [M+H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With N-Bromosuccinimide; In dichloromethane; at 20℃; for 16h; | Int-82 (200 mg, 1.12 mmol) was dissolved in DCM (10 mL) and a solution of Nbromosuccinimide (200 mg, 1.12 mmol) in DCM (5 mL) was added dropwise. The mixture was stined at rt for 16 h. The solvent was removed under reduced pressure and the residue was purified by colunm chromatography on silica gel using a mixture of petroleum ether and EtOAc (2:1) as eluent to give 3-bromo-<strong>[1221171-88-5]5-(trifluoromethoxy)pyridin-2-amine</strong> (int-83) (200 mg, 69%) as a yellow solid. MS (ESI): mlz 257.9 [M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | One drop of N,N-dimethylformamide was added to a suspension of the product of Example 8A (40 mg, 0.12 mmol) in dichloromethane (2 mL). Oxalyl chloride (2.0 M in dichloromethane, 0.121 mL) was added in one portion. After stifling at ambient temperature for20 minutes, the resulting solution was concentrated under reduced pressure. The residue was then taken up in pyridine (1 mL) and transferred to a solution of 5-(trifluoromethoxy)pyridin-2- amine (24.9 mg, 0.14 mmol, Astatech) in a solvent mixture of N,N-dimethylformamide (1.0 mL) and pyridine (1.0 mL). The reaction mixture was stirred for 30 minutes, filtered through a glass microfiber fit, and purified by preparative HPLC [YMC TriArtTM Cl 8 Hybrid 5 jim column, 50 x 100 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (13 mg, 0.027 mmol, 22 % yield). 1H NMR (501 MHz, DMSO-d6) 5 ppm 10.67 (s, 1H), 8.40 (dt, J = 2.9, 0.7 Hz, 1H), 8.21 (dd, J = 9.1, 0.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.87(ddd, J = 9.2, 3.0, 1.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.50 (s, 2H), 3.67 - 3.57 (m, 1H), 2.54 -2.43 (m, 1H), 1.91 - 1.77 (m, 4H), 1.53 - 1.42 (m, 2H), 1.39 - 1.24 (m, 2H); MS (ESf?) m/z 490 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | The product of Example 158B (62 mg, 0.11 mmol) and (1509) bis(tetramethylene)fluoroformamidinium hexafluorophosphate (50 mg, 0.16 mmol, Alfa) were charged to a sealed tube, and a solvent mixture of dichloromethane (0.26 mL) and N,N- diisopropylethylamine (0.083 mL, 0.47 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 30 minutes and <strong>[1221171-88-5]5-(trifluoromethoxy)pyridin-2-amine</strong> (22.5 mg, 0.13 mmol, Astatech) was added. The tube was sealed and stirred at 75 C for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt CI 8 Hybrid 5 mupiiota column, 50 x 100 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (12 mg, 0.023 mmol, 22% yield). JH NMR (400 MHz, DMSO-<) ppm 9.95 (s, 1H), 8.39 - 8.36 (m, 1H), 8.11 (dd, J = 9.2, 0.6 Hz, 1H), 7.83 (ddd, J = 9.2, 3.0, 1.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.00 (dd, J = 11.4, 2.8 Hz, 1H), 6.78 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 4.42 (s, 2H), 1.92 - 1.78 (m, 12H). MS (APCI+) m/z 516 (M+H)+. |
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