Structure of 4-Amino-2,6-difluoropyridine
CAS No.: 63489-58-7
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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. : | 63489-58-7 |
Formula : | C5H4F2N2 |
M.W : | 130.10 |
SMILES Code : | NC1=CC(F)=NC(F)=C1 |
MDL No. : | MFCD08436089 |
InChI Key : | OWXBXLGJIFPPMS-UHFFFAOYSA-N |
Pubchem ID : | 11286475 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 28.56 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.91 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 |
1.04 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.79 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.67 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.8 |
Solubility | 2.09 mg/ml ; 0.016 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.45 |
Solubility | 4.64 mg/ml ; 0.0357 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.19 |
Solubility | 0.846 mg/ml ; 0.0065 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 |
-6.36 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 |
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) |
1.67 |
* 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 |
---|---|---|
63.5% | With palladium 10% on activated carbon; triethylamine In ethanol at 25℃; for 24 h; Autoclave | In a 500 mL autoclave, 49.8 g (0.25 mol) of 2,6-difluoro-3,5-dichloro-4-aminopyridine,200mL ethanol,5.61 g (0.55 mol) of triethylamine,10.0 g of 10percent palladium on carbon,Keep the temperature at 25 ,Filled with hydrogen pressure 0.46 MPa,Reaction for 24 hours.After cooling, the hydrogen was released, suction filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3: 1)20.6 g of 2,6-difluoro-4-aminopyridine was obtained as a white solid,Liquid normalized content of 99.7percent, yield 63.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With hydrogen; triethylamine In ethanol for 18 h; | 4-Amino-3-chloro-2,6-difluoropyridine (6) and 4-amino-2,6-difluoropyridine (7). A suspension of 19.9 g (100 mmol) of 5, 2.2 g of 10percent Pd/C and 27 mL (190 mmol) of triethylamine in 100 mL of anhydrous ethanol was hydrogenated at 50 psi in a Parr hydrogenation apparatus overnight (about 18 h). The catalyst was filtered and carefully washed with ethanol. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was partitioned between ether and water, and the water layer was extracted with ether. The combined ether layers were dried (MgSO4) and concentrated to dryness. The residue was dissolved in ethanol and the solution was treated with 50 g of silica gel. The solvent was removed in vacuo to give a powder, which was purified by silica gel column chromatography, eluted with CH2Cl2 to afford 9.4 g (57percent) of 6 and 4.3 g (33percent) of 7. [0129] Compound 6 was isolated as a white solid: mp 8485° C.; TLC, Rf 0.55 (CH2Cl2); 1H NMR (CDCl3) δ 5.15 (br s, 2H, NH2, D2O exchangeable), 6.20 (s, 1H, 5-H). Analysis calculated for C5H3ClF2N2: C, 36.49; H, 1.84; N, 17.02. Found: C, 36.78; H, 2.09; N, 16.89. [0130] Compound 7 was isolated as a white solid: mp 126-128° C. (Lit., Secrist, et al., J. Med. Chem. 1988 31, 405-410 mp 125-127° C.); TLC, Rf 0.37 (CH2Cl2); 1H NMR (DMSO-d6) δ 6.00 (s, 2H, 3- and 5-H), 6.70 (br s, 2H, NH2, D2O exchangeable). Analysis calculated for C5H4F2N2: C, 46.16; H, 3.10; N, 21.54. Found: C, 46.01; H, 3.39; N, 21.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: With potassium fluoride; [2.2.2]cryptande In dimethyl sulfoxide at 160℃; for 72 h; Stage #2: With hydrogenchloride In methanol for 1 h; |
Anhydrous F (300 mg, 5. 16 mmol) was added to a mixture of 1 (700 mg, 1.72 mmol) and kryptofix (1.0 g, 2.65 mmol) in DM SO (2.5 mL) and the mixture was stirred at 160 °C for 72 h. After the reaction, water was added and the solid formed was filtered and dried. The solid was dissolved in ethyl acetate (25.0 mL) and washed with water and dried (Na2S04). Evaporation of the solvent gave a dark oil, which was purified by silica gel column chromatography using hexane /ethyl acetate (7/3). UV visible fractions were collected and evaporated to give an yellow oil, which solidified on standing. Yield 0.5 g. (88percent). This was found to be a mixture of 63, 64 and 62 in the ratio (13:51 : 14) by HPLC analysis. A portion of the solid (80.0 mg) was purified by preparative HPLC using CH3CN / water /0.1percent TFA. Fractions containing the pure product were collected and evaporated to give the compound 64 as a while solid. Yield 32.0 mg (42percent). MS: 389.2 (M+H)+. The trityl derivatives 63, 63 and 64 obtained in the above reaction (600 mg, 1.5 mmol) was dissolved in methanolic HQ (5.0 inL) and stirred for 1 h. Methanol was removed and the residue was triturated with ethyl acetate to remove the trityl chloride and the resulting hydrochloride was dissolved in methanol and stirred with anion exchange resin. The pH of the solution (7.0) tested and the methanolic solution was filtered and concentrated to give the free amine mixture 65, 66 and 61. Yield 200 mg (89percent). A portion of the solid (38.0 mg) was purified by preparative HPLC (Ci8 column (0.46 x 5 cm, gradient 0- 1 0 percent) CH3CN / water/ 0.1 percent) TFA. Fractions containing the pure product were collected and concentrated to give the compound 65. Yield 10.0 mg (37percent). MS: (M+H f 147.0. 1HNMR (DMSO-d6) d 6.06 (s, I H ).6.46 (s, 1 H ). 6.80 (bs, 2H). |
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