Structure of 2-Ethynyl-5-fluoropyridine
CAS No.: 884494-34-2
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CAS No. : | 884494-34-2 |
Formula : | C7H4FN |
M.W : | 121.11 |
SMILES Code : | FC1=CN=C(C#C)C=C1 |
MDL No. : | MFCD03095259 |
InChI Key : | KHCIVRLMGQEZPB-UHFFFAOYSA-N |
Pubchem ID : | 44754926 |
GHS Pictogram: |
![]() |
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 | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 32.13 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.84 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.7 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.38 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.73 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.86 |
Solubility | 1.68 mg/ml ; 0.0138 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.1 |
Solubility | 9.66 mg/ml ; 0.0798 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.34 |
Solubility | 0.555 mg/ml ; 0.00458 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) |
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 |
-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 |
2.0 |
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) |
1.9 |
* 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 |
---|---|---|
63% | With sodium hydroxide; In toluene; at 120℃; for 0.25h; | 820 mg (4.58 mmol) of Dimethylhydroxymethyl-5-fluoro-2-pyridylacetylene and 192 mg (4.81 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 23 mL of toluene was added thereto and the mixture was refluxed at 120C for 0.25 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure at 90 mmHg/70C to give 5-fluoro-2-pyridylethyne as an orange-color liquid (0.35 g, yield: 63%). 1H-NMR (300 MHz, CDCl3) delta: 8.43 (s, 1H) 7.45-7.53 (m, 1H), 7.40-7.43 (m, 1H), 3.13 (d, 1H), [MS] EI (m/z): 121 (M+-1), CI (m/z): 122 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium ethanolate; In ethanol; at 20℃; for 17h; | Under an argon atmosphere, Au(PPh3)Cl (474 mg, 0.96 mmol), <strong>[884494-34-2]5-fluoro-2-pyridylethyne</strong> (174 mg, 1.44 mmol) and ethanol (19 ml) were added to a 20 ml Schlenk tube, and then sodium ethoxide (395 mul, 1.01 mmol: 2.55 mol/L (liter) in ethanol solution) was added dropwise thereto and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the resulting white precipitate was filtered and successively washed with ethanol (12 mlxthree times), water (12 mlxthree times) and ethanol (6 mlxthree times), followed by drying under vacuum to give 0.48 g of the desired compound as a yellow powder (yield: 86%). 1H-NMR (400 MHz, CDCl3) delta: 8.37 (d, 1H), 7.23-7.59 (m, 18H), (FAB-MS) (M/Z): 580 (M+H)+ Luminescence analysis: (CHCl3, 77K, Ex250nm) lambda (nm): 418, 446, 457 Elemental analysis: Found C: 51.51, H: 3.02, N: 2.47 Theoretical C: 51.83, H: 3.13, N: 2.42 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In methanol; at 20℃; for 1.5h; | a) 2-Ethynyl-5-fluoro-pyridine To a mixture of 5-fluoro-2-formylpyridine (1.10 g, 9.0 mmol) in MeOH (38 mL) was added potassium carbonate (2.44 g, 0.018 mol) followed by a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.03 g, 11 mmol) in MeOH (12 mL). The mixture was stirred at room temperature for 90 min, then extracted with diethylether. The organic layers were then washed with sodium hydrogen carbonate solution (1 M) and brine, dried over sodium sulfate, filtered and evaporated at to give the title compound (1.01 g, 78%) as a light brown liquid. MS: m/e=121.0 [M]+. |
78% | With potassium carbonate; In methanol; at 20℃; for 90h; | a) 2-Ethynyl-5-fluoro-pyridineTo a mixture of 5-fluoro-2-formylpyridine (1.10 g, 9.0 mmol) in MeOH (38 mL) was added potassium carbonate (2.44 g, 0.018 mol) followed by a solution of (l-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (2.03 g, 11 mmol) in MeOH (12 mL). The mixture was stirred at room temperature for 90 min, then extracted with diethylether. The organic layers were then washed with sodium hydrogen carbonate solution (1 M) and brine, dried over sodium sulfate, filtered and evaporated at to give the title compound (1.01 g, 78%) as a light brown liquid. MS: m/e = 121.0 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium hydroxide; In methanol; at 20℃; for 5h; | Step 2: Preparation of 2-ethynyl-5-fluoropyridine A mixture of 5-fluoro-2-((trimethylsilyl)ethynyl)pyridine (3.5 g, 18.1 mmol) and potassium hydroxide (1.02 g, 18.1 mmol) in methanol (100 mL) was stirred at 20 C. for 5 h. The mixture was diluted with brine (100 mL), extracted with ethyl acetate (100 mL*2) and purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1) to yield 2-ethynyl-5-fluoropyridine (1.75 g, 14.5 mmol, 80%) as a yellow oil. LCMS (ESI) m/z: 122.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.27 g | N-chlorosuccinimide (0.24 g, 1.8 mmol) was added to a solution of N-[(3E)-3-(hydroxyimino)propyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (0.45 g, 1.6 mmol) prepared in Reference Example 20 in DMF (5 mL) in an ice bath. The mixture was warmed to room temperature, followed by stirring for 15 hours. Water was added to the reaction solution, followed by extraction with EtOAc.The organic layer was washed with water and brine and was dried with Na2SO4. The desiccant was then removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (3.3 mL), and a solution of <strong>[884494-34-2]2-ethynyl-5-fluoropyridine</strong> (0.30 g, 2.5 mmol) in THF (1 mL) was dropwise added to the solution in an ice bath. Et3N (0.30 mL, 2.2 mmol) was further dropwise added thereto. The mixture was warmed to room temperature, followed by stirring for 15 hours. Water was added to the reaction solution, followed by extraction with CHCl3. The organic layer was washed with brine and was washed with Na2SO4. The desiccant was then removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (HP-Sil: 50 g, CHCl3/MeOH=99/1 to 95/5). The resulting solid was washed with EtOAc with stirring and was then collected by filtration to give the titled compound (0.27 g, colorless solid). MS (ESI pos.) m/z: 393 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.05 g | With triethylamine; In tetrahydrofuran; at 20℃; for 16h;Cooling with ice; | N-Chlorosuccinimide (0.081 g, 0.60 mmol) was added to a solutionof N-[3-(hydroxylimino)propyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide (0.15 g, 0.55 mmol) in DMF (2 mL) in an ice bath.The mixture was warmed to room temperature, followed by stirringfor 16 h. Water was added to the reaction solution, followed byextraction with EtOAc. The organic layer was washed with brineand was dried over MgSO4. The desiccant was then removed by filtration,and the solvent was distilled off under reduced pressure.The residue was dissolved in THF (4 mL), and a solution of <strong>[884494-34-2]2-ethynyl-5-fluoropyridine</strong> (0.10 g, 0.83 mmol) in THF (1 mL) was dropwiseadded to the solution in an ice bath. TEA (0.084 mL,0.83 mmol) was further dropwise added thereto. The mixture waswarmed to room temperature, followed by stirring for 16 h. Waterwas added to the reaction solution, followed by extraction withEtOAc. The organic layer was washed with brine and was dried overMgSO4. The desiccant was then removed by filtration, and the solventwas distilled off under reduced pressure. The resulting residuewas purified by column chromatography (20-80% EtOAc in hexanes)to give the title compound 15 as a colorless powder(0.050 g, 8% over 4 steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | a) A solution of carbohydrate azide SI (156mg, 0.226 mmol), Alkyne (S2a) (41mg, 0.339 mmol), Cul (2mg, 0.01 13 mmol) in dry DMF (10 mL) in a 25 mL round bottomed flask was stirred under nitrogen for 1 hour. Et3N (0.016mL, 0.1 13 mmol) was then added slowly via syringe. The resulting solution was allowed to stir at room temperature for 12 hours when TLC showed complete conversion of the starting carbohydrate azide (1 :2, n -heptane -EtO Ac). Sol- vents were evaporated in vacuo and the residue was dissolved in CH2CI2 (10 mL) and washed successively with aqueous NH4CI (2x10 mL) and brine (10 mL). The organic layer was separated, dried (Na2S04) and evaporated in vacuo. The residue was purified by flash chromatography using -hepatne-EtOAc as eluent to afford pure acetylated glycosylated triazole (3a) in 86% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | c) Compound S6 (76mg, 0.093 mmol), Alkyne (S2a) (16.9mg, 0.139 mmol), Cul (0.88mg, 0.0046 mmol) in dry DMF (5 mL) was stirred under nitrogen for 1 hour. Et3N (6.0muEpsilon, 0.046 mmol) was then added slowly via syringe. The resulting solution was allowed to stir at room temperature for 12 hours when TLC showed complete conversion of the starting carbohydrate azide (6:1 CH2C12: MeOH). Solvents were evaporated in vacuo and the residue was purified by flash chromatography using CH2C12: MeOH as eluent to afford pure glycosylated triazole (Id) in 84% yield. (0263) White amorphous solid. H NMR (CD3OD, 400 MHz) delta: 8.63, 8.59 (2s, 2H, triazole-H), 8.47 (bs, 1H, Ar-H), 8.09 (bs, 1H, Ar-H), 7.72 (m, 1H, Ar-H), 7.63 (m, 1H, Ar-H) 4.95-4.91 (m, 3H, HI, HI ', H3), 4.75-4.63 (m, 3H, H2, H2', H3'), 4.17 (dd, 2H, H4, H4'), 3.91-3.80 (m, 4H, H5, H5', H6, H6'), 3.73-3.69 (m, 2H, H6, H6'). 13C NMR (CD3OD, 100 MHz) delta: 154.14, 151.67, 151.57, 147.92, 147.66, 145.52, 141.73, 139.24, 138.77, 138.52, 128.09, 125.51 , 125.31, 123.74, 122.79, 122.57, 110.82, 1 10.75, 110.65, 110.59, 86.61 (C-l), 86.52 (C-Gamma), 81.42 (C-5), 81.35 (C-5'), 69.77, 69.64, 68.92, 68.89, 68.44, 68.37, 62.81 , 62.77. HRMS m z calcd for C27H27 7O8SF4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 4-methylpiperidin; copper(l) iodide; ascorbic acid; In N,N-dimethyl-formamide; at 80℃; for 2h; | To a solution of the methanesulfonate in DMF (100 mL) wasadded NaN3 (8.10 g, 0.120 mol), and the resulting mixture was stirredat 80 C for 3 h. The reaction was quenched by the addition ofwater, and the mixture was extracted with EtOAc. The organiclayer was dried over Na2SO4, filtered, and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (20-100% EtOAc in hexanes) to obtain tert-butylN-[(2S)-1-azidopropan-2-yl]carbamate as a colorless oil (18.8 g,83% yield).tert-Butyl N-[(2S)-1-azidopropan-2-yl]carbamate(0.30 g, 2.5 mmol) and <strong>[884494-34-2]2-ethynyl-5-fluoropyridine</strong> (0.50 g,2.5 mmol) were suspended in a mixture of 4-methylpiperidine(2.0 mL) and DMF (8.0 mL). CuI (0.024 g, 0.12 mmol) and l-ascorbicacid (0.087 g, 0.50 mmol) were added to the mixture, and the mixturewas stirred at 80 C for 2 h. After cooling to room temperature,water was added, and the mixture was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na2SO4, filtered,and concentrated under reduced pressure. The resulting residuewas purified by column chromatography (20-100% EtOAc in hexanes)to obtain the title compound 30c as a colorless solid(0.58 g, 73% yield). |