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CAS No. : | 30413-58-2 | MDL No. : | MFCD08703491 |
Formula : | C8H7N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RUFOVPQUNXLVFW-UHFFFAOYSA-N |
M.W : | 117.15 | Pubchem ID : | 13400635 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.14 |
TPSA : | 12.89 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.93 cm/s |
Log Po/w (iLOGP) : | 1.97 |
Log Po/w (XLOGP3) : | 1.53 |
Log Po/w (WLOGP) : | 1.45 |
Log Po/w (MLOGP) : | 1.39 |
Log Po/w (SILICOS-IT) : | 2.43 |
Consensus Log Po/w : | 1.75 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.02 |
Solubility : | 1.11 mg/ml ; 0.00947 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.41 |
Solubility : | 4.56 mg/ml ; 0.0389 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.44 |
Solubility : | 0.424 mg/ml ; 0.00362 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
24% | 2-bromo-6-methylpyridine (0.5 g, 2.9 mmol) and trimethylsilylacetylene (0.29 g, 2.9 mmol) in Et3N (15 ml) is purged with argon. Then CuI (11 mg, 0.06 mmol) and (PPh3)2PdCl2 (42 mg, 0.06 mmol) are added and the reaction stirred under argon at room temp for 2 hours. The solvent is removed in vacuo and the residue diluted in EtOAc (50 ml) and water (50 ml). The organic is separated and washed with brine. The solvent is removed to afford a dark oil. This oil is diluted in MeOH (50 ml) and treated with a 1 N NaOH solution (10 ml) and stirred for 3 hours at room temp. The aqueous is then acidified to pH=4 with 1 N HCl and extracted with dichloromethane. The solvent is removed in vacuo to afford 1.16 g (24 %) as a light yellow oil used as is in following reactions. 1H NMR (CDCl3) delta: 7.54 (t, 1H), 7.29 (d, 1H), 7.12 (d, 1H), 3.12 (s, 1H), 2.55 (s, lH).MS ES+ m/e 118.1 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In methanol; dichloromethane; at 20℃; for 2h; | 2-methyl-6- [ (trimethylsilyl) ethynyl] pyridine (1.67 g, 8.82 mmol) was dissolved in MeOH (10 mL) and DCM (20 mL) and anhydrous potassium carbonate (3.66 g, 26.5 mmol, 3.0 eq. ) was added at room temperature. The mixture was stirred at room temperature for 2h and then concentrated in vacuo. Then the material was passed through a Si plug, 10 g, while rinsing with DCM. This gave 1.0 g (yield: 97 %) pure product. 'H NMR (400 MHz): 7.55 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 3.13 (s, 1H), 2.56 (s, 3H). |
80.6% | With potassium carbonate; In methanol; at 20℃; for 1h; | A solution of 2-methyl-6-((trimethylsilyl)ethynyl)-pyridine (2 g, 10.58 mmol) and K2CO3 (1 .46 g, 10.58 mmol) in MeOH (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed with EA. The combined the organic layers were dried and concentrated to give 2-ethynyl-6-methylpyridine (1 g, yield 80.6%) as brown oil. 1H NMR (400MHz CDC ): delta 7.38 (t, J =8.0 Hz ,1 H), 7.13 (d, J =7.6 Hz, 1 H), 6.96 (d, J =7.2 Hz, 1 H), 2.97 (s, 1 H), 2.39 (s, 3H). |
77% | With potassium carbonate; In methanol; at 20℃; for 0.5h; | To a solution of Intermediate 2 (18.4g, 0. [097MOL)] in [MEOH] (100 [ML)] was added potassium carbonate (4eq, 0. [39MOL,] 53.7g). The reaction mixture was then stirred at room temperature for 30 min and the solvent evaporated to dryness. The residue was partitioned between ethyl acetate/water. The organic layer was dried over [NA2SO4,] filtered and the solvent evaporated under reduced pressure to give the title compound (8.75g, 77%) as a brown oil ;'H NMR (300 MHz, CDC13) [8] : 7.45-7. 34 [(M,] [1H),] 7.14 (d, 1H), 6.98 (d, 1H), 2.97 (s, 1H), 2.40 (s, 3H). |
77% | With potassium carbonate; In methanol; at 20℃; for 0.5h; | To a solution of intermediate 2 [(18.] 4g, 0. [097MOL)] in MeOH (100 ml) was added potassium carbonate (4eq, 0. [39MOL,] 53.7g) and the reaction mixture was stirred at rt for 30 min. The solvent was removed and the residue was partitioned between ethyl acetate/water. The organic layer was dried over [NA2SO4,] filtered and the solvent evaporated under reduced pressure to give the title compound (8.75g, 77%) as a brown oil ;'H NMR (300 MHz, [CDCI3)] [8] ppm: 7.45-7. 34 (m, [1H),] 7.14 (d, [1H),] 6.98 (d, [1 H),] 2.97 (s, 1H), 2.40 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 1h; | <strong>[30413-58-2]2-ethynyl-6-methylpyridine</strong> (0.040 g, 0.34 mmol) was dissolved in THF (2.5 mL) and the solution was cooled to-78 C. Lithium bis (trimethylsilyl) amide (0.69 mL of a 1.0 M solution in THF, 2.0 eq. ) was added and the solution was stirred for 0. 5h at that temperature before 2-methylpropanal (0.050 g, 0.063 mL, 0.69 mmol, 2.0 eq. ) was added. After that time the temperature of the reaction mixture was allowed to reach room temperature and after stirring for 0. 5h at that temperature, the mixture was passed through a SCX column, 5 g, while eluting with THF and MeOH, respectively. To elute the compound, the column was finally eluted with a saturated solution of ammonia in MeOH. This gave 0.080 g crude product that was used for the preparation of compound 35 (see below) without further purification. 'H NMR (400 MHz) : 7.48 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7. 8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 4.38 (d, J = 5.9 Hz, 1H), 2.50 (s, 3H), 1.96 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz): 158.5, 142.0, 136.3, 124.1, 122.5, 89.6, 84.3, 67.5, 34.3, 24.1, 18.1, 17.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In DMF (N,N-dimethyl-formamide); at 55℃; for 1h; | Example 1: 3- (6-METHYL-PYRIDIN-2-YLETHYNYL)-CYCLOHEX-2-ENONE O- ["C-METHYL]-OXIME 3- (6-METHYL-PYRIDIN-2-YIETHYNYL)-CYCLOHEX-2-ENONE 0- ["C-METHYL]-OXIME is synthesized by reacting ["C]-MEL with the sodium salt of 3- (6-METHYL-PYRIDIN-2-YLETHYNYL)-CYCLOHEX-2-ENONE oxime (1MG) in dry DMF (400 PL). ["C]-Mel is introduced via a slow stream of helium and when addition is completed the reaction mixture is heated to 120C for 10 min. Product purification is accomplished by reversed phase HPLC using a C-18 U-BONDAPAK column (7. 8X300MM) and a mobile phase consisting of CH3CN/0. 1% H3PO4 (70/30) at a flow rate of 5 ML/MIN. The retention time of the desired product is between 6 and 7 min. 3-(6-METHYL-PYRIDIN-2-YLETHYNYL)-CYCLOHEX-2-ENONE O-["C-METHYL]-OXIME is formulated in a solution containing polysorbatum (2%), ethanol (10%) and saline (0.9%). LogD = 2.5 (determined using the classical shake-flask method). The starting materials are prepared as described hereafter: a) 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone A solution OF 2-ETHYNYL-6-METHYL-PYRIDINE (702 mg, 6 MMOL), 3-bromo-cyclohex-2-enone (1.26 g, 7.2 MMOL), BIS- (TRIPHENYLPHOSPHINE)-PALLADIUM-DICHLORIDE (168 mg, 0.24 MMOL), copper (L) iodide (93 mg, 0.48 mmol), triethylamine (4.8 ml, 34.4 MMOL) in 12MOI DMF is heated to 55C for 1 h. After that time the solution is diluted with ethyl acetate (500 ml) and washed with sat aq. NAHCO3 (1 X 150 ML). The water phase is extracted with ethyl acetate (1 X 150 ML) and the combined organic phases are dried over NA2SO4, filtered and concentrated in vacuo. The residue (1.88 g) is purified on column chromatography (silica gel, eluent hexane/ethyl acetate 3: 1 V/V) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 1.05 g (yield = 82 %) of the title compound as a light yellow oil. b) 3- (6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime A solution of 3- (6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone (422 mg, 2 MMOL) and hydroxylamine hydrochloride (278 mg, 4 MMOL) in pyridine (20 ml) is stirred for 17 h at RT. After that time the solvent is evaporated in vacuo. The residue is dissolved in ethyl acetate (300 ml) and washed with sat NAHCO3 (1 X 50 ML). The water phase is extracted with ethyl acetate (1 X 50 ML). The combined organic phases are dried over NA2SO4, filtered and concentrated in vacuo. The residue (0.45 g) is purified on column chromatography (Silica gel, eluent hexane/ethyl acetate 2: 1 V/V) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 0.192 g (yield = 42 %) of the title compound as light yellow crystals, m. p. 166-168C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h; | To a solution of intermediate 1 (1.85g, 7. [74MMOL)] in dry THF (40m L) were added under nitrogen, TMEDA (20mL) and intermediate 3 (1. [1EQ, 1G,] 8. 51mmol). The resulting mixture was degassed with nitrogen for 10 min, then tetrakis [(TRIPHENLYPHOSPHINE) PALLADIUM (0)] (0. [464MOL,] 537mg) and copper iodide (0.928 mmol, 177mg) were added. The resulting mixture was heated at [60C] for 4h. The mixture was poured into a saturated solution of NH4CI and extracted with EtOAc. The organic phase was dried over [NA2SO4] and filtered. Solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel [(CH2CI2/ETOAC] 90: 10) to afford the title compound as a beige solid (1. 54g, 86.4%) ; ['H] NMR (300 MHz, [CDCL3) No. ]: 8. 29 (d, 1H), 7.52 (t, 1H), 7.39 (s, 1H), 7.34-7. 24 (m, 2H), 7.10 (d, 1 H), 2.50 (s, 3H). |
86.4% | With N,N,N,N,-tetramethylethylenediamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h; | To a solution of intermediate 1 (1.85g, 7. [74MMOL)] in dry THF [(40ML)] were added under nitrogen TMEDA (20mL) and intermediate 3 (1. 1eq, 1g, 8. 51mmol). The resulting mixture was degassed with nitrogen for ten mins, tetrakis (triphenlyphosphine) palladium (0) (0.537g, 0. [464MOL)] and copper iodide (0. [177G,] 0.928 [MMOL)] were added and the mixture was heated at [60C] for 4hours. The mixture was poured into a saturated solution of NH4CI and extracted with EtOAc. The organic phase was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2CI2/EtOAc 90: 10) to afford the title compound as a beige solid (1.54g, 86.4%) [;'H] NMR (300 MHz, [CDCI3)] [8] ppm: 8.29 (d, 1H), 7.52 (t, 1H), 7.39 (s, 1H), 7.34-7. 24 (m, 2H), 7.10 (d, 1H), 2.50 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A solution of <strong>[30413-58-2]2-ethynyl-6-methyl-pyridine</strong> (0.5 g, 4.3 mmol) in THF (20 ml) is cooled to-78 C and treated with 1.6 M n-butyllithium in hexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 hours. This solution is then treated with ethyl chloroformate (2.85 ml, 30 mmol) and stirred for 3 hours while the solution warms to room temperature The reaction is diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The solvent is concentrated to afford 0.67 g (83 %) of desired product as a light yellow oil. UV (95 % EtOH) lambdamax 286 nm (e 10977), 238 nm (e 9757). TOF MS ES+ exact mass calculated for C11H11NO2 (p+1): m/z = 190.0868. Found: 190.0864 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; In water; for 2h;Sonographic reaction; | A mixture of <strong>[30413-58-2]2-ethynyl-6-methyl-pyridine</strong> (0.08 g, 0.7 mmol), 1-Boc-4-piperidinecarboxaldehyde (0.1 g, 0.47 mmol), CuI (0.001 g, 0.11 mmol) and 33% w/w aqueous dimethylamine (0.077 mL, 0.56 mmol) in water (3 mL) was sonicated for 2 h in a laboratory ultrasonic bath. Afterwards, it was extracted with EtOAc and the combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified by automated flash liquid chromatography (Horizon-Biotage) eluting with EtOAc-Petroleum Ether 1:1 affording the title product (0.11 g).1H-NMR (CDCl3, delta): 1.25-1.48 (m, 2H), 1.51 (s, 9H), 1.65-1.73 (m, 1H), 2.05-2.11 (m, 2H), 2.23-2.40 (br, 6H), 2.66 (s, 3H), 2.69-2.77 (m, 2H), 3.21-3.39 (m, 1H), 4.09-4.21 (m, 2H), 7.09-7.11 (m, 1H), 7.27-7.30 (m, 1H), 7.53-7.56 (m, 1H).MS: [M+H]+=358.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of zinc trifluoromethanesulfonate (0.07 g, 0.19 mmol) and triethylamine (0.065 mL, 0.47 mmol) in anhydrous toluene (5 mL) was stirred at room temperature under nitrogen atmosphere. After 1 h, <strong>[30413-58-2]2-ethynyl-6-methyl-pyridine</strong> (0.13 g, 1.13 mmol) prepared as described in WO200544267 was added and after 15 min was dropped a solution of 1-Boc-4-piperidinecarboxaldehyde (0.2 g, 0.938 mmol) in toluene (1 mL): the resulting mixture was heated at 100 C. for 6 h. Afterwards, it was cooled to r.t., diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified twice by automated flash liquid chromatography (Horizon-Biotage) eluting with CHCl3-MeOH 98-2 affording the title product (0.13 g) as a brown oil.1H-NMR (CDCl3, delta): 1.27-1.5 (m, 12H), 1.85-2.01 (m, 3H), 2.63 (s, 3H), 2.65-2.82 (m, 2H) 4.15-4.31 (m, 2H), 4.44-4.49 (m, 1H), 7.15-7.18 (m, 1H), 7.27-7.30 (m, 1H), 7.61-7.65 (m, 1H).MS: [M+H]+=331.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 70℃;Inert atmosphere; | A solution of <strong>[30413-58-2]2-ethynyl-6-methylpyridine</strong> (439.5 mg, 3.75 mmol), methyl (5-bromo-2- chlorobenzyl)carbamate (950 mg, 3.41 mmol), Pd(PPh3)CI2 (136.4 mg, 0.341 mmol) and Cul (65.14 mg, 0.341 mmol) in TEA (10 mL) was heated at 70 C overnight under nitrogen. The reaction mixture was filtered and the organic layer was concentrated. Subsequent purification on silica gel gave methyl (2-chloro-5-((6-methylpyridin-2-yl)ethynyl)benzyl)carbamate (270 mg, yield 20%) as yellow solid. H NMR (400MHz CDCb): delta 7.64 (s, 1 H), 7.58 (t, J =7.6 Hz,1 H), 7.45 (d, 1 H), 7.36 (d, J =8.0 Hz, 2H), 7.13 (d, J =7.6Hz, 1 H), 5.16 (brs, 1 H), 4.46 (d, J =6.0 Hz, 2H), 3.73 (s, 3H), 2.60 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium acetate; In water; N,N-dimethyl-formamide; at 120℃; for 0.25h;Microwave irradiation; | To a solution of Compound 26a (150 mg, 0.44 mmol) in DMF (1 mL) in a MW vial was added <strong>[30413-58-2]2-ethynyl-6-methyl-pyridine</strong> (0.88 mmol, 102.9 mg) )followed by sodium acetate 3H2O (0.88 mmol, 119.5 mg) and tetrakis(triphenylphosphine)palladium (0.022 mmol, 25.38 mg) and the mixture was heated under MW irradiation in Biotage Initiator 8 microwave oven at 120 C for 15min. Then water was added, the two phases were separated, the organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude residue was purified by means of a Biotage Isolera Four (coupled with Dalton MS detector), cartridge type SNAP25 (collect all mode) using a gradient from EtAcO 100% to EtAcO : MeOH 8:2.20 mg of the tile compound (brown oil) were collected along with impurities. The sample was then re-purified on a reverse phase column chromatography, cartridge type SNAP12, using a gradient from NH4HCO3 buffer : MeCN 85:15 to NH4HCO3 buffer : MeCN 1:1.9 mg of the wished compound (white powder) were collected. (0309) UPLC-MS [M+H]+ = 378.28, 380.17, 381.34 (0310) 1H NMR (400 MHz, DMSO-d6) d ppm 7.62 - 7.71 (m, 1 H), 7.45 - 7.55 (m, 3 H), 7.43 (t, 1 H), 7.31 - 7.39 (m, 1 H), 7.23 (d, 1 H), 5.02 (br. s., 2 H), 4.23 - 4.37 (m, 2 H), 3.94 - 4.21 (m, 2 H), 2.62 (s, 3 H) |