Structure of 109-04-6
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Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase-6
Togo, Takaya ; Tram, Linh ; Denton, Laura G. ; ElHilali-Pollard, Xochina ; Gu, Jun ; Jiang, Jinglei , et al.
Abstract: Heteroaromatic stacking interactions are important in drug binding, supramolecular chemistry, and materials science, making protein-ligand model systems of these interactions of considerable interest. Here we studied 30 congeneric ligands that each present a distinct heteroarene for stacking between tyrosine residues at the dimer interface of procaspase-6. Complex X-ray crystal structures of 10 analogs showed that stacking geometries were well conserved, while high-accuracy computations showed that heteroarene stacking energy was well correlated with predicted overall ligand binding energies. Empirically determined KD values in this system thus provide a useful measure of heteroarene stacking with tyrosine. Stacking energies are discussed in the context of torsional strain, the number and positioning of heteroatoms, tautomeric state, and coaxial orientation of heteroarene in the stack. Overall, this study provides an extensive data set of empirical and high-level computed binding energies in a versatile new protein-ligand system amenable to studies of other intermolecular interactions.
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Comins, Daniel L ;
Abstract: A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.
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Keywords: N-methyl-N-(2-pyridyl)formamide ; 2-methylaminopyridine amides ; 2-alkyl(aryl)aminopyridines ; Goldberg reaction ; copper-catalyzed reactions ; cross-coupling reactions ; 1,10-phenanthroline
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CAS No. : | 109-04-6 |
Formula : | C5H4BrN |
M.W : | 158.00 |
SMILES Code : | C1=CC=C(N=C1)Br |
MDL No. : | MFCD00006219 |
InChI Key : | IMRWILPUOVGIMU-UHFFFAOYSA-N |
Pubchem ID : | 7973 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 31.94 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.62 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.42 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.24 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.66 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.35 |
Solubility | 0.708 mg/ml ; 0.00448 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.3 |
Solubility | 8.0 mg/ml ; 0.0506 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.86 |
Solubility | 0.217 mg/ml ; 0.00137 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 |
-6.26 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) |
1.61 |
* 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 |
---|---|---|
55% | at 20℃; for 16 h; | Example 20; 4-Cyano- lH-imidazole-2-carboxylic acid [2-cyclohex- 1 -enyl-4-( 1 -oxy-pyridin-2-yl)-phenyl] - amide; a) 2-Bromo-pyridine 1 -oxide; A solution of 2-bromopyridine (158 mg, 1.00 mmol) and urea hydrogen peroxide (658 mg, 7.00 mmol) in 2.5 mL of formic acid was stirred at RT for 16 h. The resulting mixture was treated with H2O (30 mL) and extracted with DCM (3 x 15). The combined organic layers were dried (Na2SO4) and concentrated to give 96 mg (55 percent) of the title compound as a brown oil. Mass spectrum (ESI, m/z): Calcd. for C5H4BrNO, 174.0 (M+H), found 174.2. |
20% | With dihydrogen peroxide; acetic acid In water | i) 2-Bromopyridine-N-oxide (Den Hertog, Kolder and Combe, 1951) 2-Bromopyridine (12 g), hydrogen peroxide (30percent, 90 ml) and acetic acid (90 ml) were heated at 55-60° C. for 8 days with stirring. The solvent was then reduced under vacuum, water added, and the process repeated 3 or 4 times, to remove all solvent. A greenish oil/solid of 2-Bromopyridine-N-oxide (2.2 g,20percent) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In 1,4-dioxane at 20℃; Inert atmosphere | Under nitrogen atmosphere, and at r.t., CuT (0.06 g, 0.31 mmol), dry Et3N (1.32 mL, 9.49 mmol) and bis-(triphenylphosphine)-palladium chloride (0.13 g, 0.18 mmol) were sequentially added to a solution of 2-bromopyridine (0.60 mL, 6.33 mmol) in 1,4-dioxane (10 mL). Then, but-3-yn-1-ol (0.57 mL, 7.59 mmol) was added dropwise at the same temperature.The resulting reaction mixture was left stirred overnight, then concentrated under reduced pressure, dissolved in EtOAc (80 mL) and washed with H20 (3 x 10 mL). The organic layer was dried over Na2504 and concentrated to dryness to give an oily crude (1.1 g). Purification by typical silica gel flash chromatography using a Teledyne ISCO apparatus (Cy/EtOAc from 90:10 to 30:70) afforded the pure title compound (0.84 g, 90percent), as a white solid. R= 1.25 mm. MS(ESI) m/z: 148 EM-H], 170 EM-Na], 186 EM-K]. ‘H NMR (DMSO-d6): ö 8.55—8.49 (m, 1H),7.76 (td, 1H, J= 7.8, 1.8 Hz), 7.44 (d, 1H, J= 7.8 Hz), 7.33 (ddd, 1H, J= 7.8, 4.9, 1.8 Hz), 4.92 (t, 1H, J= 5.2 Hz), 3.62-3.58 (m, 2H), 2.58 (t, 2H, J= 6.8 Hz). |
77% | at 0 - 70℃; | Example 199 ;3 -Methoxy- N -methyl- N -( 4-(pyridin- 2-yl)but - 3 -ynyl)benzamide; 199(A) 4-(Pyridin-2-yl)but-3-yn-1-01; To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2- bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0°C under N2, 3-butyn-l-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70°C. The reaction mixture was quenched at 0°C with water, TEA was removed under low pressure, and the organic layer was extracted 3x using DCM, washed with Ammonia, water, brine, dried over MgS04, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH : from 99/1 to 95/5 as eluent) to afford 3.60 g of 4- (pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield : 77percent). LCMS (RT) : 1.58min; MS (ES+) gave m/z : 148 Rf (DCM/MeOH : 95/5) =0.23 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With n-butyllithium; In tetrahydrofuran; | Step 2 [3,4-Bis(difluoromethoxy)phenyl]-{6-[4-(methylthio)benzyloxy]-3-pyridyl}methanol To a -78 C. solution of bromopyridine from Step 1 above (1.0 g, 3.22 mmol) in 10 mL of THF, was added 1.7 mL (3.65 mmol) of a 2.1 M solution of n-BuLi. The solution was stirred 15 minutes followed by the addition of 7 mL of a THF solution of <strong>[127842-54-0]3,4-bis(difluoromethoxy)benzaldehyde</strong> (512 mg, 2.15 mmol). The resulting solution was stirred 30 minutes at -78 C., quenched with a 25% NH4OAc solution and diluted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (25% Ethyl acetate/hexane) to afford the alcohol as an oil (380 mg, 30%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 17h;Inert atmosphere; | 2-Amino-isoquinoline (301 mg, 2.09 mmol), 2-bromopyridine (181muL, 1.90 mmol), tBuOK (320 mg, 2.55 mmol), (+/-)-BINAP (47 mg, 0.08 mmol) and Pd2(dba)3 (43 mg, 0.05 mmol) were stirred in toluene (3 mL) at 9O0C under Ar(g) for 17h. The reaction mixture was then diluted with CH2CI2 (5mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (80:20 then 70:30) to furnish I as a white solid (252 mg, 60percent).1H NMR (400MHz, CDCI3) deltaH: 8.99 (s, 1H), 8.34 (d, J=4.0Hz, 1H), 8.28 (s, 1H), 7.87 (d, J=8.5Hz, 1 H), 7.78 (d, J=8.5Hz, 1 H), 7.67-7.55 (m, 2H), 7.39 (t, J=7.5Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 6.91-6.84 (m, 1H). MW: 221.26. LCMS (ES): found 222.1 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,4-dioxane; water; | Reference Production Example 22 Using <strong>[175883-62-2]4-methoxy-3-methylphenylboronic acid</strong>, 2-bromopyridine, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, potassium carbonate, 1,4-dioxane, and water, the same reaction as in Reference Production Example 20 was performed to obtain 2-(4-methoxy-3-methylphenyl)pyridine (hereinafter referred to as the intermediate (PME14)). 1H-NMR (CDCl3) delta: 2.30 (3H, s), 3.89 (3H, s), 6.91 (1H, d, J=8.3 Hz), 7.14-7.18 (1H, m), 7.65-7.73 (2H, m), 7.78-7.84 (2H, m), 8.66-8.63 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With palladium diacetate; sodium t-butanolate; XPhos; In 1,4-dioxane; at 110℃; for 2h;Schlenk technique; Inert atmosphere; | An oven dried schlenk flask was evacuated with vacuum and back filled with argon gas. The procedure was repeated for 3-4 times and cooled to room temperature. The dioxane (3 ml) was introduced with syringe and degassed for 20min with argon gas balloon. Then, the XPhos (54mg, 0.11 mmol), Pd(OAc)2 (8mg, 0.037mmol) were added together and heated at 110 C for 1minute. The reaction mixtures become clear red color solution. Then, the amine derivative 5 (50 mg, 0.37 mmol), 2-bromopyridine (61mg, 0.37mmol) and sodium tert butoxide (120mg, 1.25mmol) were added together under argon atmosphere and the reaction mixture was heated at 110 C for 2h. The reaction mixture was cooled and poured in EtOAc (150 ml). The organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed and the residue was purified on silica gel column (50:50 EtOAc:heptane) to give the compound 32 (45 mg, 39%). 1H-NMR (400 MHz, CDCl3): delta = 10.6 (s, 1H), 9.31 (s, 1H), 8.3 (d, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.64 (t, 1H), 7.20 (m, 1H), 7.08 (d, 1H), 6.87 (dd, 1H), 6.45 (dd, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 48h;Inert atmosphere; | Cuprous iodide (599.92 mg, 3.15 mmol), N,N-dimethylethylenediamine (310.99 mg, 3.53 mmol, 379.26 muL) and potassium carbonate (600.80 mg, 4.35 mmol) were added separately into compound I1 (700.00 mg, 3.15 mmol) and 2-bromopyridine (497.59 mg, 3.15 mmol, 299.75 muL) in dioxane solution. Under nitrogen atmosphere, the reaction mixture was stirred at 95C for 48 hours and then added 40 mL ammonia after concentration, then extracted by EtOAc 350 mL (70 mL×5), and washed by saturated brine 150 mL, dried over anhydrous sodium sulfate, then filtered to give the crude compound 3-A. MS m/z: 300.0[M+H]+ |
Tags: 109-04-6 synthesis path| 109-04-6 SDS| 109-04-6 COA| 109-04-6 purity| 109-04-6 application| 109-04-6 NMR| 109-04-6 COA| 109-04-6 structure
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H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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