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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. : | 626-05-1 |
Formula : | C5H3Br2N |
M.W : | 236.89 |
SMILES Code : | BrC1=CC=CC(Br)=N1 |
MDL No. : | MFCD00006223 |
InChI Key : | FEYDZHNIIMENOB-UHFFFAOYSA-N |
Pubchem ID : | 12274 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H300-H315-H319-H335 |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 |
Class: | 6.1 |
UN#: | 2811 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
Step 1: 2-Bromo-6-(1-hydroxy-1-methylethyl)pyridine. Following the procedure of Step 1 of EXAMPLE 27, but substituting 2,6-dibromopyridine for 2,5-dibromopyridine, the 2-Bromo-6-(1-hydroxy-1-methylethyl)pyridine compound was obtained as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Place a 1.6 M solution of n-butyl lithium in hexane (31.2 niL, 50 mmol) in a dry 250 rnL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry- ice acetone bath to -76 0C. Add THF (30 mL) to the solution, then add a solution of 2,6- dibromopyridine (11.5 g, 50 mmol) in THF (60 mL) slowly via syringe maintaining the temperature under -600C. Stir the dark yellow-brown solution for 30 minutes in the dry- ice bath, then add acetone (6 mL, 80 mmol). Stir the deep green solution in the dry-ice bath for 15 minutes then allow the reaction to warm to room temperature. After an hour add a 5% aqueous solution of ammonium chloride (50 mL) carefully. Extract with dichloromethane, evaporate to give 2-(6-bromo-pyridin-2-yl)-propan-2-ol (10.6 g, 98%) as an orange oil. MS (m/z): 216 and 218 (M+H) +. | |
94.3% | With n-butyllithium; In tetrahydrofuran; hexane; at -76 - 20℃; for 1.25h;Cooling with ice; | Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n-buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry-ice acetone bath to -76 C. and added THF (30 mL) to the solution, then added a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry-ice bath, then added propan-2-one (4.75 g, 6 mL, 81.7 mmol). The deep green solution was stirred in the dry-ice bath for 15 minutes and then allowed to warm to room temperature. After an hour, added carefully a saturated aqueous solution of ammonium chloride (100 mL) and product extracted with dichloromethane (3*200), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel 50 mum, 150 g, Analogix) eluting with 0 to 50% over 20 min dichloromethane/hexanes, obtained 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94.3% yield) as a light yellow clear liquid. 1H NMR (CHLOROFORM-d) delta: 7.52-7.59 (m, 1H), 7.33-7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); LC-MS 216.1, 218.1 [M+H]+. |
94% | Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n- buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry- ice acetone bath to -76 C then THF (30 mL) was added followed by a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry- ice bath, then propan-2-one (4.75 g, 6 mL, 81.7 mmol) was added. The deep green solution was stirred in the dry- ice bath for 15 minutes then was warmed to room temperature over 1 hour. A saturated aqueous solution of ammonium chloride (100 mL) was carefully added and the mixture extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over magnesium sulfate then concentrated in vacuo and purified by chromatography (silica gel 50 muiotaeta, 150g, Analogix, eluting with 0 to 50% dichloromethane in hexanes) to obtain 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94 %) as a light yellow, clear liquid. 1H NMR (CHLOROFORM-d) delta: 7.52 - 7.59 (m, 1H), 7.33 - 7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); MS (EI/CI) m/z: 216.1, 218.1 [M + H]. |
To a suspension of 2,6-dibromopyridine [(L.] Oeq. ) in Et20 (0.2M) at -78C was added dropwise n-BuLi [(1.] [05EQ.).] The mixture was stirred at-78C for [45MIN] then acetone [(1.] 5eq.) was added. The final mixture was stirred for an extra [15MIN] at-78C and quenched with saturated aqueous NaHCO3,. The mixture was extracted with EtOAc (2x). The combined organic extracts were washed with, brine, dried over [MGS04,] filtered and concentrated to afford the title compound as a white solid which was used as such. | ||
Place a 1.6 M solution ofn-BuLi in hexane (5.2 mL) in a dry 100 mL roundbottomed flask fitted with a stir bar, septum and temperature probe. Cool in adry- ice acetone bath to -76 C. Add THF (5 mL) to the solution, then add asolution of2,6- dibromopyridine (2.0 g) in THF (10 mL) slowly via syringemaintaining the temperature below -60 C. Stir the solution for 30 min in thedry- ice bath, then add acetone (13.5 mL). Stir the solution in the dry-ice bathfor 15 min then allow the reaction to warm to room temperature. After 1 h thereaction mixture was quenched with a 5% aqueous solution ofNH4Cl, andextracted with EtOAc. The combined organic layer was washed with brine anddried over Na2S04? It was filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (Heptane:CH2Cb=70:30 toCH2Cb) to obtain compound 4-1 as an orange oil. | ||
Place a 1.6 M solution of n-BuLi in hexane (5.2 mL) in a dry 100 rnL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry- ice acetone bath to -76 C. Add THF (5 mL) to the solution, then add a solution of 2,6- dibromopyridine (2.0 g) in THF (10 mL) slowly via syringe maintaining the temperature under -60 C. Stir the solution for 30 min in the dry- ice bath, then add acetone (13.5 mL). Stir the solution in the dry-ice bath for 15 min then allow the reaction to warm to room temperature. After an h the reaction mixture was quenched with a 5% aqueous solution of NH4C1, and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2S04. It was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Heptane:CH2Cl2=70:30 to 0:100) to obtain compound 21-1 as a orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: To a well stirred mixture of AgF (1.27 g, 10 mmol) in 10 ml of DMF, Me3SiCF3 (1.7 g, 12 mmol) was added at room temperature. The mixture was stirred for 20 min and copper powder (1.0 g, 15 mmol) was added. After stirring for 4 h, the formation of CuCF3 was complete. The corresponding halogen containing compound (9 mmol) (in the case of 2,6-dibromopyridine, 4.5 mmol) was added and the reaction mixture was stirred under conditions surveyed in Table 1. The reaction was terminated unless signals of CuCF3 were no longer detected in the 19F NMR spectra. The mixture was filtered from the solid precipitate and poured into 50 ml of water. The organic layer was extracted with diethyl ether and dried over MgSO4. Ether was evaporated and the remainder was distilled under reduced pressure or crystallized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene; at 120℃; | The mixture of 2,6-dibromopyridines 1a (5.9 g, 0.025 mol), 2,4-dimethoxypheny boronic acids (13.7 g, 0.075 mol), sodium carbonate (15.9 g, 0.15 mol) and PdCI2(dppf) (0.20 g, 0.25 mmol) in toluene-ethanol (4:1 , 50 mL) was stirred overnight at 120 C. After cooling down to room temperature, the reaction mixture was filtered through ceiite and the filtrate was concentrated. The residue crude was purified to afford product 3c by flash column chromatography on silica gel with hexane-ethyl acetate (9:1 ) as eluent. (0119) 2,6-Bis(2,4-dimethoxyphenyi)pyridine (3c): 8.0 g, Yield: 92%. Solid, mp 1 13- 1 14C. 1 H-NMR (CDCI3, 300Hz): 7.93 (2H, d, J = 8.4Hz), 7.73-7.62 (3H, m), 6.62 (2H, dd, J = 2.1 and 8.4 Hz), 6.55 (2H, d, J = 2.1 Hz), 3.85 (12H, s). 13C-NMR (CDCI3, 75Hz): 161 .1 , 158.3, 155.0, 135.2, 132.3, 122.7, 122.2, 105.1 , 98.8, 55.6, 55.5. MS-EI: 351 (M•). HRMS (ESI(+)): Calcd. for C21 H22NO4 (M+H) : 352.1549. Found: 352.1537 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 4h;Reflux; | Compound 2-2 14.5g (50.6mmol), 2,6 - dibromo-pyridine (2,6-dibromopyridine) 24g (101mmol), Pd (PPh3) 4 2.9g (2.53mmol), K2CO3 14g (101.2mmol) of toluene (toluene), 300ml / 60ml EtOH / H2O 60ml in the mixture was dissolved and refluxed for 4 hr. After cooling to room temperature after completion of the reaction it was isolated by extraction with EA / H2O (Sat'd NaHCO3). The organic layer was dried with MgSO4 By distillation under reduced pressure to remove the solvent. Separated by column chromatography to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 25 - 80℃; for 12h;Inert atmosphere; | Xantphos (1.145 g, 1.98 mmol) was added to 2,6-dibromopyridine (3.51 g, 14.84 mmol), <strong>[109-11-5]morpholin-3-one</strong> (1 g, 9.89 mmol), PdOAc2 (0.111 g, 0.49 mmol) and Cs2C03 (6.45 g, 19.78 mmol) in 1,4-dioxane (100 mL) at 25 C under nitrogen. The resulting mixture was stirred at 80 C for 12 h. The reaction mixture was filtered through celite, evaporated to dryness and redissolved in DCM (75 mL), and washed sequentially with water (50 mLx2) and saturated brine (50 mLx2). The organic layer was dried over Na2SC"4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% petroleum ether in EtOAc, and pure DCM. Pure fractions were evaporated to dryness to afford the title compound (1.20 g, 47%). 1H NMR (400 MHz, DMSO-dg) δ 3.88 - 4.05 (4H, m), 4.28 (2H, s), 7.49 (1H, dd), 7.80 (1H, t), 8.10 (1H, dd). |
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | To a solution of <strong>[109-11-5]morpholin-3-one</strong> (500 mg, 4.95 mmol) inl,4-dioxane (50 ml) was added 2,6-dibromopyridine (1.52 g, 6.43 mmol), palladium(II) acetate (105 mg, 0.47 mmol), Xantphos (407 mg, 0.71 mmol) and Cs2CO3 (3.1 g, 9.42 mmol). The reaction mixture was stirred at 100 C for 16 h under N2. After 16 h, the reaction mixture was cooled to temperature, concentrated in vacuo and the crude product was purified via flash chromatography on silica gel (0-30% ethyl acetate in petroleum ether) to provide 4-(6-bromopyridin-2-yl)morpholin-3- one (350 mg, 27% yield) as a pale-yellow solid. LCMS (ESI) [M+H] = 257.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With sodium hydride; In N,N-dimethyl-formamide; at 100℃; | A mixture of sodium hydride (60percent w/w) (88 mg, 2.2 mmol, 1.1 eq) in anhydrous dimethylformamide (5.0 mL) was cooled down to 0 °C and 4?fluoro-3-methoxyphenol (2d) (184 mg, 2.0 mmol, 1.0 eq) was slowly added under argon. After 5 min a solution of 2,6-dibromopyridine (2c) (474 mg, 2.0 mmol, 1.0 eq) in anhydrous dimethylformamide (5.0 mL) was slowly added at room temperature and the reaction mixture was stirred overnight at 100 °C. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (cyclohexane/ethyl acetate 19:1) to give 154 mg (0.52 mmol, 26percent) of the analytically pure compound. C12H9BrFNO2; MW 298; 1H NMR (CDCl3, 400 MHz): delta 7.52 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 10.9 Hz, 8.8 Hz, 1H), 6.79 (dd, J = 7.4 Hz, 2.6 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.66 (ddd, J = 8.8 Hz, 3.6 Hz, 2.8 Hz, 1H), 3.86 (s, 3H); 13C NMR (CDCl3, 100 MHz): delta 163.0 (d, J = 1.3 Hz), 149.8 (d, J = 241.3 Hz), 149.7 (d, J = 3.2 Hz), 148.4 (d, J = 12.1 Hz), 141.4, 139.3, 122.6, 116.3 (d, J = 20.0 Hz), 112.8 (d, J = 7.0 Hz), 109.5, 107.2 (d, J = 2.3 Hz), 56.4; MS (ESI): 298, 300 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | To a solution of 2,6-dibromopyridine (5 g, 21.11 mmol) in dichloromethane (DCM) (100 mL) cooled to about -78 C., n-butyllithium (in hexane) while maintaining the internal temperature below -74 C. 2.5M)(9.29 mL, 23.22 mmol) was added dropwise. The reaction is stirred at this temperature for 15 minutes,Then 3-oxotetrahydrofuran (2.18 g, 25.3 mmol) was added in one portion.The reaction was stirred at about -78 C. for about 40 minutes.The reaction was poured into a mixture of saturated aqueous NH 4 Cl (110 mL) and DCM (80 mL) and stirred for about 30 minutes. The organic layer is separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue that is purified by silica gel chromatography eluting with 0-50% ethyl acetate / heptane to give the product. (3.85 g, 75% yield) was obtained. |
Tags: 2,6-Dibromopyridine | Pyridines | Bromides | Organic Building Blocks | Heterocyclic Building Blocks | 626-05-1
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H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
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 |
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