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Structure of 101990-45-8
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CAS No. : | 101990-45-8 |
Formula : | C6H5Br2N |
M.W : | 250.92 |
SMILES Code : | BrCC1=CN=C(Br)C=C1 |
MDL No. : | MFCD11656267 |
InChI Key : | CRRMIKBAPPOPNW-UHFFFAOYSA-N |
Pubchem ID : | 6424660 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302+H312-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P362+P364-P405-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
With bromine; In dichloromethane; water; for 0.5h;Heating / reflux; | Generally, to a refluxing mixture of 2-bromo-methyl-pyridine (5 g, 29 mmol) in a biphasic medium of DCM (500 ml) and water (500 ml) was added Br2 (1.65 ml, 31.9 mmol). The mixture was illuminated using a halogen lamp (500 W, distance: 5-10 cm) under reflux for 30 min. The solution was cooled to room temperature and neutralized with a 10% Na2CO3 aqueous solution and solid NaCl was added. The aqueous layer was extracted three times with DCM, the combined organic extracts were dried over MgSO4 and evaporated in vacuo. HPLC analysis of the crude product showed the relative ratio of 13.6:76.5:9.9 (Retention time: 8.1, 10.6 and 13.4 min, respectively) for starting material 2-bromo-methyl-pyridine:2-bromo-5-(bromomethyl)pyridine: 2-bromo-5-(dibromomethyl)pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | In toluene; at 119℃; for 2h;Inert atmosphere; | To a solution of 2-bromo-5-(bromomethyl)pyridine (3.7 g, 14.7 mmol) in toluene (30 mL) was added triphenylphosphine (5.02 g, 19.2 mmol). The reaction mixture was degassed three times under N2 and stirred at 119C for 2 hrs. The mixture was filtrated, and theresidue was washed with hexane and filtrated again to give ((6-bromopyridin-3- yl)methyl)triphenylphosphonium bromide (7.3 g, 96.5% yield) as a white solid. LC-MS: m/z 433 [M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With phosphorus tribromide; at 0 - 160℃; for 2.5h; | Phosphorous tribromide (100 mmol, 27. 1 g, 2. 0 eq.) was added carefully to 2- CHLORO-5-HYDROXYMETHYL pyridine (50. 0 mmol, 7. 18 g, 1. 0 eq.). The pyridine clumped together and the mixture was heated to 160 degrees C. Within 5 minutes of stirring at > 150 degrees C the mixture was seen to go very dark in color with gas evolution. The mixture was stirred at this same temperature for approximately 2. 5 hours at which point it was cooled to room temperature. The mixture was cooled further to 0 degrees C whereupon saturated sodium bicarbonate was added very cautiously (highly exothermic .). As foaming became less vigorous, ice was added to the mixture until foaming subsided. Solid sodium bicarbonate was then carefully added to achieve a pH of-8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient of 0-100 % ethyl acetate in hexanes to afford the title compound as a pale yellow solid (5. 57 g, 44%). LRMS : 252 (M+H) +. 'H NMR (DMSO-d6, 400 MHz) ; 8. 39 (1H, s) 7. 59 (1H, D, J = 8. 5 Hz) 7. 48 (1H, d, J = 8. 5 Hz) 4. 46 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 85℃; for 0.5h; | (Referential Example 8) Synthesis of 2-bromo-5-(bromomethyl)pyridine (referential compound 8) N-Bromosuccinimide (16 g, 91 mmol) and 0.40 g (2.4 mmol) of 2,2'-azobis(isobutyronitrile) were added to a solution of 12 g (70 mmol) of 2-bromo-5-methylpyridine in 100 ml of 1,2-dichloroethane and the mixture was stirred at 85C. After 15 minutes, 0.40 g (2.4 mmol) of 2,2'-azobis(isobutyronitrile) was added thereto and the mixture was stirred for 15 minutes. After the reaction was finished, water was added to the reaction solution and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 10:1 to 9:1 (v/v)) and the fraction containing the aimed substance was concentrated in vacuo to give 15 g of the title compound as white powder (yield: 89%). Rf value: 0.63 (n-hexane: ethyl acetate = 9:1 (v/v)) Mass spectrum (CI, m/z): 250, 252, 254 (M+ + 1) 1H-NMR spectrum (CDCl3, δ ppm): 4.42 (s, 2H), 7.49 (d, J = 8.3Hz, 1H), 7.61 (dd, J1 = 8.3Hz, J2 = 2.7Hz, 1H), 8.39 (d, J = 2.7Hz, 1H) |
82.2% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; at 80℃; | 2-Bromo-5-methylpyridine 19a (10.0g, 58.13mmol) was dissolved in carbon tetrachloride (100mL),Add N-bromosuccinimide (10.9g, 61.24mmol) at room temperatureAnd dibenzoyl peroxide (200mg, 0.83mmol),The temperature was raised to 80C and reacted overnight.The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated.The crude product was purified by silica gel column chromatography to obtain the title compound 19b (12 g, yield 82.2%). |
61% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; at 90℃; for 2.5h; | 37A (5g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL) and N-bromosuccinimide (5.43 g, 30.52 mmol) and azodiisobutyronitrile (1.19 g, 7.27 mmol) were added to the reaction at 90 C for 2.5 h. Cooled to room temperature, concentrated reaction solution, residue separated and purified with silica gel column chromatography (PE: EA (v/v) = 10:1) to give title compound 37B (4.42g, 61%). |
59% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride;Reflux; | Synthesized from 2-bromo-5-methylpyridine (3.00 g, 17.40 mmol), NBS (3.41 g, 19.20 mmol) and DBPO (230 mg, 0.80 mmol) in carbon tetrachloride according to Method A. Yield: 2.56 g (59 %); lachrymatory yellow needles; 1 H NMR (CDCIs, 500 MHz): δΗ (ppm) = 4.14 (s, 2H), 7.47 (d, J = 8.2 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 8.38 (s, 1 H); MS (ESI): m/z = 252.37 [M+H]+.Methylpyridine was dissolved in 40 ml_ of dry carbon tetrachloride. To this solution was added /V-bromsuccinimide (NBS) (1.1 eq) and benzoyl peroxide (5 mol%) and the mixture was refluxed over night. After cooling, the succinimide was removed by filtration and the filtrate was concentrated under vacuum. The crude product was further purified by flash column chromatography on silica gel using a mixture of petroleum ether / ethyl acetate (95:5) as eluent. |
52.6% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; at 80℃; for 2h;Inert atmosphere; | To a solution of 169-51 (5.0 g, 29.1 mmol) in Cd4 (40 mL) was added NBS (5.22 g, 29.1 mmol) and BPO (350 mg, 1.4 mmol). The reaction mixture was stirred at 80 C under an atmosphere of nitrogen for 2 hours. The mixturewas diluted with DCM, washed with water and brine, dried, and concentrated to dryness. The remaining residue was purified by column chromatography on silica gel (eluted with PE/EtOAc = 120:1) to afford 169-S2 (3.81g, 52.6% yield) as a yellow oil. LC/MS (ESI) m/z: 250 (M+H)t |
50% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; at 75℃; for 2h;Inert atmosphere; | Step 1) 2-bromo-5-(bromomethyl) pyridine To a solution of 2-bromo-5-methylpyridine (17 g, 100 mmol) in carbon tetrabromide (250 mL) was added AIBN (164 mg, 1mmol) and the mixture was heated to 75 C, and then NBS (26.7 g, 150 mmol) was added, and the mixture was stirred for 2 h. TLC showed that the reaction was complete, water (150 mL) was added and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3.0g of the residue, which was purified by column chromatography (silica gel 200-300 mesh, PE/EA= 1000:1 to 10:1) to give intermediate 2-bromo -5-(bromomethyl) pyridine (13 g, 50% yield). MS (ESI), m/z, 250.9 [M+1]+. |
49% | With N-Bromosuccinimide;dibenzoyl peroxide; In Carbon tetrachloride; for 4h;Heating / reflux; | 2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1.4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHCO3/H2O. The mixture was adsorbed onto silica gel and then chromatographed. eluting with a gradient of hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49%). LC/MS (M+H)+ m/z=249.8, 251.8, 253.8. |
49% | Step A2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1 .4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHC03/H2O.The mixture was adsorbed onto silica gel and thenchromatographed. eluting with a gradient of hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49%). LC/MS (M+H)+ m/z = 249.8, 251.8, 253.8. | |
46% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane; at 55℃; for 6h;Heating; Irradiation; | Example 16 Step 1: A mixture of 2-bromo-5-methylpyridine (10 g, 58 MMOL), N-bromosuccinimide (15.5 g, 87.2 MMOL), and AZOBISISOBUTYRONITRILE (0.25 g) in anhydrous CH2CI2 (100 ml) was heated at 55 C under irradiation (200W lamp) for 6 h. The mixture was cooled down to RT, diluted with CH2CI2 (200 ML), washed with saturated NaHCO3 solution, dried (MGS04), filtered and concentrated. The residue was subjected to silica gel flash chromatography (5<7% EtOAc/hexanes) to afford the product (6.75 g, 46%). |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | Synthesis Example 18 N-[1-((6-bromopyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound 231) An amount of 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 mL of carbon tetrachloride, following which 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added and the mixture was refluxed under heating for 19 hours. Following reaction completion, the reaction mixture was returned to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 143 mg of 2-bromo-5-bromomethylpyridine (yield, 20%). 1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 ml of carbon tetrachloride, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 19 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 143 mg (yield 20%) of 2-bromo-5-bromomethylpyridine. [0250] 1H-NMR (CDCl3, δ, ppm): 4.42(2H, s), 7.47(1H, d), 7.59(1H, dd), 8.38(1H, d) |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 ml of carbon tetrachloride, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 19 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 143 mg (yield 20%) of 2-bromo-5-bromomethylpyridine. [0240] 1H-NMR (CDCl3, δ, ppm) : 4.42(2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | In 15 ml of carbon tetrachloride, 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved. To this solution, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added, followed by heating under reflux for 19 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1). Thus, 143 mg of 2-bromo-5-bromomethylpyridine was obtained (Percentage Yield: 20%). 1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) |
With N-Bromosuccinimide; azobisisobutyronitrile; In Carbon tetrachloride; ethyl acetate; | Step A 2-Bromo-5-bromomethyl-pyridine 2-Bromo-5-methylpyridine (4.01 g, 23.31 mmol), NBS (5.19 g, 29.14 mmol), and AIBN (0.19 g, 1.17 mmol) were dissolved in CCl4 (46.6 mL, 23.31 mmol). The reaction mixture was heated to 75 C. for 4 h. The residue was quenched with water and extracted from EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo in vacuo. The crude mixture was purified by flash column chromatography on silica gel eluted with 7% EtOAc/hexane to give 2.65 g of the title compound. MS m/e 251.9 (M+). | |
With N-Bromosuccinimide; In Carbon tetrachloride; hexane; ethyl acetate; | Step D Preparation of 2-bromo-5-(bromomethyl)pyridine In a three neck flask equipped with a stir bar and a reflux condenser, a solution of 2-bromo-5-methylpyridine (40.0 g, 0.225 mol) and N-bromosuccinimide (45.0 g, 0.252 mol) in carbon tetrachloride (800 mL) was irradiated with a 300 watt lamp. After 3 h, the solution was cooled, and the solvent removed in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by flash chromatography on silica gel using 7% ethyl acetate in hexane. The title product was obtained as a white solid. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; | Step 4: Preparation of 2-bromo-5-bromomethylpyridine. A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g (173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 69% monobromomethyl product): NMR (CDCl3) δ 4.42 (s, 2H), 7.48 (d, J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; | Step 2 2-bromo-5-bromomethyl pyridine To a flask was charged 2-bromo-5-methylpyridine (34.9 mmol, 6.0 g), N-bromosuccinimide (38.4 mmol, 6.83 g), benzoyl peroxide (3.49 mmol, 0.85 g) and carbon tetrachloride (60 mL). This solution was refluxed for 6 hr, cooled to ambient temperature and purified on a silica gel column. Eluted with ethyl acetate: hexane (1:9) to provide the title compound. FAB MS: calc: 250.9 found: 251.9. 1 H-NMR (CDCl3): 4.4 ppm (s, 2H); 7.5 ppm (d, 1H); 7.6 ppm (d, 1H); 8.4 ppm (s, 1H). | |
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; at 75℃; for 5h; | To a suspension of 2-bromo-5-methyl-pyridine 11 (5.0Og, 29 mmol) and NBS (5.162g, 29 mmol) in CCl4 (40 mL) is added AIBN (0.477g, 2.9 mmol). The reaction is stirred at 75 0C for 5 hours and filtered. The filter cake is washed with CCl4, and the filtrate is evaporated to give a light yellow residue. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; for 1.5h;Heating / reflux; | a) (S)-tert-Buty{ 2-amino-3-(6-bromopyridin-3-yl)propanoatePrepared according to the procedures detailed in Patent WO2006/127948.To a slurry of 2-bromo-5-methylpyridine (10.29 g) and N-bromosuccinimide (5.32 g) in carbon tetrachloride (150 mL) was added AIBN (200 mg) and the reaction vessel was purged with nitrogen. The reaction mixture was heated, under reflux, for 1.5 h then allowed to cool <n="54"/>to room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-bromo-5-(bromomethyl)pyridine (4 g). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride;Reflux; | To a solution of 2-Bromo-5-methylpyridine (3.1 g, 17.4 mmol) in carbon tetrachloride (40 mL, 400 mmol) was added benzoyl peroxide (230 mg, 950 μmol) and NBS (3.4 g, 19.2 mmol). The resulting mixture was heated at reflux overnight. The mixture was cooled at 0 C. and the NBS was removed by filtration. The filtrate was concentrated to yield 2-bromo-5-bromomethylpyridine (4.6 g), which was used directly in the next step. | |
With N-Bromosuccinimide;dibenzoyl peroxide; In Carbon tetrachloride;Inert atmosphere; Reflux; | To a solution of 2-bromo-5-methylpyridine ((3.1 g, 17.4 mmol, 1 eq.) in carbon tetrachloride (40 mL, 400 mmol) was added benzoyl peroxide (230 mg, 950 μmol) and NBS (3.4 g, 19.2 mmol, 1.1 eq.). The resulting mixture was heated at reflux overnight. The mixture was cooled at 0 C. and filtered. The filtrate was concentrated to yield 2-bromo-5-bromomethylpyridine (4.6 g), which was used without further purification. | |
With N-Bromosuccinimide; [2-(1,1'-biphenyl)-4-yl]-5-phenyloxazole; In Carbon tetrachloride; at 80℃; for 16h;Inert atmosphere; | To a solution of 2-bromo-5-methyl-pyridine (20 g, 1 16.96 mmol) in CCL, (200 mL) was added NBS (21 .56 g, 122.80 mmol) and BPO (0.4 g, 1 %) under N2. The mixture was stirred at 80 C for 16 hr, then cooled to r.t., filtered and concentrated to afford the desired crude compound which was used directly in the next step. LCMS: m/z 252 (M+l )+. | |
With N-Bromosuccinimide; In 1,2-dichloro-ethane; at 85℃; for 0.5h; | 2-bromo-5-methyl-pyridine (70.0 mmol) and N-bromosuccinimide (80.0 mmol) were dissolved in 1,2- dichioroethane (150 ml) and to this mixture 2,2’-azobis(2- ethylpropionitrile) (1.50 mmol) was added. The reaction mixture was heated under reflux at 85 C. for 15 minutes and next portion of 2,2’-azobis(2-methylpropionitrile) (1.50 mmol) was added and reaction mixture was heated at 85 C. for further 15 minutes. After cooling to room temperature was the reaction mixture kept at 5 C. for 2 hours and the precipitate was filtered off and washed with small amount of 1 ,2-dichlo- roethane. The filtrate was evaporated under reduced pressure and the crude product was used for further reaction step without purification. The crude 2-bromo-5-bromomethyl-py- ridine was dissolved in chloroform (100 ml) and urotropine (70.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off, washed with small amount of chloroform and dried on air. The crude urotropine salt was refluxed in a mixture of conc. ammonium hydroxide (12 ml) and water (80 ml) for 90 minutes and afier cooling to room temperature, 40% formaldehyde (5.0 ml) was added with stirring. The precipitate was filtered off, washed with ice-cold water and dried in vacuum dessicator. The crude product was crystallized from ethanol. Yield: 40% m.p. 105-106 C. Elemental analysis: Calcd. for C5H7HrN2 (187.04): C, 38.53; H, 3.77; N, 14.98. Found: C, 38.22; H, 3.72; N, 14.71. HPLC-MS (ESI+): 188.02(97.2%). ‘H NMR (DMSO, d5): 4.04 (t, J=5.67, 2H, CH2), 7.71 (d, J=8.19, 1H,ArH), 7.95 (dd, J=8.19, J’=i.95, 1H,ArH), 8.51 (d, J=i .95, 1H, ArH), 8.74 (s(br), 2H, NH2). | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 90℃; for 12h;Inert atmosphere; | To a solution of 2-bromo-5-methyl-pyridine (20.0 g, 116 mmol) in acetonitrile (300 mL) was added 2,2-azobisisobutyronitrile (1.91 g, 11.63 mmol) and N-bromosuccinimide (24.8 g, 139 mmol), and the mixture was stirred at 90 C for 12 hrs under nitrogen atmosphere. On completion, the reaction was concentrated to give a residue. The residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give the title compound. MR (400MHz, CDC13) δ = 8.40 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 2.6, 8.2 Hz, 1H), 7.51 (d, J= 8.3 Hz, 1H), 4.42 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium hydrogencarbonate; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; | Preparation c-80 2-Bromo-5-(bromomethyl)pyridine Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine clumped together and the mixture was heated to 160 degrees C. Within 5 minutes of stirring at >150 degrees C. the mixture was seen to go very dark in color with gas evolution. The mixture was stirred at this same temperature for approximately 2.5 hours at which point it was cooled to room temperature. The mixture was cooled further to 0 degrees C. whereupon saturated sodium bicarbonate was added very cautiously (highly[exothermic]). As foaming became less vigorous, ice was added to the mixture until foaming subsided. Solid sodium bicarbonate was then carefully added to achieve a pH of ~8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient of 0-100% ethyl acetate in hexanes to afford the title compound as a pale yellow solid (5.57 g, 44%). LRMS: 252 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (1H, s) 7.59 (1H, d, J=8.5 Hz) 7.48 (1H, d, J=8.5 Hz) 4.46 (2H, s). |
44% | With sodium hydrogencarbonate; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; | Preparation d-19 2-Bromo-5-(bromomethyl)pyridine Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine clumped together and the mixture was heated to 160 C. Within 5 minutes of stirring at >150 C. the mixture went very dark in color with gas evolution. The mixture was stirred at this same temperature for approximately 2.5 hours at which point it was cooled to room temperature. The mixture was cooled further to 0 C. whereupon saturated sodium bicarbonate was added very cautiously (highly[exothermic]). As foaming became less vigorous, ice was added to the mixture until foaming subsided. Solid sodium bicarbonate was then carefully added to achieve a pH of ~8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient of 0-100% ethyl acetate in hexanes to afford the title compound as a pale yellow solid (5.57 g, 44%). LRMS: 252 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (1H, s) 7.59 (1H, d, J=8.5 Hz) 7.48 (1H, d, J=8.5 Hz) 4.46 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ammonium chloride; lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; ethyl acetate; | Preparation c-81 Ethyl 2-[(6-bromopyridin-3-yl)methyl]tetrahydrofuran-2-carboxylate To a solution of <strong>[16874-34-3]ethyl tetrahydrofuran-2-carboxylate</strong> (52.9 mmol, 9.10 g, 1.5 eq.) cooled to -78 degrees C. in THF (90 mL) was added dropwise a solution of 2 M lithium diisopropylamide (52.9 mmol, 1.5 eq.) in a mixture of heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the same low temperature whereupon a solution of 2-bromo-5-(bromomethyl)pyridine (35.3 mmol, 8.85 g, 1.0 eq.) in THF was added dropwise. The reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage Sp4 65i over a gradient of 5% to 95% ethyl acetate in hexanes to afford a golden oil (8.70 g, 78%). LRMS: 315 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): delta 8.21 (1 H, s) 7.40-7.49 (2 H, m) 3.94 (2 H, q, J=7.0 Hz) 3.71-3.85 (2 H, m) 3.05-3.11 (1 H, m) 2.91-2.97 (1 H, m) 2.38-2.47 (1 H, m) 1.83-2.09 (3 H, m) 1.09 (3 H, t, J=7.0 Hz) |
78% | To a solution of <strong>[16874-34-3]ethyl tetrahydrofuran-2-carboxylate</strong> (52. 9 mmol, 9. 10 g, 1. 5 eq.) cooled to-78 degrees C in THF (90 mL) was added dropwise a solution of 2 M lithium DIISOPROPYLAMIDE (52. 9 mmol, 1. 5 eq.) in a mixture of heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the same low temperature whereupon a solution of 2-BROMO-5- (BROMOMETHYL) pyridine (35. 3 MMOL, 8. 85 g, 1. 0 eq.) in THF was added dropwise. The reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage SP4 65i over a gradient of 5% to 95 % ethyl acetate in hexanes to afford a golden oil (8. 70 g, 78%). LRMS : 315 (M+H) T. H NMR (DMSO-D6, 400 MHz) :. 8. 21 (1 H, s) 7. 40-7. 49 (2 H, m) 3. 94 (2 H, q, J=7. 0 Hz) 3. 71-3. 85 (2 H, m) 3. 05-3. 11 (1 H, m) 2. 91-2. 97 (1 H, m) 2. 38-2. 47 (1 H, m) 1. 83-2. 09 (3 H, m) 1. 09 (3 H, t, J=7. 0 HZ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methoxy dimethylmalonate; ethyl acetate; | Preparation d-20 Dimethyl [(6-bromopyridin-3-yl)methyl](methoxy)malonate To a slurry of potassium t-butoxide (46.6 mmol, 5.22 g, 1,3 eq.) in anhydrous DMF (250 mL) cooled to 0 C. was added methoxy dimethylmalonate (46.6 mmol, 7.55 g, 1,3 eq.) via syringe in small portions. The enolate was allowed to form over approximately 30 minutes at which point 2-bromo-5-(bromomethyl)pyridine was added portionwise. The reaction mixture was allowed to warm slowly to room temperature over 3 hours. The reaction mixture was diluted with ethyl ether and transferred to a separatory funnel containing saturated ammonium chloride. The layers were shaken and separated and the organic layer was washed with water. The organic layer was then dried over anhydrous magnesium sulfate and concentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4 65i over a gradient of 0-100% ethyl acetate in hexanes to afford a colorless oil that solidified on standing (12.1 g, quant.) LRMS: 333 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.27 (1 H, s) 7.45-7.55 (2 H, m) 3.82 (6 H, s) 3.57 (3 H, s) 3.42 (2 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 0 - 20℃; | 2-bromo-5-(bromomethyl)pyridine 1 in 5 ml dry THF was added to the solutions of 2a-c at 0 C. under argon and stirred at room temperature overnight. The reactions were monitored by HPLC. After the reaction was completed, 2 ml of MeOH-AcOH (1:1) was added to quench the reaction and the resulting solution was extracted with DCM (3*30 ml). The collected DCM phase was washed twice with H2O and dried over Mg2SO4 overnight. Purification by chromatography on silica with DCM containing MeOH (0.5~2.0%) as an eluant following evaporation solvent gave the products 3a-c as sticky oils. 2-bromo-5-((2-methoxyethoxy)methyl)pyridine 3a was obtained over two steps. CI-MS: m/z 246 (M)+; CI-HRMS [M]+ calcd. for C9H13BrNO2: 246.0130 found: 246.0131. δH (400 Hz, CDCl3): 8.27 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 3.60-3.58 (m, 2H), 3.53-3.51 (m, 2H), 3.33 (s, 3H). δC (75 Hz, CDCl3): 149.1, 141.0, 137.9, 133.0, 127.7, 71.7, 69.8, 69.7 and 58.9. 2-bromo-5-((2-(2-methoxyethoxy)ethoxy)methyl)pyridine 3b over two steps. CI-MS: m/z 290 (M)+; CI-HRMS [M]+ calcd. for C11H17BrNO3: 290.0389 found: 290.0392. δH (400 Hz, CDCl3): 8.28 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.50 (s, 2H), 3.64-3.63 (m, 4H), 3.61-3.59 (m, 2H), 3.51-3.49 (m, 2H), 3.33 (s, 3H). δC (75 Hz, CDCl3): 149.1, 141.0, 137.9, 133.0, 127.7, 71.7, 70.4(2), 70.4(1), 69.8, 69.7 and 58.9. 2-bromo-5-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)methyl)pyridine 3c over two steps. CI-MS: m/z 334 (M+H)+; CI-HRMS [M+H]+ calcd. for C13H21BrNO4: 334.0654 found: 334.0656. δH (400 Hz, CDCl3): 8.28 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 4.50 (s, 2H), 3.64-3.59 (m, 10H), 3.52-3.49 (m, 2H), 3.33 (s, 3H). δC (75 Hz, CDCl3): 149.3, 141.2, 138.0, 133.2, 127.8, 71.9, 70.6, 70.5(4), 70.4(6), 69.9, 69.8 and 59.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | The crude is dissolved in anhydrous THF (40 mL). DIEA (5.03 mL, 29mmol) is added, followed by addition of morpholine (3.0 mL, 34.3 mmol). After stirring at room temperature for 1 hour, the reaction is partitioned between saturated NaHCO3 (30 mL) and EtOAc (100 mL) and separated. EtOAc is washed with brine (30 mL), dried and evaporated. The crude is purified by flash column chromatography (SiO2, 1%NH3 in CH3OH/CH2C12 from 0 to 10%) to give a light tan colored solid: 1H NMR 400 MHz (DMSO-d6) δ 8.31 (d, J = 2.4 Hz, IH), 7.69 (dd, J = 2.4, 8.4 Hz, IH), 7.62 (d, J = 8.0 Hz, IH), 3.57 (t, J = 4.8 Hz, 4H), 3.48 (s, 2H), 2.35 (t, J = 4.4 Hz, 4H); MS m/z 257.1 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.333333h;Irradiation; | {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5- morpholin-4-ylmethyl-pyridin-2-yl)-amine (41). A suspension of (6-[3-(2,6-dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin- 4-ylamine (41) (30 g, 0.076 mmol), 4-(6-bromo-pyridin-3-ylmethyl)-morpholine 12 (29 mg, 0.1 14mmol), Xantphos (10 mg, 0.0178 mmol), palladium (II) acetate (2 mg, 0.0089 mmol) and cesium carbonate (50 mg, 0.152 mmol) in dioxane (1.5 mL) is degassed. After purging with Ar, the vial is sealed by the cap and irradiated at 15O0C for 20 minutes in Smith Synthesizer. The reaction mixture is treated with 4 ml of 5% diethyl dithiocabamyl acid sodium salt solution. The solid is collected by filtration and washed with water, then dried. The crude is purified by silica gel flash chromatography eluting with 1%NH3 in CH3OH/EtOAc from 0 to 10%) to afford the desired product {6-[3-(2,6-dichloro-3,5- dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-morpholin-4-ylmethyl-pyridin-2-yl)-amine (41) (Example 94). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In 1,3-dioxane; water; at 20℃; for 15h; | Step 3: (6-Bromopyridin-3-yl) acetonitrile To a stirred solution [OF NACN (117G,] 2. [38MOL)] in dioxane (1L) and water (1L), was added the above crude <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> (275g) and the mixture was stirred at rt for 15h. The reaction mixture was quenched with cold water [(15L)] and extracted with EtOAc [(3X1L).] The organic layer was washed with water [(3X1 L),] brine [(2X1 L),] dried with [NA2S04] and concentrated under reduced pressure to give crude title compound. The crude residue was purified by column chromatography over silica gel (pet. [ETHER/ETHYLACETATE,] 7: 3) to give 95g [(6-BROMOPYRIDIN-3-YL)] acetonitrile as a pale yellow solid (49%). [TLC, [RF=] 0.5, pet. [ETHER/ETHYLACETATE] 7: 3] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dibenzoyl peroxide; In chloroform; for 6h;Heating / reflux; | Step 2: 2-Bromo-5-bromomethylpyridine To a suspension of 2-bromo-5-methylpyridine (170g, 0. [95MO1)] in [CC14] (2L) was added NBS (193g, [1.] [08MOL)] and benzoylperoxide (15g) and the mixture was refluxed for 6h. The reaction mixture was cooled down to rt and the solid formed was filtered off. The filtrate was concentrated affording 275g of crude 2-bromo-5-bromomethylpyridine which was used without further purification in the next step (mixture of mono-bromo and di-bromo). [TLC, [RF=] 0.7, pet. ether/ethylacetate 9: 1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium tert-butylate; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 3.5h; | To a slurry of potassium t-butoxid (46. 6 mmol, 5. 22 G, 1. 3 eq.) in anhydrous DMF (250 mL) cooled to 0 C was added methoxy dimethylmalonate (46. 6 MMOL, 7. 55 G, 1. 3 eq.) via syringe in small portions. The ENOLATE was allowed to form over approximately 30 minutes at which point 2-BROMO-5- (BROMOMETHYL) pyridine was added portionwise. The reaction mixture was allowed to warm slowly to room temperature over 3 hours. The reaction mixture was diluted with ethyl ether and transferred to a separator funnel containing saturated ammonium chloride. The layers were shaken and separated and the organic layer was washed with water. The organic layer was then dried over anhydrous magnesium sulfate and concentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4 65i over a gradient of 0-100 % ethyl acetate in hexanes to afford a colorless oil that solidified on standing (12. 1 g, quant.) LRMS : 333 (M+H) +. H NMR (DMSO-D6, 400 MHz) ; 8. 27 (1 H, s) 7. 45-7. 55 (2 H, m) 3. 82 (6 H, s) 3. 57 (3 H, s) 3. 42 (2 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Step 2: To a solution of the product from Step 1 (3.5 g, 14 mmol) in anhydrous THF (60 ml) at 0 C was added benzylmagnesium chloride (2.0 M/THF, 10.6 ML, 21 MMOL). The reaction mixture was stirred at 0 C for 30 min and at RT for 2 h. The reaction was quenched with saturated NH4CI aqueous solution, extracted with EtOAc, dried (MGS04), filtered and concentrated. The residue was subjected to silica gel flash chromatography (5: 95 EtOAc/hexanes) to afford the product (2.4 g, 66%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | In DMF (N,N-dimethyl-formamide); at 20℃; for 15h; | A solution of the amine (1 equiv) and <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography. Examples a) R1 = dimethylaminoethyl The general procedure was followed using <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> (3.9 G) and dimethylamino ethylamine (5.5 g) in DMF (100 ML). Silica gel chromatography (4% MeOH in DCM) gave the pure product (0.62 g, 25%). LC-MS-SHOWS a single peak, M+H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In DMF (N,N-dimethyl-formamide); at 20℃; for 15h; | A solution of the amine (1 equiv) and <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography. Examples a) R1 = phenethyl The general procedure was followed using 2-BROMO-5-BROMOMETHYLPYRIDINE (8.7 g) and phenylethylamine (16.7 g) in DMF (250 ML). Silica gel chromatography (4% ICAEOH in DCM) gave the pure product (10.0 g, 99%). 1H NMR (CDCI3, 400MHZ) : 8 2.77-2. 90 (4H, M), 3.76 (2H, S), 7.18-7. 32 (5H, m), 7.45 (1H, d), 7.52 (1H, dd), 8.27 (1H, d). LC-MS- shows a single peak, M+H 291,293 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 2h; | Example 17 Step 1: A mixture of the product from Example 16, Step 1 (0.70 g, 2.8 MMOL), phenol (0.19 g, 2.0 MMOL), and K2CO3 (0.58 g, 4.2 mmol) in anhydrous DMF (10 ml) was heated to 90 C for 2 h. The mixture was cooled down to RT, diluted with water, extracted with ether, dried (MGS04), filtered and concentrated. The residue was subjected to flash chromatography (5: 95 EtOAc/hexanes) to afford the product as white solid (0.38 g, 71 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 20℃; for 6h; | Reference Example 76; 2-bromo-5-(1-pyrrolidinylmethyl)pyridine; [] A solution of 2-bromo-5-(bromomethyl)pyridine (9.06 g, 36.1 mmol), pyrrolidine (3.62 ml, 43.3 mmol) and potassium carbonate (9.98 g, 72.2 mmol) in acetonitrile (45 ml) was stirred at room temperature for 6 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous potassium carbonate solution and saturated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (7.31 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In methanol; at 20℃; for 3h; | 2-Bromo-5-(methoxymethyl)pyridine. 2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hekane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (M+H)+ m/z=202.0. |
90% | In methanol; at 20℃; for 3h;Inert atmosphere; | Step B2-Bromo-5-(methoxymethyl)pyridine. 2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (M+H)+ m/z = 202.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In N,N-dimethyl-formamide; at 60℃; for 0.5h; | (Referential Example 10) Synthesis of 2-bromo-5-(cyanomethyl)pyridine (referential compound 10-1) Potassium cyanide (7.80 g, 120 mmol) was added to a solution of 15.0 g (60.0 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong>(referential compound 8) in 150 ml of N,N-dimethylformamide and the mixture was slowly stirred at 60C for 15 minutes. After that, water was added thereto little by little until potassium cyanide was completely dissolved and then the mixture was stirred at 60C for 15 minutes. After the reaction was finished, the reaction solution was poured into ethyl acetate/saturated aqueous solution of ammonium chloride and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 9:1 to 7:3 (v/v)) and the fraction containing the aimed substance was concentrated in vacuo to give 9.24 g of the title compound as pale yellow powder (yield: 61%). Rf value: 0.15 (n-hexane: ethyl acetate = 4:1 (v/v)) Mass spectrum (CI, m/z): 197, 199 (M+ + 1) IR spectrum (KBr, cm-1): 2253 1H-NMR spectrum (CDCl3, δ ppm): 3.74 (s, 2H), 7.61-7.53 (m, 2H), 8.36-8.35 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropylamine; | Step B 2-[(N-Diphenylmethylene)amino]-3-(4-bromo-3-pyridinyl) propanoic acid, ethyl ester To a solution of N-(diphenylmethylene)glycine ethyl ester (4.30 g, 16.11 mmol) in TEE (25 mL) at -78 C. was added dropwise a 2.0M solution of LDA in TEE (8.0 mL, 16.0 mmol). After being stirred for 30 min at -78 C., a solution of 2-bromo-5-bromomethyl-pyridine in 10 mL of TEE was added and the reaction allowed to warm to rt. After 1 h, the reaction was diluted with EtOAc (50 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil. The oil was purified by flash column chromatography on silica gel eluted with hexane/EtOAc (10:1) to yield 2-[(N-diphenylmethylene)amino]-3-(4-bromo-3-pyridinyl) propanoic acid, ethyl ester as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver nitrate; In water; acetone; | Step E Preparation of 2-bromo-5-(hydroxymethyl)pyridine To a solution of 2-bromo-5-(bromomethyl)pyridine, as described above in Step D, (2.15 g, 8.57 mmol) in acetone (100 mL) was added a solution of silver nitrate (2.18 g, 12.9 mmol) in water (100 mL). The reaction was stirred in the dark at 25 C. for 72 hours. The reaction was filtered and the acetone was removed in vacuo. The residue was partitioned between methylene chloride (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (1*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (40→90% ethyl acetate/hexane) to provide the title compound as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; N,N-dimethyl-formamide; | REFERENCE EXAMPLE 99 (+)-6-(2-Bromopyridin-5-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin Dihydrochloride To a solution of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (0.220 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.049 g) at room temperature. The reaction mixture was stirred at 50 C. for 30 min. To the reaction mixture, cooled at 0 C., was added a solution of 2-bromo-5-pyridylmethylbromide (0.462 g) in THF (5 ml). After stirring at 0 C. for 2 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and converted into its dihydrochloride, which was recrystallized from ethanol-ethyl acetate to obtain the titled compound (295 mg). m.p.: 171-181 C. (decomposed). [α]D20=+41.2 C. (c=0.500 in methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
109 g (32% from 2-bromo-5-picoline) | In N-methyl-acetamide; water; | Step 5. Preparation of 2-bromo-5-cyanomethyl-pyridine The 476 g of crude <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5-57.5 C.; NMR (CDCl3) δ 3.74 (s, 2H), 7.54 (d, J=8 Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In tetrachloromethane; | Step 4: Preparation of 2-bromo-S-bromomethylpyridine A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) δ 4.42 (s, 2H), 7.48 (d, J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
109 g (32% from 2-bromo-5-picoline) | In N-methyl-acetamide; water; | Step 5: Preparation of 2-bromo-5-cyanomethyl-pyridine. The 476 g of crude <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5-57.5 C.; NMR (CDCl3)δ3.74 (s, 2 H), 7.54 (d, J=8 Hz, 1 H), 7.59 (dd, J=8 and 2 HZ, 1 H), 8.35 (d, J=2 Hz, 1 H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; N,N-dimethyl-formamide; | Step 3 5-(4-Cyanobenzyl)-1-(2-bromopyrid-5-ylmethyl)imidazole To a flask was charged 1-trityl -4-p-cyanobenzyl imidazole (2.77 mmol, 1.18 g) from Step 1 and 2-bromo-5-bromomethyl pyridine (2.77 mmol, 0.67 g) from Step 2 in DMF (10 mL) and the mixture heated at 100 C. for 6 hr. The DMF was then removed in vacuo and the residue was triturated with ethyl ether. The ethyl ether was then decanted off and replaced with methanol (20 mL). This solution was then refluxed for 4 hr, cooled to ambient temperature and purified on a C18 preperative hplc column to provide the title compound. High resolution FAB-MS: calc; 353.040183 found; 353.040183. 1 H-NMR (CD3 OD): 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 7.2 and 7.6 ppm (d, 2H); 8.1 ppm (s, 1H); 9.1 ppm (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In tetrachloromethane; | Step 4: Preparation of 2-bromo-5-romomethylpyridine. A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3)δ4.42 (s, 2 H), 7.48 (d, J=9 Hz, 1 H), 7.60 (dd, J=9 and 3 Hz, 1 H), 8.37 (d, J=3 Hz, 1 H). | |
With N-Bromosuccinimide; In tetrachloromethane; | Step 4: Preparation of 2-bromo-5-romomethylpyridine A solution of 296.3 g (1.72 mol) of 2-bromo-5picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) δ4.42 (s, 2H), 7.48 (d, J=9Hz, 1H), 7.60 (dd, J=9 and 3Hz, 1H), 8.37 (d, J=3Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; N-butylamine; In 1,4-dioxane; methanol; dichloromethane; ethyl acetate; | EXAMPLE VI N-(6-Bromopyridin-3-ylmethyl)-N-butylamine STR27 A solution of 2 g (7.97 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> and 2.91 g (39.85 mmol) of n-butylamine in 20 ml of dioxane is heated under reflux for 2 h. Subsequently, the solvent is removed in vacuo and the residue is taken up in ethyl acetate/dichloromethane, which is then washed with water and a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on silica gel using dichloromethane/methanol (95:5). Yield: 1.42 g (73% of theory) Rf =0.49 (dichloromethane/methanol=95:5) |
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