* 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.
15 drops of concentrated sulfuric acid are added to 5.0 g (23.1 mmol) of (5-bromopyridin-3-yl)acetic acid in 30 ml of ethanol, and the mixture is heated under reflux for 16 h. After cooling to RT, the mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with semiconcentrated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 5.2 g (91% of theory) LC-MS (Method 2): Rt=1.48 min; MS (ESIpos): m/z=244 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): delta=8.61 (d, 1H), 8.48 (d, 1H), 8.00 (dd, 1H), 4.10 (q, 2H), 3.33 (s, 2H), 1.20 (t, 3H).
91%
5.0 g (23.1 mmol) of (5-bromopyridin-3-yl)acetic acid in 30 ml of ethanol and 25 drops of conc. sulfuric acid are stirred at boiling point for 16 h. For work-up, the reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and washed repeatedly with semiconcentrated sodium bicarbonate solution, the organic phase is dried over sodium sulfate, the drying agent is filtered off, the solvent is removed completely on a rotary evaporator and the product is dried under reduced pressure for 16 h.Yield: 5.2 g (91% of theory)LC-MS (Method 1): Rt=1.48 min; MS (ESIpos): m/z=246 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=8.59 (d, 1H), 8.48 (d, 1H), 8.00 (dd, 1H), 4.11 (q, 2H), 3.78 (s, 2H), 1.21 (t, 3H).
With sulfuric acid;Reflux;
Step 1: 5-Bromo-3-pyridylacetic acid was treated with 5% concentrated sulfuric acid in EtOH at reflux overnight to give (5-bromo-pyridin-3-yl)-acetic acid ethyl ester.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 70℃;
Step 9: 3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid benzyl ester (1.96 g, 3.7 mmol), <strong>[847375-33-1](5-bromo-pyridin-3-yl)-acetic acid ethyl ester</strong> (0.99 g, 4.1 mmol), and potassium carbonate (1.79 g, 13.0 mmol) were combined in DME (40 mL) and H2O (30 mL), and the solution was purged with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.427 g, 0.37 mmol) was added, and the reaction was stirred at 70 C. overnight. The mixture was quenched with 1N aqueous HCl(13 mL) and extracted with EtOAc. The combined organic layers were washed with H2O, and then dried and concentrated to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-carboxymethyl-pyridin-3-yl)-benzoic acid benzyl ester.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;
Step 4: Cyclopropanecarboxylic acid benzyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amide (60% pure; 1.07 g, 1.4 mmol), <strong>[847375-33-1](5-bromo-pyridin-3-yl)-acetic acid ethyl ester</strong> (0.375 g, 1.5 mmol), and potassium carbonate (0.484 g, 3.5 mmol) were combined in DME (8 mL) and H2O (4 mL), and the solution was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol) was added, and the reaction was stirred at 90 C. overnight. The mixture was diluted with saturated aqueous NH4Cl and EtOAc. The aqueous layer was separated and extracted twice with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester, which was then hydrolyzed in the following step, as well as the hydrolyzed product.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 75℃; for 2h;Inert atmosphere;
Step 1: (5-Bromo-pyridin-3-yl)-acetic acid ethyl ester (1.91 g, 7.8 mmol), 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (50% pure; 2.94 g, 11.75 mmol), and potassium carbonate (3.25 g, 23.5 mmol) were combined in 2:1 DME:H2O, and the solution was purged with N2 for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.39 mmol) was added, and the reaction was purged with N2 for another 25 minutes and then stirred at 75 C. for 2 hours. The mixture was worked up with EtOAc and H2O, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give [5-(4-fluoro-2-formyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;
Step 1: To <strong>[847375-33-1](5-bromo-pyridin-3-yl)-acetic acid ethyl ester</strong> (5.0 g, 20.5 mmol) in CH2Cl2 (50 mL) was added meta-chloroperoxybenzoic acid (77 wt %; 7.03 g, 30.7 mmol), and the reaction was stirred overnight at room temperature. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3 and 1N aqueous NaOH to give (5-bromo-1-oxy-pyridin-3-yl)-acetic acid ethyl ester.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 70℃; for 1h;
Step 6: Cyclopropanecarboxylic acid benzyl-[5-cyano-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amide (1.33 g, 3.2 mmol), <strong>[847375-33-1](5-bromo-pyridin-3-yl)-acetic acid ethyl ester</strong> (1.02 g, 4.2 mmol), and potassium carbonate (1.55 g, 11.2 mmol) were combined in DME (40 mL) and H2O (30 mL), and the solution was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.370 g, 0.35 mmol) was added, and the reaction was stirred at 70 C. for 1 hour. The mixture was diluted with H2O and 1N aqueous HCl(15 mL), and extracted with EtOAc. The combined organic layers were concentrated and purified by preparative HPLC to give (5-{2-[(benzyl-cyclopropanecarbonyl-amino)-methyl]-4-cyano-phenyl}-pyridin-3-yl)-acetic acid ethyl ester, as well as the some of the hydrolyzed ester product.
Ethyl (2Z)-2-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
at 100℃; for 16h;
5.1 g (20.8 mmol) of the compound from Example 8A in 7.1 ml (6.2 g, 41.8 mmol) of dimethylformamide diethyl acetal are heated at 100 C. for 16 h. After cooling, the mixture is concentrated under reduced pressure. Yield: 6.1 g (73% of theory) LC-MS (Method 6): Rt=1.86 min; MS (ESIpos): m/z=299 [M+H]+.
5.1 g (20.9 mmol) of the compound from Example 10A are stirred in 7.2 ml (6.2 g, 41.8 mmol) of dimethylformamide diethyl acetal at a bath temperature of 100 C. for 16 h. After cooling, the mixture is concentrated under reduced pressure, the residue is stirred in diisopropyl ether, and the solid is filtered off and finally washed with diisopropyl ether. The crude product is dried under reduced pressure for 16 h.Yield: 6.1 g (73% of theory)LC-MS (Method 7): Rt=1.86 min; MS (ESIpos): m/z=299 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=8.49 (d, 1H), 8.29 (d, 1H), 7.78 (dd, 1H), 7.61 (s, 1H), 4.02 (q, 2H), 2.71 (s, 6H), 1.12 (t, 3H).
To a suspension of sodium hydride (251 mg, 5.33 mmol) in 10 mL of N,N- dimethylformamide at 0 C was added a solution of the title compound from Example 53 Step C (520 mg, 2.13 mmol) in N,N-dimethylformamide (2 mL). After 1 hour, iodomethane (0.29 mL, 4.67 mmol) in 2 mL of N,N-dimethylformamide was added. The resulting mixture was then allowed to warm to room temperature over 2 hours. The reaction was then quenched by addition of water, extracted and purified by flash chromatograph on silica gel (petroleum ethenethyl acetate = 40:1-20:1) to give the title compound: LCMS m/z 272 [M + H]+; 1H NMR (300 MHz, CDC13) delta 8.53 - 8.56 (m, 2 H), 7.80 (s, 1 H), 4.10 - 4.18 (m, 2 H), 1.60 (s, 2 H), 1.18 - 1.22 (m, 3 H).
2.4 g
To a cooled (0 C.) solution of NaH (60% dispersion in mineral oil, 822 mg, 0.034 mol) in DMF (40 mL) is added <strong>[847375-33-1](5-bromo-pyridin-3-yl)-acetic acid ethyl ester</strong> (3.8 g, 0.016 mol). After 2 h, iodomethane (6.4 g, 0.045 mol) is added. The resulting mixture is stirred at room temperature for 5 h. The reaction is quenched with the addition of water and is extracted with EtOAc. The combined organic layers are dried (Na2SO4) and concentrated. The crude product is purified by silica gel column to afford 2-(5-bromo-pyridin-3-yl)-2-methyl-propionic acid ethyl ester (2.4 g).
To a mixture of ethanol (10 mL) and cone. H2S04 (4 mL) was added the title compound from Example 53 Step B (0.50 g, 2.5 mmol) in 3 mL of ethanol at room temperature. The mixture was stirred at 90 C overnight. The reaction was poured into ice and made basic with saturated aqueous sodium bicarbonate solution. It was then extracted with ethyl acetate (2 x 30 mL), the organic layer was dried, concentrated and purified by flash chromatography on silica gel (petroleum ethenethyl acetate = 10:1) to give the title compound: LCMS m/z 244 [M + H]+; 1H NMR (300 MHz, CDC13) delta 8.60 (s, 1 H), 8.44 (s, 1 H), 7.82 (s, 1 H), 4.17 - 4.20 (m, 2 H), 3.61 (s, 2 H) , 1.27 - 1.30 (m, 3 H).
550 mg
With sulfuric acid; at 90℃; for 16h;
To a solution of 2-(5-bromopyridin-3-yl)acetonitrile (510 mg, 2.6 mmol) in ethanol (13 mL) was added con.H2SO4 (4.0 mL). The reaction was stirred at 90oC for 16 h. After the reaction was completed, the mixture?s pH was adjusted to 10 with saturated NaHCO3, then extracted with ethyl acetate (10 X 3 mL), washed with brine (5 mL). The organic phase was concentrated under vacuum. The residue was purified by column chromatography (3570) (PE:EA=2:1~1:5) to afford ethyl 2-(5-bromopyridin-3-yl)acetate (550 mg) as a yellow oil. (3571) LC/MS (ESI) m/z: 244.1 [M+1] +.
2-(5-Bromo-pyridin-3-yl)-N-(5-bromo-pyridin-2-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionamide[ No CAS ]
2-(5-Bromo-pyridin-3-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-(5-Bromo-pyridin-3-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionic acid ethyl ester The title compound was obtained starting from <strong>[847375-33-1](5-bromo-pyridin-3-yl)-acetic acid ethyl ester</strong> and 2-bromomethyl-5-methyl-furan following general procedure B1 for alkylation (0.33 g, 72%). C15H13BrF3NO3Mass (calculated) [392]; found [M+1] 392-394 bromine pattern.
1-(5-bromo-pyridin-3-yl)-cyclobutane carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With 18-crown-6 ether; In water; N,N-dimethyl-formamide; mineral oil;
1-(5-Bromo-pyridin-3-yl)-cyclobutane carboxylic acid <strong>[847375-33-1]Ethyl 2-(5-bromopyridin-3-yl)acetate</strong> (1.0 g, 4.09 mmol, 1eq) was dissolved in DMF (20 mL); 18-crown-6 ether (0.054 g, 0.205 mmol, 0.05eq) and NaH 60% dispersion in mineral oil (0.41g, 10.2 mmol, 2.5eq) were added and the mixture was stirred at room temperature for 30 minutes; 1,3-dibromopropane (0.46 mL, 4.50 mmol, 1.1 eq) was added dropwise and reaction was stirred at room temperature for 5h. NaOH 15% solution in H2O (10 mL) were added and the mixture was stirred for 16h at room temperature. H2O was added and pH was adjusted to pH=3 with HCl 6N. Aqueous solution was extracted with DCM (2 x20 mL), organic phases were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (cHex/AcOEt 5%-60%) to give the title compound (0.38 g, 37% over two steps).
37%
1-(5-Bromo-pyridin-3-yl)-cyclobutane carboxylic acid <strong>[847375-33-1]Ethyl 2-(5-bromopyridin-3-yl)acetate</strong> (1.0 g, 4.09 mmol, 1 eq) was dissolved in DMF (20 mL); 18-crown-6 ether (0.054 g, 0.205 mmol, 0.05 eq) and NaH 60% dispersion in mineral oil (0.41 g, 10.2 mmol, 2.5 eq) were added and the mixture was stirred at room temperature for 30 minutes; 1,3-dibromopropane (0.46 mL, 4.50 mmol, 1.1 eq) was added dropwise and reaction was stirred at room temperature for 5 h. NaOH 15% solution in H2O (10 mL) were added and the mixture was stirred for 16 h at room temperature. H2O was added and pH was adjusted to pH=3 with HCl 6N. Aqueous solution was extracted with DCM (2*20 mL), organic phases were collected, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (cHex/AcOEt 5%-60%) to give the title compound (0.38 g, 37% over two steps). C10H10BrNO2 Mass (calculated) [256]. found [M+1]=256-258 bromine pattern.
With copper(II) bis(trifluoromethanesulfonate); triethylamine; In N,N-dimethyl acetamide; at 20℃;Sealed tube;
General procedure: General Procedure A: Cu(OTf)2 (54.3 mg, 0.150 mmol, 0.30 equiv.) and arylboronic ester (1.00 mmol, 1.20 to 2.00 equiv.) were added sequentially to a 1 dram vial charged with a stirbar. The carboxylic acid (0.500 mmol, 1.00 equiv.) was added as a solution in anhydrous DMA (0.6 mL). Additional DMA (2×0.3 mL) was used to quantitatively transfer the solution to the reaction mixture. The solution was stirred until a homogeneous pale blue solution was formed (approximately 2 minutes, partially heterogeneous mixtures obtained when using increased Cu loadings), followed by the addition of triethylamine (0.42 mL, 3.0 mmol, 6.0 equiv.). The vial was sealed with a PTFE-lined cap, exposed to air via a needle, and gently stirred at room temperature. Upon completion of the reaction (24 to 72 h), the reaction mixture was diluted with EtOAc (40 mL), and washed sequentially with NH4Cl (15 mL), 0.5 M NaOH (2×20 mL), and brine (15 mL). The organic layer was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography. No difference was observed if reactions were prepared in an atmosphere-controlled glovebox, then exposed to ambient air.
28
[ 847375-33-1 ]
tert-butyl 4-(5-(1-ethoxy-3-methyl-1-oxobutan-2-yl)pyridin-3-yl)piperazine-1-carboxylate[ No CAS ]
ethyl 2-(5-(4-((1-(4-(3-(2,6-difluoro-3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-3-methylbutanoate[ No CAS ]
ethyl 2-(5-bromopyridin-3-yl)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
320 mg
A solution of ethyl 2-(5-bromopyridin-3-yl)acetate (100 mg, 0.41 mmol) in anhydrous THF 1mL was cooled to -78oC, LiHMDS (0.45 mL, 0.45 mmol) was added dropwise. After 30 min, 2-iodopropane (76.5 mg, 0.45 mmol) was added. The mixture was stirred at -78oC for 1 h, then left it to room temperature for 12 h. After the reaction was completed, it was quenched with water at 0oC. The mixture was extracted with EA (5 mL*3) and washed with brine (2 mL). The organic phase was concentrated under vacuum. The residue was purified by column chromatography (PE:EA=1:5~1:1) to afford 2-(5-bromopyridin-3-yl)-3-methylbutanoate (320 mg) as a yellow oil. LC/MS (ESI) m/z: 287.0 [M+1] +.
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