5-Bromo-2-methoxypyridine

Light yellow liquid

Step 1.A13k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction ; [] Step 1. 5-Bromo-2-methoxypyridine: A mixture of 2, 5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57.Reference Example 10 Reference Example 10 A mixture of 2, 5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57B3k. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction; Step 1. 5-Bromo-2-methoxypyridine; A mixture of 2, 5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2.x.100 mL). The combined organic layers were dried (NaStep 1. Step 1.A mixture of 2, 5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. 1) Step 1: 5-Bro -2-methoxypyridine A mixture of 2, 5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70°C for 1 hour and then allowed to cool to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over NaEthyl acetate (325 kg), sodium acetate (58 kg, 707 mol) and 2-methoxypyridine (68.7 kg, 630 mol) were mixed in a reactor vessel (inner volume 1000 L). To a suspension of 2-methoxypyridine (1-9) (3.96 kg; 36.3 mol), NaOAc (3.57 kg; 39.9 mol), and dichloromethane (22 L) was added a solution of bromine (2.06 L; 39.9 mol) in dichloromethane (2 L), maintaining the reaction temperature below 7°C over 2-3 hours. The mixture was aged for 1 hour at 0°C — 7°C and stirred at room temperature overnight. The reaction mixture was filtered and rinsed with dichloromethane (about 5 L) (the filtration stepmay be omitted without negatively impacting the yield). The filtrate and washings were combined, washed with cold 2 M NaOH (22 L; pH is maintained between 9 and 10) maintaining the temperature below 10°C, and with cold water (11 L). The organic layer was separated and concentrated under reduced pressure to give crude product 1-10 (6.65 kg). The crude product j 10 was purified by vacuum distillation to give pure 1-10 (5.90 kg, 86 percent). (Reference: G. Butoraet al., J. Amer. Chem. Soc. 1997, 119, 7694-7701).‘H NIVIR (250 MHz; CDC13): ö 8.18 (d, J= 2.5 Hz, 1H), 7.61 (dd, J= 8.8 and 2.5 Hz, 1H), 6.64 (d, J= 8.8 Hz, 1H), and 3.89 (s, 3H).‘3CNMR(62.9 MHz; CDC13): ö 162.9, 147.5, 141.0, 112.6, 111.7, and 53.7.Step h: A solution of 2-methoxy-pyridine (100 g, 0.92 mole), NBS (180 g, 1.0 mole) inacetonitrile (1. OL) was stirred at reflux for 21 h. TLC showed that the reaction wascomplete. The reaction mixture was cooled to room temperature and concentrated. 900ml solvent was collected. The resulting suspension was filtered and washed with n-hexane (400mL). The filtrate was concentrated again to afford crude product. The cmde product was distilled at reduced pressure (30°C[-0.3mmHg) to afford the title compound as a clearoil (146 g, 84percent). LCMS (m/z): 190.0 [M+1f ‘H NMR (400 MHz, CDC13): ö 3.90 (s, 3H), 6.65 (d, J= 8.8 Hz, 1H), 7.62 (dd, J= 8.8 Hz, 2.4Hz, 1H), 8.19 (s, 1H).A solution of bromine (13.1mL, 256.6 mMol) in glacial acetic acid (45 mL) was added drop wise into a mechanically stirred suspension of 2-Methoxy-pyridine (19 mL, 183 mMol) in glacial acetic acid (88 mL) with the temperature kept at ten degrees. a. a. a. (1) In a 500 ml reaction flask, 47 g of 2, 5-dibromopyridine, 8 g of solid sodium hydroxide and 200 ml of methanol, Stirring began to heat up to reflux, the reaction time was 5 hours, Stop the reaction, steamed most of the methanol, cooled, add 100 ml of water, Extract once with dichloromethane, remove methylene chloride to give the crude product, The crude product was distilled under reduced pressure to give 2-methoxy-5-bromopyridine, The yield is 98percent.Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL). The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was filtered through celite and concentrated. Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 12 g of the desired compound: Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL). a) Step 1. A solution of 5-bromo-2-nitropyridine (5.0 g, 24.63 mmol), in methanol (100 mL) was added sodium methoxide (2.67 g, 49.44 mmol) and stirred at 75 00 for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined extracts were washed with water (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient mixture of 5percent ethyl acetate in pet-ether as eluant to afford 2.5 g (54percent) of 5-bromo-2-methoxypyridine 122-1 as a colorless liquid. 1H NMR (400 MHz, CDCI3): c5 8.19 (d, J= 2.2 Hz, 1 H), 7.63 (dd, J= 1.8, 8.8 Hz, 1H), 6.66 (d, J= 8.7 Hz, 1H), 3.90 (5, 3H). ESI-LC/MS: m/z190.13 [(M+2)H+]; R = 3.13 mm [Agilent [C with Ion trap Detector; Waters Symmetry 018, 3.5 pm, 4.6 X 75 mm column; gradient of 50:50 H20 (0.1percent H000H): CH3CN (0.1percent H000H) to 10:90 H20 (0.1percent H000H): CH3CN (0.1percent H000H) in 4mm and hold for 3mm with flow rate of 1.0 mL/min].A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 10.4 mL, 5.19 mmol) was added to 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) dissolved in methanol (10 mL) at room temperature, stirred at 90° C. for 24 hours, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-methoxy-5-bromopyridine (97a, 160 mg, 33percent).

The structural unit of the β-alanine portion of the αvβ3 antagonist is also the structural unit for the synthesis of a potent and selective somatostatin sst3 receptor antagonist.

Molecular Weight:188.02
XLogP3:2.4
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:186.96328
Monoisotopic Mass:186.96328
Topological Polar Surface Area:22.1
Heavy Atom Count:9
Complexity:89.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes