* 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.
Stage #1: With thionyl chloride In N,N-dimethyl-formamide at 70℃; for 4 h; Stage #2: With water In N,N-dimethyl-formamide for 1 h;
Step B. 5-Bromo-2-chloro-nicotinic acid. A mixture of 5-bromo-2-hydroxy-nictonic acid (32.9 g, 0.151 mol), SOCl2 (167 mL), and DMF (10.5 mL) was heated at 70° C. for 4 h. The mixture was concentrated, cooled to 0° C., and quenched slowly with H2O to give an off-white precipitate. The precipitate was stirred in H2O for 1 h, and then was collected by filtration and dried under vacuum to give the title compound (35.5 g, 99percent). The product was carried on to the next step without purification, but alternatively may be recrystallized from hot H2O. MS (ESI): mass calcd. for C6H3BrClNO2, 234.90; m/z found, 236.2 [M+H]+. 1H NMR (acetone-d6): 8.66 (d, J=2.5, 1H), 8.43 (d, J=2.5, 1H).
47%
With thionyl chloride In N,N-dimethyl-formamide for 3 h; Reflux
5-Bromo-2-chloropyridine-3 -carboxylic acidTo 5-bromo-2-hydroxypyridine-3-carboxylic acid (Intermediate 10, 14 g, 64.2 mmol) was added thionyl chloride (70 mL) and dimethylformamide (8 mL). The reaction mixture was heated to reflux for 3 h. After cooling, the excess thionyl chloride was removed by rotary evaporation and the residue was poured into water (1 L) and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous sodium sulphate then filtered and concentrated to afford 7.0 g (47percent) of 5 -bromo-2-chloropyridine-3 -carboxylic acid. 1H NMR (400 MHz. DMSO-AO: δ 8.44 (s, IH), 8.72 (s, IH). Mass (APCI -ve Scan): m/z 235.9 (M-H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2566 - 2569
[2] Patent: US2006/287292, 2006, A1, . Location in patent: Page/Page column 26
[3] European Journal of Organic Chemistry, 2010, # 28, p. 5397 - 5401
[4] Synthetic Communications, 1989, vol. 19, # 3and4, p. 553 - 560
[5] Patent: WO2010/136817, 2010, A1, . Location in patent: Page/Page column 113
[6] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2178 - 2199
[7] Patent: US4592866, 1986, A,
[8] Patent: US4705853, 1987, A,
[9] Patent: US2003/125339, 2003, A1,
[10] Patent: US6878714, 2005, B2,
[11] Patent: US2003/225106, 2003, A1, . Location in patent: Page 104
[12] Patent: US2003/225106, 2003, A1, . Location in patent: Page 47
2
[ 609-71-2 ]
[ 29241-65-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2566 - 2569
[2] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2178 - 2199
[3] Synthetic Communications, 1989, vol. 19, # 3and4, p. 553 - 560
3
[ 2942-59-8 ]
[ 29241-65-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 760 - 763
4
[ 67-56-1 ]
[ 29241-65-4 ]
[ 78686-79-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 60℃; for 36 h; Stage #2: With sodium hydrogencarbonate In water
To 0.5 L flask charged with 5-Bromo-2-chloronicotinic acid (25.0 g, 106.4 mmol) in MeOH (250 mL) was added H2SO4 (5 mL). The mixture was heated to 60° C., stirred for 1.5 day. LC-MS indicated full conversion of starting material at this time. The reaction was cooled to RT and the volatile components removed in vacuo. The crude residue was dissolved in EtOAc (300 mL), quenched with sat. aqueous Na(HCO3)2 (200 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated to afford the compound, methyl-5-bromo-2-chloronicotinate, as a while solid (quantitative yield). LC-MS (M+H)=250.1.
89%
for 15 h; Reflux
Sulfuric acid (2 mL, 52.1 mmol) was added to the suspension of 5-bromo-2-chloronicotinic acid (1) (12.3 g, 52 mmol) was in methanol (100 mL). The mixture was stirred and refluxed for 15 hours. The solvent was evaporated and the residue was neutralized with saturated aqueous NaHC03(aq.). The result suspension was filtered and the solid was washed by water and dried by pump. Methyl 5-bromo-2-chloronicotinate (2) (11.6 g, 89 percent yield) was afforded. NMR (400 MHz, CDCL) δ 8.53 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, CDCL) δ 163.58, 152.75, 148.61, 142.49, 127.64, 118.57, 53.10. ESI-MS m/z: 251.9 (M+H+).
85%
at 90℃; for 12 h;
To a solution of 5-bromo-2-chloronicotinic acid (50 g, 211 mmol) in MeOH (200 mL) was added H2SO4 (20.7 g, 211.46 mmol) at 25 °C. The mixture heated to 90 °C and stirred for 12 hours. LCMS showed that the reaction was complete. The reaction was neutralized with Na2CO3 to pH = 7-8 and concentrated under reduced pressure to remove MeOH. The residue was extracted with EtOAc (300 mL x 3). The combined organic layer was concentrated under reduced pressure to give methyl 5-bromo-2-chloronicotinate (45 g, 180 mmol, 85percent yield) as a brown solid. ESI-MS (m/z): 249.9 (M+H)+
Reference：
[1] Patent: US2012/172391, 2012, A1, . Location in patent: Page/Page column 79
[2] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 18, p. 3533 - 3537
[3] Patent: WO2014/186398, 2014, A1, . Location in patent: Page/Page column 49; 50; 51
[4] Patent: WO2017/120429, 2017, A1, . Location in patent: Page/Page column 263
[5] Patent: US2012/178776, 2012, A1, . Location in patent: Page/Page column 42-43
5
[ 29241-65-4 ]
[ 18107-18-1 ]
[ 78686-79-0 ]
Yield
Reaction Conditions
Operation in experiment
69%
at 0℃; for 1 h;
Example 24; A. Methyl 5-bromo-2-chloropyridine-3-carboxylate; To a solution of S-bromo-l-chloropyridine-S-carboxylic acid (1.0 g, 4.2 mmol) in methanol :benzene (1 :1, 50 mL) was added trimethylsilyldiazomethane (3.2 mL, 6.5 mmol) at 0 0C. The reaction mixture was then stirred at 0 0C for 60 min. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL x 2). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous MgSO4 and evaporated under reduced pressure to provide the crude product. The crude product was purified through a filter column (Silica gel, 100-200 mesh) to provide methyl 5-bromo-2-chloropyridine-3-carboxylate as an off- white solid (0.72 g, 69percent). LC-MS: [M+H] + 251 1H NMR (400 MHz, CDCl3) δ: ppm 8.59 (s, IH) 8.35 (s, IH), 3.99 (s, 3H).
Reference：
[1] Journal of Chemical & Engineering Data, 1981, vol. 26, # 3, p. 332 - 333
7
[ 29241-65-4 ]
[ 78686-79-0 ]
Reference：
[1] Journal of Chemical & Engineering Data, 1981, vol. 26, # 3, p. 332 - 333
8
[ 29241-65-4 ]
[ 228251-24-9 ]
Reference：
[1] Patent: WO2017/133701, 2017, A1,
9
[ 29241-65-4 ]
[ 886365-47-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5578 - 5585
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 790 - 793
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4538 - 4541
10
[ 7664-41-7 ]
[ 29241-65-4 ]
[ 75291-85-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3 h; Stage #2: at -10 - 20℃; for 18 h;
Preparation 1775-Bromo-2-chloronicotinamide To a suspension of 5-bromo-2-chloronicotinic acid (20 g, 84.6 mmol) and oxalyl chloride (12.9 g,101.5 mmol) in DCM (500 mL) was added DMF (618 mg, 8.46 mmol) at room temperature. Thereaction effervesced and was stirred for 3 hours before concentrating to half volume in vacuo. The resulting solution was added carefully to a solution of 7N methanolic ammonia (50 mL) in DCM (200 mL) at -10°C, and the reaction was stirred for 18 hours at room temperature. The reaction was concentrated in vacuo, diluted with EtOAc (1 L), washed with water (500 mL), dried over sodium sulphate and concentrated in vacuo. The residue was triturated with cold DCM (200mL) to afford the title compound as a colourless solid (16.3 g, 82percent). 1H NMR (400 MHz, DMSO-d6): O ppm 7.81 (s, 1H), 8.08 (s, 1H), 8.21 (d, 1H), 8.63 (d, 1H).
Step B. 5-Bromo-2-chloro-nicotinic acid. A mixture of 5-bromo-2-hydroxy-nictonic acid (32.9 g, 0.151 mol), SOCl2 (167 mL), and DMF (10.5 mL) was heated at 70 C. for 4 h. The mixture was concentrated, cooled to 0 C., and quenched slowly with H2O to give an off-white precipitate. The precipitate was stirred in H2O for 1 h, and then was collected by filtration and dried under vacuum to give the title compound (35.5 g, 99%). The product was carried on to the next step without purification, but alternatively may be recrystallized from hot H2O. MS (ESI): mass calcd. for C6H3BrClNO2, 234.90; m/z found, 236.2 [M+H]+. 1H NMR (acetone-d6): 8.66 (d, J=2.5, 1H), 8.43 (d, J=2.5, 1H).
47%
With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux;
5-Bromo-2-chloropyridine-3 -carboxylic acidTo <strong>[104612-36-4]5-bromo-2-hydroxypyridine-3-carboxylic acid</strong> (Intermediate 10, 14 g, 64.2 mmol) was added thionyl chloride (70 mL) and dimethylformamide (8 mL). The reaction mixture was heated to reflux for 3 h. After cooling, the excess thionyl chloride was removed by rotary evaporation and the residue was poured into water (1 L) and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous sodium sulphate then filtered and concentrated to afford 7.0 g (47%) of 5 -bromo-2-chloropyridine-3 -carboxylic acid. 1H NMR (400 MHz. DMSO-AO: delta 8.44 (s, IH), 8.72 (s, IH). Mass (APCI -ve Scan): m/z 235.9 (M-H).
With thionyl chloride; In N-methyl-acetamide;
Preparation 48 5-Bromo-2-chloro-3-pyridinecarboxylic acid To 15 g (0.069 mole) of 5-bromo-2-hydroxy nicotinic acid was added 75 ml of thionyl chloride and 3 ml of dimethylformamide. The mixture was heated to reflux for 30 minutes. After cooling, the excess thionyl chloride was removed by rotary evaporation and the residue poured into water (1 liter) with vigorous agitation. The precipitate was collected and the mother liquor condensed to 1/2 the volume, yielding additional precipitate. The precipitates were combined and crystallized from toluene giving 6 g (37%) of material. The product was recrystallized from toluene, m.p. 174-177 C. Analysis: Calculated for C6 H3 NO2 ClBr: C, 30.48; H, 1.28; N, 5.92. Found: C, 30.21; H, 1.25; N, 5.89.
With thionyl chloride; In N-methyl-acetamide;
PREPARATION 48 5-Bromo-2-chloro-3-pyridinecarboxylic acid To 15 g (0.069 mole) of 5-bromo-2-hydroxy nicotinic acid was added 75 ml of thionyl chloride and 3 ml of dimethylformamide. The mixture was heated to reflux for 30 minutes. After cooling, the excess thionyl chloride was removed by rotary evaporation and the residue poured into water (1 liter) with vigorous agitation. The precipitate was collected and the mother liquor condensed to 1/2 the volume, yielding additional precipitate. The precipitates were combined and crystallized from toluene giving 6 g (37%) of material. The product was recrystallized from toluene, m.p. 174-177 C. Analysis: Calculated for C6 H3 NO2 ClBr: C, 30.48; H, 1.28; N, 5.92. Found: C, 30.21; H, 1.25; N, 5.89.
With thionyl chloride; In water; N,N-dimethyl-formamide;
Step B-Preparation of 5-bromo-2-chloronicotinic acid A solution of <strong>[104612-36-4]5-bromo-2-hydroxynicotinic acid</strong>, from Step A (8.3 g, 38.1 mmol) and SOCl2 (40 ml) in a 150 ml round bottom flask was placed in an 80 C. oil bath and stirred while adding 10 ml of DMF. The solution was heated at reflux for 4 h at 80 C. before cooling to RT. Excess SOCl2 was stripped off under reduced pressure forming a yellow-brown residue. The yellow-brown residue was placed in an ice bath and cooled to 0 C. Residual SOCl2 was neutralized and the chloro compound was precipitated by the dropwise addition of water. Precipitate was filtered, washed and dried to afford the desired chloro compound as a light yellow solid.
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 4h;Heating / reflux;
Step B-Preparation of 5-bromo-2-chloronicotinic Acid A solution of <strong>[104612-36-4]5-bromo-2-hydroxynicotinic acid</strong>, from Step A (8.3 g, 38.1 mmol) and SOCl2 (40 ml) in a 150 ml round bottom flask was placed in an 80 C. oil bath and stirred while adding 10 ml of DMF. The solution was heated at reflux for 4 h at 80 C. before cooling to RT. Excess SOCl2 was stripped off under reduced pressure forming a yellow-brown residue.The yellow-brown residue was placed in an ice bath and cooled to 0 C. Residual SOCl2 was neutralized and the chloro compound was precipitated by the dropwise addition of water.Precipitate was filtered, washed and dried to afford the desired chloro compound as a light yellow solid.
With sodium hydroxide; In tetrahydrofuran; dichloromethane; di-isopropyl ether; water;
7-Bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one To a suspension of 51.2 g of 60percent sodium hydride in oil (1.28 mole) in 1 liter of tetrahydrofuran heated to reflux, and under nitrogen atmosphere was added a solution of 144 g (0.61 mole) of 5-bromo-2-chloropyridine-3-carboxylic acid and 61.6 g (0.61 mole) of N-methyl-3-pyrrolidinol in 1 liter of tetrahydrofuran dropwise at reflux (~1 hr). Heating was continued at reflux with vigorous agitation for 1.5 hr. After cooling, approximately 5 ml of water was added and the mixture soon solidified. Additional tetrahydrofuran was added to aid in stirring. The mixture was filtered, washed with several portions of tetrahydrofuran, and dried at 50° C., 0.05 mm Hg, overnight to give 190 g of crude sodium salt. The entire amount of crude sodium salt (190 g) was added slowly to 1000 g of thionyl chloride cooled in an ice bath. The reaction mixture was stirred for 10 minutes at ~10° C. and 10 minutes at room temperature. Excess thionyl chloride was removed by rotary evaporation at 65° C., 30 mm Hg and the residue azetroped twice with toluene. The residue was taken up in ~1 liter of methylene chloride and diisopropylethyl amine and was added slowly until the solution just turned basic. The mixture was stirred for 1 hr at room temperature and washed successively with 2*200 ml of 1N hydrochloride acid, 2*200 ml of dilute sodium hydroxide and 100 ml of water. The organic phase was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The black residue was triturated 5 times with 5percent toluene in diisopropyl ether to give 60 g (31percent) of light brown crystals. A sample was recrystallized from diisopropyl ether, m.p. 71°-75° C. Analysis: Calculated for C11 H12 N2 O2 BrCl: C, 41.34; H, 3.79; N, 8.77. Found: C, 41.35; H, 3.81; N, 8.89.
60 g (31%)
With sodium hydroxide; In tetrahydrofuran; dichloromethane; di-isopropyl ether; water;
7-Bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one To a suspension of 51.2 g of 60percent sodium hydride in oil (1.28 mole) in 1 liter of tetrahydrofuran heated to reflux, and under nitrogen atmosphere was added a solution of 144 g (0.61 mole) of 5-bromo-2-chloropyridine-3-carboxylic acid and 61.6 g (0.61 mole) of N-methyl-3-pyrrolidinol in 1 liter of tetrahydrofuran dropwise at reflux (~1 hr). Heating was continued at reflux with vigorous agitation for 1.5 hr. After cooling, approximately 5 ml of water was added and the mixture soon solidified. Additional tetrahydrofuran was added to aid in stirring. The mixture was filtered, washed with several portions of tetrahydrofuran, and dried at 50° C., 0.05 mm Hg, overnight to give 190 g of crude sodium salt. The entire amount of crude sodium salt (190 g) was added slowly to 1000 g of thionyl chloride cooled in an ice bath. The reaction mixture was stirred for 10 minutes at ~10° C. and 10 minutes at room temperature. Excess thionyl chloride was removed by rotary evaporation at 65° C., 30 mm Hg and the residue azetroped twice with toluene. The residue was taken up in ~1 liter of methylene chloride and dissopropylethyl amine and was added slowly until the solution just turned basic. The mixture was stirred for 1 hr at room temperature and washed successively with 2*200 ml of 1N hydrochloride acid, 2*200 ml of dilute sodium hydroxide and 100 ml of water. The organic phase was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The black residue was triturated 5 times with 5percent toluene in diisopropyl ether to give 60 g (31percent) of light brown crystals. A sample was recrystallized from diisopropyl ether, m.p. 71°-75° C. Analysis: Calculated for C11 H12 N2 O2 BrCl: C, 41.34; H, 3.79; N, 8.77. Found: C, 41.35; H, 3.81; N, 8.89.
5-bromo-2-(2-methyl-3-trifluoromethylanilino)-nicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In methanol; sodium hydroxide;
EXAMPLE 2 5-Bromo-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid Heat in an oil bath at 170° C. a mixture of 15 g. of 5-bromo-2-chloro-nicotinic acid, 12.2 g. of <strong>[54396-44-0]2-methyl-3-trifluoromethyl aniline</strong> and 60 g. of phenol for three hours. Treat the resulting reaction mixture with ether and 5percent sodium bicarbonate solution, concentrate and steam distil to obtain an oily residue. Dissolve the oily residue in dilute sodium hydroxide solution, acidify with dilute hydrochloric acid and filter. Recrystallize the product from methanol to yield 5-bromo-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid, m.p. 222°-224° C.
Example 68 Synthesis of 4-(5-bromo-2-chloropyridin-3-yl)pyrimidine; 5-Bromo-2-chloronicotinic acid (10.0g, 42.3 mmol) was treated with thionyl chloride (10.0 mL, 137 mmol) and heated to 50 C for 18 hours. The volatiles were removed and the resulting crude acyl chloride was treated with 80 mL anhydrous THF, trimethylsilylacetylene (5.98 mL, 42.3 mmol), and copper iodide (322 mg, 1.79 mmol). The suspension was sparged with argon for 30 seconds then dichloropalladium bistriphenylphospine (594 mg, 0.846 mmol) was added followed by triethylamine (6.18 mL, 44.4 mmol). After a brief exotherm, the reaction mixture was stirred at ambient temperature for 1 hour before addition of <strong>[6313-33-3]formamidine hydrochloride</strong> (4.09 g, 50.8 mmol), sodium carbonate monohydrate (15.7 g, 127 mmol), and methanol (100 mL). After stirring at ambient temperature (mild exotherm) for 15 minutes, the reaction was heated to reflux for 3 hours. The mixture was then allowed to cool before it was filtered through Celite and concentrated in vacuo. The resulting oil was purified by column chromatography using 10-70% EtOAc/hexanes and triturated with diethyl ether to afford the title compound as a tan, crystalline solid. MS m/z = 270 (M+H)+. Calc'd for C9H5BrClN3: 270.52.
4.1
To a solution of 5-bromo-2- chloronicotinic acid (1.00 g, 4.23 mmol) in ethanol (8.5 mL) was added concentrated H2SO4 (1.40 mL, 25.38 mmol) drop wise over a minute. The reaction was heated to reflux for 2 hours. All solvent was removed in vacuo and the residue was taken up in ethyl acetate (20 mL) and washed once with 1 M NaOH (20 mL) and then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ethyl acetate was removed in vacuo. The remaining oil was used in the next step without further purification. MS (EI) for C8H7BrClNO2 found 263.90 (MH+).
With thionyl chloride for 6h; Reflux;
37.1 Step 1: Synthesis of ethyl 5-bromo-2-chloronicotinate
Add 5-bromo-2-chloronicotinic acid (140g, 0.592mol) to the flask, add ethanol (1.4L), ice-bath to 0 ° C, add dichlorosulfoxide (70.91g, 5.9mol), and heat to reflux Reaction for 6h.TLC showed the reaction was complete. The reaction solution was poured into ice water and extracted with EA (1000 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (200.0 g of crude product).
Example 24; A. Methyl 5-bromo-2-chloropyridine-3-carboxylate; To a solution of S-bromo-l-chloropyridine-S-carboxylic acid (1.0 g, 4.2 mmol) in methanol :benzene (1 :1, 50 mL) was added trimethylsilyldiazomethane (3.2 mL, 6.5 mmol) at 0 0C. The reaction mixture was then stirred at 0 0C for 60 min. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL x 2). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous MgSO4 and evaporated under reduced pressure to provide the crude product. The crude product was purified through a filter column (Silica gel, 100-200 mesh) to provide methyl 5-bromo-2-chloropyridine-3-carboxylate as an off- white solid (0.72 g, 69%). LC-MS: [M+H] + 251 1H NMR (400 MHz, CDCl3) delta: ppm 8.59 (s, IH) 8.35 (s, IH), 3.99 (s, 3H).
To 0.5 L flask charged with 5-Bromo-2-chloronicotinic acid (25.0 g, 106.4 mmol) in MeOH (250 mL) was added H2SO4 (5 mL). The mixture was heated to 60 C., stirred for 1.5 day. LC-MS indicated full conversion of starting material at this time. The reaction was cooled to RT and the volatile components removed in vacuo. The crude residue was dissolved in EtOAc (300 mL), quenched with sat. aqueous Na(HCO3)2 (200 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated to afford the compound, methyl-5-bromo-2-chloronicotinate, as a while solid (quantitative yield). LC-MS (M+H)=250.1.
89%
With sulfuric acid; for 15h;Reflux;
Sulfuric acid (2 mL, 52.1 mmol) was added to the suspension of 5-bromo-2-chloronicotinic acid (1) (12.3 g, 52 mmol) was in methanol (100 mL). The mixture was stirred and refluxed for 15 hours. The solvent was evaporated and the residue was neutralized with saturated aqueous NaHC03(aq.). The result suspension was filtered and the solid was washed by water and dried by pump. Methyl 5-bromo-2-chloronicotinate (2) (11.6 g, 89 % yield) was afforded. NMR (400 MHz, CDCL) delta 8.53 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, CDCL) delta 163.58, 152.75, 148.61, 142.49, 127.64, 118.57, 53.10. ESI-MS m/z: 251.9 (M+H+).
85%
With sulfuric acid; at 90℃; for 12h;
To a solution of 5-bromo-2-chloronicotinic acid (50 g, 211 mmol) in MeOH (200 mL) was added H2SO4 (20.7 g, 211.46 mmol) at 25 C. The mixture heated to 90 C and stirred for 12 hours. LCMS showed that the reaction was complete. The reaction was neutralized with Na2CO3 to pH = 7-8 and concentrated under reduced pressure to remove MeOH. The residue was extracted with EtOAc (300 mL x 3). The combined organic layer was concentrated under reduced pressure to give methyl 5-bromo-2-chloronicotinate (45 g, 180 mmol, 85% yield) as a brown solid. ESI-MS (m/z): 249.9 (M+H)+
With hydrogenchloride;
Compounds are represented in generic form, with sub stituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. In one aspect, ethers of type 6.7 can be prepared beginning with the commercially available 5-bromo-2-chloronicotinic acid, which is converted to the corresponding ester by reaction with methanol in the presence of an acid such as hydrochloric acid to yield compound 6.2. Alkylation to provide compound 6.3 is accomplished by use of a Suzuki cross coupling reaction using potassium allyltrifluoroborate in the presence of [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II). Reaction with 4-methoxybenzylamine affords compound 6.4. A cross-coupling reaction between compound 6.4 and benzyl alcohol in the presence of CuI, Cs2CO3, and a diamine ligand yields the aryl ether, compound 6.5. The p-methoxybenzyl protecting group is removed using cerium(IV) ammonium nitrate (CAN), followed by reduction of the carbonyl using lithium aluminum hydride. The amide, compound 6.7, is formed by reaction of the 3-(benzyloxy)-5,6,7,8-tetrahydro-1,6-naphthyridine, formed in the previous step, with benzoyl chloride.
With thionyl chloride; at 0 - 20℃; for 48h;
Add 25g Compound 1 to 75ml methanol,Cool to 0 , add 62.89g thionyl chloride dropwise,After the drop, the temperature is raised to room temperature for 2d;Sampling LCMS, the raw materials are basically reacted, most of the methanol is distilled off,The residue was poured into ice water, extracted with EA, the organic phases were combined, washed with salt, dried,Spin to dry to obtain 22.7g crude product.The crude product is directly invested in the next step.
Preparation 1775-Bromo-2-chloronicotinamide To a suspension of 5-bromo-2-chloronicotinic acid (20 g, 84.6 mmol) and oxalyl chloride (12.9 g,101.5 mmol) in DCM (500 mL) was added DMF (618 mg, 8.46 mmol) at room temperature. Thereaction effervesced and was stirred for 3 hours before concentrating to half volume in vacuo. The resulting solution was added carefully to a solution of 7N methanolic ammonia (50 mL) in DCM (200 mL) at -10C, and the reaction was stirred for 18 hours at room temperature. The reaction was concentrated in vacuo, diluted with EtOAc (1 L), washed with water (500 mL), dried over sodium sulphate and concentrated in vacuo. The residue was triturated with cold DCM (200mL) to afford the title compound as a colourless solid (16.3 g, 82%). 1H NMR (400 MHz, DMSO-d6): O ppm 7.81 (s, 1H), 8.08 (s, 1H), 8.21 (d, 1H), 8.63 (d, 1H).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
9 (S)-5-Bromo-2-chloro-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)nicotinamide (15)
General procedure: To a solution of 5-bromo-2-chloronicotinic acid (5 g, 21.2 mmol) and 5 (4.19 g, 25.4 mmol) in DMF (50 mL) were added DIPEA (11.08 mL, 63.4 mmol) and BOP reagent (10.29 g, 23.3 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h, quenched with water (200 mL) and extracted with [EtOAc/hexane = 1: 1] solution. The organic phase was washed with brine, dried over Na2SO4 and filtered. After removal of the solvent in vacuo, the residue was recrystallized from AcOEt and n-hexane to yield 15 as a white solid (4.82 g, 93%).
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