* 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 hydrogen; sodium hydrogencarbonate In water at 20℃; for 50 h; Stage #2: With hydrogenchloride In water
(2) Manufacture of 3-aminopyridine-2-carboxylic acid 3-nitropyridine-2-carboxylic acid (2.72 g, 16.2 mmol) and sodium hydrogencarbonate (1.34 g, 16.2 mmol) were dissolved in distilled water (20 mL), and the atmosphere in the system was replaced by nitrogen. After adding 10percent palladium charcoal (1.72 g), the atmosphere in the system was replaced by hydrogen, and the mixture stirred at room temperature for 50 hours. 1N hydrochloric acid aqueous solution was added, and the pH of the reaction solution was adjusted to weak acidity. The solvent was distilled off under reduced pressure, a small amount of ethanol and ethyl acetate were added to the residue, and the precipitate produced was filtered off. The filtrate was concentrated, and the target substance (1.50 g, 67percent) was thus obtained as a light yellow solid.
A suspension of 3-aminopicolinic acid (1-18) (28 g, 200 mmoL, 1.0 eq) in EtOH (800 mL) at room temperature was bubbled with HCI (g) for 10 min. The reaction turned into a clear yellow solution. After being stirred at 100°C for 1 day, LCMS indicated that about 50percent of starting material remained. The reaction mixture was cooled to rt and bubbled with HCI (g) for 10 min. The mixture was then re-heated to 100 °C. After being stirred at 100 °C for 1 day, LCMS indicated that about 50percent of the starting material remained. The reaction mixture was cooled to rt and all solvents were removed under reduced pressure. The residue was resolved in EtOH (800 mL) and was bubbled with HCI (g) for 10 min. The resulting mixture was refluxed at 100°C oil bath for 1 day. LCMS indicated about 70-75 percent conversion. The reaction mixture was cooled to rt and all solvents were removed under reduced pressure. The solid was dissolved in 250 mL water and the solution was quenched to pH = 8-9 with saturated aq Na2C03. A gas was generated and a white solid formed. The suspension was filtered, washed with water, and dried under vacuum at 65°C to afford 22 g of ethyl 3-aminopicolinate (1-19) in 65percent yleld as a white solid. LCMS (APCI, M+ + 1 ) 167.0; 1H NMR (300 MHz, DMSO-c/6) 8 ppm 7.84 (dd, J = 4.05, 1 .60 Hz, 1 H), 7.23 - 7.30 (m, 1 H), 7.16 - 7.23 (m, 1 H), 6.65 (br. s., 2 H), 4.27 (q, J = 7.10 Hz, 2 H), 1 .30 (t, J = 7.06 Hz, 3 H).
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 1, p. 54 - 61
[2] Patent: WO2016/97918, 2016, A1, . Location in patent: Page/Page column 55
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 7, p. 2196 - 2207
[4] Journal of the Chemical Society, 1949, p. 3304,3310
[5] Journal of the Chemical Society, 1956, p. 1045,1053
[6] Journal of the Chemical Society, 1949, p. 3304,3310
[7] Journal of the Chemical Society, 1956, p. 1045,1053
[8] Bulletin de la Societe Chimique de France, 1992, # 1, p. 79 - 84
[9] Patent: WO2008/24438, 2008, A2, . Location in patent: Page/Page column 44
[10] Patent: WO2008/24433, 2008, A2, . Location in patent: Page/Page column 46
[11] Patent: WO2008/66664, 2008, A2, . Location in patent: Page/Page column 44
[12] Patent: WO2012/74951, 2012, A1, . Location in patent: Page/Page column 47
[13] Patent: WO2009/121036, 2009, A2, . Location in patent: Page/Page column 42
13
[ 1462-86-8 ]
[ 37538-67-3 ]
Reference：
[1] Journal of the Chemical Society, 1956, p. 1045,1053
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 973,974
[3] Patent: US5034393, 1991, A,
14
[ 1462-86-8 ]
[ 77287-34-4 ]
[ 37538-67-3 ]
Reference：
[1] Journal of the Chemical Society, 1956, p. 1045,1053
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 914
15
[ 1462-86-8 ]
[ 39551-54-7 ]
Reference：
[1] Journal of the Chemical Society, 1956, p. 1045,1053
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 973,974
[3] Patent: US2012/122838, 2012, A1,
[4] Patent: WO2013/12915, 2013, A1,
[5] Patent: CN106083742, 2016, A,
[6] RSC Advances, 2017, vol. 7, # 36, p. 22360 - 22368
16
[ 1462-86-8 ]
[ 57-13-6 ]
[ 37538-68-4 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 200℃; for 5 h;
(1) 4 g of 3-aminopyridine-2-carboxylic acid (starting material A3), 20 g of urea was refluxed at 200 ° C for 5 h to give intermediate B3, The yield of 27percent; specific reaction equation is as follows:
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 9, p. 2663 - 2670
[2] Patent: CN106083742, 2016, A, . Location in patent: Paragraph 0185; 0186; 0187
[3] Journal of the Chemical Society, 1956, p. 1045,1053
17
[ 1462-86-8 ]
[ 37538-68-4 ]
Reference：
[1] Chemische Berichte, 1952, vol. 85, p. 1012,1019
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 973,974
18
[ 67-56-1 ]
[ 1462-86-8 ]
[ 36052-27-4 ]
Yield
Reaction Conditions
Operation in experiment
77%
for 120 h; Reflux
(Step 1) (1070) To a solution of 3-aminopyridine-2-carboxylic acid (20 g, 144.9 mmol) in methanol (300 mL) was added conc. sulfuric acid (5.4 mL), and the mixture was heated under reflux for 5 days. The reaction mixture was concentrated under reduced pressure, water was added thereto, and sodium carbonate was added thereto until the complete of foaming. The mixture was extracted with dichloromethane (x3), the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 3-aminopyridine-2-carboxylate (17.0 g, 77percent) as a pale yellow solid. 1H-NMR(300MHz,CDCl3):δ3.95(3H,s),5.72(2H,brs),7.03(1H,dd,J=0.99,8. 35Hz),7.18-7.21(1H,m),8.05(1H,dd,J=0.96,4.04Hz).
76%
Stage #1: at 80℃; for 168 h; Stage #2: With sodium carbonate In water
A solution of 3-aminopyridine-2-carboxylic acid(Bioorg. Med Chem. 2001,9, 2061) (1.0 g, 7.25 mmol) andH2SO4 (2.75 ml) in methanol (15 ml) was heated at 80 oC for 7 days. The reaction was cooled and the methanol removed by evaporation. The residue was poured into water (ca. 30 ml) and solid sodium carbonate was added until effervescence ceased(pH ~7). The mixture was extracted with dichloromethane (4 x 50 ml) and the combined organic fractions dried over MgS04 and concentrated to give the title compound as a beige solid (0. 84 g, 76 percent). 1H NMR (360 MHz,CDCl3) 8 8.07(1H, dd, J4. 2,1. 4), 7.22(1H, dd,J8. 4,4. 2), 7.05(1H, dd, J8. 4,1. 4), 5.73 (2H, brs), 3.98 (3H, s).Mlz (ES+) 153 (M+H+).
54.47%
at 15 - 80℃; for 120 h;
To a suspension of 3-aminopicolinic acid (100 g, 724 mmol, 1.0 eq.) in dry MeOH (1.5 L) was added conc.H2SO4 (460 g, 4.69 mol, 6.48 eq.) dropwise at 15° C. and the mixture was heated to 80° C. and stirred for 5 days. The reaction mixture was concentrated to about 500 mL and diluted with cold water (2 L). The resulting mixture was adjusted to about 9 with solid Na2CO3 at 0° C. and extracted with DCM/MeOH (10:1, 1.0 L*5). The combined orange layers were dried over Na2SO4, filtered and concentrated to give methyl 3-aminopicolinate (60 g, 394.35 mmol, 54.47percent yield, 100percent purity) as a brown solid. 1H NMR (400 MHz, CDCl3) δ=8.08-8.06 (m, 1H), 7.24-7.20 (m, 1H), 7.06-7.01 (m, 1H), 5.75 (br. s, 1H), 3.97 (s, 3H). ESI [M+H]=153.1
41%
With hydrogenchloride In water at 85℃; for 12 h;
3-Aminopyridine-2-carboxylic acid (10.0 g, 72.5 mmol) was dissolved in methanol (100 ml). After cooling to 0° C., concentrated hydrochloric acid (25 ml) was added dropwise thereto, and the reaction solution was stirred at 85° C. for 12 hours. After the solvent was removed under reduced pressure, water and sodium hydrogen carbonate (10 g) were added to the obtained residue, followed by stirring and extraction with ethyl acetate (80 ml×4). The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was stirred in petroleum ether/ ethyl acetate=8:1, and the obtained solid was filtered and dried under reduced pressure to obtain the title compound (4.50 g, 41percent). [1164] 1H-NMR (400 MHz, DMSO-d6): δ 7.85-7.83 (m, 1H), 7.27-7.20 (m, 2H), 6.66 (s, 2H), 3.80 (s, 3H).; MS (ESI) m/z 153 (M+H)+
Reference：
[1] Patent: EP2975031, 2016, A1, . Location in patent: Paragraph 1070
[2] Patent: WO2005/49613, 2005, A1, . Location in patent: Page/Page column 39
[3] Patent: US2017/190713, 2017, A1, . Location in patent: Paragraph 0260
[4] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 1163-1164
[5] Chemical Communications, 2016, vol. 52, # 59, p. 9283 - 9286
19
[ 1462-86-8 ]
[ 18107-18-1 ]
[ 36052-27-4 ]
Yield
Reaction Conditions
Operation in experiment
54%
at 20℃;
Example 6; Synthesis of (+/-)-9- [acetyl -(3 ,5-bis-trifluoi"omethylbenzyl)amino] -2-bromo-6,7 ,8 ,9- tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid'isopropyl ester; Step 1;. Preparation of 3-amino-pyridine-2-carboxylic acid methyl ester; Add dropwise a solution of trimethylsilyl diazomethane (2.0 M in toluene, 7.24 mL, 14.48 mmol) to a solution of 3-amino-pyridine-2-carboxylic acid (1.0 g, 7.24 mmol) in ethyl acetate (5 mL) and methanol (5 mL) at room temperature. After the addition is complete, remove the solvent under reduced pressure. Suspend the residue in water (5 mL), add a saturated solution of sodium bicarbonate, and extract with ethyl acetate. Separate the organic layer, dry over sodium sulfate, and filter. Remove the solvent under reduced pressure to afford the title compound (590 mg, 54percent). MS (ES+): 153 (M+H).
A suspension of 3-aminopicolinic acid (1-18) (28 g, 200 mmoL, 1.0 eq) in EtOH (800 mL) at room temperature was bubbled with HCI (g) for 10 min. The reaction turned into a clear yellow solution. After being stirred at 100C for 1 day, LCMS indicated that about 50% of starting material remained. The reaction mixture was cooled to rt and bubbled with HCI (g) for 10 min. The mixture was then re-heated to 100 C. After being stirred at 100 C for 1 day, LCMS indicated that about 50% of the starting material remained. The reaction mixture was cooled to rt and all solvents were removed under reduced pressure. The residue was resolved in EtOH (800 mL) and was bubbled with HCI (g) for 10 min. The resulting mixture was refluxed at 100C oil bath for 1 day. LCMS indicated about 70-75 % conversion. The reaction mixture was cooled to rt and all solvents were removed under reduced pressure. The solid was dissolved in 250 mL water and the solution was quenched to pH = 8-9 with saturated aq Na2C03. A gas was generated and a white solid formed. The suspension was filtered, washed with water, and dried under vacuum at 65C to afford 22 g of ethyl 3-aminopicolinate (1-19) in 65% yleld as a white solid. LCMS (APCI, M+ + 1 ) 167.0; 1H NMR (300 MHz, DMSO-c/6) 8 ppm 7.84 (dd, J = 4.05, 1 .60 Hz, 1 H), 7.23 - 7.30 (m, 1 H), 7.16 - 7.23 (m, 1 H), 6.65 (br. s., 2 H), 4.27 (q, J = 7.10 Hz, 2 H), 1 .30 (t, J = 7.06 Hz, 3 H).
63.6%
With sulfuric acid; at 0 - 90℃; for 25h;
To a stirred suspension of 3-aminopicolinic acid (150 g, 1086 mmol) in ethanol (1500 mL) at 0-5 C was added H2SO4 (463 mL, 8688 mmol) through a 1 L addition funnel over 60 min. After completion of the addition, the reaction mixture turned to a clear brown solution which was refluxed at 90 C for 24 h. The reaction mixture was cooled to room temperature and poured onto ice pellets in a 10 L beaker with overhead stirring, basified using NH4OH solution (~2 L required) to pH ~9, and stirred at room temperature for 60 min. Solid material was observed in the beaker which was filtered through Buchner funnel, washed with water (1 L) and dried under line vacuum to yield 60 g of product as an off-yellow solid. The mother liquor contained product which was extracted out thrice using DCM (3 x 1000 mL), the combined organic layer washed with brine solution (1 x 1.5 L) and then dried over Na2SO4 and concentrated to yield ethyl 3- aminopicolinate (116 g, 691 mmol, 63.6 % yield) including first 60 g of compound. LCMS: m/z = 167.2 (M+H); RT 0.783 min; Method: Column-KINETEX-XB-C18 (75 X 3mm- 2.6 ^m); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile(2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL/min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL/min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL/min
A mixture of 3-aminopyridine-2-carboxylic acid (6.4 g, 46.3 mmol) in 26 mL of EtOH and 8 mL of concentrated sulfuric acid is heated to reflux for 2 days. After cooling, the mixture is concentrated to about 15-20 mL and poured into 20 g of ice. The mixture is basified to pH 8-9 with concentrated NH4OH while cooling in an ice bath. The resulting brown precipitate is filtered off, and the filtrate is extracted with ether (4 x 60 mL). The combined ether extracts are washed with brine (4 * 60 mL), dried (Na2SO4), filtered, and evaporated to give a yellow/brown solid. This solid is combined with that from the above filtration and the whole is triturated with cold ether to give the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) delta 8.08 (IH, m), 7.21 (IH, m), 7.03 (IH, m), 5.74(2H, bs), 4.44 (2H, q, J 7.2, 6.9), 1.45 (3H, t, J 6.9).
A mixture of 3-ammopyridine-2-carboxylic acid (6.4 g, 46.3 mmol) in 26 mL ofEtOH and 8 mL of concentrated sulfuric acid is heated to reflux for 2 days. After cooling, the mixture is concentrated to about 15-20 mL and poured into 20 g of ice. The mixture is basified to a pH of 8-9 with concentrated NH4OH while cooling in an ice bath. The resulting brown precipitate is removed by filtration, and the filtrate is extracted with ether (4 x 60 mL). The combined ether extracts are washed with brine (4 x 60 mL), dried (Na2SO4), filtered, and evaporated to give a yellow/brown solid. This solid is combined with that from the above filtration and the whole is triturated with cold ether to give the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) d 8.08 (IH, m), 7.21 (IH, m), 7.03 (IH, rn), 5.74 (2H, bs), 4.44 (2H, q, J7.2, 6.9), 1.45 (3H, t, J 6.9).
A mixture of 3-aminopyridine-2-carboxylic acid (6.4 g, 46.3 mmol) in 26 mL of EtOH and 8 mL of concentrated sulfuric acid is heated to reflux for 2 days. After cooling, the mixture is concentrated to about 15-20 mL and poured into 20 g of ice. The mixture is basified to a pH of 8-9 with concentrated NH4OH while cooling in an ice bath. The resulting brown precipitate is removed by filtration, and the filtrate is extracted with ether (4 x 60 mL). The combined ether extracts are washed with brine (4 * 60 mL), dried (Na2SO4), filtered, and evaporated to give a yellow/brown solid. This solid is combined with that from the above filtration and the whole is triturated with cold ether to give the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) delta 8.08 (IH, m), 7.21 (I H, m), 7.03 (I H, m), 5.74 (2H, bs), 4.44 (2H, q, J 7.2, 6.9), 1.45 (3H, t, J 6.9). m/z = 167.13 (M+H).
A mixture of 3-aminopyridine-2-carboxylic acid (6.4 g, 46.3 mmol) in 26 mL of EtOH and 8 mL of concentrated sulfuric acid is heated to reflux for 2 days. After cooling, the mixture is concentrated to about 15-20 mL and poured into 20 g of ice. The mixture is basified to a pH of 8-9 with concentrated NH4OH while cooling in an ice bath. The resulting brown precipitate is removed by filtration, and the filtrate is extracted with ether (4 x 60 mL). The combined ether extracts are washed with brine (4 x 60 mL), dried (Na2SO4), filtered, and evaporated to give a yellow/brown solid. This solid is combined with that from the above filtration and the whole is triturated with cold ether to give the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) delta 8.08 (IH, m), 7.21 (IH, m), 7.03 (IH, m), 5.74 (2H, bs), 4.44 (2H, q, / 7.2, 6.9), 1.45 (3H, t, J 6.9).
Multi-step reaction with 2 steps
1: 20 h / 150 °C
2: 96 percent / toluene / 2 h / 140 °C
Multi-step reaction with 3 steps
1: xylene / 1.5 h / 135 - 140 °C
2: 49 percent / xylene / 18 h / 140 - 145 °C
3: 96 percent / toluene / 2 h / 140 °C
Multi-step reaction with 2 steps
1: xylene / 1.5 h / 135 - 140 °C
2: 34 percent / 2.5 h / 140 °C
Multi-step reaction with 4 steps
1: xylene / 1.5 h / 135 - 140 °C
2: 48 h / 90 - 100 °C
3: 47 percent / 1,3,5-trimethyl-benzene / 15 h / 160 °C
4: 96 percent / toluene / 2 h / 140 °C
Multi-step reaction with 2 steps
1: 12 h / 140 - 150 °C
2: 96 percent / toluene / 2 h / 140 °C
Preparation 2 Pyrido[3,2-d]pyrimidin-4(3H)one A mixture of 6.5 g of 3-amino-pyridine-2-carboxylic acid in 9 g of formamide was heated in an oil bath while stirring. The temperature was increased from 130 C. to 180 C. over a two hour period, then the mixture was allowed to cool. The mixture was then diluted with water. The solids were collected and washed with fresh water, then dried. Yield 4.6 g. M.P. 346-347 C.
Example 6; Synthesis of (+/-)-9- [acetyl -(3 ,5-bis-trifluoi"omethylbenzyl)amino] -2-bromo-6,7 ,8 ,9- tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid'isopropyl ester; Step 1;. Preparation of 3-amino-pyridine-2-carboxylic acid methyl ester; Add dropwise a solution of trimethylsilyl diazomethane (2.0 M in toluene, 7.24 mL, 14.48 mmol) to a solution of 3-amino-pyridine-2-carboxylic acid (1.0 g, 7.24 mmol) in ethyl acetate (5 mL) and methanol (5 mL) at room temperature. After the addition is complete, remove the solvent under reduced pressure. Suspend the residue in water (5 mL), add a saturated solution of sodium bicarbonate, and extract with ethyl acetate. Separate the organic layer, dry over sodium sulfate, and filter. Remove the solvent under reduced pressure to afford the title compound (590 mg, 54%). MS (ES+): 153 (M+H).
[00278] 400 mg (2.9 mmol) of 3-amino-pyridine-2-carboxylic acid was dissolved in 3 ml_ of methanol. To this solution 1.6 ml_ of 2 M (trimethylsilyl)diazomethane solution in diethyl ether was added dropwise at O0C, followed by stirring of the mixture for 2 hours at room temperature The solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. Flash chromatography afforded the ester product. LC- MSD, m/z for C7H8N2O2 [M+H]+ = 153.0; HPLC retention time: 0.2 minutes.
(Step 1) (1070) To a solution of 3-aminopyridine-2-carboxylic acid (20 g, 144.9 mmol) in methanol (300 mL) was added conc. sulfuric acid (5.4 mL), and the mixture was heated under reflux for 5 days. The reaction mixture was concentrated under reduced pressure, water was added thereto, and sodium carbonate was added thereto until the complete of foaming. The mixture was extracted with dichloromethane (x3), the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 3-aminopyridine-2-carboxylate (17.0 g, 77%) as a pale yellow solid. 1H-NMR(300MHz,CDCl3):delta3.95(3H,s),5.72(2H,brs),7.03(1H,dd,J=0.99,8. 35Hz),7.18-7.21(1H,m),8.05(1H,dd,J=0.96,4.04Hz).
76%
A solution of 3-aminopyridine-2-carboxylic acid(Bioorg. Med Chem. 2001,9, 2061) (1.0 g, 7.25 mmol) andH2SO4 (2.75 ml) in methanol (15 ml) was heated at 80 oC for 7 days. The reaction was cooled and the methanol removed by evaporation. The residue was poured into water (ca. 30 ml) and solid sodium carbonate was added until effervescence ceased(pH ~7). The mixture was extracted with dichloromethane (4 x 50 ml) and the combined organic fractions dried over MgS04 and concentrated to give the title compound as a beige solid (0. 84 g, 76 %). 1H NMR (360 MHz,CDCl3) 8 8.07(1H, dd, J4. 2,1. 4), 7.22(1H, dd,J8. 4,4. 2), 7.05(1H, dd, J8. 4,1. 4), 5.73 (2H, brs), 3.98 (3H, s).Mlz (ES+) 153 (M+H+).
54.47%
With sulfuric acid; at 15 - 80℃; for 120h;
To a suspension of 3-aminopicolinic acid (100 g, 724 mmol, 1.0 eq.) in dry MeOH (1.5 L) was added conc.H2SO4 (460 g, 4.69 mol, 6.48 eq.) dropwise at 15 C. and the mixture was heated to 80 C. and stirred for 5 days. The reaction mixture was concentrated to about 500 mL and diluted with cold water (2 L). The resulting mixture was adjusted to about 9 with solid Na2CO3 at 0 C. and extracted with DCM/MeOH (10:1, 1.0 L*5). The combined orange layers were dried over Na2SO4, filtered and concentrated to give methyl 3-aminopicolinate (60 g, 394.35 mmol, 54.47% yield, 100% purity) as a brown solid. 1H NMR (400 MHz, CDCl3) delta=8.08-8.06 (m, 1H), 7.24-7.20 (m, 1H), 7.06-7.01 (m, 1H), 5.75 (br. s, 1H), 3.97 (s, 3H). ESI [M+H]=153.1
41%
With hydrogenchloride; In water; at 85℃; for 12h;
3-Aminopyridine-2-carboxylic acid (10.0 g, 72.5 mmol) was dissolved in methanol (100 ml). After cooling to 0 C., concentrated hydrochloric acid (25 ml) was added dropwise thereto, and the reaction solution was stirred at 85 C. for 12 hours. After the solvent was removed under reduced pressure, water and sodium hydrogen carbonate (10 g) were added to the obtained residue, followed by stirring and extraction with ethyl acetate (80 ml×4). The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was stirred in petroleum ether/ ethyl acetate=8:1, and the obtained solid was filtered and dried under reduced pressure to obtain the title compound (4.50 g, 41%). [1164] 1H-NMR (400 MHz, DMSO-d6): delta 7.85-7.83 (m, 1H), 7.27-7.20 (m, 2H), 6.66 (s, 2H), 3.80 (s, 3H).; MS (ESI) m/z 153 (M+H)+
Stage #1: 3-nitropyridine-2-carboxylic acid With hydrogen; sodium hydrogencarbonate In water at 20℃; for 50h;
Stage #2: With hydrogenchloride In water
268.2
(2) Manufacture of 3-aminopyridine-2-carboxylic acid 3-nitropyridine-2-carboxylic acid (2.72 g, 16.2 mmol) and sodium hydrogencarbonate (1.34 g, 16.2 mmol) were dissolved in distilled water (20 mL), and the atmosphere in the system was replaced by nitrogen. After adding 10% palladium charcoal (1.72 g), the atmosphere in the system was replaced by hydrogen, and the mixture stirred at room temperature for 50 hours. 1N hydrochloric acid aqueous solution was added, and the pH of the reaction solution was adjusted to weak acidity. The solvent was distilled off under reduced pressure, a small amount of ethanol and ethyl acetate were added to the residue, and the precipitate produced was filtered off. The filtrate was concentrated, and the target substance (1.50 g, 67%) was thus obtained as a light yellow solid.
Stage #1: 3-amino-pyridine-2-carboxylic acid; cyclohexylmethylamine With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 0.5h;
Stage #2: With HATU In DMF (N,N-dimethyl-formamide) at 0 - 20℃;
8.B
Step B. 3-Amino-N-(cyclohexylmethyl)pyridine-2-carboxamide; 3-Aminopyridine-2-carboxylic acid (138 mg, 1.0 mmol) was added to a solution of cyclohexane methylamine (226 mg, 2.0 mmol) and DIPEA (259 mg, 0.35 mmol) in DMF (5 mL). After stirring for 30 min, HATU (456 mg, 1.2 mmol) was added at 0 °C. The resulting mixture was stirred overnight at room temperature, quenched with water (5 ml), concentrated to a small volume, diluted with EtOAc (100 mL), washed with water (2x5 mL) and brine (5 mL), then dried with sodium sulphate. After filtration and concentration, the crude product was purified by MPLC using Hex/EtOAc (1:1) on Si02 to provide the title compound (124 mg, 53 %). ¹H NMR (400 MHz, CDC13) No. 0.93 - 1.07 (m, 2 H), 1.13 - 1.32 (m, 3 H), 1.51 - 1.70 (m, 2 H), 1.70 - 1.86 (m, 4 H), 3.26 (t, J=6.64 Hz, 2 H), 6.00 (s, 2 H), 7.00 (dd, J=8.40, 1.37 Hz, 1 H), 7.15 (dd, J=8.40, 4.30 Hz, 1 H), 7.85 (dd, J=4.30, 1.37 Hz, 1 H), 8.22 (s, 1 H). (MS (ESI) (M+H)+ 233.89.
53%
With N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 0 - 20℃;
82.B
Step B. 3-Amino N (cyclohexylmethyl)pyridine-2-carboxamide; 3-Aminopyridine-2-carboxylic acid (138 mg, 1.0 mmol) was added to a solution of cyclohexane methylamine (226 mg, 2.0 mmol) and DIPEA (259 mg, 0.35 mmol) in DMF (5 mL). After stirring for 30 min, HATU (456 mg, 1.2 mmol) was added at 0 °C. The resulting mixture was stirred overnight at room temperature, quenched with water (50 ml), and extracted with EtOAc (3x40 mL). The combined organic phases were washed with water (2x5 mL), brine (5 mL), and dried with Na2S04. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) (124 mg, 53 %). ¹H NMR (400 MHz, CDCl3) No. 0.93 - 1.07 (m, 2 H), 1.13 - 1.32 (m, 3 H), 1.51 - 1.70 (m, 2 H), 1.70 - 1.86 (m, 4 H), 3.26 (t, J=6.64 Hz, 2 H), 6.00 (s, 2 H), 7.00 (dd, J=8.40,1.37 Hz, I H), 7.15 (dd, J=8.40, 4.30 Hz, I H), 7.85 (dd, J=4.30,1.37 Hz, I H), 8.22 (s, 1 H). (MS (ESI) (M+H)+ 233.89.
With N-ethyl-N,N-diisopropylamine; HATU; In methanol; DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
Step B. 3-Amino-N-(cyclobutylmethyl)-2-pyridinecarboxamide; HATU (3.03 g, 7.96 mmol) was added to a solution of 3-aminopyridine-2-carboxylic acid (1.0 g, 7.24 mmol), cyclobutanemethylamine (2.7 mL, 5.3 M in MeOH, 14.5 mmol), and DIPEA (3.8 g, 30 mmol) in DMF (50 ml) at room temperature. After 24 hr, the reaction mixture was quenched with H20 (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine, and condensed in vacuo to provide the title compound (1.22 g, 82 %).
28%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1 - 2h;
The title compound was prepared by applying general procedure 5 to 3-aminopyridine-2- carboxylic acid. The reaction mixture was subjected to aqueous work-up (NaHCO3) and the organic layer was separated and dried. The crude product was purified using silica based chromatography with an eluent system containing EtO Ac/heptane (1 : 1) to afford the title compound (28%).1HNMR (CDCl3, 400 MHz) J(ppm) 1.71 (m, 2H), 1.86-1.96 (m, 2H), 2.06-2.15 (m, 2H), 2.53-2.65 (m, IH), 3.41-3.46 (m, 2H), 5.95 (bs, 2H), 6.98 (d, IH), 7.14 (dd, IH), 7.85 (d, IH), 8.09 (bs, IH).
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 50℃; for 3h;
Step B. 3-Amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide; HATU (2.63 g, 6.93 mmol) and 4-aminomethyltetrahydropyran (0.80 g, 6.94 mmol) were added to a solution of 3-amino-2-pyridine carboxylic acid (0.91 g, 6.60 mmol) and DIPEA (1.26 mL, 7.26 mmol) in DMF (120 mL) at 0C. The reaction mixture was allowed to warm to ambient temperature and heated to 50C for 3 hrs. The solvent was concentrated and the residue was recovered in EtOAc (300 mL). The solution was washed with water, saturated NaHC03 solution, brine and dried over anhydrous Na2S04. The solvent was concentrated and the product was purified on silica gel by flash chromatography using Et3N 0.1%, MeOH 3% and Acetone 5% inDCM to provide the title compound as white solid (1.40 g, 90 %).
Methyl 3-aminopicolinate (116) 3-Aminopicolinic acid (115) (0.585 g, 4.24 mmol) was dissolved in MeOH (absolute, 45 mL). The solution was stirred while an ethereal solution of diazomethane was added until a yellow color persisted (~30 mL). The solution was stirred an additional 30 min, and the solvent rota-evaporated. The resulting residue was dried under reduced pressure at room temperature to yield 0.635 g (98.5%) of crude 116 as a yellow residue. The crude residue was chromatographed on a column of silica (12 g, Mallinckrodt, grade 62, mesh 60-200, used as received) using CHCl3 -MeOH ?19:1, (180 mL), 7:3 (100 mL), 1:1 (100 mL), 100% MeOH (150[mL)]. After collecting appropriate fractions, rota-evaporating off the solvent and drying under reduced pressure at 25 C., 0.333 g (51.7%) of 116 was obtained as a yellow solid; mp 139-146 C.; Rf =0.54 ?CHCl3 -MeOH[(9:1)]. IR (KBr) 3455, 3295, 3160, 1689, 1617, 1408, 1335, 1244, 1115. 1 H NMR (CDCl3) delta3.98 (t, J=7.2, 3, CH3 O--), 5.73 (d, J=1.8, 2, NH2), 7.05 (dd, J1 =1.2, J2 =8.4, 1, H-4), 7.22 (dd, J1 =4.2, J2 =8.4, 1, H-5), 8.07 (dd, J1 =1.2, J2 =4.2, 1, H-6).
With methanol; In diethyl ether; toluene; at 20℃;Inert atmosphere;
1. Reactions which are covered by Scheme 1; Example 1.1: Preparation of 2-amino-nicotinic acid methyl ester; To a solution of 3-amino-pyridine-2-carboxylic acid (1 g) in methanol (8 ml) and toluene (10 ml), under nitrogen atmosphere, was added a solution of (trimethylsilyl)- diazomethane (3.625 ml) (2M in diethylether). When the effervescence from the reaction had subsided a further portion of (trimethylsilyl)diazomethane (3.625 ml) (2M in diethylether) was added. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction was quenched by addition of acetic acid (0.2 ml). The mixture was concentrated and the residue partitioned between dichloromethane and aqueous potassium carbonate (5% by weight). The phases were separated and the aqueous phase was extracted with further dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to give 2-amino-nicotinic acid methyl ester as a light yellow solid (968 mg). IH-NMR (400 MHz, CDCl3): 8.21-8.23 (m, IH), 8.12-8.14 (m, IH), 6.61-6.64 (m, IH), 3.89 (s, 3H) ppm.
To a solution of 321 mg of S-aminopyridine-l-carboxylic acid in pyridine (5.0 rnL) is added 377 mg of l,l'-carbonyldiimidazole and the mixture is stirred for 2 h at room temperature. The resulting mixture is treated with 300 mg of <strong>[1236525-13-5](S)-3-aminopentanoic acid methyl ester hydrochloride</strong> and the mixture is stirred for 16 h at room temperature. Then the solvent is removed under vaccum and the residue is purified by flash chromatography on silica gel to give 250 mg (56 %) of (S)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester.
3-Aminopicolinic acid (145 mg, 1.05 mmol) was carefully added in 3 aliquots to a slurry of UAIH4 (143 mg, 3.78 mmol) in dry tetrahydrofuran (6 ml). The resulting mixture was stirred at 15C overnight. After cooling in an ice bath, the reaction mixture was quenched with careful addition of water (1 ml) dropwise, followed by 15% aqueous NaOH (1 ml), and then water (3 ml). The resulting solid was filtered and washed several times with tetrahydrofuran. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 5% CH3OH (NH3) /ethyl acetate as eluent to yield the title compound as a yellow oil. 1 0 mg.MS (electrospray): m/z [M+H]+ = 125
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