5-METHOXY-PYRIDIN-2-YLAMINE

Dark Red Oil

A mixture of 118 (1.0 equiv., 257 mmol, 52.0 g), hydroxylamine hydrochloride(6.5 equiv., 1671 mmol, 69.5 g), triethylamine (2.0 equiv., 514 mmol, 52.0 g), ethanol(400 ml) and water (200 ml) was refiuxed for 20 h. The solution was cooled and A mixture of 4 (7 mmol, 1.41 g), hydroxylamine hydrochloride (45.5 mmol, 1.89g), triethylamine (14 mmol, 1.41 g), ethanol (20 mL) and water (10 mL) was refluxed for 20 h. The solution was cooled and quenched with 2 M HCl, washed with isopropyl ether and the pH was adjusted to 9-10 with 6 M NaOH. The resulting mixture was extracted several times with diethyl ether. The combined organic phases were dried with MgSO2-Ammo-5-methoxypyridineA mixtrure of 2-bromo-3-methoxy-6-nitropyridine (1.20 g, 5.15 mmol), hydrazine hydrate (6 mL), Pd on carbon (10 percent, 400 mg) in ethanol (40 mL) was heated at reflux for 45 min. The mixture was allowed to cool, filtered through CeliteA mixture of 2-bromo-3-methoxy-6-nitroρyridine (1.20 g, 5.15 mmol)To a solution of 2-bromo-3-methoxy-6-nitropyridine (33.0 g) in methanol (400 mL) and EA (100 mL) was added potassium acetate (15.3 g) and Pd/C (1.5 g). The mixture was stirredat 50°C for 48 hours under H2 (50 psi). The mixture was filtered. The filtrate was concentrated in vacuo to afford 5-methoxypyridin-2-amine (16.0 g).5-methoxypyridin-2-amine (P5).; Method a: 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a screw cap vial (Pyrex glass) together with 2.0 mL of anhydrous MeOH and a stirrer bar. The vial was closed and put in an oil bath at 135°C and stirred for 14 h. The mixture was cooled, diluted with MeOH (5.0 mL) and filtered through an SPE silica gel cartridge and the product eluted with AcOEt. The fractions were A mixture of 2-amino-5-bromopyridine (5.0 g, 28.9 mmol), sodium methoxide (6.3 g, 116.6 mmol) and copper powder (1.85 g, 28.9 mmol) in methanol (30 mL) was heated in sealed tube for 48 h at 100° C. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water, extracted with dichloromethane (2.x.100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous NaMethod b:; 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a microwave glass tube with 1.5 mL of anhydrous DMF and sealed. The tube was introduced in the microwave cavity and heated for 30 min at 140°C (140C30M75W300Psi). Although DMF is a high boiling solvent, high pressure was observed, probably caused by the partial methanolysis of the DMF resulting in low boiling products such as methyl formate and dimethylamine. The mixture was diluted with 10 mL of 2 M NH2-Amino-5-methoxy-pyridine. A mixture OF 2-AMINO-5-IODO-PYRIDINE (1 g, 4.54 mmol) in 20 mL of absolute methanol with 400 mg of copper powder and sodium methoxide (6 mmol) was heated at 160 °C overnight in a seal tube. The reaction mixture was cooled to room temperature, diluted with 80 mL of methanol and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography (80percent ethyl acetate/hexane) to give the title compound (174 mg, 31percent). 1H NMR (CDCl3) : 7.78 (d, J = 2.7, 1H), 7.09 (dd, J = 3.0, 9.0, 1H), 6.48 (d, J= 9.0, 1H), 3.78 (s, 3H).A mixture of 118 (1.0 equiv., 257 mmol, 52.0 g), hydroxylamine hydrochloride(6.5 equiv., 1671 mmol, 69.5 g), triethylamine (2.0 equiv., 514 mmol, 52.0 g), ethanol(400 ml) and water (200 ml) was refiuxed for 20 h. The solution was cooled and A mixture of 4 (7 mmol, 1.41 g), hydroxylamine hydrochloride (45.5 mmol, 1.89g), triethylamine (14 mmol, 1.41 g), ethanol (20 mL) and water (10 mL) was refluxed for 20 h. The solution was cooled and quenched with 2 M HCl, washed with isopropyl ether and the pH was adjusted to 9-10 with 6 M NaOH. The resulting mixture was extracted several times with diethyl ether. The combined organic phases were dried with MgSO4 and the solvent was removed in vacuo. The oily residue was purified by column chromatography on silica gel (gradient elution: CH2Cl2/CH3COOC2H5 = 1:3 ' pure ethyl acetate) to give dark brown liquid 5 (0.87 g, yield = 100 percent). 1H NMR (400 Hz, CDCl3), delta (ppm): 3.772 (s, 3H, OCH3), 4.213 (br, 2H, NH2), 6.493-6.462 (dd, 1H, pyr-H), 7.070-7.110 (dd, 1H, pyr-H), 7.766-7.775 (d, 1H, pyr-H). 13C NMR (100 MHz, CDCl3), delta (ppm): 56.28, 109.49, 125.73, 133.11, 148.60, 153.09.5-methoxypyridin-2-amine (P5).; Method a: 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a screw cap vial (Pyrex glass) together with 2.0 mL of anhydrous MeOH and a stirrer bar. The vial was closed and put in an oil bath at 135°C and stirred for 14 h. The mixture was cooled, diluted with MeOH (5.0 mL) and filtered through an SPE silica gel cartridge and the product eluted with AcOEt. The fractions were A mixture of 2-amino-5-bromopyridine (5.0 g, 28.9 mmol), sodium methoxide (6.3 g, 116.6 mmol) and copper powder (1.85 g, 28.9 mmol) in methanol (30 mL) was heated in sealed tube for 48 h at 100° C. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water, extracted with dichloromethane (2.x.100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude material was purified over silica gel column chromatography eluting with EtOAc:Hexane (6:4) to afford Int-1 (1.2 g, 34.3percent) as brown color oil. To a solution of Int-1 (3.0 g, 24.2 mmol) in dimethoxy ethane (30 mL) was added 3-chloro-2, 4-pentanedione (4.9 g, 36.4 mmol) at room temperature and the mixture was stirred at reflux temperature for 16 hours. The volatile was concentrated under reduced pressure. The residue was purified over silica gel column chromatography eluting with MeOH:DCM (1:9) to afford Int-2 (2.3 g, 46.6percent) as brown color oil. A solution of Int-2 (1.5 g, 7.35 mmol) in DMF DMA (15 mL) was stirred at reflux temperature for 24 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether (15 mL) and stirred for 15 minutes. The precipitated solid was filtered, washed with ether (2.x.10 mL) and dried under vacuum to afford Int-3 (1.2 g, 63percent) as brown solid. Mass (m/z): 260 [M++1]. 1H NMR (200 MHz, CDCl3): delta 9.43 (d, J=2.2 Hz, 1H), 7.8 (d, J=12.4 Hz, 1H), 7.44 (d, J=9.8 Hz, 1H), 7.09 (dd, J=2.2, 9.6 Hz, 1H), 5.58 (d, J=12 Hz, 1H), 3.86 (s, 3H), 3.06 (brs, 6H), 2.75 (s, 3H). To a solution of Int-3 (1.6 g, 6.17 mmol) in DMF (25 mL) was added Int-3B (2.38 g, 12.3 mmol) followed by K2CO3 (2.13 g, 15.4 mmol) at room temperature under inert atmosphere and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, poured into ice water (70 mL) and stirred for 15 minutes. The precipitated solid was filtered, washed with water (2.x.10 mL) and dried under vacuum to afford Int-4 (1.2 g, 50percent) as brown solid. Mass (m/z): 390 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.13 (s, 1H), 9.17 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.-6.90 (m, 4H), 7.55 (d, J=10 Hz, 1H), 7.25-7.14 (m, 2H), 3.8 (s, 3H), 3.66 (s, 3H), 2.6 (s, 3H). A mixture of Int-4 (0.8 g, 2.05 mmol) and 4 N HCl (30 mL) was stirred at reflux temperature for 4 hours. The reaction mixture was cooled to room temperature and pH adjusted to about 5 using NaHCO3 and stirred for 20 minutes. The precipitated solid was filtered, washed with water (2.x.10 mL) and dried under vacuum to afford Int-5 (0.7 g, 90.9percent yield) as brown color solid. Mass (m/z): 376 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.29 (s, 1H), 9.18 (d, J=1.8 Hz, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.-7.78 (m, 6H), 7.64 (dd, J=2.2, 10 Hz, 1H), 3.71 (s, 3H), 2.69 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.86 mmol) in DMF (10 mL) were added HOBt (0.25 g, 1.86 mmol), EDCI (0.71 g, 3.7 mmol), N-ethyldiisopropylamine (0.7 mL, 5.58 mmol) at 0° C. After being stirred for 10 minutes, and then added o-phenylenediamine (0.2 g, 1.86 mmol) to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was poured into ice cold water (50 mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (3.x.10 mL) and dried under vacuum. The crude material was purified over silica gel column chromatography eluting with 4percent MeOH/DCM to afford the title compound (0.27 g, 31.1percent yield) as off white solid. Mass (m/z): 465.2 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.02 (s, 1H), 9.53 (s, 1H), 9.18 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 7.86-7.98 (m, 4H), 7.60 (d, J=9.6 Hz, 1H), 7.13-7.25 (m, 3H), 6.85-7.0 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.45-6.61 (m, 1H), 4.86 (brs, 2H), 3.69 (s, 3H), 2.60 (s, 3H). 13C NMR (125 MHz, dmso-d6): delta 164.69, 159.26, 158.17, 156.83, 148.74, 146.45, 143.33, 143.03, 142.42, 128.49, 127.05, 126.55, 126.21, 123.65, 120.66, 118.59, 118.10, 116.37, 116.29, 116.15, 110.27, 110.15, 55.90, 16.36.Method b:; 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a microwave glass tube with 1.5 mL of anhydrous DMF and sealed. The tube was introduced in the microwave cavity and heated for 30 min at 140°C (140C30M75W300Psi). Although DMF is a high boiling solvent, high pressure was observed, probably caused by the partial methanolysis of the DMF resulting in low boiling products such as methyl formate and dimethylamine. The mixture was diluted with 10 mL of 2 M NH4Cl solution and extracted 3 times with AcOEt. The organic phase was washed 2 times with 2 M NH4Cl solution and 1 time with water to remove the remaining DMF, dried on NaSO4, and filtered. After the solvent was removed, the crude product was purified by FCC (AcOEt) to afford 12 mg (yield 17percent) of the title compound as brown oil. 1H NMR (270 MHz; CDCl3), delta 7.74 (1 H, d, 3JHH = 3.0 Hz), 7.06 ( IH, dd, 3JHH = 9.0 Hz, 4JHH = 3.0 Hz), 6.45 (1 H, d, 3JHH = 9.0 Hz), 3.95 (2H, bs, NH2), 3.74 (3H, s, OCH3); m/z (EI-MS): 124 (M+), 109 ([M-CH3]+).; Substitution of halide by OCH3 and SEt group is more challenging. The first attempts to prepare P5 by a nucleophilic aromatic displacement of the bromide with a methoxy group catalyzed by Cu powder in a conventional way11 or with microwave heating or an ultrasound bath were frustrated by the apparent unreactivity of the substrate.; In order to decrease the reaction time, the transformation in eq 3 was carried out with microwave irradiation according to Table 3.Preparation 177; In order to decrease the reaction time, the transformation in eq 3 was carried out with microwave irradiation according to Table 3.The reaction of p-nitrophenyl-3-tert. butyl-5-nitro-6-methyl salicylate in the process of Example I (iii) with the following 2-aminopyridines:a. 2-amino-5-cyanopyridineb. 2-amino-5-carboethoxypyridinec. (1) Methyl 5-methoxy-2-pyridyldithiocarbamate To a solution of