* 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.
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc In acetonitrile at 80℃; for 3 h; Inert atmosphere; Sealed tube
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn(CN)2 (0.8mmol) , 93.9mg), p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88percent, and 1H NMR purity was greater than 98percent.
Reference：
[1] Organic Letters, 2017, vol. 19, # 8, p. 2118 - 2121
[2] Patent: CN108623495, 2018, A, . Location in patent: Paragraph 0043; 0045; 0178-0180
N-[4-(5-Cyano-2-methoxy-pyridin-3-yl)-benzyl]-2-trifluoromethoxy-benzenesulfonamide To a solution of 4-aminomethylphenylboronic acid hydrochloride (2.0 g, 13.2 mmol) in methanol (20 ml) was added di-tert-butyl dicarbonate (3.16 g, 15.5 mmol) and sodium bicarbonate (3.32 g, 19.8 mmol). The mixture was sonicated for 4 h then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give (4-bromo-benzyl)-carbamic acid tert-butyl ester (1.8 g, 13.2 mmol, 100percent) as a white solid. To 6-chloro-nicotinonitrile (15 g, 0.11 mol) under argon atmosphere was added 25percent sodium methoxide in methanol (11.7 g, 0.22 mol) and the mixture heated under reflux for 20 h. The methanol was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give 6-methoxy-nicotinonitrile (17.0 g, 0.13 mol, 117percent) as a white solid. To 6-methoxy-nicotinonitrile (13.2 g, 99 mmol) in acetic acid (32 ml) was added sodium acetate (8.1 g, 99 mmol). The mixture was stirred and a solution of bromine (31.5 g, 197 mmol) in acetic acid (32 ml) added. The mixture was heated to 80° C. for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5percent sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile (11.9 g, 56 mmol, 57percent). To a solution of 2-methoxy-5-cyanopyridine-3-boronic acid (1.0 g, 4.0 mmol) in 1,2-dimethoxyethane (10 ml) was added (4-bromo-benzyl)-carbamic acid tert-butyl ester (0.42 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 0.1 mmol) and 2M aqueous sodium carbonate (1 ml, 2.0 mmol). The reaction was heated to 150° C. for 10 min in a microwave over. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was washed with water, then brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on silica gel eluting with 5:1 heptane/ethyl acetate to give [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester as a white solid (0.5 g, 1.47 mmol, 37percent). To a solution of [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester (0.5 g, 1.5 mmol) in dichloromethane (5 ml) at 0° C. was added trifluoroacetic acid (5 ml, 28 mmol). The reaction mixture was stirred for 30 min at 0° C. before the solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) to give 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile as a clear glass (0.39 g, 1.6 mmol, 107percent). To a solution of 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile (57.3 mg, 0.24 mmol) in dichloromethane (2 ml) was added triethylamine (73.0 mg, 0.72 mmol) and 2-(trifluoromethoxy)benzenesulfonyl chloride. The reaction mixture was agitated for 20 hours and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (19.1 mg, 0.04 mmol, 17percent). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, 1H), 8.47 (t, 1H), 8.15 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.45-7.55 (m, 4H), 7.31 (d, 2H), 4.19 (d, 2H), 3.96 (s, 3H) ppm; MS (ESI) m/z: 464.3 [M+H]+.
8.8 g
Reflux
A) 6-methoxynicotinonitrile To a solution of 6-chloronicotinonitrile (10.0 g) in methanol (100 mL) was added sodium methoxide (7.80 g). The reaction mixture was heated at reflux overnight, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.8 g). 1H NMR (400 MHz, DMSO-d6) δ 4.00 (3H, s), 6.83 (1H, dd, J= 8.8, 0.8 Hz), 7.78 (1H, dd, J= 8.6, 2.4 Hz), 8.50 (1H, d, J = 1.4 Hz).
Reference：
[1] Patent: US2007/149577, 2007, A1, . Location in patent: Page/Page column 17-18
[2] Journal of the Chemical Society, 1948, p. 1939,1942
[3] Patent: EP2848618, 2015, A1, . Location in patent: Paragraph 0660
5
[ 13472-85-0 ]
[ 544-92-3 ]
[ 15871-85-9 ]
Yield
Reaction Conditions
Operation in experiment
56.5%
at 120 - 140℃; for 41 h;
2) 6-Methoxynicotinonitrile Copper cyanide (24.6 g) was added to the above-obtained 5-bromo-2-methoxypyridine (31.0 g) in N,N-dimethylformamide (600 mL). The resultant mixture was stirred at 120°C for 19 hours, and at 140°C for 22 hours, followed by cooling in air. The reaction mixture was subjected to filtration, and then the filtrate was partitioned between water and methylene chloride. The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure. The residue still contained N,N-dimethylformamide, therefore water and ethyl acetate were added thereto for partitioning the residue again. The organic layer was dried over magnesium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 6-methoxynicotinonitrile as a solid product (12.5 g, 56.5percent). 1H-NMR(300MHz,CDCl3)δ:4.00(3H,s), 6.82(1H,d,J=8.81Hz), 7.77(1H,dd,J=8.81,2.39Hz), 8.49(1H,d,J=2.39Hz).
Reference：
[1] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 27
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
Reference：
[1] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1540 - 1545
9
[ 75-05-8 ]
[ 163105-89-3 ]
[ 15871-85-9 ]
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 38, p. 13246 - 13252
10
[ 5006-66-6 ]
[ 15871-85-9 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1939,1942
11
[ 6271-78-9 ]
[ 15871-85-9 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1939,1942
12
[ 15871-85-9 ]
[ 262295-96-5 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1939,1942
[2] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
[3] Patent: EP1122242, 2001, A1,
[4] Tetrahedron Letters, 2009, vol. 50, # 26, p. 3654 - 3656
[5] Chemistry - A European Journal, 2008, vol. 14, # 31, p. 9491 - 9494
[6] Patent: US6673799, 2004, B1, . Location in patent: Page column 18
[7] Patent: WO2012/68251, 2012, A2, . Location in patent: Page/Page column 47-48
[8] Catalysis Science and Technology, 2014, vol. 4, # 3, p. 629 - 632
13
[ 15871-85-9 ]
[ 66572-55-2 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: With water; sodium hydroxide In methanol at 100℃; Stage #2: With hydrogenchloride In water
A reaction mixture of 6-metoxynicotinonitrile (4g, 29.8mmol) in 60ml of MeOH and 5M NaOH (60ml, 300mmol) was stirred overnight at 10O0C. The mixture was concentrated and redissolved in water (50ml). A 2N solution of HCI was added until pH acid and a solid was formed, filtered and washed with water twice and with hexane twice. 3.04g of the title compound were obtained as a white solid (yield=66percent).LRMS: m/z 154 (M+1 )+ Retention time: 2.22min (method A)
4.2 g
With water; potassium hydroxide In ethanol for 2 h; Reflux
B) 6-methoxynicotine acid To a solution of 6-methoxynicotinonitrile (5.00 g) in ethanol (100 mL) was added 2 M aqueous potassium hydroxide solution (20 mL). The reaction mixture was heated at reflex for 2 hr, and the solvent was evaporated under reduced pressure. To the residue was added water, the pH of the mixture was adjusted to 4-5 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.2 g). 1H NMR (400 MHz, DMSO-d6) δ 3.92 (3H, s), 6.86-6.92 (1H, m), 8.11-8.15 (1H, m), 8.73 (1H, d, J = 2.0 Hz), 13.0 (1H, s).
With formaldehyd; sodium acetate In hydrogenchloride; ethanol; water
(a) A mixture of 2-methoxy-5-cyanopyridine (61.26 g), semi-carbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1,300 ml) and water (400 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml, water (1,000 ml) was added and the mixture was allowed to stand at 0° overnight. The mixture was filtered and the solid was washed with water and dissolved in 10percent hydrochloric acid (1,000 ml). Formaldehyde solution (36percent w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50percent), m.p. 48-49°.
50%
With formaldehyd; sodium acetate In hydrogenchloride; ethanol; water
(i) A mixture of 2-methoxy-5-cyanopyridine (61.26 g), semicarbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml, water (1000 ml) was added and the mixture was allowed to stand at 0° overnight. The mixture was filtered and the solid was washed with water and dissolved in 10percent hydrochloric acid (1000 ml). Formaldehyde solution (36percent w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether (3*500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50percent) m.p. 48°-49°.
Reference：
[1] Patent: US4255428, 1981, A,
[2] Patent: US4234588, 1980, A,
15
[ 15871-85-9 ]
[ 65873-72-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1993, vol. 28, # 7-8, p. 601 - 608
N-[4-(5-Cyano-2-methoxy-pyridin-3-yl)-benzyl]-2-trifluoromethoxy-benzenesulfonamide To a solution of 4-aminomethylphenylboronic acid hydrochloride (2.0 g, 13.2 mmol) in methanol (20 ml) was added di-tert-butyl dicarbonate (3.16 g, 15.5 mmol) and sodium bicarbonate (3.32 g, 19.8 mmol). The mixture was sonicated for 4 h then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give (4-bromo-benzyl)-carbamic acid tert-butyl ester (1.8 g, 13.2 mmol, 100%) as a white solid. To 6-chloro-nicotinonitrile (15 g, 0.11 mol) under argon atmosphere was added 25% sodium methoxide in methanol (11.7 g, 0.22 mol) and the mixture heated under reflux for 20 h. The methanol was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give 6-methoxy-nicotinonitrile (17.0 g, 0.13 mol, 117%) as a white solid. To 6-methoxy-nicotinonitrile (13.2 g, 99 mmol) in acetic acid (32 ml) was added sodium acetate (8.1 g, 99 mmol). The mixture was stirred and a solution of bromine (31.5 g, 197 mmol) in acetic acid (32 ml) added. The mixture was heated to 80 C. for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5% sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile (11.9 g, 56 mmol, 57%). To a solution of 2-methoxy-5-cyanopyridine-3-boronic acid (1.0 g, 4.0 mmol) in 1,2-dimethoxyethane (10 ml) was added (4-bromo-benzyl)-carbamic acid tert-butyl ester (0.42 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 0.1 mmol) and 2M aqueous sodium carbonate (1 ml, 2.0 mmol). The reaction was heated to 150 C. for 10 min in a microwave over. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was washed with water, then brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on silica gel eluting with 5:1 heptane/ethyl acetate to give [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester as a white solid (0.5 g, 1.47 mmol, 37%). To a solution of [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester (0.5 g, 1.5 mmol) in dichloromethane (5 ml) at 0 C. was added trifluoroacetic acid (5 ml, 28 mmol). The reaction mixture was stirred for 30 min at 0 C. before the solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) to give 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile as a clear glass (0.39 g, 1.6 mmol, 107%). To a solution of 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile (57.3 mg, 0.24 mmol) in dichloromethane (2 ml) was added triethylamine (73.0 mg, 0.72 mmol) and 2-(trifluoromethoxy)benzenesulfonyl chloride. The reaction mixture was agitated for 20 hours and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (19.1 mg, 0.04 mmol, 17%). 1H NMR (400 MHz, DMSO-d6): delta 8.68 (d, 1H), 8.47 (t, 1H), 8.15 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.45-7.55 (m, 4H), 7.31 (d, 2H), 4.19 (d, 2H), 3.96 (s, 3H) ppm; MS (ESI) m/z: 464.3 [M+H]+.
8.8 g
In methanol;Reflux;
A) 6-methoxynicotinonitrile To a solution of 6-chloronicotinonitrile (10.0 g) in methanol (100 mL) was added sodium methoxide (7.80 g). The reaction mixture was heated at reflux overnight, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.8 g). 1H NMR (400 MHz, DMSO-d6) delta 4.00 (3H, s), 6.83 (1H, dd, J= 8.8, 0.8 Hz), 7.78 (1H, dd, J= 8.6, 2.4 Hz), 8.50 (1H, d, J = 1.4 Hz).
With ammonium hydroxide;aluminum nickel; In ethanol; hydrogen;
Reference Example 21 5-Aminomethyl-2-methoxypyridine A 1.00 g portion of 5-cyano-2-methoxypyridine was dissolved in 30 ml of ethanol and 10 ml of 28percent aqueous ammonia, mixed with 1 g of Raney nickel and then stirred at room temperature for 4 hours at atmospheric pressure in a stream of hydrogen. After filtration through celite, the solvent was evaporated to obtain 962 mg of the title compound.
With ammonia; hydrogen;nickel; In ethanol; at 20℃; under 760.051 Torr; for 4h;
Reference Example 21 5-Aminomethyl-2-methoxypyridine A 1.00 g portion of 5-cyano-2-methoxypyridine was dissolved in 30 ml of ethanol and 10 ml of 28percent aqueous ammonia, mixed with 1 g of Raney nickel and then stirred at room temperature for 4 hours at atmospheric pressure in a stream of hydrogen.. After filtration through celite, the solvent was evaporated to obtain 962 mg of the title compound.
With borane-THF; In tetrahydrofuran;Inert atmosphere; Reflux;
Example 7: Preparation -(6-methoxypyridin-3-yl)methanamine (1-31).1 -31 [0122] To a stirred solution of 2-methoxypyridine-5-carbonitrile (0.95 g, 7.1 mmol) in tetrahydrofuran (25 mL) under a dry nitrogen atmosphere, boraneTHF (1.0 M in THF, 8.0 mL, 8.0 mmol) was added dropwise. The resulting solution was heated to reflux overnight, additional boraneTHF (8 mL, 8.0 mmol) was added and the mixture was heated to reflux overnight. Additional boraneTHF (18 mL, 18.0 mmol) was added and the mixture was stirred at reflux overnight, then at room temperature for 7 days. The reaction was cooled to 0 °C, quenched with water, acidified with aqueous hydrochloric acid (6 N), and heated to reflux for 2 h. The resulting mixture was extracted with dichloromethane (4 times). The aqueous layer was basified with aqueous sodium hydroxide (I N) and extracted with dichloromethane (5 times). The organic extracts of the basic aqueous layer were combined, washed sequentially with saturated aqueous sodium bicarbonate (twice) and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1-31 as a dense brown syrup (0.30 g).
With trimethylaluminum; ammonium chloride; In toluene; at 0 - 80℃; for 18h;
To a stirred solutionof <strong>[15871-85-9]6-methoxynicotinonitrile</strong> (0.2 g, 1.4919 mmol) in toluene(10 mL) at 0 C was slowly added NH4Cl(0.53 g), followed by Al(CH3)3(0.72 g). The reaction was then heated at 80 C for 18 h. Thereaction mixture was cooled to room temperature and concentrated under reducedpressure. The obtained crude was purified on Combiflash purifier with 7%methanol in dichloromethane as eluent to afford the title compound as whitesolid (0.12 g, 54.5%). To a stirred solution of <strong>[15871-85-9]6-methoxynicotinonitrile</strong>(0.2 g, 1.4919 mmol) in toluene (10 mL) at 0 C was slowly added NH4Cl(0.53g), followed by Al(CH3)3 (0.72 g). The reaction was then heated at80 C for 18 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The obtained crude was purified onCombiflash purifier with 7% methanol in dichloromethane as eluent to afford thetitle compound as white solid (0.12 g, 54.5%). 1H NMR (DMSO-d6, 400 MHz) delta 3.93 (s, 3H), 7.02 (d, J = 8.0 Hz, 1H), 8.12 (d, J= 4.0 Hz, 1H), 8.70 (s, 1H), 9.20 (bs , 2H),9.41(bs, 1H); MS (ESI) m/z 152.1 (M+H)+; HPLC Purity 254nm 99.85%.
In N,N-dimethyl-formamide; at 120 - 140℃; for 41h;
2) 6-Methoxynicotinonitrile Copper cyanide (24.6 g) was added to the above-obtained 5-bromo-2-methoxypyridine (31.0 g) in N,N-dimethylformamide (600 mL). The resultant mixture was stirred at 120C for 19 hours, and at 140C for 22 hours, followed by cooling in air. The reaction mixture was subjected to filtration, and then the filtrate was partitioned between water and methylene chloride. The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure. The residue still contained N,N-dimethylformamide, therefore water and ethyl acetate were added thereto for partitioning the residue again. The organic layer was dried over magnesium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 6-methoxynicotinonitrile as a solid product (12.5 g, 56.5%). 1H-NMR(300MHz,CDCl3)delta:4.00(3H,s), 6.82(1H,d,J=8.81Hz), 7.77(1H,dd,J=8.81,2.39Hz), 8.49(1H,d,J=2.39Hz).
[0034] 170 ml (170 mmol) of a 1 M solution of ethylmagnesium bromide in tetrahydrofuran were added dropwise at 0 C. under argon in the course of 30 minutes to a solution of 20 g (150 mmol) of <strong>[15871-85-9]6-methoxynicotinonitrile</strong> and 0.62 g (3.3 mmol) of copper(I) iodide in 125 ml of anhydrous tetrahydrofuran. After 30 minutes, the reaction mixture was allowed to come to room temperature and was stirred for a further 3 h. 200 ml of methanol were then added dropwise at 5-10 C. and 11.3 g (299 mmol) of sodium borohydride were then added in portions. After stirring overnight at room temperature, 300 ml of water were added and the mixture was extracted 3 times using 250 ml of ethyl acetate each time. The organic phase was dried over magnesium sulfate, then concentrated and the residue was purified by chromatography. 5.5 g of racemic 1-(6-methoxypyridin-3-yl)propylamine were obtained.
With sodium methylate; In methanol; 2-ethoxy-ethanol; at 130℃; for 16h;
COMPOUND (6-45)2-[4-({4-[5-(6-Hydroxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}methyl) phenyll-3-phenyl-l,6-naphthyridin-5(6H)-one (6-45)2-Methoxy-5-(5-piperidin-4-yl-4//-l,2,4-triazol-3-yl)pyridine te7?-Butyl 4-(hydrazinocarbonyl)-piperidine-1 -carboxylate (800 mg, 3.29 mmol) was dissolved in anhydrous 2-ethoxyethanol (10 mL) and 5-methoxypyridine-3-carbonitrile (662 mg, 4.9 mmol) was added to the solution. A solution of 0.5M sodium methoxide in methanol (3 mL, -1.5 mmol) was added and the mixture was heated at 1300C for 16 h. The cooled reaction mixture was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaEtaCtheta3- The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vacuum. This residue was triturated with diethyl ether to give tert-butyl 4-[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3- ~ yl]piperidine-1-carboxylate as a white solid. This material was dissolved in methylene chloride (10 mL) and TFA (10 mL) was added. After one hour the solvent was evaporated under reduced pressure to give 2-methoxy-5-(5-piperidin-4-yl-4H-1,2,4-triazol-3-yl)pyridine. NMR(MeOD): 58.75 (1Eta, s), 8.19 (1Eta, d, J=6Etaz), 6.93 (IH, d , J=6Hz), 3.95 (3H, s), 3.51 (2H,m), 3.22 (3H, m), 2.32 (2H, m), 2.11 (2H, m).
In methanol; dichloromethane; chloroform; toluene;
Step 1 Preparation of 2;methoxy-N-[4-(methylsulfonyl)phenyl]-5-pyridinecarboximidamide To a suspension of 4-(methylsulfonyl)aniline hydrochloride (1.8 g, 8.7 mmol) in toluene (50 ml) at 0 C., trimethylaluminum (2M solution in toluene, 5.2 ml, 10.4 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of <strong>[15871-85-9]6-methoxy-3-cyanopyridine</strong> (1.75 g, 13 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85-90 C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered.
The 3-aminomethyl-6-hydroxypyridine, used as a starting material, was obtained from <strong>[15871-85-9]3-cyano-6-methoxypyridine</strong> using the procedure described in the portion of Example 33 which is concerned with the preparation of 4-aminomethyl-2-hydroxypyridine except that, in the second step described therein, 48% aqueous hydrobromic acid was used in place of concentrated hydrochloric acid.
With formaldehyd; sodium acetate;aluminum nickel; In hydrogenchloride; ethanol; water;
(a) A mixture of <strong>[15871-85-9]2-methoxy-5-cyanopyridine</strong> (61.26 g), semi-carbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1,300 ml) and water (400 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml, water (1,000 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and dissolved in 10% hydrochloric acid (1,000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%), m.p. 48-49.
50%
With formaldehyd; sodium acetate;aluminum nickel; In hydrogenchloride; ethanol; water;
(i) A mixture of <strong>[15871-85-9]2-methoxy-5-cyanopyridine</strong> (61.26 g), semicarbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml, water (1000 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and dissolved in 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether (3*500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%) m.p. 48-49.
REFERENCE EXAMPLE 45 6-Methoxy-3-pyridinecarbonitrile A solution of sodium methoxide (2.42 g, 44.8 mmol) and 6-chloronicotinonitrile (3.04 g, 21.9 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 10 hours. The reaction solution was poured into water, and the organic material was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resultant residue was purified by a column chromatography on a silica gel (hexane/ethyl acetate, 2:1) to obtain the title compound (2.28 g, yield: 78%). 1H NMR (CDCl3) delta 4.00 (3H, s), 6.83 (1H, dd, J = 8.8, 0.8 Hz), 7.78 (1H, dd, J = 8.6, 2.4 Hz), 8.50 (1H, d, J = 1.4 Hz).
37
[ 15871-85-9 ]
[ 943153-51-3 ]
Yield
Reaction Conditions
Operation in experiment
57%
With bromine; sodium acetate; In acetic acid; at 80℃; for 48h;
N-[4-(5-Cyano-2-methoxy-pyridin-3-yl)-benzyl]-2-trifluoromethoxy-benzenesulfonamide To a solution of 4-aminomethylphenylboronic acid hydrochloride (2.0 g, 13.2 mmol) in methanol (20 ml) was added di-tert-butyl dicarbonate (3.16 g, 15.5 mmol) and sodium bicarbonate (3.32 g, 19.8 mmol). The mixture was sonicated for 4 h then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give (4-bromo-benzyl)-carbamic acid tert-butyl ester (1.8 g, 13.2 mmol, 100%) as a white solid. To 6-chloro-nicotinonitrile (15 g, 0.11 mol) under argon atmosphere was added 25% sodium methoxide in methanol (11.7 g, 0.22 mol) and the mixture heated under reflux for 20 h. The methanol was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give 6-methoxy-nicotinonitrile (17.0 g, 0.13 mol, 117%) as a white solid. To 6-methoxy-nicotinonitrile (13.2 g, 99 mmol) in acetic acid (32 ml) was added sodium acetate (8.1 g, 99 mmol). The mixture was stirred and a solution of bromine (31.5 g, 197 mmol) in acetic acid (32 ml) added. The mixture was heated to 80 C. for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5% sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile (11.9 g, 56 mmol, 57%). To a solution of <strong>[15871-85-9]2-methoxy-5-cyanopyridine</strong>-3-boronic acid (1.0 g, 4.0 mmol) in 1,2-dimethoxyethane (10 ml) was added (4-bromo-benzyl)-carbamic acid tert-butyl ester (0.42 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 0.1 mmol) and 2M aqueous sodium carbonate (1 ml, 2.0 mmol). The reaction was heated to 150 C. for 10 min in a microwave over. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was washed with water, then brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on silica gel eluting with 5:1 heptane/ethyl acetate to give [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester as a white solid (0.5 g, 1.47 mmol, 37%). To a solution of [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester (0.5 g, 1.5 mmol) in dichloromethane (5 ml) at 0 C. was added trifluoroacetic acid (5 ml, 28 mmol). The reaction mixture was stirred for 30 min at 0 C. before the solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) to give 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile as a clear glass (0.39 g, 1.6 mmol, 107%). To a solution of 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile (57.3 mg, 0.24 mmol) in dichloromethane (2 ml) was added triethylamine (73.0 mg, 0.72 mmol) and 2-(trifluoromethoxy)benzenesulfonyl chloride. The reaction mixture was agitated for 20 hours and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (19.1 mg, 0.04 mmol, 17%). 1H NMR (400 MHz, DMSO-d6): delta 8.68 (d, 1H), 8.47 (t, 1H), 8.15 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.45-7.55 (m, 4H), 7.31 (d, 2H), 4.19 (d, 2H), 3.96 (s, 3H) ppm; MS (ESI) m/z: 464.3 [M+H]+.
41.9%
With bromine; sodium acetate; acetic acid; at 80℃; for 48h;
To <strong>[15871-85-9]6-methoxynicotinonitrile</strong> (1 g, 7.49 mmol) in Acetic Acid (6.4 ml.) was added sodium acetate (0.612g, 7.46 mmol). The mixture was stirred and a solution of Br2 (0.768 ml_, 14.9 mmol) in Acetic Acid (6.4 ml.) was added. The mixture was heated to 80 C for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5 percent sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile.The sample was loaded using MeOH and purified on CombiFlash reverse phase (C18) 50g using a 20-50% MeOH-Water(0.01 % NH4HC03 ) over 30 mins. The appropriate fractions were combined and evaporated in vacuo to give the product 5-bromo-<strong>[15871-85-9]6-methoxynicotinonitrile</strong> (700 mg, 3.12 mmol, 41 .9 % yield) as a white soild. m/z: [M + H]+ Calcd for C7H6BrN20 213; Found 212
To 5-bromo-2-methoxypyridine (1.00 g, 5.32 mmol) in THF (20 mL) at -78 C. was added n-butyllithium (3.13 mL, 7.83 mmol, 2.5 M in hexane). The reaction was aged at -78 C. for about 25 min at which point the cold bath was removed. <strong>[15871-85-9]6-methoxypyridine-3-carbonitrile</strong> (1.00 g, 7.46 mmol) in THF (10 mL) was added and the reaction aged for about 40 min warming to rt at which point the reaction was concentrated. The residue was diluted with MeOH (20 mL) and NaBH4 (0.282 g 7.46 mmol) was added. The reaction aged about 90 min at rt. The reaction was concentrated and diluted with EtOAc and aq HCl (15 mL, 2 M). The aq portion was extracted twice with EtOAc before adding aq NaOH (20 mL, 2M). The aq portion was then extracted three times with EtOAc. The combined organic portion was concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc/hexane followed by 0-20% MeOH (containing 1.5% triethylamine)/EtOAc affording the title compound. HPLC/MS: 246 (M+1); Rt=1.61 min.
6-oxo-1,6-dihydro-pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
A solution of 1 (134 mg, 1 mmol), EtSNa (168 mg, 2 mmol) in DMF (5 ml) was heated to 60 C. for 4 h. To the reaction mixture was added HCl (aq.) until pH was about 6. The mixture was evaporated in vacuo to give 2. (110 mg, 92%).
UnderNitrogen gas, to a solution of p-anisidine (2.75g, 22. 4MMOL) intetrahydrofuran (15ML) was added dropwise 1. OM sodium bis(trimethylsilyl) amide IN TETRAHYDROFURAN (23. 5ML, 23. 5MMOL) AT ROOMtemperature. After the mixture was stirred for 20min,<strong>[15871-85-9]6-methoxynicotinonitrile</strong> (3. 0g, 22. 4MMOL) was added.The reaction mixture was stirred for 4hrs, then poured into 300ML ofice-water. The precipitates were collected by filtration, washed withdiisopropyl ether to give 3.36g of desired compound (58. 4%) (mixture).This material was used without further purification.NMR (DMSO-d6, A) : 3.73 (3H, s), 3.90 (3H, s), 6.27 (2H, brs), 6.70-7.00 (5H, m), 8.24 (1H, dd, J=9Hz and 2Hz), 8.72 (1H, d, J=2 Hz).MS : 258 (M+H) +.
A reaction mixture of 6-metoxynicotinonitrile (4g, 29.8mmol) in 60ml of MeOH and 5M NaOH (60ml, 300mmol) was stirred overnight at 10O0C. The mixture was concentrated and redissolved in water (50ml). A 2N solution of HCI was added until pH acid and a solid was formed, filtered and washed with water twice and with hexane twice. 3.04g of the title compound were obtained as a white solid (yield=66%).LRMS: m/z 154 (M+1 )+ Retention time: 2.22min (method A)
4.2 g
With water; potassium hydroxide; In ethanol; for 2h;Reflux;
B) 6-methoxynicotine acid To a solution of 6-methoxynicotinonitrile (5.00 g) in ethanol (100 mL) was added 2 M aqueous potassium hydroxide solution (20 mL). The reaction mixture was heated at reflex for 2 hr, and the solvent was evaporated under reduced pressure. To the residue was added water, the pH of the mixture was adjusted to 4-5 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.2 g). 1H NMR (400 MHz, DMSO-d6) delta 3.92 (3H, s), 6.86-6.92 (1H, m), 8.11-8.15 (1H, m), 8.73 (1H, d, J = 2.0 Hz), 13.0 (1H, s).
(Z)-N'-hydroxy-6-methoxynicotinimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; at 85℃;
To a solution of <strong>[15871-85-9]6-methoxynicotinonitrile</strong>12 (200mg, 1.49 mmol) dissolvedin EtOH (10 mL), potassium carbonate (618 mg, 4.47 mmol) was added. This wasfollowed by the addition of hydroxylamine hydrochloride (155 mg, 2.24 mmol) andthe reaction mixture was refluxed at 85C overnight. Completion of the reactionwas monitored by LCMS. After completion of the reaction, solvent was evaporatedand the residue was dissolved in EtOAc (50mL). The organic layer was washedtwice with water, dried over Na2SO4 and evaporated todryness. The resulting crude product was purified through pre-loaded silica gel column using EtOAc-hexane to obtain 0.27g of pure N-hydroxy-6-methoxynicotinimidamide 13 in quantitative yield. ESMS calcd.167.2; Found: 169.2 (MH+)
Example HA3-Amino-3-(6-methoxypyridin-3-yl)prop-2-enenitrile A solution of 0.258 ml (1.844 mmol) diisopropylamine in dry THF (1.5 ml) was cooled to -7O0C under inert gas atmosphere, and 1.152 ml (1.844 mmol) n-butyllithium (1.6 M solution in hexanes) were added dropwise. Then, a solution of 85.6 mul (1.627 mmol) acetonitrile in dry THF (1.5 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at -7O0C before a solution of 150 mg (1.085 mmol) 2-methoxypyridine-5-carbonitrile in dry THF (1.5 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 h before water (2 ml) was added slowly. The mixture was extracted several times with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 188 mg (99% of th.) of the crude title compound which was used in the next step without further purification.GC-MS (method 3): R1 = 6.45 min; MS (EIpos): m/z = 175 (M)+.
3) 6-Methoxy-N-phenylnicotinamidine In a nitrogen atmosphere, aniline (5.29 g) in tetrahydrofuran (20 mL) was added dropwise to sodium bis(trimethylsilyl)amide (10.4 g) in tetrahydrofuran (100 mL) over 10 minutes, followed by stirring for 20 minutes. The above-obtained <strong>[15871-85-9]6-methoxynicotinonitrile</strong> (8.00 g) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture over 10 minutes, followed by stirring at room temperature for 15 hours. The crystals that precipitated were collected by filtration, washed with hexane-diethyl ether, and dried, to thereby give 6-methoxy-N-phenylnicotinamidine (6.79 g). Hexane was further added to the filtrate, and the crystals that precipitated were collected by filtration, washed with hexane-diethyl ether, and dried, to thereby give 6-methoxy-N-phenylnicotinamidine (4.95 g). In total, 6-methoxy-N-phenylnicotinamidine was obtained in an amount of 11.7 g (88.6%). 1H-NMR(300MHz,CDCl3)delta:3.99(3H,s), 6.81(1H,d,J=8.72Hz), 6.96-7.10(3H,m), 7.43-7.39(2H,m), 8.18(1H,dd,J=8.72,2.39Hz), 8.61(1H,d,J=2.39Hz). MS (FAB)m/z:228 (M+H)+.
Step A: Preparation of 2-(6-Methoxypyridin-3-yl)propan-2-amine. fMethod Ll To a flame dried flask containing cerium(III) chloride (4.59 g, 18.64 mmol) was addedTHF (60 mL) under nitrogen atmosphere. The suspension was stirred at room temperature for 2 h, cooled down below -50 0C, then added methyllithium (11.65 mL, 18.64 mmol) in hexanes. The whole reaction mixture was stirred for 30 min at that temperature, and 6- methoxynicotinonitrile (0.5 g, 3.73 mmol) in THF (2 mL) was added. The cooling bath was removed, and the reaction was stirred at room temperature for 18 h, quenched with concentrated NH4OH (15 mL) at below -40 0C. The mixture was brought to 25 0C and filtered through Celite. The solid was washed with 10% MeOH/CH2Cl2. The combined filtrates were concentrated, and the residue was purified by HPLC. The fractions collected were neutralized with saturated NaHCO3, then extracted with 1:4 iPrOH/CH2Cl2. The organics were dried and concentrated to give the title compound (180 mg). LCMS mlz = 167.3 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.50 (s, 6H), 3.92 (s, 3H), 6.71 (d, J= 8.7 Hz, IH), 7.75 (ddd, J= 1.4, 2.6 and 8.7 Hz, IH), 8.29 (dd, J= 1.4 and 2.6 Hz, IH).
5-cyano-2-methoxy-N-methylpyridinium tetrafluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; at 20℃; for 2h;Glovebox;
General procedure: A 3 mL glass vial was equipped with a rubber septum and magnetic stir bar. The vial was brought into a glove box and charged with methyl trifluoromethylsulfonate (MeOTf, 51 muL, 0.46 mmol) by micropipette with polypropylene tip. The vial was sealed and removed from the glove box. A separate 3 mL vial was charged with substrate (68 mg, 0.46 mmol) and was dissolved in PhMe (0.5 mL). The solution of pyridine was added via syringe onto the sealed vial of MeOTf at room temperature. The vial which contained the pyridine was rinsed with PhMe (0.2 mL) and the rinse solution was injected into the reaction vial. The reaction vial was kept at room temperature and stirring was maintained at ca. 400-600 rpm. Over the course of the reaction (2 hr), a precipitate formed. At the end of the reaction, PhMe (2 mL) was added after which stirring was stopped. Any solid or oil was allowed to settle and the solvent was removed by glass pipette. The residue was then rinsed with several portions of hexanes to remove any unreacted starting materials, again removing the solvent by pipette. Residual solvent was then removed in vacuo to provide the title compound (53 mg, 37%).
[1 014] At -78 C., 19.4 ml oflithium diisopropylamide (2molar in THF/heptane/ethylbenzene, 1.3 eq.) were added to asolution of 4.0 g (29.8 mmol) of <strong>[15871-85-9]6-methoxypyridine-3-carbonitrile</strong>in 120m ofTHF, and the mixture was stirred at -78C. for 1 h. At-78 C., a solution of9 .1 g (35 .8 mmol) of iodinein 20 ml ofTHF was then added, and the reaction mixture wasstirred at-78 C. for 1 hand then carefully added to saturatedaqueous ammonium chloride solution. After addition of ethylacetate, the reaction mixture was extracted three times withethyl acetate. The combined organic phases were dried (magnesiumsulphate), filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography(silica gel 60, mobile phase: cyclohexane/ethyl acetatemixtures). Yield: 4.0 g (purity 92%, 48% of theory)[1015] GC [Method 7]: R,=5.08 min; MS (EI) m/z=260(Mt[1016] 1H-NMR (400 MHz, DMSO-d6): ll [ppm]=8.63 (s,lH), 7.61 (s, lH), 3.92 (s, lH).
4 g
At -78 C, 19.4 ml of lithium diisopropylamide (2 molar inTHF/heptane/ethylbenzene, 1.3 eq.) were added to a solution of 4.0 g (29.8mmol) of <strong>[15871-85-9]6-methoxypyridine-3-carbonitrile</strong> in 120 ml of THE', and the mixturewas stirred at -78 C for 1 h. At -78 C, a solution of 9.1g (35.8 mmol) of iodine in 20 ml of THF was then added, and the reactionmixture was stirred at -78 C for 1 h and then carefully added to saturatedaqueous ammonium chloride solution. After addition of ethyl acetate, thereaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried (magnesium sulphate), filtered andconcentrated under reduced pressure. The crude product was purified by flashchromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 4.0 g (purity 92%, 48% of theory)
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc; In acetonitrile; at 80℃; for 3h;Inert atmosphere; Sealed tube;
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn(CN)2 (0.8mmol) , 93.9mg), p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88%, and 1H NMR purity was greater than 98%.
With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; at 120℃; for 48h;
To a solution of<strong>[15871-85-9]6-methoxynicotinonitrile</strong> (0.1 g, 0.7454 mmol) in DMF (10 mL) was added NaN3(0.15 g) followed by NH4Cl (0.12 g) at room temperature. Thereaction mixture was then heated at 120 C for 48 h. The reactionmixture was poured into water and pH was adjusted to 3 using aq.2N HCl solutionand then the reaction mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na2SO4, filteredand concentrated to afford the title compound as off-white solid (0.1 g, 77 %). Toa solution of <strong>[15871-85-9]6-methoxynicotinonitrile</strong> (0.1 g, 0.7454 mmol) in DMF (10 mL) wasadded NaN3 (0.15 g) followed by NH4Cl (0.12 g) at roomtemperature. The reaction mixture was then heated at 120 C for 48h. The reaction mixture was poured into water and pH was adjusted to 3 using aq.2NHCl solution and then the reaction mixture was extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na2SO4,filtered and concentrated to afford the title compound as off-white solid (0.1g, 77 %).1H NMR (DMSO-d6,400 MHz) delta 3.92 (s, 3H), 7.03 (d, J = 12.0 Hz, 1H), 8.24 (d, J= 4.0 Hz, 1H), 8.81 (s, 1H); MS(ESI) m/z 178.1 (M+H)+;HPLC Purity 254nm, 99.73%.
With hydroxyamino hydrochloride; potassium carbonate In ethanol at 80℃;
4.1.22. 5-[2-(1-Cyclopentylpyrrolidin-3-yl)oxyphenyl]-3-(6-methoxy-3-pyridyl)-1,2,4-oxadiazole (27)
A mixture of 6-methoxynicotinonitrile (1.0 g, 7.45 mmol, 1 eq), hydroxylamine hydrochloride(0.777 g, 11.2 mmol, 1.5 eq) and K2CO3 (3.09 g, 22.4 mmol, 3 eq) in EtOH (50mL) was heated at 80 °C overnight. The reaction mixture was concentrated under reducedpressure. The residue was partitioned between EtOAc and water. The phases were separated.The organic phase was dried over Na2SO4, filtered, and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel using a gradientof THF (0-40%) in hexane to afford 0.200 g (16%) of N-hydroxy-6-methoxynicotinimidamideas an off-white solid. LC-MS (ESI, m/z): 168 [M + H]+. 1H NMR (400 MHz, DMSO-d6) d9.62 (s, 1H), 8.43 (s, 1H), 7.93 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.86 (br. s., 2H), 3.86 (s, 3H).
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In methanol Reflux;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
