* 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 Acetaldehyde oxime; oxygen; 1N,3N,5N-trihydroxy-1,3,5-triazin-2,4,6[1H,3H,5H]-trione In water at 100℃; for 34 h; Green chemistry
General procedure: A mixture of primary amine (1 mmol), THICA (5 molpercent), acetaldoxime(10 molpercent), and H2O (5 mL) was placed in a three-neckedflask. O2 was stirred into the flask at a flow rate of 20 mL/min. The reaction mixture was stirred at 100 °C for several hours, and the reaction progress was monitored by TLC. When the final reaction mixture was cooled to r.t. and extracted with Et2O, the organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was pure enough. When necessary,the crude product was purified by chromatography using EtOAc–PE (1:8) as eluent.
Reference：
[1] Synlett, 2014, vol. 25, # 13, p. 1873 - 1878
[2] New Journal of Chemistry, 2015, vol. 39, # 8, p. 6677 - 6682
2
[ 696-60-6 ]
[ 20059-73-8 ]
Reference：
[1] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 8, p. 4442 - 4452
3
[ 123-08-0 ]
[ 696-60-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With ammonia; hydrogen In methanol; water at 20℃; for 21 h;
Preparation Example A+-1. Sodium 4-(((2-Aminopyridine-3-carbonyl)-amino)-methyl)-phenolate To a solution of 4-hydroxybenzaldehyde (10g, 81.9mmol) in methanol (45mL) was added Raney nickel (3g) and 7N aqueous ammonia solution (45mL), and the solution was stirred under hydrogen atmosphere (1 atm) at room temperature for 21 hours. The reaction solution was filtered through Celite pad to remove the catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol (10g, quantitatively) was obtained as a pale green solid. Then, a solution of 2-aminonicotinic acid (3.0g, 21.7mmol) in N,N-dimethylformamide (30mL) was cooled with an ice water, 1-hydroxybenzotriazole (3.51 g, 26mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide (4.04g, 26mmol) and a solution of the resulting 4-aminomethyl-phenol (3.0g, 21.7mmol) in N,N-dimethylformamide (20mL) were added, and the solution was stirred for 18 hours at this temperature. The reaction solution was partitioned into brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, filtration was carried out using NH silica gel, and the filtrate was concentrated. The residue was dissolved in methanol (90mL), 1 N sodium hydroxide (17.8mL, 17.8mmol) was added thereto, followed by stirring at room temperature for an hour and a half. The reaction solution was concentrated in vacuo, and the title compound (5.66g) was obtained as a pale yellow solid.
100%
With ammonia; hydrogen In methanol; water at 20℃; for 21 h;
To a solution of 4-hydroxybenzaldehyde (10g, 81.9mmol) in methanol (45mL) was added Raney nickel (3g) and 7N aqueous ammonia solution (45mL), and the solution was stirred under hydrogen atmosphere (1 atm) at room temperature for 21 hours. The reaction solution was filtered through Celite pad to remove the catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol (10g, quantitatively) was obtained as a pale green solid. Then, a solution of 2-aminonicotinic acid (3.0g, 21.7mmol) in N,N-dimethylformamide (30mL) was cooled with an ice water, 1-hydroxybenzotriazole (3.51g, 26mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide (4.04g, 26mmol) and a solution of the resulting 4-aminomethyl-phenol (3.0g, 21.7mmol) in N,N-dimethylformamide (20mL) were added, and the solution was stirred for 18 hours at this temperature. The reaction solution was partitioned into brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, filtration was carried out using NH silica gel, and the filtrate was concentrated. The residue was dissolved in methanol (90mL), 1 N sodium hydroxide (17.8mL, 17.8mmol) was added thereto, followed by stirring at room temperature for an hour and a half. The reaction solution was concentrated in vacuo, and the title compound (5.66g) was obtained as a pale yellow solid.
88.9%
With ammonium hydroxide; hydrogen; sodium hydroxide In water at 50℃; Autoclave; Large scale
Sodium hydroxide was added to dissolve 60kg 700kg of water, then add hydroxybenzaldehyde 150kg and stir until completely dissolved clear, the solution is sucked 2000L autoclave, and then put Raney nickel 25kg (wet weight), 25percent aqueous ammonia 500kg, added 8 hydrogen pressure, reaction temperature 50 up until hydrogen absorption had ceased, the cooling, pressure filtration of catalyst, washed with water and then 100kg.The catalyst was collected in buckets of water storage.The filtrate was transferred to a processing vessel, hydrochloric acid and then adjusting the pH value to 9 to 10, cooling to 5 Crystallization two hours, rejection filter, and dried to give p-hydroxy benzyl amine monohydrate 154kg, yield 88.9percent, HPLC purity 98.9percent
80%
With ammonia; hydrogen In methanol; water at 25 - 40℃; for 5 - 20.5 h;
Methanol (2.0L ) is charged in an autoclave, p-hydroxybenzaldehyde (250 gms; 2.049M) is added followed by 25 gms (50 gms wet) of Raney Nickel, and aqueous ammonia(25percent) ( 800ml ;11.7647M) . The hydrogenator is evacuated and flushed with nitrogen, a few times .The autoclave is initially pressurized to 3 Kg/cm with hydrogen and then maintained at 5Kg/cm2 hydrogen pressure for 15-20 hours at 25-280C. The reaction is monitored by TLC and continued till the starting material is less than 2 percent. After releasing hydrogen pressure , the reaction mixture is further heated for 30 minutes at about 400C. The catalyst is filtered and washed with methanol, followed by purging of the solution with nitrogen for about one hour till the evolution of ammonia ceases. The solvent is distilled off at 40-450C to 1/4 of the total volume under vacuum , cooled to O0C and stirred for two hours. The solid is filtered and the cake is washed with 2x250ml of water, followed by washing with 2x250ml of toluene. The material is dried at 70-750C till the moisture content is < 1 percent. The product analysis is as follows. Product weight : 210-215 gms. Purity by HPLC : 95-98 percent Yield : 80-85 percentMelting range : 115-1190C; Methanolic ammonia (13-15percent) (700 ml) is charged into an autoclave, p- hydroxybenzaldehyde (100 gm; 0.82 moles) is charged followed by Raney Nickel (15 gms ; 30 gms wet) . The hydrogenator is evacuated and flushed with nitrogen, a few times .The autoclave is pressurized to 5 Kg/cm2 with hydrogen and maintained at 5 Kg/cm2 for 5-6 hours at 25-28°C. The reaction is monitored on HPLC and the reaction is continued till the starting material is less than 2 percent. Hydrogen pressure is released and . the catalyst is filtered and washed with methanol. Nitrogen gas is purged in the solution for one hour till the evolution of ammonia gas ceases. The solvent is distilled off up to l/3r of the total volume under vacuum at 40-45°C. The reaction mass is cooled to O0C and stirred for two hours. The solid is filtered and washed with 2x100ml of water , followed by 100 ml of methanol. The material is dried in oven at 50-55°C under vacuum till the moisture content is < 1 percent. Product weight : 80-85 gms. Purity by HPLC : 95-98 percent Yield : 80-85 percent
80%
With ammonia; hydrogen In methanol; water at 25 - 40℃; for 15.5 - 20.5 h;
Example-1 Preparation of P_Hydroxy Benzylamine Methanol (2.0 L) is charged in an autoclave, p-hydroxybenzaldehyde (250 gms; 2.049M) is added followed by 25 gms (50 gms wet) of Raney Nickel, and aqueous ammonia (25percent) (800 ml; 11.7647M). The hydrogenator is evacuated and flushed with nitrogen, a few times. The autoclave is initially pressurized to 3 Kg/cm2 with hydrogen and then maintained at 5 Kg/cm2 hydrogen pressure for 15-20 hours at 25-28° C. The reaction is monitored by TLC and continued till the starting material is less than 2percent. After releasing hydrogen pressure, the reaction mixture is further heated for 30 minutes at about 40° C. The catalyst is filtered and washed with methanol, followed by purging of the solution with nitrogen for about one hour till the evolution of ammonia ceases. The solvent is distilled off at 40-45° C. to 1/4 of the total volume under vacuum, cooled to 0° C. and stirred for two hours. The solid is filtered and the cake is washed with 2*250 ml of water, followed by washing with 2*250 ml of toluene. The material is dried at 70-75° C. till the moisture content is < 1percent. The product analysis is as follows. Product weight: 210-215 gms. Purity by HPLC: 95-98percent Yield: 80-85percent Melting range: 115-119° C.
80%
With ammonia; hydrogen In methanol at 25 - 28℃; for 5 - 6 h;
Example-2 Preparation of P_Hydroxy Benzylamine Methanolic ammonia (13-15percent) (700 ml) is charged into an autoclave, p-hydroxybenzaldehyde (100 gm; 0.82 moles) is charged followed by Raney Nickel (15 gms; 30 gms wet). The hydrogenator is evacuated and flushed with nitrogen, a few times. The autoclave is pressurized to 5 Kg/cm2 with hydrogen and maintained at 5 Kg/cm2 for 5-6 hours at 25-28° C. The reaction is monitored on HPLC and the reaction is continued till the starting material is less than 2percent. Hydrogen pressure is released and the catalyst is filtered and washed with methanol. Nitrogen gas is purged in the solution for one hour till the evolution of ammonia gas ceases. The solvent is distilled off up to 1/3rd of the total volume under vacuum at 40-45° C. The reaction mass is cooled to 0° C. and stirred for two hours. The solid is filtered and washed with 2*100 ml of water, followed by 100 ml of methanol. The material is dried in oven at 50-55° C. under vacuum till the moisture content is < 1percent. Product weight: 80-85 gms. Purity by HPLC: 95-98percent Yield: 80-85percent
Reference：
[1] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 46-47
[2] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 55
[3] Patent: CN105481701, 2016, A, . Location in patent: Paragraph 0016
[4] Patent: WO2007/74386, 2007, A2, . Location in patent: Page/Page column 8
[5] Patent: US2009/177008, 2009, A1, . Location in patent: Page/Page column 2-3
[6] Patent: US2009/177008, 2009, A1, . Location in patent: Page/Page column 3
[7] Green Chemistry, 2017, vol. 19, # 4, p. 1134 - 1143
[8] Patent: US4391805, 1983, A,
[9] Green Chemistry, 2016, vol. 18, # 2, p. 487 - 496
[10] Patent: JP2017/25012, 2017, A, . Location in patent: Paragraph 0034; 0035
[11] RSC Advances, 2018, vol. 8, # 40, p. 22490 - 22497
4
[ 767-00-0 ]
[ 696-60-6 ]
Reference：
[1] Patent: EP696593, 1996, A2,
[2] Bulletin des Societes Chimiques Belges, 1996, vol. 105, # 10-11, p. 721 - 727
[3] Journal of Chemical Research, 2009, # 1, p. 5 - 7
[4] Tetrahedron, 1992, vol. 48, # 21, p. 4301 - 4312
[5] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7800 - 7805
[6] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2771 - 2777
[7] Helvetica Chimica Acta, 1936, vol. 19, p. 581,586
[8] Hoppe-Seyler's Zeitschrift fuer physiologische Chemie, 1965, vol. 343, # 1, p. 52 - 60
[9] Journal of the American Chemical Society, 1984, vol. 106, # 11, p. 3344 - 3353
[10] Magnetic Resonance in Chemistry, 1995, vol. 33, # 9, p. 717 - 723
[11] Journal of the American Chemical Society, 1996, vol. 118, # 43, p. 10662 - 10663
[12] Journal of Medicinal Chemistry, 2000, vol. 43, # 17, p. 3315 - 3321
[13] Phytochemistry, 1997, vol. 46, # 5, p. 833 - 837
[14] Canadian Journal of Chemistry, 1997, vol. 75, # 6, p. 825 - 828
[15] Journal of the American Chemical Society, 2009, vol. 131, # 36, p. 13132 - 13141
[16] Catalysis Science and Technology, 2014, vol. 4, # 3, p. 629 - 632
5
[ 22171-15-9 ]
[ 696-60-6 ]
Reference：
[1] Patent: US6017919, 2000, A,
[2] Phytochemistry, 1997, vol. 46, # 5, p. 833 - 837
[3] Canadian Journal of Chemistry, 1997, vol. 75, # 6, p. 825 - 828
Reference：
[1] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 823
[2] Journal of the American Chemical Society, 1964, vol. 86, p. 3075 - 3084
[3] Molecules, 2013, vol. 18, # 6, p. 6990 - 7003
8
[ 52805-36-4 ]
[ 696-60-6 ]
Reference：
[1] Phytochemistry, 1997, vol. 46, # 5, p. 833 - 837
[2] Canadian Journal of Chemistry, 1997, vol. 75, # 6, p. 825 - 828
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1961, vol. 9, # 12, p. 945 - 948
[2] Science China Chemistry, 2012, vol. 55, # 3, p. 435 - 442
12
[ 108-95-2 ]
[ 696-60-6 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 2011, vol. 88, # 8, p. 1229 - 1237
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1700
13
[ 17564-64-6 ]
[ 696-60-6 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1701
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1700
14
[ 60221-52-5 ]
[ 696-60-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1921, vol. 425, p. 328
[2] Journal of the Chemical Society, 1925, vol. 127, p. 2597
15
[ 52447-43-5 ]
[ 696-60-6 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 2011, vol. 88, # 8, p. 1229 - 1237
16
[ 86386-69-8 ]
[ 696-60-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1961, vol. 9, # 12, p. 945 - 948
17
[ 4403-71-8 ]
[ 696-60-6 ]
Reference：
[1] Chemische Berichte, 1889, vol. 22, p. 2142
18
[ 7409-30-5 ]
[ 696-60-6 ]
Reference：
[1] Chemische Berichte, 1889, vol. 22, p. 2142
19
[ 100-14-1 ]
[ 696-60-6 ]
Reference：
[1] Chemische Berichte, 1889, vol. 22, p. 2142
20
[ 7647-01-0 ]
[ 64-17-5 ]
[ 7732-18-5 ]
[ 24124-24-1 ]
[ 696-60-6 ]
[ 88-99-3 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1701
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1700
21
[ 120-72-9 ]
[ 696-60-6 ]
[ 151358-47-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
With iron(II) triflate; oxygen In chlorobenzene at 110℃; for 8 h; Schlenk technique
General procedure: To a Schlenk tube were added benzylamine 1 (1.3 mmol), indole 2(2.0 mmol), Fe(OTf)2 (10 molpercent), and anhydrous chlorobenzene (2 mL).The tube was equipped with an O2 balloon, and the mixture wasstirred at 110 °C until complete consumption of indole (TLC monitoring).When the reaction was complete, the mixture cooled to r.t., dilutedwith CH2Cl2 (10 mL), and washed with H2O (2 × 10 mL). The organicextract was dried (anhyd Na2SO4) and concentrated under reducedpressure, and the resulting residue was purified by columnchromatography (silica gel, hexane–EtOAc) to afford the correspondingbis(indolyl)methane products 3 and 4.
In 1L with thermometer, dropping funnel, adjustable power heating jacket, 970.9 g (3.0 mol) of 25% hydrobromic acid was put into the reactor of the agitator and distillation device, Under stirring, 103.7 g (0.7558 mol) of 4-methoxybenzylamine was slowly added dropwise using a dropping funnel, Drop by drop, Raise the excess water to remove excess water until the distillation temperature reaches above 120C (in this case, the temperature in the reactor reaches above 126 C ), Reduce the heating rate, make it into a reflux state or distill at a very slow rate, Keep the temperature in the reactor above 126 C , The generated gas is absorbed by solvent or recovered by freezing method to protect the environment, When no more gas is observed, increase the heating rate again and continue the distillation. Recover excess hydrobromic acid until the temperature in the reactor reaches above 132 C , slightly colder, Add 200 milliliters of water, dropwise add a pre-cooled mass concentration of 40% sodium hydroxide aqueous solution under water cooling, Precipitate and drop again until the precipitate completely disappears, extract and wash twice with 50 ml of toluene, The organic phase recovers toluene, the water phase is adjusted with 30.0% hydrochloric acid under ice-cooling to pH: 9-10, stirred for crystallization, Filtration with suction, the filter cake was washed with 240 ml of water and then vacuum dried, It is the state when the absolute pressure is less than 10 mm Hg. After rotating and vacuum drying at room temperature for 2 hours, Then increase it to 80 according to the heating rate of 10 / hour, and bake it to constant weight to get the finished product. Total: 86.9 g, water content determined by Karl Fischer method: 0.2%, molar yield: 92.5%.
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 1.66667h;Product distribution / selectivity;
To a stirred solution of <strong>[696-60-6]4-aminomethylphenol</strong> (1g, 8.13mmol) in tetrahydrofuran / water (1 :1 ratio, 20ml) at O0C was added solid NaHCO3 (0.888g ,10.16mmol) followed by dropwise EPO <DP n="64"/>addition of benzyl chloroformate (1.16ml, 8.13mmol). The mixture was stirred at 00C for 10 minutes then allowed to warm slowly to r.t. After stirring the mixture for 90 minutes the tetrahydrofuran was removed in vacuo. The aqueous layer was extracted with EtOAc (2 x 10ml). The organic layer was washed with water (2 x 10ml), dried (MgSO4), and the solvent removed in vacuo to a residue. Trituration with heptane gave the product as a white solid (2.1Og, 100% yield). LCMS purity 100%, m/z 258 [M++H]+.
100%
With sodium hydroxide; In tetrahydrofuran; water; at 0℃; for 19h;Product distribution / selectivity;
A solution of 4-hydroxybenzylamine (1g, 8.1mmol) in THF (20ml) and water (20ml) was cooled down to O0C with sodium hydroxide (357mg, 8.9mmol). Benzyl chloroformate (1.27ml, 8.9mmol) was added slowly and the reaction mixture was stirred at O0C for 1h and at r.t. for 18 hours. Brine (20ml) and ethyl acetate (2OmL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (2OmL). The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield a light pink solid (2.45g, 100%). 1H NMR (300 MHz, CDCI3), delta: 4.30 (2 H, d, J=5.8 Hz, CH2NH), 5.15 (2 H, s, OCH2), 6.67 (1 H, br. S, NH), 6.78 (2 H, d, J=8.5 Hz, Ar), 7.12 (2 H, d, J=8.1 Hz, Ar), 7.29 - 7.44 (5 H, m, Ar)
97%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 1.5h;
Stage 1; - Benzyl (4-hydroxybenzyl)carbamateTo a suspension of 4-(aminomethyl)phenol (300mg, 2.44mmol) in 10% THF/H2O (1OmL) was added NaHCO3 (266mg, 3.17mmol). The mixture was cooled to 00C and benzylchloroformate (344mul_, 2.44mmol) added slowly. The reaction was stirred for 1.5 hours at RT. The reaction mixture was partitioned between water (4OmL) and EtOAc EPO <DP n="44"/>(4OmL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (2OmL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with heptane to afford the product as a white solid (610mg, 97% yield). ESMS: m/z 258 [M+H]+
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
10 g of 4-Aminomethyl-phenol was dissolved in 200 mL DMF, the solution was cooled to 0 C, 13.6 mL of triethylamine followed by 11.6 mL of benzyl chloroformate was added and stirring was continued at rt overnight. The reaction mixture was diluted with water and extracted 2x with EtOAc, the combined organic layers were washed 2x with 2N hydrochloric acid, 5% sodium bicarbonate solution, dried over Na2S04 and evaporated to dryness to give an almost colourless oil. The product was chromatographed over silica gel (eluant: toluene/EtOAc = 10: 1) and yielded the title compound as almost colourless oil.
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
10 g of 4-Aminomethyl-phenol was dissolved in 200 mL DMF, the solution was cooled to 0 C., 13.6 mL of triethylamine followed by 11.6 mL of benzyl chloroformate was added and stirring was continued at rt overnight. The reaction mixture was diluted with water and extracted 2* with EtOAc, the combined organic layers were washed 2* with 2N hydrochloric acid, 5% sodium bicarbonate solution, dried over Na2SO4 and evaporated to dryness to give an almost colourless oil. The product was chromatographed over silica gel (eluant: toluene/EtOAc=10:1) and yielded the title compound as almost colourless oil.
palladium-carbon catalyst; In tetrahydrofuran; water; hydrogen;
PREPARATIVE EXAMPLE 67 10% Palladium-carbon catalyst (water content 50%, 50 mg) was added to a solution of <strong>[22171-15-9]4-benzyloxybenzylamine</strong> (530 mg, 2.485 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred for 3 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=1/1) to give 4-hydroxybenzylamine (260 mg, 85.0%). 1 H-NMR (CDCl3)delta: 7.1(2 H, d, J=9 Hz), 6.77(2 H, d, J=9 Hz), 3.8(2 H, s), 2.9(3 H, bs).
With sodium hydrogencarbonate; In tetrahydrofuran; water;
13A: tert-Butyl 4-hydroxybenzylcarbamate; [00185] To 4-(aminomethyl)phenol (123 mg, 1.0 mmol) in THF (2 mL) was added sodium bicarbonate (250 mg, 3.0 mmol) in water (2 mL) followed by di-tert- butyl-dicarbonate (240 mg, 1.1 mmol). After stirring at rt for 2 h, the reaction was diluted with ethyl acetate, washed with brine, dried (^2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography eluting with 0-40% ethyl acetate/hexane to provide 13A (223 mg, 100%). LC-MS: 246.17 (M + Na)+.
99%
With sodium hydrogencarbonate; In methanol; for 16h;Reflux;
4-Hydroxybenzylamine 13 (4.00 g, 32.5 mmol), (Boc)2O (7.80 g,35.8 mmol) and NaHCO3 (3.41 g, 81.2 mmol) were refluxed inmethanol overnight (16 h). Afterwards, the reaction was cooled tort and methanol was evaporated. To the resulting slurry, water andethyl acetate were added and the aqueous phase was extractedwith ethyl acetate. Organic layers were collected, washed withwater and brine, dried over anhydrous MgSO4 and evaporated,giving crude product as brown oil. The crude product was precipitatedand washed with diethyl ether/petroleum ether (approx. 1:1)giving compound 14 as light brown solid with 99% (7.17 g) yield[24].mp: 87 C; NMR: 1H (600 MHz, CDCl3): delta 7.10 (d, J=7.3 Hz, 2H),6.77 (dt, J =8.6, 2.0 Hz, 2H), 4.86 (s, 1H), 4.22 (s, 2H),1.46 (s, 9H); 13C(151 MHz, CDCl3): delta 156.3, 155.5, 130.5, 129.0, 115.6, 79.9, 44.3, 28.6;IR (ATR) [cm-1]: 3340, 3153, 2974, 1673, 1615, 1598, 1549, 1517,1448, 1367, 1292, 1257, 1227, 1160; Elemental analysis: Calcd forC12H17NO3: C, 64.55; H, 7.67; N, 6.27, found: C, 64.69; H, 7.50; N,6.09; LC-MS (DAD/ESI): tR 5.31 min, Calcd for C12H17NO3 (m/z):[M-H]- 222.26, found: [M-H]- 222.10.
99%
With sodium hydrogencarbonate; In methanol; for 16h;Reflux;
General procedure: The 4-hydroxybenzylamine or 4-hydroxyphenethylamine (1.0 equiv.), (Boc)2O (1.1 equiv.) and NaHCO3 (2.1 equiv.) were refluxed in methanol overnight (16 h). Afterwards, the reaction was cooled to rt and methanol was evaporated. To the resulting slurry, water and dichloromethane were added and the aqueous phase was extracted with dichloromethane. Organic layers were collected, washed with water, dried over anhydrous MgSO4 and evaporated, giving crude product as brown oil. The crude product was precipitated and washed with diethyl ether/petroleum ether (approx. 1:1) giving the corresponding compounds.
94%
In methanol; water; at 20℃; for 1h;
To a solution of 4-(aminomethyl)phenol (1.2 g, 10 mmol) in methanol (70 mL) and water (5 mL) was added B0C2O (2.4 g, 11 mmol) dropwise by syringe at RT. The resulting mixture was stirred at RT for an hour until 4-(aminomethyl)phenol was totally consumed, which was monitored by LCMS and TLC. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate (150 mL). The solution was washed with sat. aq. citric acid (50 mL x 2) and brine, dried over sodium sulfate and concentrated in vacuo to give N-Boc-<strong>[696-60-6]4-aminomethylphenol</strong> (2.1 g, 94% yield) as brown oil. ESI m/z: 246 (M + Na)+. MR (500 MHz, CDCh) delta 7.12 (d, J= 7.8 Hz, 2H), 6.82-6.71 (m, 2H), 4.84 (s, 1H), 4.23 (d, J = 5.3 Hz, 2H), 1.46 (s, 9H) ppm.
83%
With sodium hydroxide; In water; tert-butyl alcohol; at 20℃; for 1h;
Example 2-21; Ethyl 2-((4-aminomethyl)phenoxy)-2-methylpropanoate; This amine was obtained in 3 steps from 4-hydroxybenzylamine; Step 1; (4-(tert-butoxycarbonyl)aminomethyl)phenol; Di-tert-butyldicarbonate (11.1 g, 50.8 mmol) was added portionwise to a solution of 4-hydroxybenzylamine (6.25 g, 50.8 mmol) in tert-butanol (200 ml) and 1M sodium hydroxide (100 ml). The solution was stirred for 1 hour at room temperature. Water was added, pH was ajusted to 7 by addition of 1M hydrochloric acid, and the product was extracted by ethyl acetate. The organic layer was dried with magnesium sulfate (MgSO4) and evaporated. The expected product was purified by silica gel chromatography (cyclohexane/ethyl acetate 7/3). Yield: 83%
83%
With sodium hydrogencarbonate; In methanol; at 20℃;
fert-Butyl 4-hvdroxybenzylcarbamate[0142] 4-(Aminomethyl)phenol (4.9 mmol, Ig) was dissolved in methanol. Boc- anhydride (5.8 mmol, 1.3 g) and NaHCO3 (14.7 mmol, 1.2 g) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated and CH2Cl2 and water were added. The organic phase was separated and the aqueous phase was extracted 3 times with CH2Cl2. The combined organic phases were dried (Na2SO4) and evaporated. The crude product was purified by column chromatography using combiflash (Heptane: EtOAc 0-40%) to give 1.5 g (83%) of the title compound: LC-MS [M+H]+= 224.
83%
In methanol; at 4℃; for 2h;Inert atmosphere;
Putting 12.3 g (100 mmol) of the monomer p-hydroxybenzylamine in a 100 mE two-necked flask equipped with a stir bar and bubbling nitrogen for 10 mm, adding 40 mE of clean methanol to the reaction flask and stirring it to get dissolved, cooling the reaction flask in an ice bath to a solution temperature of 4 C. under the protection of nitrogen, slowly adding 26.2 g (120 mmol) of di-tert-butyl dicarbonate dropwise to the reaction solution, continuing the reaction for 2 h in the ice bath, concentrating afier completion of the reaction, and distillating under reduced pressure to obtain 18.3 g of the product at a yield of 83%
71%
at 20℃; for 8h;
Tert-butyl [(4-hydroxyphenyl)methyl]carbamate was synthesized according to the protecting method previously published {1) ACS Medicinal Chemistry Letters, 8(10), 1025-1030; 2017. 2) European Journal of Medicinal Chemistry, 126, 384-407; 2017. 3) Tetrahedron Letters, 47(46), 8039-8042; 3006} the contents of which are hereby incorporated by reference. Product 8 1,4-Hydroxybenzylamine (0.62 g, 5 mmol) slowly added with stirring to a solution of 9 di-tert-butyl dicarbonate (1.2 g, 5.1 mmol) at room temperature. After the reaction mixture was stirred for 8 h, the oily residue was purified by column chromatography [SiO2:EtOAc/hexanes (1:4)] to afford 0.82 g of 6 N-Boc-4-hydroxybenzylamine as a colorless oil with 71% yield.
70%
To a 100-mL flask, 500 mg (4.06 mmol) of 4-hydroxy benzylamine was added, and 9.4 ml of tetrahydrofuran and 4 ml of water were added thereto, followed by stirring. Then, 570 ul (4.06 mmol, 1.0 eq) of triethylamine was added thereto, followed by stirring. To the reaction solution, 886 mg (4.06 mmol, 1.0 eq) of di-t-butyl dicarbonate was added, followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and diluted with ethyl acetate (10 ml) and washed with water (20 mL). After separation of layers, the layer was washed with a NaCl aqueous solution, and dehydrated and dried over MgSO4, and concentrated under reduced pressure to obtain 550 mg (70%) of a title compound. Mass[M+H] : 224.12
66%
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;Product distribution / selectivity;
To a stirred solution of 4-(amino methyl)phenol (5 g, 40.60 mmol) in CH2Cl2 (100 mL) was added Et3N (12.13 g, 120.0 mmol) followed by (Boc)2O (10.58 g, 48.31 mmol) drop wise at 0 C. under inert atmosphere. The resulting reaction mixture was warmed up to room temperature and stirred for 3 h. After the consumption of starting material (by TLC), the reaction mixture was quenched with saturated citric acid solution and separated organic layer. The combined organic extracts were washed with water (2x100 mL) followed by brine solution (2x50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography to afford Tert-butyl 4-hydroxybenzylcarbamate (6 g, 66%).
With sodium hydrogencarbonate; In methanol; at 20℃; for 72h;
Stage 1; - terf-Butyl (4-hydroxybenzyl)carbamateTo a solution of 4-(aminomethyl)phenol (200mg, 1.62mmol) in MeOH (2.5ml_) was added sodium bicarbonate (476mg, 5.68mmol) and BOC2O (390mg, 1.79mmol). The solution was stirred at RT for 72 hours. The reaction mixture was partitioned between water (2OmL) and EtOAc (2OmL). The organic layer was separated and the aqueous layer was extracted with EtOAc (1OmL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the product as a yellow oil (360mg). ESMS: m/z 224 [M+H]+.
1.02 g
With sodium hydroxide; In 1,4-dioxane; water; for 2h;pH Ca. 10;
85. PREPARATION OF /KP^- -HYDROXYBENZYLCARBAMATE (MLAG-067)[00571] The synthetic scheme for the preparation of the title compound, as well as MLAG- 070, MLAG-070, and MLAG-082, beginning with 4-(aminomethyl)phenol is given below.MLAG-067 MLAG-070 36% MLAG-071BBr3, DCM -78 C to rt O/N, 31%[00572] Briefly, the title compound was prepared as follows: A mixture of 4- (aminomethyl)phenol (500 mg, 4.06 mmol), ind (10 mL), and water (10 mL), at 0 C, was adjusted to pH -10 using 1M NaOH. Boc20 (1.131 mL, 4.87 mmol) was added and the solution stirred for 2 h. 1M HCl was added to the reaction mixture to a pH 2.5 and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine, dried over Na2S04, filtered, and concentrated to give the desired product (1.02g), which was used in the next step without further purification.
With pyridine; In N,N-dimethyl-formamide; at 4 - 20℃;Inert atmosphere;
To 4-hyroxybenzylamine (5 g, 40 mmol) in DMF/pyridine (20 mL 5: 1) was added Boc20 XS at 4 oC and the reaction was stirred overnight at RT. At this point approx. 0.5 mL 10 M NaOH was added to the reaction and stirring was continued. After 30 minutes 250 mL water and 200 mL EtOAc were added and the phases separated. The organic layer was washed sequentially with 10% copper sulfate (2 times), sodium bicarbonate and brine. Organic phase was then dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (elution 60-70% EtOAc in hexane) yielded the purified product as a white solid. deltaEta (400 mHz, CD3SOCD3) 1.144 (9H, s); 3.936 (2H, d, J=5.6Hz); 6.630 (2H, d, J=8.4Hz); 6.951 (2H, d, J=8.4Hz); 7.081 (1H, br s); 9.171 (1H, s).
980 mg
With triethylamine; In tetrahydrofuran; water; at 20℃; for 4h;
To 4-hydroxybenzylamine (500 mg, 4.1 mmol) were added BOC2O (1.1 g, 4.9 mmol), triethylamine (840 muL), water (2 mL) and THF (10 mL), and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with ethyl acetate, and washed with 0.1 mol/L aqueous hydrochloric acid solution. The organic layer was dried over sodium sulfate, and the desiccant was filtered off. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (980 mg).MS (ESI) m/z 224 (M+H)+
With triethylamine; In tetrahydrofuran; at 20℃; for 3h;
To a solution of the 4-hydroxybenzylamine (2.0g, 16.2mmol) in THF (20mL) was added TEA (3.4mL, 24.3mmol), followed by the slow addition of di-tert butyl dicarbonate (5.30g, 24.3mmol in 20mL of THF). The reaction mixture was stirred at room temperature for 3h, after which time the solvent was removed in vacuo. The crude mixture was partitioned between H2O and diethyl ether. The organic layer was collected and dried using anhydrous MgSO4. The solution was filtered, concentrated, and purified by chromatography (hexane:ethyl acetate=1:2) to provide t-boc-4-hyroxy benzyl amine. 1H NMR (300MHz, CDCl3, delta in ppm): 7.16-7.10 (2H, d, aromatic), 6.79-6.74 (2H, d, aromatic), 4.83-4.67 (1H, broad, -CH2-NH-COO-), 4.27-4.15 (2H, d, -C-CH2-NH-), and 1.46-1.42 (9H, s, -C(CH3)3)
980 mg
With triethylamine; In tetrahydrofuran; water; at 20℃; for 4h;
To 211 4-hydroxybenzylamine (500 mg, 4.1 mmol) were added 212 di-tert-butyl dicarbonate (1.1 g,4.9 mmol), 14 triethylamine (840 muL), 52 water (2 mL) and 213 THF (10 mL), and the mixture wasstirred at room temperature for 4 hr was stirred. The reaction mixture was diluted with ethyl acetate andwashed with 0.1 mol/L aqueous hydrochloric acid solution. The organic layer was dried over sodium sulfate,and then the desiccant was filtered off, and the solvent was evaporated. The obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate) to give the 214 title compound ( 980 mg ). MS(ESI) m/z 224 (M+H)+
With pyridine; In N,N-dimethyl-formamide; at 20℃;
General procedure: To 4-hyroxybenzylamine (5 g, 40 mmol) in DMF/pyridine (20 mL 5:1) was added Boc2O XS at 4oC and the reaction was stirred overnight at RT. At this point approx 0.5 ml 10 M NaOH was addedto the reaction and stirring was continued. After 30 min 250 mL water and 200 mL EtOAc wereadded and the phases separated. The organic layer was washed sequentially with 10% coppersulfate (2 times), sodium bicarbonate and brine. Organic phase was then dried over magnesiumsulfate, filtered and concentrated in vacuo. Chromatography on silica gel (elution 60-70% EtOAcin hexane) yielded the purified product as a white solid. dH (400 MHz, CD3SOCD3) 1.144 (9H, s);3.936 (2H, d, J=5.6Hz); 6.630 (2H, d, J=8.4Hz); 6.951 (2H, d, J=8.4Hz); 7.081 (1H, br s); 9.171(1H, s).
With ammonia; hydrogen;nickel; In methanol; water; at 20℃; under 760.051 Torr; for 21h;
Preparation Example A+-1. Sodium 4-(((2-Aminopyridine-3-carbonyl)-amino)-methyl)-phenolate To a solution of 4-hydroxybenzaldehyde (10g, 81.9mmol) in methanol (45mL) was added Raney nickel (3g) and 7N aqueous ammonia solution (45mL), and the solution was stirred under hydrogen atmosphere (1 atm) at room temperature for 21 hours. The reaction solution was filtered through Celite pad to remove the catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol (10g, quantitatively) was obtained as a pale green solid. Then, a solution of 2-aminonicotinic acid (3.0g, 21.7mmol) in N,N-dimethylformamide (30mL) was cooled with an ice water, 1-hydroxybenzotriazole (3.51 g, 26mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide (4.04g, 26mmol) and a solution of the resulting 4-aminomethyl-phenol (3.0g, 21.7mmol) in N,N-dimethylformamide (20mL) were added, and the solution was stirred for 18 hours at this temperature. The reaction solution was partitioned into brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, filtration was carried out using NH silica gel, and the filtrate was concentrated. The residue was dissolved in methanol (90mL), 1 N sodium hydroxide (17.8mL, 17.8mmol) was added thereto, followed by stirring at room temperature for an hour and a half. The reaction solution was concentrated in vacuo, and the title compound (5.66g) was obtained as a pale yellow solid.
100%
With ammonia; hydrogen;Raney nickel; In methanol; water; at 20℃; under 760.051 Torr; for 21h;
To a solution of 4-hydroxybenzaldehyde (10g, 81.9mmol) in methanol (45mL) was added Raney nickel (3g) and 7N aqueous ammonia solution (45mL), and the solution was stirred under hydrogen atmosphere (1 atm) at room temperature for 21 hours. The reaction solution was filtered through Celite pad to remove the catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol (10g, quantitatively) was obtained as a pale green solid. Then, a solution of 2-aminonicotinic acid (3.0g, 21.7mmol) in N,N-dimethylformamide (30mL) was cooled with an ice water, 1-hydroxybenzotriazole (3.51g, 26mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide (4.04g, 26mmol) and a solution of the resulting 4-aminomethyl-phenol (3.0g, 21.7mmol) in N,N-dimethylformamide (20mL) were added, and the solution was stirred for 18 hours at this temperature. The reaction solution was partitioned into brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, filtration was carried out using NH silica gel, and the filtrate was concentrated. The residue was dissolved in methanol (90mL), 1 N sodium hydroxide (17.8mL, 17.8mmol) was added thereto, followed by stirring at room temperature for an hour and a half. The reaction solution was concentrated in vacuo, and the title compound (5.66g) was obtained as a pale yellow solid.
88.9%
With ammonium hydroxide; hydrogen; sodium hydroxide; In water; at 50℃; under 6080.41 Torr;Autoclave; Large scale;
Sodium hydroxide was added to dissolve 60kg 700kg of water, then add hydroxybenzaldehyde 150kg and stir until completely dissolved clear, the solution is sucked 2000L autoclave, and then put Raney nickel 25kg (wet weight), 25% aqueous ammonia 500kg, added 8 hydrogen pressure, reaction temperature 50 up until hydrogen absorption had ceased, the cooling, pressure filtration of catalyst, washed with water and then 100kg.The catalyst was collected in buckets of water storage.The filtrate was transferred to a processing vessel, hydrochloric acid and then adjusting the pH value to 9 to 10, cooling to 5 Crystallization two hours, rejection filter, and dried to give p-hydroxy benzyl amine monohydrate 154kg, yield 88.9%, HPLC purity 98.9%
80 - 85%
With ammonia; hydrogen;nickel; In methanol; water; at 25 - 40℃; under 2206.72 - 3677.86 Torr; for 5 - 20.5h;Product distribution / selectivity;
Methanol (2.0L ) is charged in an autoclave, p-hydroxybenzaldehyde (250 gms; 2.049M) is added followed by 25 gms (50 gms wet) of Raney Nickel, and aqueous ammonia(25%) ( 800ml ;11.7647M) . The hydrogenator is evacuated and flushed with nitrogen, a few times .The autoclave is initially pressurized to 3 Kg/cm with hydrogen and then maintained at 5Kg/cm2 hydrogen pressure for 15-20 hours at 25-280C. The reaction is monitored by TLC and continued till the starting material is less than 2 %. After releasing hydrogen pressure , the reaction mixture is further heated for 30 minutes at about 400C. The catalyst is filtered and washed with methanol, followed by purging of the solution with nitrogen for about one hour till the evolution of ammonia ceases. The solvent is distilled off at 40-450C to 1/4 of the total volume under vacuum , cooled to O0C and stirred for two hours. The solid is filtered and the cake is washed with 2x250ml of water, followed by washing with 2x250ml of toluene. The material is dried at 70-750C till the moisture content is < 1 %. The product analysis is as follows. Product weight : 210-215 gms. Purity by HPLC : 95-98 % Yield : 80-85 %Melting range : 115-1190C; Methanolic ammonia (13-15%) (700 ml) is charged into an autoclave, p- hydroxybenzaldehyde (100 gm; 0.82 moles) is charged followed by Raney Nickel (15 gms ; 30 gms wet) . The hydrogenator is evacuated and flushed with nitrogen, a few times .The autoclave is pressurized to 5 Kg/cm2 with hydrogen and maintained at 5 Kg/cm2 for 5-6 hours at 25-28C. The reaction is monitored on HPLC and the reaction is continued till the starting material is less than 2 %. Hydrogen pressure is released and . the catalyst is filtered and washed with methanol. Nitrogen gas is purged in the solution for one hour till the evolution of ammonia gas ceases. The solvent is distilled off up to l/3r of the total volume under vacuum at 40-45C. The reaction mass is cooled to O0C and stirred for two hours. The solid is filtered and washed with 2x100ml of water , followed by 100 ml of methanol. The material is dried in oven at 50-55C under vacuum till the moisture content is < 1 %. Product weight : 80-85 gms. Purity by HPLC : 95-98 % Yield : 80-85 %
80 - 85%
With ammonia; hydrogen;nickel; In methanol; water; at 25 - 40℃; under 2206.72 - 3677.86 Torr; for 15.5 - 20.5h;Product distribution / selectivity;
Example-1 Preparation of P_Hydroxy Benzylamine Methanol (2.0 L) is charged in an autoclave, p-hydroxybenzaldehyde (250 gms; 2.049M) is added followed by 25 gms (50 gms wet) of Raney Nickel, and aqueous ammonia (25%) (800 ml; 11.7647M). The hydrogenator is evacuated and flushed with nitrogen, a few times. The autoclave is initially pressurized to 3 Kg/cm2 with hydrogen and then maintained at 5 Kg/cm2 hydrogen pressure for 15-20 hours at 25-28 C. The reaction is monitored by TLC and continued till the starting material is less than 2%. After releasing hydrogen pressure, the reaction mixture is further heated for 30 minutes at about 40 C. The catalyst is filtered and washed with methanol, followed by purging of the solution with nitrogen for about one hour till the evolution of ammonia ceases. The solvent is distilled off at 40-45 C. to 1/4 of the total volume under vacuum, cooled to 0 C. and stirred for two hours. The solid is filtered and the cake is washed with 2*250 ml of water, followed by washing with 2*250 ml of toluene. The material is dried at 70-75 C. till the moisture content is < 1%. The product analysis is as follows. Product weight: 210-215 gms. Purity by HPLC: 95-98% Yield: 80-85% Melting range: 115-119 C.
80-85%
With ammonia; hydrogen;nickel; In methanol; at 25 - 28℃; under 3677.86 Torr; for 5 - 6h;Product distribution / selectivity;
Example-2 Preparation of P_Hydroxy Benzylamine Methanolic ammonia (13-15%) (700 ml) is charged into an autoclave, p-hydroxybenzaldehyde (100 gm; 0.82 moles) is charged followed by Raney Nickel (15 gms; 30 gms wet). The hydrogenator is evacuated and flushed with nitrogen, a few times. The autoclave is pressurized to 5 Kg/cm2 with hydrogen and maintained at 5 Kg/cm2 for 5-6 hours at 25-28 C. The reaction is monitored on HPLC and the reaction is continued till the starting material is less than 2%. Hydrogen pressure is released and the catalyst is filtered and washed with methanol. Nitrogen gas is purged in the solution for one hour till the evolution of ammonia gas ceases. The solvent is distilled off up to 1/3rd of the total volume under vacuum at 40-45 C. The reaction mass is cooled to 0 C. and stirred for two hours. The solid is filtered and washed with 2*100 ml of water, followed by 100 ml of methanol. The material is dried in oven at 50-55 C. under vacuum till the moisture content is < 1%. Product weight: 80-85 gms. Purity by HPLC: 95-98% Yield: 80-85%
With sulfuric acid;aluminum nickel; In ethanol;
EXAMPLE 31 4-Hydroxybenzylamine Ammonia is passed into 500 ml of ethanol at 10 C. until saturation is reached, 122.1 g=1 mole of p-hydroxybenzaldehyde, 20 g of Raney nickel and 0.1 ml of concentrated sulfuric acid are added and the mixture is stirred in an autoclave for 6 hours at room temperature and under a hydrogen pressure of 100 atmospheres. After releasing the pressure, the catalyst is filtered off and the filtrate is boiled up with active charcoal, filtered and concentrated. The residue is recrystallized from a mixture of ethanol and ether. This gives 104 g (85% of theory), melting point: 104 C.
With ammonium hydroxide; 5% rhodium on activated aluminium oxide; hydrogen; at 80℃; under 15001.5 Torr; for 3h;Autoclave;
General procedure: For the synthesis reaction, a 50 mL stainless steel autoclave was used. Into the autoclave, the raw material furfural (0.2 g, 2 mM), the catalyst 5 wt% Rh / Al 2 O 3 (0.002 g, Rh average particle diameter 40 nm), 28 wt% ammonia water (4.0 mL, 66 mM), finally a magnetic stir bar were put and covered, then the temperature was raised while stirring. After about 1 hour, when the vessel reached the reaction temperature of 80 C, hydrogen gas (2 MPa) was introduced to start the reaction. After a reaction time of 2 hours, cooled to 5 C or less with ice water, then the remaining hydrogen gas was released by opening the valve slowly, and then after filtering with filter paper (No. 1), Qualitative and quantification were carried out using GC-MS (CP-3800 + 1200 L made by Bruker Daltonics Co) or GC (HP6890 manufactured by Agilent Technologies). As a result, the conversion rate of raw material furfural was 100% and disappeared and the target product methyl amino furan was obtained in a yield of 91.7% (based on mol%, same in the following examples also). Other by-products are 8.3% of N,N-bis(furanyl methyl)amine and no other by-products were detected.The reaction was carried out under the same conditions as in Example 1 except that various kinds of raw materials were used instead of furfural as the aromatic compound or furan derivative having an aldehyde group. The results are summarized in Table 2. In all the raw materials, the structure of the aromatic or furan ring was maintained even after the reaction. In the case of having a nitro group as a substituent, it was found that the nitro group was reduced to be converted to an amino group, but otherwise the aldehyde group was converted to a methyl amino group.
R.3 N-(t-butoxycarbonyl)-4-hydroxybenzylamine
REFERENCE EXAMPLE 3 N-(t-butoxycarbonyl)-4-hydroxybenzylamine Using the method of L. Farber and P. Gradeff, U.S. Pat. No. 4,388,250, 4-hydroxybenzaldehyde was reductively aminated to produce 4-hydroxy benzylamine, obtained as a crystalline monohydrate after dilution of the filtered reaction mixture with water. This material (12 g, 85 mmol) was suspended in THF (150 mL), cooled in an ice bath, and di-t-butyl dicarbonate (19 g, 87 mmol) was added. The mixture was stirred overnight, then concentrated to a viscous oil. Addition of water (250 mL) and vigorous stirring overnight converted the oil into a white powder, mp 88°-91° C. (21 g).
(L)-N-(4-Hydroxybenzyl)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With triethylamine; In tetrahydrofuran;
B. (L)-N-(4-Hydroxybenzyl)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetamide The product from Part A, above, (5.3 g., 0.02 mole) was dissolved in dry tetrahydrofuran (50 ml.) and the solution was stirred and cooled to 0 C. Triethylamine (2.1 g., 0.021 mole) was added followed by isobutyl chloroformate (2.77 g., 0.0203 mole), and the mixture was stirred and allowed to stand at -5 C. to 0 C. for a few minutes. A solution of 4-hydroxybenzylamine (2.82 g., 0.02 mole) in dry tetrahydrofuran (10 ml.) was then added dropwise over a period of 10 minutes to the stirred solution which was allowed to warm to room temperature and stirred for a further three hours. The suspension was evaporated to dryness and the residual solid was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered, and the solvent evaporated to yield an oil which solidified on trituration with petroleum ether (b.p. 60-80 C.) to give the amide (3.9 g., 50%), M.P. 60 C. [α]D25 +50.7 (1% in methanol).
With triethylamine; In dichloromethane; at 15 - 20℃; for 1 - 1.5h;
Dichloromethane (750 ml) is charged into a IL 4neck RBF equipped with mechanical stirrer, thermowel, addition funnel and calcium chloride guard tube, p- hydroxybenzylamine (50 gms ; 0.4065 moles) is charged, followed by triethyl amine (56.6 ml ; 0.4065 moles) . The flask is cooled to 150C. 3,4-dimethoxybenzoyl chloride (81.5 gms.;0.4065 moles) dissolved in 100 ml of dichloromethane is added over a period of 30-45 minutes, maintaining the temperature of the reaction between 15-200C. The reaction mixture is stirred for 30-45 minutes at 15-200C. The progress of the reaction is monitored on HPLC and the reaction is continued till the starting material is <2% . Dichloromethane is distilled off under vacuum (at 40-450C). The residue is triturated with 500 ml of water and stirred for 2 hours.The solid is filtered and washed with 3xl00ml of water. The material is dried in oven at 70-750C for 10-15 hours till moisture content is <3%.Product weight 110-112 gms. Purity by HPLC 94-96 % Yield 95-97 %
95 - 97%
With triethylamine; In dichloromethane; at 15 - 20℃; for 1 - 1.5h;
Example-4 Preparation of N-(4-Hydroxy Benzyl)-3,4-Dimethoxy Benzamide Dichloromethane (750 ml) is charged into a 1 L 4 neck RBF equipped with mechanical stirrer, thermowel, addition funnel and calcium chloride guard tube, p-hydroxybenzylamine (50 gms; 0.4065 moles) is charged, followed by triethyl amine (56.6 ml; 0.4065 moles). The flask is cooled to 15 C. 3,4-dimethoxybenzoyl chloride (81.5 gms; 0.4065 moles) dissolved in 100 ml of dichloromethane is added over a period of 30-45 minutes, maintaining the temperature of the reaction between 15-20 C. The reaction mixture is stirred for 30-45 minutes at 15-20 C. The progress of the reaction is monitored on HPLC and the reaction is continued till the starting material is <2%. Dichloromethane is distilled off under vacuum (at 40-45 C.). The residue is triturated with 500 ml of water and stirred for 2 hours. The solid is filtered and washed with 3*100 ml of water. The material is dried in oven at 70-75 C. for 10-15 hours till moisture content is <3%. Product weight: 110-112 gms. Purity by HPLC: 94-96% Yield: 95-97%
95%
With pyridine; In dichloromethane; at 20℃; for 2h;Reflux;
p-Hydroxybenzylamine 200 g and 3,4-dimethoxybenzoyl chloride 326 g were placed in a dry reaction flask containing 1000 ml of dichloromethane.Stir 129 g of pyridine carefully at room temperature and heat at reflux for 2 h. The reaction is complete and the solvent is distilled off.The residue was washed with water and dried to give the product as a yellow solid, weight 448 g, purity 98%. Yield 95%.
3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (Compound G) Ethyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (4 g, 9.46 mmol) and 4-hydroxybenzylamine (2.33 g, 18.91 mmol) were heated in EtOH (150 mL) at 80 C. forming a yellow solution. After 1 h a colourless precipitate formed and the mixture was cooled to room temperature. The solid was filtered off, washed with EtOH and dried in a vacuum oven giving the title compound (4.16 g, 8.32 mmol, 88%) as a colourless solid. 1H NMR delta (ppm) (DMSO-d6): 3.81 (2H, s), 4.41 (2H, d, J=6.08 Hz), 5.12 (2H, s), 6.76 (2H, d, J=8.08 Hz), 7.00 (2H, d, J=8.20 Hz), 7.20 (2H, d, J=8.06 Hz), 7.49 (2H, d, J=8.18 Hz), 8.13 (2H, s), 9.38 (1H, s), 9.95 (1H, t, J=6.15 Hz). LCMS (10 cm_esci_AmmBicarb_MeCN) tR 4.18 min; m/z 498 [M]-.
88%
In ethanol; at 80℃; for 1h;
Ethyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (4 g, 9.46 mmol) and 4-hydroxybenzylamine (2.33 g, 18.91 mmol) were heated in EtOH (150 mL) at 80 C. forming a yellow solution. After 1 h a colourless precipitate formed and the mixture was cooled to room temperature. The solid was filtered off, washed with EtOH and dried in a vacuum oven giving the title compound (4.16 g, 8.32 mmol, 88%) as a colourless solid. 1H NMR delta (ppm) (DMSO-d6): 3.81 (2H, s), 4.41 (2H, d, J=6.08 Hz), 5.12 (2H, s), 6.76 (2H, d, J=8.08 Hz), 7.00 (2H, d, J=8.20 Hz), 7.20 (2H, d, J=8.06 Hz), 7.49 (2H, d, J=8.18 Hz), 8.13 (2H, s), 9.38 (1H, s), 9.95 (1H, t, J=6.15 Hz). LCMS (10 cm_esci_AmmBicarb_MeCN) tR4.18 min; m/z 498 [M]-.
In ethanol; at 80℃;
[0113] Ethyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-l,2,4-oxadiazole-5- carboxylate (4 g, 9.46 mmol) and 4-hydroxybenzylamine (2.33 g, 18.91 mmol) are heated in EtOH (150 mL) at 80 C forming a yellow solution. After 1 h a colourless precipitate forms and the mixture is cooled to room temperature. The solid is filtered off, washed with EtOH and dried in a vacuum oven giving the title compound as a colourless solid.
With potassium pyrosulfate; potassium aquapentachlororuthenate(III); potassium hydroxide; at 20℃; for 0.5h;Sonication;Catalytic behavior;
General procedure: To 50 cm3 of trans-[RuO3(OH)2]2-/S2O8 2- reagent, primary amine (2mmol) was added, the reaction mixture turned dark green. The reaction mixture was further irradiated for half an hour, after which time, the reaction is completed since the original orange color of ruthenate reappears. The mixture was then extracted with diethyl ether(3 × 25 cm3). The ether extracts were dried over anhydrous MgSO4then filtered and evaporated to give the product. Similarly, nitriles were hydrated to their respective amides at 100 C. Also, primary alcohols were oxidized to their respective carboxylicacids. The alkaline aqueous layer was acidified with 2 M H2SO4 to pH 2 and extracted with diethyl ether. The extract was dried over anhydrous MgSO4 then filtered and evaporated to give the product.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 4h;Microwave irradiation;
(1.2.1 ) (SHe/f-butyl 3-((6-(2-chlorophenyl)-2-(4-hvdroxybenzylamino)-7/-/-pyrrolor2,3- c/1pyrimidin-7-yl)methyl)piperidine-1-carboxylate. <n="24"/> BocTo a solution of compound 1.1.3 (100 mg, 0.22 mmol) in NMP (0.5 ml.) were added 4-hydroxybenzylamine (534 mg, 4.3 mmol) and DIEA (76 uL, 0.44 mmol). The reaction mixture was heated in the microwave for 4 hours at 150 0C. The reaction mixture was then diluted with DCM and washed with NH4CI solution (2x), water (2x) and brine. The organic layer was dried (Na2SC>4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, heptane/EtOAc; 50% EtOAc as mobile phase) and the title compound was obtained as a solid in 66% yield (79 mg, 0.14 mmol). LC-MS: peak at 3.67 min., mass [M+H] = 548.
With hydrogen bromide; bromine; In acetonitrile; at 20℃;
To a suspension of 4-hydroxybenzylamine (1 g, 8.12 mmol) in AcOH, HBr (33% in AcOH, 4 mL) and a solution of Br2 (0.458 mL, 8.93 mmol) in AcOH (2.8 mL) were successively added over 1 h. The reaction mixture was stirred at room temperature for 48h. The precipitate was filtered and washed several times with AcOH and Et20 to obtain 4-(aminomethyl)-2-bromophenol.HBr as a white powder (1 .785 g , 78%). 1 H NMR (300 MHz, DMSO-c 6) delta 10.45 (s, 1 H), 8.06 (bs, 3H), 7.63 (d, J = 2.1 Hz, 1 H), 7.26 (dd, J = 8.4, 2.1 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 3.93-3.89 (m, 2H).
58%
With hydrogen bromide; bromine; In acetic acid; at 20℃;
A. 4-Aminomethyl-2-bromo-phenol hydrobromideTo a mixture of 4-hydroxybenzylamine (6.0 g, 48.7 mmol) in acetic acid (30 mL) is added HBr in acetic acid (33% wt, 24 mL) dropwise. After the addition is completed, bromine (25 mL, 48.7 mmol) in acetic acid (25 mL) is added dropwise. The resulting mixture is stirred at room temperature overnight. The precipitate is collected by suction filtration, washed with acetic acid and Et2O, dried in vacuo to yield the product (8.05 g, 58%) as a white powder. 1 H NMR (300 MHz, DMSO-c/6) 5 8.00 (br s, 3H), 7.65 (s, 1 H), 7.30-7.20 (m, 1 H), 7.05-6.85 (m, 1 H), 4.05-3.75 (m, 2H).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 1h;Reflux;
Step 2: To a suspension of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-l,3,5- triazin-2-ylamino)benzoate (10 g, 24.71 mmol) and Hunig'sBase (8.63 mL, 49.4 mmol) in THF (100 mL) was added 4-(aminomethyl)phenol (3.19 g, 25.9 mmol) . The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed andt the crude product was purified by silica gel chromatography using 20- 40-100% EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6- (2,2,2-trifluoroethoxy)-l,3,5-triazin-2-yl)amino)benzoate (10.3 g, 85%) as white solid.Flow Rate 1 mL/minWavelength 220Solvent Pair Water - Methanol- TFAColumn PHENOMENEX-LUNA 2.0 x 30mm S 10 3 muMu
12 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 48h;
To a solution of 2,4,6-trichloro-l,3,5-triazine (8 g) in acetone (250 mL) was added a solution of 2,2,2-trifluoroethanol (4.77 g) and 2,4,6-Collidine (6.31 mL) in acetone (100 mL) dropwise over 20 minutes. The resulting mixture was stired at room temperature for 16 hours. All the solvents were removed under vacuum to give a residue which was diluted with NMP (100 mL), followed by addition of tert-butyl 4-aminobenzoate (9.22 g) and DIPEA (22.73 mL). After stirring at room temperature for 16 hours, 4-(aminomethyl)phenol (5.88 g) was added. The resulting mixture was stirred for 2 days at room temperature. Then, the mixture was diluted with 300 mL of water and extracted with EtOAc (2 x 300 mL). The organic layers were combined, washed with brine (2 x 150 mL), dried over MgSC^ and concentrated. The residue was purified by silica gel column (hexane : EtOAc = 3:2) to give tert-butyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-l,3,5-triazin-2-ylamino)benzoate (12 g)
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 120℃; for 30h;
Step 4: To a solution of tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (30 mg, 0.07 mmol), and Hunig's Base (0.026 mL, 0.15 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (33 mg, 0.27 mmol). The resulting mixture was stirred at 120 C. for 30 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 20% -40% of EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (27 mg, 74%) as white solid.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h;
Step 4: To a solution of tert-butyl 4-((2-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (80 mg, 0.18 mmol), and Hunig's Base (0.062 mL, 0.36 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (44 mg, 0.36 mmol). The resulting mixture was stirred at r.t for 16 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 40-70%-100% EtOAc/Hexanes to give tert-butyl 4-((2-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (72 mg, 83%) as white solid.
1-methyl-3-ethyl-4-chloro-1H-pyrazol-5-ylformylic acid chloride[ No CAS ]
[ 696-60-6 ]
[ 1374595-90-0 ]
Yield
Reaction Conditions
Operation in experiment
85.2%
With triethylamine; In dichloromethane; at 20℃;
To a solution of 4-(aminomethyl)phenol 1.23 g (0.01 mol) and triethylamine 1.2 g (0.012 mol) in 50 mE dichloromethane was dropwise added 4-chloro-3-ethyl-1 - methyl-i H-pyrazole-5-carbonyl formyl chloride (111-2) 2.3 g (0.011 mol) in 30 mE dichloromethane. The reaction mixture was continued stirring at room temperature for 4-5 hour, and monitored by TEC until the reaction was over, then the mixture was poured into 50 mE of water to separate the organic layer, the organic phase was washed with 10 ml of 5% diluted hydrochloric acid, 10 ml of saturated sodium bicarbonate solution and 10 ml of brine successively, dried via anhydrous magnesium sulfate and evaporated, the residual was purified via silica gel column chromatography to obtain 2.50 g intermediate (VIII-2) with yield of 85.2%, m.p. 167-168 C.
85.2%
With triethylamine; In dichloromethane; at 20℃;
To a solution of 4- (aminomethyl) phenol 1.23g (0.01mol) and triethylamine 1.2g (0.012mol) in 50 mL dichloromethanewas dropwise added 4- chloro- 3- ethyl- 1- methyl- 1H- pyrazole- 5- carbonyl formyl chloride (III- 2) 2.3g(0.011mol) in 30 mL dichloromethane. The reaction mixture was continued stirring at room temperature for 4- 5 hour,and monitored by TLC until the reaction was over, then the mixture was poured into 50mL of water to separate theorganic layer, the organic phase was washed with 10ml of 5% diluted hydrochloric acid, 10ml of saturated sodiumbicarbonate solution and 10ml of brine successively, dried via anhydrous magnesium sulfate and evaporated, the residualwas purified via silica gel column chromatography to obtain 2.50g intermediate (VIII- 2) with yield of 85.2%, m.p. 167-168 C.
4-(4-(aminomethyl)phenoxy)phthalonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h;Inert atmosphere;
4-nitrophthalonitrile (1.41 g, 8.14 mmol), compound 4-(aminomethyl)phenol (1.50 g, 12.18 mmol) and dry K2CO3 (2.24 g, 16.21 mmol) were mixed in dry DMF (6 mL) under nitrogen at 60 C, then CH2Cl2 (10 mL) was added as solvent, and they were left to stir for 6 h. During the whole process, the reaction was monitored by TLC using ethyl acetate and a few drops of triethylamine for elution. After cooling to room temperature, the solution was poured into water (80 mL) and a little saturated salt water was added into the above solution. A few minutes later, the mixture was automatically divided into two layers. The upper tangerine solution was the product of synthesis and dried over anhydrous sodium sulfate. In the end, compound 3 was purified by column chromatography with silica gel as column material and methanol/ethyl acetate (2:1) solvent system as elution. Yield: 1.41 g (69.5%). MP.79 C. IR (KBr, cm1): 3364 (NH2), 3080 (AreH), 2840 (CH2), 2230(CN), 1590, 1490, 1250, 1070, 710. 1H NMR (400 MHz, DMSO-d6):d (ppm) 8.08 (d, 1H, J 8.8 Hz, Ar), 7.72 (d, 1H, J 2.8 Hz, Ar),7.46 (d, 2H, J 8.8 Hz, Ar), 7.31e7.34 (m, 1H, Ar), 7.13 (d, 2H,J 8.4Hz, Ar), 3.76 (s, 2H, CH2), 2.28 (s, 2H, NH2). 13C NMR(100 MHz, DMSO-d6): d (ppm) 161.9, 152.4, 142.3, 136.7, 129.6,122.7, 122, 120.6, 117.1, 116.4, 115.9, 108.3, 45.4. Anal. Calcd. ForC15H11N3O: C, 72.28; H, 4.45; N, 16.86; O, 6.42. Found: C, 72.12; H,4.30; N, 16.78.
59.4%
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 5h;Inert atmosphere;
Under nitrogen atmosphere, a mixture of 4-(aminomethyl) phenol (1.00 g, 8.12 mmol), 4-Nitrophthalonitrile (1.41 g, 8.12 mmol)and finely ground anhydrous K2CO3 (2.24 g, 16.24 mmol) in DMF (10 mL) was heated at 40C for 5 h. The mixture was cooled and poured into ice water. After filtration, the cake was washed with water and then purified by silica gel column chromatography using methanol/ethyl acetate (1:3, v/v) as the eluent to give 4 as a sallow solid (1.20 g, 59.4%). M.P. =82C. IR (KBr, cm-1): 3378, 3320, 3050,2235 (CN), 1595, 1480, 1250, 1200, 710. 1H NMR (400 MHz, DMSO-d6): (ppm) 8.04 (d, 1H, 8.8 Hz, Ar), 7.74 (s, 1H, Ar), 7.46 (d, 2H,8.0 Hz, Ar), 7.34 (t, 1H, 4.2 Hz, Ar), 7.14 (d, 2H, 8.0 Hz, Ar), 3.76 (s,2H, CH2). 13C NMR (100 MHz, DMSO-d6): (ppm) 161.86, 152.45,142.01, 136.74, 129.69, 122.81, 122.05, 120.59, 117.10, 116.39,115.87, 108.32, 45.29. Anal. Calcd. For C15H11N3O: C, 72.28; H, 4.45;N, 16.86. Found: C, 72.10; H, 4.65; N, 16.80.
57.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 2h;
A mixture of 4-(aminomethyl) phenol (0.62 g, 4.99 mmol), 4-nitrophthalonitrile (0.91 g, 5.25 mmol) and K2CO3 (1.38 g,9.98 mmol) in DMF (20 mL) was stirred at 40 C for 2 h undernitrogen atmosphere. During the whole process, the reaction wasmonitored by TLC using methanol/ethyl acetate (1:3) system aseluent. The reaction mixture was poured into water (200 mL) andvigorously stirred. The resulting light yellow solid was collectedby filtration and purified by column chromatographic separationswith methanol/ethyl acetate (1:3) as the elution. Yield: 0.72 g(57.5%).
56.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 8h;Inert atmosphere;
2.3.2. Synthesis of 4-(4-Aminophenoxy) phthalonitrile (B1)Under a nitrogen atmosphere, to a solution of 4-nitrophthalonitrile (1.50 g, 8.66 mmol) and P-hydroxybenzylamine (1.60 g, 13.00 mmol) dissolved in dry DMF (8 mL) were reacted with K2CO3 (2.39 g,17.33 mmol). Then, the mixture was stirred at 65 C for 8 h. The reaction was monitored by TLC in a silica plate, the Rf of product is 0.6using petroleum methanol/ethyl acetate (3:1, v/v) as mobile phase.After cooling to room temperature, alkaline water (50 mL) was poured into the solution and extracted with CH2Cl2 (50 mL). The organic phasewas the product of synthesis and dried over anhydrous sodium sulfate.After the solvent was removed by evaporation, the residue was purifiedby column chromatography with silica gel that petroleum methanol/ethyl acetate (3:1, v/v) solvent system as elution to obtain compoundB1. Yield: 1.17 g (56.6%). M.P. 79-80 C. IR (KBr, cm-1): 3363 (NH2),3080 (Ar-H), 2840 (CH2), 2232 (CN), 1590, 1480, 1250 (C-O-C), 1070,710. 1H NMR (400 MHz, d6-DMSO): delta (ppm) 8.09 (d, 1 H, J = 8 Hz, Ar-H), 7.73 (d, 1 H, J = 4 Hz, Ar-H), 7.46 (d, 2 H, J = 8 Hz, Ar-H),7.35-7.32 (m, 1 H, Ar-H), 7.14 (d, 2 H, J = 8 Hz, Ar-H), 3.75 (s, 2 H,CH2). 13C NMR (100 MHz, d6-DMSO): d (ppm) 161.7, 152.2, 142.5,136.6, 129.8, 122.7, 121.7, 120.4, 117.1, 116.4, 115.9, 108.2, 45.4.Anal. Calcd. For C15H11N3O: C, 72.28; H, 4.45; N, 16.86. Found: C,72.22; H, 4.64; N, 16.78; O, 6.36.
With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 50℃; for 5h;Inert atmosphere;
Under nitrogen, 4-nitro-phthalonitrile, p-hydroxy benzyl amine and K2CO3A molar ratio of 1: 1.5: 2 added to the reaction flask in 10ml of anhydrous DMF as solvent, the reaction at 40-50 5H, give an intermediate of phthalonitrile
With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 60℃; for 6h;Inert atmosphere;
Under the protection of nitrogen, 4-nitrophthalonitrile, p-hydroxybenzylamine and K2CO3 were added to DMF at a molar ratio of 1: 1: 2 and then 10 mL of dichloromethane was added as solvent. The reaction was carried out at 60 C 6h to give intermediate 3;
In N,N-dimethyl-formamide; at 40℃; for 4h;Inert atmosphere; Alkaline conditions;
(1) A mixture of p-hydroxybenzylamine, basic catalyst and 4-nitrophthalonitrile was added to DMF at a molar ratio of 1: 2: 1.2 under nitrogen atmosphere and reacted at 40 C for 4 h to give Intermediate 14 ';
With pyridine; silver methyl sulfide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Molecular sieve; Inert atmosphere;
General procedure: To a round bottom flask was added molecular sieves and a stir bar and theflask was heated to dryness over a Bunsen flame, then cooled over vacuum for 20 min. The aminewas added to the flask, then a stopper was added and the flask flushed with dry nitrogen.DMF/pyridine (1:1) was then added and the flask cooled to 4 C. The chloroformate was thenadded drop-wise (neat if liquid or as a solution in DMF, if solid). After 1 h the reaction was warmedto rt and run overnight. After this time NaHCO3 and EtOAc was added and the reaction stirred for5 min. The aqueous phase was extracted, then the organic phase was washed 3 times with 10%CuSO4, three times with water, then once with brine. Organic phase was then dried withmagnesium sulfate, filtered and concentrated
With Acetaldehyde oxime; oxygen; 1N,3N,5N-trihydroxy-1,3,5-triazin-2,4,6[1H,3H,5H]-trione; In water; at 100℃; for 34h;Green chemistry;
General procedure: A mixture of primary amine (1 mmol), THICA (5 mol%), acetaldoxime(10 mol%), and H2O (5 mL) was placed in a three-neckedflask. O2 was stirred into the flask at a flow rate of 20 mL/min. The reaction mixture was stirred at 100 C for several hours, and the reaction progress was monitored by TLC. When the final reaction mixture was cooled to r.t. and extracted with Et2O, the organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was pure enough. When necessary,the crude product was purified by chromatography using EtOAc-PE (1:8) as eluent.
With indium(III) chloride; Acetaldehyde oxime; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; In toluene; at 100℃; for 8h;
General procedure: A mixture of 2 mmol primary amine, acetaldoxime (6.2 mmol),InCl3 (0.1 mmol), TEMPO (0.2 mmol), and Toluene (10 ml) was placed in a 20 ml three-necked flasks. O2 was bubbled into the flask at a flow rate of 20 ml/min. The reaction mixture was stirred at 100 C for several hours and the reaction progress was monitored by TLC. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane = 1:8)to give the corresponding oximes.
2-chloro-N-(2-chloro-6-fluorophenyl)-4-(2-(propylsulfonyl)phenylamino)pyrimidine-5-carboxamide[ No CAS ]
[ 696-60-6 ]
C27H25ClFN5O4S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
To a solution of 4-(aminomethyl)phenol (0.015 g, 0.124 mmol) in DMF (0.7 mL) at 0 C was added EtN(iPr)2 (0.0 16 g, 0.124 mmol) and stirred for an hour, followed by the addition of lic YL7-052 (0.050 g, 0.104 mmol). The mixture was heated at 100 C for 20 h (reaction was monitored by HPLC15 MS). 1M HC1 (20 mL) was added upon cooling. The resulting solution was extracted withEtOAc (50 mL). The organic phase was washed with sat. NaHCO3 (20 mL), then dried over Na2SO4, filtered, and concentrated to dryness. The resulting solid was recrystalized with EtOAc/Hexane (3 mL/5 mL), sonicated, and filtered, and dried under high vacuum to afford the title compound as a white solid (0.053 g, 90%). Mp: 187 C (dec). HPLC 93.9% (tR = 7.87 mm,55% CH3OH in 0.1% TFA water, 20 mm); The ?H NMR showed 2:1 ratio of atropisomers. ?H NMR (400 MHz, DMSO-d6): oe 10.98 (s, 1H, [10.96 minor isomer]), 9.94 (s, 1H, [9.97 minor isomer]), 9.20 (s, 1H, [9.24 minor isomer]), 8.82 (s, 1H, [8.84 minor isomer]), 8.24(t, J= 6.4 Hz, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.57 (t, J= 7.6 Hz, 1H, [7.66 minor isomer]), 7.44-7.30 (m, 4H), 6.85 (d, J= 8.4 Hz, 2H, [7.09 minor isomer]), 6.57 (d, J 8.4 Hz,2H, [6.66 minor isomer]), 4.18 (d, J= 6.0 Hz, 2H, [4.40 minor isomer]), 3.04 (t, J= 7.6 Hz, 2H, [3.15 minor isomer]), 1.40-1.34 (m, 2H, [1.52-1.46 minor isomer]), 0.66 (t, J= 7.6 Hz, [0.78 minor isomer]); ?9F NMR (376 MHz, DMSO-d6): oe -116.12- -116.18 (m); LC-MS (ESI+) m/z 570.13 (M+H) HRMS (ESI+) m/z calculated for C27H26C1FN504S (M+H) 570.1373, found570.1387.
With iron(II) triflate; oxygen; In chlorobenzene; at 110℃; for 8h;Schlenk technique;
General procedure: To a Schlenk tube were added benzylamine 1 (1.3 mmol), indole 2(2.0 mmol), Fe(OTf)2 (10 molpercent), and anhydrous chlorobenzene (2 mL).The tube was equipped with an O2 balloon, and the mixture wasstirred at 110 °C until complete consumption of indole (TLC monitoring).When the reaction was complete, the mixture cooled to r.t., dilutedwith CH2Cl2 (10 mL), and washed with H2O (2 × 10 mL). The organicextract was dried (anhyd Na2SO4) and concentrated under reducedpressure, and the resulting residue was purified by columnchromatography (silica gel, hexane?EtOAc) to afford the correspondingbis(indolyl)methane products 3 and 4.
(2S)-1-(5-chlorothiophene-2-sulfonyl)-N-[(4-hydroxyphenyl)methyl]pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
To A-1 (0.36 g, 1.2 mmol) and 4-(aminomethyl)phenol (0.15 g, 1.2 mmol), WSC hydrochloride (0.46 g, 2.4 mmol) and HOAt (0.33 g, 2.4 mmol) were added triethylamine (510 muL, 3.7 mmol), dichloromethane (12 mL), and the mixture was stirred at room temperature for several hours. Ethyl acetate was added, and the mixture was washed successively with water and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate, and the desiccant was filtered off. The solvent was evaporated, and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.35 g, 0.87 mmol, 72%).MS (ESI) m/z 401 (M+H)+1H NMR (400 MHz, DMSO) delta 9.26 (br-s, 1H), 8.40 (t, J=5.9 Hz, 1H), 7.64 (d, J=4.1 Hz, 1H), 7.35 (d, J=4.1 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.74-6.65 (m, 2H), 4.22 (dd, J=14.8, 6.2 Hz, 1H), 4.14 (dd, J=14.8, 5.7 Hz, 1H), 4.07 (t, J=5.9 Hz, 1H), 3.54-3.47 (m, 1H), 3.23 (dt, J=10.2, 7.2 Hz, 1H), 1.89-1.79 (m, 3H), 1.67-1.56 (m, 1H).
General procedure: To a solution of <strong>[1458-18-0]methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate</strong> (1.0 eq.) in 2-propanol (5 mL/mmol), an appropriate primary or secondary amine(3-6 eq.) was added, and the reaction mixture wasrefluxed for 2 h.10) The solution was cooled to roomtemperature, concentrated under reduced pressure, andthe residue was purified by silica-gel column chromatography(Wako gel C-200, 30-40% ethyl acetate/n-hexane) to afford the series 1 intermediate (yield:32-95%). The regioselectivity of the nucleophilicsubstitution at the 5-position of the pyrazine ring wasconfirmed by an X-ray structural analysis (Fig. S1).
3,4-Dihydroxy-5-[6-(4-hydroxybenzylamino)-purin-9-yl]-tetrahydrofur an-2-carboxylic acid ethylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In propan-1-ol; water; N,N-dimethyl-formamide; acetonitrile;
3,4-Dihydroxy-5-[6-(4-hydroxybenzylamino)-purin-9-yl]-tetrahydrofur an-2-carboxylic acid ethylamide (15) The acetonide derived from 6-chloropurine ribofuranoside (17-acetonide, 158 mg, 0.48 mmol) was stirred with PhI(OAc)2 (509 mg, 1.56 mmol) and 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO, 15.4 mg, 0.1 mmol) in a degassed CH3CN/H2O solution (1:1, 2.6 mL) at 40 C. for 4 h. The mixture was concentrated under reduced pressure to yield a crude acid product 18. The crude acid was treated with ethylamine (117 mg, as the hydrochloric salt), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 375 mg, 0.72 mmol) and diisopropylethylamine (0.5 ml, 2.89 mmol) in anhydrous DMF (11.6 mL) at room temperature for 14 h. The mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; EtOAc/hexane (1:1)) to yield an amide product 19 as colorless oil. The amide product was treated with 4-hydroxybenzylamine (385 mg, 2.4 mmol as the hydrochloric salt) and diisopropylethylamine (2.8 mL, 16.9 mmol) in 1-propanol (28 mL) at 70 C. for 2 h. The mixture was concentrated under reduced pressure, and the residue was extracted with CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; CH2Cl2/MeOH (97:3)) to give 15-acetonide (179 mg, 82%). C23H23N6O5; colorless oil; TLC (EtOAc/hexane (4:1)) Rf=0.13; [alpha]22D=-32.0 (EtOAc, c=1.0); IR numax (neat) 3347, 3103, 2982, 2933, 1732, 1667, 1615, 1516, 1479, 1461, 1376, 1332, 1295, 1245, 1212, 1154, 1088 cm-1; 1H NMR (CDCl3, 400 MHz) delta 9.01 (1H, br s), 8.35 (1H, br s), 7.81 (1H, s), 7.14 (1H, br s), 7.04 (2H, d, J=8.0 Hz), 6.68 (2H, d, J=8.0 Hz), 6.49 (1H, t, 4.8 Hz), 6.03 (1H, d, J=2.4 Hz), 5.33-5.38 (2H, m), 4.70 (3H, s), 3.09-3.16 (2H, m), 1.62 (3H, s), 1.37 (3H, s), 0.90 (3H, t, J=7.2 Hz); 13C NMR (CDCl3, 100 MHz) delta 168.7, 155.8, 154.2, 153.1, 147.7, 139.1, 128.8 (3*), 119.6, 115.4 (2*), 114.3, 91.6, 85.6, 83.3, 82.4, 43.9, 34.0, 27.0, 25.1, 14.2; ESI-HRMS calcd for C22H26N6O5: 455.2043. found: m/z 455.2037 [M+H]+.
6-fluoro-3-((4-hydroxybenzyl)amino)pyrazine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
In tetrahydrofuran at 20℃; for 3h;
2.1 Step 1:6-fluoro-3 - ((4-hydroxybenzy) amino) pyrazine-2-carbonitrile synthesis of
The 4 - (amino-methyl) phenol (87 mg, 0 . 71mmol, 1eq.) dissolved in anhydrous THF (8 ml) in, then adding 3,6- [...] -2-a nitrile (100 mg, 0 . 71mmol, 1eq.), stirring at room temperature the reaction mixture is 3h, then concentrated under reduced pressure, the residue is purified by silica gel column chromatography (eluant: PE/EtOAc (V/V) = 3/1) to obtain white solid title compound (66 mg, 38%).
4-(((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino)methyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.1%
With triethylamine; In isopropyl alcohol; at 100℃; for 15h;Inert atmosphere;
To a stirred solution of <strong>[1127-85-1]2,4-dichloro-5,6,7,8-tetrahydroquinazoline</strong> (1 g, 4.92 mmol) in i-PrOH (30 mL) were added TEA (996 mg, 9.85 mmol) and 4- (aminomethyl)phenol (667 mg, 5.42 mmol). The mixture was stirred at 100 C under N2 atmosphere for 15 hrs, concentrated and purified on silica gel column (hexane/ethyl acetate) to afford 4-(((2-chloro-5,6,7,8-tetrahydroquinazolin-4- yl)amino)methyl)phenol (830 mg, 58.1% yield ) as a light yellow solid. LCMS (M+H+) m/z: Calcd: 290.1; Found: 290.2.
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
General procedure: To a stirred solution of sarsasapogenin (1.664 g, 4 mmol) and pyridine (0.5 mL) in 20 mL DCM, 4-Nitrophenyl chloroformate (6 mmol) was added at 0oC slowly. Then the mixture was stirred at room temperature for 4 h. After completion of the reaction, water (100 mL) was added, then extracted with DCM (3*100 mL). The combined organic extract was washed with brine, dried with dry Na2SO4, filtered, and concentrated under reduced pressure. The products was purified by chromatography on silica gel column (Acetone/PE = 1/30 to 1/20 v/v) to give the product S1 2.19 g (95%). To a stirred solution of S1 (58.1 mg, 1 mmol) and TEA (0.05 mL) in 4 mL DCM, various amines (1.5 mmol) was added at 0oC slowly. Then the mixture was stirred at room temperature for 3 h. After completion of the reaction, water (30 mL) was added, and the solution was extracted with DCM (3*30 mL). Then combined organic extract was washed with brine, dried with dry Na2SO4, filtered, and concentrated under reduced pressure. The products was purified by chromatography on silica gel column (EtOAc/PE = 1/30 to 1/5 v/v) to give the products AA1-AA14 in 25-85% yields.
N-(4-hydroxybenzyl)-3,5,6-trimethylpyrazine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.5%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;
N-(4-hydroxybenzyl)-3,5,6-trimethylpyrazine-2-carboxamide(3a) Add in round bottom bottles246 mg (2.0 mmol) of 4-hydroxybenzylamine,332mg (2.0mmol) TMP acid,458 mg (2.4 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride,324 mg (2.4 mmol) of 1-hydroxybenzotriazole,308 mg (2.4 mmol) of N,N-diisopropylethylamine;Further, 20 mL of N,N-dimethylformamide was added, and the reaction was stirred at room temperature for 12 hours.TLC [V (petroleum ether): V (acetone) = 2:1] The reaction was found to be substantially complete, the reaction was stopped and filtered. The filtrate was added with a 5-fold amount of a saturated aqueous solution of sodium chloride, and extracted with EtOAc (3 mL).The residue silica gel column separates white solid506.94 mg.M.P.: 187.6-188.4 C,The yield is 93.5%.
ethyl 5-hydroxy-3-[(4-hydroxybenzyl)amino]-2-methyl-2,3-dihydroisoxazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: To a mixture of diethyl 2-(ethoxymethylene)malonate (4) (0.6 mmol) and hydroxylamine 5 (0.6 mmol) was added pyridine (0.1 mmol), andthe resulting mixture was stirred at 85 C for 4 h. After cooling the reaction mixture to r.t., amine 2 (0.5 mmol), K2CO3 (0.5 mmol or 1.0mmol) and EtOAc (3 mL) were added. The mixture was stirred at r.t. until the reaction was complete (as detected by TLC monitoring). The insoluble salt (K2CO3) was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc, 10:1 to 4:1) to afford the desired product 3.
General procedure: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 equivalents) was added to a solution of compound 1 (1 equivalent) and N-ethyldiisopropylamine (3 equivalents) in CH2Cl2 (5 ml) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Then, in a typical experiment, primary amine (1.1 equivalents) was added and stirred for 1-6 h, diluted with CH2Cl2 (50 ml), washed with brine (3×50 ml), dried over Na2SO4, filtered and evaporated in vacuo. Chromatography on silica gel using petroleum ether : ethyl acetate as the eluent gave 5a-5m.
1-(4-hydroxyphenyl)imidazo[1,5-a]quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With oxygen; copper(II) sulfate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 20h;
General procedure: According to the raw material ratio and reaction conditions of Table 1 and Table 2, First, copper sulfateis added to a 20 mL dry three-neck reaction tube, suction vacuum pumping and replacement oxygen three times, and then 2-methylquinoline compound (II), fatty amine compound (III), cyano source (IV) and 1- Methyl-2-pyrrolidone are sequentially added, was mixed and stirred at room temperature. After completion of the reaction under the reaction conditions of Table 2 under an oxygen atmosphere, the reaction solution was cooled to room temperature, and the reaction liquid was transferred to a separating funnel. To the separatory funnel, 30 ml of water was added, and the mixture was extracted with ethyl acetate (3×10 mL), dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (eluent mixture of ethyl acetate and petroleum ether with volume ratio of 1:4~8) to obtain corresponding 3-cyanoimidazo[1,5-a]quinoline compound (I).
6-isothiocyanato-2,2,4,4-tetramethylthiochroman[ No CAS ]
1-(4-hydroxybenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In tetrahydrofuran; dichloromethane; at 23℃; for 18h;Inert atmosphere;
General procedure: To a stirred solution of 13 (0.115 g, 0.44 mmol) in THF:DCM (1:1,5 mL) were added substituted benzylamines (16a-i) (0.46 mmol), followed by Et3N (56 mg, 77 mL, 0.55 mmol, 1.2 equiv), and the reaction was stirred at 23 C for 18 h. The reaction mixture was concentrated and purified on a silica gel column eluted with increasing concentrations of EtOAc in hexanes to afford the desired products.
(R)/(S)-tert-butyl (1-((4-hydroxybenzyl)amino)-1-oxobutan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
The compound (0.1 M) synthesized in the Synthesis Example 1 and N-methylmorpholine (NMM) (0.15 M, 1.5eq.) were added to anhydrous tetrahydrofuran at a low temperature of -78C, and the mixture was stirred for 5 minutes.Then, isobutyl chloroformate (IBCF) (0.13 M, 1.3 eq.) was added thereto, and the resultant was stirred for 5 minutes.Then, 4-hydroxybenzylamine derivative (0.12 M, 1.2 eq.) was added thereto and the resultant was stirred for 5 minutes.The temperature of the reaction mixture was raised to room temperature, and then it was identified whether the reactionproceeded while performing stirring for 30 minutes to 60 minutes. After completion of the reaction, the mixture wasfiltered and dried under reduced pressure, and then purified by silica gel column chromatography.
1-(4-hydroxybenzyl)-3-(3-methoxy-4-oxazol-5-yl-phenyl)thiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
Compound 3-methoxy-4- (oxazol-5-yl) aniline (1.0 mmol) andA mixture of 1,1'-thiocarbonyldiimidazole (TCDI, 1.1 mmol) in anhydrous tetrahydrofuran (THF, 4.0 mL) was stirred at room temperature for 2 hours,4-hydroxy-benzylamine (2.0 mmol) was added and then 4-dimethylaminopyridine (DMAP, 0.1 mmol) was added to the solution. willThe mixture was further stirred at reflux temperature overnight. The solvent was removed under reduced pressure. Extracted with ethyl acetate (3 × 20mL), separatedThe organic layer was washed with a saturated aqueous potassium hydrogen sulfate solution and water, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was passed throughPurification by flash chromatography on silica gel,Elution with a gradient of 30-60% ethyl acetate in petroleum ether,Compound 1 was obtained. Light yellow solid, yield 35%.
Stage #1: tert-butyldicarbonate; 4-aminomethylphenol With triethylamine In dichloromethane at 20℃; for 3h; Inert atmosphere;
Stage #2: With potassium carbonate In methanol at 20℃;
A.1 Step 1
To a solution of 4-hydroxybenzylamine in dry dichloromethane (10ml_) under N2 was added triethylamine (2eq) followed by di-tert-butyl carbonate (2eq). The reaction was allowed to stir at rt for 3h before being quenched with saturated NH4CI solution and then extracted with EtOAc (2x). The extracts were combined and dried over MgS04, filtered and concentrated in vacuo. The crude material was taken up in MeOH and treated with K2CO3 (excess) at rt overnight. The reaction mixture was concentrated in vacuo and 10% citric acid solution was added. The mixture was extracted with EtOAc (2x). The extracts were combined and dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using an ethyl acetate/dichloromethane gradient as eluent.
2-(3-hydroxy-2-oxopyridin-1(2H)-yl)-N-(4-hydroxybenzyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 2.5h;Inert atmosphere;
General procedure: To a mixture of 4-hydroxybenzylamine (20 mg, 0.16 mmol 1.1 eq) andDIPEA (26 mul, 0.15 mmol, 1.0 eq) in 0.5 mL of anhydrous DMF, the activatedester (shown for P1, 50 mg, 0.15 mmol, 1.0 eq) was addeddropwise as a solution in DMF (0.5 mL). The reaction mixture was thenstirred under an Ar atmosphere at 25 C for 2.5 h and evaporated underreduced pressure. The product P5 (23 mg, 55%) was isolated asamorphous white solid after the addition of THF (2 mL), filtration of theformed precipitate and washing of the solid with THF (3×0.5 mL). P5:Rf=0.3 (silica gel, 5% MeOH in CH2Cl2); 1H NMR (500 MHz, d6-DMSO) delta 9.29 (s, 1H), 8.98 (s, 1H), 8.52 (t, J=6.4 Hz, 1H), 7.08 (d,J=7.5 Hz, 3H), 6.70 (d, J=7.5 Hz, 3H), 6.07 (t, J=7.5 Hz, 1H), 4.58(s, 2H), 4.18 (d, J=5.1 Hz, 2H) ppm; 13C NMR (125 MHz, d6-DMSO) delta166.6, 157.9, 156.3, 146.6, 129.5, 129.2, 128.6 (2C), 115.0 (2C),114.9, 104.7, 51.3, 41.8 ppm; HRMS calcd for C14H15N2O4 [M+H+]275.1032 found 275.1028.
N-(4-hydroxybenzyl)-5-nitrothiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;
General procedure: To a solution of 17a-c (10 mmol), 5-nitrothiophene-2-carboxylicacid (1.73 g, 10 mmol) and triethylamine (2.7 mL, 20 mmol) in DMF(30 mL) was added HATU (3.80 g, 10 mmol) at 0 C. The reactionmixture was allowed to warm to room temperature and stirred for2 h. Then, EA (100 mL) and water (100 mL) was added andextracted. The organic phase was evaporated to afford compounds18a-c.
2,6-dimethoxy-4-(3-(phenylamino)phenoxy)benzaldehyde[ No CAS ]
4-(((2,6-dimethoxy-4-(3-(phenylamino)phenoxy)benzyl)amino)methyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48.73%
With sodium tris(acetoxy)borohydride; acetic acid; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
General procedure: To a solution of 6(a-d) (0.30 mmol), sodium triacetoxyborohydride(127 mg, 0.60 mmol), different amines (0.36 mmol),added acetic acid (0.03 mmol) under argon atmosphere in anhydrousDMF(2 mL) was stirred at 80 C for over night and monitoredby TLC. The reaction was quenched by cold water (100 mL),extracted with ethyl acetate, dried over anhydrous MgSO4,concentrated in vacuo to get crude products, and purified by flash column chromatography to get desired compounds.
(E)-2-(benzyloxycarbonyl)-1-(4-hydroxybenzyl)-guanidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With triethylamine; mercury(II) oxide In tetrahydrofuran at 20℃;
Synthesis of the guanidine derivatives
General procedure: To a solution of 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (358 mg, 1.0 mmol), mercury oxide (218 mg, 1.0 mmol) and triethylamine (158 mg, 1.0 mmol), in THF (15 ml), 4-(aminomethyl)phenol (141 mg, 1.0 mmol) was added and stir the reaction mixture at rt overnight. Then the solvent was evaporated, and reaction mixture was subjected to column purification using 50% EtOAc/Hexanes and it was obtained as a white solid (100 mg, 55%, m.p. 176-178 °C).
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