* 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 potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5 h;
[00546] To a solution of 4-nitrophenol (2.78 g, 20 mmol) and 2-bromoethyl methyl ether (3.6 g,26 mmol) in DMF (10 mL) were added K2C03 (5.52 g, 40 mmol) and the reaction was stirred at80°C for 5 h. The mixture was cooled down tort and then quenched with H20 (30 mL) andEtOAc ( 40 mL ). The layers were separated and the aqueous layer was extracted with EtOAc (2x 25 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried (Na2S04)and concentrated to afford 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 100percent) as a yellowsolid.
97.6%
With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 4 h;
To a solution of 4-nitrophenol (18.2 g, 130 mmol) and 1-bromo-2-methoxyethane (20 g, 144 mmol) in DMF (60 ml), K2CO3 (36 g, 260 mmol) was added. The reaction mixture was stirred at 65~70°C for 4 h and then cooled to room temperature. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL x3). The combined organic layers were washed with water (200 ml x3), dried over Na2SO4. The solvent was removed under reduced pressure to yield the desired product (3) as white solid (25 g, 97.6percent yield), which was used for the next step without further purification.
Reference：
[1] Patent: WO2014/130693, 2014, A1, . Location in patent: Paragraph 00544; 00546
[2] Patent: WO2015/6754, 2015, A2, . Location in patent: Paragraph 00243; 00244
[3] European Journal of Medicinal Chemistry, 1980, vol. 15, # 5, p. 399 - 404
[4] Patent: US2005/277668, 2005, A1, . Location in patent: Page/Page column 17
2
[ 109-86-4 ]
[ 350-46-9 ]
[ 22483-40-5 ]
Yield
Reaction Conditions
Operation in experiment
53.7%
With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 60℃; for 16 h;
Synthesis of compound 130.2. To a solution of 130.1 (2.0g, 14.1 8mmol, l .Oeq) in DMF (25 mL) were added 2-methoxyethan-l-ol (7.0g, 92.13mmol, 6.5eq) and potassium tert- butoxide (1.43, 12.8 mmol, 0.95eq). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, mixture was poured into water and product was extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 130.2 (1.5 g, 53.7 percent). MS (ES): m/z 197.1 [M+H]+.
Reference：
[1] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00768; 00769
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5177 - 5181
[3] Patent: WO2017/102014, 2017, A1, . Location in patent: Page/Page column 24
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol at 20℃; for 10 h;
To a solution of 13 (2.06 g, 10.5 mmol) and AcOH (1.25 g, 20.9 mmol) in MeOH (100mL) was added 10percent Pd/C (100 mg) and the mixture was stirred at rt under H2atmosphere (H2 balloon) for 10 h. The solution was filtered through alayer of Celite and the filtrate was concentrated in vacuo to provide compound 14 as a brown oil (1.72 g, 98percent). 1HNMR (600 MHz, CDCl3) δ 6.77 (d, J= 8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz,2H), 4.06-4.03 (m, 2H), 3.72-3.70 (m, 2H), 3.44 (s, 3H), 3.42 (br s, 2H). HRMS(ESI+) calcd for C9H14NO2 (M+H)+168.1019, found 168.1019.
95.7%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16 h;
1- (2-methoxyethoxy) -4-nitrobenzene (1.97 g, 10 mmol)Was added to 50 mL of a methanol solution,10percent Pd / C197 mg was added,The reaction was carried out at room temperature for 16 h.The solid was removed by suction filtration,The filtrate was concentrated to give 1.6 g of a pale red oil,Yield 95.7percent.
94.34%
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 2 h; Inert atmosphere
Synthesis of compound 130.3. To a suspension of Pd/C (0.200g,) in MeOH (20ml) was added compound 130.2 (1.5g, 7.61mmol, l .Oeq) under nitrogen atmosphere. Reaction mixture was purged with H2 (gas) at room temperature for 2 hours. After completion of the reaction, mixture was filtered through celite. Solvent was removed under reduced pressureto afford compound 130.3 (1.2g, 94.34percent). MS (ES): m/z 167.2 [M+H]+.
93%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
[00547] 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 20 mmol), MeOH (80 mL), and 10percentPd on activated carbon ( 400 mg) were charged in a hydrogenation vessel and the reactionmixture was stirred at rt overnight under H2 atmosphere. The mixture was filtered through thecelite. The filtrate was concentrated in vacuo to afford 4-(2-methoxyethoxy)aniline (39) (3.1 g,93percent) as a black oil. LC-MS (ESI): m/z (M+1) 168.1.
56.7%
With iron; ammonium chloride In tetrahydrofuran; water for 4 h; Reflux
To a solution of compound 3 (25 g, 127 mmol) inTHF (180 mL), water (60 mL) was added. After stirred for ~ 5 min, NH4Cl (28 g, 523 mmol) and Fe (36 g, 635 mmol) were sequentially added. The reaction mixture was heated to refluxing and stirred for 4h. After cooled to room temperature, the mixture was filtered through Celite® and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude was re- dissolved in ethyl acetate (500 mL), washed with saturated NaHCO3 (200 mL) and water (200 mL). The organic layer was concentrated under reduced pressure. The crude was further purified by flash column chromatography to yield the desired product 4 (12 g, 56.7percent yield, M+H+= 168.5).
700 mg
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 3 h;
Compound 115 (lg, 5.08 mmol) was hydrogenated with 100 mg of Pd/C in 20mL of methanol under a hydrogen atmosphere for 3h. The reaction mixture was filtrated on Celite, washed with 20mL of methanol and concentrated under vacuum to yield 700 mg of the pure aniline 116. Light brown oil. Yield = 68percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5177 - 5181
[2] Patent: CN103864792, 2017, B, . Location in patent: Paragraph 0313; 0314; 0315; 0316
[3] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00768; 00770
[4] Patent: WO2014/130693, 2014, A1, . Location in patent: Paragraph 00544; 00547
[5] European Journal of Medicinal Chemistry, 1980, vol. 15, # 5, p. 399 - 404
[6] Patent: WO2015/6754, 2015, A2, . Location in patent: Paragraph 00243; 00245
[7] Collection of Czechoslovak Chemical Communications, 1971, vol. 36, p. 2527 - 2539
[8] Patent: US2005/277668, 2005, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2017/4543, 2017, A1, . Location in patent: Page/Page column 67
[10] Patent: WO2017/102014, 2017, A1, . Location in patent: Page/Page column 24
With palladium 10% on activated carbon; hydrogen; acetic acid; In methanol; at 20℃; for 10h;
To a solution of 13 (2.06 g, 10.5 mmol) and AcOH (1.25 g, 20.9 mmol) in MeOH (100mL) was added 10% Pd/C (100 mg) and the mixture was stirred at rt under H2atmosphere (H2 balloon) for 10 h. The solution was filtered through alayer of Celite and the filtrate was concentrated in vacuo to provide compound 14 as a brown oil (1.72 g, 98%). 1HNMR (600 MHz, CDCl3) delta 6.77 (d, J= 8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz,2H), 4.06-4.03 (m, 2H), 3.72-3.70 (m, 2H), 3.44 (s, 3H), 3.42 (br s, 2H). HRMS(ESI+) calcd for C9H14NO2 (M+H)+168.1019, found 168.1019.
95.7%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;
1- (2-methoxyethoxy) -4-nitrobenzene (1.97 g, 10 mmol)Was added to 50 mL of a methanol solution,10% Pd / C197 mg was added,The reaction was carried out at room temperature for 16 h.The solid was removed by suction filtration,The filtrate was concentrated to give 1.6 g of a pale red oil,Yield 95.7%.
94.34%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 2h;Inert atmosphere;
Synthesis of compound 130.3. To a suspension of Pd/C (0.200g,) in MeOH (20ml) was added compound 130.2 (1.5g, 7.61mmol, l .Oeq) under nitrogen atmosphere. Reaction mixture was purged with H2 (gas) at room temperature for 2 hours. After completion of the reaction, mixture was filtered through celite. Solvent was removed under reduced pressureto afford compound 130.3 (1.2g, 94.34%). MS (ES): m/z 167.2 [M+H]+.
93%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
[00547] 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 20 mmol), MeOH (80 mL), and 10%Pd on activated carbon ( 400 mg) were charged in a hydrogenation vessel and the reactionmixture was stirred at rt overnight under H2 atmosphere. The mixture was filtered through thecelite. The filtrate was concentrated in vacuo to afford 4-(2-methoxyethoxy)aniline (39) (3.1 g,93%) as a black oil. LC-MS (ESI): m/z (M+1) 168.1.
56.7%
With iron; ammonium chloride; In tetrahydrofuran; water; for 4h;Reflux;
To a solution of compound 3 (25 g, 127 mmol) inTHF (180 mL), water (60 mL) was added. After stirred for ~ 5 min, NH4Cl (28 g, 523 mmol) and Fe (36 g, 635 mmol) were sequentially added. The reaction mixture was heated to refluxing and stirred for 4h. After cooled to room temperature, the mixture was filtered through Celite and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude was re- dissolved in ethyl acetate (500 mL), washed with saturated NaHCO3 (200 mL) and water (200 mL). The organic layer was concentrated under reduced pressure. The crude was further purified by flash column chromatography to yield the desired product 4 (12 g, 56.7% yield, M+H+= 168.5).
With hydrogen;palladium 10% on activated carbon; In methanol; under 2068.65 Torr; for 1h;
The 4-nitrophenol (3.05 g), MeOH (30 mL), 10% Pd on activated carbon, (304 mg) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 1 h at 40 psi of hydrogen. The mixture was filtered through celite, the cake washed with MeOH and the solvent from the eluent removed in vacuo to afford the desired aniline (1.75 g, 68% 2 step) as a brown oil: 1H NMR (CDCl3) delta 3.44 (s, 3H), 3.70-3.73 (m, 2H), 4.03-4.06 (m, 2H), 6.64 (d, 2H, J=9 Hz), 6.78 (d, 2H, J=9 Hz).
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
PREPARATION 5 PREPARATION OF 4- 2-METHOXYETHOXY)ANILINE 1 -(2-Methoxyethoxy)-4-nitrobenzene (1 .02 g, 5.17 mmol) and 10% palladium on carbon (150 mg) were mixed in methanol (30 mL). After degassing, hydrogen gas balloon was applied to the mixture. The reaction mixture was stirred for 2 hours at ambient temperature, and then filtered through Celite. The filtrate was concentrated, and the residue was dried in vacuo to afford the title compound as a brown liquid in 70% yield (604 mg) and used for next step reaction without further purification.
700 mg
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 760.051 Torr; for 3h;
Compound 115 (lg, 5.08 mmol) was hydrogenated with 100 mg of Pd/C in 20mL of methanol under a hydrogen atmosphere for 3h. The reaction mixture was filtrated on Celite, washed with 20mL of methanol and concentrated under vacuum to yield 700 mg of the pure aniline 116. Light brown oil. Yield = 68%.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;
[00546] To a solution of 4-nitrophenol (2.78 g, 20 mmol) and 2-bromoethyl methyl ether (3.6 g,26 mmol) in DMF (10 mL) were added K2C03 (5.52 g, 40 mmol) and the reaction was stirred at80C for 5 h. The mixture was cooled down tort and then quenched with H20 (30 mL) andEtOAc ( 40 mL ). The layers were separated and the aqueous layer was extracted with EtOAc (2x 25 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried (Na2S04)and concentrated to afford 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 100%) as a yellowsolid.
97.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 65 - 70℃; for 4h;
To a solution of 4-nitrophenol (18.2 g, 130 mmol) and 1-bromo-2-methoxyethane (20 g, 144 mmol) in DMF (60 ml), K2CO3 (36 g, 260 mmol) was added. The reaction mixture was stirred at 65~70C for 4 h and then cooled to room temperature. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL x3). The combined organic layers were washed with water (200 ml x3), dried over Na2SO4. The solvent was removed under reduced pressure to yield the desired product (3) as white solid (25 g, 97.6% yield), which was used for the next step without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 80℃; for 5h;
To a solution of 4-nitrophenol (2.16 g, 15.5 mmol) in DMF (8 mL) was added 2-bromoethyl methyl ether (1.9 mL, 20.2 mmol) and K2CO3 (4.08 g, 29.6 mmol) and the reaction stirred at 60 C. for 3 h then at 80 C. for 2 h. The mixture was cooled and diluted with H2O (30 mL) and EtOAc (40 mL) and the aqueous layer extracted again with EtOAc (1*25 mL). The combined organic extracts were washed with brine (2*20 mL), dried (Na2SO4) and concentrated to afford the desired ether (3.05 g) as a white solid.
With potassium tert-butylate; In 2-methoxy-ethanol; N,N-dimethyl-formamide;
The <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> used as starting material was obtained as follows: Potassium tert-butoxide (2 g) was added portionwise to a stirred mixture of 4-fluoronitrobenzene (2.8 g), 2-methoxyethanol (10 ml) and DMF (20 ml). The mixture was stirred and heated to 60 C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4)- and evaporated. The residue was recrystallized from a mixture of hexane and ethyl acetate. There was thus obtained 4-(2-methoxyethoxy)nitrobenzene (1.06 g), m.p. 86 C. The product so obtained was dissolved in ethyl acetate and hydrogenated in the presence of a 10% Pd/C catalyst to give <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (0.7 g). NMR Spectrum: (CD3 SOCD3) 3.3 (s, 3H), 3.6 (t, 2H), 3.9 (t, 2H), 4.6 (s, 2H), 6.5 (d, 2H), 6.7 (d, 2H).
With hydrogenchloride; sodium hydroxide; In water; ethyl acetate; acetone;
A 4-(2-Methoxyethoxy)-1-nitrobenzene A mixture of 40 g of 4-nitrophenol, 41 g of 1-bromo-2-methoxyethane, 45 g of K2 CO3 and 80 ml of tris[2-(2-methoxyethoxy)ethyl]amine in 80 ml of acetone is refluxed for 20 hours. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, washed with a 1N solution of NaOH, with water, with a 1N solution of HCl and with water and dried over Na2 SO4 and the solvent is evaporated off under vacuum to give 59 g of the expected product, which is used as such in the next step.
With potassium tert-butylate; In N,N-dimethyl-formamide; at 60℃; for 16h;
Synthesis of compound 130.2. To a solution of 130.1 (2.0g, 14.1 8mmol, l .Oeq) in DMF (25 mL) were added 2-methoxyethan-l-ol (7.0g, 92.13mmol, 6.5eq) and potassium tert- butoxide (1.43, 12.8 mmol, 0.95eq). The reaction mixture was stirred at 60C for 16 hours. After completion of the reaction, mixture was poured into water and product was extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 130.2 (1.5 g, 53.7 %). MS (ES): m/z 197.1 [M+H]+.
With potassium hydroxide; In dimethyl sulfoxide; at 60℃;
To a solution of1-fluoro-4-nitrobenzene (11, 2.00 g,14.2 mmol) and 2-methoxyethanol (12,1.30 g, 17.0 mmol) in DMSO (40 mL) was added KOH (1.19 g, 21.3 mmol). After themixture was heated at 60 C overnight and then cooled to rt, the reactionmixture was diluted with EtOAc. The organic phase was washed with water andbrine and then concentrated in vacuo to provide crude compound 13 as a yellow solid (2.06 g, 73%),which was used in the next step without further purification. 1H NMR(600 MHz, CDCl3) delta 8.20 (d, J= 9.2 Hz, 2H), 6.99 (d, J = 9.2 Hz,2H), 4.23-4.20 (m, 2H), 3.80-3.77 (m, 2H), 3.46 (s, 3H).
With potassium hydroxide; In dimethyl sulfoxide; at 60℃; for 16h;
A mixture of 5 g of 1 -fluoro-4-nitro-benzene (35.46 mmol), 4.04 g of 2-methoxyethanol (1.5eq, 53.19 mmol) and 3.97 g of KOH (2 eq, 70.92 mmol) in 50 mL of DMSO were heated to 60C for 16h. Then, 300 mL of water were added and the reaction mixture was extracted twice with 30mL of ethyl acetate. The organic layers were combined and concentrated under vacuum yielding 4.4 g of pure product 115, used directly in the next step. [H NMR (CDCI3, 250 MHz): delta = 3.45 (s, 3H), 3.78 (t, J= 4.7 Hz, 2H), 4.20 (t, J= 4.6 Hz, 2H), 6.98 (d, J= 8.8 Hz, 2H), 8.19 (d, J= 8.9 Hz, 1H) ; purity = 90% ; yellow solid. Yield = 63%.
1-(1-(2-hydrazinyl-2-oxoethyl)-3-(4-(2-methoxyethoxy)phenyl)-5,5-dimethyl-2-oxoimidazolidin-4-yl)-1-hydroxy-3-(4-(2-methoxyethoxy)phenyl)urea[ No CAS ]
3-(4-chlorophenyl)-1-hydroxy-1-(3-(4-(2-methoxyethoxy)phenyl)-5,5-dimethyl-1-(2-((E)-2-((E)-3-(5-nitrofuran-2-yl)allylidene)hydrazinyl)-2-oxoethyl)-2-oxoimidazolidin-4-yl)urea[ No CAS ]
1-(3-(4-chlorophenyl)-5,5-dimethyl-1-(2-((E)-2-((E)-3-(5-nitrofuran-2-yl)allylidene)hydrazinyl)-2-oxoethyl)-2-oxoimidazolidin-4-yl)-1-hydroxy-3-(4-(2-methoxyethoxy)phenyl)urea[ No CAS ]
2.17. 1-hydroxy-3-(4-(2-methoxyethoxy)phenyl)-1-(3-(4-(2-methoxyethoxy)phenyl)-5,5-dimethyl-1-(2-((E)-2-((E)-3-(5-nitrofuran-2-yl)allylidene)hydrazinyl)-2-oxoethyl)-2-oxoimidazolidin-4-yl)urea[ No CAS ]
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