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Structure of 16554-45-3 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.666667 h; Stage #2: With copper(I) bromide In water at 0 - 60℃; for 2 h; Heating / reflux
A solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold (0-5° C.) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90° C. for 2 h). The reaction mixture was maintained for 40 min and was filtered. The filtrate was added dropwise to a cold (0-5° C.) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 min. The reaction mixture was warmed to 60° C. and was maintained for 30 min. The reaction mixture was warmed to reflux and was maintained for 1 h. The reaction mixture was diluted with water (2 L) and was extracted with dichloromethane (3*1 L). The combined organic layers were washed with 10percent sodium hydroxide (1.0 L), water (2.0 L), 10percent hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethanol to provide the bromide in 50percent yield as a yellow solid.
Reference：
[1] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 67
[2] Bulletin of the Chemical Society of Japan, 1978, vol. 51, p. 2437 - 2438
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
Reference：
[1] Journal of the Chemical Society, 1926, p. 1319
9
[ 16554-45-3 ]
[ 3970-39-6 ]
Yield
Reaction Conditions
Operation in experiment
16.5 g
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.25 h; Stage #2: With hydrogenchloride; copper(l) chloride In water at 0 - 50℃; for 0.5 h;
INTERMEDIATE: (5-Methoxy-3-methyl-quinoxalin-2-yl)-hydrazine (lie). 2-Methoxy-6-nitro- phenylamine (25.0 g) was dissolved in 37percent aq HC1, and the mixture ws cooled on an ice/water bath. A solution of NaN02 (11.8 g) in water (3 mL) was added, and the resulting mixture was stirred at 0 °C for 15 min. The reaction mixture was added to a solution of cuprous monochloride (14.7 g) in 37percent aq HC1 (10 mL) under stirring at 45-50 °C. The resulting mixture was stirred at 50 °C for 15 min, cooled at 5 °C for 15 min. The solid was filtered off and dried to give 2-chloro-l-methoxy-3- nitrobenzene (16.5 g). A mixture of 16 g of this material, racemic alanine (17 g), and K2CO3 (12 g) was heated in DMSO (180 mL) at 100 °C for 24h. The volatiles were removed using a freeze dryer. The residue was acidified with 2M aq HC1 (50 mL) and extracted into EtOAc. The organic extract was extracted with 2M aq Na2C03 and water. The combined aq extracts were acidified with 2M aq HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenylamino)-propionic acid. This material was dissolved in ethanol (600 mL) and 96percent> sulphuric acid (6 mL) was added. The mixture was heated at 80 °C overnight. The volatiles were removed in vacuo and the residue was dissolved in EtOAc and washed with 2M aq Na2C03. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenylamino)-propionic acid ethyl ester (8.0 g). This material was dissolved in ethanol (300 mL) and 5percent palladium on carbon was added. The mixture was treated with 3 bars of hydrogen pressure on a Parr shaker for 3h. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes→ EtOAc) to afford 5-methoxy-3-methyl-3,4-dihydro- lH-quinoxalin-2-one (3.0 g). This material was dissolved in ethanol (300 mL) and treated with 30percent aq hydrogen peroxide at 80 °C overnight. Most of the volatiles were removed in vacuo. The residue was suspended in ethanol (10 mL) and cooled on an ice/water bath before the solid was filtered off, washed with ice-cold ethanol, and dried to afford 5-methoxy-3-methyl-lH-quinoxalin-2-one (2.2 g). This material was dissolved in phosphoryl chloride (24 mL) and heated at 130 °C for 2h. The volatiles were removed in vacuo. The residue was partitioned between chloroform and ice + 2M aq NaOH. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 2- chloro-5-methoxy-3-methyl-quinoxaline (2.5 g). This material was dissolved in ethanol (22 mL), hydrazine hydrate (2.9 mL) was added, and the mixture was refluxed for 2h. The volatiles were removed in vacuo, and water was added. The solid was filtered off, washed with water and heptanes and dried to afford lie (1.70 g) sufficiently pure for the next step.
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
[2] Journal fuer Praktische Chemie (Leipzig), 1930, vol. <2> 127, p. 20,22
[3] Patent: WO2005/68433, 2005, A1, . Location in patent: Page/Page column 38
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 17, p. 5161 - 5164
[5] Patent: WO2013/34755, 2013, A1, . Location in patent: Page/Page column 18
10
[ 16554-45-3 ]
[ 37466-89-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 2 h;
At room temperature, to a solution of 2-methoxy-6-nitroaniline (4.75 g, 28.25 minol) in methanol (150 mL) was added Pd/C (10percent, 500 mg) under nitrogen atmosphere. The reaction flask was vacuumed and flushed with hydrogen. The reactionminxture was hydrogenated for 2 h at room temperature under H2 atmosphere using a hydrogen balloon. When the reaction was done, the reactionminxture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to yield 3-methoxybenzene-1,2-diamine as dark red oil (3.66 g, 94percent). MS: m/z = 139.1 [M+Hj.
77%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 2 h;
The mixture of 2-methoxy-6-nitroaniline (1, 300mg, 1.78mmol) and 10percent Pd/C (60mg) in ethanol (15mL) was stirred under hydrogen atmosphere at room temperature and atmospheric pressure for 2h. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography on silicagel with petroleum ether–AcOEt (v/v=3/1). The title compound 2 (190mg, 77percent yield) was obtained as off-white powder. M.p. 77–78°C; 1H NMR (CDCl3, 300MHz, δ ppm): 6.68 (1H, t, J=7.8Hz), 6.41 (2H, td, J1=7.5Hz, J2=1.2Hz), 3.84 (3H, s), 3.31 (4H, br s); HRMS (ESI): m/z, calcd. For C7H11N2O [M+H]+ 138.0866, found 138.0870.
Reference：
[1] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00459
[2] Journal of Asian Natural Products Research, 2011, vol. 13, # 4, p. 330 - 340
[3] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 222 - 232
[4] Journal of the Chemical Society, 1954, p. 2977
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3515 - 3527
[6] Patent: US2004/6119, 2004, A1, . Location in patent: Page/Page column 17
[7] Patent: EP508800, 1992, A1,
[8] Patent: US2007/10542, 2007, A1, . Location in patent: Page/Page column 72
[9] Patent: US2004/19058, 2004, A1,
[10] Patent: US6353010, 2002, B1, . Location in patent: Page column 9
[11] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7105 - 7126
[12] Patent: WO2012/40040, 2012, A1, . Location in patent: Page/Page column 48
[13] Applied Organometallic Chemistry, 2014, vol. 28, # 6, p. 389 - 395
[14] Archives of Pharmacal Research, 2017, vol. 40, # 4, p. 469 - 479
[15] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6289 - 6304
11
[ 603-85-0 ]
[ 74-88-4 ]
[ 16554-45-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate In N,N-dimethyl-formamide for 14 h;
Step 1: 2-methoxy-6~nitroaniline; A mixture of 2-amino-3-nitrophenol (1 1.66 g, 76 mmol) and K2C03 (12.55 g, 91 mmol) were stirred in DMF (100 ml) for 1 hour. Iodomethane (5.68 ml, 91 mmol) in DMF (lOmL) was added dropwise, and the mixture was stirred 14 hours. The reaction was diluted with H2 and extracted with EtOAc (2x). The organics were washed with brine, dried over Na2S04, filtered, concentrated to a dark solid. The crude solid was purified by crystallization from hexane to give the title compound as an orange solid (11 ,6g, 91percent). LCMS (ES+) m/z 169.0 (M+H)+.
90%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To a mixture of 2-amino-3-nitrophenol (19.25 g) and K2CO3 (19 g) in DMF (100 mL) was added MeI (11 mL) at room temperature and the mixture was stirred over night and then poured into water. The resulting precipitate was collected by filtration and the solid was washed with water to afford the desired product (19 g, 90percent). 1H NMR (300 MHz, CDCl3) δ ppm 3.92 (s, 1H), 6.43 (br s, 1H), 6.61 (dd, 1H, J=7.5, 9.0 Hz), 6.89 (dd, 1H, J=0.9, 7.5 Hz), 7.73 (dd, 1H, J=0.9, 9.0 Hz); LC-MS: m/e=169 [M+1]+
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5 h;
The mixture of 2-amino-3-nitrophenol (308mg, 2mmol) and K2CO3 (552mg, 4mmol) in DMF (5mL) were stirred at room temperature for 30min before addition of MeI (0.15mL, 2.5mmol). After stirred at room temperature for 1h, the reaction mixture was diluted with water (30mL) and extracted with ethyl ether (15mL×3). The combined organic layer was washed with water and brine and then dried over anhydrous MgSO4, filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel with petroleum ether/AcOEt (v/v=12:1). The title compound (300mg, 89percent yield) was afforded as salmon pink powder. M.p. 68–69°C; 1H NMR (CDCl3, 300MHz, δ ppm): 7.73 (1H, d, J=9.3Hz), 6.88 (1H, d, J=7.8Hz), 6.60 (1H, t, J=7.5Hz), 6.42 (2H, br s), 3.92 (3H, s); HRMS (ESI): m/z, calcd. For C7H9N2O3 [M+H]+: 169.0608, found 169.0607.
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;
2-Methoxy-6-nitroaniline To a solution of 2-amino-3-nitrophenol (35 g, 227 mmol) in DMF (400 ml_), K2C03(37.7 g, 273 mmol) and Mel (17.04 ml_, 273 mmol) were added at RT. The reaction mixture was stirred at RT for 16 h. Then it was poured into water. The resulting precipitate was collected by filtration and the solid was washed with water to give 35 g (89percent) of the title compound. LC-MS m/z 168.9 (M+H)+, 1.71 (ret. time).
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;
Intermediate 4 2-Methoxy-6-nitroaniline To a solution of 2-amino-3-nitrophenol (35 g, 227 mmol) in Ν,Ν-dimethylformamide (DMF) (400 mL), K2C03 (37.7 g, 273 mmol) and iodomethane (17.04 mL, 273 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. Then it was poured into water. The resulting precipitate was collected by filtration and the solid was washed with water to give 35 g (89percent) of the title compound. LC-MS m/z 168.9 (M+H)+, 1 .71 min (ret. time).
87%
With potassium hydroxide In N,N-dimethyl-formamide at 20℃;
c) 2-methoxy-6-nitro-phenylamine: 85percent potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried. Yield: 23.8 g (87percent); mass spectroscopy: [M+H]+=169.
87%
With potassium hydroxide In DMF (N,N-dimethyl-formamide) at 20℃;
85percent potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried. Yield: 23.8 g (87percent); mass spectroscopy: [M+H]+=169
87%
With potassium hydroxide In water; N,N-dimethyl-formamide at 0 - 20℃;
c) 2-methoxy-6-nitro-phenylamine 85percent potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried. Yield: 23.8 g (87percent); mass spectroscopy: [M+H]+=169.
81%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.0833333 h; Stage #2: at 20℃; for 2 h;
To a solution of 2-amino-3-nitrophenol (2.55 g, 16.55 mmol) dissolved in N,Ndimethylformamide (35 mL) was added potassium carbonate (2.52 g, 18.20 mmol). The mixturewas stirred for 5 mm before iodomethane (1 .138 mL, 18.20 mmol) was added and the reactionallowed to stir at ambient temperature for 2 h. water75 mL) was added to quench the reactionand the precipitate product was collected by filtration, washed with water to afford the titlecompound 2-methoxy-6-nitroaniline (2.26 g, 81 percent). LC-MS m/z 168.9 (M+H), 0.74 mm (ret.time)
81%
at 20℃; for 2 h;
To a solution of 2-amino-3-nitrophenol (2.55 g, 16.55 mmol) dissolved in N,N- dimethylformamide (35 mL) was added potassium carbonate (2.52 g, 18.20 mmol). The mixture was stirred for 5 min before iodomethane (1.138 mL, 18.20 mmol) was added and the reaction allowed to stir at ambient temperature for 2 h. water75 mL) was added to quench the reaction and the precipitate product was collected by filtration, washed with water to afford the title compound 2-methoxy-6-nitroaniline (2.26 g, 81 percent). LC-MS m/z 168.9 (M+H)+, 0.74 min (ret. time)
76%
With potassium carbonate In water; N,N-dimethyl-formamide
Step 1. 2-Methoxy-6-nitrophenylamine. To a solution of 2-amino-3-nitrophenol (5 g, 32.4 mmol) in DMF (165 ml) were sequentially added potassium carbonate (9.0 g, 65 mmol) and methyl iodide (2.2 ml, 35 mmol). The mixture was heated at 50° C. overnight before it was cooled to room temperature, mixed with water (300 ml), and extracted with ethyl acetate (3*50 ml). The extracts were combined, washed with water (150 ml), brine (80 ml), and dried (MgSO4). Removal of the solvent under reduced pressure gave a dark orange solid that was triturated with 1:1 hexane/ether. The solids were collected by filtration to give product 136 as orange needles (4.1 g, 76percent).
50%
With caesium carbonate In tetrahydrofuran at 18 - 25℃; for 144 h;
In the case of SM Ic an additional step needed to be carried out as shown below: 2-amino-3-nitro-6methoxybenzene:Into a 250ml round bottom flask was fed 2-amino-3-nitrophenol (2.04g, 13.24mmol) and 50ml anhydrous THF. Cesium carbonate (18.98g, 58.26mmol) was added into the solution followed by methyl iodide (2.07g, 14.56mmol). The mixture was stirred 6 days at room temperature. The resulting mixture was filtered and washed with DCM. The solvent was removed on a rotary evaporator. The crude material was purified by silica gel chromatography (gradient elution; EtOAc: Hexane 20percent) to afford title compound (l.lg, 50percent) M/Z 168.
29.4 g
With tetra-(n-butyl)ammonium iodide; sodium hydroxide In tetrahydrofuran; water at 20℃;
INTERMEDIATE (7-Bromo-5 -methoxy-3 -methyl-quinoxalin-2-yl)-hydrazine (Ilq). 2-Amino-3-nitrophenol (25 g) and NaOH (25.0 g) were dissolved in a mixture of THF (500 mL) and water (200 mL). TBAI (2.5 g) and methyl iodide (21.2 mL) were added. The mixture was stirred overnight at ambient temperature. Most of the THF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-methoxy-6-nitro-phenyl amine (29.4 g). 22 g of this material and NaOAc (17.8 g) were mixed in acetic acid (300 mL) at ambient temperature. Bromine (6.9 mL) in acetic acid (5 mL) was added drop-wise over 15 min. The precipitated solid was filtered off, washed with water and heptanes, and dried to afford 4-bromo-2-methoxy-6-nitro-phenylamine (25.5 g). 2.47 g of this material dissolved in DCM (100 mL). DMAP (1.22 g) and Boc20 (2.62 g) were added, and the mixture was overnight at ambient temperature. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc). Fractions containing the desired material were pooled and most of the EtOAc was removed in vacuo. The residual solution was diluted with heptanes, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitated solid was filtered off and dried to afford (4-bromo- 2-methoxy-6-nitro-phenyl)-iminocarbonicacid-bis-(tert-butyl ester) (3.94 g). A larger portion of this material (25.6 g) prepared in a similar manner was dissolved in ethanol (700 mL). 5percent Platinum on charcoal (4.0 g) was added, and the mixture was treated with hydrogen gas (1 bar) for 45 min using a Parr shaker instrument. The catalyst was filtered off. The filtrate was concentrated in vacuo. The residual solid was suspended in heptanes, filtered, and dried to afford 6-amino-4-bromo-2-methoxy- phenyl)-iminocabonicacid-bis (fert-butyl ester) (22.0 g). This material was dissolved in DCM (250 mL) and treated with TFA (5 mL) overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M aq NaOH (until pH was 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford the mono-deprotected material (ca 11 g). This material was dissolved in a mixture of DCM (100 mL) and TFA (50 mL) and stirred overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M NaOH (until pH 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 5-bromo-3-methoxy-benzene-l,2-diamine (3.63 g). This material was dissolved in methanol (200 mL). 2-Oxo-propanoic acid methyl ester (2.0 g) was added, and the mixture was stirred overnight at ambient temperature. The precipitated 7-bromo-5-methoxy-3- methyl-lH-quinoxalin-2-one was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford more 7-bromo- 5-methoxy-3-methyl-lH-quinoxalin-2-one as the first eluting isomer followed by 6-bromo-8- methoxy-3-methyl-lH-quinoxalin-2-one as the second eluting isomer. The two crops of 7-bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one were mixed and washed with a little acetone to afford 7- bromo-5-methoxy-3 -methyl- lH-quinoxalin-2-one (1.7 g) sufficiently pure for the next step. The fractions containing the second eluting isomer were pooled and concentrated in vacuo; the residual solid was washed with a little acetone to afford 6-bromo-8-methoxy-3-methyl-lH-quinoxalin-2-one (0.61 g) sufficiently pure for the next step. The structure of the isomers were elucidated by identifying the nitrogen carrying a proton by 2D HSQC and comparing with the shift of the nitrogen having long range correlation to an aromatic proton in 2D HMBC. 7-Bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) was refluxed in phosphoryl chloride (23 mL) for 2h. The volatiles were removed in vacuo. The residue was partitioned between DCM and ice/water. The mixture was basified with 2M aq Na2C03. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 7-bromo-2-chloro-5-methoxy-3-methyl-quinoxaline (0.61 g). This material was dissolved in ethanol (38 mL). Hydrazine hydrate (3 mL) was added and the mixture was refluxed for 2h. The volatiles were removed in vacuo. The residual solid was suspended in water, filtered off, washed with heptanes, and dried to afford Ilq (0.58 g) sufficiently pure for the next step.
29.4 g
With tetra-(n-butyl)ammonium iodide; sodium hydroxide In tetrahydrofuran; water at 20℃;
INTERMEDIATE 6-Bromo-8-methoxy-3-methyl-quinoxalin-2-yl)-hydrazine (Ilf). 2-Amino-3-nitrophenol (25 g) and NaOH (25.0 g) were dissolved in a mixture of THF (500 mL) and water (200 mL). TBAI (2.5 g) and methyl iodide (21.2 mL) were added. The mixture was stirred overnight at ambient temperature. Most of the THF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-methoxy-6-nitro-phenyl amine (29.4 g). 22 g of this material and NaOAc (17.8 g) were mixed in acetic acid (300 mL) at ambient temperature. Bromine (6.9 mL) in acetic acid (5 mL) was added drop-wise over 15 min. The precipitated solid was filtered off, washed with water and heptanes, and dried to afford 4-bromo-2-methoxy-6-nitro- phenylamine (25.5 g). 2.47 g of this material dissolved in DCM (100 mL). DMAP (1.22 g) and B0C2O (2.62 g) were added, and the mixture was overnight at ambient temperature. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc). Fractions containing the desired material were pooled and most of the EtOAc was removed in vacuo. The residual solution was diluted with heptanes, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitated solid was filtered off and dried to afford (4-bromo-2-methoxy-6-nitro-phenyl)-iminocarbonicacid-bis-(tert-butyl ester) (3.94 g). A larger portion of this material (25.6 g) prepared in a similar manner was dissolved in ethanol (700 mL). 5percent Platinum on charcoal (4.0 g) was added, and the mixture was treated with hydrogen gas (1 bar) for 45 min using a Parr shaker instrument. The catalyst was filtered off. The filtrate was concentrated in vacuo. The residual solid was suspended in heptanes, filtered, and dried to afford 6-amino-4-bromo-2-methoxy-phenyl)-iminocabonicacid-bis (tert- butyl ester) (22.0 g). This material was dissolved in DCM (250 mL) and treated with TFA (5 mL) overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M aq NaOH (until pH was 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford the mono-deprotected material (ca 11 g). This material was dissolved in a mixture of DCM (100 mL) and TFA (50 mL) and stirred overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M NaOH (until pH 9). The organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford 5-bromo-3-methoxy-benzene-l,2-diamine (3.63 g). This material was dissolved in methanol (200 mL). 2-Oxo-propanoic acid methyl ester (2.0 g) was added, and the mixture was stirred overnight at ambient temperature. The precipitated 7-bromo-5-methoxy-3-methyl-lH- quinoxalin-2-one was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford more 7-bromo-5-methoxy- 3-methyl-lH-quinoxalin-2-one as the first eluting isomer followed by 6-bromo-8-methoxy-3- methyl-lH-quinoxalin-2-one as the second eluting isomer. The two crops of 7-bromo-5-methoxy- 3-methyl-lH-quinoxalin-2-one were mixed and washed with a little acetone to afford 7-bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) sufficiently pure for the next step. The fractions containing the second eluting isomer were pooled and concentrated in vacuo; the residual solid was washed with a little acetone to afford 6-bromo-8-methoxy-3-methyl-lH-quinoxalin-2-one (0.61 g) sufficiently pure for the next step. The structure of the isomers were elucidated by identifying the nitrogen carrying a proton by 2D ^N-'H HSQC and comparing with the shift of the nitrogen having long range correlation to an aromatic proton in 2D ^N-'H HMBC. 6-bromo- 8-methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) was dissolved in phosphoryl chloride (23 mL) was refluxed for 2h. The volatiles were removed in vacuo. The residue was partitioned between DCM and a little ice. The biphasic mixture was basified with 2M aq Na2C03 and was filtered. The organic part of the filtrate was dried over MgSO i, filtered, and concentrated in vacuo to afford 7- bromo-3-chloro-5-methoxy-2-methyl-quinoxaline (1.1 g). This material was dissolved in ethanol (38 mL). Hydrazine hydrate (3 mL) was added, and the mixture was refluxed for 2h. The volatiles were removed in vacuo. The residue was suspended in water (50 mL). The solid was filtered off, washed with heptanes and dried to afford Ilf (1.6 g) sufficiently pure for the next step.
9.85 g
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
C) 2-Methoxy-6-nitroaniline To a solution of 2-amino-3-nitrophenol (9.12 g) and potassium carbonate (13.6 g) in DMF (100 mL), iodomethane (4.44 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture at room temperature. The deposited solid was collected by filtration and washed with water and hexane to obtain the title compound (9.85 g). 1H NMR (300MHz, DMSO-d6) δ 3.88 (3H, s), 6.61 (1H, dd, J = 8.9, 7.7 Hz), 6.95-7.17 (3H, m), 7.59 (1H, dd, J = 8.9, 1.3 Hz).
Reference：
[1] Patent: WO2012/40040, 2012, A1, . Location in patent: Page/Page column 47-48
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
[3] Patent: US2012/88767, 2012, A1, . Location in patent: Page/Page column 16; 22
[4] Journal of Asian Natural Products Research, 2011, vol. 13, # 4, p. 330 - 340
[5] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 222 - 232
[6] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 69; 154; 155
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 8, p. 3991 - 4006
[8] Patent: WO2016/203400, 2016, A1, . Location in patent: Page/Page column 45; 46
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3515 - 3527
[10] Patent: US2007/249595, 2007, A1, . Location in patent: Page/Page column 8-9
[11] Patent: US2006/63817, 2006, A1, . Location in patent: Page/Page column 12
[12] Patent: US2007/203125, 2007, A1, . Location in patent: Page/Page column 35
[13] Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4003 - 4015
[14] Patent: US6369235, 2002, B1, . Location in patent: Example 46
[15] Patent: WO2016/203401, 2016, A1, . Location in patent: Page/Page column 102
[16] Patent: WO2016/202253, 2016, A1, . Location in patent: Page/Page column 129
[17] Patent: WO2018/104766, 2018, A1, . Location in patent: Page/Page column 102
[18] Patent: US2005/54850, 2005, A1,
[19] Patent: WO2008/56150, 2008, A1, . Location in patent: Page/Page column 180
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[21] Patent: WO2005/70906, 2005, A1, . Location in patent: Page/Page column 21
[22] Patent: US5128356, 1992, A,
[23] Patent: WO2008/42282, 2008, A2, . Location in patent: Page/Page column 131
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12
[ 116496-81-2 ]
[ 16554-45-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 60℃; for 2 h;
A solution of the nitroacetamide (1.27 mol) in water (1.27 L) was treated with sodium hydroxide (5.07 mol) and the reaction mixture was heated at 60° C. for 2 h. The precipitated solids were collected by filtration, washed with water, and dried to provide the nitroaniline in 85percent yield as an orange solid.
Reference：
[1] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 67
[2] Journal of the Chemical Society, 1926, p. 1319
[3] Letters in Drug Design and Discovery, 2013, vol. 10, # 4, p. 369 - 373
Reference：
[1] Journal of the Chemical Society, 1954, p. 2977
26
[ 16315-07-4 ]
[ 7664-41-7 ]
[ 16554-45-3 ]
Reference：
[1] Chemische Berichte, 1878, vol. 11, p. 2101
[2] Chem. Zentralbl., 1908, vol. 79, # II, p. 1826
27
[ 116496-81-2 ]
[ 15969-08-1 ]
[ 16554-45-3 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 1319
28
[ 16554-45-3 ]
[ 112970-44-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
[2] Bulletin of the Chemical Society of Japan, 1978, vol. 51, p. 2437 - 2438
29
[ 16554-45-3 ]
[ 113206-03-4 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
b) 2-Chloro-1-methoxy-3-nitro-benzene; To a mixture consisting of 15.5g (92. 26mmol) 2-methoxy-6-nitro-phenylamine, 31 ml water and 31ml conc. HCI, a solution of 6.36g (92. 26mmol) NaNO2 in 38ml water is slowly added dropwise at-10C-0C. After stirring for 0.5h the mixture is slowly added to a solution of 11.88g (120mol) CuCI in 93ml conc. HCI. After completion of the addition stirring is continued for 1.5h at room temperature and for 0.5h at reflux temperature. The reaction mixture is allowed to cool to room temperature and is poured on water and extracted (3x) with ethyl acetate. The combined organic layers are washed with water (2x) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash- chromatography on silica gel (hexane: EtOAc = 3: 1) to afford 12. 6g of the title compound as a crystalline solid.
16.5 g
INTERMEDIATE: (5-Methoxy-3-methyl-quinoxalin-2-yl)-hydrazine (lie). 2-Methoxy-6-nitro- phenylamine (25.0 g) was dissolved in 37% aq HC1, and the mixture ws cooled on an ice/water bath. A solution of NaN02 (11.8 g) in water (3 mL) was added, and the resulting mixture was stirred at 0 C for 15 min. The reaction mixture was added to a solution of cuprous monochloride (14.7 g) in 37% aq HC1 (10 mL) under stirring at 45-50 C. The resulting mixture was stirred at 50 C for 15 min, cooled at 5 C for 15 min. The solid was filtered off and dried to give 2-chloro-l-methoxy-3- nitrobenzene (16.5 g). A mixture of 16 g of this material, racemic alanine (17 g), and K2CO3 (12 g) was heated in DMSO (180 mL) at 100 C for 24h. The volatiles were removed using a freeze dryer. The residue was acidified with 2M aq HC1 (50 mL) and extracted into EtOAc. The organic extract was extracted with 2M aq Na2C03 and water. The combined aq extracts were acidified with 2M aq HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenylamino)-propionic acid. This material was dissolved in ethanol (600 mL) and 96%> sulphuric acid (6 mL) was added. The mixture was heated at 80 C overnight. The volatiles were removed in vacuo and the residue was dissolved in EtOAc and washed with 2M aq Na2C03. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenylamino)-propionic acid ethyl ester (8.0 g). This material was dissolved in ethanol (300 mL) and 5% palladium on carbon was added. The mixture was treated with 3 bars of hydrogen pressure on a Parr shaker for 3h. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 5-methoxy-3-methyl-3,4-dihydro- lH-quinoxalin-2-one (3.0 g). This material was dissolved in ethanol (300 mL) and treated with 30% aq hydrogen peroxide at 80 C overnight. Most of the volatiles were removed in vacuo. The residue was suspended in ethanol (10 mL) and cooled on an ice/water bath before the solid was filtered off, washed with ice-cold ethanol, and dried to afford 5-methoxy-3-methyl-lH-quinoxalin-2-one (2.2 g). This material was dissolved in phosphoryl chloride (24 mL) and heated at 130 C for 2h. The volatiles were removed in vacuo. The residue was partitioned between chloroform and ice + 2M aq NaOH. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 2- chloro-5-methoxy-3-methyl-quinoxaline (2.5 g). This material was dissolved in ethanol (22 mL), hydrazine hydrate (2.9 mL) was added, and the mixture was refluxed for 2h. The volatiles were removed in vacuo, and water was added. The solid was filtered off, washed with water and heptanes and dried to afford lie (1.70 g) sufficiently pure for the next step.
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
At room temperature, to a solution of 2-methoxy-6-nitroaniline (4.75 g, 28.25 minol) in methanol (150 mL) was added Pd/C (10%, 500 mg) under nitrogen atmosphere. The reaction flask was vacuumed and flushed with hydrogen. The reactionminxture was hydrogenated for 2 h at room temperature under H2 atmosphere using a hydrogen balloon. When the reaction was done, the reactionminxture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to yield 3-methoxybenzene-1,2-diamine as dark red oil (3.66 g, 94%). MS: m/z = 139.1 [M+Hj.
78%
With hydrogenchloride; tin(II) chloride dihdyrate; In ethanol; water; at 20℃;
General procedure: The respective nitrobenzene derivative (1 eq) was dissolved in EtOH and concentrated hydrochloric acid (each 1 ml/mmol) before slowly adding a suspension of tinn(II) chloride dihydrate (4-5 eq) in concentrated hydrochloric acid (~1-1.5 ml/mmol). After stirring at room temperature for 2-5 h, the reaction mixture was basified to a pH of 9 with 6 N sodium hydroxide solution and the formed precipitate was filtered. The filtrate was then extracted with DCM (3×). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and filtered. DCM was removed under reduced pressure. The crude solid was purified by column chromatography (DCM/MeOH, 95:5).
77%
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 2h;
The mixture of 2-methoxy-6-nitroaniline (1, 300mg, 1.78mmol) and 10% Pd/C (60mg) in ethanol (15mL) was stirred under hydrogen atmosphere at room temperature and atmospheric pressure for 2h. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography on silicagel with petroleum ether-AcOEt (v/v=3/1). The title compound 2 (190mg, 77% yield) was obtained as off-white powder. M.p. 77-78C; 1H NMR (CDCl3, 300MHz, delta ppm): 6.68 (1H, t, J=7.8Hz), 6.41 (2H, td, J1=7.5Hz, J2=1.2Hz), 3.84 (3H, s), 3.31 (4H, br s); HRMS (ESI): m/z, calcd. For C7H11N2O [M+H]+ 138.0866, found 138.0870.
With hydrogen;nickel; at 20℃; under 2250.23 Torr;
3-Methoxy-1,2-diaminobenzene was obtained as a brown oil by hydrogenation of 2-methoxy-6-nitroaniline using hydrogen gas and Raney nickel as catalyst at room temperature and a pressure of 3 bar. The product was converted into the thiourea without further purification.
palladium; In ethanol;
REFERENCE EXAMPLE 10 Preparation of 2,3-diaminoanisole. A mixture of 2-methoxy-6-nitroaniline (40.3g) and palladium black (0.45g) in ethanol (500ml) was vigorously stirred at 45C under an atmosphere of hydrogen. After the uptake of hydrogen ceased the catalyst was removed, washed with ethanol and the combined organic solutions evaporated to give the title compound as a brown oil (33.5g,100%) with the H1N.M.R of the oil (CDCl3) giving peaks at d= 3.5 (4H, br, s), 3.85 (3H, s), 6.3 (1H, dd), 6.4 (1H, dd) and 6.7 (1H, t) ppm.
With hydrogen;palladium 10% on activated carbon; In methanol; for 4h;
A mixture of 2-methoxy-6-nitroaniline (1 g, 5.95 mmol), 10% palladium carbon (300 mg) and methanol (25 ml) was stirred in a hydrogen atmosphere for 4 hours. The reaction vessel was purged with nitrogen and a catalyst was removed by filtration. To the reaction mixture, carbon disulfide (15 ml) was added and the mixture was stirred at room temperature overnight. Triethylamine (1 ml) was added to the reaction mixture, which was stirred at 50 C. for 3 hours. After the reaction mixture was concentrated, methanol (2 ml) and diethyl ether (20 ml) were added to the residue. The generated solid was collected by filtration to obtain the title compound (950 mg, yield: 88.6%) as a light orange solid.
400 mg (98%)
palladium; In methanol;
To a solution of 2-amino-3-nitroanisole (465 mg, 2.94 mmol) in methanol (50 mL) was added palladium on carbon (10% Pd, 100 mg). The mixture was then placed under an atmosphere of hydrogen gas (1 atm) and was stirred for one hour. The mixture was then filtered through celite and concentrated to give 2,3-diaminoanisole as a yellow foam in a yield of 400 mg (98%). 1H NMR (CDCl3) delta 3.45 (br s, 4H(NH)), 3.84 (s, 3H), 6.40 (m, 2H), 6.67 (t, 11H, J=7.8 Hz)
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃;
2-Amino-3-nitroanisole (4.3 g) was hydrogenated in ethyl acetate (200 ml) using catalytic 10% palladium on charcoal under an atmosphere of hydrogen at ambient temperature. Once complete the reaction mixture was filtered through Celite and the filtrate evaporated in vacuo to afford the title compound as a brown liquid (3.60 g). TLC Rf 0.65 (ethyl acetate)
With hydrogen;palladium on activated charcoal; In ethanol; for 6.5h;
Step 2: 3-methoxybenzene-l,2-diamine; To a degassed solution of 2-methoxy-6-nitroaniline from step 1 (6.9 g, 41.0 mmol) in EtOH (200 ml) Pd/C (0.873 g, 0.821 mmol) was added, and the mixture was placed under a hydrogen atmosphere (balloon). After 6.5 hours, the reaction was filtered through a CELITE pad, and the filtrate was concentrated to yield the crude title compound as an orange oil (5.6g, 99%).
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
General procedure: In a 250 mL parr shaker vessel, a mixture of the corresponding alkyl substituted nitro aminophenol 3 (3.99 mmol) in methanol (30 mL) was placed and then added 10% Pd-C (20% w/w). The resulting solution was stirred at ambient temperature for 2 h in the presence of hydrogen gas. After completion of the reaction, the mixture was filtered through celite bed and washed with methanol, and then the filtrate was evaporated under vacuum to afford the title compounds. These compounds were used for the next step without further purification.
2.5 g
With palladium 10% on activated carbon; hydrogen; In ethanol; at 0.1 - 0.35℃; for 3h;Inert atmosphere;
To a solution of 2-methoxy-6-nitroaniline (3.0 g) in EtOH (30 mL) was added 10% Pd/C (50% wet) (0.3 g) under nitrogen atmosphere, and then the reaction system was replaced with hydrogen and stirred at room temperature for 3 hours. Insoluble substances were filtered, and then the filtrate was concentrated under reduced pressure to give 3-methoxybenzene-1,2-diamine (2.5 g).
A solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold (0-5 C.) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90 C. for 2 h). The reaction mixture was maintained for 40 min and was filtered. The filtrate was added dropwise to a cold (0-5 C.) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 min. The reaction mixture was warmed to 60 C. and was maintained for 30 min. The reaction mixture was warmed to reflux and was maintained for 1 h. The reaction mixture was diluted with water (2 L) and was extracted with dichloromethane (3*1 L). The combined organic layers were washed with 10% sodium hydroxide (1.0 L), water (2.0 L), 10% hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethanol to provide the bromide in 50% yield as a yellow solid.
With N-chloro-succinimide; In acetonitrile; at 20 - 60℃; for 18h;Heating / reflux;
To a solution of the title compound of Example 21, Step A (26.6 mmol, 4.5 g) in MeCN (30 mL) at 60 C was added N-chlorosuccinimide (29 mmol, 3.9 g). The solution was brought to reflux for 2 h and allowed to stand at ambient temperature for 16 h. The reaction mixture was partitioned between CH2C12 and saturated NaHC03. The organic phase was washed with brine, dried with Na2SO4, and concentrated in vacuo to afford the product as a brown solid. LC-MS (ESI, Method B): 2.14 min, m/z 203.11 (M + 1).
With N-Bromosuccinimide In dichloromethane at 20℃; Inert atmosphere;
21.A 4-bromo-2-methoxy-6-nitroaniline
To a solution of 2-methoxy-6-nitroaniline (2.8 g, 16.65 mmol) in dry DCM (90 mL) at room temperature under nitrogen was added NBS (3.85 g, 21.65 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to obtain 4-bromo-2-methoxy-6- nitroaniline (4.01 g, 16.23 mmol, 97 % yield). 1H NMR (400MHz, CHLOROFORM-d) δ 7.91 (d, J=2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.47 (br. s., 2H), 3.94 (s, 3H); LC/MS (ESI) m/e 247.0, 249.0 Br pattern [(M+H)+, calcd for C7H8BrN203 247.0].
97%
With bromine; sodium acetate; acetic acid at 20℃;
1 4-bromo-2-methoxy-6-nitroaniline
2-methoxy-6-nitrophenylamine (5.0 g, 29.8 mmol) was dissolved in AcOH (70 mL) and NaOAc (2.69 g, 32.8 mmol) was added. Br2 (2.4 mL, 48 mmol) was then added slowly while stirring at room temperature, and a precipitate formed. After stirring for 1 hour, water was added. The solid was then filtered, and washed with water to yield 4-bromo-2-methoxy-6- nitroaniline (7.2 g, 29.0 mmol, 97%) as an orange solid. LC/MS m/z calculated for [M+H]+ 247.0, found 247.0.
95%
With bromine; sodium acetate; acetic acid at 20℃; for 0.333333h;
1 4-Bromo-2-methoxy-6-nitroaniline
4-Bromo-2-methoxy-6-nitroanilineTo a solution of 2-methoxy-6-nitroaniline (35 g, 208 mmol) in Acetic Acid (500 ml_),NaOAc (27.3 g, 333 mmol) and bromine (11.80 ml_, 229 mmol) were added. Then the reaction mixture was stirred at RT for 20 min. The resulting precipitate was filtered and washed with water and dried in-vacuum pump to give 50 g (95%) of the title compound. LC-MS m/z 248.9 (M+H)+, 1.78 (ret. time).
95%
With bromine; sodium acetate In acetic acid at 20℃; for 0.333333h;
95%
With bromine; sodium acetate; acetic acid at 20℃; for 0.333333h;
Intermediate 5 4-Bromo-2-methoxy-6-nitroaniline
Intermediate 5 4-Bromo-2-methoxy-6-nitroaniline To a solution of 2-methoxy-6-nitroaniline (35 g, 208 mmol) in acetic acid (500 mL), sodium acetate (27.3 g, 333 mmol) and bromine (1 1 .80 mL, 229 mmol) were added. Then the reaction mixture was stirred at ambient temperature for 20 minutes. The resulting precipitate was filtered and washed with water and dried in-vacuum pump to give 50 g (95%) of the title compound. LC-MS m/z 248.9 (M+H+2)+, 1 .78 min (ret. time).
88%
With bromine; sodium acetate In acetic acid at 20℃; for 0.333333h;
84%
With bromine; sodium acetate; acetic acid at 20℃; for 0.5h;
15 4-Bromo-2-methoxy-6-nitroaniline
To a solution of 2-methoxy-6-nitroaniline (2.26 g, 13.44 mmol) dissolved in acetic acid (50 mL) was added sodium acetate (1.654 g, 20.16 mmol) and bromine (0.762 mL, 14.78 mmol) and themixture was stirred at ambient temperature for 30 mm. Water was added (75 mL) to quench the reaction and the precipitate product was collected by filtration, washed with water and dried over vacuum to give 2.78 g of 4-bromo-2-methoxy-6-nitroaniline (84 %). LC-MS m/z 246.9/248.9 (M+H), 0.93 mm (ret. time).
84%
With bromine; sodium acetate; acetic acid at 20℃; for 0.5h;
84%
With bromine; sodium acetate; acetic acid at 20℃; for 0.5h;
15 4-Bromo-2-methoxy-6-nitroaniline
To a solution of 2-methoxy-6-nitroaniline (2.26 g, 13.44 mmol) dissolved in acetic acid (50 mL) was added sodium acetate (1.654 g, 20.16 mmol) and bromine (0.762 mL, 14.78 mmol) and the mixture was stirred at ambient temperature for 30 min. Water was added (75 mL) to quench the reaction and the precipitate product was collected by filtration, washed with water and dried over vacuum to give 2.78 g of 4-bromo-2-methoxy-6-nitroaniline (84 %). LC-MS m/z 246.9/248.9 (M+H)+, 0.93 min (ret. time).
83%
With bromine; sodium acetate In acetic acid at 20℃; for 0.333333h;
III; 6.b
NaOAc (17.6 g) and Br2 (6.76 mL) was added to a solution of 2-methoxy-6-nitrobenzenamine (21.74 g) in HOAc (250 mL). The mixture was stirred at room temperature for 20 min. The resulting precipitate was filtered, washed with water and dried in-vacuo to afford the desired product as a yellow solid (26.43 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.18 (d, 1H, J=1.8 Hz), 7.70 (d, 1H, J=1.8 Hz); LC-MS: m/e=247 [M+1]+.
80%
With N-Bromosuccinimide In dichloromethane at 20℃;
39 EXAMPLE 39 - 4-Methoxy-6-morpholino-N-phenethyl-1H-benzo[d]imidazole-1- carboxamide
To a solution of 2-methoxy-6-nitrobenzenamine (1.0 g, 0.60 mmol) in DCM (2.0 mL) was added NBS (0.11 g, 0.60 mmol). The mixture was stirred overnight at RT and purified by flash column chromatography to give 4-bromo-2-methoxy-6-nitrobenzenamine (1.20 g, 80%) as a brick-red solid. LC-MS m/z: 248.9 [M+H]+. HPLC Purity (254 nm): 95%; tR = 2.58 min.
With bromine; sodium acetate; acetic acid for 0.333333h;
4-Bromo-2-methoxv-6-nitro-phenvlamine; Sodium acetate (3.37 g) and bromine (1.3 ml) are added to a solution of 2-methoxy-6- nitrophenylamine (4.16 g) in acetic acid (50 ml). After 20 minutes. the resultant precipitate is filtered off, washed with water and dried in vacuo to give the title compound as an orange solid.
With bromine; sodium acetate In acetic acid at 20℃; for 0.25h;
INTERMEDIATE (7-Bromo-5 -methoxy-3 -methyl-quinoxalin-2-yl)-hydrazine (Ilq). 2-Amino-3-nitrophenol (25 g) and NaOH (25.0 g) were dissolved in a mixture of THF (500 mL) and water (200 mL). TBAI (2.5 g) and methyl iodide (21.2 mL) were added. The mixture was stirred overnight at ambient temperature. Most of the THF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-methoxy-6-nitro-phenyl amine (29.4 g). 22 g of this material and NaOAc (17.8 g) were mixed in acetic acid (300 mL) at ambient temperature. Bromine (6.9 mL) in acetic acid (5 mL) was added drop-wise over 15 min. The precipitated solid was filtered off, washed with water and heptanes, and dried to afford 4-bromo-2-methoxy-6-nitro-phenylamine (25.5 g). 2.47 g of this material dissolved in DCM (100 mL). DMAP (1.22 g) and Boc20 (2.62 g) were added, and the mixture was overnight at ambient temperature. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc). Fractions containing the desired material were pooled and most of the EtOAc was removed in vacuo. The residual solution was diluted with heptanes, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitated solid was filtered off and dried to afford (4-bromo- 2-methoxy-6-nitro-phenyl)-iminocarbonicacid-bis-(tert-butyl ester) (3.94 g). A larger portion of this material (25.6 g) prepared in a similar manner was dissolved in ethanol (700 mL). 5% Platinum on charcoal (4.0 g) was added, and the mixture was treated with hydrogen gas (1 bar) for 45 min using a Parr shaker instrument. The catalyst was filtered off. The filtrate was concentrated in vacuo. The residual solid was suspended in heptanes, filtered, and dried to afford 6-amino-4-bromo-2-methoxy- phenyl)-iminocabonicacid-bis (fert-butyl ester) (22.0 g). This material was dissolved in DCM (250 mL) and treated with TFA (5 mL) overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M aq NaOH (until pH was 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford the mono-deprotected material (ca 11 g). This material was dissolved in a mixture of DCM (100 mL) and TFA (50 mL) and stirred overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M NaOH (until pH 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 5-bromo-3-methoxy-benzene-l,2-diamine (3.63 g). This material was dissolved in methanol (200 mL). 2-Oxo-propanoic acid methyl ester (2.0 g) was added, and the mixture was stirred overnight at ambient temperature. The precipitated 7-bromo-5-methoxy-3- methyl-lH-quinoxalin-2-one was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford more 7-bromo- 5-methoxy-3-methyl-lH-quinoxalin-2-one as the first eluting isomer followed by 6-bromo-8- methoxy-3-methyl-lH-quinoxalin-2-one as the second eluting isomer. The two crops of 7-bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one were mixed and washed with a little acetone to afford 7- bromo-5-methoxy-3 -methyl- lH-quinoxalin-2-one (1.7 g) sufficiently pure for the next step. The fractions containing the second eluting isomer were pooled and concentrated in vacuo; the residual solid was washed with a little acetone to afford 6-bromo-8-methoxy-3-methyl-lH-quinoxalin-2-one (0.61 g) sufficiently pure for the next step. The structure of the isomers were elucidated by identifying the nitrogen carrying a proton by 2D HSQC and comparing with the shift of the nitrogen having long range correlation to an aromatic proton in 2D HMBC. 7-Bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) was refluxed in phosphoryl chloride (23 mL) for 2h. The volatiles were removed in vacuo. The residue was partitioned between DCM and ice/water. The mixture was basified with 2M aq Na2C03. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 7-bromo-2-chloro-5-methoxy-3-methyl-quinoxaline (0.61 g). This material was dissolved in ethanol (38 mL). Hydrazine hydrate (3 mL) was added and the mixture was refluxed for 2h. The volatiles were removed in vacuo. The residual solid was suspended in water, filtered off, washed with heptanes, and dried to afford Ilq (0.58 g) sufficiently pure for the next step.
25.5 g
With bromine; sodium acetate; acetic acid at 20℃; for 0.25h;
INTERMEDIATE 6-Bromo-8-methoxy-3-methyl-quinoxalin-2-yl)-hydrazine (Ilf). 2-Amino-3-nitrophenol (25 g) and NaOH (25.0 g) were dissolved in a mixture of THF (500 mL) and water (200 mL). TBAI (2.5 g) and methyl iodide (21.2 mL) were added. The mixture was stirred overnight at ambient temperature. Most of the THF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-methoxy-6-nitro-phenyl amine (29.4 g). 22 g of this material and NaOAc (17.8 g) were mixed in acetic acid (300 mL) at ambient temperature. Bromine (6.9 mL) in acetic acid (5 mL) was added drop-wise over 15 min. The precipitated solid was filtered off, washed with water and heptanes, and dried to afford 4-bromo-2-methoxy-6-nitro- phenylamine (25.5 g). 2.47 g of this material dissolved in DCM (100 mL). DMAP (1.22 g) and B0C2O (2.62 g) were added, and the mixture was overnight at ambient temperature. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc). Fractions containing the desired material were pooled and most of the EtOAc was removed in vacuo. The residual solution was diluted with heptanes, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitated solid was filtered off and dried to afford (4-bromo-2-methoxy-6-nitro-phenyl)-iminocarbonicacid-bis-(tert-butyl ester) (3.94 g). A larger portion of this material (25.6 g) prepared in a similar manner was dissolved in ethanol (700 mL). 5% Platinum on charcoal (4.0 g) was added, and the mixture was treated with hydrogen gas (1 bar) for 45 min using a Parr shaker instrument. The catalyst was filtered off. The filtrate was concentrated in vacuo. The residual solid was suspended in heptanes, filtered, and dried to afford 6-amino-4-bromo-2-methoxy-phenyl)-iminocabonicacid-bis (tert- butyl ester) (22.0 g). This material was dissolved in DCM (250 mL) and treated with TFA (5 mL) overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M aq NaOH (until pH was 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford the mono-deprotected material (ca 11 g). This material was dissolved in a mixture of DCM (100 mL) and TFA (50 mL) and stirred overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M NaOH (until pH 9). The organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford 5-bromo-3-methoxy-benzene-l,2-diamine (3.63 g). This material was dissolved in methanol (200 mL). 2-Oxo-propanoic acid methyl ester (2.0 g) was added, and the mixture was stirred overnight at ambient temperature. The precipitated 7-bromo-5-methoxy-3-methyl-lH- quinoxalin-2-one was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford more 7-bromo-5-methoxy- 3-methyl-lH-quinoxalin-2-one as the first eluting isomer followed by 6-bromo-8-methoxy-3- methyl-lH-quinoxalin-2-one as the second eluting isomer. The two crops of 7-bromo-5-methoxy- 3-methyl-lH-quinoxalin-2-one were mixed and washed with a little acetone to afford 7-bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) sufficiently pure for the next step. The fractions containing the second eluting isomer were pooled and concentrated in vacuo; the residual solid was washed with a little acetone to afford 6-bromo-8-methoxy-3-methyl-lH-quinoxalin-2-one (0.61 g) sufficiently pure for the next step. The structure of the isomers were elucidated by identifying the nitrogen carrying a proton by 2D ^N-'H HSQC and comparing with the shift of the nitrogen having long range correlation to an aromatic proton in 2D ^N-'H HMBC. 6-bromo- 8-methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) was dissolved in phosphoryl chloride (23 mL) was refluxed for 2h. The volatiles were removed in vacuo. The residue was partitioned between DCM and a little ice. The biphasic mixture was basified with 2M aq Na2C03 and was filtered. The organic part of the filtrate was dried over MgSO i, filtered, and concentrated in vacuo to afford 7- bromo-3-chloro-5-methoxy-2-methyl-quinoxaline (1.1 g). This material was dissolved in ethanol (38 mL). Hydrazine hydrate (3 mL) was added, and the mixture was refluxed for 2h. The volatiles were removed in vacuo. The residue was suspended in water (50 mL). The solid was filtered off, washed with heptanes and dried to afford Ilf (1.6 g) sufficiently pure for the next step.
11.77 g
With N-Bromosuccinimide In acetonitrile at 70℃; for 4h;
45B.D D) 4-Bromo-2-methoxy-6-nitroaniline
D) 4-Bromo-2-methoxy-6-nitroaniline To a solution of 2-methoxy-6-nitroaniline (9.12 g) in acetonitrile (100 mL), N-bromosuccinimide (10.8 g) was added at room temperature, and the mixture was stirred at 70°C for 4 hours. An aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature. The deposited solid was collected by filtration and washed with water and hexane to obtain the title compound (11.77 g). 1H NMR (300MHz, DMSO-d6) δ 3.91 (3H, s), 7.20 (1H, d, J = 2.1 Hz), 7.25 (2H, brs), 7.72 (1H, d, J = 2.1 Hz).
With iodine; silver sulfate In ethanol at 20℃; for 2h;
With iodine; silver sulfate; acetic acid at 60℃; for 12h;
30.c
c) 4-lodo-2-methoxy-6-nitro-phenylamine; A mixture of 6.2g (36. 9mmol) 2-methoxy-6-nitro-phenylamine, 9.4g (37mmol) iodine and 5. 8g (18. 5mmol) silver sulfate in 90ml glacial acetic acid is stirred at 60°C for 12h. The reaction mixture is cooled to room temperature, poured on water and extracted (3x) with ethyl acetate. The combined organic layers are washed with water (2x) and brine, dried over MgS04, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane : EtOAc = 2: 1) to afford 8.57g of the title compound as bright red crystals.
(1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-aminobutan-4-yl)-amine[ No CAS ]
[ 16554-45-3 ]
Yield
Reaction Conditions
Operation in experiment
465 mg (29%)
In water; ethyl acetate; N,N-dimethyl-formamide;
Example 99 Compound 99: Preparation of (1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-aminobutan-4-yl)-amine To a 0 C. solution of potassium t-butoxide (5.87 g, 52.3 mmol) in DMF (40 mL) under an inert atmosphere of argon was added copper (I) chloride (0.2 g, 2.0 mmol). The resulting suspension was stirred for 10 minutes, then a solution of 3-nitroanisole (1.55 g, 10.1 mmol) and methoxylamine hydrochloride (1.08 g, 12.9 mmol) in DMF (15 mL) was added in a dropwise manner over 15 minutes. The mixture was then allowed to slowly warm to room temperature and was stirred for 48 hours. Water (20 mL) was then added to the reaction, and the mixture was poured into a separatory funnel containing 100 mL ethyl acetate. The aqueous and organic layers were then separated, and the organic layer was extracted 5 times with 20 mL portions of water. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography using a 3:1 hexanes:ethyl acetate mixture as an eluent. Three isomeric products were isolated consecutively from the column, the first being the desired 2-amino-3-nitroanisole, which was isolated as an orange powder in a yield of 465 mg (29%). 1H NMR (CDCl3) delta 3.95 (s, 3H), 6.44 (br s, 2H (NH)), 6.61 (dd, 1H, J=7.8, 7.1 Hz), 6.87 (d, 1H, J=7.1 Hz), 7.73 (d, 1H, J=7.8 Hz)
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In N,N-dimethyl-formamide; at 115℃; for 0.5h;Microwave irradiation; Inert atmosphere; Sealed tube;
Step 7: Synthesis of 6-(2,6-dichloro-3 ,5-dimethoxyphenyl)-N- (2-methoxy-6- nitrophenyl)quinazolin-2-amine. 2-Chloro-6-(2,6-dichloro-3 ,5-dimethoxyphenyl)quinazoline (35) (100 mg, 0 .27mmol), 2-methoxy-6-nitroaniline (36) (57 mg, 0.40 mmol), Cs2CO3 (176 mg, 0.54 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), and 2-Dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (Xphos) (26 mg, 0.054 mmol) were taken up in DMF (3 ml) in a microwave vial and purged with N2 for 5 minutes. The vial was capped and heated to 115C in microwave for 30 minutes. After cooling to room temperature the reaction mixture was diluted with DCM and washed with brine threetimes. The organic mixture was dried over sodium sulfate and loaded directly onto silica gel and purified using 0-100% EtOAc/Hexanes gradient. 6- (2,6-dichloro-3 ,5-dimethoxyphenyl)-N- (2- methoxy-6-nitrophenyl)quinazolin-2-amine (37) was recovered as a yellow solid (100 mg, 73% yield). MS (ES+) C23H18C12N405, 501 [M + H].
Multi-step reaction with 3 steps
1.1: acetic acid; sodium acetate; bromine / 0.33 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3.1: acetic acid; zinc / 0.33 h / 20 °C
3.2: 0.5 h / 4 °C
Multi-step reaction with 4 steps
1: acetic acid; sodium acetate; bromine / 0.33 h / 20 °C
2: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3: acetic acid; zinc / 10 h / 20 °C
4: sulfuric acid; sodium nitrite / 0.83 h / 0 °C
Multi-step reaction with 4 steps
1.1: sodium acetate; bromine / acetic acid / 0.33 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
2.2: 0.5 h / 0 °C
3.1: zinc; acetic acid / 10 h / 20 °C
4.1: sulfuric acid; sodium nitrite / water / 0.83 h / 0 °C
Multi-step reaction with 4 steps
1.1: acetic acid; sodium acetate; bromine / 0.33 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
2.2: 0.5 h
3.1: acetic acid; zinc / 10 h / 20 °C
4.1: sulfuric acid; sodium nitrite / water / 0.83 h / 0 °C
Multi-step reaction with 3 steps
1.1: bromine; acetic acid; sodium acetate / 0.5 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3.1: acetic acid; zinc / 3 h / 20 °C
3.2: 1.75 h / 0 °C
Multi-step reaction with 3 steps
1.1: bromine; sodium acetate; acetic acid / 0.5 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3.1: zinc; acetic acid / 3 h / 20 °C
3.2: 1.75 h / 0 °C
Multi-step reaction with 3 steps
1.1: bromine; acetic acid; sodium acetate / 0.5 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3.1: acetic acid; zinc / 3 h / 20 °C
3.2: 1.75 h / 0 °C
Multi-step reaction with 4 steps
1.1: bromine; sodium acetate / acetic acid / 0.33 h / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C
3.1: tin(II) chloride hydrate / ethanol / 2 h / 75 °C
3.2: pH 14
4.1: sodium nitrite; sulfuric acid / 0.83 h / 0 °C
Multi-step reaction with 4 steps
1.1: bromine; sodium acetate; acetic acid / 20 °C
2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C
2.2: 0.58 h
3.1: acetic acid; zinc / 1 h / 20 °C
4.1: sulfuric acid; sodium nitrite / water / 1 h / 0 °C
Multi-step reaction with 3 steps
1.1: sodium nitrite; hydrogenchloride / water; acetonitrile / 0.25 h / 20 °C
1.2: 3 h / 60 °C
2.1: ammonium chloride; iron / water; ethanol / 12 h / 95 °C
3.1: hydrogen bromide; sodium nitrite / water; acetonitrile / 0.5 h / 20 °C
3.2: 60 °C
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