* 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 caesium carbonate In DMF (N,N-dimethyl-formamide) at 18 - 22℃;
The nitrophenol starting material C2 (1.3 g; 7.49 MMOL) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 MMOL), followed by Mel (1. 4 mL; 22. 5 MMOL). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 ML), washed with water (150 mL), brine (4x 100 mL), and then dried over (MGSO4) THE organic phase was filtered and evaporated to afford the crude 2- CHLORO-3-NITROANISOLE C3 (98percent; 1.38 g) as an orange solid. Homogeneity by HPLC (TFA) 220 nm: 93percent.
98%
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
Step B:; The nitrophenol starting material 1c1 (1.3 g; 7.49 mmol) was dissolved inDMF (10 ml) and to this solution was added ground cesium carbonate (2.92 g; 8.96mmol), followed by Mel (1.4 ml; 22.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated in vacuo and the residue taken upin ether (150 ml), washed with water (150 ml), brine (4 X 100 mL), and then driedover (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 1c2 (98percent; 1.38 g) as an orange solid.
98%
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;
The nitrophenol starting material 1c1 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by MeI (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4.x.100 mL), and then dried over (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 1c2 (98percent; 1.38 g) as an orange solid.
98%
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
The nitrophenol starting material 2c1 (1.3 g; 7.49 mmol) was dissolved inDMF (10 ml) and to this solution was added ground cesium carbonate (2.92 g; 8.96mmol), followed by Mel (1.4 ml; 22.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated in vacua and the residue taken upin ether (150 ml), washed with water (150 ml), brine (4 X 100 ml), and then driedover (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 2c2 (98percent; 1.38 g) as an orange solid.Homogeneity by HPLC (TFA) (at) 220nm: 93percent.
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
4
[ 603-84-9 ]
[ 77-78-1 ]
[ 3970-39-6 ]
Reference：
[1] Journal of the American Chemical Society, 1939, vol. 61, p. 2828
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
2-Chloro-3-nitroanisole C3 (1.38 g; 7.36 MMOL) was dissolved in a mixture of glacial acetic acid (19 ML)/ETHANOI (19 mL). To this solution was added iron powder (1.64 g; 29.4 MMOL). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 mL), neutralized with solid NA2CO3 and the product extracted with CH2CI2 (3X 150 mL). The extracts were combined and washed with saturated. brine and then dried over (NA2SO4), filtered and concentrated in vacuo to afford the crude product, 2-chloro-3-methoxyaniline C4 (100percent; 1.2 g) as a yellow oil. This material was used as such in the following steps. MS 157.9 (MH) + ; Homogeneity by HPLC (TFA) 220 nm: 86percent.
100%
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
Step C:; 2-Chloro-3-nitroanisole 1c2 (1.38 g; 7.36 mmol) was dissolved in a mixture ofglacial acetic acid (19 mL)/ethanol (19 mL). To this solution was added iron powder(1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. Thereaction mixture was diluted with water (70 ml_), neutralized with solid Na2CO3 and theproduct extracted with CH2CI2 (3 X 150 ml). The extracts were combined and washedwith sat. brine and then dried over (Na2SO4), filtered and concentrated in vacua toafford the crude product, 2-chloro-3-methoxyaniline 1c3 (100percent; 1.2 g) as a yellow oil.This material was used as such in the following steps. MS 157.9 (MH)+; Homogeneityby HPLC (TFA) (at) 220nm: 86percent.
100%
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
2-Chloro-3-nitroanisole 1c2 (1.38 g; 7.36 mmol) was dissolved in a mixture of glacial acetic acid (19 mL)/ethanol (19 mL). To this solution was added iron powder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2 (3*150 mL). The extracts were combined and washed with sat. brine and then dried over (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-chloro-3-methoxyaniline 1c3 (100percent; 1.2 g) as a yellow oil. This material was used as such in the following steps. MS 157.9 (MH)+; Homogeneity by HPLC (TFA)at;220 nm: 86percent.
100%
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
2-Chloro-3-nitroanisole 2c2 (1.38 g; 7.36 mmol) was dissolved in a mixtureof glacial acetic acid (19 ml_ )/ethanol (19 ml_). To this solution was added ironpowder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and workedup. The reaction mixture was diluted with water (70 ml), neutralized with solidNa2CO3 and the product extracted with CH2CI2( 3X 150 ml). The extracts werecombined and washed with sat. brine and then dried over (Na2SO4), filtered andconcentrated in vacua to afford the crude product, 2-chloro-3-methoxyaniline 2c3(100percent; 1.2 g) as a yellow oil. This material was used as such in the following steps.MS 157.9 (MH)+; Homogeneity by HPLC (TFA) (at) 220nm: 86percent.
Reference：
[1] Patent: WO2004/103996, 2004, A1, . Location in patent: Page 42-43
[2] Patent: WO2006/7700, 2006, A1, . Location in patent: Page/Page column 62
[3] Patent: US2006/19905, 2006, A1, . Location in patent: Page/Page column 25
[4] Patent: WO2006/85, 2006, A1, . Location in patent: Page/Page column 77-78
[5] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
[6] Journal of the Chemical Society, 1950, p. 1481,1483
[7] Chemische Berichte, 1893, vol. 26, p. 2467
[8] Patent: WO2010/125103, 2010, A1, . Location in patent: Page/Page column 104
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
2-Chloro-3-nitroanisole C3 (1.38 g; 7.36 MMOL) was dissolved in a mixture of glacial acetic acid (19 ML)/ETHANOI (19 mL). To this solution was added iron powder (1.64 g; 29.4 MMOL). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 mL), neutralized with solid NA2CO3 and the product extracted with CH2CI2 (3X 150 mL). The extracts were combined and washed with saturated. brine and then dried(NA2SO4), filtered and concentrated in vacuo to afford the crude product, 2-chloro-3-methoxyaniline C4 (100%; 1.2 g) as a yellow oil. This material was used as such in the following steps. MS 157.9 (MH) + ; Homogeneity by HPLC (TFA) 220 nm: 86%.
100%
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
Step C:; 2-Chloro-3-nitroanisole 1c2 (1.38 g; 7.36 mmol) was dissolved in a mixture ofglacial acetic acid (19 mL)/ethanol (19 mL). To this solution was added iron powder(1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. Thereaction mixture was diluted with water (70 ml_), neutralized with solid Na2CO3 and theproduct extracted with CH2CI2 (3 X 150 ml). The extracts were combined and washedwith sat. brine and then dried(Na2SO4), filtered and concentrated in vacua toafford the crude product, 2-chloro-3-methoxyaniline 1c3 (100%; 1.2 g) as a yellow oil.This material was used as such in the following steps. MS 157.9 (MH)+; Homogeneityby HPLC (TFA) (at) 220nm: 86%.
100%
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
2-Chloro-3-nitroanisole 1c2 (1.38 g; 7.36 mmol) was dissolved in a mixture of glacial acetic acid (19 mL)/ethanol (19 mL). To this solution was added iron powder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2 (3*150 mL). The extracts were combined and washed with sat. brine and then dried(Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-chloro-3-methoxyaniline 1c3 (100%; 1.2 g) as a yellow oil. This material was used as such in the following steps. MS 157.9 (MH)+; Homogeneity by HPLC (TFA)a220 nm: 86%.
100%
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
2-Chloro-3-nitroanisole 2c2 (1.38 g; 7.36 mmol) was dissolved in a mixtureof glacial acetic acid (19 ml_ )/ethanol (19 ml_). To this solution was added ironpowder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and workedup. The reaction mixture was diluted with water (70 ml), neutralized with solidNa2CO3 and the product extracted with CH2CI2( 3X 150 ml). The extracts werecombined and washed with sat. brine and then dried(Na2SO4), filtered andconcentrated in vacua to afford the crude product, 2-chloro-3-methoxyaniline 2c3(100%; 1.2 g) as a yellow oil. This material was used as such in the following steps.MS 157.9 (MH)+; Homogeneity by HPLC (TFA) (at) 220nm: 86%.
With iron; acetic acid; at 45 - 80℃; for 2.0h;
(iii) Iron powder (3.63 g, 65.0 mmol) was suspended in acetic acid (50 ml) and warmed to 4O0C with mechanical stirring. 2-Chloro-3-nitrophenyl methyl ether (2.44 g, 13.01 mmol) dissolved in acetic acid (25 ml) was added at such a rate as to maintain a temperature of 45-5O0C. The mixture was heated at 80 0C for 2 hours after the addition had been completed. The mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% 0.880 ammonia solution. Solids were removed by filtration through celite and the aqueous extracted in to ethyl acetate (x3). The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated to an oil. The crude product was purified by flash-silica gel chromatography, eluting with a 0-100% gradient of ethyl acetate in isohexane to afford 2-chloro-3-(methyloxy)aniline (1.66 g).
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 caesium carbonate; In DMF (N,N-dimethyl-formamide); at 18 - 22℃;
The nitrophenol starting material C2 (1.3 g; 7.49 MMOL) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 MMOL), followed by Mel (1. 4 mL; 22. 5 MMOL). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 ML), washed with water (150 mL), brine (4x 100 mL), and then dried(MGSO4) THE organic phase was filtered and evaporated to afford the crude 2- CHLORO-3-NITROANISOLE C3 (98%; 1.38 g) as an orange solid. Homogeneity by HPLC (TFA) 220 nm: 93%.
98%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step B:; The nitrophenol starting material 1c1 (1.3 g; 7.49 mmol) was dissolved inDMF (10 ml) and to this solution was added ground cesium carbonate (2.92 g; 8.96mmol), followed by Mel (1.4 ml; 22.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated in vacuo and the residue taken upin ether (150 ml), washed with water (150 ml), brine (4 X 100 mL), and then driedover (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 1c2 (98%; 1.38 g) as an orange solid.
98%
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
The nitrophenol starting material 1c1 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by MeI (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4×100 mL), and then dried(MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 1c2 (98%; 1.38 g) as an orange solid.
98%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
The nitrophenol starting material 2c1 (1.3 g; 7.49 mmol) was dissolved inDMF (10 ml) and to this solution was added ground cesium carbonate (2.92 g; 8.96mmol), followed by Mel (1.4 ml; 22.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated in vacua and the residue taken upin ether (150 ml), washed with water (150 ml), brine (4 X 100 ml), and then driedover (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 2c2 (98%; 1.38 g) as an orange solid.Homogeneity by HPLC (TFA) (at) 220nm: 93%.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
3-Nitrophenol (10 g, 72 mmol) was dissolved in hot concentrated hydrochloric acid (100 ml) and cooled rapidly (ice-brine bath) to give a fine suspension. Potassium chlorate (8.8 g, 72 mmol) was dissolved in water (100 ml) and added to the mixture and stirring continued at 0C for 2 hours. The reaction mixture was extracted with ethyl acetate (2X100 ml) and the combined organic extracts washed with water (100 ml), brine (100 ml), dried over sodium sulfate and evaporated in vacuo (water bath temp <45C) to give 2-chloro-3-nitrophenol (not purified) (Rf 0. 38,33% EtOAc/Pet spirit). The crude residue was dissolved in DMF and to this was added potassium carbonate (19.3 g, 140 mmol) and methyl iodide (5.6 ml, 90 mmol). The reaction mixture was stirred overnight at room temperature before diluting with ethyl acetate (200 ml) and washing with water (4X100 ml) and brine (100 ml). The organic phase was dried over sodium sulfate to give 2-chloro-3-nitroanisole (not purified) (Rf 0. 61. 33% EtOAc/Pet spirit). The crude residue obtained was dissolved in 2-aminoethylmorpholine 15.7 ml, 120 mmol) and butanol (50 ml) and heated at 100C for 16 hours under an atmosphere of nitrogen. Excess reagent and solvent were removed in vacuo and the residue diluted with EtOAc (200 ml) and 1M NaOH (100 ml). The organic phase was separated and the remaining aqueous solution extracted with EtOAc (2X100 ml). The organic extracts were combined and washed with brine (100 ml), dried over sodium sulfate, filtered and evaporated. The crude product was columned (silica) using a gradient from petroleum spirit to EtOAc (Rf 0.17, 50% EtOAc/Pet Spirit) to give 2-methoxy-N-(2-morpholinoethyl)-6- nitrobenzenamine (7.0 g, 35% yield over 3 steps). ESMS 282 (M+H).
With potassium carbonate; In acetone; at 70℃; for 4h;
(ii) 2-Chloro-3-nitrophenol (2.61 g, 15.04 mmol) and potassium carbonate (3.12 g, 22.56 mmol) were suspended in acetone (50 ml). Methyl iodide (1.034 ml, 16.54 mmol) was added and the mixture heated at 70 0C for 4 hours. The solids were filtered, washed with acetone and the filtrate concentrated to a solid. The crude product was purified by flash-silica gel chromatography, eluting with a 0-100% gradient of ethyl acetate in isohexane to afford 2-chloro-3-nitrophenyl methyl ether (2.44 g).
2-methoxy-N-(2-morpholinoethyl)-6-nitrobenzenamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
In butan-1-ol; at 100℃; for 16h;
3-Nitrophenol (10 g, 72 mmol) was dissolved in hot concentrated hydrochloric acid (100 ml) and cooled rapidly (ice-brine bath) to give a fine suspension. Potassium chlorate (8.8 g, 72 mmol) was dissolved in water (100 ml) and added to the mixture and stirring continued at 0C for 2 hours. The reaction mixture was extracted with ethyl acetate (2X100 ml) and the combined organic extracts washed with water (100 ml), brine (100 ml), dried over sodium sulfate and evaporated in vacuo (water bath temp <45C) to give 2-chloro-3-nitrophenol (not purified) (Rf 0. 38,33% EtOAc/Pet spirit). The crude residue was dissolved in DMF and to this was added potassium carbonate (19.3 g, 140 mmol) and methyl iodide (5.6 ml, 90 mmol). The reaction mixture was stirred overnight at room temperature before diluting with ethyl acetate (200 ml) and washing with water (4X100 ml) and brine (100 ml). The organic phase was dried over sodium sulfate to give <strong>[3970-39-6]2-chloro-3-nitroanisole</strong> (not purified) (Rf 0. 61. 33% EtOAc/Pet spirit). The crude residue obtained was dissolved in 2-aminoethylmorpholine 15.7 ml, 120 mmol) and butanol (50 ml) and heated at 100C for 16 hours under an atmosphere of nitrogen. Excess reagent and solvent were removed in vacuo and the residue diluted with EtOAc (200 ml) and 1M NaOH (100 ml). The organic phase was separated and the remaining aqueous solution extracted with EtOAc (2X100 ml). The organic extracts were combined and washed with brine (100 ml), dried over sodium sulfate, filtered and evaporated. The crude product was columned (silica) using a gradient from petroleum spirit to EtOAc (Rf 0.17, 50% EtOAc/Pet Spirit) to give 2-methoxy-N-(2-morpholinoethyl)-6- nitrobenzenamine (7.0 g, 35% yield over 3 steps). ESMS 282 (M+H).
With N-ethyl-N,N-diisopropylamine; at 180℃; for 0.416667h;
c) (2-Methoxy-ethyl)- (2-methoxy-6-nitro-phenyl)-amine; A mixture of 7.5g (40mol) <strong>[3970-39-6]2-chloro-1-methoxy-3-nitro-benzene</strong>, 14ml diisopropylethylamine and 35ml 2-methoxyethyl amine is heated (180C oil bath temperature) in a closed steel reactor for 25 min. Then the reaction mixture is cooled to room temperature and is concentrated in vacuo (3 x coevaporation with toluene) to obtain ca. 20g (which contains 85% of the title compound) of a red oil which is used without further purification in the next step.
a. 2,2'-Dichloro-3,3'-dimethoxyhydrazobenzene To a stirred solution of THF (30 ml) and <strong>[3970-39-6]2-chloro-3-methoxynitrobenzene</strong> (10 g, 53.3 mM), was added 50% NaOH (2.5 ml, 62.5 mM) and the resultant solution was heated to 65 C. Zinc dust (8.0 g, 0.12 mM) was added by portions, ensuring that reaction temperature remained below 70 C. Following the addition, the reaction was maintained at 65 C. for 30 minutes. To this mixture was added 10% NaOH (40 ml, 0.1M) and additional zinc dust (10.5 g, 0.16M). The resulting mixture was stirred at 65 C. for 3 hours and then cooled to room temperature. Ether (100 ml) was then added, the mixture stirred, and the ether decanted. This procedure was repeated twice. The ether fractions were combined and dried over MgSO4, filtered, and the solvent was concentrated under reduced pressure. This afforded the titled compound as a solid in quantitative yield and was used in the next step without further purification. MS(CI): 313 (m+1).
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.
To a solution of <strong>[3970-39-6]2-chloro-1-methoxy-3-nitro-benzene</strong> (500 mg, 2.67 mmol) in THF (1 0.0ml) was added bromo(vinyl)magnesium (1.00 M, 8.00 ml, 8.00 mmol) at -78C. Thereaction mixture was stirred at same temperature for 3h. Progress was monitored by TLC.25 The reaction mixture was quenched with the addition of a saturated NH4CI solution (15ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with abrine solution (30 ml), separated and concentrated under reduced pressure.The crudecompound was purified by column chromatography (silica gel, 100-200 mesh, in 2%EtOAc in hexanes) to afford 7 -chloro-6-methoxy-1 H-ind ole Xl-12 (0.15 g) as a white solid.Yield: 30%5 1H NMR (400 MHz, DMSO-d5) o 3.86 (s, 3 H) 6.44 (s, 1 H) 6.92 (d, J=8.80 Hz, 1 H) 7.26(s, 1 H) 7.45 (d, J=8.80 Hz, 1 H) 11.15 (br s, 1 H)
(2-methoxy-6-nitrophenyl)(2-trifluoromethylbenzyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; at 180℃; for 3.5h;
A mixture of BB-6 (1 eq) and BB-5 (8.3 eq) in DIPEA (2 eq) was heated to 180C and stirred for a given temperature (see Table 20). It was partitioned between DCM and water and the org. phase was washed with brine, dried over MgSCh and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); sodium 2,2,2-trifluoroacetate; C35H38NO4P; sodium t-butanolate In 1,4-dioxane at 100℃; for 18h;
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