* 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.
Intermediate 3 : 2-Iodo-4-methoxybenzonitrile; To a solution of 4-methoxy-2-nitrobenzonitrle (5.00 g, 22.46 mmol) in EtOH (93 mL) was added 5percent Pd-C (0.500 g) under nitrogen atmosphere. The resulting mixture was hydrogenated at 1 atm. After stirring for 1 O h, the mixture was filtered through celite, washed with EtOAc/MeOH. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph on SiO2 using 80 to 100 percent gradient of EtOAc in hexanes to afford 4-methoxy-2-amiobenzonitrle (3.23 g, 99percent). 4-Methoxy-2-aminobenzonitrle (1.0 g, 6.58 mmol) was dissolved in a mixture of H2O (7 niL), acetic acid (7 niL), and cone. HCl at rt, followed by addition of a solution Of NaNO2 (0.513 g, 7.43 mmol) in H2O (2 niL) at 0 0C for 5 min. To the above mixture KI (2.18 g, 13.2 mmol) was added and after stirring for 10 h at rt, the resulting mixture was treated with solid NaHSO3 and diluted with water. The product portion was extracted with CH2Cl2, washed with satd. NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 using 10 to 50percent gradient of EtOAc in hexane to provide the example intermediate (1.0 g, 59percent).
Reference:
[1] Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9276 - 9287
[2] Patent: WO2009/65035, 2009, A1, . Location in patent: Page/Page column 66-67
[3] Journal of the Chemical Society, 1947, p. 437,44
[4] Journal of the Chemical Society, 1945, p. 861,864
Reference:
[1] Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9276 - 9287
[2] Journal of the Chemical Society, 1945, p. 861,864
[3] Journal of the Chemical Society, 1947, p. 437,44
5
[ 38469-83-9 ]
[ 38487-91-1 ]
[ 38487-85-3 ]
Reference:
[1] Journal of the Chemical Society, 1948, p. 1759,1765
6
[ 110-86-1 ]
[ 109128-43-0 ]
[ 7732-18-5 ]
[ 98-59-9 ]
[ 38487-85-3 ]
[ 120-92-3 ]
Reference:
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 126,135
With hydrogen;5% palladium over charcoal; In ethanol; under 760.051 Torr; for 10h;
Intermediate 3 : 2-Iodo-4-methoxybenzonitrile; To a solution of 4-methoxy-2-nitrobenzonitrle (5.00 g, 22.46 mmol) in EtOH (93 mL) was added 5% Pd-C (0.500 g) under nitrogen atmosphere. The resulting mixture was hydrogenated at 1 atm. After stirring for 1 O h, the mixture was filtered through celite, washed with EtOAc/MeOH. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph on SiO2 using 80 to 100 % gradient of EtOAc in hexanes to afford 4-methoxy-2-amiobenzonitrle (3.23 g, 99%). 4-Methoxy-2-aminobenzonitrle (1.0 g, 6.58 mmol) was dissolved in a mixture of H2O (7 niL), acetic acid (7 niL), and cone. HCl at rt, followed by addition of a solution Of NaNO2 (0.513 g, 7.43 mmol) in H2O (2 niL) at 0 0C for 5 min. To the above mixture KI (2.18 g, 13.2 mmol) was added and after stirring for 10 h at rt, the resulting mixture was treated with solid NaHSO3 and diluted with water. The product portion was extracted with CH2Cl2, washed with satd. NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 using 10 to 50% gradient of EtOAc in hexane to provide the example intermediate (1.0 g, 59%).
Intermediate 3 : 2-Iodo-4-methoxybenzonitrile; To a solution of 4-methoxy-2-nitrobenzonitrle (5.00 g, 22.46 mmol) in EtOH (93 mL) was added 5% Pd-C (0.500 g) under nitrogen atmosphere. The resulting mixture was hydrogenated at 1 atm. After stirring for 1 O h, the mixture was filtered through celite, washed with EtOAc/MeOH. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph on SiO2 using 80 to 100 % gradient of EtOAc in hexanes to afford 4-methoxy-2-amiobenzonitrle (3.23 g, 99%). 4-Methoxy-2-aminobenzonitrle (1.0 g, 6.58 mmol) was dissolved in a mixture of H2O (7 niL), acetic acid (7 niL), and cone. HCl at rt, followed by addition of a solution Of NaNO2 (0.513 g, 7.43 mmol) in H2O (2 niL) at 0 0C for 5 min. To the above mixture KI (2.18 g, 13.2 mmol) was added and after stirring for 10 h at rt, the resulting mixture was treated with solid NaHSO3 and diluted with water. The product portion was extracted with CH2Cl2, washed with satd. NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 using 10 to 50% gradient of EtOAc in hexane to provide the example intermediate (1.0 g, 59%).
1-(3,5-dimethoxy-phenoxy)-7-methoxy-5-methyl-9b-phenyl-5,9b-dihydro-1<i>H</i>-2a,5-diaza-benzo[<i>a</i>]cyclobuta[<i>c</i>]cycloheptene-2,4-dione[ No CAS ]
With p-toluenesulfonic acid monohydrate; potassium carbonate;copper(l) chloride; In tetrahydrofuran; methanol; butanone; benzene;
EXAMPLE 28 9-Amino-3,4-dihydro-6-methoxyacridin-1(2H)-one <strong>[38487-85-3]2-Amino-4-methoxybenzonitril</strong>e (7.51 g) was suspended in 75 ml of benzene containing 6.0 g of cyclohexane-1,3-dione and 1.1 g of p-toluenesulfonic acid monohydrate. The reaction mixture was brought to reflux, at which time a homogeneous solution was obtained. After 15 minutes a thick precipitate developed, which was stirred in the refluxing solvent for an additional 15 minutes. At the end of this time thin layer chromatography (TLC, hereafter) showed that the starting material had been consumed, so the precipitate was filtered off, taken up in 2-butanone, and washed with sodium bicarbonate solution. The organic phase was dried and evaporated to a solid, which was triturated with ether to give 10.61 g of the enamine, mp 194-196 C. This material was suspended in 250 ml of tetrahydrofuran to which was then added 11.9 g of milled potassium carbonate and 0.85 g of CuCl. The reaction mixture was then refluxed for a total of 48 hours, with additional portions of CuCl (0.50 g at a time) added at 6 hours and at 30 hour. At the end of this time methanol (100 ml) was added to the reaction mixture and reflux was continued for 15 minutes. It was then filtered through diatomaceous earth, evaporated, and purified by flash chromatography (10% methanol-dichloromethane). Obtained in this manner was 5.1 g of product that was suitable to be carried on to the next step. A 1.5 g portion was recrystallized from methanol to give 1.12 g of analytically pure material, mp 244-246 C. ANALYSIS: Calculated for C14 H14 N2 O2: 69.40% C, 5.82% H, 11.57% N. Found: 69.34% C, 5.80% H, 11.53% N.
With potassium carbonate;copper(l) chloride; In tetrahydrofuran; methanol; butanone; benzene;
EXAMPLE 28 9-Amino-3,4-dihydro-6-methoxyacridin-1(2H)-one <strong>[38487-85-3]2-Amino-4-methoxybenzonitril</strong>e (7.51 g) was suspended in 75 ml of benzene containing 6.&sl0; g of cyclohexane-1,3-dione and 1.1 g of p -toluenesulfonic acid monohydrate. The reaction mixture was brought to reflux, at which time a homogeneous solution was obtained. After 15 minutes a thick precipitate developed, which was stirred in the refluxing solvent for an additional 15 minutes. At the end of this time thin layer chromatography (TLC, hereafter) showed that the starting material had been consumed, so the precipitate was filtered off, taken up in 2-butanone, and washed with sodium bicarbonate solution. The organic phase was dried and evaporated to a solid, which was triturated with ether to give 1&sl0;.61 g of the enamine, mp 194-196C. This material was suspended in 25&sl0; ml of tetrahydrofuran to which was then added 11.9 g of milled potassium carbonate and &sl0;.85 g of CuCl. The reaction mixture was then refluxed for a total of 48 hours, with additional portions of CuCl (&sl0;.5&sl0; g at a time) added at 6 hour and at 3&sl0; hour. At the end of this time methanol (1&sl0;&sl0; ml) was added to the reaction mixture and reflux was continued for 15 minutes. It was then filtered through diatomaceous earth, evaporated, and purified by flash chromatography (1&sl0;% methanol-dichloromethane). Obtained in this manner was 5.1 g of product that was suitable to be carried on to the next step. A 1.5 g portion was recrystallized from methanol to give 1.12 g of analytically pure material, mp 244-246C.
With N-Bromosuccinimide; In acetonitrile; at 0℃; for 1h;
To a stirred solution of <strong>[38487-85-3]2-amino-4-methoxy benzonitrile</strong> (19.4 g, 131 mmol) in acetonitrile (582 mL) was added NBS (18.66 g, 104 mmol) and the mixture was stirred for 1 h at 0 C. The reaction was quenched by addition of ice. The volatiles were concentrated under reduced pressure and the residue was extracted with ethylacetate (2 x 200 mL). The combined organic layers were washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-amino-5-bromo-4-methoxy benzonitrile (26 g, 114 mmol, 87% yield) as a brown solid. LCMS (ESI) m/e 227.6 (bromo pattern) [(M+H), calcd for C8H8BrN2O, 227.06]; LC/MS retention time (method C): ti = 1.46 mm.
81%
With bromine; In 1,4-dioxane; at 0℃; for 1h;
2-Amino-5-bromo-4-methoxybenzonitrile <strong>[38487-85-3]2-Amino-4-methoxybenzonitril</strong>e (4.47 g, 30.2 mmol) is dissolved in 70 ml of dioxane and treated at 0 C. with bromine (1.71 ml, 33.2 mmol). It is subsequently stirred at 0 C. for one hour. After addition of diethyl ether, the resulting crystals are filtered off with suction. The desired product is obtained in 81% yield (5.52 g). 1H-NMR (400 MHz, DMSO-d6): delta 3.75 (s, 3H), 6.30-6.50 (m, 3H), 7.54 (s,1H).
81%
With bromine; In 1,4-dioxane; at 0℃; for 1h;
Compound 1.1.a.12-Amino-5-bromo-4-methoxybenzonitrile <strong>[38487-85-3]2-Amino-4-methoxybenzonitril</strong>e (4.47 g, 30.2 mmol) is dissolved in 70 ml of dioxane and treated at 0 C. with bromine (1.71 ml, 33.2 mmol). It is subsequently stirred at 0 C. for one hour. After addition of diethyl ether, the resulting crystals are filtered off with suction. The desired product is obtained in 81% yield (5.52 g).1H-NMR (400 MHz, DMSO-d6): delta 3.75 (s, 3H), 6.30-6.50 (m, 3H), 7.54 (s, 1H).
A solution of phenylmagnesium bromide (6.75 ml, 3M solution in diethyl ether, 20.2 mmol) in diethyl ether (15 ml) was added drop wise to a solution of 2-amino-4- methoxybenzonitrile (1000 mg, 6.75 mmol) in diethyl ether (20 ml) at 0C. The resulting suspension was heated to reflux for 2 h. The mixture was then cooled to 0C and 2N HCl (40 ml) was added very carefully. After complete addition, the mixture was heated to 55C for 2 h. Then 3N NaOH (-20 ml) was added at 0C to adjust the pH to 9. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried with Na2S04 and evaporated. The remaining residue was purified by columnchromatography (silica gel, heptane/EtOAc 85: 15 - 70:30) to afford the title compound (1300 mg, 85%) as yellow solid. MS (ESI): 228.4 (M+H)+.
85%
Step A: (2-Amino-4-methoxy-phenyl)-phenyl-methanone A solution of phenylmagnesium bromide (6.75 ml, 3M solution in diethyl ether, 20.2 mmol) in diethyl ether (15 ml) was added dropwise to a solution of <strong>[38487-85-3]2-amino-4-methoxybenzonitrile</strong> (1000 mg, 6.75 mmol) in diethyl ether (20 ml) at 0 C. The resulting suspension was heated to reflux for 2 h. The mixture was then cooled to 0 C. and 2N HCl (40 ml) was added very carefully. After complete addition, the mixture was heated to 55 C. for 2 h. Then 3N NaOH (?20 ml) was added at 0 C. to adjust the pH to 9. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 85:15-70:30) to afford the title compound (1300 mg, 85%) as yellow solid. MS (ESI): 228.4 (M+H)-.