* 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.
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 1, p. 74 - 75
[2] Journal of the Chemical Society, 1957, p. 290,293
[3] Patent: WO2018/178226, 2018, A1,
2
[ 59557-91-4 ]
[ 16817-43-9 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 5, p. 1705 - 1722
With 2,4,4,6-tetrabromocyclohexadione In dichloromethane at -10 - 20℃;
o-Anisidine (470 mg, 3.60 mmol) was dissolved in dichloromethane (8 mL) and cooled to -10 °C. 2,4,4,6-Tetrabromocyclohexadione (1.56 g, 3.60 mmol) was slowly added into the above stirred solution, while the temperature was kept below -5 °C. The reaction was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was washed with sodium hydroxide (10 mL, 2 M) and then water (15 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed (silica gel, dichloromethane) to afford 2,4-dibromo-6-methoxyaniline (90 mg, 9percent) as a dark brown liquid. 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H, OCH3), 4.20 (br s, 2H, NH2), 6.83 (d, J 2.1 Hz, 1H, ArH), 7.19 (d, J 2.1 Hz, 1H, ArH). The spectral data are in agreement with those reported in the literature.65 Continued elution afforded 4-bromo-2-methoxyaniline (579 mg, 83percent) as a brown solid: mp 57-59 °C (lit.66 56.5-58 °C; lit.65 60-61 °C). 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H, OCH3), 3.85 (br s, 2H, NH2) 6.60 (d, J 7.8 Hz, 2H, ArH), 6.88-6.90 (m, 2H, ArH). The spectral data are in agreement with those reported in the literature.65 J.-M. Chretien, F. Zammattio, E. Le Grognec, M. Paris, B. Cahingt, G. Montavon and J.-P. Quintard, J. Org. Chem. 70 (2005), pp. 2870-2873. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)65
Reference：
[1] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
[2] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
5
[ 90-04-0 ]
[ 59557-91-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
With o-xylylene bis(triethylammonium tribromide) In acetonitrile at 20℃; for 0.05 h;
General procedure: To a magnetic solution of aromatic compound (1 mmol)in acetonitrile (5 mL), OXBTEATB (0.233 g, 0.5 mmol) wasadded and stirred at room temperature for the appropriatetime (Table 1). The reaction was monitored by TLC (eluent:n-hexane/ethyl acetate: 5/1). The reaction mixture was transferredinto a separatory funnel after filtration of OXBTEABand was extracted with water (15 mL) and dichloromethane(20 mL). The organic layer was dried over anhydrousNa2SO4, and the solvent was concentrated in a rotary evaporator.The crude product was purified by passing it over acolumn of silica gel using a mixture of n-hexane and ethylacetate as the eluent. In order to regenerate the reagent, whitesolid was treated with liquid bromine. All the product structureswere confirmed by comparison of melting point or 1HNMR spectra with ones reported in the literature [29a-29e].
85%
With N-Bromosuccinimide In dichloromethane at -30 - 20℃;
To a solution of o-anisidine (15 g) in dry dichloromethane (250 ml) at -10 0C under argon was added N-bromosuccinimide (22.8 g) portionwise while keeping the internal temperature below -5 0C. The reaction mixture was stirred overnight and then the dichloromethane was evaporated and the residue dissolved in ethyl acetate (300 ml). The organic layer was washed with water (3 x 250 ml), the aqueous combined and extracted with ethyl acetate (150 ml). The combined organic layers were dried (MgSO4) and evaporated and the residue loaded onto six Biotage Si 40+M columns. Purification was carried out on the Biotage SP4 eluting with dichloromethane to afford the title compound (6.0 g and 5.76 g) as a dark red oil.LC/MS (ES) Rt=2.11 min (Method A). Molecular ion observed [M+H]+ 204, consistent with molecular formula C7H8NO81Br; To a solution of (2-methoxyphenyl)amine (125g, 1.01 mol) in dry DCM (2500ml) at - 3O0C was added NBS (19Og, 1.07mol) portionwise while the internal temperature was kept below -250C. The reaction mixture was stirred at rt overnight. Then the solvent was removed and the residue was dissolved in EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. Purification via the CombiFlash system (DCM:MeOH=100:1 ) then afforded the title compound as a red oil (175g, 85percent): LC-MS m/z 203 (M+H)+, 1.56 min (ret time).
75%
With trimethylbenzylammonium bromide; calcium carbonate In methanol; dichloromethane at 20℃; for 2 h;
o-Anisidine (0.18 ml, 20 mg, 1.63 mmol, 1 eq) is dissolved in a mixture of 10 ml of dichloromethane and 4 ml of methanol. Subsequently, TBMABr3 (761 mg, 1.95 mmol, 1.2 eq) and calcium carbonate (650 mg, 6.50 mmol, 4 eq) are added, and the mixture is stirred at RT for 2 h. The calcium carbonate is filtered off, and water is added. The aqueous phase is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator. Purification by column chromatography with dichloromethane/hexane 7/3 as the eluent yielded the desired product in a yield of 75percent, 247 mg. C7H8BrNO; MW 202; 1H-NMR (CDCl3): δ 6.89 (m, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.92 (bs, 1H), 3.82 (s, 3H); 13C-NMR (CDCl3): δ 148.0, 134.9, 123.7, 115.9, 113.8, 109.9, 56.7; IR: 3470, 3375 (amine), 1616, 1503, 1409 (phenyl) 1/cm
59%
With bromine In dichloromethane at 0℃;
Preparation 80; 4-Bromo-2-methoxy-phenylamine; Add dropwise a solution of bromine (0.83 mL, 16.2 mmol) in CH2Cl2 (130 mL) to a solution of 2-methoxy-phenylamine (2.0 g, 16.2 mmol) in dichloromethane (100 mL) at 0 0C over a period of 45 min. Stir the mixture at 0 0C to RT overnight. Wash the mixture with water, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography eluting with 10percent EtOAc/hexane to give 1.95 g (59percent) of the title compound. GC m/z (81Br) 203 [M+].
55%
With N-Bromosuccinimide In acetonitrile at 15℃; for 0.25 h;
2-methoxyaniline (3 g, 24.36 mmol) in acetonitrile (30 mL) was added N- bromosuccinimide (4.34 g, 24.36 mmol) and the reaction mixture was stirred at 15 deg.C for 15 minutes. To the reaction mixture sodium sulfite solution (40 mL) to quench the reaction, the mixture was extracted with ethyl acetate (50ml); the organic layer was dried over sodium sulfate, and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (2.7 g, 55percent yield) as a yellow solid.
Reference：
[1] Russian Journal of Applied Chemistry, 2009, vol. 82, # 9, p. 1570 - 1576
[2] Letters in Organic Chemistry, 2018, vol. 15, # 8, p. 682 - 687
[3] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1936 - 1942
[4] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 744 - 748
[5] Heterocycles, 2010, vol. 81, # 1, p. 73 - 77
[6] Patent: WO2009/50227, 2009, A1, . Location in patent: Page/Page column 17; 76-77
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4016 - 4019
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 15, p. 5444 - 5453
[9] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1222 - 1231
[10] Synthetic Communications, 2010, vol. 40, # 6, p. 868 - 876
[11] Patent: US2010/204234, 2010, A1, . Location in patent: Page/Page column 14
[12] Patent: WO2007/146758, 2007, A2, . Location in patent: Page/Page column 58
[13] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0708; 0709; 0710; 0711
[14] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1013 - 1030
[15] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 254 - 272
[16] Patent: US2005/20619, 2005, A1, . Location in patent: Page 40
[17] Patent: US2007/27125, 2007, A1, . Location in patent: Page/Page column 13
[18] Patent: WO2009/50227, 2009, A1, . Location in patent: Page/Page column 16-17
[19] Patent: US2007/27201, 2007, A1, . Location in patent: Page/Page column 17
6
[ 90-04-0 ]
[ 59557-91-4 ]
[ 367521-06-0 ]
Yield
Reaction Conditions
Operation in experiment
82.9%
at 10℃; for 2 h;
To a solution of 2-methoxy-phenylamine (11.27 mL, 12.31 g, 0.1 mol) in glacial acetic acid (250 mL) maintained at about 10 °C a solution of bromine (5.65 mL, 17.58 g, 0.11 mol) in glacial acetic acid (7 mL) was added over 2 h. A purple precipitate was formed, that was filtered on a Buchner funnel and rinsed with glacial acetic acid and petroleum ether (3 x 100 mL) to afford a whitish solid mixture of 4-bromo-2-methoxy-phenylamine and 4,5-dibromo-2-methoxy- phenylamine (26.9 g). The mixture was separated by flash chromatography on silica gel (hexane/EtOAc 40/60) and the desired compound was crystallized from fert-butyl methyl ether (18.73 g, 82.9percent).1H NMR (400 MHz, DMSO-cie) δ ppm 3.83 (s, 3 H) 6.83 (d, J=8.42 Hz, 1 H) 6.98 (dd, J=8.30, 2.08 Hz, 1 H) 7.11 (d, J=1.95 Hz, 1 H).HRMS mil calcd for [M + H] 201.9862; found 201.9866.
With water; iron; ammonium chloride In tetrahydrofuran at 65℃; for 4 h; Inert atmosphere
Step 3 4-bromo-2-methoxyaniline (Compound 12-5) At room temperature, the reduced iron powder (4.48 g, 80 mmol) and ammonium chloride (2.65 g, 50 mmol) were added to a mixed solution of compound 12-4 (2.3 g, 10.0 mmol) in 60 ml of THF/water (volume ratio of THF and water is 2:1), and vigorously stirred at 65° C. for 4 h. After completion of the reaction, the reaction mixture was filtered, the filtrate was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-5 (2.0 g) which was used directly in the next step. MS m/z (ESI): 201.9 [M+H]+.
4-bromo-2-methoxyaniline A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at -5° C. Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature. Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned. The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89percent) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1*50 mm; 5percent-95percent acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89percent).
89%
With sodium hydroxide In dichloromethane
4-bromo-2-methoxyaniline A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at -5° C. Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature. Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned. The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89percent) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1*50 mm; 5percent-95percent acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89percent).
Reference：
[1] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 440 - 447
19
[ 59557-91-4 ]
[ 791642-68-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With hydrogenchloride; sodium nitrite In water; acetic acid at 10 - 20℃; Stage #2: With hydrogen bromide; potassium iodide In water; acetic acid at 20℃; for 1 h; Stage #3: With ammonium hydroxide; sodium carbonate In dichloromethane; water
A stirred solution of NaN02 (5.63 g, 81.7 mmol) in cone. HC1 (6.2 ml) was cooled to 10 °C. 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 °C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48 percent HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H20, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2C03 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgS04), filtered and evaporated to yield a brown solid.The mother liquor (b) was basified by the addition of solid Na2C03 and was then extracted with DCM. The combined organic extracts were washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgS04), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91 percent).
91%
Stage #1: With hydrogenchloride; sodium nitrite In water; acetic acid at 10 - 20℃; for 0.5 h; Stage #2: With hydrogen bromide; potassium iodide In water; acetic acid at 20℃; for 1 h; Stage #3: With sodium carbonate In water
A stirred solution of NaN02 (5.63 g, 81.7 mmol) in cone. HC1 (6.2 ml) was cooled to 10 °C. 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 °C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48 percent HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H20, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2CC>3 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSC>4), filtered and evaporated to yield a brown solid.The mother liquor (b) was basified by the addition of solid Na2C03 and was then extracted with DCM. The combined organic extracts were washed with a dilutedNH4OH solution until the disappearance of blue colour. The organic phase was dried(MgS04), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91 percent).
91%
Stage #1: at 10 - 20℃; for 0.5 h; Stage #2: With hydrogen bromide; potassium iodide In water at 20℃; for 1 h;
A stirred solution of NaNO2 (5.63 g, 81.7 mmol) in conc. HCl (6.2 ml) was cooled to 10° C. 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10° C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48percent HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H2O, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2CO3 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSO4), filtered and evaporated to yield a brown solid. The mother liquor (b) was basified by the addition of solid Na2CO3 and was then extracted with DCM. The combined organic extracts were washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSO4), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91percent).
78%
Stage #1: With sulfuric acid; sodium nitrite In water at 0 - 10℃; for 1 h; Stage #2: With potassium iodide In water at 0 - 20℃;
4-Bromo-2-methoxy-aniline (20 g, 99 mmol) was dissolved in water (695 mL) and concentrated sulphuric acid (113 ML). The solution was cooled to 0 °C and sodium nitrite (7.5 g, 109 mmol) dissolved in water (32 mL) was added and stirred for 1 hour at 5-10 °C. POTASSIUM iodide (21.4g, 129 mmol) dissolved in water (100 mL) was added slowly whilst the mixture was virgorously stirred. After addition, the mixture was allowed to warm to room temperature. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted with ethyl acetetate (3 X). The combined organic phases were then washed with 1M NAOH, 1M Na2S203,1M HCl,- 1M saturated NAHCO3 and brine. The separated organic phase was dried (MGS04), filtered and concentrated in vacuo. The product was purified by flash chromatography using silica gel and eluting with HEPTANE/ETHYL acetate 1: 1. The product was identified from relevant fractions which were combined and concentrated IN VACUO. Yield: 24.12g, 78percent
73%
Stage #1: With hydrogenchloride; acetic acid; sodium nitrite In water at 10 - 20℃; for 0.5 h; Stage #2: With hydrogen bromide; potassium iodide In water at 20℃; for 1 h;
To a mixed solution of 2.0 g (9.0 mmol) of 4-bromo-2-methoxy aniline (Tokyo Chemical Industry Co., Ltd.) in acetic acid (15 ml)-concentrated hydrochloric acid (1 ml) was added 0.75 g (11 mmol) of sodium nitrite under ice cooling while stirring so that the internal temperature did not exceed 10°C, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was added dropwise to a solution of 1.0 g (30 mmol) of potassium iodide in a 48percent by weight aqueous hydrobromic acid solution (30 ml) at room temperature while stirring, and the mixture was stirred at the same temperature for one hour. After completion of the reaction, to a mixture of an aqueous sodium carbonate solution and methylene chloride was added the reaction mixture portionwise, the basicity of the aqueous layer was confirmed, and an extraction with methylene chloride from the mixed solution was subsequently conducted. The organic layer was washed sequentially with a 10percent by weight aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 100:0 to 91:9 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.2 g (7.2 mmol, yield 73percent) of the title compound as an orange solid. Mass spectrum (EI, m/z): 312 [M]+. 1 H-NMR spectrum (400 MHz, CDCl3) δ : 7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s).
73%
Stage #1: at 10 - 20℃; for 0.5 h; Cooling with ice Stage #2: With hydrogen bromide; potassium iodide In water at 20℃; for 1 h;
(Reference Example 3) 4-Bromo-1-iodo-2-methoxybenzene In an ice bath and while performing stirring, 0.75 g (11 mmol) of sodium nitrite was added to an acetic acid (15 ml)-concentrated hydrochloric acid (1 ml) solution of 2.0 g (9.0 mmol) of 4-bromo-2-methoxyaniline (Tokyo Chemical Industry Co., Ltd.) in such a manner that the inside temperature did not exceed 10°C. The mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture liquid was added dropwise to an aqueous solution of 1.0 g (30 mmol) of potassium iodide in a 48 wtpercent aqueous hydrobromic acid solution (30 ml) at room temperature while performing stirring. The resultant mixture was stirred at the temperature for 1 hour. After the completion of the reaction, the reaction mixture liquid was added in small portions to a mixture of an aqueous sodium carbonate solution and methylene chloride. After the basicity of the aqueous phase was confirmed, the liquid was separated. The organic phase was washed sequentially with a 10 wtpercent aqueous sodium hydrogensulfite solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent: hexane:ethyl acetate = 100:0 to 91:9 (V/V)), and the fraction containing the target compound was concentrated under reduced pressure to give the title compound weighing 2.2 g (7.2 mmol, yield 73percent) as an orange solid. Mass spectrum (EI, m/z): 312 [M]+. 1H-NMR spectrum (400MHz, CDCl3) δ: 7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s).
62%
With toluene-4-sulfonic acid; potassium iodide; sodium nitrite In water; acetonitrile at 10 - 20℃; for 2.16667 h;
To a solution of 4-bromo-2-methoxyphenyl)amine (11 Og, 0.54mol) in CH3CN (2000ml) at rt was added TsOH-H2O (281 g, 1.63mol). The mixture was cooled to 10-150C and mixed with a solution of NaNO2 (75g, 1.09mol) and Kl (226g, 1.36mol) in water. The mixture was stirred for 10min, allowed to warm to rt, and stirred for 2h before the reaction was quenched by the addition of water and 2M Na2S2O3 solution. It was then basified to pH of 9-10 by mixing with saturated NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated. Purification via the CombiFlash system (PE) then afforded the title compound as a colorless oil (107g, 62percent): LC-MS 1.87 min (ret time).
52.2%
With toluene-4-sulfonic acid; potassium iodide; sodium nitrite In water at 10 - 20℃; for 1 h;
4-Bromo-2-methoxy-phenylamine (2.02 g, 10 mmol) was added to a solution of p-toluensulphonic acid monohydrate (3.80 g, 20 mmol) in acetonitrile (30 mL). The mixture was cooled in an ice bath and treated with an solution of sodium nitrite (0.69 g, 10 mmol) and potassium iodide (4,15 g, 25 mmol) in water (7 mL) over 15 min maintaining the internal temperature below 10 °C. After stirring at that temperature for 15 min and then for 0.5 h at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (5 x 50 mL). The combined organic extracts were washed with 2M sodium thiosulfate (10 mL), brine (4 x 20 mL), water (20 mL), anhydrified over sodium sulphate, and evaporated to dryness affording a black oil that was purified by flash chromatography (petroleum ether/ferf-butylmethyl ether 5/1) to yield the title compound (1.63 g, 52.2percent).1H NMR (400 MHz, DMSO-cie) δ ppm 3.85 (s, 3 H) 6.95 (dd, J=8.24, 2.14 Hz, 1 H) 7.19 (d, J=2.08 Hz, 1 H) 7.69 (d, J=8.18 Hz, 1 H).
Reference：
[1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1222 - 1231
[2] Patent: WO2011/86098, 2011, A1, . Location in patent: Page/Page column 77
[3] Patent: WO2011/86099, 2011, A1, . Location in patent: Page/Page column 66
[4] Patent: US2012/295891, 2012, A1, . Location in patent: Page/Page column 31
[5] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1013 - 1030
[6] Patent: WO2004/96761, 2004, A1, . Location in patent: Page 43
[7] Patent: EP2940013, 2015, A1, . Location in patent: Paragraph 0513
[8] Patent: EP3162801, 2017, A1, . Location in patent: Paragraph 0149; 0150
[9] Patent: WO2009/50227, 2009, A1, . Location in patent: Page/Page column 77
[10] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4016 - 4019
[11] Patent: WO2013/14039, 2013, A1, . Location in patent: Page/Page column 43
[12] Journal of the American Chemical Society, 1935, vol. 57, p. 1592,1594
[13] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 3981 - 3984
[14] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 3248
20
[ 90-04-0 ]
[ 59557-91-4 ]
[ 88149-47-7 ]
Yield
Reaction Conditions
Operation in experiment
83%
With 2,4,4,6-tetrabromocyclohexadione In dichloromethane at -10 - 20℃;
o-Anisidine (470 mg, 3.60 mmol) was dissolved in dichloromethane (8 mL) and cooled to -10 °C. 2,4,4,6-Tetrabromocyclohexadione (1.56 g, 3.60 mmol) was slowly added into the above stirred solution, while the temperature was kept below -5 °C. The reaction was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was washed with sodium hydroxide (10 mL, 2 M) and then water (15 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed (silica gel, dichloromethane) to afford 2,4-dibromo-6-methoxyaniline (90 mg, 9percent) as a dark brown liquid. 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H, OCH3), 4.20 (br s, 2H, NH2), 6.83 (d, J 2.1 Hz, 1H, ArH), 7.19 (d, J 2.1 Hz, 1H, ArH). The spectral data are in agreement with those reported in the literature.65 Continued elution afforded 4-bromo-2-methoxyaniline (579 mg, 83percent) as a brown solid: mp 57-59 °C (lit.66 56.5-58 °C; lit.65 60-61 °C). 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H, OCH3), 3.85 (br s, 2H, NH2) 6.60 (d, J 7.8 Hz, 2H, ArH), 6.88-6.90 (m, 2H, ArH). The spectral data are in agreement with those reported in the literature.65 J.-M. Chretien, F. Zammattio, E. Le Grognec, M. Paris, B. Cahingt, G. Montavon and J.-P. Quintard, J. Org. Chem. 70 (2005), pp. 2870-2873. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)65
Reference：
[1] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
[2] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
21
[ 59557-91-4 ]
[ 88149-47-7 ]
Reference：
[1] Russian Journal of Applied Chemistry, 2009, vol. 82, # 9, p. 1570 - 1576
22
[ 59557-91-4 ]
[ 177476-76-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 254 - 272
With tetrakis(triphenylphosphine) palladium(0); potassium acetate In dimethyl sulfoxide at 150℃; for 0.666667 h; Microwave irradiation
Example 27E (500 mg, 2.47 mmol) in DMSO (5mL) solution was added bis(pinacolato)diboron(628.4 mg, 2.47 mmol), tetrakis triphenylphosphine palladium (150 mg, 0.13 mmol ) and potassium acetate (485 mg, 4.95 mmol) and the reaction mixture was stirred at 150 deg.C by microwave for 40 minutes. The reaction mixture was diluted with ethyl acetate (50mL) and water (30mL). The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether 1:: ethyl acetate = 10) to give the title compound (160 mg, 26percent yield) as a yellow oil.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 966 - 970
[2] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0712; 0713; 0714; 0715
A stirred solution of NaN02 (5.63 g, 81.7 mmol) in cone. HC1 (6.2 ml) was cooled to 10 C. <strong>[59557-91-4]4-bromo-2-methoxy-phenylamine</strong> (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48 % HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H20, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2C03 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgS04), filtered and evaporated to yield a brown solid.The mother liquor (b) was basified by the addition of solid Na2C03 and was then extracted with DCM. The combined organic extracts were washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgS04), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91 %).
91%
A stirred solution of NaN02 (5.63 g, 81.7 mmol) in cone. HC1 (6.2 ml) was cooled to 10 C. <strong>[59557-91-4]4-bromo-2-methoxy-phenylamine</strong> (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48 % HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H20, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2CC>3 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSC>4), filtered and evaporated to yield a brown solid.The mother liquor (b) was basified by the addition of solid Na2C03 and was then extracted with DCM. The combined organic extracts were washed with a dilutedNH4OH solution until the disappearance of blue colour. The organic phase was dried(MgS04), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91 %).
91%
A stirred solution of NaNO2 (5.63 g, 81.7 mmol) in conc. HCl (6.2 ml) was cooled to 10 C. <strong>[59557-91-4]4-bromo-2-methoxy-phenylamine</strong> (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48% HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H2O, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2CO3 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSO4), filtered and evaporated to yield a brown solid. The mother liquor (b) was basified by the addition of solid Na2CO3 and was then extracted with DCM. The combined organic extracts were washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSO4), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91%).
78%
4-Bromo-2-methoxy-aniline (20 g, 99 mmol) was dissolved in water (695 mL) and concentrated sulphuric acid (113 ML). The solution was cooled to 0 C and sodium nitrite (7.5 g, 109 mmol) dissolved in water (32 mL) was added and stirred for 1 hour at 5-10 C. POTASSIUM iodide (21.4g, 129 mmol) dissolved in water (100 mL) was added slowly whilst the mixture was virgorously stirred. After addition, the mixture was allowed to warm to room temperature. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted with ethyl acetetate (3 X). The combined organic phases were then washed with 1M NAOH, 1M Na2S203,1M HCl,- 1M saturated NAHCO3 and brine. The separated organic phase was dried (MGS04), filtered and concentrated in vacuo. The product was purified by flash chromatography using silica gel and eluting with HEPTANE/ETHYL acetate 1: 1. The product was identified from relevant fractions which were combined and concentrated IN VACUO. Yield: 24.12g, 78%
73%
To a mixed solution of 2.0 g (9.0 mmol) of <strong>[59557-91-4]4-bromo-2-methoxy aniline</strong> (Tokyo Chemical Industry Co., Ltd.) in acetic acid (15 ml)-concentrated hydrochloric acid (1 ml) was added 0.75 g (11 mmol) of sodium nitrite under ice cooling while stirring so that the internal temperature did not exceed 10C, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was added dropwise to a solution of 1.0 g (30 mmol) of potassium iodide in a 48% by weight aqueous hydrobromic acid solution (30 ml) at room temperature while stirring, and the mixture was stirred at the same temperature for one hour. After completion of the reaction, to a mixture of an aqueous sodium carbonate solution and methylene chloride was added the reaction mixture portionwise, the basicity of the aqueous layer was confirmed, and an extraction with methylene chloride from the mixed solution was subsequently conducted. The organic layer was washed sequentially with a 10% by weight aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 100:0 to 91:9 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.2 g (7.2 mmol, yield 73%) of the title compound as an orange solid. Mass spectrum (EI, m/z): 312 [M]+. 1 H-NMR spectrum (400 MHz, CDCl3) delta : 7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s).
73%
(Reference Example 3) 4-Bromo-1-iodo-2-methoxybenzene In an ice bath and while performing stirring, 0.75 g (11 mmol) of sodium nitrite was added to an acetic acid (15 ml)-concentrated hydrochloric acid (1 ml) solution of 2.0 g (9.0 mmol) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (Tokyo Chemical Industry Co., Ltd.) in such a manner that the inside temperature did not exceed 10C. The mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture liquid was added dropwise to an aqueous solution of 1.0 g (30 mmol) of potassium iodide in a 48 wt% aqueous hydrobromic acid solution (30 ml) at room temperature while performing stirring. The resultant mixture was stirred at the temperature for 1 hour. After the completion of the reaction, the reaction mixture liquid was added in small portions to a mixture of an aqueous sodium carbonate solution and methylene chloride. After the basicity of the aqueous phase was confirmed, the liquid was separated. The organic phase was washed sequentially with a 10 wt% aqueous sodium hydrogensulfite solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent: hexane:ethyl acetate = 100:0 to 91:9 (V/V)), and the fraction containing the target compound was concentrated under reduced pressure to give the title compound weighing 2.2 g (7.2 mmol, yield 73%) as an orange solid. Mass spectrum (EI, m/z): 312 [M]+. 1H-NMR spectrum (400MHz, CDCl3) delta: 7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s).
62%
With toluene-4-sulfonic acid; potassium iodide; sodium nitrite; In water; acetonitrile; at 10 - 20℃; for 2.16667h;
To a solution of 4-bromo-2-methoxyphenyl)amine (11 Og, 0.54mol) in CH3CN (2000ml) at rt was added TsOH-H2O (281 g, 1.63mol). The mixture was cooled to 10-150C and mixed with a solution of NaNO2 (75g, 1.09mol) and Kl (226g, 1.36mol) in water. The mixture was stirred for 10min, allowed to warm to rt, and stirred for 2h before the reaction was quenched by the addition of water and 2M Na2S2O3 solution. It was then basified to pH of 9-10 by mixing with saturated NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated. Purification via the CombiFlash system (PE) then afforded the title compound as a colorless oil (107g, 62%): LC-MS 1.87 min (ret time).
52.2%
With toluene-4-sulfonic acid; potassium iodide; sodium nitrite; In water; at 10 - 20℃; for 1h;
4-Bromo-2-methoxy-phenylamine (2.02 g, 10 mmol) was added to a solution of p-toluensulphonic acid monohydrate (3.80 g, 20 mmol) in acetonitrile (30 mL). The mixture was cooled in an ice bath and treated with an solution of sodium nitrite (0.69 g, 10 mmol) and potassium iodide (4,15 g, 25 mmol) in water (7 mL) over 15 min maintaining the internal temperature below 10 C. After stirring at that temperature for 15 min and then for 0.5 h at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (5 x 50 mL). The combined organic extracts were washed with 2M sodium thiosulfate (10 mL), brine (4 x 20 mL), water (20 mL), anhydrified over sodium sulphate, and evaporated to dryness affording a black oil that was purified by flash chromatography (petroleum ether/ferf-butylmethyl ether 5/1) to yield the title compound (1.63 g, 52.2%).1H NMR (400 MHz, DMSO-cie) delta ppm 3.85 (s, 3 H) 6.95 (dd, J=8.24, 2.14 Hz, 1 H) 7.19 (d, J=2.08 Hz, 1 H) 7.69 (d, J=8.18 Hz, 1 H).
With toluene-4-sulfonic acid; potassium iodide; sodium nitrite; In water; acetonitrile; for 0.0833333h;
Step 1: To a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (2.0 g, 9.9 mmol) in MeCN (50 mL) was added para-toluenesulfonic acid (5.1 g, 27 mmol). The resulting mixture was cooled in an ice water bath. A solution of NaNO2 (1.36 g, 19.7 mmol) and KI (4.11 g, 24.8 mmol) in water (50 mL) was then added, and the resulting mixture was stirred for 5 min. The mixture was then removed from the ice water bath. Once consumption of starting material was observed, the reaction mixture was partitioned between water and EtOAc. The organic phase was concentrated and the resulting crude residue was purified by silica gel chromatography to afford 4-bromo-1-iodo-2-methoxybenzene
With sulfuric acid; sodium 3-nitrobenzenesulfonate; In water; at 0 - 120℃; for 24.5h;Inert atmosphere;
<strong>[59557-91-4]4-Bromo-2-methoxyaniline</strong> (50.0 g, 247 mmol) was added to a mixture of sodium 3- nitrobenzenesulfonate (86.8 g, 385 mmol) and propane-1 ,2,3-triol (108 g, 1 .18 mol) in cone. H2SO4 (97 ml.) and water (75.7 ml.) at 0 C over a period of 30 min under nitrogen. After stirring at 120 C for 24 h and then cooling to RT, the reaction mixture was quenched slowly with 2M NaOH (1 L). The aq. solution was extracted with EtOAc (3 x 500 ml_). The combined organic phases were dried over Na2S04, filtered and concentrated to afford 6-bromo-8- methoxyquinoline (Intermediate 49, 60.0 g, 100%); M/Z (ES+), [M+H]+= 237.1H NMR (300 MHz, DMSO-ofe) delta 3.99 (s, 3H), 7.30 (d, 1 H), 7.58-7.60 (m, 1 H), 7.79 (s, 1 H), 8.28 (dd, 1 H), 8.86 (dd, 1 H).
87.4%
At room temperature, concentrated sulfuric acid (185 mL) and deionized water (144 mL) were added with mechanical stirring in a three-necked flask.Glycerol (768.5 mmol, 207.5 g) was added and the temperature was lowered to room temperature. Sodium 3-nitrobenzenesulfonate (733 mmol, 165 g) was added in portions and the reaction was carried out at 80 C for 3 hours, <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (compound shown by the formula (I-1)) (495 mmol, 100.0 g) was added portionwise with vigorous stirring to giveHeat to 120 C and react overnight. Add water (600 mL) and adjust pH to approx. 7.0 with concentrated aqueous ammonia. Extract with water and ethyl acetateAfter the extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was spinned to give 103 g of tan by column chromatographyThe oily product (compound represented by the formula (I)) had a yield of 87.4% and a purity of 94%.
With o-xylylene bis(triethylammonium tribromide); In acetonitrile; at 20℃; for 0.05h;
General procedure: To a magnetic solution of aromatic compound (1 mmol)in acetonitrile (5 mL), OXBTEATB (0.233 g, 0.5 mmol) wasadded and stirred at room temperature for the appropriatetime (Table 1). The reaction was monitored by TLC (eluent:n-hexane/ethyl acetate: 5/1). The reaction mixture was transferredinto a separatory funnel after filtration of OXBTEABand was extracted with water (15 mL) and dichloromethane(20 mL). The organic layer was dried over anhydrousNa2SO4, and the solvent was concentrated in a rotary evaporator.The crude product was purified by passing it over acolumn of silica gel using a mixture of n-hexane and ethylacetate as the eluent. In order to regenerate the reagent, whitesolid was treated with liquid bromine. All the product structureswere confirmed by comparison of melting point or 1HNMR spectra with ones reported in the literature [29a-29e].
85%
With N-Bromosuccinimide; In dichloromethane; at -30 - 20℃;Product distribution / selectivity;
To a solution of o-anisidine (15 g) in dry dichloromethane (250 ml) at -10 0C under argon was added N-bromosuccinimide (22.8 g) portionwise while keeping the internal temperature below -5 0C. The reaction mixture was stirred overnight and then the dichloromethane was evaporated and the residue dissolved in ethyl acetate (300 ml). The organic layer was washed with water (3 x 250 ml), the aqueous combined and extracted with ethyl acetate (150 ml). The combined organic layers were dried (MgSO4) and evaporated and the residue loaded onto six Biotage Si 40+M columns. Purification was carried out on the Biotage SP4 eluting with dichloromethane to afford the title compound (6.0 g and 5.76 g) as a dark red oil.LC/MS (ES) Rt=2.11 min (Method A). Molecular ion observed [M+H]+ 204, consistent with molecular formula C7H8NO81Br; To a solution of (2-methoxyphenyl)amine (125g, 1.01 mol) in dry DCM (2500ml) at - 3O0C was added NBS (19Og, 1.07mol) portionwise while the internal temperature was kept below -250C. The reaction mixture was stirred at rt overnight. Then the solvent was removed and the residue was dissolved in EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. Purification via the CombiFlash system (DCM:MeOH=100:1 ) then afforded the title compound as a red oil (175g, 85%): LC-MS m/z 203 (M+H)+, 1.56 min (ret time).
75%
With trimethylbenzylammonium bromide; calcium carbonate; In methanol; dichloromethane; at 20℃; for 2h;
o-Anisidine (0.18 ml, 20 mg, 1.63 mmol, 1 eq) is dissolved in a mixture of 10 ml of dichloromethane and 4 ml of methanol. Subsequently, TBMABr3 (761 mg, 1.95 mmol, 1.2 eq) and calcium carbonate (650 mg, 6.50 mmol, 4 eq) are added, and the mixture is stirred at RT for 2 h. The calcium carbonate is filtered off, and water is added. The aqueous phase is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator. Purification by column chromatography with dichloromethane/hexane 7/3 as the eluent yielded the desired product in a yield of 75%, 247 mg. C7H8BrNO; MW 202; 1H-NMR (CDCl3): delta 6.89 (m, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.92 (bs, 1H), 3.82 (s, 3H); 13C-NMR (CDCl3): delta 148.0, 134.9, 123.7, 115.9, 113.8, 109.9, 56.7; IR: 3470, 3375 (amine), 1616, 1503, 1409 (phenyl) 1/cm
71%
With tetrabutylammomium bromide; copper(ll) bromide; In ethanol; at 25℃;
General procedure: A round bottom flask was charged with Bu4NBr (2 mmol, 0.64 g), EtOH (8 mL) and 2-methylaniline (2 mmol, 0.21 g) followed by CuBr2 (3 mmol, 0.67 g). The resulted mixture was stirred at 25 C. After the completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure. To the residue was added ammonium hydroxide (5 mL, 25% w/v) and water (5 mL) with stirring, and the suspension was extracted with DCM(10 mL×4) The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The product 2b was obtained using flash chromatograph column eluted with PE : EA (5 : 1).
69.95%
With N-Bromosuccinimide; In acetonitrile; at 0℃; for 1h;
In a 500 mL three-necked flask, 18.47 g (150.00 mmol) of 2-methoxyaniline and 120 mL of acetonitrile were added and dissolved by stirring. At 0 C, 26.70 g of NBS (150.00 mmol) was slowly added portionwise and stirred at this temperature.After 1 hour, the reaction was completed.To the reaction system was added 100 mL of a saturated aqueous solution of Na2S2O3, and extracted with ethyl acetate (300 mL*3).The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was isolated as a 4-bromo-2-methoxy aniline 21.20 g (104.92 mmol), 69.95% yield by silica gel column chromatography (PE / EA = 10/1)
59%
With bromine; In dichloromethane; at 0℃;
Preparation 80; 4-Bromo-2-methoxy-phenylamine; Add dropwise a solution of bromine (0.83 mL, 16.2 mmol) in CH2Cl2 (130 mL) to a solution of 2-methoxy-phenylamine (2.0 g, 16.2 mmol) in dichloromethane (100 mL) at 0 0C over a period of 45 min. Stir the mixture at 0 0C to RT overnight. Wash the mixture with water, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography eluting with 10% EtOAc/hexane to give 1.95 g (59%) of the title compound. GC m/z (81Br) 203 [M+].
55%
With N-Bromosuccinimide; In acetonitrile; at 15℃; for 0.25h;
2-methoxyaniline (3 g, 24.36 mmol) in acetonitrile (30 mL) was added N- bromosuccinimide (4.34 g, 24.36 mmol) and the reaction mixture was stirred at 15 deg.C for 15 minutes. To the reaction mixture sodium sulfite solution (40 mL) to quench the reaction, the mixture was extracted with ethyl acetate (50ml); the organic layer was dried over sodium sulfate, and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (2.7 g, 55% yield) as a yellow solid.
With 2,4,4,6-Tetrabromo-2,5-cyclohexadien-1-one; In dichloromethane; at 10 - 20℃; for 1.5h;
A mixture of o-anisidine (27.1 g, 219 mmol) and dichloromethane (500 mL) was stirred under an atmosphere of nitrogen and treated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (90.0 g, 219 mmol) in four roughly equal portions over the course of 20 minutes. The temperature of the reaction was maintained between 10 and 15 C. by cooling with a cold water bath during the addition of the 2,4,4,6-tetrabromo-2,5-cyclohexadienone. The mixture was warmed to ambient temperature and stirred for an additional 1.5 hours at which time HPLC [Hypersil HS C18, 5 ?m, 100A, 250?4.6 mm; 25-100% acetonitrile/0.1M ammonium acetate over 10 minutes, 1 ml/min) o-anisidine tr=7.63 min, 4-bromo-2-methoxyaniline Rt=9.77 min] indicated very little o-anisidine remaining. The mixture was washed with 0.67N NaOH (300 mL) and 1N aqueous sodium hydroxide (300 mL). The combined aqueous washes were extracted with dichloromethane (150 mL) and the combined organic solutions were then washed with water (2?200 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated to provide about 48 g of the desired product
With bromine;acetic acid; In dichloromethane; for 2.5h;
(2-methoxyphenyl) aniline (2.42 g, 12 mmol) and catalytic acetic acid were combined in dichloromethane (20 mL). Bromine (0.17 mL, 3.43 mmol) was added dropwise and the reaction allowed to stir for 2.5 hours. The mixture was then poured into brine and extracted with diethylether. The organic layer was dried over magnesium sulfate, evaporated in vacuo, and used without further purification.
With 2,4,4,6-Tetrabromo-2,5-cyclohexadien-1-one; In dichloromethane; at -10 - -5℃; for 2h;Product distribution / selectivity;
To a solution of o-anisidine (3.0 g) in dry dichloromethane (50 ml) at -10 0C under argon was added 2,4,4,6-tetrabromo-2,5,cyclohexadienone (9.7g) portionwise while keeping <n="18"/>the internal temperature below -5 0C. The reaction mixture was stirred for an additional two hours and then diluted with dichloromethane and washed with 2N aqueous sodium hydroxide solution (2 x 30 ml) and brine. The organic layer was dried (MgSO4) and evaporated and the residue was dissolved in dichloromethane and loaded onto a Biotage Si 40+M column. Purification was carried out on the Biotage SP4 (t.l.c. method based on a t.l.c. run in 20% ethyl acetate / hexane) to afford a 1 :4 mixture of o-anisidine and the title compound (3.34g) as a brown oil.LC/MS (ES) Rt=2.12 min (Method A). Molecular ion observed [M+H]+ 204, consistent with molecular formula C7H8NO8IBr
With bromine;acetic acid; In dichloromethane; for 2.5h;
Example 35; [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methoxyphenycyanamide; (2-methoxyphenyl) aniline (2.42 g, 12 mmol) and catalytic acetic acid were combined in dichloromethane (20 mL). Bromine (0.17 mL, 3.43 mmol) was added dropwise and the reaction stirred for 2.5 hours. The mixture was then poured into brine and extracted with diethylether. The organic layer was dried over magnesium sulfate, evaporated in vacuo, and used without further purification.
EXAMPLE 2 tert-butyl-N-(4-bromo-2-methoxyphenyl)carbamate 4 In a 250 ml single-necked flask placed under an inert atmosphere, 6.4 g (31.7 mmol) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> 2 and 7.6 g (34.9 mmol, 1.1 eq) of (Boc)2O are dissolved in 80 ml of anhydrous THF. Heat the THF under a reflux condenser for 15 hours. The medium is allowed to cool and the solvent is evaporated. The residue is taken up in CH2Cl2, washed with a saturated aqueous solution of NaHCO3 (3*). The organic phase is dried on MgSO4. A concentration under vacuum is implemented to produce a brown oil which is purified by column chromatography (eluent petroleum ether/AcOEt 9:1). 9.6 g of 4 is obtained as a colorless oil (yield: 100%). C12H16BrNO3 M=302.19 g/mol 1H NMR (CDCl3) delta (ppm): 7.95 (d, J=8.6 Hz, 1H, CH(6)); 7.07-6.94 (m, 3H, NH, CH(3), CH(5)); 3.84 (s, 3H, OCH3); 1.52 (s, 9H, CH3). 13C NMR (CDCl3) delta (ppm): 152.5 (CO2); 148.1 (C2); 127.4 (CI); 123.8 (C5); 119.1 (C6); 114.3 (C4); 113.4 (C3); 80.5 (C(CH3)3); 55.9 (OCH3); 28.3 (3C, CH3).
81.6%
In tetrahydrofuran; for 22h;Inert atmosphere; Reflux;
(0677) <strong>[59557-91-4]4-Bromo-2-methoxyaniline</strong> (6.8 g, 33.7 mmol) and di-tert-butyl dicarbonate (8.9 g, 40.8 mmol) were dissolved in tetrahydrofuran (100 mL). Under the protection of nitrogen gas, the reaction was carried out under reflux for 22 h, and the mixture was cooled. The solvent was removed by distillation under reduced pressure, and ethyl acetate (150 mL) was added. The mixture was washed with 1 mol/L hydrochloric acid, and the water phase and the organic phase were separated. The organic phase was dried with anhydrous sodium sulfate, and filtrated under suction. The filtrate was concentrated to get the title compound (8.3 g, yield: 81.6%).
80%
In tetrahydrofuran; ethyl acetate;
a) tert-Butyl N-(4-bromo-2-methoxyphenyl)carbamate. A mixture of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (34.0 g, 0.17 mol) and di-tert-butyl dicarbonate (44.5 g, 0.20 mol) in tetrahydrofuran (350 ml) was heated at reflux for 22 h. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (350 ml) and washed with 1 N citric acid (200 ml), dried over magnesium sulfate, filtered and evaporated to give tert-butyl N-(4-bromo-2-methoxyphenyl)carbamate as a yellow oil (80% pure, 57.10 g, 0.15 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.01 (s, 1H), 7.63 (d, 1H), 7.17 (d, 1H), 7.07 (dd, 1H), 3.82 (s, 3H), 1.45 (s, 9H); TLC (n-heptane/ethyl acetate=2:1) Rf 0.67.
In tetrahydrofuran; for 25h;Heating / reflux;
A mixture of Example 175A (36.4 g, 180 mmol), and di-tert-butyl dicarbonate (47.2 g, 216 mmol) in THF (500 mL) was heated to reflux for 20 hours and cooled to ambient temperature. HPLC (using the conditions from Example 175A, product Rt=13.55 min and TLC (8:2 heptane/ethyl acetate, Rf of product=0.53, Rf of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong>=0.27) indicated approximately 10% starting material was remaining. Additional di-tert-butyl dicarbonate (3.9 g, 18 mmol) was added and heating was continued for another 5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was applied to a 400 gram silica gel column and eluted with 8:2 heptane/ethyl acetate. The fractions showing the desired product were combined and washed with saturated NaHCO3 and then brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide 61.3 g of a mixture of the desired product and di-tert-butyl dicarbonate which was used directly in the next step
In tetrahydrofuran; n-heptane;
EXAMPLE 175B tert-butyl 4-bromo-2-methoxyphenylcarbamate A mixture of Example 175A (36.4 g, 180 mmol), and di-tert-butyl dicarbonate (47.2 g, 216 mmol) in THF (500 mL) was heated to reflux for 20 hours and cooled to ambient temperature. HPLC (using the conditions from Example 175A, product Rt=13.55 min and TLC (8:2 heptane/ethyl acetate, Rf of product=0.53, Rf of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong>=0.27) indicated approximately 10% starting material was remaining. Additional di-tert-butyl dicarbonate (3.9 g, 18 mmol) was added and heating was continued for another 5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was applied to a 400 gram silica gel column and eluted with 8:2 heptane/ethyl acetate. The fractions showing the desired product were combined and washed with saturated NaHCO3 and then brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide 61.3 g of a mixture of the desired product and di-tert-butyl dicarbonate which was used directly in the next step.
In tetrahydrofuran; for 25h;Heating / reflux;
EXAMPLE 175B tert-butyl 4-bromo-2-methoxyphenylcarbamate A mixture of Example 175A (36.4 g, 180 mmol), and di-tert-butyl dicarbonate (47.2 g, 216 mmol) in THF (500 mL) was heated to reflux for 20 hours and cooled to ambient temperature. HPLC (using the conditions from Example 175A, product Rt=13.55 min and TLC (8:2 heptane/ethyl acetate, Rf of product=0.53, Rf of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong>=0.27) indicated approximately 10% starting material was remaining. Additional di-tert-butyl dicarbonate (3.9 g, 18 mmol) was added and heating was continued for another 5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was applied to a 400 gram silica gel column and eluted with 8:2 heptane/ethyl acetate. The fractions showing the desired product were combined and washed with saturated NaHCO3 and then brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide 61.3 g of a mixture of the desired product and di-tert-butyl dicarbonate which was used directly in the next step.
14.7 g
In tetrahydrofuran; at 40℃; for 5h;
10.0 g (0.049 mol) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> in a three-necked flask,Take 13.0 g (0.060 mol) of di-tert-butyl dicarbonate,It was dissolved in tetrahydrofuran.After reacting for 5 hours at 40 C., the solvent is distilled off and represented by the formula (K-1)14.7 g of compound was obtained.
With 2,4,4,6-tetrabromocyclohexadione; In dichloromethane; at -10 - 20℃;
o-Anisidine (470 mg, 3.60 mmol) was dissolved in dichloromethane (8 mL) and cooled to -10 C. 2,4,4,6-Tetrabromocyclohexadione (1.56 g, 3.60 mmol) was slowly added into the above stirred solution, while the temperature was kept below -5 C. The reaction was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was washed with sodium hydroxide (10 mL, 2 M) and then water (15 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed (silica gel, dichloromethane) to afford 2,4-dibromo-6-methoxyaniline (90 mg, 9%) as a dark brown liquid. 1H NMR (400 MHz, CDCl3) delta 3.84 (s, 3H, OCH3), 4.20 (br s, 2H, NH2), 6.83 (d, J 2.1 Hz, 1H, ArH), 7.19 (d, J 2.1 Hz, 1H, ArH). The spectral data are in agreement with those reported in the literature.65 Continued elution afforded 4-bromo-2-methoxyaniline (579 mg, 83%) as a brown solid: mp 57-59 C (lit.66 56.5-58 C; lit.65 60-61 C). 1H NMR (400 MHz, CDCl3) delta 3.83 (s, 3H, OCH3), 3.85 (br s, 2H, NH2) 6.60 (d, J 7.8 Hz, 2H, ArH), 6.88-6.90 (m, 2H, ArH). The spectral data are in agreement with those reported in the literature.65 J.-M. Chretien, F. Zammattio, E. Le Grognec, M. Paris, B. Cahingt, G. Montavon and J.-P. Quintard, J. Org. Chem. 70 (2005), pp. 2870-2873. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)65
Trifluoroacetic anhydride (3.45 ml) was added dropwise to a pyridine (10 ml) solution of 4-bromo-2-(methyloxy)aniline (3.34 g) under ice cooling and the reaction mixture was stirred at 0 0C for one hour. Iced water (100 ml) was added and the mixture extracted with ethyl acetate (2 x 50 ml). The combined ethyl acetate was washed with water, dried (MgSO4), evaporated and the residue loaded onto three Biotage Si 40+M columns. Purification was carried out on the Biotage SP4 (t.l.c. method based on a t.l.c. run in 25% dichloromethane / hexane) to afford a 1 :3 mixture of 2,2,2-trifluoro-λ/-[2- (methyloxy)phenyl]acetamide and the title compound (3.46 g) as a white solid. LC/MS (ES) Rt=3.08 min(Method A). Molecular ion observed [M-H]" 296, consistent with molecular formula C9H7F3NO279Br
In pyridine at 0℃; for 1h;
75
Trifluoroacetic anhydride (24 mL) was added dropwise to a pyridine (48 mL) solution of 4-bromo-2-methoxyaniline (23.4 g) under ice-cooling. The reaction solution was stirred for an hour and iced water was added thereto. Crystals deposited were separated by filtering, and air-dried overnight. 32.4 g of the title compound was obtained. 1H-NMR (CDCl3) δ (ppm): 3.93 (s, 3H), 7.07 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.8, 2.4 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.47 (brs, 1H).
Preparation 81; N-(4-Bromo-2-methoxy-phenyl)-2-chloro-acetamide; Add chloroacetic anhydride (1.78 g, 10.1 mmol) to a solution of 4-bromo-2- methoxy-phenylamine (1.94 g, 9.60 mmol) in CH2Cl2 (48 mL) at 0 0C. Stir the mixture at RT for 2 h. Dilute the mixture with CH2Cl2, then wash with IN NaOH, brine, and water. Dry the organic layer over Na2SO4, filter, and concentrate to give 2.6 g (97%) of the title compound. LC-ES/MS m/z (81Br, 35Cl) 280.0 [M+H]+.
benzyl (4-bromo-2-methoxyphenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0 - 20℃; for 0.333333h;Inert atmosphere;
(0900) Under the protection of nitrogen gas, <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (15 g, 74.24 mmol) was dissolved in 1,4-dioxane (250 mL), and a solution of sodium bicarbonate (15.8 g, 188.07 mmol) in water (150 mL) was added. At 0 C., carbobenzoxy chloride (19.1 g, 111.96 mmol) was added dropwisely to the reaction system. After the addition, the reaction was carried out at room temperature for 20 min. TLC detection showed that raw materials disappeared. The mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated saline solution (100 mL×2), dried with anhydrous sodium sulfate, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:5) to get the title compound as a white solid (15 g, yield: 60%).
With sodium hydrogencarbonate; In 1,4-dioxane; n-heptane; water;
Benzyl N-(4-bromo-2-methoxyphenyl)carbamate (Intermediate AM) A solution of sodium bicarbonate (3.12 g, 0.0371 mol) in water (35 mL) was added to a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (3.00 g, 0.0148 mol) in dioxane (50 mL). The resulting mixture was stirred for 5 minutes and benzyl chloroformate (3.8 g, 0.022 mol) was added dropwise over 3 minutes. The reaction mixture was for two hours, then dioxane was removed under reduced pressure and the water phase was extracted twice with ethyl acetate (100 mL each). The combined organic extracts were dried over magnesium sulfate and after filtration concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield benzyl N-(4-bromo-2-methoxyphenyl)carbamate (3.75 g, 0.011 mol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) 8.72 (s, 1H), 7.61 (d, 1H), 7.38 (m, 5H), 7.20 (s, 1H), 7.10 (d, 1H), 5.14 (s, 2H), 3.81 (s, 3H)
With sodium hydrogencarbonate; In 1,4-dioxane; n-heptane; water;
Benzyl N-(4-bromo-2-methoxyphenyl)carbamate (Intermediate AM) A solution of sodium bicarbonate (3.12 g, 0.0371 mol) in water (35 mL) was added to a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (3.00 g, 0.0148 mol) in dioxane (50 mL). The resulting mixture was stirred for 5 minutes and benzyl chloroformate (3.8 g, 0.022 mol) was added dropwise over 3 minutes. The reaction mixture was for two hours, then dioxane was removed under reduced pressure and the water phase was extracted twice with ethyl acetate (100 mL each). The combined organic extracts were dried over magnesium sulfate and after filtration concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield benzyl N-(4-bromo-2-methoxyphenyl)carbamate (3.75 g, 0.011 mol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) 8.72 (s, 1H), 7.61 (d, 1H), 7.38 (m, 5H), 7.20 (s, 1H), 7.10 (d, 1H), 5.14 (s, 2H), 3.81 (s, 3H).
To a solution of 4-thiazolecarboxylic acid (0.24 g) and HATU (0.70 g) in N, N- dimethylformamide (5 ml.) was added DIPEA (0.80 ml.) and the reaction was stirred at room temperature under nitrogen for 10 mins. 4-Bromo-2-(methyloxy)phenyl]amine (0.31 g) was added and the reaction stirred at room temperature under nitrogen for 20 h. The reaction mixture was evaporated in vacuo and loaded onto a 5 g aminopropyl cartridge in DCM. The cartridge was eluted with DCM (3 column volumes) and methanol (3 column volumes). The fractions were evaporated in vacuo. The crude material was purified using a 40 g silica Silicycle cartridge eluting with a gradient of 0 - 100percent EtOAc in cyclohexane to give the title compound.MS calcd for (C28H30F3N3O4S2 + H)+ : 313/315 MS found (electrospray) : (M+H)+ = 313/315
To a round bottom flask at r.t. containing formic acid (85%, 27 mL, 624.4 mmol) was added acetic anhydride (16 mL, 169.5 mmol) dropwise. The reaction stirred for 45 min. followed by the dropwise addition of a solution of 4-bromo-2- methoxyaniline (9.01 g, 44.6 mmol) in THF (56 mL). The reaction mixture was quenched with ice-water after 23 h and the resulting precipitate was filtered to afford compound 74a (9.20 g, 90%) as a brown solid. 1HNMR (CDCI3, 400 MHz) 8.45 (d, 1H), 8.26 (d, 1H), 7.72 (s, 1H)1 7.11-7.01 (m, 2H), 3.89 (s, 3H); MS (M-NHCOH+1)+ m/z calcd for C7H6BrO+ = 187.0, found m/z = 187.1
90%
Step A:To a round bottom flask at room temperature, containing formic acid (85%, 27 rrsL, 624.4 mmoi) was added acetic anhydride (16 mL, 169.5 mmoi) dropwise. The reaction stirred for 45 min. followed by the dropwise addition of a solution of 4-bromo- 2-methoxyaniline (9.01 g, 44.6 mmoi) in THF (56 mL). The reaction mixture was quenched with ice-water after 23 h and the resulting precipitate was filtered to afford compound 100.1 (9.20 g, 90%) as a brown solid.
With water; iron; ammonium chloride; In tetrahydrofuran; at 65℃; for 4h;Inert atmosphere;
Step 3 4-bromo-2-methoxyaniline (Compound 12-5) At room temperature, the reduced iron powder (4.48 g, 80 mmol) and ammonium chloride (2.65 g, 50 mmol) were added to a mixed solution of compound 12-4 (2.3 g, 10.0 mmol) in 60 ml of THF/water (volume ratio of THF and water is 2:1), and vigorously stirred at 65 C. for 4 h. After completion of the reaction, the reaction mixture was filtered, the filtrate was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-5 (2.0 g) which was used directly in the next step. MS m/z (ESI): 201.9 [M+H]+.
With ammonium chloride; zinc; In methanol; at 25℃; for 2h;Inert atmosphere;
To a solution of 4-bromo-2-methoxy-1-nitro-benzene (1.07 g, 4.63 mmol, 1 eq) in MeOH (20 mL) was added Zn (3.03 g, 46.30 mmol, 10 eq) and NH4Cl (2.48 g, 46.30 mmol, 1.62 mL, 10 eq). The mixture was stirred at 25 C. for 2 h under N2 atmosphere. The reaction mixture was filtered, concentrated and water (80 mL) was added, extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield 4-bromo-2-methoxy-aniline (830 mg, 4.11 mmol, 88.7% yield, crude) as a black solid which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.89 (d, J=2.2 Hz, 1H), 6.80 (dd, J=2.1, 8.3 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.87 (s, 2H), 3.75 (s, 3H); ES-LCMS m/z 204.0, 206.0 [M+H]+.
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 110℃; for 48h;
STEP 2: tert-Butyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydrobenzoxazepine-4(5H)-carboxylate (500 mg, 2.33 mmol), 4-bromo-2- methoxyaniline (296 mg, 1.47 mmol), potassium carbonate (737 mg, 5.34 mmol) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (97.5 mg, 0.13 mmol) were heated at HO0C in DME (7 mL) and water (1 mL) over 48 h. The mixture was then cooled to room temperature and diluted with an excess of ethyl acetate and filtered through a bed of celite. The filtrate was partitioned with water and the organic phase washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated and the residue purified by silica chromatography using 85:15 hexanes: ethyl acetate as eluent to give 1,1-dimethylethyl 7-[4-amino-3- (methyloxy)phenyl]-2,3-dihydro-l,4-benzoxazepine-4(5H)-carboxylate (198 mg, 40%). MS (EI) C2IH26N2O4: 371 (MH+).
With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In dimethyl sulfoxide; at 150℃; for 0.666667h;Microwave irradiation;
Example 27E (500 mg, 2.47 mmol) in DMSO (5mL) solution was added bis(pinacolato)diboron(628.4 mg, 2.47 mmol), tetrakis triphenylphosphine palladium (150 mg, 0.13 mmol ) and potassium acetate (485 mg, 4.95 mmol) and the reaction mixture was stirred at 150 deg.C by microwave for 40 minutes. The reaction mixture was diluted with ethyl acetate (50mL) and water (30mL). The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether 1:: ethyl acetate = 10) to give the title compound (160 mg, 26% yield) as a yellow oil.
At 5 C., a solution of bromine (9.8 mL, 192.5 mmol, 1.1 eq) in dichloromethane (120 mL) was added slowly to a dichloromethane solution (240 mL) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (35.35 g, 175 mmol) under vigorous stirring. The reaction mixture was kept at this temperature for 2 h. After the completion monitored by TLC, the reaction mixture was poured into ice water and extracted with ethyl acetate (3*200 mL). The organic layer was combined, washed with brine (3*50 mL) and dried over sodium sulfate. Then the reaction mixture was purified by flash column chromatography (ethyl acetate/hexanes (v/v)=5/95). The product (40.3 g, yield=82%) was obtained as a red liquid. 1H NMR (600 MHz, CDCl3) delta 7.20 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H), 4.21 (s, 2H), 3.86 (s, 3H). LRMS m/z 280.0 [M+H]+.
2,8-dibromo-4,10-dimethoxy-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
<strong>[59557-91-4]4-Bromo-2-methoxyaniline</strong> (670 mg, 3.31 mmol) and paraformaldehyde (160 mg, 5.30 mmol) were dissolved in trifluoroacetic acid (30 mL) and the resulting reaction mixture was stirred under an argon atmosphere in dark for 48 h. The reaction mixture was then basified with a solution of concentrated ammonia (30 mL) in water (80 mL). A saturated sodium hydrogen carbonate solution (100 mL) was added and the aqueous mixture was extracted into dichloromethane (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford a transparent light brown solid. The crude material was chromatographed (silica, ethyl acetate/hexane 1:1) to afford (+/-)-21 (570 mg, 79%) as a white solid: mp 233-234 C; Rf (50% EtOAc/CH2Cl2) 0.55; IR (neat) numax 2965, 2939, 1564, 1470, 1410, 1257, 1220, 826 cm-1; 1H NMR (400 MHz, CDCl3) delta 3.90 (s, 6H, OCH3), 4.20 (d, J 17.2 Hz, 2H, CH2), 4.26 (s, 2H, CH2), 4.47 (d, J 17.2 Hz, 2H, CH2), 6.71 (d, J 1.7 Hz, 2H, ArH), 6.82 (d, J 1.7 Hz, 2H, ArH). 13C NMR (100 MHz, CDCl3) delta 53.8, 55.8, 67.6, 112.3, 117.1, 121.7, 130.8, 134.3, 153.5; Anal. Calcd for C17H16Br2N2O2: C 46.39; H 3.66; N 6.36. Found: C 46.43; H 3.62; N 6.30%.
To a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (4.0 g, 20 mmol) in concentrated hydrochloric acid (40 mL) was added dropwise sodium nitrite (1.4 g, 21 mmol) and water (2 mL) solution while maintaining at -20C, and the mixture was stirred at the same temperature for 15 min. The mixture was warmed to 0C, and the mixture was stirred at the same temperature for 20 min, and further, a solution of tin chloride·2 hydrate (17 g, 74 mmol) in concentrated hydrochloric acid (140 mL) was added dropwise to the reaction mixture while maintaining at -20C. After stirring at the same temperature for 10 min, and the mixture was stirred at room temperature for 40 min. The precipitate was collected by filtration, and washed with ice water and diethyl ether. To the filtered material was added ethyl acetate and 10% aqueous potassium carbonate, and the insoluble material was filtered off. The aqueous layer of the filtrate was extracted with ethyl acetate, the organic layer was combined, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (3.4 g, 78%). 1H NMR (CDCl3) delta: 3.49 (2 H, br), 3. 84 (3 H, s), 5.61 (1 H, br), 6.85 - 6.88(2 H, m), 7.06 (1 H, dd, J=2.1, 8.7 Hz).
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 15h;Inert atmosphere;
EXAMPLE 99 7-[(cyclopropylmethyl)amino]-5-{ [2-methoxy-4-(piperidin-4-yl)phenyl]amino}pyrido[3,4- d]pyridazin-4-ol EXAMPLE 99A itri-buty l 4-(4-amino-3-methoxyphenyl)-5,6-dihvdropyridine- l (2/J)-carbox late A mixture of <strong>[59557-91-4]4-bromo-2-methoxybenzenamine</strong> ( 1.21 g, 6.0 mmol), tert-butyl 4- (3,3,4,4-tetramethylborolan-l-yl)-5,6-dihydropyridine- l (2/ )-carboxylate ( 1 .95 g. 6.3 mmol), sodium carbonate (1.91 g, 18 mmol) and 1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 g, 0.3 mmol) in dioxane (25 mL) and water (5 mL) was degassed with nitrogen and heated at 90C for 1 hours. After coohng to ambient temperature, the mixture was filtered, concentrated and purified by flash" chromatography eluting with 200: 1 dichloromethane/methanol to give the title compound.MS: 305 (M+rf).
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 15h;Inert atmosphere;
Example 62 5-(2,3-dichlorobenzyl)-7-{ [2-methoxy-4-(piperidin-4-yl)phenyl]amino} [l ,2,4]triazolo[4,3- c]pyrimidine-8-carboxamide Example 62A feri-butyl 4-(4-amino-3-methoxyphenyl)-5,6-dihydropyridine-l(2//)-carboxylate A mixture of <strong>[59557-91-4]4-bromo-2-methoxybenzenamine</strong> (1.21 g, 6.0 mmol), tert-butyl 4- (3,3,4,4-tetramethylborolan-l -yl)-5,6-dihydropyridine-l (2//)-carboxylate (1.95 g, 6.3 mmol), sodium carbonate (1 .91 g, 18 mmol) and 1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 g, 0.3 mmol) in dioxane (25 mL) and water (5 mL) was degassed with nitrogen and heated to 90C for 15 hours. After cooling to ambient temperature, the mixutre was filtered, concentrated and purified by flash chromatography eluting with 200: 1 dichloromethane:methanol to give the title compound. MS: 305 (M+Hf).
With sulfuric acid; guanidine nitrate; at 0 - 5℃; for 0.5h;
Embodiment 8A 4-Bromo-2-methoxy-5-nitroaniline 2-Methoxy-4-bromoaniline (5.00g, 24.75mmol) was added to concentrated H2SO4 (50mL) at 0 to 5C and then guanidine nitrate (3.02g, 24.75mmol) was added in batches. The mixture was stirred at 0 to 5C for 30 minutes. TLC showed the reaction was complete and the reaction mixture was slowly added dropwise to a solution of NaHCO3 (100g) in water (1L), the temperature was controlled below 15C. The resulting mixture was filtered to deliver the title compound (yellow solid, 5.40g, yield 83.90%). 1H NMR (400MHz, CDCl3): delta, 7.39 (s, 1H), 7.01 (s, 1H), 4.09 (br. s., 2H), 3.96 (s, 3H).
80.19%
With sulfuric acid; cerous nitrate; at 0 - 5℃; for 0.75h;
Add in 100mL single-mouth bottles85% sulfuric acid (39 mL) and <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (5 g, 24.8 mmol),The temperature was lowered to 0-5 C, and cerium nitrate (3.2 g, 26.1 mmol) was added in portions.After the addition, the temperature was reacted for 45 minutes.The reaction solution was poured into iced 50% aqueous sodium hydroxide (100 mL, pH > 8).The temperature was controlled to stir at 5-10 C, filtered, and the filter cake was rinsed with 100 mL of water.drying. The crude product was beaten with 50 mL of n-hexane for 20 min and filtered.The filter cake was dried to give 4.9 g of a yellow solid. Yield: 80.19%.
74%
With sulfuric acid; guanidine nitrate; In water; at 0 - 5℃; for 0.916667h;
85% Sulfuric acid was made by adding 98% sulfuric acid (13 mL) cautiously to ice (2 g). Guanidine nitrate (1.221 g, 10.00 mmol) was added portionwise over a period of 10 minutes to a cooled (0-5C) mixture of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (2.020 g, 10 mmol) in 85%o sulfuric acid (15.68 mL, 250.00 mmol). The resulting dark blue mixture was stirred at 0-5C for 0.75h and was then poured very slowly into a well-stirred mixture of 50% aq NaOH (40 mL) and ice (120 g). An orange precipitate was collected by filtration, washed with water (4 x 50 mL) and air dried. This material was dissolved into diethyl ether (100 mL) and filtered through a silica plug. The resulting solution was diluted with isohexane and purified by evaporative crystallisation from diethyl ether/isohexane to give the title compound (1.821 g, 74%) as an orange crystalline solid; 1H NMR: 3.90 (3H, s), 5.52 (2H, s), 7.14 (1H, s), 7.32 (1H, s).
57.48%
With sulfuric acid; guanidine nitrate; at 0 - 5℃; for 1h;
To 80 mL of a 85% sulfuric acid solution at 0-5 C, 10.10 g (50.00 mmol) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> was added and dissolved by stirring. At this temperature, thereto was added 6.10 g (50.00 mmol) of guanidine nitrate. After the addition, the temperature was controlled at 0-5 C and stirred for 1 hour. Then, the reaction system was slowly poured into 200 mL of a 50% NaOH solution, and a solid precipitated. The precipitate was filtered, washed, dried, and purified by column chromatography (PE/EA = 10/1, 6/1) to give 7.10 g (28.70 mmol) of 4-bromo-5-nitro 2-methoxyaniline. The yield was 57.48%
1.2 g
With sulfuric acid; guanidine nitrate; at 0℃; for 0.75h;
Step 1 Guanidine nitrate (1.22 g, 10.00 mmol) was added portionwise to a cooled mixture of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (2.02 g, 10.00 mmol) in 85% sulfuric acid (15.68 mL, 250.00 mmol). The resulting blue mixture was stirred for 45 min at 0 C. and was slowly poured over a well-stirred mixture of 1N NaOH (40 mL) and ice (120 g). The aqueous layer was extracted with ethyl acetate and the organic layer was concentrated in vacuo. Purified by column chromatography (0-40% ethyl acetate in hexane) to give 1.20 g of 4-bromo-2-methoxy-5-nitrobenzenamine; MS (ESI) m/z 247.0 [M+H]+.
300 mg
With sulfuric acid; potassium nitrate; at -20℃; for 0.0833333h;Inert atmosphere;
Step 4 4-bromo-2-methoxy-5-nitroaniline (compound 12-6) Potassium nitrate (217 mg, 2.25 mmol) was added to a solution of compound 12-5 (400 mg, 2.0 mmol) in 3.5 ml of concentrated sulfuric acid at -20 C., and vigorously stirred at -20 C. for 5 min. After completion of the reaction, the reaction mixture was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-6 (300 mg) which was used directly in the next step. MS m/z (ESI): 246.9 [M+H]+.
With sulfuric acid; guanidine nitrate; at 0℃; for 1h;
Guanidinium nitrate (6.10 g, 50 mmol) was added in portions to a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (10.10 g, 50 mmol) in sulfuric acid (85%, 80 mL) at 0 C, over 10 minutes. After stirring 1 hr at 0 C, the reaction mixture was poured slowly onto ice (600 g) and 50% NaOH solution (200 mL), and the solid was collected by vacuum filtration, rinsed with water (3x100 mL), and dried to give 4-bromo-2-methoxy-5-nitroaniline (7.10 g, 57.5%) as a light yellow solid. 1H NMR (CDCl3) : 7.17 (s, 1H), 6.90 (s, 1H), 3.98 (br, 2H), 3.84 (s, 3H).
To a solution of 2-methoxy-phenylamine (11.27 mL, 12.31 g, 0.1 mol) in glacial acetic acid (250 mL) maintained at about 10 C a solution of bromine (5.65 mL, 17.58 g, 0.11 mol) in glacial acetic acid (7 mL) was added over 2 h. A purple precipitate was formed, that was filtered on a Buchner funnel and rinsed with glacial acetic acid and petroleum ether (3 x 100 mL) to afford a whitish solid mixture of 4-bromo-2-methoxy-phenylamine and 4,5-dibromo-2-methoxy- phenylamine (26.9 g). The mixture was separated by flash chromatography on silica gel (hexane/EtOAc 40/60) and the desired compound was crystallized from fert-butyl methyl ether (18.73 g, 82.9%).1H NMR (400 MHz, DMSO-cie) delta ppm 3.83 (s, 3 H) 6.83 (d, J=8.42 Hz, 1 H) 6.98 (dd, J=8.30, 2.08 Hz, 1 H) 7.11 (d, J=1.95 Hz, 1 H).HRMS mil calcd for [M + H] 201.9862; found 201.9866.
With toluene-4-sulfonic acid In 1,4-dioxane at 100℃; for 2h;
5.1 N2-(4-Bromo-2-methoxyphenyl)-N4-methyl-5(trifluoromethyl)pyrimidine-2,4-diamine
A mixture of 2 -chloro-N-methyl-5 -(trifluoromethyl)pyrimidin-4-amine (0.5 g, 2.36 mmol), 4-bromo-2-methoxyaniline (0.72 g, 0.38 mmol) and p-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane (10 mL) was heated at 100 oC for 2 h. The mixture was cooled, filtered and the solid washed with dioxane. The solid was dried in a vacuum ovento give crude N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5 -(trifluoromethyl)pyrimidine2,4-diamine (1.31 g) which was used in the next step without any further purification.
2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 92h;
A mixture of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (208 mg, 1.03 mmol), 1 ,2,4-triazole (80 mg, 1.13 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and Cul (20 mg, 0.103 mmol) in DMF was heated at 110 oC for 20 h. Further portions of 1,2,4-triazole (0.1 g, 1.44 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and Cul (0.1 g, 0.52 mmol) were added and the mixturewas heated a further 72 h at 110 oC. The mixture was cooled, diluted with ethyl acetate (20 mL) and washed with water (2 x 20 mL). The combined aqueous washes were reextracted with ethyl acetate (20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate isohexane)gave 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline as a light red solid (92 mg, 47%). ?H NMR (400 MHz, CDC13): oe 8.41 (s, 1H); 8.05 (s, 1H); 7.11 (d, J = 2.3, 1H); 6.99 (dd, J = 8.3, 2.3, 1H); 6.74 (d, J = 8.3, 1H); 3.97 (s, 2H); 3.92 (s, 3H).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In tetrahydrofuran; water; at 60℃; for 18h;
General procedure: The following Preparations were prepared according to Preparation 66 using the appropriate halo aniline and boronic acid or ester as described below. The crude reaction residues were purified as described or according to one of the following methods: Method A: Silica gel column chromatography eluting with Method B: Silica gel column chromatography eluting with
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 120℃; for 0.5h;Microwave irradiation;
Preparation 48: 4-(1 ,5-dimethyl-1 -/-pyrazol-4-yl)-2-methoxyaniline To a solution of 2-methoxy-4-bromoaniline (100 mg, 0.495 mmol) in dioxane (2 mL) and water (1 mL) was added boronate ester (143 mg, 0.643 mmol), Pd(PPh3)4 (57 mg, 0.049 mmol) and sodium carbonate (91 mg, 1 .089 mmol). The reaction was heated to 120 C for 30 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (30 mL) and water (30 mL). The aqueous layer was re-extracted with EtOAc (30 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in EtOAc to give the title compound (35 mg, 33%). 1 H NMR (500 MHz, CDCI3): delta 7.63 (s, 1 H), 6.91 (dd, J = 8.0, 2.0 Hz, 1 H), 6.89 (d, J = 2.0 Hz, 1 H), 6.85 (app s, 1 H), 3.97 (s, 6H), 2.41 (s, 3H). LCMS (ESI, ) Rt = 1 .12 minutes MS m/z 218.20 [M+H]+
4-(dipropylphosphoryl)-2-methoxyaniline hydrochlride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
4-(Dipropylphosphoryl)-2-methoxyaniline To a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (0.100 g, 0.495 mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150 C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield).
4-(diethylphosphoryl)-2-methoxyaniline hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
4-(Diethylphosphoryl)-2-methoxyaniline (0786) (0787) To a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (0.100 g, 0.495 mmol) in 2 mL DMF was added diethylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150 C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(diethylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield).
2-methoxy-4-(1-methyl-1H-pyrazol-5-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 70℃; for 18h;
General procedure: Preparation 45 (1126) -methoxy-4-(1 -methyl-1 -/-pyrazol-3-yl)aniline (1127) (1128) To a solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (310 mg, 1 .244 mmol) and 3-bromo-1 -methyl-1 -/-pyrazole (154 mg, 0.957 mmol) in THF (3 ml_) was added Pd(dppf)Cl2-DCM (40 mg, 0.049 mmol) and 2M aqueous Na2CC>3 (1 ml_) and the reaction was heated to 65 C for 18 hours. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, the combined organic layers were washed with water and brine, dried (MgS04) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-60% EtOAc in cyclohexane to afford the title compound (34 mg, 18%). (1129) 1 H NMR (500 MHz, CDCI3): delta ppm 7.33 (d, J = 18.8 Hz, 2H), 7.28 (d, J = 1 .2 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1 H), 6.74 (dd, J = 7.9, 1 .2 Hz, 1 H), 6.45 (dd, J = 2.2, 1 .2 Hz, 1 H), 3.95 (m, 6H), 3.85 (br s, 2H). (1130) HRMS (ESI) MS m/z calcd for C11 H14N3O [M+H]+ 204.1 131 , found 204.1 141 .
N-(4-bromo-2-methoxyphenyl)-3-chloropropanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With potassium carbonate; In water; acetone; at 0℃; for 0.583333h;
To stirred a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (10 g, 49.49 mmol) and K2C03 (10.24 g, 74.22mmol) in a mixture of acetone (20 mL) and water (40 mL) was added dropwise 3-chloro propanyl chloride (6.28 mL, 61.87 mmol) at 0 C and the reaction mixture was stirred for 5 mm at same temperature. The mixture was then transferred into ice water (1 L) and stirred for 30 mm and the resulting solid was recuperated by filtration to afford title compound (10 g, 69%). 1H NMR (400MHz, DMSO) O ppm 9.41 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2Hz, 1H), 7.11-7.09 (dd, J = 8.2 Hz, 1H), 3.86-3.83 (m, 5H), 2.93 (t, J = 6.4 Hz, 2H).
Intermediate 10 4-Bromo-2-methoxy-N /V-dimethylaniline [00406] Formaldehyde (3.7 mL, 49 mmol, 37% aqueous) and acetic acid (57 uL, 1 mmol) were added to a solution of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (2.0 g, 9.9 mmol) in methanol (10 mL) at 25 C. The mixture was stirred for 2 h, and then sodium cyanoborohydride (3.11 g, 49.5 mmol) was added in portions. The resulting mixture was stirred for 12 h, poured into a saturated NaHC03 solution (40 mL), and then extracted with ethyl acetate (3 x20 mL). The combined organic phases were washed with brine (2x20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate; 15/1) to give 4-bromo-2-methoxy-N,N-dimethylaniline (2.0 g, 80%) as a brown oil. 1H MR (CDC13): delta 7.02 (dd, 1H), 6.95 (d, 1H), 6.78 (d, 1H), 3.87 (s, 3H), 2.76 (s, 6H); MS: 230.0 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere;
21.2 (2) Preparation of 4-(4-amino-3-methoxyphenyl)pyridin-2(1H)-one
(0694) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.27 g, 5.7 mmol), 4-bromo-2-methoxyaniline (1.16 g, 5.7 mmol) and potassium carbonate (1.97 g, 14.3 mmol) were added to 1,4-dioxane (50 mL) and water (10 mL). Under the protection of nitrogen gas, [1,1′-bis(diphenyphosphino)ferrocene]dichloropalladium ( II) (417 mg) was added. The mixture was heated to 90° C. and reacted for 12 h, and then filtrated under suction. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to get the title compound (600 mg, yield: 48.8%).
(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
(rac)-tert-butyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29.7%
A 100-mL round-bottom flask was charged with (E)-tert-buty 3-(3-methoxy-3-oxoprop-l-en-l-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (Preparation 3a, 3.00 g, 7.22 mmol), 2-amino-5-bromoanisole (Alfa Asear, 1.61 g, 7.94 mmol), xantphos (0.52 g, 0.90 mmol), cesium carbonate (7.06 g, 21.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.33 g, 0.36 mmol), and 1,4-dioxane (36 mL) then sparged with nitrogen for 15 min. The reaction mixture stirred vigorously for 20 h at ambient temperature. The reaction mixture was subsequently vacuum filtered through a 1.0 cm plug of silica gel and the pad was rinsed with EtOAc (3 x 50 mL). The filtrate was concentrated under reduced pressure to give a brown foam that was used immediately without further purification.The brown foam was diluted with MeOH (72 mL) and transferred to a 125-mL pressure vessel equipped with a stir bar. The reaction vessel was subsequently charged with sodium methoxide (25 wt. % in MeOH, 0.80 ml, 3.61 mmol) and sealed with a Teflon cap equipped with a pressure-relief valve. The reaction vessel was placed in a 70 C oil bath and stirred vigorously. After 5 h, the reaction mixture was allowed to cool to ambient temperature, transferred to a 250-mL round-bottom flask with additional MeOH and concentrated under reduced pressure. The brown oil was redissolved in DCM (50 mL) and filtered through a pad of Celite (3 cm) to facilitate loading the material onto a column. The Celite pad was rinsed with DCM (3 x 50 mL). The brown filtrate was concentrated under reduced pressure and purified by flash column chromatography (100-g silica gel Biotage column, eluent: gradient, 5 to 70% 3:1 EtOAc/EtOH in heptane with DCM as a 10% additive) to afford (rac)-tert-butyl 1-(4-bromo-2-methoxypheny l)-2-oxo-1,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (933 mg, 2.143 mmol, 29.7 % yield) as a tan foam.
4-bromo-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)benzenesulfonamide[ No CAS ]
4-((4-bromo-2-methoxyphenyl)amino)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1?-biphenyl]palladium(II) dichloromethane; In 1,4-dioxane; at 100℃; under 760.051 Torr; for 4h;Inert atmosphere;
4-bromo-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)benzenesulfonamide (1 g, 2.362 mmol), <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (0.477 g, 2.362 mmol), xantphos palladacycle precatalyst: [Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthenej [2-amino- 1,1?- biphenyljpalladium(II) dichloromethane adductj (0.112 g, 0.118 mmol), and finely ground potassium phosphate (1.504 g, 7.09 mmol) were dissolved in 1,4-dioxane (9.45 ml) in a 40 ml vial and the vial was evacuated and backfilled three times with N2 before being fitted with a fresh cap and heated to 100 C on an aluminum block. After 4 hours, complete conversion was observed. THF was added and the reaction was filtered over CELITE and concentrated. MPLC purification (bOg snap ultra, 2-75% EtOAc:Heptane) provided N-(isoxazol-3-yl)-4-(isoxazol-3 -yl(4-methoxybenzyl)amino)-N-(4- methoxybenzyl)benzenesulfonamide LC/MS m+H = 544.0, 545.0
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 80℃; for 12h;Inert atmosphere;
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (1 g, 4.95 mmol, 1 equiv), toluene (10 mL), EtOH (10 mL), H2O (10 mL), K2CO3 (2.1 g, 14.85 mmol, 3 equiv), phenylboronic acid (0.7 g, 5.74 mmol, 1.2 equiv), Pd(PPh3)4 (0.6 g, 0.52 mmol, 0.1 equiv). The resulting solution was stirred for 12 h at 80 C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 550 mg (55.77%) of 20.1 as a yellow solid.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 15h;Inert atmosphere;
General procedure: 4-Bromobenzenamines 1a-c (6.4 mmol) were dissolved in the mixed solvents (2M K2CO3:DMF = 1:1, 24 mL), and then added corresponding 4-substituent phenylboronic acids 2a-h (7.7 mmol) and Pd (PPh3)4 (0.22 mmol) under argon. The reaction mixture was refluxed at 100 for 15 h (TLC monitored the reaction). The reaction was then cooled to room temperature and filtered. The filtrate was added 10 times the amount of water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, concentrated under reduced pressure, and dried to give a crude product. The crude product was purified by flash column chromatography (ethyl acetate/petroleum ether, 1:8-1:5) to afford 1,1'-biphenyl-4-amines 3a-x, yield: 77-95%.
ethyl 1-(4-bromo-2-methoxyphenyl)-1H-1,2,4-triazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.1%
<strong>[59557-91-4]4-Bromo-2-methoxyaniline</strong> (2.00 g, 9.90 mmol) were dissolved in water (10 mL) and concentrated hydrochloric acid (3 mL). The mixture was cooled in ice-salt bath, then a solution of sodium nitrite (0.69 g, 9.8 mmol) in water (4 mL) was added dropwise slowly while maintaining the temperature at 0-5 C. After the addition, the mixture was stirred at 0C for 5 min. The mixture described above was added to a mixture of sodium acetate trihydrate (8.75 g, 64.3 mmol), ethyl isocyanoacetate (1.0 mL, 9.15 mmol) and MeOH/H2O (22 mL, 10/1) while maintaining the temperature at 0-5 C. After the addition, the mixture was stirred at 0C for 30 min, then warmed to rt for further 3 h. After the reaction was completed, the mixture was concentrated to remove most of the solvent. The residue was filtered, and the filter cake was washed with cool water. The filter cake was dried in vacuo to give a reddish brown solid (2.65 g, 82.1%). MS (ESI, pos.ion) m/z: 327.1 (M+2)
With copper(l) iodide; caesium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 120℃; for 24h;Inert atmosphere;
To compound <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong> (lOg, 4.95mmol, 1.2eq) and pyrrolidin-2-one (0.351g, 4.l2mmol, 1.Oeq) in 1,4-dioxane (l5mL), argon was purged for 15 mm. Then Cs2CO3 (2.7g, 8.24mmol, 2.Oeq) was added, degassed by argon for 5 mm. Then N,N-dimethylethylenediamine (0.363g, 4.l2mmol, 1.Oeq) was added and again degassed for 5 mm. Then copper iodide (0.391g, 2.O6mmol, 0.5eq) was added followed by argon purging for another 5 mm. Then reaction mixture was stirred at 120 C for 24hr. After completion of the reaction, the reaction mixture was cooled to r.t. and filtered through celite which was washed with ethyl acetate. The combined filtrate was concentrated in vacuo to obtain crude product. This was purified by column chromatography and compound was eluted in 1.5% MeOH in CH2C12 as eluent to obtain the pure 18.1 (O.5g, 48.98 %). MS(ES): m/z 207.49 [M+H]t
N-(4-bromo-2-methoxyphenyl)propane-1-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With pyridine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
General procedure: To a solution of 3k (300 mg, 1.48 mmol) in anhydrous CH2C12 (15 mL) was added pyridine (0.24 mL, 2.97 mmol) and 1-propanesulfonyl chloride (0.18 mL, 1.63 mmol) under argon, and the mixture was stirred at room temperature for 16 h. After being quenched with 1 N HC1(aq) (1.0 mL), water, and CH2C12 were added, the layers were separated. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 10:90 to 15:85) to give 6k (490.1 mg, 99%) as a light yellow oil; ?H NMR (CDC13, 500 MHz) 7.41 (1 H, d, J = 8.6 Hz), 7.08 (1 H, dd, J = 8.3, 2.3 Hz), 7.03 (1 H, d, J = 2.5 Hz), 6.74 (1 H, br) , 3.88 (3 H, s), 3.02-2.98 (2 H, m), 1.83-1.79 (2 H, m), 1.00 (3 H, t, J = 7.4 Hz); ?3C NMR (CDC13, 125 MHz) 149.5, 125.5, 124.2, 121.0, 117.5, 114.3, 56.1, 53.1, 17.1, 12.8.
2-(4-bromo-2-methoxy-anilino)-N-isopropylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With potassium carbonate; In ethanol; at 80℃;
To a solution of <strong>[2895-21-8]2-chloro-N-isopropylacetamide</strong> (201 mg, 1.48 mmol) in ethanol (1.73 mL) was added 4-bromo-o-anisidine (300 mg, 1.48 mmol) and potassium carbonate (615 mg, 4.45 mmol). The reaction mixture was then allowed to stir at 80 C overnight. The reaction was cooled to r.t. and concentrated under reduced pressure. The residue was taken up in EtOAc, and washed with NaOH (4.0 M). The aqueous layer was extracted with EtOAc (x3), the organic layers combined, washed with saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 30-50% acetonitrile (0.1% formic acid additive) in water (0.1% formic acid additive) to yield 2-(4-bromo-2-methoxy-anilino)-N-isopropylacetamide (110 mg, 0.36 mmol, 25% yield) as a white solid. UPLC-MS (ES+, Method A): 1.65 min, m/z 301.2 [M+H]+.1H NMR (400 MHz, CDCl3) delta6.98 (dd, J = 8.3, 2.7 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.47-6.41 (m, 1H), 6.34 (d, J = 8.3 Hz, 1H), 4.18-4.08 (m, 1H), 3.87 (s, 3H), 3.73 (s, 2H), 1.11 (d, J = 6.6 Hz, 6H).
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of 4-bromo-o-anisidine (300 mg, 1.48 mmol) and triethylamine (0.21 mL, 1.48 mmol) in DCM (1.86 mL) was added propionyl chloride (0.13 mL, 1.48 mmol) dropwise at r.t. The reaction mixture was allowed to stir for 1 h. The reaction mixture was diluted with DCM, washed with water and saturated brine. The organic layer was dried over Na2SO4, filtered and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 0-40% EtOAc in Pet. Ether to give N-(4-bromo-2-methoxyphenyl)propanamide (309 mg, 1.19 mmol, 81% yield) as a yellow oil. UPLC-MS (ES+, Method A): 1.64 min, m/z 258.1 [M+H]+.1H NMR (400 MHz, CDCl3) delta 8.30 (d, J = 8.7 Hz, 1H), 7.72-7.62 (m, 1H), 7.08 (dd, J = 8.6, 2.4 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 3.88 (s, 3H), 2.42 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H).
phenyl N-(4-bromo-2-methoxyphenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With pyridine; In ethyl acetate; at 0 - 20℃;
To a solution of 4-bromo-o-anisidine (300 mg, 1.48 mmol) and pyridine (0.01 mL, 0.11 mmol) in ethyl acetate (2.55 mL) was added phenyl chloroformate (0.2 mL, 1.56 mmol) with stirring at 0C. The reaction mixture was stirred overnight at r.t.. The reaction mixture was washed with water (x3) and dried over Na2SO4 before filtering. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography eluting with 0-45% EtOAc in Pet. Ether to yield phenyl N-(4-bromo-2-methoxyphenyl)carbamate (400 mg, 1.24 mmol, 84% yield) as an off white solid. UPLC-MS (ES+, Method A): 1.99 min, m/z 322.2 [M+H]+.1H NMR (400 MHz, CDCl3) delta 8.03 (d, J = 8.2 Hz, 1H), 7.53 (br s, 1H), 7.45-7.39 (m, 2H), 7.28-7.24 (m, 1H), 7.24-7.19 (m, 2H), 7.13 (dd, J = 8.7, 2.1 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 3.94 (s, 3H)
With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; sodium t-butanolate; In toluene; at 110℃; for 24h;Inert atmosphere;
1) In a 250 ml three-necked flask,Add 10g (49.5mmol) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong>,15 g (49.9 mmol) of 1-bromo-3-fluoro-4-iodobenzene, 9.5 g (99 mmol) of sodium tert-butoxide,0.5g palladium acetate,2.48g of 1,1'-bis(diphenylphosphino)ferrocene, 150ml toluene,Under nitrogen protection, heat to 110 reflux for 24 hours; the reaction is completed,It was cooled to room temperature, vacuum-dried, and extracted with 600 ml of petroleum ether.Distilling petroleum ether,Spinning to obtain pure first intermediate 16.4g, yield 88%.
N-(4-bromo-2-methoxyphenyl)-4,5-dihydro-1H-imidazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; for 18h;Reflux;
4-bromo-2-methoxyaniline (500 mg, 1.0 equiv.) and <strong>[5391-39-9]N-acetylimidazolidin-2-one</strong> (1.3 equiv.) were taken up in POCh (5 mL) and refluxed for 18 hours. After cooling to room temperature the remaining POC13 was removed in vacuo. The residue was taken up in EtOAc and then slowly added to a stirred solution of saturated sodium bicarbonate at 0 C. Stirring was maintained for 1 hour and the biphasic mixture was allowed to warm to room temperature. The organic layer was separated and the aqueous layer was extracted 1 x 10 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was subjected to column chromatography (0% - 10% MeOH/DCM + 0.1% NEt3) to afford N-(4-bromo-2-methoxyphenyl)-4,5-dihydro-lH-imidazol-2- amine.
(4-bromo-2-methoxyphenyl)(methyl)sulfane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With isopentyl nitrite; In tetrahydrofuran; at 70℃; for 3h;
To a solution of dimethyl disulfide (35 g, 371 mmol) and isopentyl nitrite (57.9 g, 495 mmol) in THF (600 mL) was added <strong>[59557-91-4]4-bromo-2-methoxybenzenamine</strong> (50 g, 247.46 mmol) slowly. The mixture was stirred at about 70 C. for about 3 h. The reaction mixture was concentrated. The residue was purified by column chromatography (silica) and eluted with pet. ether/EtOAc (100:0 to 90:10) to afford (4-bromo-2-methoxyphenyl)(methyl)sulfane (50 g, 87%). 1H NMR (CDCl3, 400 MHz): delta 7.07-7.12 (m, 1H), 6.99-7.03 (m, 1H), 6.96 (d, J=2.0 Hz, 1H), 3.90 (s, 3H), 2.42 (s, 3H). LCMS m/z=233.0 [MH]+.
Multi-step reaction with 6 steps
1.1: sodium sulfate; hydrogenchloride / water; 1,4-dioxane / 0.17 h / 50 °C
1.2: 6 h / 80 °C
2.1: sulfuric acid / 1 h / 40 °C
3.1: sodium hydroxide; dihydrogen peroxide / 1 h / 60 °C
4.1: thionyl chloride / chloroform / 3 h / 60 °C
5.1: ammonium hydroxide / 0.5 h / 20 °C
6.1: phosphorus pentoxide / toluene / 1 h / 110 °C
With dmap; triethylamine In dichloromethane at 20℃; for 3h;
6.3 (3) Synthesis of compound 1e:
At room temperature, dissolve compound 1d (1.00 g, 4.95 mmol, 1.0 eq), triethylamine (1.45 mL, 10.4 mmol, 10.0 eq) and 4-(dimethylamino)pyridine (60.0 mg, 0.50 mmol, 0.1 eq) In 20 mL CH2Cl2, then 5 mL 1,2-bis(chlorodimethylsilyl)ethane (1.17 g, 5.45 mmol, 1.1 eq) in CH2Cl2 solution was slowly dropped into the above mixture and stirred for 3 h. After the reaction, 30 mL of n-hexane was added to precipitate the chlorinated triethylamine salt, which was then filtered out. The obtained goose yellow oil was purified by column chromatography (alumina substrate, 5% ethyl acetate/petroleum ether), and finally compound 1e (1.58 g, 4.60 mmol, yield 93%) was obtained as a colorless oil.
93%
With dmap; triethylamine In dichloromethane at 20℃; for 3h; Inert atmosphere;
80.1 Step 80-1:
Step 80-1: Synthesis of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline A mixture of 4-bromo-2-methoxyaniline (1 g; 4.95 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.90 g; 7.48 mmol), cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) (202 mg; 0.247 mmol) and potassium acetate (1.45 g; 14.77 mmol) in 12 mL dioxane is stirred at 100°C in aergon atmosphere for 4hr. Excess water and EtOAc are added. The aqueous layer is extracted with additional EtOAc. The combined organic phases are dried and concentrated. The residue is purified by flash chromatography (hexane/ethyl ether from 0 to 60%) to give 0.93 g (75%) of title compound. uPLC-MS: tr = 1.51 min. (100 %). LRMS (m/z): 250 (M+1)
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