* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 60℃; for 0.416667 h; Stage #2: With hydrogenchloride In water; acetonitrile
Copper (II) bromide (6.37 g, 28.5 mmol) was dissolved in acetonitrile (40 mL) with stirring. /-Butyl nitrite (5.0 mL, 42 mmol) was added via syringe, and the reaction was heated to 602C. 4-Bromo-5-fluoro-2-nitroaniline (4.46 g, 19.0 mmol) was dissolved in acetonitrile (60 mL) and added via addition funnel over 15 minutes. The reaction was stirred an additional 10 minutes and cooled to room temperature. The reaction was poured onto aqueous 2 N HCI EPO <DP n="123"/>(400 ml_). The mixture was extracted with diethyl ether, and the organic layer was washed with brine. The combined aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 4.46 g (76percent) of the title compound. 1H NMR (300 MHz, DMSO-αfe): δ 8.59 (d, 1 H1 J= 6.5 Hz)1 8.17 (d, 1 H, J= 8.1 Hz).
With ammonium formate; zinc In methanol at 0 - 20℃; Inert atmosphere
To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 °C. Once complete it was cooled to room temperature and poured into 3 L of water. The resulting suspension was filtered and the solid was washed with 500 mL of water. Solid was air dried overnight (12.7 g, 91 percent). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 7.3 Hz, 1H), 7.73 (br. S., 2H), 6.94 (d, J = 11.0 Hz, 1H). 4-bromo-5-fluoro-2-nitroaniline (0.53 g, 2.255 mmol), zinc (0.89 g, 13.5 mmol), and methanol (32 ml) were added to the flask and argon was bubbled through the solution for 1 hour. Ammonium formate (1.42 g, 22.6 mmol) was then added in several portions. The reaction was then stirred at room temperature overnight and was complete by LCMS in the morning. It was filtered through a pad of celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was collected. The aqueous layer was back-extracted using EtOAc (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated (378 mg, 82 percent). MS (m/z) 205.0, 207.0 (M+, M+2+).
81%
With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 95℃; for 4 h;
Intermediate 11C; 4-bromo-5 -fluorobenzene- 1 ,2-diamine; To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H20 (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture was heated at 95 °C for 4 hours. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H20, brine, dried (Na2S04), filtered and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81percent).
43%
With tin(ll) chloride In ethanol for 14 h; Reflux
step 2: To a suspension of 96 (1.57 g, 6.74 mmol) in EtOH (16 mL) was added SnC¾ (3.82 g, 20.2 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and sat'd. aq. NaHCC>3 (200 mL). The resulting slurry was filtered through a pad of Celite® and the wet cake was washed with EtOAc (3 x 50 mL). The organic layer was washed sequentially with saturated NaHC03, water, and brine, dried (MgSO i), filtered and concentrated in vacuo to afford 600 mg (43percent) of 44oromo-5-fluorobenzene-l,2-diamine (98) as yellow solid: MS (ESI) m/z = 205 [M+l]
Intermediate 1 IB; 4-bromo-5 -fluoro-2-nitroaniline; To A^-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol) was added CH3OH (30mL) followed by 1.0 K2CO3 (10.5mL, 10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P.S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H20 and stirred for 1 hour. The resulting orange solid was collected by filtration and dried in a vacuum oven to give the title compound (2.1,g, 8.8 mmol, 84percent).
76%
With sodium hydroxide; water In 1,4-dioxane at 20 - 50℃; for 5.75 h;
ΛA(4-Bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide was dissolved in1 ,4-dioxane (80 mL) with stirring. Aqueous 1 N sodium hydroxide solution (50 ml_) was added, and the mixture was stirred for 45 minutes. The reaction was heated to 50 2C and was stirred at that temperature for 5 h. The reaction was cooled to room temperature and poured into diethyl ether and brine. The layers were separated, and the aqueous was extracted further with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 4.46 g (76percent) of the title compound. 1H NMR (300 MHz, DMSO-flfe): δ 8.29 (d, 1 H, J= 7.30 Hz), 7.74 (br s, 2H), 6.97 (d, 1 H, J= 10.7 Hz).
To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 °C. Once complete it was cooled to room temperature and poured into 3 L of water. The resulting suspension was filtered and the solid was washed with 500 mL of water. Solid was air dried overnight (12.7 g, 91 percent). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 7.3 Hz, 1H), 7.73 (br. S., 2H), 6.94 (d, J = 11.0 Hz, 1H). 4-bromo-5-fluoro-2-nitroaniline (0.53 g, 2.255 mmol), zinc (0.89 g, 13.5 mmol), and methanol (32 ml) were added to the flask and argon was bubbled through the solution for 1 hour. Ammonium formate (1.42 g, 22.6 mmol) was then added in several portions. The reaction was then stirred at room temperature overnight and was complete by LCMS in the morning. It was filtered through a pad of celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was collected. The aqueous layer was back-extracted using EtOAc (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated (378 mg, 82 percent). MS (m/z) 205.0, 207.0 (M+, M+2+).
76%
for 1.5 h; Reflux
Example 10 N4 -(5-Cyclopropyl-lH-pyrazol-3-yl)- N2 -((6-fluoro-lH-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4- diamine (1-28) step 1 : A solution of 5-fluoro-2-nitroaniline (1.5 g, 9.61 mmol) and NBS (1.7 g, 9.55 mmol) in HO Ac (75 mL) was heated at reflux for 90 min. The reaction mixture was then poured into ice water (300 mL) and stirred for 10 min. A bright yellow precipitate was collected by filtration and dried in vacuo overnight to afford 1.57 g (76percent) of 4-bromo-5-fluoro-2-nitroaniline (96): MS (ESI) m/z = 235 [M+l] +.
Reference：
[1] Patent: EP2566477, 2015, B1, . Location in patent: Paragraph 0172; 0173
[2] Chemical Science, 2016, vol. 8, # 1, p. 734 - 741
[3] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 133
[4] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 69
[5] Patent: KR2017/1093, 2017, A, . Location in patent: Paragraph 0107-0110
[6] Patent: KR2017/59925, 2017, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078
6
[ 351-30-4 ]
[ 153505-36-3 ]
Yield
Reaction Conditions
Operation in experiment
45%
Stage #1: at 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 120℃; for 0.333333 h; Microwave irradiation Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water
INTERMEDIATE 16; 4-Bromo-5-fluoro-2-nitrophenylaminePotassium nitrate (914 mg, 9.05 mmol) was added to a stirred solution of 4-bromo- 3-fluoroacetanilide (2 g, 8.6 mmol) in sulfuric acid (10 mL) at r.t. After 1.5 h the mixture was poured onto ice (approximately 100 g) and extracted with EtOAc (100 mL). The organic phase was dried (MgSO4) and the solvent removed in vacuo to give a brown solid (2.48 g). 1.9 g of this material was dissolved/suspended in THF (10 mL). Hydrochloric acid (2M, 10 mL) was added, and the mixture heated in a microwave for 20 minutes at 12O0C. The mixture was partitioned between EtOAc and sodium hydrogencarbonate solution (100 mL each) and the aqueous phase extracted with EtOAc (50 mL). The combined organic phases were dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 10 to 100percent EtOAc in heptane) to give an orange-brown solid (1.5 g) which was washed with 9:1 heptane:diethyl ether to give, after air-drying, the title compound (900 mg, 45percent) as an orange-yellow solid. 6H (CDCl3) 8.39 (d, IH), 6.59 (d, IH), 6.21 (br, 2H).
4-bromo-3-fluoromethyl aniline (3.8 g, 0.02 mol) was added in portions to a stirred ice-cold trifluoroacetic anhydride (50 mL). To the solution was added KNO3 (2.22 g, 0.022 mol, 1.1 eq) in portions. The reaction mixture was stirred at 0 C. for 1 h and then allowed to warm to room temperature overnight. The reaction mixture was diluted with ice water (150 mL) and the solid was collected by vacuum filtration. The solid was washed with water (50 mL) and dried in vacuo to provide the title Compound 13a as a bright yellow solid (5.42 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 8.66 (d, 1H, J=10.0 Hz) 8.60 (d, 1H, J=11.3 Hz). MS (ESI, pos. ion) m/z: 402.0 (M+Na).
With ammonium formate; zinc; In methanol; at 0 - 20℃;Inert atmosphere;
To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 C. Once complete it was cooled to room temperature and poured into 3 L of water. The resulting suspension was filtered and the solid was washed with 500 mL of water. Solid was air dried overnight (12.7 g, 91 %). 1H NMR (400 MHz, DMSO-d6) delta 8.27 (d, J = 7.3 Hz, 1H), 7.73 (br. S., 2H), 6.94 (d, J = 11.0 Hz, 1H). <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (0.53 g, 2.255 mmol), zinc (0.89 g, 13.5 mmol), and methanol (32 ml) were added to the flask and argon was bubbled through the solution for 1 hour. Ammonium formate (1.42 g, 22.6 mmol) was then added in several portions. The reaction was then stirred at room temperature overnight and was complete by LCMS in the morning. It was filtered through a pad of celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was collected. The aqueous layer was back-extracted using EtOAc (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated (378 mg, 82 %). MS (m/z) 205.0, 207.0 (M+, M+2+).
81%
With iron; ammonium chloride; In tetrahydrofuran; ethanol; water; at 95℃; for 4h;
Intermediate 11C; 4-bromo-5 -fluorobenzene- 1 ,2-diamine; To a solution of <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H20 (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture was heated at 95 C for 4 hours. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H20, brine, dried (Na2S04), filtered and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81%).
43%
With tin(ll) chloride; In ethanol; for 14h;Reflux;
step 2: To a suspension of 96 (1.57 g, 6.74 mmol) in EtOH (16 mL) was added SnC¾ (3.82 g, 20.2 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and sat'd. aq. NaHCC>3 (200 mL). The resulting slurry was filtered through a pad of Celite and the wet cake was washed with EtOAc (3 x 50 mL). The organic layer was washed sequentially with saturated NaHC03, water, and brine, dried (MgSO i), filtered and concentrated in vacuo to afford 600 mg (43%) of 44oromo-5-fluorobenzene-l,2-diamine (98) as yellow solid: MS (ESI) m/z = 205 [M+l]
With ammonium chloride; zinc; In ethanol; at 20℃; for 16h;
Compound 13b (1.88 g, 0.008 mol) was dissolved in 20 mL of ethanol. Zinc powder (4.71 g, 0.072 mol) was added in portions followed by the addition of the ammonium chloride (0.86 g, 0.016 mol). The reaction mixture was stirred at room temperature overnight (16 h). The reaction mixture was filtered over a pad of celite and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate (30 mL) and washed with 25 mL of brine. The organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH, 96:4-94:6)) to provide the title Compound 13c as a dark yellow solid (1.02 g) that was used immediately in the next reaction. MS (ESI, pos. ion) m/z: 235.7 (M+1).
With tin(II) chloride dihdyrate; In ethanol; at 70℃; for 3h;
To a solution of <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (3.2 g, 13.6 mmol) in ethanol (75 mL) was added tin(II) chloride dihydrate (9.2 g, 40.8 mmol) and the reaction was heated at 70 degrees C. for 3 h. The reaction was allowed to cool, then was diluted with saturated sodium bicarbonate and water, and was extracted with ethyl acetate (3×). The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified via chromatography (50% ethyl acetate/hexanes), providing the product, 4-bromo-5-fluoro-1,2-benzenediamine, as a tan solid.1H NMR (400 MHz, CDCl3) delta 3.5 (br s, 4H), 6.49 (d, J=9.52 Hz, 1H), 6.82 (d, J=6.6 Hz, 1H).
With N-Bromosuccinimide; In N,N-dimethyl-formamide;
4-Bromo-3-fluoro-6-nitroaniline 4-Bromo-3-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 3-fluoro-6-nitroaniline (500 mg, 3.2 mmol) in dry DMF (15 mL) under N2 was added dropwise a solution of N-bromosuccinimide (626 mg, 3.2 mmol) in dry DMF. The reaction was allowed to stir 48 h. The solution was then poured into 100 mL H2 O. The cloudy yellow suspension which formed was then extracted with 4*25 mL of methylene chloride. The combined organic extracts were washed with 4*25 mL of H2 O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1 H NMR showed this solid to be a mixture of mono- and dibrominated products in a 3.8:1 ratio. The mixture was separated by flash chromatography (2:1 hexanes:ethyl acetate) to yield 324 mg of a yellow solid (43%). 1 H NMR (CDCl3) delta6.19(br s, 2H, NH2); 6.58(d, 1H, JHF =9.6, ArH); 8.39(d, 1H, JHF =6.9, ArH).
Copper (II) bromide (6.37 g, 28.5 mmol) was dissolved in acetonitrile (40 mL) with stirring. /-Butyl nitrite (5.0 mL, 42 mmol) was added via syringe, and the reaction was heated to 602C. 4-Bromo-5-fluoro-2-nitroaniline (4.46 g, 19.0 mmol) was dissolved in acetonitrile (60 mL) and added via addition funnel over 15 minutes. The reaction was stirred an additional 10 minutes and cooled to room temperature. The reaction was poured onto aqueous 2 N HCI EPO <DP n="123"/>(400 ml_). The mixture was extracted with diethyl ether, and the organic layer was washed with brine. The combined aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 4.46 g (76%) of the title compound. 1H NMR (300 MHz, DMSO-alphafe): delta 8.59 (d, 1 H1 J= 6.5 Hz)1 8.17 (d, 1 H, J= 8.1 Hz).
Intermediate 1 IB; 4-bromo-5 -fluoro-2-nitroaniline; To A^-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol) was added CH3OH (30mL) followed by 1.0 K2CO3 (10.5mL, 10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P.S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H20 and stirred for 1 hour. The resulting orange solid was collected by filtration and dried in a vacuum oven to give the title compound (2.1,g, 8.8 mmol, 84%).
76%
With sodium hydroxide; water; In 1,4-dioxane; at 20 - 50℃; for 5.75h;
LambdaA(4-Bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide was dissolved in1 ,4-dioxane (80 mL) with stirring. Aqueous 1 N sodium hydroxide solution (50 ml_) was added, and the mixture was stirred for 45 minutes. The reaction was heated to 50 2C and was stirred at that temperature for 5 h. The reaction was cooled to room temperature and poured into diethyl ether and brine. The layers were separated, and the aqueous was extracted further with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 4.46 g (76%) of the title compound. 1H NMR (300 MHz, DMSO-flfe): delta 8.29 (d, 1 H, J= 7.30 Hz), 7.74 (br s, 2H), 6.97 (d, 1 H, J= 10.7 Hz).
With methanol; potassium carbonate; at 20℃; for 10h;
Compound 13a (5.0 g, 0.015 mol) was dissolved in a mixture of methanol (25 mL) and saturated aqueous K2CO3 (15 mL) and the mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with water (25 mL) and the product was collected by vacuum filtration to provide the title Compound 13b as a yellow solid (2.5 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 8.39 (d, 1H, J=7.1 Hz) 6.75 (d, 1H, J=9.6 Hz) 6.19 (bs, 2H). MS (ESI, pos. ion) m/z: 236.9 (M+1).
EXAMPLE 356-Fluoro-7-[3-(piperidin- 1 -ylmethyDphenyliquinoxalineTin(II) chloride (0.82 g, 4.35 mmol) was added to a solution/suspension of Intermediate 16 (204 mg, 0.87 mmol) in water (0.16 g, 8.7 mmol), isopropanol (2 mL) and EtOAc (10 mL) at r.t. The mixture was heated for 4 h at 600C. Glyoxal (0.5 mL, 40% in water) was added, and the mixture was allowed to cool to r.t. The mixture was adsorbed onto silica and purified by column chromatography (SiO2, 10-100% EtOAc in heptane) to give an orange-brown gum (48 mg). This material was dissolved in DME (0.6 mL), and 3-(piperidin-l-ylmethyl)phenylboronic acid pinacol ester hydrochloride (70 mg, 0.21 mmol), 2M aqueous sodium carbonate solution (0.3 mL, 0.6 mmol) andPd(PPh3 )4 (8 mg, 0.007 mmol) were added. The mixture was heated to 1200C in a sealed tube, under microwave irradiation, for 20 minutes. After cooling, the organic phase was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (4 mg, 1.4% over the three steps) as a pale yellow-brown gum. 5H (CDCl3) 8.85 (m, 2H), 8.21 (d, IH), 7.84 (d, IH), 7.64 (s, IH), 7.37-7.59 (m, 3H), 3.57 (s, 2H), 2.34-2.50 (m, 4H), 1.51-1.70 (m, 4H), 1.39-1.49 (m, 2H). LCMS (ES+) 322 (M+H)+, RT 2.48 minutes.
INTERMEDIATE 16; 4-Bromo-5-fluoro-2-nitrophenylaminePotassium nitrate (914 mg, 9.05 mmol) was added to a stirred solution of 4-bromo- 3-fluoroacetanilide (2 g, 8.6 mmol) in sulfuric acid (10 mL) at r.t. After 1.5 h the mixture was poured onto ice (approximately 100 g) and extracted with EtOAc (100 mL). The organic phase was dried (MgSO4) and the solvent removed in vacuo to give a brown solid (2.48 g). 1.9 g of this material was dissolved/suspended in THF (10 mL). Hydrochloric acid (2M, 10 mL) was added, and the mixture heated in a microwave for 20 minutes at 12O0C. The mixture was partitioned between EtOAc and sodium hydrogencarbonate solution (100 mL each) and the aqueous phase extracted with EtOAc (50 mL). The combined organic phases were dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 10 to 100% EtOAc in heptane) to give an orange-brown solid (1.5 g) which was washed with 9:1 heptane:diethyl ether to give, after air-drying, the title compound (900 mg, 45%) as an orange-yellow solid. 6H (CDCl3) 8.39 (d, IH), 6.59 (d, IH), 6.21 (br, 2H).
To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 C. Once complete it was cooled to room temperature and poured into 3 L of water. The resulting suspension was filtered and the solid was washed with 500 mL of water. Solid was air dried overnight (12.7 g, 91 %). 1H NMR (400 MHz, DMSO-d6) delta 8.27 (d, J = 7.3 Hz, 1H), 7.73 (br. S., 2H), 6.94 (d, J = 11.0 Hz, 1H). 4-bromo-5-fluoro-2-nitroaniline (0.53 g, 2.255 mmol), zinc (0.89 g, 13.5 mmol), and methanol (32 ml) were added to the flask and argon was bubbled through the solution for 1 hour. Ammonium formate (1.42 g, 22.6 mmol) was then added in several portions. The reaction was then stirred at room temperature overnight and was complete by LCMS in the morning. It was filtered through a pad of celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was collected. The aqueous layer was back-extracted using EtOAc (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated (378 mg, 82 %). MS (m/z) 205.0, 207.0 (M+, M+2+).
76%
With N-Bromosuccinimide; acetic acid; for 1.5h;Reflux;
Example 10 N4 -(5-Cyclopropyl-lH-pyrazol-3-yl)- N2 -((6-fluoro-lH-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4- diamine (1-28) step 1 : A solution of 5-fluoro-2-nitroaniline (1.5 g, 9.61 mmol) and NBS (1.7 g, 9.55 mmol) in HO Ac (75 mL) was heated at reflux for 90 min. The reaction mixture was then poured into ice water (300 mL) and stirred for 10 min. A bright yellow precipitate was collected by filtration and dried in vacuo overnight to afford 1.57 g (76%) of 4-bromo-5-fluoro-2-nitroaniline (96): MS (ESI) m/z = 235 [M+l] +.
With N-Bromosuccinimide; In acetic acid; for 1.5h;Reflux;
A solution of 5-fluoro-2-nitroaniline (3.0 g, 19.2 mmol) and N-bromosuccinimide (3.4 g, 18.8 mmol) in acetic acid (150 mL) was heated at reflux for 90 min. The reaction mixture was then allowed to cool and was poured into water (1.5 L). After stirring for 10 min., the bright yellow precipitate was isolated via filtration and dried under vacuum overnight. This provided the product, 4-bromo-5-fluoro-2-nitroaniline. 1H NMR (400 MHz, CDCl3) delta 6.19 (br s, 2H), 6.58 (d, J=9.8 Hz, 1H), 8.38 (d, J=7.08 Hz, 1H).
With N-Bromosuccinimide; acetic acid; for 3h;Reflux;
A mixture of the compound of (1) of the above synthetic method and bromosuccinimide(N-bromosuccineimide) in a 1: 1.05 ratio round bottom flaskThe mixture was stirred at reflux for 3 hours using acetic acid as a solvent.After the reaction was completed, the reaction solution was warmed to room temperature, and the reaction solution was added to waterUpon release, a pale yellow solid formed and the resulting yellow solidFiltered to obtain the target material in the form of a yellow solid.
With N-Bromosuccinimide; acetic acid; In water;
The material of step (1) of the above synthesis method and N-bromosuccineimide are added to a round bottom flask at a ratio of 1: 1.05, and the mixture is refluxed with acetic acid for 3 hours. After the reaction is completed, the reaction solution is warmed to room temperature, and then the reaction solution is dissolved in water to form a pale yellow solid. The resulting yellow solid is recovered through a filter to obtain a yellow solid target material.
General procedure: Preparation 90 4'-Amino-2'-fluoro-5'-nitrobiphenyl-4-carbonitrile A suspension of <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (0.8 g, 3.8 mmol), 4- cyanophenylboronic acid (0.58 g, 3.87 mmol) and sodium carbonate (1 g, 9.50 mmol) in THF/water (15 mL/2 ml_) was degassed with nitrogen for 10 minutes. To the suspension was added dichloro [1 ,1 ' bis(di-te/t-butylphosphino)]ferrocene palladium (II) (80 mg, 0.095 mmol) and the reaction was heated to 60C for 18 hours. The reaction was filtered through celite and the filtrate diluted with water and EtOAc. The organic layer was collected and concentrated in vacuo to afford the title compound as a yellow solid (0.91 g, 91 %). 1H NMR (400MHz, CDCI3): delta ppm 6.12 (br s, 2H), 6.58 (d, 1 H), 7.58 (d, 2H), 7.72 (d, 2H), 8.14 (d, 1 H).
4-bromo-5-(2,4-difluorophenoxy)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With caesium carbonate; In dimethyl sulfoxide; at 80℃; for 0.5h;
Step 1. 4-Bromo-5-(2,4-difluorophenoxy)-2-nitroaniline A solution of <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (1.08 g, 4.60 mmol) [Combi-Blocks, AN-1501] and cesium carbonate (1.80 g, 5.52 mmol) in dimethyl sulfoxide (5.0 mL) was treated with 2,4-difluorophenol (0.90 mL, 5.53 mmol) [Acros Organics, 24320] and stirred at 80 C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (1.50 g, 95%) as a yellow solid that was used without further purification. LCMS calculated for C12H8BrF2N2O3 (M+H)+: m/z=345.0, 347.0. found: 345.0, 346.9.
4-bromo-5-(cyclobutylmethoxy)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
Step 1. 4-Bromo-5-(cyclobutylmethoxy)-2-nitroaniline Sodium hydride (0.82 g, 60% w/w, 20 mmol) was added at 0 C. to a solution of cyclobutyl/methanol (1.8 mL, 20 mmol) in THF (40 mL). The 0 C. bath was removed, and the reaction mixture was stirred for 30 min. The reaction mixture was again cooled to 0 C. with an ice bath, and <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (2.5 g, 11 mmol) was added. The ice bath was removed, and the reaction mixture was stirred for 18 h at room temperature. The reaction was quenched with sat. NH4Cl and then diluted with H2O. The aqueous solution was extracted with EtOAc (125 mL), and the organic layer was separated and washed with brine (100 mL). The resulting organic layer was dried over MgSO4, filtered, and concentrated. Recrystallization from CH2Cl2/hexanes upon cooling at 0 C. overnight afforded the title compound as a red-brown solid (2.3 g, 72%). 1H NMR (300 MHz, CDCl3) delta 8.28 (d, J=1.0 Hz, 1H), 6.07 (s, 1H), 3.90 (d, J=6.0 Hz, 2H), 2.88-2.61 (m, 1H), 2.09 2.25-2.00 (m, 2H), 2.01-1.71 (m, 4H). LCMS calculated for C11H14BrN2O3 (M+H)+: m/z=301.0, 303.0. found: 301.1, 303.1.
4-[6-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzimidazol-5-yl]-6-methyl-1-[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one[ No CAS ]
5-(2,4-difluorophenoxy)-6-{6-methyl-1-[(4-methylphenyl)sulfonyl]-1-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one[ No CAS ]
To a solution of 2-96 (700 mg, 2.99 mmol) in EtOH (20 mL) at 0 C, was added 4 mL 60% H2S04, then NaNO2 (414 mg, 5.98 mmol) was added slowly in portions. Upon completion of the addition, the stirring was continued for 1 h while the temperature was kept during 0-5 C. ?2 (918 mg, 3.59 mmol) was then added and the resulting mixture was stirred at 45 C for another 8 h. The reaction mixture was concentrated, water (30 mL) was added, and then the mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (Pet Ether/ethyl acetate = 30/1 to give 2-97 (yellow solid, 221 mg, yield 28%).
Intermediate (2) was added to (85.1 mmol) of acetic acid (79 ml), sulfuric acid and water 2: 1 (80 ml: 40 ml)Slowly add the mixed solution at 0 C.NaNO2 (93.6 mmol) was dissolved in 15 ml of waterThe solution is added over 1 hour and then stirred for 1 hour.Next, a solution prepared by dissolving KI (102.1 mmol) in 15 ml of water was added dropwise over 1 hourAfter the addition, the mixture was refluxed at 60 C for 3 hoursAnd stirred. After 3 hours, the temperature was lowered to room temperature and NaHCO3 It is dissolved in saturated solution.The mixed solution was washed with methylene chlorideTo extract the organic material and the solvent is removed in vacuoTo obtain a target material in the form of an orange solid.
The intermediate (2) was added to (85.1 mmol) of acetic acid (79 ml)After dispersing, slowly add 2: 1 mixture of sulfuric acid and water (80 ml: 40 ml) at 0 . After adding NaNO2 (93.6 mmol) in 15 ml of water, add the solution over 1 hour and stir for 1 hour. Next, KI (102.1 mmol) was dissolved in 15 ml of water. After the addition, the solution was refluxed for 3 hours at 60 C. After 3 hours, the temperature was lowered to room temperature, and the solution was dissolved in a saturated NaHCO 3 solution give.The mixed solution is treated with methylene chloride to extract the organic material and the solvent is removed in vacuo to obtain the target material in the form of an orange solid
With sodium hydrogencarbonate; In ethanol; ethyl acetate;
4-Bromo-5-fluoro-1,2-diaminobenzene 4-Bromo-5-fluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of <strong>[153505-36-3]4-bromo-3-fluoro-6-nitroaniline</strong> (320 mg, 1.36 mmol) and SnCl2 2H2 O (1.53 g, 6.81 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75 C. for 8 h. Some starting material had remained (by TLC) after only 1 h heating. All the starting material had reacted after 8 h as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 50 mL H2 O. Sufficient sat'd NaHCO3 solution was added (foaming) to bring the pH to 5. The resulting mixture was extracted with 3*25 mL ethyl acetate and the combined organic extracts washed with 20 mL sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a white powder 277 mg (99%). 1 H NMR (CDCl3) delta3.22 (br s, 2H, NH2); 3.60 (br s, 2H, NH2); 6.50 (d, 1H, JHF =9.6 Hz, H-6); 6.83 (d, 1H, JHF =6.6 Hz, H-3).
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