* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With tert.-butylnitrite; copper dichloride In acetonitrile at 60℃; for 1 h; Inert atmosphere
A mixture of 2-bromo-6-nitroaniline (16.0 g, 74.10 mmol), tert-butyl nitrite (11.40 g 111.15mmol) and CuCl2 (12.0 g, 88.90 mmol) in CH3CN (160 mL) was stirred at 60 °C under argon for 1 h. The mixture was allowed to cool to RT, quenched with H20, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica (ethyl acetate/petroleum ether = 1 : 100) to yield the product (15.0 g, 86.2percent yield).
82.7%
With tert.-butylnitrite; copper dichloride In acetonitrile at 60℃; for 1 h; Inert atmosphere
1-Bromo-2-chloro-3-nitrobenzene A mixture of 2-bromo-6-nitroaniline (3.0 g, 13.84 mmol), tert-butyl nitrite (2.85 g 27.68 mmol) and CuCl2 (3.7 g, 27.68 mmol) in CH3CN (60 mL) was stirred at 60 °C under argon for 1 h. The mixture was allowed to cool to RT, quenched with H2O, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1:100) to yield the product as an off-white solid (2.7 g, 82.7percent yield).
Reference：
[1] Patent: WO2017/15562, 2017, A1, . Location in patent: Page/Page column 100
[2] Patent: WO2015/54572, 2015, A1, . Location in patent: Page/Page column 271
[3] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
[4] Patent: WO2010/125103, 2010, A1, . Location in patent: Page/Page column 78
3
[ 59255-95-7 ]
[ 32337-96-5 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
[2] Journal of the Chemical Society, 1961, p. 5029 - 5037
4
[ 59255-95-7 ]
[ 1575-36-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With tin(ll) chloride In ethanol for 2 h; Reflux
Referential Example 14 l-(l-(Tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)ethanamine (103) step 1 : A suspension of 2-bromo-6-nitrobenzenamine (2.0 g, 9 mmol) and SnC¾ (10.2 g, 54 mmol) in EtOH (20 mL) was heated at reflux for 2 h, then cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with saturated NaHCC>3 solution (200 mL). The resulting slurry was filtered through a pad of Celite® and washed with EtOAc (50 mL x 3). The filtrate was washed with saturated NaHC03, water, and brine, dried (MgS04), filtered and concentrated in vacuo to afford 3-bromobenzene-l,2-diamine as a brown oil (1.5 g, 90 percent). MS (ESI): m/z = 186.9 [M+l]+
87%
Stage #1: With hydrogenchloride; tin(ll) chloride In water at 20℃; for 0.583333 h; Heating / reflux Stage #2: With sodium hydroxide In water at 0℃;
Step 1: l,2-Diamino-3-bromobenzene; To a stirring slurry of tin(II) chloride dihyrate (11.8 g, 52.3 mmol) in cone, hydrochloric acid (55 mL) was added 2-bromo-6-nitroaniline (2.84 g, 13.1 mmol), and the resulting mixture was stirred at room temperature for 5 minutes - an exotherm was observed. The mixture was then stirred at reflux for 30 minutes. After cooling to room temperature, the slurry was poured onto crushed ice (200 mL), and the pΗ was adjusted to 14 by the addition of sodium hydroxide pellets. The resulting mixture was washed with diethyl ether (5 x 100 mL), then the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on a Biotage SPl apparatus, on a 4OS silica gel column, eluting with 5percent to 50percent ethyl acetate in dichloromethane, yielding the product as a yellow- brown oil, which solidified upon standing (2.02 g, 87percent) 1H NMR (400 MHz, CDCl3): δ 6.97 (1 H, dd, J = 1.4, 8.0 Hz), 6.64 (1 H, dd, J = 1.4, 7.8 Hz), 6.56 (1 H, t, J = 7.9 Hz), 3.61 (3 H, s); m/z (ES+) 187, 189 [MH+].
87%
With hydrogenchloride; tin(ll) chloride In water at 20℃; for 0.583333 h; Heating / reflux
To a stirring slurry of tin(II) chloride dihydrate (8.28 g, 37 mmol) in conc. hydrochloric acid (40 mL) was added 2-bromo-6-nitroaniline (prepared as described in WO 02/22600, 1.99 g, 9.2 mmol), and the resulting mixture was stirred at room temperature for 5 min - an exotherm was observed. The mixture was stirred at reflux for 30 min, then allowed to cool to room temperature. The resulting slurry was poured onto crushed ice (~ 100 mL), and the pH was adjusted to' 14 by addition of sodium hydroxide pellets. The mixture was washed with diethyl ether (5 x 100 mL), then the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on a Biotage SP1 apparatus, using a 2percent - 20percent ethyl acetate in dichloromethane eluant system on a 25M silica column, yielding 1,2diamino-3-bromobenzene as a brown oil, which solidified upon standing (1.50 g, 87percent) m/z (ES+) 187, 189 [MH]+.
87%
Stage #1: at 20℃; for 0.583333 h; Heating / reflux Stage #2: at 0℃;
Example 24 4-({4-[(2,4-difluorophcnoxy)mcthyl]phcnyl}sulfonyl)-l//-bcnzimidazolc Step 1: l,2-Diamino-3-bromobenzene; To a stirring slurry of tin(II) chloride dihyrate (11.8 g, 52.3 mmol) in cone, hydrochloric acid (55 mL) was added 2-bromo-6-nitroaniline (2.84 g, 13.1 mmol), and the resulting mixture was stirred at room temperature for 5 minutes - an exotherm was observed. The mixture was then stirred at reflux for 30 minutes. After cooling to room temperature, the slurry was poured onto crushed ice (200 mL), and the pH was adjusted to 14 by the addition of sodium hydroxide pellets. The resulting mixture was washed with diethyl ether (5 x 100 mL), then the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on a Biotage SPl apparatus, on a 4OS silica gel column, eluting with 5percent to 50percent ethyl acetate in dichloromethane, yielding the product as a yellow- brown oil, which solidified upon standing (2.02 g, 87percent). 1H NMR (400 MHz, CDCl3): δ 6.97 (1 H, dd, J 1.4, 8.0 Hz), 6.64 (1 H, dd, J 1.4, 7.8 Hz), 6.56 (1 H, t, J 7.9 Hz), 3.61 (3 H, s); m/z (ES+) 187/189 [MH+].
To a solution of 2-nitroaniline (34.5 g, 0.25 mol) in aceticacid (400 ml), N-bromosuccinimide (44.5 g, 0.25 mol) wasadded portionwise over a period of 30 min at 308–318 K(Fig. 1). The mixture was stirred for 3 h at 318 K, warmed to363 K and stirred for 2 h. After cooling the mixture to roomtemperature, it was poured into intensively stirred cold water (4 l). After 10 min, an orange precipitate was filtered off andwashed with water (2 200 ml). The obtained crude productwas recrystallized from 80percent EtOH and dried under vacuum togive pure 4-bromo-2-nitroaniline (yield 39.9 g, 74percent) as anorange crystalline solid. From the filtrate, a second crystallizationcrop was obtained (yield 6.81 g), comprised of 4-bromo-2-nitroaniline and 2-bromo-6-nitroaniline in a 1:0.3ratio. The NMR spectra are consistent with those published inthe literature (Manley et al., 2003; Lemaire et al., 1989). Analytical data for 4-bromo-2-nitroaniline, 1H NMR(300 MHz, CDCl3): 8.26 (dd, J = 2.3, 0.4 Hz, 1H), 7.42 (dd, J =8.9, 2.3 Hz, 1H), 6.73 (dd, J = 8.9, 0.4 Hz, 1H), 6.10 (s, 2H).Analytical data for 2-bromo-6-nitroaniline, 1H NMR(400 MHz, CDCl3): 8.14 (dd, J = 8.7, 1.5 Hz, 1H), 7.70 (dd, J =7.7, 1.5 Hz, 1H), 6.63 (s, 2H), 6.62 (dd, J = 8.7, 7.7 Hz, 1H).Single crystals of 4-bromo-2-nitroaniline were obtained byslow evaporation from chloroform and of 2-bromo-6-nitroanilineby sublimation of the second crystallization crop underreduced pressure (323 K, 10 mbar; 1 bar = 105 Pa).
With ammonia In methanol at 100℃; for 16 h; Sealed tube
2-Bromo-6-nitroaniline A mixture of 1-bromo-2-fluoro-3-nitrobenzene (6.0 g, 27.27 mmol) and NH3 in CH3OH (7 M, 20 mL) was stirred in a sealed tube at 100 °C for 16 h. The solvent was removed and the residue was dissolved in H2O, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1:100) to afford the product as a yellow solid (5.4 g, 91.3percent yield).
81.2%
With ammonia In methanol at 100℃; for 16 h; Sealed tube
A mixture of l-bromo-2-fluoro-3 -nitrobenzene (20.0 g, 91.37 mmol) and H3 in CH3OH (7M, 60 mL) was stirred at 100 °C in a sealed tube for 16 h. The solvent was removed and the residue was dissolved in H20, extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography eluting with (ethyl acetate/petroleum ether = 1 : 100) to afford the desired product as a yellow solid (16.0 g, 81.2percent yield).
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
11
[ 98775-19-0 ]
[ 59255-95-7 ]
Reference：
[1] Journal of the Chemical Society, 1898, vol. 73, p. 687
12
[ 88-74-4 ]
[ 59255-95-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 159
13
[ 614-76-6 ]
[ 59255-95-7 ]
Reference：
[1] Journal of the Chemical Society [Section] C: Organic, 1969, p. 268 - 272
[2] Journal fuer Praktische Chemie (Leipzig), 1921, vol. <2>102, p. 184
14
[ 583-53-9 ]
[ 59255-95-7 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
15
[ 26429-41-4 ]
[ 7664-41-7 ]
[ 59255-95-7 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
16
[ 615-36-1 ]
[ 59255-95-7 ]
[ 13296-94-1 ]
Reference：
[1] Synthesis, 1989, # 10, p. 761 - 763
N- (2-bromo-6-nitrophenyl) acetamide (28.0 g, 0.108 mol)Add to 500mL reaction flask, add hydrochloric acid (6M, 150mL),The solid was suspended in the reaction liquid. Heat to reflux with stirring for 3 h.After cooling to room temperature, the reaction solution was poured into a mixture of NaOH (80 g, 2.0 mol) and ice (300 g). Ethyl acetate (400 mL) was added for extraction, and the layers were separated.The aqueous phase was extracted once with ethyl acetate (200 mL), and the organic phases were combined,It was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness.23.2 g of 2-bromo-6-nitroaniline was obtained in a yield of 99%.
(iii) Lambda/-(2-Bromo-6-nitrophenyl)acetamide (28.0 g, 0.108 mol) was suspended in 6 M aqueous hydrochloric acid (300 ml.) and the resultant reaction mixture was heated at reflux with vigorous stirring for 3 h before being allowed to cool to room temperature. The reaction was then poured into a mixture of sodium hydroxide (80 g, 2.0 mol) and ice (300 g) to which was added ethyl acetate. The organic layer was separated and the aqueous phase was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate), and the solvent was removed in vacuo to give 2-bromo-6-nitroaniline as a solid, mp 70-720C. Rf 0.39 (1 :3 ethyl acetate/hexane).
Referential Example 14 l-(l-(Tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)ethanamine (103) step 1 : A suspension of <strong>[59255-95-7]2-bromo-6-nitrobenzenamine</strong> (2.0 g, 9 mmol) and SnC¾ (10.2 g, 54 mmol) in EtOH (20 mL) was heated at reflux for 2 h, then cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with saturated NaHCC>3 solution (200 mL). The resulting slurry was filtered through a pad of Celite and washed with EtOAc (50 mL x 3). The filtrate was washed with saturated NaHC03, water, and brine, dried (MgS04), filtered and concentrated in vacuo to afford 3-bromobenzene-l,2-diamine as a brown oil (1.5 g, 90 %). MS (ESI): m/z = 186.9 [M+l]+
87%
Step 1: l,2-Diamino-3-bromobenzene; To a stirring slurry of tin(II) chloride dihyrate (11.8 g, 52.3 mmol) in cone, hydrochloric acid (55 mL) was added <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (2.84 g, 13.1 mmol), and the resulting mixture was stirred at room temperature for 5 minutes - an exotherm was observed. The mixture was then stirred at reflux for 30 minutes. After cooling to room temperature, the slurry was poured onto crushed ice (200 mL), and the pEta was adjusted to 14 by the addition of sodium hydroxide pellets. The resulting mixture was washed with diethyl ether (5 x 100 mL), then the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on a Biotage SPl apparatus, on a 4OS silica gel column, eluting with 5% to 50% ethyl acetate in dichloromethane, yielding the product as a yellow- brown oil, which solidified upon standing (2.02 g, 87%) 1H NMR (400 MHz, CDCl3): delta 6.97 (1 H, dd, J = 1.4, 8.0 Hz), 6.64 (1 H, dd, J = 1.4, 7.8 Hz), 6.56 (1 H, t, J = 7.9 Hz), 3.61 (3 H, s); m/z (ES+) 187, 189 [MH+].
87%
With hydrogenchloride; tin(ll) chloride; In water; at 20℃; for 0.583333h;Heating / reflux;
To a stirring slurry of tin(II) chloride dihydrate (8.28 g, 37 mmol) in conc. hydrochloric acid (40 mL) was added <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (prepared as described in WO 02/22600, 1.99 g, 9.2 mmol), and the resulting mixture was stirred at room temperature for 5 min - an exotherm was observed. The mixture was stirred at reflux for 30 min, then allowed to cool to room temperature. The resulting slurry was poured onto crushed ice (~ 100 mL), and the pH was adjusted to' 14 by addition of sodium hydroxide pellets. The mixture was washed with diethyl ether (5 x 100 mL), then the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on a Biotage SP1 apparatus, using a 2% - 20% ethyl acetate in dichloromethane eluant system on a 25M silica column, yielding 1,2diamino-3-bromobenzene as a brown oil, which solidified upon standing (1.50 g, 87%) m/z (ES+) 187, 189 [MH]+.
87%
Example 24 4-({4-[(2,4-difluorophcnoxy)mcthyl]phcnyl}sulfonyl)-l//-bcnzimidazolc Step 1: l,2-Diamino-3-bromobenzene; To a stirring slurry of tin(II) chloride dihyrate (11.8 g, 52.3 mmol) in cone, hydrochloric acid (55 mL) was added <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (2.84 g, 13.1 mmol), and the resulting mixture was stirred at room temperature for 5 minutes - an exotherm was observed. The mixture was then stirred at reflux for 30 minutes. After cooling to room temperature, the slurry was poured onto crushed ice (200 mL), and the pH was adjusted to 14 by the addition of sodium hydroxide pellets. The resulting mixture was washed with diethyl ether (5 x 100 mL), then the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on a Biotage SPl apparatus, on a 4OS silica gel column, eluting with 5% to 50% ethyl acetate in dichloromethane, yielding the product as a yellow- brown oil, which solidified upon standing (2.02 g, 87%). 1H NMR (400 MHz, CDCl3): delta 6.97 (1 H, dd, J 1.4, 8.0 Hz), 6.64 (1 H, dd, J 1.4, 7.8 Hz), 6.56 (1 H, t, J 7.9 Hz), 3.61 (3 H, s); m/z (ES+) 187/189 [MH+].
With ammonia; In methanol; at 100℃; for 16h;Sealed tube;
2-Bromo-6-nitroaniline A mixture of 1-bromo-2-fluoro-3-nitrobenzene (6.0 g, 27.27 mmol) and NH3 in CH3OH (7 M, 20 mL) was stirred in a sealed tube at 100 C for 16 h. The solvent was removed and the residue was dissolved in H2O, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1:100) to afford the product as a yellow solid (5.4 g, 91.3% yield).
81.2%
With ammonia; In methanol; at 100℃; for 16h;Sealed tube;
A mixture of l-bromo-2-fluoro-3 -nitrobenzene (20.0 g, 91.37 mmol) and H3 in CH3OH (7M, 60 mL) was stirred at 100 C in a sealed tube for 16 h. The solvent was removed and the residue was dissolved in H20, extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography eluting with (ethyl acetate/petroleum ether = 1 : 100) to afford the desired product as a yellow solid (16.0 g, 81.2% yield).
2-(5-fluoro-thiophen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane[ No CAS ]
2-(5-fluorothiophen-2-yl)-6-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.7%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
A solution of <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (CVI) (800 mg, 3.67 mmol, 1.0 eq), 2-(5 -fluorothiophen-2-yl)-4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolane (CVII) (1.0 g, 4.4 mmol, 1.2 eq), Pd(PPh3)4 (268 mg, 0.37 mmol, 0.10 eq) and Cs2CO3 (2.39 g, 7.34 mmol, 2.0 eq) in dioxane (20 mL) and H20 (4 mL) was de-gassed and then heated to 100C under N2 for 3 h. TLC (PE:EtOAc= 1: 1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EtOAc=10: 1) to afford the 2-(5-fluorothiophen-2-yl)-6-nitroaniline (CVIII) (540 mg, 2.27 mmol, 61.7 % yield). ESIMS found for C,0H7FN2025 m/z 239.1 (M+H).
61.7%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
Step 1 (0890) A solution of <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (C) (800 mg, 3.67 mmol, 1.0 eq), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CI) (1.0 g, 4.4 mmol, 1.2 eq), Pd(dppf)Cl2 (268 mg, 0.37 mmol, 0.10 eq) and Cs2CO3 (2.39 g, 7.34 mmol, 2.0 eq) in dioxane (20 mL) and H2O (4 mL) was de-gassed and then heated to 100 C. under N2 for 3 h. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography (PE:EtOAc=10:1) to afford the 2-(5-fluorothiophen-2-yl)-6-nitroaniline (CII) (540 mg, 2.27 mmol, 61.7% yield). ESIMS found for C10H7FN2O2S m/z 239.1 (M+H).
N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) methanesulfonamide[ No CAS ]
N-((2’-amino-5-fluoro-3‘-nitro-[1,1'-biphenyl]-3-yl)methyl)methanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.6 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
A solution of <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (CVI) (1.80 g, 8.29 mmol, 1 eq), N-(3- fluoro-5 -(4,4,5,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (CXVII) (3.27 g, 9.95 mmol, 1.2 eq), Na2CO3 (3.08 g, 29.01 mmol, 3.5 eq) and Pd(dppf)C12 (307.47 mg, 414.50 .imol, 0.05 eq) in dioxane (30 mL) and water (6 mL) was de-gassed and then heated to 80C overnight under N2. TLC (PE:EtOAc=1: 1) showed the starting material was consumed completely. The reaction mixture was poured into H20 (300 mL). The mixture was extracted with EtOAc (3 x 250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2SO4, concentrated in vacuum to give a residue. The cmde product was purified by silica gel chromatography (PE: EtOAc= 10:1) to give N-((2?-amino-5 -fluoro-3 ?-nitro-[ 1,1 biphenylj-3-yl)methyl)methanesulfonamide (CXVIII) (1.60 g, 4.72 mmol, 56.9% yield) as a brown solid. ESIMS found for C,4H,4FN304S mlz 340.1 (M+H).
1.60 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 4 (0899) A solution of <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (C) (1.80 g, 8.29 mmol, 1 eq), N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) methanesulfonamide (CX) (3.27 g, 9.95 mmol, 1.2 eq), Na2CO3 (3.08 g, 29.01 mmol, 3.5 eq) and Pd(dppf)Cl2 (307.47 mg, 414.50 mumol, 0.05 eq) in dioxane (30 mL) and water (6 mL) was de-gassed and then heated to 80 C. overnight under N2. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3×250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2SO4, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10:1) to give N-((2?-amino-5-fluoro-3?-nitro-[1,1?-biphenyl]-3-yl)methyl)methanesulfonamide (CXI) (1.60 g, 4.72 mmol, 56.9% yield) as a brown solid. ESIMS (0900) found for C14H14FN3O4S m/z 340.1 (M+H).
The 2 - bromo -6 - nitroaniline (5.65 g, 26.0 mmol) is dissolved in acetic acid (40 ml), then add N - iodo succinimide (5.4 g, 31.2 mmol), the reaction liquid 50 C stirring overnight, then cooled to room temperature. Water and dilute the reaction liquid, continuing to stir 10 minutes. Filtered to obtain the title compound crude product (9 g), as an orange solid.
Add <strong>[59255-95-7]2-bromo-6-nitroaniline</strong> (21.7g, 0.1mol) to a 500mL reaction flask,Anhydrous ethanol (200 mL) was added.The temperature was lowered from 0 to 10 C, and an aqueous solution of hexafluorophosphoric acid (40%) (44.9 g) was added dropwise.Control temperature is 10-15 . After the addition was completed, the temperature was maintained for 2 hours.The temperature was lowered to 0 C, and isoamyl nitrite (14.1 g, 0.12 mol) was added dropwise. After the dropwise addition was completed,Reaction at 0-5 C for 2h. Filtration and washing with absolute ethanol (20 mL) gave hexafluorophosphate.Xylene (200 mL) was added to a 500 mL reaction flask, and the temperature was raised to 120 to 130 C.Add the hexafluorophosphate obtained in the previous step and incubate for 2h. Cool to room temperature,The reaction solution was poured into a saturated sodium carbonate solution, the layers were separated, and the organic phase was dried over anhydrous sodium sulfate.Distillation under reduced pressure gave 11.6 g of a pale yellow liquid. The yield was 52.7%,HPLC purity was 99.1%.
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