* 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 bromine; mercury(II) oxide In tetrachloromethane at 20℃; for 4.5 h; Heating / reflux; Irradiation
To a solution of 2-chloro-3-nitro-benzoic acid (15.0 g, 74.4 mmol) in carbon tetrachloride (350 ML) was added mercury (II) oxide (24.2 g, 112 mmol) at room temperature. The mixture was heated to reflux and irradiated with light. Bromine (5.75 mL, 112 mmol) was added dropwise into the mixture in 0.5 hour. The reaction was kept at refluxing temperature for 4 hours. After cooling, the reaction mixture was quenched with 100 mL of aqueous sodium bicarbonate and stirred for 0. 5 hours. After removal of the solid by filtration, the filtrate was washed with saturated sodium bicarbonate and water. Concentration gave 16.65 g of the title compound in 95percent YIELD. 1H NMR (400 MHZ, CDC13) : 8 7.86 (dd, 1H), 7.73 (dd, 1H), 7.30 (t, 1H).
83%
Stage #1: With mercury(II) oxide In tetrachloromethane for 0.25 h; Photolysis; Reflux Stage #2: for 4.5 h; Reflux
A. Preparation of 1-Bromo-2-chloro-3-nitro-benzene (1); 24.2 g (0.111 mol) Hg(II)O was added to a suspension of 15.0 g (0.0744 mol) 2-chloro-3-nitro-benzoic acid in 350 mL CCl4, stirred under N2 and heated to reflux and irradiated by a 120 W sunlamp for 15 minutes. 5.75 mL bromine was then added dropwise over 30 minutes and allowed to reflux for 4 h. The reaction mixture was then cooled to r.t., 100 mL saturated NaHCO3 was slowly added, the solution then filtered using a Buchner funnel, and the filtrate rinsed with DCM. The combined organic layers were separated and washed with 100 mL saturated NaHCO3 and then with 200 mL H20. The organic layer was then dried over MgSO4, filtered, the solvent removed in vacuo to yield 14.78 g product (83percent).
67%
With bromine; mercury(II) oxide In tetrachloromethane at 87℃; for 3 h; Heating / reflux; Irradiation
To a stirred solution of 2-chloro-3-nitrobenzoic acid (15g, 74.4 mmol) in 350 mL of CCI4 under N2 at room temperature was added red HgO (24.3 g, 111.62 mmol). The mixture was irradiated by light and heated to reflux at 870C and Br2 (5.75 mL, 111.6 mmol) was added dropwise. After the addition was complete, the mixture was refluxed for additional 3 h and then cooled to room temperature. The reaction was quenched with saturated NaHCO3 aqueous solution. The mixture was stirred for 10 min and filtered through a pad of celite. The cake was further rinsed with CH2CI2 . The organic layer was separated and washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give 11.55 g of 1- bromo-2-chloro-3-nitrobenzene (67percent). 400 MHz 1H NMR (CDCI3) δ 7.84 (d, 1H), 7.71 (d, 1H), 7.27 (dd, 1 H); MS (M+1) 235, 237, 239.
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 23, p. 4654 - 4666
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 20, p. 5392 - 5397
[3] Patent: WO2004/69832, 2004, A2, . Location in patent: Page 126-127
[4] Patent: US2009/197932, 2009, A1, . Location in patent: Page/Page column 5
[5] Patent: WO2008/12623, 2008, A1, . Location in patent: Page/Page column 61
[6] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 936 - 948
2
[ 59255-95-7 ]
[ 3970-37-4 ]
Yield
Reaction Conditions
Operation in experiment
86.2%
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
[ 3970-41-0 ]
[ 3970-37-4 ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 5℃; for 0.5 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 70℃; for 1 h;
To an ice-cold solution of 3 (3.46 g, 20 mmol) in 30 mL 48percent HBr was dropwise added NaNO2 (1.42 g, 20.5mmol) solution with the inner temperature between 0-5°C. After 30 min, a solution of CuBr (5.74g, 40mmol) in 20 mL HBr was slowly added to the reaction system and then the reaction was gradually heated to 70 °C and stirred for 1h. Ethyl acetate (3×50 mL) and H2O (100 mL) was added for extraction and the combined organic phase was washed with NaHCO3 and brine successively. The solvent was removed in vacuo and the residue was subjected to column chromatography (eluted by 100percent petroleum ether) to afford 4 as a yellow solid. Yield: 71percent, m. p. 59–60 °C, 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.12, 1.52 Hz, 1H, Ph-H), 7.75 (dd, J = 8.14, 1.53 Hz, 1H, Ph-H), 7.32 (t, J = 8.10 Hz, 1H, Ph-H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3365 - 3369
[2] Patent: EP1847541, 2007, A1, . Location in patent: Page/Page column 71-72
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3365 - 3369
7
[ 26429-41-4 ]
[ 3970-37-4 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1988, vol. 42, # 4, p. 237 - 241
[2] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1988, vol. 42, # 5, p. 289 - 293
[3] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1906, vol. <5> 15 I, p. 526
8
[ 583-53-9 ]
[ 3970-37-4 ]
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
9
[ 32337-96-5 ]
[ 3970-37-4 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1988, vol. 42, # 4, p. 237 - 241
10
[ 3970-37-4 ]
[ 58534-94-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 20, p. 5392 - 5397
[2] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1975, vol. 29, p. 981 - 982
[3] Patent: WO2004/69832, 2004, A2, . Location in patent: Page 127
11
[ 3970-37-4 ]
[ 124-41-4 ]
[ 98775-19-0 ]
Yield
Reaction Conditions
Operation in experiment
58%
at 100℃; for 3 h; Autoclave
(v) To a stirred solution of 1-bromo-2-chloro-3-nitrobenzene (24.5 g, 0.10 mol) in methanol (250 ml.) in a 1 L autoclave was added sodium methoxide (8.43 g, 0.16 mol). The autoclave was then sealed and heated at 100°C for 3 h. Upon being allowed to cool to room temperature the majority of the solvent was removed under vacuum. Water and ethyl acetate were then added, the two layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic fractions were washed with 1 M aqueous sodium hydroxide (3χ), water and brine, dried (magnesium sulfate), and the solvent was removed in vacuo. The crude product was recrystallised from hexane to give 1-bromo-2-methoxy-3-nitrobenzene (14.1 g, 58percent) as a solid, mp 64-65°C. Rf 0.36 (1 :3 ethyl acetate/hexane).
Reference：
[1] Patent: WO2010/125103, 2010, A1, . Location in patent: Page/Page column 78-79
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 805 - 810
12
[ 3970-37-4 ]
[ 56131-46-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With iron; acetic acid In ethanol; water at 20℃; for 16 h;
To a mixture of l-bromo-2-chloro-3 -nitrobenzene (15.0 g, 63.60 mmol), HOAc (20 mL), EtOH (120 mL) and H20 (40 mL) at RT, iron powder (10.7 g, 190.70 mmol) was added in portions. The resulting mixture was stirred at RT for 16 h and then was neutralized with NaOH (5 N) solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the desired product (14.0 g, 100percent yield).
93.88%
With iron; ammonium chloride In ethanol; water at 60℃; for 4 h;
A mixture of 1-bromo-2-chloro-3-nitrobenzene (36.61g, 154.83mmol) , iron powder (43.35g, 774.16mmol) , NH4Cl (8.28g, 154.83mmol) , EtOH (100mL) and H2O (50mL) was heated to 60 for 4 hours, then cooled to 10. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to remove the EtOH. The residual solution was extracted with EA (100mL×2) . The combined organic extracts were washed with brine (100mL) , dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the compound 1a (30.01g, 93.88) . MS: 206 (M+H)+.
55.2%
With tin(ll) chloride In ethanol for 3 h; Reflux
3-Bromo-2-chloroaniline A mixture of 1-bromo-2-chloro-3-nitrobenzene (2.7 g, 11.44 mmol) and SnCl2 (12.97 g, 57.20 mmol) in CH3CH2OH (60 mL) was stirred at reflux for 3 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 = 1:50) to yield the product as an off-white solid (1.3 g, 55.2percent yield).
10.5 mmol, 79%
With ammonium chloride In methanol; ethyl acetate
Step 2. Preparation of 3-bromo-2-chloroaniline To a solution of 1-bromo-2-chloro-3-nitrobenzene (3.0 g, 12.7 mmol) in MeOH (127 ml) was added Zn dust (8.30 g, 127 mmol) followed by NH4Cl (6.79 g, 127 mmol) which resulted in a significant exotherm. The heterogeneous reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite and concentrated to an off-white solid. To this solid was added EtOAc and the resulting mixture was sonicated for 10 minutes. The mixture was filtered through Celite and washed with EtOAc. The combine filtrates were concentrated in vacuo to afford 2.17 g (10.5 mmol, 79percent) of 3-bromo-2-chloroaniline: LCMS(m/z): 205.9 (MH+); tR=0.87 minute: 1H NMR (400 MHz, CDCl3) δ 6.62-6.66 (m, 1H) 6.87 (t, J=8.0 Hz, 1H) 6.97 (d, J=7.8 Hz, 1H) 7.22 (d, J=9.0 Hz, 1H).
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 60℃; for 1h;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, 86.2% yield).
82.7%
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 60℃; for 1h;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, 82.7% yield).
(iv) Sodium nitrate (8.20 g, 0.12 mol) was added portionwise to concentrated sulfuric acid (85 ml.) and the resultant mixture was heated at 60-700C before being cooled to 25-30C. A solution of 2-bromo-6-nitroaniline (23.5 g, 0.11 mol) in hot glacial acetic acid (215 ml.) was then added dropwise while the temperature of the reaction mixture was kept below 35C. Upon complete addition, the solution was warmed at 35C for 30 min and was then added portionwise to a mixture of copper(l) chloride (23.5 g, 0.24 mol) in concentrated hydrochloric acid (215 ml_). Upon complete addition, the reaction was heated to 700C, an equal volume of water was then added, and the mixture was cooled to 00C. The resultant yellow solid was collected by filtration and washed with water. The material was subsequently dissolved in ethyl acetate and the insoluble material filtered off. The filtrate was washed with 1 M aqueous hydrochloric acid, water and brine, dried (magnesium sulfate), and the solvent was removed in vacuo. The crude product was recrystallised from hexanes/ethyl acetate to give 1-bromo-2-chloro-3-nitrobenzene (18.4 g) as a solid, mp 58-59C. Rf 0.33 (1 :3 ethyl acetate/hexanes).
With potassium fluoride; cesium fluoride; In DMF (N,N-dimethyl-formamide); for 5h;Heating / reflux;
To a solution of 1-BROMO-2-CHLORO-3-NITRO-BENZENE (9.47 g, 40 mmol) in N, N-dimethylformamide (20 mL) was added potassium fluoride (4.65 g, 80 mmol) and cesium fluoride (6.08 g, 40 MMOL). The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was diluted with 200 mL of chloroform. The solid was collected by filtration. The filtrate was washed with saturated sodium bicarbonate and water. After removal of the solvent, the residue was purified by chromatography using chloroform as eluent to give the title compound which also contained 20% of <strong>[3970-37-4]1-bromo-2-chloro-3-nitro-benzene</strong>. Yield 8.0 G. LH NMR (400 MHZ, CDC13) : B 8.05 (m, 1H), 7.80 (M, 1H), 7.20 (M, 1H).
(v) To a stirred solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (24.5 g, 0.10 mol) in methanol (250 ml.) in a 1 L autoclave was added sodium methoxide (8.43 g, 0.16 mol). The autoclave was then sealed and heated at 100C for 3 h. Upon being allowed to cool to room temperature the majority of the solvent was removed under vacuum. Water and ethyl acetate were then added, the two layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic fractions were washed with 1 M aqueous sodium hydroxide (3chi), water and brine, dried (magnesium sulfate), and the solvent was removed in vacuo. The crude product was recrystallised from hexane to give 1-bromo-2-methoxy-3-nitrobenzene (14.1 g, 58%) as a solid, mp 64-65C. Rf 0.36 (1 :3 ethyl acetate/hexane).
With bromine; mercury(II) oxide; In tetrachloromethane; at 20℃; for 4.5h;Heating / reflux; Irradiation;
To a solution of 2-chloro-3-nitro-benzoic acid (15.0 g, 74.4 mmol) in carbon tetrachloride (350 ML) was added mercury (II) oxide (24.2 g, 112 mmol) at room temperature. The mixture was heated to reflux and irradiated with light. Bromine (5.75 mL, 112 mmol) was added dropwise into the mixture in 0.5 hour. The reaction was kept at refluxing temperature for 4 hours. After cooling, the reaction mixture was quenched with 100 mL of aqueous sodium bicarbonate and stirred for 0. 5 hours. After removal of the solid by filtration, the filtrate was washed with saturated sodium bicarbonate and water. Concentration gave 16.65 g of the title compound in 95% YIELD. 1H NMR (400 MHZ, CDC13) : 8 7.86 (dd, 1H), 7.73 (dd, 1H), 7.30 (t, 1H).
83%
A. Preparation of 1-Bromo-2-chloro-3-nitro-benzene (1); 24.2 g (0.111 mol) Hg(II)O was added to a suspension of 15.0 g (0.0744 mol) 2-chloro-3-nitro-benzoic acid in 350 mL CCl4, stirred under N2 and heated to reflux and irradiated by a 120 W sunlamp for 15 minutes. 5.75 mL bromine was then added dropwise over 30 minutes and allowed to reflux for 4 h. The reaction mixture was then cooled to r.t., 100 mL saturated NaHCO3 was slowly added, the solution then filtered using a Buchner funnel, and the filtrate rinsed with DCM. The combined organic layers were separated and washed with 100 mL saturated NaHCO3 and then with 200 mL H20. The organic layer was then dried over MgSO4, filtered, the solvent removed in vacuo to yield 14.78 g product (83%).
67%
With bromine; mercury(II) oxide; In tetrachloromethane; at 87℃; for 3h;Heating / reflux; Irradiation;
To a stirred solution of 2-chloro-3-nitrobenzoic acid (15g, 74.4 mmol) in 350 mL of CCI4 under N2 at room temperature was added red HgO (24.3 g, 111.62 mmol). The mixture was irradiated by light and heated to reflux at 870C and Br2 (5.75 mL, 111.6 mmol) was added dropwise. After the addition was complete, the mixture was refluxed for additional 3 h and then cooled to room temperature. The reaction was quenched with saturated NaHCO3 aqueous solution. The mixture was stirred for 10 min and filtered through a pad of celite. The cake was further rinsed with CH2CI2 . The organic layer was separated and washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give 11.55 g of 1- bromo-2-chloro-3-nitrobenzene (67%). 400 MHz 1H NMR (CDCI3) delta 7.84 (d, 1H), 7.71 (d, 1H), 7.27 (dd, 1 H); MS (M+1) 235, 237, 239.
With iron; acetic acid; In ethanol; water; at 20℃; for 16h;
To a mixture of l-bromo-2-chloro-3 -nitrobenzene (15.0 g, 63.60 mmol), HOAc (20 mL), EtOH (120 mL) and H20 (40 mL) at RT, iron powder (10.7 g, 190.70 mmol) was added in portions. The resulting mixture was stirred at RT for 16 h and then was neutralized with NaOH (5 N) solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the desired product (14.0 g, 100% yield).
93.88%
With iron; ammonium chloride; In ethanol; water; at 60℃; for 4h;
A mixture of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (36.61g, 154.83mmol) , iron powder (43.35g, 774.16mmol) , NH4Cl (8.28g, 154.83mmol) , EtOH (100mL) and H2O (50mL) was heated to 60 for 4 hours, then cooled to 10. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to remove the EtOH. The residual solution was extracted with EA (100mL×2) . The combined organic extracts were washed with brine (100mL) , dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the compound 1a (30.01g, 93.88) . MS: 206 (M+H)+.
93.88%
With iron; ammonium chloride; In ethanol; water; at 60℃; for 4h;
<strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (36.61 g, 154.83 mmol), iron powder (43.35 g, 774.16 mmol), Ammonium chloride (8.28 g, 154.83 mmol), ethanol (100 mL) and water (50 mL) were mixed and heated to 60 C for 4 hours, then the system was cooled to 10 C.The reaction liquid was filtered through Celite, and the filtrate was concentrated under reduced pressure to remove ethanol.The remaining aqueous solution was extracted with EA (100 mL x 2).The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 1c (30.01 g, 93.88%)
55.2%
With tin(ll) chloride; In ethanol; for 3h;Reflux;
3-Bromo-2-chloroaniline A mixture of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (2.7 g, 11.44 mmol) and SnCl2 (12.97 g, 57.20 mmol) in CH3CH2OH (60 mL) was stirred at reflux for 3 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 = 1:50) to yield the product as an off-white solid (1.3 g, 55.2% yield).
With hydrogenchloride; iron; In ethanol; water; at 60℃; for 0.5h;
Reference Example 13 3-Bromo-2-chloroaniline To a solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (6.8 g) in ethanol (150 ml), reduced iron (8.0 g) was added. Concentrated hydrochlolic acid (36 ml) was added to the mixture, and the mixture was stirred at 60C for 30 min, and allowed to cool to room temperature. Aqueous sodium hydrogen carbonate solution was added, and the mixture was neutralized, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object (5.8 g) as an oily substance. 1H-NMR (CDCl3) delta4.20 (2H, br s), 6.70 (1H, dd), 6.91 (1H, t), 7.01 (1H, dd).
2.17 g (10.5 mmol, 79%)
With ammonium chloride; In methanol; ethyl acetate;
Step 2. Preparation of 3-bromo-2-chloroaniline To a solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (3.0 g, 12.7 mmol) in MeOH (127 ml) was added Zn dust (8.30 g, 127 mmol) followed by NH4Cl (6.79 g, 127 mmol) which resulted in a significant exotherm. The heterogeneous reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite and concentrated to an off-white solid. To this solid was added EtOAc and the resulting mixture was sonicated for 10 minutes. The mixture was filtered through Celite and washed with EtOAc. The combine filtrates were concentrated in vacuo to afford 2.17 g (10.5 mmol, 79%) of 3-bromo-2-chloroaniline: LCMS(m/z): 205.9 (MH+); tR=0.87 minute: 1H NMR (400 MHz, CDCl3) delta 6.62-6.66 (m, 1H) 6.87 (t, J=8.0 Hz, 1H) 6.97 (d, J=7.8 Hz, 1H) 7.22 (d, J=9.0 Hz, 1H).
To a stirred solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> in 50 mL of ethanol was added methyl amine solution (40% in methanol, 50 mL) at room temperature. The mixture was then heated to 85C under N2 for 1h. LC-MS showed small amount of starting material. Additional methylamine solution (10 mL) was added and the reaction mixture was heated for another hour and then cooled to room temperature. The mixture was extracted with CHeCI2 and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was removed in vacuo to give 4.5 g of 2-bromo-N-methyl-6-nitrobenzenamine (92%). 400 MHz 1H NMR (CDCI3) delta 7.84 (d, 1 H), 7.65 (d, 1 H), 6.65 (dd, 1 H), 3.0 (s, 3H); MS (M+1) 231 , 233, 234.
With potassium hydroxide; In tetrahydrofuran; at 45℃; for 72h;
Example 31 7-Bromo-6-(3-chloropropylthio)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride Step A.; To a solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (750 mg, 3.2 mmol) and 3-chloropropane-1-thiol (354 mg, 3.2 mmol) in THF (6.4 mL) was added KOH (270 mg, 4.8 mmol). The reaction mixture was heated at 45 C. for 3 days and cooled to 20 C. The reaction mixture was chromatographed in silica gel to give (2-bromo-6-nitrophenyl)(3-chloropropyl)sulfane (714 mg, 2.3 mmol).
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In tetrahydrofuran; at 20 - 85℃; for 16.5h;
i) Palladium(ii) acetate (23.74 mg, 0.106 mmol), BINAP (99 mg, 0.159 mmol) and caesium carbonate (517 mg, 1.586 mmol) were combined in tetrahydrofuran (THF) (7 ml) and stirred under argon at room temperature for 30 minutes. 1-bromo-2-chloro-3- nitrobenzene (250 mg, 1.057 mmol) and morpholine (0.276 ml, 3.17 mmol) were added and the reaction heated to reflux at 85 0C under argon for 16 hours. LCMS (N4669-19-A1 :HHJ22983) shows desired product at LOOmin (32%).The reaction mixture was diluted with ethyl acetate (20ml) and the catalyst residues filtered off. The filtrate was concentrated in vacuo to yield an orange oil. The crude material was dissolved in a minimum of DCM and loaded onto a 25+S Biotage cartridge. This was eluted with a 0-100% gradient of ethyl acetate in hexane using the SP4. The product did not elute cleanly, but product fractions were concentrated in vacuo to yield crude 4-(2-chloro-3-nitrophenyl)morpholine (0.1498 g, 0.617 mmol, 58.4 % yield) as a yellow solid. The crude material will be taken forward to the next reaction,
49.50%
With palladium diacetate; caesium carbonate; In tetrahydrofuran; at 85℃; for 16h;Inert atmosphere;
To a solution of 1 (2.0 g, 8.46 mmol, 1.0 eq) in tetrahydrofuran (3 mE) was added palladium acetate (0.189 g, 0.846 mmol, 0.1 eq) and cesium carbonate (4.1 g, 12.69 mmol, 1.5 eq). The reaction mixture was degassed for 10 mm under argon atmosphere followed by addition of 1.1 (2.20 g, 25.38 mmol, 3 eq) and again degassed for 5 mm. The reaction was stirred at 85 C. for 16 h. Afier completion of reaction, reaction mixture was cooled to room tempera- tare, transferred into water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 1.2 (1.1 g, 49.50%). MS(ES): mlz 243.60 [M+H].
With sodium hydroxide; In dimethyl sulfoxide; at 18.5 - 22℃;
B. Preparation of (2-Bromo-3-chloro-4-nitro-phenyl)-acetonitrile (2) 15.0 g (0.0634 mol) <strong>[3970-37-4]1-bromo-2-chloro-3-nitro-benzene</strong> and 8.28 mL (0.0634 mol) (phenylthio)acetonitrile both dissolved in 30 mL dry DMSO were rapidly added over 1 minute to 25.38 g (0.634 mol) NaOH in 150 mL dry DMSO under N2 and cooled to 18.5 C. with an ice bath. The reaction was allowed to stir for an additional minute at 22 C. and then poured into a mixture of 80 mL, conc. HCl in 500 g ice. 200 mL EtOAc was then added, the organic phase separated and the aqueous phase extracted with 2*200 mL EtOAc, the organic layers combined and washed with 3*200 mL, partial brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The resulting 22.978 g crude product was then dissolved in 20 mL EtOAc, refrigerated for 2 h, the resulting crystals filtered, washed with 20 mL 1:1 EtOAc/hexane and the solid was dried to yield 3.423 g product (19%).
Step 1. Preparation of 1-bromo-2-chloro-3-nitrobenzene To an oven dried round-bottom flask fitted with stir bar and an oven dried condenser under N2 at room temperature was added 2-chloro-3-nitrobenzoic acid (6.0 g, 29.8 mmol), mercuric oxide, red (9.67 g, 44.7 mmol) and carbon tetrachloride (200 mL). The reaction mixture heated to 90 C. for 30 minutes with irradiation from a 150W TYPE A utility light bulb. The reaction mixture was then cooled to approximately 60 C. and bromine (2.30 mL, 44.7 mmol) added dropwise via syringe and the nitrogen inlet was replaced with an Ar balloon. The reaction mixture was heated again to 90 C. for 4 hours under constant irradiation from the light bulb. The reaction was allowed to cool to room temperature, quenched with saturated aqueous NaHCO3 solution and DCM and stirred for 30 minutes. The phases partitioned upon standing and then were separated. The aqueous portion was extracted with DCM. The combined organic phases were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 7.04 g of 1-bromo-2-chloro-3-nitrobenzene: 1H NMR (400 MHz, CDCl3) delta 7.31 (t, J=8.0 Hz, 1H) 7.74 (dd, J=8.2, 1.2 Hz, 1H) 7.87 (dd, J=8.0, 1.4 Hz, 1H).
To a solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitro-benzene</strong> (5.0 g, 21.1 mmol) in THF (80 mL) was added vinyl magnesium bromide (1M solution in THF, 84.6 mL, 84.6 mmol) dropwise at - 78C and the reaction mixture was stirred at the same temperature for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (3 * 100 mL). The organic layer was separated, washed with brine (70 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 3 to 5% EtOAc in hexanes) to afford 6-bromo-7-chloro-1H-indole XI-6a (2.5 g) as a yellow solid. Yield: 49% Basic LCMS Method 2 (ES-): 228 (M-H)-, 96% purity.
32%
In tetrahydrofuran; at -40℃; for 1h;Inert atmosphere;
nitrogen under gas , <strong>[3970-37-4]1-bromo-2-chloro-3-nitrobenzene</strong> (25g, 0.107mol) was dissolved in THF (250mL) and - 40 degree celcius vinylmagnesium bromide (1M in THF, 321mL, 0.321mol) was slowly added dropwise, and then , it was stirred at -40 degree celcius for 1 hour. After completion of the reaction with NH4Cl aqueous solution was raised to room temperature.Then, the organic layer was extracted with ethyl acetate, MgSO4to remove moisture in the organic layer, filtered and concentrated and purified by column chromatography to the compound 6-bromo-7-chloro- 1H-indole (7.89g,Yield: 32% ) it was obtained.
32%
In tetrahydrofuran; at -78℃; for 3h;
To a solution of <strong>[3970-37-4]1-bromo-2-chloro-3-nitro-benzene</strong> (500 mg, 1.9 mmol) in THF (6 ml) wasadded vinyl magnesium bromide (7.6 ml, 1M, 7.6 mmol) dropwise at -78C and thereaction mixture was stirred at -78C for 3h. Progress of the reaction was monitored by10 TLC and LCMS. After completion, the reaction mixture was quenched with saturatedNH4CI (60 ml) and extracted with EtOAc (3x50 ml). The organic layer was separated,dried over anhydrous Na2S04 and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 2-5% EtOAc in hexanes) toafford 6-bromo-7-chloro-1 H-indole Xl-11 (0.15 g) as an off-white solid.15 Yield: 32%Basic LCMS Method 2 (ES-): 228 (M-H)-, 95 % purity.1H NMR (400 MHz, DMSO-d6) o 6.59-6.60 (m, 1 H) 7.26 (t, J=2.4 Hz, 1 H) 7.34 (d, J=8.4Hz,1 H) 7.42 (d, J=8.4 Hz,1 H) 8.41 (brs, 1 H).
In tetrahydrofuran; at -40℃; for 1h;
To a solution of l-bromo-2-chloro-3-nitro-benzene (5 g, 21.15 mmol, 1 eq) in THE (50 mL) was added bromo(vinyl)magnesium (1 M, 105.73 mL, 5 eq) at -40C slowly. The mixture was stirred at -40C for 1 h. The reaction mixture was diluted with water (1000 Ml) and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (100 mLx3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. It was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=8/l) to afford the title compound (13 g, 45.12 mmol, 42.68% yield, 80% purity) as white solid. (Note: The reaction was combined with other 4 batch in 5 g scale for work-up.)
General procedure: Small pieces of Na (230 mg, 10 mmol) were added to absolute ethanol (50 mL) at room temperature and the mixture was stirred until the solid disappeared. Benzyl mercaptan (1.24g, 10 mmol) was slowly added via a syringe. After 5 minutes, 2-chloronitrobenzene derivative (10 mmol) was added to the reaction system and then the reaction was heated to reflux for 1 h. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography which was eluted by 0.5% ethyl acetate in petroleum ether to obtain compounds 1 as light yellow solids.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 120℃; for 3h;
36 g of compound A (125.38 mmol), 27 g of <strong>[3970-37-4]3-bromo-2-chloro-nitrobenzene</strong> (113.98 mmol), 4 g of tetrakis(triphenylphosphine)palladium (3.42 mmol), 30 g of sodium carbonate (284.95 mmol), 570 mL of toluene, 140 mL of ethanol, and 140 mL of distilled water were introduced into a reaction vessel, and the mixture was stuffed at 120C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate. The extracted organic layer was then dried with magnesium sulfate, and the solvent was removed with a rotary evaporator. Thereafter, the resulting product was purified by column chromatography to obtain 30 g of compound 1-1 (yield: 66%).
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In tetrahydrofuran; at 85℃; for 18h;
To a solution of 1 (1 g, 4.23 mmol, 1.0 eq) in tetrahydroffiran (15 mE) was added palladium acetate (0.09 5 g, 0.423 mmol, 0.1 eq), cesium carbonate (2.06 g, 6.33 mmol, 1.5 eq) and (2,2?-bis(diphenylphosphino)-l,l?-bi- naphthyl) (0.394 g, 0.63 mmol, 0.15 eq). The reaction mixture was degassed for 10 mm under argon atmosphere and 1.1 (1.2 g, 16.91 mmol, 4.0 eq) was added, again degassed for 5 mm. The reaction mixture was stirred at 85 C. for 18 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred into water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 2% ethyl acetate in hexane to obtain pure 1.2 (0.380 g, 39.64%). MS(ES): mlz 227.66[M+H].
tert-butyl N-[(1S,2S)-2-[[4-[6-bromo-7-chloro-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclopentyl]carbamate[ No CAS ]
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