* 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.
Step B. N-(4-Fluoro-3-nitrophenyI)acetamide 4-Fluoro-3-nitroaniline (5.0g, 32.0 mmol) was dissolved in 50 mL of DCM at 0°C containing TEA (6.7 mL, 48.0 mmol). Acetyl chloride (2.75 mL, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5percent KHSO4 solution, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was crystallized from DCM. Yield: 5.3g (84percent). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.04 (s, 3 H), 7.51 (dd, J=11.23, 9.08 Hz, 1 H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).
84%
With triethylamine In dichloromethane at 0 - 20℃;
Step B. N-(4-FLUORO-3-NITROPHENYL) acetamide; 4-Fluoro-3-nitroaniline (5. 0G, 32.0 mmol) was dissolved in 50 mL of DCM at 0°C containing TEA (6.7 ML, 48.0 mmol). Acetyl chloride (2. 75 ML, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5percent KHS04 solution, saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. The product was crystallized from DCM. Yield: 5.3g (84percent) ; 1H NMR (400 MHz, CHLOROFORM-D): 8 2.04 (s, 3 H), 7.51 (dd, J=11. 23, 9.08 Hz, 1 H), 7.80 (ddd, J=9. 08,4. 00,2. 93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).; Step B. N-(4-fluoro-3-nitrophenyl) acetamide; Acetyl Chloride (2.39 mL, 33.6 mmol) was slowly added to a solution of 3-nitro-4- fluoroaniline (5.00 g, 32.0 mmol) and Et3N in DCM (500 mL) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water, saturated NAHC03 solution, brine, dried over anhydrous MGS04 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield : 5.65 g (87percent) ; MS (ESI) (M+H) + : 199. 1.
84%
With triethylamine In dichloromethane at 0 - 20℃;
4-Fluoro-3-nitroaniline (5.0g, 32.0 mmol) was dissolved in 50 mL of DCM at 0°C containing TEA (6.7 mL, 48.0 mmol). Acetyl chloride (2.75 mL, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5percent KHSO4 solution, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was crystallized from DCM. Yield: 5.3g (84percent). 1H NMR (400 MHz, CHLOROFORM-D): δ 2.04 (s, 3 H), 7.51 (dd, J=I 1.23, 9.08 Hz, 1 H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).
Step B: N-(4-Fluoro-3-nitrophenyl)acetamide; 4-Fluoro-3-nitro-aniline (54.2 g, 0.347 mol) was added in portions to acetic anhydride (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The brown solid was collected and dried in vacuo to give the title compound. Yield: 67.5 g (98percent). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.04 (s, 3H), 7.51 (dd, J=11.23, 9.08 Hz, 1H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1H), 8.47 (dd, J=7.03, 2.73 Hz, 1H), 10.38 (s, 1H).
98%
at 20℃;
Step B: N-(4-Fluoro-3-nitrophenyl)acetamide4-Fluoro-3-nitro-aniline (54.2 g, 0.347 mol) was added in portions to acetic anhydride (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The brown solid was collected and dried in vacuo to give the title compound. Yield: 67.5 g (98percent). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.04 (s, 3H), 7.51 (dd, J=11.23, 9.08 Hz, 1H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1H), 8.47 (dd, J=7.03, 2.73 Hz, 1H), 10.38 (s, 1H).
92%
at 20℃; Inert atmosphere
4-Fluoro-3-nitrophenylamine (10 g, 64.1 mmol) was added in portions to a stirred solution of acetic anhydride (35 mL, 371 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then quenched with ice water and neutralized with solid Na2COs. The solid precipitate was filtered and dried in vacuo. The product was collected as a dark brown solid (11.74 g, 92percent), and used in the next step without further purification. LC/MS MH+ = 198.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (s, IH), 8.50 (s, IH), 7.77-7.90 (m, IH), 7.47-7.61 (m, IH), 2.05 (s, 3H).
70%
at 20℃; for 2 h;
4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the desired title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
70%
at 20℃; for 2 h; Neat (no solvent)
Step B. N- (4-FLUORO-3-NITROPHENYL) acetamide; 4-Fluoro-3-nitro-aniline (45.0 g, 288. 2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDC13) : 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2 h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature EPO <DP n="31"/>for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CHLOROFORM-D): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
70%
at 20℃; for 2 h;
4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H), 7.26 (m, 1H), 7.50 (s broad, 1H), 7.87 (m, 1H), 8.23 (dd, J=6.44, 2.73 Hz, 1H).
70%
at 20℃; for 2 h;
Step B. N- (4-fluoro-3-nitrophenyl) acetamide; 4-Fluoro-3-nitro-aniline (45.0 g, 0. 288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDC13): 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (DD, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2 h;
Step B. N-(4-fluoro-3-nitrophenyl)acetamide; 4-FLUORO-3-NITRO-ANILINE (45.0 g, 0.288 mol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried ITT vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDC13) : 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (DD, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2 h;
Step B. N- (4-fluoro-3-nitrophenyl) acetamide; 4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDC13): 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (DD, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2 h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz5 1 H).
70%
at 20℃; for 2 h;
Step B. iV-(4-fluoro-3-nitrophenyl)acetamide 4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz3 CDCl3): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
70%
at 20℃; for 2 h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1HNMR (400 MHz, CDCl3): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H)
70%
at 20℃; for 2 h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70percent). 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
EXAMPLE 43 Hydrogenation of 2,4-Dinitrofluorobenzene Using 5percent Rhodium on Alumina as Catalyst Using the method described in Example 25, 18.61 grams (0.10 mole) of 2,4-dinitrofluorobenzene was hydrogenated in the presence of 0.50 gram of rhodium on alumina hydrogenation catalyst in 100 mL each of glacial acetic acid and anhydrous ethanol. During the reaction which required two hours, a total of 370 psi of hydrogen was consumed. The 2-fluoro-5-nitroaniline recovered by column chromatography weighed 2.79 grams, a 17.6percent yield. Also, 0.85 gram of 4-fluoro-3-nitroaniline was recovered as a second fraction.
Reference：
[1] Tetrahedron Letters, 1990, vol. 31, # 43, p. 6141 - 6144
[2] Tetrahedron Letters, 1990, vol. 31, # 43, p. 6141 - 6144
[3] Patent: US5105012, 1992, A,
[4] Recueil des Travaux Chimiques des Pays-Bas, 1946, vol. 65, p. 329,330
[5] Russian Journal of General Chemistry, 2006, vol. 76, # 1, p. 76 - 81
[6] Chemistry Letters, 2008, vol. 37, # 9, p. 974 - 975
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 654,656
[2] Recueil des Travaux Chimiques des Pays-Bas, 1904, vol. 23, p. 238
[3] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[4] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
9
[ 348-54-9 ]
[ 364-76-1 ]
Reference：
[1] Patent: US3944612, 1976, A,
10
[ 369-36-8 ]
[ 7647-10-1 ]
[ 70-34-8 ]
[ 364-76-1 ]
Reference：
[1] Patent: US5105012, 1992, A,
11
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 371-40-4 ]
[ 364-76-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1904, vol. 23, p. 236
12
[ 364-76-1 ]
[ 124-41-4 ]
[ 577-72-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 22, p. 3599 - 3605
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1247 - 1251
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, p. S113 - S113
[4] Advanced Synthesis and Catalysis, 2008, vol. 350, # 6, p. 863 - 868
[5] Patent: CN104151178, 2016, B, . Location in patent: Paragraph 0055; 0057
13
[ 364-76-1 ]
[ 577-72-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride; sodium methylate In methanol; water
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis. USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2 O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2 SO4, and concentrated under vacuum to yield 17.5 g (97percent) of product as a dark brown solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
97%
With hydrogenchloride; sodium methylate In methanol; water
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5 g (97percent) of product as a dark brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5562 - 5586
15
[ 364-76-1 ]
[ 52692-09-8 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1927, vol. 36, p. 375,376[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 886
16
[ 364-76-1 ]
[ 364-73-8 ]
Reference：
[1] Bl. Acad. Belg., vol. <5> 12, p. 804,815[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 884
[3] Helvetica Chimica Acta, 1983, vol. 66, # 1, p. 68 - 75
17
[ 364-76-1 ]
[ 364-75-0 ]
Yield
Reaction Conditions
Operation in experiment
14%
at 20 - 70℃; for 2 h;
Add isoamyl nitrite (18. 6 g, 160 mmol) to a suspension of 4-fluoro-3- nitrophenylamine (5. 0 g, 32 mmol) in diiodomethane (150 mL). Stir under nitrogen at room temperature for 1 h. Heat at 70 °C for 1 h. Cool to room temperature and concentrate. Dilute with dichloromethane (500 mL) and water (100 mL). Collect the organic, concentrate and purify (silica gel chromatography, eluting with a gradient of 100 : 0 to 80 : 20 hexanes : ethyl acetate), to give the title compound as a yellow oil (1. 22 g, 14percent). 1H NMR (300 MHz, CDC13) 6 7. 02-7. 11 (m, 1H), 7. 89-7. 97 (m, 1H), 8. 32-8. 39 (dd, J = 2. 2 Hz, 6. 9 Hz, 1H).
Reference：
[1] Bulletin des Societes Chimiques Belges, 1927, vol. 36, p. 375,376[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 886
19
[ 364-76-1 ]
[ 345-18-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[2] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
20
[ 364-76-1 ]
[ 89-64-5 ]
[ 345-18-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[2] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
21
[ 364-76-1 ]
[ 6264-67-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
With silver tetrafluoroborate; 4,4'-Dimethoxy-2,2'-bipyridin; potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 80℃; for 48 h; Autoclave
In Example 1, the m-nitroacetophenone used was replaced with equimolar 4-fluoro-3-nitroaniline,the reaction was carried out at 80 °C for 48 hours at 4.0 MPa. The other procedure was the same as in Example 1 to give 4-fluoro-1,3-diaminobenzene in a yield of 94percent, _: A solution of 16.44 mg (0.04 mmol) 4,4'-dimethoxy-2,2'-bipyridine silver 11.22 mg (0.1 mmol) of potassuim t-butoxide and 1 mL of 1,4-dioxane were charged into an autoclave. After stirring, 165.15 mg (1 mmol) of m-nitroacetophenone was added and the mixture was stirred at 80 °C. The reaction was carried out for 8 hours. After the reaction has finishedm the reaction solution was extracted with water and dichloromethane to collect the organic phase. Then, the organic phase was dried over anhydrous Na2SO4, suction filtered, rotary evaporated and chromatographed to give a yellow solid 3-acetanilide. Yield 96 percent.
Reference：
[1] Patent: CN106748834, 2017, A, . Location in patent: Paragraph 0016; 0069; 0072
[2] Patent: US4552882, 1985, A,
22
[ 70-34-8 ]
[ 364-76-1 ]
[ 369-36-8 ]
Yield
Reaction Conditions
Operation in experiment
17.6%
With hydrogen In ethanol; acetic acid
EXAMPLE 43 Hydrogenation of 2,4-Dinitrofluorobenzene Using 5percent Rhodium on Alumina as Catalyst Using the method described in Example 25, 18.61 grams (0.10 mole) of 2,4-dinitrofluorobenzene was hydrogenated in the presence of 0.50 gram of rhodium on alumina hydrogenation catalyst in 100 mL each of glacial acetic acid and anhydrous ethanol. During the reaction which required two hours, a total of 370 psi of hydrogen was consumed. The 2-fluoro-5-nitroaniline recovered by column chromatography weighed 2.79 grams, a 17.6percent yield. Also, 0.85 gram of 4-fluoro-3-nitroaniline was recovered as a second fraction.
Reference：
[1] Tetrahedron Letters, 1990, vol. 31, # 43, p. 6141 - 6144
[2] Tetrahedron Letters, 1990, vol. 31, # 43, p. 6141 - 6144
[3] Patent: US5105012, 1992, A,
[4] Recueil des Travaux Chimiques des Pays-Bas, 1946, vol. 65, p. 329,330
[5] Russian Journal of General Chemistry, 2006, vol. 76, # 1, p. 76 - 81
[6] Chemistry Letters, 2008, vol. 37, # 9, p. 974 - 975
23
[ 364-76-1 ]
[ 74-88-4 ]
[ 18542-98-8 ]
Reference：
[1] Journal of the Chemical Society [Section] B: Physical Organic, 1968, p. 238 - 241
[2] Patent: US2007/259910, 2007, A1, . Location in patent: Page/Page column 17
Step B: N-(4-Fluoro-3-nitrophenyl)acetamide; 4-Fluoro-3-nitro-aniline (54.2 g, 0.347 mol) was added in portions to acetic anhydride (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The brown solid was collected and dried in vacuo to give the title compound. Yield: 67.5 g (98%). 1H NMR (400 MHz, CHLOROFORM-D) delta 2.04 (s, 3H), 7.51 (dd, J=11.23, 9.08 Hz, 1H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1H), 8.47 (dd, J=7.03, 2.73 Hz, 1H), 10.38 (s, 1H).
98%
at 20℃;
Step B: N-(4-Fluoro-3-nitrophenyl)acetamide4-Fluoro-3-nitro-aniline (54.2 g, 0.347 mol) was added in portions to acetic anhydride (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The brown solid was collected and dried in vacuo to give the title compound. Yield: 67.5 g (98%). 1H NMR (400 MHz, CHLOROFORM-D) delta 2.04 (s, 3H), 7.51 (dd, J=11.23, 9.08 Hz, 1H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1H), 8.47 (dd, J=7.03, 2.73 Hz, 1H), 10.38 (s, 1H).
92%
at 20℃;Inert atmosphere;
4-Fluoro-3-nitrophenylamine (10 g, 64.1 mmol) was added in portions to a stirred solution of acetic anhydride (35 mL, 371 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then quenched with ice water and neutralized with solid Na2COs. The solid precipitate was filtered and dried in vacuo. The product was collected as a dark brown solid (11.74 g, 92%), and used in the next step without further purification. LC/MS MH+ = 198.8. 1H NMR (400 MHz, DMSO-d6) delta ppm 10.40 (s, IH), 8.50 (s, IH), 7.77-7.90 (m, IH), 7.47-7.61 (m, IH), 2.05 (s, 3H).
70%
at 20℃; for 2h;
4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the desired title compound (42.0 g, 70%). 1H NMR (400 MHz, CDCl3): delta 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
70%
at 20℃; for 2h;Neat (no solvent);
Step B. N- (4-FLUORO-3-NITROPHENYL) acetamide; 4-Fluoro-3-nitro-aniline (45.0 g, 288. 2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDC13) : 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature EPO <DP n="31"/>for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CHLOROFORM-D): delta 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
70%
at 20℃; for 2h;
4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDCl3): delta 2.23 (s, 3H), 7.26 (m, 1H), 7.50 (s broad, 1H), 7.87 (m, 1H), 8.23 (dd, J=6.44, 2.73 Hz, 1H).
70%
at 20℃; for 2h;Product distribution / selectivity;
Step B. N- (4-fluoro-3-nitrophenyl) acetamide; 4-Fluoro-3-nitro-aniline (45.0 g, 0. 288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDC13): 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (DD, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2h;
Step B. N-(4-fluoro-3-nitrophenyl)acetamide; 4-FLUORO-3-NITRO-ANILINE (45.0 g, 0.288 mol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried ITT vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDC13) : 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (DD, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2h;
Step B. N- (4-fluoro-3-nitrophenyl) acetamide; 4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDC13): 8 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (DD, J=6. 44,2. 73 Hz, 1 H).
70%
at 20℃; for 2h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDCl3): delta 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz5 1 H).
70%
at 20℃; for 2h;
Step B. iV-(4-fluoro-3-nitrophenyl)acetamide 4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz3 CDCl3): delta 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
70%
at 20℃; for 2h;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1HNMR (400 MHz, CDCl3): delta 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H)
70%
at 20℃; for 2h;Product distribution / selectivity;
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDCl3): delta 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
With sulfuric acid; In methanol; at -0.16 - 59.84℃; for 1h;Heating / reflux;
100 g 4-fluoro-3nitroanilin are added to a stirred mass of 80 g methanol and heated to 333 K. 0.1 ml sulfuric acid and 90 ml of acetic anhydride are added during 15 minutes. Heating and boiling are continued for 15 minutes. Then the reaction mixture is cooled slowly to 273 K with stirring. At the final temperature stirring is continued for 30 minutes, then the suspension is filtered off, washed with cold methanol, dryed in the vacuum dryer getting 114 g acetyl derivative which is worked up further. The acetyl derivative is solved in 520 ml ethanol and continuously added to 130 g iron in 35 ml concentrated hydrochloric acid and 220 ml water at 363K during 1 hour. The temperature drops to 353 K. The reaction mixture is stirred for further 3 hours. The hot mass is separated through filtration the residue washed with 100 ml ethanol. The filtrate and wash solution are cooled to 380 K with mixing, when cristallization of the product takes place. The product is separated by filtration, washed with cold ethanol and dryed in a vacuum dryer.
With sulfuric acid; In methanol; at -0.16 - 59.84℃; for 1h;Heating / reflux;
Example A1; Preparation of the compound of formula (101 a); a. 100 g 4-fluoro-3-nitro-anilin are added to a stirred mass of 80 g methanol, 0.1 mi sulfuric acid, 90 ml of acetic anhydride during 15 minutes at 333K. Heating and boiling are continued for 15 minutes. The reaction mixture is cooled down slowly to 273K under stirring. At the final temperature stirring is continued for 30 minutes, then the suspension is filtered, washed with cold methanol and dryed in the vacuum dryer. 114 g of the acetyl derivative are obtained which is worked up further.
With potassium carbonate; In N,N-dimethyl-d6-formamide; at 80℃; for 10.0h;
To a solution of compound 24 (0.31 g, 2 mmol) and K2CO3 (1.38 g, 10 mmol) in anhydrous N,N-dimethylformamide (DMF) (5 ml) was added CH3I (0.35 g, 2.5 mmol), and the reaction mixture was stirred for 10 h at 80 C. After cooling down the reaction to room temperature was added DCM (50 ml) to the solution, and washed with saturated NaHCO3. The organic layer dried over by MgSO4 and concentrated in vacuo to give the product 25 (0.34 g, 92%). 1H NMR (DMSO-d6, 400 MHz): delta 7.41-7.36 (m, 1H), 7.23-7.21 (m, 1H), 7.12-7.09 (m, 1H), 2.95 (s, 6H). ESI-HRMS: m/z calcd for C8H9FN2O2 [M+H]+ 185.0682 found 185.0749.
With potassium carbonate; In N,N-dimethyl-formamide; at 5 - 20℃; for 63.0h;
The (4-fluoro-3-nitrophenyl)dimethylamine can be prepared in the following way: 13.27 g (96 mmol) of potassium carbonate are added, at a temperature in the region of 20 C., under an argon atmosphere, to 5 g (32 mmol) of 4-fluoro-3-nitroaniline in solution in 50 cm3 of dimethylformamide, followed, at a temperature in the region of 5 C., by 4.6 cm3 (73.6 mmol) of iodomethane. After stirring for 63 hours at a temperature in the region of 20 C., the reaction mixture is poured into 100 cm3 of water and then extracted with 3 times 100 cm3 of dichloromethane. The organic phases are combined, washed with 3 times 100 cm3 of water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 5.5 g of a residue which is purified by flash chromatography [eluent: ethyl acetate/cyclohexane (2/8 by volume)]. After concentration under reduced pressure of the fractions containing the expected product, 2.78 g of (4-fluoro-3-nitrophenyl)dimethylamine are obtained in the form of an orange-red solid; MS-ES+: m/z=185(+)=(M+H) (+)
In methanol; at 20 - 60℃; for 1.5h;Inert atmosphere;
the reactor was washed and dried, and the nitrogen was cooled to 20 to 25 C. The reactor was charged with 640 kg of anhydrous methanol and 720 kg of sodium methoxide at a mass concentration of 30% (the solvent was passed through a cooling solution) Frequency of 40Hz, the control temperature of 20 ~ 25 , adding 230kg 3-nitro-p-fluoroaniline, the heating temperature<40and then control the temperature of 50 ~ 60 reaction 1.5h, and then filtered through the salt filter,
6-(4-fluoro-3-nitrophenylazo)pyridoxal-5'-phosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: 4-Fluoro-3-nitroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.0833333h;
Stage #2: pyridoxal 5'-phosphate With sodium hydroxide In water at 0℃; for 0.5h;
N-(3-hydroxypropyl)-4-methoxy-3-nitro-aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 2 Preparation of N-(3-hydroxypropyl)-4-methoxy-3-nitro-aniline 4-Fluoro-3-nitro-aniline (20.0 g) is dissolved in 100 ml dimethylacetamide. Then 3-chloropropyl-chloroformate (22.12 g) is added dropwise within 30 minutes under external cooling to keep the reaction temperature below 60 C. After the addition is completed, the reaction mixture is allowed to cool. Then a 30% methanolic solution of sodium methoxide (92.3 g) is added dropwise. The rate of addition and external cooling is adjusted to maintain an internal temperature of from about 60 C. to about 70 C. When the temperature rise ceases, the reaction mixture is poured into 200 ml water, neutralized with 2n sulfuric acid, and extracted twice with 400 ml ethylacetate. The combined organic layers are dried over sodium sulphate, filtered, and evaporated to dryness. Yield: 18.8 g of a viscous reddish product. 1H-NMR (DMSO-d6/300 MHz): delta=7.13 (d, 1H); 6.97 (d, 1H); 6.87 (dd, 1H); 5.75 (t, 1H); 4.50 (t, 1H); 3.78 (s, 3H); 3.49 (m, 2H); 3.03 (m, 2H); 1.67 ppm (m, 2H).
Acetic acid (10 mL, 174 mmol) was added to a mixture of Example C2 (10 g, 54.6 mmol) and 4-fluoro-3-nitroaniline (8.5 g, 54.6 mmol) in water (350 mL) and the mixture was stirred at RT overnight. The solid was collected by filtration and washed with MeOH (2 x 20 mL) to give 5-((4-fluoro-3-nitrophenylimino)methyl)-N-methyl-2-(methylthio)pyrimidin-4- amine (8.0 g, 46 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-c/6): delta 9.39 (m, 1 H), 8.71 (s, 1 H), 8.33 (s, 1 H), 8.18 (m, 1 H), 7.80 (m, 1 H), 7.61 (t, J- 6.9 Hz, 1 H), 3.05 (d, J = 3.6 Hz, 3 H), 2.48 (s, 3 H); MS (ESI) m/z: 322.2 (M+H4).
With sodium tris(acetoxy)borohydride; trifluoroacetic acid In ethyl acetate for 0.5h;
A6
Sodium triacetoxy borohydride (2.70 g, 12.8 mmol) was added to a solution of Example C5 (2.10 g, 10.6 mmol), 4-fluoro-3-nitroaniline (1.66g, 10.6mmol) and TFA (2.43 g, 21.3mmol) in EtOAc (5OmL). After stirring for 30 min. the reaction mixture was diluted with water (50 mL), and 2N NaOH was added to adjust the pH to alkaline. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give yellow orange solid. The solid was slurried in MTBE5 collected by Filtration, washed and dried in vacuo to give N-ethyl-5- ((4-fluorθ'3-nitrophenylammo)methyl)-2-(methylthio)pyrimidin-4-amine (2.2 g, 61% yield) as a bright yellow solid.
13
Preparation 13. 2-Chloro-4-fluoro-N- (4-fluoro-3- nitrophenyl) benzamide; Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL), then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10-30% ethyl acetate in hexanes to obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray) : m/z = 313.0 (M+1).
With triethylamine; In dichloromethane; at 0 - 20℃;
Step B. N-(4-Fluoro-3-nitrophenyI)acetamide 4-Fluoro-3-nitroaniline (5.0g, 32.0 mmol) was dissolved in 50 mL of DCM at 0C containing TEA (6.7 mL, 48.0 mmol). Acetyl chloride (2.75 mL, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was crystallized from DCM. Yield: 5.3g (84%). 1H NMR (400 MHz, CHLOROFORM-D) delta 2.04 (s, 3 H), 7.51 (dd, J=11.23, 9.08 Hz, 1 H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).
84 - 87%
With triethylamine; In dichloromethane; at 0 - 20℃;Product distribution / selectivity;
Step B. N-(4-FLUORO-3-NITROPHENYL) acetamide; 4-Fluoro-3-nitroaniline (5. 0G, 32.0 mmol) was dissolved in 50 mL of DCM at 0C containing TEA (6.7 ML, 48.0 mmol). Acetyl chloride (2. 75 ML, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5% KHS04 solution, saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. The product was crystallized from DCM. Yield: 5.3g (84%) ; 1H NMR (400 MHz, CHLOROFORM-D): 8 2.04 (s, 3 H), 7.51 (dd, J=11. 23, 9.08 Hz, 1 H), 7.80 (ddd, J=9. 08,4. 00,2. 93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).; Step B. N-(4-fluoro-3-nitrophenyl) acetamide; Acetyl Chloride (2.39 mL, 33.6 mmol) was slowly added to a solution of 3-nitro-4- fluoroaniline (5.00 g, 32.0 mmol) and Et3N in DCM (500 mL) at 0C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water, saturated NAHC03 solution, brine, dried over anhydrous MGS04 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield : 5.65 g (87%) ; MS (ESI) (M+H) + : 199. 1.
84%
With triethylamine; In dichloromethane; at 0 - 20℃;
4-Fluoro-3-nitroaniline (5.0g, 32.0 mmol) was dissolved in 50 mL of DCM at 0C containing TEA (6.7 mL, 48.0 mmol). Acetyl chloride (2.75 mL, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was crystallized from DCM. Yield: 5.3g (84%). 1H NMR (400 MHz, CHLOROFORM-D): delta 2.04 (s, 3 H), 7.51 (dd, J=I 1.23, 9.08 Hz, 1 H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).
N-(4-fluoro-3-nitrophenyl)-3-(pyrimidin-4-yl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 130℃;
Step 1. Preparation of N-(4-fluoro-3-nitrophenyl)-3- (pyrimidin-4-yl) pyridin-2-amine; 4- (2-Chloro-pyridin-3-yl)-pyrimidine (60 mg', 0.30 mmol), 4- fluoro-3-nitrobenzenamine (56 mg, 0.36 mmol), Pd(OAc)2 (4 mg, 0 . 012 mmol), rac-BINAP (8 mg, 0 . 012 mmol) and K2C03 (829 mg, 6.0 mmol) in toluene (3.0 mL) were reacted overnight at 130 C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04, filter, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes) yielding the title compound. MS m/z = 312 [M+1]+. Calc'd for C15H10FN5O2: 311.28.
With diiodomethane; isopentyl nitrite; at 20 - 70℃; for 2h;
Add isoamyl nitrite (18. 6 g, 160 mmol) to a suspension of 4-fluoro-3- nitrophenylamine (5. 0 g, 32 mmol) in diiodomethane (150 mL). Stir under nitrogen at room temperature for 1 h. Heat at 70 C for 1 h. Cool to room temperature and concentrate. Dilute with dichloromethane (500 mL) and water (100 mL). Collect the organic, concentrate and purify (silica gel chromatography, eluting with a gradient of 100 : 0 to 80 : 20 hexanes : ethyl acetate), to give the title compound as a yellow oil (1. 22 g, 14%). 1H NMR (300 MHz, CDC13) 6 7. 02-7. 11 (m, 1H), 7. 89-7. 97 (m, 1H), 8. 32-8. 39 (dd, J = 2. 2 Hz, 6. 9 Hz, 1H).
1. Preparation of 4-Fluoro-3-nitroacetanilide 4-Fluoro-3-nitroaniline (5.2 g) is treated with acetic anhydride (1.1 eq.) in dichloromethane at room temperature for 1 h. The reaction is concentrated, the residue taken up in dichloromethane and washed with aqueous sodium bicarbonate (2*) then with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 4.7 g of crude 4-Fluoro-3-nitroacetanilide.
With hydrogenchloride; sodium methylate; In methanol; water;
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis. USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0 C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2 O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2 SO4, and concentrated under vacuum to yield 17.5 g (97%) of product as a dark brown solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) delta7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
17.5 g (97%)
With hydrogenchloride; sodium methylate; In methanol; water;
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0 C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5 g (97%) of product as a dark brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) delta7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 10h;
Method 53; 3 -( 1 -Cyano- 1 -methylethy 1 yiV-(4-fluoro-3 -nitrophenvDbenzamide; To a stirring solution of 3 -(I -cyano- 1 -methylethy l)-benzoic acid (Method 73; 200 mg, 1.06 mmol) in DMF (5 ml) were added 4-fluoro-3-nitroaniline (174 mg, 1.06 mmol), HATU (603 mg, 1.59 mmol) and DIEA (0.55 ml, 3.15 mmol) and the reaction mixture was stirred for 10 hours at 25 C. The reaction mixture was partitioned between EtOAc and H2O. The organics were washed with H2O, brine and dried (MgSO4 (s)). The solvent was removed under reduced pressure affording 330 mg (95%) of the title compound; m/z 328.
EXAMPLE 8 Hydrogenation of 2,4-Dinitrofluorobenzene Using Palladium Chloride as Catalyst Using the method described in Example 25, 8.16 grams (0.044 mole) of 2,4-dinitrofluorobenzene was hydrogenated in the presence cf 0.20 gram (0.0011 mole) of <strong>[7647-10-1]palladium (II) chloride</strong> in 100 mL each of glacial acetic acid and anhydrous ethanol. The crude product that was isolated weighed 1.67 grams and was determined to be 68% 2-fluoro-5-nitroaniline by NMR, a yield of 16.5%. The sample was purified by column chromatography, yielding 1.1 grams of 2-fluoro-5-nitroaniline, an isolated yield of 16.1%. A 0.18 gram fraction of 4-fluoro-3-nitroaniline was also recovered.
With silver tetrafluoroborate; 4,4'-Dimethoxy-2,2'-bipyridin; potassium tert-butylate; hydrogen; In 1,4-dioxane; at 80℃; under 30003.0 Torr; for 48.0h;Autoclave;
In Example 1, the m-nitroacetophenone used was replaced with equimolar 4-fluoro-3-nitroaniline,the reaction was carried out at 80 C for 48 hours at 4.0 MPa. The other procedure was the same as in Example 1 to give 4-fluoro-1,3-diaminobenzene in a yield of 94%, _: A solution of 16.44 mg (0.04 mmol) 4,4'-dimethoxy-2,2'-bipyridine silver 11.22 mg (0.1 mmol) of potassuim t-butoxide and 1 mL of 1,4-dioxane were charged into an autoclave. After stirring, 165.15 mg (1 mmol) of m-nitroacetophenone was added and the mixture was stirred at 80 C. The reaction was carried out for 8 hours. After the reaction has finishedm the reaction solution was extracted with water and dichloromethane to collect the organic phase. Then, the organic phase was dried over anhydrous Na2SO4, suction filtered, rotary evaporated and chromatographed to give a yellow solid 3-acetanilide. Yield 96 %.
With sodium hydroxide; In hydrogenchloride;
EXAMPLE 2 Preparation of 4-fluoro-m-phenylenediamine To a solution of 9 grams of SnCl2.2H2 O in 12 ml of concentrated HCl, are added in a single batch, with stirring, 1.6 grams of 4-fluoro-3-nitroaniline, which dissolves as a brisk reaction occurs, the temperature reaching 95 to 100 C. The reaction mixture is allowed to cool to room temperature, and poured into 70 ml of 50% NaOH solution in ice, so that the temperature remains below 20 C. The resultant strongly alkaline solution is extracted 3 times with 50 ml of ethyl ether. The ethyl ether extracts are combined, washed with 30 ml of distilled water and dried with anhydrous sodium sulfate. The ethyl ether solution is evaporated to dryness and 1.2 gram of a dark colored oil is obtained.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;
114.114A
Example 114; N-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2)3-d]pyrimidin-4-ylammo)-phenyl]-3- trifluoromethyl-benzamide; Example 114A; N-(4-Fluoro-3 -nitro-phenyl)-3 -trifluoromethyl-benzamide; [0503] A solution of 4-Fluoro-3-nitro-aniline (2.0Og, 12.8mmol), 3-Trifluoromethyl-benzoyl chloride (1.895mL, 12.8mmol), Hunig's base (4.463mL, 25.6mmol) in tetrahydrofuran (50ml) was stirred at room temperature for 1 hour. Afterwards water (450 mL) was added to the solution and the resultant solid was collected by filtration and dried in a vacuum oven to provide the title compound(3.3 Hg, 97%).
48%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere; Schlenk technique;
Stage #1: 4-Fluoro-3-nitroaniline With hydrogenchloride In water at 20℃; for 0.5h;
Stage #2: With hydrogenchloride; sodium nitrite In water at -25℃; for 1h;
Stage #3: With hydrogenchloride; tin(ll) chloride In water at -25 - 20℃; for 1h;
2.A
2a2 A mixture of compound 2a1 (10 g, 1 eq.) and aqueous HCI (12M, 50 mL) is stirred at room temperature for 30 minutes, then cooled to -25°C and a mixture of NaNO2 (4.8 g, 1.1 eq.) and aqueous HCI (12M, 40 mL) is added. The mixture is allowed to stir at -25°C for 1 hour and a mixture of SnCI2 (29.1 g, 2.4 eq.) and aqueous HCI (12M, 30 mL) is added. The mixture is allowed to warm to room temperature and stir for 1 hour, then is filtered. The solid is washed with Et2O and dried under reduced pressure to provide compound 2a2 as the hydrochloride salt.
A mixture of 3,5-dibromo-l-methyl-2(lH)pyrazinone (1Og;37.5mmol), 4-fluoro-3-nitroaniline (5.9g; 37.5mmol), and l-methyl-2-pyrollidinone (3OmL) was heated at 140 degrees for lhr. The mixture was cooled to room temperature, diluted with ethyl acetate (10OmL) and filtered to give 5-bromo-3-(4- fluoro-3-nitro-phenylamino)-l-methyl-leta-pyrazin-2-one (1) as a yellow solid (8.9g).
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;
18.18a
The title compound was synthesized from 4-fluoro-3-nitro-phenylamine (2.00 g,12.81 mmol) dissolved in THF (25 ml) and Hunig's base (3.312 g, 25.62 mmol) to which was added furan-2-carbonyl chloride (1.672 g, 12.81 mmol) drop wise over 10 minutes. Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration providing the title compound (2.90 g, 90 %).
A mixture of 4-fluoro-3-nitroaniline (3.45 g, 22.1 mmol), 4-hydroxy-3-methoxyphenylacetic <n="53"/>acid (4.03 g, 22.1mmol) and cesium carbonate (18.Og, 55.3mmol) in methylsulfoxide (40 mL) was heated to 120 C (external temperature, oil bath) overnight. After 16 h the reaction was poured into water and the pH adjusted to <4 by addition of citric acid. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark brown oil. The product was isolated by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient, to afford an orange foamy solid. LC-MS ESI (neg.) m/z: 317.0 (M-H). 1H NMR (400 MHz) (CDCl3) delta 7.27 (d, J=8.4 Hz, IH); 6.93 (s, IH); 6.84-6.79 (m, 4H); 5.90 (br s, 2H); 3.85 (s, 3H); 3.63 (s, 2H) ppm.
With pyridine;dmap; In tetrahydrofuran; 1,2-dichloro-ethane; at 65℃; for 1.5h;
Intermediate B80: lambda/1-(3-amino-4-fluorophenyl)-lambda/2,lambda/2-dimethylglycinamide; Step A/Intermediate B81 : lambda/1-(4-fluoro-3-nitrophenyl)-lambda/2,lambda/2-dimethylglycinamide; To a solution of 4-fluoro-3-nitroaniline (2.48 g, 15.9 mmol) in 1 :1 THF/DCE (200 ml.) was added pyridine (7.54 g, 95.4 mmol, Aldrich), 2-dimethylaminoacetyl chloride hydrochloride (0.66g, 4.20 mmol, Lancaster), and catalytic DMAP (~ 0.10Og). After heating at 650C for 1.5 hrs, the crude reaction mixture was diluted with dichloromethane (300 ml_), washed with saturated NaHCOs (50 ml_), evaporated, and purified by column chromatography (dichloromethane to 5% methanol/dichloromethane) to provide lambda/1-(4-fluoro-3-nitrophenyl)-lambda/2,lambda/2- dimethylglycinamide (3.0 g, 78%) as a brown solid. ESIMS (M+H)+ = 242.
With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 16h;
40.ii
To a solution of 2, 2, 2-trifluoro-N- (3- hydroxyphenyl) acetamide (5.O g, 24.4 mmol) and 4-fluoro-3- nitroaniline (3.8 g, 24.4 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (8.0 g, 24.5 mmol), and the mixture was stirred at 1200C for 16 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the filtrate was diluted with ethyl acetate (250 mL) , washed successively with water (250 mL) and saturated brine (250 mLχ2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→70/30) , and the obtained solution was concentrated under reduced pressure to give the title compound (3.03 g, 36%) as a yellow powder.1H-NMR (DMSO-d6, 300 MHz) δ 5.75 (2H, s), 6.77 (IH, d, J = 8.1 Hz), 6.93 (IH, d, J = 9.0 Hz), 7.02 - 7.11 (IH, m) , 7.20 (2H, br s), 7.35 (IH, t, J = 8.1 Hz), 7.40 - 7.50 (IH, m) , 11.24 (IH, s).
N-(4-fluoro-3-nitrophenyl)-2,3-dihydro-1,4-benzodioxine-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dimethyl amine; at 20 - 40℃;Inert atmosphere;
Preparation of Compound 133, N-(4-Fluoro-3-nitrophenyl)-2,3-dihydro-1,4- benzodioxine-7-carboxamide[00173] 2,3-Dihydrobenzo[b][1 ,4]dioxine-6-carboxylic acid (2.77 g, 15.37 mmol) was dissoved in DMA (25 mL) and DIPEA (6.69 mL, 38.43 mmol) and HATU (5.85 g, 15.37 mmol) added under an inert atmosphere. The reaction was allowed to stir for 15 minutes then 4-fluoro-3-nitroaniline (2.000 g, 12.81 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was heated for a further 16 hours at 40 °C then concentrated in vacuo and water added. The solids were isolated by filtration, washed with water and dried in a vacuum oven. The solids were stirred in EtOAc for an hour and then filtered. The filtrate was evaporated down and the solids were triturated with DCM then filtered. The collected solids were combined to afford the desired material as a cream solid (3.50 g, 86 percent).1H NMR (400 MHz, DMSO, 30 °C) d 4.29 - 4.36 (4H, m), 7.02 (1 H, d), 7.50 - 7.63 (3H, m), 8.15 (1 H, ddd), 8.69 (1 H, dd), 10.46 (1 H, s). m/z (ES+) (M+H)+ = 319.
methyl 2-((4-amino-2-nitrophenyl) thio)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With caesium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 3h; Inert atmosphere;
17 Synthesis of methyl 2-((4-amino-2-nitrophenyl) thio) benzoate (142)
[000169] To a stirred solution of 4-fluoro-3-nitroaniline 141 (500 mg, 3.20 mmol) in DMF (6 mL) under inert atmosphere was added cesium carbonate (1.14 g, 3.50 mmol) at RT and heated to 40 °C. To this was added methyl 2-mercaptobenzoate 1 (592 mg, 3.50 mmol) in DMF (1 mL) drop wise for 3 mm and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (35 mL) and extracted with CH2C12 (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 142 (600 mg, 62%) as brown syrup. TLC: 30% EtOAc/ hexanes (R 0.5); 1H-NMR (DMSO-d6, 400 MHz): ö 7.91 (d, J 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.10 (s, 1H), 6.87-6.84 (m, 1H), 6.79 (d, J= 8.0 Hz, 1H), 6.24 (s, 2H), 3.84 (s, 3H).
2-chloro-N-(4-fluoro-3-nitrophenyl)-5-(trifluoromethyl)pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46.5%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;
4-Fluoro-3-nitroaniline (1.0 g, 6.41 mmol)And 2-chloro-4-iodo-5- (trifluoromethyl) pyridine (2.36 g, 7.69 mmol)And cesium carbonate (4.17 g, 12.81 mmol) were dissolved in 1,4-dioxane (40 mL)Pd2 (dba) 3 (283 mg, 0.31 mmol) and Xantphos (359 mg, 0.62 mmol) were added to the system under nitrogen and the oil bath was heated at 110 C for 16 hours.The reaction was completed, concentrated and the residue was purified by silica gel column chromatography (PE: EA = 5: 1) to give the title compound (1.0 g, yield 46.5%).
Stage #1: 4-Fluoro-3-nitroaniline With formaldehyd; sulfuric acid at 30 - 45℃; for 2h; Large scale;
Stage #2: methanol With ammonia at 10 - 15℃; for 10h; Large scale;
2 synthesis of 4-fluoro-N-methyl-3-nitroaniline
1000L enamel reactor R1 in the inhalation mass concentration of 98% sulfuric acid 1125kg, put 4-fluoro-3-nitroaniline 250kg, put 4-fluoro-3-nitroaniline reaction exothermic, R1 jacket through the circulating water control temperature In 30 ~ 35 , after the vote heated to 45 .At this temperature, 250kg of paraformaldehyde (25kg of paraformaldehyde was added every 0.5h), and after 2h of incubation, the reaction was carried out by HPLC to the reaction of 4-fluoro-3-nitroaniline. , spare.5000L enamel reactor R2 inhaled 25% ammonia 1752kg and methanol 1440kg, R2 jacket through the brine to 10 below the drop, dropping methylation reaction solution, control the dropping temperature at 12 ~ 15 , dropping time 10h After the completion of the dropwise addition, the temperature was raised to 65 to 70 ° C and refluxed for 1 hour. The main content of 4-fluoro-N-methyl-3-nitroaniline was detected by HPLC, then cooled to below 5 ° C, The filtrate was washed with 2400 kg of water and then centrifuged to obtain 270 mL of 4-fluoro-N-methyl-3-nitroaniline and the crude 4-fluoro-N-methyl-3-nitroaniline Methanol 1300kg, the temperature to 60 , keep heating for 30min, and then cooled to 5 ~ 10 , discharged into the filter, centrifuged, dried to get 4-fluoro-N-methyl-3-nitroaniline refined products 260kg, the yield was 95.4%, the product HPLC≥99.9%.
3-chloropropyl (4-fluoro-3-nitrophenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In chloroform; at 0 - 20℃; for 16h;
In a glass RBF equipped with a Teflon-coated magnetic stirrer was dissolved 4-fluoro-3-nitro-phenylamine (1 eq.) in chloroform (0.25 M). To this was then added, at 0C, sequentially pyridine (2 eq.) and 3- chloropropyl carbonochloridate (1.5 eq.). The resulting suspension was allowed to warm slowly to RT over 16 h. The crude reaction mixture was diluted with dichloromethane and washed sequentially with water, sat. aq. NH4C1 and brine. The organic extract was then dried over Na2SO4 and filtered. Concentration of the filtrate thus obtained in vacuo furnished the desired product.
3-(4-fluoro-3-nitrophenyl)-1,5,3-dithiazonane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: formaldehyd; 1,4-Butanedithiol In water at 20℃; for 0.5h;
Stage #2: 4-Fluoro-3-nitroaniline With samarium(III) chloride hexahydrate In chloroform; water at 40℃;
Cyclothiomethylation of nitroanilines 4f,g with CH2O and aliphatic α,ω-dithiols (General method)
General procedure: A mixture ofthe appropriate α,ω-dithiol (1 mmol) and 37% formalin(0.15 ml, 2 mmol) was stirred for 30 min at roomtemperature. Then a solution of nitroaniline 4f,g (1 mmol) and SmCl3·6H2O (0.02 g, 5 mol %) in 5 ml of suitable solvent (compound 4f - CHCl3, compound 4g - Me2CO) was added dropwise. The mixture was stirred for 3-4 h at 40°C, then evaporated on a rotary evaporator. The product was purified by column chromatography.
3-(4-fluoro-3-nitrophenyl)-1,5-dithia-3-azacyclotridecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
General procedure: A mixture ofthe appropriate α,ω-dithiol (1 mmol) and 37% formalin(0.15 ml, 2 mmol) was stirred for 30 min at roomtemperature. Then a solution of nitroaniline 4f,g (1 mmol) and SmCl3·6H2O (0.02 g, 5 mol %) in 5 ml of suitable solvent (compound 4f - CHCl3, compound 4g - Me2CO) was added dropwise. The mixture was stirred for 3-4 h at 40C, then evaporated on a rotary evaporator. The product was purified by column chromatography.
6-(4-Fluoro-3-nitrophenyl)-1,11-dioxa-4,8-dithia-6-azacyclotridecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In water at 20℃; for 0.5h;
Stage #2: 4-Fluoro-3-nitroaniline With samarium(III) chloride hexahydrate In chloroform; water at 40℃;
Cyclothiomethylation of nitroanilines 4f,g with CH2O and 3,6-dioxa-1,8-octanedithiol (General method)
General procedure: A mixture of 3,6-dioxa-1,8-octanedithiol (0.16 ml, 1 mmol) and 37% formalin (0.15 ml, 2 mmol) was stirred for 30 minat room temperature. Then a solution of nitroaniline 4f,g (1 mmol) and SmCl3·6H2O (0.02 g, 5 mol %) in 5 ml of suitable solvent (compound 4f - CHCl3, compound 4g -Me2CO) was added dropwise. The mixture was stirred for 3-4 h at 40°C, the product was then evaporated on a rotary evaporator and purified by column chromatography. 3-(4-Fluoro-3-nitrophenyl)-1,11-dioxa-4,8-dithia-6-azacyclotridecane(8a). Yield 0.27 g (74%), yellow powder,mp 114-117°C, Rf 0.76 (PhH-tOAc, 1:2). IR spectrum, ν,cm-1: 549 (C-H), 592 (C-S), 686 (C-S), 707 (C-H), 756(C-S-C), 807 (C-H), 1072 (C-O-C), 1112 (C-N), 1138(C-O-C), 1215 (C-N), 1245 (NO2-), 1266 (C-O-C),1281 (C-F), 1349 (NO2-), 1386 (O-H), 1422 (C-OH),1450 (CH2), 1539 (NO2-). 1H NMR spectrum, δ, ppm (J, Hz):2.69 (4H, t, J = 4.6, 2SCH2CH2O); 3.71 (4H, s,OCH2CH2O); 3.92 (4H, t, J = 4.6, 2SCH2CH2O); 5.11 (4H,s, SCH2NCH2S); 7.15-7.22 (2H, m, H Ar); 7.60-7.62 (1H,m, H Ar). 13C NMR spectrum, δ, ppm (J, Hz): 29.2(2SCH2CH2O); 55.0 (SCH2NCH2S); 70.2 (OCH2CH2O);74.8 (2SCH2CH2O); 109.5 (d, 4JCF = 2.2, C Ar); 118.7 (d,2JCF = 17.4, C Ar); 119.8 (d, 3JCF = 5.5, C Ar); 137.5 (d,JCF = 6.1, C Ar); 142.5 (s, C Ar); 148.5 (d, 1JCF = 203.6, C Ar). 19F NMR spectrum, δ, ppm: -132.9. Found, m/z: 361.039[M-H]+. 1418FN24S2. Calculated, m/z: 361.069. Found, %: 46.45; 5.22; N 7.81; S 17.76. 1419FN24S2.Calculated, %: C 46.39; H 5.28; N 7.73; S 17.69.
With N-ethyl-N,N-diisopropylamine In acetonitrile for 12h; Reflux;
1 Preparation of 4-(4-methylpiperazin-1-yl)-3-nitroaniline (IIb):
The compound 4-fluoro-3-nitroaniline (II) (6 g, 38.4 mmol) was dissolved in 50 mL of acetonitrile and N-methylpiperazine (5.8 g, 6.3 mL, 57.6 mmol) andN,N-Diisopropylethylamine (9.5 mL, 57.6 mmol) was heated and refluxed for 12 h.After spinning, the crude product was separated and purified by silica gel column chromatography.(dichloromethane: methanol = 20:1)Reddish brown solid(8.9g, 97.8%).
97.8%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; Reflux;
4.1.3.1 4-(4-methylpiperazin-1-yl)-3-nitroaniline (40)
To a solution of compound 4-fluoro-3-nitroaniline (6g, 38.4mmol) in CH3CN (50mL) at room temperature was added N-methyl piperazine (5.8g, 6.3mL, 57.6mmol), followed by N, N-diisopropylethylamine (9.5mL, 57.6mmol). After refluxing for 12h, the reaction mixture was concentrated and purified by column chromatography on silica gel using a common 6% MeOH/DCM gradient to afford compound 40 as red brown solid (8.9g). 1H NMR (300MHz, DMSO-d6) δ 7.06 (d, J=8.6Hz, 1H), 6.76 (s, 1H), 6.69 (d, J=8.5Hz, 1H), 5.34 (s, 2H), 2.70 (t, J=4.4Hz, 4H), 2.27 (br s, 4H), 2.09 (s, 3H). m/z (EI-MS): 259.1 [M+ Na]+. Yield: 97.8%. m.p. > 250°C.
95.5%
With N-ethyl-N,N-diisopropylamine In acetonitrile for 12h; Reflux;
46.1 Step 1: Preparation of 4-(4-methylpiperazin-1-yl)-3-nitroaniline
4-F-3-Nitroaniline (5 g, 32 mmol) was dissolved in acetonitrile (50 mL).DIPEA (7.9 mL, 47.8 mmol) and 1-methylpiperazine (5.3 mL, 67.8 mmol) were added.Reflux for 12h,The reaction solution was spun dry to a crude red solid.Wash with acetonitrile, suction filtration, drying, yield 95.5%
95%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 5h;
93%
at 90℃; for 3h;
1.9 (9) Synthesis of 4-(4-methylpiperazine)-3-nitroaniline (18):
The 4-fluoro-3-nitroaniline (7.8g, 0.05mol),N-methylpiperazine (28ml, 0.25mol),The mixed solution of 30ml acetonitrile was reacted at 90°C for more than 3h. The reaction is over,Put it to room temperature,Spin dry. Separation by silica gel column chromatography (eluent: CH2Cl2) to obtain 11 g of brown solid product (Compound 18),Yield: 93%.
86%
In ethanol for 24h; Reflux;
2
A mixture of 4-fluoro-3-nitroaniline (lOOg, 0.64mol),and N-methylpiperazine (256g, 2.56mol) are dissolved in ethanol, The mixture was maintained at reflux for 24h, and then the mixture was allowed to cool to room temperature, the reaction was concentrated in vacuum and filtered to give 4-(4-methylpiperazin-1-yl)-3-nitroaniline as a red solid (13 lg, 86%) 1H-NMR (300MHZ, CDCl3) 7.11(d,lH), 7.02(d,lH), 6.807-6.845(m,lH), 3.76(s,2H),2.98(m,4H), 2.557(m,4H), 2.35(s,3H).
86.6%
With N-ethyl-N,N-diisopropylamine In acetonitrile for 12h; Reflux;
20.1 Example 20
1. Weigh 2.0 g (12.8 mmol) of 4-fluoro-3-nitroaniline, 1.9 g (19.1 mmol) of N-methylpiperazine, and 2.5 g (19.1 mmol) of N,N-diisopropylethylamine (DIEA). mmol) in a round-bottomed flask, add 25 mL of acetonitrile, and react at reflux temperature for 12 h.After the solvent was evaporated, the residue was separated by silica gel column chromatography (methanol:dichloromethane=1:20, V/V) to obtain 2.6 g of orange-red solid 4-(4-methylpiperazinyl)-3-nitroaniline , the yield is 86.6%,
With sodium methylate In methanol at 20℃; for 16h;
1 Step 1: 4-fluoro-N-methyl-3-nitroaniline.
To a stirred solution of 4-fluoro-3- nitroaniline (1.0 g, 6.41 mmol) in MeOH (20 mL), was slowly added paraformaldehyde (0.769 g, 25.6 mmol) dissolved in MeOH (20 mL). Upon completion of the addition, the reaction mixture was stirred at rt, while NaOMe (0.173 g, 3.02 mmol) in MeOH (10 mL) was slowly added dropwise. Upon completion of the addition, the reaction mixture was stirred at rt for 16 h. Completion of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was poured into 1M KOH aqueous solution and stirred to precipitate a yellow solid. The precipitate was filtered and was dried. The precipitate was purified by combi-flash column chromatography using EtOAc in Hexane. Product eluted with 22% EtOAc in Hexane and was isolated as yellow solid (0.6 g, 55%).
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