* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 6, p. 790 - 802
3
[ 369-36-8 ]
[ 593-51-1 ]
[ 41939-61-1 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: at 20℃; for 14 h; Stage #2: With potassium hydroxide In ethanol; water at 60℃;
2-flouro-5-nitroaniline (468 mg, 3.00 mmol) and methylamine hydrochloride (486 mg, 9.00 mmol) were dissolved in 15 mL EtOH and stirred at room temperature for 10 min. An aqueous solution of potassium hydroxide (1.009 g, 18.0 mmol) in 5 mL H20 was introduced and the mixture was stirred at reflux at 60 °C overnight. Then poured into water (100 mL) and precipitate formed was extracted with ethyl acetate (3 >< 30 mL). The organic extracts were dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (2: 1) as eluent, and gave N'-methyM-nitrobenzene-l^-diamine as red solid (429 mg, 86 percent); 1H NMR (400 MHz, DMSO) δ 7.56 (dd, J= 8.8, 2.7 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 6.43 (d, J= 8.9 Hz, 1H), 6.12 (s 1H), 5.08 (s, 2H), 2.85 (s, 3H); 13C NMR (101 MHz, DMSO) δ 144.09, 136.99, 134.89, 116.46, 107.42, 106.94, 30.12; LRMS (ESI): calcd for: C7H9N3O2 [M+H]+ = 168.2, obsd [M+H]+ = 168.
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
With 5%-palladium/activated carbon; hydrogen In ethanolFlow reactor
General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.
Reference：
[1] Bulletin de la Societe Chimique de France, 1995, vol. 132, p. 306 - 313
[2] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
18
[ 70-34-8 ]
[ 369-36-8 ]
Yield
Reaction Conditions
Operation in experiment
17.6%
With hydrogen In ethanol; water; acetic acid
EXAMPLE 25 Hydrogenation of 2,4-Dinitrofluorobenzene Using 5percent Palladium on Carbon as Catalyst In a 500 mL Parr hydrogenation apparatus were placed 18.61 grams (0.10 mole) Of 2,4-dinitrofluorobenzene, 0.5 gram of 5percent palladium on carbon catalyst, 100 mL glacial acetic acid, 100 mL of anhydrous ethanol. The apparatus was equipped with a thermocouple and a cooling jacket. The temperature of the reaction mixture was maintained at 20°-25° C. during the reaction which consumed 370 psi of hydrogen and required 2.5 hours. The reaction mixture was then poured into 400 mL of water. This mixture was extracted twice with 200 mL, and the extracts were dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a pad of silica gel, eluding with methylene chloride. This solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, eluding with methylene chloride:heptane (80:20). After evaporation of the solvent under reduced pressure, the 2-fluoro-5-nitroaniline that was isolated weighed 2.75 grams, a 17.6percent yield.
Reference：
[1] Patent: US5105012, 1992, A,
[2] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[3] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
[4] Patent: US5105012, 1992, A,
[5] Patent: US5105012, 1992, A,
[6] Patent: US5105012, 1992, A,
19
[ 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
20
[ 369-36-8 ]
[ 140-89-6 ]
[ 58759-63-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 110℃;
5-Mtro-2-mercapto benzothiazole (12): A mixture of 2-fluoro-5-nitro aniline (11,1.00 g, 6.40 mmol) and potassium O-ethyl dithiocarbonate (1.53 g, 9.60 mmol) inDMF (15 mL) was heated overnight at 110-110 0C under N2. After cooling, the reaction mixture was diluted with water and acidified with IN HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield compound 12 (1.27 g, 94percent).
3.99 g
at 100℃; for 5 h;
To a solution of 2-fluoro-5-nitroaniline (3.12 g, 20 mmol) in DMF (15 mL) potassium ethyl xanthogenate (3.93 g, 24 mmol) was added. The mixture was stirred at 100°C for 5 h before it was cooled to rt, diluted with water (25 mL) and 1 M aq. HCI (35 mL). The precipitate that formed was collected, washed with water (15 mL) and dried to give the title compound (or tautomer) (3.99 g) as a beige solid; LC-MS: tR= 0.76 min; [M+H]+= not detectable;1H NMR (400 MHz, D6-DMSO) δ: 14.17 (s, 1 H), 8.15 (dd, J, = 2.2 Hz, J2= 8.8 Hz, 1 H), 7.99 (d, J = 9.0 Hz), 7.97 (d, J = 2.3 Hz).
Reference：
[1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 4, p. 727 - 730
[2] Patent: WO2006/122156, 2006, A2, . Location in patent: Page/Page column 126
[3] Patent: WO2016/207785, 2016, A1, . Location in patent: Page/Page column 45
21
[ 369-36-8 ]
[ 140-90-9 ]
[ 58759-63-0 ]
Yield
Reaction Conditions
Operation in experiment
66.3%
at 10℃; for 4 h; Inert atmosphere
5-nitro-2-fluoroaniline (200 mg, 1.28 mmol)And sodium ethyl xanthate (250 mg, 1.73 mmol)Was dissolved in dry DMF (10 mL)Solution, nitrogen protection to warm up to 100 reaction 4h.After completion of the reaction, the temperature was lowered to room temperature,Slowly add water (10 mL) and 1 M / L hydrochloric acid solution (10 mL)Precipitation of solid, continue stirring 30min,Suction filtration, solid water washing,The filter cake was then dissolved with ethyl acetate,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a tan solid product which was used directly in the next step.(180 mg, 66.3percent);
Reference：
[1] Patent: CN106957279, 2017, A, . Location in patent: Paragraph 0174; 0175; 0176; 0177
Commercially available <strong>[369-36-8]2-fluoro-5-nitrophenylamine</strong> (7.8 g, 50 mmol) was suspended in acetic acid (50 ml_) and heated to reflux. Then acetic acid anhydride (8 ml_) was added over a period of 10 minutes. After the addition was completed, the mixture was heated at reflux for another 30 minutes. The mixture was allowed to cool to ~40C and poured into ice-water (800 ml_). The precipitate was collected by filtration, washed with water (50 ml_) and air-dried to afford the title compound as a beige solid (8.9 g, 89 %). 1H-NMR (400 MHz, CDCI3): delta = 2.27 (s, 3H), 7.23-7.26 (m, 1 H), 7.50 (br-s, 1 H), 7.97-8.01 (m, 1 H), 9.31 (s, 1 H)
85%
at 25℃;
2 [000152] A mixture of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (9.8 g, 62.7 mmol) and acetic anhydride (60 mL) in a 250-mL flask was stirred at 25 C overnight. The mixture was concentrated to dryness in vacuo to give a brown solid that was suspended in Et20 (30 mL), collected and dried to give N-(2-fluoro-5- nitrophenyl)acetamide as an off- white solid (10.6 g, 85%). [000153] m/z 199.
In acetic acid; for 0.666667h;Heating / reflux;
Acetic anhydride (8.0 ml_) was added dropwise over a period of 10 minutes to a mixture of <strong>[369-36-8]2-fluoro-5-nitrophenylamine</strong> (7.8 g) and acetic acid (50 mL) at reflux. The resulting mixture was heated at reflux for 30 minutes and cooled to 40 0C. The mixture was poured into cold water (800 mL) and the resulting precipitate collected by filtration, washed with 1.0 M aqueous hydrochloric acid and water and dried to give title compound as a light brown solid, 9.2 g.1H NMR (DMSO-d6): delta 2.15 (s, 3H), 7.55 (dd, J = 9.1 , 10.3 Hz, 1 H), 8.00-8.05 (ddd, J = 2.9, 4.2, 9.1 Hz, 1 H), 9.00 (dd, J = 2.9, 6.8 Hz, 1 H), 10.20 (s, 1 H).
With hydrogen;palladium; In ethanol; water; acetic acid;
EXAMPLE 25 Hydrogenation of 2,4-Dinitrofluorobenzene Using 5% Palladium on Carbon as Catalyst In a 500 mL Parr hydrogenation apparatus were placed 18.61 grams (0.10 mole) Of 2,4-dinitrofluorobenzene, 0.5 gram of 5% palladium on carbon catalyst, 100 mL glacial acetic acid, 100 mL of anhydrous ethanol. The apparatus was equipped with a thermocouple and a cooling jacket. The temperature of the reaction mixture was maintained at 20-25 C. during the reaction which consumed 370 psi of hydrogen and required 2.5 hours. The reaction mixture was then poured into 400 mL of water. This mixture was extracted twice with 200 mL, and the extracts were dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a pad of silica gel, eluding with methylene chloride. This solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, eluding with methylene chloride:heptane (80:20). After evaporation of the solvent under reduced pressure, the 2-fluoro-5-nitroaniline that was isolated weighed 2.75 grams, a 17.6% yield.
With hydrogen; iron;palladium; In ethanol; water; acetic acid;
EXAMPLE 23 Hydrogenation of 2,4-Dinitrofluorobenzene Using 5% Palladium on Carbon and Powdered Iron To a 500 ml Parr hydrogenation reactor were charged 8.1 g (0.0438 mole) of 2,4-dinitrofluorobenzene, 0.5 g of 5% palladium on carbon catalyst, 1.0 g (0.018 mole) of powdered iron, 150 ml of ethanol, 50 ml of glacial acetic acid, and 5 ml of water. The reaction was stopped after 152 psi of hydrogen had been absorbed. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure leaving a red solid. This solid was passed through a pad of silica gel, eluding with methylene chloride. The solvent was evaporated from the elude, producing 5.85 g of crude 2-fluoro-5-nitroaniline, m.p. 94-96 C.
With hydrogen; iron; acetic acid; In ethanol; water;
EXAMPLE 40 Hydrogenation of 2,4-Dinitrofluorobenzene Using 5% Rhodium on Alumina and Powdered Iron In a 500 ml Parr hydrogenation reactor were placed 8.50 g (0.0457 mole) of 2,4-dinitrofluorobenzene, 1.0 g (0.018 mole) of powdered iron, 0.15 g of 5% rhodium on alumina, 100 ml of ethanol, 100 ml of acetic acid, and 5 ml of water. The reaction was stopped after 140 psi of hydrogen had been absorbed, and the reaction mixture was then filtered. The filtrate was concentrated under reduced pressure, and water was added to the residue. Filtration yielded 5.62 g of crude 2-fluoro-5-nitroaniline.
With hydrogen; iron; In ethanol; water; acetic acid;
EXAMPLE 30 Hydrogenation of 2,4-Dinitrofluorobenzene Using Platinum Oxide and Powdered Iron To a mixture of 40 ml of glacial acetic acid, 5 ml of water, and 8.32 g (0.0447 mole) of 2,4-dinitrofluorobenzene were added 0.10 g (0.00044 mole) of platinum oxide and 0.50 g (0.0090 mole) of powdered iron. Subsequently, 160 ml of ethanol was added to this mixture, and the entire reaction mixture was placed in a 500 ml Parr hydrogenation reactor. The reaction was stopped after 144 psi of hydrogen had been absorbed, and the reaction mixture was then filtered. The filtrate was evaporated under reduced pressure, and the residue was passed through a pad of silica gel, eluding with methylene chloride. The solvent was evaporated from the elude under reduced pressure, producing 6.23 g of crude 2-fluoro-5-nitroaniline, m.p. 90-92 C.
Preparation 1 Synthesis of 1-(2-fluoro-5-nitrophenyl)-1H-pyrrole (P-1) 5-Nitro-2-fluoroaniline (7.0 g, 44.8 mmol) was taken up in acetic acid (60 mL) in a 250 mL round bottomed flask and treated with 2,5-dimethoxytetrahydrofuran (6.3 mL, 49.8 mmol). The resulting mixture was heated to 110 C. for 4 hours. TLC analysis indicated complete conversion of starting material to product after 4 hours. Thus, the reaction mixture was cooled to ambient temperature, transferred to a separatory funnel and partitioned (CH2Cl2//H2O). The organic phase was washed with H2O (3*50 mL), brine (3*50 mL), dried over Na2SO4 and evaporated in vacuo to give a light brown residue. The residue was purified by flash chromatography (hexanes?1:9 EtOAc/hexanes) to afford the title compound as a light yellow solid (7.2 g, 78%). 1H NMR (DMSO-d6, 300 MHz) 8.34 (dd, 1H), 8.16-8.20 (m, 1H), 7.69 (t, 1H), 7.27 (d, 2H), 6.32 (d, 2H) ppm; MS (ES) 207 (M+H).
With hydrogenchloride; sodium hydroxide; In pyridine;
(5-1) 2-Fluoro-5-nitroaniline (15.7 g) solution in pyridine (100 ml) was added drop-wise with methanesulfonylchloride (17.2 g) in an ice bathing. After being stirred for 2 hours at room temperature, the reaction mixture was added with 2N sodium hydroxide (200 ml) and washed with hexane (200 ml) two times. 2N HCl (300 ml) was added into the resultant aqueous layer and solids separated were collected by filtration, washed with water and dried under vacuum to obtain 2'-fluoro-5'-nitromethanesulfonanilide (21.8 g) as brownish solid.
With pyridine; In water;
(1) To 1300 ml of a pyridine solution containing 204.0 g of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> was added 165.0 g of methanesulfonyl chloride under ice cooling, followed by stirring at room temperature for 24 hours. To the reaction solution was added 3000 ml of water, and the precipitate was collected by filtration, air-dried overnight and recrystallized from ethanol to give 230.0 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide as colorless needles. m.p. 128-129 C.
With pyridine; In water;
(1) To 334 ml of a pyridine solution containing 52.1 g of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> was added 42.1 g of methanesulfonyl chloride under ice cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and the crude crystals were recrystallized from ethanol to give 56.9 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide as pale yellow needles. m.p. 162.5~163.5 C.
With pyridine; In water;
(1) To 334 ml of a pyridine solution containing 52.1 g of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> was added 42.1 g of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and the crude crystals were recrystallized from ethanol to give 56.9 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide as pale yellow needles. m.p. 128-129 C.
4.00 g
2-Fluoro-5-nitroaniline (3.00 g) was dissolved in tetrahydrofuran (77 mL), TEA (8.0 mL) and methanesulfonylchloride (4.5 mL) were added at 0C, and the mixture was stirred at 0C for one hour. DIPEA (9.5 mL) and methanesulfonylchloride (4.0 mL) were added and the mixture was stirred at 25C for two hours. A 5 M aqueous sodium hydroxidesolution (15 mL) was added to the reaction solution and the mixture was stirred at 25C for three hours. 5 M hydrochloricacid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was concentratedunder reduced pressure and the resulting residue was washed by suspending in tert-butyl methyl ether to givethe target compound (4.00 g).
With 5%-palladium/activated carbon; hydrogen; In ethanol; under 12001.2 Torr;Flow reactor;
General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.
Example 4 Synthesis of ethyl 2-fluoro-5-nitrocarbanilate STR38 10.7 g (98.9 mmol) of ethyl chloroformate was added dropwise to a mixture of 15.0 g (94.2 mmol) of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong>, 8.20 g (104 mmol) of pyridine and 150 ml of dichloromethane at a temperature of not higher than 5 C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the dichloromethane layer was separated out by adding water to the reaction mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with hexane, thereby obtaining 21.1 g of the objective product (yield: 98%) in the form of ocher crystals. Melting point: 90 to 92 C. 1H-NMR (CDCl3): delta 1.34 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 7.22 (1H, br, s), 7.22 (1H, t, J=9 Hz), 7.91 (1H, ddd, J=3, 6, 9 Hz), 9.03 (1H, dd, J=3, 6 Hz)
A mixture of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (6.24g, 40 mmol) and 5.6 mLdimethylamine in ethanol was allowed to stirred at room temperature for 15 days, and thereaction was completed (monitored by TLC). The solvent was evaporated under vacuum,and the residue was washed with water to give the compound 2 as a red solid (yield95%).
With 1-methyl-pyrrolidin-2-one; potassium carbonate; In tetrahydrofuran; at 120℃; for 16h;Product distribution / selectivity;
Intermediate Example 1; N5- (2-chloropyrimidin-4-yl)-N-isopropyl-N5, 1-dimethyl-1H-benzimidazole-2, 5- diamine; A. N'-Methyl-4-nitro-benzene-1, 2-diamine; To a solution of 2-fluoro-5-nitroaniline (5 g, 32mmol) in 40 ml N- methylpyrrolidinone in a sealed reaction vessel was added potassium carbonate (9.0 g, 50.0 mmol) and a solution of methyl amine (32 ml, 2M in THF) and the reaction was heated to 120 °C. After 16 h, the reaction mixture was cooled to room temperature and poured into 400 ml of water. The resulting precipitate was filtered and dried to give the title compound as a red solid. 'H NMR (300 MHz, d6-DMSO) 67. 54 (dd, J = 8.7 and 2.7 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1 H), 6.41 (d, J = 8.7 Hz, 1H), 6.13 (s, 1 H), 5.08 (s, 2H), 2.83 (s, 3H); Intermediate Example 40; N'-Methyl-4-nitro-benzene-1, 2-diamine; To a solution of 2-fluoro-5-nitroaniline (3.0 g, 19.2 mmol) in 24 ml N- methylpyrrolidinone in a sealed reaction vessel was added potassium carbonate (5.4g, 30.0 mmol) and a solution of methyl amine (20 ml, 2M in THF) and the reaction was heated to 120 °C. After 16 h, the reaction mixture was cooled to room temperature and poured into 200 ml of water. The resulting precipitate was filtered and dried to give the title compound as a red solid. MS (ESI) m/z = 168 [M+H]
With potassium carbonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 120℃;Sealed tube; Inert atmosphere;
Intermediate Example 16 Preparation of N1-methyl-4-nitrobenzene-1,2-diamine In a 350 mL pressure flask, 2-fluoro-5-nitroaniline (10 g, .064 mol), methylamine as a 2M solution in THF (65 mL, .13 mol) and potassium carbonate (18 g, .13 mol) in 1-Methyl-2-pyrrolidinone (80 mL) were combined. The flask was sealed and heated to 120 degrees C overnight. The reaction was monitored by TLC. When reaction was judged to be complete based upon consumption of 2-fluoro-5-nitroaniline, it was cooled to room temperature and poured into 2-3 times the total reaction volume of water. When a precipitate was formed, it was filtered and dried. The product was carried on without purification. 1H NMR (300 MHz, d6DMSO) delta 7.54 (dd, J = 8.79, 2.64 Hz, 1H), 7.39 (d, J = 2.64 Hz, 1H), 6.41 (d, J = 8.79 Hz, 1H), 6.11 (d, J = 4.39 Hz, 1H), 5.07 (s, 2H), 2.83 (d, J = 4.83 Hz, 3H).
In tetrahydrofuran; at 120℃; for 48h;
A mixture of compound 9a1 (10 g, 64 mmol) and CH3NH2 in THF (1 M, 80 mL, 80 mmol) is heated at 120°C for 48 h. The reaction mixture is concentrated to dryness, and diluted with EtOAc. The resulting solid is filtered to provide compound 9a2.
5-Mtro-2-mercapto benzothiazole (12): A mixture of 2-fluoro-5-nitro aniline (11,1.00 g, 6.40 mmol) and potassium O-ethyl dithiocarbonate (1.53 g, 9.60 mmol) inDMF (15 mL) was heated overnight at 110-110 0C under N2. After cooling, the reaction mixture was diluted with water and acidified with IN HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield compound 12 (1.27 g, 94%).
3.99 g
In N,N-dimethyl-formamide; at 100℃; for 5h;
To a solution of 2-fluoro-5-nitroaniline (3.12 g, 20 mmol) in DMF (15 mL) potassium ethyl xanthogenate (3.93 g, 24 mmol) was added. The mixture was stirred at 100C for 5 h before it was cooled to rt, diluted with water (25 mL) and 1 M aq. HCI (35 mL). The precipitate that formed was collected, washed with water (15 mL) and dried to give the title compound (or tautomer) (3.99 g) as a beige solid; LC-MS: tR= 0.76 min; [M+H]+= not detectable;1H NMR (400 MHz, D6-DMSO) delta: 14.17 (s, 1 H), 8.15 (dd, J, = 2.2 Hz, J2= 8.8 Hz, 1 H), 7.99 (d, J = 9.0 Hz), 7.97 (d, J = 2.3 Hz).
With sodium sulfide; sodium hydrogencarbonate; In water; at 125℃; for 0.0833333h;Microwave;
2-Fluoro-5-nitroaniline (Ig, 6.41mmol), sodium sulfide nonahydrate (1.7g, 7.05mmol), sodium bicarbonate (600mg, 7.05mmol) and water (15mL) were combined and heated in the microwave at 1250C for 5min. After cooling, dichloromethane was added, and the organic layer was washed with 2M aqueous hydrochloric acid and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford l.lg (33%) of the title compound. 1H NMR (DMSO): 7.61-7.55 (2H, m), 7.47 (IH, d, J 8.2 Hz), 7.31 (3H, s)
With triethylamine; In dichloromethane; at 0 - 20℃; for 24h;
2-Fluoro-5-nitro-N-trifluoroacetylaniline (32-NO2-H) :2-Fluoro-5-nitroaniline (7.0 g, 45 mmol) was dissolved in CH2Cl2 (200 mL) and Et3N (7.0 mL, 49 mmol) was added. Then(CF3CO)2O (7.5 mL, 11.3 g, 54 mmol) in 25 mL of CH2Cl2 was added dropwise at 0 0C, and the mixture was stirred for 24 h at room temperature. The reaction mixture was washed with water (3x300 mL) and saturated aq. NaHCO3 (300 mL) . The organic layer was separated, and an aqueous layer was extracted with CH2Cl2 (2x100 mL) . Combined organic solutions were dried over Na2SO4, evaporated, and the title compound was isolated as a light beige solid with m.p. 112-113 0C; yield - 10.5 g (93%). 1H NMR (CDCl3, 300 MHz, ppm) : delta = 7.35(t, Jm= 3JHF =9.2, 1 H, H-3), 8.14 (ddd, 4JHH= 2.8, 4JHF = 4.2, 3JHH=9.2, 1 H, H-4), 8.22 (br s, NH), 9.18 (dd, 3JHH = 2.9, 4JHF=6.4, 1 H, H-6) ; 13C NMR (CDCl3, 75.5 MHz, ppm): delta = 115.1(q, 1JcF= 289, CF3), 116.1 (d, 2JCF = 22, C-3), 117.8 (d, 3JCF =2.3, C-4/6), 122.3 (d, 3JCF = 9.5, C-6/4), 124.6 (d, 2JCF = 12.7, C-I), 144.5 (C-5), 154.4 (q, 2JCF = 42, CO), 155.8 (d, 1JcF = 256, C-2); EI-MS: m/z (rel. int., %) = 223 (100)[M-HCO]+ , 154 (21) , 126 (18) , 99 (17).
With triethylamine; In dichloromethane; at 0℃; for 1h;
To a solution of <strong>[369-36-8]2-fluoro-5-nitro-phenylamine</strong> (4.68g, 30 mmol), triethylamine (13.8 mL, 100 mmol) in dichloromethane (100mL) was added trifluoroacetic anhydride (5.7 mL, 40 mmol) dropwise at 0C. After 1h, the reaction mixture was washed with water, diluted HCl (pH 2) and water, concentrated to give crude 2,2,2-trifluoro-N-(2-fluoro-5-nitro-phenyl)-acetamide (12.9g).
[2-(2-Fluoro-5-nitro-phenylamino)-ethoxy]-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Alkylation of 2-Fluoro-5-nitro-phenylamine with <strong>[83881-47-4](2-Chloro-ethoxy)-acetic acid methyl ester</strong> in an inert solvent in the presence of base will give [2-(2-Fluoro-5-nitro-phenylamino)-ethoxy]-acetic acid methyl ester.
27 4-(3-Benzamido-4-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
The 3-benzamido-4-fluoroaniline (alternatively named as N-(5-amino-2-fluorophenyl)benzamide) used as a starting material was prepared as follows: Triethylamine (5.85 ml) was added to a an ice-cooled solution of 2-fluoro-5-nitroaniline (3.9 g) in dry methylene chloride under an argon atmosphere. Benzoyl chloride (4.18 ml) was added gradually. The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between water and methylene chloride, the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate, filtered and evaporated to dryness to give a sticky solid. Trituration with hot isohexane and diethyl ether gave N-(2-fluoro-5-nitrophenyl)benzamide as a solid (3.2 g, 49%); NMR (CDCl3) 7.26 (dd, 1H), 7.6 (m, 3H), 7.91 (d, 2H), 8.03 (m, 1H), 8.15 (broad s, 1H), 9.48 (dd, 1H); m/s: M+H+261.
a. 2-methylamino-5-nitro-aniline 12.5 g (0.079 mol) of 2-fluoro-5-nitroaniline and 100 ml methylamine (40percent in water) are stirred for 48 hours at ambient temperature. The precipitated product is diluted with water, suction filtered, washed and dried. Yield: 12.0 g (91percent of theory), Rf value: 0.5 (silica gel; ethyl acetate/petroleum ether=6:4).
In methylamine;
a. 2-methylamino-5-nitro-aniline 3.3 g (20 mmol) of 2-fluoro-5-nitro-aniline are dissolved in 50 ml of methylamine solution (40percent) and stirred for 3 days at ambient temperature. The precipitate is suction filtered and dried. Yield: 3.3 g (98.8percent of theory), Rf value: 0.65 (silica gel; ethyl acetate).
EXAMPLE 1 2-(2-Fluoro-5-nitrophenyloxy)tetrahydropyran 2-Fluoro-5-nitroaniline (3.2 g) is dissolved in 30 mL H2 SO4 and 80 mL H2 O is mixed with 1.5 g NaNO2 in water below 5 C. After 10 minutes the mixture is filtered, the filtrate added to 400 mL of boiling 50% H2 SO4, and the mixture heated for 15 min., then cooled and the phenol thus obtained, filtered, washed and recrystallized (hexane) to yield 2-fluoro-5-nitrophenol.
With sulfuric acid; sodium nitrite; In water;
A. 2-Fluoro-5-nitrophenol A solution of 3.2 grams of 2-fluoro-5-nitroaniline, sulfuric acid (3 cc., d 1.84) and 8 ml. of water is stirred into a solution of 1.5 grams of sodium nitrite in water, maintained below 5 C. After 10 minutes, the excess nitrous acid is destroyed by urea, the reaction mixture filtered, and the filtrate added to 40 ml. of boiling 50% sulfuric acid. After complete addition, the mixture is boiled an additional 15 minutes, cooled, and the separated phenol filtered and washed with water. It is then purified by recrystallization from hexane.
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 MeNH2; potassium carbonate; In methanol; 1,2-dimethoxyethane; hexane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate;
Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a) A mixture of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (861 mg; 5.52 mmol; 1.02 eq); Im2CS (960.3 mg; 5.39 mmol) and dry K2CO3 (1.45 g) was suspended in dry DME (10 mL) and stirred under nitrogen for 90 min at room temperature. The yellow suspension was made fluid by diluting with DME (10 mL) followed by addition of 40% MeNH2 in water (4.0 mL; 46.5 mmol; 8.6 eq). The system was heated up to 65C and stirred at this temperature for 3.5 h, cooled down, diluted with ethyl acetate and washed with saturated NaCl (*2). After conventional work-up procedures, the dark crude mixture was purified through chromatographic column on silica gel (elution 50% EtOAc in hexane, then 5% MeOH in DCM), to afford 836.8 mg (4.0 mmol; 72% yield) of compound 456a.
72%
With MeNH2; potassium carbonate; In methanol; 1,2-dimethoxyethane; hexane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate;
Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a) A mixture of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (861 mg; 5.52 mmol; 1.02 eq); Im2CS (960.3 mg; 5.39 mmol) and dry K2CO3 (1.45 g) was suspended in dry DME (10 mL) and stirred under nitrogen for 90 min at room temperature. The yellow suspension was made fluid by diluting with DME (10 mL) followed by addition of 40% MeNH2 in water (4.0 mL; 46.5 mmol; 8.6 eq). The system was heated up to 65C and stirred at this temperature for 3.5 h, cooled down, diluted with ethyl acetate and washed with saturated NaCl (*2). After conventional work-up procedures, the dark crude mixture was purified through chromatographic column on silica gel (elution 50% EtOAc in hexane, then 5% MeOH in DCM), to afford 836.8 mg (4.0 mmol; 72% yield) of compound 456a.
72%
With MeNH2; potassium carbonate; In methanol; 1,2-dimethoxyethane; hexane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate;
Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a) A mixture of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (861 mg; 5.52 mmol; 1.02 eq); Im2CS (960.3 mg; 5.39 mmol) and dry K2CO3 (1.45 g) was suspended in dry DME (10 mL) and stirred under nitrogen for 90 min at room temperature. The yellow suspension was made fluid by diluting with DME (10 mL) followed by addition of 40% MeNH2 in water (4.0 mL; 46.5 mmol; 8.6 eq). The system was heated up to 65C and stirred at this temperature for 3.5 h, cooled down, diluted with ethyl acetate and washed with saturated NaCl (*2). After conventional work-p procedures, the dark crude mixture was purified through chromatographic column on silica gel (elution 50% EtOAc in hexane, then 5% MeOH in DCM), to afford 836.8 mg (4.0 mmol; 72% yield) of compound 456a.
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 60℃;Combinatorial reaction / High throughput screening (HTS);
Step 2. Catalytic amination of the solid supported 8-iodo-l-methyl-4,5-dihydro- lH-pyrazolo [4,3-h] quinazoline-3-carboxamide; <n="82"/>Using a 4 niL Argonaut Trident synthesizer cassette, 200 mg (0.11 mmol) of the resin from step 1 above, were charged into separate vials. To each of the reactor vials flushed with argon, finely divided potassium carbonate (0.15 g, 1.1 mmol), palladium acetate [Pd(OAc)2] (2.5mg, 0.011 mmol, 10%), (HK)-BINAP (6.8 mg, 0.011 mmol, 10%) and the corresponding amine (0.22 mmol, 2 equivalents) in degassed (argon) dimethyacetamide (2 mL) were added. The resulting mixture was agitated at 600C for 10 hours on the Argonaut Trident Automated Library Synthesizer (ALS) station. The Trident ALS station was programmed to continuously mechanically agitate the resin at 6O0C while a nitrogen gas "sparge" was incorporated to re-suspend the scarcely soluble potassium carbonate. Nitrogen gas sparging was incorporated once per hour, for a 30 second duration, throughout the 16-hour heating cycle.The resin was drained from the synthesis cocktail and washed using the Argonaut Trident External Agitation Thermal Unit (EATU) synthesis station with DMA (3 x 2 mL, 5 min.). The above catalytic amination cycle was repeated a second time using the previously described procedure.Upon completion of the second amination cycle, the resin was drained from the synthesis cocktail and washed using the Argonaut Trident EATU synthesis station with DMF (1 x 2 mL, 5 min.), with water (1 x 2 mL, 5 min.), with DMF/water (1 : 1) (3 x 2 mL, 5 min.), with DMF (3 x 2 mL, 5 min.), with methanol (3 x 2 mL, 5 min.) and with DCM (3 x 2 mL, 5 min.).
With potassium tert-butylate; In N,N-dimethyl-formamide; at 5℃;Cooling with ice;
Potassium tert-butoxide (36 g, 0.32 mol) was added to a solution of 2-cyanoacetamide (27 g, 0.32 mol) in anhydrous N,N-dimethylformamide (700 mL), and a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (25 g, 0.16 mol) in anhydrous N,N-dimethylformamide (80 mL) was added dropwise thereto under ice-cooling. After the reaction mixture was stirred at 5 C for 18 hours, it was poured into a saturated ammonium chloride aqueous solution (1.0 L) under ice-cooling. The whole was extracted with ethyl acetate (1.0 L). The organic layer was washed with water (500 mL), brine (300mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, toluene (100 mL) and dichloromethane (100 mL) were added to the residue. The precipitated solid was filtered off, and dried under reduced pressure to give the title reference compound (33 g) as a brown solid (yield 94 %). 2-(2-Amino-4-nitrophenyl)-2-cyanoacetamide (Reference compound 3-1) [Show Image] 1H-NMR (400 MHz, DMSO-d6) delta 5.21 (s, 1H), 6.01 (s, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.86 (s, 1H)
Stage #1: 2,2-dimethylthiirane; 6-fluoro-3-nitroaniline With copper(II) bis(trifluoromethanesulfonate) at 40℃; neat (no solvent);
Stage #2: With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 50℃; for 8h;
Preparation example 3: synthesis of methyl 2-fluoro-5-(N-parafluorobenzyl-N-propargyl-imino)-aniline formate (K10) 3.1. Synthesis of methyl 2-fluoro-5-nitro aniline formate 2-fluoro-3-nitro group aniline (156mg, 1mmol) was dissolved in dried THF (5mL) under an atmosphere of nitrogen. The resulting solution was cooled to 0C in an ice-bath and sodium hydride (40mg, 60%, 1mmol) was added thereto. Then the solution was warmed to room temperature with stirring for 60 min. Thereafter, the solution was cooled to 0C and then methyl chloroformate (85.2muL, 1.1mmol) was added. After stirring for 10min, the mixture was diluted with water (10mL) and extracted with EtOAc (10mLx3). The combined organic phases were washed with saturated saline solution (15mLx3), dried with anhydrous Na2SO4, concentrated and then loaded on chromatography column (PE/EtOAc=10:1-5:1). A product of methyl 2-fluoro-5-nitro aniline formate (245mg, 84.5%) was obtained.
84.5%
3.1. Synthesis of methyl 2-fluoro-5-nitro aniline formate [0076] aniline (156 mg, 1 mmol) was dissolved in dried THF (5 mL) under an atmosphere of nitrogen. The resulting solution was cooled to 0 C. in an ice-bath and sodium hydride (40 mg, 60%, 1 mmol) was added thereto. Then the solution was warmed to room temperature with stirring for 60 min. Thereafter, the solution was cooled to 0 C. and then methyl chloroformate (85.2 muL, 1.1 mmol) was added. After stirring for 10 min, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with saturated saline solution (15 mL×3), dried with anhydrous Na2SO4, concentrated and then loaded on chromatography column (PE/EtOAc=10:1-5:1). A product of methyl 2-fluoro-5-nitro aniline formate (245 mg, 84.5%) was obtained.
65.6%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Intermediate 59A: Preparation of methyl 2-fluoro-5-nitrophenylcarbamate [00187] A solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (500 mg, 3.20 mmol) in THF (20 mL) was treated with DIEA (0.84 mL, 4.8 mmol) followed by methyl chloroformate (0.25 mL, 3.20mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiC^, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 59A (450 mg, 65.6 %). HPLC: Rt = 2.868 min. (YMC S5 ODS 4.6 x 50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). 1H NMR (400 MHz, DMSO-d6) delta ppm 9.94 (1 H, s), 8.72 (1 H, dd, J = 6.80, 2.77 Hz), 7.87 - 8.09 (1 H, m), 7.52 (1 H, t), 3.72 (3 H, s).
With pyridine; chloro-trimethyl-silane; triethylamine; at 100℃; for 4h;
Intermediate 28A: Preparation of 4-(2-fluoro-5-nitroprienyl)-4H-l,2,4-triazole[00169] A solution of 2-fluoro-5-nitroaniline (415 mg, 2.7 mmol) in pyridine (15 mL) was treated with <strong>[628-36-4]N'-formylformohydrazide</strong> (703 mg, 7.98 mmol), and TMS-Cl (5.10 mL, 39.9 mmol) was then added dropwise. After the addition, Et3N (2.60 mL, 18.6 mmol) was added, and the reaction mixture was heated to 100 0C for 4 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was suspended in H2O (25 mL) and filtered. The filtrate was extracted with EtOAc (4 x 20 mL), and the organics were dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, hexanes to 100percent EtOAc, 40 g column, 40 min. gradient) to afford Intermediate 28A (210 mg, 37.9 percent). HPLC: Rt = 1.497 min. (YMC S5 ODS 4.6 x 50 mm, 10-90percent aqueous methanol containing 0.2percent H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z = 209.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.05 (1 H, s), 9.05 (1 H, s), 8.72 (1 H, dd, J = 6.55, 2.77 Hz), 8.39 - 8.45 (1 H, m), 7.85 (1 H, t, J = 9.57 Hz).
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Sealed tube;
To a solution of <strong>[369-36-8]2-fluoro-5-nitro-aniline</strong> (607.8 mg, 3.89 mmol) and potassium carbonate (824.2 mg, 5.96 mmol) in DMSO (10 mL) was added cyclopropylmethanamine (376.4 mg, 5.29 mmol). The mixture was placed in a sealed tube and stirred at 100 C overnight. The mixture was cooled down to rt and diluted with water (80 mL), then extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (50 mLx 5), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtO Ac/PE (v/v) = 1/3) to give the title compound as a brown solid (640 mg, 79.3%).MS (ESI, pos.ion) m/z: 208.2 [M+H]+;1H NMR (600 MHz, CDCl3): d (ppm) 7.81 (dd, J = 8.8, 1.7 Hz, 1H), 7.62 (d, j = 1.7 Hz, 1H),6.50 (d, J = 8.8 Hz, 1H), 4.41 (s, 1H), 3.40 (s, 2H), 3.07 - 3.05 (m, 2H), 1.18 - 1.12 (m, 1H),0.62 (q, J= 5.0 Hz, 2H), 0.30 (q, J= 4.8 Hz, 2H).
79.3%
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Sealed tube;
To <strong>[369-36-8]2-fluoro-5-nitro-aniline</strong> (607.8 mg, 3.89 mmol)And potassium carbonate (824.2 mg, 5.96 mmol)DMSO (10mL) solution was addedCyclopropylmethylamine (376.4 mg, 5.29 mmol).The reaction mixture was placed in a sealed tube and stirred at 100 C.After the reaction,The reaction mixture was cooled to room temperature.Then diluted with water (80 mL),The resulting mixture was extracted with EtOAc (EtOAc (EtOAc)The combined organic phases were washed with water (50 mL×5).Dry over anhydrous sodium sulfate,Filter and concentrate under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc /EtOAcThe title compound was obtained as a brown solid (640 mg, 79.3%).
In dimethyl sulfoxide; at 80℃; for 48h;
1 ~(cyclopropylmethyl)-5-nitro- 1 H-benzotriazole (6)A solution of 2-fluoro-5-nitroamline (I5 5.00 g, 32.0 mmol, 1 equiv) and 1- cyclopropylmethanamine (3.33 mL, 38.4 mmol, 1.20 equiv) in DMSO (40 mL) was heated at 80 0C for 48 h, then allowed to cool to 23 0C. Acetic acid (20 mL) was added followed by a solution of sodium nitrite (2.65 g, 38.4 mmol, 1.20 equiv) in water (50 mL), and the resulting mixture was stirred for 45 min, diluted with water, and neutralized with solid sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (3 x 150 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (hexanes, grading to 100% ethyl acetate) to give l-(cyclopropylmethyl)-5-nitro-l H-benzotriazole (6) as an orange oil. 1H NMR (300 MHz, CDCl3) d 9.03 (dd, IH5 J- 1.2, 0.6 Hz)5 8.41 (dd, IH, J - 9.2, 2.1 Hz)3 7.69 (dd, IH, J- 9.2, 0.6 Hz), 4.59 (d, 2H5 J = 7.3 Hz), 1.26 (m, IH), 0.72 (m, 2H), 0.53 (m, 2H). LRMS m/z (M+H) 219.0 found, 219.1 required.
2-Fluoro-5-nitroaniline (2-1) (10.22 g, 65.5 mmol, 1.0 equiv.) was dissolved in anhydrous DMSO (100 ml), and treated with neopentylamine (2-2) (7.71 ml, 65.5 mmol, 1.0 equiv.). The reaction mixture was heated at 120 C for 2 days when LCMS showed mostly product with trace of starting material. The reaction mixture was cooled to room temperature and treated with acetic acid (25 ml), followed by addition of 2.0 M aqueous solution of sodium nitrite (121 ml, 79 mmol, 1.2equiv.). LCMS showed product after the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture was then neutralized to pH = 7 with NaOH (IN) and diluted with water which caused a precipitation. The solid was collected on top of filter and washed twice with water. The crude solid was purified with silica gelchromatography (EtOAc/hexanes gradient from 0 to 100%) to yield l-(2>2-dimethylpropyl)-5- nitro-lH--1,2,3-benzotriazole (2-3). 1H NMR (CDCl3) delta 9.02 (d, 1H, J= 2.0 Hz), 8.40 (dd, 1H, J = 9.1, 2.0 Hz), 7.62 (d, 1H, J= 9.1 Hz), 4.47 (s, 2H), 1.07 (s, 9H) ppm. LRMS m/z (M+H) 235.1 found, 235.3 required.
Example 2; 4-Bromo-1-(2,2-dimethylpropyl)-1H-benzotriazol-5-ol (Example 1-2) Step 1: 1-(2,2-Dimethylpropyl)-5-nitro-1H-1,2,3-benzotriazole (8)2-Fluoro-5-nitroaniline (6, 10.22 g, 65.5 mmol, 1.0 equiv.) was dissolved in anhydrous DMSO (100 ml) and treated with neopentylamine (1-2) (7.71 ml, 65.5 mmol, 1.0 equiv.). The reaction mixture was heated at 120 C. for 2 days, cooled to room temperature and treated with acetic acid (25 ml), followed by addition of 2.0 M aqueous solution of sodium nitrite (121 ml, 79 mmol, 1.2 equiv.). LCMS showed product after the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture was then neutralized to pH=7 with NaOH (1N) and diluted with water which caused precipitation. The solid was collected on top of filter and washed twice with water. The crude solid was purified with normal phase silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to yield 1-(2,2-dimethylpropyl)-5-nitro-1H-1,2,3-benzotriazole (8). 1H NMR delta (CDCl3): 9.02 (d, 1H, J=2.0 Hz), 8.40 (dd, 1H, J=9.1, 2.0 Hz), 7.62 (d, 1H, J=9.1 Hz), 4.47 (s, 2H), 1.07 (s, 9H) ppm. LRMS m/z (M+H) 235.1 found, 235.3 required.'
EXAMPLE 1-Butyl 4-[4-bromo-l-(2,2-dimethylpropyl)-lH-benzotriazol-5-yl]ethynyl}piperidine- lateScheme for Preparation of Example 1 : Step 1 Preparation of l-(2,2-dimethylpropyl)-5-nitro-l -l,2 -benzotriazole:2-Fluoro-5-nitroaniline (10.22 g, 65.5 mmol, 1.0 equiv.) was dissolved in anhydrous dimethylsulfoxide (100 ml) and treated with neopentylamine (7.71 ml, 65.5 mmol, 1.0 equiv.). The mixture was heated at 120 C for 2 days, cooled to ambient temperature and treated with acetic acid (25 ml), followed by addition of 0.65 M aqueous solution of sodium nitrite (121 ml, 79 mmol, 1.2 equiv.). After 20 minutes at ambient temperature, the mixture was neutralized to pH 7 with NaOH (IN aqueous) and diluted with water. The mixture was filtered and the solid was collected on top of filter and washed twice with water. The residue was purified via silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to provide the titled compound: NMR (500 MHz, CDC13) delta 9.02 (d, 1H, J= 2.0 Hz), 8.40 (dd, 1H, J= 9.1, 2.0 Hz), 7.62 (d, 1H, J= 9.1 Hz), 4.47 (s, 2H), 1.07 (s, 9H) ppm. LRMS m/z (M+H) 235.1 found, 235.3 required.
2-Fluoro-5-nitroaniline (10.2 g, 65.5 mmol, 1.0 equiv.) was dissolved in anhydrous dimethylsulfoxide (100 ml) and treated with neopentylamine (7.71 ml, 65.5 mmol, 1.0 equiv.). The mixture was heated at 120 C for 48 hours, cooled to ambient temperature and treated with acetic acid (25 ml), followed by addition of 0.65 M aqueous solution of sodium nitrite (121 ml, 79 mmol, 1.2equiv.). The mixture was then neutralized to pH 7 with sodium hydroxide (IN aqueous) and diluted with water, which caused precipitation. The solid was collected on top of filter and washed twice with water, which was further purified via silica gel chromatography (100:0 to 0:100; hexanes : ethyl acetate), providing the titled compound: 1H NMR (500 MHz, CDC13) delta 9.02 (d, 1H, J= 2.0 Hz), 8.40 (dd, 1H, J= 9.1, 2.0 Hz), 7.62 (d, 1H, J= 9.1 Hz), 4.47 (s, 2H), 1.07 (s, 9H) ppm. LRMS m/z (M+H) 235.1 found, 235.3 required.
2-Fluoro-5-nitroaniline (10.22 g, 65.5 mmol, 1.0 equiv.) was dissolved in anhydrous dimethylsulfoxide (100 ml) and treated with neopentylamine (7.71 ml, 65.5 mmol, 1.0 equiv.). The mixture was heated at 120 C for 2 days, cooled to room temperature and treated with acetic acid (25 ml), followed by addition of 0.65 M aqueous solution of sodium nitrite (121 ml, 79 mmol, 1.2 equiv.). After stirring at ambient temperature for 20 minutes, the mixture was neutralized to pH 7 with NaOH (1 N aqueous) and diluted with water, which causedprecipitation. The solid was collected by filtration and washed twice with water. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient from 0 to 100%) to provide the titled compound: 1H NMR (500 MHz, CDC13) delta 9.02 (d, 1H, J= 2.0 Hz), 8.40 (dd, 1H, J = 9.1 , 2.0 Hz), 7.62 (d, 1H, J= 9.1 Hz), 4.47 (s, 2H), 1.07 (s, 9H) ppm. LRMS m/z (M+H) 235.1 found, 235.3 required.
With triethylamine; In dichloromethane; at 55℃; for 12h;
To a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 22 (15.6 g, 100 mmol) in dichloromethane (200 mL) were added di-tert-butyl bicarbonate (87.2 g, 400 mmol) and Et3N (20.4 g, 200 mmol), and the mixture was stirred at 55 C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give di-tert-butyl (2-fluoro-5-nitrophenyl)imidodicarbonate (19.3 g, 72%) as yellow powder. 1H NMR (CDCl3) delta 1.44 (18H, s), 8.12-8.16 (1H, m), 8.21-8.25 (2H, m).
54%
With triethylamine; In dichloromethane; at 55℃;
(i) Production of di-tert-butyl (2-fluoro-5-nitrophenyl)imidodicarbonateTo a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (15.6 g, 100 mmol) in dichloromethane (200 mL) were added di-tert-butyl bicarbonate (87.2 g, 400 mmol) and triethylamine (20.4 g, 200 mmol), and the mixture was stirred at 55 C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (19.3 g, 54%) as a yellow powder.1H-NMR (CDCl3, 300 MHz) delta 1.44 (18H, s), 8.12-8.16 (1H, m), 8.21-8.25 (2H, m).
With pyridine; In dichloromethane; at 0 - 20℃; for 3h;
To a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (0.50 g, 3.20mmol) in anhydrous dichloromethane (10 mL) was added2-chloro-4-fluoro-3-methylbenzoyl chloride (0.79 g, 3.84 mmol) at 0 C.This was followed by the addition of pyridine (0.34 mL, 4.16 mmol), and the resultingsolution was stirred at room temperature for 3 h. The reaction was subsequentlydiluted with dichloromethane (20 mL), and washed with 2M/HCl (5 x 20 mL), thenwater (20 mL). The organic phase was then separated, dried (Na2SO4),filtered, and concentrated. The residue was purified by column chromatographyon silica gel using PE: EA=40:1 as the eluent, providing 1 as a white solid (0.81 g, 77.1%). m.p. 181-183 C. 1H NMR (300 MHz, DMSO- d6)d 10.82 (s, 1H), 8.93 (dd, J =6.6, 2.8 Hz, 1H), 8.16-8.10 (m, 1H), 7.66-7.52 (m, 2H), 7.36-7.27 (m, 1H), 2.31(d, J = 2.0 Hz, 3H). HRMS (ESI): calcd. for m/z C14H9ClF2N2O3[M + H]+ 327.0343, found 327.0348.
N-(2-fluoro-5-nitrophenyl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium hydrogencarbonate; In dichloromethane; at 20℃;Inert atmosphere;
Cyclopropanecarbonyl chloride (5.4 mL, 60 mmol) was added dropwise over 5 min to a stirred solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (1.56 g, 10.0 mmol) and solid NaHC03 (7.65 g, 90 mmol) in DCM (50 mL) at room temperature under nitrogen. The mixture was stirred overnight then diluted with DCM (50 mL) and H20 (100 mL) and stirred for 30 min. The aqueous and organic layers were partitioned and the aqueous layer extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2S04), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded onto silica gel and purified by column chromatography on silica gel using EtOAc / heptane (1:9 to 4:6) as eluent to give the product (2.2g, 98% yield) as a solid. [00871] 1H NMR ( -DMSO, 300 MHz): delta 10.39 (br. s, 1H), 9.02-8.97 (m, 1H), 8.01- 7.95 (m, 1H), 7.57-7.48 (m, 1H), 2.13-2.06 (m, 1H), 0.86-0.74 (m, 4H); 19F NMR (d6- DMSO, 282 MHz): -115.2 (s).
To a suspension of NaH (0.67 g, 5 eq) in THF (30 mL) was added dropwise a solution of <strong>[7748-36-9]oxetane-3-ol</strong> (0.24 g, 1 eq) in THF (5 mL) under N2 at r.t. After the mixture was stirred at r.t. for 1 hr, 2-fluoro-5- nitroaniline (0.51 g, 1 eq) was added. The resulting mixture was heated at 70 oC for 3hr and then quenched with water. Concentration removed THF and the residue was taken up in DCM. Extraction, concentration and purification on silica gel column (0 - 100percent EtOAc in heptane) furnished intermediate A as a yellow oil (52percent).
With dmap; In tetrahydrofuran;Reflux; Inert atmosphere;
To a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (4.68 g, 30 mmol) in THF (150 mL) were added Boc2O (9.82 g. 45 mmol) and DMAP (7.33 g, 60 mmol). The reaction mixture was refluxed overnight under N2, then cooled to rt and concentrated in vacuo. The residue was dissolved in EtOAc (250 mL), and the organic phase was washed with water (200 mL x 3) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (PE / EtOAc (V / V) 8 : 1) to give the title compound as a yellowish solid (3.54 g, 40%).
95 g (608.5 mmol) of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> were dissolved together with 83.1 g (691.9 mmol) of glutaric anhydride (95%) in 490 g of toluene. Subsequently, the mixture was heated at ca. 85 C. for 4 h and the resulting crystal mush concentrated to dryness at up to 70 C. under vacuum. To this dried crystal mush were added 284 g of 40% methylamine aqueous solution and 94 g water. The residue dissolved quickly and the mixture began to boil after a short time (15-25 minutes). The solution was held at 75 C. (to limit consumption of methylamine) for approximately 3 h and then diluted with 966 g of water and 680 g of propan-2-ol. 156 g of 37% hydrochloric acid were added with stirring at 55-60 C. to neutralize the reaction mixture. Compound ( 4) was subsequently precipitated through further addition of 37% hydrochloric acid. The precipitate was filtered, washed with water and dried. The yield of compound (4) was 157 g (596.4. mmol) with a content of >99%. (98.0% of theory). Instead of 40% methylamine aqueous solution, also a 25% methylamine alcoholic solution, for example a methylamine methanol or ethanol solution, can be used.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With potassium carbonate; In neat (no solvent); at 130℃; for 12h;
General procedure: <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 1 (1mmol), benzoyl chloride derivative 2 (1mmol), and potassium carbonate (1mmol) was heated at 130C. After the completion of reaction (12-13h, checked by TLC), the crude product was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (9:1) as eluent.
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;
General procedure: To a de-gassed mixture of quinazoline derivative (0.313 mmol), arylamine (0.376 mmol), and Cs2CO3 (0.438 mmol) in dioxane (5 ml) under argon was added Pd(OAc)2 (0.016 mmol) and BINAP (0.023 mmol). The mixture was stirred at 80C for 16 hours. The reaction mixture was concentrated and the residue was adsorbed on silica gel and purified by flash column chromatography on silica gel (eluents Hex/EA: 1/0 -->1/1) to afford title compound, which was converted to hydrochloric salt by treatment with HCl ethanol. The reaction of 4-chloro-2-(pyridin-3-yl)-7-(trifluoromethyl)quinazoline (50 mg, 0.16 mmol) and <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (31 mg, 0.20 mmol) according to general procedure F gave the title compound (62 mg, 90 %) as a red-brown solid. 1H NMR (500 MHz, DMSO-d6) delta 9.62 (bs, 1H), 9.21 (bdd, J= 6.6 Hz, J= 2.9 Hz, 1H), 8.76 (dt, J= 8.0 Hz, J=1.9 Hz, 1H), 8.72 (bd, J = 8.7 Hz, 1H), 8.70 (m, 1H), 8.24-8.27 (m, 2H), 7.89 (m, 1H), 7.64 (t, J=9.5 Hz, 1H), 7.49 (m, 1H). 13C NMR (125 MHz, DMSO-d6) delta 159.14-161.18 (m), 152.46, 151.60, 150.80, 145.16, 136.19, 135.30 (q, J= 32.8 Hz), 133-92,126.88 (q, J= 4.0 Hz), 125.47, 124.24, 122.69-122.99 (m), 117.63 (d, J = 23.1 Hz), 117.20. HRMS calculated for C20H12F4N5O2, 430.0922; found, 430.0920.
90%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;
General procedure: To a de-gassed mixture of quinazoline derivative (0.313 mmol), arylamine (0.376 mmol), and CS2CO3 (0.438 mmol) in dioxane (5 ml) under argon was added Pd(OAc)2 (0.016 mmol) and BINAP (0.023 mmol). The mixture was stirred at 80C for 16 hours. The reaction mixture was concentrated and the residue was adsorbed on silica gel and purified by flash column chromatography on silica gel (eluents Hex/EA: 1/0- >1/1) to afford title compound, which was converted to hydrochloric salt by treatment with HC1 ethanol.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -50℃; for 0.5h;
To a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (l .Og, 6.4mmol) and diisopropyl ethylamine (2.06g, 16.0mmol) in DCM (5mL) at -50 C, acryloyl chloride (0.58g, 6.4mmol) was added slowly and the resulting mixture was stirred at the same temperature for 30min. The reaction mixture was diluted with water (50.0mL) and extracted with DCM (50.0mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by silica gel column chromatography to obtain 1 (1.0g, 74.4%) as a yellow solid. 1H NMR (400 MHz, CDC13): delta 5.88-5.91(dd, J = 0.7,10.2 Hz, 1H), 6.27-6.34 (dd, J = 10.2, 16.8 Hz, 1H), 6.50-6.54 (dd, J = 0.7, 16.8 Hz, 1H) , 7.25 (t, J = 11.3 Hz, 1H), 7.54 (s, 1H), 8.0 (dd, J = 2.9, 4.4 Hz, 1H), 9.39-9.42 (dd, J = 2.7, 6.7 Hz, 1H). MS m/z (M+H): 211.1
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
To a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (2.0g, 12mmol) in DMF (16.0mL), Cs2C03 (8.3g, 25mmol) and N-methyl piperazine (1.53g, 15mmol) were added, and the resulting mixture was heated to 80C for 16h. The reaction mixture was cooled to room temperature, diluted with water (50.0mL) and extracted with ethyl acetate (50.0mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by silica gel column chromatography to obtain 1 (2.3g, 82%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 2.22 (s, 3H), 2.49 (m, 4H), 2.9 (brs, 4H), 5.2 (s, 2H), 6.98 (d, J = 8.6 Hz, 1H), 7.41-7.44 (dd, J = 2.7, 8.6 Hz, 1H), 7.52 (d, J = 2.7 Hz, 1H). MS m/z (M+H): 237.1
53%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 8h;
2-Fluoro-5-nitroaniline (2 g, 12.8 mmol) was dissolved in DMF (20 mL) and DIPEA (3.3 g, 25.6 mmol)1-methylpiperazine (25.6 mmol) was stirred at 100 C for 8 h. 100 mL of water was added to the reaction mixture, and ethyl acetate was extracted (3×50 mL), and the organic layer was combined.And dried with anhydrous Na2SO4,After distillation under reduced pressure, a crude product was obtained.Washing with CH3CN gave a yellow solid.Yield 53.0%
46.1%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 8h;
To a solution of 15 (0.50 g, 3.2 mmol) in DMF (5 mL) at room temperature was added N-methyl piperazine (0.64g, 0.70mL, 6.4 mmol), followed by N,N-diisopropylethylamine (1.1 mL, 6.4 mmol). The resulting solution was then heated to 80C for 8 h, and subsequently cooled to room temperature. 50 mL water was added to the solution, the crude compound 16 was obtained after filtrating the suspension. The yellow solid was washed with petroleum ether (3 x 10 mL) to give the purified yellow solid (0.345g, 46.1%). m.p. 200-202 oC. 1H NMR (300 MHz, DMSO- d6) 7.53(d, J = 2.3 Hz, 1H), 7.43 (dd, J = 8.7, 2.3 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 5.26 (s, 2H), 2.91 (br s, 4H), 2.49 (br s, 4H), 2.24 (s, 3H). HRMS (ESI): calcd. for m/z C11H17N4O2 [M + H]+ 237.1316, found 237.1342.
46.1%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 10h;
into a 25ml of eggplant shaped bottle, 0.5 g (3.2mmol) of 4-fluoro-5-nitroaniline is dissolved in DMF, added the 0.7 ml (6.4mmol) of N-methyl piperazine, and again added 1.8 g (12.8mmol) of DIPEA and reacted at 80 C for 10 hours. The reaction solution is cooled at room temperature and poured into water; filter the crude yellow solid, after drying the petroleum ether will be solid beating, by filtration obtained a light yellow solid intermediate C 0.35g (yield 46.1%).
[0305] To a solution of 2-(dimethylamino)ethanol (2.67 g, 0.03 mol, 3.0 eq.) in DMF (100 mL)was added NaH (1.32g, 0.033 mol, 3.3 eq.) at 0C under N2. After 0.5h, 2-fluoro- 5-nitroaniline (1.56g, 0.01 mol, 1.0 eq.) was added to the mixture. The resulting mixture was stirred at r.t. for 0.5 h, then poured into water and extracted with EA (100 mL X 2). Thecombined organic layers were dried over Na2SO4 and concentrated to afford 2-(2- (dimethylamino)ethoxy)-5 -nitroaniline (2 g, 88.5% yield).
6.49 g
To a stirred solution of N, N-dimethylethanolamine (8.58g, 96mmol) in DMF (80 ml) at 0C, NaH (1.54 g, 64mmol) was added slowly. After the mixture was stirred at 0-5C for 30 minutes,Compound liSa (5.01 g, 32mmol) in DMF was added dropwise. Then the reaction mixture was stirred with warming naturally to the room temperature for 4 hours. The reaction was complete detected by TLC (PE:EA=1:1). Then water (80m1) was added to the solution to quench the overdose NaH. Afterwards, the mixture was extracted with ethyl acetate (80m1 X 2). The combined organic phase was washed with brine (80m1) and dried over sodium sulfate and concentrated underreduced pressure to give 6.49g Compound 115b.
5-nitro-2-((tetrahydrofuran-3-yl)oxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium tert-butylate; In N,N-dimethyl-formamide; tert-butyl alcohol; at 27 - 40℃; for 6h;
To a stirred solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 61 ( 2.0 g, 12.8 mmol) & tetrahydrofuran-3-ol (1.4 g, 16.65 mmol) in t-BuOH (20 ml) & DMF (4 ml) was dropwise added potassium tert Buoxide (1M in t-BuOH) (46 ml, 46.12 mmol) at RT was stirred at RT for 2h, Reaction mixture was warmed to 40C for 4h, reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with EtOAc and washed with brine solution. The organic phase was dried and concentrated to get crude material. The crude material was purified by flash column chromatography (Si02), eluting with 40 % EtOAc in hexane to get 5-nitro-2-((tetrahydrofuran-3-yl) oxy) aniline as brown liquid (1.0 g, 35% yield). ?HNMR (400 MHz, CDCI3): oe 7.66-7.63 (dd, 1H), 7.57-7.56 (m, 1H), 6.73 (d, lH), 5.05-5.04 (m, 1H), 4.13-3.94 (m, 6H), 2.35-2.26 (m, 2H), MS: 225.03 (M+H)
226 mg
To a stirred solution of 3-hydroxy tetrahydrofuran (203mg) in DMF (lOml) at 0C, NaH (92mg) was added slowly. After the mixture was stirred at 0-5C for 30 minutes, the compound 124a (3 00mg) in DMF was added dropwised. Then the reaction mixture was stirred with warmingnaturally to the room temperature. The reaction was complete detected by TLC (PE:EA=1 :1) after4 hours. Then lSml H20 was added to the solution. Afterwards, the mixture was extracted by EA(lSmlX2). The combined organic phase was combined and washed with aqueous solution ofNaC1 and dried over Na2SO4 and concentrated under reduced pressure to give crude Compound124b. The crude product was purified by column chromatography to give 226mg Compound124b.
2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
To an ice-cold suspension of solution of NaH (5.20 g, 218 mmol) in THF(100 mL) was added <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (8.50 g, 54 mmol) & reaction mixture wasstirred at 0C to RT for 15-20 mm followed by addition of 2,4,5-trichioropyrimidine 77(10.0 g, 54 mmol) dropwise. The reaction mixture was heated at 60C for 16 h. The reaction mixture was quenched with ice water & was extracted with EtOAc (x 3). The combined organic layer was was hed with brine and concentrated under reduced pressure. The crude thus obtained was purified by column chromatography (60% EtOAc in Hexane) to obtain 2,5-dichloro-N-(2-fluoro-5-nitrophenyl) pyrimidin-4-amine 142 (9.25 g, 57% yield) as yellow solid. ?HNMR (400 MHz, CDC13): 6 9.45-9.47 (m, 1H), 8.35 (s, 1H), 8.05-8.09 (m, 111), 7.61 (s, 1H), 7.3 1-7.36 (m, 1H); MS: 302.98 (M+HY.
N-(2-fluoro-5-nitrophenyl)-2-methylquinoline-6-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10.42 g
Compound 224, A -(2-fluoro-5-nitrophenyl)-2-methylquinoline-6-carboxamide[00312] Oxalyl chloride (3.25 mL, 38.4 mmol) was added dropwise to a solution of <strong>[635-80-3]2-methylquinoline-6-carboxylic acid</strong> (6.59 g, 35.2 mmol) and DMF (0.0062 mL, 0.080 mmol) in dry DCM (80 mL). The reaction mixture was stirred at room temperature for 3 h, and then concentrated. The residue was dissolved in DCM and concentrated again. This residue was dissolved in pyridine (80 mL) and 2-fluoro-5-nitroaniline (5.00 g, 32.00 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h, and then poured onto water (100 mL). The green precipitate was filtered and washed several times with water, Et20 and finally with a minimum amount of DCM to afford the title compound (10.42 g, 100%) as a light green solid which does not require further purification. 1H NMR (500 MHz, DMSO) 5 10.70 (s, 1 H), 8.72 (dd, J = 6.45, 2.93 Hz, 1 H), 8.63 (d, J = 2.02 Hz, 1 H), 8.43 (d, J = 8.46 Hz, 1 H), 8.23 (dd, J = 8.48, 2.02 Hz, 1 H), 8.21 -8.16 (m, 1 H), 8.05 (d, J = 8.86 Hz, 1 H), 7.65 (app t, J = 9.25 Hz, 1 H), 7.54 (d, J = 8.46 Hz, 1 H), 2.71 (s, 3H). HRMS (ESI+): Found [M+H]+326.0934 C17H13FN3O3 requires 326.0935.
[00205] In an oven dried 250 mL RBF under an inert atmosphere, oxalyl chloride (3.25 mL, 38.4 mmol) was added dropwise to a solution of <strong>[635-80-3]2-methylquinoline-6-carboxylic acid</strong> (6.59 g, 35.2 mmol) and DMF (0.0062 mL, 0.080 mmol) in anhydrous dichloromethane (80 mL). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and concentrated again under reduced pressure. The obtained dry residue was dissolved in pyridine (80 mL) and 2-fluoro-5- nitroaniline (5.00 g, 32.00 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h, and then poured onto water (100 mL). The green precipitate was filtered and washed several times with water, diethyl ether and finally with a minimum amount of dichloromethane to afford the title compound (10.42 g,) as a light green solid which was carried onto the next step as a crude. 1 H NMR (500 MHz, DMSO-d6) delta 10.70 (s, 1H), 8.72 (dd, J = 6.45, 2.93 Hz, 1H), 8.63 (d, J = 2.02 Hz, 1H), 8.43 (d, J = 8.46 Hz, 1H), 8.23 (dd, J = 8.48, 2.02 Hz, 1H), 8.21 - 8.16 (m, 1H), 8.05 (d, J = 8.86 Hz, 1H), 7.65 (app t, J = 9.25 Hz, 1H), 7.54 (d, J = 8.46 Hz, 1H), 2.71 (s, 3H). HRMS (ESI+): Found [M+H]+ 326.0934 C17H13FN3O3 requires 326.0935.
With sodium cyanoborohydride; acetic acid; In methanol; water; at 20℃; for 18h;
Commercially available <strong>[369-36-8]2-fluoro-5-nitro-aniline</strong> (2 g, 12.8 mmol) was dissolved in methanol (100 mL) and a 37% aqueous formaldehyde solution (10 mL, 128 mmol) was added. After the addition of sodium cyanoborohydride (4.2 g, 68 mmol) and acetic acid (15 mL) an exotherm was observed and the reaction mixture was stirred at room remperature for 18 hours. The solvents were evaporated under reduced pressure and the residue was dissolved in dichloromethane (150 mL) and water (50 mL). The pH was adjusted to pH -10/1 1 by the addition of solid sodium hydroxide. The organic phase was separated and the aqueous layer was extracted with dichloromethane (75 mL). The combined organic phase was dried over Na2S04, filtered and the solvent was removed under reduced pressure. The residue was purified by chromatography on HP-Sil SNAP cartridges using a Biotage Isolera Onepurification system employing an ethyl acetate/n-heptane gradient (5/95 -> 30/70) to afford the less polar title compound Frl as a yellow oil (2.09 g, 88 %) and the more polar title compound Frll as a yellow solid (0.2 g, 9 %). Less polar Frl: 1H-NMR (400 MHz, DMSO-d6): delta = 2.88 (s, 6H), 7.36 (dd, 1 H), 7.65 (dd, 1 H), 7.73 (dt, 1 H) More polar Frll: 1H-NMR (400 MHz, DMSO-d6): delta = 2.78 (d, 3H), 6.27-6.31 (br-s, 1 H), 7.26 (dd, 1 H), 7.35 (dd, 1 H), 7.44 (dt, 1 H)
88%; 9%
With sodium cyanoborohydride; acetic acid; In methanol; water; at 20℃; for 18h;
Preparative Example 31 Step A Commercially available <strong>[369-36-8]2-fluoro-5-nitro-aniline</strong> (2 g, 12.8 mmol) was dissolved in methanol (100 mL) and a 37% aqueous formaldehyde solution (10 mL, 128 mmol) was added. After the addition of sodium cyanoborohydride (4.2 g, 68 mmol) and acetic acid (15 mL) an exotherm was observed and the reaction mixture was stirred at room temperature for 18 hours. The solvents were evaporated under reduced pressure and the residue was dissolved in dichloromethane (150 mL) and water (50 mL). The pH was adjusted to pH?10/11 by the addition of solid sodium hydroxide. The organic phase was separated and the aqueous layer was extracted with dichloromethane (75 mL). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by chromatography on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing an ethyl acetate/n-heptane gradient (5/95->30/70) to afford the less polar title compound FrI as a yellow oil (2.09 g, 88%) and the more polar title compound FrII as a yellow solid (0.2 g, 9%). Less polar FrI: 1H-NMR (400 MHz, DMSO-d6): delta=2.88 (s, 6H), 7.36 (dd, 1H), 7.65 (dd, 1H), 7.73 (dt, 1H). More polar FrII: 1H-NMR (400 MHz, DMSO-d6): delta=2.78 (d, 3H), 6.27-6.31 (br-s, 1H), 7.26 (dd, 1H), 7.35 (dd, 1H), 7.44 (dt, 1H).
2-flouro-5-nitroaniline (468 mg, 3.00 mmol) and methylamine hydrochloride (486 mg, 9.00 mmol) were dissolved in 15 mL EtOH and stirred at room temperature for 10 min. An aqueous solution of potassium hydroxide (1.009 g, 18.0 mmol) in 5 mL H20 was introduced and the mixture was stirred at reflux at 60 °C overnight. Then poured into water (100 mL) and precipitate formed was extracted with ethyl acetate (3 >< 30 mL). The organic extracts were dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (2: 1) as eluent, and gave N'-methyM-nitrobenzene-l^-diamine as red solid (429 mg, 86 percent); 1H NMR (400 MHz, DMSO) delta 7.56 (dd, J= 8.8, 2.7 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 6.43 (d, J= 8.9 Hz, 1H), 6.12 (s 1H), 5.08 (s, 2H), 2.85 (s, 3H); 13C NMR (101 MHz, DMSO) delta 144.09, 136.99, 134.89, 116.46, 107.42, 106.94, 30.12; LRMS (ESI): calcd for: C7H9N3O2 [M+H]+ = 168.2, obsd [M+H]+ = 168.
General procedure: 2-flouro-5-nitroaniline (468 mg, 3.00 mmol) and methylamine hydrochloride (486 mg, 9.00 mmol) were dissolved in 15 mL EtOH and stirred at room temperature for 10 min. An aqueous solution of potassium hydroxide (1.009 g, 18.0 mmol) in 5 mL H20 was introduced and the mixture was stirred at reflux at 60 C overnight. Then poured into water (100 mL) and precipitate formed was extracted with ethyl acetate (3 >< 30 mL). The organic extracts were dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (2: 1) as eluent, and gave as red solid N1- ethyl-4-nitrobenzene-l,2-diamine (451 mg, 83 %): 1H NMR (400 MHz, CDC13) delta 7.91 - 7.79 (m, 1H), 7.70 - 7.58 (m, 1H), 6.57 (t, J= 9.6 Hz, 1H), 4.27 (s, 2H), 3.33 - 3.21 (m, 2H), 1.27 (t, 3H); I3C NMR (101 MHz, CDC13) delta 144.96, 138.13, 131.79, 119.39, 112.44, 108.15, 38.23, 14.51
<strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (20.0g, 128.2mmol) and paraformaldehyde (16.0g, 533.3mmol) was dissolved in 500mL of methanol then stirred at room temperature. Then added dropwise NaOMe (3.4g, 63mmol) in methanol 100mL. The reaction was stirred at room temperature for 16 hours then was added NaBH4 (9.7g, 255.2mmol) in two aliquots, stirred for 15 minutes. LCMS traced the reaction. After completion of the reaction was poured into 1M KOH aqueous solution, and stirred to precipitate a solid. Filtered to give a yellow solid 2-fluoro-N-methyl-5-nitroaniline (19.0g, 87% yield).
87%
<strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (20.Og, 128.2 mmol) (3.4 g, 63 mmol)paraformaldehyde was dissolved in 500 mL of methanol and stirred at room temperature. Then, 100 mL of a methanol solution of NaOMe (3.4 g, 63 mmol) was added dropwise. The reaction solution was stirred at room temperature for 16 hours, NaBH4 (9.7 g, 255.2 mmol) was added in two equal portions and stirred for 15 min. LCMS followed the reaction. After completion of the reaction, the solution was poured into 1M aqueous KOH and stirred to precipitate a solid which was filtered to give 2-fluoro-N-methyl-5-nitroaniline as a yellow solid (19. 0 g, 87% yield).
In N,N-dimethyl-formamide; at 10℃; for 4h;Inert atmosphere;
5-nitro-2-fluoroaniline (200 mg, 1.28 mmol)And sodium ethyl xanthate (250 mg, 1.73 mmol)Was dissolved in dry DMF (10 mL)Solution, nitrogen protection to warm up to 100 reaction 4h.After completion of the reaction, the temperature was lowered to room temperature,Slowly add water (10 mL) and 1 M / L hydrochloric acid solution (10 mL)Precipitation of solid, continue stirring 30min,Suction filtration, solid water washing,The filter cake was then dissolved with ethyl acetate,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a tan solid product which was used directly in the next step.(180 mg, 66.3%);
2-Fluoro-5-nitro-aniline 22 (5.0 g, 32.03 mmol) was dissolved in dry DMSO (50 mL), treated with ethylamine (2M in THF, 56 mL, 112.10 mmol) in a sealed flask and heated at 120C. After 2 days the reaction mixture was cooled to RT and acetic acid (20 mL) was added followed by addition of NaNO2 (2 M aq solution, 19.2 mL, 38.4 mmol). Stirring was continued for 20 min, then the reaction mixture was acidified to pH=2 with HCl (1M aq solution), water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The remainder was purified by preparative MPLC (silica gel, cyclohexane/ethyl acetate, gradient 0-45% ethyl acetate over 40 min) to afford product 23. Yield: 2.87 g (47%). LCMS (ESI+) calculated for C8H8N4O2 [M + H]+ m/z 193.0726, found 193.0. 1H NMR (400 MHz, (CD3)2SO) delta 9.03 (m, 1H), 8.40 (dd, J = 9.2, 2.0 Hz, 1H), 8.16 (m, 1H), 4.84 (q, J = 7.4 Hz, 2H), 1.55 (t, J = 7.4 Hz, 3H). HPLC (Method 3): Rt = 0.44 min.
47%
l-Ethyl-5-nitro-lH-benzotriazole (23). 2-Fluoro-5-nitro-aniline 22 (5.0 g, 32.03 mmol) was dissolved in dry DMSO (50 mL), treated with ethylamine (2M in THF, 56 mL, 112.10 mmol) in a sealed flask and heated at 120C. After 2 days the reaction mixture was cooled to RT and acetic acid (20 mL) was added followed by addition of NaN02 (2 M aq solution, 19.2 mL, 38.4 mmol). Stirring was continued for 20 min, then the reaction mixture was acidified to pH=2 with HCI (1M aq solution), water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgS04 and concentrated under reduced pressure. The remainder was purified by preparative MPLC (silica gel, cyclohexane/ethyl acetate, gradient 0- 45% ethyl acetate over 40 min) to afford product 23. Yield: 2.87 g (47%). LCMS (ESI+) calculated for C8H8N402 [M + H]+ m/z 193.0726, found 193.0. XH NMR (400 MHz, (CD3)2SO) <5 9.03 (m, 1H), 8.40 (dd, J = 9.2, 2.0 Hz, 1H), 8.16 (m, 1H), 4.84 (q, J = 7.4 Hz, 2H), 1.55 (t, J = 7.4 Hz, 3H). HPLC (Method 3): Rt = 0.44 min.
4-fluoro-N1-(1-phenylbutyl)benzene-1,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With nickel(II) iodide; 6,6'-dimethyl-2,2'-bipyridine; (dimethoxy)methylsilane; In N,N-dimethyl acetamide; at 0 - 50℃; for 12.1667h;Inert atmosphere; Sealed tube;
General procedure: 6,6'-Dimethyl-2,2'-bipyridine L1 (4.1 mg, 0.022 mmol, 11 mol %) was added to an oven-dried 8 mL screw-cap vialequipped with a magnetic stir bar. The vial was introduced into a nitrogen-filled glove box, NiI2(6.3 mg, 0.020 mmol, 10 mol %), anhydrous DMPU (0.10 mL) and anhydrous DMA (0.10 mL)were added. The mixture was then stirred for 10 min, at which time DMMS(dimethoxymethylsilane, 147 muL, 1.2 mmol, 6.0 equiv) was added and the stirring was continuedfor another 10 min at room temperature before 4-phenyl-1-butene (60 muL, 0.40 mmol, 2.0 equiv)was added. The tube was sealed with a teflon-lined screw cap, removed from the glove box andstirred at 0C before a solution of 4-nitrotoluene (27.4 mg, 0.20 mmol, 1.0 equiv) in anhydrousDMPU (0.10 mL) and anhydrous DMA (0.10 mL) was added dropwise by syringe. Then thereaction mixture was stirred at 25C for 10 min, and then stirred at 50C for up to 12 hr (stirred at750 rpm). After the reaction was complete, the reaction mixture was immediately filtered througha short pad of silica gel (using ethyl acetate in hexanes) to give the crude product. Tetradecane(20 muL) was added as an internal standard for GC analysis. 1, 1, 2, 2-Tetrachloroethane (10.5 muL,0.10 mmol) was added as internal standard for 1H NMR analysis of the crude material. Theproduct was purified by chromatography on silica gel for each substrate. The yields reported arethe average of at least two experiments, unless otherwise indicated.
To BF^OEt (33.1 mL, 269 mmol, 4.2 eq) was added <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (10 g, 64.6 mmol, 1.00 eq) in dry THF (140 mL) at -20 C followed by the addition of ieri-butyl nitrite (25.3 mL, 211 mmol, 3.3 eq) dissolved in THF (60 mL) slowly. The mixture was gradually warmed to 0 C and then cold diethyl ether (250 mL) was added to the mixture and the resultant mixture was stirred at 0 C for 10 min to obtain a white precipitate which was filtered off. The solid white precipitate obtained was added in portions to a cooled solution of iodine (5.7 g, 45.4 mmol, 0.71 eq) and potassium iodide (10.5 g, 91 mmol, and 1.42 eq) in MeCN (200 mL). The mixture was warmed to room temperature and stirred for lh and monitored by TLC. The reaction was complete after lh and to the mixture was added saturated Na2S203 (150 mL) solution. The aqueous layer was then extracted with DCM (50 mL x 4). The combined organic layers were washed with water (50 mL), brine (50 mL) dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford l-fluoro-2-iodo-4-nitrobenzene (16 g, 93%) a yellow solid. (1540) NMR (400 MHz, CDCh): d 8.67 (dd, J = 5.3, 2.6 Hz, 1H), 8.25 (s, 1H), 7.21 (dd, J = 9.0, 6.8 Hz, 1H).
The compound BB-33-1 (1.20 g, 7.69 mmol, 1.00 eq) was dissolved in hydrochloric acid (4.00 mL), and cooled to 0 C. Sodium nitrite (583.67 mg, 8.46 mmol, 459.58 uL, 1.10 eq) was dissolved in 2.6 mL of water, and added dropwise to the reaction solution. After being stirred for 15 minutes, the mixed solution was slowly added to an aqueous solution (16 mL) of potassium iodide (4.47 g, 26.92 mmol, 3.50 eq), and heated to 10 C. and stirred for 16 hours. With TLC (petroleum ether:ethyl acetate=10:1) monitoring showing completion of reaction of raw materials, a target compound was generated. The resulting compound was diluted by addition of ethyl acetate (30 mL), followed by washing with 10% sodium hydroxide (25 mL*2), washing with 5% sodium sulfite (25 mL*2), drying over anhydrous sodium sulfate, and filtration. A filtrate was dried by rotary evaporation under reduced-pressure distillation. Purification was performed by flash silica gel column chromatography (petroleum ether:ethyl acetate=10:1). The reaction succeeded, and a yellow solid product BB-33-2 (550.00 mg, yield: 21.22%, purity: 79.22%) was obtained. 1H NMR (400 MHz, CDCl3) delta 8.60 (dd, J=5.3, 2.8 Hz, 1H), 8.19 (ddd, J=9.0, 4.3, 2.8 Hz, 1H), 7.09-7.17 (m, 1H).
(E)-N'-(2-fluoro-5-nitrophenyl)-N,N-dimethylformimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
To a 250 mL flask equipped with a magnetic stirrer bar was added DMF (60 mL) and benzene sulfonyl chloride (27.2 g, 154 mmol). The solution was stirred for 20 minutes and the solution turned to a slight yellow color. 2-Fluoro-5-nitroaniline (12 g, 77 mmol) was added as a solid and the mixture stirred for 30 minutes at room temperature. The solid was filtered and washed with diethyl ether and dried under vacuum. The crude material was transferred into a flask and neutralized by adding NaOH (4 M) and ethyl acetate (150 mL). The solution was transferred into a funnel, separated and the organic layers was extracted with ethyl acetate (2 x 100 mL). After combining the organic layer, it was washed with brine and dried with Na2SO4 for 3 h. A yellow solid was obtained, 15.5 g, 95% yield. 1H NMR (500 MHz, DMSO-d6) delta ppm 2.97 (s, 3 H), 3.07 (s, 3 H), 7.35 (t, J=9.77 Hz, 1 H), 7.79 (dt, J=8.77, 3.40 Hz, 1 H), 7.90 (dd, J=7.63, 2.75 Hz, 1 H), 7.98 (s, 1 H); 13C NMR (126 MHz, DMSO-d6) delta ppm 33.92, 116.15, 117.21, 141.24 (d, 3JC-F = 11.34 Hz)), 144.20, 155.73, 159.21(1JCF = 254.52 Hz); HRMS calcd. for C9H10FN3O2: 211.0757, found 211.0750
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Sealed tube;
To a solution of <strong>[369-36-8]2-fluoro-5-nitro-aniline</strong> (408.6 mg, 2.62 mmol) and potassium carbonate (714.4 mg, 5.17 mmol) in DMSO (4 mL) was added l-aminopropan-2-ol (294.4 mg, 3.92 mmol). The mixture was placed in a sealed tube and stirred at 100 C overnight. The mixture was cooled down to rt and diluted with water (60 mL), then extracted with EtOAc (100 mL x 3). The combined organic phases were dried over Na2SC>4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/DCM (v/v) = 1/33) to give the title compound as a brown solid (520 mg, 94.1%).MS (ESI, pos.ion) m/z: 212.2 [M+H]+;1H NMR (600 MHz, DMSO-76): d (ppm) 7.51 (dd, J= 8.8, 2.5 Hz, 1H), 7.41 (d, J= 2.5 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 5.88 (t, J= 5.3 Hz, 1H), 5.15 (s, 2H), 4.81 (d, J = 4.7 Hz, 1H), 3.89 - 3.83 (m, 1H), 3.17 - 3.08 (m, 2H), 1.13 (d, 7= 6.2 Hz, 3H).
94.1%
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Sealed tube;
To <strong>[369-36-8]2-fluoro-5-nitro-phenylamine</strong> (408.6 mg, 2.62 mmol)And potassium carbonate (714.4 mg, 5.17 mmol)In DMSO (4mL) solution1-Aminopropan-2-ol (294.4 mg, 3.92 mmol).The reaction mixture is placed in a sealed tube,It was stirred at 100 C overnight.The reaction mixture was cooled to room temperature.It was diluted with water (60 mL) and then extracted with EtOAc (100 mL×3).The combined organic phases were dried over anhydrous sodium sulfate.Filter and concentrate under reduced pressure.The residue obtained was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/33).The title compound was obtained as a brown solid (520 mg, 94.1%).
1-((2-amino-4-nitrophenyl)amino)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.2%
With potassium carbonate; In dimethyl sulfoxide; at 100℃;
To a solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (500 mg, 3.20 mmol) and l-amino-2- methylpropan-2-ol (342 mg, 3.84 mmol) in DMSO (6 mL) was added potassium carbonate (660 mg, 4.78 mmol). The reaction mixture was stirred at 100 C overnight, then cooled down to rt and quenched with water (50 mL). The resulted mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 1/2) to give the title compound as a red solid (600 mg, yield 83.2%).MS (ESI, pos. ion) m/z: 226.2 [M+H] +;1H NMR (400 MHz, DMSO-^): d (ppm) 7.51 (dd, J= 8.9, 2.5 Hz, 1H), 7.43 (d, J= 2.6 Hz, 1H), 6.57 (d, j = 9.0 Hz, 1H), 5.55 (t, j = 5.4 Hz, 1H), 5.18 (s, 2H), 4.59 (s, 1H), 3.13 (d, j = 5.6 Hz, 2H), 1.18 (s, 6H).
With potassium carbonate; In dimethyl sulfoxide; at 80℃;
To a solution of 2-fhioro-5-nitroaniline (1.00 g, 6.44 mmol) and K2C03 (1.76 g, 12.72 mmol) in DMSO (10 mL) was added propan- 1 -amine (0.8 mL, 10 mmol). The reaction mixture was stirred at 80 C overnight and concentrated in vacuo. The residue was added water (40 mL) and extracted with EtOAc (400 mL). The organic phase was washed with water (10 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was a purified by flash column chromatography (EtOAc/PE (v/v) = 1/4) to give the title compound as a red solid (1.02 g, 81.4%).MS (ESI, pos. ion) m/z: 196.1 [M+H]+;1H NMR (400 MHz, CDCl3): d (ppm) 7.83 (dd, J = 8.9, 2.4 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.54 (d, j= 8.9 Hz, 1H), 4.32 (s, 1H), 3.34 (s, 2H), 3.19 (s, 2H), 1.78 - 1.67 (m, 2H), 1.04 (t, j = 7.4 Hz, 3H).
81.4%
With potassium carbonate; In dimethyl sulfoxide; at 80℃;
To <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (1.00 g, 6.44 mmol)And K2CO3 (1.76g, 12.72mmol)Add in DMSO (10mL) solutionPropane-1-amine (0.8 mL, 10 mmol).The reaction mixture was stirred at 80 C overnight.It was then concentrated under reduced pressure.The residue obtained was diluted with water (40 mL).It was then extracted with EtOAc (100 mL x 3).The organic phase was washed with water (10 mL x 3).Dry over anhydrous sodium sulfate,Filter and concentrate under reduced pressure.The residue was purified by flash column chromatography (EtOAc /EtOAcThe title compound was obtained as a red solid (1.02 g, 81.4%).
1-((2-amino-4-nitrophenyl)amino)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.2%
With potassium carbonate; In dimethyl sulfoxide; at 100℃;
To <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> (500 mg, 3.20 mmol)And 1-nitro-2-methylpropan-2-ol (342 mg, 3.84 mmol)Potassium carbonate (660 mg, 4.78 mmol) was added to a solution of DMSO (6 mL).The reaction mixture was stirred at 100 C overnight.Then cool to room temperature,The reaction was quenched with water (50 mL).The resulting mixture was extracted with EtOAc (100 mL×3).The combined organic phases were washed with brine (100 mL×2) and dried over anhydrous sodium sulfate.Filter and concentrate under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc /EtOAcThe title compound was obtained as a red solid (600 mg, 83.2%).
5-fluoro-N-(2-fluoro-5-nitrophenyl)-1H-pyrrolo[2,3-b]-pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In <i>tert</i>-butyl alcohol at 100℃; for 4h; Inert atmosphere;
2-(((2-fluoro-5-nitrophenyl)amino)(1-(3,4,5-trimethoxybenzyl)-1H-tetrazol-5-yl)methyl)-3-methoxyphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: 6-methoxysalicylaldehyde; 6-fluoro-3-nitroaniline In methanol at 20℃; for 0.5h;
Stage #2: 3,4,5-trimethoxy-α-tolueneisonitrile With trimethylsilylazide In methanol at 20℃; for 12h;
Procedure A: General procedure for Ugi-tetrazole adducts
General procedure: A solution of amine 1 (1.0 mmol) and aldehyde 2 (1.0 mmol) in methanol (1 mL) was stirred at room temperature for 30 min. Then TMSN3 3 (1.1 mmol) followed byisocyanides 4 (1.1 mmol) was added to the solution and the reaction was stirred at room temperature for 12 h. The reaction was concentrated in vacuo and purified by column chromatography to give the desired products 5.
2-(((2-fluoro-5-nitrophenyl)amino)(1-(2-isopropylphenyl)-1H-tetrazol-5-yl)methyl)-5-methylphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
Stage #1: 4-methylsalicylaldehyde; 6-fluoro-3-nitroaniline In methanol at 20℃; for 0.5h;
Stage #2: 1-isocyano-2-isopropylbenzene With trimethylsilylazide In methanol at 20℃; for 12h;
Procedure A: General procedure for Ugi-tetrazole adducts
General procedure: A solution of amine 1 (1.0 mmol) and aldehyde 2 (1.0 mmol) in methanol (1 mL) was stirred at room temperature for 30 min. Then TMSN3 3 (1.1 mmol) followed byisocyanides 4 (1.1 mmol) was added to the solution and the reaction was stirred at room temperature for 12 h. The reaction was concentrated in vacuo and purified by column chromatography to give the desired products 5.
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