* 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 Medicinal Chemistry, 2012, vol. 55, # 16, p. 7262 - 7272
2
[ 453-71-4 ]
[ 15017-52-4 ]
Reference：
[1] Patent: WO2012/171488, 2012, A1,
3
[ 453-71-4 ]
[ 20274-70-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1968, vol. 11, p. 225 - 227
4
[ 456-22-4 ]
[ 453-71-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 20℃;
To a cold solution of 4-fluorobenzoic acid (50.0 g, 0.36 mol, 1.0 equiv) in concentrated H2SO4 (180 ml) was added portionwise potassium nitrate (39.7 g, 0.39 mol, 1.1 equiv). The reaction mixture was stirred overnight at rt and then poured on crushed ice (800 g) with constant stirring. The resulting mixture was kept overnight at rt, filtered and washed thoroughly with water, and finally dried by making an azeotrope with toluene to yield 59.5 g (90percent) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 7.69-7.74 (m, 1H), 8.29-8.32 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 13.75 (br s, 1H).
75%
at 20℃; for 10 h;
To a solution of 4-fluoro-benzoic acid (5.0 g, 36 mmol) in conc. H2SO4 (36 mL) at 0 °C was added HNO3 (5.6 mL). After the stirring at room temperature for 10 h, the mixture was poured into H2O (200 mL). The precipitate was collected by filtration, washed with water and dried to give 4-fluoro-3-nitrobenzoic acid (5.0 g, 75 percent) as a white solid. 1H NMR (CDCl3, 500 MHz) δ: 7.44 (1H, dd, J = 10.5, 9.0 Hz), 8.39 (1H, m), 8.83 (1H, dd, J = 7.0, 2.0 Hz).
Reference：
[1] Patent: US2008/249101, 2008, A1, . Location in patent: Page/Page column 20
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1905 - 1917
[3] Tetrahedron Letters, 2017, vol. 58, # 43, p. 4145 - 4148
[4] Journal of Organic Chemistry, 2014, vol. 79, # 11, p. 5134 - 5144
[5] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1921, vol. <5> 7, p. 536[6] Chem. Zentralbl., 1922, vol. 93, # I, p. 22
[7] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
[8] Patent: WO2012/93101, 2012, A1, . Location in patent: Page/Page column 240-241
[9] Chemistry - A European Journal, 2015, vol. 21, # 20, p. 7571 - 7581
5
[ 1009-35-4 ]
[ 453-71-4 ]
Yield
Reaction Conditions
Operation in experiment
52%
at 120℃; for 8 h; Sealed tube
A stirred solution of 4-fluoro-3-nitrobenzonitrile (1.00 g, 6.02 mmol) in 70percent H2S04 (12 mL) was heated in a sealed tube at 120°C for 8 h. The reaction mixture waspoured into ice-cold H20 (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with H20 (100 mL) and brine (100 mL), then separated, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by crystallisation with DCM:hexanes (1:10, 100 mL) to afford the title compound (0.58 g, 52percent) as an off-white solid. OH (400 MHz, DMSO-d6) 7.64-7.74 (m, 1H), 8.24-8.36 (m,1H), 8.53-8.60 (m, 1H), 13.77 (br s, 1H).
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 39, p. 9338 - 9342
9
[ 459-57-4 ]
[ 453-71-4 ]
Reference：
[1] Archiv der Pharmazie, 1963, vol. 296, p. 324 - 336
10
[ 352-32-9 ]
[ 453-71-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
11
[ 456-22-4 ]
[ 7697-37-2 ]
[ 453-71-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
12
[ 456-22-4 ]
[ 7697-37-2 ]
[ 453-71-4 ]
[ 350-46-9 ]
Reference：
[1] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1921, vol. <5> 7, p. 536[2] Chem. Zentralbl., 1922, vol. 93, # I, p. 22
13
[ 453-71-4 ]
[ 71254-71-2 ]
Reference：
[1] Patent: US2013/79306, 2013, A1,
14
[ 453-71-4 ]
[ 455-75-4 ]
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 2305
15
[ 453-71-4 ]
[ 74-89-5 ]
[ 41263-74-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 10 h;
To a solution of 4-fluoro-3-nitrobenzoic acid (4.9 g, 27 mmol) in MeOH was added MeNH2 (40 percent in MeOH, 20 mL). After the stirring at room temperature for 10 h, the reaction mixture was poured into H2O (75 mL). The reaction was acidified with 12 M HCl. The product was collected by filtration, washed with H2O and dried to give 4-(methylamino)-3-nitrobenzoic acid (5.0 g, 98 percent) as a yellow solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.97 (3H, d, J = 5.5 Hz), 7.02 (1H, d, J = 9.0 Hz), 7.95 (1H, dd, J = 9.5, 2.5 Hz), 8.52 (1H, m), 8.58 (1H, d, J = 2.0 Hz).
87%
at 20℃; for 1 h;
Step 1. 4-(Methylamino)-3-nitrobenzoic acid A solution of 4-fluoro-3-nitrobenzoic acid (1.85 g, 9.99 mmol) and methylamine (5 ml, 33percent aq) in DMF (10 ml) was stirred for 1 hour at room temperature, and then diluted with water (20 ml). The solids precipitated and were collected by filtration, and the filter cake was washed with ether (20 ml) to afford 4-(methylamino)-3-nitrobenzoic acid as a yellow solid (1.7 g, 87percent). LC/MS (ES, m/z): [M+H]+. 197.1 1H-NMR (300 MHz, DMSO) δ 12.84 (s, 1H), 8.61 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.97-8.00 (m, 1H), 7.04 (d, J=9.3 Hz, 1H), 3.00 (s, 3H)
Reference：
[1] Organic Letters, 2008, vol. 10, # 6, p. 1183 - 1186
[2] Organic Letters, 2017, vol. 19, # 19, p. 5276 - 5279
[3] Tetrahedron Letters, 2017, vol. 58, # 43, p. 4145 - 4148
[4] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 41
[5] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1924 - 1928
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6619 - 6622
[7] Patent: US2008/125358, 2008, A1, . Location in patent: Page/Page column 15-16
[8] Patent: US2011/201604, 2011, A1, . Location in patent: Page/Page column 115; 117
[9] Patent: WO2015/84606, 2015, A1, . Location in patent: Page/Page column 133
[10] Journal of the American Chemical Society, 2015, vol. 137, # 22, p. 7197 - 7209
[11] Organic Letters, 2018, vol. 20, # 14, p. 4306 - 4309
16
[ 453-71-4 ]
[ 51818-99-6 ]
Reference：
[1] Patent: CN107400092, 2017, A,
[2] Patent: CN108264511, 2018, A,
17
[ 453-71-4 ]
[ 2365-85-7 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogen In methanol for 6 h;
A mixture of 3-nitro-4-fluorobenzoic acid (1.85 g, 10.0 mmol) in MeOH (10 mL) and 5percent Pd/C (100 mg) was stirred under an atmosphere of hydrogen and for 6 h. The catalyst was removed by filtration, washed with methanol and the volatiles were removed in vacuo to give compound 8A, 3-amino-4-fluorobenzoic acid, as a light yellow solid (1.50 g, 9.67 mmol, 97percent).
96%
With hydrogen In methanol for 3 h;
To a solution of 4-fluoro-3-nitrobenzoic acid (15.0 g, 81 mmol) in MeOH (150 mL) under an atmosphere of nitrogen was added 10percent Pd/C (0.80 g). The mixture was then stirred under 1 atm H2 for 3 h. The reaction mixture was vacuum filtered through a thin pad of Celite, and the filtrate concentrated in vacuo to give the product as a solid, 12.0 g (96percent). LC-MS (ES) m/z = 156.2 (M+H)+ 1H NMR (400 MHz, DMSOd6) δ ppm 7.49(m, 1 H), 7.23(m, 1 H), 6.88 (m, 1 H), 4.78 (br, 1 H).
95%
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.
90%
With palladium 10% on activated carbon; hydrogen In ethanol for 24 h;
Following a literature procedure [2], 4-fluoro-3-nitrobenzoic acid (1.0 g, 5.4 mmol) was reduced with hydrogen in the presence of Pd/C (60 mg, 10percent on charcoal) in EtOH (10 ml) over 24 h. The reaction mixture was passed through Celite, the filtrate was evaporated, and the residue was purified on a silica gel plug (EtOAc) to give 0.75 g (90percent yield) of 3-amino-4-fluorobenzoic acid as a white solid.
Reference：
[1] Patent: US2004/77696, 2004, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2010/126922, 2010, A1, . Location in patent: Page/Page column 60
[3] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
[4] Journal of Organic Chemistry, 2014, vol. 79, # 11, p. 5134 - 5144
[5] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1873 - 1880
[6] Journal of the American Chemical Society, 1939, vol. 61, p. 3005
[7] Journal of Medicinal Chemistry, 2006, vol. 49, # 25, p. 7413 - 7426
[8] Patent: US2010/227894, 2010, A1, . Location in patent: Page/Page column 33
[9] Advanced Synthesis and Catalysis, 2011, vol. 353, # 8, p. 1306 - 1316
[10] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2261 - 2268
18
[ 453-71-4 ]
[ 66315-15-9 ]
Reference：
[1] Patent: US2012/277224, 2012, A1,
[2] Journal of the American Chemical Society, 2015, vol. 137, # 22, p. 7197 - 7209
[3] Tetrahedron Letters, 2017, vol. 58, # 43, p. 4145 - 4148
[4] Organic Letters, 2017, vol. 19, # 19, p. 5276 - 5279
[5] Organic Letters, 2018, vol. 20, # 14, p. 4306 - 4309
19
[ 453-71-4 ]
[ 369-26-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 5, p. 942 - 950
[2] Patent: WO2013/33620, 2013, A1,
20
[ 453-71-4 ]
[ 66315-23-9 ]
Reference：
[1] Patent: US2013/79306, 2013, A1,
21
[ 453-71-4 ]
[ 20274-69-5 ]
Yield
Reaction Conditions
Operation in experiment
99.1%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 1 h; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 3 h;
Sodium borohydride (2.70 g, 64.83 mmol)Dissolved in 100mL of tetrahydrofuran,Cool to 0 ° C,4-Fluoro-3-nitrobenzoic acid 5a (12.0 g, 64.83 mmol) was added portionwise0 ° C for 1 hour.Then at 0 ° CAdd boron trifluoride diethyl ether solution dropwise(6.55 mL, 71.31 mmol),The reaction was warmed to room temperature for 3 hours.The reaction mixture was added with 500 mL of ethyl acetate and 300 mL of water, the layers were separated, the organic phase was washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 4- Nitrobenzyl alcohol 5b (11.0 g, pale yellow solid), yield: 99.1percent.
99.1%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 1 h; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 3 h;
Sodium borohydride (2.70 g, 64 . 83 mmol) dissolved in 100 ml in tetrahydrofuran, cooled to 0 °C, batch by adding 4 - fluoro -3 - nitro benzoic acid 4a (12.0 g, 64 . 83 mmol), 0 °C reaction 1 hours. Then in 0 °C [...] boron trifluoride ethyl ether solution under (6.55 ml, 71 . 31 mmol), the reaction temperature to room temperature the reaction solution 3 hours. To the reaction solution by adding 500 ml ethyl acetate and 300 ml water, layered, organic phase using saturated sodium chloride solution (500 ml) washing, drying with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, to obtain 4-fluoro-3-nitrobenzyl alcohol is yellow 4b (11.0 g, yellow solid), yield: 99.1percent.
97.4%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 1 h; Stage #2: With boron trifluoride dimethyl etherate In tetrahydrofuran at 0 - 20℃; for 3 h;
Example 2: Synthesis of dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(piperidinylethyl) aminosulfonylbenzyl)-4-methyl-6-chloro- l -benzopyran-7-yl ester (subject compound 13)Subject compound 13 is synthesized following the procedure described in Scheme 2. 4-Fluoro-3-nitrobenzyl alcohol (2):Sodium borohydride (22.6 g, 590 mmol) is dissolved in 700ml of tetrahydrofuran, and is cooled to 0°C with an ice-salt bath. To this solution is added portion-wise 4-fluoro-3-nitrobenzoic acid (100 g, 540 mmol, subject compound 1) at 0°C, and the resulted solution is stirred at 0°C for 1 h. To the solution is then added dropwise a tetrahydrofuran solution of boron trifluoride-dimethyl ether (54.2 mL, 590 mmol) at 0°C. After adding, the reaction is continued at room temperature for 3 h. After the reaction is completed as indicated by TLC, the reaction is quenched with ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed to give a white solid (subject compound 2, 90 g, 97.4percent).
87%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 16 h;
To a solution of Intermediate 46(1.00 g, 5.40 mmol) in THF (10 mL) was added asuspension of NaBH4 (0.24 g, 5.94 mmol) in THF (10 mL) at 0°C. The reaction mixturewas stirred at room temperature for 1 h. Boron trifluoride diethyl etherate (0.84 g, 5.94 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 h, then quenched with brine (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was separated, washed with H20 (100 mL) and brine (100 mL), then dried overanhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 50percent EtOAc in hexanes) to afford the title compound (0.80 g, 87percent) as a colourless liquid. oH (400 MHz, CDC13) 4.78 (d, J3.34 Hz, 2H), 7.24-7.34 (m, 1H), 7.61-7.71 (m, 1H), 8.09 (d, J6.68 Hz, 1H) (OH signal absent).
Reference：
[1] Patent: CN107400092, 2017, A, . Location in patent: Paragraph 0293; 0295-0298
[2] Patent: CN108264511, 2018, A, . Location in patent: Paragraph 0280; 0283-0286
[3] Patent: WO2012/171488, 2012, A1, . Location in patent: Page/Page column 22-23
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5546 - 5550
[5] Patent: WO2017/89453, 2017, A1, . Location in patent: Page/Page column 54
[6] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 21, p. 5505 - 5513
[7] Journal of Medicinal Chemistry, 1968, vol. 11, p. 225 - 227
[8] Patent: US2003/144286, 2003, A1,
22
[ 453-71-4 ]
[ 20274-69-5 ]
Reference：
[1] Patent: US2003/78251, 2003, A1,
23
[ 453-71-4 ]
[ 18107-18-1 ]
[ 329-59-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
With methanol In hexanes; dichloromethane at 0℃; for 1 h;
Preparation of 4-Fluoro-3-nitro-benzoic acid methyl ester; <n="25"/>An ice-cold solution of acid (4-Fluoro-3-nitro-benzoic acid, 25.Og, 135.2mmole) (Chem. Abstr. Reg. No. 329-59-9) in a mixture of dichloromethane (DCM, 250 ml) and methanol (MeOH, 70 ml) was treated dropwise with a trimethylsilyldiazomethane solution (2.0M in hexanes) until bubbling stopped (-95 ml). The reaction mixture was stirred for 1 hour and concentrated to yield a slightly yellow solid which was dried on a vacuum pump at room temperature to yield solid. (26.7g, 99percent) Experimental Data; LCMS 50percent H2O, Retention time 1.75 min., C8H6FNO4, MW 199.1 ; Found APCI" 199.3(M+); 1H NMR (CDCI3) δ 8.60-8.57 (m, 1 H), 8.18-8.14 (m, 1H), 7.25-7.20 (m, 1 H), 3.82 (s, 3H).
92%
at 0 - 20℃; for 0.5 h;
4-Fluoro-3-nitrobenzoic acid (500 mg, 2.70 mmol) was dissolved in 20 mL of a 5:1 /toluene :MeOH mixture at 0°C under nitrogen. Trimethylsilyl diazomethane (2M in hexanes)(1.6 mL, 3.24 mmol) was added dropwise and the solution stirred at rt for 30 min. Thesolvent was concentrated. The product was purified by flash chromatography using 4:17hexanes:EtOAc as eluent on silica gel, to yield the desired title compound. Yield: 494 mg(92percent).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
Step-A 4-Fluoro-3-nitro-benzoic Acid Methyl Ester To a solution of 4-fluoro-3-nitrobenzoic acid (16.0 g, 0.0864 mol) in dry DMF (100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by methyl iodide (24.5 g, 0.173 mol) and the mixture was stirred for 3 h at ambient temperature. The reaction mixture was diluted with ice water (500 mL), extracted with EtOAc (3*100 mL) and the combined organic phases were washed with water (3*100 mL) and saturated brine solution (100 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording 17.0 g (99percent) of 4-fluoro-3-nitro-benzoic acid methyl ester.
Reference：
[1] Patent: US2009/118259, 2009, A1, . Location in patent: Page/Page column 44
[2] Patent: US5378704, 1995, A,
25
[ 67-56-1 ]
[ 453-71-4 ]
[ 329-59-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 0 - 20℃; Stage #2: With water; sodium hydrogencarbonate In ethyl acetate
Step A: Methyl 4-fluoro-3-nitrobenzoate; To a solution of 4-fluoro-3-nitrobenzoic acid (5.7 g, 30.8 mmol) in MeOH (50 ml_), cooled to 0 0C, was added thionyl chloride (3.37 mL, 46 mmol) dropwise over 10 min. The reaction was stirred overnight at rt. The MeOH was removed on the rotovap, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to generate the desired product as a yellow solid (6.57 g, quantitative yield). 1H-NMR-(400 MHz, d6-DMSO): δ 8.56 (dd, 1 H, J = 2.2 Hz, 7.3 Hz), 8.29 - 8.33 (m, 1 H), 7.73 (dd, 1 H, J = 8.9 Hz, 11 Hz), and 3.88 (s, 3 H).
100%
at 80℃;
Synthesis of 4-Fluoro-3-nitro-benzoic acid methyl ester (25)Starting material 24 (10 g, 54 mmol) was placed in 60 ml methanol and 0.5 ml sulfuric acid was added dropwise. Now the reaction was stirred over night at 80 0C. The reaction mixture was then distributed between water and ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated yielding the desired product 25 quantitatively as amorphous solid (10.8 g, 54 mmol).
100%
at 65℃; for 36 h; Large scale
To a 100L flask was charged 12.7kg of 4-fluoro-3-nitrobenzoic acid was added 40kg of methanol and 2.82kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C) for 36 hours. The reaction mixture was cooled to 0° C. Crystals formed at 38° C. The mixture was held at 0° C for 4 hrs then filtered under nitrogen. The 100L flask was washed and filter cake was washed with 10kg of methanol that had been cooled to 0° C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).
100%
at 65℃; for 36 h; Large scale
To a 100 L flask was charged 12.7 kg of 4-fluoro-3-nitrobenzoic acid was added 40 kg of methanol and 2.82 kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C.) for 36 hours. The reaction mixture was cooled to 0° C. Crystals formed at 38° C. The mixture was held at 0° C. for 4 hrs then filtered under nitrogen. The 100 L flask was washed and filter cake was washed with 10 kg of methanol that had been cooled to 0° C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695 kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).
100%
at 65℃; for 36 h; Large scale
To a 100 L flask was charged 12.7 kg of 4-fluoro-3-nitrobenzoic acid was added 40 kg of methanol and 2.82 kg concentrated sulfuric acid. The mixture was stirred at reflux (65 °C) for 36 hours. The reaction mixture was cooled to 0 °C. Crystals formed at 38 °C. The mixture was held at 0° C for 4 hrs then filtered under nitrogen. The 100 L flask was washed and filter cake was washed with 10 kg of methanol that had been cooled to 0 °C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695 kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).
100%
at 65℃; for 36 h; Large scale
To a 100 L flask was charged 12.7 kg of 4-fluoro-3-nitrobenzoic acid was added 40 kg of methanol and 2.82 kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C) for 36 hours. The reaction mixture was cooled to 0 °C. Crystals formed at 38 °C. The mixture was held at 0 °C for 4 hrs then filtered under nitrogen. The 100 L flask was washed and filter cake was washed with 10 kg of methanol that had been cooled to 0 °C. The solidfilter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695 kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).
99%
at -78 - 20℃;
a) Preparation of methyl 4-fluoro-3-nitrobenzoate 3-Nitro-4-fluorobenzoic acid (25.6 g, 138 mmol) was dissolved in methanol (300 mL), added thionyl chloride (18.4 mL, 258 mmol) under -78° C. The mixture was stirred at -78° C. for 10 minutes, and then stirred at room temperature overnight. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate). The title compound (29.6 g (yield >99percent)) was obtained as a white crystal. 1H-NMR (CDCl3) δ: 3.98 (3H, s), 7.39 (1H, dd, J=8.8, 10.3 Hz), 8.32 (1H, ddd, J=2.4, 4.3, 8.8 Hz), 8.75 (1H, dd, J=2.4, 7.2 Hz).
98%
for 48 h; Reflux
4-Fluoro-3-nitrobenzoicacid (7, 0.85 g, 4.59 mmol) and acatalytic amount of sulfuric acid (0.40 mL) were dissolved in 18 mL of CH3OH.The mixture was stirred at reflux for around 2 d. After removal of solvent in vacuo the residue was dispersed inwater and extracted with CH2Cl2. The combined organicphases were dried over anhydrous Na2SO4. After filtrationthe solvent was removed in vacuo to yield9 as a beige solid (0,90 g, 4.52mmol, 98percent). 1H-NMR (300 MHz, CDCl3): δ 3.92 (s, 3 H, OCH3), 7.36 (m, 1 H), 7.27 (m, 1H), 8.64 (m, 1 H) (3 C(ar)H) ppm. 13C-NMR (75.5MHz, CDCl3): δ 52.89 (CH3),118.69, 118.98 (CH), 127.21, 127.26 (C), 127.75, 127.77 (CH), 136.53, 136.66(CH), 137.17, 137.28 (C), 156.22, 159.82 (CF), 164.08 (CO) ppm. MS (EI): m/z 199.1 [M]+.
97%
at 0℃; for 1 h; Reflux
Example 1: Preparation of (2-methyl-1-m-tolyl-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone (Compound 98)[Step 1] Preparation of methyl 4-fluoro-3-nitrobenzoate 4-Fluoro-3-nitrobenzoic acid (3.00 g, 16.2 mmol) was dissolved in methanol 40 mL, and thionyl chloride (3.5 mL, 48.6 mmol) was slowly added thereto at 0°C. The temperature was slowly raised to room temperature, and then stirred under reflux for 1 hour. The solvent was removed by concentration under reduced pressure, to obtain a target compound as an ivory solid (3.12 g, 97percent). 1H NMR (600MHz, chloroform-d1) d = 8.73 (dd, J = 2.4 Hz, 7.5 Hz, 1H), 8.34 (m, 1H), 7.42 (t, J = 9.0 Hz, 1H), 3.99 (s, 3H)
97%
at 0℃; for 1 h; Reflux
[Step 1] Preparation of methyl 4-fluoro-3-nitrobenzoate 4-Fluoro-3-nitrobenzoic acid (3.00 g, 16.2 mmol) was dissolved in methanol 40 mL, and thionyl chloride (3.5 mL, 48.6 mmol) was slowly added thereto at 0° C. The temperature was slowly raised to room temperature, and then stirred under reflux for 1 hour. The solvent was removed by concentration under reduced pressure, to obtain a target compound as an ivory solid (3.12 g, 97percent). 1H NMR (600 MHz, chloroform-d1) d=8.73 (dd, J=2.4 Hz, 7.5 Hz, 1H), 8.34 (m, 1H), 7.42 (t, J=9.0 Hz, 1H), 3.99 (s, 3H)
97%
for 12 h; Heating / reflux
Synthesis of intermediate J; To a solution of compound I (30.Og, 162mmol) in methanol (300ml) was added cone, sulfuric acid (5ml) and the mixture was stirred at reflux for 12 hours and then concentrated in vacuo. The concentrate was partitioned between ethyl acetate and saturated, aqueous bicarbonate. The organic layer was washed with water and brine, successively, and concentrated to afford J (31.5g, 97percent).
95%
for 24 h; Reflux
4-fluoro-3-nitrobenzoic acid (1.110 g, 6 mmol) was dissolved in MeOH (30 mL). Then, cone. H2S04 (298 μ, 12 mmol) was added to the solution and was stirred at reflux for 24h (monitored by TLC) [26]. The solvent was concentrated under reduced pressure. After extraction with EtOAc (50 mL), the solution was washed with distilled water (3 x 20 mL) and saturated NaHC03 (20 mL), and dried over Na2S04. The solution was evaporated and purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :8) as eluent, to give methyl 4-fluoro-3-nitrobenzoate as a yellow solid (1.135 g, 95 percent): 1H NMR (400 MHz, CDC13) δ 8.76 (dd, J= 7.2, 2.2 Hz, 1H), 8.34 (ddd, J= 8.7, 4.2, 2.2 Hz, 1H), 7.41 (dd, J= 10.2, 8.7 Hz, 1H), 4.00 (s, 3H); 13C NMR (101 MHz, CDC13) δ 164.07, 159.41, 156.71, 136.44, 127.83, 127.23, 118.67, 52.89.
95%
at 80℃; for 0.166667 h; Microwave irradiation
4-Fluoro-3-nitrobenzoic acid (0.5 g, 2.7 mmol) was dissolvedin methanol (5 mL) and conc. H2SO4 (0.5 mL) atroom temperature. The reaction mixture was heated withstirring in a 10 mL microwave process vial for 10 min at80 °C. After completion of the reaction (as evident fromthin layer chromatography (TLC)), the solvent was evaporatedunder reduced pressure, the reaction mixture basifiedby sodium bicarbonate and the aqueous layer extracted intoethyl acetate (3 × 5 mL). The organic layer was dried overanhydrous Na2SO4 and concentrated under reduced pressureto yield 2 as a cream-colored powder (95percent).1H NMR (CDCl3, 400 MHz) δ 8.73 (1H, dd, J = 7.2, 2.2Hz, H-2), 8.31 (1H, m, H-6), 7.38 (1H, dd, J = 10.2, 8.8 Hz,H-5), 3.95 (3H, s, H-8); 13C NMR (CDCl3, 100 MHz) δ164.1 (C-7), 158.1 (d, JCF = 270.0 Hz, C-4), 137.3 (C-3),136.5 (d, J = 9.7 Hz, C-6), 127.8 (C-2), 127.2 (d, J = 4.2 Hz,C-1), 118.8 (d, J = 21.2 Hz, C-5), 52.9 (C-8); 19F NMR(CDCl3, 376.5MHz) δ −110.55.
95%
for 12 h; Reflux
[00220] To a solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH (30 mL), H2SO4 (5 mL, 0.3 M) was added and the reaction mixture was heated to reflux for 12 h. The solvent was removed under reduced pressure, crude reaction mixture was dissolved in EtOAc (150 mL), washed with saturated NaHCO3 (20 mL _ 2), water (10 mL _ 2) and brine (10 mL). The EtOAc layer was dried over anhydrous MgSO4 and evaporated to get methyl 4-fluoro-3-nitrobenzoate 2 (95percent) as a white solid.
93%
at 0℃; Reflux
Thionyl chloride (191.4 g, 1.61 mol) was added to a solution of 4-fluoro-3-nitrobenzoic acid (150.0 g, 810.81 mmol) in methanol (500 ml) at 0°C. The resulting solution was heated to reflux overnight, concentrated in vacuo, the product was precipitated by the addition of petroleum ether (200 ml), and the solids were collected by filtration to afford methyl 4-fluoro-3-nitrobenzoate as a light yellow solid (150 g, 93percent).'H-NMR (300 MHz, CDC13) δ 8.74 - 8.77 (m, 1H), 8.31 - 8.37 (m, 1H), 7.37 - 7.43 (m, 1H), 3.99 (s, 3H).
91%
Reflux; Inert atmosphere
To a solution of 4-fluoro-3-nitrobenzoic acid (2 g, 11 mmol) in MeOH (20 mL) was slowly added SOCl2 (2.6 g, 22 mmol). The mixture was heated to reflux overnight before it was concentrated in vacuo to give the crude product. The crude product was washed with 2N aq. NaOH, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated in vacuo to give the desired product as a solid (2 g, 91percent). 1H NMR (400 MHz, CDCl3-d3) δ ppm 8.71 (m, 1 H), 8.34 (m, 1 H), 7.42 (m, 1 H), 4.00 (s, 3 H).
90%
for 3 h; Reflux
5.55 g of 4-Fluoro-3-nitro-benzoic acid were dissolved in 50 ml of methanol, 6.4 ml of concentrated sulfuric acid were added and the reaction was heated to reflux for 3 h. The reaction was cooled, poured unto ice and the precipitated product was collected by suction and dried in vacuo. 5.40 g (90percent) of 4-fluoro-3-nitro-benzoic acid methyl ester were obtained. C8H6FNO4 (199.14), LCMS (method 7_1_1 ): Rt = 1 .28 min, m/z= 200.05 [M+H]+
90%
for 3 h; Reflux
a) 4-Fluoro-3-nitro-benzoic acid methyl ester [1938] 4-Fluoro-3-nitro-benzoic acid were dissolved in 50 ml of methanol, 6.4 ml of concentrated sulfuric acid were added and the reaction was heated to reflux for 3 h. The reaction was cooled, poured unto ice and the precipitated product was collected by suction and dried in vacuo. 5.40 g (90percent) of 4-fluoro-3-nitro-benzoic acid methyl ester were obtained. [1940] C8H6FNO4 (199.14), LCMS (method 7—1—1): Rt=1.28 min, m/z=200.05 [M+H]+
88%
for 2 h; Reflux
A mixture of acid 5 (1.85 g, 1 mol), methanol (15 mL) and 96percent H2SO4 (1 mL) was heated under reflux with stirring for 2 h. The reaction progress was monitored by TLC and after complete disappearance of the starting material 5 the solvent was concentrated under vacuum to one half of the original volume. The solid formed was collected by filtration and washed with methanol (2 .x. 0.5 mL), to afford compound 6. White solid, 88percent yield; m.p: 97-98 °C. FTIR ν (cm-1): 3065, 2961, 1716 (CO), 1619 (CC), 1541 and 1352 (NO2), 1126 (C-O); 1H NMR (CDCl3) δ 3.99 (s, 3H, OCH3), 7.40 (bt, 1H, J = 8.7 Hz), 8.34 (m, 1H), 8.75 (bd, 1H, J = 7.0 Hz) ppm; 13C NMR (CDCl3) δ 52.9 (OCH3), 118.7 (d, J = 21.3 Hz), 127.2 (d, J = 4.1 Hz, Cq), 127.8 (d, J = 1.3 Hz), 136.5, 136.6 (Cq), 158.1 (d, J = 269.9 Hz, Cq), 164.1 (CO) ppm. MS (EI) m/z (percent): 199 (100, M+), 184 (42), 168 (14, M - OCH3). Anal. Calcd. for C8H6FNO4: C, 48.25; H, 3.04; N, 7.03. Found: C, 48.50; H, 3.17; N, 6.99.
36%
for 4 h; Reflux
[Example 49] Preparation of methyl 1-(4-chlorobenzyl)-2-(4-ethoxyphenylamino)-1H-benzo [d]imidazole-4-carboxylate (I-362) A mixture of 4-fluoro-3-nitrobenzoic acid (5 g, 27 mmol), concentrated sulphuric acid (0.144 mL, 2.7 mmol) and methanol (50 mL) was heated at reflux for 4 hours. The reaction mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give methyl(4-fluoro-3-nitro)benzoate (1.94 g, Yield: 36percent) as white powder. 1H-NMR (δ ppm TMS/CDCl3): 3.98 (3H, s), 7.39 (1H, dd, J= 10.1, 8.8 Hz), 8.33 (1H, ddd, J= 8.8, 2.2, 1.1 Hz), 8.74 (1H, dd, = 7.1, 2.2 Hz).
36%
for 4 h; Reflux
EXAMPLE 49 Preparation of methyl 1-(4-chlorobenzyl)-2-(4-ethoxyphenylamino)-1H-benzo[d]imidazole-4-carboxylate (I-362) A mixture of 4-fluoro-3-nitrobenzoic acid (5 g, 27 mmol), concentrated sulphuric acid (0.144 mL, 2.7 mmol) and methanol (50 mL) was heated at reflux for 4 hours. The reaction mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give methyl(4-fluoro-3-nitro)benzoate (1.94 g, Yield: 36percent) as white powder. 1H-NMR (δ ppm TMS/CDCl3): 3.98 (3H, s), 7.39 (1H, dd, J=10.1, 8.8 Hz), 8.33 (1H, ddd, J=8.8, 2.2, 1.1 Hz), 8.74 (1H, dd, J=7.1, 2.2 Hz).
Reference：
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[4] Patent: US2018/177814, 2018, A1, . Location in patent: Paragraph 0342; 0343
[5] Patent: WO2018/118662, 2018, A1, . Location in patent: Page/Page column 94; 95
[6] Patent: WO2018/118627, 2018, A1, . Location in patent: Page/Page column 94
[7] Patent: US2010/280013, 2010, A1, . Location in patent: Page/Page column 19
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[9] Chemistry - A European Journal, 2009, vol. 15, # 39, p. 10144 - 10157
[10] Chimia, 2010, vol. 64, # 3, p. 136 - 139
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[12] Patent: US2013/158047, 2013, A1, . Location in patent: Paragraph 0062; 0063
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[14] Patent: WO2005/19186, 2005, A1, . Location in patent: Page/Page column 18
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26
[ 453-71-4 ]
[ 149-73-5 ]
[ 329-59-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With trifluorormethanesulfonic acid In methanol for 96 h; Heating / reflux
TRIFLUOROMETHANESULFONIC acid (600 UL, 6.8 MMOL) was added to a solution of 4-fluoro-3-nitro-benzoic acid (25.00 g, 135 MMOL) and trimethyl orthoformate (29.5 mL, 270 MMOL) in MEOH (250 mL), which was refluxed and monitored to completion over 4 days with 1 H-NMR. The resulting solution was concentrated to remove most of the methanol, and then was diluted with 2 volumes of water to precipitate the product. The filter cake was washed with additional water and vacuum dried to afford 25.45 g (95percent) desired product as a slightly off-white solid. 1H NMR (300 MHz, CDCl3 6 8.68 (dd, J=2.2 Hz, J=7.25 Hz, 1 H), 8.35 (ddd, J=2.2 Hz, 1 H), 7.55 (dd, J=10.8 Hz, J=8.8 Hz, 1 H), 3.96 (s, 3 H). F NMR (300 MHz, CDCI3) # - 114. 33 (symmetric 7 line multiplet).
Step 1: ethyl 4-fluoro-3-nitro-benzoate 5.00 g (27.0 mmol) 4-fluoro-3-nitro-benzoic acid are refluxed for 15 hours in 50 mL saturated, ethanolic hydrochloric acid solution (1.25 M). The reaction mixture is evaporated down using the rotary evaporator and purified by flash column chromatography [silica gel, petroleum ether/ethyl acetate (4/1)]. 5.48 g (25.7 mmol, 95percent) ethyl 4-fluoro-3-nitro-benzoate are obtained as a colourless solid. Rf=0.48 [silica gel, petroleum ether/ethyl acetate (4/1)] MS [ESI (M+H)+]=214
93%
for 8 h; Reflux
Step 1-1-1 Ethyl 4-fluoro-3-nitrobenzoate To a suspension of 4-fluoro-3-nitrobenzoic acid (150 g, 0.810 mol) in ethanol (1000 ml), concentrated sulfuric acid (25 ml) was added dropwise, and the mixture was heated under reflux for 8 hours. After being allowed to cool, the mixture was concentrated under a reduced pressure, and water was added thereto under stirring. The precipitate was separated by filtration, washed with water and then subjected to through circulation drying to give the title compound (160 g, 93percent) as a yellow solid. 1H-NMR (DMSO-d6) δ: 8.56 (dd, J=2.3, 7.3 Hz, 1H), 8.35-8.31 (m, 1H), 7.76-7.71 (m, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H) Mass, m/z: 213 (M+), 185, 168 (base)
75%
for 8 h; Reflux
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 h.After completion of reaction (as evident from TLC), the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL Χ 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-colored powder (75percent).
75%
for 8 h; Reflux
4.1.1 Procedure for the preparation of ethyl-4-fluoro-3-nitrobenzoate (1) 4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 hours. After completion of reaction (as evident from TLC), the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL * 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-coloured powder (75percent).
75%
for 8 h; Reflux
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 h. After completion of reaction (as evident from TLC), the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL×3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-colored powder (75percent).
75%
for 8 h; Reflux
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed inethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 h.After completion of reaction (as evident from TLC), thesolvent was evaporated under reduced pressure. The aqueouslayer was extracted with ethyl acetate (25 mL × 3).The organic layer was dried over Na2SO4 and concentratedunder reduced pressure to yield 1 as cream-colored powder(75percent).
70%
for 6 h; Reflux
General procedure: The starting material, 4-fluoro-3-nitro benzoic acid was esterified in the presence of catalytic sulfuric acid in ethanol by refluxing for 6hto afford 1 in 70percent yield. Ethyl-4-fluoro-3-nitrobenzoate, 1 (0.5g, 2.34mmol) and amine (2.58mmol) [a–h: 1-(3-aminopropyl)-2-pyrrolidinone; i–p: aniline] were mixed in ethanol (5mL) and stirred at room temperature for 1h. The solvent was evaporated under reduced pressure and resuspended in ethyl acetate. The organic layer was then washed with water (10mL×3), dried over Na2SO4 and evaporated to dryness to yield 2 (90percent). The nitroethyl ester, 2 (1mmol), ammonium formate (3mmol) and 10percent Pd/C (100mg) were mixed in ethanol (10mL). The reaction mixture was stirred at room temperature until completion (solution turned colorless). The reaction mixture was then filtered through Celite 545. The filtrate was evaporated under reduced pressure. It was resuspended in ethyl acetate and washed with water, dried over Na2SO4 and evaporated to dryness to yield 3 (71percent). The aminoethyl ester, 3 (1mmol) and various benzaldehydes (1mmol) and sodium metabisulfite (1mmol) were mixed in water (5mL). The reaction mixture was stirred at room temperature for 2h. Precipitate formed were then filtered, washed with cold water and dried under reduced pressure to yield final compounds 4a–p (76–90percent).
Reference：
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32
[ 453-71-4 ]
[ 109-63-7 ]
[ 367-80-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 120℃; for 4 h;
General procedure: In a 50 mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser and a calcium chloride drying tube was placed nicotinic acid (1 g, 8.1 mmol) suspended in boron trifluoride etherate (10 mL). The reaction mixture was stirred and heated to 120 °C overnight during which the creamy reaction mixture changed into a brownish solution. Thin layer chromatography (hexane/ethyl acetate 3:1) revealed complete reaction. The cooled reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extract was washed to the end of effervescence with a saturated solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo giving a crude yield of 1.11 g (92percent).
Reference：
[1] Bulletin of the Chemical Society of Ethiopia, 2018, vol. 32, # 2, p. 387 - 392
1.1
To a cold solution of 4-fluorobenzoic acid (50.0 g, 0.36 mol, 1.0 equiv) in concentrated H2SO4 (180 ml) was added portionwise potassium nitrate (39.7 g, 0.39 mol, 1.1 equiv). The reaction mixture was stirred overnight at rt and then poured on crushed ice (800 g) with constant stirring. The resulting mixture was kept overnight at rt, filtered and washed thoroughly with water, and finally dried by making an azeotrope with toluene to yield 59.5 g (90%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 7.69-7.74 (m, 1H), 8.29-8.32 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 13.75 (br s, 1H).
88%
With sulfuric acid; potassium nitrate at 20℃;
75%
With sulfuric acid; nitric acid at 20℃; for 10h;
4-Fluoro-3-nitrobenzoic acid
To a solution of 4-fluoro-benzoic acid (5.0 g, 36 mmol) in conc. H2SO4 (36 mL) at 0 °C was added HNO3 (5.6 mL). After the stirring at room temperature for 10 h, the mixture was poured into H2O (200 mL). The precipitate was collected by filtration, washed with water and dried to give 4-fluoro-3-nitrobenzoic acid (5.0 g, 75 %) as a white solid. 1H NMR (CDCl3, 500 MHz) δ: 7.44 (1H, dd, J = 10.5, 9.0 Hz), 8.39 (1H, m), 8.83 (1H, dd, J = 7.0, 2.0 Hz).
67%
With sulfuric acid; potassium nitrate at 20℃; Cooling with ice;
65%
With sulfuric acid; potassium nitrate at 20℃; Cooling with ice;
Compound 19 [51]
To a solution of 4-fluorobenzoic acid (2.80 g, 20 mmol) in concentrated H2SO4 (25ml) in an ice bath was added potassium nitrate (2.20 g, 22 mmol) in portions within 30 min. The ice bath was removed and the mixture was stirred at ambient temperature overnight. To the mixture was added crushed ice at room temperature, the residue was filtered to give the product 19 (2.41 g, 65%). 1H NMR (DMSO-d6, 400 MHz): δ 13.69 (br, 1H), 8.57 (d, J=5.64 Hz, 1H), 8.32-8.30 (m, 1H), 7.75-7.70 (m, 1H). ESI-HRMS: m/z calcd for C8H10N2O [M+H]+ 186.0158 found 186.0174..
durch Nitrierung;
With nitric acid
With sulfuric acid; nitric acid at 0 - 20℃; for 4h;
A
Cone. HNO3 (79 mL) was dropwise added to a solution of 4-fluoro-benzoic acid (70 g, 0.5 mol) in cone. H2S04 (500 mL) at 0°C. The mixture was stirred for 4 h at RT and then poured into ice-water (3.0 L). The precipitate was filtered off, washed twice with water (0.5 L) and dried to give the title compound as a white solid. 1 H-NMR (300 MHz, CDCI3): δ (ppm) 11.0 (s, br, 1 H), 8.86 (m, 1 H), 8.42 (m, 1 H), 7.47 (m, 1 H).
With hydrogen;5%-palladium/activated carbon; In methanol; for 6h;
A mixture of 3-nitro-4-fluorobenzoic acid (1.85 g, 10.0 mmol) in MeOH (10 mL) and 5% Pd/C (100 mg) was stirred under an atmosphere of hydrogen and for 6 h. The catalyst was removed by filtration, washed with methanol and the volatiles were removed in vacuo to give compound 8A, 3-amino-4-fluorobenzoic acid, as a light yellow solid (1.50 g, 9.67 mmol, 97%).
96%
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 3h;
To a solution of 4-fluoro-3-nitrobenzoic acid (15.0 g, 81 mmol) in MeOH (150 mL) under an atmosphere of nitrogen was added 10% Pd/C (0.80 g). The mixture was then stirred under 1 atm H2 for 3 h. The reaction mixture was vacuum filtered through a thin pad of Celite, and the filtrate concentrated in vacuo to give the product as a solid, 12.0 g (96%). LC-MS (ES) m/z = 156.2 (M+H)+ 1H NMR (400 MHz, DMSOd6) delta ppm 7.49(m, 1 H), 7.23(m, 1 H), 6.88 (m, 1 H), 4.78 (br, 1 H).
95%
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.
90%
With palladium 10% on activated carbon; hydrogen; In ethanol; for 24h;
Following a literature procedure [2], 4-fluoro-3-nitrobenzoic acid (1.0 g, 5.4 mmol) was reduced with hydrogen in the presence of Pd/C (60 mg, 10% on charcoal) in EtOH (10 ml) over 24 h. The reaction mixture was passed through Celite, the filtrate was evaporated, and the residue was purified on a silica gel plug (EtOAc) to give 0.75 g (90% yield) of 3-amino-4-fluorobenzoic acid as a white solid.
With hydrogen;palladium 10% on activated carbon; In methanol; for 6h;
4-Fluoro-3-nitrobenzoic acid (270 mg, 2 mmol) and 10% Pd/C (80 mg) in MeOH (10 mL) was hydrogenated with a hydrogen balloon for 6.0 h. LC-MS indicated a completion of reaction. The mixture was filtered and the filtrate was concentrated to give 19A. 1H NMR (400 MHz, CDOD3) delta ppm 7.00 (dd, J=10.99, 8.79 Hz, 1H) 7.27-7.36 (m, 1H) 7.49 (dd, J=8.79, 2.20 Hz, 1H).
With sulfuric acid; In methanol;Reflux;
General procedure: 4-fluoro-3-nitrobenzoic acid (15g, 81.0mmol) and H2SO4 (0.43mL, 8.10mmol) were dissolved in MeOH (200mL) and the mixture was refluxed over night. The solvent was evaporated leaving a white solid. This solid was dissolved in DCM and K2CO3 (1M in water). The phases were separated and the aqueous layer was extracted three times with DCM. The combined organic layer was dried through a phase-separator and finally evaporated leaving the product as a white solid (16g, 99%). The product was taken to the next step without further purification. Rf=0.8 (CHCl3/MeOH, 9:1).
Sodium borohydride (2.70 g, 64.83 mmol)Dissolved in 100mL of tetrahydrofuran,Cool to 0 C,4-Fluoro-3-nitrobenzoic acid 5a (12.0 g, 64.83 mmol) was added portionwise0 C for 1 hour.Then at 0 CAdd boron trifluoride diethyl ether solution dropwise(6.55 mL, 71.31 mmol),The reaction was warmed to room temperature for 3 hours.The reaction mixture was added with 500 mL of ethyl acetate and 300 mL of water, the layers were separated, the organic phase was washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 4- Nitrobenzyl alcohol 5b (11.0 g, pale yellow solid), yield: 99.1%.
99.1%
Sodium borohydride (2.70 g, 64 . 83 mmol) dissolved in 100 ml in tetrahydrofuran, cooled to 0 C, batch by adding 4 - fluoro -3 - nitro benzoic acid 4a (12.0 g, 64 . 83 mmol), 0 C reaction 1 hours. Then in 0 C [...] boron trifluoride ethyl ether solution under (6.55 ml, 71 . 31 mmol), the reaction temperature to room temperature the reaction solution 3 hours. To the reaction solution by adding 500 ml ethyl acetate and 300 ml water, layered, organic phase using saturated sodium chloride solution (500 ml) washing, drying with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, to obtain 4-fluoro-3-nitrobenzyl alcohol is yellow 4b (11.0 g, yellow solid), yield: 99.1%.
97.4%
Example 2: Synthesis of dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(piperidinylethyl) aminosulfonylbenzyl)-4-methyl-6-chloro- l -benzopyran-7-yl ester (subject compound 13)Subject compound 13 is synthesized following the procedure described in Scheme 2. 4-Fluoro-3-nitrobenzyl alcohol (2):Sodium borohydride (22.6 g, 590 mmol) is dissolved in 700ml of tetrahydrofuran, and is cooled to 0C with an ice-salt bath. To this solution is added portion-wise 4-fluoro-3-nitrobenzoic acid (100 g, 540 mmol, subject compound 1) at 0C, and the resulted solution is stirred at 0C for 1 h. To the solution is then added dropwise a tetrahydrofuran solution of boron trifluoride-dimethyl ether (54.2 mL, 590 mmol) at 0C. After adding, the reaction is continued at room temperature for 3 h. After the reaction is completed as indicated by TLC, the reaction is quenched with ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed to give a white solid (subject compound 2, 90 g, 97.4%).
87%
To a solution of Intermediate 46(1.00 g, 5.40 mmol) in THF (10 mL) was added asuspension of NaBH4 (0.24 g, 5.94 mmol) in THF (10 mL) at 0C. The reaction mixturewas stirred at room temperature for 1 h. Boron trifluoride diethyl etherate (0.84 g, 5.94 mmol) was added at 0C. The reaction mixture was stirred at room temperature for 16 h, then quenched with brine (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was separated, washed with H20 (100 mL) and brine (100 mL), then dried overanhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 50% EtOAc in hexanes) to afford the title compound (0.80 g, 87%) as a colourless liquid. oH (400 MHz, CDC13) 4.78 (d, J3.34 Hz, 2H), 7.24-7.34 (m, 1H), 7.61-7.71 (m, 1H), 8.09 (d, J6.68 Hz, 1H) (OH signal absent).
With BH3-THF; In tetrahydrofuran;
(a) (4-Fluoro-3-nitrophenyl)-methanol To a 2 L flask containing 75.0 g 4-fluoro-3-nitrobenzoic acid (405.4 mmol, 1.0 equiv) was carefully added 668.2 ml of 1.0 M BH3-THF in 100 mL THF over 2 h via addition funnel. The reaction was allowed to stir for 2 h at which time it was diluted with sat. NaHCO3 and extracted (2*EtOAc). The EtOAc solution was then washed (1*brine), dried (Na2SO4), and concentrated under reduced pressure to give 6.24 g of the product as a yellow solid (364.9 mmol).
4-[8-Carbamoyl-10-(2,6-dichloro-pyridin-4-ylmethyl)-11-oxo-10,11-dihydro-dibenzo[b,e][1,4]diazepin-5-ylmethyl]-3-methoxy-benzoic acid methyl ester[ No CAS ]
[2-Carbamoyl-13-(5-chloro-benzo[b]thiophen-3-ylmethyl)-12-oxo-12,13-dihydro-5,13-diaza-benzo[4,5]cyclohepta[1,2-b]naphthalen-5-yl]-acetic acid methyl ester[ No CAS ]
To a solution of 4-fluoro-3-nitrobenzoic acid (4.9 g, 27 mmol) in MeOH was added MeNH2 (40 % in MeOH, 20 mL). After the stirring at room temperature for 10 h, the reaction mixture was poured into H2O (75 mL). The reaction was acidified with 12 M HCl. The product was collected by filtration, washed with H2O and dried to give 4-(methylamino)-3-nitrobenzoic acid (5.0 g, 98 %) as a yellow solid. 1H NMR (DMSO-d6, 500 MHz) delta: 2.97 (3H, d, J = 5.5 Hz), 7.02 (1H, d, J = 9.0 Hz), 7.95 (1H, dd, J = 9.5, 2.5 Hz), 8.52 (1H, m), 8.58 (1H, d, J = 2.0 Hz).
87%
In N,N-dimethyl-formamide; at 20℃; for 1h;
Step 1. 4-(Methylamino)-3-nitrobenzoic acid A solution of 4-fluoro-3-nitrobenzoic acid (1.85 g, 9.99 mmol) and methylamine (5 ml, 33% aq) in DMF (10 ml) was stirred for 1 hour at room temperature, and then diluted with water (20 ml). The solids precipitated and were collected by filtration, and the filter cake was washed with ether (20 ml) to afford 4-(methylamino)-3-nitrobenzoic acid as a yellow solid (1.7 g, 87%). LC/MS (ES, m/z): [M+H]+. 197.1 1H-NMR (300 MHz, DMSO) delta 12.84 (s, 1H), 8.61 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.97-8.00 (m, 1H), 7.04 (d, J=9.3 Hz, 1H), 3.00 (s, 3H)
With N-ethyl-N,N-diisopropylamine;
In the first step of Scheme 7, the fluoro group of 4-fluoro-3-nitrobenzoic acid 2 was displaced with methylamine followed by conversion of the acid to a primary amide, and nitro reduction giving the diamine intermediate 3. The diamine was then oxidatively condensed under standard conditions with 4-aryloxybenzaldehyde giving compound 4 in good yield. Compound 7 was prepared in a similar fashion starting from 3-fluoro-4-nitrobenzoic acid.
In tetrahydrofuran; at 20℃; for 16h;
To a DMF solution of a nitrohaloarene would be added an amine or sodium alkoxide, and the reaction mixture would be stirred at room temperature for 16 h. It would be poured into water and extracted with ethyl acetate. The combined organic extracts would be washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give the product, which would not be purified further and would be used directly in the next step.; 4-Methylamino-3-nitro-benzoic acid (825 mg) was prepared by following General Procedure A starting from 4-fluoro-3-nitro-benzoic acid (1.0 g) and methylamine (2 M in THF, 8.1 mL) in THF. The crude product was used in the next step without further purification.
In tetrahydrofuran; methanol; at 20℃; for 2h;
STEP A: 4-Methylamino-3-nitro-benzoic acidA 2M solution of methylamine in THF (6.88 ml, 13.76 mmol) was added to (4-fluoro-3-nitro-benzoic acid (0.51 g, 2.70 mmol) in MeOH (3 ml). The reaction was stirred for 2 hours at room temperature and then concentrated to dryness. The residue was subjected to column chromatography over silica gel with gradient of MeOH in DCM from 0 to 10% to yield 4-methylamino-3-nitro-benzoic acid. 1H NMR (300 MHz, DMSO-d6) ppm 2.99 (d, J=5.0 Hz, 3 H), 6.95 (d, J=8.9 Hz, 1 H), 8.01 (d, J=8.9 Hz, 1 H), 8.32 (q, J=5.0 Hz, 1 H), 8.59 (s, 1 H). MS m/z 197 (M+H)+
Step 1: ethyl 4-fluoro-3-nitro-benzoate 5.00 g (27.0 mmol) 4-fluoro-3-nitro-benzoic acid are refluxed for 15 hours in 50 mL saturated, ethanolic hydrochloric acid solution (1.25 M). The reaction mixture is evaporated down using the rotary evaporator and purified by flash column chromatography [silica gel, petroleum ether/ethyl acetate (4/1)]. 5.48 g (25.7 mmol, 95%) ethyl 4-fluoro-3-nitro-benzoate are obtained as a colourless solid. Rf=0.48 [silica gel, petroleum ether/ethyl acetate (4/1)] MS [ESI (M+H)+]=214
93%
With sulfuric acid; for 8h;Reflux;
Step 1-1-1 Ethyl 4-fluoro-3-nitrobenzoate To a suspension of 4-fluoro-3-nitrobenzoic acid (150 g, 0.810 mol) in ethanol (1000 ml), concentrated sulfuric acid (25 ml) was added dropwise, and the mixture was heated under reflux for 8 hours. After being allowed to cool, the mixture was concentrated under a reduced pressure, and water was added thereto under stirring. The precipitate was separated by filtration, washed with water and then subjected to through circulation drying to give the title compound (160 g, 93%) as a yellow solid. 1H-NMR (DMSO-d6) delta: 8.56 (dd, J=2.3, 7.3 Hz, 1H), 8.35-8.31 (m, 1H), 7.76-7.71 (m, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H) Mass, m/z: 213 (M+), 185, 168 (base)
75%
With sulfuric acid; for 8h;Reflux;
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 h.After completion of reaction (as evident from TLC), the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL Chi 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-colored powder (75%).
75%
With sulfuric acid; for 8h;Reflux;
4.1.1 Procedure for the preparation of ethyl-4-fluoro-3-nitrobenzoate (1) 4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 hours. After completion of reaction (as evident from TLC), the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL * 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-coloured powder (75%).
75%
With sulfuric acid; for 8h;Reflux;
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 h. After completion of reaction (as evident from TLC), the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL×3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-colored powder (75%).
75%
With sulfuric acid; for 8h;Reflux;
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed inethanol (50 mL) and concentrated H2SO4 (2 mL) for 8 h.After completion of reaction (as evident from TLC), thesolvent was evaporated under reduced pressure. The aqueouslayer was extracted with ethyl acetate (25 mL × 3).The organic layer was dried over Na2SO4 and concentratedunder reduced pressure to yield 1 as cream-colored powder(75%).
70%
With sulfuric acid; for 6h;Reflux;
General procedure: The starting material, 4-fluoro-3-nitro benzoic acid was esterified in the presence of catalytic sulfuric acid in ethanol by refluxing for 6hto afford 1 in 70% yield. Ethyl-4-fluoro-3-nitrobenzoate, 1 (0.5g, 2.34mmol) and amine (2.58mmol) [a-h: 1-(3-aminopropyl)-2-pyrrolidinone; i-p: aniline] were mixed in ethanol (5mL) and stirred at room temperature for 1h. The solvent was evaporated under reduced pressure and resuspended in ethyl acetate. The organic layer was then washed with water (10mL×3), dried over Na2SO4 and evaporated to dryness to yield 2 (90%). The nitroethyl ester, 2 (1mmol), ammonium formate (3mmol) and 10% Pd/C (100mg) were mixed in ethanol (10mL). The reaction mixture was stirred at room temperature until completion (solution turned colorless). The reaction mixture was then filtered through Celite 545. The filtrate was evaporated under reduced pressure. It was resuspended in ethyl acetate and washed with water, dried over Na2SO4 and evaporated to dryness to yield 3 (71%). The aminoethyl ester, 3 (1mmol) and various benzaldehydes (1mmol) and sodium metabisulfite (1mmol) were mixed in water (5mL). The reaction mixture was stirred at room temperature for 2h. Precipitate formed were then filtered, washed with cold water and dried under reduced pressure to yield final compounds 4a-p (76-90%).
1. 4-fluoro-3-nitrobenzoic acid (1 equivalent) was dissolved in ethanol (5.3 equivalents), and concentrated sulfuric acid (0.25 equivalent) was added thereto, and the resulting mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the reaction mixture was concentrated under reduced pressure until the volume was reduced to about half the initial value. The resulting mixture was then neutralized by adding sodium carbonate and was subjected to extraction with ether three times. The obtained extracted liquid was washed with saturated brine and then with water, and the ether layer was dried over anhydrous sodium sulfate. The resulting layer was then evaporated to dryness under reduced pressure, whereby ethyl 4-fluoro-3-nitrobenzoate was obtained.
With sulfuric acid; In toluene; for 5h;Inert atmosphere; Reflux; Dean Stark trap;
Example 4; Ethyl 1-(trans-4-hydroxycyclohexyl)-2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carboxylate; Step 1: Ethyl 4-fluoro-3-nitrobenzoate; 4-Fluoro-3-nitrobenzoic acid (5.3 g, 0.029 mol), ethanol (15 mL, 0.26 mol), toluene (40 mL, 0.4 mol) and sulfuric acid (1.75 mL, 0.0328 mol) were added to a 100 mL round-bottomed flask fitted with a Dean Stark trap and reflux condenser. The reaction mixture was heated with stirring under nitrogen to reflux and maintained at reflux for 5 hours. The reaction mixture was concentrated to about half volume diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and dried over sodium sulfate. Concentration yielded a straw colored oil (5.68 g, 93%), which was used in the next step without further purification.
With sulfuric acid; for 8h;Reflux;
The 4-fluoro-3-nitrobenzoic acid (5 g, 27 mmol) in ethanol (50 mL) and concentrated H2SO4 (2 mL) were heated under reflux for 8 h. Based on evidence from TLC, after completion of reaction the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and the product was separated by using vacuum filtration to yield Ethyl-4-fluoro-3-nitrobenzoate [23, 24].
With sulfuric acid; for 8h;Reflux;
The 4-fluoro-3-nitrobenzoic acid (5 g, 27 mmol) in ethanol (50 mL) and concentrated H2SO4 (2 mL) were heated under reflux for 8 h. Based on evidence from TLC, after completion of reaction the solvent was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and the product was separated by using vacuum filtration to yield Ethyl-4-fluoro-3-nitrobenzoate [23, 24].
With sulfuric acid; at 65℃; for 6h;
4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (lOmL) by refluxing at 65 C for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (II) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with benzaldehyde (0.3mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (lOmL), washed with 10% sodium carbonate (2OmL) and water (2OmL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography(silica gel, 70-230 mesh; CHC13-MeOH 9:1) to obtain the final products (70-90%). The synthetic scheme for this compound is shown in Figure 1.
With sulfuric acid; for 8h;
4-Fluoro-3-nitrobenzoic acid (5 g, 27 mmol) was refluxed in ethanol (50 mL) and concentrated H2SO4 (2mL) for 8 hours. After completion of reaction (as evident from TLC), the solvent was evaporated underreduced pressure. The aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic layer wasdried over Na2SO4 and concentrated under reduced pressure to yield 1 as cream-coloured powder.
With sulfuric acid; at 65℃; for 6h;
P reparation of ethyl 2-phenyl-1 H-benzo[d]imidazole-5-carboxylate 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (10mL) by refluxing at 65 eC for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (Pi) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with benzaldehyde (0.3 mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (10mL), washed with 10% sodium carbonate (20mL) and water (20mL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, 70- 230 mesh; C HC I3-MeOH 9:1 ) to obtain the final products (70-90%).
With sulfuric acid; for 6h;Reflux;
The synthetic scheme of 5 utilized a facile and efficient sequential one-pot protocol (Scheme 1) in mild reaction conditions, similar to the published method in the previous report [7]. One major advantage of this synthesis is that it does not require any purification steps prior to obtaining the final product 5. Apart from that, expensive catalysts were also not needed during the course of the reaction making it highly scalable. Briefly, 4-fluoro-3-nitrobenzoic acid 1, was esterified in the presence of catalytic sulfuric acid in ethanol by refluxing for 6 h to afford ethyl 4-fluoro-3-nitrobenzoate 2. Ammonium formate was subsequently added into the solution, and the mixture stirred at room temperature for 0.5 h. The resultant intermediate, ethyl 4-amino-3-nitrobenzoate 3, was then reduced to ethyl 3,4-diaminobenzoate 4 using stannous chloride. Cyclization of intermediate 4 with 4-anisaldehyde and catalytic amounts of sodium metabisulfite proceeded in a fast and smooth manner to afford final compound 5 in good yield (90%). Recrystallization of crude product 5 in ethyl acetate yielded light brown crystals, which are suitable for X-ray crystallographic analysis.
With potassium carbonate; In acetone; for 6h;Heating / reflux;
A mixture of 4-fluoro-3-nitrobenzoic acid (10 g, 54 mmol), diethyl sulfate (8.5 mL) and potassium carbonate (10 g) in anhydrous acetone (120 [ML)] was heated to reflux for 6 h. The reaction mixture was then filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound (11.2 g) as a yellow oil. 1H NMR [(CDCL3)] [5] 8.64 (dd, 1H), 8.32 (m, 1H), 7.38 (t, 1H), 4.44 (q, 2H), 1.40 (t, [3H).]
With potassium carbonate; In acetone; for 6h;Heating / reflux;
EXAMPLE 13; Preparation of N [5- (4, 5-dihydro-2-oxazolyl)-2-fluorophenyl]-3- (1, 1-dimethylethyl) -1-ethyl- lH-pyrazole-5-carboxamide (Compound 31); Step A: Preparation of ethyl 4-fluoro-3-nitrobenzoate; A mixture of 4-fluoro-3-nitrobenzoic acid (10 g, 54 mmol), diethyl sulfate (8.5 mL) and potassium carbonate (10 g) in anhydrous acetone (120 mL) was heated to reflux for 6 h. The reaction mixture was then filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound (11.2 g) as a yellow oil. 1H NMR (CDC13) 8 8.64 (dd, 1H), 8.32 (m, 1H), 7.38 (t, 1H), 4.44 (q, 2H), 1.40 (t, 3H).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
[4-FLUORO-3-NITROBENZOIC] acid (3.00 g, 16.2 mmoles) was dissolved in dichloromethane (100 mL) and cooled in an ice bath to [0-5 C. EDC] (3.73 g, 19.5 mmoles) was added followed by dropwise addition of methylamine solution (8.1 mL, 16.2 mmoles, 2.0 M solution in THF). The mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was then diluted with ethyl acetate and washed successively with [1] M HC1, saturated aqueous [NAHCO3] and brine. The organic extracts were dried over [MGS04,] filtered and concentrated in vacuo to leave [4-FLUORO-3-NITRO-N-] methylbenzamide as a yellow solid (2.94 g, [91%)] which was used directly in the next step.
PREPARATION 14-fluoro-/V-methyl-3-nitrobenzamideOxalyl chloride (7.09 mL, 81 mmol,) was dissolved in dichloromethane (DCM) (100 mL) under nitrogen and cooled in an ice/brine bath. A/JV-dimethylformamide (DMF) (0.42 mL, 5.4 mmol) was added dropwise and the mixture was stirred cooled for 10 minutes. Then 4-fluoro-3-nitrobenzoic acid (10.0 g, 54.0 mmol) was added slowly and reaction mixture was stirred cooled for 30 minutes. Methyl amine solution (135 mL, 270 mmol, 2M in THF) was added and reaction mixture was stirred at room temperature overnight. Reaction was diluted with satd. NaHC03 and more DCM, layers were separated and organics were dried over sodium sulfate. Organics were concentrated to give a solid which was triturated in diethyl ether, filtered and dried to give the title compound as a bright orange/yellow solid (9.72 g, 82%, >90% pure). 1H NMR (400 MHz, CHLOROFORM-d) delta 8.48 (dd, J = 2.27, 7.07 Hz, 1 H), 8.15 (m, 1 H), 7.41 (dd, J = 8.72, 10.23 Hz, 1 H), 6.34 (br. s., 1 H), 3.07 (d, J = 3.79 Hz, 3H); MS (m/z) 198.9 M+.
5-Chloro-4-methylpyridine-2. 3-diamine (Example 249b) (1.47 g, 9 mmol) and 4-fluoro-3- nitrobenzoic acid (1.73 g, 9 mmol) were mixed in phosphorous oxychloride (50 ml) and heated to [110 C] for 64 h. When cool, the excess phosphorous oxychloride was removed in vacuo to afford a brown semi-solid (about 4 g) consisting of [6-CHLORO-2- (4-FLUORO-3-] nitrophenyl)-7-methyl-3H-imidazo [4, [5-B]] pyridine and various inorganic material. To 1.0 g of this crude material, [(2-MORPHOLIN-4-YLETHYL)] amine (2 ml) was added and the mixture heated in the microwave oven [(180 C,] 20 min). The reaction mixture was diluted with DMF and subjected to semi-preparative [HPLC-C18] affording the product as a TFA salt. The salt was dissolved in EtOAc (10 ml) and washed with aqueous 10% NaHCO3 solution (5 [ML),] brine (5 ml) and dried [(MGS04).] Evaporation of the solvent yielded the product (using these conditions the nitro group was reduced and no trace of the nitro compound could be isolated) as an off-white powder (34 mg, [39%).] APCI-MS m/z 387. 3,389. 3 [MH+]. 1H-NMR (300 MHz, DMSO-d6) : [6] 13. 10 (s, 1H), 8.14 (s, [1H),] 7.50 (s, 1H), 7.42 (d, [J] 8.4Hz, 1H), 6.54 (d, [J] 8.2Hz, [I H),] 5.00 (s, [1H),] 4.76 (s, 2H), 3.60 (t, [J 4.] 6Hz, 4H), 3.28- 3.22 [(M,] 2H), 2.62-2. 53 (m, 5H), 2.45 (t, J 4. 4Hz, 4H).
With boron trifluoride diethyl etherate; In diethyl ether; at 20℃;Inert atmosphere;
4-Fluoro-3-nitrobenzoic acid (5.O g, 27.0 mmol) was dissolved in diethyl ether (70 mL) followed by addition of tert-butyl 2,2,2-trichloroacetimidate (6.05 ml, 32.4 mmol). BF3 OEt2 (0.137 mL, 1.08 mmol) was added dropwise via syringe, and the contents were stirred at room temperature overnight. Solid NaHCO3 (1.5 g) was added, and the mixture was stirred for an additional 30 min. The reaction mixture was diluted with ether, and the contents then concentrated in vacuo to dryness. The crude residue was purified by silica gel chromatography (eluent: 5-10% EtOAc in hexanes) to afford the product as an oil which solidifies on hi-vacuum drying (3.78 g, 58%). LC-MS (ES) m/z = 185.5 (M - t-butyl)+ 1H NMR (400 MHz, DMSO-d6) delta 8.51 (dd, J=I.3, 2.0 Hz, IH), 8.28 (ddd, J=8.6, 4.29, 2.3 Hz, IH), 7.73 (dd, J=I L l, 8.8 Hz, IH), 1.59 (s, 9 H).
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 3h;
To a solution of 4-fluoro-3-nitrobenzoic acid (185 mg, 1.00 mmol) in DMSO (2 mL) was added ethyl-3-amino-3-phenylpropanoate (231 mg, 1.20 mmol) and potassium carbonate (166 mg, 1.20 mmol). The suspension was heated to 100 C. for 3 hours, cooled to room temperature and diluted with water. The solution was partitioned between ethyl acetate and dilute hydrochloric acid (2N), and the aqueous phase separated, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluding with a mixture of dichloromethane and methanol (96:4) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.19 min, MH+ 359].
Method B: A 1M solution of borane-tetrahydrofuran (67 ml, 67 mmol) was added dropwise to a solution of 4-fluoro-3-nitrobenzoic acid (5.0 g, 27.0 mmol) in tetrahydrofuran (50 ml) under ice-cooling, and the mixture was stirred at 70 C. for 2 hours. Water (10 ml) was added to the reaction solution under ice-cooling to stop the reaction, and the solvent was distilled off. Water (100 ml) was added to the residue, the mixture was extracted with ethyl acetate (100 ml) 2 times. The extract was washed with 1N hydrochloric acid and an aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, and the solvent was distilled off under the reduced pressure. The residue was purified by silica gel column chromatography [eluent:hexane-ethyl acetate=4:1, then 2:1] to obtain 4-fluoro-3-nitrobenzyl alcohol (4.5 g, 97%) as a colorless oil. 1H-NMR (CDCl3) delta: 2.05 (1H, t, J=5.6 Hz), 4.78 (2H, d, J=5.6 Hz), 7.30 (1H, dd, J=10.6, 8.8 Hz), 7.60-7.75 (1H, m), 8.09 (1H, dd, J=6.6, 2.2 Hz).
EXAMPLE 1; -V-(Pyridin-3-ylmethyl')-l-(4-f[4-(trifluoro-nethoxy'>benzylloxy)phenylVl/r-benzotriazole-5- carboxamide; 4-[4-(Benzyloxy)phenyl]amino}-3-nitrobenzoic acid; [88] A solution of 4-fluoro-3-nitrobenzoic acid (10.Og, 54.0mmol), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (12.7g, 54.0mmol) and Et3N (7.5mL, 54.0mmol) in EtOH (54mL) was heated at reflux under N2 overnight. The reaction was then cooled to rt and acidified with aq HCl (4mL, few drops) to afford 4- [4-(benzyloxy)phenyl]amino}-3-nitrobenzoic acid as a red solid which was collected by filtration.
A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature.
<strong>[111-95-5]Bis(2-methoxyethyl)amine</strong> (Aldrich B4, 820-7; 1.6 g; 12 mmol; 3 eq.) was added to a solution of 4-fluoro-3-nitrobenzoic acid (740 mg; 4 mmol; 1 eq.) in EtOH (20 ml.) and the resulting mixture was stirred at room temperature for 2 hours then at 7O0C for 20 hours. The solution was concentrated in vacuo and the residue was partitionned between NaOH 0.5M and Et2O. The aqueous layer was acidified to pH 2 with HCI 5M, extracted with ethyl acetate (3X) and the combined organic phase was dried over magnesium sulfate. After evaporation of the solvent, the residue was crystallised from ethyl acetate/n-pentane to afford the title compound (1.12 g, 94%) as a yellow solid. 1H NMR (DMSO-de, 300 MHz) delta 12.95 (s, 1 H), 8.17 (d, J = 2.2 Hz, 1 H), 7.93 (dd, J = 8.9, 2.2 Hz, 1 H), 7.39 (d, J = 8.9 Hz, 1 H) 3.50-3.36 (m, 8H), 3.18 (s, 6H).
To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in t- butanol (2.5 L), DMAP (13.18 g, 108.04 mmol) and di tert-butyl dicarbonate (248 mL, 1080.4 mmol) were added and the reaction mixture was heated at 40C overnight. Upon completion, the reaction mixture was diluted with FLO and the aqueous phase was extracted with EtOAc (3 x 1.5 L). The combined organic layer was washed further with H20 (lx 1L), brine (lx 1L), and dried over Na2S04. The solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (100-200 mesh size S1O2 gel, eluting with a gradient of 100% Hex to 5% EtOAc in Hex) affording pure ter?-butyl-4-fluoro-3-nitrobenzoate (70 g, 54%) as light yellow solid.
54%
With dmap; In tert-butyl alcohol; at 40℃;
To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in tbutanol (2.5 L), DMAP (13.18 g, 108.04 mmol) and di tert-butyl dicarbonate (248 mL, 1080.4 mmol) were added and the reaction mixture was heated at 40C overnight. Upon completion, the reaction mixture was diluted with H20 and the aqueous phase was extracted with EtOAc (3 x 1.5 L). The combined organic layer was washed further with H20 (lx 1L), brine (lx 1L), and dried over Na2SO4. Thesolvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (100-200 mesh size Si02 gel, eluting with a gradient of 100% hexane to 5% EtOAc in hexane) affording pure tertbutyl-4-fluoro-3-nitrobenzoate (70 g, 54%) as light yellow solid.
54%
With dmap; In tert-butyl alcohol; at 40℃;
To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in /-butanol (2.5 L), DMAP (13.18 g, 108.04 mmol) and di tert-butyl dicarbonate (248 mL, 1080.4 mmol) were added and the reaction mixture was heated at 40C overnight. Upon completion, the reaction mixture was diluted with H2O and the aqueous phase was extracted with EtOAc (3 x 1.5 L). The combined organic layer was washed further with H2O (lx 1L), brine (lx 1L), and dried over Na2SC>4. The solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (100-200 mesh size S1O2 gel, eluting with a gradient of 100% Hex to 5% EtOAc in Hex) affording pure tert- butyl - 4-fluoro-3-nitrobenzoate (70 g, 54%) as light yellow solid.
49.8%
With dmap; In tert-butyl alcohol; for 24h;
To a solution of 4-fluoro-3-nitro benzoic aicd (370 mg, 2 mmol) in 10 mL of t-BuOH were added (BoC)2O (872 mg, 4 mmol) and DMAP (24 mg, 0.2 mmol). The solution was stirred for 24 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with IN HCl. The separated organic phase was evaporated. The residue was subjected to a flash column chromatography on silica gel eluting with 12.5% EtOAc/Petroleum ether to give compound 0201 (240mg, 49.8%). 1H NMR (DMSO-J6): delta 1.55 (s, 9H), 7.69 (m, IH), 8.26 (m, IH), 8.48 (m, IH).
43%
With dmap; In tetrahydrofuran; at 20℃; for 24h;
To a solution of 4-fluoro-3-nitro benzoic aicd (33) (5 g, 27 mmol) in 30 mL ofTHF were added (Boc)2O (6.25 mL, 54 mmol) and DMAP (329 mg, 2.7 mmol). Thesolution was stirred at room temperature for 24 h. The solvent was evaporated. Theresidue was dissolved in ethyl acetate and washed with 1 N HCl. The separatedorganic phase was evaporated. The residue was subjected to a flash columnchromatography on silica gel eluting to give tert-butyl 4-fluoro-3-nitrobenzoate (34)(2.24 g, 43% yield).
To a 2L high pressure vessel were added 4-fluoro-3-nitrobenzoic acid (25 g, 135 mmol), dimethylformamide di-t-butylacetal (162 ml, 675 mmol), and toluene (200 ml). The vessel was sealed and heated to 1000C for 20 hours. The mixture was cooled to ambient temperature. The mixture was transferred to 100 mL of EtOAc and 100 ml of IN HCl and the layers were separated. The organic layer was washed with IN HCl, water, and brine, dried over MgSO4, filtered through a medium frit filter, and concentrated. The crude was purified on silica gel (EtOAc in hexanes gradient) to provide 5. Ig of the title compound were obtained as light yellow solid (16%).
With potassium dichromate; sulfuric acid; acetic acid;Reflux;
EXAMPLE 82 4-cyclopropyl-3,4-dihydro-7-phenylaminocarbonyl-2H-1,2,4-benzothiadiazine 1,1-dioxideStep A: 4-fluoro-N-phenyl-3-sulphamoylbenzamideThe expected product is obtained in 4 steps, starting from <strong>[446-11-7]4-fluoro-3-nitrotoluene</strong>. The <strong>[446-11-7]4-fluoro-3-nitrotoluene</strong> (6.5 mmol) is added in small portions to a solution of potassium dichromate (4 g) in glacial acetic acid (10 mL). After stirring for 15 minutes, sulphuric acid (4 mL) is added and the solution is heated at reflux for 2 hours. The mixture is then cooled, water (100 mL) is added and extraction with ethyl acetate (3.x.100 mL) is carried out. The organic phases are collected, dried over anhydrous MgSO4 and evaporated. The residue is recrystallised from an ethyl acetate/hexane (1/1) mixture and used in the next step.
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; acetonitrile; at 0 - 20℃; for 4h;
To a solution of4(1.0 g, 5.4 mmol) in 4:1 CH3CN/DMF (20 ml/ 5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.7 g, 10.8 mmol) and HOBt-NH3(1.6 g, 10.8 mmol) at 0oC. After stirring at rt for 4 h, the mixture was diluted with distilled water and extracted three times with EtOAc. The combined organic layers were washed with sat?d aq. NaHCO3solution and brine, dried over MgSO4, and concentrated under reduced pressure to give a crude product which was purified by column chromatography (SiO2, Hexane:EtOAc = 1:3) to give 4-fluoro-3-nitrobenzamide (960 mg, 5.2 mmol, 97% yield) as a yellow powder;1H NMR (400 MHz, CD3OD) delta (ppm) 8.64 (dd,J= 7.1, 2.3 Hz, 1H), 8.23 - 8.27 (m, 1H), 7.53 (dd,J= 10.7, 8.7 Hz, 1H).A solution of 4-fluoro-3-nitrobenzamide obtained above (50 mg, 1.3 mmol) ini-PrOH (5 ml) was treated with DIPEA (0.14 ml, 3.8 mmol) and 2-aminoethanol (0.05 ml, 3.8 mmol). After stirring at 90oC for 5 h, solvent was removed under reduced pressure to give a crude product which was purified by column chromatography (SiO2, CH2Cl2:MeOH:NH4OH:H2O = 80:20:1:1) to give5aas a yellow powder (50 mg, 0.21 mmol, 79% yield)
96%
A mixture of 4-fluoro-3-nitrobenzoic acid (10 g, 54.0 mmcl) in thionyl chloride (30 mL was stirred at 80 C for 2 hr, then the mixture was concentrated. The residue was dissolved in dry dichloromethane (DCM) (100 mL), cooled to 0 C, and a solution of ammonia in dry THEwas added dropwise at 0 C. The reaction mixture was stirred at 0 C for 1 h then water (50mL) was added and the solid was isolated by filtration, washed with Et20 and dried in vacua to give 4-fluoro-3-nitrobenzamide (9.5 g, 51.6 mmol, 96 % yield) as a yellow solid. LCMS (LCMS Method A): Rt = 1.259 mi [M+H] = 185.0
Intermediate 5: Step a 4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.
Intermediate 14: Step a4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.
Intermediate 13: Step a 4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.
Intermediate 23: Step a 4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.
With N-Bromosuccinimide; sulfuric acid; at 65.0℃; for 5.0h;
A mixture of 4-fluoro-3-nitrobenzoic acid (2-43, 2.5 g, 13.5 mmol) and NBS (2.4 g, 13.5 mmol) in 98% H2S04 (5 mL) was stirred at 65 C for 5 h. Upon reaction completion, water (25 mL) was added and the resulting mixture was filtered and the solid was collected. The solid obtained was dried to provide intermediate 2-44 (white solid, 2.8 g, 80% yield). LCMS (m/z): 262 [M - Hj -.
With N-Bromosuccinimide; sulfuric acid; at 65.0℃; for 5.0h;
NBS (47.9 g, 0.268 mol) was added portion-wise to a solution of 4-fluoro-3-nitro-benzoic acid (41.5 g, 0.224 mol) in cone. H2S04 (0.35 L). The reaction mixture was stirred for 5 h at 65C and then poured into ice-water (1.5 L). The precipitate was filtered off, washed twice with water (300 mL) and dried to give the title compound as a white solid. 1 H-NMR (300 MHz, CDCI3): delta (ppm) 10.7 (s, br, 1 H), 8.76 (m, 1 H), 8.62 (m, 1 H).
With N-Bromosuccinimide; sulfuric acid; at 60.0℃; for 6.0h;
To a solution of 4-fluoro-3-nitrobenzoic acid (24a, 5 g, 27.01 mmol) in H2SO4 (30 mL) was added NBS (5.77 g, 32.41 mmol). The mixture was stirred at 60 C. for 6 hr. The mixture was added to ice-water (2 L) drop-wise with vigorous stirring. The precipitate was filtered to afford 24b as a white solid. 1H NMR (400 MHz, CDCl3-d) delta 8.72 (dd, J=2.2, 6.4 Hz, 1H), 8.58 (dd, J=2.2, 5.5 Hz, 1H).
Step 2Synthesis of methyl 4-(2-methoxy-2-oxo-1-phenylethylamino)-3-nitrobenzoateA solution of methyl 2-amino-2-phenylacetate hydrochloride (2.5 g, 12.38 mmol, 1.00 equiv) in DMF (30 mL), methyl 4-fluoro-3-nitrobenzoate (5 g, 25.13 mmol, 2.00 equiv), and DIEA (5 g, 38.76 mmol, 3.13 equiv) was reacted overnight at 30 C. in a 100-mL round-bottom flask. The reaction was then quenched by the addition of 200 mL of water, and the solids were collected by filtration. Purification via silica gel column (petroleum ether/EtOAc (50:1)) yielded 3.82 g (90%) of methyl 4-(2-methoxy-2-oxo-1-phenylethylamino)-3-nitrobenzoate as a yellow solid. LC-MS (ES, m/z): 345 [M+H]+.
EXAMPLE 107 (S)-3-[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-5-methyl-hexanoic acid [1848] (S)-3-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-methyl-hexanoic acid, 173 mg of DIC, and 14 mg of DMAP were added in DMF in a 20 ml scintillation bottle. The reaction was kept at rt for 18 h. To deprotect the Fmoc-group 50% Piperidine in DMF was added and the reaction was kept for 30 min at rt. Afterwards the resin was washed thoroughly with DMF. For the amide formation the resin was reacted with 217 mg 4-Fluoro-3-nitrobenzoic acid, 185 mg HOBt, and 173 mg DIC in DMF for 18 h at rt. In the next step nucleophilic substitution was achieved by reacting the resin with 680 mg of 1-Ethyl-propylamine in DMF at it for 24 h. Subsequently, the reduction of the nitro group took place by reaction with 10 ml of 1M SnCl2 in DMF at rt for 23 h. Then, to the resin in dry DMF were added 139 mg 2-thienyl acetic acid, 371 mg of HATU and 250 mg of DIPEA and the reaction was left at it for 4 h to achieve amide formation. The cleavage from the resin took place by reaction with 3 ml of 95% aqueous TFA for 2 hrs. Then additional 2 ml of aqueous of 95% TFA, 3 ml of acetonitrile and 3 ml water were added and the cleavage solution was heated to 60 C. for 24 h. After filtration the solvents were removed and the resulting residue was purified by HPLC to afford 37 mg (8%) of (S)-3-[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-5-methyl-hexanoic acid. [1850] C25H33N3O3S (455.62), LCMS (method 6-1-1): Rt=1.62 min, m/z=456.40 [M+H]+
To 300 mg of Wang resin (NovaBioChem 70-90 mesh, loading capacity 1 .3 mmol/g), 430 mg of (S)-3-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-methyl-hexanoic acid, 173 mg of DIC, and 14 mg of DMAP were added in DMF in a 20 ml scintillation bottle. The reaction was kept at rt for 18 h. To deprotect the Fmoc-group 50% Piperidine in DMF was added and the reaction was kept for 30 min at rt. Afterwards the resin was washed thoroughly with DMF. For the amide formation the resin was reacted with 217 mg 4-Fluoro-3-nitrobenzoic acid, 185 mg HOBt, and 173 mg DIC in DMF for 18 h at rt. In the next step nudeophilic substitution was achieved by reacting the resin with 680mg of 1 -Ethyl-propylamine in DMF at rt for 24 h. Subsequently, the reduction of the nitro group took place by reaction with 10 ml of 1 M SnCI2 in DMF at rt for 23 h. Then, to the resin in dry DMF were added 139 mg 2-thienyl acetic acid, 371 mg of HATU and 250 mg of DIPEA and the reaction was left at rt for 4 h to achieve amide formation. The cleavage from the resin took place by reaction with 3 ml of 95% aqueous TFA for 2 hrs. Then additional 2 ml of aqueous of 95% TFA, 3 ml of acetonitrile and 3 ml water were added and the cleavage solution was heated to 60C for 24 h. After filtration the solvents were removed and the resulting residue was purified by HPLC to afford 37 mg (8%) of (S)-3-[1 -(1 -Ethyl-propyl)-2-thiophen-2- ylmethyl-1 H-benzoimidazole-5-carbonyl]-amino}-5-methyl-hexanoic acid. C25H33N3O3S (455.62), LCMS (method 6_1_1 ): Rt = 1 .62 min, m/z= 456.40 [M+H]+
4-Fluoro-3-nitro-benzoic acid (2.0g, 10.8mmol) was dissolved in ethanol (100ml), and benzyl amine (1.3ml, 11.9mmol) was added thereto. The mixture was stirred at 100 for 3 hours and then distilled under reduced pressure. [1446] The obtained compound was dissolved in tetrahydrofuran (100ml) and 0.25M solution of diazomethane in diethyl ether (48ml, 11.9mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 30 minutes and then distilled under reduced pressure to obtain the title compound (1.8g, 58%).
With potassium hydroxide In water at 60℃; for 15h;
1
Compound 4 (25 g) was added in portions to water (170 ml) KOH (31.8 g) solution, after its dissolution compound 3 (30 g) was added and the resultant mixture was stirred at 60° C for 15 h. Then the reaction mixture was cooled, acidified with HCl (10%) to pH=3, filtered, washed with water and dried. It gave compound 5, yield 70%. Compound 5 (50 g) was dissolved in aqueous ammonia (500 ml) and dithionite (80 g) was added in portions, after that the reaction mixture was refluxed for 1 h, cooled, ammonia was evaporated on rotary evaporator, and water solution was acidified with conc. HCl to pH=1, stirred for 1 h, the solid was filtered off, washed with water and dried. It gave compound 6, yield 60%. Compound 6 (45 g) was added in portions to polyphosphoric acid (200 ml) at 50°C, then the reaction mixture was stirred for 10 h at 90 °C, cooled and poured out on ice (500 ml), the solid was filtered off, washed with water and dried. It gave compound 7, yield 60%. Compound 7 (30 g) was dissolved in acetic acid (500 ml), 33% hydrogen peroxide (70 ml) was added, stirring was continued for night at 70°C. After cooling acetic acid was evaporated on rotary evaporator and water (600 ml) was added to the residue. The precipitated solid was filtered off, washed with water and dried. It gave compound 8, yield 70%. To a solution of compound 8 (22 g) in ethanol (300 ml) thionyl chloride (8 ml) was dropped at 10°C, then the mixture was refluxed for 5 h, cooled, evaporated on rotary evaporator, after that water (300 ml) was added. The precipitated solid was filtered off, washed with water and dried. It gave compound 9, yield 90%. To a solution of compound 9 (8.2 g) in DMF (80 ml) were added in turn potassium carbonate (7 g) and m-chlorobenzyl chloride (5.2 g). The reaction mixture was stirred for night at 50°C, evaporated on rotary evaporator, water (200 ml) was added to the residue. The precipitated solid was filtered off, washed with water and dried. It gave compound 10, yield 90%. To a solution of compound 10 (11 g) in 50% water ethanol (150 ml) KOH (2.7 g) was added, the resultant mixture was stirred at room temperature for night. Then ethanol was evaporated on rotary evaporator, water solution was acidified with 10% HCl to pH=3. The precipitated solid was filtered off, washed with water and dried. It gave compound 11, yield 80%. To a solution of compound 11 (1.8 g) in THF (50 ml) at stirring in argon atmosphere N-hydroxysuccinimide (0.48 g) and dicyclohexylcarbodiimide (0.87g) were added. The reaction mixture was stirred for night at room temperature, the precipitated solid was filtered off, mother liquor was evaporated, the residue was purified by flash chromatography on silica (eluent-ethyl acetate). It gave compound 1(1), yield 50%. NMR Spectrum of compound 1(1) is given on Fig.1.
N-((1-ethylpyrrolidin-2-yl)methyl)-4-fluoro-3-nitrobenzamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
General procedure: A 50 mL oven-dried flask was charged with the carboxylic acid (30.0 mmol, 1 eq)and thionyl chloride (7.5 mL) and heated to reflux. After 4 h, the resulting homogeneousmixture was concentrated to dryness under reduced pressure. The residue obtained was thendissolved in dry toluene or dichloromethane (5 mL) and the solvent was evaporated. Thisprocess was repeated twice yielding the acyl chloride. Dry dichloromethane (20 mL) and 4-dimethylaminopyridine (0.1 mol%) were introduced and the flask was cooled to 0 C. Asolution of the amine (1 eq) in dry dichloromethane (10 mL) was added dropwise over 15mm and the resulting solution was slowly warmed to room temperature. After 3 h, asuspension was obtained and the solid was filtered, washed with diethyl ether (3 x 20 mL)and dried under high vacuum to yield the pure product.Following the general procedure B-3 using 4-fluoro-3-nitrobenzoic acid and 2-(aminomethyl)-1-ethylpyrrolidine. White solid (89%). ?H NMR (400 MHz, DMSO-d6)10.7 1 (bs, 1H), 9.50 (t, J = 5.6 Hz, 1H), 8.69 (dd, J = 7.3, 2.2 Hz, 1H), 8.43 (ddd, J = 8.7, 4.1,2.3 Hz, 1H), 7.74 (dd, J= 11.1, 8.8 Hz, 1H), 3.89-3.78 (m, 1H), 3.71-3.60 (m, 2H), 3.55 (dq,J = 12.1, 5.6 Hz, 1H), 3.50-3.36 (m, 1H), 3.13-3.02 (m, 2H), 2.17-2.06 (m, 1H), 2.03-1.74(m, 3H), 1.30 (t, J = 7.2 Hz, 3H). ?3C NMR (100 MHz, DMSO-d6) 163.8, 156.4 (d, JCF =266.4 Hz), 136.7 (d, JCF = 7.8 Hz), 135.1 (d, JCF = 10.1 Hz), 130.5 (d, JCF = 3.6 Hz), 125.6(d, JCF= 2.0 Hz), 118.9 (d, JCF= 21.4 Hz), 65.9, 52.6, 48.5, 38.9, 27.1, 21.7, 10.2. JR (thinfilm): 3249, 3058, 2946, 2655, 2508, 1655, 1618, 1534, 1492, 1352, 1316, 1269 cnf?. mp:161 C.
With triethylamine; In ethanol; at 78℃; for 10.5h;Inert atmosphere; Large scale;
To the reaction vessel, in a stream of nitrogen, 4-fluoro-3-nitro-benzoic acid (990g), ethanol (4950g), 4- amino tetrahydropyran -2H- pyran hydrochloride (920g) was added, dropwise triethylamine (2190g). The reaction mixture was stirred for 10.5 hours at 78 . After cooling the reaction mixture to room temperature, water (14.85kg) was added and dropped 20percent hydrochloric acid (3221g). After a while stirring, the resulting solid filtered, washed with water (9.9 kg), under reduced pressure circulation drying at 55 ° C., to give the title compound (1374g).
1374 g
With triethylamine; In ethanol; at 78℃; for 10.5h;Large scale;
In a reaction vessel, 4-fluoro-3-nitrobenzoic acid (990 g),Ethanol (4950 g), 4-aminotetrahydro-2H-pyran hydrochloride (920 g) was added and triethylamine (2190 g) was added dropwise.The reaction solution was stirred at 78 ° C. for 10.5 hours. After cooling the reaction mixture to room temperature, water (14.85 kg) was added and 20percent hydrochloric acid (3221 g) was added dropwise.After stirring for a while, the obtained solid was filtered, washed with water (9.9 kg)And dried under reduced pressure at 55 ° C. to give the title compound (1374 g).
To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in t15 butanol (2.5 L), DMAP (13.18 g, 108.04 mrnol) and di tert-butyl dicarbonate (248mL, 1080.4 rnmoi) were added and the reaction mixture was heated at 40 C overnight. On completion, the reaction mixture was diluted with waler and the aqueous phase was extracted with ethyl acetate (3 x 1.5 L). The combined organic layer was washed further with water (ix iL), brine (ix IL) and dried over sodiumsulfate. The solvent was removed under reduced pressure and the crude matemial thus obtained was purified by column chromatography (100-200 mesh size silica gel, eluting with a gradient of 100% hexanes to 5% Ethyl acetate in hexanes) affording pure tert-butyl-4-fluoro-3-nitrobenzoate (7() g, 54%) as light yellow solid. Rf: 0.5 in 5% ethyl acetate in hexane.
General procedure: In a 50 mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser and a calcium chloride drying tube was placed nicotinic acid (1 g, 8.1 mmol) suspended in boron trifluoride etherate (10 mL). The reaction mixture was stirred and heated to 120 C overnight during which the creamy reaction mixture changed into a brownish solution. Thin layer chromatography (hexane/ethyl acetate 3:1) revealed complete reaction. The cooled reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extract was washed to the end of effervescence with a saturated solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo giving a crude yield of 1.11 g (92%).
4-((4-methoxybenzyl)thio)-3-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium hydroxide In ethanol; water at 20℃; Inert atmosphere;
3.4. General Procedure 1 for the Synthesis of (4-Methoxybenzyl)(2-Nitrophenyl)sulfanes (1b-1r)
General procedure: The following description is for a 30 mmol scale reaction. The solvent quantities andflask size were adjusted accordingly for smaller-scale reactions.A 500 mL round-bottomed flask equipped with a stir bar was loaded with the 1-fluoro-2-nitrobenzene derivative (1 equiv.) and 200 mL of ethanol and placed under anatmosphere of argon. (4-methoxyphenyl)methanethiol (1 equiv.) was added with a syringe,followed by a dropwise addition of NaOH (1 equiv.) dissolved in 10 mL of H2O. Thereaction mixture was stirred at room temperature until TLC indicated the completion ofthe reaction (typically within 2 h). After removing the solvent under reduced pressure,the residue was diluted with 150 mL of H2O and extracted twice with dichloromethane.The organic phases were combined, dried over MgSO4, filtered, and concentrated. Theresulting crude product was purified by recrystallization or column chromatography asdescribed below.
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