* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iron(III) chloride; sodium hydroxide; hydrazine In water; isopropyl alcohol at 75℃; for 2 h;
2) To 4-bromo-2-nitrobenzoic acid (1.80 g, 7.83 mmol) were added 0.88N aqueous sodium hydroxide solution (10 ML), iron(III) chloride (133 mg) and isopropyl alcohol (0.7 ML) and the mixture heated to 75° C. While stirring the mixture, hydrazine (1.1 ML) was slowly added, and the mixture was reacted at 75° C. for 2 hrs.The reaction mixture was filtered and the filtrate was concentrated.The precipitated solid was washed with water to give 4-bromoanthranilic acid (1.73 g, 96percent). 1H NMR (DMSO-d6) δ ppm: 6.62 (dd, J=1.5, 8.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H).
58%
With hydrogen In tetrahydrofuran; ethanol for 66.5 h;
EXAMPLE 14 7-(3-Amino-propyl)-3H-quinazolin-4-one14A. 2-Amino-4-bromo-benzoic acid; 4-Bromo-2-nitro-benzoic acid (0.5g, 2.03 mmol) (Matrix, 009241) was dissolved in a 1 : 1 mixture of ethanol/ tetrahydrofuran (22 ml). This solution was added to 5percent platinum on carbon (0.2g, 50percent water content) under an atmosphere of nitrogen. The reaction was shaken under an atmosphere of hydrogen for 2.5 hours. A further batch of platinum on carbon was added (0.2g) and the mixture was shaken for 64 hours under an atmosphere of hydrogen. The reaction mixture was filtered, washing through with a 1 : 1 mixture of ethanol/ tetrahydrofuran. The solvent was removed under reduced pressure and the residue was purified by flash silica chromatography, eluting with methanol/ dichloromethane (2:98) to yield the title compound as a yellow solid (0.253g, 58percent). LC/MS: (PS-Al) R12.62 [M+H]+ 215.88.
Reference：
[1] Patent: US2004/116422, 2004, A1, . Location in patent: Page/Page column 31
[2] Organic Letters, 2011, vol. 13, # 19, p. 5220 - 5223
[3] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1240 - 1256
[4] Patent: WO2006/51290, 2006, A2, . Location in patent: Page/Page column 111; 144
[5] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[6] Chemische Berichte, 1912, vol. 45, p. 2078
[7] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 43, p. 204
[8] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
[9] Patent: US2004/167128, 2004, A1, . Location in patent: Page 38
[10] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 321
7
[ 99277-71-1 ]
[ 20776-50-5 ]
Reference：
[1] Patent: US2005/261307, 2005, A1,
8
[ 610-36-6 ]
[ 99277-71-1 ]
[ 162046-38-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With sodium nitrite In water; hydrogen bromide
Step 1: 4-Bromo-2-nitro-benzoic acid A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62,1240-1256. A solution of NaNO2 (1.9 g, 27.4 mmol) in water (65 mL) was added to a stirred solution of 4-amino-2-nitro-benzoic acid (1) (5 g, 27.4 mmol) in aqueous 48percent HBr (40 mL) and water (82 mL) at 0° C. The cloudy reaction mixture turned into a clear orange-yellow solution after about 15 minutes. After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) in aqueous 48percent HBr (90 mL) at 0° C. A yellow foam developed and gas was evolved from the purple-brown mixture. After stirring at 0° C. for 1 hour, the mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (4*300 mL) which was dried with Na2SO4 and concentrated to dryness giving a dark solid. The crude product was filtered through a plug of florisil (~20 g) eluding with EtOAc. The combined organic fractions were evaporated to approx. 200 mL and washed with 1 M HCl (2*50 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91percent yield and >90percent purity by HPLC.
91%
With sodium nitrite In water; hydrogen bromide
Step 1: 4-Bromo-2-nitro-benzoic Acid A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62, 1240-1256. A solution of NaNO2 (1.9 g, 27.4 mmol) in water (65 mL) was added to a stirred solution of 4-amino-2-nitro-benzoic acid (1) (5 g, 27.4 mmol) in aqueous 48percent HBr (40 mL) and water (82 mL) at 0° C. The cloudy reaction mixture turned into a clear orange-yellow solution after about 15 minutes. After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) in aqueous 48percent HBr (90 mL) at 0° C. A yellow foam developed and gas was evolved from the purple-brown mixture. After stirring at 0° C. for 1 hour, the mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (4*300 mL) which was dried with Na2SO4 and concentrated to dryness giving a dark solid. The crude product was filtered through a plug of florisil (-20 g) eluding with EtOAc. The combined organic fractions were evaporated to approx. 200 mL and washed with 1 M HCl (2*50 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91percent yield and >90percent purity by HPLC.
Stage #1: With potassium permanganate In pyridine; water at 60℃; for 32 h; Stage #2: for 0.5 h; Heating / reflux
1.1.a. 4-Bromo-2-nitro-benzoic acid To a reaction mixture of 82 g (0.379 mol) 4-bromo-2-nitro-toluene in 700 ml of pyridine and 500 ml of water are added batchwise 174.5 g (1.104 mol) of potassium permanganate within eight hours. The reaction mixture is stirred for 12 hours at 60° C. Then a further 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are added one after another. The reaction mixture is stirred for 12 hours at 60° C., combined with 200 ml of ethanol and refluxed for 30 minutes. Then the reaction mixture is filtered hot and the filtrate is evaporated down in the rotary evaporator. The residue remaining is made alkaline with 10percent sodium hydroxide solution and extracted with diethyl ether. The aqueous phase is separated off and acidified with dilute hydrochloric acid. The crystals formed are filtered off, washed with water, azeotropically dried with tetrahydrofuran and stirred with diisopropylether.
26%
With potassium permanganate; sodium carbonate In water at 105℃; Heating / reflux
Sodium carbonate (4.53 g, 42 mmol) was added to a suspension of 4-bromo-2- nitrotoluene (2.00 g, 9.26 mmol) in 140 mL of water. The mixture was heated to 80°C. Potassium permanganate (5.85 g, 37 mmol) was added and the temperature was raised to 105°C and heating was continued under a reflux condenser overnight. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was acidified with 6N aqueous HCI and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 0.59 g (26percent yield) of desired product as a beige solid.
22%
With potassium permanganate In waterHeating / reflux
A. 4-bromo-2-nitrobenzoic acid A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with water. The basic filtrate was acidified to pH1 with concentrated HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide pure benzoic acid (1.22 g, 22percent). 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). MS (ESI): neg. ion m/z 244 [M-H]-.
22%
Stage #1: With potassium permanganate In waterHeating / reflux Stage #2: With hydrogenchloride In water
A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (1 g, 70 mmol), and H2O (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with H2O. The basic filtrate was acidified to pH 1 with concentrated HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure benzoic acid (1.22 g, 22percent). MS (ESI) calculated for C7H4BrNO4, 244.9; found, m/z 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H).
22%
Heating / reflux
A. 4-Bromo-2-nitrobenzoic acid. ; A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight. The mixture was filtered through a pad of diatomaceous earth, washing with water. The basic filtrate was acidified to pH1 with conc. HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated to provide the desired benzoic acid (1.22 g, 22percent). MS (ESI-): mass calcd. for C7H4BrNO4, 244.9; m/z found, 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9, 1H), 7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6371 - 6390
[2] Patent: US2004/242572, 2004, A1, . Location in patent: Page/Page column 34
[3] Patent: WO2006/52722, 2006, A1, . Location in patent: Page/Page column 87-88
[4] Patent: US2004/224983, 2004, A1, . Location in patent: Page 13
[5] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 11
[6] Patent: US2006/69286, 2006, A1, . Location in patent: Page/Page column 29; 61
[7] Journal of the Chemical Society, 1926, p. 1803
[8] Journal of the Chemical Society, 1926, p. 1803
[9] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[10] Journal of the American Chemical Society, 1952, vol. 74, p. 5621
[11] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
[12] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6905 - 6909
[13] Patent: US2004/167128, 2004, A1, . Location in patent: Page 38
[14] Patent: US6323155, 2001, B1,
[15] Patent: US2004/157836, 2004, A1,
[16] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1287 - 1291
10
[ 610-36-6 ]
[ 99277-71-1 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1240 - 1256
[2] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 320-321
Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 72 h; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran
Step 1. Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96percent). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67 (d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).
95%
Stage #1: With borane In tetrahydrofuran at 0 - 20℃; for 48 h; Stage #2: With methanol In tetrahydrofuran at 0℃;
Example 25 Synthesis of 4-(7-( 1 -isobutyl- 1 H-pyrazol-4-yl)quinazolin-2-ylamino)-N-(3-(pyrrolidin- 1 - yl)propyl)benzenesulfonamide (Compound 709)Stepl. (4-Bromo-2-nitrophenyl)methanolTo a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M /THF, 4eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95percent yield.
Reference：
[1] Patent: US2007/191603, 2007, A1, . Location in patent: Page/Page column 40
[2] Patent: WO2007/117607, 2007, A2, . Location in patent: Page/Page column 333
[3] MedChemComm, 2018, vol. 9, # 5, p. 862 - 869
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8402 - 8416
19
[ 99277-71-1 ]
[ 59278-65-8 ]
Reference：
[1] Patent: WO2007/117607, 2007, A2,
20
[ 99277-71-1 ]
[ 112734-21-1 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 18, p. 5814 - 5819
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6905 - 6909
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6371 - 6390
[4] Patent: US2004/224983, 2004, A1, . Location in patent: Page 13
[5] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 13
[6] Patent: US2006/25460, 2006, A1, . Location in patent: Page/Page column 124
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 22, p. 6373 - 6375
[8] Patent: US2010/160314, 2010, A1, . Location in patent: Page/Page column 69
[9] Patent: WO2012/162254, 2012, A1, . Location in patent: Page/Page column 151
[10] Patent: US2013/143907, 2013, A1, . Location in patent: Paragraph 0315; 0316; 0317
[11] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 233 - 247
[12] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2488 - 2500
21
[ 99277-71-1 ]
[ 74-88-4 ]
[ 158580-57-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
Compound 7 A (10.0 g, 40.7 mmol) was dissolved in DMF (100 mL). Cs2CO3 (27.0g, 81.3 mmol) and methyl iodide (7.60 mL, 122.0 mmol) were added. The solution was stirred at room temperature overnight. EtOAc (250 mL) and water (100 mL) were added. The organic phase was separated and washed with water (100 mL) three times and brine (50 mL), then dried over Na2SO4) filtered, and concentrated using a rotary evaporator. The product was dried under vacuum to give compound 7B (10.3 g, 97percent).
94%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h;
Example I-XVIIPreparation of Compound 321General Procedure I-ESTo a mixture of 4-bromo-2-nitrobenzoic acid (10 g, 41 mmol) and K2CO3 (11.3 g, 82 mmol) in 100 mL of DMF was added CH3I (7.1 g, 50 mmol) dropwise and the mixture was stirred at 80° C. for 3 hrs. After cooling to r.t, the mixture was filtered, the filtrated was concentrated under reduced pressure to remove DMF, and the residue was dissolved with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give methyl 4-bromo-2-nitrobenzoate (I-XVIIa, 10 g, yield 94percent). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 3.92 (s, 3H).
94%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h;
To a mixture of 4-bromo-2-nitrobenzoic acid (10 g, 41 mmol, 1 eq) and K2CO3 (11.3 g, 82 mmol, 2 eq) in 100 mL of DMF was added CH3I (7.1 g, 50 mmol, 1.2 eq) dropwise and the mixture was stirred at 80 °C for 3 hrs. After cooling to rt, the mixture was filtered, the filtrated was poured into water and extracted with EtOAc (150 mL x 3), washed with water (150 mL x 3) and brine (150 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give methyl 4-bromo-2-nitrobenzoate (10 g, 94percent). 1HNMR (300 MHz, DMSO-d6): G 8.34 (s, 1H), 8.08- 8.05 (m, 1 H), 7.85- 7.82 (m, 1 H), 3.85 (s, 3 H).
90%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In DMF (N,N-dimethyl-formamide) at 0 - 20℃;
A. Methyl 2-amino-4-bromobenzoate To a stirred solution of 4-bromo-2-nitrobenzoic acid (EXAMPLE 5) (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU) (10.3 mL, 75 mmol) followed by methyl iodide (4.67 mL, 75 mmol). The reaction mixture was stirred 15 min at 0° C. then allowed to warm to room temperature and stir overnight. The mixture was poured into water and extracted with EtOAc (2*). The combined organic extracts were washed with water (2*), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90percent).
90%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 20℃;
B. Methyl 2-amino-4-bromobenzoate. ; To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by Mel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2.x.). The combined organic extracts were washed with water (2.x.), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90percent). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3.x.). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93percent). 1H NMR (400 MHz, CDCl3): 7.70(d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
90%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 20℃; for 48.25 - 72.25 h;
Example 62:; N-[7-ethyI-6-(l-methyI-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yI]- methanesulfonamide; 4-Bromo-2-nitro-benzoic acid methyl ester; To a solution of 4-bromo-2-nitrobenzoic acid (25.3 g, 103 mmol) in DMF (200 mL) at 0 0C were added DBU (79.1 mL, 514.8 mmol) and MeI (32.2 mL, 515 mmol). The reaction mixture was stirred for 15 min at this temperature and for 72 h at r.t. The mixture was poured into water and extracted with EtOAc (2X). The combined organic layers were washed with water (2X), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 7:3 hexanes:EtOAc) to provide the title compound (26.24 g, 98percent) as a yellow oil.; Example 71:; N-[7-(l,l-difluoro-ethyl)-6-(2-isopropyl-2H-pyrazol-3-yl)-2,4-dioxo-l,4-dihydro-2H- quinazolin-3-yl]-methanesulfbnamide; 4-Bromo-2-nitro-benzoic acid methyl ester; To solution of 4-bromo-2-nitro-benzoic acid (9 g, 36.58 mmol) in dimethylforrnamide (36 mL) cooled to 0 0C were added l,8-diazabicyclo[5.4.0]und-7-ene (28.09 mL, 182.9 mmol) and MeI (11.4 mL, 182.5 mmol). The reaction mixture was stirred at 0 0C for 15 min and at r.t. for 48 h. The mixture was poured into water and extracted with EtOAc (2X). The combined organic phases were washed with water (2X), dried (Na2SO4) and concentrated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to give 4-bromo-2-nitro-benzoic acid methyl ester (8.62 g, 33.147 mmol, 90percent). 1H-NMR (CDCl3, 400 MHz) 8.02 (s, 1 H), 7.81 (dd, J= 2.3, 10.5Hz IH), 7.66 (d, J= 8.2 Hz, IH), 3.92 (s, 3H).
0.9%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In DMF (N,N-dimethyl-formamide) at 0 - 20℃;
To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.8 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.0 mL, 75.0 mmol) followed by iodomethane (4.7 mL, 75 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2.x.). The combined organic extracts were washed with H2O (2.x.), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 0.90percent). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at room temperature was added SnCl2.2H2O (15 g, 67 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2.x.). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a white solid (2.89 g, 93percent). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.6, 1.9 Hz, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
With sulfuric acid In water for 16 h; Heating / reflux
Step 1. Preparation of Methyl 4-bromo-2-nitrobenzoate Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4- bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2 x 250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78percent)
Reference：
[1] Patent: WO2005/37796, 2005, A1, . Location in patent: Page/Page column 50-51
[2] Patent: EP2471792, 2012, A1, . Location in patent: Page/Page column 65
[3] Journal of the American Chemical Society, 2018, vol. 140, # 33, p. 10553 - 10561
1.1.a. 4-Bromo-2-nitro-benzoic acid To a reaction mixture of 82 g (0.379 mol) 4-bromo-2-nitro-toluene in 700 ml of pyridine and 500 ml of water are added batchwise 174.5 g (1.104 mol) of potassium permanganate within eight hours. The reaction mixture is stirred for 12 hours at 60 C. Then a further 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are added one after another. The reaction mixture is stirred for 12 hours at 60 C., combined with 200 ml of ethanol and refluxed for 30 minutes. Then the reaction mixture is filtered hot and the filtrate is evaporated down in the rotary evaporator. The residue remaining is made alkaline with 10% sodium hydroxide solution and extracted with diethyl ether. The aqueous phase is separated off and acidified with dilute hydrochloric acid. The crystals formed are filtered off, washed with water, azeotropically dried with tetrahydrofuran and stirred with diisopropylether.
26%
With potassium permanganate; sodium carbonate; In water; at 105℃;Heating / reflux;
Sodium carbonate (4.53 g, 42 mmol) was added to a suspension of 4-bromo-2- nitrotoluene (2.00 g, 9.26 mmol) in 140 mL of water. The mixture was heated to 80C. Potassium permanganate (5.85 g, 37 mmol) was added and the temperature was raised to 105C and heating was continued under a reflux condenser overnight. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was acidified with 6N aqueous HCI and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 0.59 g (26% yield) of desired product as a beige solid.
22%
With potassium permanganate; In water;Heating / reflux;
A. 4-bromo-2-nitrobenzoic acid A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with water. The basic filtrate was acidified to pH1 with concentrated HCl and extracted with EtOAc (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide pure benzoic acid (1.22 g, 22%). 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). MS (ESI): neg. ion m/z 244 [M-H]-.
22%
A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (1 g, 70 mmol), and H2O (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with H2O. The basic filtrate was acidified to pH 1 with concentrated HCl and extracted with EtOAc (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure benzoic acid (1.22 g, 22%). MS (ESI) calculated for C7H4BrNO4, 244.9; found, m/z 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H).
22%
With potassium permanganate; water;Heating / reflux;Product distribution / selectivity;
A. 4-Bromo-2-nitrobenzoic acid. ; A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight. The mixture was filtered through a pad of diatomaceous earth, washing with water. The basic filtrate was acidified to pH1 with conc. HCl and extracted with EtOAc (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated to provide the desired benzoic acid (1.22 g, 22%). MS (ESI-): mass calcd. for C7H4BrNO4, 244.9; m/z found, 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9, 1H), 7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).
With potassium permanganate; In pyridine; water; for 8h;Heating / reflux;
EXAMPLE 125 4-bromo-2-[(phenylsulfonyl)amino]benzoic acid EXAMPLE 125A 4-bromo-2-nitrobenzoic acid [0354] A mixture of 4-bromo-2-nitrotoluene (10 g, 46.2 mmol), pyridine (85 mL) and water (65 mL) was heated to reflux and treated portionwise with potassium permanganate (21.9 g, 138.9 mmol) over 8 hours. Ethanol (7.8 mL) was added and the mixture was filtered while hot through diatomaceous earth (Celite 8). The filtrate was concentrated and partitioned between water (200 mL), 10% NaOH (25 mL), and diethyl ether (250 mumL). The aqueous phase was acidified to pH 1 with concentrated HCl and the resulting solid was collected by filtration and dried to provide the desired product. MS (ESI(-)) m/e 244, 246 (M-H)-; 1H NMR (300 MHz, DMSO-d6) delta 14.06 (br s, 1H), 8.28 (d, 1H), 7.99 (dd, 1H), 7.81 (d, 1H).
With potassium permanganate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;
Reference Example 19 A suspension of 4-bromo-2-nitrotoluene (50 g) in water was heated to 97 C. Potassium permanganate (240 g) was then added over a period of 4.5 hours. The resulting suspension was heated at reflux overnight. The mixture was filtered whilst hot (through 'HYFLO' silica). The filter cake was washed through with boiling water. The cooled filtrates were washed with diethyl ether then acidified to pH 1 with concentrated hydrochloric acid. The resulting suspension was cooled in ice water and then filtered. The solid was dried to yield 4-bromo-2-nitrobenzoic acid (10.83 g) as a cream solid, m.p. 164-167 C.
With pyridine; potassium permanganate; In ethanol; water;
EXAMPLE 125A 4-bromo-2-nitrobenzoic acid A mixture of 4-bromo-2-nitrotoluene (10 g, 46.2 mmol), pyridine (85 mL) and water (65 mL) was heated to reflux and treated portionwise with potassium permanganate (21.9 g, 138.9 mmol) over 8 hours. Ethanol (7.8 mL) was added and the mixture was filtered while hot through diatomaceous earth (Celite). The filtrate was concentrated and partitioned between water (200 mL), 10% NaOH (25 mL), and diethyl ether (250 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and the resulting solid was collected by filtration and dried to provide the desired product. MS (ESI(-)) m/e 244, 246 (M-H)-; 1H NMR (300 MHz, DMSO-d6) delta 14.06 (br s, 1H), 8.28 (d, 1H), 7.99 (dd, 1H), 7.81 (d, 1H).
With iron(III) chloride; sodium hydroxide; hydrazine; In water; isopropyl alcohol; at 75℃; for 2h;
2) To <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (1.80 g, 7.83 mmol) were added 0.88N aqueous sodium hydroxide solution (10 ML), iron(III) chloride (133 mg) and isopropyl alcohol (0.7 ML) and the mixture heated to 75 C. While stirring the mixture, hydrazine (1.1 ML) was slowly added, and the mixture was reacted at 75 C. for 2 hrs.The reaction mixture was filtered and the filtrate was concentrated.The precipitated solid was washed with water to give 4-bromoanthranilic acid (1.73 g, 96%). 1H NMR (DMSO-d6) delta ppm: 6.62 (dd, J=1.5, 8.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H).
58%
With hydrogen;platinum on carbon; In tetrahydrofuran; ethanol; for 66.5h;
EXAMPLE 14 7-(3-Amino-propyl)-3H-quinazolin-4-one14A. 2-Amino-4-bromo-benzoic acid; <strong>[99277-71-1]4-Bromo-2-nitro-benzoic acid</strong> (0.5g, 2.03 mmol) (Matrix, 009241) was dissolved in a 1 : 1 mixture of ethanol/ tetrahydrofuran (22 ml). This solution was added to 5% platinum on carbon (0.2g, 50% water content) under an atmosphere of nitrogen. The reaction was shaken under an atmosphere of hydrogen for 2.5 hours. A further batch of platinum on carbon was added (0.2g) and the mixture was shaken for 64 hours under an atmosphere of hydrogen. The reaction mixture was filtered, washing through with a 1 : 1 mixture of ethanol/ tetrahydrofuran. The solvent was removed under reduced pressure and the residue was purified by flash silica chromatography, eluting with methanol/ dichloromethane (2:98) to yield the title compound as a yellow solid (0.253g, 58%). LC/MS: (PS-Al) R12.62 [M+H]+ 215.88.
With ferrous ammonium sulphate; ammonia; In water; for 0.0333333h;Heating / reflux;
EXAMPLE 125B 2-amino-4-bromobenzoic acid [0355] A mixture of Example 125A (5.1 g, 20.7 mmol) in concentrated ammonium hydroxide (102 mL) was treated with a solution of ammonium iron (II) sulfate (49 g, 125.1 mmol) in water (102 mL) over 5 minutes, heated to reflux for 2 minutes, cooled to room temperature, filtered through diatomaceous earth (Celite), acidified to pH 1 with concentrated HCl, and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(-)) m/e 214, 216 (M-H)-, 1H NMR (300 MHz, DMSO-d6) delta 7.59 (d, 1H), 6.97 (d, 1H), 6.63 (dd, 1H), 3.32 (br s, 3H).
With ferrous ammonium sulphate; ammonium hydroxide; In water; at 20℃; for 16h;
A modification of a procedure in the following reference herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thomson, L. A. ; Ellman, J. A. J. Org. Chem. , 1997,62, 1240-1256. A solution of (NH4) 2FE (L) (SO4) 2-6 H20 (24.4 g, 63 MMOL) in water (60 mL) was added to a stirred solution of 4- bromo-2-nitro-benzoic acid (2) (3.05 g, 12.45 MMOL) in concentrated aqueous NH40H (40 mL) at room temperature. The iron sulfate solution flask was washed with an additional portion of water (20 mL) which was added to the reaction. After 16 hours, the reaction had changed from a dark green solution to a rusty-brown mixture which was filtered through a plug of Celite and washed with concentrated aqueous NH40H (80 mL) and water (4 x 80 mL). The combined aqueous fractions were acidified to pH 1-2 with aqueous concentrated HCI and extracted with EtOAc (4 x 500 mL). The organic fractions were evaporated under reduced pressure to a brown solid. The crude product was dissolved in EtOAc (300 mL), washed with water (40 mL), brine (40 mL), dried with NA2SO4, filtered, and concentrated to dryness giving 2.47 g of product (3) as a brown solid in 91 % yield and >90% purity by HPLC.
B. 4-Bromo-2-nitrobenzoic acid piperidine amide A suspension of 4-bromo-2-nitrobenzoic acid (0.60 g, 2.44 mmol) in thionyl chloride (8 mL) was heated to reflux for 2 h. The reaction mixture became homogeneous. The mixture was cooled and concentrated in vacuo to give 4-bromo-2-nitrobenzoyl chloride as a white solid, which was used immediately in the following reaction. 1H NMR (400 MHz, CDCl3): 8.20 (d, J=1.9 Hz, 1H), 7.92 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). To a solution of 4-bromo-2-nitrobenzoyl chloride (2.44 mmol) in DCM (15 mL) at ambient temperature was added piperidine (1.2 mL, 12.2 mmol). The reaction mixture was stirred for 3 h then poured into water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford the title amide as a white solid (0.52 g, 76%). MS (ESI): m/z 313 [M+H]+. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.33 (d, J=1.9 Hz, 1H), 7.82 (dd, J=8.1, 1.9 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 3.82-3.65 (bm, 2H), 3.16 (t, J=5.6 Hz, 2H), 1.90-1.35 (bm, 6H).
With thionyl chloride; for 0.5h;Heating / reflux;
A suspension of 4-bromo-2-nitrobenzoic acid (EXAMPLE 1, Step G; 8.0 g, 32 mmol) in thionyl chloride (25 mL) was heated at reflux for 30 min. The reaction became homogeneous. The mixture was cooled to room temperature and concentrated in vacuo to provide the acid chloride as a yellow liquid. The liquid was re-concentrated from DCM (3×) to ensure complete removal of thionyl chloride. 1H NMR (400 MHz, CDCl3): 8.20 (d, J=1.9 Hz, 1H), 7.92 (dd, J 8.3, 1.9 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H). To a solution of the acid chloride (32.5 mmol) in DCM (60 mL) at 0 C. was added (R)-1-(2,4-difluorophenyl)-ethylamine hydrochloride (6.61 g, 34.1 mmol) and Huenig's base (14 mL, 81 mmol). The mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was washed twice with 1 N HCl, and each aqueous wash was back-extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the desired amide as a pale yellow solid (12.3 g, 98%). HPLC (reverse phase): RT=9.190 min. 1H NMR (500 MHz, CDCl3): 8.20 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.1, 1.8 Hz, 1H), 7.35 (ddd, J=8.6, 8.6, 6.3 Hz, 1H), 6.91-6.85 (m, 2H), 6.20 (br d, J=6.7 Hz, 1H), 5.38 (quint, J=7.5 Hz, 1H), 1.61 (d, J=7.0 Hz, 3H).
With thionyl chloride; for 1h;Heating / reflux;
A flask containing 4-bromo-2-nitrobenzoic acid (500 mg) and a stir bar was treated with SOCl2 (3 mL) and heated under reflux during 1 h. The SOCl2 was allowed to distill off; benzene (5 mL) was added and allowed to distill as well. The residue was cooled in an ice bath, dissolved in DCM (3 mL), and treated with 2.0M dimethylamine in THF (4 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with EtOAc (80 mL), then washed with 20 mL each 2M HCl, 2M NaOH, and water. The organic layer was dried on MgSO4, filtered and the residue recrystalized from hexanes (50 mL) to give fine off yellow needles of N,N-dimethyl-4-bromo-2-nitrobenzamide (453 mg), m.p. 104.5-105.5 C.
With thionyl chloride; In chloroform; at 20℃;Reflux;
Synthesis of 2:To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.0 g, 12.2 mmol) in CHCl3 (20 mL) was added thionyl chloride (1.1 mL, 14.6 mmol) at room temperature. Heating at reflux was continued until a clear solution formed. This solution was used for the next step.To a stirred mixture of NH4OH (85 mL of 35% solution) in CHCl3 (25 mL) was added dropwise the above acid chloride solution at ca -25 C. After stirring at 0 C. for 15 min the reaction mixture was poured onto ice cold water. The solid obtained was filtered, washed with H2O, and dried to provide 2 (3.09 g) as a white solid.
With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; for 3h;Reflux;
4-Bromo-2- nitrobenzoic acid (59, 10 g, 40.6 mmol) was dissolved in 133 mL of THF and the resulting solution was cooled to 0 C. Oxalyl chloride (7.09 mL, 81.3 mmol) was added over 5 minutes followed by 2 drops of DMF and the reaction mixture was heated to reflux for 3 hours, after which the solution was concentrated and dried under vacuum to provide the desired compound 60.
With thionyl chloride; at 80℃; for 3h;
A solution of 4-bromo-2-nitrobenzoic acid (2.5 g) in thionyl chloride (2.93 mL) was stirred at 80 C. for 3 hours. The reaction mixture was concentrated under reduced pressure. Toluene (3 mL) was added to the residue and the mixture was concentrated again under reduced pressure. A solution of the resulting acid chloride in acetonitrile (8 mL) was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (1.46 g) and TEA (2.83 mL) in acetonitrile (30 mL) at room temperature over 6 minutes. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned by adding ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/heptane, 33 to 66%) to give the title compound (2.55 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 0.91 (t, J=7.2 Hz, 3H), 3.11 (s, 3H), 3.39 (s, 3H), 3.89 (q, J=7.2 Hz, 2H), 7.25 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0, 1.6 Hz, 1H), 8.00 (s, 1H), 8.19 (d, J=1.6 Hz, 1H). ESI-MS m/z 393 [M+Na]+
With phosphorus pentachloride; In chlorobenzene; at 20℃; for 12h;
A solution of 4-bromo-2-nitrobenzoic acid 21 (1g, 4.34mmol) and phosphorous pentachloride (1g, 4.77mmol) in dry chlorobenzene (10mL) was stirred at rt. After 12h the solvent was removed to give 4-bromo-2-nitrobenzoyl chloride as yellow oil. The crude mixture was washed with n-hexane (2×10mL) and used directly for the Friedel-Crafts reaction. A solution of 4-bromo-nitrobenzoyl chloride (2mL, 23mmol) in benzene was cooled to 0C and treated with anhydrous ferric chloride (0.77g, 4.7mmol) added over a period of 30min. After stirring for 2h at rt the reaction mass was added to 250mL of ice and water. The benzene was removed by distillation as its water azeotrope and the reaction mass was extracted with 200mL of EtOAc .The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (1:10, EtOAc/n-hexane) affording title compound as an orange solid (yield 24%).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: (COCl)2 (1.5 equiv.) was added dropwise to the solution of benzoic acid (5 mmol, 1 equiv.) and few drops of DMF in DCM (20 mL)at 0 C. Reaction mixture was stirred at r. t. for 4 h, then solvent evaporated.
With sodium nitrite;copper(I) bromide; In water; hydrogen bromide;
Step 1: 4-Bromo-2-nitro-benzoic acid A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62,1240-1256. A solution of NaNO2 (1.9 g, 27.4 mmol) in water (65 mL) was added to a stirred solution of <strong>[610-36-6]4-amino-2-nitro-benzoic acid</strong> (1) (5 g, 27.4 mmol) in aqueous 48% HBr (40 mL) and water (82 mL) at 0 C. The cloudy reaction mixture turned into a clear orange-yellow solution after about 15 minutes. After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) in aqueous 48% HBr (90 mL) at 0 C. A yellow foam developed and gas was evolved from the purple-brown mixture. After stirring at 0 C. for 1 hour, the mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (4*300 mL) which was dried with Na2SO4 and concentrated to dryness giving a dark solid. The crude product was filtered through a plug of florisil (~20 g) eluding with EtOAc. The combined organic fractions were evaporated to approx. 200 mL and washed with 1 M HCl (2*50 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91% yield and >90% purity by HPLC.
91%
With sodium nitrite;copper(I) bromide; In water; hydrogen bromide;
Step 1: 4-Bromo-2-nitro-benzoic Acid A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62, 1240-1256. A solution of NaNO2 (1.9 g, 27.4 mmol) in water (65 mL) was added to a stirred solution of <strong>[610-36-6]4-amino-2-nitro-benzoic acid</strong> (1) (5 g, 27.4 mmol) in aqueous 48% HBr (40 mL) and water (82 mL) at 0 C. The cloudy reaction mixture turned into a clear orange-yellow solution after about 15 minutes. After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) in aqueous 48% HBr (90 mL) at 0 C. A yellow foam developed and gas was evolved from the purple-brown mixture. After stirring at 0 C. for 1 hour, the mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (4*300 mL) which was dried with Na2SO4 and concentrated to dryness giving a dark solid. The crude product was filtered through a plug of florisil (-20 g) eluding with EtOAc. The combined organic fractions were evaporated to approx. 200 mL and washed with 1 M HCl (2*50 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91% yield and >90% purity by HPLC.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
Compound 7 A (10.0 g, 40.7 mmol) was dissolved in DMF (100 mL). Cs2CO3 (27.0g, 81.3 mmol) and methyl iodide (7.60 mL, 122.0 mmol) were added. The solution was stirred at room temperature overnight. EtOAc (250 mL) and water (100 mL) were added. The organic phase was separated and washed with water (100 mL) three times and brine (50 mL), then dried over Na2SO4) filtered, and concentrated using a rotary evaporator. The product was dried under vacuum to give compound 7B (10.3 g, 97%).
94%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;
Example I-XVIIPreparation of Compound 321General Procedure I-ESTo a mixture of 4-bromo-2-nitrobenzoic acid (10 g, 41 mmol) and K2CO3 (11.3 g, 82 mmol) in 100 mL of DMF was added CH3I (7.1 g, 50 mmol) dropwise and the mixture was stirred at 80 C. for 3 hrs. After cooling to r.t, the mixture was filtered, the filtrated was concentrated under reduced pressure to remove DMF, and the residue was dissolved with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give methyl 4-bromo-2-nitrobenzoate (I-XVIIa, 10 g, yield 94%). 1H NMR (400 MHz, CDCl3) delta 8.02 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 3.92 (s, 3H).
94%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;
To a mixture of 4-bromo-2-nitrobenzoic acid (10 g, 41 mmol, 1 eq) and K2CO3 (11.3 g, 82 mmol, 2 eq) in 100 mL of DMF was added CH3I (7.1 g, 50 mmol, 1.2 eq) dropwise and the mixture was stirred at 80 C for 3 hrs. After cooling to rt, the mixture was filtered, the filtrated was poured into water and extracted with EtOAc (150 mL x 3), washed with water (150 mL x 3) and brine (150 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give methyl 4-bromo-2-nitrobenzoate (10 g, 94%). 1HNMR (300 MHz, DMSO-d6): G 8.34 (s, 1H), 8.08- 8.05 (m, 1 H), 7.85- 7.82 (m, 1 H), 3.85 (s, 3 H).
94.2%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a solution of compound 267a (5 g, 4.07 mmol), 4-bromo-2-nitrobenzoic acid in N, N-dimethylformamide (50 mL), cesium carbonate (13.5 g, 40.5 mmol) and methyl iodide (3.8 mL, 61 mmol).The mixture was stirred at room temperature for 16 hours, then the mixture was concentrated under reduced pressure to remove some solvents, water was added to the residue and extracted with ethyl acetate (160 mL × 2), and washed with saturated brine (60 mL × 3),After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 91: 9) to obtain a white solid compound 267b, namely 4-bromo-2-nitrobenzene Methyl formate (4.98 g, 94.2% yield.
90%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 0 - 20℃;
A. Methyl 2-amino-4-bromobenzoate To a stirred solution of 4-bromo-2-nitrobenzoic acid (EXAMPLE 5) (3.81 g, 15 mmol) in DMF (30 mL) at 0 C. was added 1,8-diazabicycloundecane (DBU) (10.3 mL, 75 mmol) followed by methyl iodide (4.67 mL, 75 mmol). The reaction mixture was stirred 15 min at 0 C. then allowed to warm to room temperature and stir overnight. The mixture was poured into water and extracted with EtOAc (2*). The combined organic extracts were washed with water (2*), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%).
90%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 0 - 20℃;
B. Methyl 2-amino-4-bromobenzoate. ; To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0 C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by Mel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0 C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water (2×), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70(d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
90 - 98%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 0 - 20℃; for 48.25 - 72.25h;Product distribution / selectivity;
Example 62:; N-[7-ethyI-6-(l-methyI-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yI]- methanesulfonamide; 4-Bromo-2-nitro-benzoic acid methyl ester; To a solution of 4-bromo-2-nitrobenzoic acid (25.3 g, 103 mmol) in DMF (200 mL) at 0 0C were added DBU (79.1 mL, 514.8 mmol) and MeI (32.2 mL, 515 mmol). The reaction mixture was stirred for 15 min at this temperature and for 72 h at r.t. The mixture was poured into water and extracted with EtOAc (2X). The combined organic layers were washed with water (2X), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 7:3 hexanes:EtOAc) to provide the title compound (26.24 g, 98%) as a yellow oil.; Example 71:; N-[7-(l,l-difluoro-ethyl)-6-(2-isopropyl-2H-pyrazol-3-yl)-2,4-dioxo-l,4-dihydro-2H- quinazolin-3-yl]-methanesulfbnamide; 4-Bromo-2-nitro-benzoic acid methyl ester; To solution of 4-bromo-2-nitro-benzoic acid (9 g, 36.58 mmol) in dimethylforrnamide (36 mL) cooled to 0 0C were added l,8-diazabicyclo[5.4.0]und-7-ene (28.09 mL, 182.9 mmol) and MeI (11.4 mL, 182.5 mmol). The reaction mixture was stirred at 0 0C for 15 min and at r.t. for 48 h. The mixture was poured into water and extracted with EtOAc (2X). The combined organic phases were washed with water (2X), dried (Na2SO4) and concentrated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to give 4-bromo-2-nitro-benzoic acid methyl ester (8.62 g, 33.147 mmol, 90%). 1H-NMR (CDCl3, 400 MHz) 8.02 (s, 1 H), 7.81 (dd, J= 2.3, 10.5Hz IH), 7.66 (d, J= 8.2 Hz, IH), 3.92 (s, 3H).
78%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;
To a solution of 4-bromo-2-nitrobenzoic acid (10 g, 40.6 mmol) in DMF (100 mL) was added potassium carbonate (11.24 g, 81 mmol) followed by methyl iodide (3.30 mL, 52.8 mmol) dropwise. The mixture was stirred at 80 C. for 3 h. After cooling to room temperature, the mixture was filtered and residue was dissolved in ethyl acetate (2*200 mL). The organic layer was washed with water (200 mL) followed by brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude sample was purified by flash chromatography (5% Ethyl acetate: Pet ether; 80 g silica gel column) to afford 1A (off white solid, 8.2 g, 31.5 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.35 (d, J=2.0 Hz, 1H), 8.07 (dd, J=8.0, 1.6 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 3.85 (s, 3H).
0.90%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 0 - 20℃;
To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.8 g, 15 mmol) in DMF (30 mL) at 0 C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.0 mL, 75.0 mmol) followed by iodomethane (4.7 mL, 75 mmol). The reaction mixture was stirred 15 min at 0 C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 0.90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at room temperature was added SnCl2.2H2O (15 g, 67 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.6, 1.9 Hz, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A. ; Ellman, J. A. J. Org. CHEM., 1997,62, 1240-1256. A solution OF NAN02 (1-9 9, 27.4 MMOL) in water (65 mL) was added to a stirred solution of 4-amino-2- nitro-benzoic acid (1) (5 g, 27.4 MMOL) in aqueous 48% HBr (40 mL) and water (82 mL) at 0 C. The cloudy reaction mixture turned into a clear orange- yellow solution after about 15 minutes. After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 MMOL) in aqueous 48% HBr (90 mL) at 0 C. A yellow foam developed and gas was evolved from the purple-brown mixture. After stirring at 0 C for 1 hour, the mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (4 x 300 mL) which was dried with NA2SO4 and concentrated to dryness giving a dark solid. The crude product was filtered through a plug OF FLORISIL (# 20 g) eluting with EtOAc. The combined organic fractions were evaporated to approx. 200 mL and washed with 1 M HCI (2X50 mL), brine (50 mL), dried with NA2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91% YIELD and >90% purity by HPLC.
3.1 (7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine
1) A solution (250 ML) of 2,5-dibromo-1-nitrobenzene (4.32 g, 15.4 mmol) in THF was cooled to -105° C. and 0.88 M phenyllithium/THF solution (19.8 ML, 17.4 mmol) was slowly added dropwise.After 30 min, DMF (5.4 ML, 69.6 mol) was slowly added dropwise and the temperature was slowly raised to -20° C. Dilute aqueous sulfuric acid solution (100 ML) was added to the reaction mixture and the mixture was concentrated.The product was extracted with ethyl acetate (80 ML*2).The organic layer was dried, concentrated and the resulting brown solid (5.66 g) was dissolved in acetone (50 ML). Jone's reagent (20 ML) was slowly added to this solution under ice-cooling, and the temperature was slowly raised to room temperature.isopropanol was added to the reaction mixture and the mixture was concentrated. 2 mol/L aqueous sodium hydroxide solution (100 ML) was added and the mixture was filtered.concentrated hydrochloric acid was added to acidify the filtrate.The precipitate was collected by filtration and the residue was washed with water and dried to give 4-bromo-2-nitrobenzoic acid (1.95 g, 52%). 1H NMR (DMSO-d6) δ ppm: 7.80 (br s, 1H), 7.98 (br s, 1H), 8.25 (br s, 1H), 14.1 (br s, 1H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; at 20℃;Heating / reflux;
2.64a. 3-nitro-biphenyl-4-carboxylic acid 150 mg (0.13 mmol) of tetrakis-(triphenylphosphine)-palladium are added to a solution of 1.0 g (4.07 mmol) of <strong>[99277-71-1]4-bromo-2-nitro-benzoic acid</strong> in 20 mL toluene and stirred for 10 min at RT. Then a solution of 0.5 g (4.10 mmol) of phenylboric acid in 10 mL MeOH and a solution of 1.0 g Na2CO3 in 10 mL water are added. The reaction mixture is refluxed for 5 h and stirred at RT over the weekend. The solvents are eliminated in vacuo, the residue is combined with water, acidified with conc. HCl, extracted with EtOAc, the organic phase is dried over Na2SO4 and then the solvent is removed. Yield: 0.87 g (87.5% of theory); Rf value: 0.40 (silica gel, dichloromethane/ethanol 3:1).
4'-chloro-3-nitro-biphenyl-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.9%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; methanol; water; at 110℃; for 1h;Microwave 300 Watt;
1.1.b. 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid 0.288 g (0.25 mmol) of tetrakis-(triphenylphosphine)-palladium, 1.25 g (7.99 mmol) of 4-chloro-phenyl-boric acid in 30 ml of methanol and 2.31 g (21.7 mmol) of sodium carbonate in 14 ml of water are added one after another to a solution of 1.92 g (7.81 mmol) of <strong>[99277-71-1]4-bromo-2-nitro-benzoic acid</strong> in 30 ml dioxane. The reaction mixture is heated to 110 C. in a microwave at 300 Watt for one hour. Then the reaction mixture is evaporated down in the rotary evaporator, the residue is taken up in water and adjusted to pH 3 with 1 M hydrochloric acid. The aqueous solution is extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is distilled off using the rotary evaporator and the residue is stirred with diisopropylether. Yield: 2.04 g (93.9% of theory); C13H8ClNO4 (M=277.666); calc.: molar peak (M-H)-: 276 fnd.: molar peak (M-H)-: 276; Rf value: 0.5 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1).
With sulfuric acid; In water; for 16h;Heating / reflux;
Step 1. Preparation of Methyl 4-bromo-2-nitrobenzoate Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4- bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2 x 250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78%)
With sulfuric acid; for 4h;Reflux;
(Example 22-1) To a methanol solution (50 ml) of 4-bromo-2-nitrobenzoic acid (2.54 g) was added concentrated sulfuric acid (1.0 ml), followed by heating at reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and water (20 ml) was added to the residue. Under ice cooling, 5 N aqueous sodium hydroxide solution (2.0 ml) and a saturated aqueous sodium hydrogen carbonate solution were added, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford methyl 4-bromo-2-nitrobenzoate (619 mg). 1H NMR (500 MHz, CDCl3) delta: 3.95 (s, 3H), 7.69 (d, 1H, J = 8.3 Hz), 7.84 (dd, 1H, J = 8.3, 2.0 Hz), 8.05 (d, 1H, J = 2.0 Hz).
With potassium carbonate; In acetone; at 20 - 50℃; for 1h;
To acetone 40mL solution of 4-bromo-2-nitrobenzoic acid 4.0g were added potassium carbonate 3.4g and dimethylsulfate 2.3mL at room temperature, and it was stirred at 50C for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution, 1.0mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give methyl 4-bromo-2-nitrobenzoate 4.1g of white solid. 1H-NMR(CDCl3) delta value: 3.97(3H,s),7.85(1H,d,J=8.3Hz),8.07(1H,dd,J=8.3,2.0Hz),8 .47(1H,d,J=2.0Hz).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
HATU (1.35 g, 3.55 mmol) was added to a solution of 4-bromo-2-nitrobenzoic acid (0.585 g, 2.37 mmol), <strong>[14328-63-3]methyl (2S)-amino(cyclohexyl)ethanoate hydrochloride</strong>(0.592 g, 2.85 mmol) and diisopropylethylamine (0.62 ml_, 3.55 mmol) in 25 ml_ of DMF. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. Chromatography on silica gel with hexane/ethyl acetate gave 0.704 g (74% yield) of desired product as a white solid.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In methanol; N,N-dimethyl acetamide; water; ethyl acetate;
Referential Example 2 To 50 mL of N,N-dimethylacetamide solution containing 5.0 g of 4-bromo-2-nitrobenzoic acid, 41 g of potassium carbonate, 4.6 g of benzyltriethylammonium chloride and 69 mL of 2-bromo-2-methylpropane were added at room temperature and stirred at 55C for 10 hours. After the reaction mixture was cooled to room temperature, 12 mL of 2-bromo-2-methylpropane was added and stirred at 55C for 4 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Methanol was added to the obtained residue and solid substances were separated by filtration to obtain 3.0 g of tert-butyl 4-bromo-2-nitrobenzoate as white solid. 1H-NMR (CDCl3) delta: 1.55 (9H, s), 7.63 (1H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 8.3, 1.9 Hz), 7.95 (1H, d, J = 1.9 Hz).
With potassium carbonate;N-benzyl-N,N,N-triethylammonium chloride; In ISOPROPYLAMIDE; at 20 - 55℃; for 14.0h;
To N,N-dimethylacetamide 50mL solution of 4-bromo-2-nitrobenzoic acid 5.0g were added potassium carbonate 41g, benzyltriethylammonium chloride 4.6g and 2-bromo-2-methylpropane 69mL at room temperature and it was stirred at 55C for 10 hours. After the reaction mixture was cooled to room temperature, 2-bromo-2-methylpropane 12mL was added to it, and it was stirred at 55C for 4 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Methanol was added to the obtained residue, solid matter was filtrated to give tert-butyl 4-bromo-2-nitrobenzoate 3.0g of white solid. 1H-NMR(CDCl3) delta value: 1.55(9H,s),7.63(1H,d,J=8.3Hz),7.77(1H,dd,J=8.3,1.9Hz),7 .95(1H,d,J=1.9Hz).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
Production Example 17-1 4-Bromo-2-nitro-N-(3-pyrrolidin-1-ylpropyl)benzamide N,N-diisopropylethylamine (1.0 mL) was added to a DMF solution (5 mL) of <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (500 mg), (3-pyrrolidin-1-ylpropyl)amine (290.6 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (912 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with a mixed solvent of chloroform/methanol (10:1). The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the entitled compound (629 mg) as a yellow oily substance.
With N-ethyl-N,N-diisopropylamine; HATU; at 20℃; for 16h;
Step 1: 4-bromo-N-(3-chlorophenyl)-2-nitrobenzamideTo a solution (0.2 M) of <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> in CH2CI2, 3-chloro aniline (1.1 eq.), DIPEA (2.2 eq.) and HATU (1.1 eq.) were added. The reaction mixture was stirred at RT for 16 h. Then, it was treated with aqueous NaHC?3 (saturated solution) and the organic phase was separated and washed with IN HCl and dried. Evaporation of the solvent gave a solid that was washed with Et2O affording (67%) the title compound as a white solid. 1H NMR (400 MHz, DMSOd6, 300 K) ? 7.21 (d, IH, ./ 8.1), 7.41 (t, IH, J8.1), 7.51 (d, IH, J 8.8), 7.77 (d, IH, J 8.1), 7.85 (s, IH), 8.13 (d, IH, J 8.1), 8.40 (s, IH), 10.89 (s, IH); MS (ES+) m/z 355, 357, 359 (M+H)+.
With potassium carbonate; dimethyl sulfate; In water; ethyl acetate; acetone;
Referential Example 1 To 40 mL of acetone solution containing 4.0 g of 4-bromo-2-nitrobenzoic acid, 3.4 g of potassium carbonate and 2.3 mL of dimethyl sulfate were added at room temperature and stirred at 50C for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution, 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure to obtain 4.1 g of methyl 4-bromo-2-nitrobenzoate as white solid. 1H-NMR (CDCl3) delta: 3.97 (3H, s), 7.85 (1H, d, J = 8.3 Hz), 8.07 (1H, dd, J = 8.3, 2.0 Hz), 8.47 (1H, d, J = 2.0 Hz).
Step 1. Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96%). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67 (d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).
95%
Example 25 Synthesis of 4-(7-( 1 -isobutyl- 1 H-pyrazol-4-yl)quinazolin-2-ylamino)-N-(3-(pyrrolidin- 1 - yl)propyl)benzenesulfonamide (Compound 709)Stepl. (4-Bromo-2-nitrophenyl)methanolTo a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M /THF, 4eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95% yield.
4-Bromo-2-nitrobenzoic acid (30.0 g, 118.3 mmol) was placed in 300 mL dichloromethane and 16.5 mL triethylamine was added. Then the reaction solution heated up and a change in color from yellow to greenish brown was observed. The mixture was then cooled to 5 C. and isobutyl chloroformate (16 mL, 118.3 mmol) was added by drops without dilution. The reaction mixture was allowed to come to room temperature while stirring and stirring was continued for 1.5 hours. The mixture was cooled again to 5 C. and 2,6-dimethoxybenzylamine (19.8 g, 118.3 mmol) was added by portions. Again 300 mL dichloromethane was added for dilution and stirring was continued for 15 minutes at 5 C. and then for 12 hours at room temperature. The clear reaction mixture ultimately changed color from red to brown and the reaction was monitored by thin-layer chromatography. The batch was extracted with water, the separated organic phase was extracted with 5% citric acid (2×), washed with sodium bicarbonate solution until neutral (1×) and extracted with saturated sodium chloride solution. The organic phase was dried over sodium sulfate, the solvent was removed in vacuo. The residue was dissolved in diethyl ether/pentane solvent and the precipitate which gradually formed therefore was ultimately filtered out. Crystalline 4-bromo-N-(2,6-dimethoxybenzyl)-2-nitrobenzamide was isolated. Yield: 35.4 g (89.6 mmol, 76%).ESI-MS [M+H+]=396.05 Calculated for C16H15BrN2O5=395.2
With hydrogen; sodium hydrogencarbonate;palladium on activated carbon; In methanol; at 20℃; for 0.416667h;Inert atmosphere;
EXAMPLESExample 12-Nitrobenzoic acidTo a dry 3-necked, 50-mL flask under a N2 atmosphere, was added, <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (0.12 g, 0.49 mmol), 10 wt. % Pd/C (4.3 mg, 0.82 mol %), NaHCO3 (0.133 g, 3.2 mmol) and 1.8 ml of freshly distilled, dry CH3OH. With a balloon on the center neck, the flask was filled with H2 with three vacuum-fill cycles, and the reaction mixture was vigorously stirred at room temperature for the indicated time (Table 1). After 25 minutes, the solution was filtered through Celite, and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel using 1:4 CH3OH/CH2Cl2 as the eluant. 2-Nitrobenzoic acid was isolated as light yellow crystals (75 mg, 0.45 mmol, 92%). Mp: 145-148 C. (lit. mp: 146-148 C21). 1H NMR (300 MHz, CDCl3+DMSO-d6): delta 7.51 (t, J=7.7 Hz, 1H), 7.60 (t, J=7.4 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H). 13C NMR (300 MHz, CDCl3+DMSO-d 6): delta 127.9, 134.6, 134.9, 137.2, 138.7, 153.6, 173.7.
The compound has been previously reported.7 <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (2b, 24.0 g, 97.7 mmol)was dissolved in ethanol (200 mL) and cooled on an ice-water bath. Concentrated H2SO4 was addedin portions to the cooled solution over 10 min. The reaction mixture was then heated at reflux for 22h before it was cooled to room temperature. Most of the ethanol was removed under reducedpressure. Water (500 mL) was added to the oily residue, followed by extraction with CH2Cl2 (200 mL,2x100 mL). The organic phase was washed with water (500 mL), sat. NaHCO3 (500 mL), and brine(500 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the residuewas filtered through silica gel (1:1 CH2Cl2:hexane). This gave 3b as a yellow oil, which was useddirectly in the next reaction without further purification. Yield: 23.7 g, 88.6 mmol, 89%.
With sulfuric acid; In toluene; for 20h;Reflux;
A mixture of <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (49,67 gr, 0,20 mol), H2SO4 (5 ml) and ethanol (50 ml) in toluene was heated at reflux for 20 hours. The reaction mixture was washed with 1M NaOH and brine, dried over Na2SO4 and the solvent was evaporated. Crude yield: 98,6% (53,68 gr, 0,196 mol). The crude product (ethyl 4-bromo-2-nitrobenzoate) was used in the following reaction without further purification. Ethyl 4-bromo-2-nitrobenzoate (20,08 grams, 0,073 mol) was added to a solution of zinc dust (47,92 gr, 0,73 mol) in MeOH (600 ml). Then AcOH (600 ml) was added dropwise to the vigorously stirred mixture, while the temperature was maintained at 0oC. Stirring continued at r.t. for 1h. after addition. The solids were removed by filtration and the solvent was evaporated. The residue was diluted with EtOAc and Zn(OAc)2 was removed by filtration. The organic solution was washed with NaOH and brine and dried over Na2SO4.The solvents were evaporated to give a yield of ethyl 2-amino-4-bromobenzoate: 116% (20,88 gram, 0,085 mol, some residual acetic acid observed by NMR) that was used in the next step without further purification.
With dichloro bis(acetonitrile) palladium(II); silver carbonate; tricyclohexylphosphine In 1,2-dimethoxyethane; dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere;
General procedure: Powdered substituted 2-nitrobenzoic acid (10 mmol)was added to a well stirred solution of KOH (10 mmol) in CH3OH (10 mL). The resulting suspension was stirred at room temperature for 10 min and then cooled to 0 C and treated with methyl 2-amino-2-(4-chlorophenyl)acetate hydrochloride (10 mmol) or 2-amino-2-(4-fluorophenyl)acetate hydrochloride (10 mmol) (3), a solution of 1-isocyanocyclohexene (4) (11 mmol) in CH3OH (2 mL) and a solution of p-chlorobenzaldehyde or 4-fluorobenzaldehyde (5) (10 mmol) in CH3OH (2 mL), in the order given. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 day. Removal of the solvent under reduced pressure left a residue which was stirred with H2O (10 mL) and CH2Cl2 (80 mL). The organic layer was dried (Na2SO4) and evaporated to dryness. The residue was stirred with boiling hexanes (50 mL) for 5 min. The supernatant liquid was discarded while still warm. An analogous treatment was performed with boiling H2O (50 mL x 2). The resulting solid product was stirred with AcOH (60 mL). The resulting solution was heated at 50 C and treated under vigorous stirring with iron powder (40 mmol) in one portion. When the exothermic reaction had subsided, the reaction mixture was heated at 70 C for 1 h and then allowed to cool and stirred with CH2Cl2 (50 mL) and H2O (50 mL). The resulting suspension was filtered to remove the unreacted iron and the filtrate transferred to a separating funnel. The organic layer was washed with H2O (50 mL), NaHCO3 (aq. 2%, 50 mL), H2O (50 mL) and then separated, dried (Na2SO4), and evaporated to dryness. The residue was purified by column chromatography (n-hexane-ethyl acetate, 5:1) togive 7a-r, yield: 45-52%.
Step 1 : To a solution of <strong>[99277-71-1]2-nitro-4-bromobenzoic acid</strong> (9.3 mmol) in DMF (6 mL) was added NMM (1.87 g, 18.6 mmol) followed by addition of HATU (5.3 g, 13.95 mmol) and the mixture was stirred at rt for 30 min. l-Methylpiperazine (1.39 g, 13.95 mmol) was added and stirred at rt for an additional 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give ((4-bromo-2-methylyphenyl)(4-methylpiperazin- 1 -yl)methanone (1.9 g, 70%, AUC HPLC 98%) as a brown solid. 1H NMR (400 MHz, CDC13): <5 8.4 (s, 1 H), 8.01 (d, J= 6.2 Hz, 1 H), 7.4 (d, J = 8.3 Hz, 1 H) 3.8 (bs, 2 H), 2.3-2.5 (s, 7 H).
To a solution of <strong>[99277-71-1]2-nitro-4-bromobenzoic acid</strong> (9.3 mmol) in DMF (6 mL) was added NMM (1.87 g, 18.6 mmol) followed by addition of HATU (5.3 g, 13.95 mmol) and the mixture was stirred at rt for 30 min. 1-Methylpiperazine (1.39 g, 13.95 mmol) was added and stirred at rt for an additional 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give ((4-bromo-2-methylyphenyl)(4-methylpiperazin-1-yl)methanone (1.9 g, 70%, AUC HPLC 98%) as a brown solid. 1H NMR (400 MHz, CDCl3): delta 8.4 (s, 1H), 8.01 (d, J=6.2 Hz, 1H), 7.4 (d, J=8.3 Hz, 1H) 3.8 (bs, 2H), 2.3-2.5 (s, 7H).
To a solution of 4-bromo-2-nitrobenzoic acid (30 g, 122 mmol) in anhydrous THF (500 mL) , asolution of vinylmagnesium bromide (51.2 mL, 512 mmol, 1 N) in THF was added dropwise at about-30 to -50 C. The reaction mixture was stilTed at about -30 to -40 C for about 2 h. Then the reaction mixture was poured into saturated aqueous NH4C1 solution and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, dried over andydrous Na2504, filtered and concentrated under reduced pressure to provide 4-bromo-]H-indole-7-carboxylic acid (33g crude), which was used directly for next step without further purification. ?H NMR (400 MHz, DMSO-d6) 11.42 (m, 1H), 8.11 (bs, 1H), 7.63 (dd, J = 17.4, 8.0 Hz, 1H), 7.45 (dt, J = 14.2, 2.8 Hz, 1H), 7.32 (dd, J = 21.9, 8.0 Hz, 1H), 6.47 (ddd, J = 25.5, 3.1, 2.1 Hz, 1H).
With trichlorophosphate; at 120℃; for 1h;Sealed tube;
Equipped with magnetic sub 20mL reaction flask was added 2,6-dimethoxy-benzoic acid (0.055 g, 0.3 mmol), of POCl3(lequiv), of DMF (2mL), tighten the cap, an external temperature of 120 sealed reactor IH; complete reaction was monitored by gas chromatography; after the reaction solutionwas cooled, to which was added 10mL of saturated of Na2CO.3aqueous solution, extracted with ethyl acetate (3 × 10mL), the combined organic phase was dried over anhydrousmagnesium sulfate, and solvent was removed by rotary evaporation , by column chromatography: after separation (ethyl acetate n-hexane = 1/1) to give a pale yellow solid,yield 79%
93%
With trichlorophosphate; at 120℃; for 1h;
General procedure: Carboxylic acids (0.3 mmol), POCl3(1equiv.) and N-substituted formamides (2 mL) were mixed in a 20 mL tube. Tighten the cap and the mixture was stirred at 120 C for 1h. The mixture was cooled to room temperature, and Na2CO3 saturated solution (10 mL) was added. Then the solution was extracted with ethyl acetate (3×10 mL), combined the organic layers and dried with anhydrous MgSO4 over night. The solution was evaporated under reduced pressure and the crude product was purified by column chromatography (silica gel, n-hexane-EtOAc, 1:1).
(R)-tert-butyl 3-(4-bromo-2-nitrobenzamido)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 10 - 35℃; for 4h;
HATU (12.49 g, 32.84 mmol) was added to a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (5.06 g, 25.26 mmol), <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (6.22 g, 25.26 mmol) and DIEA (8.80 mL, 50.53 mmol) in DMF (120 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 37?58% ethyl acetate/hexane) to give (R)-tert-butyl 3-(4-bromo-2-nitrobenzamido)piperidine-1-carboxylate (10.16 g, 23.72 mmol, 94%) as a pale-gray amorphous solid. 1H NMR (300 MHz, CDCl3):delta 1.44(9H,s), 1.59-1.74(2H,m), 1.88(2H,brs), 3.26(1H,brs), 3.44-3.64(3H,m), 4.14-4.22(1H,m), 6.03(1H,brs), 7.41(1H,d,J=7.9 Hz), 7.80(1H,dd,J=7.9,1.9 Hz), 8.20(1H,d,J=1.5 Hz).
4-bromo-2-nitrophenyl phenyl selenoether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With 1,10-Phenanthroline; oxygen; copper diacetate; potassium carbonate; In toluene; at 100℃; for 24h;
At room temperature, <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (0.4 mmol, 1 equiv), elemental selenium (1.2mmol, 3equiv), iodobenzene (1.2mmol, 3equiv), Cu (OAc) 2 (0.04mmol), 1,10-phenanthroline (0.04 mmol), potassium carbonate (1.2mmol, 3equiv) and 2mL of toluene was added to the reaction tube, then filled with oxygen, and substituted three times, the reaction in an oxygen environment at a reaction temperature of 100 deg.] C stir 24h. By the end of the reaction was monitored by thin layer chromatography, the reaction mixture was cooled, filtered and then ethyl acetate was added, and then spin off the solvent, the product obtained was isolated by column chromatography (eluent: petroleum ether: diethyl ether = 98), the product is yellow liquid, yield 83%, by weight of the product is 118mg.
4-bromo-2-nitrophenyl phenyl selenoether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With 1,10-Phenanthroline; oxygen; copper diacetate; potassium carbonate; In toluene; at 150℃; for 24h;
At room temperature, <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (0.4 mmol, 1 equiv), diphenyl diselenide (0.8mmol, 2equiv), Cu (OAc) 2 (0.06mmol), 1,10- ortho phenanthroline (0.06 mmol), potassium carbonate (1.2mmol, 3equiv) and 2mL of toluene was added to the reaction tube, then filled with oxygen, and substituted three times, the reaction in an oxygen environment, at a temperature of 150 deg.] C the reaction was stirred 24h. By the end of the reaction was monitored by thin layer chromatography, the reaction mixture was cooled, filtered and then ethyl acetate was added, and then spin off the solvent, the product obtained was isolated by column chromatography (eluent: petroleum ether: diethyl ether = 98), the product is yellow liquid, yield 83%, by weight of the product is 118mg.
With copper(I) oxide; potassium phosphate; bismuth (III) nitrate pentahydrate; palladium(II) trifluoroacetate; oxygen; sodium iodide; In dimethyl sulfoxide; at 170℃; for 20h;Schlenk technique;
In a Schlenk reaction tube equipped with a magnetic stirrer, 6.7 mg of palladium trifluoroacetate was added. Cuprous oxide 28.6mg,Potassium phosphorus 6.4mg,<strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> 49.2 mg,Sodium iodide 36mg,bismuth nitrate pentahydrate194 mg and 2 mL of dimethyl sulfoxide.The reaction was heated at 170C for 20 hours in the presence of oxygen. After the reaction is completed, distilled water is added to quench the reaction.Ethyl acetate was extracted 3 times for 10 mL each time, and the combined organic phases were concentrated to give 1-bromo-3-iodo-5-nitrobenzene.50.5 mg, yield 77%.
4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)aniline[ No CAS ]
4-bromo-N-(4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)phenyl)-2-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.3%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: To a 50 mL three-necked round-bottomed flask equipped with a magnetic stirrer, the key intermediate 3 (0.02 mol),aromatic acid (0.02 mol), and dimethylaminopyridine (0.0002 mol) dissolved in dichloromethane (10 mL), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.03 mol) were added. The reactions were reacted for 8-10 h at room temperature. Then, the solvent wasremoved under vacuum and recrystallized from ethanol to give the pure target compounds 4a-4aa with the yields of 78.0-91.0%.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper diacetate; silver sulfate; In dimethyl sulfoxide; at 140℃; under 760.051 Torr; for 20h;Schlenk technique; Green chemistry;
General procedure: An oven-dried Schlenk tube equipped with a stir bar was charged with aryl carboxylic acid (0.2 mmol), Ag2SO4 (6.2 mg, 0.02 mmol, 0.1 equiv.), Cu(OAc)2 (36.3 mg, 0.2 mmol, 1 equiv.), K4Fe(CN)6 (13.2 mg, 0.036 mmol, 0.18 equiv.) and 2,9-dimethyl-1,10-phenanthrolinium (12.5 mg, 0.06 mmol, 0.3 equiv.). The tube was fitted with a rubber septum, and then it was evacuated and refilled with dioxygen three times. Under dioxygen, DMSO (4 mL) was added via syringe. The rubber septum was replaced with a Teflon screwcap under dioxygen flow, and the Schlenk tube was pressurized to 1 atm. With stirring, the reaction mixtures were heated at 140 C for the indicated amount of time (unless otherwise specified). After cooling to room temperature, the reaction mixtures were diluted with ether (10 mL) and filtered through a pad of silica gel that was then washed with ether (10 mL *3). The combined organic phase was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using flash column chromatography over silica gel to provide the corresponding product with ethyl acetate/hexane as eluent.
tert-butyl (1-[5-amino-2-(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate[ No CAS ]
tert-butyl (1-[5-(4-bromo-2-nitrobenzamido)-2-(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;
A solution of tert-butyl (l -[5-amino-2-(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (285 mg, 759 muetaiotaomicron), <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (205 mg, 835 muetaiotaomicron) and N,N-diisopropylethylamine (400 mu, 2.3 mmol) in DMF (1.9 ml) was treated with HATU (577 mg, 1.52 mmol) and stirred at rt overnight. After 18 h the reaction mixture was partitioned between water and EtOAc. After phase separation, the aqueous layer was extracted (x3) wwith EtOAc. The combined organic extracts were washed with brine, dried, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/EtOAc from 90: 10 to 50:50 to provide the title product 377 mg (82 % yield).LC-MS (Method 6): Rt= 2.16 min; MS (ESIneg): m/z = 601 [M-H]"- MR (500 MHz, DMSO-d6) delta [ppm]: 1.039 (0.85), 1.048 (2.36), 1.055 (2.26), 1.063 (0.95), 1.364 (1.24), 1.372 (2.84), 1.379 (2.81), 1.388 (2.45), 1.398 (16.00), 1.403 (11.93), 7.428 (0.85), 7.430 (0.84), 7.446 (1.09), 7.561 (0.95), 7.565 (0.92), 7.578 (0.72), 7.583 (0.70), 7.745 (2.39), 7.761 (2.55), 8.093 (1.52), 8.097 (1.47), 8.109 (1.33), 8.113 (1.34), 8.370 (2.85), 8.374 (2.73), 8.500 (0.42), 9.053 (0.48), 10.895 (2.38).
N-[5-amino-2-(trifluoromethoxy)phenyl]-1-(6-oxa-3-azabicyclo [3.1.1 ]heptan-3-yl)cyclopropane-1-carboxamide[ No CAS ]
4-bromo-2-nitro-N-[3-[1-(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane-1-carbonyl]amino}-4-(trifluoromethoxy)phenyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2.25h;
A solution of <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (197 mg, 800 muetaiotaomicron) and N,N-diisopropylethylamine (380 mu, 2.2 mmol) in DMF (1.0 ml) was treated with HATU (553 mg, 1.46 mmol) and stirred at rt for 15 min. To this solution was added a solution of N-[5-amino-2-(trifluoromethoxy)phenyl]-l -(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l -carboxamide (260 mg, 728 muiotaetaomicron) in DMF (1.0 ml) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was partitioned between water and ethyl acetate. After phase separation, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 93:7 to 40:60 to provide 318 mg (99 % purity, 82 % yield) of the title compound.LC-MS (Method 6): Rt= 2.08 min; MS (ESIpos): m/z = 585 [M+H]+- MR (400 MHz, DMSO-d6) delta [ppm] : -0.008 (0.90), 1.157 (4.35), 1.175 (8.84), 1.193 (4.59), 1.241 (1.25), 1.266 (12.77), 1.284 (12.43), 1.308 (1.12), 1.398 (1.24), 1.909 (0.80), 1.988 (16.00), 2.263 (2.99), 2.284 (3.13), 2.662 (0.47), 2.907 (3.88), 2.934 (8.60), 2.972 (10.56), 3.000 (4.52), 3.017 (1.38), 3.033 (2.89), 3.054 (2.82), 3.070 (1.26), 4.003 (1.28), 4.021 (3.83), 4.039 (3.80), 4.056 (1.29), 4.503 (7.91), 4.518 (7.81), 7.430 (2.63), 7.433 (2.72), 7.452 (3.77), 7.456 (3.62), 7.554 (4.47), 7.561 (4.45), 7.577 (3.05), 7.583 (3.17), 7.739 (7.16), 7.759 (7.88), 8.092 (4.56), 8.096 (4.70), 8.112 (3.99), 8.117 (4.20), 8.369 (8.20), 8.374 (8.09), 8.624 (6.69), 8.630 (6.64), 9.840 (4.31), 10.895 (8.02).
82%
A solution of <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (197 mg, 800 jimol) and N,N-diisopropylethylamine (380 jil,2.2 mmol) in DMF (1.0 ml) was treated with HATU (553 mg, 1.46 mmol) and stirred at rt for 15 mm.To this solution was added a solution of N-[5-amino-2-(trifluoromethoxy)phenyl]-1-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropane-1-carboxamide (260 mg, 728 jimol) in DMF (1.0 ml) and thereaction mixture was stirred at rt for 2 h. The reaction mixture was partitioned between water andEtOAc. After phase separation, the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/EtOAc from 93:7 to 40:60 to provide 318 mg (99 % purity, 82 % yield) of the title compound.LC-MS (Method 6): R = 2.08 mm; MS (ESIpos): m/z = 585 [M+H]1HNMR (400 MHz, DMSO-d6) [ppm]: -0.008 (0.90), 1.157 (4.35), 1.175 (8.84), 1.193 (4.59), 1.241(1.25), 1.266 (12.77), 1.284 (12.43), 1.308 (1.12), 1.398 (1.24), 1.909 (0.80), 1.988 (16.00), 2.263(2.99), 2.284 (3.13), 2.662 (0.47), 2.907 (3.88), 2.934 (8.60), 2.972 (10.56), 3.000 (4.52), 3.017 (1.38),3.033 (2.89), 3.054 (2.82), 3.070 (1.26), 4.003 (1.28), 4.021 (3.83), 4.039 (3.80), 4.056 (1.29), 4.503(7.91), 4.518 (7.81), 7.430 (2.63), 7.433 (2.72), 7.452 (3.77), 7.456 (3.62), 7.554 (4.47), 7.561 (4.45),7.577 (3.05), 7.583 (3.17), 7.739 (7.16), 7.759 (7.88), 8.092 (4.56), 8.096 (4.70), 8.112 (3.99), 8.117 (4.20), 8.369 (8.20), 8.374 (8.09), 8.624 (6.69), 8.630 (6.64), 9.840 (4.31), 10.895 (8.02).
N-[5-amino-2-(trifluoromethoxy)phenyl]-2-(3-oxa-7-azabicyclo [3.3.1 ]nonan-7-yl)propanamide[ No CAS ]
4-bromo-2-nitro-N-[3-[2-(3-oxa-7-azabicyclo [3.3.1 ]nonan-7-yl)propanoyl]amino}-4-(trifluoromethoxy)phenyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
A solution of <strong>[99277-71-1]4-bromo-2-nitrobenzoic acid</strong> (210 mu, 2.0 M, 420 muetaiotaomicron) and N,N-diisopropylethylamine (200 mu, 1.2 mmol) in DMF (1.0 ml) was treated with HATU (293 mg, 771 muiotaetaomicron) and stirred at rt for 10 min. To this solution was added N-[5-amino-2-(trifluoromethoxy)phenyl]-2-(3-oxa-7- azabicyclo[3.3.1]nonan-7-yl)propanamide (144 mg, 386 muiotaetaomicron) and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted in acetonitrile and directly submitted to preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid). The residue was dissolved in dichloromethane and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried. Filtered and evaporated to dryness to deliver 127 mg (99 % purity, 55 % yield) of the title compound.LC-MS (Method 4): Rt= 1.05 min; MS (ESIneg): m/z = 599 [M-H]"- MR (400 MHz, DMSO-d6) delta [ppm] : 0.008 (1.73), 1.155 (12.08), 1.172 (12.21), 1.603 (2.41), 1.634 (3.02), 1.705 (6.65), 1.816 (3.44), 1.847 (2.76), 2.328 (1.29), 2.366 (1.22), 2.523 (4.88), 2.627 (2.47), 2.651 (3.28), 2.710 (1.35), 2.767 (3.37), 2.793 (2.57), 2.849 (2.25), 2.877 (3.69), 2.939 (3.73), 2.964 (2.35), 3.336 (3.66), 3.682 (3.34), 3.711 (7.84), 3.744 (6.20), 3.784 (3.98), 3.812 (2.54), 3.877 (4.18), 3.904 (3.15), 7.389 (3.86), 7.410 (5.01), 7.547 (8.48), 7.553 (8.29), 7.569 (6.30), 7.576 (6.27), 7.745 (14.55), 7.765 (16.00), 8.097 (8.61), 8.102 (8.77), 8.118 (7.58), 8.122 (7.90), 8.312 (12.24), 8.319 (11.69), 8.373 (13.43), 8.378 (13.08), 10.376 (8.61), 10.890 (8.61).
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