Abstract: Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-pos. and -neg. bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.
* 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] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
2
[ 367-12-4 ]
[ 7440-44-0 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Yield
Reaction Conditions
Operation in experiment
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5° C. After the addition was complete, stirring was continued at 0° C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5°C. After the addition was complete, stirring was continued at 0°C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
6
[ 403-19-0 ]
[ 394-50-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
7
[ 100-02-7 ]
[ 403-19-0 ]
Reference：
[1] Journal of the American Chemical Society, 1990, vol. 112, # 23, p. 8563 - 8575
[2] Journal of Organic Chemistry, 1984, vol. 49, p. 806 - 813
[3] Patent: CN104844399, 2016, B,
8
[ 402-67-5 ]
[ 403-19-0 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4199 - 4208
9
[ 100-02-7 ]
[ 403-19-0 ]
[ 658-07-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 2007, vol. 128, # 1, p. 29 - 33
[2] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
[3] Journal of the Chemical Society, Chemical Communications, 1995, # 1, p. 17 - 18
10
[ 367-12-4 ]
[ 7440-44-0 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Yield
Reaction Conditions
Operation in experiment
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5° C. After the addition was complete, stirring was continued at 0° C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5°C. After the addition was complete, stirring was continued at 0°C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference：
[1] Journal of Fluorine Chemistry, 2007, vol. 128, # 1, p. 29 - 33
[2] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
[3] Journal of the Chemical Society, Chemical Communications, 1995, # 1, p. 17 - 18
21
[ 403-19-0 ]
[ 399-96-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen In methanol at 20℃;
A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) were stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100percent), as a solid which was used without further purification. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS (ESI+) m/z 128 (M+H)+.
100%
With hydrogen In methanol at 20℃;
A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite.(R). and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100percent), as a solid which was used without further purification. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
100%
With hydrogen In methanol at 20℃;
B) 2-Fluoro-4-aminophenol; A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite.(R). and the filtrate concentrated in vacuo to afford the desired compound (1.00 g, 100percent), as a solid which was used without further purification. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
[0223] To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10percent). The reaction was stirred at rt overnight in a H2 atmosphere. The mixture was filtered through a pad of CELITE®, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99percent). MS (ESI, pos. ion) m/z: 128.1 [M+H]+.
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
Step 1) 4-amino-2-fluorophenol To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10percent). The reaction was stirred at rt overnight in a H2 atmosphere. The mixture was filtered through a pad of CELITE®, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99percent). MS (ESI, pos. ion) m/z: 128.1 [M+H]+.
96%
With hydrogen In ethanol; water for 0.5 h;
A mixture of 2-fluoro-4-nitrophenol (5.78 g, 36.8 mmol) and palladium on carbon (10percent, 50percent water, Degussa type, 0.525 g, 0.247 mmol) in 100 mL EtOH was shaken in a Parr shaker at 40 psi for 30 min. The reaction mixture was filtered though Celite.(R)., washing with additional EtOH. The filtrate and washings were combined, concentrated, and dried under high vacuum to give the title compound (4.47 g, 96percent) as a brown solid. Exact mass calculated for C6H6FNO: 127.04, found: LCMS mlz = 128.0 [M+H]+; lU NMR (400 MHz, DMSO- ) δ ppm 4.69 (s, 2H), 6.19-6.22 (m, 1H), 6.33-6.37 (m, 1H), 6.60-6.65 (m, 1H), 8.54 (s, 1H).
90%
With hydrogen In methanol at 20℃;
35 (1 .19g, 7.57mmol) was dissolved in methanol (40mL) and hydrogenated over 10percent Pd/C (125 mg), at rt and atmospheric pressure. The suspension was filtered over celite and washed with excess eOH. Removal of excess solvent under reduced pressure afforded 867 mg of light brown solid.
87%
With hydrogen In methanol at 20℃; for 3 h;
4-Amino-2-fluorophenol (4); To a degassed solution of 4-nitro-2-fluorophenol (3) (16 g, 102 mmol) in MeOH (150 mL) was added palladium on charcoal (10percent) Degussa type (3.0 g, 2.82 mmol). The mixture was stirred at r.t. under hydrogen atmosphere for 3h, filtered through a celite pad and evaporated under reduced pressure. The residue was triturated with Et2O (50 mL) to afford compound 4 (11.264 g, 87percent yield) as a dark-brown solid. MS (m/z): 128.1 (M+H). 1H NMR (400 MHz, DMSO-de) δ (ppm): 8.57 (s, IH), 6.62 (dd, J = 10.0, 8.4 Hz, IH), 6.34 (dd, J = 13.4, 2.6 Hz, IH), 6.20 (ddd, J = 8.6, 2.6, 1.2 Hz, IH), 4.67 (s, 2H).
85%
With hydrogen In ethanol at 20℃; for 3 h;
Preparation 26 4-amino-2-fluoro -phenol; A solution of 2-fluoro-4-nitro-phenol (400 mg, 2.55 mMol) and ethanol (6 ml_) was treated with 10percent Pd/C (42.6 mg). The reaction mixture was hydrogenated for 3 hours at 40 psi at room temperature. The reaction mixture was filtered through a pad of Arbocel .(R). with ethanol and then evaporated to dryness to give a dark solid (248mg, 85percent).1H NMR (400MHz, CD3OD) δ =6.29-6.31(d, 1 H), 6.39-6.43 (dd, 1 H), 6.58-6.62 (m, 1 H). GC/MS: 1.66 mins m/z (Cl) = 128 [MH+]
81%
With ammonium chloride; zinc In tetrahydrofuran; methanol at 0 - 20℃;
To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 0° C. was added zinc dust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a thin pad of Celite.(R). with methanol and the filtrate was concentrated in vacuo to give 4-amino-2-fluorophenol as a brown solid which was used without further purification (656 mg, 81percent). 3-(4-Fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 197 mg, 1.00 mmol) was dissolved in dimethylformamide (4 mL). Triethylamine (140 μL, 1.00 mmol) was added and the solution was cooled to 0° C. 4-Amino-2-fluorophenol (Step A of Example 19, 127 mg, 1.00 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69percent) as a white solid. 1H NMR (CD3OD) δ 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08-6.99 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS (ESI+) m/z 307.44 (M+H)+.
55.1%
With iron; ammonium chloride In ethanol; water at 20℃; for 0.5 h;
To a solution of 2-fluoro-4-nitrophenol (1.57 g, 10 mmol) in EtOH (50 mL) and H20 (18 mL) was added Fe (2.24 g, 40 mmol) and NH4C1 (4.24 g, 80 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was added Η20 (50 mL) and extracted by EtOAc (60 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was beaten by PE/EtOAc (v/v, 10 mL/15 mL), filtered to give the title compound as a brown solid (700 mg, 55.1percent).LC-MS (ESI, pos, ion): 128.3 [M+H]+;H NMR (400 MHz, DMSO-Λ) δ (ppm): 8.56 (s, 1H), 6.62 (dd, J = 10.0, 8.6 Hz, 1H), 6.34 (dd, J= 13.4, 2.6 Hz, 1H), 6.24-6.15 (m, 1H), 4.66 (s, 2H).
55.1%
With water; iron; ammonium chloride In ethanol at 20℃;
Iron powder (2.24 g, 40 mmol) and NH4Cl (4.24 g, 80 mmol)Add to 2-fluoro-4-nitrophenol (1.57g, 10mmol)EtOH (50mL)And H2O (18mL) solution,The reaction was stirred at room temperature overnight.The reaction solution was filtered through silica gel.The filtrate was concentrated under reduced pressure.The residue obtained was added to water (50 mL).Extract and separate the organic phase with EtOAc (60 mL x 2).Combine the resulting organic phases,Wash with saturated brine,After drying with anhydrous sodium sulfate,Concentrated under reduced pressure,The residue obtained was beaten in a mixed solvent of PE/EtOAc (v/v, 10 mL / 15 mL).filter,The title compound (700 mg, 55.1percent) was obtained.
38%
With hydrogen In ethanol at 20℃; for 16 h;
2-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10percent on activated carbon, 31 mg), and EtOH (20 mL) were combined and stirred under atmospheric H2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated, and purified by preparative thin layer chromatography (30percent EtOAc in hexanes) to afford 4-amino-2-fluorophenol as a tan solid of sufficient purity for subsequent transformations (152 mg, 1.20 mmol; 38percent yield).
Reference：
[1] Patent: US2005/245530, 2005, A1, . Location in patent: Page/Page column 35-36
[2] Patent: US2006/241104, 2006, A1, . Location in patent: Page/Page column 14
[3] Patent: US2007/78140, 2007, A1, . Location in patent: Page/Page column 25-26
[4] Patent: WO2014/22116, 2014, A2, . Location in patent: Paragraph 0223
[5] Patent: US2015/37280, 2015, A1, . Location in patent: Paragraph 0445; 0446
[6] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[7] Patent: WO2012/145361, 2012, A1, . Location in patent: Page/Page column 168
[8] RSC Advances, 2013, vol. 3, # 11, p. 3697 - 3706
[9] Patent: WO2012/4549, 2012, A1, . Location in patent: Page/Page column 35
[10] Patent: WO2009/26720, 2009, A1, . Location in patent: Page/Page column 93; 94
[11] Patent: WO2009/144632, 2009, A1, . Location in patent: Page/Page column 66
[12] Patent: US2005/245530, 2005, A1, . Location in patent: Page/Page column 35
[13] Patent: WO2015/164161, 2015, A1, . Location in patent: Paragraph 0295
[14] Patent: CN104974162, 2018, B, . Location in patent: Paragraph 0609; 0610
[15] Patent: WO2005/121125, 2005, A1, . Location in patent: Page/Page column 45-46
[16] Journal of the Chemical Society, 1949, p. 642,645
[17] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6525 - 6538
[18] Synthetic Communications, 2013, vol. 43, # 21, p. 2949 - 2954
22
[ 403-19-0 ]
[ 437-83-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
23
[ 455-93-6 ]
[ 403-19-0 ]
[ 636-93-1 ]
[ 452-11-9 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1925 - 1934
24
[ 403-19-0 ]
[ 320-76-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
25
[ 403-19-0 ]
[ 13790-39-1 ]
[ 228559-87-3 ]
Reference：
[1] Patent: EP1243582, 2002, A1,
26
[ 403-19-0 ]
[ 168268-00-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691
[2] Chinese Chemical Letters, 2010, vol. 21, # 11, p. 1326 - 1329
[3] Patent: WO2005/30140, 2005, A2,
[4] Patent: WO2006/108059, 2006, A1,
27
[ 403-19-0 ]
[ 1394820-98-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6277 - 6292
With hydrogen;platinum(IV) oxide; In methanol; at 20℃; under 2585.81 Torr;
A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) were stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) delta 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS (ESI+) m/z 128 (M+H)+.
100%
With hydrogen;platinum(IV) oxide; In methanol; at 20℃; under 2585.81 Torr;
A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) delta 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
100%
With hydrogen;platinum(IV) oxide; In methanol; at 20℃; under 2585.81 Torr;
B) 2-Fluoro-4-aminophenol; A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to afford the desired compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) delta 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
> 99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
[0223] To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10%). The reaction was stirred at rt overnight in a H2 atmosphere. The mixture was filtered through a pad of CELITE, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99%). MS (ESI, pos. ion) m/z: 128.1 [M+H]+.
> 99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
Step 1) 4-amino-2-fluorophenol To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10%). The reaction was stirred at rt overnight in a H2 atmosphere. The mixture was filtered through a pad of CELITE, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99%). MS (ESI, pos. ion) m/z: 128.1 [M+H]+.
96%
With hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 0.5h;
A mixture of 2-fluoro-4-nitrophenol (5.78 g, 36.8 mmol) and palladium on carbon (10%, 50% water, Degussa type, 0.525 g, 0.247 mmol) in 100 mL EtOH was shaken in a Parr shaker at 40 psi for 30 min. The reaction mixture was filtered though Celite, washing with additional EtOH. The filtrate and washings were combined, concentrated, and dried under high vacuum to give the title compound (4.47 g, 96%) as a brown solid. Exact mass calculated for C6H6FNO: 127.04, found: LCMS mlz = 128.0 [M+H]+; lU NMR (400 MHz, DMSO- ) delta ppm 4.69 (s, 2H), 6.19-6.22 (m, 1H), 6.33-6.37 (m, 1H), 6.60-6.65 (m, 1H), 8.54 (s, 1H).
90%
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 760.051 Torr;
35 (1 .19g, 7.57mmol) was dissolved in methanol (40mL) and hydrogenated over 10% Pd/C (125 mg), at rt and atmospheric pressure. The suspension was filtered over celite and washed with excess eOH. Removal of excess solvent under reduced pressure afforded 867 mg of light brown solid.
87%
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 3h;
4-Amino-2-fluorophenol (4); To a degassed solution of 4-nitro-2-fluorophenol (3) (16 g, 102 mmol) in MeOH (150 mL) was added palladium on charcoal (10%) Degussa type (3.0 g, 2.82 mmol). The mixture was stirred at r.t. under hydrogen atmosphere for 3h, filtered through a celite pad and evaporated under reduced pressure. The residue was triturated with Et2O (50 mL) to afford compound 4 (11.264 g, 87% yield) as a dark-brown solid. MS (m/z): 128.1 (M+H). 1H NMR (400 MHz, DMSO-de) delta (ppm): 8.57 (s, IH), 6.62 (dd, J = 10.0, 8.4 Hz, IH), 6.34 (dd, J = 13.4, 2.6 Hz, IH), 6.20 (ddd, J = 8.6, 2.6, 1.2 Hz, IH), 4.67 (s, 2H).
85%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2068.65 Torr; for 3h;
Preparation 26 4-amino-2-fluoro -phenol; A solution of 2-fluoro-4-nitro-phenol (400 mg, 2.55 mMol) and ethanol (6 ml_) was treated with 10% Pd/C (42.6 mg). The reaction mixture was hydrogenated for 3 hours at 40 psi at room temperature. The reaction mixture was filtered through a pad of Arbocel with ethanol and then evaporated to dryness to give a dark solid (248mg, 85%).1H NMR (400MHz, CD3OD) delta =6.29-6.31(d, 1 H), 6.39-6.43 (dd, 1 H), 6.58-6.62 (m, 1 H). GC/MS: 1.66 mins m/z (Cl) = 128 [MH+]
81%
With ammonium chloride; zinc; In tetrahydrofuran; methanol; at 0 - 20℃;
To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 0 C. was added zinc dust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a thin pad of Celite with methanol and the filtrate was concentrated in vacuo to give 4-amino-2-fluorophenol as a brown solid which was used without further purification (656 mg, 81%). 3-(4-Fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 197 mg, 1.00 mmol) was dissolved in dimethylformamide (4 mL). Triethylamine (140 muL, 1.00 mmol) was added and the solution was cooled to 0 C. 4-Amino-2-fluorophenol (Step A of Example 19, 127 mg, 1.00 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69%) as a white solid. 1H NMR (CD3OD) delta 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08-6.99 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS (ESI+) m/z 307.44 (M+H)+.
55.1%
With iron; ammonium chloride; In ethanol; water; at 20℃; for 0.5h;
To a solution of 2-fluoro-4-nitrophenol (1.57 g, 10 mmol) in EtOH (50 mL) and H20 (18 mL) was added Fe (2.24 g, 40 mmol) and NH4C1 (4.24 g, 80 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was added Eta20 (50 mL) and extracted by EtOAc (60 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was beaten by PE/EtOAc (v/v, 10 mL/15 mL), filtered to give the title compound as a brown solid (700 mg, 55.1%).LC-MS (ESI, pos, ion): 128.3 [M+H]+;H NMR (400 MHz, DMSO-Lambda) delta (ppm): 8.56 (s, 1H), 6.62 (dd, J = 10.0, 8.6 Hz, 1H), 6.34 (dd, J= 13.4, 2.6 Hz, 1H), 6.24-6.15 (m, 1H), 4.66 (s, 2H).
55.1%
With water; iron; ammonium chloride; In ethanol; at 20℃;
Iron powder (2.24 g, 40 mmol) and NH4Cl (4.24 g, 80 mmol)Add to 2-fluoro-4-nitrophenol (1.57g, 10mmol)EtOH (50mL)And H2O (18mL) solution,The reaction was stirred at room temperature overnight.The reaction solution was filtered through silica gel.The filtrate was concentrated under reduced pressure.The residue obtained was added to water (50 mL).Extract and separate the organic phase with EtOAc (60 mL x 2).Combine the resulting organic phases,Wash with saturated brine,After drying with anhydrous sodium sulfate,Concentrated under reduced pressure,The residue obtained was beaten in a mixed solvent of PE/EtOAc (v/v, 10 mL / 15 mL).filter,The title compound (700 mg, 55.1%) was obtained.
38%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 16h;
2-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10% on activated carbon, 31 mg), and EtOH (20 mL) were combined and stirred under atmospheric H2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated, and purified by preparative thin layer chromatography (30% EtOAc in hexanes) to afford 4-amino-2-fluorophenol as a tan solid of sufficient purity for subsequent transformations (152 mg, 1.20 mmol; 38% yield).
With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; for 4h;
2-fluoro-4-nitrophenol (1.15 g, 7.3 mmol) was dissolved inethanol (10 mL) and added to Pd/C (66 mg). Subsequently the flaskwas charged with hydrogen (H2) gas and the black suspension wasstirred at room temperature for 4 h. After 4 h the starting materialdisappeared as analyzed by TLC. The resulting mixture was filteredand the solvent was evaporated under reduced pressure to providethe crude product that was used directly for the next reaction step.The crude product was dissolve inwater (10 mL) with concentratedHCl (2 mL). Subsequently, NaNO2 (1.0 g, 15 mmol) and NaN3 (0.95 g,15 mmol) were added sequentially to yield 4-azido-2-fluorophenol.1H NMR (500 MHz, DMSO-d6) d 9.94 (s, 1H), 7.06e6.90 (m, 2H), 6.79(d, J 6.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) d 151.67 (d,J 242.8 Hz), 142.89 (d, J 12.1 Hz), 130.75 (d, J 8.6 Hz), 119.09,115.70, 108.26 (d, J 22.0 Hz).
(E)-methyl-2-[2-((2-fluoro-4-nitrophenoxy)methyl)phenyl]-3-methoxyacrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; In acetonitrile; for 15h;Heating / reflux;
1.2 g (3.6 mmol) of (E)-methyl-2-(2-bromomethyl)phenyl-3-methoxyacrylate was dissolved in 20 ml of acetonitrile, 1.0 g (7.2 mmol) of K2C03 and 0.57 g (3.6 mmol) of 2-fluoro-4-nitrophenol were added thereto, followed by refluxing the mixture for 15 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, 50 ml of ethyl acetate was added thereto. The resulting mixture was washed twice with water, dried over anhydrous MgS04, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 30% ethyl acetate/hexane as a eluent to obtain 1.07 g (yield 82%) of (E)-methyl-2-[2-((2-fluoro-4-nitrophenoxy)methyl)phenyl]-3- methoxyacrylate as a white solid.
With potassium carbonate; In diphenylether; at 120℃; for 2h;
Step 4: 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline-3-carbonitrile (37) A reaction mixture of quinoline 36 (836 mg, 3.36 mmol), 2-fluoro-4-nitrophenol (1056 mg, 6.72 mmol) and potassium carbonate (929 mg, 6.72 mmol) in Ph2O (13 mL) was stirred at 120 C. for another 2 hours before cooling to room temperature. The reaction mixture was diluted with EtOAc, washed with brine. The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound 37 (460 mg, 37% yield). MS (m/z): 370 (M+H).
With N-ethyl-N,N-diisopropylamine In chlorobenzene at 140℃; for 18h;
5 Production Example 5 (Starting compound 5)
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (81 g), 2-fluoro-4-nitrophenol (51 g), N,N-diisopropylethylamine (94 ml), and chlorobenzene (40 ml) were added, and the mixture was stirred with heating at 140°C for 18 hr. After the completion of the reaction, a 2 N aqueous sodium hydroxide solution (40 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the target compound (100 g, yield 92%). 1H-NMR (CDCl3, 400 MHz) : δ 8.45 (d, J = 5.4 Hz, 1H), 7.53 - 7.34 (m, 7H), 7.07 - 7.03 (m, 1H), 6.89 - 6.82 (m, 2H), 6.43 (d, J = 5.4 Hz, 1H) , 5.29 (s, 2H), 3.94 (s, 3H) Mass spectrometric value (m/z) : 421 [M+H]+
82%
With N-ethyl-N,N-diisopropylamine In chlorobenzene for 48h; Reflux;
81%
With N-ethyl-N,N-diisopropylamine In 5,5-dimethyl-1,3-cyclohexadiene at 140℃;
18.c1 Step c1: Preparation of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline
To a reaction flask were added 7-benzyloxy-4-chloro-6-methoxyquinoline (4.5 g, 15 mmol), 2-fluoro-4-nitrophenol (2.4 g, 15 mmol), DIEA (18 mL) and xylene (9 mL), the mixture was heated to 140 °C and reacted overnight, then cooled to room temperature. A solid was precipitated, then the mixture was filtered, washed with ethanol, and then suction-dried to give 3.7 g (81.0%) of a white solid. 1HNMR (300 MHz, d6-DMSO) δ 8.56 (d, J = 5.1 Hz, 1H), 8.45 (dd, J = 10.5, 2.5 Hz, 1H), 8.20 (m, 1H), 7.61 (dd, J = 8.8, 8.8 Hz, 1H), 7.56 (s, 1H), 7.53 (m, 2H), 7.48 (s, 1H), 7.32-7.47 (m, 3H), 6.78 (d, J = 5.1 Hz, 1H), 5.33 (s, 2H), 3.93 (s, 3H). MS (ESI), m/z: 421[M+H]+.
80%
With N-ethyl-N,N-diisopropylamine In toluene at 120℃; for 48h;
2.1 Step 1): 7 - benzyloxy -4 - (2 - fluoro 4 - nitrophenoxy) -6 - methoxy quinoline synthesis
To 7 - benzyloxy -4 - chloro -6 - methoxy quinoline (2.5g, 8 . 3mmol), 2 - fluoro -4 - nitro phenol (2.6g, 16 . 6mmol) adding heavy steaming in toluene (25 ml), in magnetic stirring, add DIPEA (2.7g, 20 . 9mmol), heating to 120 °C reflux 48h, TLC monitoring (petroleum ether: acetone=20:8, Rf=0.4). Cooling to room temperature by adding 200 ml ethyl acetate, for 1M NaOH solution washing the organic phase, until colorless aqueous phase, the organic phase is dried with anhydrous sodium sulfate, concentrated organic phase, adding ethyl ether recrystallization, to obtain the solid. Yield: 80%.
80%
With N-ethyl-N,N-diisopropylamine In toluene for 8h; Reflux;
5.2.6 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (7)
A solution of 7-(benzyloxy)-4-chloro-6-methoxyquinoline 6 (12g, 40mmol), 2-fluoro-4-nitrophenol (60mmol) and DIPEA (120mmol) in toluene (150mL) was refluxed for 8h, then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and purified by chromatography (PE/EA=30:1) to yield the title compound 7 as a yellow solid (13.4g, 80%). m.p. 169-170°C (170-171°C, ref 24); 1H NMR (600MHz, CDCl3) δ 8.56 (d, J=5.1Hz, 1H, Ar-H), 8.19 (dd, J=9.6, 2.4Hz, 1H, Ar-H), 8.15-8.10 (m, 1H, Ar-H), 7.52 (d, J=7.2Hz, 2H, Ar-H), 7.50 (s, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.40 (t, J=7.5Hz, 2H, Ar-H), 7.34 (t, J=8.4Hz, 2H, Ar-H), 6.54 (d, J=5.1Hz, 1H, Ar-H), 5.34 (s, 2H, PhCH2-), 4.04 (s, 3H, -OCH3). MS (ESI) m/z: 421.1 [M+H]+.
63%
With N-ethyl-N,N-diisopropylamine In chlorobenzene Heating;
1; 2 Synthesis procedure of 1-(2-fluoro-4-nitrophenyl)-6-benzyl-7-methoxy-quinoline
1-chloro-6-benzyl-7-methoxy-quinoline (10 g, 30 mmol) was dissolved in chlorobenzene (100 mL), 2-fluoro-4-nitrophenol (5 g, 30 mmol) and DIPEA (3 g, 30mmol), Stir under heating overnight. The reaction solution was diluted with water, extracted with dichloromethane, and washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness. Purified by silica gel column chromatography, obtained a yellow solid (9g, 63%)
47%
Stage #1: 7-(benzyloxy)-4-chloro-6-methoxyquinoline; 2-fluoro-4-nitrophenol With 2,6-dimethylpyridine for 5h; Reflux;
Stage #2: With potassium carbonate In water at 70℃;
C.C2 Step C2:7-Benzyloxy-4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline (C.2)
The resulting solid (20.8 g, 69 mmol), 2-fluoro-4-nitrophenol (14.1 g, 90 mmol)Was dissolved in anhydrous 2,6-lutidine (200 mL) and heated under reflux for 5 hours. The reaction was cooled to about 70 degrees,Water (200 mL), K2CO3 aqueous solution (2.0 M, 50 mL) was added. The resulting compound was cooled to 0 ° C,A large amount of solid precipitated, filtered and dried to give 13.6 g of product (47%).
45%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
1.A Step A: 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline
Dissolve 29.9g (100mmol, 1.0eq) 7-(benzyloxy)-4-chloro-6-methoxyquinoline and 23.4g (150mmol, 1.5eq) 2-fluoro-4-nitrophenol in 10mL DMF. Then, 41.4g (300mmol, 3.0eq) potassium carbonate powder was added at room temperature. After that, the reaction solution was stirred at room temperature overnight. After the reaction was complete monitored by TLC, the reaction system was poured into 550mL water, extracted with 600mL ethyl acetate, and the organic phase was sequentially washed twice with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography to afford the product (18.9 g, yield=45%).
45%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
1.A Step A: 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline
Dissolve 29.9g (100mmol, 1.0eq) 7-(benzyloxy)-4-chloro-6-methoxyquinoline and 23.4g (150mmol, 1.5eq) 2-fluoro-4-nitrophenol in 10mL DMF. Then, 41.4g (300mmol, 3.0eq) potassium carbonate powder was added at room temperature. After that, the reaction solution was stirred at room temperature overnight. After the reaction was complete monitored by TLC, the reaction system was poured into 550mL water, extracted with 600mL ethyl acetate, and the organic phase was sequentially washed twice with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography to afford the product (18.9 g, yield=45%).
39%
Stage #1: 7-(benzyloxy)-4-chloro-6-methoxyquinoline; 2-fluoro-4-nitrophenol In chlorobenzene for 48h; Reflux;
Stage #2: With sodium carbonate In chlorobenzene for 3h; Cooling;
1
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinoline (2.04 g, 6.8 mmol), 2- fluoro-4-nitrophenol (2.34g 14.9 mmol) and chlorobenzene (40 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled, diluted with saturated sodium carbonate solution (30ml) and stirred for 3 hours. The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with chloroform (3x30 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography. The pure product was solidified under diisopropyl ether to give 1.11 g of product [F]. Yield: 39%.
2.65 g
In diethyl ether at 160℃; for 5h; Inert atmosphere;
1.6 Step 6. Synthesis of 7-benzyloxy-4- (2-fluoro-4-nitro-phenoxy) -6-methyl-quinoline
The 3.0g 7-benzyloxy-4-chloro-6-methyl-quinoline, 3.2g 2-fluoro-4-nitrophenol, 50ml ether was added to a 100ml three-necked flask, heated to 160° C under a nitrogen blanket the reaction, after about 5h, cooled to room temperature, filtered, the filter cake washed with a saturated sodium light yellow powder, 2.65 g of, was used directly in the next step without purification.
In chlorobenzene for 16h; Reflux;
5.1.1. General procedure for the synthesis of intermediates 6a-c
General procedure: To a mixture of 7-(benzyloxy)-4-chloro-6-methoxyquinoline (30.0 g ,0.1 mol) in dry PhCl (180 mL) was added nitrophenols (0.15 mol). The reaction mixture was refluxed for 16 h, allowed to cool to room temperature, and concentrated under vacuum. The residue was treated with CH2Cl2 (500 mL), washed with 10% NaOH aqueous solution (3 × 50 mL) and water (50 mL) subsequently. The organic layers were dried over Na2SO4 and concentrated give the crude products which were used for the next step without further purification.
With sodium hydride; In tetrahydrofuran; at 60℃; for 2.5h;Product distribution / selectivity;
General Scheme J; General Method J; Preparation of 3- (2-Fluoro-4-nitrophenoxymethyl)-1-methylpiperidine; 3-Hydroxymethyl-l-methylpiperidine (2 g, 9.66 mmol) was dissolved in DCM (15 mL), the solution was cooled to 0 °C and methanesulfonyl chloride (0.9 mL, 11.6 mmol) was added dropwise. The reaction was then allowed to warm up to room temperature and left stirring for 24 h. After this time water (20 mL) was added to the reaction and the organic layer was separated, dried over Na2S04, filtered and solvent removed to give a colorless oil. 1H NMR indicated a mixture of the starting piperidine and the desired product. This was then dissolved in acetonitrile (30 mL) along with 2-fluoro-4-nitrophenol (1.52 g. , 9.66 mmol) ; potassium carbonate (2.67 g. , 19.32 mmol) was added and the reaction was heated at 90 °C for 18 h, then allowed to cool to room temperature. The solids were filtered and solvent removed from the filtrate. This gave 3.5 g of an orange oil. Column chromatography (5percent MeOH/DCM) gave a yellow solid which was shown to be a mixture of 2-fluoro-4-nitrophenol and 3-(2-fluoro-4-nitrophenoxymethyl)-1- methylpiperidine. The material was partitioned between DCM (30 mL) and saturated potassium carbonate solution (30 mL). The DCM layer was removed and washed with 5M HC1 (20 mL). The acidic layer was then basified to pH 10 and extracted twice with DCM (30 mL). The organics combined, dried over Na2SO4, filtered and solvent removed to give 3-(2-fluoro-4-nitrophenoxymethyl)-1- methylpiperidine as a yellow oil. 1NMR (400 MHz, (CD30D) 8.16-8. 06 (2 H, m), 7. 33 (1 H, t, J8. 8), 4.17 (1 H, m), 4.09 (1 H, m), 3. 32 (1 H, d, J 10. 8), 3.02 (1 H, t, J 11.5), 2.47 (3 H, s), 2.22 (3 H, m), 1. 89 (3 H, m), 1.75 (1 H, m), 1. 28 (1 H, m).; Alternatively, the nitro derivative was prepared as follows: 3,4-Difluoronitro phenol (3 g, 18. 7 mmol) and 3-hydroxy-1-methylpiperidine (2.5 g, 19.3 mmol) were dissolved in dry THF (100 mL) under nitrogen. Sodium hydride (60percent, 1 g, 25 mmol) was slowly added under positive nitrogen pressure. The resulting light yellow solution was heated at 60 °C for 2.5 h. The dark-red solution was left to cool to room temperature and quenched with a solution of acetic acid (0.3 mL, 5.2 mmol) in methanol (10 mL). Solvent was removed under reduced pressure to yield an orange solid that was purified by column chromatography using DCM: MeOH (75: 25) as eluent to yield 3- (2-fluoro-4-nitro phenoxymethyl)-l- methylpiperidine as an orange oil.
A solution of 2 (20 g, 0.117 mol) and 2-fluoro-4-nitrophenol (27.5 g, 0.175 mol) in chlorobenzene (400 mL) was stirred under reflux for 12 h. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was dissolved in CH2Cl2 (500 mL), and then washed with saturated aqueous K2CO3 (3×250 mL), followed by brine (200 mL). The organic phase were dried over Na2SO4 and concentrated to yield a gray solid, which was recrystallized from absolute ethanol to generate 3 as a pale-yellow solid (15.5 g, yield 45.4%). M.p. 86-88 C; 1H NMR (300 MHz, CDCl3) delta 8.70 (d, J=5.5 Hz, 1H), 8.19-8.17 (m, 1H), 8.16 (t, J=3.0 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.40-7.34 (m, 1H), 7.11 (dd, J=5.5, 2.5 Hz, 1H), 4.01 (s, 3H); ESI-MS m/z: 315.0 [M+Na]+.
40.0%
In methanol; chlorobenzene; at 20 - 120℃; for 4.5h;
After dissolving 4-chloropyridine-2-carboxylic acid methyl ester (30 g) and 2-fluoro-4-nitrophenol (41.2 g) in chlorobenzene (24 ml), the reaction mixture was stirred for 4 hours at 120 C. under a nitrogen atmosphere. The reaction mixture was brought to room temperature, methanol (100 ml) was added, and the mixture was stirred for 30 minutes. After distilling off the solvent under reduced pressure, the resultant residue was partitioned between ethyl acetate (300 ml) and 1N aqueous sodium hydroxide (150 ml). The separated organic layer was washed with 1N aqueous sodium hydroxide (100 ml) and brine (150 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then ethanol (200 ml) was added to the resultant residue and the mixture was stirred for 30 minutes. After filtering the solid, the filtrate was purified by silica gel column chromatography (YMC, SIL-60-400/230W, eluent; heptane:ethyl acetate=1:1). Fractions containing the target compound were concentrated under reduced pressure, and the obtained solid was combined with the previously obtained solid to provide 4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester (20.0 g, 40.0%) as a pale brown solid.
40.0%
(Production Example 22) 4-(4-Amino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester dihydrochloride 4-Chloropyridine-2-carboxylic acid methyl ester (30 g) and 2-fluoro-4-nitrophenol (41.2 g) were dissolved in chlorobenzene (24 ml), followed by stirring under a nitrogen atmosphere at 120 C for 4 hr. The reaction mixture was allowed to cool down to room temperature, methanol (100 ml) was added, and stirred for 30 min. The solvent was removed under reduced pressure, then the resultant residue was partitioned between ethyl acetate (300 ml) and a 1N aqueous solution of sodium hydroxide (150 ml). The separated organic layer was washed with a 1N aqueous solution of sodium hydroxide (100 ml) and brine (150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, ethanol (200 ml) was added to the resultant residue, followed by stirring for 30 min. The solid was collected by filtration and the filtrate was purified by silica gel column chromatography (YMC, SIL-60-400/230W, eluent; heptane:ethyl acetate = 1:1). Fractions containing the target compound were concentrated under reduced pressure, the resultant solid was combined to the solid above to provide 4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester as a pale brown solid (20.0 g, 40.0 %).
With sodium carbonate; In diphenylether; at 170℃; for 4h;
Step 1. 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (52)[00376] To a stirred solution of 47 (346 mg, 1.445 mmol) in diphenyl ether (6 ml) was added sodium carbonate (459 mg, 4.34 mmol) and 2-fluoro-4-nitrophenol (681 mg, 4.34 mmol). The reaction mixture was heated to 17O0C for four hours then cooled-down to room temperature. The reaction mixture was diluted with dichloromethane, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (0% to 35% EtOAc in hexanes) to afford the title compound 52 (400 mg, 1.1 11 mmol, 77%) as a yellow solid. MS: 361.0 (M+ 1).
43%
With N-ethyl-N,N-diisopropylamine; In N-methylpyrrolidinone (NMP); at 75 - 150℃; for 16h;
A mixture of <strong>[89167-34-0]4-chloro-3-iodopyridine</strong> (1.50 g, 6.30 mmol, prepared according to Tabanella, S. et al. Org. Biomol. Chem. 2003, 1, 4254-4261.), 2-fluoro-nitrophenol (Lancaster, 2.0 g, 12.7 mmol), DIPEA (5 mL), and NMP (10 mL) was heated at 150 C. After 12 h, more 2-fluoro-nitrophenol (0.50 g, 3.18 mmol) was added to the reaction mixture and heating was continued for 4 h. Most of the volatile components were removed under vacuum at 75 C., the residue treated with saturated aq. NaHCO3 solution (150 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by flash chromatography on silica gel, using 0-100% CH2Cl2/hexanes then 2% MeOH/CH2Cl2 gave the title compound (1.0 g, 43%) as a yellow solid. 1H NMR (DMSO-d6) delta 8.96 (s, 1H), 8.47 (d, 2H, J=5.5 Hz), 8.44 (dd, 1H, J=2.7, 9.2 Hz), 7.49 (dd, 1H, J=8.8, 8.2 Hz), 7.07 (d, 1H, J=5.5 Hz); MS (ESI+): m/z 361.05 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In N-methylpyrrolidinone (NMP); at 170℃; for 18h;
A mixture of <strong>[417721-69-8]4-chloro-3-iodopyridin-2-amine</strong> (3.6 g, 14.2 mmol) and 2-fluoro-4-nitrophenol (Lancaster, 4.5 g, 28.4 mmol), DIPEA (3.6 mL, 20.7 mmol) and NMP (8 mL) was placed in a glass pressure vessel and heated rapidly to 170 C. and the heating continued for 18 h. The volatile components were distilled off under reduced pressure and the viscous residue poured into ice-water (150 mL). The mixture was sonicated for 15 min in order to break up the gummy solid and the pH of the mixture was adjusted to 7.5 with saturated aq. NaHCO3 solution. The solid was collected by vacuum filtration, washed with H2O, sucked partially dry on the funnel. The partially dried solid was suspended in toluene (150 mL) and the mixture concentrated in vacuo and the process repeated 3 times to give a brown solid. The product was dissolved in MeOH (150 mL), treated with 4 M HCl/1,4-dioxane (8 mL) and stirred at room temperature for 5 min and then the mixture was concentrated in vacuo. The hydrochloride thus obtained was washed and triturated with EtOAc and partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was separated washed with brine, and then dried (MgSO4). The EtOAc solution was treated with activated charcoal, stirred at room temperature for 10 min and the charcoal filtered off. The solution was concentrate in vacuo to give the title compound (3.9 g, 74%) as a yellow solid. 1H NMR (DMSO-d6) delta 8.39 (dd, 1H, J=2.5, 10.7 Hz), 8.12 (dd, 1H, J=1.5, 9.2 Hz), 7.86 (d, 1H, J=5.6 Hz), 7.32 (dd, 1H, J=8.6, 8.6 Hz), 6.40 (br s, 2H), 6.18 (d, 1H, J=5.6 Hz).
General procedure: A mixture of 15a or 15b (0.03 mol) and 2-fluoro-4-nitrophenolor 4-nitrophenol 16a-b (45 mmol) in chlorobenzene (50 mL) wasreacted at 190 C for 30 h. Then the mixture was then poured into abeaker containing petroleum ether (100 mL). The precipitate wascollected by filtration, and dried to afford the desired product 17ad.
56.1%
In diphenylether at 180℃; for 4h;
57.18 Preparation of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (Intermediate b3)
In a 250mL three-necked flask, preheat diphenyl ether (50.289g, 0.295mol) to dissolve completely,Then 4-chloro-1H-pyrrolo[2,3-b]pyridine (10.214g, 0.067mol) and 2-fluoro-4-nitrophenol (10.274g, 0.073mol) were added in sequence, and the temperature was raised to 180°C to react During 4h, there will be a large amount of solids that cannot be stirred. When the temperature rises to 130°C, the solids dissolve and the solution appears light yellow. As the temperature rises, the color of the solution darkens, and the appearance is dark brown. After the reaction liquid is cooled, it is slowly added dropwise to 400 mL iced petroleum ether and stirred for 1 hour. During the period, the liquid is pink and the petroleum ether needs to be changed continuously until the liquid is colorless. The precipitated solid is suction filtered, and the filter cake is dried to obtain an earthy yellow powder 9.537 g, which is intermediate b3, with a yield of 56.1%.
43%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h; Microwave irradiation;
1.A
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Thibault, C. et al. Org. Lett. 2003, 5, 5023; 457 mg, 3.0 mmol, the disclosure of which is hererin incorporated by reference) and 2-fluoro-4-nitrophenol (Aldrich, 706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in NMP (3 mL) was heated at 200° C. under microwave irradiation for 1 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluding with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford a brown solid (350 mg, 43% yield). LC/MS (ESI+) m/z 274 (M+H)+.
43%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h; Microwave irradiation;
1.B
B) 4-(2-Fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine; A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (457 mg, 3.0 mmol, prepared generally according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) and 2-fluoro-4-nitrophenol (706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in 1-methyl-2-prolidinone (NMP) (3 mL) was heated at 200° C. under microwave irradiation for 1 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), and dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluting with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford the desired compound (350 mg, 43%) as a brown solid. MS(ESI+) m/z 274 (M+H)+.
43%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h; Microwave irradiation;
40%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h; Microwave irradiation;
5 Preparation of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine
The compound 4-chloro-7-azaindole(703 mg, 4.2 mmol) and 2-fluoro-4-nitrophenol (456 mg, 3 mmol) were dissolved in 1 ml of NMP,The mixture was thoroughly stirred and DIEA (583 mg, 4.2 mmol)Then microwave reaction at 200 for 1h,After the reaction is complete,Dissolved in ethyl acetate and washed with water, saturated aqueous ammonium chloride. After drying the solvent to give a bright yellow oil, the yellow color powder 5a (330 mg, 40%) was obtained by column chromatography (petroleum ether: ethyl acetate = 1: 1).
14%
Inert atmosphere;
41.1 Step 1: Preparation: 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine
4-chloro-1H-pyrrolo[2,3-b]pyridine (1g,6.6 mmol) and 2-fluoro-4-nitrophenol (1.5g,9.8 mmol) were added to 5mL of diphenyl ether, and the mixture was reacted at 190 °C under argon protection. After 1 hour, the temperature was cooled to room temperature, the reaction solution was poured into cold ethyl acetate, standing, and then the solid was filtered out. The solid was purified by column chromatography to obtain 246 mg of product, yield: 14%.
14%
Inert atmosphere;
41.1 Step 1: Preparation: 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine
4-chloro-1H-pyrrolo[2,3-b]pyridine (1g,6.6 mmol) and 2-fluoro-4-nitrophenol (1.5g,9.8 mmol) were added to 5mL of diphenyl ether, and the mixture was reacted at 190 °C under argon protection. After 1 hour, the temperature was cooled to room temperature, the reaction solution was poured into cold ethyl acetate, standing, and then the solid was filtered out. The solid was purified by column chromatography to obtain 246 mg of product, yield: 14%.
14%
Inert atmosphere;
41.1 Step 1: Preparation: 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine
4-chloro-1H-pyrrolo[2,3-b]pyridine (1g,6.6 mmol) and 2-fluoro-4-nitrophenol (1.5g,9.8 mmol) were added to 5mL of diphenyl ether, and the mixture was reacted at 190 °C under argon protection. After 1 hour, the temperature was cooled to room temperature, the reaction solution was poured into cold ethyl acetate, standing, and then the solid was filtered out. The solid was purified by column chromatography to obtain 246 mg of product, yield: 14%.
In diphenylether at 190℃; for 1h;
General procedure for the key intermediates 11a,b
General procedure: The mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (10g, 66mmol) and 4-nitrophenol 9a (13.62g, 98mmol) or 2-fluoro-4-nitrophenol 9b (15.56g, 99mmol) were refluxed in ether at 190°C for 1h and monitored by TLC. The mixture was cooled to 70°C and poured into 400mL ethyl acetate in an ice bath for 30min, light yellow solid was precipitated, filtered off and dried to obtain the title compounds 10a or 10b.
In diphenylether at 190℃; for 1h;
General procedure: The mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (10 g,66 mmol) and 4-nitrophenol 11a (13.62 g, 98 mmol) or2-fluoro-4-nitrophenol 11b (15.56 g, 99 mmol) were refluxedin diphenyl ether at 190 C for 1 h and monitored by TLC. Themixture was cooled to 70 C and poured into 400 mL ethylacetate in an ice bath for 30 min, light yellow solid wasprecipitated, filtered off and dried to obtain the title compound12a or 12b.
With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine at 200℃; Microwave irradiation;
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10 C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5 C. After the addition was complete, stirring was continued at 0 C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119-121 C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70-86 C.
13.5 g (30%)
With nitric acid; In hexane; dichloromethane;
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5C. After the addition was complete, stirring was continued at 0C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86C.
methyl 2-(2-fluoro-4-nitrophenoxy)propanoic acid[ No CAS ]
[ 7170-38-9 ]
Yield
Reaction Conditions
Operation in experiment
22.5 g (92.6%)
With potassium carbonate; In dimethyl sulfoxide; pentane;
B. Methyl 2-(2-fluoro-4-nitrophenoxy)propanoic acid A stirred mixture of 2-fluoro-4-nitrophenol (15.7 g, 0.1 mole), methyl 2-bromopropionate (16.7 g, 0.1 mole), and potassium carbonate (18.1 g, 0.13 mole) in DMSO (150 ml) was heated at 100 C. (bath temperature) for 45 minutes. After cooling, the mixture was poured into ice-water (1000 ml) and the resulting mixture extracted with ether (3*200 ml). The ether fractions were combined, pentane (150 ml) added, and the resulting solution washed with water. The organic phase was dried (MgSO4) and the solvent evaporated to give 22.5 g (92.6 percent) of the desired phenoxypropionate as a yellow liquid. This material solidified upon standing. Recrystallization from ether-hexane gave an off-white cyrstalline solid: m.p. 53-55 C.; NMR (CDCl3) was consistent with the assigned structure.
22.5 g (92.6%)
With potassium carbonate; In dimethyl sulfoxide; pentane;
B. Methyl 2-(2-fluoro-4-nitrophenoxy)propanoic acid A stirred mixture of 2-fluoro-4-nitrophenol (15.7 g, 0.1 mole), methyl 2-bromopropionate (16.7 g, 0.1 mole), and potassium carbonate (18.1 g, 0.13 mole) in DMSO (150 ml) was heated at 100C (bath temperature) for 45 minutes. After cooling, the mixture was poured into ice-water (1000 ml) and the resulting mixture extracted with ether (3 x 200 ml). The ether fractions were combined, pentane (150 ml) added, and the resulting solution washed with water. The organic phase was dried (MgSO4) and the solvent evaporated to give 22.5 g (92.6 percent) of the desired phenoxypropionate as a yellow liquid. This material solidified upon standing. Recrystallization from ether-hexane gave an off-white cyrstalline solid: m.p. 53-55C; NMR (CDCl3) was consistent with the assigned structure.
Production Example 2: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline 4-Chloro-6,7-dimethoxyquinazoline (10.23 g) and 2-fluoro-4-nitrophenol (14.37 g) were suspended in monochlorobenzene (100 ml), and the suspension was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, and the residue was washed with toluene, was filtered, and was dried. The crystal thus obtained was then suspended in an aqueous sodium hydroxide solution, and the suspensionwas filtered, followed by drying to give 4-(3-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (14.2 g, yield 90%).
With potassium carbonate In diphenylether at 180 - 190℃; for 3h;
8; 48.2
A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) was heated at 190°C in diphenylether (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM andfiltered. The filtrate was concentrated under reduced pressure and the residue was purifiedby column chromatography (eluent EtOAc:hexane, 3:1) to afford title compound 42 as ayellow solid (5.4 g, 71% yield). 1RNMR (400 MHz, DMSO-d6) 5 (ppm): 8.55 (d, J= 5.28Hz, 1H), 8.46 (dd, J= 2.5 and 10.4 Hz, 1H), 8.19 (d, J= 8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J= 8.4 Hz), 6.99 (d, J= 5.47 Hz, 1H).
71%
In diphenylether at 190℃; for 3h;
22.2
Step 2. 2-Bromo-7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridine (50); A mixture of 49 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) was heated at 190° C. in Ph2O (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM and filtered. The filtrate was concentrated and the residue was purified by column chromatography (eluent ethyl acetate/hexane 3:1) to afford title compound 50 as a yellow solid (5.4 g, 71% yield). 1H NMR (DMSO-d6) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d, J=5.47 Hz, 1H).
With potassium carbonate; In diphenylether; at 170℃; for 8h;
A mixture of 266 (180mg, l.lSmmol), 2-fluoro-4-nitrophenol (558mg,3.55mmol) and K2CO3(981mg, 7.10mmol) in Ph2O(4mL) was heated at 170C for 8 hours,cooled to room temperature and partitioned between EtOAc and water. Organic phase wascollected, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by flashcolumn chromatography with gradient elution of hexane, to hexane/EtOAc (1:1), to affordthe title compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z): 274.1(M+H)(found).
With potassium carbonate; In diphenylether; at 200℃; for 6h;
A mixture of 259 (420mg, 2.76mmol), 2-fluoro-4-nitrophenol (65 Img,4.14mmol) and K2CO3(1.14g, 8.28mmol) in Ph2O (15 mL) was heated at 200C for 6 hours,cooled to room temperature and partitioned between EtOAc and water. Organic phase wascollected, dried and concentrated. The residue was purified by flash columnchromatography with gradient elution from hexane to hexane/EtOAc (3:1), to afford the titlecompound 260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
With hydrogenchloride; In diphenylether; diethyl ether; at 120 - 200℃; for 4h;
To a suspension of 27 (0,400g, 2,60mmol) FG.B. Evans. R.H. Furneaux, et.al J.Ore. Chem.. 2001, 66. 17. 5723-5730] in diphenylether (25ml) was added 2-fluoro-4-nitrophenol (614 mg, 3.90mmol) and HC1 (2N in Et2O) (0.19 ml, 3.90mmol). The reactionmixture was heated at 120C for 4 hours, cooled to room temperature and concentratedunder reduced pressure, to afford title compound 243 (610 mg, 86% yield) as a black solid.MS(m/z):274.1(M+l).
15
A mixture of 4-chloro-5-methyl-5H-pyrrolo [3, 2- d] pyrimidine (210 mg, 1.25 mmol) , 2-fluoro-4-nitrophenol (236 mg, 1.50 mmol) and o-xylene (10 iαL) was stirred at 1000C for 2 days. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (260 mg, 72%) as a yellow solid. 1H-NMR (DMSOd6, 200 MHz) δ 4.10 (3H, s) , 6.64 - 6.65 (IH, m) , 7.81 - 7.86 (2H, m) , 8.20 - 8.24 (IH, m) , 8.30 (IH, d, J = 1.2 Hz) , 8.36 - 8.41 (IH, m) .
49%
With caesium carbonate In diphenylether at 140℃;
5; 28.2
A suspension of 4-chloro-5-methyl-5No.-pyrrolo[3,2-
With potassium carbonate In diphenylether at 180℃; for 5h;
7; 34.2
A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0 mmol)and K2CO3 (12.1 g, 87.5 mmol) in Ph2O was heated at 180°C for 5 hours. The mixture wascooled to room temperature, diluted with EtOAc and washed with water. The organic phasewas collected, dried over anhydrous sodium sulfate and the solvents were removed underreduced pressure. The residue was purified by flash chromatography using hexane - AcOEt(70:30) as an eluent. The product from the column was re-crystallized from a mixture ofethyl acetate-hexanes to afford 38 (3.6 g, 59% yield) as a white solid. *H NMR (400 MHz,DMSO-J6) 5(ppm): 8.69 (d, J = 5.2 Hz, 1H), 8.47 (dd, J = 2.4 and 10.0 Hz, 1H), 8.27 (s,1H), 8.21 (m, 1H), 7.77 (dd, J = 8.0 and 9.2 Hz, 1H), 7.06 (dd, J = 0.8 and 5.2 Hz, 1H), 3.93(s,3H).
With potassium carbonate In diphenylether at 180℃;
4-(2-fluoro-4-nitrophenoxy)-7H-pyrrolo[2,3,-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In bromobenzene at 130℃; for 4h;
4
To a sealed tube equipped with a magnetic stir bar was added 4-chloro-7H-pyrrolo[2,3-cflpyrimidine (1.0 g, 6.5 mmol, 1.0 eq.), 2-Fluoro-4-nitro-phenol (1.5 g, 9.5 mmol, 1.5 eq) and bromobenzene (5 ml). The mixture was stirred at 130° C for 4 hours. The reaction mixture was then cooled to room temperature and ether was added (5 ml). After addition of ether the resulting precipitate was filtered and washed with ether. The product was recrystallized from methanol to give 4-(2- fluoro-4-nitro-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine as an off white solid (1.6g, 89% yield). 1H NMR (400 MHz, DMSO): 12.44 (s, IH), 8.41(dd, IH), 8.34 (s, IH), 8.24 (m, IH), 7.80 (m, IH), 7.61 (m, IH), 6.69 (d, IH); MS (ESI) for C12H7FN4O3: 275 (MH+).
85%
at 130℃; for 4h; Sealed tube; Inert atmosphere;
4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3-fluoroaniline (11).
The solution of 4-chloro-7H-pyrrolo-[2,3-d]pyrimidine (1.0 g, 6.5 mmol) and 2-fluoro-4-nitrophenol (1.5 g, 9.5 mmol) in bromobenzene (5 mL) was heated at 130 °C for 4 h in a sealed tube. After that, the reaction mixture was cooled to room temperature, diluted with Et2O (5 mL) and filtered. Recrystallization in MeOH gave 4-(2-fluoro-4-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (1.6 g, 85%), which was used for the next step directly. To a solution of this nitro compound in THF (5 mL) and MeOH (5 mL) was added zinc powder (130 mg, 2 mmol) and NH4Cl (270 mg, 5 mmol). The reaction mixture was stirred at room temperature for 5 h before filtered through a Celite pad. The filtrate was diluted with EtOAc, washed with water, dried over Na2SO4 and concentrated. The residue was purified by column chromatographygiving compound 11 (115 mg, 69%) as a brown solid.
85%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h; Microwave irradiation;
With potassium carbonate In diphenylether at 200℃; for 3h;
7
Scheme 7; 7-(2-Fluoro-4-nitrophenoxy)-2-iodothieno[3,2-Z>]pyridine (24); A mixture of the 7-chloro-2-iodothieno[3,2-]pyridine (23) (Ragan J. A. et al, Organic Process Research and Development 2003, 7, 676-683) (7.0 g, 23.7 mmol), 2-fluoro-4- nitrophenol (3) (11.15 g, 71.1 mmol), K2CO3 (13.08 g, 94.8 mmol) in Ph2O (30 ml) was heated at 200 0C for 3 h. The reaction mixture was cooled to room temperature, diluted with DCM and filtered; the filtrate was collected and then concentrated. The resultant solid was triturated with diethyl ether, to afford intermediate 24 (7.3 g, 74% yield), which was used directly in the next step with no additional purification. MS (m/z): 417.0 (M+H).
With potassium carbonate In diphenylether at 180℃;
With N-ethyl-N,N-diisopropylamine; In toluene; for 24h;Reflux;
Add <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> 5.0g (25.91mmol), 2-fluoro-4-nitrophenol 4.1g (25.91mmol), toluene 50mL and DIPEA 10.1g (77.73mmol) in a 100 mL single-necked flask. After 24 hours of reflux reaction, the reaction was complete by TLC.The reaction liquid was cooled to room temperature, and sand was obtained. Column chromatography gave 5.2 g of pale yellow solid, yield 64.1%
49%
With pyridine; dmap; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;
To <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (0.900 g, 4.6 mmol), 2-fluoro-4-nitrophenol (2.3 g, 14 mmol), and N,N-dimethylpyridin-4-amine (0.068 g, 0.56 mmol) was added dioxane (10 mL) and pyridine (6.4 ml, 79 mmol). The resulting mixture was heated at 110 0C in an argon-purged sealed tube for 16 hours. An aliquot was analyzed by LCMS and indicated the presence of desired product. The reaction mixture was concentrated in vacuo and diluted with 2 N NaOH. The resulting solid was filtered, and the filtrate was extracted with CH2CI2. The organic layers were dried over sodium sulfate and filtered through a pad of silica gel along with the solids using 10% MeOH/CH2Cl2 as eluent. The collected fractions were concentrated in vacuo to yield 4-(2-fluoro-4-nitrophenoxy)-7- methoxyquinoline (0.900 g, 2.3 mmol, 49% yield) as a brownish solid. Calcd for Ci6H11FN2O4: [M]+= 314. Found: [M+H]+= 315.
With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
244.5
To a stirred solution of 5' (0.1 g, 0.3 mmol) in THF (6 mL) were added 6' (0.047 g, 0.3 mmol), PPh3 (0.16 g, 0.64 mmol) and Et3N (0.048 g, 0.48 mmol) under N2 atmosphere. The reaction mixture was cooled to 0 0C and to it was added DIAD (0.094 g, 0.48 mmol). The reaction mixture was allowed to come to rt and stirred at it for 1 h. It was quenched with water, was extracted with ethyl acetate (2x5 mL) and the combined ethyl acetate extract was washed with water and brine solution (5 mL each). The residue obtained after concentration under reduced pressure was purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 9/1) to give T (0.120 g, 85%) as a yellow solid
1.G 4- (2-Fluoro-4-nitro-1-phenoxy) -6-methoxy-7 - [(3-morpholinopropyl) oxy] quinoline (A7-1)Of the preparation
Will be thoroughly dried with intermediate A6-1(0.02 mol) and2-fluoro-4-nitrophenol (0.03 mol) was added to 50 mL of dry chlorobenzene,The temperature was raised to 135 ° C for about 8 hours. After completion of the reaction, the reaction solution was cooled,Precipitation of a large number of yellow solid,The filter cake is dissolved in an appropriate amount of dichloromethane,Washed with saturated aqueous sodium carbonate solution for 6-7 times, the organic layer was dried,Evaporated to dryness as a black oil, adding isopropyl ether beating, precipitation of a large number of yellow solid,After stirring for 1 h, the mixture was filtered and dried to obtain 8.23 g of a yellow solid powder,Yield 90.4%.
82.5%
In chlorobenzene at 140℃; for 30h;
4 7.7 General procedure for preparation of nitro compounds (7a-7d)
General procedure: A stirring mixture of an appropriate 4-chloroquinoline (0.2 mol) and 2-fluoro-4-nitrophenol (0.4 mol) in chlorobenzene (450 mL, 5 v/w) was heated to 140 °C for 30 h. The resulting mixture was cooled, and filtered. The filter cake was washed with saturated K2CO3 solution, and recrystallized with ethanol to give the corresponding nitro compounds 7a-7d. 7.7.4 4-(3-(4-(2-Fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)propyl) morpholine (7d) Light yellow solid; yield: 82.5%; mp 135-136 °C; MS (ESI) m/z (%): 458.4 [M+1]+, 480.4 [M+23]+.
82.5%
In chlorobenzene at 140℃; for 30h;
82.5%
In chlorobenzene at 140℃; for 30h;
1.8. Generalprocedure for preparation of nitro compounds (20a-20e)
General procedure: Astirring mixture of an appropriate 4-chloroquinoline (0.2 mol) and 2-fluoro-4-nitrophenol(0.4 mol) in chlorobenzene (450 mL, 5v/w) was heated to 140 for 30h. The resulting mixture was cooled, and filtered. The filter cake was washedwith saturated K2CO3 solution, and recrystallized withethanol to give the corresponding nitro compounds 20a-20e.
82.5%
In chlorobenzene at 140℃; for 30h;
5.8 General procedure for preparation of nitro compounds (7a-d)
General procedure: A stirring mixture of an appropriate 4-chloroquinoline (0.2mol) and 2-fluoro-4-nitrophenol (0.4mol) in chlorobenzene (450mL, 5v/w) was heated to 140°C for 30h. The resulting mixture was cooled, and filtered. The filter cake was washed with saturated K2CO3 solution, and recrystallized with ethanol to give the corresponding nitro compounds 7a-d.
67%
With 2,6-dimethylpyridine at 145℃; for 2h;
1 Step 1.
A mixture of 4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine (0.9 g 2.68 mmol) and 2-fluoro-4-nitrophenol (0.53 g, 3.35 mol) in 2,6-iutidine (10 mL) was stirred at 145 °C for 2 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was separated and dried over sodium sulfate. The drying agent was filtered off, and the filtrate concentrated under reduced pressure to give a residue, wTiich was purified by chromatography (100% ethyl acetate) to provide 4-(3-((4-(2-fluoro-4-nitrophenoxy)-6- methoxyquinolin-7-y])oxy)propyl)morpholine as a off-white solid (0.82 g, 67%). fH NMR (DMSO-de, 300 MHz) 8.55 (d, J= 5 1 Hz„ 1H), 8.44 (dd, J= 10.4, 2.7 Hz, 1H), 8 18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 2H), 7.52 (s, 1H), 6.76 (d, J = 5.4 Hz, 1H), 4.20 (m, 2H), 3.91 (s, 3H), 3 57 (m, 41 1). 2.46 (m, 21 1).. 2 38 (m, 4H), 1.96 (m, 21 1) ppm; MS m/e: 458.2 (M - I I) .
62%
In chlorobenzene at 140℃; for 20h;
1 7.1.7.1 4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(3-morpholino-propoxy) quinoline (16a)
General procedure: A stirring mixture of an appropriate 15a-d (20.0mmol) and 2-fluoro-4-nitrophenol (24.1mmol) in chlorobenzene (40mL) was heated to 140°C for about 20h. The reaction was considered complete when less than 5% starting material remained. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to yield a pale solid. The solid was dissolved in CH2Cl2 (80mL), and washed with saturated K2CO3 aqueous solution (2×20mL), then water (20mL), and dried over anhydrous Na2SO4, concentrated under reduced pressure to afford a wheat solid, which was recrystallized from anhydrous ethanol (30mL) to yield corresponding 16a-d.
62%
In chlorobenzene at 140℃; for 20h;
4 6.8. General procedure for preparation of nitro compounds(16a-d)
General procedure: A stirring mixture of an appropriate 15a-d (20.0 mmol) and 2-fluoro-4-nitrophenol (24.1 mmol) in chlorobenzene (40 mL) washeated to 140 C for about 20 h. The reaction was considered completewhen less than 5% starting material remained. After coolingto room temperature, the reaction mixture was concentratedunder reduced pressure to yield a pale solid. The solid was dissolvedin CH2Cl2 (80 mL), and washed with saturated K2CO3 aqueoussolution (2 20 mL), then water (20 mL), and dried overanhydrous Na2SO4, concentrated under reduced pressure to afforda wheat solid, which was recrystallized from anhydrous ethanol(30 mL) to yield corresponding 16a-d.
59.4%
In chlorobenzene at 140℃; for 20h;
4.1.9. General procedure for preparation of nitro compounds (7a-f)
General procedure: A stirring mixture of an appropriate 5a-b/6a-c (20.0 mmol) and 2-fluoro-4-nitrophenol or 4-nitrophenol (24.1 mmol) in chlorobenzene(40 mL) was heated to 140 °C for about 20 h. The reaction was considered complete when less than 5% starting material remained. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to yield a pale solid. The solid was dissolved inCH2Cl2 (80 mL), and washed with saturated K2CO3 aqueous solution(2×20 mL), then water (20 mL), and dried over anhydrous Na2SO4,concentrated under reduced pressure to afford a wheat solid, which waspurified by silica gel column chromatography (4.0%-8.0% MeOH/CH2Cl2) to yield the title compounds 7a-f as yellow solid, respectively.
With 2,6-dimethylpyridine at 140 - 145℃; for 2h; Industry scale;
Preparation of 4-f2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholm-4-yl propoxy)qumoline[00107] A solution of 4-chloro-6-rnethoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fiuoro-4-nitroρhenol (1.169 kg, 7.44 mol) in 2,6-lutidine was heated to 140-145°C, with stirring, for approximately 2 hours, at which time it was sampled for in processHPLC analysis. The reaction was considered complete when less than 5% starting material remained. The reaction mixture was then cooled to approximately 75°C and water was added.Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-600C under reduced pressure to afford the title compound (1.7 kg).1HNMR (400MHz, DMSO-d6): δ 8.54 (d, IH), 8.44 (dd, IH), 8.18 (m, IH), 7.60 (m,IH), 7.43 (s, IH), 7.42 (s, IH), 6.75 (d, IH), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]+ 337.1, 339.1, found 337.0,339.0.
With 2,6-dimethylpyridine In dichloromethane at 160℃; for 3h; Industry scale;
A solution of the product (from the previous step) and 2-fluoro-4-nitrophenol (16.8 kg) in 2,6-lutidine (55 L) was heated to approximately 160°C, with stirring, for approximately 3 hours, at which time it was sampled for in-process HPLC analysis. The reaction was considered complete with the conversion of compound from the previous step (> 83 %, HPLC). The reaction mixture was then cooled to approximately 750C, and water (315 L) was added. Potassium carbonate (47.5 kg) dissolved in water (90 L) was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, and then washed with water (82 L). The wet solid was dissolved in methylene chloride (180 L) and aqueous potassium carbonate (65 L, 5%, by weight) charged, stirred for 0.4 h and the phases were separated. This operation was repeated four times and the resulting solution was concentrated under vacuum at 35 0C (residual volume, 40 L). T-butylmethylether (85 L) was then charged and distillation continued under vacuum at 35 0C (residual volume, 50 L). This operation was repeated three times. The wet solid was then heated to approximately 52 0C in MTBE (70 L) for 0.3 h. The solid was filtered, washed with MTBE (28 L). This operation was repeated twice. The wet solid was dried under vacuum at 35-45°C under reduced pressure to afford 4-(2-fluoro-4-nitro-phenoxy)-6- methoxy-7- (3-morpholin-4-yl-propoxy) quinoline, the title compound (20.2 kg, 99% AUC). Two batches of the title compound were produced.
1.7 kg
With 2,6-dimethylpyridine at 140 - 145℃; Large scale;
Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline
Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline[0080] A solution of 4-chloro-6-methoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1.169 kg, 7.44 mol) in 2,6-lutidine was heated to 140 to 145 °C, with stirring, for approximately 2 hours, at which time it was sampled for in process HPLC analysis. The reaction was considered complete when less than 5 percent starting material remained. The reaction mixture was then cooled to approximately 75 °C, and water was added. Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55 to 60 °C under reduced pressure to afford the title compound (1.7 kg). ? NMR (400MHz, DMSO-d6): ? 8.54 (d, IH), 8.44 (dd, IH), 8.18 (m, IH), 7.60 (m, IH), 7.43 (s, IH), 7.42 (s, IH), 6.75 (d, IH), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]+ 337.1, 339.1, found 337.0, 339.0.
In chlorobenzene at 140℃; for 30h;
In chlorobenzene at 140℃; for 30h;
In chlorobenzene at 140℃; for 30h;
In chlorobenzene at 145℃; for 20h;
1.6 Step six4-(3-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholinePreparation of (VIII)
2-Fluoro-4-nitrophenol (36.73 g, 0.234 mol) was added to dry chlorobenzene (5 v/w, 250 mL).The mixture was heated to 145 ° C, and Intermediate VII (0.2 mol) was added to the reaction mixture, and the mixture was reacted at this temperature for 20 h.After completion of the reaction, the solvent was evaporated to give a white solid.After washing with a saturated potassium carbonate solution, the organic layer was collected, dried, evaporated to drynessIntermediate VIII was obtained.
In chlorobenzene at 140℃; for 20h;
59.4 g
In chlorobenzene at 145℃; for 30h;
1.10 Step 10 Synthesis of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline
Add 2-fluoro-4-nitrophenol (36.73g, 0.234mol) to dry chlorobenzene (5v/w, 250mL) and heat to 145°C, 4-chloro-6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinoline (67.4g, 0.2mol) to the reaction solution, and react at this temperature for 30h. After the reaction, the solvent was evaporated to obtain a gray solid, which was dissolved in dichloromethane, washed with saturated potassium carbonate solution, the organic layer was collected, dried, the solvent was evaporated, and the solid product was recrystallized with ethanol to obtain 59.4 g of solid product.
In chlorobenzene at 145℃; for 20h;
1.7 Preparation of 4-(3-((4-(2-Fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholine (Intermediate VIII)
Add 2-fluoro-4-nitrophenol (36.73g, 0.234mol) to dry chlorobenzene (5v/w, 250mL),Heat to 145° C., add Intermediate VII (0.2 mol) to the reaction solution, and react at this temperature for 20 hours. After the reaction is completed, the solvent is evaporated to obtain a gray solid, which is dissolved in dichloromethane, washed with saturated potassium carbonate solution, the organic layer is collected, dried, the solvent is evaporated, and recrystallized with ethanol to obtain Intermediate VIII.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1.33333h;Inert atmosphere;
(Step 4) 4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-f][1,2,4]triazine; A solution of <strong>[888720-29-4]4-chloropyrrolo[1,2-f][1,2,4]triazine</strong> (4.30 g, 28.0 mmol), 2-fluoro-4-nitrophenol (5.28 g, 33.6 mmol) and potassium carbonate (7.74 g, 56.0 mmol) added to anhydrous N-dimethylformamide (60 mL) under nitrogen atmosphere was heated at 60 C. for 1 hour and 20 minutes. The resulting mixture was allowed to cool to room temperature and then extracted with ethyl acetate. The resulting extract was concentrated and purified by silica gel chromatography (25% ethyl acetate in n-hexane) to give the target compound as a white solid (5.50 g, 20.0 mmol, 72% yield).1H NMR (400 MHz, CDCl3): 8.21-8.14 (m, 2H), 7.97 (s, 1H), 7.86 (dd, J=2.8 Hz, 1.2 Hz, 1H) 7.54 (t, J=8.0 Hz, 1H), 7.07 (dd, J=4.4 Hz, 1.2 Hz, 1H), 6.93 (dd, J=4.4 Hz, 2.8 Hz, 1H).
With N-ethyl-N,N-diisopropylamine; In toluene; at 115℃; for 12h;
Step 4) 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)quinoline To a suspension of <strong>[178984-56-0]7-(benzyloxy)-4-chloroquinoline</strong> (45 g, 0.17 mol) and 2-fluoro-4-nitrophenol (28.9 g, 0.18 mol) in toluene (42 mL) was added DIPEA (25.9 g, 0.2 mol). The suspension was heated to 115 C. for 12 hours and then concentrated in vacuo. The residue was diluted with EtOH (45 mL), stirred at 60 C. for 30 minutes, and then allowed to cool down to 0 C. in an ice bath. The solid was collected through filtration, dried in vacuo at 45 C. for 24 hours to afford the title compound as a light grey solid (59.1 g, 91%) MS (ESI, pos. ion) m/z: 391.1 [M+1]; 1H NMR (400 MHz, DMSO-d6): delta 5.33 (s, 2H), 6.79 (d, J=4.8 Hz, 1H), 7.37 (t, 1H), 7.39-7.44 (m, 3H), 7.52-7.57 (m, 3H), 7.64 (t, J=8.4 Hz, J=8.8 Hz, 1H), 8.16-8.21 (m, 2H), 8.46 (dd, J=2.8 Hz, J=10.4 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H).
Stage #1: 2-fluoro-4-nitrophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h;
Stage #2: 2-iodo-propane In N,N-dimethyl-formamide at 20 - 45℃; for 8h;
29.a
To a stirring solution of 2-fluoro-4-nitrophenol (1.6 g, 10.2 mmol) and potassium carbonate (K2CO3, 2.5 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature for 5 min. Isopropyl iodide (iPrI, 2 mL, 20.0 mmol) was then added to the reaction and the resulting mixture was stirred at room temperature for 2 h, and then heated at 45° C. for 6 h. The reaction mixture was cooled to room temperature and diethyl ether was added. The mixture was washed with deionized water and aqueous saturated sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used directly without further purification (2.0 g, 10.1 mmol, 99%).
Stage #1: 2-fluoro-4-nitrophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h;
Stage #2: 2-iodo-propane at 20 - 45℃; for 8h;
29.a Synthesis of 3-fluoro-4-isopropoxy-N-(3 -methyl-i -(quinolin-5-yl)-1 H-pyrazol-5-yl)benze-nesulfonamide
To a stirring solution of 2-fluoro-4-nitrophenol (1.6 g, 10.2 mmol) and potassium carbonate (K2C03, 2.5 g, 18.1 mmol) in DMF (10 mE) was stirred at room temperature for 5 mi Isopropyl iodide (iPri, 2 mE, 20.0 mmol) was then added to the reaction and the resulting mixture was stirred at room temperature for 2 h, and then heated at 45° C. for 6 h. The reaction mixture was cooled to room temperature and diethyl ether was added. The mixture was washed with deionized water and aqueous saturated sodium bicarbonate. The organic layer was dried (Na2504), filtered, and concentrated in vacuo. The crude product was used directly without further purification (2.0 g, 10.1 mmol, 99%)
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 120℃; for 24.0h;
<strong>[188577-69-7]3,4-dichloro-2-aminopyridine</strong> (500 mg, 3.07 mmol, prepared with reference to document: Synthetic Communications, 1997, 27(5), 861-870.) and 2-fluoro-4-nitrophenol (1.928 g, 12.27 mmol) were heated to 120 C. and melted, and stirred for 24 hrs. The molten was cooled to room temperature, and subjected to silica gel column chromatography (the eluent was dichloromethane to dichloromethane/methanol=50/1) for purification, to obtain a white solid (137 mg, 16%). 1H NMR (DMSO-d6, 300 MHz) delta 8.38 (dd, 1H, J=10.5, 2.4 Hz), 8.148.09 (m, 1H), 7.86 (d, 1H, J=5.4 Hz), 7.427.36 (m, 1H), 6.60 (br, 2H), 6.27 (d, 1H, J=5.4 Hz).
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 0.5h;
18.B B) 1-(cyclopropylmethoxy)-2-fluoro-4-nitrobenzene
B) 1-(cyclopropylmethoxy)-2-fluoro-4-nitrobenzene To a solution of 2-fluoro-4-nitrophenol (10.0 g) in DMF (100 mL) were added potassium carbonate (17.6 g) and (bromomethyl)cyclopropane (9.26 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated to give the title compound (13.8 g). 1H NMR (300 MHz, CDCl3) δ 0.32-0.51 (2H, m), 0.62-0.81 (2H, m), 1.27-1.42 (1H, m), 3.99 (2H, d, J=7.2 Hz), 7.00 (1H, t, J=8.5 Hz), 7.95-8.08 (2H, m).
2-((2-fluoro-4-nitrophenoxy)methyl)-5-phenyl-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.2%
With potassium carbonate In acetonitrile Reflux;
4.4. Synthesis of 2-((2-fluoro-4-nitrophenoxy)methyl)-5-substitutedphenyl-1,3,4-oxadiazole (5aec)
General procedure: To a solution of compound 4a-c (0.5 mmol) and 2-fluoro-4-nitrophenol (0.1 g, 0.6 mmol) in dry acetonitrile (50 mL), anhydrous potassium carbonate (0.2 g, 1.5 mmol) was added and the mixture was refluxed for 24-36 h till completion of the reaction. The solvent was evaporated under reduced pressure till dryness, and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, and the aqueous layer was extracted with water (3 x 50 mL). The combined organic extracts were washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to the get the corresponding nitro compound. The product was crystalized from methanol:ethyl acetate 4:1 v/v to give the pure title compounds.
With triethylamine In acetonitrile at 20 - 50℃; for 6h;
20.1 Step 1: preparation of 1-ethoxy-2-fluoro-4-nitrobenzene
Under room temperature, will be sequentially 2-fluoro-4-nitro-phenol (5.0 g, 31.8 mmol), bromo-ethane (8.67 g, 79.6 mmol) and triethylamine (8.05 g, 79.6 mmol) in acetonitrile (40 ml) in. After the completion of the addition, the obtained mixture is heated to 50 °C, and stirring the reaction 6 hours. After the completion of the reaction, the obtained mixture is concentrated under reduced pressure, adding water to the residue. The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated under reduced pressure to obtain 5.3 g of light yellow solid (yield 89.9%).
2-(2-fluoro-4-nitrophenoxy)-N-(4-methoxybenzyl)-3,3-dimethylhex-5-enamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With 1,4-diaza-bicyclo[2.2.2]octane In neat (no solvent) at 80℃; for 12h;
4.2. General Procedure B for Passerini-Smiles Reaction with 2-Fluoro-4-nitrophenol Derivatives
General procedure: To 1.0 equiv. of phenol were added successively 1.0 equiv. of DABCO, 2.0 equiv. of aldehyde, and 1.0 equiv. of isocyanide. The resulting mixture was stirred neat at 80 °C for 12 h. The crude product was dissolved in dichloromethane. The organic layer was washed with 1 M NaOH, water, dried over MgSO4 and then concentrated. The crude product was purified by flash chromatography on silica gel.
4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 2h;
<strong>[99586-65-9]4-chloropyridine-2-carboxamide</strong> was dissolved in 10 ml of DMF with 4-nitro-2-fluorophenol (4.0 mL, 50 mmol)Then potassium tert-butoxide as the base,The temperature was raised to 80 C for 2 h.After completion of the reaction, the solvent was removed and then extracted with ethyl acetate,Dried over anhydrous magnesium sulfate and yielded 11a (0.73 g, 45%) by column chromatography.
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 2h;
18.A (A) 1-ethoxy-2-fluoro-4-nitrobenzene
(A) 1-ethoxy-2-fluoro-4-nitrobenzene (0296) To a mixture of 2-fluoro-4-nitrophenol (1.0 g), cesium carbonate (4.2 g) and DMF (6.4 mL) was added iodoethane (1.0 mL), and the mixture was stirred at 60 °C for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.1 g). 1H NMR (300 MHz, CDCl3) δ1.44-1.58 (3H, m), 4.22 (2H, q, J = 7.0 Hz), 6.94-7.08 (1H, m), 7.92-8.12 (2H, m).
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 160℃; for 2h;
Compound 4 (1.8 g, 7.63 mmol), NMP (40 mE), Compound la (1.797 g, 11.45 mmol) and DIPEA(5.9 g, 45.78 mmol) were sequentially added to a 150 mE three-necked flask. The mixture was heated to 160 C. for 2 hours. Afier cooling to room temperature, the reaction mixture was added to water to precipitate a solid. The mixture was filtered, and the filter cake was washed with water and dried to give Intermediate 5 (2.2 g, 80% yield) as a gray solid. ECMS showed a molecular ion peak mIz[MH]: 358.1.
Multi-step reaction with 4 steps
1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 0.5 h / 20 °C
1.2: 12 h / 170 °C
2.1: ammonium chloride; iron / water; ethanol / 3 h / 80 °C
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.5 h / 0 - 20 °C
3.2: 2 h / 0 - 20 °C
4.1: sodium hydride / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere
4-(2-fluoro-4-nitrophenoxy)-6,7-bis(2-methoxyethoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With N-ethyl-N,N-diisopropylamine In toluene for 8h; Reflux;
5.2.6. 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinazoline (14a)
General procedure: A solution of 13 (13 g, 43.3 mmol), 2-fluoro-4-nitrophenol(65 mmol) and DIPEA (130 mmol) in toluene (150 mL) wasrefluxed for 8 h, and then cooled to room temperature. The reactionmixture was concentrated under reduced pressure, and purified bychromatography (PE/EA 30:1) to yield 14a as a yellow solid(15.8 g, 87%).
With N-ethyl-N,N-diisopropylamine In chlorobenzene at 140℃; for 20h;
31.1 Step 1 : 6-chloro-4-(2-fluoro-4-nitro-phenoxy)-1,7-naphthyridine
[00370] A solution of 4,6-dichloro-1,7-naphthyridine (160 mg, 0.804 mmol), DIPEA (280 uL, 1.61 mmol) and 2-fluoro-4-nitrophenol (152 mg, 0.965 mmol) in chlorobenzene (8 mL) was stirred at 140 °C for 20 h. The reaction was cooled to room temperature and water (10 mL) was added, the resulting suspension was extracted with DCM (10 mL) and 2:1 CHCh/IPA (2 x 10 mL), the combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford 6-chloro-4-(2-fluoro-4-nitro-phenoxy)-1,7-naphthyridine (276 mg) as a brown solid. LC-MS (Method 3A): 1.42 min; MS m/z 320.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 0.8 Hz, 1H), 8.95 (d, J = 5.1Hz, 1H), 8.52 (dd, J = 10.4, 2.7 Hz, 1H), 8.30 (d, J = 0.8 Hz, 1H), 8.27 (ddd, J = 9.0, 2.7, 1.4 Hz, 1H), 7.80 (dd, J = 8.9, 8.1Hz, 1H), 7.22 (dd, J = 5.1, 0.9 Hz, 1H).
P.1.A Step A:
Step A: 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline Dissolve 29.9g (100mmol, 1.0eq) 7-(benzyloxy)-4-chloro-6-methoxyquinoline and 23.4g (150mmol, 1.5eq) 2-fluoro-4-nitrophenol in 10mL DMF. Then, 41.4g (300mmol, 3.0eq) potassium carbonate powder was added at room temperature. After that, the reaction solution was stirred at room temperature overnight. After the reaction was complete monitored by TLC, the reaction system was poured into 550mL water, extracted with 600mL ethyl acetate, and the organic phase was sequentially washed twice with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by silica gel column chromatography to afford the product (18.9 g, yield=45%).
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