There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 394-41-2 * Storage: {[proInfo.prStorage]}
* 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.
3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
With potassium carbonate In acetone at 20 - 40℃; for 3 h;
To a solution of 3-fluoro-4-nitro-phenol (25.3 g, 0.16 mol) in acetone (160 ml), potassium carbonate (41.7 g, 0.30 mol) and methyl iodide (20.0 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is stirred at 40 C for 3 h. After cooling down to room temperature, dichloromethane is added to the reaction mixture, which is filtrated and evaporated. Dichloromethane is added to the residue and the organic phase is washed with H2O and brine, dried over sodium sulfate and evaporated down to give 2-fluoro-4-methoxy-1-nitro-benzene in 98 percent yield. Rf=0.5 (n-hexane:ethyl acetate = 10:1). 1H-NMR (400MHz, CDCl3) δ: 3.90 (s, 3H), 6.72-6.79 (m, 2H), 8.06-8.13 (m, 1H)
98%
With potassium carbonate In acetonitrile for 5 h; Heating / reflux
4-Methoxy-2-fluoro-1-nitrobenzene A 2 L round bottom flask equipped with a stir bar and reflux condenser was charged with acetonitrile (1 L), K2CO3 (263 g, 1.9 mol) and 4-hydroxy-2-fluoro-1-nitrobenzene (100 g, 0.64 mol). Methyl iodide (271 g, 1.9 mol) was added to the reaction mixture and heated at reflux temperatures with vigorous stirring for 5 h. The acetonitrile was removed and ethyl acetate (1 L) and H2O (700 mL) were added. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2*200 mL). The organic phases were combined and washed with H2O (2*500 mL), brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a slightly yellow solid (107 g, 98percent).
97%
With potassium carbonate In 2,4-dimethylpentan-3-one at 20 - 40℃; for 15 h;
Potassium carbonate (79.0 g, 0.57 mol) was added to a stirred solution of 3-fluoro-4- nitrophenol (45.0 g, 0.29 mol) and methyl iodide (50.0 mL, 0.81 mol) in methylethyl ketone (450 mL) at room temperature. The suspension was stirred at 40 0C for 15 hours and then allowed to cool. The mixture was diluted with water (200 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2 x 200 mL). The organic extracts were combined, dried over MgSO4 and evaporated under reduced pressure to give the title compound (48.0 g, 97percent yield) as a light yellow solid.
88%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 0 - 50℃; for 17.1667 h;
A solution of 3-fluoro-4-nitrophenol (75 g, 0.48 mol) in acetone (700 mL) was cooled in an ice-water bath. 1,8-Diazabicyclo [5,4, [0]] undec-7-ene (145 g, 0.96 mol) was then added over ca. 5 min. Finally, [IODOMETHANE] (135 g, 0.96 mol) was added over 10 min. The mixture was stirred at room temperature for 16 hr. Additional 1, 8-diazabicyclo [5,4, [0]] undec-7-ene (73 g, 0.48 mol) and iodomethane (68 g, 0.48 mol) were added, and the mixture was warmed to 50 [C] for 1 hr. After a solid was removed by filtration, the concentrated filtrate was mixed with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with additional hydrochloric acid and aqueous sodium bicarbonate, concentrated, and stirred in 1percent ethyl acetate in hexanes. The resulting solid was collected and dried to give 72 g (88percent) of the title compound.
88%
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 0 - 20℃; for 16.25 h; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 50℃; for 1 h;
A solution of 3-fluoro-4-nitrophenol (75 g, 0.48 mol) in acetone (700 mL) was cooled in an ice-water bath. 1,8-Diazabicyclo[5,4,0]undec-7-ene (145 g, 0.96 mol) was then added over ca. 5 min. Finally, iodomethane (135 g, 0.96 mol) was added over 10 min. The mixture was stirred at room temperature for 16 hr. Additional 1,8-Diazabicyclo[5,4,0]undec-7-ene (73 g, 0.48 mol) and iodomethane (68 g, 0.48 mol) were added, and the mixture was warmed to 50° C. for 1 hr. After a solid was removed by filtration, the concentrated filtrate was mixed with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with additional hydrochloric acid and aqueous sodium bicarbonate, concentrated, and stirred in 1percent ethyl acetate in hexanes. The resulting solid 3-fluoro-4-nitroanisole (72 g, 88percent) was collected and air-dried.
88%
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 0℃; for 0.0833333 h; Stage #2: at 20℃; for 16.16 h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetone at 50℃; for 1 h;
[0157] A solution of 3-fluoro-4-nitrophenol (75 g, 0.48 mol) in acetone (700 mL) was cooled in an ice-water bath. 1,8-Diazabicyclo[5,4,0]undec-7-ene (145 g, 0.96 mol) was then added over ca. 5 min. Finally, iodomethane (135 g, 0.96 mol) was added over 10 min. The mixture was stirred at room temperature for 16 hr. Additional 1,8-diazabicyclo[5,4,0]undec-7-ene (73 g, 0.48 mol) and iodomethane (68 g, 0.48 mol) were added, and the mixture was warmed to 50° C. for 1 hr. After a solid was removed by filtration, the concentrated filtrate was mixed with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with additional hydrochloric acid and aqueous sodium bicarbonate, concentrated, and stirred in 1percent ethyl acetate in hexanes. The resulting solid was collected and dried to give 72 g (88percent) of the title compound.
88%
With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 1 h;
[0303j Step A: Preparation of 2-fluoro-4-methoxy- 1 -nitrobenzene: To a suspension of 3-fluoro-4-nitrophenol (0.16 g, 1 mmol) and potassium carbonate (0.42 g, 3 mmol) in DMF (10 mL) was added iodomethane (0.24 g, 2.0 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 hour and water (50 mL) was added. The solid formed was collected by filtration, washed with water and dried to give 2-fluoro-4-methoxy-1-nitrobenzene (0.15 g, 88percent) as solid.
83%
Stage #1: With potassium carbonate In butanone at 20℃; for 0.5 h; Stage #2: at 40℃; for 22 h;
2-Fluoro-4-methoxy-l-nitro-benzeneK2C03 (35.20 g, 255 mmol) was added to a stirred solution of 3-Fluoro- 4-nitro-phenol (20.00 g, 127.30 mmol) in 2-butanone (60 mL) at room temperature. After 30 minutes methyl iodide (8.72 mL, 140.00 mmol) was added and the reaction mixture was heated at 40°C 22 hours. The mixture was concentrated under reduced pressure. AcOEt (400 mL) and H2O (600 mL) were added. The organic phase was separated and the acqueous phase was back extracted with AcOEt (3 xlOO mL). The organic layers were collected, washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The obtained solid was dissolved in DCM (300 mL) and washed with NaOH IN (200 mL). The DCM solution was concentrated under reduced pressure to afford 18.1 g of the titled compound (yield 83percent).1HNMR (CDC13) δ: 3.90 (s, 3H), 6.71-6.78 (2H, m), 8.07-8.12 (m, 1H).
83%
Stage #1: With potassium carbonate In butanone at 20℃; for 0.5 h; Stage #2: at 40℃; for 22 h;
2-Fluoro-4-methoxy-1-nitro-benzene K2CO3 (35.20 g, 255 mmol) was added to a stirred solution of 3-Fluoro-4-nitro-phenol (20.00 g, 127.30 mmol) in 2-butanone (60 mL) at room temperature. After 30 minutes methyl iodide (8.72 mL, 140.00 mmol) was added and the reaction mixture was heated at 40° C. 22 hours. The mixture was concentrated under reduced pressure. AcOEt (400 mL) and H2O (600 mL) were added. The organic phase was separated and the aqueous phase was back extracted with AcOEt (3*100 mL). The organic layers were collected, washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The obtained solid was dissolved in DCM (300 mL) and washed with NaOH 1N (200 mL). The DCM solution was concentrated under reduced pressure to afford 18.1 g of the titled compound (yield 83percent). 1HNMR (CDCl3) δ: 3.90 (s, 3H), 6.71-6.78 (2H, m), 8.07-8.12 (m, 1H).
91%
With potassium carbonate In water; N,N-dimethyl-formamide
Step 5a. 2-nitro-5-methoxy-fluorobenzene To a solution of 2.30 g (14.6 mmole) of 3-fluoro-4-nitrophenol (Aldrich) and 2.26 mL (36.6 mmole) of iodomethane in 30 mL of DMF was added 4.04 g (2.93 mmole) of potassium carbonate. The mixture was stirred at room temperature for 16 hours, then poured into 250 mL of water and extracted with 250 mL of ether. Concentration in vacuo gave a yellow solid which was purified by sublimation to give 2.27 g (91percent) of pale yellow crystals.: MS (DCl/NH3) M/Z: 189 [M+NH3 ], 224 [M+NH3 +2NH4 ].
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 4, p. 885 - 900
[2] Chemistry - A European Journal, 2014, vol. 20, # 39, p. 12553 - 12558
[3] Patent: WO2004/76455, 2004, A1, . Location in patent: Page 24
[4] Patent: US2007/232603, 2007, A1, . Location in patent: Page/Page column 16
[5] Chemistry - A European Journal, 2013, vol. 19, # 29, p. 9599 - 9605
[6] Patent: WO2007/36711, 2007, A1, . Location in patent: Page/Page column 48
[7] Organic and Biomolecular Chemistry, 2007, vol. 5, # 22, p. 3665 - 3673
[8] Patent: WO2004/9583, 2004, A2, . Location in patent: Page 190
[9] Patent: US2005/38076, 2005, A1, . Location in patent: Page/Page column 28
[10] Patent: US2005/38076, 2005, A1, . Location in patent: Page/Page column 21
[11] Patent: WO2015/175845, 2015, A1, . Location in patent: Paragraph 0303
[12] Patent: WO2012/136492, 2012, A1, . Location in patent: Page/Page column 56-57
[13] Patent: US2014/5164, 2014, A1, . Location in patent: Paragraph 0238-0240
[14] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 286 - 291
[15] Patent: US5262390, 1993, A,
[16] Patent: US5362747, 1994, A,
[17] Patent: US5399543, 1995, A,
[18] Patent: WO2004/69256, 2004, A1, . Location in patent: Page/Page column 44-45
[19] Patent: US2004/204427, 2004, A1, . Location in patent: Page/Page column 20
3
[ 394-41-2 ]
[ 77-78-1 ]
[ 446-38-8 ]
Yield
Reaction Conditions
Operation in experiment
52%
With potassium carbonate In acetone at 20℃; for 2 h; Heating / reflux
To a stirred solution of 3-fluoro-4-nitrophenol (5 g, 31.8 mmol) in acetone (100 mL) at room temperature was added potassium carbonate (15.4O g, 111 mmol) in one portion followed by dimethyl sulphate (6.04 mL, 63.7 mmol) dropwise. The resulting yellow suspension was stirred at reflux for 2 h. The reaction mixture was then cooled to room temperature, filtered and the filtrate was evaporated. The resulting yellow liquid was <n="72"/>purified by column chromatography (petroleum ether/ethyl acetate, 9/1). Homogeneous fractions were pooled and evaporated and the resulting yellow oil was crystallized from diethyl ether/petroleum ether to give 2-fluoro-4-methoxy-l -nitrobenzene as pale yellow crystals, (2.81 g, 52 percent).
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 394 - 400
[2] Patent: WO2009/84970, 2009, A1, . Location in patent: Page/Page column 70-71
[3] Australian Journal of Chemistry, 1972, vol. 25, p. 2621 - 2629
[4] Journal of the Chemical Society, 1940, p. 1268,1270
[5] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
4
[ 394-41-2 ]
[ 18107-18-1 ]
[ 446-38-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With N-ethyl-N,N-diisopropylamine In methanol; acetonitrile at 0℃; for 0.5 h; Stage #2: With methanol In acetonitrile at 20℃; for 18 h;
Preparation 7; Preparation of 4-ethenyl-3,8-difluoro-6-(methoxy)quinoline; a) 3-fluoro-4-nitrophenyl methyl ether; A solution of 3-fluoro-4-nitrophenol (25 g, 0.159 mmol) in acetonitrile (500 mL) and methanol (500 mL) was treated with diisopropyl ethylamine (28 mL). The reaction mixture was cooled in an ice-bath and after 30 minutes, trimethylsilyldiazomethane was added dropwise. The mixture was stirred at room temperature for 18 hours then evaporated under vacuum to afford the product as an oil (29.4 g, 100percent). MS (+ve ion electrospray) m/z 172 (MH+).
Reference：
[1] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[2] Patent: WO2007/129960, 2007, A2, . Location in patent: Page/Page column 35-36
[3] Patent: CN105801433, 2016, A, . Location in patent: Paragraph 0020; 0023
6
[ 5470-65-5 ]
[ 394-41-2 ]
Reference：
[1] Patent: CN107954878, 2018, A, . Location in patent: Paragraph 0022; 0029; 0036; 0038; 0043; 0050
7
[ 446-38-8 ]
[ 394-41-2 ]
Reference：
[1] Patent: CN106220516, 2016, A, . Location in patent: Paragraph 0045
8
[ 372-20-3 ]
[ 446-36-6 ]
[ 385-01-3 ]
[ 394-41-2 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 15 - 26℃; for 1.5 - 2 h;
3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13415 - 13422
10
[ 1160363-27-8 ]
[ 394-41-2 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13415 - 13422
11
[ 1160363-28-9 ]
[ 394-41-2 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13415 - 13422
12
[ 1200828-97-2 ]
[ 394-41-2 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13415 - 13422
13
[ 1160363-26-7 ]
[ 394-41-2 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13415 - 13422
14
[ 372-19-0 ]
[ 394-41-2 ]
Reference：
[1] Patent: CN105801433, 2016, A,
15
[ 372-20-3 ]
[ 446-36-6 ]
[ 394-41-2 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 1881
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1602[3] Journal of the Chemical Society, 1926, p. 159
16
[ 446-35-5 ]
[ 394-41-2 ]
Reference：
[1] Patent: CN106220516, 2016, A,
17
[ 394-41-2 ]
[ 124-41-4 ]
[ 16292-95-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 50℃; Stage #2: With hydrogenchloride In methanol; water
A solution of 3-fluoro-4-nitrophenol (0.5 g, 3.2 mmol) in 0.5M sodium methoxide in methanol (7 mL, 3.5 mmol) was stirred at 500C for 12 h. Additional 0.5M sodium methoxide in methanol (7 mL, 3.5 mmol) was added and the reaction mixture was stirred at 500C until the reaction was complete. The reaction mixture was diluted with water (50 mL), neutralised with 2M hydrochloric acid and was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated to afford J- methoxy-4-nitrophenol as a yellow solid (0.5 g, 100percent). 1H NMR (d6-DMSO) δ 10.92 (br s, IH), 7.88 (d, IH), 6.60 (d, IH), 6.46 (dd, IH), 3.86 (s, 3H); LCMS method A, (ES+) 170, RT = 1.87 min.
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3881 - 3891
[2] Patent: WO2010/142766, 2010, A2, . Location in patent: Page/Page column 43-44
18
[ 67-56-1 ]
[ 394-41-2 ]
[ 16292-95-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
for 72 h; Reflux
Step 1:To a solution of 3-fluoro-4-nitrophenol (5.00 g, 31.8 mmol) in anhydrous MeOH (100 mL) was added NaOMe (10.2 g, 192 mmol). The reaction mixture was heated atreflux for 72 h, adjusted to pH 6 with 2 M citric acid, and extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, concentrated under reduced pressure and recrystallised with EtOAc to give3-methoxy-4-nitrophenolas a brown powder (4.80 g, 88percent).1H-NMR(DMSO-d6):δ3.86 (s, 3H, CH3), 6.46 (dd, 1H,J= 9.0 & 2.2 Hz, Ph-H), 6.59 (d, 1H,J= 2.3 Hz, Ph-H), 7.89 (d, 1H,J= 9.0 Hz, Ph-H), 10.98 (s, 1H, OH).
2.7 g
for 60 h; Reflux
To a solution of 3-fluoro-4-nitrophenol (3.0 g, 19.0 mmol) in methanol (50 mL) was addedNaOMe (3.09 g, 57.32 mmol). The reaction mass was heated at reflux for 60 h. After thereaction completion, the reaction mass was concentrated, diluted with water, acidified with dil. HC1 and extracted with DCM. The organic portion was dried over Na2504 and concentrated to afford 2.7 g of the title product.’H NMR (300 MHz, DMSO-d6): 10.90 (s, 1H), 7.89-7.86 (d, J = 9.3 Hz, 1H), 6.59 (s, 1H), 6.48-6.45 (d, J = 9.3 Hz, 1H), 3.86 (s, 3H); MS [M-Hj:168.07
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 139, p. 762 - 772
[2] Patent: WO2016/55947, 2016, A1, . Location in patent: Page/Page column 66
[3] Patent: WO2009/144632, 2009, A1, . Location in patent: Page/Page column 77
Reference：
[1] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[2] Journal of the Chemical Society, 1940, p. 1268,1270
[3] Australian Journal of Chemistry, 1972, vol. 25, p. 2621 - 2629
21
[ 394-41-2 ]
[ 399-95-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen In tetrahydrofuran; ethanol at 20℃; for 4.5 h;
To a solution of 3-fluoro-4-nitrophenol (20 g) in ethanol (200 ml)-tetrahydrofuran (125 ml) was added 10percent palladium carbon (6.0 g), followed by stirring under a hydrogen atmosphere at room temperature for 4.5 hrs. The mixture was filtered to remove the catalyst, which was washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (16.1 g, 100percent) as a pale yellow solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.38 (2H, m), 6.34 (1H, m), 6.43 (1H, m), 6.59 (1H, dd, J=8.4, 10.4 Hz), 8.78 (1H, s).
98%
With iron; acetic acid In ethyl acetate for 3 h; Heating / reflux
A mixture of 4-nitro-3-fluorophenol (0.314 g, 2 mmol) and iron (0.56 g, 10 mmol) in ethyl acetate (4 ml) and acetic acid (2 ml) was refluxed for 3 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated to yield 4-amino-3-fluorophenol (53a) (0.25 g, 19.6 mmol, 98percent) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 6.48-6.58 (m, 2H), 6.61-6.70 (m, IH), 7.87 (bs, 3H).
97%
With hydrogen In ethyl acetate for 4 h;
To a dry flask purged with Argon was added 10percent PD/C (80 mg) followed by 3-fluoro- 4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an Hz atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol ; 97 percent yield) ; IH-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6. 35 (M, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6. 62 (M, 1H), 8.76 (s, 1H)
97%
With hydrogen In ethyl acetate for 4 h;
To a dry flask purged with Argon was added 10percent Pd/C (80 mg) followed by 3-flυoro-4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97 percent yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6.62 (m, 1H), 8.76 (S, 1H).
97%
With hydrogen In ethyl acetate for 4 h;
To a dry flask purged with Argon was added 10percent Pd/C (80 mg) followed by 3- fluoro-4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 ml_). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97 percent yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1 H), 6.41 (dd, J=2.5, 12.7, 1 H), 6.52-6.62 (m, 1 H), 8.76 (s, 1 H).
97%
With hydrogen In ethyl acetate for 4 h;
To a dry flask purged with Argon was added 10percent Pd/C (80 mg) followed by 3-fluoro-4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97percent yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6.62 (m, 1H), 8.76 (s, 1H).
97%
With hydrogen In ethyl acetate for 4 h;
Preparation of 4-amino-3-fluorophenol; To a dry flask purged with Argon was added 10percent Pd/C (80 mg) followed by 3-fluoro-4- nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97 percent yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6.62 (m, 1H), 8.76 (s, 1H).
96%
With hydrogen In ethyl acetate
Preparation 51; 4-Amino-3-fluoro-phenol; A mixture of 3-fluoro-4-nitrophenol (2.20 g, 14.0 mmol) in 25 mL ethyl acetate is evacuated under reduced pressure and filled with nitrogen three times. Palladium, 10percent by weight on carbon (220 mg) is added. The mixture is evacuated under reduced pressure and filled with nitrogen three times. The mixture is evacuated under reduced pressure and filled with hydrogen. The mixture is stirred under hydrogen atmosphere (balloon) over night. The mixture is then filtered over diatomaceous earth and concentrated to provide the title compound (1.7 g, 96percent) as a brown solid. 1H NMR (400 MHz, DMF-d7) δ 8.75 (s, IH), 6.78 (m, IH), 6.40 (m, IH), 6.50 (m, IH), 4.38 (s, 2H).
94%
With palladium on activated charcoal; hydrogen In ethyl acetate for 16 h;
To a stirred solution of 3-fluoro-4- nitrophenol (1, 10 g, 0.064 mol) in ethyl acetate (140 mL), Pd/C (4.0 g, 0.038 mol) was added under nitrogen atmosphere. The reaction mixture was stirred under hydrogen bladder pressure for 16h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite bed, and the filtrate was concentrated under reduced pressure to afford 4-amino-3-fluorophenol as light pink colored solid (6.9 g, 94percent). LCMS (ESI positive ion); m/z: calculated: 127.12; Observed; 128.2 (M+l).
90%
With hydrogen In ethanol at 20℃; for 3 h;
Preparation 22; 4-amino-3-fluoro -phenol; A solution of 3-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 (290mg, 90percent).1H NMR (400MHz, CD3OD) δ = 6.32-6.41(dd, 2H), 6.58-6.63 (m, 1 H).GC/MS: 1.9 mins m/z (Cl) = 128 [MH+]
82%
With hydrogen In ethanol at 20℃; for 16 h;
3-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10percent on activated carbon, 62 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 under vacuum, and purified by preparative thin layer chromatography (30percent EtOAc in hexanes) to afford 4-amino-3-fluorophenol as a tan solid of sufficient purity for subsequent transformations (331 mg, 2.60 mmol; 82percent yield).
72.3%
With palladium 10% on activated carbon; potassium formate In tetrahydrofuran; water at 50℃; for 5 h;
Step 1) 4-amino-3-fluorophenol [0204] A suspension of 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10percent Pd/C (0.4 g) and HCOOK (8.75 g, 101.85 mmol) in THF/H20 (70 mL/20 mL) was stirred at 50 °C for 5 hours, then cooled to rt, and filtered through CELITE®. The filtrate was diluted with water (30 mL) and extracted with THF (50 mL). The organic layer was dried over a2S04 and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (50mL). The organic layer was dried over anhydrous a2S04 and concentrated in vacuo to give the title compound as a brown solid (1.17 g, 72.3percent). MS (ESI, pos, ion) m/z: 128.1 [M+H]+, Rt = 0.204 min.
72.3%
With palladium 10% on activated carbon; potassium formate In tetrahydrofuran; water at 50℃; for 5 h;
Step 1) 4-amino-3-fluorophenol A suspension of 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10percent Pd/C (0.4 g) and HCOOK (8.75 g, 101.85 mmol) in THF/H2O (70 mL/20 mL) was stirred at 50° C. for 5 hours, then cooled to rt, and filtered through CELITE®. The filtrate was diluted with water (30 mL) and extracted with THF (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (50mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.17 g, 72.3percent). MS (ESI, pos, ion) m/z: 128.1 [M+H]+, Rt=0.204 min.
Reference：
[1] Patent: US2005/277652, 2005, A1, . Location in patent: Page/Page column 72-73
[2] Patent: WO2006/124118, 2006, A1, . Location in patent: Page/Page column 74
[3] Patent: WO2005/9961, 2005, A2, . Location in patent: Page/Page column 46
[4] Patent: WO2008/89388, 2008, A2, . Location in patent: Page/Page column 16
[5] Patent: WO2008/89389, 2008, A2, . Location in patent: Page/Page column 13
[6] Patent: US2006/58358, 2006, A1, . Location in patent: Page/Page column 6
[7] Patent: WO2011/130728, 2011, A1, . Location in patent: Page/Page column 58-59
[8] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3881 - 3891
[9] Patent: WO2007/140174, 2007, A2, . Location in patent: Page/Page column 44
[10] Patent: WO2018/178338, 2018, A1, . Location in patent: Page/Page column 106-107
[11] Patent: US2004/209886, 2004, A1,
[12] Patent: WO2009/144632, 2009, A1, . Location in patent: Page/Page column 63
[13] Patent: WO2005/121125, 2005, A1, . Location in patent: Page/Page column 46
[14] Patent: WO2014/22116, 2014, A2, . Location in patent: Paragraph 0204
[15] Patent: US2015/37280, 2015, A1, . Location in patent: Paragraph 0391; 0392
[16] Journal of the Chemical Society, 1941, p. 645
[17] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6525 - 6538
[18] Patent: US2007/66542, 2007, A1, . Location in patent: Page/Page column 15
[19] Patent: EP1042295, 2005, B1, . Location in patent: Page/Page column 33
[20] Patent: CN105801433, 2016, A, . Location in patent: Paragraph 0020; 0024
[21] Patent: US2016/347717, 2016, A1, . Location in patent: Paragraph 0607; 0608
[22] Patent: CN106220516, 2016, A, . Location in patent: Paragraph 0046
22
[ 394-41-2 ]
[ 7439-89-6 ]
[ 399-95-1 ]
Reference：
[1] Patent: US5798316, 1998, A,
23
[ 394-41-2 ]
[ 256935-98-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 8, p. 1697 - 1711
24
[ 35654-56-9 ]
[ 394-41-2 ]
[ 228559-87-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6277 - 6292
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 875 - 879
[4] Patent: US2008/4273, 2008, A1, . Location in patent: Page/Page column 72
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6525 - 6538
27
[ 394-41-2 ]
[ 220000-87-3 ]
[ 757251-39-1 ]
Yield
Reaction Conditions
Operation in experiment
92.5%
Stage #1: With potassium carbonate In acetonitrile for 4 h; Green chemistry Stage #2: With iron(III) chloride; hydrazine hydrate; pyrographite In methanol for 3 h; Reflux; Green chemistry
In a 250mL three-necked bottle with a magnetic stirrer, thermometer and reflux condenser,0.09 mol of 3-fluoro-4-nitrophenol, 0.10 mol of anhydrous potassium carbonate, 0.10 mol of 4-chloro-N-methylpyridine-2-carboxamide,0.003 mol of PEG-400 and 100 mL of acetonitrile were stirred under electromagnetic stirring for 4 hours in a water bath.Cool, filter, and pump to dilute acetonitrile under reduced pressure.The obtained residue, 1 g of sugar with activated carbon, 0.1 mmol of ferric chloride, 50 mL of methanol were mixed in a 250 mL four-necked flask.85percent of hydrazine hydrate was added dropwise at reflux temperature, and the addition time was 1 h. After the completion of the dropwise addition, the mixture was refluxed for 2 h.After the reaction was stopped, the mixture was filtered, and the activated carbon was washed with 40 mL of diethyl ether, and the filtrate was distilled to remove methanol. After the distillation, the solution was extracted with 240 mL of diethyl ether.The ether layers were combined, dried and concentrated to give a pale yellow liquid, ie, 21.75 g of Intermediate I, yield 92.5percent, purity 99.92percent.
92.4%
for 1.5 h;
A magnetic stirring device in the vicinity of, a thermometer and a reflux condenser 100 ml three-neck bottle in, adding 0.09 µM of 3 - fluoro -4 - nitro phenol, after heating by adding 0.10 µM of KOH, the reaction under stirring 10 min, then added to the reaction system in the 0.10 µM of 4 - chloro - N - methyl pyridine -2 - carboxamide, temperature control reaction; to TLC endpoint is detected, 1.5 h reaction end; and adding heat to the reaction system of 5percent NaOH solution, heat preservation in 80 °C -85 °C washing 3 times, at the same temperature with water washing 3 times, the reaction mixture is hot and cold water in pouring, cooling, filtering, drying to obtain the solid. The resulting solid, 1 g of the active carbon for sugar, 0.12 mmol of iron trichloride, 50 ml methanol mixed 250 ml four-mouth bottle in, at the reflux temperature next adds by drops 85percent hydrazine hydrate 0.33 µM, dropping time 1 h, after dropping, reflux 2 h. After stopping the reaction, filtration, for 40 ml ethyl ether washing activated carbon, distillation of the filtrate from methanol, after [...], for 240 ml ethyl ether extract the residue, the merger [...], drying, concentration, a pale yellow liquid that shall 21.72 g intermediate I, yield 92.4percent, purity 99.92percent.
Reference：
[1] Patent: CN108440403, 2018, A, . Location in patent: Paragraph 0018; 0024; 0025
[2] Patent: CN108558747, 2018, A, . Location in patent: Paragraph 0024-0025; 0027; 0029; 0031; 0033; 0035; 0037
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; ethanol; at 20℃; for 4.5h;
To a solution of 3-fluoro-4-nitrophenol (20 g) in ethanol (200 ml)-tetrahydrofuran (125 ml) was added 10% palladium carbon (6.0 g), followed by stirring under a hydrogen atmosphere at room temperature for 4.5 hrs. The mixture was filtered to remove the catalyst, which was washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (16.1 g, 100%) as a pale yellow solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.38 (2H, m), 6.34 (1H, m), 6.43 (1H, m), 6.59 (1H, dd, J=8.4, 10.4 Hz), 8.78 (1H, s).
98%
With iron; acetic acid; In ethyl acetate; for 3h;Heating / reflux;
A mixture of 4-nitro-3-fluorophenol (0.314 g, 2 mmol) and iron (0.56 g, 10 mmol) in ethyl acetate (4 ml) and acetic acid (2 ml) was refluxed for 3 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated to yield 4-amino-3-fluorophenol (53a) (0.25 g, 19.6 mmol, 98%) as a brown solid. 1H NMR (CDCl3, 400 MHz) delta 6.48-6.58 (m, 2H), 6.61-6.70 (m, IH), 7.87 (bs, 3H).
97%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 4h;
To a dry flask purged with Argon was added 10% PD/C (80 mg) followed by 3-fluoro- 4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an Hz atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol ; 97 % yield) ; IH-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6. 35 (M, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6. 62 (M, 1H), 8.76 (s, 1H)
97%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 4h;
To a dry flask purged with Argon was added 10% Pd/C (80 mg) followed by 3-flupsilonoro-4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97 % yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6.62 (m, 1H), 8.76 (S, 1H).
97%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 4h;
To a dry flask purged with Argon was added 10% Pd/C (80 mg) followed by 3- fluoro-4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 ml_). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97 % yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1 H), 6.41 (dd, J=2.5, 12.7, 1 H), 6.52-6.62 (m, 1 H), 8.76 (s, 1 H).
97%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 4h;
To a dry flask purged with Argon was added 10% Pd/C (80 mg) followed by 3-fluoro-4-nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97% yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6.62 (m, 1H), 8.76 (s, 1H).
97%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 4h;
Preparation of 4-amino-3-fluorophenol; To a dry flask purged with Argon was added 10% Pd/C (80 mg) followed by 3-fluoro-4- nitrophenol (1.2 g, 7.64 mmol) as a solution in ethyl acetate (40 mL). The mixture was stirred under an H2 atmosphere for 4 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97 % yield); 1H-NMR (DMSO-d6) 4.38 (s, 2H), 6.29-6.35 (m, 1H), 6.41 (dd, J=2.5, 12.7, 1H), 6.52-6.62 (m, 1H), 8.76 (s, 1H).
96%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate;
Preparation 51; 4-Amino-3-fluoro-phenol; A mixture of 3-fluoro-4-nitrophenol (2.20 g, 14.0 mmol) in 25 mL ethyl acetate is evacuated under reduced pressure and filled with nitrogen three times. Palladium, 10% by weight on carbon (220 mg) is added. The mixture is evacuated under reduced pressure and filled with nitrogen three times. The mixture is evacuated under reduced pressure and filled with hydrogen. The mixture is stirred under hydrogen atmosphere (balloon) over night. The mixture is then filtered over diatomaceous earth and concentrated to provide the title compound (1.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMF-d7) delta 8.75 (s, IH), 6.78 (m, IH), 6.40 (m, IH), 6.50 (m, IH), 4.38 (s, 2H).
95%
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; at 20℃; under 2250.23 Torr; for 8h;Autoclave;
Step B: Add 3-fluoro-4-nitrophenol (7.9 g, 50 mmol), 10% Pd/C (0.4 g, 5 wt%) and 20 mL THF to the autoclave under a hydrogen pressure of 0.3 Mpa, 20 . C reaction 8h. After the reaction is completed, the system is filtered and the filtrate is used directly in the step C operation. The organic phase was analyzed by HPLC to obtain the product compound IIIX 6.0 g, and the external standard yield was 95%.
94%
With palladium on activated charcoal; hydrogen; In ethyl acetate; for 16h;
To a stirred solution of 3-fluoro-4- nitrophenol (1, 10 g, 0.064 mol) in ethyl acetate (140 mL), Pd/C (4.0 g, 0.038 mol) was added under nitrogen atmosphere. The reaction mixture was stirred under hydrogen bladder pressure for 16h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite bed, and the filtrate was concentrated under reduced pressure to afford 4-amino-3-fluorophenol as light pink colored solid (6.9 g, 94%). LCMS (ESI positive ion); m/z: calculated: 127.12; Observed; 128.2 (M+l).
92%
427A-Preparation of 4-amino-3-fluoro-phenol Compound 427A (1.49 g, 92%) was prepared from 3-fluoro-4-nitro-phenol (2.0 g, 12.7 mmol) by a route analogous to that used for the preparation of compound 426B. It is a yellow solid and has a retention time of 4.79 min (standard LC1 method, 8 min run). MS Found: (M+H)+=128.1
90%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2068.65 Torr; for 3h;
Preparation 22; 4-amino-3-fluoro -phenol; A solution of 3-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 (290mg, 90%).1H NMR (400MHz, CD3OD) delta = 6.32-6.41(dd, 2H), 6.58-6.63 (m, 1 H).GC/MS: 1.9 mins m/z (Cl) = 128 [MH+]
82%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 16h;
3-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10% on activated carbon, 62 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 under vacuum, and purified by preparative thin layer chromatography (30% EtOAc in hexanes) to afford 4-amino-3-fluorophenol as a tan solid of sufficient purity for subsequent transformations (331 mg, 2.60 mmol; 82% yield).
72.3%
With palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 50℃; for 5h;
Step 1) 4-amino-3-fluorophenol [0204] A suspension of 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10% Pd/C (0.4 g) and HCOOK (8.75 g, 101.85 mmol) in THF/H20 (70 mL/20 mL) was stirred at 50 C for 5 hours, then cooled to rt, and filtered through CELITE. The filtrate was diluted with water (30 mL) and extracted with THF (50 mL). The organic layer was dried over a2S04 and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (50mL). The organic layer was dried over anhydrous a2S04 and concentrated in vacuo to give the title compound as a brown solid (1.17 g, 72.3%). MS (ESI, pos, ion) m/z: 128.1 [M+H]+, Rt = 0.204 min.
72.3%
With palladium 10% on activated carbon; potassium formate; In tetrahydrofuran; water; at 50℃; for 5h;
Step 1) 4-amino-3-fluorophenol A suspension of 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10% Pd/C (0.4 g) and HCOOK (8.75 g, 101.85 mmol) in THF/H2O (70 mL/20 mL) was stirred at 50 C. for 5 hours, then cooled to rt, and filtered through CELITE. The filtrate was diluted with water (30 mL) and extracted with THF (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (50mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.17 g, 72.3%). MS (ESI, pos, ion) m/z: 128.1 [M+H]+, Rt=0.204 min.
With hydrogen;palladium 10% on activated carbon; In ethanol; under 1125.11 Torr; for 2h;
In a 1 l reactor, 10 g of 4-nitro-3-fluorophenol (0.0637 mol) with a catalytic quantity of palladium adsorbed on carbon (10% by mass) in ethanol (250 ml) is hydrogenated for 2 hours under a hydrogen pressure of 1.5 bars. The reaction medium is then filtered on a millipore filter then rinsed with ethanol, followed by evaporation to dryness and the residue is triturated with diethyl ether and the reaction medium stirred in a mixture of diisopropyl ether and isopentane (1:4). After filtration of the solid and drying, a beige-coloured powder is obtained. NMR 1H (delta ppm, DMSO): 4.35 (s, 2H); 6.32-6.61 (m, 3H); 8.75 (s, 1H)
With ammonium formate;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20℃; for 1h;
EXAMPLE 3 N-[(4-Chlorophenyl)methyl]-8-fluoro-4,6-dihydroxy-3-quinolinecarboxamide [] To a mixture of 10% Pd/C and 2.0 g of 3-fluoro-4-nitrophenol in 10 mL of tetrahydrofuran and 10 mL of methanol is added 4.817 g of ammonium formate. After the reaction stirred at room temperature for 1 h, it is filtered through celite and condensed. To the residue is then added 2.57 mL of diethylethoxymethylenemalonate and 10 mL xylene. The mixture is heated to 135 C for 1 h with a Dean-Stark trap to remove formed ethanol. The reaction is cooled. The resulting solid is collected, washed with hexanes, and dried. The solid is then dissolved in 50 mL of diphenyl ether and heated to 250 C for 3 h with a Dean-Stark trap to collect ethanol. The solution is cooled and diluted with hexanes. The resulting solid is collected and dried to yield 0.527 g. A solution of 0.415 g of that solid in 4 mL of 4-chlorobenzylamine is heated to 180 C for 1 h. The solution is cooled and diluted with diethyl ether. The resulting solid is collected and recrystallized from acetone/hexanes to yield 0.226 g of the title compound as a tan solid. Physical characteristics are as follows: Mp 310-313 C.1H NMR (DMSO) delta 12.73, 10.34, 8.51, 7.35, 7.18, 4.52.IR (mull) 3195, 3127, 3097, 3068, 1651, 1639, 1612, 1538, 1493, 1399, 1352, 1283, 1193, 1142, 797 cm-1.MS (EI) m/z 346 (M+), 348, 346, 207, 206, 179, 151, 150, 142, 140, 125.
With sodium sulfide; for 0.0833333h;Microwave irradiation; Ionic liquid;
(4) the step (3) the obtained 3-fluoro -4 nitro-phenol 5mol and sodium sulphide 1mol, uniform mixing and stirring the ionic liquid, microwave heating, reaction 5 min, after the reaction, cooling to room temperature, the reaction liquid extract with methylene chloride, then dried, concentrated, to obtain 3-fluoro-4-aminophenol.
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; ethanol; for 16h;
10608] A mixture of 3-fluoro-4-nitrophenol (6 g, 38.4 mmol) and 10% Pd/C (1.8 g) inEtOH (60 mE) andTHF (36 mE) was stirred under H2 (1 atm) for 16 h. After filtration, the filtrate was concentrated to yield 4.68 g (96.5%) of4-amino -3 -fluorophenol.
With tetrabutoxytitanium; hydrogen; nickel(II) nitrate; palladium dichloride; In ethanol; at 45℃; under 1500.15 Torr; for 2h;
3-fluoro-4-nitrophenol obtained in step (3) in a weight ratio of 6: 18: 1, ethanol and the composite catalyst obtained in step (1) were charged into a four-Hydrogen was bubbled through until the hydrogen pressure in the four-necked flask was 0.2 MPamix,Maintaining hydrogen pressure,After heating to 45 C, the reaction was stirred for 2 hours,After cooling to room temperature, the resulting product was filtered,The filtrate was evaporated to distill off ethanol,To give 3-fluoro-4-aminophenol.
With sodium tetrahydroborate; water; triethylamine;
An efficient synthesis method of 4-amino-3-fluorophenol, comprising the following steps: (1) Dissolving the styrene monomer in an organic solvent, stirring and mixing uniformly, transferring to a three-necked flask, and then adding an initiator, and stirring at 60 C for 10 hours under nitrogen protection.After the reaction is completed, it is filtered and dried under vacuum to obtain polystyrene microspheres;Wherein, the mass ratio of the styrene monomer and the initiator is 3: 0.02; (2) Dispersing the polystyrene microspheres prepared above in deionized water under the action of a dispersing agent to prepare a dispersion, and adding it to a three-necked flask, followed by adding liquid paraffin, dicumyl peroxide And styrene, reacted at 60 C, filtered, and dried to obtain porous polystyrene microspheres; wherein the components are used in parts by weight:8 parts of polystyrene microspheres, 0.1 parts of dispersant, 15 parts of deionized water, 1 part of liquid paraffin, 0.05 parts of dicumyl peroxide, and 10 parts of styrene; (3) Dispersing the porous polystyrene microspheres prepared above in absolute ethanol, and then adding titanium tetrachloride to anhydrous ethanol. After the addition is completed, nitrogen gas with water is introduced, and refluxing is performed at 100 C. After reacting for 10 hours, after the reaction is finished, the precipitate is washed successively with deionized water and absolute ethanol, and finally dried to obtain a supported catalyst; wherein the mass ratio of the porous polystyrene microspheres and the nano titanium dioxide in the supported catalyst is 1:2; (4) using p-nitrophenol as a raw material, and catalytically reacting with potassium fluoride under the catalysis of copper powder to obtain 3-fluoro-4-nitrophenol; (5) Mixing 3-fluoro-4nitrophenol with deionized water, adding triethylamine dropwise, stirring and mixing uniformly, adding the supported catalyst prepared above, and adding sodium borohydride solution dropwise, after cooling to room temperature, the supported catalyst was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic phase was collected, and then distilled under reduced pressure to give a crude product which was purified by petroleum ether and dried to give the desired product.
A mixture of B9 (500 mg, 2.24 mmol, 1 eq) and 3-fluoro-4-nitro-phenol (703 mg, 4.47 mmol, 2 eq) in chlorobenzene (10 mL) was stirred at 131 C for 12 hours to give an off-white suspension. LCMS (Rt = 1.045-1.107 min) showed -25% of 545-1 and -75% of desired MS value. The reaction mixture were filtered, filtrate cake was washed with toluene (10 mL) and dried under vacuum to give a crude compound. The crude compound was basified with 10% aq.NaOH, and the suspension was stirred for 1 hour at room temperature. The mixture was filtered, filtrate cake was dried in high vacuum to give B10 (300 mg, 37.6% yield, 96.5% purity) as a yellow solid.
In diphenylether; at 140.0℃; for 24h;
Step 1. 4-(3-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (52) A stirred suspension of 4 (500 mg, 2.24 mmol) and 3-fluoro-4-nitrophenol (862 mg, 5.49 mmol) in diphenylether (10 mL) was heated at 140 C. for one day. The reaction mixture was allowed to cool to room temperature, then purified by flash column chromatography on silica gel (eluents MeOH/DCM: 0/100-05/95) and triturated with Et2O to afford the title compound 52 (857 mg, contaminated with the phenol starting material) as a pale yellow solid. MS (m/z): 345.2 (M+H).
With caesium carbonate; In butanone; for 19h;Heating / reflux;
To a cooled solution (0 C.) of 2-methoxyethanol (0.8 mL) in CH2Cl2 (50 mL) and TEA (2 mL) is added dropwise methanesulfonyl chloride (1.3 mL). After 5 min, the bath is removed and the reaction mixture allowed to warm to RT and stir for 1 hour at which point it is washed with 1.0 N NaOH, brine, dried (MgSO4), and concentrated to give an oil. Yield quantitative. MS (ESI+) for C4H10O4S m/z 155.1 (M+H)+. To a solution of <strong>[16427-44-4]2-methoxyethyl methanesulfonate</strong> (1.54 g) in 2-butanone (150 mL) is added cesium carbonate (6.50 g) and 3-fluoro-4-nitrophenol (1.52 g). The resulting mixture is refluxed for 19 hours, cooled, filtered, concentrated, and purified using silica gel chromatography (EtOAc/Heptanes). Yield 98%. 1H NMR (400 MHz, DMSO-d6) delta 7.95, 6.82, 6.67, 4.25, 3.92, 3.68, 3.33, 3.31. To a mixture of 2-methoxy-4-(2-methoxyethoxy)-1-nitrobenzene (2.0 g), 10% Pd/C (1.0 g) in MeOH (200 mL) is added conc. HCl (1.8 g). The resulting mixture is shaken at 40 psi H2 for 15 minutes. The mixture is filtered and crystallized from EtOH/Et2O to give 2-methoxy-4-(2-methoxyethoxy)aniline hydrochloride. Yield 76%. MS (ESI+) for C10H15NO3 m/z 198.1 (M+H)+. Example 156 (from 2-methoxy-4-(2-methoxyethoxy)aniline hydrochloride and 2-isocyanato-5-(trifluoromethyl)-1,3,4-thiadiazole) is prepared using Method B. Yield 50%. HRMS (ESI) calcd for C14H15N4O4SF3+H 393.0844, found 393.0838.
98%
With caesium carbonate; In butanone; for 19h;Heating / reflux;
To a cooled solution (0 C.) of 2-methoxyethanol (0.8 mL) in CH2Cl2 (50 mL) and TEA (2 mL) is added dropwise methanesulfonyl chloride (1.3 mL). After 5 minutes, the bath is removed and the reaction mixture allowed to warm to RT and stir for 1 hour, it is washed with 1.0 N NaOH, brine, dried (MgSO4), and concentrated to give an oil. Yield quantitative. MS (ESI+) for C4H10O4S m/z 155.1 (M+H)+. To a solution of <strong>[16427-44-4]2-methoxyethyl methanesulfonate</strong> (1.54 g) in 2-butanone (150 mL) is added cesium carbonate (6.50 g) and 3-fluoro-4-nitrophenol (1.52 g). The resulting mixture is refluxed for 19 hours, cooled, filtered, concentrated, and purified using silica gel chromatography (EtOAc/Heptanes). Yield 98%. 1H NMR (400 MHz, DMSO-d6) delta 7.95, 6.82, 6.67, 4.25, 3.92, 3.68, 3.33, 3.31. To a mixture of 2-methoxy-4-(2-methoxyethoxy)-1-nitrobenzene (2.0 g), 10% Pd/C (1.0 g) in MeOH (200 mL) is added conc. HCl (1.8 g). The resulting mixture is shaken at 40 psi H2 for 15 minutes. The mixture is filtered and crystallized from EtOH/Et2O. Yield 76%. MS (ESI+) for C10H15NO3 m/z 198.1 (M+H)+. Example 313 (from from 2-methoxy-4-(2-methoxyethoxy)aniline hydrochloride and phenyl 5-methylisoxazol-3-ylcarbamate) is prepared using Method C, making non-critical changes. Yield 91%. HRMS (ESI) calcd for C15H19N3O5+H 322.1403, found 322.1394
3 Preparation Example 3 (Starting compound 3)
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (9.00 g) and 3-fluoro-4-nitrophenol (5.66 g) were added to chlorobenzene (60 ml), and the mixture was stirred at 120°C for 21 hr. Chloroform (100 ml) and an aqueous sodium hydroxide solution (prepared by dissolving sodium hydroxide (2.4 g) in water (100 ml)) were added to the reaction solution, and the mixture was stirred at room temperature overnight. The organic layer was extracted with chloroform, and the chloroform layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine. The chloroform layer was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The crude thus obtained was washed with hexane/ethyl acetate (1/1), then the target compound was collected by filtration, dried and given (10.39g, yield 82%).
82%
Stage #1: 7-(benzyloxy)-4-chloro-6-methoxyquinoline; 3-fluoro-4-nitrophenol In chlorobenzene at 120℃; for 21h;
Stage #2: With sodium hydroxide In chloroform; water; chlorobenzene at 20℃;
2
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (9.00 g) and 3-fluoro-4-nitrophenol (5.66 g) were added to chlorobenzene (60 ml), and the mixture was stirred at 120°C for 21 hr. Chloroform (100 ml) and an aqueous sodium hydroxide solution (2.4 g of sodium hydroxide dissolved in 100 ml of water) were added to the reaction solution, and the mixture was stirred at room temperature overnight. The organic layer was extracted with chloroform, and the chloroform layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine. The chloroform layer was dried over sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The crude was washed with hexane/ethyl acetate (1/1), was filtered, and was dried to give a contemplated compound (10.39 g, yield 82%).
50%
With N-ethyl-N,N-diisopropylamine In chlorobenzene at 140℃; for 15h;
1 Production Example 1 (Starting compound 1)
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (29 g), 3-fluoro-4-nitrophenol (20 g), N,N-diisopropylethylamine (33 ml), and chlorobenzene (14 ml) were added, and the mixture was stirred with heating at 140°C for 15 hr. After the completion of the reaction, a 2 N aqueous sodium hydroxide solution (30 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 (40 g, yield 50%). 1H-NMR (CDCl3, 400 MHz): δ 8.58 (d, J = 5.1 Hz, 1H), 8.48 - 8.44 (m, 1H), 8.21 - 8.19 (m, 1H), 7.64 - 7.35 (m, 8H), 6.79 (d, J = 5.1 Hz, 1H), 5.33 (s, 2H), 3.94 (s, 3H) Mass spectrometric value (m/z): 421 [M+H]+
47%
With sodium hydroxide In chloroform; chlorobenzene
P.17 Production Example 17:
Production Example 17: 7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (300 mg)and 3-fluoro-4-nitrophenol (785 mg) were dissolved in chlorobenzene (3 ml), and the solution was stirred at 130°C for 5 hr. Chloroform and an aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was stirred for one hr. The reaction solution was extracted with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with hexane/ethyl acetate (1/1) to give 197 mg (yield 47%) of the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ 3.83 (s, 3H), 5.25 (s, 2H), 6.91 (d, J = 5.1 Hz, 1H), 7.29 - 7.50 (m, 9H), 8.18 - 8.23 (m, 1H), 8.56 (d, J = 5.1 Hz, 1H)
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.
In tetrahydrofuran; methanol; for 18.0h;Heating / reflux;
To a solution of 3-Fluoro-4-nitro-phenol (15.7g, 100 MMOL) in THF (300 mL), 30% KOME in Methanol (49mL, 210mmol) is added at 0C. The mixture is heated to gentle reflux for 18 hours.
a 3-(2-Fluorenylamino)-4-nitrophenol 2.17 g of 3-fluoro-4-nitrophenol and 5 g of <strong>[153-78-6]2-aminofluorene</strong> were mixed and stirred for 9 hours at 140 C. The raw mixture was taken up in ethyl acetate and water and washed with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed three times with 2N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel. 1H-NMR (D6-DMSO): delta=3.96 ppm s (2H); 6.30 dd (J=10, 2 Hz, 1H); 6.52 d (J=2 Hz, 1H); 7.28-7.45 m (3H); 7.57 s (broad) (1H); 7.60 d (J=8 Hz, 1H); 7.92 d (J=8 Hz, 1H); 7.98 d (J=8 Hz, 1H); 8.10 d (J=10 Hz, 1H); 9.70 s (1H); 10.80 s (broad) (1H).
6.A Step A
Step A 4-Isopropoxy-2-fluoronitrobenzene By the method of Example 3, Step A, 23.15 g (0.147 mole) of 3-fluoro-4-nitrophenol and 29.92 g (0.175 mole) of 2-iodopropane were reacted in the presence of 20.73 g (0.150 mole) of anhydrous potassium carbonate in 450 mL of acetone, yielding 28.0 g of 4-isopropoxy-2-fluoronitrobenzene as an oil. The NMR was consistent with the proposed structure.
2-fluoro-4-[2-(3,4-dichlorophenyl)ethoxy]-1-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; In tetrahydrofuran; for 1h;
3-Fluoro-4-nitro-phenol (10 mmoles), 2-(3,4-Dichloro-phenyl)-ethanol (10 mmoles) and triphenylphosphine (10 mmoles) were mixed together in 50 mis of THF and DIAD (10 mmoles) was added slowly. The reaction mixture was stirred for 1 hour following which the crude product was purified by column chromatography eluting 40% ethyl acetate/hexanes.
Stage #1: 2-nitro-5-hydroxy-1-fluorobenzene; isopropanol With 2-(diphenylphosphino)pyridine; di-tert-butyl-diazodicarboxylate In tetrahydrofuran at 20℃; for 22h;
Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether at 20℃; for 2h;
Stage #3: With hydrogenchloride In diethyl ether; lithium hydroxide monohydrate for 2h;
46
A mixture of 5-fluoro-4-nitrophenol (314mg, 2.0mmol), propan-2-ol (120mg, 2.0mmol), diphenyl-2-pyridylphosphine (789mg, 3.0mmol) and di-tert-butyl azodicarboxylate (691 mg, 3.0mmol) in tetrahydrofuran (15ml) was stirred at room temperature under argon for 22hrs. The mixture was treated with 1 M HCI/diethyl ether (15ml) and stirred at room temperature for 2hrs, then concentrated under vacuum and the residue dissolved in diethyl ether (10ml), treated with 5M HCI acid and stirred for 2 hrs. The organic layer was separated, washed with 5M HCI acid (15ml), then 10% Na2CO3 solution (2 x 10ml), dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 5-70% ethyl acetate/60-80 petrol ether to afford the title compound as a yellow oil (276mg, 69%).
55.14%
With di-isopropyl azodicarboxylate; triphenylphosphine In N,N-dimethyl-formamide at 20℃; for 16h; Cooling with ice;
178.1 6-((2,6-Dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((4-isopropoxy-2-(N-methylsulfonamido)phenyl) amino)nicotinamide
Step 1: Weigh 3-fluoro-4-nitrophenol (178-a, 500 mg, 3.184 mmol), isopropanol (287.03 mg, 4.776 mmol), triphenylphosphine (1.253 g, 4.776 mmol) in 100 ml of double-hole DIAD (965.75 mg, 4.776 mmol) was added dropwise under an ice bath after nitrogen replacement three times, the ice bath was removed immediately after the dropwise addition, and the reaction was stirred at room temperature for 16 hours, and the reaction was completed by TLC detection. Add 200-300 mesh silica gel to the reaction solution and mix the samples, concentrate under reduced pressure at 40°C to dryness, separate and purify by column chromatography, elute to PE:EA=20:1 with the mobile phase PE:EA=100:1, and obtain the target intermediate Form 2-fluoro-4-isopropoxy-1-nitrobenzene (178-b, 349 mg, 1.754 mmol, 55.14% yield).
With nitric acid; acetic acid; at 15 - 26℃; for 1.5 - 2h;Product distribution / selectivity;
3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) delta 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) delta - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) delta 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) delta -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
With potassium carbonate; In N,N-dimethyl-formamide; for 3h;
d) 4-Bromo-2-(3-fluoro-4-nitro-phenoxy)-butyric acid methyl ester; To the solution of 5.5 g (35.0 mmol) 3-fluoro-4-nitrophenol in 55 mL N,N-dimethylformamide, 11.8 g (45.5 mmol) <strong>[29547-04-4]methyl 2,4-dibromobutyrate</strong> and 6.3 g (45.5 mmol) potassium carbonate were added. After stirring for 3 h the reaction mixture was poured on ethyl acetate and 1 M aqueous hydrochloric acid and extracted. The organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (1:0 to 1:1 v/v) to afford the title compound as a light yellow oil (64%) which was pure enough to be used in the next step.
64%
With potassium carbonate; In N,N-dimethyl-formamide; for 3h;
15.1 4-Bromo-2-(3-fluoro-4-nitro-phenoxy)-butyric acid methyl ester To the solution of 5.5 g (35.0 mmol) 3-fluoro-4-nitrophenol (CAS Reg. No. 399-95-1) in 55 mL N,N-dimethylformamide, 11.8 g (45.5 mmol) <strong>[29547-04-4]methyl 2,4-dibromobutyrate</strong> (CAS Reg. No. 29547-04-4) and 6.3 g (45.5 mmol) potassium carbonate were added. After stirring for 3 h the reaction mixture was poured on ethyl acetate and 1 M aqueous hydrochloric acid and extracted. The organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluding with a gradient of heptane:ethyl acetate (1:0 to 1:1 v/v) to afford the title compound as a light yellow oil (64%) which was pure enough to be used in the next step.
MeOH (10 mL) and Na (368 mg, 2.0 eq.) were stirred in a 100 mL round flask. 3-fluoro-4-nitrophenol (1.26 g, 8.0 mmol) was added and reacted under reflux for 12 hours. After the reaction ended, the reactant was cooled at ambient temperature, and then the solvent was removed with a rotavapor. The reactant was extracted with 1N HCl (50ml) and DCM (50 mL x 3), and then the organic solvent layer was dried over MgSO 4 and concentrated in vacuo to provide the compound (1.23 g) (yield: 91%).
88%
With sodium methylate; for 72.0h;Reflux;
Step 1:To a solution of 3-fluoro-4-nitrophenol (5.00 g, 31.8 mmol) in anhydrous MeOH (100 mL) was added NaOMe (10.2 g, 192 mmol). The reaction mixture was heated atreflux for 72 h, adjusted to pH 6 with 2 M citric acid, and extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, concentrated under reduced pressure and recrystallised with EtOAc to give3-methoxy-4-nitrophenolas a brown powder (4.80 g, 88%).1H-NMR(DMSO-d6):delta3.86 (s, 3H, CH3), 6.46 (dd, 1H,J= 9.0 & 2.2 Hz, Ph-H), 6.59 (d, 1H,J= 2.3 Hz, Ph-H), 7.89 (d, 1H,J= 9.0 Hz, Ph-H), 10.98 (s, 1H, OH).
2.7 g
With sodium methylate; for 60.0h;Reflux;
To a solution of 3-fluoro-4-nitrophenol (3.0 g, 19.0 mmol) in methanol (50 mL) was addedNaOMe (3.09 g, 57.32 mmol). The reaction mass was heated at reflux for 60 h. After thereaction completion, the reaction mass was concentrated, diluted with water, acidified with dil. HC1 and extracted with DCM. The organic portion was dried over Na2504 and concentrated to afford 2.7 g of the title product.?H NMR (300 MHz, DMSO-d6): 10.90 (s, 1H), 7.89-7.86 (d, J = 9.3 Hz, 1H), 6.59 (s, 1H), 6.48-6.45 (d, J = 9.3 Hz, 1H), 3.86 (s, 3H); MS [M-Hj:168.07
Preparation 49; 3-Methoxy-4-nitro-phenol; Sodium (1.27 g, 55.38 mMol) was dissolved in MeOH (20 ml_). To this solution was added 3-fluoro-4- nitro-phenol (2.90 g, 18.46 mMol) in one portion. The brown reaction mixture was then heated at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, was acidified to pH 1 with 1 M HCI (aq), and was then extracted with EtOAc (2 x 50 ml_) and washed with water (3 x 20 ml_). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a brown solid that was used in crude form for the next reaction.
A solution of 3-fluoro-4-nitrophenol (0.5 g, 3.2 mmol) in 0.5M sodium methoxide in methanol (7 mL, 3.5 mmol) was stirred at 500C for 12 h. Additional 0.5M sodium methoxide in methanol (7 mL, 3.5 mmol) was added and the reaction mixture was stirred at 500C until the reaction was complete. The reaction mixture was diluted with water (50 mL), neutralised with 2M hydrochloric acid and was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated to afford J- methoxy-4-nitrophenol as a yellow solid (0.5 g, 100%). 1H NMR (d6-DMSO) delta 10.92 (br s, IH), 7.88 (d, IH), 6.60 (d, IH), 6.46 (dd, IH), 3.86 (s, 3H); LCMS method A, (ES+) 170, RT = 1.87 min.
With potassium carbonate at 85℃; Cooling with dry ice;
131A
N,N-Dimethylformamide (15 mL) was added to 3-fluoro-4-nitrophenol (1.01 g, 6.43 mmol) and potassium carbonate (5.33 g, 38.6 mmol) in a 50 mL stainless steel reactor. The vessel was sparged briefly with CF2HCl, chilled with dry ice, and then chlorodifluoromethane (3.34 g, 38.6 mmol) was transferred into the reactor through a polypropylene tube. The mixture was stirred at 85 0C for 2 hours. The supernatant mixture was concentrated onto silica gel. Purification via flash chromatography (0-40% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-J6) δ ppm 8.28 (t, J=9.16 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.50 (t, J=72.39 Hz, 1 H), 7.21 - 7.29 (m, 1 H)
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃;
25.D
To a mixture of 3-fluoro-4-nitrophenol (2.02 g) , tert- butyl [ (IS) -2-hydroxy-l-methylethyl] carbamate (5.62 g) ,triphenylphosphine (8.41 g) and THF (60 mL) was added dropwise a toluene solution (1.9 M, 16.9 mL) of diisopropyl azodicarboxylate. ' at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (4.03 g) .XH NMR (300 MHz, CDC13) δ 1.30 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 3.94-4.14 (3H, m) , 4.62 (1H, brs) , 6.68-6.87 (2H, m) , 8.02-8.17 (1H, m) .
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
Step (i): Preparation of tert-Butyl 4-(3-fluoro-4-nitro phenoxy) piperidine-l-carboxylate3-Fluoro-4-nitro phenol (5 g, 0.032 moles), potassium carbonate (6.34 g, 0.047 moles) and tert-Butyl 4-(toluene-4-sulfonyloxy) piperidine-l-carboxylate (14 g, 0.04 moles) in dimethylformamide (50 mL) were stirred at 100 C. After completion of reaction, the mass was quenched on to water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The resulting organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate: hexane, 0.5:9.5) to afford the title compound 9.23 g (Yield: 85 %).
85%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
Step (i): Preparation of tert-Butyl 4-(3-fluoro-4-nitro phenoxy)piperidine-1-carboxylate 3-Fluoro-4-nitro phenol (5 g, 0.032 moles), potassium carbonate (6.34 g, 0.047 moles) and tert-Butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (14 g, 0.04 moles) in dimethylformamide (50 mL) were stirred at 100 C. After completion of reaction, the mass was quenched on to water (100 mL) and extracted with ethyl acetate (2*100 mL). The resulting organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 0.5:9.5) to afford the title compound 9.23 g (Yield: 85%). 1H-NMR (delta ppm): 1.47 (9H, s), 1.75-1.82 (2H, m), 1.94-1.99 (2H, m), 3.35-3.41 (2H, m), 3.67-3.73 (2H, m), 4.54-4.59 (1H, m), 6.72-6.77 (2H, m), 8.07-8.11 (1H, m); Mass (m/z): 341.3 (M+H)+.
A mixture of 3-fluoro- 4-nitrophenol (0.644 g, 4.10 mmol) and 60percent sodium hydride (0.215 g, 5.60 mmol) in dimethylformamide (20 mL) was stirred 15 min. 4-Bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol) was added and the mixture stirred at 110 °C for 18 h. After partitioning between water and ethyl acetate, the organics were washed with water and brine. The solvent was removed under vacuum, and the residue was purified by columnchromatography (0-5percent methanol in dichloromethane).
2-[(3-fluoro-4-nitrophenoxy)methyl]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60℃; for 1.5h;
General procedure: To a mixture of 3-bromo-4-nitrophenol (26, 4.91 g, 22.5 mmol), 2-(chloromethyl)quinoline hydrochloride (5.79 g, 27.0 mmol) and potassium iodide (374 mg, 2.25 mmol) in DMF (50 mL) was added K2CO3 (7.47 g, 54.1 mmol), and the mixture was stirred at 60 C for 90 min. After cooling at room temperature, the mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was washed with EtOAc-hexane to give 27 (6.89 g, 85%) as a pale yellow solid.
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18h; Inert atmosphere;
3-(3-fluoro-4-nitrophenoxyl)-N,N-dimethylpropan-1-amine (9f)
To a 250 ml round-bottom flask was added 3-fluoro-4-nitrophenol (2.0 g, 12.7 mmol), DMF (100 ml), N,N-dimethylaminopropylchloride hydrochloride (2.4 g, 15.3 mmol, 1.2 eq), and K2CO3 (3.9 g, 28.0 mmol). The reaction was stirred and heated to 60 °C for 18 hours before cooling to RT, filtration and concentration. The crude was purified via flash column (DCM - MeOH : 90 % - 10 %) to yield a yellow oil as the product (2.0 g, 64 % yield).
64%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18h; Inert atmosphere;
113-(3-fluoro-4-nitrophenoxyl)-N,N-dimethylpropan-1-amine (9f)
To a 250 ml round-bottom flask was added 3-fluoro-4-nitrophenol (2.0 g, 12.7 mmol), DMF (100 ml), N,N-dimethylaminopropylchloride hydrochloride (2.4 g, 15.3 mmol, 1.2 eq), and K2CO3 (3.9 g, 28.0 mmol). The reaction was stirred and heated to 60 °C for 18 hours before cooling to RT, filtration and concentration. The crude was purified via flash column (DCM -MeOH : 90 % - 10 %) to yield a yellow oil as the product (2.0 g, 64 % yield).
2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.9%
With potassium carbonate; potassium iodide; In acetonitrile; at 60℃; for 2h;Inert atmosphere;
3-fluoro-4-nitrophenol (200.0 g, 1.27 mol) was added to a solution of <strong>[71670-70-7]2-(chloromethyl)-5-methylpyridine hydrochloride</strong> (222 g, 1.25 mol), powdered potassium carbonate (383.6 g, 2.75 mol), potassium iodide (207 g, 1.25 mol), and acetonitrile (3.4 L). The resulting mixture was stirred at 60 Celsius for 2 h. The reaction was cooled to RT, concentrated to dryness and partitioned between H2O (1.5 L) and ethyl acetate (1.5 L). The organic layers were separated and the aqueous layer was extracted with ethyl acetate (1.0 L). The combined organic layers were washed with brine (1 L) then dried over magnesium sulfate, filtered, and concentrated to dryness. The crude solid was recrystallized from i-PrOH (1.5 L) at 70 Celsius. After cooling to 0 Celsius the solid was collected by filtration and rinsed with i-PrOH (2×200 mL) and heptanes (2×200 mL) to yield the title compound as a dark solid (242.0 g, 73.9%). MS (ESI): mass calcd. for C13H11FN2O3, 262.10; m/z found, 263.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta 8.44 (s, 1H), 8.16 (t, J=9.2, 1H), 7.76-7.62 (m, 1H), 7.45 (d, J=7.9, 1H), 7.30 (dd, J=13.7, 2.5, 1H), 7.07 (dd, J=9.3, 1.9, 1H), 5.30 (s, 2H), 2.31 (s, 3H).
2-((4-fluoro-3-nitrophenoxy)methyl)quinolone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
Intermediate A: 2-((4-Fluoro-3-nitrophenoxy)methyl)quinolone To a mixture of 3-fluoro-4-nitrophenol (25 g, 159 mmol), <strong>[3747-74-8]2-(chloromethyl)-quinoline hydrochloride</strong> (34 g, 159 mmol) and cesium carbonate (129 g, 398 mmol) was added DMF (530 mL) and the resulting suspension was allowed to stir at RT for 24 h. The reaction mixture was then poured into a large excess of water. The resulting solids were isolated by filtration and were dried to afford the title compound. MS (ESI): mass calcd. for C16H11FN2O3, 298.08; m/z found, 299.1 [M+H]+. 1H NMR (500 MHz, CDCl3) 8.22 (d, J=8.5, 1H), 8.09 (d, J=8.4, 1H), 7.84 (d, J=8.2, 1H), 7.79-7.72 (m, 2H), 7.61 (d, J=8.5, 1H), 7.58 (ddd, J=8.1, 6.9, 1.1, 1H), 7.29 (dt, J=9.2, 3.4, 1H), 7.20 (dd, J=10.1, 9.3, 1H), 5.41 (s, 2H).
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
A mixture of 3-fluoro-4-nitrophenol (2.56 g; 16.30 mmol), diethyl (3-bromopropyl)-phosphonate (3.26 ml; 16.98 mmol) and potassium carbonate (2.48 g; 17.9 mmol) in ACN (20 ml) is stirred for 4 h at 80 C. After cooling to r.t. the insoluble material is filtered off and discarded. The mother liquor is evaporated. [0183] C13H19FNO6P ESI Mass spectrum: m/z=336 [M+H]+
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
A mixture of 3-fluoro-4-nitrophenol (2.56 g; 16.30 mmol), diethyl (3-bromopropyl)-phosphonate (3.26 ml; 16.98 mmol) and potassium carbonate (2.48 g; 17.9 mmol) in ACN (20 ml) is stirred for 4 h at 80 C. After cooling to r.t. the insoluble material is filtered off and discarded. The mother liquor is evaporated. C13H19FNO6P ESI Mass spectrum: m/z=336 [M+H]+
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
Intermediate VII.1 A mixture of 3-fluoro-4-nitrophenol (2.56 g; 16.30 mmol), diethyl (3-bromopropyl)-phosphonate (3.26 ml; 16.98 mmol) and potassium carbonate (2.48 g; 17.9 mmol) in ACN (20ml) is stirred for 4 h at 80C. After cooling to r.t. the insoluble material is filtered off and discarded. The mother liquor is evaporated. Ci3H19FN06P ESI Mass spectrum: m/z = 336 [M+H]+
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
Intermediate VII.1A mixture of 3-fluoro-4-nitrophenol (2.56 g; 16.30 mmol), diethyl (3-bromopropyl)-phosphonate (3.26 ml; 16.98 mmol) and potassium carbonate (2.48 g; 17.9 mmol) in ACN (20ml) is stirred for 4 h at 80C. After cooling to r.t. the insoluble material is filtered off and discarded. The mother liquor is evaporated.Ci3H19FN06P ESI Mass spectrum: m/z = 336 [M+H]+
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 30℃; for 8h;
Preparation of L8 (many synthetic processes are available for this type of monomers; herein convenient processes areexemplified):
[0055] To a reaction system, 120mL dichloromethane, 15g (1.0eq.) 4-pentylbenzoic acid, 12.5 g (1.02 eq.) 3-fluoro-4-nitrophenol, 16.9 g (1.05 eq.) DCC and a catalytic amount of DMAP (0.05 g) are added and stirred for 8 hours at 30°Cfor reaction, and then are processed to give 20 g product. [H-NMR (400M, CDCl3) δ: (ppm) 7-8 (d, 7H), 2.5 (m, 2H),1.2-1.7 (m, 8H), 0.95 (m, 3H)].
3-fluoro-4-nitrophenyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-galactopyranoside[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
Stage #1: 3-fluoro-4-nitrophenol; 2-acetamido-2,4,6,-tri-O-acetyl-1-chloro-1,2-dideoxy-α-D-galactopyranose With N-benzyl-N,N,N-triethylammonium chloride In dichloromethane
Stage #2: With sodium hydroxide In dichloromethane at 20℃;
General Procedure A: Synthesis of Aryl 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-galactopyranosides(S5e-j).
General procedure: To a mixture of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-galactopyranosyl chloride (S4, 1 equiv), benzyltriethylammoniumchloride (1 equiv), and acceptor phenol (2equiv) was added sufficient dichloromethane (1 volume) toyield a solution of 200 mM chlorosugar. An equal volume of 1M sodium hydroxide was added, and the resulting biphasicmixture was stirred vigorously at room temperature for 1-3 h.Upon completion, ethyl acetate (5 volumes) was added, andthe organic phase was washed successively with 1 M NaOH (1volume), water (2 × 1 volume), and brine (1 volume). Thecombined organic layers were dried (MgSO4), filtered, andconcentrated under vacuum. The crude product was purified bycolumn chromatography to produce aryl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-galactopyranosides as crystalline solids inyields ranging from 39 to 68%.
9-(3-fluoro-4-nitrophenoxy)-1,6,6-trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In chlorobenzene at 120℃; for 36h; Sealed tube; regioselective reaction;
Typical experimental procedure for the catalyst-free Aromatic ethers reaction.
General procedure: A 10 mL sealed tube was charged with Tan-IIA substrates (0.1 mmol), various phenol (0.17 mmol), and TEMPO (0.2 mmol). PhCl (1 mL) was added, and the resulting mixture was stirred at 120°C. The reaction was monitored by TLC until the starting material disappeared. Then the solvent was removed under vacuum, and the resulting residue was purified by chromatography on a silica gel column to furnish the desired compound 4 as red solids.
4-(4,4-dimethylcyclohexoxy)-2-fluoro-1-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
Diisopropyl azodiformate (1.3 g, 6.1 mmol) was added dropwise to a solution of triphenylphosphine (1.6 g, 6.1 mmol), 3-fluoro-4-nitrophenol (1.0 g, 6.1 mmol) and 4.4- dimethylcyclohexanol (0.65 g, 5.1 mmol) in 20 ml of tetrahydrofuran. The reaction mixture was stirred for 16 h at room temperature, then diluted with ethyl acetate and water. The phases were separated, the organic layer was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The remainder was purified by chromatography on silica gel, using ethyl acetate and cyclohexane as eluents, to deliver 4-(4,4-dimethylcyclohexoxy)-2-fluoro-1-nitro-benzene. H-NMR (400 MHz, CDCI3): delta = 0.98 (s, 3H), 0.99 (s, 3H), 1.25 - 1.31 (m, 2H), 1 .50 - 1.56 (m, 2H), 1 .69 - 1.77 (m, 2H), 1.86 - 1.92 (m, 2H), 4.32 (q, 1 H), 6.68 - 6.75 (m, 2H), 8.07 (t, 1 H).
2-methyl-4-[(2-nitro-5-[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.6 g
Step (i): Preparation of 2-methyl-4-[(2-nitro-5-[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol (Compound 86) To a solution of Compound 76 (0.35 g) in NMP (7.5 mL) at room temperature was added diisopropylethylamine (1.01 g). To the mixture was added 4-amino-2-methylbutan-2-ol hydrochloride (0.37 g), and the reaction solution was heated to 110 C., and stirred for 3.5 hours. The reaction solution was cooled to room temperature. To reaction solution were added cesium carbonate (0.95 g) and <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (0.42 g), and the reaction solution was heated to 110 C., and stirred for 4 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added thereto, and the objective product was extracted in the organic layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate=65/35) to give Compound 86 (0.6 g).
0.6 g
Diisopropylethyl amine (1.01 g) was added at room temperature to a solution of compound 76 (0.35 g) in NMP (7.5 mL).4-amino-2-methylbutan-2-ol hydrochloride (0.37 g) was added,The reaction solution was heated to 110 C.,And the mixture was stirred for 3.5 hours.The reaction solution was cooled to room temperature,Cesium carbonate (0.95 g) and 2-fluoro-5- (trifluoromethyl) pyridine (0.42 g)The reaction solution was heated to 110 C.,And the mixture was stirred for 4 hours.The reaction solution was cooled to room temperature,Ethyl acetate and water were added,The target product was extracted into an organic layer.The aqueous layer was extracted with ethyl acetate,Together with the initially obtained organic layer,It was washed with water.The organic layer was concentrated under reduced pressure,The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 65/35)Compound 86 (0.6 g) was prepared.
2-methyl-1-[(2-nitro-5-[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]propan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.5%
With sodium hydrogencarbonate; potassium carbonate;
Preparation of 2-methyl-1-((2-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol Synthetic Step 1-1 Under nitrogen atmosphere, a solution of 1-amino-2-methylpropan-2-ol (16.65 g) and sodium bicarbonate (6.68 g) in N-methylpyrrolidone (50 g) was warmed to 120 C., and a solution of 3-fluoro-4-nitrophenol (25 g) in N-methylpyrrolidone (75 g) was added thereto dropwise. The reaction mixture was stirred at 120 C. for 4 hours, and then cooled to room temperature. <strong>[69045-82-5]2-Fluoro-5-(trifluoromethyl)pyridine</strong> (31.53 g) and potassium carbonate (37.39 g) were added to the reaction mixture, and the reaction mixture was stirred at 100 C. for 4 hours. The reaction mixture was cooled to 75 C., and then water (125 g) was added thereto to separate layers. The mixture was cooled to 50 C., and methanol (37.5 g) was added thereto. The mixture was cooled to 7 C., and stirred at 7 C. for 2 hours. Water (50 g) was added thereto dropwise, and the mixture was stirred for 2 more hours. The precipitated crystal was collected on a filter, washed with cooled 67% aqueous methanol (56 g) twice, and dried in vacuo to give the title compound (55.27 g, yield 93.5%). HPLC area percentage: 99.7% (254 nm) 1H-NMR (CDCl3, 400 MHz) delta: 8.55-8.43 (m, 2H), 8.26 (d, J=9.4 Hz, 1H), 7.97 (dd, J=8.6, 2.4 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.42 (dd, J=9.4, 2.4 Hz, 1H), 3.26 (d, J=5.5 Hz, 2H), 1.37 (s, 6H).
1.53 g
Step (i): Preparation of 2-methyl-1-[(2-nitro-5-[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]propan-2-ol (Compound 28a) To a solution of Compound 76 (1.00 g) in NMP (16 mL) at room temperature was added diisopropylethylamine (2.06 g). To the mixture was added 1-amino-2-methylpropan-2-ol (0.74 g), and the reaction mixture was heated to 100 C. and stirred for 4 hours. The reaction solution was cooled to room temperature, and cesium carbonate (3.11 g) and <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (1.37 g) were added thereto. The reaction mixture was heated to 100 C. and stirred for 3 hours. The reaction solution was cooled to room temperature, and ethyl acetate, hexane and water were added thereto. And, the objective product was extracted in the organic layer. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was slurry-washed (eluate: hexane/ethyl acetate=9/1) to give Compound 28a (1.53 g).
1.53 g
Diisopropylethylamine (2.06 g) was added to a solution of Compound 76 (1.00 g) in NMP (16 mL) at room temperature. 1-amino-2-methylpropan-2-ol (0.74 g)The reaction solution was heated to 100 C.,And the mixture was stirred for 4 hours.The reaction solution was cooled to room temperature,Cesium carbonate (3.11 g) and2-fluoro-5- (trifluoromethyl) pyridine (1.37 g) was added,The reaction solution was heated to 100 C. and stirred for 3 hours.The reaction solution was cooled to room temperature, ethyl acetate,Hexane and water were added,The target product was extracted into an organic layer.The organic layer was washed with water,And dried using anhydrous sodium sulfate.The organic layer was concentrated under reduced pressure,The obtained residue was washed with slurry (eluent: hexane / ethyl acetate = 9/1) to prepare compound 28a (1.53 g).
21.8 g
3-fluoro-4-nitrophenol (10.0 g), 1-amino-2-methylpropan-2-ol (6.2 g)A mixture of diisopropylethylamine (23.0 mL) and NMP (60 mL) was stirred at 110 C. for 3 h. Cesium carbonate (27.0 g) and 2-fluoro-5- (trifluoromethyl) pyridine (8.8 mL) were added to the reaction mixture, and the mixture was stirred at 110 C. for 2 hours. After cooling to room temperature, water and seed crystals were added and the resulting solid was collected by filtration and washed with a water-methanol solution (1: 1) to prepare compound 21 (21.8 g).
1.53 g
To a solution of 3-fluoro-4-nitrophenol (1.0 g) in NMP (15.9 mL) were added 1-amino-2-methylpropan-2-ol (0.74 g) and diisopropylethylamine (2.78 mL), and the mixture was stirred at 110C for 3 hours. The reaction solution was cooled to room temperature, and <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (1.37 g) and cesium carbonate (3.11 g) were added to the reaction solution. The mixture was stirred at 110C for 2 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate/hexane (3/1) were added to the reaction solution. The desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. To the obtained residue were added ethyl acetate (10 mL) and then hexane (100 mL). The mixture was treated with an ultrasonication to give a precipitated solid. The solid was collected on a filter, washed with hexane, and dried in vacuo to give the title compound (1.53 g). LC-MS, m/z; 372 [M+H]+
1.5 g
A mixture of 3-fluoro-4-nitrophenol (Compound 34, 1.0 g), diisopropylethylamine (2.1 g), 1-amino-2-methylpropan-2-ol (0.7 g), and NMP (16 mL) was stirred at 100 C. for 4 hours. To the reaction mixture were added cesium carbonate (3.1 g) and <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (1.4 g), and the mixture was stirred at 100 C. for 3 hours. The reaction mixture was cooled to room temperature, and water, ethyl acetate, and hexane were added thereto to separate layers. The organic layer was washed with water, dried over sodium sulfate, and then concentrated in vavuo. The obtained residue was slurry-washed with hexane/ethyl acetate (=9/1) to give Compound 35 (1.5 g).
With potassium fluoride; In dimethyl sulfoxide; at 40℃; for 5h;
(2) The prepared <strong>[5470-65-5]3-bromo-4-nitrophenol</strong> is added into DMSO and added to polyethylene glycol-400 , stirred and mixed until heated to 40° C., potassium fluoride is added thereto, and the reaction is stirred for 5 hours.After the reaction was completed, distillation under reduced pressure followed by recrystallization gave 3-fluoro-4-nitrophenol. The molar volume ratio of <strong>[5470-65-5]3-bromo-4-nitrophenol</strong> to DMSO in the step (2) is 0.4 mol/L;The volume ratio of DMSO to polyethylene glycol-400 was 11:2; the molar ratio of <strong>[5470-65-5]3-bromo-4-nitrophenol</strong> to potassium fluoride was 1:1.2.
Stage #1: 3-fluoro-4-nitrophenol; 4-chloro-N-methylpicolinamide With potassium carbonate In acetonitrile for 4h; Green chemistry;
Stage #2: With iron(III) chloride; hydrazine hydrate; pyrographite In methanol for 3h; Reflux; Green chemistry;
1-1 Example 1-1 Synthesis of Intermediate I
In a 250mL three-necked bottle with a magnetic stirrer, thermometer and reflux condenser,0.09 mol of 3-fluoro-4-nitrophenol, 0.10 mol of anhydrous potassium carbonate, 0.10 mol of 4-chloro-N-methylpyridine-2-carboxamide,0.003 mol of PEG-400 and 100 mL of acetonitrile were stirred under electromagnetic stirring for 4 hours in a water bath.Cool, filter, and pump to dilute acetonitrile under reduced pressure.The obtained residue, 1 g of sugar with activated carbon, 0.1 mmol of ferric chloride, 50 mL of methanol were mixed in a 250 mL four-necked flask.85% of hydrazine hydrate was added dropwise at reflux temperature, and the addition time was 1 h. After the completion of the dropwise addition, the mixture was refluxed for 2 h.After the reaction was stopped, the mixture was filtered, and the activated carbon was washed with 40 mL of diethyl ether, and the filtrate was distilled to remove methanol. After the distillation, the solution was extracted with 240 mL of diethyl ether.The ether layers were combined, dried and concentrated to give a pale yellow liquid, ie, 21.75 g of Intermediate I, yield 92.5%, purity 99.92%.
92.4%
With potassium hydroxide for 1.5h;
1-1 Embodiment 1 - 1 synthesis of intermediate I
A magnetic stirring device in the vicinity of, a thermometer and a reflux condenser 100 ml three-neck bottle in, adding 0.09 µM of 3 - fluoro -4 - nitro phenol, after heating by adding 0.10 µM of KOH, the reaction under stirring 10 min, then added to the reaction system in the 0.10 µM of 4 - chloro - N - methyl pyridine -2 - carboxamide, temperature control reaction; to TLC endpoint is detected, 1.5 h reaction end; and adding heat to the reaction system of 5% NaOH solution, heat preservation in 80 °C -85 °C washing 3 times, at the same temperature with water washing 3 times, the reaction mixture is hot and cold water in pouring, cooling, filtering, drying to obtain the solid. The resulting solid, 1 g of the active carbon for sugar, 0.12 mmol of iron trichloride, 50 ml methanol mixed 250 ml four-mouth bottle in, at the reflux temperature next adds by drops 85% hydrazine hydrate 0.33 µM, dropping time 1 h, after dropping, reflux 2 h. After stopping the reaction, filtration, for 40 ml ethyl ether washing activated carbon, distillation of the filtrate from methanol, after [...], for 240 ml ethyl ether extract the residue, the merger [...], drying, concentration, a pale yellow liquid that shall 21.72 g intermediate I, yield 92.4%, purity 99.92%.
4-(4-nitro-3-fluorophenoxy)-N-methylpyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.1%
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 3h; Inert atmosphere;
1 Example 1: Synthesis of 4-(4-nitro-3-fluorophenoxy)-N-methylpyridine-2-carboxamide
Add 3-fluoro-4-nitrophenol (15.7g, 0.1mol) to a 500ml three-necked flask, 4-chloro-N-methylpyridine-2-carboxamide (17.0g, 0.1mol), dried to obtain DMF100ml,Potassium carbonate (27.6g, 0.2mol), protected by nitrogen, heated to 110°C,Incubate the reaction for 3 hours, the reaction is over, the insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure.The residue was recrystallized with a mixed solvent of ethyl acetate and petroleum ether,20.4 g of 4-(4-nitro-3-fluorophenoxy)-N-methylpyridine-2-carboxamide was obtained, and the yield was 70.1%.
With potassium carbonate In diethylene glycol dimethyl ether for 6h; Reflux;
1; 2; 3; 8 Best Practice 8:
In a 500 mL closed four-neck reaction flask, 31.4 g of 3-fluoro-4-nitrophenol (II), 34.1 g of N-methyl-4-chloro-2-pyridinecarboxamide, 27.8 g of potassium carbonate and 150 g were added. Diethylene glycol dimethyl ether, heating under reflux, stirring reaction for 6 hours, adding 200 g of water to precipitate a solid at the end of the reaction, and filtering to obtain 4-(4-nitro-3-fluorophenoxy)-2-(methylamine) 56.4 g of crude formyl)pyridine (III),56.4 g of the obtained III was added to a 500 mL closed high-pressure reaction vessel, 1.16 g of Raney nickel and 200 g of methanol, 2 atm of hydrogen was introduced, the temperature was controlled at 20 ° C, and the reaction was stirred for 3 hours. The reaction was filtered to recover Raney nickel. The methanol was distilled off to give 50.2 g of IV, then 50.2 g of IV was added to a 500 mL closed four-neck reaction flask, and 42.6 g of 4-chloro-3-(trifluoromethyl)phenylisocyanate and 200 g of tetrahydrofuran were added at room temperature. The reaction was stirred for 5 hours at ° C, and 75 g of 10% dilute hydrochloric acid was added dropwise to the end of the reaction to precipitate a solid. The residue was filtered to obtain the hydrochloride salt of the rufefenib. The aqueous solution of the sodium carbonate was filtered and then ethyl acetate was evaporated. The product is 73.7 grams of regomafenib with a total yield of 86.4%.
1-amino-2-methyl (1,1-<SUP>2</SUP>H<SUB>2</SUB>)propan-2-ol monohydrochloride[ No CAS ]
[ 69045-82-5 ]
C16H14(2)H2F3N3O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.7 g
A mixture of 3-fluoro-4-nitrophenol (Compound 34, 2.1 g), a crude product of Compound 5 (Reference example 1) (2.0 g), diisopropylethylamine (8.0 mL), and NMP (25 mL) was stirred at 110 C. for 4 hours. To the reaction solution were added cesium carbonate (6.4 g) and <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (2.0 mL), and the mixture was stirred at 110 C. for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto to separate layers. The organic layer was washed with water, dried over sodium sulfate, and then concentrated in vavuo. The obtained residue was purified by silica gel column chromatography (eluting solution: hexane/ethyl acetate=1/1) to give Compound 42 (3.7 g).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
