* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
3
[ 446-35-5 ]
[ 124-41-4 ]
[ 446-38-8 ]
[ 448-19-1 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
[3] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[4] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
4
[ 446-36-6 ]
[ 77-78-1 ]
[ 448-19-1 ]
Yield
Reaction Conditions
Operation in experiment
94.1%
With potassium carbonate In N,N-dimethyl-formamide at 60 - 100℃;
In a 5L four-necked flask, DMF 2500 g, 4-fluoro-2-hydroxy nitrobenzene (500 g, 3.20 mol) and potassium carbonate (483 g, 3.50 mol) were added and heated to 60°C. 424 g (3.36 mol) of dimethyl sulfate was added dropwise for about 2-3 hours. After completion of dripping, heated to 90-100°C for 5-6 hours. Sampling GC analysis of 4-fluoro-2-hydroxy nitrobenzene was found to<0.5percent. The mixture was cooled to 50°C, generating monomethyl sulfate potassium salt. The filtrate was distilled under reduced pressure to recover DMF to give 515 g of 4-fluoro-2-methoxynitrobenzene as a yellow oily liquid. GC content of 99.5percent, yield 94.1percent.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2323 - 2332
[2] Patent: CN106083536, 2016, A, . Location in patent: Paragraph 0035; 0036
[3] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[4] Patent: WO2010/71885, 2010, A1, . Location in patent: Page/Page column 443
[5] Patent: WO2010/115688, 2010, A1, . Location in patent: Page/Page column 146
5
[ 446-36-6 ]
[ 74-88-4 ]
[ 448-19-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; Cooling with ice
Example 127; Preparation of 3-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)-2-methoxyphenethyl)-5-(1-(1-methylethoxy)phenyl-4-yl)-5-methylimidazolidine-2,4-dione; 127-a-1) Preparation of 4-fluoro-2-methoxy-1-nitro-benzene; A solution of 4-fluoro-2-hydroxy-1-nitrobenzene (100 mg, 0.637 mmol) in N,N-dimethylformamide (3.2 mL) was added with potassium carbonate (132 mg, 0.955 mmol), then added with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at room temperature for 1 hour. The reaction solution was further added with potassium carbonate (132 mg, 0.955 mmol), then with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at 60° C. for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 4-fluoro-2-methoxy-1-nitro-benzene (118 mg, yield >100percent) was obtained as a yellow oil.1H-NMR (CDCl3) δ: 3.97 (3H, s), 6.74 (1H, ddd, J=2.4, 7.8, 9.0 Hz), 6.80 (1H, dd, J=2.4, 10.2 Hz), 7.97 (1H, dd, J=6.1, 9.0 Hz).
99%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1 h;
To a stirred suspension of 4-fluoro-2-hydroxy- 1-nitrobenzene(35) (100 mg, 0.64 mmol) and K2CO3(132 mg, 0.96 mmol) in DMF (3.2 mL) was added methyl iodide (108 mg, 0.76 mmol)at 0 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo to give thetitle compound (118 mg, 99percent) as a yellow oil;
99.1%
Stage #1: With potassium carbonate In acetone at 20℃; for 0.5 h; Inert atmosphere Stage #2: at 60℃;
5-fluoro-2-nitrophenol (10 g, 63.65 mmol), potassium carbonate (8.8 g, 63.65 mmol) and acetone (100mL) wereadded in a 250 mL three-necked flask and stirred at room temperature for 30 minutes under the protection of nitrogengas. Iodomethane (9.03 g, 63.65 mmol) was then slowly added dropwise thereto, and the mixture was warmed up to60°C and reacted overnight. After the reaction was completed, the reaction solution was added with water (200 mL),extracted with ethyl acetate (100 mL 3 4), washed with 1M sodium hydroxide (100mL 3 3) and saturated brine (100mL 3 2) successively, dried over anhydrous sodium sulfate, filtered by suction and evaporated under reduced pressureto remove the solvent, to give 4-fluoro-2-methoxynitrobenzene (10.8 g, 99.1percent yield).
98%
Stage #1: With potassium carbonate In acetone at 20℃; for 0.5 h; Stage #2: at 20 - 60℃; for 30 h;
4-fluoro-2-methoxy-1-nitro-benzene 20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10percent aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo. Yield: 21.1 g (123 mmol; 98percent) UV max: 230/266/322 nm.
98%
With potassium carbonate In acetonitrile at 50℃; for 3 h;
(0540) 5-Fluoro-2-nitrophenol (7.85 g, 0.05 mol), iodomethane (8.52 g, 0.06 mol) and potassium carbonate (10.35 g, 0.075 mol) were added to acetonitrile (150 mL). The mixture was heated at 50° C. for 3 h, and the solvent was removed under reduced pressure. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried and concentrated to get the product (8.4 g, yield: 98percent).
97%
With potassium carbonate In acetone for 4 h; Heating / reflux
5.60.1 4-Fluoro-2-methoxy-1-nitrobenzene A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3.x.250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97percent yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H).
96%
With potassium carbonate In acetone for 3 h; Reflux
To a stirred solution of 23 (0.60 g, 3.82 mmol) in acetone (20 mL) was added K2CO3 (1.1 g, 7.6 mmol) and iodomethane (0.5 mL, 7.6 mmol). The reaction mixture was refluxed for 3 h and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 24 as a white solid (0.63 g, 96percent).
94%
With potassium carbonate In acetonitrile at 16 - 85℃; for 5 h;
Step 1 : K2C03 (131 g, 955 mmol) and CH3I (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in MeCN (750 mL) at rt and the resulting mixture was heated to 85°C for 5 h. The RM was chilled, filtered and washed with MeCN. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reduced pressure to give the desired compound (75 g, 94percent).
94%
With potassium carbonate In acetonitrile at 85℃; for 5 h;
Step 1: K2C03 (131 g, 955 mmol) and Mel (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in acetonitrile (750 mL) at rt and the resulting mixture was heated to 85 C for 5 h. The reaction mixture was chilled, filtered and washed with acetonitrile. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reducedpressure to give the desired compound (75 g, 94percent).
92%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To 2-nitro-5-fluoro-phenol (56.0 g, 357 mmol) and iodomethane (24.5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54.2 g, 393 mmol). Significant bubbling occurred. The mixture was stirred at rt overnight. The mixture was poured into H2O (800 mL) and the H2O washed with diethyl ether (3.x.200 mL). The ether washes were combined and washed with H2O (2.x.400 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (56.0 g, 327 mmol, 92percent) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 1H), 6.79-6.67 (m, 2H), 3.93 (s, 3H).
92%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere
To 2-nιtro-5-fluoro-phenol (56 0 g, 357 mmol) and iodomethane (24 5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54 2 g, 393 mmol) Significant bubbling occurred The mixture was stirred at rt overnight The mixture was poured into H2O (800 mL) and the H2O washed with ether (3 x 200 mL) The ether washes were combined and washed with H2O (2 x 400 mL) The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (56 0 g, 327 mmol, 92 percent) as a yellow solid 1H-NMR (400 MHz, CDCI3) δ 7 96 - 7 90 (m, 1 H), 6 79 - 6 67 (m, 2 H) and, 3 93 (s, 3 H)
88%
With potassium carbonate In acetone at 20℃; for 96 h;
Methyl iodide (11.94 mL, 191 mmol) was added dropwise to a stirred suspension of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol) and potassium carbonate (17.59 g, 127 mmol) in acetone (318 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 days, whereupon the acetone was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralised with concentrated hydrochloric acid. The organic layer was separated, washed with water and brine, dried (MgSO.)), filtered and evaporated to give an off-white solid that was recrystallised from isopropanol/dichloromethane to give 4-fiuoro-2-methoxy-l- nitrobenzene as an off-white solid (9.6 g, 88percent).
38%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 23 h;
A mixture of commercially available 5-fluoro-2-nitrophenol (1.00 g, 6.37 mmol), MeI (1.36 g, 9.58 mmol), and potassium carbonate (1.32 g, 9.55 mmol) in DMF (10 mL) was heated at 140° C. for 23 hours. The reaction was diluted with aq. 0.5 N NaOH (50 mL) and extracted with EtOAc (2.x.50 mL). The EtOAc-extracts were washed once more with aq. 0.5 N NaOH (50 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness in vacuo. The crude product was purified by flash column chromatography (EtOAc/heptane: 1/1) to obtain 4-fluoro-2-methoxy-nitrobenzene (416 mg, 38percent, purity (GC)>95percent).MS: [M]+=171.
26%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; Sealed pressure flask
4-Fluoro-2-methoxy-l-nitro-benzene was synthesized by suspending 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol, 1.0 equiv.), potassium carbonate (6.59 g, 47.7 mmol, 1.5 equiv.), and Iodomethane (2.98 mL, 47.7 mmol, 1.5 equiv.) in DMF (50 mL) and allowing the resulting reaction mixture to stir overnight at 14O0C inside a sealed pressure flask. The reaction mixture was partitioned between ethyl acetate and distilled water three times. The organic layer was washed once with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The product was isolated by column chromatography in 30percent ethyl acetate and hexanes as a yellow solid (1.44 g, 26percent). 1H NMR (300 MHz, CDCl3): δ(pρm) 7.98(dd, IH), 6.77(m, 2H), 3.99(s, 3H).
9.7%
With potassium carbonate In ethanol for 12 h; Heating / reflux
Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7percent). NMR (CDCl3): 4.0 (s, 3H), 6.8 (m, 2H), 8.0 (m, 1H).
4.5 g
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: at 60℃; for 2 h;
To a solution of 4-fluoro-2-hydroxy-l -nitrobenzene (5.0 g, 31.8 mmol) in DMF (10 mL) was added K2CO3 (13.1 g, 95.4 mmol). The reaction mixture was stirred at RT for 1 h followed by addition of methyl iodide (9.93 g, 69.9 mmol) and the reaction mixture was stirred at 60 C for 2 h. The reaction mass was concentrated and quenched in water. The reaction mass was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.93 (s, 3H), 6.97 (t, J= 7.8 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H).
Reference：
[1] Patent: US2010/48610, 2010, A1, . Location in patent: Page/Page column 73
[2] Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13860 - 13869
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 7025 - 7048
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3436 - 3446
[5] Patent: EP3381925, 2018, A1, . Location in patent: Paragraph 0159;
[6] Patent: US2006/46990, 2006, A1, . Location in patent: Page/Page column 6
[7] Patent: US2017/112833, 2017, A1, . Location in patent: Paragraph 0539-0540
[8] Journal of Molecular Structure, 2017, vol. 1147, p. 266 - 280
[9] Patent: US2007/49618, 2007, A1, . Location in patent: Page/Page column 82
[10] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 233 - 243
[11] Patent: WO2015/22073, 2015, A1, . Location in patent: Page/Page column 52
[12] Patent: WO2015/90580, 2015, A1, . Location in patent: Page/Page column 32
[13] Patent: US2008/300242, 2008, A1, . Location in patent: Page/Page column 51
[14] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 1004 - 1008
[15] Patent: WO2010/104899, 2010, A1, . Location in patent: Page/Page column 143
[16] Patent: WO2009/84970, 2009, A1, . Location in patent: Page/Page column 73
[17] Patent: US2010/280268, 2010, A1, . Location in patent: Page/Page column 48
[18] Patent: WO2006/71730, 2006, A1, . Location in patent: Page/Page column 78
[19] Patent: US6352993, 2002, B1, . Location in patent: Page column 29-30
[20] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
[21] Patent: US2003/93866, 2003, A1,
[22] Patent: US6455528, 2002, B1,
[23] Patent: US2004/97589, 2004, A1,
[24] Patent: US2009/23773, 2009, A1, . Location in patent: Page/Page column 59
[25] Patent: WO2005/35520, 2005, A1, . Location in patent: Page/Page column 62-63
[26] Patent: WO2006/44823, 2006, A2, . Location in patent: Page/Page column 166
[27] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 22, p. 6192 - 6196
[28] Patent: WO2013/186692, 2013, A1, . Location in patent: Page/Page column 86; 87
[29] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 75 - 83
[30] Patent: US2015/152069, 2015, A1, . Location in patent: Paragraph 0180; 0181
[31] Patent: EP2883875, 2015, A1, . Location in patent: Paragraph 0064
[32] Patent: WO2018/45104, 2018, A1, . Location in patent: Paragraph 00125
6
[ 67-56-1 ]
[ 446-35-5 ]
[ 448-19-1 ]
Yield
Reaction Conditions
Operation in experiment
87.38%
With potassium <i>tert</i>-butylate In toluene at 0 - 20℃;
Toluene (500 ml) was added into clean and dry round bottom flask, then 2,4- difluoro-1 -nitrobenzene (500 gms) was added. The reaction mass was cooled to 0°C then methanol (100 ml) was slowly added to reaction mass at 0°C. To the reaction mass potassium tert-butoxide (PTB) (353 gms) was added in lots (10 lots) at 0°C. The reaction mass was stirred at 0°C for 15-30 minutes, then temperature raised to 20°C and the reaction mass was stirred at 20°C for 4 hrs. The reaction mass was decomposed in water (1500 ml). The contents were stirred for 10-15 minutes followed by toluene was added to the reaction mass. The layers were separated, and the aqueous layer was extracted with toluene followed by separated the organic layer. Total organic layer was washed with water (1000 ml). The organic layer was then washed with brine solution (NaCl (50 gms) + water (500 ml)) and dried over sodium sulphate. The solvent was distilled out under vacuum. Petroleum ether (1000 ml) was added to the residue and the contents were cooled to below 10°C then stirred for 30 minutes. The solid was filtered off and washed with petroleum ether (200 ml). The solid was dried at 50-60°C for 3-5 hrs (Yield - 470 gms; 87.38percent).
Reference：
[1] Patent: WO2018/207120, 2018, A1, . Location in patent: Page/Page column 11
[2] Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918
7
[ 446-36-6 ]
[ 448-19-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; dimethyl sulfate In acetone at 20℃; for 24 h;
A mixture of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol), potassium carbonate (2.50 g, 21.0 mmol) and dimethyl sulfate (2.65 g, 21.0 mmol) in acetone was stirred at ambient temperature for 24 hours. The solvents were removed under reduced pressure and then water (30 mL) and dichloromethane (30 mL) was added to the residue. The combined organics solutions were dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to provide an oil. This was purified by flash chromatography on silica gel using dichloromethane/heptane (7:3) as an eluent to provide the title compound as a crystalline solid (3.24 g, 100percent): 1H NMR (CDCl3, 400 MHz) δ7.96 (M, 1H), 6.80 (m, 1H), 6.73 (m, 1H), 3.96 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100A, 250.x.4.6 mm; 5percent-100percent acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 17.82 min; MS:MH+ 172.2
Reference：
[1] Organic Mass Spectrometry, 1992, vol. 27, # 6, p. 720 - 723
[2] Patent: US4801717, 1989, A,
9
[ 450-91-9 ]
[ 448-19-1 ]
Yield
Reaction Conditions
Operation in experiment
4 g
at 20℃;
2-methoxy-4-fluoro-nitrobenzene (10g, 58.44mmol) was dissolved in methanol, was added 1g of palladium / carbon, substituted with hydrogen, the reaction under a hydrogen atmosphere for three days. Filtered and the filtrate was collected, methanol was distilled off to give an oily crude product. Was added at 0 crude product concentrated sulfuric acid was dissolved solid mixture, in batches added potassium nitrate (5.91g). The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water and NaHC03, adjustment pH6.0-8.0. The aqueous phase was thrice extracted with dichloromethane, the organic phase was collected, dried. The organic solvent was distilled off, the residue was purified by column chromatography to give 4-fluoro-2-methoxy-5-nitroaniline (4.0g).
Reference：
[1] Patent: CN105503827, 2016, A, . Location in patent: Paragraph 0070; 0071
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
13
[ 67-56-1 ]
[ 446-35-5 ]
[ 865-47-4 ]
[ 448-19-1 ]
[ 1369809-57-3 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918
14
[ 446-35-5 ]
[ 124-41-4 ]
[ 448-19-1 ]
[ 4920-84-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[2] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
15
[ 446-35-5 ]
[ 124-41-4 ]
[ 446-38-8 ]
[ 448-19-1 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
[3] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178[4] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382
16
[ 448-19-1 ]
[ 16292-95-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With water; sodium hydroxide In dimethyl sulfoxide at 80℃; for 20 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 20℃;
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the "pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95percent).
95%
Stage #1: With sodium hydroxide In water; dimethyl sulfoxide at 80℃; for 20 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide
Step a: To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the "pH" of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95percent).
95%
Stage #1: With sodium hydroxide In dimethyl sulfoxide at 80℃; for 20 h; Stage #2: With hydrogenchloride In dimethyl sulfoxide
Step a: To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the "pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95percent).
95%
With sodium hydroxide In water; dimethyl sulfoxide at 80℃; for 20 h;
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks) (3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the "pH" of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95percent).
95%
With sodium hydroxide In water; dimethyl sulfoxide at 80℃; for 20 h;
Step 1. To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40mmol). The reaction mixture was heated at 80 oC for 20 h. The mixture was cooled toroom temperature, and the “pH” of the solution was adjusted to 5 by aqueous HClsolution. The mixture was extracted with ethyl acetate three times. The combinedorganic extract was washed with water, brine, dried over MgSO4, and concentrated togive 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95percent).
90.1%
at 80℃; for 20 h;
A solution of sodium hydroxide (39 mL, 117 mmol, 3M)Was added to a solution of 4-fluoro-2-methoxy-1-nitrobenzene (10.0 g, 58.4 mmol)Of thionyl chloride(100 mL)Followed by reaction at 80 ° C for 20 hours in an oil bath.After the reaction, pH = 5 was adjusted with concentrated hydrochloric acid,Then extracted with ethyl acetate (100 mL x 3)The organic phases were combined, concentrated under reduced pressure,The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (9.0 g, yield 90.1percent).
74.4%
With sodium hydroxide In dimethyl sulfoxide at 50℃; for 3 h;
(0915) 2-Methoxy-4-fluoronitrobenzene (3.4 g, 19.88 mmol) was dissolved in dimethyl sulfoxide (30 mL), and NaOH solution (1 N, 40 mL, 40 mmol) was added. The mixture was heated to 50° C., and reacted for 3 h. After the reaction, water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to get the title compound (2.5 g, yield: 74.4percent).
60%
With sodium hydroxide In dimethyl sulfoxide at 20℃; for 21 h;
To a stirred solution of 24 (0.63 g, 3.7 mmol) in DMSO (5.3 mL) was added 30percent NaOH (2.5 mL, 18.0 mmol) solution. The mixture was stirred for 21 h at room temperature, cooled to 0 °C and acidified with 6 N HCl. The mixture was pour into 5percent HCl and extracted with ether several times. The combined organic layers were washed with 5percent HCl three times, then with brine, and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 25 as a white solid (0.37 g, 60percent).
28%
Stage #1: With sodium hydroxide In water; dimethyl sulfoxide at 90℃; for 15 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 0℃;
To a solution of 5-fluoro-2-nitroanisole (11.0 g, 64.3 mmol) in dimethylsulfoxide (30 mL) /water (5 mL) was added sodium hydroxide (5.36 g, 129 mmol), and the mixture was stirred at 9O0C for 15 hr. The reaction solution was cooled to 00C, 6N hydrochloric acid was added to adjust to pH 7. The precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90_>50/50) and recrystallized from ethyl acetate-hexane to give the title compound (3.05 g, 28percent) as a white solid.1H-NMR (DMSOd6, 300 MHz) δ 3.88 (3H, s) , 6.47 (IH, dd, J = 9.1, 2.7 Hz), 6.61 (IH, d, J = 2.7 Hz), 7.89 (IH, d, J = 9.1 Hz) , 10.90 (IH, s) .
Reference：
[1] Patent: US2011/130398, 2011, A1, . Location in patent: Page/Page column 60
[2] Patent: US2011/269809, 2011, A1, . Location in patent: Page/Page column 12
[3] Patent: US2012/46306, 2012, A1, . Location in patent: Page/Page column 36
[4] Patent: US2012/71499, 2012, A1, . Location in patent: Page/Page column 10
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 15, p. 4001 - 4009
[6] Patent: CN105884695, 2016, A, . Location in patent: Paragraph 0266; 0267; 0268
[7] Organic Letters, 2008, vol. 10, # 5, p. 997 - 1000
[8] Patent: US2017/112833, 2017, A1, . Location in patent: Paragraph 0914-0915
[9] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1547 - 1554
[10] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 233 - 243
[11] Patent: WO2007/4749, 2007, A1, . Location in patent: Page/Page column 130
[12] Patent: US6344570, 2002, B1, . Location in patent: Example 67
[13] Patent: WO2006/44823, 2006, A2, . Location in patent: Page/Page column 166-167
[14] Patent: WO2018/45104, 2018, A1, . Location in patent: Paragraph 00125
Paladium/carbon(Pd/C, 5percent, 0.5 g) was added to a solution of 4-fluoro-2-methoxynitrobenzene (1.65 g, 9.6 mmol) in ethanol, which was then stirred for 1 hour under 30 psi of hydrogen pressure. The reaction mixture was filtered to remove paladium/carbon, and concentrated to give 1.35 g of the titled compound. (Yield 100percent). NMR (CDCl3): 3.8 (s, 3H), 6.5 (m, 3H).
100%
With hydrogen In methanol at 20℃; for 12 h;
2-methoxy-4-fluoronitrobenzene (50.0 g, 0.29 mol) was added to a one-necked flask,Add 650 mL of methanol and 10 g of Raney nickelAt room temperature, a pressure of 1.5 atm hydrogen gas was allowed to react for 12 h.After the reaction is complete,The reaction solution was filtered through celite,A light pink solution was obtained,Concentrated under reduced pressure to get brown liquid,Is 2-methoxy-4-fluoroaniline (41.2 g)
100%
With hydrogen In methanol at 15 - 26℃; for 12 h;
2-methoxy-4-fluoronitrobenzene (50.0 g, 0.29 mol) was added to a 1 L vial,Add 650mL methanol, stirring at 15 ~ 26 , then add 10g Raney nickel and pass 1.1atm of hydrogen, after 12h reaction. The reaction solution was filtered through celite to give a pale pink solution,The filtrate was concentrated under reduced pressure to give 41.2 g of 2-methoxy-4-fluoroaniline in 100percent yield.
98%
With hydrogen In methanol at 20℃; for 6 h;
Example 2294-fluoro-2-methoxyanilineA solution of 5-fluoro-2-nitroanisole (5.0 g, 29.22 mmol, 1 equiv) in the presence of 250 mg of Pd/C (5percent) in MeOH (60 mL) was hydrogenated at room temperature for 6 hours. The reaction mixture was filtered over a pad of Celite and then concentrated to give a brown oil (4.06 g, 98percent) which was directly used in the next step. m/z=142 (M+H)+.
98%
With hydrogen In methanol at 25 - 30℃; Autoclave
In an autoclave methanol (4000 ml) and 4-fluoro-2-methoxy-l -nitrobenzene (470 gms) were added. A mixture of Raney Ni (47 gms) and methanol (470 ml) was added to the reaction mass under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 10-15 minutes. Hydrogen gas was slowly fed into the autoclave upto 3.0 kgs (slight exothermic temperature observed). The reaction mass was stirred at 25-30°C for 8-10 hrs till there was no hydrogen consumption. The reaction mass was filtered through celite and the celite bed was washed with methanol (250 ml). Organic solvent was distilled under vacuum to give black color liquid (Yield - 380 gms; 98.0percent).
94.3%
With palladium on activated charcoal; hydrogen In methanol for 16 h;
4-fluoro-2-methoxy-1-nitrobenzene (15.00 g, 87.67 mmol) was added to methanol (200 mL)Palladium carbon (200 mg) was added under nitrogen atmosphere,Hydrogen atmosphere for 16 hours, suction filtration,The filtrate was concentrated to give the title compound (11.67 g, yield 94.3percent).
93%
With iron; ammonium chloride In tetrahydrofuran; water at 25 - 65℃; for 3 h;
Step a: Compound 1a1 (10.6 g, 58 mmol) was added into a 500 ml reaction flask, and THF/water (100 ml/60 ml) mixed solution was added to dissolve the compound. Ammonium chloride (15.5 g, 292 mmol) and reduced iron powder (26 g, 467 mmol) were sequentially added with stirring at room temperature, and then the reaction system was heated to 65° C. and stirred continually for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the excess iron powder was removed by filtration, and the filter cake was washed for three times with EA. Filtrate was extracted with EA/water system for three times, and the organic layer was separated, washed with water, saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 1a2 (8.0 g) which was used directly in the next reaction. Yield: 93percent; purity: 90percent; MS m/z (ESI): 142.0 [M+H]+.
93.28%
With palladium 10% on activated carbon; hydrogen In methanol at 40℃; for 12 h; Inert atmosphere
2-Methoxy-4-fluoronitrobenzene (100.00g, 584.35mmol) was dissolved in methanol (400mL), Pd/C (10percent, 10g) was added after sweeping with nitrogen. The mixture was heated to 40°C under H2 (50Psi) and stirred for 12 hours. TLC showed the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to dryness to deliver the title compound (red oil, 83.00g, yield 93.28percent). LCMS (ESI) (10-80CD): m/z: 142.1 [M+1].
92%
With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 30 - 35℃; Autoclave; Inert atmosphere
In a 1L autoclave, ethyl acetate 600 g, 4-fluoro-2-methoxynitrobenzene (257.5 g, 1.50 mol), 5percent Pd / C 3g were added, and the autoclave was closed. Nitrogen was purged 3-4 times, and maintained in a hydrogen pressure at 0.5-1.0MPa, temperature between 30-35°C for 7-8 hours. Sampling of GC analysis was carried out, 4-fluoro-2-methoxy nitrobenzene <0.5percent. After completion of the reaction, the hydrogen in the kettle was replaced with nitrogen. After the nip with nitrogen, filtered, and Pd / C was recovered. The filtrate was recovered with ethyl acetate. The residual material was distilled under reduced pressure, and the liquid was collected as a pale yellow oily liquid 4-fluoro-2-methoxyaniline 195 g. GC content of 98.5percent. Yield 92percent.
91%
With iron; ammonium chloride In ethanol; water at 55 - 85℃; for 2 h;
2-methoxy-4-fluoro-1-nitrobenzene (Intermediate 101) (20 g, 0.12 mol, 1.0 eq), ammonium chloride (13 g, 0.24 mol, 2.0 eq) and water (50 mL) were dissolved in ethanol (200 mL). After heated to 55°C, iron powder (13 g, 0.24 mol, 2.0 eq) was added portionwise. The temperature was raised to 85 °C and after reaction for 2 hours, the temperature was lowered to room temperature, filtration was performed and the solvent was rotary evaporated. The residue was dissolved in ethyl acetate which was then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain 4-fluoro-2-methoxyaniline as a light green product (15 g, yield: 91percent). LCMS (ESI): m/z 142 [M + H]+.
7 g
With ammonium chloride; zinc In water; acetone at 0 - 20℃;
To a suspension of 5-fluoro-2-nitroanisole (50 mmol, 8.5 g) and zinc powder (3.5 eq, 11.4 g) in acetone (45 mL) and water (5 mL) was added ammonium chloride (11 eq, 29.3 g) at 0 °C in multiple portions. After the mixture was stirred at r.t. overnight, HPLC indicated a complete conversion. Acetone was removed on rotavap and the residue was suspended in DCM and water. Filtration was carried out and the filtrate was extracted with DCM. Concentration of combined organic layers gave crude aniline (~ 7.0 g), which was used in the next step without purification.
8.0 g
With iron; ammonium chloride In tetrahydrofuran; water at 65℃; for 3 h;
The reaction substrate 2-a-1 (10.6g, 58mmol) is placed in the 500mL reaction flask, was dissolved in a mixed solution oftetrahydrofuran / water (100mL / 60mL) . At room temperature, to the stirred reaction flask were sequentially added ammonium chloride (15.5g, 292mmol) and reduced iron powder (26g, 467mmol), then the reaction system was heated to 65 deg. C and stirring was continued for 3 hours. The progress of the reaction by TLC, until complete reaction substrate, the excess iron was removed by filtration, the filter cake rinsed three times with ethyl acetate. Filtrate was washed with ethyl acetate / water system was extracted three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2-a-2 (8.0g), was used directly in the next reaction step. Yield: 93percent ; purity: 90percent.
Reference：
[1] Patent: US6352993, 2002, B1, . Location in patent: Page column 30
[2] Patent: CN106366072, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0090; 0091; 0092
[3] Patent: CN106366022, 2017, A, . Location in patent: Paragraph 0051; 0052; 0056
[4] Patent: US2011/130415, 2011, A1, . Location in patent: Page/Page column 102
[5] Patent: WO2018/207120, 2018, A1, . Location in patent: Page/Page column 11; 12
[6] Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13860 - 13869
[7] Patent: CN105884695, 2016, A, . Location in patent: Paragraph 0230; 0231; 0232
[8] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0135; 0136; 0137
[9] Patent: EP3290419, 2018, A1, . Location in patent: Paragraph 0074; 0075
[10] Patent: CN106083536, 2016, A, . Location in patent: Paragraph 0037; 0038
[11] Patent: EP3345900, 2018, A1, . Location in patent: Paragraph 0042
[12] Journal of the American Chemical Society, 2018, vol. 140, # 14, p. 4893 - 4904
[13] Journal of the Chemical Society, 1940, p. 1268,1270
[14] Journal of the Chemical Society, 1931, p. 981
[15] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[16] Organic Mass Spectrometry, 1992, vol. 27, # 6, p. 720 - 723
[17] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
[18] Patent: US2009/23773, 2009, A1, . Location in patent: Page/Page column 59
[19] Patent: WO2012/151561, 2012, A1, . Location in patent: Page/Page column 60
[20] Patent: WO2013/169401, 2013, A1, . Location in patent: Page/Page column 61-62
[21] Journal of Chemical Research, 2015, vol. 39, # 6, p. 318 - 320
[22] Patent: WO2015/175632, 2015, A1, . Location in patent: Paragraph 447
[23] Patent: WO2015/195228, 2015, A1, . Location in patent: Paragraph 454
[24] Patent: CN105524068, 2016, A, . Location in patent: Paragraph 0181; 0182
[25] Patent: CN105503827, 2016, A, . Location in patent: Paragraph 0070; 0071
[26] Patent: WO2016/183278, 2016, A1, . Location in patent: Paragraph 00394; 00395
[27] Patent: US2017/57957, 2017, A1, . Location in patent: Paragraph 0209-0210
[28] Patent: CN106083736, 2016, A, . Location in patent: Paragraph 0096; 0103
[29] Patent: EP3173412, 2017, A1, . Location in patent: Paragraph 0112; 0113
[30] Patent: CN108558835, 2018, A, . Location in patent: Paragraph 0048; 0049
21
[ 448-19-1 ]
[ 7440-02-0 ]
[ 450-91-9 ]
Reference：
[1] Patent: US6455528, 2002, B1,
22
[ 448-19-1 ]
[ 450-89-5 ]
Reference：
[1] Journal of the Chemical Society, 1931, p. 981
23
[ 448-19-1 ]
[ 450-88-4 ]
Reference：
[1] Journal of the Chemical Society, 1931, p. 981
[2] Patent: CN106083536, 2016, A,
24
[ 448-19-1 ]
[ 122833-04-9 ]
Reference：
[1] Patent: WO2011/79231, 2011, A1,
[2] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 82 - 90
[3] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 75 - 83
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 12, p. 2767 - 2780
[5] Patent: EP2952510, 2015, A1,
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4948 - 4964
[7] Patent: CN105384694, 2016, A,
[8] Patent: CN105218561, 2016, A,
[9] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4206 - 4217
[10] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4832 - 4837
[11] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 995 - 1006
[12] Patent: US2018/208564, 2018, A1,
[13] Patent: EP3372594, 2018, A1,
25
[ 109-01-3 ]
[ 448-19-1 ]
[ 122833-04-9 ]
Reference：
[1] Patent: CN106905245, 2017, A,
26
[ 448-19-1 ]
[ 944317-92-4 ]
Reference：
[1] Patent: CN106083536, 2016, A,
27
[ 448-19-1 ]
[ 1089279-91-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4948 - 4964
[2] Patent: KR2016/37844, 2016, A,
[3] Patent: CN106905245, 2017, A,
[4] Patent: CN106905245, 2017, A,
[5] Patent: EP3372594, 2018, A1,
[6] Patent: EP3372594, 2018, A1,
[7] Patent: WO2010/138576, 2010, A1,
49.2 4-fluoro-2-methoxy-aniline
Paladium/carbon(Pd/C, 5%, 0.5 g) was added to a solution of 4-fluoro-2-methoxynitrobenzene (1.65 g, 9.6 mmol) in ethanol, which was then stirred for 1 hour under 30 psi of hydrogen pressure. The reaction mixture was filtered to remove paladium/carbon, and concentrated to give 1.35 g of the titled compound. (Yield 100%). NMR (CDCl3): 3.8 (s, 3H), 6.5 (m, 3H).
100%
With hydrogen In methanol at 20℃; for 12h;
3; 11 Example 3 Preparation of 2-methoxy-4-fluoroaniline (1)
2-methoxy-4-fluoronitrobenzene (50.0 g, 0.29 mol) was added to a one-necked flask,Add 650 mL of methanol and 10 g of Raney nickelAt room temperature, a pressure of 1.5 atm hydrogen gas was allowed to react for 12 h.After the reaction is complete,The reaction solution was filtered through celite,A light pink solution was obtained,Concentrated under reduced pressure to get brown liquid,Is 2-methoxy-4-fluoroaniline (41.2 g)
100%
With hydrogen In methanol at 15 - 26℃; for 12h;
1 Example 1 Preparation of 2-methoxy-4-fluoro-5-nitroaniline (1)
2-methoxy-4-fluoronitrobenzene (50.0 g, 0.29 mol) was added to a 1 L vial,Add 650mL methanol, stirring at 15 ~ 26 , then add 10g Raney nickel and pass 1.1atm of hydrogen, after 12h reaction. The reaction solution was filtered through celite to give a pale pink solution,The filtrate was concentrated under reduced pressure to give 41.2 g of 2-methoxy-4-fluoroaniline in 100% yield.
100%
With palladium 10% on activated carbon; ammsnium formate In methanol at 20℃;
98%
With hydrogen In methanol at 20℃; for 6h;
229
Example 2294-fluoro-2-methoxyanilineA solution of 5-fluoro-2-nitroanisole (5.0 g, 29.22 mmol, 1 equiv) in the presence of 250 mg of Pd/C (5%) in MeOH (60 mL) was hydrogenated at room temperature for 6 hours. The reaction mixture was filtered over a pad of Celite and then concentrated to give a brown oil (4.06 g, 98%) which was directly used in the next step. m/z=142 (M+H)+.
98%
With hydrogen In methanol at 25 - 30℃; Autoclave;
1.B Step-B - process for the preparation of 4-fluoro-2-methoxyaniline:
In an autoclave methanol (4000 ml) and 4-fluoro-2-methoxy-l -nitrobenzene (470 gms) were added. A mixture of Raney Ni (47 gms) and methanol (470 ml) was added to the reaction mass under nitrogen atmosphere. The reaction mass was stirred at 25-30°C for 10-15 minutes. Hydrogen gas was slowly fed into the autoclave upto 3.0 kgs (slight exothermic temperature observed). The reaction mass was stirred at 25-30°C for 8-10 hrs till there was no hydrogen consumption. The reaction mass was filtered through celite and the celite bed was washed with methanol (250 ml). Organic solvent was distilled under vacuum to give black color liquid (Yield - 380 gms; 98.0%).
97%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 22h;
1 Compound (2): Synthesis of 4-Fluoro-2-methoxyaniline (2)
Compound (1) (1.10 g, 6.43 mmol) was dissolved in methanol (30.0 mL) and 10% Pd / C (55.0 mg) was added. After stirring under a hydrogen atmosphere at room temperature for 22 hours, the mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain 877 mg of compound (2) (yield: 97%).
95%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 24h;
94.3%
With palladium on activated charcoal; hydrogen In methanol for 16h;
6 Preparation Example 6 4-fluoro-2-methoxyaniline preparation
4-fluoro-2-methoxy-1-nitrobenzene (15.00 g, 87.67 mmol) was added to methanol (200 mL)Palladium carbon (200 mg) was added under nitrogen atmosphere,Hydrogen atmosphere for 16 hours, suction filtration,The filtrate was concentrated to give the title compound (11.67 g, yield 94.3%).
93%
With iron(0); ammonia hydrochloride In tetrahydrofuran; lithium hydroxide monohydrate at 25 - 65℃; for 3h;
Step a:
Step a: Compound 1a1 (10.6 g, 58 mmol) was added into a 500 ml reaction flask, and THF/water (100 ml/60 ml) mixed solution was added to dissolve the compound. Ammonium chloride (15.5 g, 292 mmol) and reduced iron powder (26 g, 467 mmol) were sequentially added with stirring at room temperature, and then the reaction system was heated to 65° C. and stirred continually for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the excess iron powder was removed by filtration, and the filter cake was washed for three times with EA. Filtrate was extracted with EA/water system for three times, and the organic layer was separated, washed with water, saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 1a2 (8.0 g) which was used directly in the next reaction. Yield: 93%; purity: 90%; MS m/z (ESI): 142.0 [M+H]+.
93.28%
With palladium 10% on activated carbon; hydrogen In methanol at 40℃; for 12h; Inert atmosphere;
A1 Embodiment A1 4-Fluoro-2-methoxyaniline
2-Methoxy-4-fluoronitrobenzene (100.00g, 584.35mmol) was dissolved in methanol (400mL), Pd/C (10%, 10g) was added after sweeping with nitrogen. The mixture was heated to 40°C under H2 (50Psi) and stirred for 12 hours. TLC showed the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to dryness to deliver the title compound (red oil, 83.00g, yield 93.28%). LCMS (ESI) (10-80CD): m/z: 142.1 [M+1].
92%
With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 30 - 35℃; Autoclave; Inert atmosphere;
3 (3) Preparation of 4-fluoro-2-methoxyaniline
In a 1L autoclave, ethyl acetate 600 g, 4-fluoro-2-methoxynitrobenzene (257.5 g, 1.50 mol), 5% Pd / C 3g were added, and the autoclave was closed. Nitrogen was purged 3-4 times, and maintained in a hydrogen pressure at 0.5-1.0MPa, temperature between 30-35°C for 7-8 hours. Sampling of GC analysis was carried out, 4-fluoro-2-methoxy nitrobenzene <0.5%. After completion of the reaction, the hydrogen in the kettle was replaced with nitrogen. After the nip with nitrogen, filtered, and Pd / C was recovered. The filtrate was recovered with ethyl acetate. The residual material was distilled under reduced pressure, and the liquid was collected as a pale yellow oily liquid 4-fluoro-2-methoxyaniline 195 g. GC content of 98.5%. Yield 92%.
91%
With iron(0); ammonia hydrochloride In ethanol; lithium hydroxide monohydrate at 55 - 85℃; for 2h;
1.1a Step 1a: Preparation of 4-fluoro-2-methoxyaniline (Intermediate 102)
2-methoxy-4-fluoro-1-nitrobenzene (Intermediate 101) (20 g, 0.12 mol, 1.0 eq), ammonium chloride (13 g, 0.24 mol, 2.0 eq) and water (50 mL) were dissolved in ethanol (200 mL). After heated to 55°C, iron powder (13 g, 0.24 mol, 2.0 eq) was added portionwise. The temperature was raised to 85 °C and after reaction for 2 hours, the temperature was lowered to room temperature, filtration was performed and the solvent was rotary evaporated. The residue was dissolved in ethyl acetate which was then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain 4-fluoro-2-methoxyaniline as a light green product (15 g, yield: 91%). LCMS (ESI): m/z 142 [M + H]+.
88%
With tetrahydroxydiborane; isopropanol In ethanol at 20℃; for 12h; Schlenk technique; Inert atmosphere; Irradiation; Sealed tube; Green chemistry; chemoselective reaction;
General procedure for the deoxygenative hydrogenation of nitro compounds
General procedure: An oven-dried 10 mL Schlenk tube containing a magnetic stirring bar was charged with substrates (0.2 mmol, 1.0 equiv.). Then the tube was evacuated and refilled with N2 (x 3 times). Isopropanol (3 mmol, 15 equiv.) and 0.6 mL degassed solvent (General procedure I: EtOH; General procedure II: THF with the addition of 5 equiv. of H2O) were sequentially added and the mixture was stirred at room temperature for 12 hours under the irradiation of 400 nm LED (10 W power). After reaction, the solvents were evaporated under reduced pressure. The residue was then subjected to flash column chromatography on silica gel or preparative layer chromatography using petroleum ether and dichloromethane as eluents to give products.
86%
With palladium on activated charcoal; hydrogen In methanol at 20℃;
1.2 Synthesis of compound 5-a
Add 5-fluoro-2-nitroanisole (2.00g, 11.7mmoL)Put it in a 100mL single-necked reaction flask, add 65mL of anhydrous methanol solvent,Then add a dilution of Pd/C (300mg, 15% by mass) anhydrous methanol (5mL), the resulting suspension, stir for 4-5h at room temperature under H2 environment,After the completion of the TLC detection reaction, the suspension was poured into a funnel filled with filter paper and diatomaceous earth, and filtered under reduced pressure. The resulting filtrate was concentrated to dryness under reduced pressure.A purple solid crude product was obtained, which was separated by silica gel chromatography column(Use petroleum ether: ethyl acetate = 15:1 to 10:1 for elution),Compound 5-a (1.42g, yield 86.0%) was obtained,It is a purple solid.
57%
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate for 12h; Reflux;
46%
With hydrazine monohydrate In ethanol at 75℃; for 12h; Inert atmosphere;
2.4. The process for the hydrogenation of nitroarenes
General procedure: To an 10 mL glass reactor was added 1 mmol of nitro compound, 0.1mmol of FeO(OH)/C nanoparticles, 2 mL of ethanol and 2 mmol of 80%N2H4.H2O at N2 atmosphere. Next, the reactant was stirred at 75 C forabout 2-12 h. After the reaction was finished, the catalyst was filteredoff and washed with dichloromethane or ethyl acetate, the solvents wereremoved in vacuo, and the target product was purified by columnchromatography or directly dried over in vacuo
With iron(0); glacial acetic acid
With hydrogen
With hydrogen
With hydrogen In ethanol for 16h;
With hydrogen In methanol at 20℃; for 6h; Heating / reflux;
14
;A mixture of 5-fluoro-2-nitro-phenol (4.90 g, 31.8 mmol), MeI (4 mL, 63.6 mmol), and K2CO3 (8.82 g, 63.6 mmol) in acetone (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated, diluted with EtOAc, and washed with water. The organic layer was concentrated to yield a light yellow solid. The crude intermediate was dissolved in methanol (50 mL). Pd/C (10%, 0.42 g) was added the solution. The reaction was stirred at room temperature under H2 at atmosphere pressure for 6 hours. TLC showed the reaction was complete. The reaction was filtered through the celites and concentrated under reduced pressure to give the desired product as brown oil (3.43 g).
With ammonia hydrochloride In lithium hydroxide monohydrate; propan-2-one at 0 - 20℃;
24.1
Step 1 : To a suspension of 5-fluoro-2-nitroanisole (50 mmol, 8.5 g) and zinc powder (3.5 eq, 1 1 .4 g) in acetone (45 mL) and water (5 mL) was added ammonium chloride (1 1 eq, 29.3 g) at 0 °C in multiple portions. After the mixture was stirred at r.t. overnight, HPLC indicated a complete conversion. Acetone was removed on rotavap and the residue was suspended in DCM and water. Filtration was carried out and the filtrate was extracted with DCM. Concentration of combined organic layers gave crude aniline (~ 7.0 g), which was used in the next step without purification.
7 g
With ammonia hydrochloride; zinc In lithium hydroxide monohydrate; propan-2-one at 0 - 20℃;
24.1
To a suspension of 5-fluoro-2-nitroanisole (50 mmol, 8.5 g) and zinc powder (3.5 eq, 11.4 g) in acetone (45 mL) and water (5 mL) was added ammonium chloride (11 eq, 29.3 g) at 0 °C in multiple portions. After the mixture was stirred at r.t. overnight, HPLC indicated a complete conversion. Acetone was removed on rotavap and the residue was suspended in DCM and water. Filtration was carried out and the filtrate was extracted with DCM. Concentration of combined organic layers gave crude aniline (~ 7.0 g), which was used in the next step without purification.
With palladium on activated charcoal; hydrogen at 20℃;
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
4-fluoro-2-methoxyani line
[447] To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (100 g, 0.584 mol) in MeOH (1.5 L) was added 10%-Pd/C (10 g). The mixture was stirred under a hydrogen atmosphere at it overnight.Subsequently, the reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 4- fluoro-2-methoxyaniline (A3) as a brown oil.
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
4-fluoro-2-methoxyaniline
To a solution of 4-fluoro-2-methoxy-1 -nitrobenzene (100 g, 0.584 mol) in MeOH (1.5 L) was added 10%-Pd/C (10 g). The mixture was stirred under a hydrogen atmosphere at rt overnight. Subsequently, the mixture was filtered and the filtrate was concentrated in vacuo to afford 4-fluoro-2- methoxyaniline (A1) as a brown oil.
8.0 g
With iron(0); ammonia hydrochloride In tetrahydrofuran; lithium hydroxide monohydrate at 65℃; for 3h;
2-a.a Step a:
The reaction substrate 2-a-1 (10.6g, 58mmol) is placed in the 500mL reaction flask, was dissolved in a mixed solution oftetrahydrofuran / water (100mL / 60mL) . At room temperature, to the stirred reaction flask were sequentially added ammonium chloride (15.5g, 292mmol) and reduced iron powder (26g, 467mmol), then the reaction system was heated to 65 deg. C and stirring was continued for 3 hours. The progress of the reaction by TLC, until complete reaction substrate, the excess iron was removed by filtration, the filter cake rinsed three times with ethyl acetate. Filtrate was washed with ethyl acetate / water system was extracted three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2-a-2 (8.0g), was used directly in the next reaction step. Yield: 93% ; purity: 90%.
With palladium on activated charcoal; hydrogen In methanol for 72h;
1
2-methoxy-4-fluoro-nitrobenzene (10g, 58.44mmol) was dissolved in methanol, was added 1g of palladium / carbon, substituted with hydrogen, the reaction under a hydrogen atmosphere for three days. Filtered and the filtrate was collected, methanol was distilled off to give an oily crude product. Was added at 0 crude product concentrated sulfuric acid was dissolved solid mixture, in batches added potassium nitrate (5.91g). The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water and NaHC03, adjustment pH6.0-8.0. The aqueous phase was thrice extracted with dichloromethane, the organic phase was collected, dried. The organic solvent was distilled off, the residue was purified by column chromatography to give 4-fluoro-2-methoxy-5-nitroaniline (4.0g).
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
Intermediate Al4-fluoro-2-methoxyaniline
[00395] To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (100 g, 0.584 mol) in MeOH (1.5 L) was added Pd/C (10%-loading, 10 g). The mixture was stirred under a hydrogen atmosphere at rt overnight. Subsequently, the mixture was filtered and the filtrate was concentrated in vacuo to afford 4-fluoro-2- methoxyaniline (Al) as a brown oil.
With iron(0); ammonia hydrochloride In tetrahydrofuran; lithium hydroxide monohydrate at 65℃; for 3h;
a Step a:
Compound 1 (10.6 g, 58 mmol) was placed in a 500 ml one-necked reaction flask, and THF/water (100 ml/60 ml) mixed solution was added to dissolve the substrate. Ammonium chloride (15.5 g, 292 mmol) and reductive iron powder (26 g, 467 mmol) were sequentially added with stirring at room temperature, and then the reaction system was heated to 65° C. and stirred continually for 3 h. The reaction progress was monitored by TLC. After the substrate was completely consumed, the excess iron powder was removed by filtration, and the filter cake was washed for three times with ethyl acetate. Filtrate was extracted with ethyl acetate/water system for three times, and the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (8.0 g) which was used directly in the next reaction. Yield: 93%; purity: 90%; MS m/z(ESI):142.0 [M+H]+.
With palladium on activated charcoal; hydrogen In methanol at 35℃; for 48h;
B2.1 1) Synthesis of compound b2-2:
50 g of compound b2-1 was added, 500 ml of methanol was completely dissolved, and 10 g of Pd / C(Palladium carbon), hydrogenation reaction at 35 for two days; point board monitoring, raw material reaction is completed, direct filtration of Pd / C, spin dry methanol phaseCompound b2-2 crude 39g.
With iron(0); ammonia hydrochloride In tetrahydrofuran; lithium hydroxide monohydrate at 20 - 65℃; for 3h;
a
The reaction substrate a1-1 (10.6 g, 58 mmol) was placed in a 500 mL single-necked reaction flask and a mixedsolution of tetrahydrofuran/water (100 mL/60 mL) was added to dissolve the substrate. Ammonium chloride (15.5 g, 292mmol) and reduced iron powder (26 g, 467 mmol) were added sequentially to the reaction flask under stirring at roomtemperature, after which the reaction was heated to 65 °C and stirred continuously for 3 hours. The progress of thereaction was monitored by TLC. After the reaction of the substrate was complete, the excess iron powder was removedby filtration and the filter cake was rinsed three times with ethyl acetate. The filtrate was extracted three times with ethylacetate/water system, and the organic layer was separated, washed with water and then saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure to give compound a1-2 (8.0 g), which was directlyused in the next step. Yield: 93%; purity: 90%; MS m/z(ESI):142.0 [M+H]+.
With palladium on activated charcoal; hydrogen In methanol at 35℃; for 48h;
Synthesis of B1-2:
B1-1 material weighed 50g, 500ml methanol was added to dissolve the whole, was added Pd / C 10g, 35 two days under the hydrogenation reaction. Sheet monitoring point, the reaction is completed material treatment. Direct was filtered off Pd / C, methanol rotary evaporation to give the crude product with 39g, administered directly next.
With palladium on activated charcoal; hydrogen In methanol at 35℃; for 48h;
With lithium hydroxide monohydrate; iron(0); ammonia hydrochloride In tetrahydrofuran; methanol at 50℃;
4.06 g
With palladium 10% on activated carbon In methanol at 20℃; for 23h; Inert atmosphere;
STEP A: 2-nitro-5-fluoro-anisole A mixture of 32 ml of nitric acid and 95 ml of acetic acid anhydride was added dropwise with stirring at 0 to -5 C. to a solution of 12.6 g of 3-fluoro-anisole in 100 ml of acetic acid anhydride and the mixture was stirred at 0 to 5 C. for one hour. The reaction was poured over ice and was vacuum filtered. The recovered precipitate was dried to obtain 6.77 g of 2-nitro-5-fluoro-anisole with a melting point <50 C.
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80 C. for 20 h. The mixture was cooled to room temperature, and the "pH? of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
95%
Step a: To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80 C. for 20 h. The mixture was cooled to room temperature, and the ?pH? of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
95%
Step a: To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80 C. for 20 h. The mixture was cooled to room temperature, and the "pH? of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
95%
With sodium hydroxide; In water; dimethyl sulfoxide; at 80℃; for 20.0h;
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks) (3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80 C. for 20 h. The mixture was cooled to room temperature, and the ?pH? of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
95%
With sodium hydroxide; In water; dimethyl sulfoxide; at 80℃; for 20.0h;
Step 1. To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40mmol). The reaction mixture was heated at 80 oC for 20 h. The mixture was cooled toroom temperature, and the ?pH? of the solution was adjusted to 5 by aqueous HClsolution. The mixture was extracted with ethyl acetate three times. The combinedorganic extract was washed with water, brine, dried over MgSO4, and concentrated togive 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
90.1%
With thionyl chloride; sodium hydroxide; at 80℃; for 20.0h;
A solution of sodium hydroxide (39 mL, 117 mmol, 3M)Was added to a solution of 4-fluoro-2-methoxy-1-nitrobenzene (10.0 g, 58.4 mmol)Of thionyl chloride(100 mL)Followed by reaction at 80 C for 20 hours in an oil bath.After the reaction, pH = 5 was adjusted with concentrated hydrochloric acid,Then extracted with ethyl acetate (100 mL x 3)The organic phases were combined, concentrated under reduced pressure,The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (9.0 g, yield 90.1%).
74.4%
With sodium hydroxide; In dimethyl sulfoxide; at 50℃; for 3.0h;
(0915) 2-Methoxy-4-fluoronitrobenzene (3.4 g, 19.88 mmol) was dissolved in dimethyl sulfoxide (30 mL), and NaOH solution (1 N, 40 mL, 40 mmol) was added. The mixture was heated to 50 C., and reacted for 3 h. After the reaction, water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to get the title compound (2.5 g, yield: 74.4%).
60%
With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 21.0h;
To a stirred solution of 24 (0.63 g, 3.7 mmol) in DMSO (5.3 mL) was added 30% NaOH (2.5 mL, 18.0 mmol) solution. The mixture was stirred for 21 h at room temperature, cooled to 0 C and acidified with 6 N HCl. The mixture was pour into 5% HCl and extracted with ether several times. The combined organic layers were washed with 5% HCl three times, then with brine, and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 25 as a white solid (0.37 g, 60%).
28%
To a solution of 5-fluoro-2-nitroanisole (11.0 g, 64.3 mmol) in dimethylsulfoxide (30 mL) /water (5 mL) was added sodium hydroxide (5.36 g, 129 mmol), and the mixture was stirred at 9O0C for 15 hr. The reaction solution was cooled to 00C, 6N hydrochloric acid was added to adjust to pH 7. The precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90_>50/50) and recrystallized from ethyl acetate-hexane to give the title compound (3.05 g, 28%) as a white solid.1H-NMR (DMSOd6, 300 MHz) delta 3.88 (3H, s) , 6.47 (IH, dd, J = 9.1, 2.7 Hz), 6.61 (IH, d, J = 2.7 Hz), 7.89 (IH, d, J = 9.1 Hz) , 10.90 (IH, s) .
With potassium hydroxide; In water; at 90℃; for 5.0h;
4-Fluoro-2-methoxynitrobenzene (4.68g, 27.4mmol) was suspended in a 5M potassium hydroxide solution (50 ml) and heated to 900C for 5h. The red solution was cooled to room temperature and acidified to pH 6 with IM HCl. The aqueous solution was extracted three times with ethyl acetate and the combined organics were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure, followed by purification by flash column EPO <DP n="168"/>chromatography (1:1 hexane/ethyl acetate) afforded the title compound as a yellow solid.
With sodium hydroxide; In dimethyl sulfoxide;Reflux;
General procedure: FIG, 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group, e.g., Compounds lr-lt. Generally, reagents and conditions for synthesis of compounds according to FIG, 2C included: a) RI, K2C03, sealed tube, 80C; b) NaOH, DMSO, reflux; c) 1,8-Dibromooctane, K2C03, CH3CN, reflux; d) imidazole, K2C03, CH3CN, reflux; e) 8etaOmicron2'2Eta20, EtOAc, refux; f) S~(2~ naphih}'lmethyl)thioimidaie hydrobromide, CH3CN/EtOH, rt..
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane for 67h; Ambient temperature;
94.1%
With potassium carbonate In N,N-dimethyl-formamide at 60 - 100℃;
2 (2) Preparation of 4-fluoro-2-methoxynitrobenzene
In a 5L four-necked flask, DMF 2500 g, 4-fluoro-2-hydroxy nitrobenzene (500 g, 3.20 mol) and potassium carbonate (483 g, 3.50 mol) were added and heated to 60°C. 424 g (3.36 mol) of dimethyl sulfate was added dropwise for about 2-3 hours. After completion of dripping, heated to 90-100°C for 5-6 hours. Sampling GC analysis of 4-fluoro-2-hydroxy nitrobenzene was found to<0.5%. The mixture was cooled to 50°C, generating monomethyl sulfate potassium salt. The filtrate was distilled under reduced pressure to recover DMF to give 515 g of 4-fluoro-2-methoxynitrobenzene as a yellow oily liquid. GC content of 99.5%, yield 94.1%.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
251.251a
To a suspension of 5-Fluoro-2-nitro-phenol (0.85 g, 0.0054 mol) and Potassium carbonate (1.6 g, 0.012 mol) in N,N-Dimethylformamide (10 mL, 0.1 mol) was added Dimethyl sulfate (0.56 mL, 0.0060 mol). The mixture was allowed to stir at room temperature for 18 hours. To the yellow suspension was added l-Methyl-4-piperidin-4-yl- piperazine (1.0 g, 0.0054 mol). The suspension was stirred at room temperature for 1 hour. Reaction mixture was heated to 600C for 18 hours. The reaction was monitired by HPLC. The mixture was allowed to cool to room temperature then cooled to 0°-5°C in a ice/salt/water bath. To the vigrously stirring mixture was added aqueous saturated sodium chloride and stirrred for 1 hour. The mixture was filtered and rinsed with a minimum of cold aqueous saturated sodium chloride. The yellow filter cake was dissolved in methanol and evporated to dryness. The yellow solids were partially dissolved in dichloromethane (100 ml), filtered, dried over magnesium sulfate, filtered and evaporated to yield yellow solids. The solids were triturated with ether (30 mL) with stirring for 72 hours. The solids were filtered, rinsed with ether and dried by suction. l-[l-(3-Methoxy-4-nitro-phenyl)- piperidin-4-yl]-4-methyl-piperazine was recovered as a yellow solid (0.95 g). mp=140- 143°C. 1H NMR (400 MHz, CDC13, δ, ppm): 8.00 (d, IH, J=9.3 Hz), 6.42 (dd, IH, J=9.5 Hz and 1.6 Hz), 6.32-6.29 (m, IH), 3.98-3.91 (m, 5H), 3.02-2.95 (m, 2H), 2.70-2.55 (m, 4H), 2.55-2.40 (m, 5H), 2.29 (s, 3H), 2.01-1.93 (m, 2H), 1.68-1.56 (m, 2H). LC/MS = 335.20 (MH)+
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;
38
Example 38. Preparation of 4-fluoro-2-methoxy-l-nitro-benzene intermediate.5-Fluoro-2-nitrophenol (3.14 g; 20 mmol) and potassium carbonate (2.76 g; 20 mmol) are place in a round bottom flask and are flushed with argon. Dry dimethylformamide (60 mL) is added followed by dimethylsulfate (3.8 mL; 40 mmol). The reaction is stirred for 2 days at room temperature. Dichloromethane (120 mL) and water (60 mL) are then added. The aqueous phase is extracted with dichloromethane (100 mL) and the combined organic layers are washed three times with aq. sat. sodium hydrogencarbonate (50 mL), twice with aq. IN hydrochloric acid (50 mL) and with brine (50 mL). The organic layer is then dried over magnesium sulfate and is concentrated under reduced pressure. The desired product is isolated in the presence of dimethylformamide (4.39 g).
With sodium hydroxide In N,N-dimethyl-formamide at 20℃;
24.1 (1) Synthesis of Diethyl 2- (3-fluoro-4-nitrophenyl) -2-methylmalonate (Intermediate 2a)
General procedure: Dissolving 2,4-difluoronitrobenzene 1a (2.2ml, 20mmol) in DMF solution,A solid NaOH (800 mg, 20 mmol) was added, and diethyl methylmalonate (3.68 ml, 21.6 mmol) was added dropwise to the reaction solution, followed by stirring at room temperature overnight.After the reaction was completed, 120 ml of water was added, extracted with DCM three times, washed with brine three times, and the organic layers were combined and dried over anhydrous sodium sulfate.Spin dry and separate by column chromatography (eluent: PE / EA = 20/1, v / v).A light yellow oily liquid was obtained with a yield of 87%.
With potassium carbonate In N,N-dimethyl-formamide at 60℃; Cooling with ice;
127.127-a-1
Example 127; Preparation of 3-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)-2-methoxyphenethyl)-5-(1-(1-methylethoxy)phenyl-4-yl)-5-methylimidazolidine-2,4-dione; 127-a-1) Preparation of 4-fluoro-2-methoxy-1-nitro-benzene; A solution of 4-fluoro-2-hydroxy-1-nitrobenzene (100 mg, 0.637 mmol) in N,N-dimethylformamide (3.2 mL) was added with potassium carbonate (132 mg, 0.955 mmol), then added with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at room temperature for 1 hour. The reaction solution was further added with potassium carbonate (132 mg, 0.955 mmol), then with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at 60° C. for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 4-fluoro-2-methoxy-1-nitro-benzene (118 mg, yield >100%) was obtained as a yellow oil.1H-NMR (CDCl3) δ: 3.97 (3H, s), 6.74 (1H, ddd, J=2.4, 7.8, 9.0 Hz), 6.80 (1H, dd, J=2.4, 10.2 Hz), 7.97 (1H, dd, J=6.1, 9.0 Hz).
100%
With potassium carbonate In acetone at 0℃; for 5h;
3.2.6. Synthesis of 4-Fluoro-2-methoxy-1-nitrobenzene (6)
To a stirred mixture of 5-fluoro-2-nitrophenol (C6H4FNO3) (1.0 g, 6.43 mmol, 1.0 eq.) and acetone(15 mL), potassium carbonate (K2CO3) (1.77 g, 12.80 mmol, 2.0 eq.) and iodomethane (CH3I) (0.80 mL,12.80 mmol, 2.0 eq.) were added. The mixture was stirred at 0 C for 5 h. After the reaction wascompleted, ethyl acetate and water (1:1) were added to the mixture. The organic layer was separated,dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to aord 6(1.1 g, 100%) as an orange crystal. 1H-NMR (400 MHz, CDCl3): 3.97 (3H, s), 6.74 (1H, dt, J = 8.4,2.0 Hz), 6.80 (1H, dd, J = 10.4, 2.4 Hz), 7.96 (1H, dd, J = 8.4, 6.4 Hz). 13C-NMR (100 MHz, (CD3)2SO): 56.7, 101.5, 107.0, 128.0, 155.3, 164.3, 167.0. HRMS (DART+) calculated for C7H6FNO3 [M + H]+:m/z = 172.0331, found 172.0345.
99%
With potassium carbonate In acetone at 20℃; for 12h; Reflux;
99%
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In acetone for 0.5h; Inert atmosphere;
Stage #2: methyl iodide In acetone at 60℃; Inert atmosphere;
99%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1h;
4-Fluoro-2-methoxy-1-nitro-benzene(36b):
To a stirred suspension of 4-fluoro-2-hydroxy- 1-nitrobenzene(35) (100 mg, 0.64 mmol) and K2CO3(132 mg, 0.96 mmol) in DMF (3.2 mL) was added methyl iodide (108 mg, 0.76 mmol)at 0 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo to give thetitle compound (118 mg, 99%) as a yellow oil;
99.1%
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In acetone at 20℃; for 0.5h; Inert atmosphere;
Stage #2: methyl iodide In acetone at 60℃;
3.1 Step 1: Preparation of 4-fluoro-2-methoxynitrobenzene (the compound of Formula I-21)
5-fluoro-2-nitrophenol (10 g, 63.65 mmol), potassium carbonate (8.8 g, 63.65 mmol) and acetone (100mL) wereadded in a 250 mL three-necked flask and stirred at room temperature for 30 minutes under the protection of nitrogengas. Iodomethane (9.03 g, 63.65 mmol) was then slowly added dropwise thereto, and the mixture was warmed up to60°C and reacted overnight. After the reaction was completed, the reaction solution was added with water (200 mL),extracted with ethyl acetate (100 mL 3 4), washed with 1M sodium hydroxide (100mL 3 3) and saturated brine (100mL 3 2) successively, dried over anhydrous sodium sulfate, filtered by suction and evaporated under reduced pressureto remove the solvent, to give 4-fluoro-2-methoxynitrobenzene (10.8 g, 99.1% yield).
98%
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In acetone at 20℃; for 0.5h;
Stage #2: methyl iodide In acetone at 20 - 60℃; for 30h;
1.a
4-fluoro-2-methoxy-1-nitro-benzene 20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo. Yield: 21.1 g (123 mmol; 98%) UV max: 230/266/322 nm.
98%
With potassium carbonate In acetonitrile at 50℃; for 3h;
8.3 (3) Preparation of 4-fluoro-2-methoxy-1-nitrobenzene
(0540) 5-Fluoro-2-nitrophenol (7.85 g, 0.05 mol), iodomethane (8.52 g, 0.06 mol) and potassium carbonate (10.35 g, 0.075 mol) were added to acetonitrile (150 mL). The mixture was heated at 50° C. for 3 h, and the solvent was removed under reduced pressure. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried and concentrated to get the product (8.4 g, yield: 98%).
98%
With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 12h;
97%
With potassium carbonate In acetone for 4h; Heating / reflux;
5.60.1
5.60.1 4-Fluoro-2-methoxy-1-nitrobenzene A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3×250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97% yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H).
96%
With potassium carbonate In acetone for 3h; Reflux;
4.1.17 4-Fluoro-2-methoxy-1-nitro-benzene (24)
To a stirred solution of 23 (0.60 g, 3.82 mmol) in acetone (20 mL) was added K2CO3 (1.1 g, 7.6 mmol) and iodomethane (0.5 mL, 7.6 mmol). The reaction mixture was refluxed for 3 h and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 24 as a white solid (0.63 g, 96%).
94%
With potassium carbonate In acetonitrile at 16 - 85℃; for 5h;
26.1
Step 1 : K2C03 (131 g, 955 mmol) and CH3I (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in MeCN (750 mL) at rt and the resulting mixture was heated to 85°C for 5 h. The RM was chilled, filtered and washed with MeCN. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reduced pressure to give the desired compound (75 g, 94%).
94%
With potassium carbonate In acetonitrile at 85℃; for 5h;
5.1
Step 1: K2C03 (131 g, 955 mmol) and Mel (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in acetonitrile (750 mL) at rt and the resulting mixture was heated to 85 C for 5 h. The reaction mixture was chilled, filtered and washed with acetonitrile. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reducedpressure to give the desired compound (75 g, 94%).
94%
With potassium carbonate In acetone at 20℃; for 50h; Cooling with ice;
1 Compound (1): Synthesis of 4-Fluoro-2-methoxy-1-nitrobenzene (1)
A solution of 5-fluoro-2-nitrophenol (3.00 g, 19.1 mmol) in acetone (42.0 mL) is dissolved in methyl iodide (2.37 mL, 38.2 mL) with stirring under ice-cooling. Add mmol) dropwise,Potassium carbonate (5.30 g, 38.2 mmol) was added.room temperatureAfter stirring for 50 hours, the solvent was evaporated under reduced pressure, dissolved in ethyl acetate, and washed with distilled water. The organic layer was washed with saturated brine and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.00 g of a compound (1) (yield 94%).
92%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
22.A
To 2-nitro-5-fluoro-phenol (56.0 g, 357 mmol) and iodomethane (24.5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54.2 g, 393 mmol). Significant bubbling occurred. The mixture was stirred at rt overnight. The mixture was poured into H2O (800 mL) and the H2O washed with diethyl ether (3×200 mL). The ether washes were combined and washed with H2O (2×400 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (56.0 g, 327 mmol, 92%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 1H), 6.79-6.67 (m, 2H), 3.93 (s, 3H).
92%
With potassium carbonate In N,N-dimethyl-formamide
92%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
20.A
To 2-nιtro-5-fluoro-phenol (56 0 g, 357 mmol) and iodomethane (24 5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54 2 g, 393 mmol) Significant bubbling occurred The mixture was stirred at rt overnight The mixture was poured into H2O (800 mL) and the H2O washed with ether (3 x 200 mL) The ether washes were combined and washed with H2O (2 x 400 mL) The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (56 0 g, 327 mmol, 92 %) as a yellow solid 1H-NMR (400 MHz, CDCI3) δ 7 96 - 7 90 (m, 1 H), 6 79 - 6 67 (m, 2 H) and, 3 93 (s, 3 H)
91%
With potassium carbonate In acetone at 0 - 20℃; for 144h;
90%
With potassium carbonate In N,N-dimethyl-formamide for 1h;
4-fluoro-2-methoxy-1-nitrobenzene (6).
To a solution of 5 (2 g, 12.8 mmol) and K2CO3 (2.64 g, 19.2 mmol) in DMF (20 ml) was added MeI (2.16g, 15.2 mmol) dropwise at 0 °C. The reaction mixture was heated for 1 h at 60 °C followed by cooling to room temperature. Water (20 ml) was added and the mixture was extracted with EtOAc (20 mL) for three times. The combined organic layer was washed with water and dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 6 as a light yellow solid in an 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.23 (dd, J = 11.0, 2.6 Hz, 1H), 6.92 (ddd, J = 9.0, 7.8, 2.6 Hz, 1H), 3.90 (s, 3H).
88%
With potassium carbonate In acetone at 20℃; for 96h;
11.a
Methyl iodide (11.94 mL, 191 mmol) was added dropwise to a stirred suspension of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol) and potassium carbonate (17.59 g, 127 mmol) in acetone (318 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 days, whereupon the acetone was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralised with concentrated hydrochloric acid. The organic layer was separated, washed with water and brine, dried (MgSO.)), filtered and evaporated to give an off-white solid that was recrystallised from isopropanol/dichloromethane to give 4-fiuoro-2-methoxy-l- nitrobenzene as an off-white solid (9.6 g, 88%).
81%
With potassium carbonate at 67 - 69℃; for 6h;
79%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; Sealed tube;
38%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 23h;
A mixture of commercially available 5-fluoro-2-nitrophenol (1.00 g, 6.37 mmol), MeI (1.36 g, 9.58 mmol), and potassium carbonate (1.32 g, 9.55 mmol) in DMF (10 mL) was heated at 140° C. for 23 hours. The reaction was diluted with aq. 0.5 N NaOH (50 mL) and extracted with EtOAc (2×50 mL). The EtOAc-extracts were washed once more with aq. 0.5 N NaOH (50 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness in vacuo. The crude product was purified by flash column chromatography (EtOAc/heptane: 1/1) to obtain 4-fluoro-2-methoxy-nitrobenzene (416 mg, 38%, purity (GC)>95%).MS: [M]+=171.
26%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; Sealed pressure flask;
73
4-Fluoro-2-methoxy-l-nitro-benzene was synthesized by suspending 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol, 1.0 equiv.), potassium carbonate (6.59 g, 47.7 mmol, 1.5 equiv.), and Iodomethane (2.98 mL, 47.7 mmol, 1.5 equiv.) in DMF (50 mL) and allowing the resulting reaction mixture to stir overnight at 14O0C inside a sealed pressure flask. The reaction mixture was partitioned between ethyl acetate and distilled water three times. The organic layer was washed once with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The product was isolated by column chromatography in 30% ethyl acetate and hexanes as a yellow solid (1.44 g, 26%). 1H NMR (300 MHz, CDCl3): δ(pρm) 7.98(dd, IH), 6.77(m, 2H), 3.99(s, 3H).
9.7%
With potassium carbonate In ethanol for 12h; Heating / reflux;
49.1 4-fluoro-2-methoxynitrobenzene
Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7%). NMR (CDCl3): 4.0 (s, 3H), 6.8 (m, 2H), 8.0 (m, 1H).
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 15h;
With potassium hydroxide; sodium hydroxide In water; dimethyl sulfoxide
2 Synthesis of 4-fluoro-2-methoxy-1-nitrobenzene (1):
Synthesis of 4-fluoro-2-methoxy-1-nitrobenzene (1): 25 g (0.159 mol) of 5-fluoro-2-nitrophenol are added to 125 ml of DMSO. 22.5 g (0.159 mol) of methyl iodide are then added, followed by dropwise addition, while keeping the temperature below 25° C., of 17.8 g of aqueous 50% potassium hydroxide solution. The mixture is stirred for one hour at ambient temperature and a further 22.5 g (0.159 mol) of methyl iodide are then added. After stirring for 24 hours, the reaction medium is poured into 125 ml of water and then extracted with 60 ml of dichloromethane. The organic phase is washed with 90 ml of aqueous sodium hydroxide solution (1N) and then with 60 ml of water. After drying over MgSO4, the organic phase is concentrated under reduced pressure. 20.59 g (76%) of 4-fluoro-2-methoxy-1-nitrobenzene (1) are thus recovered.
In <i>N</i>-methyl-acetamide
40.1 (1)
(1) Synthesis of 4-Fluoro-2-methoxynitrobenzene To a suspension of sodium hydride (1.3 g) in dimethylformamide (10 ml) was added a solution of 5-fluoro-2-nitrophenol (5.0 g) in dimethylformamide (20 ml)under ice-cooling. This reaction mixture was stirred at room temperature for 1 hr. To this solution was added methyl iodide (2.0 ml) and the mixture was left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a red solid. This solid was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (4.3 g) as a yellow solid. 1H-NMR(CDCl3)δ: 3.97(3H, s), 6.69-6.82(2H, m), 7.96(1H, dt, J=3.3, 2.6 Hz). IR(KBr): 3124, 3086, 2994, 1624, 1587 cm-1; MS(EI): 171(M+).
With potassium carbonate In acetone
32.a 3,5-Diisopropyl-4-(7-2H-1,4-benzoxazinoxy-3(4H)-one)phenylpropionic Acid
(a) 5-Fluoro-2-nitrophenol (10.3 g), potassium carbonate (27.1 g), methyl iodide (11.1 g) and acetone (100 mL) was heated at reflux until the starting materials were consumed. After cooling down to room temperature, the reaction mixture was diluted with ethylacetate, washed with hydrogen chloride (1 N) and brine. After puridication on column (silica gel, ethyl acetate/petrolium ether, 1:9), 10.8 g (96%) of of 5-fluoro-2-nitroanisole was obtained.
With potassium carbonate In acetone for 3h; Heating / reflux;
14
;A mixture of 5-fluoro-2-nitro-phenol (4.90 g, 31.8 mmol), MeI (4 mL, 63.6 mmol), and K2CO3 (8.82 g, 63.6 mmol) in acetone (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated, diluted with EtOAc, and washed with water. The organic layer was concentrated to yield a light yellow solid. The crude intermediate was dissolved in methanol (50 mL). Pd/C (10%, 0.42 g) was added the solution. The reaction was stirred at room temperature under H2 at atmosphere pressure for 6 hours. TLC showed the reaction was complete. The reaction was filtered through the celites and concentrated under reduced pressure to give the desired product as brown oil (3.43 g).
Stage #1: 5-fluoro-2-nitrophenol; methyl iodide With sodium hydride In tetrahydrofuran at 20℃; for 10h;
Stage #2: With caesium carbonate In tetrahydrofuran at 20℃; for 4h;
75
To a solution of 5-fluoro-2-nitro-phenol (369 mg, 2.35 mmol) in 5 mL THF, sodium hydride (96 mg, 2.46 mmol) was added at room temperature, followed by methyl iodide (0.88 ml, 14 mmol). The mixture was stirred at room temperature for 10 hours, and then cesium carbonate (744mg, 2. 35 mmol) was added. The mixture was stirred at room temperature for additional 4 hours, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give pure 4-fluoro- 2-methoxy-1-nitro-benzene.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;
157.1
5-Fluoro-2-nitrophenol (6 g, 38.2 mmol) was dissolved in anhydrous DMF (20 ml). Potassium carbonate (5.3g, 38.2 mmol) was added, followed by iodomethane (2.28 ml, 38.2 mmol) . The reaction was stirred at room temperature for 16h, then partitioned between dichloromethane and water. The organic layer was washed three times with IM sodium hydroxide and once with brine, then dried over sodium sulfate. Removal of the solvent in vacuo afforded the title compound as a yellow oil, which solidified upon standing.
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h;
4.5 g
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 2h;
32.1 Preparation of 4-fluoro-2-methoxy- 1 -nitrobenzene
To a solution of 4-fluoro-2-hydroxy-l -nitrobenzene (5.0 g, 31.8 mmol) in DMF (10 mL) was added K2CO3 (13.1 g, 95.4 mmol). The reaction mixture was stirred at RT for 1 h followed by addition of methyl iodide (9.93 g, 69.9 mmol) and the reaction mixture was stirred at 60 C for 2 h. The reaction mass was concentrated and quenched in water. The reaction mass was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.93 (s, 3H), 6.97 (t, J= 7.8 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H).
With potassium carbonate In acetone for 4h; Reflux;
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
1.1 Step 1: Preparation of 4-fluoro-2-methoxy-1-nitrobenzene
5-fluoro-2-nitrophenol (300 mg), methyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
1.1 Step 1: Preparation of 4-fluoro-2-methoxy-1-nitrobenzene
Step 1: Preparation of 4-fluoro-2-methoxy-1-nitrobenzene 5-fluoro-2-nitrophenol (300 mg), methyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50°C overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
With potassium carbonate at 80℃; Sealed tube;
2C Example 2C: Synthesis of orf/w-S bstit ted Phenoxyalkyl Linker Anti-Parasitic Compounds
General procedure: FIG, 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group, e.g., Compounds lr-lt. Generally, reagents and conditions for synthesis of compounds according to FIG, 2C included: a) RI, K2C03, sealed tube, 80°C; b) NaOH, DMSO, reflux; c) 1,8-Dibromooctane, K2C03, CH3CN, reflux; d) imidazole, K2C03, CH3CN, reflux; e) 8ηΟ2'2Η20, EtOAc, refux; f) S~(2~ naphih}'lmethyl)thioimidaie hydrobromide, CH3CN/EtOH, rt..
With potassium carbonate In acetone at 0℃; for 5h;
With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; at 18 - 60℃; for 18h;
To a solution of 4-Fluoro-2-methoxy-1-nitrobenzene (Apollo Scientific; 4.28 g, 25 mmol) in toluene (20 mL) and 25percent KOH aq. (20 mL), were added at room temperature, <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong> (5.0 g, 50 mmol) and tetra-n-butylammonium bromide (1.66 g, 5 mmol). The mixture was heated at 60° C. for 18 hrs. The reaction mixture was cooled to room temperature, poured onto ice-water (200 mL) and extracted with Ethyl Acetate (3.x.100 mL). The organic layer was washed with 2 M HCl (250 ml) and then loaded onto a 50 g SCX-2 cartridge, washing with water and eluting with 7 N methanolic ammonia to give the title compound as a yellow oil, which solidified on standing (5.50 g, 87percent).1H NMR (399.902 MHz, DMSO-D6) delta 1.73-1.84 (m, 1H), 2.27 (s, 3H), 2.31-2.37 (m, 2H), 2.65 (dd, 1H), 2.68-2.73 (m, 1H), 2.77 (dd, 1H), 3.92 (s, 3H), 5.02-5.07 (m, 1H), 6.62 (dd, 1H), 6.73 (d, 1H), 7.95 (d, 1H); MS m/z 253.23 [M+H]+.
87%
With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; at 60℃; for 18h;
l-Methylpyrrolidin-3-ol (4.96 g) and tetra-n-butylammonium bromide (2.26 g) were added to a stirred mixture of 4-fiuoro-2-methoxy-l -nitrobenzene (6.00 g) in toluene (25 mL) and KOH (5.90 g) in water (25 mL). The mixture was heated at 600C for 18h and was then diluted with ice-water (250 mL), EtOAc (400 mL) and toluene (100 mL). The phases were separated. The organic portion was washed with water (200 mL), sat. brine and was then dried (MgSO4). Concentration in vacuo and purification by FCC using 0-10percent MeOH in DCM afforded the title compound (7.70 g, 87 percent) as a yellow gum; 1H NMR: 1.78 (IH, m), <n="90"/>2.26 (3H, s), 2.35 (2H, m), 2.69 (2H, m), 2.77 (IH, m), 3.91 (3H, s), 5.04 (IH, m), 6.62 (IH, dd), 6.72 (IH, d), 7.95 (IH, d); m/z: MH+ 253.
With potassium carbonate; dimethyl sulfate In acetone at 20℃; for 24h;
5 PREPARATION 5; 4-Fluoro-2-methoxy-1-nitrobenzene
A mixture of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol), potassium carbonate (2.50 g, 21.0 mmol) and dimethyl sulfate (2.65 g, 21.0 mmol) in acetone was stirred at ambient temperature for 24 hours. The solvents were removed under reduced pressure and then water (30 mL) and dichloromethane (30 mL) was added to the residue. The combined organics solutions were dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to provide an oil. This was purified by flash chromatography on silica gel using dichloromethane/heptane (7:3) as an eluent to provide the title compound as a crystalline solid (3.24 g, 100%): 1H NMR (CDCl3, 400 MHz) δ7.96 (M, 1H), 6.80 (m, 1H), 6.73 (m, 1H), 3.96 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 17.82 min; MS:MH+ 172.2
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 80℃; for 17h;
1-(3-methoxy-4-nitro-phenyl)-4-pyrrolidin-1-yl-piperidine 200 mg (1.170 mmol) 4-fluoro-2-methoxy-1-nitro-benzene are dissolvedjin 1 ml NMP, combined with 198 mg (1.284 mmol) 4-pyrrolidin-1-yl-piperidine and 300 mul diisopropylethylamine and stirred for 17 h at 80 C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point. Yield: 321 mg (1.053 mmol; 90%) UV max: 398 nm MS (ESI): 306 (M+H)+.
2 Synthesis of 1-(3-methoxy-4-nitrophenyl)pyrrolidin-3-ol (2):
Synthesis of 1-(3-methoxy-4-nitrophenyl)pyrrolidin-3-ol (2): 8 g (46 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene 1,80 ml of dioxane and 8.14 g (0.095 mol) of (R)-(+)-3-pyrrolidinol are respectively placed in the reactor. The mixture is refluxed for one hour. The reaction medium is poured into a mixture of water (100 ml)-ice (200 g). A yellow product precipitates. This product is filtered off, washed with water (3*30 ml) and then dried under vacuum at 45° C. 8.38 g (75%) of 1-(3-methoxy-4-nitrophenyl)pyrrolidin-3-ol (2) are thus recovered.
40.2 (2)
(2) Synthesis of 4-Fluoro-2-methoxyaniline To a solution of 4-fluoro-2-methoxynitrobenzene (4.2 g) in ethanol (50 ml) was added Raney-nickel (0.4 g) at room temperature. To this solution was added dropwise hydrazine monohydrate (6 ml) under ice-cooling. This reaction mixture was stirred at room temperature for 1 hr and passed through Celite. The solvent was evaporated to give an oil. The oil was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give a brown oil. The oil was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) to give the title compound (3.1 g) as a brown oil. 1H-NMR(CDCl3)δ: 3.51(2H, br.s), 3.82(3H, s), 6.45-6.64(3H, m). IR(KBr): 3452, 3369, 2964, 1612, 1514 cm-1; MS(EI): 141(M+).
Step (a): Preparation of 5-fluoro-2-methoxyaniline Reduction of 1-fluoro-3-methoxy-4-nitrobenzene (0.11 mol) (prepared by methylation of 5-fluoro-2-nitrophenol with methyl iodide was carried out according to Step (b) of Example XII to provide 14.8 g (98% yield) of 5-fluoro-2-methoxyaniline used without further purification.
In hexane; diethylene glycol dimethyl ether; dimethyl sulfoxide
3 Preparation of 2-fluoro-4,6-dichloro-3'-methoxy-4'-nitrodiphenyl ether
EXAMPLE 3 Preparation of 2-fluoro-4,6-dichloro-3'-methoxy-4'-nitrodiphenyl ether 9.95 g. (0.055 mole) of 2-fluoro-4,6-dichlorophenol is converted to the sodium salt by treatment with 1.35 g. (0.055 mole of oil-free sodium hydride in 130 ml. of diglyme. To this solution is added 9.4 g. (0.055 mole) of 2-nitro-5-fluoroanisole dissolved in 50 ml. of diglyme. After heating under reflux for 3 days, 80 ml. of diglyme is distilled from the reaction mixture and 100 ml. of dimethylsulfoxide is added. The mixture is then heated at 75° C. overnight, then at 95° C. over two nights, and finally at 150° C. overnight. The reaction mixture is diluted with water and extracted with ether. The ether extract is washed with water, dried, and the solvent removed to give 9 g. of oil. This is dissolved in hexane, the solution filtered and the solvent removed to give 6.1 g. of oil. This is chromatographed on 300 g. of 10% deactivated neutral alumina. The product is eluted with 5% benzene in hexane and is recrystallized from pure heptane to give 1.3 g. of 2-fluoro-4,6-dichloro-3'-methoxy-4'-nitrodiphenyl ether, melting point 115.5°-117° C.
With potassium carbonate In acetonitrile at 70℃; for 18h;
78 Preparation 78: 4-(3-methoxy-4-nitrophenyl)morpholine
Preparation 78: 4-(3-methoxy-4-nitrophenyl)morpholine To a solution of 4-fluoro-2-methoxy-1 -nitrobenzene (750 mg, 4.38 mmol) in MeCN (10 ml_) was added morpholine (3.83 ml_, 43.8 mmol) and potassium carbonate (606 mg, 4.38 mmol). The reaction mixture was heated at 70°C for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (30 ml_) and washed with water (2 x 30 ml_), dried (MgS04) and concentrated in vacuo, to give the title compound (1 .0 g, 96%). 1 H NMR (500 MHz, CDCI3): δ 8.03 (d, J = 9.0 Hz, 1 H), 6.48 (dd, J = 9.0, 2.5 Hz, 1 H), 6.44 (d, J = 2.5 Hz, 1 H), 3.98 (s, 3H), 3.90 (app, t , J = 5.0 Hz, 4H), 3.38 (app t, J = 5.0 Hz, 4H). LCMS (ESI) Rt = 1 .95 minutes MS m/z 239.28 [M+H]+
95.5%
With potassium carbonate at 80℃; for 1h;
12.1 Step 1) Preparation of 4-(3-methoxy-4-nitrophenyl)morpholine
4-fluoro-2-methoxy-1-nitrobenzene (0.1 g, 0.584 mmol) was dissolved in 3 ml of morpholine, potassium carbonate (161 mg, 1.17 mmol) was added and the reaction was carried out for 1 hour at 80°C. Solidified by the addition of water, suction filtration, infrared drying to give 133 mg of a yellow solid. Yield: 95.5%.
94%
With N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 90℃; Inert atmosphere;
7
N,N-diisopropylethylamine (2.45 ml, 14.0 mmol) and morpholine (1.12 ml, 12.9 mmol) were added to a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 11.7 mmol) in DMA (10 ml). The resulting solution was stirred at 90° C. overnight under argon. The mixture was allowed to cool to room temperature and water was added. The yellow precipitate was filtered, washed with water and dried under vacuum at 50° C. over P2O5 to afford 4-(3-methoxy-4-nitrophenyl)morpholine (2.63 g, 94% yield); NMR spectrum: 3.38-3.44 (m, 4H), 3.70-3.76 (m, 4H), 3.91 (s, 3H), 6.55 (d, 1H), 6.60 (dd, 1H), 7.70 (d, 1H).
90.22%
With potassium carbonate In N,N-dimethyl-formamide at 70℃;
8.1 Step (1) 4- (3-Methoxy-4-nitrophenyl) morpholine (25)
Compound 15 (10.0 g, 58.44 mmol) was added to the reaction flask, respectively,Compound 24 (6.11 g, 70.12 mmol) was dissolved in DMF,K2CO3 (11.31 g, 81.81 mmol) was added.70 ° C under the conditions of reaction.TLC tracking. To be complete,The reaction system is poured into ice water,There is a yellow solid precipitation. Filter solids,Dried to give 12.55 g of compound 25,Yield: 90.22%.
90%
With potassium carbonate In acetonitrile at 75℃; for 3h;
42.a a) 4-(3-methoxy-4-nitrophenyl)morpholine
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (8.00 g, 47 mmol) in acetonitrile (100 mL) were added morpholine (4.07 g, 467 mmol) and potassium carbonate (7 mg, 51 mmol), and the reaction was stirred at 75° C. for 3 hours. The reaction was concentrated under reduced pressure. The residue was mixed with water (30 mL), the suspension was filtered. The filter cake was collected, washed with water (30 mL), dried in vacuum to afford the titled compound (10.0 g, yield; 90%). LC-MS (ESI): m/z 239.1 [M+H]+.
90%
With potassium carbonate In acetonitrile at 75℃; for 3h;
42.a a) 4-(3-methoxy-4-nitrophenyl)morpholine
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (8.00 g, 47 mmol) in acetonitrile (100 mL) were added morpholine (4.07 g, 467 mmol) and potassium carbonate (7 mg, 51 mmol), and the reaction was stirred at 75° C. for 3 hours. The reaction was concentrated under reduced pressure. The residue was mixed with water (30 mL), the suspension was filtered. The filter cake was collected, washed with water (30 mL), dried in vacuum to afford the titled compound (10.0 g, yield; 90%). LC-MS (ESI): m/z 239.1 [M+H]+.
90%
With potassium carbonate In acetonitrile at 75℃; for 3h;
42.a a) 4-(3-methoxy-4-nitrophenyl)morpholine
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (8.00 g, 47 mmol) in acetonitrile (100 mL) were added morpholine (4.07 g, 467 mmol) and potassium carbonate (7 mg, 51 mmol), and the reaction was stirred at 75° C. for 3 hours. The reaction was concentrated under reduced pressure. The residue was mixed with water (30 mL), the suspension was filtered. The filter cake was collected, washed with water (30 mL), dried in vacuum to afford the titled compound (10.0 g, yield; 90%). LC-MS (ESI): m/z 239.1 [M+H]+.
86%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h;
67
4-(3-Methoxy-4-nitrophenyl)morpholine; To a solution of 4-fluoro-2-methoxy-l -nitrobenzene (24.4 g, 0.14 mol) in 200 mLDMF was added morpholine (25.7 mL, 0.28 mol), followed by the addition OfK2CO3 (23.6 g, 0.17 mol). The mixture was stirred at room temperature for 48 h. The mixture was poured into 0.7 L H2O and the precipitate was collected by filtration. The precipitate was further rinsed with 0.5 L H2O. The resulting solid was air dried by purging with a flow of air for 24 h, thus affording 29.3 g of 4-(3-methoxy-4- nitrophenyl)morpholine (0.12 mol, 86%).
86.3%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;
4.1.1. General procedures for the preparation of compound 2a-r
General procedure: To a solution of 1a-c (3.0 mmol, 1 eq) in DMF (10 mL) was addedpotassium carbonate (4.5 mmol,1.5 eq) and amine (3.0 mmol,1 eq).The resulting mixture was stirred at room temperature or 70 C for24 h. The reaction mixturewas then diluted withwater (50 mL) andextracted with ethyl acetate (3 30 mL). The yellow extract waswashed with brine (20 mL), dried over anhydrous sodium sulfateand evaporated to dryness to obtain a crude product. The crudewaspurified by flash chromatography with 98:2 (v/v) dichloromethane- methanol.
82.4%
With potassium carbonate In dimethyl sulfoxide at 50℃; for 3h;
1
A mixture of 4-fluoro-2-methoxy- 1 -nitrobenzene (2.05 g, 11. 98mmol), morpholine (2 .09g, 23.96mmol), K2C03 (3.31g, 23.96mmol) and DMSO (3OmL) was heated to 50°C for3 hours, then cooled to 10°C and water (300mL) was added, the precipitate was filtered to afford the compoundla as a yellow solid (2.35g,82.4%).
79%
With triethylamine In acetonitrile at 120℃; for 3h; Sealed tube; Microwave irradiation;
1.1 4-(3-methoxy-4-nitrophenyl)morpholine
4-Fluoro-2-methoxy-1-nitrobenzene (171 mg, 1.00 mmol), morpholine (174 mg, 2.00 mmol, 2.0 eq.) and triethylamine (0.56 ml, 405 mg, 4.00 mmol, 4.0 eq.) were dissolved in acetonitrile (3 ml) and heated for three hours in a sealed reaction vial in a microwave reactor (P≦300 watt) to 120° C. The solvent was subsequently removed under reduced pressure and the residual was dissolved in aqueous dilute hydrochloric acid (5%) and ethyl acetate. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The raw product was adsorbed to silica gel and purified by column chromatography (isohexane:ethyl acetate=gradient from 2:1 to 1:1) to yield the title compound (188 mg, 79%, yellow solid matter). 1H-NMR (399.788 MHz, CDCl3): δ=8.01 (d, 3JH,H=9.4 Hz, 1H, 5′-H), 6.43 (dd, 3JH,H=9.4, 4JH,H=2.5 Hz, 1H, 6′-H), 6.35 (d, 3JH,H=2.5 Hz, 1H, 2′-H), 3.96 (br. s, 3H, OCH3), 3.87 (br. t, 3JH,H=4.9 Hz, 4H, 2-H2, 6-H2), 3.35 (br. t, 3JH,H=4.9 Hz, 4H, 3-H2, 5-H2). MS (ESI): m/z (%)=239 (100) [M+H]+, 261 (41) [M+Na]+. HRMS (EI): calculated: 238.095357. found: 238.093980 [M]+.
72%
With potassium carbonate In dimethyl sulfoxide at 70℃; for 6h;
B1.A
jnterroedsate B1 y-4-nitrophenyi)morpholine To a solution of 4-f.uoro-2-methoxy-1 -nitrobenzene (100 g, 0.584 mol) and morpho.ine (60 g, 0.689 mol) in dimethyl sulfoxide (60 mL) was added potassium carbonate (120 g, 0.870 mol). The mixture was stirred at 70 °C for 6 hours, and then poured into ice-water. The precipitate was collected by filtration and washed by water, dried to afford the product 4-(3-methoxy-4-nitrophenyl)morpho.ine (100 g, yield 72 %).
65.8%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 85℃; for 6h;
5.1 (1) 4-(3-methoxy-4-nitrophenyl)morpholine
4-Fluoro-2-methoxy-1-nitrobenzene (8.55 g, 49.97 mmol),N, N-diisopropylethylamine (12.90 g, 100.00 mmol)And morpholine (4.79 g, 54.99 mmol) were added to N, N-dimethylformamide (80 mL)The temperature was raised to 85 ° C and the reaction was carried out for 6 hours. Cooled to room temperature,Poured into water (400 mL), filtered, the filter cake washed with water,Dried to give the crude product, and the resulting crude product was added to ethyl acetate (250 mL)The whole was dissolved, cooled to room temperature, and a large amount of solid was precipitated. The filter cake was washed with ethyl acetate and dried in vacuo to give the title compound (7.83 g, yield 65.8%).
for 3h; Reflux;
8A
Example 8-{3-[({2-[(2-methoxy-4-moφholin-4-ylphenyl)amillo]-7H-pyrrolo[2,3-d]pyrimidin-4- yl}amino)methyl]phenyl}-N-methylmethanesulfonamideExample 8A4-(3-methoxy-4-nitrophenyl)moipholine A solution of 4-fluoro-2-methoxy- 1 -nitrobenzene (7.12 g, 41.6 mmol) and morpholine (45 ml, 520 mmol) was heated at reflux for 3 hours. The reaction mixture was cooled and the precipitate was filtered, and washed with ether and hexane. The solid was then washed with a copious amount of water and dried in vacuum oven at 50 °C overnight to give the title compound. MS ESI (+) m/z 238.9 [M+H]+.
at 80℃; Neat (no solvent);
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
With potassium carbonate In acetonitrile at 80℃;
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;
3.1 Step 1 Preparation of compound 3A-2
To an anhydrous DMF solution (10 mL) was added compound 1A-1 (0.5 g, 2.92 mmol), compound 2A-2 (254.5 mg, 2.92. mmol) and potassium carbonate (1.21 g, 8.77 mmol), and then the mixture was heated to 80°C and stirred for 5 hours. After TLC indicated the reaction was completed, the reaction mixture wad extracted with ethyl acetate (100 mL), and washed with saturated aqueous sodium chloride three times, followed by phase separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product 3A-2 (566 mg, yield 81.3%), which was directly used for the next step without purification.
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 3h;
1.6 Step 6: Preparation of 4-(3-methoxy-4-nitrophenyl)morpholine
4-fluoro-2-methoxy-1-nitrobenzene (200mg, 1.17mmol) Soluble in N,N-dimethylformamide (4ml), Add potassium carbonate (323mg, 2.34mmol) And morpholine (203mg, 2.34mmol), React for 3 hours at 90°C, dilute with water and extract with ethyl acetate, Dry over anhydrous sodium sulfate, Concentrate under reduced pressure directly into the next reaction.
With potassium carbonate
42.a a)
a) 4-(3-methoxy-4-nitrophenyl)morpholine To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (8.00 g, 47 mmol) in acetonitrile (100 mL) were added morpholine (4.07 g, 467 mmol) and potassium carbonate (7 mg, 51 mmol), and the reaction was stirred at 75° C. for 3 hours. The reaction was concentrated under reduced pressure. The residue was mixed with water (30 mL), the suspension was filtered. The filter cake was collected, washed with water (30 mL), dried in vacuum to afford the titled compound (10.0 g, yield; 90%). LC-MS (ESI): m/z 239.1 [M+H]+.
147
Example 147 Preparation of 1'-(4-amino-3-methoxy-phenyl)-[4,4']bipiperidinyl-1-carboxylic acid tert-butyl ester A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.02 g, 5.97 mmol), [4,4']bipiperidinyl (3.6 g, 14.9 mmol), 2N sodium hydroxide (30 mL), toluene (15 mL) and n-butylammonium bromide (96 mg, 0.30 mmol) is vigorously stirred at 80° C. for 18 hours. After 10 mL of water is added, the mixture is filtrated. The residue is washed with water and then dried to give 1-(3-methoxy-4-nitro-phenyl)-[4,4']bipiperidine (1.79 g, 94% yield) as yellow solids. 1H-NMR (400 MHz, δ, ppm) CDCl3: 1.12-1.44 (m, 6H), 1.65-1.73 (m, 2H), 1.77-1.89 (m, 2H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 2H), 3.05-3.14 (m, 2H), 3.89-3.98 (m, 2H), 3.95 (s, 3H), 6.30 (d, 1H), 6.41 (dd, 1H), 8.00 (d, 1H).
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 72h;
To 5-fluoro-2-nitrophenyl methyl ether (26.0 g, 152 mmol), 1,4'-bipiperidine (25.5 g, 152 mmol) and K2CO3 (22.9 g, 166 mmol) was added DMSO (260 mL). The mixture was stirred at room temperature for 3 days. The mixture was poured into H2O (1000 mL) and the H2O washed with EtOAc (2.x.500 mL). The EtOAc washes were combined and washed with H2O (2.x.500 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (47.9 g, 150 mmol, 99percent) as a yellow solid.1H NMR (400 MHz, CDCl3) delta 7.98 (d, J=9.5 Hz, 1H), 6.40 (dd, J=9.5 and 2.6 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 3.99-3.93 (m, 2H), 3.93 (s, 3H), 2.98-2.89 (m, 2H), 2.58-2.48 (m, 5H), 1.99-1.90 (m, 2H), 1.70-1.55 (m, 8H), 1.48-1.40 (m, 2H).
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 20h;
10 g of compound 15 was weighed,Add 250mL three bottles,To the flask was added 100 mL of DMSO,And then added to the reaction bottle11.5 g of compound 22 and 24.2 g of potassium carbonate,The reaction flask was placed in an oil bath at 80 C for 20 h.The reaction was terminated by filtration to remove potassium carbonate,The filtrate was added to 100 mL of water,A large amount of yellow solid precipitation,Filter, water filter cake,Filter cake 70 vacuum drying 6h,18 g of a yellow solid 23 was obtained in a yield of 98.7%.
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 21h;
[00575] l-(3-methoxy-4-nitro-phenyl)-4-methylsulfonyl-piperazine (103) : To a solution of 4-fluoro-2-methyl-l -nitrobenzene 98 (2.2 g, 12.7 mmol) and N-methylsulfonyl piperazine (2.5 g, 15.2 mmol) in DMSO (35 mL) was added potassium carbonate (2.1 g, 15.2 mmol). The reaction was heated to 80 0C for 21 hours. Upon cooling, water (250 mL) was added to the reaction followed by extraction with diethyl ether (2 x 250 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 103 (5.37 g, >;100% yield) used without further purification.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
19.1 Step 1:
Step 1: Preparation of 8-(3-methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane While DMF (75 mL) of 4-fluoro-2-methoxy-1-nitrobenzene (5 g, 29.21 mmol) was stirred at ambient temperature, 1,4-dioxa-8-azaspiro[4.5]decane (5.0 g, 35.0 mmol) and potassium carbonate (8.0 g, 58.0 mmol) were added. The above reaction mixture was stirred overnight at ambient temperature. The above reaction mixture was quenched with cold water and stirred for 15 minutes. The precipitated solid was filtered and dried to obtain 8-(3-methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (8.0 g, 94%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 9.3 Hz, 1 H), 6.45 (dd, J = 9.4, 2.6 Hz, 1 H), 6.35 (d, J = 2.5 Hz, 1 H), 4.02 (s, 4 H), 3.96 (s, 3 H), 3.72-3.46 (m, 4 H), 2.24-1.72 (m, 4 H).
92%
With potassium carbonate In N,N-dimethyl-formamide at 70℃;
8-(3-Methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]-decane (21)
To a mixture of 4-fluoro-2-methoxy-1-nitrobenzene3a (15 g, 87.7 mmol) and K2CO3 (30.0 g, 217 mmol)in DMF (150 mL) was added 1,4-dioxa-8-azaspiro[4.5] decane(15 g, 105 mmol), and the reaction mixture was stirred at 70°Covernight. The insoluble material was removed by filtration,and ice water was added to the filtrate. The resulting solid was filtered and washed with Et2O to give 21 (23.8 g, 92%)as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 1.78-1.85(4H, m), 3.51-3.59 (4H, m), 3.95 (3H, s), 4.01 (4H, s), 6.33(1H, d, J=2.8 Hz), 6.43 (1H, dd, J=2.4, 9.2 Hz), 8.00 (1H, d,J=9.2 Hz). ESI-MS m/z: 295 [M+H]+.
With potassium carbonate In N,N-dimethyl-formamide at 70℃;
To a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (5 g), potassium carbonate (10 g) and N,N-dimethylformamide (50 mL), 1,4-dioxa-8-azaspiro[4.5]decane (5 g) was added and stirred overnight at 70°C. The reaction mixture was diluted with water (150 mL), and the precipitated solid was collected by filtration and washed with diethyl ether to give 8-(3-methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (7.86 g) as a light-yellow solid.
To a suspension of <strong>[33631-05-9]2-aminopyridin-4-ol</strong> (483 mg, 4.38 mmol) in MeCN (2.0 ml.) was added DBU (661 mul_, 4.38 mmol) and the reaction mixture maintained at RT until a homogeneous solution had formed at which time, 1-fluoro-3-methoxy-4-nitrobenzene (500 mg, 2.92 mmol) was added. The reaction mixture was kept at RT for 5hr, was heated to 800C for a further 16 hr. and was then cooled to RT, The reaction was diluted with water (5.0 ml.) and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc (20 ml.) and water (20 ml.) and the aq layer was separated and extracted with EtOAc (20 ml_). The combined organic extracts were washed with brine (50 ml.) and dried (Na2SO4) and were evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in DCM, 0- 100%, gradient elution) to afford 4-(3-methoxy-4-nitrophenoxy)pyridin-2-amine as a yellow solid (420 mg, 55%); R1 1.30 min (Method 2); m/z 262 (M+H)+ (ES+).
2-methoxy-4-(4-methyl piperazin-1-yl)nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
2 2.2.2. 1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine (10)
2.2.2 1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine (10) To a solution of 1-methyl-4-piperazine (1.56 mL, 11.7 mmol) in DMF (20 mL) was added potassium carbonate (2.42 g, 17.5 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 11.7 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3 * 30 mL). The organic extract was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily crude product. The crude was purified by flash silica gel chromatography using DCM/MeOH (97/3, v/v) as eluent to obtain 2.9 g of the desired product 10 (11.5 mmol, 98%) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 9.4 Hz, 1H), 6.58 (dd, J = 9.4, 2.4 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 3.90 (s, 3H), 3.49-3.37 (m, 4H), 2.46-2.36 (m, 4H), 2.22 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 155.99, 155.48, 128.17, 128.02, 105.15, 96.93, 56.26, 54.34, 46.31, 45.62.
96%
With triethylamine In N,N-dimethyl acetamide at 150℃; for 0.25h; Microwave irradiation;
12
A solution of commercially available 4-fluoro-2-methoxy-1-nitrobenzene (22) (200 mg, 1.17 mmol), N-methyl piperazine (154 μL, 1.40 mmol) and Et3N (329 μL, 2.34 mmol) in DMA (2.00 mL) was stirred at 150 °C for 15 min utilizing a microwave reactor. The solution was purified by column chromatography utilizing NH silica gel (DCM/Methanol) to afford 1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine (282 mg, 96%).
95.6%
With potassium carbonate In N,N-dimethyl acetamide at 80℃; for 5h;
12.1 1st step: 1 - (3-methoxy-4-nitro-phenyl) - 4-methyl piperazine (12B)
Weighing 5-fluoro-2-nitroanisole (3a) (8.55g, 50mmol), in the 250 ml round-bottom flask. Sequentially adding to the reaction bottle 150mLN, N-dimethyl formamide, 1-methyl piperazine (6.01g, 60mmol), potassium carbonate (13.8g, 100mmol), the reaction temperature is increased to 80 °C stirring under 5 hours. After cooling to room temperature to be reacted, the reaction solution is poured into ice water (100 ml) in, the residue with dichloromethane (150 ml × 2) extraction, the combined organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain the title product yellow solid of 1 - (3-methoxy-4-nitro-phenyl) - 4-methyl piperazine (12B) (12.0g, yield 95.6%).
93%
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
84%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;
1.1 1) Preparation of Compound (1-1):
5-Fluoro-2-nitroanisole (502.0 mg, 2.94 mmol) andN-methylpiperazine (400 mg, 4 mmol)Dissolved in N,N-dimethylformamide (5 mL),Potassium carbonate (609 mg, 4.41 mmol) was added to the above mixed system.The system reacted at room temperature for 24 hours.The organic layer was washed with saturated brine (10 mL), and dried and concentrated.Column chromatography purification (petroleum ether: ethyl acetate = 5:1) gave compound (1-1)(yellow solid, 633.0 mg, yield: 84%);
83%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 22h;
31 Example 31: 1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine
To a solution of 1-methyl-4-piperazine (1.6 mL, 14.9 mmol) in N,N-dimethylformamide (20 mL) was added K2CO3 (3.43 g, 24.8 mmol) followed by the slow addition of 4-fluoro-2-methoxy-1-nitrobenzene (1.7 g, 9.9 mmol) and the resultant mixture was stirred at room temperature for 22 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (3*500 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and filtered. The title compound was obtained by evaporation of the filtrate to dryness as a yellow solid (2 g, yield 83%). 1H NMR 400 MHz (DMSO-d6) δ 7.87 (d, J=9.6 Hz, 1H), 6.58 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 7.87 (d, J=2.8 Hz, 1H), 3.90 (s, 3H), 3.43 (t, J=4.8 Hz, 4H), 2.50 (t, J=4.8 Hz, 4H), 2.22 (s, 3H); LCMS m/e: 252 [M+1]+.
81.6%
With potassium carbonate In N,N-dimethyl-formamide for 5h; Reflux;
4.1.7. General procedure for preparation of compounds (9a-d)
General procedure: Tetrahydropyrrole, piperidine, N-methylpiperazine or hydroxyethylpiperazine (5.6 mmol) was added to a mixture of 4-fluoro-2-methoxy-1-nitrobenzene 8 (0.68 g, 4 mmol) and potassium carbonate (1.1 g,8 mmol) in DMF (5 mL), then refluxed for 5 h. After cooling, the reactionmixture was poured into water to give a yellow precipitate whichwas collected by filtration to afford 9a-d.
79%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
3.6.i
To a solution of 1 -methyl-4-piperazine (11, 7.8 mL, 70) in DMF (100 mL) was added K2C03 (9.68 g, 70 mmol) followed by the addition of 4-fluoro-2-methoxy-l -nitrobenzene (10, 10 g, 58 mmol) to form a mixture. The resultant mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness to afford. a thick oily compound, and was triturated with diethyl ether. The obtained solid was filtered and dried to afford l -(3-methoxy-4-nitrophenyl)-4-methylpiperazine (12, 1 1 .5 g, 79%) as yellow solid. NMR (CDC ): 8.03-7.99 (d, I H), 6.46-6.41 (d, I H), 6.33 (s, I H), 3.96 (s, 3H) 3.43-3:37 (m, 4H), 2.60- 2.55 (m, 4H), 2.37 (s, 3H).
75%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine (37)
1-Methyl-piperazine (7.8 mL, 70 mmol) was dissolved in DMF (100 mL) followed by the addition of K2CO3 (9.68 g, 70 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (100 mL) and extracted three times with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness to afford the desired product as a yellow solid in 75% (10.7 g) yield. TLC: Rf = 0.76 (DCM:MeOH, 95:5). 1H NMR (CDCl3, δ ppm): 7.99 (d, J = 9.4 Hz, 1H), 6.42 (d, J = 9.4 Hz, 1H), 6.31 (ds, 1H), 3.93 (s, 3H), 3.40 (m, 4H), 2.53 (m, 4H), 2.35 (s, 3H).
74.7%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
6.1 Step 1) 1- (3-Methoxy-4-nitrophenyl) -4-methylpiperazine (21)
Take 7.8 mL of compound 19,Was added to a 250 mL reaction flask,To the flask was added 100 mL of DMF,10 g of compound 15 and 9.68 g of potassium carbonate were weighed,Followed by adding to the reaction flask,80 ° C oil bath stirring reaction,TLC monitoring reaction,5h raw material reaction finished,The reaction solution was cooled to room temperature,The potassium carbonate was removed by filtration,100 mL of water,75 mL x 3 ethyl acetate,Take the organic phase,50 mL x 3 water to wash the organic phase,The organic phase was dried over anhydrous sodium sulfate,Concentrated to give 10.87 g of a yellow solid 7-3,Yield 74.7%.
74%
With potassium carbonate In N,N-dimethyl-formamide for 4h; Heating;
General procedure for preparation of compounds (7a-7f).
General procedure: To a solution of 6 (6 mmol) in DMF (12 ml), K2CO3 and the corresponding amine was added and the mixture was heated at 100 °C for 4 h. The reaction was filtered and evaporated to dryness and the residue was purified by column chromatography to afford compounds (7a-7f).
68.1%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
4 Step 4: Synthesis of 1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine (2-9) :
To a dimethyl formamide solution (50 ml) of 4-fluoro-2-methoxy-1-nitrobenzene (5.0g, 29.2 mmol) was added 1-methylpiperazine (3.5g, 35.0 mmol) and K2CO3 (6.0g, 43.8 mmol) in a round-bottomed flask, which was heated to 80 °C for 16 hours. TLC and LCMS of the reaction indicated complete consumption of starting material. The reaction mixture was quenched with ice-cold water, and the solid was filtered through a Buchner funnel to get pure 1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine (5.0g, 19.9 mmol, 68.1% yield) as a yellow-colored solid, LCMS (ES+, m/z): 252.2 (M+1).
With potassium carbonate In dimethyl sulfoxide at 90℃; for 8h;
33.33a
In, 20OmL round bottom flask, 4-Fluoro-2-methoxy-l-nitro-benzene (2.00 g, 0.0117 mol) was treated with Piperazine, 1- methyl- (2.59 mL, 0.0234 mol), Dimethyl sulfoxide (20 mL, 0.3 mol) and Potassium carbonate (4.84 g, 0.0351 mol) heated to 90 0C for 8 hours. The reaction was cooled to room temperature and added into ice water. The solid was filtered and dried under vacuum overnight. The solid was treated with Ethanol (50 mL, 0.8 mol) and 10 % Pd/C(10:90, Palladium: carbon black, 500 mg, 0.0005 mol) in a parr bottle. The reaction was placed into par shaker, evacuated and charged with hydrogen at 50 pSi The reaction mixture was shaken for 3 hours. The solid was filtered and stipped tove a gummy solid. The solid was partitioned with hexane/Et2θ (9/1). The resulting solid was decanted and dried under vacuum to give 2-Methoxy-4-(4-methyl-piperazin-l-yl)-phenylamine as a white solid (1.35g, 53%). NMR 1H (DSMO-d6)- 6.50 (d, IH, J= 8.37 Hz), 6.48 (d, IH, J= 1.96 Hz), 6.27(dd, IH, JJ= 2.20, 6.92 Hz), 4.18 (s, 3H), 3.73 (s, 3H), 2.93 (t, 4H, J= 4.41 Hz), 2.42 (t, 4H, J= 4.56 Hz), 2.20 (s, 3H)
With potassium carbonate In dimethyl sulfoxide at 20℃;
20.9 g
With potassium carbonate In water; dimethyl sulfoxide at 90℃;
Step 1: 1-(3-methoxyl-4-nitrophenyl)-4-methylpiperazine
Step 1: 1-(3-methoxyl-4-nitrophenyl)-4-methylpiperazine 5-Fluoro-2-nitroanisole (14.0 g, 83 mmol), N-methylpiperazine (9.1 g, 91 mmol), and potassium carbonate (34.5 g, 250 mmol) were added into DMSO (200 mL). The resultant was stirred at 90°C overnight. After the resultant cooled, water (3 L) was added, and the precipitated solid was filtered and dried to give 1-(3-methoxyl-4-nitrophenyl)-4-methylpiperazine (20.9 g). MS m/z [ESI]: 252.1 [M+1].
With potassium carbonate In acetonitrile at 80℃;
0.71 g
With potassium carbonate In dimethyl sulfoxide at 90℃; for 0.5h;
1.1 Step 1:Synthesis of 2-methoxy-4- (4-methyl-piperazin-1-yl) nitrobenzene
5-Fluoro-2-nitroanisole (0.51 g of) was dissolved in 20ml of dimethylsulfoxide, followed by adding N- methylpiperazine (1.3 ml of), potassium carbonate (1.25g), the reaction temperature was raised to 90 deg.] C. The reaction was stirred for 0.5 hours the reaction was stopped and the reaction was stirred at ice-water was poured into the compound 100ml, yellow needle crystallization, filtration, drying, to give a yellow solid 0.71g.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;
5.1 Step 1 Preparation of compound 3A-3
To an anhydrous DMF solution (10 mL) was added compound 1A-1 (0.5 g, 2.92 mmol), compound 2A-3 (0.30 g, 2.92 mmol) and potassium carbonate (1.21 g, 8.77 mmol), and then the mixture was heated to 80°C and stirred for 5 hours. After TLC indicated the reaction was completed, the reaction mixture wad extracted with ethyl acetate (100 mL), and washed with saturated aqueous sodium chloride three times, followed by phase separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product 3A-3 (0.61 g, yield 83.3%), which was directly used for the next step without purification.
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h;
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h;
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0446) To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol) in 3 mL of DMF was added 1-methyl-4-(piperidin)piperazine (0.536 g, 2.92 mmol) and potassium carbonate (0.808, 5.84 mmol). The mixture was heated at 120° C. for 18 h. The mixture was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was purified by chromatography to give final product as yellow solid (0.95 g, 95percent yield). MS/ES+: m/z=334.
90%
With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 70℃;
Example 42A 1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine To a solution of <strong>[53617-36-0]1-methyl-4-(piperidin-4-yl)piperazine</strong> (4.2 g, 22.91 mmol) in anhydrous DMF (40 mL) was added 4-fluoro-2-methoxy-1-nitrobenzene (3.92 g, 22.91 mmol) and potassium carbonate (3.80 g, 27.5 mmol). This suspension was heated at 70° C. overnight. After cooling, the reaction mixture was concentrated, and the residue partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated. The residue was separated by flash chromatography (eluted with 0-15percent of 2percent ammonium hydroxide MeOH solution in dichloromethane) to give 6.88 g of the title compound. Yield: 90percent. MS (DCI) m/z 335 (M+H)+; 1H NMR (300 MHz, CDCl3): delta 1.58-1.68 (m, 2H), 1.93-1.99 (m, J=11.53 Hz, 2H), 2.29 (s, 3H), 2.44-2.51 (m, 4H), 2.62 (s, 4H), 2.92-3.02 (m, 2H), 3.90-3.98 (m, 7H), 6.31 (d, J=2.37 Hz, 1H), 6.42 (dd, J=9.32, 2.54 Hz, 1H), 7.99 (d, J=9.49 Hz, 1H).
In N,N-dimethyl-formamide; at 20 - 60℃; for 19h;
To a suspension of 5-Fluoro-2-nitro-phenol (0.85 g, 0.0054 mol) and Potassium carbonate (1.6 g, 0.012 mol) in N,N-Dimethylformamide (10 mL, 0.1 mol) was added Dimethyl sulfate (0.56 mL, 0.0060 mol). The mixture was allowed to stir at room temperature for 18 hours. To the yellow suspension was added l-Methyl-4-piperidin-4-yl- piperazine (1.0 g, 0.0054 mol). The suspension was stirred at room temperature for 1 hour. Reaction mixture was heated to 600C for 18 hours. The reaction was monitired by HPLC. The mixture was allowed to cool to room temperature then cooled to 0°-5°C in a ice/salt/water bath. To the vigrously stirring mixture was added aqueous saturated sodium chloride and stirrred for 1 hour. The mixture was filtered and rinsed with a minimum of cold aqueous saturated sodium chloride. The yellow filter cake was dissolved in methanol and evporated to dryness. The yellow solids were partially dissolved in dichloromethane (100 ml), filtered, dried over magnesium sulfate, filtered and evaporated to yield yellow solids. The solids were triturated with ether (30 mL) with stirring for 72 hours. The solids were filtered, rinsed with ether and dried by suction. l-[l-(3-Methoxy-4-nitro-phenyl)- piperidin-4-yl]-4-methyl-piperazine was recovered as a yellow solid (0.95 g). mp=140- 143°C. 1H NMR (400 MHz, CDC13, delta, ppm): 8.00 (d, IH, J=9.3 Hz), 6.42 (dd, IH, J=9.5 Hz and 1.6 Hz), 6.32-6.29 (m, IH), 3.98-3.91 (m, 5H), 3.02-2.95 (m, 2H), 2.70-2.55 (m, 4H), 2.55-2.40 (m, 5H), 2.29 (s, 3H), 2.01-1.93 (m, 2H), 1.68-1.56 (m, 2H). LC/MS = 335.20 (MH)+
With triethylamine; In acetonitrile; at 130℃; for 0.666667h;Irradiation with microwave;
Into a 5 niL microwave tube was charged 4-fluoro-2-methoxy-l -nitrobenzene (1 g, 0.584 mmol), l-methyl-4-(piperidin-4-yl)piperazine (0.321 g, 1.753 mmol), triethylamine (0.244 rnL, 1.753 mmol), and acetonitrile (1.948 mL). The reaction was heated in Biotage microwave reactor at 130 0C for 40 minutes. The solvent was removed under reduced pressure, and the reaction purified by flash chromatography using a gradient 100percent CH2Cl2 to 1: 1 CH2Cl2/methanol to provide the title compound. MS(ESI) m/e 335 (M+H)+.
With triethylamine; In acetonitrile; at 130℃; for 0.5h;Microwave irradiation;
EXAMPLE 47A l-(l-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine In a 5 niL microwave tube was placed 4-fluoro-2-methoxy- 1 -nitrobenzene (.638 g, 3.73 mmol), l-methyl-4-(piperidin-4-yl)piperazine (0.888 g, 4.85 mmol), and triethylamine (1.559 ml, 11.18 mmol) in acetonitrile (12.43 ml) to give a yellow solution. The solution was heated in a Biotage microwave reactor at 130 0C for 30 minutes. The solvent was stripped off and the residue was placed under house vacuum. The yellow residue was purified by flash chromatography using an Argonaut Flashmaster Solo, using a gradient of 100percent dichloromethane to 1:1 dichloromethane/methanol to afford a yellow solid. (ESI(+)) m/e 335.0 (M+H)+.
With potassium carbonate; In acetonitrile;Reflux;
[00371] A mixture of 5-fluoro-2-nitroanisde (85.6 g, 0.5 moL 1.0 eq.), 1-methy4?(pipendin-4-ypiperazine (91.7 g. 0.5 moL 1.0 eq.), and potassium carbonate (138.5 q. 1.0moi, 20 eq) ri MeCN (500 mL) was stirred at reflux for ?-13 h. Upon coohnq to it, 0CM (1L) was added to the mixture and the resu[ting mixture was fi[tered The coAected residuewas washed with 0CM (500 mL). The combined filtrates were washed with water (400 mL) and brine (20percent w/w, 300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1 -(1 -(3-methoxy-4-nitrophenyhpiperidin-4-yl)-4rnethylpiperazine as a yellow solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;
To an anhydrous DMF solution (10 mL) was added compound 1A-1 (0.5 g, 2.92 mmol), compound 2A-7 (0.53, 2.92 mmol) and potassium carbonate (1.21 g, 8.77 mmol), and then the mixture was heated to 80°C and stirred for 5 hours. After TLC indicated the reaction was completed, the reaction mixture wad extracted with ethyl acetate (100 mL), and washed with saturated aqueous sodium chloride three times, followed by phase separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product 3A-7 (0.826 g, yield 84.5percent), which was directly used for the next step without purification.
With triethylamine; In acetonitrile; at 130℃; for 0.666667h;Irradiation with microwave;
Into a 5 niL microwave tube was charged 4-fluoro-2-methoxy-l -nitrobenzene (.1 g, 0.584 mmol), l-methyl-4-(piperidin-4-yl)piperazine (0.321 g, 1.753 mmol), triethylamine (0.244 ml, 1.753 mmol), and acetonitrile (1.948 ml). The reaction was heated in Biotage microwave reactor at 130 0C for 40 minutes. The solvent was removed under reduced pressure, and the reaction purified by flash chromatography using a gradient 100percent CH2Cl2 to 1: 1 CH2Cl2/methanol to provide the title compound. MS(ESI) m/e 335 (M+H)+.
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 95℃; for 20h; Sealed tube;
18
Preparation of tert-butyl 4-(4-amino-3-methox- yphenyl)piperazine- 1 -carboxylate (1 8a): A solution of 1 -tertbutyl 1-piperazinecarboxylate (SigmaAldrich, 3.37 g, 18.12 mmol), 5-fluoro-2-nitroanisole (Oakwood Products, West Columbia, S.C., 3.10 g, 18.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.31 mE, 36.2 mmol) in DMSO (11 mE) in a 20 mE glass microwave tube was sealed and heated in a heating block at 95° C. overnight (20 h). Upon cooling, the reaction mixture crystallized to a yellow solid. It was diluted with 150 mE of EtOAc, washed sequentially with 20 mE of water, 20 mE of NaHCO3 and brine (20 mE). The organic solution was dried over Mg504 and concentrated affording tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1 -carboxylate (6.14 g, 18.20 mmol, 99% yield) as a yellow crystalline solid. mlz (ESI, +ve ion) 359.9 (M+Na). ‘H NMR (400 MHz, MeOH-d4) ö ppm 7.96 (1H, d, J=9.2 Hz), 6.59 (1H, dd, J=9.4, 2.5 Hz), 6.55 (1H, d, J=2.3 Hz), 3.97 (3H, s), 3.56-3.65 (4H, 3.45-3.52 (4H, m), 1.51 (9H, s). Pd/C (lOwt.%, dry basis, wet activated, 284 mm, 0.267 mmol) and tertbutyl 4-(3-methoxy-4-nitrophenyl)piperazine- 1 -carboxylate (600 mg, 1.78 mmol) were treated with EtOH (30 mE) and allowed to stir under an atmosphere of hydrogen (balloon) for 23 h. The reaction mixture was filtered through an acrodisc (0.20 um), the resulting purple solution was then concentrated on the rotovap and then under vacuum overnight affording tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1 - carboxylate (539 mg, 1.76 mmol, 99% yield) as a purple film. mlz (ESI, +ve ion) 307.0/309.0 (M+H). ‘H NMR (400 MHz, MeOH) ö ppm 6.71 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=2.3 Hz), 6.46 (1H, dd, J=8.3, 2.4 Hz), 3.85 (3H, s), 3.51-3.61 (4H, m),2.92-3.02 (4H, m), 1.47-1.52 (9H, s).
99%
With potassium carbonate In acetonitrile at 50℃; Sealed tube;
99%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
4.1.1. Tert-butyl 4-(3-methoxy-4-nitrophenyl) piperazine-1-carboxylate(4)
The mixture of tert-butyl piperazine-1-carboxylate (2, 6.5 g, 35mmol), 4-fluoro-2-methoxy-1-nitrobenzene (3, 5 g, 29.2 mmol) andK2CO3 (8.1 g, 58.4 mmol) in DMF (70 ml) was stirred at 80 °C for 16 h.The resulting mixture was cooled to room temperature, washed with icewater, filtered, and dried to obtain 4 (9.76 g, 99% yield). 1H NMR (400MHz, CDCl3) δ 8.01 (s, 1H), 6.45 (d, J = 3.9 Hz, 1H), 6.34 (s, 1H), 4.00(s, 3H), 3.63 (s, 4H), 3.46-3.36 (m, 4H), 1.52 (s, 9H). ESI-MS: m/z339.29 [M+H]+.
99%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
4.1.1. Tert-butyl 4-(3-methoxy-4-nitrophenyl) piperazine-1-carboxylate(4)
The mixture of tert-butyl piperazine-1-carboxylate (2, 6.5 g, 35mmol), 4-fluoro-2-methoxy-1-nitrobenzene (3, 5 g, 29.2 mmol) andK2CO3 (8.1 g, 58.4 mmol) in DMF (70 ml) was stirred at 80 °C for 16 h.The resulting mixture was cooled to room temperature, washed with icewater, filtered, and dried to obtain 4 (9.76 g, 99% yield). 1H NMR (400MHz, CDCl3) δ 8.01 (s, 1H), 6.45 (d, J = 3.9 Hz, 1H), 6.34 (s, 1H), 4.00(s, 3H), 3.63 (s, 4H), 3.46-3.36 (m, 4H), 1.52 (s, 9H). ESI-MS: m/z339.29 [M+H]+.
96%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
1.2 Step 2: Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (1-2)
4-fluoro-2-methoxy-1-nitrobenzene (5.0 g, 29.22 mmol),A mixture of Boc-piperazine (6.5 g, 35.06 mmol) and potassium carbonate (6.0 g, 43.24 mmol) in N,N-dimethylformamide (43 mL) was stirred at room temperature. After stirring overnight, potassium carbonate (3.0 g) was added and the mixture was stirred for 2 days. Water was added to the reaction mixture, stirred, filtered, washed with water, and dried under vacuum to obtain the title compound (9.5 g, 96%).
95%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h;
93%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12h;
1 Step 1: Preparation of intermediates II-a-int-1:
General procedure: Condition A: To a dimethyl formamide solution (2.0 ml/mmol) of arylhalide (1.0 equivalent) was added piperazine (1.1 equivalent) and K2CO3 (1.5 equivalent) in a round- bottomed flask. The resulting reaction mixture was heated to 80 °C for 16h. TLC and LCMS of the reaction indicated complete consumption of starting material. The reaction mixture was quenched with ice cold water, and the solid was filtered through a Buchner funnel to get corresponding intermediate II-a-int-1 (yields 80-90%).
91%
With Cs2CO3 In N,N-dimethyl-formamide at 80℃;
19.1 Step 1 Preparation of 4-(3-methoxy-4-nitrophenyl) piperazine-1-tert-butyl carboxylate
Compound 4-fluoro-2-methoxy-1 nitrobenzene (3 g, 17.53 mmol) was dissolved in DMF (10 mL), and 48 tert-butyl piperazine-1-carboxylate (3.59 g, 19.28 mmol) and cesium carbonate (17.14 g, 52.6 mmol) were added under stirring. The mixture was heated to 80°C and reacted overnight. After TLC indicated the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100 mL water, and extracted with DCM/i-PrOH (3:1) (50mL×3). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent, thus obtaining a yellow oily product (5.4 g, yield 91%). LCMS: t=3.88 min, 282.0 (M-55).
91.2%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
89.68%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
12.1 Step (1) tert-Butyl 4- (3-methoxy-4-nitrophenyl) piperazine-1-carboxylate (37)
Compound 15 (12.0 g, 70.12 mmol) was added to the reaction flask, respectively,Compound 36 (14.38 g, 77.13 mmol) was dissolved in DMF,K2CO3 (14.58 g, 105.18 mmol) was added.80 under the conditions of reaction, TLC tracking. ,To be complete,The reaction system is poured into ice water,There is a yellow solid precipitation,Filter the solid, beat with ether,21.2 g of compound 37 was obtained by drying,Yield: 89.68%.
87%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 3h;
80%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
1 Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (SIAIS 1197111):
Under open conditions, 5-fluoro-2-nitroanisole (7 g, 40.9 mmol) was dissolved in 60 mL of DMF solution.K2CO3 (8.4 g, 60.8 mmol), N-tert-butoxycarbonylpiperazine (9.1 g, 48.9 mmol) was added sequentially and stirred at room temperature overnight.After the reaction is completed, the water is quenched, extracted with ethyl acetate, and the organic phase is washed with water and washed with brine.Dry over anhydrous sodium sulfate, spin dry, beat with petroleum ether: ethyl acetate = 5:1 mixed solvent,The sand core was filtered to obtain 11.1 g of a yellow target solid SIAIS 1197111, with a yield of 80%.
80%
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 12h;
Typical procedure for the synthesis of (2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) dimethylphosphine oxide 1 (Brigatinib A).
To a solution of 5-fluoro-2-nitroanisole (7g, 40.9mmol) in DMF (60mL) were added K2CO3 (8.4g, 60.8mmol) and tert-butyl piperazine-1-carboxylate (9.1g, 48.9mmol) at room temperature under air. After stirring at the same temperature overnight, then the reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under the reduced pressure and the residue was purified by recrystallization (eluent: petroleum ether/ethyl acetate=5:1) to afford tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate s-1a in 80% yield (11.1g) as a yellow solid. 1H NMR (500MHz, DMSO) δ 7.89 (d, J=9.3Hz, 1H), 6.57 (d, J=9.5Hz, 1H), 6.52 (s, 1H), 3.90 (s, 3H), 3.49-3.41 (m, 8H), 1.42 (s, 9H). HRMS (ESI) calcd for C16H24N3O5+ [M+H]+, 338.1710; found, 338.1705.
80%
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 12h;
75.1 Step 1: Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (SIAIS1197111) according toScheme 14
Under open conditions, to a solution of 5-fluoro-2-nitroanisole (7 g, 40.9 mmol) in N,N-dimethylformamide (60mL) were added potassium carbonate (8.4 g , 60.8 mmol) and N-tert-butoxycarbonylpiperazine (9.1 g, 48.9 mmol). Themixture was stirred at room temperature overnight. After the reaction is complete, the reaction mixture was quenchedwith water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried withanhydrous sodium sulfate, concentrated to remove the solvent, slurried with mixed solvent of petroleum ether and ethylacetate (5:1) , and filtered with sand core to obtain the compound (SIAIS1197111) (yellow solid, 11.1 g, yield 80%). 1HNMR (500 MHz, DMSO) δ 7.89 (d, J = 9.3 Hz, 1H), 6.57 (d, J = 9.5 Hz, 1H), 6.52 (s, 1H), 3.90 (s, 3 H), 3.46 (s, 8H),1.42(s, 9H). HRMS (ESI) calcd for, C16H24N3O5+ [M+H]+, 338.1710; found, 338.1610.
75%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h;
1.1 Step 1: Tert-Butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-ethyl carbonate (12)
5-Fluoro-2-nitroanisole (5 g, 29.2 mmol) and N-Boc-piperazine (6.54 g, 35.2 mmol) were dissolved in DMF (50 mL) and K2CO3 (8.1 g, 58.7Heat to 60 ° C, reaction for 8 h. The filtrate is first evaporated to dryness.Dilute with ethyl acetate,Wash with water and wash with saturated brine.Dry with anhydrous Na2SO4, filter off the desiccant, and evaporate the solvent.Column chromatography gave a yellow solid 12 (7.4 g, 75%).
73.7%
With potassium carbonate In acetonitrile at 80℃; for 4h;
tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate(A2)
A well stirred mixture of A1 (2.00 g, 11.69 mmol), 1-Boc-piperazine(2.61 g, 14.03 mmol) and K2CO3 (2.42 g17.54 mmol) in acetonitrile(20 mL) was heated to 80 C for 4 h. Cooling to room temperature,slowly pouring the reaction solution into ice water (20 mL). The mixturewas extracted with ethyl acetate (3 × 20 mL), washed the organic layerwith brine and dried over anhydrous Na2SO4. The desiccant was filteredand the filtrate was concentrated under reduced pressure to obtain intermediate A2 (white solid, 2.91 g, 73.7% yield).
73.7%
With potassium carbonate In acetonitrile at 80℃; for 4h;
tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate(A2)
A well stirred mixture of A1 (2.00 g, 11.69 mmol), 1-Boc-piperazine(2.61 g, 14.03 mmol) and K2CO3 (2.42 g17.54 mmol) in acetonitrile(20 mL) was heated to 80 C for 4 h. Cooling to room temperature,slowly pouring the reaction solution into ice water (20 mL). The mixturewas extracted with ethyl acetate (3 × 20 mL), washed the organic layerwith brine and dried over anhydrous Na2SO4. The desiccant was filteredand the filtrate was concentrated under reduced pressure to obtain intermediate A2 (white solid, 2.91 g, 73.7% yield).
55%
With potassium carbonate In dimethyl sulfoxide at 80℃; Inert atmosphere;
33.3%
With potassium carbonate In 1,4-dioxane at 120℃;
4.1 1st step: 4 - (3-methoxy-4-nitrophenyl) piperazine-1-carboxylic acid T-butyl ester (4B)
The 5-fluoro-2-nitroanisole (4A) (2g, 11.6mmol) dissolved in 1,4-dioxane (20 ml) in, add 1-tert-butoxycarbonyl piperazine (4.3g, 23 . 4mmol) and potassium carbonate (3.2g, 23 . 4mmol), after adding heated to 120 °C reaction sleepovers. Cooling to room temperature, the reaction solution after concentrating under reduced pressure by adding dichloromethane (30 ml), with water (10 ml × 3) and saturated sodium chloride (10 ml × 3) washing, dry anhydrous sodium sulfate, after concentrating under reduced pressure, the residue is dissolved in ethyl acetate/petroleum ether (v/v =1:9) (100 ml) pulping, filtration, collection filter cake drying to obtain the title compound 4 - (3-methoxy-4-nitrophenyl) piperazine-1-carboxylic acid T-butyl ester (4B), yellow solid (1.3g, yield 33.3%).
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h;
5
Example 5tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-l-carboxylate The mixture of 2-nitro- 5-fluoroanisole (2.Og, 1 1.7mmol), N-Bocpiperazine (2.18g, 1 1.7mmol), potassium carbonate (3.2g, 23.4 mmol) in DMF (3OmL) was heated to 7O0C for 12 hours. The solution was diluted with ethyl acetate (10OmL) and washed with water three times. The organic layer was dried over sodium sulfate and concentrated to afford the title compound. MS (M+1): 338.3.
at 80℃; Neat (no solvent);
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;
1.1F
EXAMPLE I F tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-l-carboxylate A suspension of 4-fluoro-2-methoxy-l -nitrobenzene (15 g, 87 mmol), tert-butyl piperazine- l -carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethylformamide (1 0 mL) was heated at 8()°C for 8 hours. After cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound. MS: 338 (M+H+).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;
14.14D
A suspension of 4-fluoro-2-methoxy-l -nitrobenzene (15 g, 87 mmol), tert-butyl piperazine-l -carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethy]forrnamide (150 mL) was heated at 80°C for 8 hours. After cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound. MS: 338 (M+H+).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;
13.13A
Example 13 7-{ [2-methoxy-4-(piperazin- 1 -y l)pheny l]amino } -5-(pyrrolidin- 1 -y l)imidazo[ 1 ,2- c]pyrimidine-8-carboxamide Example 13 A tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine- 1-carboxy late A suspension of 4-fluoro-2-methoxy-l -nitrobenzene (15 g, 87 mmol), tert-butyl piperazine-l -carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethylformamide (1 50 mL) was heated at 80°C for 8 hours. After cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound. MS: 338 (M+HJ).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;
14D tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine- 1-carboxylate
A suspension of 4-fluoro-2-methoxy-1 -nitrobenzene (15 g, 87 mmol), tert-butyl piperazine-1-carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethylformamide (150 mL) was heated at 80° C. for 8 hours. Afier cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound.MS: 338 (M+Hj.
With potassium carbonate In acetonitrile at 80℃; for 4h;
a
a) Add 4-fluoro-2-methoxy-1-nitrobenzene (15.0 mmol), 1-Boc piperazine (15.0 mmol) and K2CO3 (45.0 mmol) into the solvent acetonitrile, and increase the temperature to 80° C. to react for 4 hours. After cooling to room temperature, the reaction solution was slowly poured into 100 ml ice water, extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 1-2.
With N-ethyl-N,N-diisopropylamine In butan-1-ol for 14h;
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;Sealed tube;
Step 1: Preparation of 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine The reaction tube containing DMF (30 mL) of a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (5.00 g, 29.22 mmol), N,N-dimethylpiperidin-4-amine (6.53 g, 35.06 mmol), and K2CO3 (6.06 g, 43.83 mmol) was sealed with a Teflon-lined cap, and the above reaction mixture was stirred for 2 hours at 90 C. The above mixture was concentrated under reduced pressure. The above reaction mixture was diluted in ethyl acetate (300 mL), washed with water (100 mL), and then, washed with brine (100 mL). The residue was purified by silica gel flash column chromatography (CH2Cl2/meOH, 9:1) to obtain 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine (9.73 g, pale yellow solid) in a yield of 99%. 1H NMR (300 MHz, CDCl3) delta 7.99 (d, J = 9.4 Hz, 1 H), 6.42 (dd, J = 9.4, 2.6 Hz, 1 H), 6.31 (sd, J = 2.5 Hz, 1 H), 3.94 (s, 3 H), 3.92 (d, J = 13.0 Hz, 2 H), 2.97 (td, J = 12.3, 2.8 Hz, 2 H), 2.43-2.33 9 (m, 1 H), 2.30 (s, 6 H), 1.95 (d, J = 13.0 Hz, 2 H), 1.58 (qd, J = 11.9, 4.0 Hz, 2 H); LC-MS calcd for C14H21N3O3 279.2, found 280.0 (M + H+)
88%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h;
1) . N,N- dimethyl piperidine -4- amines (374 mg, 2.92 mM) and K2CO3s (0.808 g, 5.84 mM) were added in the solution of 5- fluoro -2- nitroanilines (500 mg, 2.92 mM) among DMF of 3 ml. In 120 the reaction mixture, it was stirred for 18 hours. The NaHCO3saturated solution was added in the reaction mixture and the obtained mixture was extracted in the ethyl acetate. The organic phase was refined with chromatography. It is manufactured: 11a of 88% (0.712 g).
A solution of 4-fluoro-2-methoxy-l -nitrobenzene (1.711 g, 10 mmol), N,N- dimethylpiperidin-4-amine (1.410 g, 11.00 mmol) and N-ethyl-N-isopropylpropan-2- amine (3.48 mL, 20.00 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred at 70 0C overnight. The mixture was concentrated and the residue was mixed with water (60 mL), adjusted to pH 12, then extracted with CH^C^- The crude product was purified on a silica el column eluting with 7.5 % methanol in CH2CI2 saturated with NH3 to provide the title compound. (ESI+) m/e 280.1 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃;
EXAMPLE 12AA solution of 4-fluoro-2-methoxy-l -nitrobenzene (1.711 g, 10 mmol), N,N- dimethylpiperidin-4- amine (1.410 g, 11.00 mmol) and N-ethyl-N-isopropylpropan-2- amine (3.48 ml, 20.00 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred at 70 0C overnight. The mixture was cooled, concentrated and the residue was mixed with water (60 mL), adjusted to pH 12, then extracted with CIH^C^. The crude product was purified on a silica gel column eluting with 7.5 % methanol in CH2CI2 saturated with NH3 to give 2.76 g of a yellow oil which turned into a solid upon standing.(ESI(+)) m/e 280.1 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;
To an anhydrous DMF solution (10 mL) was added compound 1A-1 (0.5 g, 2.92 mmol), compound 2A-5 (0.375, 2.92 mmol) and potassium carbonate (1.21 g, 8.77 mmol), and then the mixture was heated to 80C and stirred for 5 hours. After TLC indicated the reaction was completed, the reaction mixture wad extracted with ethyl acetate (100 mL), and washed with saturated aqueous sodium chloride three times, followed by phase separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product 3A-5 (0.684 g, yield 83.8%), which was directly used for the next step without purification.
A 100 ml flask was charged with 4-fluoro-2-methoxy- 1 -nitrobenzene (5.13 g, 30 mmol), N,N-dimethylpiperidin-4-amine (4.23 g, 33.0 mmol) and N,N- dimethylformamide (60 ml). To the mixture was added N-ethyl-N-isopropylpropan-2- amine (10.45 ml, 60.0 mmol) and the mixture was heated at 70 0C overnight under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was partitioned between brine (100 ml) and methylene chloride (100 ml) and the pH adjusted to ca. 12-14 with sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride (3 x 100 ml). The combined organics were dried over sodium sulfate, filtered and adsorbed directly on to silica gel (ca. 25 g). This was split in two portions each of which was purified on a silica gel cartridge (150 g) eluted with a 2.5, 4.5, 6 % 7N methanolic ammonia in methylene chloride step gradient. The combined product fractions were concentrated to provide the title compound. MS (DCI(+)) m/e 280.2 (M+H)+.
With potassium carbonate; In acetonitrile; at 90℃; for 15h;
Intermediate 8 tert-Butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate <strong>[205059-24-1]tert-Butyl 4-(piperidin-4-yl)piperazine-1-carboxylate</strong> (1.842 g, 6.84 mmol) was added to a stirring mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.17 g, 6.84 mmol) and K2CO3 (2.83 g, 20.51 mmol) in acetonitrile (15 mL) and the reaction mixture was stirred at 90 C. for 15 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (hexanes/EtOAc) to give the title product (2.5 g, 87%). m/z 421.
73.3%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;Inert atmosphere;
Compound M (10.0 g, 58.44 mmol) was added to DMF (50 mL)Stirring completely,Compound L (18.89 g, 70.12 mmol) was addedAnd potassium carbonate (12.11g, 87.65mmol),The temperature was raised to 70 C under a nitrogen atmosphere and stirred to react overnight.TLC (PE/EA = 1/1) showed that the reaction was completed, cooled to room temperature, poured into cold water (500 mL), and a large amount of yellow solid was precipitated, filtered and washed with water (100 mL).Drying at 60 C in vacuo yielded 18.0 g.The yield was 73.3% and the HPLC purity was >95%.
With potassium carbonate; In ISOPROPYLAMIDE; at 100℃; for 16h;
EXAMPLE 66 7-(2,6-dichlorobenzyl)-5-{ [4-(hexahydropyrrolo[l,2-a]pyrazin-2( l H)-yl)-2- methoxyphenyl]amino}pyrido[3,4-d]pyridazin-4(3H)-one EXAMPLE 66A 2-(3-methoxy-4-nitropheny l)octahy dropyrrolo[ 1 ,2-o]pyrazine-30- A mixture of 4-fhioro-2-methoxy-l -nitrobenzene (342 mg, 2 mmol), octahydropyrrolo[l ,2-i7]pyrazine (252 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol) in dimethylacetamide (10 mL) was heated at 100 C for 16 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS : 278 (M+rT)
With potassium carbonate; In ISOPROPYLAMIDE; at 100℃; for 16h;
Example 47 4-(2,6-dichlorobenzyl)-6-{ [4-(hexahydropyrrolo[l ,2-a]pyrazin-2(lH)-yl)-2- methoxyphenyl]amino}-lH-imidazo[4,5-c]pyridine-7-carboxamide Example 47A 2-(3 -methoxy -4-nitropheny l)octahy dropyrrolof 1 ,2-a]py razine A mixture of 4-fluoro-2-methoxy- l -nitrobenzene (342 mg, 2 mmol),octahydropyrrolo[l ,2-o]pyrazine (252 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol) in dimethylacetamide (10 mL) was heated at 100 C for 16 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS : 278 (M+rf).
1 Example 1 preparation of compound (IV) 2-methoxy-4 - (4-acetyl-1-piperazinyl)nitrobenzene
To a dry 500 ml three-neck bottle compound is added in (II) 2-methoxy-4-fluoro-nitrobenzene 140g (0.82mol), then adding 1,4-dioxane 150 ml and compound (III) acetylprotoaescigenin piperazine 500g (3.90mol), heating reflow 2-3h (100 °C), TLC monitoring the reaction, to the raw dematerialised, concentrated reaction system after cooling, most of the form to dioxane, adding water to 250 ml, stirring about 0.5h rear, filtered, the filter cake is washed with water 200 ml eluviation obtain yellow solid, 50-60 °C drying to obtain the product 217.56g, the yield is 95%.
90%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 90℃; Inert atmosphere;
87%
Stage #1: N-acetylpiperidine; 4-fluoro-2-methoxy-1-nitrobenzene In N,N-dimethyl-formamide for 12.5h; Heating;
Stage #2: With acetic anhydride In N,N-dimethyl-formamide at 20℃; for 12h;
Specific steps of the invention was prepared as follows:
A solution of 5-fluoro-2-nitroanisole (200 g, 1 eq) and piperazine (302 g, 3 eq) in DMF was stirred for 30 minutes and heated for 12 hours. Acetic anhydride (358 g, 3 eq) was slowly added to the reaction solution, and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution for dilution, and the solid was filtered and washed twice with water. After drying at 50 °C, the product was obtained as a yellow solid (284 g, 87%).
86%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;
24 Preparation Example 24 Preparation of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one
(0452) 1-(Piperazin-1-yl)ethan-1-one (2.56 g, 20 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (3.42 g, 20 mmol) were dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (5.52 g, 40 mmol) was added. The reaction was carried out at 70° C. for 16 h. The reaction solution was cooled to room temperature, and poured into water (150 mL). The mixture was extracted with ethyl acetate (150 mL×4), and the water phase and the organic phase was separated. The organic phases were combined, washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:10-2:1) to get the title compound as a light yellow solid (4.8 g, yield: 86.0%).
86.4%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 90℃;
4.1 Step (1) 1- (4- (3-Methoxy-4-nitrophenyl) piperazin-1-yl) ethanone (17)
A solution of the compound of formula 15 (9.0 g, 52.6 mmol) was added to the reaction flask at room temperature,30 mL of N, N-dimethylacetamide,The compound of formula 16 (7.4 g, 57.8 mmol)N, N-diisopropylethylamine (8.1 g, 63.1 mmol)90 reaction 5 ~ 6h,TLC monitoring reaction is complete,The reaction solution was poured into 200 mL of water,Extracted with ethyl acetate (60 mL x 3)Combined organic layer,Washed with saturated brine,Dried over anhydrous sodium sulfate,The compound of formula 17 (12.71 g) was obtained by steaming,As a yellow solid (yield 86.4%).
83%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 90℃; Inert atmosphere;
3.2.8. Synthesis of 1-(4-{3-Methoxy-4-nitrophenyl}piperazine-1-yl)ethan-1-one (8)
To a stirred mixture of 7 (1.90 g, 11.0 mmol, 1.0 eq.) and dimethylacetamide (DMA) (6.0 mL), 6(1.40 g, 11.0 mmol, 1.0 eq.) and N,N-diisopropylethylamine (DIPEA) (2.0 mL) were added at 90 °C.The mixture was stirred overnight under nitrogen atmosphere with a reux condenser. After thereaction was completed, the reaction mixture was quenched with water and extracted with ethylacetate. The organic layer was dried over sodium sulfate (Na2SO4), filtered and concentrated underreduced pressure. The crude product was purified using column chromatography on silica gel(chloroform/methanol = 150/1) to aord 8 (2.61 g, 83%) as a pale brown solid. 1H-NMR (400 MHz,CDCl3): 2.16 (3H, s), 3.40-3.50 (4H, m), 3.67 (2H, t, J = 4.0 Hz), 3.81 (2H, t, J = 4.0 Hz), 3.97 (3H, s),6.33 (1H, d, J = 1.6 Hz), 6.42 (1H, dd, J = 6.0, 1.6 Hz), 8.02 (1H, d, J = 6.4 Hz). 13C-NMR (100 MHz,CDCl3): , 21.2, 40.5, 45.2, 46.5, 46.6, 56.0, 97.0, 105.1, 128.4, 129.5, 155.0, 156.0, 169.0. HRMS (FAB+)calculated for C13H17N3O4 [M + H]+: m/z = 280.1219, found 280.1295.
68%
With potassium carbonate In N,N-dimethyl-formamide for 4h; Heating;
General procedure for preparation of compounds (7a-7f).
General procedure: To a solution of 6 (6 mmol) in DMF (12 ml), K2CO3 and the corresponding amine was added and the mixture was heated at 100 °C for 4 h. The reaction was filtered and evaporated to dryness and the residue was purified by column chromatography to afford compounds (7a-7f).
45%
With potassium carbonate In N,N-dimethyl acetamide at 120℃; for 5h;
15.3 (3) N-acetyl-N-(3-methoxy-4-nitrophenyl)piperazine preparation
Fluoro-2-methoxy-1-nitrobenzene (2.55 g, 14.9 mmol),N-acetylpiperazine (1.91 g, 14.9 mmol),Potassium carbonate (2.47 g, 17.9 mmol)Was added to N, N-dimethylacetamide (25 mL).The reaction was heated to 120 ° C for 5 hours. Ethyl acetate (50 mL) was added and the mixture was washed with saturated brine (50 mL). The organic layer was dried, dried and column chromatographed (petroleum ether: ethyl acetate = 5: 1) to give the product as a white solid (1.87 g, yield 45.0 %).
45%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
1.2 Step 2 1- (4- (3-methoxy-4-nitrophenyl) piperazin-1-yl) ethan-1-one (2)
A solution of 1- (piperazin-1-yl) ethan-1-one (3.59 g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) were added to N, N-dimethylformamide (40 mL)Then 4-fluoro-2-methoxy-1-nitrobenzene (4.09 g, 23 mmol) was added to the suspension and stirred at 80 ° C overnight. The mixture was poured into water, The solid precipitate was filtered off. The resulting solid was dried in vacuo at 50 ° C, A yellow solid (3.5 g, yield: 45%)
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
1.2 Step 2: Preparation of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone
Step 2: Preparation of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80°C overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid. 1H-NMR(300 MHz, CDCl3) δ 8.00(d, J = 9.1 Hz, 1H), 6.42(d, J = 9.1 Hz, 1H), 6.32(s, 1H), 3.96(s, 3H), 3.80-3.79(m, 2H), 3.67-3.65(m, 2H), 3.47-3.40(m, 4H), 2.15(s, 3H); Mass (M+H+) calcd for C13H17N3O4 279.12, found 279.20
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
1.2 Preparation of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ 8.00 (d, J=9.1 Hz, 1H), 6.42 (d, J=9.1 Hz, 1H), 6.32 (s, 1H), 3.96 (s, 3H), 3.80-3.79 (m, 2H), 3.67-3.65 (m, 2H), 3.47-3.40 (m, 4H), 2.15 (s, 3H); Mass (M+H+) calcd for C13H17N3O4 279.12, found 279.20
With potassium carbonate In acetonitrile at 80℃;
With potassium carbonate In dimethyl sulfoxide at 90℃; for 4h;
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h;
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 90℃;
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃;Inert atmosphere;
Add compound 1 to a 50 mL single-mouth flask equipped with magnetic stirring(1.71 g, 10 mmol) and acetonitrile(20 mL), stirred and dissolved, and added <strong>[40064-34-4]4-piperidone hydrochloride monohydrate</strong> (2.0 g, 13 mmol)And DIPEA (N,N-diisopropylethylamine, 3.90 g, 30 mmol),The reaction mixture was warmed to 80 C under a nitrogen atmosphere and stirred to react overnight.Cool to room temperature, distill off the solvent under reduced pressure and add water (60 mL).A large amount of yellow solid was precipitated, filtered, and washed with plenty of water (100 mL).Drying the yellow solid2.1g,The yield was 84.0%.
ethyl 2-((3-methoxy-4-nitrophenyl)thio)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12h;
5.1.11 Ethyl 2-((3-methoxy-4-nitrophenyl)thio)acetate(12)
Using intermediate 5-fluoro-2-nitroanisole (17.1g, 0.1mol) and ethyl mercaptoacetate (50mL)as starting materials, a light yellow solid was obtained according to the preparation method of intermediate 7 (21.1g, 78% yield).
76%
With potassium carbonate In acetonitrile at 80℃; for 18h;
26.2
Step 2: K2C03 (120 g, 876 mmol) and ethyl mercaptoacetate (49 mL) were added to a solution of the intermediate of step 1 (75 g, 438 mmol) in MeCN (750 mL) and the mixture was heated to 80°C for 18 h. The mixture was filtered and the volatiles were removed under reduced pressure. The residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were remove under reduced pressure to yield the desired compound (90 g, 76%).
76%
With potassium carbonate In acetonitrile at 80℃; for 18h;
5.2
Step 2: K2C03 (120 g, 876 mmol) and ethyl mercapto acetate (49 mL) were added to a solution of the intermediate of step 1 (75 g, 438 mmol) in acetonitrile (750 mL) and the mixture was heated to80 C for 18 h. The mixture was filtered and the volatiles were removed under reduced pressure. The residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were remove under reduced pressure to yield the desired compound (90 g, 76%).
4-(2,3-difluoro-phenoxy)-2-methoxy-1-nitro-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;
A mixture of 4-fluoro-2-methoxy-1-nitro-benzene (3 g, 17.4 mmol), <strong>[6418-38-8]2,3-difluorophenol</strong> (2.27 g,17.4 mmol) and Cs2CO3 (6.81 g, 20.9 mmol) in DMF was heated at 120 C for 3 h. The mixturewas cooled. EtOAc was added and the mixture was washed with water and brine. The organiclayer was dried (Na2504), filtered, and evaporated to give 4-(2,3-difluoro-phenoxy)-2-methoxy-1-nitro-benzene (4.80 g, 98%) as a yellow solid.
1-(2-(3-methoxy-4-nitrophenoxy)ethyl)pyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 2h;
1.1.5
To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (5g, 0.0292mo1e) in DMF (20m1) was added Cs2CO3 (1 4.3g, 0.0438mo1e) and 2-(pyrrolidin-1 -yl)ethan-1 -ol (4gm, 0.0351 mole). The mixture was agitated 2hrs at 90°C. The solvent was evaporated to dryness and water (50m1) was added. The thus obtained crude precipitate was extracted with ethyl acetate (50m1 x 3). Combined organic layers were washed with brine (50m1 x 3), dried over sodium sulfate andevaporated under vacuum. The obtained crude was purified by column chromatograph (3.92g,Yield: 51%).LCMS: 99.58% ESl-MS (m/z): 267.48 [M+1].
8-(3-methoxy-4-nitrophenyl)-2,8-diazaspiro[4.5]decane-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;
Example 3D (550 mg, 3.57 mmol) in DMF (15mL) solution was added potassium carbonate (1.5 g, 10.7 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (855 mg , 5.0 mmol; then, the reaction mixture was heated to 90 deg. C and stirred for 12 hours .TLC (DCM: methanol = 20: 1) showed the reaction was complete the reaction mixture was diluted with EtOAc (50mL), washed successively with water (20 mL), saturated NaHCO3 (. 20 mL), brine (20 mL), dried organic phase was dried over anhydrous Na2SO4, then filtered and concentrated to give a brown oil. The crude product was purified by column chromatography (the DCM: methanol = 20: 1), yielding the title compound (1.02 g, yield 95%) as a yellow solid.
With boron tribromide In dichloromethane at 0℃; for 1.5h;
11.11A Example 11A 5-fluoro-2-nitrophenol
At 0 deg.C, to a stirred solution of 4-fluoro-2-methoxynitrobenzene (3 g, 17.53 mmol) in dichloromethane (30 mL) was added dropwise boron tribromide. The reaction was stirred at 0 deg.C for 1.5 h. TLC (petroleum ether: ethyl acetate = 10: 1) Display 2-methoxy-4-fluoro-nitrobenzene disappears. The solution was slowly added to ice water (100 mL), and and (50mL × 3) and extracted with dichloromethane. The organic phase was dried and concentrated to give the title compound (2.5 g of, yield 90.8%) as a yellow oil.
1 Intermediate 1: 4-Fluoro-2-methoxy-5-nitroaniline
2-methoxy-4-fluoro-nitrobenzene (10g, 58.44mmol) was dissolved in methanol, was added 1g of palladium / carbon, substituted with hydrogen, the reaction under a hydrogen atmosphere for three days. Filtered and the filtrate was collected, methanol was distilled off to give an oily crude product. Was added at 0 crude product concentrated sulfuric acid was dissolved solid mixture, in batches added potassium nitrate (5.91g). The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water and NaHC03, adjustment pH6.0-8.0. The aqueous phase was thrice extracted with dichloromethane, the organic phase was collected, dried. The organic solvent was distilled off, the residue was purified by column chromatography to give 4-fluoro-2-methoxy-5-nitroaniline (4.0g).
N-(3-methoxy-4-nitrophenyl)tetrahydrofuran-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.1%
With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 8h;
4-Fluoro-2-methoxy-1-nitrobenzene (3.93 g, 23.0 mmol),<strong>[88675-24-5]3-aminotetrahydrofuran</strong> (2.0 g, 23.0 mmol),Triethylamine (2.32 g, 23.0 mmol) was added to N, N-dimethylformamide (50 mL).And heated at 100 ° C for 8 hours.Ethyl acetate (200 mL) was added and the mixture was washed with saturated brine. The organic phase was dried and dried. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1)The product was purified (3.89 g, 71.1percent yield).
With potassium carbonate; In acetonitrile; at 50℃;
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (3.423 g, 20 mmol) and 2, 6-dimethylpiperazine (2.284 g, 20 mmol) in acetonitrile (40 mL), K2CO3 (5.528 g, 40 mmol) wasadded. The suspension was stirred at 50 C overnight. 100 mLof water was added to the reaction mixture and then it was extracted with DCM,washed with brine and dried over Na2SO4. Afterfiltration, evaporation, the condensation was purified with a silica gel columnto yield compound S24 (3.34 g, 74 %). To a solution of S24 (2.653 g, 10 mmol) was added dropwise CH3I (1.3 mL, 20 mmol) followedby the addition of DIPEA (3.5 mL, 20 mmol). After the reaction the mixture was extractedwith DCM, washed with brine and dried over Na2SO4. Afterfiltration, evaporation, the condensation was purified with a silica gel columnto yield compound S25 (1.683 g, 60.3 %). 1H NMR (400 MHz, CDCl3), delta 8.00(d, 1 H, J = 9.2 Hz), 6.41 (d, 1 H, J = 11.6 Hz), 6.29 (s, 1 H),3.96 (s, 3 H), 3.66 (d, 2 H, J = 12.0 Hz), 2.87 (br, 2 H), 2.45 (br, 2H), 2.37 (s, 3 H), 1.25 (d, 6 H, J = 5.6 Hz).
tert-butyl 6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptan-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.47%
With potassium carbonate; In acetonitrile; at 80℃; for 16h;
(0812) 4-Fluoro-2-methoxy-1-nitrobenzene (0.2 g, 1.17 mmol), tert-butyl 2,6-diazaspiro[3.3]heptan-2-carboxylate (0.23 g, 1.17 mmol) and potassium carbonate (0.32 g, 2.34 mmol) were added to acetonitrile (4 mL). The mixture was heated to 80 C. and reacted for 16 h. After the reaction, the mixture was filtrated. The filtrate was distilled under reduced pressure to remove the solvent and get the title compound (0.3 g, yield: 73.47%).
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;
4-Fluoro-2-methoxynitrobenzene (520 mg, 3.0 mmol) was dissolved in DMF (20 mL)Then tert-butyl 2,6-diazaspiro [3.3] heptane-2- carbamate (300 mg, 1.7 mmol) and K2CO3 (840 mg, 6.08 mmol) were added.The reaction was reacted at 70 C overnight, then quenched with water. The resulting mixture was extracted with ethyl acetate.The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude tert-butyl 6- (3-methoxy-4-nitrophenyl) -2,6- diazaspiro [3.3] heptane- Ester (300 mg, yield: 56%) which was used directly in the next reaction.
tert-butyl 1-(3-methoxy-4-nitrophenyl)-4-methylpiperidin-4-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate; In N,N-dimethyl acetamide; at 70℃; for 24h;
tert-Butyl 1-(3-methoxy-4-nitrophenyl)-4-methylpiperidin-4-ylcarbamate (C, in Preparative Example Scheme 1) (0850) 171 mg of 4-fluoro-2-methoxy-1-nitrobenzene (1 mmol), 214 mg of 4-N-Boc-4-methyl-piperidine (1 mmol), and 200 mg of K2CO3 were heated at 70 C. in 5 mL of N,N-dimethylacetamide (DMA) for 24 hr. After cooling down, the reaction mixture was diluted with 60 mL of EtOAc, washed with water 10 mL×2, brine 10 mL, and dried over anhydrous Na2SO4. After concentration, 350 mg the desired product was obtained as yellow solid after flash column chromatography on silica gel with eluent (heptane/EtOAc 2/1) (96%). LC-MS: m/z 366.2 (ES+).
3-benzyl-9-(3-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 4h;Large scale;
To 5 - fluoro -2 - nitroanisole (1.0 kg, 5 . 84 muM, 1 equivalent) and 3 - benzyl - 3, 9 - diaza spiro [5.5] undecane (1.70 kg, 5 . 57 muM, 0 . 95 equivalent) of N - methyl pyrrolidone (4 L) are added in the solution of the N, N - diisopropyl serotonin reuptake (1.13 kg, 8 . 77 muM, 1 . 55 equivalent) in the reaction liquid after 100 C under stirring for 4 hours. TLC (dichloromethane: methanol=6:1, Rf=0.5) display the reaction is complete. After the reaction cooled to room temperature water (16 L) is slowly added to the reaction solution, a large number of solid precipitation, suspension to continue stirring 1 hour after-filtration, the filter cake is added to ethanol (5 L) in, reflux beating 1 hour, cooling to room temperature and filtered. The flotation cake re-ethanol (5 L) reflux beating, then filtered, the filter cake drying to obtain the product (1.92 kg, 83% yield) as a yellow solid.
83%
With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine; at 100℃; for 4h;Large scale;
To 5-fluoro-2-nitroanisole (1.0 kg, 5.84 mol, 1 equivalent) and3-Benzyl-3,9-diaza-spiro [5.5] undecane (1.70 kg, 5.57 mol, 0.95 equivalent)After adding N, N-diisopropylethylamine (1.13 kg, 8.77 mol, 1.55 equivalents) to a solution of N-methylpyrrolidone (4 L), the reaction solution was stirred at 100 C for 4 hours.TLC (dichloromethane: methanol = 6: 1, Rf = 0.5) showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (16L) was slowly added to the reaction solution, and a large amount of solids precipitated. The suspension was stirred for 1 hour and then filtered. The filter cake was added to ethanol (5L), and refluxed for 1 hour.After cooling to room temperature, it was filtered. After the filter cake was re-slurried with ethanol (5L) under reflux,It was then filtered and the filter cake was dried to give the product (1.92 kg, 83% yield) as a yellow solid.
3-(3-methoxy-4-nitrophenyl)-9-methyl-3,9-diazaspiro[5.5]undecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 80℃; for 16.0h;
To 3 - methyl - 3, 9 - diaza spiro [5.5] undecane (4.83 g, 1 equivalent) and 4 - fluoro -2 - methoxy -1 - nitrobenzene (5.6 g, 1 . 55 equivalent) of acetonitrile (100 ml) solution is added potassium carbonate (30 g, 10.26 equivalent), then the reaction liquid rises to the 80 C stirring 16 hours. TLC detection after the reaction the reaction liquid filtering, the filtrate is concentrated after column purification (eluting agent is petroleum ether: ethyl acetate=10:1 to 1:1) to obtain the title compound as a yellow solid (9.0 g, crude).
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16.0h;
Potassium carbonate (323.41 mg, 2.34 mmol) and compound 32-B (334.71 mg, 1.99 mmol) were added into the compound 5-fluoro-2-nitroanisole (200.00 mg, 1.17 mmol) in dimethyl sulfoxide (7.00 mL) solution. The reaction mixture was stirred at 100C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and give the crude product. The crude compound preparative HPLC (neutral) to give the compound 37-A. MS m/z: 320.1 [M+H]+
With potassium carbonate; In acetonitrile; at 85℃;Large scale;
At room temperature, a 100-L reaction kettle was charged with Compound 1 (13.80 kg), Compound 2 (9.78 kg), and acetonitrile (70 L), and stirred to dissolve. Potassium carbonate (27.66 kg) was added, mechanically stirred, the temperature was raised to 85 C, and the reaction was allowed to proceed overnight. The mixture was filtered under reduced pressure to room temperature, and the filtrate was distilled under reduced pressure. The obtained solid was mechanically slurried with n-heptane (40L) and isopropyl ether (20L) overnight. The compound 3 was 16.22 kg as a yellow powdery solid with a filtration rate of 85.3%. .
75.9%
With potassium carbonate; In acetonitrile; at 60℃; for 3h;Inert atmosphere;
Add compound 1 to a 50 mL single-mouth flask equipped with magnetic stirring(887 mg, 4.72 mmol) and acetonitrile(20 mL), stirred and dissolved, added the dihydrochloride salt of compound 22 (1.1 g, 5.66 mmol)And potassium carbonate (2.2 g, 15.57 mmol),The reaction mixture was heated to 60 C under a nitrogen atmosphere and stirred for 3 hours while stirring.Cool to room temperature, distill off the solvent under reduced pressure and add water (60 mL).A large amount of yellow solid was precipitated, filtered, washed with water (10 mL) and dried to give a yellow solid1.0g,The yield was 75.9%.
With potassium carbonate; In acetonitrile; at 70℃; for 3h;Inert atmosphere;
Add compound 1b to a 50 mL single-mouth flask equipped with magnetic stirring in sequence(887 mg, 4.72 mmol) and acetonitrile (20 mL), stirred and dissolved.Compound 2b (1.0 g, 4.72 mmol) and potassium carbonate (2.2 g, 15.57 mmol) were added.The reaction mixture was heated to 70 C under a nitrogen atmosphere and stirred for 3 hours while stirring.Cool to room temperature and distill off the solvent under reduced pressure.Add water (60 mL), precipitate a large amount of yellow solid, and filter.Washed (10 mL) and dried to obtain the yellow solid1.4 g, yield 81.7%.
2-fluoro-5-(3-methoxy-4-nitrophenoxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 2h;
To <strong>[62257-16-3]3-amino-4-fluorophenol</strong> (337mg, 2.656mmol) and 1-fluoro-2-methoxy-4-nitrobenzene at room temperature(500mg, 2.143mmol) in DMSO (10ml) was added K2CD3 (1.1g, 7.968mmol).Stir the solution at 90CStir for 2 hours, and the solution was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5:1-4:1), and the resulting solutionConcentrate under reduced pressure to obtain 680 mg of yellow solid with a yield of 92%.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
