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Chemical Structure| 448-19-1
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Product Details of [ 448-19-1 ]

CAS No. :448-19-1 MDL No. :MFCD00077541
Formula : C7H6FNO3 Boiling Point : -
Linear Structure Formula :- InChI Key :WLKUSVNHZXUEFO-UHFFFAOYSA-N
M.W :171.13 Pubchem ID :2779250
Synonyms :

Calculated chemistry of [ 448-19-1 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.71
TPSA : 55.05 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.48
Log Po/w (XLOGP3) : 1.69
Log Po/w (WLOGP) : 2.16
Log Po/w (MLOGP) : 1.05
Log Po/w (SILICOS-IT) : 0.1
Consensus Log Po/w : 1.3

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.2
Solubility : 1.07 mg/ml ; 0.00626 mol/l
Class : Soluble
Log S (Ali) : -2.46
Solubility : 0.592 mg/ml ; 0.00346 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.18
Solubility : 1.13 mg/ml ; 0.00661 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.88

Safety of [ 448-19-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P273 UN#:N/A
Hazard Statements:H302-H412 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 448-19-1 ]

* 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.

  • Upstream synthesis route of [ 448-19-1 ]
  • Downstream synthetic route of [ 448-19-1 ]

[ 448-19-1 ] Synthesis Path-Upstream   1~34

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Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 27, p. 3776 - 3779
  • 2
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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
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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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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] Patent: US2003/225098, 2003, A1, . Location in patent: Page 28 - 29
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Reference: [1] Organic Mass Spectrometry, 1992, vol. 27, # 6, p. 720 - 723
[2] Patent: US4801717, 1989, A,
  • 9
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YieldReaction ConditionsOperation 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
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Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 27, p. 3776 - 3779
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Reference: [1] Patent: CN106083536, 2016, A,
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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
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  • [ 865-47-4 ]
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  • [ 1369809-57-3 ]
Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918
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  • [ 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
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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
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YieldReaction ConditionsOperation 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) .

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[4] Patent: US2012/71499, 2012, A1, . Location in patent: Page/Page column 10
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YieldReaction ConditionsOperation in experiment
100% With hydrogen In ethanol for 1 h; 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.

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