* 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 Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
2
[ 771-69-7 ]
[ 124-41-4 ]
[ 66684-59-1 ]
[ 66684-60-4 ]
[ 155020-44-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
3
[ 771-69-7 ]
[ 124-41-4 ]
[ 155020-44-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 4 - 20℃; for 0.5 h;
A freshly prepared solution of sodium methoxide [0.58 g (25 mmol) of sodium dissolved in 3 niL of anhydrous methanol] was added dropwise to a solution of 2 g (11.2 mmol) of l52,3-trifluoro-4-nitrobenzene in 30 mL of anhydrous methanol under nitrogen at +40C. The resulting mixture was stirred overnight at room temperature and quenched with 1 M aqueous citric acid (0.1 eq) and methanol was evaporated under reduced pressure. The residue was taken up with ether, washed with 1 M citric acid, brine and dried over anhydrous magnesium sulfate and filtered off. The filtrate was evaporated under reduced pressure to give 2.2 g (99percent yield) of the crude product, which was purified by crystallisation from hexane. H1 NMR (CDCl3) 3.95 (s, 3H, OMe); 4.06 (d, 3H5 J= 1.6 Hz); 6.72 (dd, IH, CH5 J = 9.4 Hz5 J = 7.5 Hz) 7.72 (dd, IH, CH, J = 9.4 Hz, J = 2.23 Hz).
80%
at 0 - 20℃;
Example 25 N-(2-cvano- 1 -(7-fluoro- 1 -hydroxy- 1.3 -dihydrobenzo [c] [ 1.2"|oxaborol-6-yloxy)propan-2-v l)-4-(trifluoromethoxy)benzamide To a stirring solution of l,2,3-trifluoro-4-nitrobenzene (80 g, 0.45 mmol) in MeOH (800 mL) is slowly added MeONa (54 g, 0.99 mmol) in portions at 0°C. The resulting mixture is stirred at rt overnight. TLC showed the reaction is completed. The solvent is evaporated and the residue is washed with water, acidified with diluted HC1 solution to pH=7.0 and extracted with EtOAc. The separated organics is dried and concentrated to give a residue, which is purified by silica gel chromatography (PE:EtOAc=100:l to 30:1) to give the desired product (72 g, 80percent yield).
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 19, p. 6469 - 6475
[2] Patent: WO2006/84338, 2006, A1, . Location in patent: Page/Page column 90
[3] Journal of the American Chemical Society, 2011, vol. 133, # 9, p. 2989 - 2997
[4] Patent: WO2014/149793, 2014, A1, . Location in patent: Page/Page column 85
4
[ 67-56-1 ]
[ 771-69-7 ]
[ 155020-44-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
for 48 h; Reflux
Step 1:To a solution of 1,2,3-trifluoro-4-nitrobenzene(5.00 g, 28.2 mmol) in anhydrous MeOH (100 mL) was added NaOMe (6.86 g, 12.7 mmol). The reaction mixture was heated at reflux for 48 h, adjusted to pH 6 with 2 M citric acid, and extracted with EtOAc (2 × 400 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure to give 2-fluoro-1,3-dimethoxy-4-nitrobenzene as a yellow powder (5.10 g, 89percent).1H-NMR(CDCl3):δ3.97 (s, 3H, CH3), 4.07 (d, 3H,J= 1.1 Hz, CH3), 6.74 (dd, 1H,J= 9.3 & 7.6 Hz, Ph-H), 7.74 (dd, 1H,J= 9.4 & 2.1 Hz, Ph-H).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 139, p. 762 - 772
5
[ 771-69-7 ]
[ 155020-44-3 ]
Reference：
[1] Patent: US6162931, 2000, A,
6
[ 771-69-7 ]
[ 124-41-4 ]
[ 66684-59-1 ]
[ 66684-60-4 ]
[ 155020-44-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1362 - 1370
7
[ 155020-44-3 ]
[ 103068-40-2 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 19, p. 6469 - 6475
[2] Journal of the American Chemical Society, 2011, vol. 133, # 9, p. 2989 - 2997
A freshly prepared solution of sodium methoxide [0.58 g (25 mmol) of sodium dissolved in 3 niL of anhydrous methanol] was added dropwise to a solution of 2 g (11.2 mmol) of l52,3-trifluoro-4-nitrobenzene in 30 mL of anhydrous methanol under nitrogen at +40C. The resulting mixture was stirred overnight at room temperature and quenched with 1 M aqueous citric acid (0.1 eq) and methanol was evaporated under reduced pressure. The residue was taken up with ether, washed with 1 M citric acid, brine and dried over anhydrous magnesium sulfate and filtered off. The filtrate was evaporated under reduced pressure to give 2.2 g (99% yield) of the crude product, which was purified by crystallisation from hexane. H1 NMR (CDCl3) 3.95 (s, 3H, OMe); 4.06 (d, 3H5 J= 1.6 Hz); 6.72 (dd, IH, CH5 J = 9.4 Hz5 J = 7.5 Hz) 7.72 (dd, IH, CH, J = 9.4 Hz, J = 2.23 Hz).
80%
In methanol; at 0 - 20℃;
Example 25 N-(2-cvano- 1 -(7-fluoro- 1 -hydroxy- 1.3 -dihydrobenzo [c] [ 1.2"|oxaborol-6-yloxy)propan-2-v l)-4-(trifluoromethoxy)benzamide To a stirring solution of l,2,3-trifluoro-4-nitrobenzene (80 g, 0.45 mmol) in MeOH (800 mL) is slowly added MeONa (54 g, 0.99 mmol) in portions at 0C. The resulting mixture is stirred at rt overnight. TLC showed the reaction is completed. The solvent is evaporated and the residue is washed with water, acidified with diluted HC1 solution to pH=7.0 and extracted with EtOAc. The separated organics is dried and concentrated to give a residue, which is purified by silica gel chromatography (PE:EtOAc=100:l to 30:1) to give the desired product (72 g, 80% yield).
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; for 5h;
A mixture of 1.81 g (9 mmol) of above product and 0.24 g of 10% palladium on charcoal in 30 mL of ethanol/ethyl acetate (1 : 1) was stirred under hydrogen for 5 hours. When the reduction was completed, the catalyst was collected on celite over a glass frit via filtration. The filtrate was evaporated to dryness giving 1.54 g (100 % yield) of pure 2,4-dimethoxy- 3-fluoro-aniline as an oil. This was dissolved in 30 mL of water/cone, hydrochloric acid chilled in an ice-salt bath and treated with a cold solution of 0.65 g (9.4 mmol) of sodium nitrite in 2 mL of water. The resulting solution was stirred for 15 minutes and then 1.51 g (9.1 mmol) of potassium iodide in 5 mL of water was added dropwise. The resulting mixture was stirred for 2 hours at room temperature and the product was taken up by extraction with ether (3 x 20 mL). The organic phase was washed with 10% aqueous sodium metabisulfite, brine, and dried over anhydrous magnesium sulfate and filtered off. Evaporation of the solvent and purification by flash column chromatography gave 1.26 g (50%) of pure product as a colourless crystals. H1NMR (CDCl3) 3.85 (s, 3H, MeO); 3.922 (d, 3H, MeO, J = 1.43); 6.5 (tr, IH, CH, J = 8.63); 7.4 (dd, IH CH, J = 8.63, J = 2.31).
97%
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; at 25℃; under 3800.26 Torr; for 18h;
3-Fluoro-2,4-dimethoxyaniline2-Fluoro-l,3-dimethoxy-4-nitrobenzene (5.82 g, 28.9 mmol) and 10% palladium on carbon (0.72 g, 6.77 mmol) in a mixture of ethanol (45 mL) and ethyl acetate (45.0 mL) was stirred under an atmosphere of hydrogen at 5 atm and 25 0C for 18 hours. The reaction mixture was filtered through celite and the resulting filtrate was evaporated to dryness to afford crude 3-fiuoro-2,4-dimethoxyaniline (4.82 g, 97 %). MS (+ve ESI) : Rt = 1.35, no mass ion (M+H)+1R NMR (400.132 MHz, CDC13) delta 3.64 (2H, s), 3.82 (3H, s), 3.93 (3H, s), 6.42 (IH, m), 6.54 (IH, t)
3.67 g (92%)
Example 6 Preparation of 1-Amino-2,4-dimethoxy-3-fluorobenzene (6) Using general method C, treatment of Compound 2 (4.66 g, 23.2 mmol) gives Compound 6 as 3.67 g (92%) of a pale yellow oil: 1 H NMR (CDCl3) 6.52 (t, 1H), 6.40 (d, 1H), 3.92 (s, 3H), 3.80 (s, 3H); 19 F NMR (CDCl3) 152.9 (d). Anal. calc. for C8 H10 NO2 F: C, 56.14; H, 5.89; N, 8.18. Found: C, 56.14; H, 6.05; N, 8.03.
With iron; ammonium chloride; In ethanol; water; for 3h;Reflux; Inert atmosphere;
To a mixture of 2-fluoro-l,3-dimethoxy-4-nitrobenzene (30.0 g, 0.15 mol) and NH4C1 (31.2 g, 0.6 mol) in mixed solvents of H20 (155 mL) and ethanol (620 mL) is added iron powder (67.2 g, 1.2 mol) in small portions. After completing the addition, the mixture is refluxed for 3 h under nitrogen, filtered through celite and concentrated in vacuo. The residue is extracted with CH2C12 (3x300 mL). The separated organics is dried and concentrated to give crude 3-fluoro-2,4-dimethoxyaniline, which is used for next step without further purification.
Example 2 Preparation of 2,4-Dimethoxy-3-fluoronitrobenzene (2) Beginning with 2,3,4-trifluoronitrobenzene (5.53 g, 31.2 mmol, Aldrich), Compound 2 is obtained as 6.30 g (99%) as a pale yellow crystalline solid. An analytical sample is obtained by crystallization from light petroleum ether/dichloromethane: m.p. 59-61 C.; 1 H NMR (CDCl3) 7.72 (dd, 1H), 6.71 (dd, 1H), 4.08 (s, 3H), 3.95 (s, 3H); 19 F NMR (CDCl3) 149.1 (d). Anal. calc. for C8 H8 NO4 F: C, 47.77; H, 4.01; N, 6.96. Found: C, 47.64; H, 4.05; N, 6.80.
To a solution of <strong>[155020-44-3]2-fluoro-1,3-dimethoxy-4-nitrobenzene</strong> (1.5 g) in toluene (100 mL) was added 1 M tribromoborane hexane solution (16 ml) at 0 C., and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture at 0 C., and the mixture was stirred at room temperature for 10 min. The reaction solution was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (860 mg).1H NMR (300 MHz, DMSO-d6) delta 4.01 (3H, s), 6.63 (1H, dd, J=9.8, 7.2 Hz), 7.95 (1H, dd, J=9.7, 2.1 Hz), 10.61 (1H, s).
Step 1:To a solution of 1,2,3-trifluoro-4-nitrobenzene(5.00 g, 28.2 mmol) in anhydrous MeOH (100 mL) was added NaOMe (6.86 g, 12.7 mmol). The reaction mixture was heated at reflux for 48 h, adjusted to pH 6 with 2 M citric acid, and extracted with EtOAc (2 × 400 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure to give 2-fluoro-1,3-dimethoxy-4-nitrobenzene as a yellow powder (5.10 g, 89%).1H-NMR (CDCl3):delta3.97 (s, 3H, CH3), 4.07 (d, 3H,J= 1.1 Hz, CH3), 6.74 (dd, 1H,J= 9.3 & 7.6 Hz, Ph-H), 7.74 (dd, 1H,J= 9.4 & 2.1 Hz, Ph-H).
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