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Structure of 367-12-4 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
EXAMPLE 5 Preparation of 2-[4-(4-bromo-2-fluorophenoxy)phenoxy]propionic acid methyl ester STR29 To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mol) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mol). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent). The NMR (CDCl3) was consistent with the assigned structure.
90%
With bromine In dichloromethane; water
EXAMPLE 5 Preparation of 2-[4-(4-bromo-2-fluorophenoxy)phenoxy propionic acid methyl ester STR29 To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mmol) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mol). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent). The NMR (CDCl3) was consistent with the assigned structure.
90%
With bromine In dichloromethane; water
STR34 To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent). The NMR (CDCl3) was consistent with the assigned structure. The gc of this material showed that it contained only a trace of the 2,6-isomer. This material was used directly in the following step without additional purification.
90%
With bromine In dichloromethane; water
EXAMPLE 5 Preparation of α[4(4'-bromo-2'-fluorophenoxy)phenoxy]propionic acid methyl ester STR30 To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent). The NMR (CDCl3) was consistent with the assigned structure.
Reference：
[1] Patent: US4642338, 1987, A,
[2] Patent: US4725683, 1988, A,
[3] Patent: US4808750, 1989, A,
[4] Patent: US4550192, 1985, A,
[5] Chemistry - A European Journal, 2017, vol. 23, # 5, p. 1044 - 1047
[6] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
[7] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3112 - 3129
[9] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[10] Patent: WO2005/123748, 2005, A1, . Location in patent: Page/Page column 84 - 85
[11] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 58
[12] Patent: WO2006/137770, 2006, A1, . Location in patent: Page/Page column 33
[13] Canadian Journal of Chemistry, 2011, vol. 89, # 3, p. 364 - 384
Reference：
[1] Chinese Chemical Letters, 2010, vol. 21, # 11, p. 1283 - 1286
[2] Patent: WO2013/28474, 2013, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2014/126944, 2014, A2, . Location in patent: Page/Page column 54
[4] Patent: EP2744499, 2016, B1, . Location in patent: Paragraph 0192
8
[ 367-12-4 ]
[ 7440-44-0 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Yield
Reaction Conditions
Operation in experiment
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5° C. After the addition was complete, stirring was continued at 0° C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5°C. After the addition was complete, stirring was continued at 0°C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
11
[ 367-12-4 ]
[ 1526-17-6 ]
[ 681227-38-3 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 810
12
[ 367-12-4 ]
[ 1526-17-6 ]
[ 351-49-5 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 810
13
[ 50-00-0 ]
[ 367-12-4 ]
[ 394-50-3 ]
Reference：
[1] Organic Syntheses, 2005, vol. 82, p. 64 - 68
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 13, p. 1823 - 1832
[3] Tetrahedron Letters, 2005, vol. 46, # 19, p. 3357 - 3358
[4] Tetrahedron Letters, 2005, vol. 46, # 32, p. 5285 - 5287
[5] Organic Letters, 2018, vol. 20, # 10, p. 2880 - 2883
14
[ 67-66-3 ]
[ 367-12-4 ]
[ 394-50-3 ]
[ 405-05-0 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 2502
15
[ 367-12-4 ]
[ 394-50-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[2] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[3] Journal of the American Chemical Society, 2013, vol. 135, # 10, p. 3964 - 3970
16
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 367-27-1 ]
Yield
Reaction Conditions
Operation in experiment
41 %Spectr.
With Selectfluor; 1-(n-butyl)-3-methylimidazolium triflate In methanol at 80℃; for 5 h; Inert atmosphere
General procedure: A mixture of phenol (20 mg), F‐TEDA‐BF4 (1.1 equivalents), IL(0‐15 equivalents) and the organic solvent (5 mL) was stirred for 5 h at various temperatures under an argo atmosphere (Tables 1‐5). The mixture was evaporated at a reduced pressure and analysed by 1H, 19F NMR assolution in CDCl3 or CDCl3‐DMSO‐d6. Cl2CHCHCl2 and PhCF3 were used as internal standards for peakintegration.
Reference：
[1] Journal of the American Chemical Society, 1990, vol. 112, # 23, p. 8563 - 8575
[2] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[3] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[4] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[5] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[6] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[7] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[8] Russian Journal of Organic Chemistry, 2009, vol. 45, # 10, p. 1468 - 1473
[9] Arkivoc, 2017, vol. 2018, # 2, p. 60 - 71
17
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 367-27-1 ]
[ 28177-48-2 ]
Reference：
[1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0054-0058
18
[ 367-12-4 ]
[ 55660-73-6 ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: With dipotassium peroxodisulfate; sodium hydroxide In water at 20℃; Stage #2: With hydrogenchloride In water for 1 h; Reflux
To the 2-fluorophenol 1 (5.6 g, 50.0 mmol) dissolved in 6percent aqueous NaOH (200 mL), was added solid potassium persulfate (13.5 g, 50.0 mmol) with stirring in several portions over 10 min to result in a dark solution. This dark solutionwas stirred overnight at room temperature, then concentrated to ca. one third of its original volume under reduced pressure. The solution was cooled to 0 oC, neutralized to pH 6.5 with concentrated HCl and extracted once with diethyl ether (100 mL). This organic phase was dried (MgSO4) and concentrated under reduced pressure to reisolate the unreacted starting material, 2-fluorophenol, using flash silica gel column chromatography with hexane/ethyl acetate (V/V 6:1) as eluent to give 2.0 g 2-fluorophenol. The aqueous solution was acidified with concentrated HCl (50 mL), refluxed for 1 h, then concentrated to ca. 50 mL under reduced pressure. Addition of acetone (100 mL) precipitated the inorganic salts, which were removed by filtration. The filtrate was taken to dryness on the rotary evaporator and the dark residue, dissolved in acetone, was coated on silica gel (10 g). The dry material was subjected to column chromatography (hexane/ethyl acetate 3:1) to give the product 2.2 g, white solid, m.p. 120- 121 oC, yield 52percent, Rf 0.30 (20percent EtOAc in hexane). 1H NMR (300 M, CDCl3): 6.51-6.56 (m, 1H), 6.64-6.69 (m, 1H), 6.85-6.92 (m, 1H), 4.77 (brs, 2H, 2x OH). EI-MS Calcd. for C6H5FO2 128 (M+), found 129 (M+1)+,128 (M+).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 72 - 83
[2] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 23, p. 2719 - 2728
[3] Tetrahedron, 2014, vol. 71, # 23, p. 3915 - 3923
19
[ 367-12-4 ]
[ 2040-90-6 ]
Reference：
[1] ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 5904,5905
[3] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[4] Synthesis, 2006, # 10, p. 1578 - 1589
[5] Tetrahedron Letters, 2008, vol. 49, # 31, p. 4575 - 4578
20
[ 29650-44-0 ]
[ 367-12-4 ]
[ 403-14-5 ]
[ 699-92-3 ]
Yield
Reaction Conditions
Operation in experiment
58%
With aluminum (III) chloride In chlorobenzene at 120℃; Inert atmosphere; Large scale
A solution of 2-fluorophenyl acetate (3, 1.070 Kg, 6.94 moles) and monochlorobenzene (5.34 Lit.) was heated to 120oC. Aluminum trichloride (1.39 Kg, 10.42 moles) was added lot wise at 120 °C over 70–75min. The rise in temperature (~5oC) was controlled by rate of addition. The reaction was maintained at the same temperature for additional 3 h. The reaction mass was cooled to 0 – 5oC. Water (1.07 Lit.) followed by 3.5percent aq. HCl (2.14 Lit.) was added gradually by maintaining internal temperature <30oC using ice bath with vigorous stirring. The mixture was stirred vigorously at 5–10oC for 1 h and filtered, washed the solid cake with water (1 Lit.), suck dried the cake to get beige solid which gave para-isomer 4 (416 g, 38.8percent, >98percent HPLC purity). The organic layers was separated from the filtrate and washed with water (2 Lit.). Concentration of organic layer at normal pressure provided the crude product (530 g) which was then purified by steam distillation. The first fraction was a liquid enriched with 2-fluorophenol (45.2 g, LC: 70 percent 2-fluorophenol, 4 percent 4, 21 percent 5) and second fraction of pale yellow solid as ortho-isomer 5. The product 5 was then isolated by filtration, washed with water (80 mL) and dried under vacuum to yield the title compound (257.6 g, 24percent, > 98.2 percent HPLC) as a pale yellow solid. Steam distillation residue (HPLC: 92.7 percent 4,3.63 percent 5) crystallized from MTBE:Hexane to furnish compound 4 (205.4g, 19.2percent, >98percent HPLC purity). 3-fluoro-4-hydroxyacetophenone (4).1H NMR (CDCl3, 400 MHz) δ: 7.75-7.67 (m, 2H, ArH), 7.06 (t, 1H, J = 8.4 Hz, ArH), 5.98 (d,1H, J = 4 Hz, Ar-OH), 2.56 (s, 3H, Ac). Observed LCMS 153.00. 3-fluoro-2-hydroacetophenone (5).1HNMR (CDCl3, 400 MHz) δ:12.29 (s, 1H, OH), 7.56-7.51 (m, 1H, ArH), 7.32-7.25 (m, 1H, ArH), 6.88-6.81 (m, 1H, ArH), 2.66 (s, 3H, CH3). Observed LCMS 153.00.
Reference：
[1] Journal of Medicinal Chemistry, 1980, vol. 23, # 7, p. 738 - 744
22
[ 367-12-4 ]
[ 403-14-5 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 3, p. 1018 - 1025
[2] Journal of Fluorine Chemistry, 1994, vol. 67, # 1, p. 47 - 52
[3] Journal of the Indian Chemical Society, 1985, vol. 62, # 5, p. 388 - 390
[4] Helvetica Chimica Acta, 1989, vol. 72, p. 594 - 607
[5] Journal of Organic Chemistry, 1952, vol. 17, p. 1425,1429
[6] Patent: US6124323, 2000, A,
[7] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2426 - 2429
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 132 - 140
[9] Patent: US2002/28832, 2002, A1,
23
[ 367-12-4 ]
[ 29650-44-0 ]
[ 403-14-5 ]
Reference：
[1] Patent: US5516931, 1996, A,
24
[ 367-12-4 ]
[ 7440-44-0 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Yield
Reaction Conditions
Operation in experiment
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5° C. After the addition was complete, stirring was continued at 0° C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5°C. After the addition was complete, stirring was continued at 0°C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
27
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 28177-48-2 ]
Reference：
[1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0044-0048
28
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 367-27-1 ]
[ 28177-48-2 ]
Reference：
[1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0054-0058
29
[ 367-12-4 ]
[ 455-91-4 ]
Reference：
[1] Journal of Organic Chemistry, 1952, vol. 17, p. 1425,1429
[2] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2426 - 2429
[3] Patent: WO2006/136829, 2006, A2,
30
[ 367-12-4 ]
[ 443-26-5 ]
Reference：
[1] Chemistry - An Asian Journal, 2017, vol. 12, # 17, p. 2323 - 2331
31
[ 367-12-4 ]
[ 363-52-0 ]
Yield
Reaction Conditions
Operation in experiment
45%
Stage #1: With triethylamine; magnesium chloride In acetonitrile for 0.333333 h; Molecular sieve; Inert atmosphere Stage #2: With formaldehyd In acetonitrile at 50℃; for 6 h; Inert atmosphere; Molecular sieve Stage #3: With dihydrogen peroxide; sodium hydroxide In water; acetonitrile at 20 - 30℃; for 1.5 h; Cooling with ice; Inert atmosphere; Molecular sieve
O-fluorophenol (20 g, 0.2 mol) was dissolved in acetonitrile (500 mL, dried over molecular sieves) and protected by argon. Anhydrous magnesium chloride (68 g, 0.72 mol) was added with stirring. Triethylamine (150 mL, 1.08 mol) was added and the mixture was exothermic. After stirring for 20 min, paraformaldehyde (42 g) was added and reacted at 50 ° C for 6 h. TLC showed that some of the starting material remained and the reaction time was not changed significantly. The temperature was lowered to room temperature, and a mixture of sodium hydroxide and water (22.8 g of sodium hydroxide dissolved in 80 mL of 7 jO) was added under ice-water bath. Hydrogen peroxide (30 wtpercent, 140 mL) was then slowly added dropwise with significant exotherm to keep the temperature below The reaction mixture was stirred at 30 ° C for 1.5 h, concentrated hydrochloric acid (12 mol / L) was added to adjust the pH value to 1, and the mixture was extracted with ethyl acetate (4 × 100 mL). The combined organic phases were added with saturated aqueous sodium thiosulfate (200 mL) The mixture was stirred for 1 h. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1 × 100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (PE / EtOAc 15: 1 by volume as Eluent) to give 10.3 g of the pale yellow oily liquid (intermediate C-1a) in 45percent yield and recovery of o-fluorophenol 4.3goC-1a: 6H (300MHζ; CDC13) 6.63-6.45 (3H, m) (D, J = 15.5Ηζ), 120.3 (d, J = 15.5Ηζ) J = 8.9Hz), 111.6 (d, J = 2.6Hz), 108.1 (d, J = 18.4Hz)
7.21 g
Stage #1: With formaldehyd; triethylamine; magnesium chloride In tetrahydrofuran for 4 h; Inert atmosphere; Reflux Stage #2: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran at 20℃; for 8 h;
Under a nitrogen atmosphere, 600 mL of anhydrous tetrahydrofuran was added 16.2 mL of o-fluorophenol, 35 g of MgCl2,50 mL of triethylamine and 16.2 g of paraformaldehyde were added and heated under reflux for 4 h.Cooled to room temperature, dropping 500mL0.05mol / L NaOH solution, all the components dissolved after the drop of 72mL 30percent hydrogen peroxide, the reaction 2h; then add 72mL 30percent H2O2, stirring reaction 6h.Then add 1.0mol / L hydrochloric acid, adjust the pH 4-5, extracted with methylene chloride,The extract was washed three times with 80percent aqueous Na2S2O3 and dried over anhydrous sodium sulfate overnight.The organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography,Eluting with methylene chloride and collecting the desired fractions and evaporated to dryness under reduced pressure to give 7.21 g of a crystalline solid as white
7.5 g
Stage #1: With formaldehyd; triethylamine; magnesium chloride In tetrahydrofuran for 4 h; Inert atmosphere; Reflux Stage #2: With dihydrogen peroxide In tetrahydrofuran for 8 h;
Under the protection of nitrogen,Add 16 mL of o-fluorophenol to 600 mL of anhydrous tetrahydrofuran.35g MgCl2,50mL of triethylamine and 16g of paraformaldehyde,The reaction was heated to reflux for 4 h.Cool to room temperature,Add 500mL of 0.05mol/L NaOH solution dropwise.After all the components were dissolved, 72 mL of 30percent hydrogen peroxide was added dropwise.Reaction 2h;Add 70mL of 30percent H2O2,The reaction was stirred for 6 h.Then add 1.0 mol/L hydrochloric acid dropwise.Adjust the pH to 4-5,Extracted with dichloromethane,The extract was washed 3 times with an 80percent Na2S2O3 aqueous solution.It was dried over anhydrous sodium sulfate overnight.Evaporating the organic solvent under reduced pressure,The residue was separated by silica gel column chromatography.Elution with dichloromethane,Collect the required components,Evaporation to dryness under reduced pressure gave 7.5 g of white crystals.Intermediate 2.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0091-0093
[3] Tetrahedron Letters, 2005, vol. 46, # 19, p. 3357 - 3358
[4] Tetrahedron Letters, 2014, vol. 55, # 15, p. 2426 - 2429
[5] Patent: CN102850335, 2017, B, . Location in patent: Paragraph 0018-0019
[6] Patent: CN108947989, 2018, A, . Location in patent: Paragraph 0010; 0011; 0012
32
[ 367-12-4 ]
[ 363-52-0 ]
[ 120-80-9 ]
Reference：
[1] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9608 - 9612,5[2] Angewandte Chemie, 2014, vol. 53-126, # 36, p. 9762 - 9766,5
33
[ 367-12-4 ]
[ 348-62-9 ]
Reference：
[1] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
34
[ 367-12-4 ]
[ 2713-28-2 ]
Yield
Reaction Conditions
Operation in experiment
42%
at 20℃;
To a stirred solution of 2-fluorophenol (0.47 g;4.18 mmol) in concentrated NH4OH (22 ml) a solution of 12 (1.06 g; 4.18 mmol) was added at once at room temperature. After stirring overnight at room temperature themixture was evaporated to dryness under reduced pressure and the residue was partitioned between EtOAc (100 ml) and H20 (40 ml). The organic phase was washed with 5percent NaHSO3, brine (10 ml), dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (SiC2, CH2CI2 /EtOAc 9:1) to give the title compound (0.42 g; 42percent), as colourless solid. 1H-NMR (CDCI3) 7.3—7.4 (m,2H); 6.75 (tr, 8.8 Hz); 5.17 (m, 1 H).
5.7 g
With tert.-butylhydroperoxide; potassium iodide In methanol at 20℃; for 12 h;
10523] A mixture of 2-fluorophenol (5 g, 44 mmol) and potassium iodide (8.i4 g, 49 mmol) in methanol (150 mE) was added tert-butyl hydroperoxide (6.43 mE, 66.9 mmol) and stirred at room temperature for i 2 h. Afier completion of reaction, reaction mixture was quenched with sodium thiosulphate and extracted with EtOAc. Organic layer was washed water followed by brine, concentrated under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230- 400 mesh silica gel using i 5percent EtOAc in n-hexane to give the title compound (5.7 g)
Reference：
[1] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[2] Synthesis, 2006, # 10, p. 1578 - 1589
38
[ 367-12-4 ]
[ 100-39-0 ]
[ 368-21-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0076-0078
39
[ 367-12-4 ]
[ 100-44-7 ]
[ 368-21-8 ]
Reference：
[1] Journal of the Chemical Society, 1938, p. 1414[2] Journal of the Chemical Society, 1942, p. 418
40
[ 367-12-4 ]
[ 79-11-8 ]
[ 348-10-7 ]
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 1555
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4597 - 4601
[3] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187
41
[ 367-12-4 ]
[ 348-10-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 2006, vol. 127, # 2, p. 291 - 295
[2] Journal of Fluorine Chemistry, 2012, vol. 142, p. 24 - 28
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2013, vol. 188, # 6, p. 663 - 671
[4] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 1, p. 173 - 179
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603
42
[ 367-12-4 ]
[ 399-96-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
43
[ 367-12-4 ]
[ 350-29-8 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
44
[ 367-12-4 ]
[ 70163-98-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 7, p. 963 - 964
[2] Patent: US4140769, 1979, A,
45
[ 367-12-4 ]
[ 341-27-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 7, p. 963 - 964
[2] Canadian Journal of Chemistry, 2001, vol. 79, # 11, p. 1541 - 1545
[3] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 2502
[5] Patent: US4140769, 1979, A,
46
[ 56-45-1 ]
[ 367-12-4 ]
[ 7423-96-3 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 8, p. 1175 - 1179
47
[ 367-12-4 ]
[ 127-17-3 ]
[ 7423-96-3 ]
Reference：
[1] Journal of the American Chemical Society, 1998, vol. 120, # 28, p. 6851 - 6858
[2] Biochemistry, 2010, vol. 49, # 8, p. 1557 - 1559
[3] Journal of the American Chemical Society, 2011, vol. 133, # 40, p. 15942 - 15945
[4] Journal of the American Chemical Society, 2014, vol. 136, # 21, p. 7643 - 7654
48
[ 367-12-4 ]
[ 113-24-6 ]
[ 7423-96-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 4, p. 731 - 736
49
[ 367-12-4 ]
[ 76-05-1 ]
[ 405-05-0 ]
Yield
Reaction Conditions
Operation in experiment
50%
at 100℃; for 12 h;
To a well stirred solution of 2-fluorophenol (1.0 mmol) in CF3COOH (1.5 ml) was added hexamethylenetetramine (1.1 mmol) and the resulting mixture was allowed to react for 12 h at 100 °C. The solution was then poured into icy water (100 ml), neutralized with NaHCO3 (aq) 5percent, and extracted with Et2O (2 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness. The desired product was obtained after crystallization from H2O. Yield = 50 percent. Analytical data were identical to those already reported for the same compound.1 Anal. Calcd for C7H5FO2: C, 60.01; H, 3.60; O, 22.84. Found: C, 59.95; H, 3.62, O, 22.82 .
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 769 - 772
50
[ 67-66-3 ]
[ 367-12-4 ]
[ 394-50-3 ]
[ 405-05-0 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 2502
51
[ 367-12-4 ]
[ 405-04-9 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
52
[ 367-12-4 ]
[ 437-83-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[2] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[3] Patent: WO2013/28474, 2013, A1,
[4] Patent: WO2014/126944, 2014, A2,
[5] Patent: EP2744499, 2016, B1,
53
[ 367-12-4 ]
[ 452-11-9 ]
Reference：
[1] Patent: WO2006/136829, 2006, A2,
54
[ 367-12-4 ]
[ 2357-52-0 ]
Reference：
[1] Patent: CN104557654, 2017, B,
55
[ 367-12-4 ]
[ 484-94-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[2] Patent: WO2013/28474, 2013, A1,
[3] Patent: WO2014/126944, 2014, A2,
[4] Patent: EP2744499, 2016, B1,
56
[ 367-12-4 ]
[ 458-09-3 ]
Reference：
[1] Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 1993, vol. 237, p. 399 - 406
57
[ 367-12-4 ]
[ 320-76-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
58
[ 367-12-4 ]
[ 103438-86-4 ]
Reference：
[1] South African Journal of Chemistry, 1997, vol. 50, # 1, p. 40 - 47
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 10, p. 1982 - 1988
D 1. 1 -Fluoro-2-methoxy-benzeneTo a slurry of NaH (28.8g, O.?Omol) in dry DMF (500ml) at 0 0C was added 2-fluoro phenol (5Og, 0.446mol) slowly over a period of 30min and stirred for Ih at room EPO <DP n="125"/>temperature. To this was added methyl iodide (19Og, 1.33mol) and the reaction mixture was stirred for 16h under nitrogen and poured into ice-water (1.5L). The product was extracted with ethyl acetate (2 x 200ml), washed with water, brine and dried. The solvent was removed under vacuum to afford 55g (98%) of the title compound.
To a stirred solution of 2-fluorophenol (0.47 g;4.18 mmol) in concentrated NH4OH (22 ml) a solution of 12 (1.06 g; 4.18 mmol) was added at once at room temperature. After stirring overnight at room temperature themixture was evaporated to dryness under reduced pressure and the residue was partitioned between EtOAc (100 ml) and H20 (40 ml). The organic phase was washed with 5percent NaHSO3, brine (10 ml), dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (SiC2, CH2CI2 /EtOAc 9:1) to give the title compound (0.42 g; 42percent), as colourless solid. 1H-NMR (CDCI3) 7.3?7.4 (m,2H); 6.75 (tr, 8.8 Hz); 5.17 (m, 1 H).
With sodium hydrogencarbonate; In hexane; water; toluene;
1) 1.4 l of water containing 210 g of sodium bicarbonate were added with 187 g of orthofluorophenol and allowed to be cooled down to temperature below 10 °C. The mixture was added with 423 g of grain iodine in five aliquot parts. Upon confirmation that iodine color had disappeared, extraction of mixture took place using toluene. The resulted toluene layer was washed with water, then with sodium hydrogen sulfite solution in water, and again with water. And then toluene was evaporated therefrom. The fluid in reddish purpul color obtained through distillation under reduced pressure (b.p. 124 to 145 °C/18mmHg) was subjected to a recrystallization using hexane, whereupon 120 g of o-fluoro-p-iodophenol were finally yielded in white crystal.
With sodium hydrogencarbonate; In hexane; water; toluene;
1) 1.4 l of water containing 210 g of sodium bicarbonate were added with 187 g of o-fluorophenol and allowed to be cooled down to temperature below 10 °C. The mixture was added with 423 g of grain iodine in five aliquot parts. Upon confirmation that iodine color has disappeared, extraction of mixture took place using toluene. The resulted toluene layer was washed with water, then with sodium hydrogen sulfite solution in water, and again with water. And then toluene was evaporated therefrom. The fluid in reddish purpul color obtained through distillation under reduced pressure (b.p. 124 to 145 °C/18mmHg) was subjected to a recrystallization using hexane, whereupon 120 g of o-fluoro-p-iodophenol was finally yielded in white crystal.
With sodium hydroxide; iodine; In methanol; n-heptane; ethyl acetate;
Preparation 182-Fluoro-4-iodophenol.2-Fluorophenol (1.12 g) was diluted in methanol, 15 ml, and sodium hydroxide (720 mg, 1.8 eq.) was added.When the alkali had dissolved, the reaction mixture was cooled to 0° C. and iodine (2.54 g, 1 eq.) was added.After 5 min. the mixture was worked up with EtOAc and water.The organics were dried, concentrated in vacuo and purified by chromatography (7percent EtOAc in Heptane).714 mg obtained. P 1H NMR (300 MHz, CDCl3) delta 7.39 (m, 1H), 7.33 (m, 1H), 6.76 (m, 1H), 5.23 (br, 1H).
5.7 g
With tert.-butylhydroperoxide; potassium iodide; In methanol; at 20℃; for 12h;
10523] A mixture of 2-fluorophenol (5 g, 44 mmol) and potassium iodide (8.i4 g, 49 mmol) in methanol (150 mE) was added tert-butyl hydroperoxide (6.43 mE, 66.9 mmol) and stirred at room temperature for i 2 h. Afier completion of reaction, reaction mixture was quenched with sodium thiosulphate and extracted with EtOAc. Organic layer was washed water followed by brine, concentrated under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230- 400 mesh silica gel using i 5percent EtOAc in n-hexane to give the title compound (5.7 g)
To the 2-fluorophenol 1 (5.6 g, 50.0 mmol) dissolved in 6% aqueous NaOH (200 mL), was added solid potassium persulfate (13.5 g, 50.0 mmol) with stirring in several portions over 10 min to result in a dark solution. This dark solutionwas stirred overnight at room temperature, then concentrated to ca. one third of its original volume under reduced pressure. The solution was cooled to 0 oC, neutralized to pH 6.5 with concentrated HCl and extracted once with diethyl ether (100 mL). This organic phase was dried (MgSO4) and concentrated under reduced pressure to reisolate the unreacted starting material, 2-fluorophenol, using flash silica gel column chromatography with hexane/ethyl acetate (V/V 6:1) as eluent to give 2.0 g 2-fluorophenol. The aqueous solution was acidified with concentrated HCl (50 mL), refluxed for 1 h, then concentrated to ca. 50 mL under reduced pressure. Addition of acetone (100 mL) precipitated the inorganic salts, which were removed by filtration. The filtrate was taken to dryness on the rotary evaporator and the dark residue, dissolved in acetone, was coated on silica gel (10 g). The dry material was subjected to column chromatography (hexane/ethyl acetate 3:1) to give the product 2.2 g, white solid, m.p. 120- 121 oC, yield 52%, Rf 0.30 (20% EtOAc in hexane). 1H NMR (300 M, CDCl3): 6.51-6.56 (m, 1H), 6.64-6.69 (m, 1H), 6.85-6.92 (m, 1H), 4.77 (brs, 2H, 2x OH). EI-MS Calcd. for C6H5FO2 128 (M+), found 129 (M+1)+,128 (M+).
With dipotassium peroxodisulfate;
This hydroquinone was prepared through the oxidation of 2-fluorophenol with potassium persulfate according to the literature method
O-fluorophenol (20 g, 0.2 mol) was dissolved in acetonitrile (500 mL, dried over molecular sieves) and protected by argon. Anhydrous magnesium chloride (68 g, 0.72 mol) was added with stirring. Triethylamine (150 mL, 1.08 mol) was added and the mixture was exothermic. After stirring for 20 min, paraformaldehyde (42 g) was added and reacted at 50 ° C for 6 h. TLC showed that some of the starting material remained and the reaction time was not changed significantly. The temperature was lowered to room temperature, and a mixture of sodium hydroxide and water (22.8 g of sodium hydroxide dissolved in 80 mL of 7 jO) was added under ice-water bath. Hydrogen peroxide (30 wtpercent, 140 mL) was then slowly added dropwise with significant exotherm to keep the temperature below The reaction mixture was stirred at 30 ° C for 1.5 h, concentrated hydrochloric acid (12 mol / L) was added to adjust the pH value to 1, and the mixture was extracted with ethyl acetate (4 × 100 mL). The combined organic phases were added with saturated aqueous sodium thiosulfate (200 mL) The mixture was stirred for 1 h. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1 × 100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (PE / EtOAc 15: 1 by volume as Eluent) to give 10.3 g of the pale yellow oily liquid (intermediate C-1a) in 45percent yield and recovery of o-fluorophenol 4.3goC-1a: 6H (300MHzeta; CDC13) 6.63-6.45 (3H, m) (D, J = 15.5Etazeta), 120.3 (d, J = 15.5Etazeta) J = 8.9Hz), 111.6 (d, J = 2.6Hz), 108.1 (d, J = 18.4Hz)
7.21 g
Under a nitrogen atmosphere, 600 mL of anhydrous tetrahydrofuran was added 16.2 mL of o-fluorophenol, 35 g of MgCl2,50 mL of triethylamine and 16.2 g of paraformaldehyde were added and heated under reflux for 4 h.Cooled to room temperature, dropping 500mL0.05mol / L NaOH solution, all the components dissolved after the drop of 72mL 30percent hydrogen peroxide, the reaction 2h; then add 72mL 30percent H2O2, stirring reaction 6h.Then add 1.0mol / L hydrochloric acid, adjust the pH 4-5, extracted with methylene chloride,The extract was washed three times with 80percent aqueous Na2S2O3 and dried over anhydrous sodium sulfate overnight.The organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography,Eluting with methylene chloride and collecting the desired fractions and evaporated to dryness under reduced pressure to give 7.21 g of a crystalline solid as white
7.5 g
Under the protection of nitrogen,Add 16 mL of o-fluorophenol to 600 mL of anhydrous tetrahydrofuran.35g MgCl2,50mL of triethylamine and 16g of paraformaldehyde,The reaction was heated to reflux for 4 h.Cool to room temperature,Add 500mL of 0.05mol/L NaOH solution dropwise.After all the components were dissolved, 72 mL of 30percent hydrogen peroxide was added dropwise.Reaction 2h;Add 70mL of 30percent H2O2,The reaction was stirred for 6 h.Then add 1.0 mol/L hydrochloric acid dropwise.Adjust the pH to 4-5,Extracted with dichloromethane,The extract was washed 3 times with an 80percent Na2S2O3 aqueous solution.It was dried over anhydrous sodium sulfate overnight.Evaporating the organic solvent under reduced pressure,The residue was separated by silica gel column chromatography.Elution with dichloromethane,Collect the required components,Evaporation to dryness under reduced pressure gave 7.5 g of white crystals.Intermediate 2.
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Heating;
Step B 4-Chloro-2- (2-fluoro-phenoxy)-benzaldehyde A solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.0 g, 6.3 mmol) and 2- fluorophenol (0. 78 g, 6.9 mmol) in DMSO (10 mL) is treated with potassium carbonate (1.04 g, 7.6 mmol). The reaction is heated to 100 C and stirred overnight. The reaction is cooled to room temperature and quenched with 1N aqueous hydrochloric acid to pH=6. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 4: 1 hexanes: acetone to elute the pure product. The solvent is removed to afford about 0. 8 g (51%) of product. 1H NMR (400 MHz, CDC13), TLC (1: 1 hexanes: EtOAc) Rf=0. 8
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 24h;
Step 1. Preparation of 4- (2-Fluoro-phenoxy)-2-nitrotoluene. To <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (25 g, 0. 016 mol), 2-fluorophenol (15.8 mL, 0.017 mol) in NMP (350 mL) was added potassium carbonate (22.27g, 0. 016 mol) and the mixture was stirred at 160C for 48 h. After cooling at RT, water (350 mL) was added and the solution was extracted into ethyl acetate (2x 150 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated and the residue was purified by flash chromatography eluting with Hex: EtOAc 95: 5 to yield 15.17 g of 4- (2-fluoro-phenoxy)-2-nitrotoluene : MS: 248 (M+H).
1) Synthesis of 2'-fluorophenyl acetate: To a mixture of 2-fluorophenol (5 g, 45 mmol), 50 ml ether, and potassium carbonate (16 g), 5 ml acetic anhydride was added. After stirring under reflux for 3 hours, the reaction mixture was stirred at room temperature overnight. The solid was removed by filtration and washed with ether for several times. The filtrate was then evaporated to remove the solvent and distilled to obtain the product (4.43 g, 64%). 1 H NMR, delta: 2.32 (s, 3H, CH3), 6.90-7.27 (m, 4H, H-Ar) ppm; 13 C NMR, delta: 20.3 (CH3 CO), 116.6 (4 JC-F =19 Hz, C5'), 123.7 (C4'/C6'), 124.4 (3 JC-F =4 Hz, C6'/C4'), 127.0 (2 JC-F =7 Hz, C3'), 138.1 (2 JC-F =13 Hz, C1'), 154.1 (JC-F =249 Hz, C2'), 168.3 (C=O) ppm. 2) Synthesis of 3'-fluoro-4'-hydroxyacetophenone: A mixture of 2'-fluorophenyl acetate (1.54 g, 10 mmol) and aluminum chloride (1.70 g, 12.5 mmol) in 10 ml nitrobenzene was stirred at 140-150 C. for 3 hours. After cooling to room temperature, 15 ml ice-water was added and followed 30 ml of 3N HCl. The water layer was extracted with ether (3*30 ml) and the combined organic layers were washed with concentrated potassium carbonate solution for three times.
With sulfuric acid; dihydrogen peroxide; In dichloromethane; water;
EXAMPLE 24 7.6 g (25mmol) of 2,4,5-trichloro-2'-fluorobenzophenone, 4.3 g (0.115 mol) of 90% hydrogen peroxide and 0.25 g of 2-nitrobenzoselenic acid were stirred for 24 h in 50 ml of dichloromethane. The insoluble constituents were then filtered off, water was added and the organic phase was separated off. After removal of the solvent, the residue was heated with 120 g of 60% sulfuric acid for 8 h to hydrolyze the ester present. 1.55 g (13.8 mmol, 55%) of 2-fluorophenol could then be separated off by steam distillation. 4.8 g (21 mmol, 85%) of 2,4,5-trichlorobenzoic acid (crude (GC) ca. 95%) were isolated from the mother liquor.
With triphenylphosphine; In ethyl acetate; benzene;
EXAMPLE 68 1-Benzyl-4-(4'-Fluorophenoxymethyl)piperidine A mixture of 4 fluorophenol (6.01 g, 54 mmol), triphenylphosphine (6.87 g, 64 mmol), and <strong>[67686-01-5]1-benzyl-4-hydroxymethylpiperidine</strong> (11.0 g, 54 mmol) in benzene (300 mL) was stirred at 10°-15° C. Diethyl azodicarboxylate (11.2 g, 10.1 mL, 64 mmol) was added dropwise. The reaction mixture was heated to reflux temperature and stirred for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; the organic solution was washed with water three times, a 2N sodium hydroxide solution three times, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give crude product. Column chromatography (ethyl acetate:hexanes::1:1) gave, after removal of solvent, a pale yellow oil (3.88 g, 24percent yield): 7.40-7.25 (m, 5H), 7.0-6.7 (m, 4H), 3.75 (d, 2H, J=4), 3.50 (s, 2H), 2.9 (br d, 2H, J=4), 2.1-1.25 (m, 7H); IR (neat): 3084(m), 3062(m), 2921(s), 2802(s), 2758(s), 1601(m), 1505(s), 1467(s), 1454(s), 1394(s); HR-MS: Calcd. for C19 H22 FNO: 299.1684; Found: 299.1685.
3-(2-Fluorophenoxy)propanoic acid.; A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5 g of less pure compound.
A solution of 2-fluorophenol (compound 1-1, 3.0 g) in N,N-dimethylformamide (7.0 ml) was added to a solution of 50% sodium hydride (3.22 g) in N,N- dimethylformamide (100 ml) in a nitrogen atmosphere with cooling in an ice bath. After stirring at the same temperature for 30 minutes, a solution of 3-bromo- propionic acid (4.91 g) in N, N-dimethylformamide (8.0 ml) was added. The mixture was returned to room temperature and stirred at the same temperature for 24 hours. The pH was adjusted to 1 to 2 with 1 N hydrochloric acid (100 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine . The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a mixed solvent of 20% ethyl acetate-hexane to obtain the title compound (1.53 g) .; IH NMR (400 MHz, DMSO-d6) (ppm) : 2.73 (t, J=6.0 Hz,2H) , 4.24 (t, J=6.0 Hz, 2H) , 6.90-7.00 (m, IH) , 7.09-7.24 (m, 3H) , 12.41 (br. S., IH) .
3-(2-Fluorophenoxy)propanoic acid. A mixture of 2-fluorophenol (15 g), 3- bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 5OmL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a EPO <DP n="98"/>white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5g of less pure compound.
Example 15 Synthesis of 8-fluorochroman-4-amine 3-(2-fluorophenoxy)propanoic acid (36). A mixture of 2-fluorophenol (35) (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to RT and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted three times with EtOAc to yield 2.5 g of less pure compound (36). 3-(2-Fluorophenoxy)propanoic acid. A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5 g of less pure compound.
A mixture of 2-fluorophenol (35) (15 g), 3-bromoprorhoanoic acid (20 g) and NaOH (11 g) was refluxed in 5OmL of water. The solution was cooled to RT and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted three times with EtOAc to yield 2.5g of less pure compound (36).
b) The procedure of a) was followed except that 2.96 g of <strong>[348-62-9]2-fluoro-4-chlorophenol</strong>, 2.72 g of sodium formate, 0.2 g of catalyst, and 40 ml of 2-propanol were employed. The mixture was heated to 65 C. and allowed to react at that temperature for 3 hours. It was then allowed to cool, was filtered, and the filtrate was concentrated by evaporation under reduced pressure. Analysis of the residue by standardized gas-liquid chromatography using a mass spectrometer detector indicated that it was 98 percent the title compound. The residue was flash distilled to obtain 1.84 g (81 percent of theory) of the title compound boiling at 90-92 C. under 70 mm Hg (9.3 kPa) pressure.
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10 C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5 C. After the addition was complete, stirring was continued at 0 C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119-121 C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70-86 C.
13.5 g (30%)
With nitric acid; In hexane; dichloromethane;
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5C. After the addition was complete, stirring was continued at 0C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86C.
EXAMPLE 2 2-[(2-Fluorophenoxy)methyl]quinoline To a solution of 2-fluorophenol (7.8 g, 70 mmol) in 20 mL ethanol is added 2-(chloromethyl)quinoline hydrochloride (15.0 g, 70 mmol) followed by a solution of potassium hydroxide (7.86 g, 140 mmol) in 50 mL ethanol. The reaction mixture is refluxed overnight. After filtering while still hot, the reaction mixture is cooled to 8 C. to afford 9.3 g (53%) of brown crystals, m.p. 84-86 C. Analysis for: C16 H12 FNO. Calculated: C, 75.87; H, 4.78; N, 5.53. Found: C, 75.49; H, 4.71; N, 5.54.
A solution of bromine (140.6 g) in carbon disulphide (50 cm3) was added over 3 hours to a stirred solution of 2-fluorophenol (89.68 g) in carbon disulphide (150 cm3), the temperature being maintained at ca. 10 C. throughout the addition by external cooling. The reaction mixture was allowed to stand at the ambient temperature (ca. 20 C.) for 18 hours, and was then poured into an aqueous solution of sodium metabisulphite (100 cm3). The organic layer was separated, washed with aqueous sodium bicarbonate solution (2*100 cm3) and dried over anhydrous sodium sulphate. Removal of the solvent by evaporation under reduced presure gave an oil, which was purified by distillation under reduced pressure to give two fractions, each shown by gas liquid chromatography to contain 97% 4-bromo-2-fluorophenol.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 50℃; for 3h;
To a suspension of 2-fluorophenol (3.0 g, 26.8 mmol) in THF (30 mL) at 0-5C was dropped a solution of potassium tert-butoxide (1N in THF, 28.1 mL, 28.1 mmol), followed by beta-propiolactone (1.85 mL, 29.4 mmol) in one portion. The mixture was warmed to room temperature for 1 hour and then heated at 50C for 2 hours. After cooling to room temperature, the mixture was quenched with a saturated solution of sodium hydrogenocarbonate and diluted with water. The aqueous layer was washed with ethyl acetate, acidified with 1 M hydrochloric acid until pH 2 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound (174a) (3.73 g, 20.3 mmol, 76%) which was used without further purification. MS m/z ([M-H]-) 183.
Potassium t-butoxide (2.42 g) was added to a solution of the compound 1-1 (2.20 g) in tetrahydrofuran (100 ml) at room temperature. After stirring for five minutes at the same temperature, beta-propiolactone (2.71 ml) was added. Because of heat generation, the mixture was moved to an ice bath and stirred at the same temperature for one hour. After further stirring at room temperature for four hours, the mixture was made acidic with 1 N hydrochloric acid to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a mixed solvent of 20% ethyl acetate-hexane to obtain the title compound (1.44 g) . IH NMR (400 MHz, DMSO-d6) (ppm) : 2.73 (t, J=6.0 Hz,2H) , 4.24 (t, J=6.0 Hz, 2H) , 6.90-7.00 (m, IH) , 7.09-7.24 (m, 3H) , 12.41 (br. S., IH) .
To a well stirred solution of 2-fluorophenol (1.0 mmol) in CF3COOH (1.5 ml) was added hexamethylenetetramine (1.1 mmol) and the resulting mixture was allowed to react for 12 h at 100 °C. The solution was then poured into icy water (100 ml), neutralized with NaHCO3 (aq) 5percent, and extracted with Et2O (2 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness. The desired product was obtained after crystallization from H2O. Yield = 50 percent. Analytical data were identical to those already reported for the same compound.1 Anal. Calcd for C7H5FO2: C, 60.01; H, 3.60; O, 22.84. Found: C, 59.95; H, 3.62, O, 22.82 .
With nitric acid; In dichloromethane; at 0℃; for 1h;
Step A: 2-fluoro-6-nitrophenol: Concentrated HN03 (95 %, 44 g, 0.62 mol) was added dropwise at 0-5 C to the solution of2-fluorophenol (64.6 g, 0.58 mol) in 1 L ofDCM. The mixture wasstirred at 0 C for 1 hour before filtration. The filtrate was washed with water and brine, driedover anhydrous Na2S04 and concentrated. The residue was purified by column chromatography(DCM: PE = 1 : 2) to afford 2-fluoro-6-nitrophenol.
With nitric acid; In dichloromethane; at 0 - 5℃; for 1h;
Concentrated HNO3 (95 %? 44 g, 0.62 mol) was added dropwiseat 0-5 Oc to the solution of 2-fluorophenol (64.6 g, 0.58 mol) in 1 L of DCM. The mixture wasstirred at o Oc for 1 hour before filtration. The filtrate was washed with water and brine, dried oyer anhydrous Na2504 and concentrated. The residue was purified by column chromatography (DCM : PE = 1 : 2) to afford 2-fluoro-6-nitrophenol.
With nitric acid; In dichloromethane; at 0℃; for 1h;
General procedure: Concentrated HNO3 (95 %, 44 g, 0.62 mol) was added dropwise at 0-5 C to thesolution of 2-fluorophenol (64.6 g, 0.58 mol) in 1 L of DCM. The mixture was stirred at 0 C for 1 hour before filtration.The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue waspurified by column chromatography (DCM : PE = 1 : 2) to afford 2-fluoro-6-nitrophenol.
With potassium carbonate; In acetonitrile; at 80℃;
General procedure: The solution of substituted phenol 3 (6.0 mmol, 1.2 equiv), K2CO3 (7.5 mmol, 1.5 equiv), 2-chloro-N-(pyridin-3-yl)acetamide 2 (5.0 mmol, 1.0 equiv) in CH3CN (50 mL) was refluxed and monitored by TLC. After completion of the reaction, the solution was cooled; solvent was evaporated under reduced pressure. The residue was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine and dried over anhydrous MgSO4. Filtration of MgSO4 and evaporation of solvent under vacuum gave the crude product. The residueo btained was purified by silica gel column chromatography to obtain the corresponding compound 4.
7-(2-fluorophenoxy)thieno[3,2-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Schlenk technique; Inert atmosphere;
General procedure: A dry Schlenk tube was charged under Ar with dry dioxane (3 mL), the fluoro or methoxyphenol (1.1 equiv.), N,N-dimethylglycine (30 mol%), CuI (20 mol%), Cs2CO3 (2 equiv.) and compound 1. The mixture was heated with stirring under Ar at 100 C for 18 h. After cooling water (5 mL) and ethyl acetate (5 mL) were added. The phases were separated and the aqueous phase was extracted with more ethyl acetate (2 × 5 mL). The organic phase was dried (MgSO4) and filtered. Removal of the solvent gave an oil which was submitted to column chromatography.
methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;
Methyl 4-(l-(2-fluorophenoxy)ethyl) benzoate. To a solution of methyl 4-(l- hydroxyethyl)benzoate (0.9 g, 5 mmol), 2-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0C. The mixture was stirred at 20C for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL x 3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5: 1) to give methyl 4-(l-(2- fluorophenoxy)ethyl) benzoate (450 mg, 33%).
33%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 2-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0 C. The mixture was stirred at 20 C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate (450 mg, 33%).
With aluminum (III) chloride; In chlorobenzene; at 120℃;Inert atmosphere; Large scale;
A solution of 2-fluorophenyl acetate (3, 1.070 Kg, 6.94 moles) and monochlorobenzene (5.34 Lit.) was heated to 120oC. Aluminum trichloride (1.39 Kg, 10.42 moles) was added lot wise at 120 C over 70-75min. The rise in temperature (~5oC) was controlled by rate of addition. The reaction was maintained at the same temperature for additional 3 h. The reaction mass was cooled to 0 - 5oC. Water (1.07 Lit.) followed by 3.5% aq. HCl (2.14 Lit.) was added gradually by maintaining internal temperature <30oC using ice bath with vigorous stirring. The mixture was stirred vigorously at 5-10oC for 1 h and filtered, washed the solid cake with water (1 Lit.), suck dried the cake to get beige solid which gave para-isomer 4 (416 g, 38.8%, >98% HPLC purity). The organic layers was separated from the filtrate and washed with water (2 Lit.). Concentration of organic layer at normal pressure provided the crude product (530 g) which was then purified by steam distillation. The first fraction was a liquid enriched with 2-fluorophenol (45.2 g, LC: 70 % 2-fluorophenol, 4 % 4, 21 % 5) and second fraction of pale yellow solid as ortho-isomer 5. The product 5 was then isolated by filtration, washed with water (80 mL) and dried under vacuum to yield the title compound (257.6 g, 24%, > 98.2 % HPLC) as a pale yellow solid. Steam distillation residue (HPLC: 92.7 % 4,3.63 % 5) crystallized from MTBE:Hexane to furnish compound 4 (205.4g, 19.2%, >98% HPLC purity). 3-fluoro-4-hydroxyacetophenone (4).1H NMR (CDCl3, 400 MHz) delta: 7.75-7.67 (m, 2H, ArH), 7.06 (t, 1H, J = 8.4 Hz, ArH), 5.98 (d,1H, J = 4 Hz, Ar-OH), 2.56 (s, 3H, Ac). Observed LCMS 153.00. 3-fluoro-2-hydroacetophenone (5).1HNMR (CDCl3, 400 MHz) delta:12.29 (s, 1H, OH), 7.56-7.51 (m, 1H, ArH), 7.32-7.25 (m, 1H, ArH), 6.88-6.81 (m, 1H, ArH), 2.66 (s, 3H, CH3). Observed LCMS 153.00.
With caesium carbonate; In tetrahydrofuran; for 12h;
A solution of 500 mg (4.46 mmol) of 2-fluorophenol 1.769 g (8.92 mmol) of 1,1?-sulfonyldiimidazole in 15 mL of tetrahydrofuran was treated with 727 mg (2.23 mmol) of cesium carbonate. The reaction was stirred for 12 h, concentrated, and the residue was partitioned between the ethyl acetate and water (10 mL each). The organic layer was washed sequentially with saturated ammonium chloride solution and brine. After drying over the anhydrous sodium sulfate, the organic layer was concentrated and chromatographed on silica with 1:5 ethyl acetate / hexane as the eluant to afford 880 mg (90%) of 11bas a clear oil: 1H NMR (400 MHz, CDCl3) delta 7.80 (s, 1H),7.35-7.31 (m, 2H), 7.16-7.14 (m, 3H), 7.06-7.01 (m, 1H); 13C NMR(100 MHz, CDCl3) delta 155.3, 152.8, 137.4, 136.2 (d, J = 13 Hz), 131.3, 129.8 (d, J= 7 Hz), 125.0 (d, J = 4 Hz), 123.6,117.5 (dd, J = 158 and 18 Hz );ESI-MS m/z 243.2 MH+.
tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
With pyridine; copper; caesium carbonate; at 120℃;Sealed tube;
Step 1: Synthesis of tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate A mixture of <strong>[374930-88-8]tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate</strong> (684 mg, 2.0 mmol), 2-fluorophenol (1.1 g, 10.0 mmol), copper (650 mg, 10.0 mmol) and cesium carbonate (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120 0 C. in a sealed tube overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 20:1) to give tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 6%) as a yellow solid. MS (ES+) C19H23FN4O3 requires: 374, found: 397 [M+Na]+.
With potassium carbonate; In tetrahydrofuran; at 50℃; for 1h;
Dissolve o-fluorophenol (4.0 g, 35.7 mmol) in tetrahydrofuran (30 mL) and add potassium carbonate (18.5 g, 0.13 mol) and dimethylsulfate (4.2 mL, 44.3 mmol) Reaction 1h, TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure (water pump) to give a pale yellow oily liquid (Intermediate A-1c) (3.74 g, Yield 83%). delta H (300 MHz; CDCl 3) 7.07-6.84 (4H, m), 3.87 (3H, s)
O-fluorophenol (5.0 g, 44.6 mmol) was dissolved in tetrahydrofuran (20 mL) was slowly added to tetrahydrofuran (20 mL) suspended in 60% by weight of sodium hydride (2.3 g, 57.5 mmol). After stirring for 5 min, 0.2 mmol of tetrabutylammonium iodide (TBAI) was added and then benzyl bromide (7.3mL, 61.4mmol), a significant exotherm, plus the reaction 0.5h, TLC showed that the raw material has been reacted. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated to give 11.9 g of the crude product (intermediate A-1a) as a colorless oily liquid. The crude product was dissolved in acetonitrile (50 mL), N-bromosuccinimide (7.3 g, 44.8 mmol) was added and the reaction was carried out at 70 C for 3 h. TLC showed that the starting material had been reacted and most of the acetonitrile was distilled off. 50 mL of water, stirred for 15 min and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous magnesium sulfate and purified by column chromatography (pure petroleum ether (PE)) to afford the bromo product (Intermediate A- 2a) as a light yellow oily liquid which solidified to a pale yellow solid (10.5 g, 84% yield). Intermediate A-2a: Murho (singlet): 56-59 C; 6H (300MuEtazeta; CDC13) 7.36-7.7.31 (5H, m), 7.22 (1H, dd, J = 8.1Etazeta, 2.4Etazeta) 7.12 (1H, dt, J = 8.7Hz, 1.8Etazeta), 6.84 (1H, t, J = 8.7Hz), 5.09 (2H, s)
3,4,6-trichloro-5-(2-fluoro-phenoxy)-phthalonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;
Five grams of 3,4,5,6-<strong>[1953-99-7]tetrachlorophthalonitrile</strong>, 2.10 grams of 2-fluorophenol, 3.9 grams of K2CO3, and 25 milliliters of N, N-dimethylformamide were placed in a 100 milliliter flask , Followed by stirring while heating at 70 °C. EIA (ethyl acetate) was used for extraction when the reaction was completed. After extraction, the resultant was concentrated to obtain a solid. The obtained solid was dissolved in a small amount of dichloromethane, washed several times with hexane, filtered and dried under vacuum to obtain 3,4,6-dichloro-5- (2-fluoro-phenoxy) Dinitrile.
With potassium carbonate; In acetone; at 70℃;
Synthesis Example 7: Synthesis of 3,4,6-trichloro-5-(2-fluoro-phenoxy)-phthalonitrile 5 g of 3,4,5,6-<strong>[1953-99-7]tetrachlorophthalonitrile</strong>, 2.10 g of 2-fluorophenol, 3.9 g of K2CO3, and 25 ml of N,N-dimethyl formamide were put in a 100 ml flask, and then stirred while heated at 70° C. When the reaction was complete, EA (ethyl acetate) was used for an extraction. After the extraction, the resultant was concentrated to obtain a solid. The obtained solid was dissolved in a small amount of dichloromethane, several times washed with hexane, filtered, and vacuum-dried to obtain 3,4,6-trichloro-5-(2-fluoro-phenoxy)-phthalonitrile.
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃;
Take a 150mL eggplant-shaped bottle,Weigh 1.0 g of intermediate III-2 (5.0 mmol; 1.0 equiv),0.56 g of 2-fluorophenol (5.0 mmol; 1.0 equiv),2.5 g cesium carbonate (7.5 mmol; 1.5 equiv),0.6g potassium iodide (3.0mmol; 0.6equiv),40mL of N,N-dimethylformamide added to the bottle,Stir well,Then it was heated to 40C and reacted overnight.Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction.Then the reaction solution was filtered and evaporated to dryness.The resulting residue was treated with 2 mol/L NaOH aqueous solution,The ethyl acetate was re-dissolved and added to a separatory funnel.The aqueous phase is extracted 2 to 3 times with an equal volume of ethyl acetate.Combine the ethyl acetate layers,Add saturated aqueous sodium chloride solution.Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 5g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 10:1.The resulting etherification reaction product is collected,A total of 0.36g of light yellow solid IV-4a was obtained,Yield: 28.7%.
3-bromo-5-(2-fluorophenoxy)-1-(propan-2-yl)-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 145℃; for 1h;Microwave irradiation;
To a solution of <strong>[1240567-67-2]3,5-dibromo-1-(propan-2-yl)-1H-1,2,4-triazole</strong> (lnt-2, 400 mg, 1.5 mmol) and 2-fluorophenol (0.1 mL, 1.5 mmol) in DMF (4 mL) was added K2CO3(411 mg, 2.9 mmol). The stirring was continued in microwave at 145C for 1 h. After complete consumption of starting material (as monitored by TLC) reaction mixture was poured into water and extracted with MTBE. The organic layer was separated and dried over sodium sulphate. Solvent was evaporated under reduced pressure and purified by combi-flash column chromatography (silica gel, eluting with ethyl acetate / n-hexane 2:98 v/v) to afford the title compound as white solid (320 mg, 72%). 1H NMR (DMSO-d6, 400 MHz): 1.43 (d, J = 6.6 Hz, 6 H), 4.66 (p, J = 6.6 Hz, 1 H), 7.30 (t, 7 = 7.8 Hz, 1 H), 7.34 - 7.41 (m, 1 H), 7.42 - 7.48 (m, 1 H), 7.57 (td, 7 = 8.1, 1.5 Hz, 1 H). MS (ES+) m/z 302.2 [M+H] .
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;
o-Fluorophenol (6.71 mL) and K2C03 (12.99 g) were suspended in DMF (100 mL), after which <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (10 g) was added and stirred for 8 hours at room temperature. Water was added to the reaction solution, and the resulting solid was washed with water to obtain the object compound (13.67 g).NMR2: 7.20-7.38(4H, m), 9.33(2H, s).
2-Fluorophenol (31.36 g, 280 mmol) was added to a three-neck bottle.Stir at 0 C, then slowly add acetyl chloride (24.22 g, 308 mmol) to the above solution.After the addition was completed, the mixture was stirred at room temperature for 2 h at 25 C.The temperature was raised to 130 C and anhydrous aluminum trichloride (52.00 g, 389 mmol) was slowly added to the above mixed solution.After the addition, stir at 130 C for 2 h.Then, water (500 mL) was added to the above reaction mixture and stirred.Ethyl acetate (300 mL) was extracted in three portions.The organic phase is combined to remove the solvent under reduced pressure.Column chromatography (eluent: Petroleum ether / EtOAc (v / v) = 10/1),Yielding 6.30 g of a brown solid,Yield: 15%.
15%
With aluminum (III) chloride; at 130℃; for 2h;
2-Fluorophenol (31.36 g, 280 mmol) was added into a three-neck flask, and stirred at 0 , then acetyl chloride (24.22 g, 308 mmol) was added dropwise slowly into the flask. After dropwise addition, the mixture was stirred at 25 for 2 h, then heated to 130 , and anhydrous aluminium trichloride (52.00 g, 389 mmol) was added slowly into the mixture. After addition, the resulting mixture was stirred at 130 for 2 h, then to the mixture was added water (500 mL) , and the mixture was stirred. The mixture was extracted with ethyl acetate (300 mL) for three times, and the combined organic layers were concentrated in vacuo to remove the solvent. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc (v/v) = 10/1) to give a brown solid (6.30 g) , yeild: 15%.[0474]MS-ESI: m/z 155.1 [M+H]+.
2-(2-fluorophenoxy)-4-chloro-6-methoxy-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.5h;
General procedure: Phenol (ca. 500 mg, 1.0 eq) in dichloromethane(5 mL) and N,N-diisopropylethylamine (1.0 eq) in dichloromethane(5 mL) were added dropwise to a solution of 2 (1.0 eq)in dichloromethane (10 mL). The mixture was stirred for30 min at room temperature, washed with aqueous hydrochloricacid and brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatographyor recrystallization.
4-chloro-6-(2-fluorophenoxy)-2-phenylpyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.48%
With potassium carbonate; In chloroform; at 90℃; for 4h;
(1) 5 g of <strong>[3740-92-9]fenclorin</strong>, 6.1 g of potassium carbonate and 2.46 g of o-fluorophenol were dissolved in 50 mL of chloroform, and the reaction was stirred at 90 C.After 4 h of reaction, it was monitored by thin layer chromatography (developing agent was petroleum ether and dichloromethane, V petroleum ether: V dichloromethane = 3:1).Stop the reaction when there is no remaining material, and cool to room temperature;(2) pouring the reaction liquid obtained in the step (1) into water,A large amount of white solid was precipitated, stirred for 4 h, and filtered with suction to give a white solid. The white solid was subjected to column chromatography.V petroleum ether: V dichloromethane = 9:1) gave 2.21 g of 4-chloro-6-(2-fluorophenoxy)-2-phenylpyrimidine (I5) in a yield of 33.48%.
4-(2-fluorophenoxy)-6-methoxy-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 80℃;
General procedure: <strong>[52854-14-5]4-chloro-6-methoxy-5-nitro-pyrimidine</strong> (Preparation R1a; 1.0 eq.), the appropriate phenol (1.2 eq.), and potassium carbonate (1.2 eq.) were dissolved in acetonitrile. It was stirred at 80 C till completion, then water was added to the reaction mixture. MeCN was evaporated. The residue extracted with DCM. The combined organic phase was dried over MgS04 and evaporated under reduced pressure to give R2a-R2ce.
2-bromo-4-(2-fluorophenoxy)-1-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;Inert atmosphere;
According to route (E), 2-fluorophenol (1.8 g, 16 mmoles, 1 eq.) was placed in AA-dimethylformamide (50 mL) with K2CO3 (4.5 g, 32 mmoles, 2 eq.). Upon addition of 2-bromo-4-fluoro-l -nitrobenzene (3.5 g, 16 mmoles, 1 eq.), the reaction mixture was heated at 70C and stirred for 16 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. Upon decantation, the organic phase was washed with a saturated aqueous solution of brine, dried over MgS04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 2-bromo-4-(2-fluorophenoxy)-l- nitrobenzene (3.8 g, 77%). (0437) ?H NMR (300 MHz, CDCb) d 7.95 (d, j = 9.1 Hz, 1H), 7.30 - 7.15 (m, 5H), 6.95 (dd, j = (0438) 9.1, 2.6 Hz, 1H).
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