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Structure of 6418-38-8 * 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.
With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;
Step 1Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2C>2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3~difluorophenol as a brown oil.
93%
With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;
Step 1into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). 3/4<3/4 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenoI as brown oil.
93%
With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;
Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.
93%
With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;
Step 1. Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL)was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.
93%
With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;
Step 1 Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.
93%
With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;
Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.
Reference：
[1] Journal of Materials Chemistry, 1999, vol. 9, # 8, p. 1669 - 1677
[2] Journal of Organic Chemistry, 2017, vol. 82, # 10, p. 5236 - 5241
[3] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15674 - 15685
[4] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13182 - 13187
[5] Patent: WO2012/158795, 2012, A1, . Location in patent: Page/Page column 87-88
[6] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 182-183
[7] Patent: WO2013/191965, 2013, A1, . Location in patent: Page/Page column 174
[8] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 66
[9] Patent: US8673925, 2014, B1, . Location in patent: Page/Page column 215
[10] Patent: US2014/142099, 2014, A1, . Location in patent: Paragraph 0206
[11] Journal of Materials Chemistry, 2007, vol. 17, # 8, p. 766 - 782
[12] Patent: US5853613, 1998, A,
[13] Patent: US5683623, 1997, A,
2
[ 124728-93-4 ]
[ 6418-38-8 ]
Yield
Reaction Conditions
Operation in experiment
10.6 g
With iron(III) chloride In ethanol at 30℃; for 3 h;
The intermediate product obtained in the step 1) and 20 mL of ethanol are added to the reactor, then 0.08 mol of ferric chloride is added, the temperature is raised to 30 ° C, and the reaction is carried out for 3 hours. After the reaction is completed, 0.1 mol/L of sodium hydroxide solution is added. And then, the organic phase and the aqueous phase are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extracts are combined, washed with saturated brine, and the solvent is evaporated to dryness to give 2,3-difluoro. The phenol was 10.6 g, the GC analysis product content was 99.4percent, and the total yield of the two-step reaction was 82.1percent.
Reference：
[1] Patent: CN108586204, 2018, A, . Location in patent: Paragraph 0015; 0041; 0043
3
[ 134364-69-5 ]
[ 6418-38-8 ]
Yield
Reaction Conditions
Operation in experiment
11.6 g
With aluminum (III) chloride In methanol at 30℃; for 5 h;
The intermediate product obtained in step 1) and 30 mL of methanol were added to the reactor, and then 0. lmol of aluminum trichloride was added, the temperature was raised to 30 ° C, and the reaction was carried out for 5 hours. After the reaction was completed, O.lmol/L of hydrogen was added. The sodium oxide solution is neutralized, and then the organic phase and the aqueous phase are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extracts are combined, washed with saturated brine, and evaporated to dryness. 3_difluorophenol 11.6g, GC analysis product content is 99.2percent, the total yield of the two-step reaction is 88.5percent
Reference：
[1] Patent: CN108586204, 2018, A, . Location in patent: Paragraph 0015; 0029; 0031; 0032; 0034; 0035; 0037
4
[ 367-11-3 ]
[ 6418-38-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 2041 - 2054
[2] Journal of Materials Chemistry, 2007, vol. 17, # 8, p. 766 - 782
[3] Journal of Materials Chemistry, 1999, vol. 9, # 8, p. 1669 - 1677
[4] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15674 - 15685
[5] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13182 - 13187
5
[ 1489-53-8 ]
[ 6418-38-8 ]
Reference：
[1] Patent: CN108586204, 2018, A,
[2] Patent: CN108586204, 2018, A,
6
[ 2646-91-5 ]
[ 6418-38-8 ]
[ 4519-39-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034
Reference：
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034
12
[ 6418-38-8 ]
[ 74-88-4 ]
[ 134364-69-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2082 - 2085
[2] Patent: WO2015/43511, 2015, A1, . Location in patent: Paragraph 00226
[3] Journal of Fluorine Chemistry, 2003, vol. 123, # 1, p. 101 - 108
[4] Patent: US6921767, 2005, B2,
[5] Patent: US2004/92538, 2004, A1, . Location in patent: Page 58
[6] Patent: CN105461762, 2016, A, . Location in patent: Paragraph 0528; 0530; 0531; 0532; 0533
13
[ 6418-38-8 ]
[ 189283-51-0 ]
Reference：
[1] Synthesis, 2004, # 10, p. 1609 - 1618
14
[ 6418-38-8 ]
[ 144292-32-0 ]
Reference：
[1] Patent: EP500210, 1992, A2,
[2] Canadian Journal of Chemistry, 2011, vol. 89, # 3, p. 364 - 384
15
[ 6418-38-8 ]
[ 123173-60-4 ]
Yield
Reaction Conditions
Operation in experiment
29%
With nitric acid In Dichlorofluoromethane; water at 0 - 20℃; for 0.5 h;
Intermediate 30: 4-fluoro-5-isopropoxyindolin-2-oneStep a: 2,3-difluoro-4-nitrophenol [0542] To a solution of 2,3-difluorophenol (52.0 g, 400.0 mmol) in DCM (500.0 mL) at 0°C was added 70percent HNO3 (28.0 mL, 400.0 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred at for 30 min. The precipitate was collected by filtration, washed with water and dried under vacuum to give 20 g of the title compound as a white solid (29percent> yield).
With potassium carbonate; In butanone;Heating / reflux;
, 3 -dif luorophenol (5Og, 0.384mol), 1-bromoheptane (75.6g, 0.422mol), K2CO3 (53.1g, 0.384mol) and butanone (400taunL) are heated together under reflux overnight. Upon completion, the inorganic salts are filtered off and the solvent is removed in vacuum after extraction with Et2O) . The heptyl ether product is purified by vacuum distillation (105-1150C / 0.5mm Hg). Yield 85g (97%)
With sodium hydroxide; In dimethyl sulfoxide;
(5) To 100 ml of DMSO containing 10 g of <strong>[6418-38-8]2,3-difluorophenol</strong> dissolved therein, were added 10 ml of aqueous solution containing 3.6 g of sodium hydroxide, and stirred to obtain a homogeneous solution. Then 13.1 g of n-heptyl bromide were added thereto and stirred for 3 days at the room temperature. The resulting solution was thrown into iced water and extracted with hexane. The hexane phase was washed with water and the hexane was removed to obtain 15.8 g of oily 1,2-difluoro-3-n-heptyloxybenzene.
To a suspension of 1 ,2-difluorobenzene (20.0 g, 175.4 mmol, 1.0 eq) in dry THF (250 mL), cooled to -78C, n-BuLi (80 mL, 1.1 eq, 1.6 M) was added dropwise, then the reaction mass stirred at -78C for 1 h. After 1 h, the reaction was quenched with trimethylborate (30.0 mL, 263.157 mmol, 1 .5 eq) then stirred for 16 h. TLC analysis indicated a polar spot. The reaction was then quenched with 30% hydrogen peroxide solution (80 mL) then stirred for 3 h. TLC analysis indicated a non-polar spot. The reaction mixture was extracted with diethyl ether (1 L) and washed with water (500 mL) The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to give the desired 2,3-difluorophenol (21 .8 g, 93.96%) as a liquid.
93.96%
To a suspension of compound 1 (20.0g,175.438mmol,1 .Oeq) in dry THF (250ml), cooled to-78C n-BuLi (80ml_,1 .1 eq, 1 6M) was added drop wise, then the reaction was stirred at -78C for 1 h . After 1 h, it was quenched with trimethylborate (30.0ml_,263.157 mmol,1 .5eq) then stirred for 16h. TLC analysis indicated of a polar spot. The reaction was quenched with hydrogen peroxide(30%) solution (80ml_) then stirred for 3h. TLC analysis indicated of a non-polar spot. The reaction mixture was diluted with diethyl ether (1 It) and washed with water (500mL). The separated organic layer was dried over with Na2So4 and concentrated under reduced pressure to give compound 2 (21.8g, 93.96%) as a liquid compound.
With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;
Step 1Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2C>2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3~difluorophenol as a brown oil.
93%
With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;
Step 1into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). ¾<¾ (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenoI as brown oil.
93%
With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;
Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
93%
With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;
Step 1. Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL)was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
93%
With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;
Step 1 Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
93%
With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;
Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
With dihydrogen peroxide;
2,3-Difluoro-phenol (3). 10% Hydrogen peroxide (135 ml, 0.396 mol) was added dropwise to a stirred refluxing solution of compound 2 (19.8 g, 0.126 mol) in ether. The stirred mixture was heated under reflux for 2.5 h and cooled. The ether layer was separated and the aqueous layer was washed with ether. The combined etheral layers were washed with sodium hydroxide (3*150 ml, 10%) and the separated aqueous layer extracted was acidified with hydrochloric acid (90 ml, 36%). The product was extracted into ether (twice), and the combined etheral extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo. This crude product was recrystallized from petroleum spirit (40-60 C.) to give an off white solid. Yield 9.84 g (60%); mp 29.5-31.5 C.; 1 H NMR (CDCl3) d 5.35(1H, s), 6.65-6.80 (2H, m), 6.95(1H, q); IR (KCl) vmax 3700-3000, 1630, 1540, 1515, 1490, 1480, 1350, 1310, 1250, 1190, 1020 cm-1; MS m/z 130 (M+), 110, 101.
With dihydrogen peroxide; In diethyl ether;
EXAMPLE 37 2,3-Difluorophenol Hydrogen peroxide (10%, 340 cm3, 1 mol) was added dropwise to a stirred solution of compound from Example 36 (47 g, 0.3 mol) in diethyl ether (350 cm3) heated under reflux. The stirred mixture was heated under reflux for a further 2.5 h then cooled. The ethereal layer was separated and the aqueous layer extracted with diethyl ether (2*200 cm3). The combined ethereal layers were washed with sodium hydroxide (10%, 4*100 cm3) and the separated aqueous layers acidified with 36% hydrochloric acid. The product was extracted into diethyl ether (3*100 cm3), and the combined ethereal extracts washed with water and dried (MgSO4). The solvent was removed in vacuo to give an off white solid. Yield=39 g (100%); m.p.=30-32 C.; 1 H NMR (CDCl3): delta5.15 (1H, d), 6.67-6.82 (2H, m), 6.90-7.00 (1H, m); IR: 3700-3000, 1630, 1535, 1513, 1492, 1482, 1360, 1310, 1255, 1182, 1025, 910, 736 cm-1; MS: 130 [M]+, 121.
With potassium carbonate; In N,N-dimethyl-formamide;
Step 1: 2,3-Difluoroanisole. 2,3-Difluorophenol (4.55 g) was dissolved in DMF (25 mL) and was treated with powdered K2CO3 (6.0 grams) and the mixture was stirred at an ambient temperature for 10 minutes under nitrogen atmosphere. The mixture was treated with iodomethane (9.0 grams), and was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and was extracted with ether. The ether extract was washed with water, dried (Na2SO4) and concentrated to afford 3.8 grams of title compound as amber oil. 1H-NMR(CDCl3): delta 6.97(m, 1H), 6.78(m, 2H), 3.90(s, 3H).
2,3-Difluorophenol (4.55 g) was dissolved in DMF (25 mL) and was treated with powdered K2CO3 (6.0 grams) and the mixture was stirred at an ambient temperature for 10 minutes under nitrogen atmosphere. The mixture was treated with iodomethane (9.0 grams), and was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and was extracted with ether. The ether extract was washed with water, dried (Na2SO4) and concentrated to afford 3.8 grams of title compound as amber oil. 1HNMR(CDCl3): delta 6.97(m, 1H), 6.78(m, 2H), 3.90(s, 3H).
With potassium carbonate; In acetone; at 20℃; for 16h;
Under room temperature, the iodomethane (1.24 ml, 19 . 98mmol), potassium carbonate (3.18g, 23 . 06mmol) are sequentially added to the 2,3-difluoro-phenol 14a (2.08g, 14 . 5mmol) acetone (50 ml) solution, stirring reaction at room temperature 16 hours. Filtering, the filtrate is added in 40 ml ethyl acetate diluted filtrate, and water (40 ml × 2) washing, the separated organic phase of drying by anhydrous sodium sulfate, filtered, concentrated filtrate under reduced pressure, to obtain title compound 14b of the crude product (2.09g, yellow oily matter), yield: 100%. The product can be directly used for the next step.
To a stirred solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (10.0 g, 76.9 mmol) in DMF (40 mL) were added TIPSCl (16.5 mL, 77.1 mmol) and imidazole (5.24 g, 77.0 mmol). After stirring for 18 h at room temperature, water was added and the resulting mixture was extracted with EtOAc. The organic layer was washed with water followed by brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (n-hexane : EtOAc = 99 : 1) to give the title compound (21.0 g, 73.3 mmol, 95%) as a colorless oil. 1H-NMR (400 MHz, CDCl3):? delta 1.12 (18H, d, J = 3.7 Hz), 1.27-1.32 (3H, m),6.72-6.75 (2H, m), 6.88-6.90 (1H, m).
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;
(2,3-Difluorophenoxy) triisopropylsilane 2,3-Difluorophenol (10.0 g) was dissolved in DMF (40 mL), and triisopropylsilyl chloride (16.5 mL) and imidazole (5.24 g) were added thereto, followed by stirring at room temperature for 18 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the extracted layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane:ethyl acetate=99:1) to obtain the desired product (21.0 g) as a colorless oil. 1H NMR (CDCl3, 400 MHz): delta 1.12 (18H, d, J=3.7 Hz), 1.27-1.32 (3H, m), 6.72-6.75 (2H, m), 6.88-6.90 (1H, m).
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;
(2,3 -Difluorophenoxy)triisopropylsilane 2,3-Difluorophenol (10.0 g) was dissolved in DMF (40 mL), and triisopropylsilyl chloride (16.5 mL) and imidazole (5.24 g) were added thereto, followed by stirring at room temperature for 18 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the extracted layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane:ethyl acetate=99:1) to obtain the desired product (21.0 g) as a colorless oil. 1H-NMR (CDCl3, 400 MHz): delta 1.12 (18H, d, J=3.7 Hz), 1.27-1.32 (3H, m), 6.72-6.75 (2H, m), 6.88-6.90 (1H, m).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;
To a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (300.0 g, 2.3 mol, 1.0 eq) in DCM (1.5 L) was added MOM-C1 (278.9 g, 3.5 mol, 1.5 eq) and DIEA (597.1 g, 4.6 mol, 2.0 eq). The mixture was stirred at 0C for 2 hours. TLC indicated that STM was consumed. The reaction mixture was quenched by addition of H20 (1500 mL) at 0C, and then was adjusted to pH = 6. The combined organic layers were washed with saturation NH4CI (500 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. l,2-difluoro-3-(methoxymethoxy)benzene (400.0 g, 2.3 mol, 99.4% yield) was obtained as yellow oil which was used into the next step without further purification. NMR (CDC13, 400MHz) delta 7.03-6.93 (m, 1H), 6.89- 6.78 (m, 1H), 5.28-5.20 (m, 2H), 3.58-3.50 (m, 3H)
70.83%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (18.0 g, 138.46 mmol, 1.0 eq) in DCM (250 mL), N,N-diisopropylamine (36.27 mL, 207.7 mmol, 1.5 eq) and MOM-CI (15.7 mL, 207.691 mmol, 1.5 eq) were added at 0C and the reaction mixture was allowed to warm to RT and stirred for 16 h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was concentrated under reduced pressure to give crude residue which was dissolved in diethyl ether (500 mL) and washed with brine (2x200 mL) & water (2x100 mL). The separated organic layer was dried over with Na2S04 and concentrated under reduced pressure to afford crude product; which was purified by column chromatography (silica gel, 100-200 mesh) using 2% diethyl ether in petroleum ether as an eluent to afford 1 ,2-difluoro-3-(methoxymethoxy)benzene (17 g, 70.83%) as a liquid.
70.83%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of compound 2 (18. Og, 138.46 mmol, 1.0eq) in DCM (250ml), N,N-diisopropylamine (36.27 mL, 207.691 mmol, 1.5eq) and MOM-CI (15.7 mL, 207.691 mmol,1 .5eq) were added at 0C and the reaction mixture was allowed to warm up to RT and stirred for 16h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was dissolved in diethyl ether (500mL) and washed with brine (2 x 200mL) & water (2x 100mL). The separated organic layer was dried over with Na2S04 and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel100-200mesh) using 2% diethyl ether in petroleum ether as an eluent to give compound 3 (17 g, 70.83%) as a liquid compound.
With dmap; triethylamine; In dichloromethane; at -15 - 0℃;Inert atmosphere;
First,2,3- difluoro phenol (1) of 76g is introduced to the dichloromethane of 400mlunder N 2 atmosphere while it is stirred in the room temperature (RT) andsubsequently after the triethylamine of 99ml and 4- dimethylaminopyridine of3.5g are added the reaction mixture is cooled in the dry ice / alcohol in bathto -15. The solution of the dimethyl -t- butylchlorosilane of 100g among the dichloromethane of 100ml is dipped with thespeed in which the temperature does not rise over 0 (suspension is formed). Subsequently, after thecold bath tub is removed the continuously is stirred in all night long. Theprecipitated ammonium chloride is and filters absorbed and the water of 500mlis added in the generated reaction mixture and after this is moved to theseparator funnel and the aqueous phase is removed the generated mixture isextracted in the methyl -t- butyl (MTB) with two times. After it washes to twotimes and sodium chloride solution and the organic phase summed is dried towater on the sodium sulfate and it filters it evaporates and the yellow liquid(2) of 147.1g is obtained.
With N-Bromosuccinimide; isopropylamine; In dichloromethane; at -10℃; for 0.5h;
Intermediate 21-difluoro-phenol (1-21)To a solution of 2,3-difluorophenol [C.A.S. 6418-38-8] (0.5 g, 3.84 mmol) and isopropylamine (0.40 ml, 3.84 mmol) in dry DCM (20 mL) was added BS (3.01 g, 16.19 mmol) portionwise at -10C. The resulting r.m. was stirred at that temperature for 30 min and then allowed to get to r.t. The resulting mixture was diluted with HC1 (IN in H20) and the organic layer was separated, dried (Na2S04), and the solvent evaporated in vacuo. The crude compound was purified by chromatography (silica gel, EtOAc in heptane 0: 100 to 20:80). The desired fractions were collected the solvent evaporated in vacuo to yield intermediate 1-21 (0.63 g, 78%).
78%
With N-Bromosuccinimide; isopropylamine; In dichloromethane; at -10 - 20℃; for 0.5h;
6-Bromo-2,3-difluoro-phenol (I-21) To a solution of 2,3-difluorophenol [C.A.S. 6418-38-8] (0.5 g, 3.84 mmol) and isopropylamine (0.40 ml, 3.84 mmol) in dry DCM (20 mL) was added NBS (3.01 g, 16.19 mmol) portionwise at -10 C. The resulting r.m. was stirred at that temperature for 30 min and then allowed to get to r.t. The resulting mixture was diluted with HCl (1N in H2O) and the organic layer was separated, dried (Na2SO4), and the solvent evaporated in vacuo. The crude compound was purified by chromatography (silica gel, EtOAc in heptane 0:100 to 20:80). The desired fractions were collected the solvent evaporated in vacuo to yield intermediate I-21 (0.63 g, 78%).
72%
With bromine; tert-butylamine; In toluene; at -78 - 20℃;
The tether Boc-T85 was constructed starting from 2,3-difluorophenol (85-1, 20 g, 154 mmol) in 21% overall yield for 5 steps.TLC: Rf: 0.13 (25/75 AcOEt/Hex), detection: UV, ninhydrin1H NMR (CDCl3): delta 6.84 (m, 2H), 4.19 (m, 2H), 3.97 (m, 2H), 3.08 (m, 2H), 2.95 (m, 2H), 2.16 (s, 1H), 1.74 (m, 2H), 1.44 (m, 9H)LC-MS (Grad A4) tR: 6.31 min
18%
With bromine; In chloroform; acetic acid; at 10℃; for 1h;
Bromine (4.33 mL, 84.56 mmol) was added dropwise to a vigorously stirred cold (10 C) solution of commercially available 2,3- difluorophenol (10.00 g, 76.90 mmol) in glacial acetic acid (16 mL) and chloroform (4.0 mL) solvent mixture. After 1 hr the reaction mixture was poured into water (60 mL) and dichloromethane (30 mL) mixture. The aqueous layer was extracted with dichloromethane (3x50 mL) and combined organic layers were washed with sat. NaHCO3 and brine sequentially. Upon drying over Na2S04, it was concentrated to a thick syrup. The crude residue was purified by flash column chromatography (10% ethyl acetate/hexanes) to yield the desired product (2.89 g) in 18% yield.'H-NMR (400 MHz, CDCl3) 07. 38-7. 33 (m, 1H), 6.80-6. 30 (m, 1H), 5.94 (brs, 1H).
2.6 g
With N-Bromosuccinimide; isopropylamine; In dichloromethane; at -10℃; for 0.5h;
To a solution of 2,3-difluorophenol (1.0 g, 7.69 mmol) and isopropyl amine (0.45 g, 7.69 mmol) in dry DCM (20 mL) was added NBS (5.48 g, 30.76 mmol) portion-wise at -10 C . Afterbeing stirred at -10 C for 30 minutes, the resulting mixture was allowed to warm naturally to rt,then diluted with 1 0 N HC1 (40 mL) and extracted with DCM (30 rnL) for three times. Thecombined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give 6-bromo-2,3-difluoro-phenol (2.6 g), which was used in the next step without purification.
With caesium carbonate; In N,N-dimethyl-formamide;
2-[4-(2,3-Difluorophenoxy)butoxy]-tetrahydropyran (20) To a solution of 2-(4-bromobutoxy)-tetrahydropyran (18) (1 equi.) and commercially available 2,3-difluorophenol (19) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile gave 2-[4-(2,3-difluorophenoxy)-butoxy]-tetrahydropyran(20), as a white solid (84%).
With caesium carbonate; In N,N-dimethyl-formamide;
2-[4-(2,3-Difluorophenoxy)-butoxy]-tetrahydropyran (20) To a solution of 2-(4-bromobutoxy)-tetrahydropyran (18) (1 equi.) and commercially available 2,3-difluorophenol (19) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile gave 2-[4-(2,3-difluorophenoxy)-butoxy]-tetrahydropyran(20), as a white solid (84%).
With potassium iodide; potassium carbonate In water
1.s (First step)
(First step) First, 100 g (0.77 mol) of 2,3-difluorophenol, 100 g (0.92 mol) of ethyl bromide, 127 g (0.92 mol) of potassium carbonate, 1.0 g (6.0 inmol) of potassium iodide, and 1.3 l of dimethyl-formamide (DMF) were mixed and heated to reflux for 7 hours. After finishing of the reaction, 1.0 Q of water was added to the reaction solution and then extracted with 2.0 Q of toluene. The organic layer thus obtained was washed with water once and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was distilled under a reduced pressure to obtain 87.5 g of 2,3-difluoroethoxybenzene (yield 71.4%).
2,3-difluoro-4-hydroxyphenylpotassium sulphate[ No CAS ]
[ 6418-38-8 ]
[ 100-44-7 ]
[ 271254-90-1 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium bicarbonate In sodium hydroxide; aqueous-alcoholic sodium hydroxide; ethanol
4 EXAMPLE 4
EXAMPLE 4 1 mol of 2,3-difluorophenol is dissolved in 2 l of 10% sodium hydroxide solution, and a saturated aqueous solution of potassium peroxodisulphate is added dropwise at 20° over the course of 3-4 hours. After the solution has been left to stand overnight, it is slightly acidified (pH 3-4), and unreacted starting material is extracted with ether. The aqueous phase is neutralized using sodium hydrogen carbonate and evaporated to dryness in vacuo. 2,3-difluoro-4-hydroxyphenylpotassium sulphate is dissolved out of the residue using 90% ethanol, and the alcohol is evaporated. 14 g of benzyl chloride are added dropwise with stirring and refluxing to 25 g of the crude product (~0.1 mol) in aqueous-alcoholic sodium hydroxide solution (7 g of NaOH in 100 ml of 50% alcohol). The reaction is left to continue for 2 hours, and the mixture is slightly acidified using hydrochloric acid and heated for a further 2 hours. After cooling, 4-benzyloxy-2,3-difluorophenol is extracted and distilled after the solvent has been stripped off.
1.S First Step
First Step : Synthesis of 1,2-Difluoro-3-n-Propyloxybenzene (2) A mixture of 2,3-difluorophenol (1) (130.1g, 1.00 mole), propyl iodide (255.0g, 1.50 mole), sodium carbonate (212.0g, 2.00 mole) and ethanol (1200 ml) was reacted under reflux for 6 hours, in a nitrogen gas atmosphere. After the completion of the reaction, the reaction solution was cooled to room temperature and then poured into a 1N dilute hydrochloric acid solution (1500 ml) with cooling. The insoluble matter formed was removed by filtration. The resulting filtrate was extracted with toluene (2000 ml), followed by washing the resulting oprganic phase with water (1000 ml) and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane) to give the title compound, 1,2-difluoro-3-n-propyloxybenzene (2)(158.4g, 0.921 mole; yield 92%). MS/172 (M +).
With sodium hydroxide; sodium hypochlorite; sodium iodide; sodium thiosulfate; In methanol;
(1) To a solution of 10.0 g of 2,3-difluorophenol, 11.5 g of sodium iodide and 3.1 g of sodium hydroxide dissolved in 200 ml of methanol, was added dropwise 135 ml of 4% aqueous solution of sodium hypochlorite, followed by continuing stirring for 2 hours in that condition. After reaction, 80 ml of 10% aqueous solution of sodium thiosulfate were added to the product, fo|lowed by adding 4N-hydrochloric acid thereto to weakly acidifying it. Separated oil was extracted with chloroform, the organic layer was washed with water, and then the solvent was removed. The resulting oil was recrystallized with hexane to obtain 8.7 g of white solid of 2,3-difluoro-4-iodophenol.
1) To 45.00 g of 2,3-difluorophenol dissolved in 250 ml of chloroform, 55.40 g of bromine dissolved in chloroform were added dropwise under cooling with ice bath, and stirred for a while at room temperature, followed by washing with water and then distilling off chloroform. Thereafter, the product was recrystallized with hexane to obtain 14.30 g of 2,3-difluoro-4-bromophenol.
With sodium hydroxide; sodium hypochlorite; sodium iodide; sodium thiosulfate; In methanol;
1) Into 100 ml of methanol, were dissolved 5.00 g of 2,3-difluorophenol; and 5.78 g of sodium iodide and 1.54 g of sodium hydroxide were added and cooled to a temperature below 5C, followed by adding thereto dropwise 90 ml of 5% aqueous solution of sodium hypochlorite at a temperature of 3-5C and then continuing stirring for additional 1 hour. Thereafter, 40 ml of 10% aqueous solution of sodium thiosulfate were added thereto, and the product was neutralized with hydrochloric acid and extracted with ether. The ether-containing layer was washed with water, and then recrystallized twice with hexane to obtain 6.40 g of 2,3-difluoro-4-iodophenol.
With potassium carbonate; In acetone; for 24h;Inert atmosphere; Reflux;
Dissolve <strong>[6418-38-8]2,3-difluorophenol</strong> (1g, 7.68mmol) in acetone (30mL), add anhydrous potassium carbonate (3.3g, 23.06mmol) and 3-bromopropyne (1mL, 11.53mmol, 1.38g / mL) ).Nitrogen was replaced three times. Under nitrogen protection, the reaction was heated at reflux for 24 hours.After the reaction was completed, it was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 100/1) to obtain 1 g of light yellow oily liquid, yield: 77.3%
With potassium carbonate; In toluene; butanone; for 3h;Heating / reflux;
1.1. Preparation of 1,2-difluoro-3-prop-2-ynyloxybenzene; 115.0 g (0.88 mol) of <strong>[6418-38-8]2,3-difluorophenol</strong> are refluxed for 3 h together with 118.2 ml (17.7 mol) of propargyl bromide (80% soln. in toluene) and 146.6 g (138.2 mol) of potassium carbonate in 1.6 l of ethyl methyl ketone. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).
With potassium carbonate; In toluene; butanone; for 3h;Reflux;
1.1 Preparation of 1,2-difluoro-3-prop-2-ynyloxybenzene; 115.0 g (0.88 mol) of <strong>[6418-38-8]2,3-difluorophenol</strong> are refluxed for 3 h in 1.6 l of ethyl methyl ketone together with 118.2 ml (17.7 mol) of propargyl bromide (80% soln. in toluene) and 146.6 g (138.2 mol) of potassium carbonate. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is evaporated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 19h;
3.1
3.1. Preparation of 1-(1-ethynylhexyloxy)-2,3-difluorobenzene 42.4 g (0.33 mol) of 2,3-difluorophenol are initially introduced in 1.2 l of THF together with 50.0 ml (0.34 mol) of 1-octyn-3-ol and 94.1 g (0.36 mol) of triphenylphosphine, and a solution of 76.1 ml (0.39 mol) of DIAD in 100 ml of THF is added dropwise. After 19 h at 20° C., the mixture is diluted with MTBE, and the batch is washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane), giving 1-(1-ethynylhexyloxy)-2,3-difluorobenzene as a colourless oil.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 19h;
2.1
2.1 Preparation of 1-(1-ethynylhexyloxy)-2,3-difluorobenzene; 2.4 g (0.33 mol) of 2,3-difluorophenol are initially introduced in 1.2 l of THF together with 50.0 ml (0.34 mol) of 1-octyn-3-ol and 94.1 g (0.36 mol) of triphenylphosphine, and a solution of 76.1 ml (0.39 mol) of DIAD in 100 ml of THF is added dropwise. After 19 h at RT, the batch is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane), giving 1-(1-ethynylhexyloxy)-2,3-difluorobenzene as a colourless oil.
3,4-DIFLUORO-2-HYDROXYBENZALDEHYDETo a solution of magnesium methoxide (6-10% in MeOH, 40 ml, 31.1 mmol) was added 2,3-difluorophenol (6.7 g, 51.8 mmol). The mixture was heated at reflux for 40 min and MeOH (20 ml) was distilled from the solution. Toluene (50 ml + 50 ml) was added and another 35 ml was distilled from the reaction mixture. Paraformaldehyde (5.6 g, 186 mmol) was added during 15 min. The resulting mixture was heated at 115C for 32 min and then cooled to ambient temperature. HCI (10% in H2O) was added and the solution stirred in room temperature over night. The phases were separated, the water phase was extracted with EtOAc and the combined organic phase was washed with brine, dried (MgSO4) and evaporated to dryness to give the title compound (5.7 g). MS m/z (rel. intensity, 70 eV) 158 (M+, 87), 157 (M+, bp), 112 (28), 101 (57), 75 (25).
With triethylamine; magnesium chloride; In acetonitrile; at 60℃; for 16h;Inert atmosphere;
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a 2,3-difluorophenol (10.0 g, 75.33 mmol), ACN (200 mL), HCHO (23.06 g, 738 mmol), Et3N (21.0 mL, 146 mmol), and MgC12 (14.6 g, 150.28 mmol). The resulting solution was stirred for 16 h at 60 C. The reaction mixture was cooled to 26 C, then was diluted with 200 mL of water. The resulting solution was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by silica gel chromatography with ethyl acetate/pet. ether (1:4) to afford 3,4-difluoro-2-hydroxybenzaldehyde as light yellow oil.
With pyridine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (30.0 g, 231 mmol) and pyridine (18.6 mL, 231 mmol) in dichloromethane (230 mL) at 0 C was carefully added acetyl chloride (16.4 mL, 231 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was then diluted with dichloromethane (100 mL), washed with IN aqueous hydrochloric acid (2 x 50 mL) and brine (75 mL), and concentrated to produce 41.0 g ( 100%) of the title compound. MS (DCI/ NH3) m/z 190 (M+NH4)+.
100%
With pyridine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (30.0 g, 231 mmol) and pyridine (18.6 mL, 231 mmol) in dichloromethane (230 mL) at 0 C was carefully added acetyl chloride (16.4 mL, 231 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was then diluted with dichloromethane (100 mL), washed with IN aqueous hydrochloric acid (2 x 50 mL) and brine (75 mL), and concentrated to produce 41.0 g ( 100%) of the title compound. MS (DCI/ NH3) m/z 190 (M+NH4)+.
100%
With pyridine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (30.0 g, 231 mmol) and pyridine (18.6 mL, 231 mmol) in dichloromethane (230 mL) at 0 C. was carefully added acetyl chloride (16.4 mL, 231 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was then diluted with dichloromethane (100 mL), washed with 1N aqueous hydrochloric acid (2*50 mL) and brine (75 mL), and concentrated to produce 41.0 g (100%) of the title compound. MS (DCI/NH3) m/z 190 (M+NH4)+.
trans-4-chloromethyl-1-pentylcyclohexane[ No CAS ]
[ 6418-38-8 ]
2,3-difluoro-4-(trans-4-pentylcyclohexylmethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.1%
With potassium phosphate; In N,N-dimethyl-formamide; at 70℃; for 7h;Inert atmosphere;
First Step: 2,3-Difluorophenol (57) (9.6 g) and tripotassium phosphate (K3PO4; 52.3 g) were added to DMF (200 ml) under a nitrogen atmosphere, and the mixture was stirred at 70 C. trans-4-Chloromethylpentylcyclohexane (52) (10.0 g) was added thereto and the mixture was stirred at 70 C for 7 hours. The reaction mixture obtained was cooled to 30 C, and then solid materials were filtered out. Toluene (200 ml) and water (200 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into organic and aqueous phases, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from Solmix A-11, and dried, giving 13.9 g of 2,3-difluoro-4-(trans-4-pentylcyclohexylmethoxy) benzene (58). The yield based on the compound (52) was 95.1%.
2,3-Difluorophenol (21) (100.0 g) and sodium hydroxide (NaOH; 36.9 g) were added to water (300 ml) under a nitrogen atmosphere, and the stirring was continued at 70 C. 1-Bromobutane (158.0 g) was added thereto, and the stirring was continued at 70 C for 2 hours. The reaction mixture obtained was cooled to 30 C, heptane (100 ml) and water (100 ml) were added, and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, fractional distillation was carried out under reduced pressure, giving 114.4 g of 4-butoxy-2,3-difluorobenzene (22). The compound (22) obtained was a colorless oil having a boiling point of 109 C to 110 C/20 mmHg. The yield based on the compound (21) was 80.0%.
4-chloromethyl-(4-ethoxy-2,3-difluorophenyl)-cyclohexane[ No CAS ]
2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluorophenoxymethyl)cyclohexyl]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.8%
With potassium phosphate; In N,N-dimethyl-formamide; at 70℃; for 7h;Inert atmosphere;
Example 9 ; Synthesis of 2-(4-(trans-4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl)methoxy)-2,3-difluorophenyl)-5-pentyl-1,3-dioxane (No. 940) [Show Image] First Step: 2,3-Difluorophenol (46) (13.8 g) and tripotassium phosphate (K3PO4; 73.4 g) were added to DMF (200 ml) under a nitrogen atmosphere, and the mixture was stirred at 70 C. The compound (15) (20.0 g) was added thereto and the stirring was continued at 70 C for 7 hours. After the reaction mixture obtained had been cooled to 30 C, solids were separated by filtration, and then toluene (100 ml) and water (100 ml) were added to and mixed with the filtrate. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and ethyl acetate (Solmix A-11: ethyl acetate= 2:1 by volume) and dried, giving 19.8 g of 2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluorophenoxymethyl)cyclohexyl]benzene (47). The yield based on the compound (15) was 74.8%.
With sodium hydroxide;tetrabutylammomium bromide; In water; at 80℃; for 6h;Inert atmosphere;
Preparation of 1-ethoxy-2,3-difluorobenzene (T-2) Sodium hydroxide (75.9 g) was added to a water (400 ml) solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (T-1) (195.0 g), bromoethane (196.2 g) and tetrabutylammonium bromide (TBAB) (24.2 g), and the mixture was heated with stirring at 80 C for 6 hours under an atmosphere of nitrogen. After the completion of the reaction, the reaction mixture was extracted with heptane, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a black oil. The oil was purified by distillation to give 1-ethoxy-2,3-difluorobenzene (T-1) as a colorless oil (230.0 g) in 97% yield.
91.7%
With tetramethlyammonium chloride; sodium hydroxide; In water; N,N-dimethyl-formamide; toluene; at 30℃;Reflux; Industrial scale;
1000L reactor was charged with sodium hydroxide 40kg, 500kg toluene, 2,3-difluoro-phenol 100kg, Bi administered warmed to reflux trap by trap until no expulsion of water up to give 2,3-difluoro sodium phenoxide. Then cooling to 5kg tetramethylammonium chloride was added after 30 , DMF5kg, plus complete solution of bromoethane 90kg, dropping Albert warmed to reflux incubation reaction to the raw material disappears. After passing cooling to 30 , filtered and the filtrate washed twice 100kg of water was added, layers were separated and the organic layer is a toluene solution of 2,3-difluorophenyl ether. Recovered by distillation of toluene, and then the tower distillation, the product 2,3-difluorophenyl ether 110kg, GC content of> 99.9% and a yield of 91.7%.
Step 2Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 nimo., 1.70 equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of l-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N, N-dimetliylformamide (50 mL) was added dropwise with stirring at 0 C in 15 min. The resulting solution was stirred for 2 h at roomtemperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of 2,3- dif.uorophenol ( 15.6 g, 1 19.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethylacetate/petroleum ether (1 :8) to give 21.2 g (84%) of 1 ,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
84%
Step 2Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethyIformamide (200 mL). A solution of l-fluoro-4-nitiObenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N, N-dimethylforniamide (50 mL) was added dropwise with stirring at 0 C in 15 min. The resulting solution was stirred for 2 h at roomtemperature. CuCI (10 g, 101.01 mmol, 1 .00 equiv) was added and a solution of 2,3- difluorophenol (15.6 g, 1 9.91 mmol, 1.20 equiv) in N,N-diniethylforraamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethylacetate/petroleum ether (1 :8) to give 21.2 g (84%) of l ,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
84%
Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethylformainide (200 mL). A solution of I -fiuoro-4-nitrobenzene (14.1 g, 99,93 mmol, 1.00 equiv) in N, N-dimethylformarnide (50 mL) was added dropwise with stirring at 0 C in 15 mm. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101 .01 mmol, 1.00 equiv) was added and a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethyiformamide (50 niL) was added dropwise with stirring. The resulting solution was allowed to react, with stiting, for an additional 12 h while the temperature was maintained at 100 C in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
84%
Step 2. Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0 C in 15 min. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
84%
Step 2 Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0 C. in 15 min. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C. in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
84%
Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0 C. in 15 min. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C. in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
With nitric acid; In Dichlorofluoromethane; water; at 0 - 20℃; for 0.5h;
Intermediate 30: 4-fluoro-5-isopropoxyindolin-2-oneStep a: 2,3-difluoro-4-nitrophenol [0542] To a solution of 2,3-difluorophenol (52.0 g, 400.0 mmol) in DCM (500.0 mL) at 0C was added 70% HNO3 (28.0 mL, 400.0 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred at for 30 min. The precipitate was collected by filtration, washed with water and dried under vacuum to give 20 g of the title compound as a white solid (29%> yield).
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Inert atmosphere;
General procedure: All reactions were carried out in vials under nitrogen atmosphere. Step 1: A solution of compound 8 (100 mumol, 1.0 equiv) and compound 9 (150 mumol, 1.5 equiv) in DMF (0.1 M) was treated with K2CO3 (300 mumol, 3.0 equiv) and stirred at 110 C for 16 h (LCMS check). The reaction was filtered and the filtrate concentrated to afford 10. The crude aldehyde 10 (100 mumol, 1.0 equiv) was dissolved in acetone:water (2:1, 0.1 M) and treated with KMnO4 (600 mumol, 6 equiv) and stirred at 30 C for 16 h (LCMS check). The reaction was filtered and the filtrate concentrated to afford 11. The crude acid 11 (100 mumol, 1.0 equiv) was treated with HATU (120 mumol, 1.20 equiv) followed by the crude amine (100 mumol, 1.0 equiv) and NEt3 (300 mumol, 3.0 equiv). The reaction was stirred at 30 C for 16 h (LCMS check). The reactions were concentrated and purified directly by reversed phase preparative HPLC using a C18 column and eluting with acetonitrile-water (0.225% formic acid or pH = 10 NH4OH) gradient. All compounds were deemed greater than 95% purity by LCMS and HPLC.
General procedure: To a solution of substituted phenol (26 mmol) in absolute ethanol (50 mL) was added sodium hydroxide (26 mmol) at room temperature. The mixture was heated to reflux for 3-5 h. After the removal of the solvent, the residue was dissolved in dimethylsulfoxide (50 mL), to the resulting mixture was added 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (5) (20 mmol) in portions. Then the solution was heated to 105 C and maintained at that temperature for 4-15 h and cooled to room temperature. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 50 mL). The organic layer was washed with water (3 25 mL) and dried over anhydrous Na2SO4, filtered and evaporated to produce the corresponding carbaldehydes 6d-6w, with yields ranging from 60% to 81% [11].
General procedure: A mixture of sodium hydroxide (13 mmol), substituted phenol (13 mmol), and ethanol (40 mL) was refluxed for 2-5 h. After the solvent was removed under reduced pressure, the residue was dissolved in DMSO (40 mL), to the above solution was added 1,3-dimethyl-5-chloro-1H-pyrazole-4-carbaldehyde (5) (10 mmol) in portions. The mixture was heated to 105 C for 8-18 h, and it was poured into water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The ethyl acetate layer was washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give a crude of intermediates 7a-7t. Compound 6 or 5 (20 mmol) was added into a solution of potassium hydroxide (40 mmol), hydroxylamine hydrochloride (30 mmol) in methanol or ethanol (80 mL) at the room temperature. Then the reaction mixture was heated to reflux for 6-17 h and poured into water (100 mL). After filtration, the precipitate was washed by water then dried to form 1,3-dimethyl-5-substituted pyrazole oxime 7 or 9, which was used in the next procedure without further purification.
With potassium carbonate; In acetone; at 70℃; for 5h;
Step 1 1-ethoxy-2,3-difluoro-benzene <strong>[6418-38-8]2,3-difluorophenol</strong> 3a (4 g, 30.7 mmol) was dissolved in 60 mL acetone, followed by addition of potassium carbonate (6.36 g, 46.1 mmol) and ethyl iodide (3.19 mL, 39.9 mmol). The reaction mixture was stirred for 5 hours at 70 C. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 100 mL ethyl acetate, and washed with water (100 mL) and saturated sodium chloride solution (100 mL), and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-ethoxy-2,3-difluoro-benzene 3b (4.82 g, yellow grease), yield: 99.4%. 1H NMR (400 MHz, CDCl3): delta 6.95-6.89 (m, 1H), 6.78-6.71 (m, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
2-methyl-1-nitro-4-(2,3-difluoro-phenoxy)-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.5h;Microwave irradiation; Sealed tube;
Step 1: 4-(2,3-Difluoro-phenoxy)-2-methyl-1-nitro-benzene A mixture of 4-chloro-2-methyl-1-nitro-benzene (5 g, 29.1 mmol), <strong>[6418-38-8]2,3-difluorophenol</strong> (4.55 g,35.0 mmol) and Cs2CO3 (14.2 g, 43.7 mmol) in DMF (10 mL) was heated in a sealed tube in a microwave oven at 150 C for 30 mi EtOAc (300 mL) was added and the mixture was washed with water (150 mL) and brine. The organic layer was dried (Na2504), filtered, and evaporated. The crude material was purified by flash chromatography (silica gel, 10% ethyl acetate inhexanes) to give 4-(2,3-difluoro-phenoxy)-2-methyl-1-nitro-benzene (5.6 g, 72%) as a light yellow oil.
5-(2,3-difluoro-phenoxy)-2-nitro-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;
A mixture of <strong>[50594-78-0]2-cyano-4-fluoro-1-nitro-benzene</strong> (6.42 g, 38.4 mmol), 2,3-difluorophenol (5 g,38.4 mmol) and Cs2CO3 (18.8 g, 57.7 mmol) in DMF (50 mL) was heated at 120 C for 3 h.EtOAc was added and the mixture was washed with water and brine. The organic layer was dried, filtered, and evaporated. The residue was purified by chromatography (silica gel, 0-20% EtOAc/hexanes) to give 5-(2,3-difluoro-phenoxy)-2-nitro-benzonitrile (6.0 g, 56%) as a yellow solid. ?H NMR (400 MHz, DMSO-d6) oe ppm 8.40 (d, J=9.0 Hz, 1 H), 7.97 (d, J=3.0 Hz, 1 H),7.51 - 7.56 (m, 1 H), 7.47 (dddd, J=10.2, 8.6, 7.2, 1.6 Hz, 1 H), 7.35 (tdd, J=8.4, 8.4, 6.1, 2.0 Hz,1 H), 7.22 - 7.30 (m, 1 H).
2-bromo-4-(2,3-difluoro-phenoxy)-1-nitro-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;
A mixture of <strong>[700-36-7]2-bromo-4-fluoro-1-nitro-benzene</strong> (4.42 g, 20 mmol), 2,3-difluorophenol (1.91 g,14.7 mmol) and Cs2CO3 (7.18 g, 22 mmol) in DMF (30 mL) was heated at 120 C for 3 h. EtOAc was added and the mixture was washed with water and brine. The organic layer was dried, filtered, and evaporated. The residue was purified by chromatography (silica gel, 0-10% EtOAc/hexanes) to give 2-bromo-4-(2,3-difluoro-phenoxy)-1-nitro-benzene (4.1 g, 70%) as alight yellow solid.
5-(2,3-difluoro-phenoxy)-1,3-dimethyl-2-nitro-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;
A mixture of 2,6-dimethyl-4-fluoro-1-nitro-benzene (2.49 g, 14.7 mmol), <strong>[6418-38-8]2,3-difluorophenol</strong> (1.91 g, 14.7 mmol) and Cs2CO3 (7.18 g, 22 mmol) in DMF (30 mL) was heated at 120 C for 3h. EtOAc was added and the mixture was washed with water and brine. The organic layer was dried, filtered, and evaporated. The residue was purified by chromatography (silica gel, 0-10% EtOAc/hexanes) to give 5- (2,3-difluoro-phenoxy)- 1 ,3-dimethyl-2-nitro-benzene (2.90 g, 79%) as a light yellow solid. MS calcd. for C14H12F2N03 [(M+H)?i 280, obsd. 279.8.
6-(2,3-difluoro-phenoxy)-2-methoxy-3-nitro-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;
A mixture of <strong>[40851-91-0]6-chloro-2-methoxy-3-nitropyridine</strong> (available from Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, SC 29172, USA; 3 g, 15.8 mmol), 2,3-difluorophenol (2.06 g,15.8 mmol) and Cs2CO3 (7.73 g, 23.7 mmol) in DMF (30 mL) was heated at 120 C for 3 h.EtOAc was added and the mixture was washed with water and brine. The organic layer was dried(Na2504), filtered, and evaporated. The residue was purified by chromatography (silica gel, 0-20% EtOAc/hexanes) to give 6-(2,3-difluoro-phenoxy)-2-methoxy-3 -nitro-pyridine (2.26 g, 50%)as a light yellow solid. MS calcd. for C12H9F2N204 [(M+H)41 283, obsd. 283.
4-(2,3-difluoro-phenoxy)-2-methoxy-1-nitro-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;
A mixture of 4-fluoro-2-methoxy-1-nitro-benzene (3 g, 17.4 mmol), <strong>[6418-38-8]2,3-difluorophenol</strong> (2.27 g,17.4 mmol) and Cs2CO3 (6.81 g, 20.9 mmol) in DMF was heated at 120 C for 3 h. The mixturewas cooled. EtOAc was added and the mixture was washed with water and brine. The organiclayer was dried (Na2504), filtered, and evaporated to give 4-(2,3-difluoro-phenoxy)-2-methoxy-1-nitro-benzene (4.80 g, 98%) as a yellow solid.
With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;
Under a nitrogen atmosphere, compound (T-32) (20.0 g), compound (T-33) (12.2 g), potassium carbonate (21.5 g), TBAB (5.02 g) and DMF (200 mL) were put in a reaction vessel, and the resulting mixture was stirred at 90C for 12 hours. The resulting reaction mixture was poured into water, and the resulting aqueous layer was subjected to extraction with ethyl acetate. Then, organic layers combined were washed with brine, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (heptane). Then, the resulting product was further purified by recrystallization from a mixed solvent of heptane and Solmix (registered trade name) A-11 (1 : 1 in a volume ratio) to give compound (T-34) (22.6 g; 83%).
4-(2-(2,3-difluorophenoxy)ethyl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With tetra-(n-butyl)ammonium iodide; caesium carbonate; In acetonitrile; at 65℃; for 4h;
First Step 4-(2-Chloroethyl)morpholine hydrochloride (4.72 g, 25.4 mmol), cesium carbonate (18.8 g, 57.7 mmol), and tetrabutylammonium iodide (0.511 g, 1.38 mmol) were added to a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (3.00 g, 23.1 mmol) in acetonitrile (46.1 mL), and the mixture was stirred at 65 C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated at reduced pressure. The residue was dissolved in ethyl acetate, washed with water, a 2 N aqueous sodium hydroxide solution, water, and a brine, and the organic layer was dried over sodium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain 4-(2-(2,3-difluorophenoxy)ethyl)morpholine (5.60 g, 99%) as colorless oil. LCMS: m/z 244[M+H]+ HPLC retention time: 0.68 minutes (analysis condition SMD-TFA05)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,2-dimethoxyethane; at 80 - 100℃;
General procedure: A mixture of2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 equiv) in anh DME (0.04 -0.5 M), phenol(2 - 4 equiv), and DBU (2 -4 equiv) was heated in a microwave reactor, an oil bath or a reaction block at temperatures 80-100 C for 1 - 4 h. Solvent was removed and the crude product was purified by flash chromatography or RP HPLC.
With phosphoric acid; In toluene; at 90℃; for 20h;
2,3-Difluorophenol (10.0 g, 104.6 mmol) and 85% phosphoric acid (2.0 g, 21.3 mmol) were added to a 250 mL three-necked flask,100 mL of toluene was added as a solvent,A 37% formaldehyde solution (3.9 g, 48.3 mol) was slowly added at a reaction temperature of 90 C,Reaction time 20h. After completion of the reaction, the obtained reaction solution was separated, and the resulting organic layer was a reaction crude product. The crude product obtained by the reaction was subjected to rotary distillation to recover toluene, and the remaining phenol was recovered by distillation under reduced pressure. The remaining product was recrystallized once from the recovered toluene to obtain pure bisphenol F
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h;Inert atmosphere;
The compound of Formula 1-4 (2.00 g, 5.74 mmol),(0.75 g, 5.74 mmol), N, N'-dicyclohexylcarbodiimide (1.19 g, 5.74 mmol) and 4-dimethylaminopyridine (0.40 g, 0.57 mmol) were dissolved in dichloro Methane (100 ml), and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. After completion of the reaction, the urea formed by filtration was filtered out and washed with distilled water three times to remove residual urea. The remaining filtrate was distilled under reduced pressure, and the resulting product was purified by column chromatography using chloroform as a developing solvent, completely dissolved in a small amount of chloroform and precipitated by adding methanol to obtain the compound of Formula 1-5 (yield : 67.2%).
With trimethylbenzylammonium bromide; potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; water; N,N-dimethyl-formamide; at 30℃;Reflux; Industrial scale;
1000L reactor was charged with potassium 50kg, 500kg xylene, 2,3-difluoro-phenol 100kg, Bi administered warmed to reflux trap by trap until no expulsion of water up to give 2,3-difluoro-phenol Potassium . Then cooled to 30 after adding benzyl trimethyl ammonium bromide 5kg, DMF5kg, plus complete solution of n-butyl chloride 80kg, dropping Albert warmed to reflux incubation reaction to the raw material disappears. After passing cooling to 30 , filtered and the filtrate washed twice 100kg of water was added, layers were separated and the organic layer is a xylene solution of 2,3-difluorophenyl ether. Recovered by distillation of toluene, and then the tower distillation, the product 2,3-difluorophenyl ether 130kg, GC content of> 99.9% and a yield of 90.8%.
With tetrabutylammomium bromide; potassium hydroxide; In water; N,N-dimethyl-formamide; toluene; at 30℃;Reflux; Industrial scale;
1000L reactor was charged with potassium 50kg, 500kg toluene, 2,3-difluoro-phenol 100kg, Bi administered warmed to reflux trap by trap until no expulsion of water up to give 2,3-difluoro-phenol and potassium. Then added after cooling to 30 tetrabutylammonium bromide 5kg, DMF5kg, plus complete solution of propyl chloride 70kg, dropping Albert warmed to reflux incubation reaction to the raw material disappears. After passing cooling to 30 , filtered and the filtrate washed twice 100kg of water was added, layers were separated and the organic layer is 2,3-difluorophenyl ether solution in toluene. Recovered by distillation of toluene, and then the tower distillation, the product 2,3-difluorophenyl ether 120kg, GC content of> 99.9% and a yield of 90.6%
5-(2,3-difluorophenoxy)-3-methoxypyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.5%
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 120℃;Inert atmosphere;
426 mg of <strong>[36057-46-2]5-bromo-3-methoxypyridine-2-carbonitrile</strong> (2.0 mmol, 1.0 equiv.), 786 mg of 2,3-difluorophenol (6.0mmol, 3.0 equiv.), 114 mg of cuprous iodide (0.6 mmol, 0.3 equiv.), 61.8 mg of N,N-dimethylglycine (0.6 mmol, 0.3equiv.), 1.3 g of cesium carbonate (4.0 mmol, 2.0 equiv.) and 6 ml of 1,4-dioxane were mixed and stirred at 120 Covernight under the protection of nitrogen. The reaction solution was concentrated and partitioned between ethyl acetate(50 ml) and water (30 ml). The ethyl acetate layer was concentrated and subjected to column chromatography to obtain160 mg of 5-(2,3-difluoro-phenoxy)-3-methoxy-pyridine-2-carbonitrile as a pale yellow solid, 30.5%.
3-bromo-5-(2,3-difluorophenoxy)-1-isopropyl-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 20h;Sealed tube;
3,5-Dibromo-1-isopropyl-1,2,4-triazole (Int-2, 1.14 g, 4.26 mmol) was dissolved in DMF (8 mL) and 2,3-difluorophenol (831 mg, 6.39 mmol) was added, followed by potassium carbonate (1.47 g, 10.6 mmol). The reaction mixture was stirred for 20 h at 110 C in a sealed tube. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with MTBE (2 x 150 mL). The combined organic layers were washed with 0.5 N sodium hydroxide solution (50 mL), water (50 mL) and brine (50 mL), dried over sodium sulphate and concentrated in vacuo to give the crude product, that was sufficiently pure, as a light brown solid (1.31 g, 97%). No further purification. 1H NMR (CDCl3, 300 MHz): 1.54 (d, J = 6.6 Hz, 6H), 4.66 (hept, J = 6.7 Hz, 1 H), 7.05-7.18 (m, 2 H), 7.21-7.28 (m, 1 H). MS (ES+) m/z 318.3, 320.3 [M+H, Br isotopes].
8,9-difluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
To a solution of <strong>[6418-38-8]2,3-difluorophenol</strong> (5 g, 37.67 mmol) in DMF (60 ml) was added potassium carbonate (5.73 g, 41.43 mmol). After 10 minutes of stirring at room temperature, methyl-4-bromobutyrate (7.90 g, 41.43 mmol) was added. The white suspension was heated at 50C for 24 hours. After cooling to room temperature, MeOH (50 ml), water (50 ml) and sodium hydroxide 32% (30 ml) were added. The reaction mixture was heated at 80C for 1 hour. After cooling to room temperature, ice (100 g) and EtOAc (300 ml) were added, then HCI 5N was added to pH 3. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the obtained oil, polyphosphoric acid (PPA, 100 g) was added, then the mixture was heated at 80C for 1 hour. Ice (300 g) was slowly added and the precipitate was filtered, and dried under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in EtOAc (100/0 to 70/30; v/v) to give 5.1 g (68%) of 8,9-difluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one as beige solid. LC/MS (m/z, MH+): 199
1-(2,2-diethoxyethoxy)-2,3-difluorobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.4%
With potassium carbonate; In dimethyl sulfoxide; at 95℃; for 16h;
Dissolve <strong>[6418-38-8]2,3-difluorophenol</strong> 1a (50 g, 0.39 mol) in 400 mL of dimethyl sulfoxide, add 2-bromo-1,1-diethoxyethane (79.50 g, 0.40 mol) and potassium carbonate (79.60g, 0.58mol), heated to 95 C, and stirred for 16 hours.The reaction solution was cooled to room temperature, 1 L of ethyl acetate was added, and the filtrate was washed with water (750 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1- (2,2- Diethoxyethoxy) -2,3-difluorobenzene 1b (80 g, colorless oil), yield: 84.4%.
With potassium carbonate; In dimethyl sulfoxide; at 95℃; for 16h;
To a stirred solution of <strong>[6418-38-8]2,3-difluoro phenol</strong> (50 g, 0.39 mol) in 400 mL DMSO was added 2-bromo-1,1-diethoxy ethane (79.50 g,0.40 mol) and K2CO3 (80 g, 0.58 mol). The reaction mixture was stirred at 95 C for 16 h. After cooled to room temperature, it was diluted with ethyl acetate. After the organic phase was washed with water and dried with Na2SO4, it was concentrated to give crude 3 of 80 g without further purification. 1H NMR(400 MHz,CDCl3): d 6.98-6.94 (m, 1H), 6.81-6.75 (m, 2H), 4.85 (t, J = 5.0 Hz,1H), 4.08 (d, J = 5.3 Hz, 2H), 3.81-3.77 (m, 2H), 3.68-3.37 (m,2H), 1.25 (t, J = 6.8 Hz, 6H).
<4-(4-n-Propylcyclohexyl)cyclohexyl>methylbromid[ No CAS ]
C22H32F2O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.8%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;
Under a nitrogen atmosphere, to a reactor (24.3 g) compound (s12), 2, 3 - (10.0 g) (s13) difluorophenols, potassium carbonate (K2CO3; 15.9 G), DMF (100 ml) and filled, stirred 2 hours at 100 C. The reaction mixture was then cooled to 25 C, precipitate was filtered, the filtrate was concentrated. Silica gel chromatography (heptane) to give a residue, was purified by recrystallization from heptane furthermore, compound (20.4 g; 75.8%) was obtained (s14).
With iron(III) chloride In diethyl ether at 30℃; for 5h;
4.2; 6.2; 7.2
The intermediate product obtained in the step 1) and 20 mL of diethyl ether were added to the reactor, then 0.1 mol of ferric chloride was added, the temperature was raised to 30 ° C, and the reaction was carried out for 5 hours. After the reaction was completed, 0.1 mol/L of sodium hydroxide solution was added. And then, the organic phase and the aqueous phase are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extracts are combined, washed with saturated brine, and the solvent is evaporated to dryness to give 2,3-difluoro. The phenol was 12.3 g, the GC analysis product content was 99.3%, and the total yield of the two-step reaction was 93.9%.
12.8 g
With boron trifluoride diethyl etherate In tetrahydrofuran at 50℃; for 10h;
4.2
2) adding the intermediate product of step 1) and 20 mL of tetrahydrofuran to the reactor,Then 0.12 mol of boron trifluoride etherate was added and the temperature was raised to 50 °C.After reacting for 10 hours, after the reaction was completed, it was neutralized by adding 0.1 mol of sodium hydroxide solution, and then the organic phase and the aqueous phase were separated, and the aqueous phase was extracted with ethyl acetate, and the organic phase and ethyl acetate extract were combined. After washing with saturated brine, the solvent was evaporated to dryness, and then distilled under reduced pressure to obtain 12.8 g of 2,3-difluorophenol. The product of GC analysis was 99.4%, and the total yield of the two-step reaction was 97.9%.
With iron(III) chloride In ethanol at 30℃; for 3h;
5.2
The intermediate product obtained in the step 1) and 20 mL of ethanol are added to the reactor, then 0.08 mol of ferric chloride is added, the temperature is raised to 30 ° C, and the reaction is carried out for 3 hours. After the reaction is completed, 0.1 mol/L of sodium hydroxide solution is added. And then, the organic phase and the aqueous phase are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extracts are combined, washed with saturated brine, and the solvent is evaporated to dryness to give 2,3-difluoro. The phenol was 10.6 g, the GC analysis product content was 99.4%, and the total yield of the two-step reaction was 82.1%.
With aluminum (III) chloride; In methanol; at 30℃; for 5h;
The intermediate product obtained in step 1) and 30 mL of methanol were added to the reactor, and then 0. lmol of aluminum trichloride was added, the temperature was raised to 30 C, and the reaction was carried out for 5 hours. After the reaction was completed, O.lmol/L of hydrogen was added. The sodium oxide solution is neutralized, and then the organic phase and the aqueous phase are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extracts are combined, washed with saturated brine, and evaporated to dryness. 3_difluorophenol 11.6g, GC analysis product content is 99.2%, the total yield of the two-step reaction is 88.5%
tert-butyl 3-(2,3-difluorophenoxy)azetidin-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triphenylphosphine; In tetrahydrofuran; at 70℃; for 20h;
Triphenylphosphine (7.11 g, 27.1 mmol) was dissolved in dry THF (100 mL).DEAD (10.8 g, 24.9 mmol) (5 min) was added dropwise, then 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (3.99 g, 22.6 mmol) was added in small portions in the order given.And <strong>[6418-38-8]2,3-difluorophenol</strong> (3.00 g, 22.6 mmol). The reaction mixture was stirred at 70 C for 20 hours and then separated between water and MTBE. Extract the aqueous solution with another portion of MTBE and dissolve the combined organic solutionThe solution was washed with aqueous KOH (10%), water and brine.After drying (Na2SO4) and filtering, the volatiles were evaporated.Purified by silica gel chromatography,Where a mixture of isooctane and EtOAc (gradient 30%-100% EtOAc) eluted5.9 g (91%) of the title compound are obtained.
With triethylamine; In dichloromethane; at 0 - 20℃;
The compound of formula 1-1 (2.6 g, 0.02 mol) was dissolved in dry dichloromethane, and the ice bath was added with triethylamine (2.63 g, 0.026 mol). Chloroacetyl chloride (2.94 g, 0.026 mol, 1.3eq), after dripping, naturally warming to room temperature overnight, TLC detection, the reaction is complete,Pour into ice water to quench, extract with dichloromethane, wash the organic phase with saturated brine,Dry over anhydrous sodium sulfate, filter,The solvent was distilled off under reduced pressure to obtain a brown liquid (4.13 g, 100%).That is, the compound of Formula 1-2 is directly used in the next reaction.
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