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Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
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Structure of 372-20-3 * 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.
Reference：
[1] Journal of the Chemical Society, 1928, p. 1881
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1602[3] Journal of the Chemical Society, 1926, p. 159
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6842 - 6851
3
[ 372-20-3 ]
[ 446-36-6 ]
[ 385-01-3 ]
[ 394-41-2 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 15 - 26℃; for 1.5 - 2 h;
3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
Reference：
[1] Journal of the Chemical Society, 1928, p. 1881
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1602[3] Journal of the Chemical Society, 1926, p. 159
5
[ 50-00-0 ]
[ 372-20-3 ]
[ 38226-10-7 ]
[ 348-28-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 13, p. 1823 - 1832
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[3] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0086-0088
6
[ 372-20-3 ]
[ 38226-10-7 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 19, p. 2925 - 2929
[2] Patent: US2017/37038, 2017, A1,
Reference：
[1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 130 - 135
9
[ 372-20-3 ]
[ 394-41-2 ]
Reference：
[1] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[2] Patent: WO2007/129960, 2007, A2, . Location in patent: Page/Page column 35-36
[3] Patent: CN105801433, 2016, A, . Location in patent: Paragraph 0020; 0023
10
[ 372-20-3 ]
[ 446-36-6 ]
[ 385-01-3 ]
[ 394-41-2 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 15 - 26℃; for 1.5 - 2 h;
3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
Reference：
[1] Journal of the Chemical Society, 1928, p. 1881
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1602[3] Journal of the Chemical Society, 1926, p. 159
12
[ 372-20-3 ]
[ 75-03-6 ]
[ 458-03-7 ]
Reference：
[1] Bl. Acad. Belg., 1913, p. 262[2] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274
13
[ 372-20-3 ]
[ 584-08-7 ]
[ 75-03-6 ]
[ 458-03-7 ]
Reference：
[1] Patent: US5593993, 1997, A,
14
[ 372-20-3 ]
[ 80-40-0 ]
[ 458-03-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2002, vol. 75, # 4, p. 789 - 800
15
[ 201230-82-2 ]
[ 372-20-3 ]
[ 345-29-9 ]
Yield
Reaction Conditions
Operation in experiment
41%
at 175℃; for 5 h;
Potassium carbonate (51.6 g, 373 mmol) was dried by heating at200 C for 12 h. This was treated with3-fluorophenol (16.5 g, 147 mmol) in a sealed container which was then pressurized with carbon monoxide to 61.2 bar (900psig). The reaction mixture was heated to175 C for 5 h. Subsequently, the reaction mixture was dissolved in water, acidified with concentrated hydrochloric acid, and filtered. The solid was washed with water, then hexanes. The, solid was then dissolved in EtOAc, dried over magnesium sulfate, and concentrated to give 12 g of solid. This crude solid was purified by flash chromatography using, CHC13/MeOH/HOAc (98/1/1) to give 11 g of a white solid which was recrystallized from toluene to give the title compound (9.5 g,41percent) as needle solids. 1NMR <Desc/Clms Page number 40>FD-MS, m/e 155(m-1) Analysis forC7H5FO3-0.1C7H8-0.3H2O :Calcd: C, 54.17 ; H, 3.78 ;Found: C, 54.12 ; H, 3.39
Reference：
[1] Journal of the Chemical Society, 1929, p. 1639
17
[ 372-20-3 ]
[ 51788-80-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 20, p. 4150 - 4160
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 8, p. 1590 - 1595
18
[ 372-20-3 ]
[ 363-52-0 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 6217 - 6229
19
[ 372-20-3 ]
[ 54788-19-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 1995, vol. 70, # 1, p. 39 - 44
20
[ 372-20-3 ]
[ 75-36-5 ]
[ 701-83-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 2-3, p. 426 - 442
[2] Pharmacy and Pharmacology Communications, 1999, vol. 5, # 5, p. 323 - 329
[3] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
[4] Journal of Medicinal Chemistry, 1988, vol. 31, # 8, p. 1590 - 1595
[5] Journal of Medicinal Chemistry, 1999, vol. 42, # 20, p. 4150 - 4160
[6] Patent: US6355796, 2002, B1,
[7] Patent: US6140270, 2000, A,
[8] Patent: EP908457, 1999, A1,
[9] Patent: US6191275, 2001, B1,
[10] Patent: WO2004/108720, 2004, A1, . Location in patent: Page 60; 61
[11] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6458 - 6467
21
[ 372-20-3 ]
[ 108-24-7 ]
[ 701-83-7 ]
Yield
Reaction Conditions
Operation in experiment
10.5 g
at 120℃;
3-Fluorophenol (10 g, 89 mmol) was dissolved in 90 mmol acetic anhydride. 3 drops of concentrated sulfuric acid are added and the temperature rises to 120°C. cold After that time, the mixture was poured into 100 ml of ice-water solution containing 1 g of NaHCO 3 and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution, dried over Na2SO4, and dried in vacuo to give 10.5 g of product for the next step.
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 5, p. 2241 - 2249
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 5, p. 814 - 820
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 3037 - 3058
[4] Patent: CN105085427, 2018, B, . Location in patent: Paragraph 0331; 0333; 0335; 0336
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 1555
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4336 - 4347
[3] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 1, p. 183 - 187
Reference：
[1] Journal of Fluorine Chemistry, 2006, vol. 127, # 2, p. 291 - 295
[2] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 1, p. 173 - 179
[3] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 10, p. 2549 - 2552
Reference：
[1] Journal of the Chemical Society, 1941, p. 645
[2] Patent: CN105801433, 2016, A,
31
[ 127682-43-3 ]
[ 372-20-3 ]
[ 399-95-1 ]
[ 53981-24-1 ]
[ 53981-23-0 ]
Reference：
[1] Journal of the American Chemical Society, 1992, vol. 114, # 25, p. 9795 - 9806
32
[ 372-20-3 ]
[ 127-17-3 ]
[ 7423-96-3 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 3, p. 926 - 935
33
[ 50-00-0 ]
[ 372-20-3 ]
[ 348-28-7 ]
Yield
Reaction Conditions
Operation in experiment
72%
With triethylamine; magnesium chloride In acetonitrile for 5 h; Heating / reflux
[1042] To the mixture of 3-fluorophenol (10 mL, 102 mmole), anhydrous magnesium chloride (28.2 g, 744.6 mmole) in 500 mL of anhydrous acetonitrile was added anhydrous triethylamine (67 mL, 382. 5 mmole) and paraformaldehyde (22.3 g, 744.6 mmole). The mixture was then heated to reflux for five hours. After cooling to r. t, 500 mL of 5percent aqueous hydrochloric acid was added. The product was extracted with ethyl acetate. The combined organic extracts were washed with 5percent hydrochloric acid (x 3), brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was a light pink solid. 11 g, yield 72percent. M. P: 67.5-69. 0°C. ESHRMS 777/Z 139.0211 (M-H, C7H4FO2 calc'd 139. 0201). 1H NMR (CDCl3/300MHz) 11.40 (s, 1H), 9.86 (s, 1H), 7.62-7. 57 (m, 1H), 6.79-6. 67 (m, 2H). 13C (CDC13/300MH) 195.4, 168.3 (d, J= 258 HZ), 164.4 (d, J=14. 9 Hz), 136.3 (d, J=12. 6 Hz), 118.2 (d, J= 2.0Hz), 108.5 (d, J= 23. 3 Hz), 104.9 (d, J=24. 4 HZ). L9F (CDCl3/400MHz) -97. 9 (m).
71%
With triethylamine; magnesium chloride In acetonitrile for 4.25 h; Reflux
To a mixture of 3-fluorophenol (415 mg, 3.70 mmol) and anhydrous MgCI2 powder (1 .06 g, 1 1 .1 mmol) in anhydrous acetonitrile (20 mL) was added anhydrous triethylamine (1 .94 mL) and paraformaldehyde (81 1 mg, 27.0 mmol). The mixture was heated to reflux for 4.25 h, during which time there was a colour change from white to pink to yellow. The reaction mixture was cooled to room temperature and 5percent aqueous HCI was added (20 mL). The product was extracted with EtOAc (2 x 50 mL) and the combined organic extracts washed with H20 (3 x 50 mL), brine (50 mL), dried over anhydrous MgS04 and the solvent removed in vacuo. FCC [dichloromethane-methanol (100:0)→(97:3)] of the crude residue afforded the title Preparation 1 (367 mg, 71 percent) as a white solid; Rf 0.83 (10percent MeOH:CH2CI2); H NMR (500 MHz, CDCI3) δ 1 1 .35 (1 H, d, J = 1 .6 Hz, CHO), 9.82 (1 H, s), 7.55 (1 H, dd, J = 6.3 and 8.6 Hz), 6.71 (1 H, dt, J = 2.4 and 8.3 Hz) and 6.66 (1 H, dd, J = 2.4 and 10.4 Hz), 19F NMR (470.7 MHz, CDCI3) δ -97.53 (m).
65%
With magnesium chloride; trimethylamine In acetonitrile for 5 h; Reflux
Example 81 Synthesis of 4-fluoro-2-hydroxybenzaldehyde To a mixture of 3-fluorophenol (5 mL, 55.3 mmol), MgCl2 (14.2 g, 149 mmol) in dry acetonitrile (250 mL) was added dry trimethylamine (27 mL) and paraformaldehyde (11 g). The resulted mixture was stirred at reflux for 5 h, and then cooled down to room temperature. The reaction was quenched by addition of hydrochloric acid (5percent, 250 mL), extracted with ethyl acetate (100*3). The combined organic layer was washed with hydrochloric acid (5percent), H2O and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=50:1˜20:1) to afford 4-fluoro-2-hydroxybenzaldehyde (5 g, yield: 65percent) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.37 (d, J=1.6 Hz, 1H), 9.83 (s, 1H), 7.55-7.59 (m, 1H), 6.65-6.75 (m, 2H).
63%
With triethylamine; magnesium chloride In acetonitrile at 80℃; for 19 h;
To a solution of 3-fluorophenol (2.0 mL, 22.3 mmol) and triethylamine (11.7 mmol) in anhydrous CH3CN (50 mL) was added p- formaldehyde (4.52 g, 151 mmol) and MgCl2 (3.19 g, 33.5 mmol) ML, 83.6 mmol). The reaction mixture was refluxed at 80 & lt; 0 & gt; C for 19 hours. After confirming the reaction with TLC, the reaction mixture was cooled to room temperature, and 3N HCl was added to the reaction mixture to adjust the pH to 2. The organic layer was extracted with ethyl acetate and distilled water and washed with brine. The separated organic layer was dried over anhydrous magnesium sulfate and then decompressed to remove the solvent. The reaction mixture was purified by flash column chromatography (CH2Cl2: Hex = 1: 1, Rf = 0.4) to obtain 4-fluoro-2-hydroxyaldehyde (1.97 g, 63percent, white solid).
51.6%
Stage #1: With magnesium methanolate In methanol; toluene at 95℃; for 3 h; Stage #2: With sulfuric acid In methanol; water; toluene for 2 h;
Preparation of intermediate (1) : 4-fluoro-2-hvdroxy-benzaldehyde: 4-Fluorophenol (5.0ml, 56.02mmol) and magnesium methoxide (44.5ml, 33.6mmol, 8percent wt in MeOH) were dissolved in methanol (30ml). Thereafter the reaction mixture was distilled until the methanol was left over about 15ml. thereto the reaction mixture was added toluene (42ml), and distilled when the reaction temperature was reached 950C. p-Formaldehyde (5.18g, 172.54mmol) was slowly added for 1 hour, and then the reaction mixture was distilled at 95°C for 1 hour. Additionally the reaction mixture was stirred at the same temperature for 1 hour and cooled down room temperature. Then 10percent sulfuric acid was added, stirred for 2 hours and aqueous layer was extract with toluene. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 8:1) to give 4.05g (yield: 51.6percent, yellow solid) of the target compound. 1H-NMR (CDCl3, 400MHz) 11.37(s, IH), 9.84(s, IH), 7.57(dd, 7=8.6, 6.4Hz, IH), 6.66~6.76(m, 2H)
36%
Stage #1: With ethylmagnesium bromide In tetrahydrofuran at 20℃; for 2 h; Stage #2: With triethylamine In benzene for 3 h; Heating / reflux Stage #3: With hydrogenchloride; water In benzene at 20℃;
Step 1 4-Fluoro-2-hydroxy-benzaldehyde; To a solution of 3-fluorophenol (1 ml, 11 mmol) in THF(20 ml) in a three-neck flask was added ethylmagnesium bromide (5.5 ml, 5.5 mmol, IM in THF). After stirring at room temperature for 2 hours, benzene was added to the reaction mixture and THF was removed by distillation at 8O0C. Additional benzene (50 ml) was added to the reaction, followed by NEt3 (2.3 ml, 16.5 mmol) and paraformaldehyde (Ig, 33.3mmol). After heating at reflux for 3 hours, the reaction mixture was allowed to cool to room temperature and was poured into 250 ml of 10percent HCl. EtOAc was added and the organic layer was separated and washed with H2O. After drying over MgSO4, the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography to give 4-fluoro-2 -hydroxy- EPO <DP n="44"/>benzaldehyde as a white solid (560mg, 36percent), 1H NMR (CDC13, 300 MHz)δ: 6.71 (m, 2H),7.56(dd, IH, J= 6.3Hz, 8.6Hz), 9.84(s, IH), 11.36(s, IH).
2.7 g
With triethylamine; magnesium chloride In acetonitrile for 2.75 h; Reflux
To the mixture of 3-fluorophenol (5 mL, 51 mmol) , anhydrous magnesium chloride (14.1 g, 372 mmol) in 250 mL of acetonitrile was added triethylamine (34 mL, 190 mmol) and paraforaldehyde (11 g, 372 mmol) . The mixture was then heated to reflux for 5 hours. After cooling to room temperature, 250 mL of 5 HCl. aq was added, extracted with EA (100 mL×2) . The combined organic layer was washed with 5 HCl. aq (100 mL×2) , brine, and dried over Na2SO4, concentrated, purified by chromatography column to give the desired product (2.7 g) .1H NMR (400 MHz, CDCl3) δ 11.36 (s, 1H) , 9.84 (s, 1H) , 7.54-7.58 (m, 1H) , 6.65-6.75 (m, 2H)
Reference：
[1] Patent: WO2004/87686, 2004, A2, . Location in patent: Page 504
[2] Patent: WO2004/87687, 2004, A1, . Location in patent: Page 504
[3] Patent: WO2017/55860, 2017, A1, . Location in patent: Page/Page column 138-139
[4] Patent: US2017/37038, 2017, A1, . Location in patent: Paragraph 0375; 0376; 0377
[5] Patent: KR101679262, 2016, B1, . Location in patent: Paragraph 0156-0158
[6] Angewandte Chemie - International Edition, 2017, vol. 56, # 49, p. 15545 - 15549[7] Angew. Chem., 2017, vol. 129, # 49, p. 15751 - 15755,5
[8] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 24, p. 8618 - 8629
[9] Patent: WO2007/8037, 2007, A1, . Location in patent: Page/Page column 34
[10] Organic and Biomolecular Chemistry, 2017, vol. 15, # 6, p. 1530 - 1536
[11] Patent: WO2008/55808, 2008, A1, . Location in patent: Page/Page column 42-43
[12] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
[13] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5591 - 5593
[14] Patent: WO2013/91096, 2013, A1, . Location in patent: Page/Page column 37
[15] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 878 - 902
[16] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
[17] Patent: WO2016/8411, 2016, A1, . Location in patent: Paragraph 0410
[18] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
[19] Chemistry - A European Journal, 2017, vol. 23, # 68, p. 17195 - 17198
[20] Organic Letters, 2017, vol. 19, # 23, p. 6340 - 6343
[21] Organic Letters, 2018, vol. 20, # 10, p. 2880 - 2883
34
[ 50-00-0 ]
[ 372-20-3 ]
[ 38226-10-7 ]
[ 348-28-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 13, p. 1823 - 1832
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[3] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0086-0088
Reference：
[1] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[2] Journal of the Chemical Society, 1929, p. 1639
[3] Journal of Organic Chemistry, 2005, vol. 70, # 16, p. 6548 - 6551
[4] Patent: EP1204660, 2004, B1,
42
[ 372-20-3 ]
[ 7664-93-9 ]
[ 443-81-2 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 1639
43
[ 372-20-3 ]
[ 331-64-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 1995, vol. 70, # 1, p. 39 - 44
44
[ 372-20-3 ]
[ 399-00-8 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 2276
[2] Journal of the Chemical Society, 1929, p. 1639
[3] Patent: WO2013/91096, 2013, A1,
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 878 - 902
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
45
[ 67-66-3 ]
[ 372-20-3 ]
[ 7726-95-6 ]
[ 399-00-8 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 2276
[2] Journal of the Chemical Society, 1929, p. 1639
46
[ 50-00-0 ]
[ 372-20-3 ]
[ 77-78-1 ]
[ 450-83-9 ]
[ 146137-74-8 ]
Yield
Reaction Conditions
Operation in experiment
15.8 g
Stage #1: With magnesium chloride In acetonitrile for 0.0833333 h; Inert atmosphere; Molecular sieve Stage #2: for 0.5 h; Inert atmosphere; Molecular sieve
The m-fluorophenol (20g, 0.2πο1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 ° C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 ° C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68percent 0B-2a: Mp: ° C; 6h (300ΜΗζ; CDC13) 10.4 (1Η, s), 7.85 (1Η, dd, J = 8.4Hz, 6.9Ηζ), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Ηζ), 130.9 (d, J = 11.6Ηζ), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Ηζ), 99.7 (d, J = 25.7Ηζ), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Μρ: 60-61 ° C ; 6H (300 MΗζ; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Ηζ, 8.4Ηζ), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Ηζ), 136.2 (d, J = 12.0Ηζ), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Ηζ), 56.3.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0086-0088
47
[ 372-20-3 ]
[ 450-83-9 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 1639
48
[ 372-20-3 ]
[ 395-82-4 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 1639
49
[ 372-20-3 ]
[ 394-42-3 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
50
[ 127682-43-3 ]
[ 372-20-3 ]
[ 399-95-1 ]
[ 53981-24-1 ]
[ 53981-23-0 ]
Reference：
[1] Journal of the American Chemical Society, 1992, vol. 114, # 25, p. 9795 - 9806
51
[ 372-20-3 ]
[ 121219-03-2 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
[2] New Journal of Chemistry, 2015, vol. 39, # 11, p. 8291 - 8301
[3] Journal of Materials Chemistry, 2001, vol. 11, # 6, p. 1590 - 1599
[4] Canadian Journal of Chemistry, 2011, vol. 89, # 3, p. 364 - 384
52
[ 372-20-3 ]
[ 82380-18-5 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
53
[ 372-20-3 ]
[ 107-30-2 ]
[ 126940-10-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 0.25 h; Stage #2: at -10 - 20℃; for 22.08 h;
A solution of 100 gm (0.892 mol) 3-fluorophenol in 800 ML dichloromethane was cooled to -10°C. To this solution were added 155 gm (1.20 mol) diisopropylethylamine dropwise over 15 minutes.. Residual diisopropylethylamine in the addition funnel was rinsed into the reaction mixture with 100 ML dichloromethane.. To the resulting solution were added 100 gm (1.24 mol) chloromethyl methyl ether over 5 minutes, resulting an exotherm from -10°C to 2°C. The reaction mixture was allowed to warm to room temperature.. After 22 hours the reaction mixture was quenched with 500 ML water.. The organic phase was washed with 500 ML 2M aqueous sodium bisulfate followed by 300 ML 1M sodium hydroxide.. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 130 gm of a yellow oil.. The oil was distilled (kugelrohr, 80°C, 0.1 torr) to provide 126 gm (91percent) of the desired compound as a colorless oil.
Reference：
[1] ChemBioChem, 2015, vol. 16, # 17, p. 2445 - 2450
[2] Patent: EP1204660, 2004, B1, . Location in patent: Page 19
[3] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
[4] Tetrahedron Letters, 2001, vol. 42, # 37, p. 6499 - 6502
[5] ChemMedChem, 2017, vol. 12, # 1, p. 23 - 27
54
[ 109-87-5 ]
[ 372-20-3 ]
[ 126940-10-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1293 - 1298
55
[ 50-00-0 ]
[ 372-20-3 ]
[ 77-78-1 ]
[ 450-83-9 ]
[ 146137-74-8 ]
Yield
Reaction Conditions
Operation in experiment
15.8 g
Stage #1: With magnesium chloride In acetonitrile for 0.0833333 h; Inert atmosphere; Molecular sieve Stage #2: for 0.5 h; Inert atmosphere; Molecular sieve
The m-fluorophenol (20g, 0.2πο1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 ° C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 ° C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68percent 0B-2a: Mp: ° C; 6h (300ΜΗζ; CDC13) 10.4 (1Η, s), 7.85 (1Η, dd, J = 8.4Hz, 6.9Ηζ), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Ηζ), 130.9 (d, J = 11.6Ηζ), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Ηζ), 99.7 (d, J = 25.7Ηζ), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Μρ: 60-61 ° C ; 6H (300 MΗζ; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Ηζ, 8.4Ηζ), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Ηζ), 136.2 (d, J = 12.0Ηζ), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Ηζ), 56.3.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0086-0088
56
[ 127682-43-3 ]
[ 372-20-3 ]
[ 399-95-1 ]
[ 53981-24-1 ]
[ 53981-23-0 ]
Reference：
[1] Journal of the American Chemical Society, 1992, vol. 114, # 25, p. 9795 - 9806
57
[ 372-20-3 ]
[ 111141-00-5 ]
Reference：
[1] Patent: WO2008/151927, 2008, A2,
58
[ 372-20-3 ]
[ 68886-07-7 ]
Reference：
[1] Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 1993, vol. 237, p. 399 - 406
59
[ 372-20-3 ]
[ 75-36-5 ]
[ 98619-07-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1986, vol. 29, # 11, p. 2329 - 2334
60
[ 372-20-3 ]
[ 65145-13-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123
[2] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
61
[ 372-20-3 ]
[ 67531-86-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123
[2] European Journal of Organic Chemistry, 2005, # 10, p. 2116 - 2123
[3] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
62
[ 590-92-1 ]
[ 372-20-3 ]
[ 113209-68-0 ]
Reference：
[1] Patent: US6316437, 2001, B1,
63
[ 372-20-3 ]
[ 113209-68-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2468 - 2477
[2] Patent: WO2008/151927, 2008, A2,
64
[ 372-20-3 ]
[ 202857-89-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
65
[ 372-20-3 ]
[ 312314-26-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
General procedure: An appropriately substituted phenol (50 mmol) was added to a solution of NaOH (187.5 mmol) in 15 mL of H2O. Chloroacetic acid (85 mmol) was added slowly at to the resulting solution at 40 C and the reaction mixture was heated to 85 C. Stirring was continued for 2 h, the reaction was cooled to room temperature and 100 mL H2O was added. The reaction was filtered and the filtrate was acidified with concentrated HCl to pH 1-2. The brown oil fraction which formed was extracted to diethylether (2 × 50 ml). The ether fraction, in turn, was extracted with an aqueous solution of 5% Na2CO3 (2 × 37.5 ml). The combined Na2CO3 fractions were acidified to pH 1-2 with concentrated HCl and the resulting precipitate was collected by filtration and oven dried to obtain the required acids.24
The m-fluorophenol (20g, 0.2piomicron1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68% 0B-2a: Mp: C; 6h (300MuEtazeta; CDC13) 10.4 (1Eta, s), 7.85 (1Eta, dd, J = 8.4Hz, 6.9Etazeta), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Etazeta), 130.9 (d, J = 11.6Etazeta), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Etazeta), 99.7 (d, J = 25.7Etazeta), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Murho: 60-61 C ; 6H (300 MEtazeta; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Etazeta, 8.4Etazeta), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Etazeta), 136.2 (d, J = 12.0Etazeta), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Etazeta), 56.3
With acetic acid; potassium bromide; In water; acetic acid; at 35℃;
General procedure: 0.11 g (1.0 mmol) of 4-methylphenol, 5 mL of acetic acid, 0.5 mL of water, and 0.12 g (1.0 mmol)potassium bromide were placed in round-bottomed flask. Then, 0.19 g (0.2 mmol)ZnAl-BrO3--LDHs was added in the flask under stirring at 35 C. After the addition, stirring wascontinued to the end of reaction (monitored by thin layer chromatography). The residualZnAl-BrO3--LDHs were removed by centrifugation. The product was extracted with 3 × 10 mLdichloromethane. The combined extract was washed with sodium sulfite solution, brine, and dried(Na2SO4). Evaporation of the solvent left the crude product. The crude product was purified bycolumn chromatography over silica gel (ethyl acetate-petroleum ether) to obtain pure product.
With bis(trichloromethyl) carbonate; tetrabutylammomium bromide; potassium bromide; In water; ethyl acetate; at 20℃; for 19h;
General procedure: To the solution of anisole (0.50 g, 4.6 mmol), TBAB (0.75 g, 2.3 mmol), KBr (0.83 g, 6.9 mmol), ethyl acetate (3.0 mL) and water (0.050 g, 2.8 mmol) were added and stirred at room temperature. A solution of BTC (1.78 g, 6.0 mmol) in ethyl acetate (6.0 mL) was dropwised to the reaction mixture. After the reaction finished, the reaction mixture was washed with water (10 mL × 2) and evaporated. The product was obtained with 99% purity by HPLC. 1 H NMR (400 MHz, DMSO-d6, ppm): delta 7.46-7.42 (m, 2H), 6.78-6.76 (m, 2H), 3.74 (s, 3H).
With triethylamine; In dichloromethane; at 20℃; for 2h;
To a solution of 3-fluorophenol (1.5 kg, 13.4 mol), Et3N (1.8 L, 13.4 mol) and DCM (6 L), acetic anhydride (1.5 L, 16.8 mol) was added dropwise at room temperature over 2 h. Water bath cooling was needed during the addition to maintain the temperature below 30 C. The mixture was stirred at 25-30 C until the disappearance of 3-fluorophenol by TLC. The reaction mixture was washed with water (2 L × 3) and brine (2 L), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6 (2.06 kg, 99.8%) as a colorless oil (Lit.[1] Bp77-78 C, Press: 13 Torr). Acetate 6 used directly for the next reaction without any purification.
82%
With sulfuric acid; at 80℃; for 0.5h;
3-fluorophenol (11 g, 98.12 mmol) was dissolved in acetic anhydride (12.0 g, 117.8 mmol),Add 3 to 5 drops of concentrated sulfuric acid and heat to 80 C for 0.5 hours.After cooling, the mixture was poured into 100 mL of an aqueous solution containing 1 g of NaHCO3,And extracted with ethyl acetate.The organic layer was washed with a saturated NaHCO3 solution until the aqueous solution was neutral,The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure.The target product was obtained as a colorless oily liquid (12.35 g, yield: 82%).
69%
With pyridine; In dichloromethane; at 0℃; for 3h;
R2 - To a solution of R 1 (200 g, 1.57 mol) in DCM (2 L) was added pyridine (155 g, 1.96 mol), AC2O (200 g, 1.96 mol) at 0C. The mixture was stirred at 0 C for 3 hrs. Ice-water (2 L) was added. The mixture was extracted with DCM (1000 mL x 2), the combined organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuum to give R2 (190 g, yield 69%) as a red oil. 1H NMR (CDCl3, 400 MHz): d (ppm) 2.29 (s, 3H), 6.84-6.96 (m, 3H), 7.29-7.37 (m, 1H).
10.5 g
With sulfuric acid; at 120℃;
3-Fluorophenol (10 g, 89 mmol) was dissolved in 90 mmol acetic anhydride. 3 drops of concentrated sulfuric acid are added and the temperature rises to 120C. cold After that time, the mixture was poured into 100 ml of ice-water solution containing 1 g of NaHCO 3 and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution, dried over Na2SO4, and dried in vacuo to give 10.5 g of product for the next step.
EXAMPLE 15 Preparation of m-Fluorophenyl acetate A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 C. to 5 C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17 C., stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1H NMR spectral analysis.
With pyridine; In dichloromethane;
EXAMPLE 13 Preparation of m-Fluorophenyl Acetate STR141 A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 C. to 5 C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17 C., stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1 H NMR spectral analysis.
With pyridine; In dichloromethane;
EXAMPLE 22 Preparation of m-Fluorophenyl acetate A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 C to 5 C, treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17 C, stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuoto obtain the title product as a yellow oil which is identified by 1H NMR spectral analysis.
With pyridine; In dichloromethane;
EXAMPLE 10 Preparation of m-Fluorophenyl acetate A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 C. to 5 C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17 C., stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1H NMR spectral analysis.
With pyridine; In dichloromethane; at 50℃; for 2h;
To a solution of 3-fluorophenol (100 g, 0.89 mol) in dry CH/2C12 was added pyridine(79.4 mL, 0.98 mol) followed dropwise by acetyl chloride (88.4 mL, 0.94 mol). The reaction mixturewas stirred for 2 h at 50 C and then diluted with EtOAc and Et2O The organic phase was washedsuccessively with HC1 IN (2x), H2O, brine, dried over Na2SC>4 and evaporated to give the titlecompound.
With caesium carbonate; In acetonitrile; at 70℃; for 1h;
To a mixture of 5-bromothiazol-2-amine (0.100 g, 0.562 mmol) and cesium carbonate (0.275 g, 0.843 mmol) in acetonitrile (2 ml_) at 70 C was added a solution of 3-fluorophenol (0.082 g, 0.731 mmol) in acetonitrile (1 ml_) dropwise. Then the reaction was stirred at 70 C for 1 h. The reaction was cooled to room temperature and diluted with water (30 ml_). The aqueous layer was extracted with ethyl acetate (20 ml_ x 3). The combined organic layers were washed with brine (30 ml_), dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(3-fluorophenoxy)thiazol-2-amine (0.100 g, crude) as a brown oil which was used directly in the next step. LCMS (ESI) m/z: 21 1 .1 [M+H]+.
With pyridine; acetyl chloride; In dichloromethane; at 0 - 20℃; for 2h;
REFERENCE EXAMPLE 12 Preparation of m-Fluorophenyl acetate A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 C to 5 C, treated with pyridine (75.0 ML, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 ML, 0.930 mol) while maintaining the reaction mixture temperature below 17 C, stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture.. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1H NMR spectral analysis.
With potassium carbonate; In acetonitrile; at 10℃; for 18h;
[00339] 11.38 g (0.085 mol) of trifluoropyrimidine are dissolved in 240 ml of acetonitrile and admixed with 15.26 g (0.11 mol) of potassium carbonate, and the mixture is cooled to 10 C. Under argon, a solution of 9.52 g (0.085 mol) of 3-fluorophenol in 80 ml of acetonitrile is added dropwise. The mixture is then stirred under argon, without further cooling, for another 18 hours. The mixture is poured into 1 litre of water and extracted three times with in each case 150 ml of ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue is subjected to kugelrohr distillation. This gives 15.2 g (79.1% of theory) of 5,6-difluoro-(3-fluorophenoxy)-pyrimidine of boiling point 95 C. at 0.5 mbar.
methyl 5-chloro-2-(3-fluorophenoxy)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In toluene; for 16h;Heating / reflux;
EXAMPLE 128 4-[1-([5-CHLORO-2-(3-FLUOROPHENOXY)PYRIDIN-3- YLLCARBONYL} AMINO) CYCLOPROPYLLBENZOIC ACID STEP 1. 5-CHLORO-2- (3-FLUOROPHENOXY) nicotinic acid; To a stirred solution of <strong>[67754-03-4]methyl 2,5-dichloronicotinate</strong> (J. Med. Chem. 1993, 36, 2676, 353 mg, 1.71 mmol) and 3-fluorophenol (291 mg, 2.6 mmol) in toluene (5 mL) was added potassium carbonate (360 mg, 2.6 mmol) in one portion. The resulting mixture was heated at reflux temperature for 16 h with azeotroping using a Dean Stark apparatus. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic extracts were washed with water (50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated under reduced pressure to give crude methyl 5-CHLORO-2- (3- fluorophenoxy) nicotinate. To a stirred solution of the crude ester in methanol (10 mL) was added 2 N sodium hydroxide aqueous solution (2 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between ether (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was acidified with 2 N hydrochloric acid (10 mL). The acidic mixture was extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated to afford 448 mg (93%) of the title compound as off white solids: 1H- NMR (CDCl3) 8 8.44 (1H, d, J = 2.6 Hz), 8.26 (1H, d, J = 2.6 Hz), 7.46-7. 36 (1H, m), 7.07-6. 89 (3H, m); MS (ESI) m/z 268 (M + H)+.
With sodium hydroxide; In water; for 2h;Heating / reflux;
SCHEME E Step 1 3-(3-Fluoro-phenoxy)-propionic acid 3-Fluorophenol (8.9 g, 79.5 mmol) and 3-<strong>[590-92-1]bromopropionic acid</strong> (12.24 g, 80.0 mmol) were placed in a flask. A solution of NaOH (6.7 g, 167 mmol) in 20 mL water was added slowly to the flask. The reaction mixture was heated to reflux for two hours and then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSC^, and solvent was evaporated under reduced pressure to give 4.57 g (25 mmol, 31.4 %) of 3-(3-fluoro-phenoxy)-propionic acid. MS: 185 (M+H)+.
31.4%
With sodium hydroxide; In water; for 2h;Heating / reflux;
3-Fluorophenol (8.9 g, 79.5 mmol) and 3-<strong>[590-92-1]bromopropionic acid</strong> (12.24 g, 80.0 mmol) were placed in a flask. A solution of NaOH (6.7 g, 167 mmol) in 20 mL water was added slowly to the flask. The reaction mixture was heated to reflux for two hours and then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, and solvent was evaporated under reduced pressure to give 4.57 g (25 mmol, 31.4 %) of 3-(3-fluoro-phenoxy)-propionic acid. MS: 185 (M+H)+.
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 16h;
5-Nitrothiophene-2-carbonitrile (2g, 13mmol), 3-fluorophenol (1.75g, 15.6mmol) and potassium carbonate (3.6g, 26mmol) were suspended in dimethylsulfoxide (15mL), and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added for partitioning, silica gel was added to the organic layer, and the solvent was evaporated in vacuo for adsorption. Purification was carried out by silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and the title compound (670mg, 3.1mmol, 23.5%) was obtained as an oil. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 6.83 (1H, d, J=4.0Hz), 7.08-7.26 (2H, m), 7.18-7.24 (1 H, m), 7.49 (1 H, ddd, J=8.0, 8.0, 8.0Hz), 7.81 (1 H, d, J=4.0Hz).
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 16h;
Preparation Example 22. 5-(3-Fluorophenoxy)thiophene-2-carbonitrile 5-Nitrothiophene-2-carbonitrile (2g, 13mmol), 3-fluorophenol (1.75g, 15.6mmol) and potassium carbonate (3.6g, 26mmol) were suspended in dimethylsulfoxide (15mL), and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added for partitioning, silica gel was added to the organic layer, and the solvent was evaporated in vacuo for adsorption. Purification was carried out by silica gel column chromatography (hexane: ethyl acetate =10:1), and the title compound (670mg, 3.1mmol, 23.5%) was obtained as an oil. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 6.83 (1H, d, J=4.0Hz), 7.08-7.26 (2H, m), 7.18-7.24 (1 H, m), 7.49 (1 H, ddd, J=8.0, 8.0, 8.0Hz), 7.81 (1 H, d, J=4.0Hz).
Step A Preparation of 7-fluoro-2,3-dihydrobenzopyran-4(4H)-one A solution of sodium hydroxide (6.7 gm, 167 mmol) in water (20 mL) was added slowly to a neat mixture of 3-fluorophenol (8.9 gm, 79.5 mmol) and 3-<strong>[590-92-1]bromopropionic acid</strong> (12.26 gm,80 mmol) as the reaction became exothermic. The mixture was refluxed gently for two hours and then allowed to cool and become semi-solid. Water was added to dissolve the semi-solid and then was acidified with concentrated HCl. The product was extracted into diethyl ether and the ethereal extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was slurried in 4:1 hexanetbenzene to give crystalline 3-(3-fluorophenoxy) propionic acid. m.p.: 90-91° C. A mixture of this phenoxy acid (6.21 gm, 33.8 mmol) and polyphosphoric acid (52 gm) was heated at 120° C. for one hour. The cooled reaction mixture was poured into ice/water and the precipitated product was extracted into diethyl ether. This etheral solution was dried (MgSO4), filtered and evaporated to give a mixture of two isomers which were separated by chromatography on silica gel eluding with a 10-12percent ethyl acetate/hexane gradient. The first component was isolated and recrystallized from hexane to give pure 7-fluoro-2,3-dihydrobenzopyran-4(4H)-one. m.p.: 61-62° C. The second component was the 5-fluoro isomer. m.p.:107-109° C.
With tetrabutylammomium bromide; sodium; oxalic acid; potassium carbonate; triethylamine;palladium dihydroxide; In ethanol; chloroform; water; methanesulfonyl chloride; toluene;
Preparation 7 3-(3-Fluorophenoxy)azetidine oxalate [1:1] A mixture of 55.1 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride [1:1] (prepared by the Method of Andersen and Lok, J. Org. Chem. 37: 3953 (1972)) and 50.5 g (0.5 mole) of triethylamine in 1.2 liters of toluene was stirred at ambient temperature under a nitrogen atmosphere for 5 hr, then cooled to 5 C. in an ice water bath and methanesulfonyl chloride added dropwise with stirring. The reaction mixture was allowed to warm to ambient temperature while stirring for approximately 18 hr. The reaction mixture was diluted with 600 ml of isopropyl ether and the solid removed by filtration. The filtrate was then treated with 22.5 g (0.2 mole) of 3-fluorophenol and 24 g (0.6 mole) of sodium in 50 ml of water. Tetrabutylammonium bromide, 1 gm, was added to the reaction mixture and the reaction mixture was stirred rapidly and heated at reflux for approximately 16 hr. The toluene layer was separated and washed with water twice (200 ml*2). Then while stirring, 20 g (0.22 mole) of oxalic acid was added as a solution in 100 ml of isopropyl alcohol and the mixture was allowed to stir for approximately 16 hr. Filtration yielded 61.6 g of white granular solid 1-diphenylmethyl-3-(3-fluorophenoxy)azetidine oxalate. A slurry of 55 g of this white granular solid in 350 ml of ethanol was treated with 5.5 g (10% w/w) of 20% palladium hydroxide on carbon under nitrogen atmosphere and hydrogenated on a Parr apparatus at 70 C. with an initial hydrogen pressure of 45 psi for 18 hr. The hydrogen uptake could not be obtained since some leakage had occurred. The product was an insoluble solid which had to be converted to the free base in warm water with potassium carbonate. This mixture was stirred with chloroform and then filtered through Celite to remove the catalyst. The chloroform portion was separated and the aqueous basic solution extracted with 400 ml of chloroform. The chloroform portions were combined, dried over magnesium sulfate and concentrated on a rotary evaporator to yield 36.45 g of oil. The oil was dissolved in ethanol and treated with 10 g of oxalic acid, yielding 15.5 g (46.4%) of crude title compound. A sample was recrystallized from ethanol, m.p. 170-171 C. Analysis: Calculated for C9 H10 FNO.C2 H2 O: C,51.37; H,4.70; N,5.45 Found: C,51.41; H,4.72; N,5.47
With tetrabutylammomium bromide; sodium; oxalic acid; potassium carbonate; triethylamine;palladium dihydroxide; In ethanol; chloroform; water; methanesulfonyl chloride; toluene;
PREPARATION 7 3-(3-Fluorophenoxy)azetidine oxalate [1:1] A mixture of 55.1 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol hydrochloride [1:1] (prepared by the Method of Andersen and Lok, J. Org. Chem. 37: 3953 (1972)) and 50.5 g (0.5 mole) of triethylamine in 1.2 liters of toluene was stirred at ambient temperature under a nitrogen atmosphere for 5 hr, then cooled to 5 C. in an ice water bath and methanesulfonyl chloride added dropwise with stirring. The reaction mixture was allowed to warm to ambient temperature while stirring for approximately 18 hr. The reaction mixture was diluted with 600 ml of isopropyl ether and the solid removed by filtration. The filtrate was then treated with 22.5 g (0.2 mole) of 3-fluorophenol and 24 g (0.6 mole) of sodium in 50 ml of water. Tetrabutylammonium bromide, 1 gm, was added to the reaction mixture and the reaction mixture was stirred rapidly and heated at reflux for approximately 16 hr. The toluene layer was separated and washed with water twice (200 ml*2). Then while stirring, 20 g (0.22 mole) of oxalic acid was added as a solution in 100 ml of isopropyl alcohol and the mixture was allowed to stir for approximately 16 hr. Filtration yielded 61.6 g of white granular solid 1-diphenylmethyl-3-(3-fluorophenoxy)azetidine oxalate. A slurry of 55 g of this white granular solid in 350 ml of ethanol was treated with 5.5 g (10% w/w) of 20% palladium hydroxide on carbon under nitrogen atmosphere and hydrogenated on a Parr apparatus at 70 C. with an initial hydrogen pressure of 45 psi for 18 hr. The hydrogen uptake could not be obtained since some leakage had occurred. The product was an insoluble solid which had to be converted to the free base in warm water with potassium carbonate. This mixture was stirred with chloroform and then filtered through Celite to remove the catalyst. The chloroform portion was separated and the aqueous basic solution extracted with 400 ml of chloroform. The chloroform portions were combined, dried over magnesium sulfate and concentrated on a rotary evaporator to yield 36.45 g of oil. The oil was dissolved in ethanol and treated with 10 g of oxalic acid, yielding 15.5 g (46.4%) of crude title compound. A sample was recrystallized from ethanol, m.p. 170-171 C. Analysis: Calculated for C9 H10 FNO.C2 H2 O: C,51.37; H,4.70; N,5.45. Found: C,51.41; H,4.72; N,5.47.
2-cyano-3-(3-fluorophenoxymethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium ethanolate; In ethanol; hexane;
Reference Example 1: 2-Cyano-3-(3-fluorophenoxymethyl)pyridine To a chilled solution of sodium ethoxide, prepared from 13.8 g of sodium metal and 240 ml of absolute ethanol, 56.9 ml of 3-fluorophenol was added and the mixture was stirred at room temperature for 30 minutes. Crude 3-bromomethyl-2-cyanopyridine (103 g) was added to the mixture at 5 C., and the mixture was reflexed for 2 hours. After being concentrated, the reaction mixture was diluted with ether, and the resultant insoluble materials were removed by filtration. The filtrate was washed with 10% aqueous sodium hydroxide solution and with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was crystallized by trituration with a mixture of ether and n-hexane to yield 58.0 g of pale brown crystals, which were recrystallized from isopropyl ether to give pale yellow needles, mp 52-53 C. Analysis for C13 H9 FN2 O Calculated C, 68.42; H, 3.97; N, 12.27 Found C, 68.37; H, 4.03; N, 12.25.
With potassium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 9 Preparation of 2-Chloro-alpha,alpha,alpha-trifluoro-p-tolyl m-fluorophenyl ether STR38 A mixture of 3-chloro-alpha,alpha,alpha,4-tetrafluorotoluene (30.0 g, 0.15 mol), 3-fluorophenol (20.18 g, 0.18 mol) and potassium carbonate (24.87 g, 0.18 mol) in N,N-dimethylformamide is stirred at 100 C. for eight hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as an amber liquid (32.6 g) which is identified by 1 H-NMR and 13 C-NMR spectral analyses.
With potassium carbonate; caesium carbonate; zinc dibromide; In water; 1,2-dichloro-ethane; acetone; Petroleum ether;
(A) 3-[(4-acetyl-3-fluorophenoxy)methyl]nitrobenzene To a solution of <strong>[98619-07-9]4-acetyl-3-fluorophenol</strong> (22.4 g) in acetone (100 ml) is added powdered potassium carbonate (anhydrous, 20 g) and cesium carbonate (catalytic amount). After 30 minutes of reflux, a solution of m-nitrobenzyl bromide (32.7 g) in acetone (100 ml) is added in one portion. The mixture is refluxed for 15 hours. Water is added to dissolve all solids followed by ether and saturated brine solution. The ether layer is dried over MgSO4 and concentrated to an orange red oil. Addition of petroleum ether gives orange-yellow crystals (31 g, 74percent yield), m.p. 92°-96° C. The above starting material is prepared as follows: To anhydrous zinc bromide (23 g) in ethylene dichloride (25 ml) at room temperature is added sequentially 3-fluorophenol (6.2 g) and acetyl chloride (4.8 g). After gas evolution ceases, the mixture is refluxed one week. The reaction mixture is cooled to room temperature and filtered through a short column of Florisil with the aid of dichloromethane. Concentration gives a red oil which solidifies upon addition of petroleum ether, m.p. 112°-116° C.
With NaOH; triphenylphosphine; In tetrahydrofuran; diethyl ether; water;
(R)-3-(3-fluorophenoxy)-3-phenylpropylchloride A solution of (S)-(-)-3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) was dissolved in THF (200 mL). The mixture was cooled to 0 C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3*50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl/satd. aq. NaCl (25 mL), 0.1 M NaOH/satd. aq. NaCl (2*25 mL), and finally H2O (2*25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an oil. The crude product was chromatographed on silica gel, elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7) of product as a colorless oil.
With nitric acid; acetic acid; at 15 - 26℃; for 1.5 - 2h;Product distribution / selectivity;
3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) delta 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) delta - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) delta 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) delta -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere;
Description 40: tert-butyl 3-((3-fluorophenoxy)methyl)pyrrolidine-1- carboxylate (D40)To a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1 -carboxylate (D39) (200 mg, 0.993 mmol) in dry tetrahydrofuran (4ml) 3-Fluorophenol (0.089ml, 0.993 mmol) was added under N2 atmosphere followed by addition of Diisopropyl azodicarboxylate (0.215ml, 1 .093 mmol) and Triphenylphosphine (286.7 mg, 1 .093 mmol). The solution was stirred overnight at room tempearture. The solvent was evaporated under vacuo and the resulting residue was purified by ISOLUTE SPE- Si cartridge (1 Og) eluting with cyclohexane/ethylacetate from 95:5 to 80:20. Collected fractions, after solvent evaporation afforded the title compound (D40) (218.5 mg)MS: (ES/+) m/z: 240.2 [M-56H+] C16H22FN03 requires 295.161 H NMR (400MHz ,CHLOROFORM-d) delta ppm: 7.26 - 7.16 (m, 1 H), 6.73 - 6.60 (m, 3 H), 4.02 - 3.83 (m, 2 H), 3.62 (dd, J = 7.6, 1 1 .0 Hz, 1 H), 3.57 - 3.45 (m, 1 H), 3.45 - 3.33 (m, 1 H), 3.22 (dd, J = 7.1 , 1 1 .0 Hz, 1 H), 2.78 - 2.60 (m, 1 H), 2.10 (dd, J = 5.4, 12.2 Hz, 1 H), 1 .81 (dd, J = 8.1 , 12.5 Hz, 1 H), 1 .49 (s, 9 H).
218.5 mg
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere;
To a solution of <strong>[114214-69-6]tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate</strong> (D39) (200 mg, 0.993 mmol) in dry tetrahydrofuran (4 ml) 3-Fluorophenol (0.089 ml, 0.993 mmol) was added under N2 atmosphere followed by addition of Diisopropyl azodicarboxylate (0.215 ml, 1.093 mmol) and Triphenylphosphine (286.7 mg, 1.093 mmol). The solution was stirred overnight at room temperature. The solvent was evaporated under vacuo and the resulting residue was purified by ISOLUTE SPE-Si cartridge (10g) eluting with cyclohexane/ethylacetate from 95:5 to 80:20. Collected fractions, after solvent evaporation afforded the title compound (D40) (218.5 mg)
7-(3-fluorophenoxy)thieno[3,2-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
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-(3-fluorophenoxy)ethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;
Methyl 4-(l-(3-fluorophenoxy)ethyl)benzoate. To a solution of methyl 4-(l- hydroxyethyl)benzoate (0.9 g, 5 mmol), 3-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 the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5:1) to give methyl 4-(l-(3-fluorophenoxy)ethyl)benzoate (400 mg, 29%).
29%
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), 3-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 the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(3-fluorophenoxy)ethyl)benzoate (400 mg, 29%).
A mixture of 3-fluorophenol (5.61 g, 50.0 mmol), <strong>[683-57-8]2-bromoacetamide</strong> (7.59 g, 55.0 mmol) and K2C03 (13.82 g, 100 mmol) in acetone (80 mL) was stirred at 70 C overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE / EtOAc (V / V) = 1: 1) to give the title compound as a white solid. (7.89 g, 93%)
93%
With potassium carbonate; In acetone; at 70℃;
A mixture of 3-fluorophenol (5.61 g, 50.0 mmol), <strong>[683-57-8]2-bromoacetamide</strong> (7.59 g, 55.0 mmol) and K2CO3 (13.82 g, 100 mmol) in acetone (80 mL) was stirred at 70 C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid. (7.89 g, 93%)
93%
With potassium carbonate; caesium carbonate; In acetone; at 70℃;Reflux;
In a 250 mL round bottom flask was added 3-fluorophenol (5.61 g, 50.0 mmol), <strong>[683-57-8]2-bromoacetamide</strong> (7.59 g, 55.0 mmol), potassium carbonate (13.82 g, 100 mmol) and acetone (80 mL),The reaction system was heated to 70C and reacted overnight.After the reaction is completed, the mixture is cooled to room temperature, filtered, the solvent is evaporated to dryness under reduced pressure, and the crude product is purified by column chromatography (petroleum ether/ethyl acetate (V/V)=1/1).A white solid (7.89 g, 93%) was obtained.
With sodium methylate; In N,N-dimethyl-formamide; at 130℃; for 10h;
5-Bromoisobenzofuran-1(3H)-one (18.0 g, 84.5 mmol) was dissolved in DMF (18 mL), and 3-fluorophenol (11.5 mL, 126.8 mmol) and sodium methoxide (28% methanol solution, 24 g, 126.8 mmol) were added. A trap bulb of an evaporator was connected, a nitrogen balloon was set, and the mixture was refluxed under heating at 130C for 10 hr. The reaction mixture was allowed to cool to room temperature, water (100 mL) and 4 mol/L aqueous sodium hydroxide solution (30 mL) were added, and the mixture was washed once with each of diethyl ether (200 mL) and toluene (550 mL). The aqueous layer was adjusted to pH 1-2 by adding 4 mol/L hydrochloric acid (about 20 mL), ethanol (70 mL) was added to a dark-brown aqueous solution, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by suction filtration with a Hirsch funnel, and washed twice with a mixed solvent of ethanol/water =1/1 (20 ml) to give 4-bromo-2-[(3-fluorophenoxy)methyl]benzoic acid (20.5 g, 75%). ESIMS m/z: 323, 325 (M - H)-; 1H NMR (270MHz, CDCl3, delta): 5.48 (s, 2H), 6.66-6.86 (m, 3H), 7.21-7.32 (m, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H).
69%
With methanol; sodium methylate; In N,N-dimethyl-formamide; at 120℃; for 23h;
To a stirred solution of <strong>[64169-34-2]5-bromoisobenzofuran-1(3H)-one</strong> (9.5 g, 45 mmol) in DMF (10 mL) was added 3-fluorophenol (6.1 mL, 67 mmol) and sodium methoxide (28% methanol solution, 13 g, 67 mmol), and the solution was stirred for 23 h at 120 C. The reaction mixture was cooled at room temperature, and was pored into 4 M NaOH. The mixture was washed with toluene and diethyl ether. The water layer was acidified with 4 M HCl, and diluted by ethanol. The mixture was stirred overnight and the resultant soid was filtered, washed with water/EtOH = 1/1, and dried under reduced pressure to give 4-bromo-2-((3-fluorophenoxy)methyl)benzoic acid (S2b) (10 g, 69%) as a white solid. 1H NMR (270 MHz, CDCl3): delta 5.48 (s, 2H), 6.66-6.86 (m, 3H), 7.21-7.32 (m, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H). The proton of carboxylic acid was not observed. LC/MS (ESI, [M - H]-, m/z) 323.
To a stirred mixture of 3-fluorophenol (100 mg, 0.893 mmol) in MeCN (5 mL) was added ethyl bromoacetate ( 222 mg , 1.34 mmol) and K2C03 (369 mg , 2.68 mmol). The mixture was stirred at 80 C for 4 hours. The mixture was then filtered and the filtrate concentrated. NaOH (71 mg, 1.79 mmol) and watenEtOH (1: 1, 10 mL) was added to the residue and the mixture stirred at 50 C for 4 hours. The mixture was acidified by adding 1M HC1, and then extracted with ethyl acetate (2x30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated. The residue was directly for the next step. LCMS (m/z): 171.0 (M+l).
To a stirred mixture of 55 3-fluorophenol (100 mg, 0.893 mmol) in 40 MeCN (5 mL) was added 41 ethyl bromoacetate (222 mg, 1.34 mmol) and 19 K2CO3 (369 mg, 2.68 mmol). The mixture was stirred at 80 C. for 4 hours. The mixture was then filtered and the filtrate concentrated. 42 NaOH (71 mg, 1.79 mmol) and 43 water:8 EtOH (1:1, 10 mL) was added to the residue and the mixture stirred at 50 C. for 4 hours. The mixture was acidified by adding 1M 44 HCl, and then extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step. LCMS (m/z): 171.0 (M+1).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: To a solution of phenols (50 mmol) in DMF (80 mL) was added potassium carbonate(10.4 g, 75 mmol) and methyl bromoacetate (5.7 mL, 60mmol). After stirring at room temperature for 12 h, the solution was dilutedwith ethyl acetate (200 mL) and washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the productas awhite solid.
The m-fluorophenol (20g, 0.2piomicron1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68% 0B-2a: Mp: C; 6h (300MuEtazeta; CDC13) 10.4 (1Eta, s), 7.85 (1Eta, dd, J = 8.4Hz, 6.9Etazeta), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Etazeta), 130.9 (d, J = 11.6Etazeta), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Etazeta), 99.7 (d, J = 25.7Etazeta), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Murho: 60-61 C ; 6H (300 MEtazeta; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Etazeta, 8.4Etazeta), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Etazeta), 136.2 (d, J = 12.0Etazeta), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Etazeta), 56.3.
2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate; In dimethyl sulfoxide; at 90℃;
To a solution of <strong>[39890-98-7]2,6-dichloro-4-(trifluoromethyl)pyridine</strong> (200 mg, 0.93 mmol) and 3 fluorophenol (0.074 mL, 0.88 mmol) in DMSO (2 mL), at RT, K2C03 (193 mg, 1.4 mmol) was added and the reaction mixture was shaken at 90 C overnight. Ether and water were added to the reaction mixture, the organic phasewas washed with water, dried and solvent removed under reduced pressure to give 2-chloro-6-(3- fluorophenoxy)-4-(trifluoromethyl)pyridine (p27, 226 mg, y= 88%) as colourless oil.MS (ES) (m/z): 292.0 [M÷H]
2-chloro-6-(3-fluorophenoxy)pyridine-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 36h;Sealed tube;
A mixture of <strong>[32710-65-9]2,6-dichloropyridine-4-carbonitrile</strong> (100 mg, 0.58 mmol), 3-fluorophenol (0.053 mL, 0.63 mmol ) and K2C03 (120 mg, 0.87 mmol) in DMSO (0.7 mL) in a sealed vial was stirred at RT for 36 hrs. Ether and water were added, the organic phase was washed with water, dried and solvent removed under reduced pressure to give 2-chloro-6-(3-fluorophenoxy)pyridine-4-carbonitrile (p28, 128 mg, y= 88%).MS (ES) (m/z): 248.9 [M÷H]
2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile[ No CAS ]
6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 2h;
To a solution of <strong>[13600-42-5]2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile</strong> (75 mg, 0.311 mmol) in DMSO (1mL) K2C03 (52 mg, 0.373 mmol) and 3-fluorophenol (28 ilL, 0.311 mmol) were added and the mixturewas heated to 70 C and shaken at that temperature for 2 hrs. The mixture was cooled down to RT, diluted with DCM and washed with water. Organic phase was dried and evaporated under reduced pressure. Crude material was purified by FC on silica gel (eluent: Cy to Cy/AcOEt 7:3) affording a mixture of the 2 regioisomers 2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile and 6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile (p29, 53 mg, y= 54%). MS (ES) (m/z): 316.9 [M÷H]
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 2h;
3-fluorophenol (0.023 mL, 0.251 mmol), <strong>[43212-41-5]2,4-dichloro-6-methoxypyrimidine</strong> (50 mg, 0.279 mmol) and K2C03 (50.13 mg, 0.363 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAC and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude material was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording a mixture of 2 regioisomers and starting material (65 mg).
tert-butyl 9-[4-(3-fluorophenoxy)-6-methoxypyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
3-fluorophenol (0.023 mL, 0.251 mmol), <strong>[43212-41-5]2,4-dichloro-6-methoxypyrimidine</strong> (50 mg, 0.279 mmol) and K2C03 (50.13 mg, 0.363 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAC and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude material was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording a mixture of 2 regioisomers and starting material (65 mg); Mixture from step a (62 mg), tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 50 mg, 0.195 mmol) and K2C03 (35 mg, 0.254 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAc and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude was purified by FC on silica gel (eluent: Cy to 10% EtOAc) togive a mixture of desired compound and chlorinated analogue (30 mg); 3-fluorophenol (7 ilL, 0.075 mmol), mixture from step b (30 mg) and K2C03 (13.54 mg, 0.098 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 12 hrs at RT. Then further 2 eq of K2C03 were added and the reaction mixture was stirred at 100 C for 48 hrs. The mixture was diluted with EtOAc and water and theorganic phase was washed several times with brine, dried, filtered and evaporated. Crude was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording tert-butyl 9-[4-(3-fluorophenoxy)-6- methoxypyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p87, 20 mg, y= 17%) as colourless oil.MS (ES) (m/z): 475.3 [M÷H]
2-bromo-1-fluoro-4-(3-fluorophenoxy)benzene[ No CAS ]
4-bromo-1-fluoro-2-(3-fluorophenoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3-fluorophenol (0.333 mL, 3.68 mmol) and KOH (206 mg, 3.68 mmol) were stirred at 50 C for 30 mm before the addition of <strong>[1435-53-6]2,4-dibromo-1-fluorobenzene</strong> (934 mg, 3.68 mmol) and Cu powder (234 mg, 3.68 mmol). The reaction mixture was heated to 150 C for 4 hrs and then shaken at 100 C overnight. Crudematerial was purified by FC on silica gel (eluent: cyclohexane), affording a mixture ?l:l of 2-bromo-1-fluoro-4-(3-fluorophenoxy)benzene and 4-bromo-1-fluoro-2-(3-fluorophenoxy)benzene (p13, 280 mg,y=26%).1H NMR (CHLOROFORM-d): 6 ppm 7.29 - 7.35 (m, 1 H) 7.21 - 7.27 (m, 1 H) 7.07 - 7.17 (m, 1 H) 6.96 -7.01 (m, 1 H) 6.81 - 6.89 (m, 1 H) 6.75 - 6.80 (m, 1 H) 6.67 - 6.74 (m, 1 H)
1-bromo-2,4-difluoro-5-(3-fluorophenoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
3-fluorophenol (0.333 mL, 3.68 mmol) and KOH (206 mg, 3.68 mmol) were stirred at 50 °C for 30 mm before the addition of <strong>[28342-75-8]1,5-dibromo-2,4-difluorobenzene</strong> (1 g, 3.68 mmol) and Cu powder (234 mg, 3.68mmol). The reaction mixture was heated to 150 ° for 5 hrs and then shaken at 100 °C overnight. Crudematerial was purified by FC on silica gel (eluent: cyclohexane), affording 1-bromo-2,4-difluoro-5-(3-fluorophenoxy)benzene (p14, 140 mg, y= 12percent)1H NMR (CHLOROFORM-d): 6 ppm 7.30 - 7.40 (m, 2 H) 7.09 (dd, 1 H) 6.82 - 6.89 (m, 1 H) 6.76 (d, 1 H)6.67 - 6.73 (m, 1 H)
1-bromo-2,5-difluoro-3-(3-fluorophenoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
3-fluorophenol (0.099 mL, 1.1 mmol) and KOH (62 mg, 1.1 mmol) were stirred at 50 °C for 30 mm before the addition of <strong>[128259-68-7]1,3-dibromo-2,5-difluorobenzene</strong> (300 mg, 1.1 mmol) and Cu powder (70 mg, 1.1 mmol).The reaction mixture was heated to 100 °C overnight. Crude material was purified by FC on silica gel(eluent: cyclohexane), affording 1-bromo-2,5-difluoro-3-(3-fluorophenoxy)benzene (p18, 61 mg, y=18percent).1H NMR (METHANOL-d4): 6 ppm 7.38-7.49 (m, 1H), 7.33 (ddd, 1H), 6.93-7.02 (m, 2H), 6.82-6.90 (m,2H)
18%
3-fluorophenol (0.099 mL, 1.1 mmol) and KOH (62 mg, 1.1 mmol) were stirred at 50 °C for 30 min before the addition of l,3-dibromo-2,5-difluorobenzene (300 mg, 1.1 mmol) and Cu powder (70 mg, 1.1 mmol). The reaction mixture was heated to 100 °C overnight. The crude material was purified by FC on silica gel (eluent: Cy), giving l-bromo-2,5-difluoro-3-(3-fluorophenoxy)benzene (P5, 61 mg, y= 18percent) as oil. Eta NMR (METHANOL-rf4): delta ppm 7.49-7.38 (m, 1H), 7.33 (ddd, 1H), 7.02- 6.93 (m, 2H), 6.90-6.82 (m, 2H )
1-bromo-2-fluoro-3-(3-fluorophenoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.5%
3-fluorophenol (0.107 mL, 1.18 mmol) and KOH (66 mg, 1.18 mmol) were stirred at 50 °C for 30 min before the addition of l,3-dibromo-2-fluorobenzene (300 mg, 1.18 mmol) and Cu powder (75 mg, 1.18 mmol). The reaction mixture was heated to 100 °C overnight. The crude material was purified by FC on silica gel (eluent: Cy), giving l-bromo-2-fluoro-3-(3-fluorophenoxy)benzene (P7, 12 mg, y= 3.5percent) as oil.
General procedure: DCC (1.3 equiv.) was added to a solution of <strong>[3482-49-3]fusidic acid</strong> 1 (1.0 equiv.) in dichloromethane (15 mL) and resulting reaction mixture was stirred at 25C for 10 min followed by addition of alcohol (1.3 equiv.) and catalytic amount of DMAP. The resulting mixture was stirred at 25C for 2h, after which the solvent was evaporated under reduced pressure. The crude mixture was washed with distilled water (3×15 ml) and extracted with dichloromethane (3×15 ml). The combined organic layers were dried over MgSO4. The crude product was subjected to column chromatography on silica gel using ethyl acetate/hexane as eluent to furnish the target compounds.
2,2-difluoro-2-(3-fluorophenoxy)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: Under inert atmosphere (N2, Schlenk flask), to a suspension of sodiumhydride (8.3 g, 346 mmol, 3.6 equiv) in freshly distilled dioxane (125 mL), phenols (144 mmol, 1.5 equiv) were introduced slowly (exothermic reaction and evolves H2 gas). To this mixture, the chlorodifluoroacetic acid (8.1 mL, 96.0 mmol, 1.0 equiv) was slowly addedat 0 C. Then, the solution was immersed in a temperature controlled oilbath to achieve a gentle reflux. The reaction progress was monitored by19F NMR. After 20-24 h, the acid was completely consumed and the mixture was concentrated in a rotary evaporator. The residue was dissolved in water (400 mL), and acidified with conc. HCl to reach pH= 1. Subsequenlty, the mixture was basified with NaHCO3 to reachpH= 8, and washed with DCM to remove the unreacted phenol. The solution was then acidified to pH= 1 and extracted with DCM(4 × 200 mL). After drying the combined organic layer with MgSO4 and filtration, the solvent was removed by rotary evaporation to obtain the compounds listed in Table 1.
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 3-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,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 0.37g of pale yellow solid IV-4b was obtained,Yield: 30.0%.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
m-Fluorophenol (5.45 mL) and K2C03 (10.40 g) were suspended in DMF (80 mL), <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (8 g) was added, and the mixture was stirred overnight at room temperature. Water was added to the residue, which was then extracted with AcOEt, and the organic layer was separated, washed with water and saturated saline, dried with sodium sulfate, and concentrated to obtain the object compound (8.63 g).NMR2: 6.93-7.12(3H, m), 7.38-7.48(1H, m), 9.34(2H, s).
2-(3-fluorophenoxy)-4-chloro-6-methoxy-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
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.
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