* 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 potassium carbonate In acetone at 60℃; for 16 h;
4-chloro-3-fluorophenol (500 mg, 3.41 mmol) in acetone (10 mL) was added potassium carbonate (942.59 mg, 6.82 mmol) and iodomethane (1.94 g, 13.64 mmol). The reaction mixture was stirred at 60 deg.C for 16 hours. TLC (petroleum ether: ethyl acetate = 20: 1) showed the reaction was complete. The mixture was concentrated to remove the solvent, to the residue was added water (20 mL) and (20mL × 3) and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (470 mg, 2.93 mmol, 85.84percent yield) as a colorless oil.
46%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: at 20℃;
Example 32 l-(5-Chloro-4-fluoro-2-methoxyphenyl)ethanone; [0355] To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3X15 mL) and the resulting organic layer was washed with water, brine and dried. l-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of l -chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AICI3 (1.36 g, 10.23 mmol) in CH3N02 at 0 °C, acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3X15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46percent). NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1 H, J= 10.5 Hz), 7.85 (d, 1H, J = 8.7 Hz).
Reference：
[1] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0593; 0594; 0595; 0596
[2] Patent: WO2011/56652, 2011, A1, . Location in patent: Page/Page column 118-119
Reference：
[1] Journal of Fluorine Chemistry, 1982, vol. 21, p. 459 - 468
8
[ 501-29-1 ]
[ 1089280-66-9 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 0℃; for 2 h;
To 1- chloro-2-fluoro-4-methoxybenzene (5.00 g, 31.2 mmol) in cone. H2SO4 (30 mL) at -10 °C to 0 °C, potassium nitrate (3.47 g, 34.4 mmol) was added portionwise to the reaction mixture. The reaction was stirred at 0 °C for 2 h. The reaction was quenched with iced water and filtered. The obtained solids were recrystallized with hexanes to give Intermediate 15A (4.8 g, 75percent).
70%
at 0℃; for 2 h;
To a mixture of 1-chloro-2-fluoro-4-methoxybenzene (5.00 g, 31.1 mmol) in cone. H2S04 (30 mL) at 0-10eC was added portionwise potassium nitrate (3.78 g, 37.4 mmol) and the reaction was stirred at OeC for 2 h. The reaction was quenched with ice water and filtered. The obtained solids were recrystallized with hexanes to give 4.50 g 3 (70percent) of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene. 1HNMR (400 MHz, DMSO- d6) U8.30 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 3.96 (s, 3H); ESI-MS (m/z) 205.76 (MH)+.
With N-Bromosuccinimide; In dichloromethane; N,N-dimethyl-formamide; at 40℃; for 72h;
Reference Example 16; 2-Bromo-4-chloro-5-fluoroaisole (Reference Compound No.16-1) A mixture of <strong>[501-29-1]4-chloro-3-fluoroanisole</strong> (124 muL, 1.00 mmol) and N-bromosuccinimide was dissolved in mixed solvent of anhydrous N,N-dimethylformamide (0.5 mL) and anhydrous dichloromethane (1 mL), and stirred at 40C for 3 days. After cooling down, chloroform (30 mL) and water (30 mL) were added and partitioned. The water layer was extracted with chloroform (30 mL, 2 times). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (195 mg) as a colorless solid. (Yield 82%)
Diisopropylamine (1.71 mL, 12 mmol) was dissolved in anhydrous THF (20 mL) and the solution was cooled to -78 C under argon. A solution of n-BuLi (2.5 M, 6.0 mL, 12 mmol) was added slowly and the solution was stirred for 0.5 h. To this solution was added a solution of l-chloro-2-fluoro-4-methoxybenzene (1.60 g, 10 mmol) in anhydrous THF (20 mL) and the mixture was stirred for another 20 min. Anhydrous DMF (2.0 mL) was then added slowly and the mixture was warmed to room temperature. Water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to give the subtitle intermediate (1.9 g, 100%) as a yellow solid.
88%
To a solution of Compound 1 (4.0 g, 24.9 mmol) in THF (40 mL) at -78 C was added LDA (2M in hexanes/THF, 12.5 mL, 24.9 mmol) dropwise over a period of 15 mm. The mixture was stirred at -78 C for another 20 mm, then DMF (2.5 mL) was added in one portion. The mixture was stirred at -78 C for 10 mm, then quenched with AcOH (5 mL) and water (30 mL). The mixture was partitioned between EtOAc and water. The organic layer was separated, concentrated and the residue purified by flash chromatography (Si02, 0-30% EtOAc/hexanes) to give 2.30 g (88%) of Compound 2 as a yellow solid. 1H NMR (400 MHz, CDC13): oe 10.42 (d, J=1.1 Hz, 1H), 7.55 (dd, J=8.8, 8.1 Hz, 1H), 6.77 (dd, J=9.1, 1.4 Hz,1H), 3.96 (s, 3H).
85%
EXAMPLE 26a Preparation of intermediate 3-chloro-2-fluoro-6-methoxy-benzaldehyde To a solution of <strong>[501-29-1]4-chloro-3-fluoroanisole</strong> (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at -78 C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at -78 C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at -78 C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%)
61%
<strong>[501-29-1]4-chloro-3-fluoroanisole</strong> (YY-1) in anhydrous THF at -78C under N2(250 mg, 1.56 mmol) was added dropwise a solution of LDA (0.86 mL, 2M,1.71 mmol) and stir for 30 minutes at -78C under N2.DMF (125 mg) was added to the above solution at -78 C under N2.1.71 mmol) and the resulting mixture was stirred at -78 C for 20 minutes.The reaction was quenched with saturated NH4Cl at -78 C. The resulting mixture was heated to 25 C. The mixture was partitioned between EtOAc and H2O.The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to provide the crude product.The crude product is via a flash column (EtOAc: petroleum ether = 1% to 12%)Purified to provide YY-2 (178 mg, 61%) as a white solid.
A solution of <strong>[501-29-1]4-chloro-3-fluoroanisole</strong> (9.0 g) in THF (20 mL) was added to a 0.51M lithium diisopropylamide/THF solution (120 mL) at -780C and the mixture was stirred for 30 min.. DMF (6.5 mL) was added and the reaction mixture was stirred at - 300C. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3-chloro-2- fluoro-6-methoxybenzaldehyde (7.6 g) as white crystals. 1H-NMR (300MHz, CDCl3): delta 3.94 (3H, s) , 6.76 (IH, dd, J=9, EPO <DP n="91"/>2Hz ) , 7 . 51-7 . 57 ( IH , m) , 10 . 40 ( IH, d, J=IHz )
With aluminum (III) chloride; In nitromethane; at 0 - 20℃;
Example 32 l-(5-Chloro-4-fluoro-2-methoxyphenyl)ethanone; [0355] To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3X15 mL) and the resulting organic layer was washed with water, brine and dried. l-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of l -chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AICI3 (1.36 g, 10.23 mmol) in CH3N02 at 0 C, acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3X15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1 H, J= 10.5 Hz), 7.85 (d, 1H, J = 8.7 Hz).
With potassium carbonate; In acetone; at 60℃; for 16h;
4-chloro-3-fluorophenol (500 mg, 3.41 mmol) in acetone (10 mL) was added potassium carbonate (942.59 mg, 6.82 mmol) and iodomethane (1.94 g, 13.64 mmol). The reaction mixture was stirred at 60 deg.C for 16 hours. TLC (petroleum ether: ethyl acetate = 20: 1) showed the reaction was complete. The mixture was concentrated to remove the solvent, to the residue was added water (20 mL) and (20mL × 3) and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (470 mg, 2.93 mmol, 85.84% yield) as a colorless oil.
46%
Example 32 l-(5-Chloro-4-fluoro-2-methoxyphenyl)ethanone; [0355] To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3X15 mL) and the resulting organic layer was washed with water, brine and dried. l-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of l -chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AICI3 (1.36 g, 10.23 mmol) in CH3N02 at 0 C, acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3X15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1 H, J= 10.5 Hz), 7.85 (d, 1H, J = 8.7 Hz).
Tetrahydrofuran (8.35 L) into a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe under N2 atmosphere. Charged 4-Chloro-3-fluoroanisole (1000 g) to a 3-L four-neck flask equipped with a mechanical stirrer, an addition funnel and a temperature probe. Cooled the reaction mass to -60 C. to -70 C. Added n-Butyl Lithium in hexanes (30%, 1.42 kg) in to reaction mass through canula under nitrogen atmosphere slowly, while maintaining the temperature of the reaction mass below -60 C. Maintained the reaction at below -60 C. for 2 h. Meanwhile Iodine solution prepared by dissolving Iodine (2.405 kg) in Tetrahydrofuran (2.4 L) at 25-28 C. Transferred the Iodine solution in step 6 into a clean addition funnel with THF (500 mL) rinse. Added Iodine solution from the addition funnel to the reaction over 120 min while maintaining the internal temperature at <-60 C. Removed cooling bath and allowed to attain -5 C. to 0 C. Submitted the IPC sample when it reaches -5 C. to 0 C.1. A sample was removed at -2 h and checked by HPLC-97.06 AP; Int-01-0.59 AP. Work Up: Quenched the reaction with 20% Na2SO2O3 solution (1.015 kg of sodium thiosulphate dissolved in 5.1 L of DM water) while maintaining the internal temperature at <10 C. Allowed RM to warm to RT. Transfer resulting biphasic mixture into separating funnel, rinse the flask with THF (1.2 L; 1.0-1.5 Vol wrt Int-1), and transfer to separating flask. Removed and retain bottom aqueous phase for further extraction. Concentrated the organic layer. Dissolved concentrated mass in EtOAc (8.0 L; 8.0-8.5 Vol wrt Int-1) Extract the retained aqueous phase with EtOAc (7.1 L: 7.0-7.5 Vol wrt Int-1). Combined all organic phases, Rinse the flask with EtOAc (1.0 L; 1.0-1.5 Vol wrt Int-1). Washed organic phases with DM water (5.7 L; 5.0-6.0 Vol wrt Int-1). Concentrated the organic layer2 on rotovap at 45-50 C. completely. Purification: Added Acetonitrile (5.1 L; 5.0-5.5 vol wrt Int-01). Warmed to 55 C. to dissolve all solid. Rotate the above mass in rotavapor flask at 55 C. for 10 min. Cooled to ambient temperature. Transferred the mass into a clean reactor, rinse the flask with Acetonitrile (1.0 L; 1.0-1.2 vol wrt Int 01) and add rinse into reactor. Added water (1 L; 1.0-1.2 vol wrt Int-01) in to reactor with stirring. Stirred the resulting slurry for 15 min. Added water (5.3 L; 5.0-5.5 Vol wrt Int-01) over 15 min. Stirred the above mass at ambient temperature for 15 min. Unload the mass into a container, rinsed the reactor with water (1 L; 1.0-1.2 vol wrt Int-01), and collected the rinse in same container. Filtered the solid. Rinsed the container with water (1 L; 1.0-1.2 vol wrt Int-01), filtered the rinse. Washed filter cake with water (3.3 L; 3.0-3.5 Vol wrt Int-01). Suck dried for 2 h, then dried at 55 C. in VTD for 15 h. Unload the material. (LOD should be less than 1%). Wt: 1533 g (85.9% yield). Description (color and appearance): Off White crystalline solid. HPLC RT Time 4.897 min Under following conditions: Detector: 210 nm; Injection volume 5.00 muL; Run Time 15 min; Column. YMC UltraHT Pro C18 (50 mm×3.0 mm), 2.0mu; Mobile Phase A-0.05% TFA in MillQ Water; Mobile Phase B-0.05% TFA in Acetonitrile; Flow: 1.0 mL/min; Column Oven-40 C.; Time (min)-0 05 10 12 15; B Conc.-10 90 90 10 10. NMR: (1H NMR, 400 MHz, dmso-d6) delta 7.58 (t, 8.8 Hz, 1H), 6.89 (m, 1H), 3.87 (s, 3H).
With sulfuric acid; potassium nitrate; at 0℃; for 2h;
To 1- chloro-2-fluoro-4-methoxybenzene (5.00 g, 31.2 mmol) in cone. H2SO4 (30 mL) at -10 C to 0 C, potassium nitrate (3.47 g, 34.4 mmol) was added portionwise to the reaction mixture. The reaction was stirred at 0 C for 2 h. The reaction was quenched with iced water and filtered. The obtained solids were recrystallized with hexanes to give Intermediate 15A (4.8 g, 75%).
70%
With sulfuric acid; potassium nitrate; at 0℃; for 2h;
To a mixture of 1-chloro-2-fluoro-4-methoxybenzene (5.00 g, 31.1 mmol) in cone. H2S04 (30 mL) at 0-10eC was added portionwise potassium nitrate (3.78 g, 37.4 mmol) and the reaction was stirred at OeC for 2 h. The reaction was quenched with ice water and filtered. The obtained solids were recrystallized with hexanes to give 4.50 g 3 (70%) of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene. 1HNMR (400 MHz, DMSO- d6) U8.30 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 3.96 (s, 3H); ESI-MS (m/z) 205.76 (MH)+.
1-chloro-2-fluoro-5-iodo-4-methoxybenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With iodine; silver trifluoroacetate; In chloroform; at 20℃; for 16h;
A mixture of <strong>[501-29-1]4-chloro-3-fluoroanisole</strong> (2.52 g, 15.7 mmol, 1.0 eq.), silver trifluoroacetate (8.57 g, 38.8 mmol, 2.5 eq.), iodine (7.95 g, 31.3 mmol, 2.0 eq.) and chloroform (100 mL) is stirred at r.t. for 16h. The reaction mixture is filtered through a silica plug on a fritted funnel and rinsed with chloroform. The filtrate is washed successively with an aqueous solution of Na2S2O3, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel to afford the expected product
With iodine; silver trifluoroacetate; In chloroform; at 20℃; for 16h;
102631 A mixture of <strong>[501-29-1]4-chloro-3-fluoroanisole</strong> (2.52 g, 15.7 mmol, 1.0 eq.), silver trifluoroacetate (8.57 g,38.8 mmol, 2.5 eq.), iodine (7.95 g, 31.3 mmol, 2.0 eq.) and chloroform (100 mL) is stirred at r.t. for 16 h. The reaction mixture is filtered through a silica plug on a fritted funnel and rinsed with chloroform. The filtrate is washed successively with an aqueous solution of Na2S2O3, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel to afford the expected product.
1-(3-chloro-2-fluoro-6-methoxyphenyl)ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 2, 2, 6, 6-tetramethylpipe dine (528 mg, 3.74 mmol) in Tetrahydrofuran (10 ml.) was added n-butyllithium in hexane(1 .5ml, 3.74 mmol) at -78 C. After completion of the addition the reaction mixture was stirred at -78 C for 1 h. Then, 1 -chloro-2-fluoro-4- methoxybenzene (200 mg, 1 .246 mmol) was added and the mixture was stirred for another 1 h. Acetaldehyde (274 mg, 6.23 mmol) was then added and the mixture was stirred for another 1 h. The reaction was quenched with saturated NH4CI (10ml_) and was extrated with EtOAc (2x10 ml_). T combined organic layers were dried over Na2S04 and concentrated, m/z: [M - OH]+ Calcd for C9H9CIFO 187.0; Found 187
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