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CAS No. : | 59280-70-5 | MDL No. : | MFCD00042520 |
Formula : | C8H7ClFNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GVRKNSAEOVXHOS-UHFFFAOYSA-N |
M.W : | 187.60 | Pubchem ID : | 853174 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | 2 Preparation of 2-Fluoro-4-chloroacetanilide EXAMPLE 2 Preparation of 2-Fluoro-4-chloroacetanilide A solution of 0.85 parts of 4-chloroacetanilide in 52 parts of acetic acid was cooled to 0° C. and stirred while 0.542 parts of fluoroxytrifluoromethane was added over a period of one hour. The reaction mixture was degassed and the solvent removed reduced pressure. Analysis of the remaining crude reaction product by gas chromatographic techniques indicated a 60% yield of 2-fluoro-4-chloro-acetanilide and a 5% yield of 2,6-difluoroacetanilide at 83% conversion. | |
Aus 2'-Fluoracetanilid u. Cl2/AcOH; | ||
4-Chlor-2-fluor-anilin, sd. Acetanhydrid; |
B Step B: Step B: Synthesis of 4-Chloro-2-fluoroacetanilide as an Intermediate To a stirred solution of 180.0 g (1.17 moles) of 2-fluoroacetanilide in 210 ml of p-dioxane was slowly added dropwise 173.4 g (9.29 moles) of sulfuryl chloride. Upon completion of addition the reaction mixture stirred at ambient temperature for 16 hours. A solid was collected by filtration, washed with water, and dried to yield 155 g of 4-chloro-2-fluoroacetanilide; m.p. 147°-148° C. | ||
B Synthesis of 4-Chloro-2-fluoroacetanilide as an Intermediate Step B Synthesis of 4-Chloro-2-fluoroacetanilide as an Intermediate To a stirred solution of 180.0 g (1.17 moles) of 2-fluoroacetanilide in 210 ml of p-dioxane was slowly added dropwise 173.4 g (9.29 moles) of sulfuryl chloride. Upon completion of addition the reaction mixture stirred at ambient temperature for 16 hours. A solid was collected by filtration, washed with water, and dried to yield 155 g of 4-chloro-2-fluoroacetanilide; m.p. 147°-148° C. | ||
Fluoracetanilid, Chlor; | ||
aus 2'-Fluoracetanilid und Ac2O; | ||
aus 2'-Fluoracetanilid und Cl2; | ||
2-Fluoracetanilid, Chlor; | ||
2-Fluor-acetanilid, Chlor, AcOH; | ||
2'-Fluoracetanilid, Chlor, Eisessig; | ||
2'-Fluoracetanilid, Chlor; | ||
aus 2'-Fluor-acetanilid und Cl2; | ||
Chlor, 2'-Fluoracetanilid, Eisessig; | ||
2'-Fluoracetanilid, Cl2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diphosphorus pentasulfide In benzene for 3h; Heating; | ||
With diphosphorus pentasulfide In benzene for 3h; Reflux; | 9.ii Step (ii): N-(4-Chloro-2-fluorophenyl)ethanethioamide Step (ii): N-(4-Chloro-2-fluorophenyl)ethanethioamide To a suspension of phosphorus pentasulfide (25.52 g, 115.5 mmol) in anhydrous benzene (400 ml) was added N-(4-chloro-2-fluorophenyl) acetamide (24.0 g, 128.34 mol) and the bright yellow suspension was heated to reflux for 3 hours. The solution was cooled to 0 °C and filtered and the precipitate was washed with diethyl ether and discarded. The combined organics were extracted with dilute aqueous sodium hydroxide solution (10 %). After cooling the aqueous layer to 0 °C, it was carefully acidified with concentrated hydrochloric acid (to pH 2-3). The precipitated product was collected by filtration and washed with water to obtain the title compound.1H NMR (DMSO-d6) δ ppm 2.57 (s, 3 H) 7.35-7.37 (m, 1 H) 7.55-7.60 (m, 2 H), 11.46 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In acetic acid; at 20℃; for 2h; | A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.0 g, 34.3 mmol) in acetic acid (3 mL) was treated with acetic anhydride (6.45 mL, 68.7 mmol) and stirred at RT for 2 h. The mixture was poured onto ice water, stirred for 2 h and the resulting solid collected via filtration and dried to afford N-(4-chloro-2-fluorophenyl)acetamide (6.12 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): delta 9.80 (s, 1H), 7.91 (t, J=8.7 Hz, 1H), 7.45 (dd, J=10.8, 2.4 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 2.07 (s, 3H). |
95% | With acetic acid; at 20℃; for 2h; | Example A45: A solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (5.0 g, 34.3 mmol) in aceticacid (3 mL) was treated with acetic anhydride (6.45 mL, 68.7 mmol) and stirred at RT for 2h. The mixture was poured onto ice water, stirred for 2 hand the resulting solid collected viafiltration and dried to afford N-( 4-chloro-2-fluorophenyl)acetamide (6.12 g, 95% yield). 1HNMR (400 MHz, DMSO-d6): 8 9.80 (s, 1 H), 7.91 (t, J = 8.7 Hz, 1 H), 7.45 (dd, J = 10.8, 2.4Hz, 1 H), 7.22 (d, J = 8.9 Hz, 1 H), 2.07 (s, 3 H). |
In acetic acid; at 20℃; for 3h; | To a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (50.0 g, 344 mmol) in AcOH (3OmL) is added Ac2O (60 ml_) and the reaction is stirred at room temperature for 2 hours. The mixture is poured into ice water (500 mL) to give a solid precipitate. The mixture is stirred for an additional 1 hour at room temperature. The solid is filtered and washed with water and hexanes, then air dried to give lambda/-(4-chloro-2-fluorophenyl) acetamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: phosphorus pentasulfide / benzene / 3 h / Heating 2: NaH / toluene / 0.5 h / Heating 3: aq. NaOH / ethane-1,2-diol / 3 h / 125 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; sulfuric acid; water; ethyl acetate | 1 Preparation of N-(4-Chloro-2-fluoro-5-nitrophenyl)acetamide EXAMPLE 1 Preparation of N-(4-Chloro-2-fluoro-5-nitrophenyl)acetamide To a stirred solution of 375.2 g (2 mole) of N-(4-chloro-2-fluorophenyl)acetamide in 600 mL of concentrated sulfuric acid and 400 mL of oleum (30%) was added 166 mL of a 1:1 mixture of nitric acid (100%) and concentrated sulfuric acid at 0° C. over a period of 1.5 hours. After the addition was complete, the reaction mixture was poured into 11 L of ice water. The precipitate was filtered and the filter cake suspended in 200 mL of water. The solid was redissolved by the addition of 2 L of ethyl acetate and neutralized with aqueous NaOH to pH 7. The two phase mixture was heated to 50° C. and separated. The organic layer was washed with 150 mL of water. 200 mL of ethyl acetate were distilled off and the remaining solution was treated with 12 g of Celite at 70° C., filtered and washed with another 200 mL of ethyl acetate. The filtrate was concentrated to 1080 g and allowed to crystallize at 5° C. overnight. After filtration and drying, 384 g of the title compound was isolated as a solid melting at 145-149° C. (purity: >99.5% by HPLC). A second crystallization from the mother liquor afforded another 45.5 g of the title compound. | |
With Concentrated HNO3 In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; di-isopropyl ether; sulfuric acid; ethyl acetate | 1.A Step A Step A Preparation of N-(4-chloro-2-fluoro-5-nitrophenyl)acetamide To a stirred solution of N-(4-chloro-2-fluorophenyl)acetamide (180.6 g, 0.96 mol) in concentrated sulfuric acid (1L) was added a mixture of 175 mL of concentrated HNO3 and 175 mL of concentrated sulfuric acid at 0 to 5° C. in 1.5 h. After the addition was finished, the reaction mixture was stirred for another 0.5 h. The solution was poured into 5 L of ice water. After the product precipitated, it was isolated by filtration and then was dissolved in 2.5 L of ethyl acetate. After separation of the water layer, the organic layer was dried over sodium sulfate and then the solvent was evaporated. The crude product was triturated in diisopropyl ether (1.5 L), isolated by filtration, and dried under reduced pressure to afford the title compound of Step A (196.2 g, 87.6%) melting at 145-146° C. 1 H NMR (Me2 SO-d6) δ 10.3-10.2 (s, 1H), 8.9 (d, 1H), 7.9-7.8 (d, 2.2-2.1 (s, 3H). | |
With nitric acid In sulfuric acid | 29 Preparation of 4'-Chloro-2'-fluoro-5'-nitroacetanilide STR109 EXAMPLE 29 Preparation of 4'-Chloro-2'-fluoro-5'-nitroacetanilide STR109 A mixture of 4'-chloro-2'-fluoroacetanilide (51 g, 0.272 mol) in concentrated sulfuric acid (100 mL) is cooled to 0° C., treated with nitric acid (90% real, 14 mL, 0.300 mol) over 45 minutes, stirred for 10 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a tan solid which is washed with water, dried overnight, and recrystallized from a chloroform/hexanes (17:1) solution to give the title product as a yellow solid. |
With nitric acid In sulfuric acid | 29 Preparation of 4'-Chloro-2'-fluoro-5'-nitroacetanilide STR108 EXAMPLE 29 Preparation of 4'-Chloro-2'-fluoro-5'-nitroacetanilide STR108 A mixture of 4'-chloro-2'-fluoroacetanilide (51 g, 0.272 mol) in concentrated sulfuric acid (100 mL) is cooled to 0° C., treated with nitric acid (90% real, 14 mL, 0.300 mol) over 45 minutes, stirred for 10 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a tan solid which is washed with water, dried overnight, and recrystallized from a chloroform/hexanes (17:1) solution to give the title product as a yellow solid. | |
With nitric acid In sulfuric acid | 29 Preparation of 4'-Chloro-2'-fluoro-5'-nitroacetanilide STR115 EXAMPLE 29 Preparation of 4'-Chloro-2'-fluoro-5'-nitroacetanilide STR115 A mixture of 4'-chloro-2'-fluoroacetanilide (51 g, 0.272 mol) in concentrated sulfuric acid (100 mL) is cooled to 0° C., treated with nitric acid (90% real, 14 mL, 0.300 mol) over 45 minutes, stirred for 10 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a tan solid which is washed with water, dried overnight, and recrystallized from a chloroform/hexanes (17:1) solution to give the title product as a yellow solid. | |
With Concentrated HNO3 In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; di-isopropyl ether; sulfuric acid; ethyl acetate | 1.A Step A: Step A: Preparation of N-(4-chloro-2-fluoro-5-nitrophenyl)acetamide To a stirred solution of N-(4-chloro-2-fluorophenyl)acetamide (180.6 g, 0.96 mol) in concentrated sulfuric acid (1L) was added a mixture of 175 mL of concentrated HNO3 and 175 mL of concentrated sulfuric acid at 0 to 5 °C in 1.5 h. After the addition was finished, the reaction mixture was stirred for another 0.5 h. The solution was poured into 5 L of ice water. After the product precipitated, it was isolated by filtration and then was dissolved in 2.5 L of ethyl acetate. After separation of the water layer, the organic layer was dried over sodium sulfate and then the solvent was evaporated. The crude product was triturated in diisopropyl ether (1.5 L), isolated by filtration, and dried under reduced pressure to afford the title compound of Step A (196.2 g, 87.6%) melting at 145-146 °C. 1H NMR (Me2SO-d6) δ 10.3-10.2 (s, 1H), 8.9 (d, 1H), 7.9-7.8 (d, 1H), 2.2-2.1 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane | 1 Preparation of bis-(5-acetamino-2-chloro-4-fluorobenzene)disulfide EXAMPLE 1 Preparation of bis-(5-acetamino-2-chloro-4-fluorobenzene)disulfide In a 100 ml reaction flask equipped with a condenser, a thermometer and a stirrer, 7.5 g (0.04 mol) of 4-chloro-2-fluoro-acetanilide was suspended in 40 cc of dichloromethane, and 10.7 g (0.08 mol) of anhydrous aluminum chloride was added thereto. The mixture was stirred at room temperature for 30 minutes, and then 4.1 g (0.03 mol) of sulfur monochloride was dropwise added thereto from a dropping funnel. After completion of the dropwise addition, the mixture was reacted at 40° C. for 3 hours. Then, the reaction solution was cooled to room temperature and poured into 200 g of ice water. The organic layer was extracted with 150 ml of ethyl acetate and dried. Then, dichloromethane and ethyl acetate as the solvents were distilled off under reduced pressure, and the residue was washed with a small amount of ethyl acetate to obtain 7.4 g of bis-(5-acetamino-2-chloro-4-fluorobenzene)disulfide (1). Yield was 84.7%. The physical properties and confirmation data are shown below. Physical property: melting point of 241°-3° C. Confirmation data 1H-NMR[SO(CD3)]: 9.8(2H,s), 7.39-8.49(4H,q), 2.10(6H,s) MS: Peaks attributable to chlorine isotope were found at P+2 and P+4 based on 436(P). |
79.3% | In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane | 2 Preparation of bis-(5-acetamino-2-chloro-4-fluorobenzene)disulfide EXAMPLE 2 Preparation of bis-(5-acetamino-2-chloro-4-fluorobenzene)disulfide In a 100 ml reaction flask equipped with a condenser, a thermometer and a stirrer, 7.5 g (0.04 mol) of 4-chloro-2-fluoro-acetanilide was suspended in 40 cc of dichloromethane, and 10.7 g (0.08 mol) of anhydrous aluminum chloride was added thereto. The mixture was stirred at room temperature for 30 minutes, and then 8.1 g (0.06 mol) of sulfur monochloride was dropwise added thereto by a dropping funnel. After the completion of the dropwise addition, the mixture was reacted at 40° C. for 3 hours. Then, the reaction solution was cooled to room temperature and poured into 200 g of ice water. The organic layer was extracted with 150 ml ethyl acetate and dried. Then, dichloromethane and ethyl acetate as the solvents were distilled off under reduced pressure, and the residue was washed with a small amount of ethyl acetate to obtain 6.9 g of bis-(5-acetamino-2-chloro-4-fluorobenzene)disulfide (1). Yield was 79.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With nitric acid | 22.a a. a. 4-chloro-2-fluoro-5-nitroacetanilide Into a 500 ml, 3-necked round-bottomed flask equipped with a mechanical stirrer was placed 4-chloro-2-fluoroacetanilide (56.3 g, 0.3 mmol) and conc. H2 SO4 (100 ml). While cooling to 0° C., fuming nitric acid (21 g, 0.33 mol) was added over 30 minutes then the reaction mixture was poured onto 2 liters of ice. When the ice had melted the solid product was collected by filtration, washed with water and dried in vacuo to give 44 g (63% yield) of the nitrated material as a tan solid. |
63% | With nitric acid | 35.a a. a. 4-chloro-2-fluoro-5-nitroacetanilide Into a 500 ml, 3-necked round-bottomed flask equipped with a mechanical stirrer was placed 4-chloro-2-fluoroacetanilide (56.3 g, 0.3 mmol) and conc. H2 SO4 (100 ml). While cooling to 0° C., fuming nitric acid (21 g, 0.33 mol) was added over 30 minutes and then the reaction mixture was poured onto 2 liters of ice. When the ice had melted the solid product was collected by filtration, washed with water and dried in vacuo to give 44 g (63 % yield) of the nitrated material as a tan solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; ethanol; | EXAMPLE 28 Preparation of 4'-Chloro-2'-fluoroacetanilide STR108 Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20 C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the title product as a white solid. | |
With triethylamine; In tetrahydrofuran; ethanol; | EXAMPLE 28 Preparation of 4'--Chloro-2'-fluoroacetanilide STR114 Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20 C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the title product as a white solid. | |
With triethylamine; In tetrahydrofuran; ethanol; | EXAMPLE 28 Preparation of 4'-Chloro-2'-fluoroacetanilide STR107 Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20 C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the title product as a white solid. |
With triethylamine; In dichloromethane; at 20 - 25℃; for 16h; | Step (i): N-(4-Chloro-2-fluorophenyl)acetamide To the solution of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (25.0 g, 172.41 mmol) in dichloromethane (500 ml) was added triethylamine (34.82 g, 344.82 mmol) and acetyl chloride (14.79 g, 189.65 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mass was quenched with water and the aqueous layer was extracted into dichloromethane. The organic layer was dried (sodium sulphate) and evaporated in vacuo to afford the crude product which was triturated from diethyl ether and used without further purification.1H NMR (DMSO-d6) delta ppm 2.09 (s, 3 H) 7.35-7.37 (m, 1 H), 7.47-7.50 (m, 1 H), 7.92 - 7.96 (m, 1 H), 9.84 (br. s, 1 H)MS ES+: 188 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | With sodium hydroxide; water In ethanol for 3h; Reflux; | |
With sodium hydroxide In ethanol; water | C Step C: Step C: Synthesis of 4-Chloro-2-fluoroaniline as an Intermediate To a stirred solution of 155 g (0.83 mole) of 4-chloro-2-fluoroacetanilide in 400 ml of ethanol was added dropwise a solution of 72.0 g (1.8 moles) of sodium hydroxide in 100 ml of water. Upon completion of addition the reaction mixture was heated under reflux for three hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether. The combined extracts were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 81.0 g of 4-chloro-2-fluoroaniline; b.p. 83-85/12 mm. | |
With sodium hydroxide In ethanol; water | C Synthesis of 4-Chloro-2-fluoroaniline as an Intermediate Step C Synthesis of 4-Chloro-2-fluoroaniline as an Intermediate To a stirred solution of 155 g (0.83 mole) of 4-chloro-2-fluoroacetanilide in 400 ml of ethanol was added dropwise a solution of 72.0 g (1.8 moles) of sodium hydroxide in 100 ml of water. Upon completion of addition the reaction mixture was heated under reflux for three hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether. The combined extracts were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 81.0 g of 4-chloro-2-fluoroaniline; b.p. 83-85/12 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; nitric acid | 5 EXAMPLE 5 EXAMPLE 5 Production of the acetonitroanilide (VII) from the acetanilide (VI): To a 20% ice-cooled fuming sulfuric acid (50 g), 4-(N-acetylamino)-1-chloro-3-fluorobenzene (9.4 g) was dissolved, followed by gradual addition of fuming nitric acid (3.5 g) while keeping the temperature at 0° to 5° C. The resultant mixture was stirred at the same temperature for 1 hour and poured into ice (50 g). The precipitated crystals were collected by filteration, and the filtrate was washed with water and dried to give 11.6 g of 4-(N-acetylamino)-1-chloro-5-fluoro-2-nitrobenzene. M.P. 124.7°-125.7° C. | |
With sulfuric acid; nitric acid | 5 EXAMPLE 5 EXAMPLE 5 Production of the acetonitroanilide (VII) from the acetanilide (VI): To 20 % ice-cooled fuming sulfuric acid (50 g), 4-(N-acetylamino)-1-chloro-3-fluorobenzene (9.4 g) was dissolved, followed by gradual addition of fuming nitric acid (3.5 g) while keeping the temperature at 0° to 5° C. The resultant mixture was stirred at the same temperature for 1 hour and poured into ice (50 g). The precipitated crystals were collected by filteration, and the filtrate was washed with water and dried to give 11.6 g of 4-(N-acetylamino)-1-chloro-5-fluoro-2-nitrobenzene. M.P., 124.7°-125.7° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrachloromethane; sulfuric acid | 8 EXAMPLE 8 EXAMPLE 8 Production of the sulfonyl chloride (X) from the acetanilide (VI): 4-Chloro-2-fluoroacetanilide (100 g) was dissolved in conc. sulfuric acid (80 ml) under ice-cooling. 60% fuming sulfuric acid (200 ml) was dropwise added thereto at 0° to 10° C., followed by stirring for 1 hour. Carbon tetrachloride (300 ml) was added to the resultant mixture at room temperature, and the mixture was stirred at 60° to 65° C. for 5 hours. After being allowed to cool to room temperature, carbon tetrachloride (300 ml) was added to the mixture, and the resulting mixture was stirred at 60° to 65° C. for 5 hours. After being allowed to cool, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 139 g of 4-chloro-2-fluoro-5-chlorosulfonylacetanilide. M.P. 138°-139° C. | |
In tetrachloromethane; sulfuric acid | 8 EXAMPLE 8 EXAMPLE 8 Production of the sulfonyl chloride (X) from the acetanilide (VI): 4-Chloro-2-fluoroacetanilide (100 g) was dissolved in conc. sulfuric acid (80 ml) under ice-cooling. 60% fuming sulfuric acid (200 ml) was dropwise added thereto at 0° to 10° C., followed by stirring for 1 hour. Carbon tetrachloride (300 ml) was added to the resultant mixture at room temperature, and the mixture was stirred at 60° to 65° C. for 5 hours. After being allowed to cool to room temperature, carbon tetrachloride (300 ml) was added to the mixture, and the resulting mixture was stirred at 60° to 65° C. for 5 hours. After being allowed to cool, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 139 g of 4-chloro-2-fluoro-5-chlorosulfonylacetanilide. M.P., 138°-139° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In methanol; sodium hydroxide; ethanol; dichloromethane; acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed under a reduced pressure of 300 mm.Hg. to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline. The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled to 10° C in an ice-acetone bath and 50% aqueous sodium hydroxide was added dropwise, with stirring, until pH 11 was obtained. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhydrous sodium sulfate and the solvent removed under reduced pressure of 300 mm Hg. to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 = 1.5541. 9.44 Parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° C to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5° C. | |
With hydrogenchloride In methanol; sodium hydroxide; ethanol; dichloromethane; acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed at a reduced pressure of 300 mm.Hg to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled to 10° in an ice-acetone bath and 50% aqueous sodium hydroxide was added dropwise, with stirring, until pH 11 was obtained. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhyrous sodium sulfate and the solvent removed at a reduced pressure of 300 mm.Hg to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 = 1.5541. 9.44 parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° C. to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide In diethyl ether; ethanol; dichloromethane | 1 Preparation of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed under a reduced pressure of 300 mm Hg. to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline. The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled in an ice-acetone bath, down to 10° C, and 50% aqueous sodium hydroxide was added until pH 11 was reached. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhydrous sodium sulfate and the solvent removed under reduced pressure of 300 mm Hg. to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 1.5541. The moist, solid hydrochloride salt of 4-chloro-2-fluoroaniline was cooled in an ice-acetone bath and treated at 10° C with 50% aqueous sodium hydroxide until pH 11 was reached. The resulting two-phase mixture was extracted four times; 500 parts of methylene chloride were used for each extraction. The combined organic extracts were dried with anhydrous sodium sulfate and the solvent removed under reduced pressure of 300 mm Hg. to leave 89 parts of light brown, oily 4-chloro-2-fluoroaniline, nD25 - 1.5541. 4.8 Parts of 4-chloro-2-fluoroaniline were added to a solution of 5 parts of 3,4,5,6-tetrahydrophthalic anhydride in 150 parts of diethyl ether and stirred for 1.5 hours. The solution was divided into two equal portions. One portion was evaporated under reduced pressure of 300 mm Hg. at 25° C to isolate 5.4 parts of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid as white crystals melting at 91°-93° C. The other portion was used in Example 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chlorine In acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid EXAMPLE 1 Preparation of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid 71 Parts of chlorine were bubbled during one hour at 25°-27° C with ice-water cooling into a solution of 140 parts of 2'-fluoroacetanilide in 500 parts of glacial acetic acid. After stirring for 4 hours at 25°-27° C, 4'-chloro-2-fluoroacetanilide precipitated. The product was collected by filtration, and the filtrate was poured into 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155° C. | |
With chlorine In acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid EXAMPLE 1 Preparation of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid A solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid was treated with 71 parts of chlorine during 1 hour at 25°-27° C with ice-water cooling. While stirring for 4 hours at 25°-27° C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of product pecipitated was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C. to yield 119 parts of 4'-chloro-2'-fluroacetanilide as white crystals melting at 152°-155° C. | |
With chlorine In acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione EXAMPLE 1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during 1 hour, at 25°-27° C, with icewater cooling. While stirring for 4 hours at 25°-27° C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2,000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C to yield 119 parts of 4'-chloro-2 '-fluoroacetanilide as white crystals melting at 152°-155° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chlorine In acetic acid | 1.a (a) (a) Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with ice water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°. | |
With chlorine In acetic acid | 1.a (a) (a) Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27° C, with icewater cooling. While stirring for 4 hours at 25°-27° C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155° C. | |
With chlorine In acetic acid | 1.a a. a. Preparation of 4-Chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with icewater cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°. |
With chlorine In acetic acid | 1 Preparation of 4-chloro-2-fluoroaniline EXAMPLE 1 Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°C, with icewater cooling. While stirring for 4 hours at 25°-27°C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45°C to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°C. | |
With chlorine In acetic acid | 1.a (a) (a) Preparation of 4-Chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with ice-water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°. | |
With chlorine In acetic acid | 1 Preparation of 3-Chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole STR9 a. Preparation of 4-Chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27° C., with ice-water cooling. While stirring for 4 hours at 25°-27° C., 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C. to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155° C. | |
With chlorine In glacial acetid acid | 1 Preparation of 4-chloro-2-fluoroaniline EXAMPLE 1 Preparation of 4-chloro-2-fluoroaniline Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetid acid, during one hour, at 25°-27°, with ice-water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 199 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,3-di(adamantan-1-yl)-1H-imidazol-3-ium tetrafluoroborate; N-chloro-succinimide; camphor-10-sulfonic acid In 1,4-dioxane at 25℃; for 24h; | General Procedure A: General procedure: A mixture of Acetylaniline (0.2 mmol), NCS (0.26 mmol), D-CSA (0.1 mmol) and 1,3-di(1-adamantl)imidazolium tetrafluoroborate (0.01 mmol) in dioxane (1 mL) wasstirred at room temperature (25 oC) under air atmosphere for 24h. The reactionmonitored by GC-MS. When the acetylaniline was consumed completely, the reactionmixture was quenched with saturated aq. NaHCO3 (4 mL). The resulting mixture wasextracted with EtOAc (4 mL x 3). The organic layer was washed with pure water (4ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered andthe solvent was removed under reduced pressure to provide the crude product. Thepurification was performed by flash column chromatography on silica gel. |
68.9% | With sulfuryl dichloride In 1,4-dioxane at 20℃; for 24h; | |
With chlorine In acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro2H-isoindole-1,3-dione EXAMPLE 1 Preparation of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro2H-isoindole-1,3-dione A solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid was treated with 71 parts of chlorine during one hour at 25°-27°C with ice-water cooling. While stirring for 4 hours at 25°-27°C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of product precipitated was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45°C. to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°C. |
With chlorine In acetic acid | 1 Preparation of 2-(4-Chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione EXAMPLE 1 Preparation of 2-(4-Chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione A solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid was treated with 71 parts of chlorine during one hour at 25°-27° C. with ice-water cooling. While stirring for 4 hours at 25°- 27° C., 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of product precipitated was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C. to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155° C. | |
With chlorine In acetic acid | 1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione Example 1 Preparation of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with ice water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured into 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; di-isopropyl ether; sulfuric acid; ethyl acetate | 1.A Step A: Step A: Preparation of N -(4-chloro-2-fluoro-5-nitrophenyl)acetamide To a stirred solution of N-(4-chloro-2-fluorophenyl)acetamide (180.6 g, 0.96 mol) in concentrated sulfuric acid (1L) was added a mixture of 175 mL of concentrated HNO3and 175 mL of concentrated sulfuric acid at 0 to 5 °C in 1.5 h. After the addition was finished, the reaction mixture was stirred for another 0.5 h. The solution was poured into 5 L of ice water. After the product precipitated, it was isolated by filtration and then was dissolved in 2.5 L of ethyl acetate. After separation of the water layer, the organic layer was dried over sodium sulfate and then the solvent was evaporated under reduced pressure. The crude product was triturated in diisopropyl ether (1.5 L), isolated by filtration, and dried under reduced pressure to afford the title compound of Step A (196.2 g, 87.6%) melting at 145-146 °C. 1H NMR ((CD3)2SO): δ 10.3-10.2 (s, 1H), 8.9 (d, 1H), 7.9-7.8 (d, 1H), 2.2-2.1 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C | ||
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C | ||
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4: dimethyl sulfoxide / 20 °C | ||
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4: dimethyl sulfoxide / 20 °C 5: hydrogenchloride / 7 h / 0 - 80 °C | ||
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 20 °C 5.1: hydrogenchloride / 7 h / 0 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4: dimethyl sulfoxide / 20 °C 5: hydrogenchloride / 7 h / 0 - 80 °C 6: potassium fluoride; aluminum oxide / N,N-dimethyl acetamide / 1 h / Sonication | ||
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 20 °C 5.1: hydrogenchloride / 7 h / 0 - 80 °C 6.1: 40% potassium fluoride/alumina / N,N-dimethyl acetamide / 1 h / Sonication |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4: dimethyl sulfoxide / 20 °C 5: hydrogenchloride / 7 h / 0 - 80 °C 6: potassium fluoride; aluminum oxide / N,N-dimethyl acetamide / 1 h / Sonication 7: water; 1,4-dioxane / 100 °C | ||
Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 20 °C 5.1: hydrogenchloride / 7 h / 0 - 80 °C 6.1: 40% potassium fluoride/alumina / N,N-dimethyl acetamide / 1 h / Sonication 7.1: 1,4-dioxane; water / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: n-butyllithium / tetrahydrofuran / 4.75 h / -78 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4: dimethyl sulfoxide / 20 °C 5: hydrogenchloride / 7 h / 0 - 80 °C 6: potassium fluoride; aluminum oxide / N,N-dimethyl acetamide / 1 h / Sonication 7: water; 1,4-dioxane / 100 °C 8: triethylamine / tetrahydrofuran / 20 - 60 °C | ||
Multi-step reaction with 8 steps 1.1: n-butyllithium / tetrahydrofuran / 2.5 h / -78 °C / Inert atmosphere 1.2: 0.25 h / -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 20 °C 5.1: hydrogenchloride / 7 h / 0 - 80 °C 6.1: 40% potassium fluoride/alumina / N,N-dimethyl acetamide / 1 h / Sonication 7.1: 1,4-dioxane; water / 100 °C 8.1: triethylamine / tetrahydrofuran / 20 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 4.75h; Inert atmosphere; | A45 Example A45 A -78° C. solution of N-(4-chloro-2-fluorophenyl)acetamide (2.00 g, 10.66 mmol) in THF (40 mL), under Ar, was treated with butyl lithium (16.66 mL, 26.7 mmol), stirred at -78° C. for 2.5 h, treated slowly with DMF (1.651 mL, 21.32 mmol), stirred for 15 min at -78° C. and slowly warmed to RT. The mixture was stirred for 2 h, treated with satd. NH4Cl, the layers separated and the aqueous layer extracted with EtOAc (1*). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 48% yield) as an off-white solid. MS (ESI) m/z: 216.0 [M+H]+. |
48% | Stage #1: 4'-chloro-2'-fluoroacetanilide With n-butyllithium In tetrahydrofuran at -78℃; for 2.5h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 0.25h; | A45 A -78°C solution ofN-(4-chloro-2-fluorophenyl)acetamide (2.00 g, 10.66 mmol) inTHF (40 mL), under Ar, was treated with butyl lithium (16.66 mL, 26.7 mmol), stirred at-78°C for 2.5 h, treated slowly with DMF (1.651 mL, 21.32 mmol), stirred for 15 min at -78oc and slowly warmed toRT. The mixture was stirred for 2 h, treated with satd. NH4Cl, thelayers separated and the aqueous layer extracted with EtOAc (1x). The combined organicswere washed with brine, dried over Na2S04, concentrated to dryness and purified via silicagel chromatography (EtOAc/Hex) to afford N-(4-chloro-2-fluoro-3-formylphenyl)acetamide(1.1 g, 48% yield) as an off-white solid. MS (ESI) m/z: 216.0 [M+Ht. |
Stage #1: 4'-chloro-2'-fluoroacetanilide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78℃; for 0.5h; | 2 <Preparation of N-(4-chloro-2-fluorophenyl)acetamide> As presented in the following reaction formula, a solution (166 mL, 0.35 mol) of n-butyllithium (n-BuLi) in hexane was added several times in a divided manner to a solution of N-(4-chloro-2-fluorophenyl)acetamide (30 g, 0.16 mol) in tetrahydrofuran (THF; 300 mL) at -78°C. The resulting reaction mixture was stirred for 1 hour. Then, anhydrous N,N-dimethylformamide (DMF; 10.5 mL, 0.18 mol) was added to the mixture at -78°C and stirred for another 0.5 hours. The reaction was terminated with saturated ammonium chloride. The organic phase was separated, dried and concentrated to obtain a crude product, which was used for the next step without purification. |
Stage #1: 4'-chloro-2'-fluoroacetanilide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78℃; for 0.5h; | 2 Preparation of N-(4-chloro-2-fluorophenyl)acetamide As presented in the following reaction formula, a solution (166 mL, 0.35 mol) of n-butyllithium (n-BuLi) in hexane was added several times in a divided manner to a solution of N-(4-chloro-2-fluorophenyl)acetamide (30 g, 0.16 mol) in tetrahydrofuran (THF; 300 mL) at -78° C. The resulting reaction mixture was stirred for 1 hour. Then, anhydrous N,N-dimethylformamide (DMF; 10.5 mL, 0.18 mol) was added to the mixture at -78° C. and stirred for another 0.5 hours. The reaction was terminated with saturated ammonium chloride. The organic phase was separated, dried and concentrated to obtain a crude product, which was used for the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In acetic acid; at 25℃; for 2h; | As presented in the following reaction formula, anhydrous acetic acid (Ac2O; 1.7 mL) was added several times in a divided manner to a mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2 g, 13.8 mmol) in acetic acid (2 mL) at room temperature (about 25C). The resulting reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was filtered to obtain a crude product, which was washed with hexane to obtain N-(4-chloro-2-fluorophenyl)acetamide (2.4 g, yield: 94%). [0138] The N-(4-chloro-2-fluorophenyl)acetamide was analyzed through proton nuclear magnetic resonance (NMR) in deuterated chloroform (CDCl3) at 400 MHz and 25C. The obtained proton nuclear magnetic resonance spectrum is presented in FIG. 3. |
With acetic anhydride; at 25℃; for 2h; | As presented in the following reaction formula, anhydrous acetic acid (Ac2O; 1.7 mL) was added several times in a divided manner to a mixture of <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2 g, 13.8 mmol) in acetic acid (2 mL) at room temperature (about 25 C.). The resulting reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was filtered to obtain a crude product, which was washed with hexane to obtain N-(4-chloro-2-fluorophenyl)acetamide (2.4 g, yield: 94%). The N-(4-chloro-2-fluorophenyl)acetamide was analyzed through proton nuclear magnetic resonance (NMR) in deuterated chloroform (CDCl3) at 400 MHz and 25 C. The obtained proton nuclear magnetic resonance spectrum is presented in FIG. 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C | ||
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C 3.1: lithium hydroxide; water / methanol; tetrahydrofuran / 2 h / 25 °C | ||
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C 3.1: lithium hydroxide; water / 2 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C 3.1: lithium hydroxide; water / methanol; tetrahydrofuran / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr | ||
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C 3.1: lithium hydroxide; water / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C 3.1: lithium hydroxide; water / methanol; tetrahydrofuran / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C | ||
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C 3.1: lithium hydroxide; water / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C 3.1: lithium hydroxide; water / methanol; tetrahydrofuran / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C 6.1: sulfuric acid / sulfuric acid / 0.5 h / 80 °C | ||
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C 3.1: lithium hydroxide; water / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C 6.1: sulfuric acid / 0.5 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C 3.1: lithium hydroxide; water / methanol; tetrahydrofuran / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C 6.1: sulfuric acid / sulfuric acid / 0.5 h / 80 °C 7.1: caesium carbonate / acetonitrile / 48 h / Reflux | ||
Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C 3.1: lithium hydroxide; water / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C 6.1: sulfuric acid / 0.5 h / 80 °C 7.1: caesium carbonate / acetonitrile / 48 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 0 - 25 °C 3.1: lithium hydroxide; water / methanol; tetrahydrofuran / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C 6.1: sulfuric acid / sulfuric acid / 0.5 h / 80 °C 7.1: caesium carbonate / acetonitrile / 48 h / Reflux 8.1: caesium carbonate / acetonitrile / 48 h / 20 °C / Reflux | ||
Multi-step reaction with 8 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hydroxide / toluene / 2 h / 0 - 25 °C 3.1: lithium hydroxide; water / 2 h / 25 °C 4.1: triethylamine; palladium on activated charcoal; hydrogen / methanol / 50 °C / 760.05 Torr 5.1: polyphosphoric acid / 2 h / 120 °C 6.1: sulfuric acid / 0.5 h / 80 °C 7.1: caesium carbonate / acetonitrile / 48 h / Reflux 8.1: caesium carbonate / acetonitrile / 48 h / 20 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: diphosphorus pentasulfide / benzene / 3 h / Reflux 2.1: sodium hydride / toluene; N,N-dimethyl-formamide / 3.5 h / 0 - 25 °C / Reflux 3.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 14 h / Reflux 4.1: toluene / 12 h / Reflux 5.1: n-butyllithium / tetrahydrofuran / 2 h / 0 - 25 °C 5.2: 16 h / 20 - 25 °C 6.1: hydrogen; platinum(IV) oxide / methanol / 2 h 7.1: hydrogenchloride / 1,4-dioxane / 1 h / 0 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diphosphorus pentasulfide / benzene / 3 h / Reflux 2: sodium hydride / toluene; N,N-dimethyl-formamide / 3.5 h / 0 - 25 °C / Reflux 3: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 14 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: diphosphorus pentasulfide / benzene / 3 h / Reflux 2: sodium hydride / toluene; N,N-dimethyl-formamide / 3.5 h / 0 - 25 °C / Reflux 3: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 14 h / Reflux 4: toluene / 12 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: diphosphorus pentasulfide / benzene / 3 h / Reflux 2.1: sodium hydride / toluene; N,N-dimethyl-formamide / 3.5 h / 0 - 25 °C / Reflux 3.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 14 h / Reflux 4.1: toluene / 12 h / Reflux 5.1: n-butyllithium / tetrahydrofuran / 2 h / 0 - 25 °C 5.2: 16 h / 20 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: diphosphorus pentasulfide / benzene / 3 h / Reflux 2.1: sodium hydride / toluene; N,N-dimethyl-formamide / 3.5 h / 0 - 25 °C / Reflux 3.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 14 h / Reflux 4.1: toluene / 12 h / Reflux 5.1: n-butyllithium / tetrahydrofuran / 2 h / 0 - 25 °C 5.2: 16 h / 20 - 25 °C 6.1: hydrogen; platinum(IV) oxide / methanol / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 °C 1.2: 3 h / -70 - 35 °C 2.1: hydrogenchloride; water / methanol / 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 °C 1.2: 3 h / -70 - 35 °C 2.1: hydrogenchloride; water / methanol / 2 h / Reflux 3.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / 120 °C / Microwave irradiation 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 10 - 35 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 °C 1.2: 3 h / -70 - 35 °C 2.1: hydrogenchloride; water / methanol / 2 h / Reflux 3.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / 120 °C / Microwave irradiation 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 10 - 35 °C 5.1: pyridine / tetrahydrofuran / 1 h / 0 - 35 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 °C 1.2: 3 h / -70 - 35 °C 2.1: hydrogenchloride; water / methanol / 2 h / Reflux 3.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / 120 °C / Microwave irradiation 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 10 - 35 °C 5.1: pyridine / tetrahydrofuran / 1 h / 0 - 35 °C 6.1: (bis(tricyclohexyl)phosphine)palladium(II) dichloride; caesium carbonate / dimethyl sulfoxide / 0.5 h / 130 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5 g | at 10 - 35℃; for 2h; | 124.a a) N-(4-chloro-2-fluorophenyl)acetamide a) N-(4-chloro-2-fluorophenyl)acetamide A mixture of 4-chloro-2-fluoroaniline (50.0 g), acetic anhydride (52.6 g) and acetic acid (500 mL) was stirred at room temperature for 2 hr. After confirmation of completion of the reaction by TLC, the reaction mixture was poured into ice water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound as a crude purified product. The obtained crude purified product of the title compound was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate and concentrated to give the title compound (62.5 g). 1H NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 7.11-7.13 (2H, m), 7.35 (1H, brs), 8.27 (1H, t, J=8.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4'-chloro-2'-fluoroacetanilide With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 2h; Stage #2: With 1,1,1-trifluoro-2-iodoethane In tetrahydrofuran; hexane at -70 - 35℃; for 3h; | 124.b b) N-(4-chloro-2-fluoro-3-iodophenyl)acetamide b) N-(4-chloro-2-fluoro-3-iodophenyl)acetamide To a solution of N-(4-chloro-2-fluorophenyl)acetamide (20.0 g) in THF (100 mL) was added 2.5M n-butyllithium/hexane solution (85.2 mL) at -70° C., and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added 2-iodo-1,1,1-trifluoroethane (21.0 mL) at the same temperature, and the mixture was stirred at room temperature for 3 hr. After confirmation of completion of the reaction by TLC, the reaction mixture was quenched with 3N hydrochloric acid and extracted 2 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give a crude purified product of the title compound (20.0 g). The product was used without further purification for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 °C 1.2: 3 h / -70 - 35 °C 2.1: hydrogenchloride; water / methanol / 2 h / Reflux 3.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / 120 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: o-bromothiophenol; 4'-chloro-2'-fluoroacetanilide With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver(I) acetate; copper(II) bis(trifluoromethanesulfonate) at 100℃; for 18h; Stage #2: With caesium carbonate; N,N`-dimethylethylenediamine at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere 3.1: hydrogenchloride; acetic acid / water / 16 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere 3.1: hydrogenchloride; acetic acid / water / 16 h / 120 °C 4.1: pyridine / 1,4-dioxane / 16 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere 3.1: hydrogenchloride; acetic acid / water / 16 h / 120 °C 4.1: pyridine / 1,4-dioxane / 16 h / 100 °C 5.1: potassium phosphate; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) / 1,4-dioxane; water / 2.25 h / 120 °C / Inert atmosphere; Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere 3.1: hydrogenchloride; acetic acid / water / 16 h / 120 °C 4.1: pyridine / 1,4-dioxane / 16 h / 100 °C 5.1: potassium phosphate; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) / 1,4-dioxane; water / 2.25 h / 120 °C / Inert atmosphere; Microwave irradiation 6.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere 3.1: hydrogenchloride; acetic acid / water / 16 h / 120 °C 4.1: pyridine / 1,4-dioxane / 16 h / 100 °C 5.1: potassium phosphate; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) / 1,4-dioxane; water / 2 h / 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 5 h / -78 °C / Inert atmosphere 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C / Inert atmosphere 2.2: 0 - 50 °C / Inert atmosphere 3.1: hydrogenchloride; acetic acid / water / 16 h / 120 °C 4.1: pyridine / 1,4-dioxane / 16 h / 100 °C 5.1: potassium phosphate; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) / 1,4-dioxane; water / 2 h / 120 °C / Inert atmosphere 6.1: hydrogenchloride / 1,4-dioxane / 3 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.14% | Stage #1: 4'-chloro-2'-fluoroacetanilide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 5h; Inert atmosphere; Stage #2: carbon dioxide | 185.1 Step 1: To a well stirred solution of N-(4-chloro-2-fluoro-phenyl)acetamide (10.0 g, 53.31 mmol) in THF (300.0 mL) was added n-butyllithium 2.8M in hexane (106.62 mmol, 38.0 mL) dropwise at -78 °C. The reaction mixture was maintained at same temperature for 3 hours and then was added crushed dry ice to the reaction mixture under nitrogen atmosphere. After stirring at -78 °C for 2 hours, 1.5N aq. HC1 was slowly added to the reaction. The reaction mixture was warmed to room temperature and extracted with ethyl acetate (2 x 300 mL). The combined organic layers are washed with water and brine, dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was stirred in 15% ethyl acetate/petroleum ether for 1 hour. The solid was filtered to yield 3-acetamido-6-chloro-2-fluoro-benzoic acid (8.0 g, 29.39 mmol, 55.14% yield) as pale brown solid. LCMS (ESI+): 232.0 [M+H] +. |
Tags: 59280-70-5 synthesis path| 59280-70-5 SDS| 59280-70-5 COA| 59280-70-5 purity| 59280-70-5 application| 59280-70-5 NMR| 59280-70-5 COA| 59280-70-5 structure
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P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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