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CAS No. : | 1895-39-2 |
Formula : | C2ClF2NaO2 |
M.W : | 152.46 |
SMILES Code : | O=C([O-])C(F)(Cl)F.[Na+] |
MDL No. : | MFCD00064771 |
InChI Key : | MRTAVLDNYYEJHK-UHFFFAOYSA-M |
Pubchem ID : | 2734985 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
53% | at 80℃; Sealed tube | In a sealed tube was added 2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.357 mmol), sodium chlorodifluoroacetate (320 mg, 2.036 mmol) in acetonitrile (5 mL). This suspension was heated to 80°C and stirred overnight. The reaction mixture was cooled down to rt, diluted with EtOAc, washed with an aqueous solution of NaHC03 and brine. The organic layer dried over MgS04, filtered and evaporated. Purification by flash chromatography on silica gel (CH2CI2/MeOH, 95/5) gave the title compound (197 mg, 53percent yield). MS: 272.8 [M+H]+, Rt (6) = 3.12 min. |
53% | at 80℃; Sealed tube | 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine In a sealed tube was added 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.357 mmol), sodium chlorodifluoroacetate (320 mg, 2.036 mmol) in acetonitrile (5 mL). This suspension was heated to 80° C. and stirred overnight. The reaction mixture was cooled down to rt, diluted with EtOAc, washed with an aqueous solution of NaHCO3 and brine. The organic layer dried over MgSO4, filtered and evaporated. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5) gave the title compound (197 mg, 53percent yield). MS: 272.8 [M+H]+, Rt(6)=3.12 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | at 80℃; Sealed tube | In a sealed tube was added 2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (300 mg, 1.357 mmol), sodium chlorodifluoroacetate (320 mg, 2.036 mmol) in acetonitrile (5 mL). This suspension was heated to 80°C and stirred overnight. The reaction mixture was cooled down to rt, diluted with EtOAc, washed with an aqueous solution of NaHC03 and brine. The organic layer dried over MgS04, filtered and evaporated. Purification by flash chromatography on silica gel (CH2CI2/MeOH, 95/5) gave the title compound (197 mg, 53percent yield). MS: 272.8 [M+H]+, Rt (6) = 3.12 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2h;Product distribution / selectivity; | To a stirred solution of <strong>[141483-15-0]2-fluoro-5-trifluoromethyl-1-phenol</strong> (9.9 g, 54.9 mmol) in 100 ml of DMF (100 mL) and water (10 mL) was added sodium chlorodifluoroacetate (20.9 g, 137.2 mmol) and cesium carbonate (26.8 g, 82.3 mmol). The reaction mixture was stirred at 100 C. for 2 hours. After it cooled to room temperature, it was diluted with ethyl acetate (700 ml), washed with water (3×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product (colorless oil, volatile) was used for the next step without further treatment. 1H NMR (CDCl3, delta ppm): 6.6 (t, 1H), 7.3 (m, 1H), 7.6 (m, 2H). | |
With potassium carbonate; In N,N-dimethyl-formamide; at 19 - 97℃; for 2h;Product distribution / selectivity; | A 100-L round bottom flask equipped with overhead stirrer, thermocouple, nitrogen inlet, condenser and steam bath was charged with <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (5.50 kg), sodium chlorodifluoroacetate (9.31 kg), and DMF (4 L). There was an exotherm to 46.7 C. when the 4 L of DMF was charged to the flask. The temperature of the reaction was immediately reduced to 19 C. by rapid cooling with an ice/water bath. An additional 37.3 L of DMF (total DMF, 41.3 L) was then slowly charged, maintaining the internal temperature below 30 C. After cooling to ambient temperature, water (5.5 L) was charged, resulting in a 10 C. exotherm. Potassium carbonate (5.28 kg) was then added. The ice water bath was removed and the batch was heated to 97 C. using a steam bath. The reaction was complete after aging for 2 h at 97 C., as evidenced by HPLC assay, with <1% starting material remaining. The reaction was cooled to ambient temperature, and water (42 L) was slowly added. The batch was transferred to a 170-L extractor and extracted with MTBE (2×18 L). The organic layers were combined and washed with water (1×11 L) and brine (1×11 L). The MTBE solution was pumped into a 22-L flask equipped with a thermocouple, distillation apparatus, and a heating mantle. The MTBE was distilled off at 55-118 C. and atmospheric pressure. The desired product was purified by distillation at 120-157 C. and atmospheric pressure, and was isolated as a clear oil. | |
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 3h; | Sodium chlorodifluoroacetate (1.091 g, 6.94 mmol) and cesium carbonate (1.357 g, 4.16 mmol) were added to an N, N-dimethylformarmde (5 mL) solution of 2-fluoro-5-trifluoromethyl phenol containing 10 volume % water (0.55 mL), and the reaction mixture was heated for 3 h at 1000C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3 X), brine (1 X) The organic layer was d?ed over sodium sulfate and concentrated to obtain the desired product (650 mg), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 4h; | To a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (1 g, 4.8 mmol) in DMF/water (45 mL/5 mL) was added sodium chlorodifluoroacetate (1.95 g, 12.0 mmol) and cesium carbonate (3.14 g, 9.64 mmol), and the reaction mixture was heated to 100 C. for 4 hours. The reaction mixture was cooled and diluted with TBME (20 mL) and water (20 mL). The organic layer was collected, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.21 g, 98%), which was used without further purification. |
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 3h; | Sodium chlorodifluoroacetate (2.5 eq.) and cesium carbonate (1.5 eq.) were added to a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> in DMF containing 10 volume % water, and the reaction mixture was heated for 3h at 100 C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3×), then with brine (1×). The organic layer was dried over sodium sulfate and concentrated to obtain the crude product which was used in the next step without further purification. | |
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 16h; | To a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (4.34 g, 20.92 mmol, Ark Pharm) in N,N-dimethylformamide (21.79 ml, 20.92 mmol) was added sodium chlorodifluoroacetate (7.34 g, 48.1 mmol), cesium carbonate (9.54 g, 29.3 mmol), and water (2.179 ml, 20.92 mmol). The reaction was heated at 100 C for 16 h. After 16 h, the reaction was partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2x70mL). The organic portions were combined and washed with water (2x50 mL), 10% aq citric acid (1x30 mL), and brine, dried over MgS04, filtered, and concentrated to provide 1- bromo-4-chloro-2-(difluoromethoxy)benzene (4.35 g, 16.90 mmol, 81 % yield) as a colorless oil. The material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | [00434] To a solution of 3,4-dihydroxybenzaldehyde (300 mg, 2.2mmol) in DMF (9.0 mL) and H2O (1.0 mL) was added sodium chlorodifluoroacetate (1.33 g) and K2CO3 (729 mg). The mixture was heated up to 100C for 2 h before cooling down to rt. Concentrated HCl (1.54 mL) and H2O (2.0 mL) were added and the reaction was stirred overnight. The mixture was neutralized with IN NaOH to pH > 9, extracted with EtOAc, washed with brine, dried over MgS O4 and concentrated. The crude product was purified by silica gel chromatography to give 132 A (470 mg, 90% yield). 1H NMR (400 MHz, CDCl3) delta ppm 6.29 - 6.89 (m, 2 H) 7.42 (d, J=8.35 Hz, 1 H) 7.66 - 7.90 (m, 2 H) 9.95 (s, 1 H). | |
65% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h; | Sodium chlorodifluoroacetate (88 g, 58mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (20 g, 14 mmol), potassiumcarbonate (80 g, 58 mmol) and water (10 mL, 58 mmol) in DMF (200 mL). Thesuspension was heated to 80 C for 16h and then cooled to rt and diluted with water. The aqueous phase was extractedwith EtOAc and the combined organic fractions were washed with water, brine,dried and concentrated. The residue was partially purified by columnchromatography, eluting with 5-10% EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde(22.5 g, 65%) as a colourless oil; deltaH (400 MHz, CDCl3)6.60 (t, J = 72 Hz, 1H, OCHF2), 6.64 (t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6= 8.0 Hz, 1H, H5), 7.76-7.78 (m,2H, H2, H6), 9.96 (s, 1H, CHO); deltaC(125 MHz, CDCl3) 115.2 (t, J= 259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm-1.The 3,4-bis(difluoromethoxy)benzaldehyde coeluted with approximately 10-20%unidentified colourless oil: deltaH (400 MHz, CDCl3) 7.13 (s,1H), 7.19 (d, J = 8.0 Hz, 1H), 7.30(s, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.61(dd, J = 1.5 Hz, 8.0 Hz, 1H), 9.91(s, 1H). |
EXAMPLE 103 ,4-Bis(difluoromethoxy)benzaldehyde ( 10-2) In a sealed tube 3,4-dihydroxybenzaldehyde (10-1, 750 mg, 5.43 mmol, 1.0 equiv), sodium chlorodifluoroacetate (3310 mg, 21.7 mmol, 4 equiv), and potassium carbonate (1800 mg, 13.03 mmol, 2.4 equiv) were suspended in DMF (24.4 mL) and water (2.7 mL). The reaction mixture was stirred at 100 C for 4 hours and was cooled to ambient temperature. HCl (6 N, 10 mL) and water (30 mL) were added and the reaction stirred for an additional 2 hours. NaOH (5 N, aq.) was added until a pH of 10 was obtained. The mixture was extracted withMTBE (3x, 50 mL), dried over MgSO4 and concentrated to afford the desired product (10-2). 1H NMR (CDCl3, 400 MHz) ? 9.97 (s, 1H), 7.76-7.79 (m, 2H), 7.43 (d, J=8.1Hz, 1H), 6.64 (t, J=73.8 Hz, 1H), 6.60 (t, J=73.8 Hz, 1H). |
3,4-Bis(difluoromethoxy)benzaldehyde (4-2)In a sealed tube 3,4-dihydroxybenzaldehyde (4-1, 750 mg, 5.43 mmol, 1.0 equiv), sodium chlorodifluoroacetate (3310 mg, 21.7 mmol, 4 equiv), and potassium carbonate (1800 mg, 13.03 mmol, 2.4 equiv) were suspended in DMF (24.4 mL) and water (2.7 mL). The reaction mixture was stirred at 100 C. for 4 hours and was cooled to ambient temperature. HCl (6 N, 10 mL) and water (30 mL) were added and the reaction stirred for an additional 2 hours. NaOH (5 N, aq.) was added until a pH of 10 was obtained. The mixture was extracted with MTBE (3×, 50 mL), dried over MgSO4 and concentrated to afford the desired product (4-2). 1H NMR (CDCl3, 400 MHz) delta 9.97 (s, 1H), 7.76-7.79 (m, 2H), 7.43 (d, J=8.1 Hz, 1H), 6.64 (t, J=73.8 Hz, 1H), 6.60 (t, J=73.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; | Hydroxy-aryl- or hydroxy-heteroaryl-carboxylic acid methyl ester to F2CHO- aryl- or heteroarylcarboxylic acid methyl ester- General procedureUnder a No atmosphere, 4-hydroxy-benzoic acid methyl or ethyl ester (1.0 eq) and sodium chlorodifluoroacetate (1.2 eq) were dissolved in DMF (20-25 mL) in a two neck round bottom flask; potassium carbonate (1.2 eq) was added and the <n="44"/>mixture was heated at 125°C until complete conversion of the starting material was observed by LC-MS. The mixture was then diluted with water and extracted with DCM; the organic phase was dried and removed under reduced pressure, and the crude was purified through Si column to obtain the product (Yields from 20 to 70percent). |
66% | With potassium carbonate; In N,N-dimethyl-formamide; at 125℃;Inert atmosphere; | Hydroxy-aryl- or hydroxy-heteroaryl-carboxylic acid methyl ester to F2CHO-aryl- or heteroarylcarboxylic acid methyl ester- General procedure; [0158] Under a N2 atmosphere, 4-hydroxy-benzoic acid methyl or ethyl ester (1.0 equiv.) and sodium chlorodifluoroacetate (1.2 equiv.) were dissolved in DMF (20-25 mL) in a two neck round bottom flask; potassium carbonate (1.2 equiv.) was added and the mixture was heated at 125 °C until complete conversion of the starting material was observed by LC-MS. The mixture was then diluted with water and extracted with DCM; the organic phase was dried and removed under reduced pressure, and the crude was purified through Si column to obtain the product (Yields from 20 to 70percent). |
With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 5h; | Sodium 2-chloro-2,2-difluoroacetate (1.18 g, 7.76 mmol) was added to a suspension of <strong>[403-01-0]methyl 3-fluoro-4-hydroxybenzoate</strong> (1.1 g, 6.47 mmol) and potassium carbonate (1.07 g, 7.76 mmol) in DMF (20 mL). The reaction was heated to 125 °C for 5 hours. The reaction was allowed to cool to RT and was partitioned between EtOAc and brine. The organic layer was dried (MgSCn) and concentrated in vacuo.The crude product was purified by column chromatography on silica, eluting with 0-20 percent ethyl acetate/petrol to afford the title compound. 1H NMR (400 MHz, DMSO-ifc)? ppm 3.87 (s, 3 H) 7.18 - 7.62 (m, 2 H) 7.81 - 7.94 (m, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 12h; | EXAMPLE 101Preparation of: 2-Amino-5-[4-(difluoromethoxy)-3-methylphenyl]-5-(3-ethoxy-4-fluorophenyl)-3- methyl-3,5-dihydro-4H-imidazol-4-oneStep 1 : 4-Bromo-1-(difluoromethoxy)-2-methylbenzene; In a 250 mL round-bottomed flask was placed 4-bromo-2-methylphenol (50 g, 267 mmol) and DMF (241 mL). Water (26.7 mL) was added to give a colorless solution. K2CO3 (148 g, 1069 mmol) was then added. Sodium 2-chloro-2,2-difluoroacetate (61.1 g, 401 mmol) was added and reaction heated to 120 0C for 12 h. The reaction was cooled to room temperature and partitioned between EtOAc (1000 mL) and water (1000 mL). The layers were separated and organic washed with water (2 x 500 mL) and brine (2x 500 mL). The organic layer was dried over Na2SO4 and filtered. The solvent was removed and crude material was passed through a plug of silica eluting with hexanes to provide 12.29 g, 19%, of the title compound as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 3h; | 2-Chloro-6-fluorophenol (1.8 g, 12.33 mmol) was dissolved in dimethylformamide (DMF; 22 mL) and water (2.2 mL). Potassium carbonate (2.55 g, 18.5 mmol) and sodium chlorodifluoroacetate (4.7 g, 30.8 mmol) were then added and the solution was heated to 100 C. for 3 h. The cooled reaction mixture was then diluted with concentrated HCl (10 mL) and the resulting solution was stirred for 2 h. The reaction mixture was diluted with diethyl ether, washed with water, washed twice with 1M NaOH, washed once with brine, dried, filtered and concentrated under vacuum to yield the title compound (1 g, 41% yield) that was used in subsequent reactions without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.7% | In water; N,N-dimethyl-formamide; at 90℃; for 24h; | Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine 2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C. for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30percent ethyl acetate/hexanes) to afford 2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7percent yield) as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]+=181.14. |
39.7% | In water; N,N-dimethyl-formamide; at 90℃; for 24h; | Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2- difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90 °C for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30 percent ethyl acetate/hexanes) to afford 2- chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7 percent yield) as a pale yellow oil. MS (LC/MS) R.T. = 1.32; [M+H]+ = 181.14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | Intermediates T18A and T18BT18.1 [0412] l-Bromo-3-(difluoromethoxy)benzene (T18.1). To a solution of 3- bromophenol (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (commercially available from Sigma-Aldrich, St. Louis, MO, USA) (2.82 g, 18.49 mmol) and Cs2CO3 (4.82 g, 14.79 mmol). The reaction mixture was heated at 100C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re- extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T18.1 as an oil that was used without further purification (yield 61%). |
61% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | l-Bromo-3-(difluoromethoxy)benzene (T7.1). To a solution of 3- bromophenol (available from Sigma Aldrich) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (available from Sigma Aldrich )(2.82 g, 18.49 mmol) and cesium carbonate (4.82 g, 14.79 mmol). The reaction mixture was heated at 100C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re-extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T7.1 as an oil that was used without further purification (yield 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5%; 15% | In acetonitrile; for 48.0h;Reflux; | 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g, 15%) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MEta+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-lH-pyridin-2-one: MS (ES+) 191 (MEta+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH). |
1.5%; 15% | In acetonitrile; for 48.0h;Reflux; | Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (1 1.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (I g, 15%) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-l//-pyridin-2-one: MS (ES+) 191 (MH+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH). |
In acetonitrile; for 48.0h;Reflux; | This example illustrates the preparation of 2-chloro-N-{r-[4-(5-chloro-pyrirnidin-2- yl)-benzyl]-6-difluoromethoxy- 1 ',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-3-yl} - isonicotinamide (Compound B6 of Table B).The title compound was obtained from 2-bromo-6-difluoromethoxy-pyridin-3-yl- amine following the procedures described in Example 5. 2-Bromo-6-difluoromethoxy-pyridin- 3-yl-amine was prepared as follows:Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g) and l-difluoromethyl-5-nitro-lH-pyridin-2- one (90 mg). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). l-Difluoromethyl-5- nitro-lH-pyridin-2-one: MS (ES+) 191 (MEta+); IH NMR (400 MHz, CDCl3) 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h; | 0097] As shown in step 3-i of Scheme 3, 2-chloro-3-hydroxypyridine (Compound 1005,2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained fromLancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 1000C for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3- (difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDCl3) delta 8.05 (m, IH), 7.45(m, IH), 6.90(m,lH), 6.60(t, IH; J=75Hz), 4.0 l(s, 3H). |
72% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 4h; | As shown in step 3-i of Scheme 3,2-chloro-3-hydroxypyridine (Compound 1005,2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained fromLancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 1000C for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3-(difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDCl3) delta 8.05 (m, IH), 7.45(m, IH), 6.90(m,lH), 6.60(t, IH; J=75Hz), 4.0 l(s, 3H). |
72% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 4h; | As shown in step 3(a)-i of Scheme 3(a), 2-chloro-3-hydroxypyridine (Compound 2005, 2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and 5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained from Lancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 100C for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2S04, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3- (difluoromethoxy)pyridine as a white solid (Compound 2006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDC13) delta 8.05 (m, 1H), 7.45(m, 1H), 6.90(m,lH), 6.60(t, 1H; J = 75Hz), 4.01(s, 3H). |
69% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h; | This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and N,N-dimethylformamide (750 mL) was heated to 100 C and slowly treated, in a drop-wise manner over 1 hour, with a solution of 2-chloropyridin-3-ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in N,N-dimethylformamide (750 mL). After completion of the addition, the reaction mixture was stirred at 100 C for 1 hour, then cooled to 25 C and partitioned between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4 x 2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6 x 2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The combined crude products from the three reactions were purified via distillation at reduced pressure (30-40 C, 1-5 mm Hg) to provide the product as a colorless oil. Yield: 192 g, 1.07 mol, 69%. LCMS m/z 180.0 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 8.26-8.30 (m, 1 H), 7.60 (br d, J=8.2 Hz, 1 H), 7.28 (br dd, J=8.0, 4.8 Hz, 1 H), 6.60 (t, JHF=72.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethyl acetate; N,N-dimethyl-formamide; | Step 1. Preparation of 1-bromo-3-(difluoromethoxy)-5-nitrobenzene To a solution of <strong>[116632-23-6]3-bromo-5-nitrophenol</strong> (3.1 g, 14.4 mmol) and powdered sodium hydroxide (0.63 g, 15.8 mmol) in DMF (14 mL), sodium chlorodifluoroacetate (4.4 g, 28.7 mmol) was added in five portions every 0.5 hour to the warmed reaction mixture at to 55° C. The reaction was maintained at to 55° C. for 1 day and then allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc and water, the layers separated, and the aqueous portion was extracted (2*25 mL) EtOAc and the combined organic layers were washed with aqueous 1.0 M NaOH solution (3*25 mL), water (3*25 mL) and brine (50 mL). The organic layer was dried (MgSO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-50percent EtOAc in hexanes) to afford 1-bromo-3-(difluoromethoxy)-5-nitrobenzene (160 mg, 0.6 mmol). 1H NMR (400 MHz, CDCl3) delta 6.61 (t, J=71.6 Hz, 1H) 7.65 (s, 1H) 7.96 (s, 1H) 8.21-8.31 (m, 1H). | |
400 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h; | A mixture of <strong>[116632-23-6]3-bromo-5-nitrophenol</strong> (460 mg, 2.11 mmol), sodium 2-chloro-2,2-difluoroacetate (804 mg, 5.28 mmol) and Cs2CO3 (1375 mg, 4.22 mmol) in DMF (8 mE) was heated at 1000 C. for 1 h. The mixture was partitioned between TBME (50 mE) and water (50 mE), the aqueous layer extracted with TBME (30 mE) and the combined organic layers washed with brine (50 mE). The organic layer was concentrated in vacuo to yield the sub-title compound (400 mg) as a colourless oil.?H NMR (400 MHz, CDC13) oe 8.25 (t, 1H), 7.96 (t, 1H), 7.69-7.62 (m, 1H), 6.60 (t, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With caesium carbonate; In N,N-dimethyl-formamide; at 100.0℃; for 15.0h; | itermediteExthp1eI5. ?sulfOnamide ?,?a) .To a solutiOn of 2-brotho-5-fludrophenol (3g. 15.7 mmol) in DMF (5 ml) was added cesium carbonate (7.7 g, 23.56 mmol, 1.5 eq) and sodium chlorodifluoroacetate(6 g, 39.26 nimol;2:5 eq) and the reaction mixture was heated at 100C for 15 h. Thereaction mixture was then exttacted with Water and ethyl acetate (3 x 50 mI) Thecombined Organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica ge110% ethyl acetate in hexane) in 58 % yield (2.2 g). |
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100.0℃; for 15.0h; | Preparation Example 3 A mixture of 2-bromo-5-fluorophenol (3 g), sodium chlorodifluoroacetate (6 g), cesium carbonate (7.7 g), water (3 mL) and DMF (30 mL) was stirred under heating at an oil temperature of 100C for 15 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide solution, further washed with water, dried and concentrated under reduced pressure to obtain 1-bromo-2-(difluoromethoxy)-4-fluorobenzene (2.77 g). | |
With water; caesium carbonate; In N,N-dimethyl-formamide; at 100.0℃; for 2.0h; | Intermediate Example Int 17.11 -Bromo-2-(dif luoromethoxy)-4-f luorobenzeneTo a stirred solution of 2-bromo-5-fluorophenol (21 .0 g) in DMF (600 mL) was added cesium carbonate (107.5 g), sodium chlorodifluoroacetate (52.3 g) and water (29.4 mL). The mixture was stirred at 100 C for 2 h. The mixture was filtrated and the resulting solution was extracted with pentane (4 x 400 mL). The combined organic layers were washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 7.14 g of the title compound as a crude product. Silica gel chromatography afforded 3.2 g of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm] = 7.10 - 7.16 (m, 1 H), 7.34 (t, 1 H), 7.33 - 7.36 (m, 1 H), 7.79 (dd, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | To a solution of <strong>[4214-79-3]5-chloropyridin-2-ol</strong> (10 g, 78 mmol) in DMF (250 mL), CS2CO3 (38.0 g, 116 mmol) followed by sodium chlorodifluoroaceate (14 g, 93 mmol) was added, and the reaction mixture was heated to 100 °C for 3 h. The reaction mixture was cooled to rt; water (300 mL) was added and extracted with Et20 (500 mL x 2). The organic part was dried over sodium sulfate, filtered and concentrated to obtain a crude product, which was further purified by column chromatography using silica gel (100-200 mesh) and 0-5percent EtOAc in hexane to afford a colorless oil as 5-chloro-2-(difluoromethoxy)pyridine. 1H NMR (400 MHz, DMSO-d6) delta 8.361(d, J=2.8Hz, 1H), 8.07-8.4 (m, 1H), 7.672 (t, 1H), 7.177(d, J=8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 72.0h;Reflux; | Step-1 -Preparation of 2-(difluoromethoxy)-5-nitropyridine To a solution of 2-hydroxy-5-nitro pyridine (10 g, 0.071 mol) in acetonitrile (100 mL) was added sodium chlorodifluoroacetate (11.5 g, 0.075 mol). The reaction mass was refluxed for 72 h. The excess of solvent was removed under vacuum and the reaction mass was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): delta 7.05 (d, J=8.7 Hz, 1H), 7.53 (d, J=71.4 Hz, 1H), 8.54 (dd, J=8.1 Hz & 5.4 Hz, 1H), 7.91 (s, 1H); MS [M-]: 190.83. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethylene glycol dimethyl ether; at 150℃; | Cap N-7 To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diglyme (3 mL) was added a solution of sodium 2-chloro-2,2-difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diglyme via syringe pump at 0.5 ml/h at 150 C. The reaction was cooled to rt, then diluted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) ppm 4.09-4.19 (2H, m), 2.29-2.45 (1H, m), 1.89-2.03 (2H, m), 1.55-1.72 (5H, m), 1.45-1.54 (1H, m), 1.31-1.39 (1H, m), 1.21-1.30 (3H, m), 0.84-0.94 (1H, m). | |
In diethylene glycol dimethyl ether; at 150℃; | To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diglyme (3 mL) was added a solution of sodium 2-chloro-2,2- difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diglyme via syringe pump at 0.5 ml/h at 150 C. The reaction was cooled to rt, then diluted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was chargedto a 40 g silica gel cartridge which was eluted with a 20 mm gradient of 0-20% EtOAc in hexane to yield ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. ?H NMR (400 MHz, CDC13) ppm 4.09 - 4.19 (2 H, m), 2.29 -2.45 (1 H, m), 1.89 -2.03 (2 H, m), 1.55 - 1.72(5 H, m), 1.45 - 1.54(1 H, m), 1.31 - 1.39 (1 H, m), 1.21 - 1.30(3 H, m), 0.84 - 0.94 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.34% | With caesium carbonate; In hexane; ethyl acetate; N,N-dimethyl-formamide; | Step 2: 7-chloro-2-(difluoromethyl)-2H-pyrazolo[3,4-c]pyridine A mixture of <strong>[76006-11-6]7-chloro-1H-pyrazolo[3,4-c]pyridine</strong> (4.99 g, 32.5 mmol), sodium chlorodifluoroacetate (14.86 g, 97 mmol), and cesium carbonate (40.2 g, 123 mmol) in DMF (81 ml) was heated at 95 C. for 4 h. The reaction was allowed to cool to rt and the solids were filtered. The filtrate was diluted with water and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 5% to 60% EtOAc in hexane, to provide a white solid (1.4117 g, 6.93 mmol, 21.34% yield). MS m/z=203.9 [M+H]+. Calculated for C7H4ClF2N3: 203. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2.0h; | To solution of <strong>[1196146-82-3]5-bromo-2-chloro-pyridin-4-ol</strong> (800 mg, 3.84 mmol) in DMF (10 ml) were added sodium chlorodifluoroacetate (700 mg, 4.61 mmol) and Cs2CO3 (1.87 g, 5.76 mmol) and the RM was heated at 100 C. for 2 h. The RM was treated with ice cold water and was extracted with diethyl ether. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reduced pressure to get a crude compound which was purified by CC (SiO2, EtOAc/Hex) to afford the desired compound (600 mg, 60%). |
With caesium carbonate; In N,N-dimethyl-formamide; at 110 - 115℃; | A solution of <strong>[1196146-82-3]5-bromo-2-chloropyridin-4-ol</strong> (200 g 0.960 mol, Intermediate 56) and sodium chlorodifluoroacetate (264 g, 1.73 mol) in DMF (1 L) was added dropwise to a 110-115 C. suspension of Cs2CO3 (469 g, 1.44 mol) in DMF (1 L), and the resulting mixture was stirred at 110-115 C. After the reaction went to completion, mixture was allowed to cool to 50-60 C., and then it was poured into ice water. The resulting mixture was extracted twice with MTBE, and the combined organic layers were washed with water and then concentrated. The concentrate was purified by distillation to afford the title compound as a colorless liquid (bp 75-78 C. at 1-2 mmHg). | |
With caesium carbonate; In N,N-dimethyl-formamide; at 110 - 115℃; | A solution of <strong>[1196146-82-3]5-bromo-2-chloropyridin-4-ol</strong> (200 g 0.960 mol, Intermediate 53) and sodium chlorodifluoroacetate (264 g, 1.73 mol) in DMF (1.0 L) was added dropwise to a 110-115 C. suspension of Cs2CO3 (469 g, 1.44 mol) in DMF (1.0 L), and the resulting mixture was stirred at 110-115 C. After the reaction went to completion, mixture was allowed to cool to 50-60 C., and then it was poured into ice water. The resulting mixture was extracted twice with MTBE, and the combined organic layers were washed with water and then concentrated. The concentrate was purified by distillation to afford the title compound as a colorless liquid (bp 75-78 C. at 1-2 mmHg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium hydride; In tetrahydrofuran; mineral oil;Reflux; | Treat a solution of 2-(dibenzylamino)ethanol (1.5 g, 6.2 mmol) and sodium chloro-2,2-difluoro-acetic acid (950 mg, 6.19 mmol) in THF (12 mL) at 0 C. with sodium hydride (60 wt % in mineral oil, 500 mg, 12.5 mmol). Heat the reaction mixture to reflux overnight. Add additional sodium hydride (60 wt % in mineral oil, 120 mg, 3 mmol) to the reaction mixture and continue heating for an additional hour. Cool the reaction to room temperature and dilute with water. Extract the mixture with diethyl ether. Separate the layers and adjust the aqueous layer to pH 6 with 6 N hydrochloric acid. Extract the aqueous solution with EtOAc. Combine all organic solutions and dry over anhydrous sodium sulfate. Filter the mixture and concentrate the filtrate under reduced pressure to give the title compound 1.03 g (49%). MS (m/z): 336 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydroxide; In water; N,N-dimethyl-formamide; at 120℃; for 1h; | To a solution of Intermediate 6A (0.625 g, 2.87 mmol) and sodium 2-chloro-2,2- difluoroacetate (0.437 g, 2.87 mmol) in DMF (15 mL) and water (0.5 mL), was addedsodium hydroxide (0.115 g, 2.87 mmol). The reaction mixture was heated at 120°C forh, then was cooled to rt and concentrated. The crude product was purified by flash chromatography (0-6percent EtOAc / pet. ether) to afford Intermediate 6B (0.505 g, 1.88 mmol, 66percent yield) as a pale yellow liquid. ?H NMR (300MHz, CDC13) oe 8.12 (d, J=2.6 Hz, 1H), 8.06 - 7.96 (m, 1H), 7.85 (d, J9.1 Hz, 1H), 6.95 - 6.39 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; In acetonitrile; at 80℃; for 32h; | (Reference Example 8) Synthesis of ethyl 1-(difluoromethyl)-1H-imidazole-2-carboxylate: Potassium carbonate (1.28 g, 9.28 mmol) and sodium chlorodifluoroacetate (1.31 g, 8.56 mmol) were added to a solution of <strong>[33543-78-1]ethyl 1H-imidazole-2-carboxylate</strong> (1.00 g, 7.14 mmol) in acetonitrile (35 mL) at room temperature and the resultant mixture was stirred at 60°C for 24 hours. Further, potassium carbonate (0.640 g, 4.63 mmol) and sodium chlorodifluoroacetate (0.660 g, 4.33 mmol) were added at room temperature and the reaction liquid was stirred at 80°C for 8 hours. The reaction liquid was cooled to room temperature and distilled water was added to the reaction liquid and the reaction liquid was extracted with ethyl acetate. The organic layer was washed with a 10percent aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to obtain ethyl 1-(difluoromethyl)-1H-imidazole-2-carboxylate (0.838 g, 4.41 mmol, 62percent) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 1.46 (3H, t, J=7.2 Hz), 4.47 (2H, q, J=7.2 Hz), 7.28 (1H, s), 7.53 (1H, d, J=1.6 Hz), 8.16 (1H, t, J=60.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | In N,N-dimethyl-formamide; at 95℃; for 0.583333h;Inert atmosphere; | The reaction was performed under an argon atmosphere . To a 25 mL three-necked flask was added 5 mL of anhydrous DMF, and the solvent was stirred at 95 C. 200 mg of 3- (chloromethyl)-2-hydroxy-5-nitrobenzaldehyde (2i) and 708 mg of SCDA were dissolved in 5 mL anhydrous DMF and slowly added to the three-necked flask with a syringe for about 5 minutes and the mixture stirred for 30 minutes. 10 mL of water was poured into the reaction mixture, and the mixture was extracted with 25 mL of ethyl acetate three times. The organic phases were dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (EA/PE=10 % as eluent ) to give 70 mg, 28 % yield, of 7-(chloromethyl)-2,2-difluoro-5-nitro-2,3- dihydrobenzofuran-3-ol 3i. |
28% | With sodium carbonate; In N,N-dimethyl-formamide; at 95℃; for 0.5h;Inert atmosphere; | Argon gas was used to protect the 25 mL three-necked flask, and the syringe was added with 5 mL of anhydrous DMF.Stir at 95 C. <strong>[16644-30-7]2-hydroxy-3-chloromethyl-5-nitrobenzaldehyde</strong> 200mgAnd 708 mg of sodium chlorodifluoroacetate dissolved in 10 mL of anhydrous DMF,Then, it was slowly added to the three-necked flask with a syringe for about 8 minutes, and then reacted for half an hour.Stop the reaction and quench the reaction by adding 15 mL of water.Ethyl acetate (30 mL x 3) was extracted three times, and the organic phases were combined.Wash the organic phase twice with saturated saline (20 mL x 2).The organic phase was dried over anhydrous sodium sulfate. The organic phase is concentrated under reduced pressure.Mix the silica gel and pass the medium pressure column.Obtained a white solid 70mg,The yield was 28%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 16h; | A mixture of 5 -fluoro-2-methoxy -phenol (1.00 g, 7.04 mmol), sodium 2-chloro-2,2-difluoro- acetate (2.68 g, 17.6 mmol) and cesium carbonate (4.58 g, 14.1 mmol) in DMF (14 mL) and water (1.5 mL) was heated at 100 C for 16 hours. The reaction mixture was diluted with dichloromethane, filtered, and the filtrate was washed with water and brine. The organic layer was dried over MgSO/t, concentrated in vacuo and purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to provide 2- (difluoromethoxy)-4-fluoro-l-methoxy-benzene (590 mg, 44%) as a colorless liquid. NMR (400 MHz, CDC13) delta 6.99 - 6.86 (m, J = 6.5, 5.1 Hz, 3H), 6.56 (t, J = 74.7 Hz, 1H), 3.86 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate; In acetonitrile; at 120℃; for 24h; | The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 °C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76percent. White solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With caesium carbonate; In acetonitrile; at 120℃; for 24h; | The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 °C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76percent. White solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With caesium carbonate; In acetonitrile; at 120℃; for 24h; | The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76%. White solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate; In acetonitrile; at 120℃; for 24h; | The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76%. White solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With caesium carbonate; In acetonitrile; at 120℃; for 24h; | The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76%. White solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | Methyl 3-hydroxy-l-methylpyrazole-5-carboxylate (10 g, 60.8 mmol) was dissolved in DM F (200 mL). sodium chlorodifluoroacetate (23.2 g, 152 mmol) was added followed by potassium carbonate (25.2 g, 182 mmol). The reaction mixture was heated to 80 C with stirring under N2 overnight. The reaction was cooled & poured into water (200 mL). The mixture was then extracted with EtOAc (3 x 200 mL) and the combined organic extracts dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-25% EtOAc in iso-hexanes to give the title compound (6.41 g, 51 % Yield). dH (300 M Hz, Chloroform-d) 6.76 (t, J = 73.1 Hz, 1H), 6.41 (s, 1H), 4.08 (s, 3H), 3.88 (s, 3H). |
Tags: Sodium chlorodifluoroacetate | Fluorinated Building Blocks | Chlorides | Carboxylic Acid Salts | Aliphatic Chain Hydrocarbons | Organic Building Blocks | 1895-39-2
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P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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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