Structure of 84832-02-0
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CAS No. : | 84832-02-0 |
Formula : | C8H7F2NO2 |
M.W : | 187.14 |
SMILES Code : | O=C(OC)C1=C(F)C=CC(N)=C1F |
MDL No. : | MFCD13195461 |
InChI Key : | IUXHGFLADBGDTR-UHFFFAOYSA-N |
Pubchem ID : | 45480188 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-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 |
---|---|---|
99% | With hydrogen;palladium 10% on activated carbon; In ethanol;Inert atmosphere; | [00176] Step B: 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step. |
99% | With hydrogen;palladium 10% on activated carbon; In ethanol; | 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by thin layer chromatography ("TLC"), N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6- difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step. |
99% | With hydrogen;palladium 10% on activated carbon; In ethanol; | Step B: 10% (wt) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by thin layer chromatography ("TLC"), N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6- difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step. |
99% | With hydrogen;palladium 10% on activated carbon; In ethanol;Inert atmosphere of nitrogen; | 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The <n="68"/>mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step. |
98% | With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; | General procedure: Pd/C (0.1 eq.) was added to a solution of the nitrobenzene (1.0 eq.) in EtOH (0.2 m). The suspension was degassed with H2and the reaction was stirred at room temperature upon complete consumption of the starting material. Then, the mixture was passed through a Celite pad and the filtrate was concentrated in vacuum. The product was used without any further purification. |
98% | With hydrogenchloride; iron; In ethanol; water; at 80℃; | Alternatively: 75 (1 g, 4.6 mmol, 1.0 eq.) was suspended in abs.Ethanol (0,25 M) and aqueous HCl solution (1 M, 4.6 ml, 1.0 eq.) andheated to 80 C. Fe0 (282 mg, 5.1 mmol, 1.1 eq.) was added to themixture and stirred at 80 C until complete consumption of the starting material. The crudewas poured through a pad of Celite andthe filtrate dried in vacuo. The productwas obtained as a white solidand was used without further purification steps. Yield: 843 mg,4.5 mmol, 98%. |
93% | With palladium 10% on activated carbon; hydrogen; In ethanol; under 2585.81 Torr; for 22h; | A solution of compound 2 (15.0 g, 69.1 mmol) in EtOH (250 mL) was hydrogenation over 10% Pd/C (4.0 g) at 50 psi for 22 h. The catalyst was filtered off through a layer of Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1-3:1 hexanes/EtOAc) to give 3 (12.9 g, 93%) as a pale yellow oil. 1H NMR (DMSO-d6): δ 6.93-6.91 (m, 2H), 5.26 (br s, 2H), 3.87 (s, 3H) |
93% | With hydrogen;5%-palladium/activated carbon; In methanol; at 25℃; under 2585.81 Torr; for 12h;Inert atmosphere; | To a solution of methyl 2,6-difluoro-3-nitrobenzoate (25 g, 1 15 mmol) in MeOH (150 ml_) was added 5% palladium on carbon (2.5 g). The mixture was stirred under H2 atmosphere (50 psi/25 C) for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under the reduced pressure to give the product. 20 g (93 % yield) 1 H NMR (400 MHz, DMSO-c/6) δ ppm 6.95-7.10 (m, 2H), 3.86 (s, 3H) |
91% | With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; | Step 4: methyl 3-amino-2,6-difluorobenzoateTo a solution of methyl 2,6-difluoro-3-nitrobenzoate (50 g, 0.23 mol) in MeOH (150 mL) was added Pd/C (10%) and the resulting reaction mixture was stirred at room temperature for overnight under H2 atmosphere. The mixture was filtered. The filtrate was concentratd in vacuo to afford the desired product (38.8 g, 91 >).1H NMR (CDCI3): ? 6.84-6.73 (2H, m), 3.94 (3H, s), 3.69 (2H, br). |
91% | With palladium on activated charcoal; hydrogen; In methanol; at 20℃; | To a solution of 2,6-difluoro-3-nitrobenzoate (50 g, 0.23mo 1) in methanol was added palladium on carbon (10%).The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere, filtered, and the resulting filtrate was concentrated in vacuo to give the title compound (38.8 g, 91%) |
With hydrogen;palladium 10% on activated carbon; In ethanol;Inert atmosphere; | Step B: 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. To the flask was added EtOH (350 mL, 0.25 M), and H2 gas was passed through the mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The balloons were recharged with H2 gas and the mixture was stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford crude methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g). The material was taken directly onto the next step. | |
With hydrogen;palladium 10% on activated carbon; In ethanol; | 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass Dulfonamid filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g). The material was taken directly onto the next step. | |
With hydrogen;palladium 10% on activated carbon; In ethanol; | 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g). The material was taken directly onto the next step. | |
With hydrogen;palladium 10% on activated carbon; In ethanol;Inert atmosphere; | Step B: 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. To the flask was added EtOH (350 mL, 0.25 M), and H2 gas was passed through the mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The balloons were recharged with H2 gas and the mixture was stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford crude methyl 3-amino-2,6-difiuorobenzoate as an oil (15.66 g). The material was taken directly onto the next step. | |
With hydrogen;palladium 10% on activated carbon; In ethanol;Inert atmosphere; | 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. To the flask was added EtOH (350 mL, 0.25 M), and H2 gas was passed through the mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The balloons were recharged with H2 gas and the mixture was stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford crude methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g). The material was taken directly onto the next step. | |
With iron; acetic acid; In methanol; water; at 110℃; | Iron powder (15.5g, 4.0 equiv.) was added to 100 mL of water, and 100 mL of acetic acid was added under stirring, followed by 2,6-difluoro-The 3-nitrobenzoic acid methyl ester compound 2309 (15.0 g, 0.069 mol) was dissolved in ethanol (100 mL) and added with a small amount of acetic acid to aid dissolution.The mixture was slowly added to the above mixed solution and heated to 110C. TLC showed that the reaction was complete. The reaction solution was distilled off under reduced pressure and the residue remainedEthyl acetate was added to the solution, which was filtered. The filtrate was washed with saturated sodium bicarbonate, washed with water, saturated brine, and dried over anhydrous sodium sulfate.This was evaporated to dryness to afford compound 2310 (13.2 g, yield: 100%) which was used in the next step without purification | |
With palladium 10% on activated carbon; hydrogen; In ethanol; | Methyl 2,6-difluoro-3-nitrobenzoate (1.13 g, 5.19 mmol) was dissolved in ethanol (17.0 ml.) and palladium on activated charcoal (10% Pd) (0.055g, 0.052 mmol) was added while stirring. The reaction was flushed with hydrogen until complete consumption of the starting material. The suspension was filtrated and the solvent of the filtrate was removed under vacuum. The residue was purified via flash chromatography (silica, gradient: 100% n-hexane -> n- hexane/ethyl acetate 6/4 v/v). The product was obtained as yellow oil. 1H-NMR (200 MHz, DMSO-de) d 7.00 - 6.82 (m, 2H), 5.26 (s, 2H), 3.86 (s, 3H). 13C-NMR (50 MHz, DMSO- d6) d 162.0, 149.8 (dd, J = 240.7, 5.4 Hz), 146.6 (dd, J = 247.6, 6.5 Hz), 133.7 (dd, J = 12.9, (0255) 2.6 Hz), 1 18.2 (dd, J = 8.9, 6.8 Hz), 1 11.6 (dd, J = 22.0, 3.6 Hz), 1 10.1 (dd, J = 20.0, 16.4 Hz), 52.8. TLC-MS (ESI-): Calculated 187.04 for C8H7F2NO2. Measured 185.6 for [M-H] . HPLC: tR = 3.980 min, purity: 97.4% (254.4 nm), 97.6% (230.4 nm). | |
With palladium 10% on activated carbon; hydrogen; In ethanol; | To a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) was added 10% wt. Pd on activated carbon (4.46 g, 4.19 mmol) under a nitrogen atmosphere. To the flask was added EtOH (350 mL), and hydrogen was passed through the mixture for 15 minutes. The reaction mixture was stirred under two hydrogen balloons overnight. The balloons were recharged with H2 (g) and the mixture was stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, nitrogen was flushed through the reaction mixture. The mixture was filtered through glass microfibre filter (GF/F) paper twice. The solution was concentrated to afford crude methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g). The material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | With pyridine; In dichloromethane;Cooling with acetone-dry ice; | 2,2,2-Trifluoroethyl-sulfonyl chloride (459 mL, 4.15 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (311 g, 1.66 mmol) and pyridine (0.806 mL, 9.97 mmol) in dichloromethane (8.92 mL, 139 mmol), while applying external cooling using an acetone dry ice bath. The reaction mixture was stirred for 45 minutes, and the dry ice bath was removed. The reaction mixture was kept stirring for another hour. The mixture was diluted with EtOAc (100 mL), washed with water (2 X 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and then concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% EtOAc/hexane to afford methyl 2,6-difluoro-3-(2-trifluoroethylsulfonamido) benzoate as a solid (513 mg, 92.6% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.10-8.01 (m, IH), 7.48 (t, IH), 4.68 (s, 2H), 4.58 (s, 2H), 3.98 (s, 3H). |
92.6% | With pyridine; In dichloromethane;Cooling with acetone-dry ice; | 2,2,2-Trifluoroethyl-sulfonyl chloride (459 mL, 4.15 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (311 g, 1.66 mmol) and pyridine (0.806 mL, 9.97 mmol) in dichloromethane (8.92 mL, 139 mmol), while applying external cooling using an acetone dry ice bath. The reaction mixture was stirred for 45 minutes, and the dry ice bath was removed. The reaction mixture was kept stirring for another hour. The mixture was diluted with EtOAc (100 mL), washed with water (2 X 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and then concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% EtOAc/hexane to afford methyl 2,6-difluoro-3-(2-trifluoroethylsulfonamido) benzoate as a solid (513 mg, 92.6% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.10-8.01 (m, IH), 7.48 (t, IH), 4.68 (s, 2H), 4.58 (s, 2H), 3.98 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | General procedure: A solution of aniline (1.0 eq.) and Et3N (2.2 eq.) in dry DCM (0.25 m) was cooled to 0C and the corresponding sulfonyl chloride was added dropwise. After complete addition the ice bath was removed and the solution was stirred at room temperature for ~1 h. The solution was then diluted with water, extracted with EtOAc and the combined organic layers were dried over Na2S04. The solvent was removed under reduced pressure and the product was purified via flash chromatography (Si02, nHex/EtOAc 9/1 ). |
75% | With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | To a solution of compound 3 (11.5 g, 61.4 mmol) and triethylamine (25.67 mL, 184.2 mmol) in CH2Cl2 (55 mL) was added propane-1-sulfonyl chloride (17.25 mL, 153.3 mmol) dropwise at 0 C. The reaction mixture was stirred at room temperature for 1 h. Water (150 mL) was added, and the organic layer was separated, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (6:1-4:1 hexanes/EtOAc) to give 4 (18.4 g, 75%) as an off-white solid, mp 76-77 C. 1H NMR (CDCl3): δ 7.51-7.47 (m, 1H), 7.07-7.03 (m, 1H), 3.97 (s, 3H), 3.67-3.61 (m, 2H), 3.52-3.46 (m, 2H), 1.99-1.91 (m, 4H), 1.10 (t, J = 7.5 Hz, 6H). |
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with water bath; | Step C: Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J =7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2. |
With triethylamine; In dichloromethane; at 20℃; for 1h; | Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5 M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added, and the organic layer was separated, washed with water (2 x 300 mL), brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(7V-(propylsulfonyl)propyl- Dulfonamide)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J= 7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃; for 1h; | Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5 M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added, and the organic layer was separated, washed with water (2 x 300 mL), brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(iV-(propylsulfonyl)propyl- sulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02- 1.89 (m, 4H), 1.10 (t, J= 7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃; for 1h;Cool water bath; | Step C: Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(7V-(propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with water bath; | [00177] Step C: Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃;Inert atmosphere; Cooling; | Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2C12 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2S04), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDC13) δ 7.52-7.45 (m, 1H), 7.08-7.02 (m, 1H), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M- (S02Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃; for 3.5h;Cooling with ice; | Methyl 2,6-difluoro-3-aminobenzoate compound 2310 (3.7 g, 0.020 mol) was dissolved in dichloromethaneTriethylamine (8.4 mL, 3.0 equiv) was added (40 mL), and propanesulfonyl chloride (4.7 mL, 2.1 mL) was added slowly under ice-cooling.Amount), stirring at room temperature for 3.5 hours, TLC test showed complete reaction. The reaction solution was quenched with water and extracted with dichloromethane for 3 times.Phase, 1M hydrochloric acid, saturated aqueous sodium bicarbonate solution, washed with water, saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressureThe oily compound 2311a was used in the next step without further purification. | |
With triethylamine; In dichloromethane; at 20℃;Cooling with water bath; | Propane- 1-sulfonyl chloride (23.46 niL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate/hexanes. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N-(propylsulfonyl) propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃;Cooling; | Step C: propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate/hexanes. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)-benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M- (SO2Pr) = 292.2. | |
With triethylamine; In dichloromethane; at 20℃;Cooling with water bath; | Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M- (SO2Pr) = 292.2. | |
24.4 g | With triethylamine; In dichloromethane; at 20℃; for 1h; | Propane-1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a cooled solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL). The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2*300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% EtOAc/hexanes to afford methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, 1H), 7.08-7.02 (m, 1H), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J=7.4 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃; for 48h;Product distribution / selectivity; | Intermediate Example Tmethyl 2,6-difluoro-3 -(3 -fluoro-N-(3 -fluoropropylsulfonyl)propylsulfonamido)benzoate [00203] 3-Fluoropropane-l-sulfonyl chloride (14.3 mL, 129 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (24.1 g, 129 mmol) and pyridine (31.2 mL, 386 mmol) in CH2Cl2 (360 mL). The reaction mixture was stirred for over two days at room temperature. The reaction mixture was diluted with methylene chloride. The reaction mixture was then washed with an aqueous solution of saturated sodium bicarbonate, IN HCl, and brine, then dried (Na2SO4), filtered and concentrated to an oil to give methyl 2,6-difluoro-3-(3-fluoro- N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38.1 g). 1H NMR (400 MHz, CDCl3, ppm) 7.69 (dt, IH), 7.00 (dt, IH), 6.55 (s, IH), 4.56 (dd, 2H), 3.28-3.17 (m, 2H), 2.32-2.15 (m, 2H). | |
With pyridine; In dichloromethane; at 20℃; for 48h;Product distribution / selectivity; | 3-Fluoropropane-l-sulfonyl chloride (14.3 mL, 129 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (24.1 g, 129 mmol) and pyridine (31.2 mL, 386 mmol) in CH2Cl2 (360 mL). The reaction mixture was stirred for over two days at room temperature. The reaction mixture was diluted with methylene chloride. The reaction mixture was then washed with an aqueous solution of saturated sodium bicarbonate, IN HCl, and brine, then dried (Na2SO4), filtered and concentrated to an oil to give methyl 2,6- difluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38.1 g). H NMR (400 MHz, CDCl3, ppm) 7.69 (dt, IH), 7.00 (dt, IH), 6.55 (s, IH), 4.56 (dd, 2H), 3.28- 3.17 (m, 2H), 2.32-2.15 (m, 2H). | |
With pyridine; In dichloromethane; at 20℃; for 48h;Product distribution / selectivity; | methyl 2,6-difluoro-3-(3-fluoro-N-('3-fluoropropylsulfonvDpropylsulfonamido)benzoate [00213] 3-Fluoropropane-l-sulfonyl chloride (14.3 mL, 129 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (24.1 g, 129 mmol) and pyridine (31.2 mL, 386 mmol) in CH2Cl2 (360 mL). The reaction mixture was stirred for over two days at room temperature. The reaction mixture was diluted with methylene chloride. The reaction mixture was then washed with an aqueous solution of saturated sodium bicarbonate, IN HCl, and brine, then dried (Na2SO4), filtered and concentrated to an oil to give methyl 2,6- difluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38.1 g). 1H NMR (400 MHz, CDCl3, ppm) 7.69 (dt, IH), 7.00 (dt, IH), 6.55 (s, IH), 4.56 (dd, 2H), 3.28- 3.17 (m, 2H), 2.32-2.15 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | With pyridine; In dichloromethane; for 0.75h;Cooling with acetone-dry ice; | [00210] Step A: 2,2,2-Trifluoroethyl-sulfonyl chloride (459 mL, 4.15 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (311 g, 1.66 mmol) and pyridine (0.806 mL, 9.97 mmol) in dichloromethane (8.92 mL, 139 mmol), while applying external cooling using an acetone dry ice bath. The reaction mixture was stirred for 45 minutes, and the dry ice bath was removed. The reaction mixture was kept stirring for another hour. The mixture was diluted with EtOAc (100 mL), washed with water (2 X 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and then concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% EtOAc/hexane to afford methyl 2,6-difluoro-3-(2- trifluoroethylsulfonamido) benzoate as a solid (513 mg, 92.6% yield). 1H NMR (400 MHz, (CD3)2SO) δ 8.10-8.01 (m, IH), 7.48 (t, IH), 4.68 (s, 2H), 4.58 (s, 2H), 3.98 (s, 3H). |
92.6% | With pyridine; In dichloromethane; for 1.75h;Cooling with acetone-dry ice; | Step A: 2,2,2-Trifluoroethyl-sulfonyl chloride (459 mL, 4.15 mmol) was slowly added to a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (311 g, 1.66 mmol) and pyridine (0.806 mL, 9.97 mmol) in dichloromethane (8.92 mL, 139 mmol), while applying external cooling using an acetone dry ice bath. The reaction mixture was stirred for 45 <n="50"/>minutes, and the dry ice bath was removed. The reaction mixture was kept stirring for another hour. The mixture was diluted with EtOAc (100 mL), washed with water (2 X 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and then concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% EtOAc/hexane to afford methyl 2,6-difluoro-3-(2-trifluoroethylsulfonamido) benzoate as a solid (513 mg, 92.6% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.10-8.01 (m, IH), 7.48 (t, IH), 4.68 (s, 2H), 4.58 (s, 2H), 3.98 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | Propylsulfamoyl chloride (0.379 mL, 2.40 mmol) was added to <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (0.150 mL, 0.802 mmol), TEA (0.335 mL, 2.40 mmol) in DCM (1.5 mL) at O0C. The solution was warmed to room temperature overnight. The solids were filtered, and the supernate was concentrated to provide crude methyl 2,6-difluoro- 3-(N-propylsulfamoylamino)benzoate, which was used directly in next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuryl dichloride; triethylamine; In dichloromethane; at -78℃; for 2h; | A solution of triethylamine (0.260 mL, 1.85 mmol) and methyl 3- amino-2,6-difluorobenzoate (0.257 mL, 1.85 mmol) was added dropwise to sulfuryl dichloride (0.156 mL, 1.85 mmol) in DCM (3 mL) at -780C. After 2 hours, N- methylethanamine (0.304 mL, 3.70 mmol) was added and then let warm to room temperature overnight. The solvent was concentrated under reduced pressure, and the residue was taken up in NaOH (2 mL, IM) and washed with EtOAc. The aqueous pH was lowered to below 3 and, the mixture was extracted with EtOAc (3 X 5 mL). The combined organic layers were dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 7:3 hexane:EtOAc to afford impure methyl 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoate (0.280 g, 49.0% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.1% | With triethylamine; In dichloromethane; at 0 - 20℃; | Benzyl 3-amino-2-chloro-6-fluorobenzoate (330 mg, 1.2 mmol) was dissolved in dry dichloromethane (11.8 mL). Triethylamine (0.494 mL, 3.54 mmol) was added, and the mixture was chilled to 0C. Propane- 1-sulfonyl chloride (0.332 mL, 2.95 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 16 hours. The mixture was diluted with dichloromethane (11 mL) and washed with water (2 X 50 mL) and brine (25 mL), dried over sodium sulfate, and concentrated. The resulting residue was applied directly to a silica gel column and eluted with a gradient (5% to 40%) of ethyl acetate-hexanes to provide benzyl 2- chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (413 mg, 0.840 mmol, 71.1% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.00-7.94 (q, IH), 7.59-7.52 (t, IH), 7.50- 7.35 (m, 5H), 5.48-5.44 (s, 2H), 3.80-3.60 (m, 4H), 1.89-1.75 (m, 4H), 1.05-0.98 (t, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With sodium hydrogencarbonate; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | To a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (75 g, 401 mmol) in THF (300 ml_), was added saturated NaHCO3 (1400 ml_). Then 2-propen-1 -yl chloridocarbonate (67.0 g, 561 mmol) was added dropwise at 0 C. The mixture was stirred at room temperature for 2 h. The solution was extracted with EtOAc (500 ml_ x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. 92.5 g (85.6% yield) 1H NMR (400 MHz, CDCI3) δ ppm 8.05-8.20 (br, 1 H), 6.88-6.95 (m, 1 H), 5.86- 6.01 (m, 1 H), 5.21 -5.40 (m, 2H), 4.54-4.69 (m, 2H), 3.92 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 4h; | Step A: Methyl 3-amino-2,6-difluorobenzoate (1.14 g, 6.092 mmol) was dissolved in DCM (30.5 mL) and treated sequentially with triethylamine (2.50 rnL, 18.27 mmol) and benzenesulfonyl chloride (1.63 mL, 12.79 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and then diluted with additional DCM and washed with water (2x) and brine (Ix). The organic phase was dried over Na2SO4 and concentrated to provide methyl 2,6- difluoro-3-(iV-(phenylsulfonyl)phenylsulfonamido)benzoate (2.848 g, 6.092 mmol). The crude material was then immediately dissolved in 60.9 mL 4:1 THF:MeOH (0.1 M) and treated with 2.0 M KOH (15.23 mL, 30.46 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The organic solvent was removed under reduced pressure and the aqueous residue acidified to pH 3 using 1.0 M HCl. Extraction with EtOAc (2x) was followed by washing the combined organic extracts with water (2x). The crude product was then extracted as its carboxylate salt with 1.0 M NaOH (2x). The combined aqueous NaOH extracts were acidified to pH 3 using 6.0 M HCl and extracted with EtOAc (2x). The combined organic extracts were washed with water (2x) and brine (Ix) and then dried over Na2SO4 and concentrated to afford 2,6-difluoro-3-(phenylsulfonamido)benzoic acid (1.53 g, 4.884 mmol, 80.17% yield). LC/MS: m/z 312.0 [M-I]. | |
With triethylamine; In dichloromethane; at 20℃; for 4h; | Methyl 3-amino-2,6-difluorobenzoate (1.14 g, 6.092 mmol) was dissolved in dichloromethane (30.5 mL) and treated sequentially with triethylamine (2.50 mL, 18.27 mmol) and benzenesulfonyl chloride (1.63 mL, 12.79 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and then diluted with additional dichloromethane and washed with water (2x) and brine (Ix). The organic phase was dried over Na2SO4 and concentrated to provide methyl 2,6-difluoro-3-(JV-(phenylsulfonyl)phenylsulfonamido)benzoate (2.848 g, 6.092 mmol). The crude material was then immediately dissolved in 60.9 mL 4:1 THF:MeOH (0.1 M) and treated with 2.0 M KOH (15.23 mL, 30.46 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The organic solvent was removed under reduced pressure and the aqueous residue acidified to pH 3 using 1.0 M HCl. Extraction with EtOAc (2x) was followed by washing the combined organic extracts with water (2x). The crude product was then extracted as its carboxylate salt with 1.0 M NaOH (2x). The combined aqueous NaOH extracts were acidified to pH 3 using 6.0 M HCl and extracted with EtOAc (2x). The combined organic extracts were washed with water (2x) and brine (Ix) and then dried over Na2SO4 and concentrated to afford 2,6-difluoro-3-(phenylsulfonamido)benzoic acid (1.53 g, 4.884 mmol, 80.17% yield). LC/MS: m/z 312.0 [M-I]. | |
With dmap; triethylamine; In dichloromethane; at 20℃; for 20h; | To a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (3.00mmol, 561mg, Combi-Blocks) and benzenesulfonyl chloride (8.00mmol, 1.02mL) in DCM (15mL) was added DMAP (30mg) and triethylamine (10.0mmol, 1.38mL). The resulting mixture was stirred at rt for 20h, after which it was diluted with Et2O (100mL) and washed with 1N HCl (2×80mL), sat. aq. NaHCO3 (80mL) and brine (80mL). The organic phase was dried (MgSO4) and the solvent was partially evaporated in vacuo. Addition of pentane resulted in the precipitation of product 21, which was used in the next step without further purification. Compound 21 (1.37mmol, 640mg) was stirred at rt for 2h in a mixture of 2N aq. KOH (10mL), THF (24mL) and methanol (6mL). The reaction mixture was diluted with AcOEt (80mL) and 1N HCl (80mL). The aqueous phase was separated and extracted with AcOEt (80mL). The combined organic fractions were washed with brine (100mL). The organic phase was dried (MgSO4) and the solvent was partially evaporated in vacuo. Addition of pentane resulted in the precipitation of product 22 as a light pink solid (420mg, 83% over two steps). Mp. 144-145C; 1H NMR (400MHz, CD3OD) δ 7.00 (t, J=9.1, 1H), 7.43-7.64 (m, 4H), 7.73 (d, J=7.3Hz, 2H). 19F NMR (376MHz, CD3OD) δ-123.31 (d, J=8.7Hz),-115.64 (t, J=7.3Hz). 13C NMR (101MHz, CD3OD) δ 111.5 (dd, J=23.0, 4.2Hz), 121.6 (dd, J=13.7, 4.0Hz), 126.7, 128.8, 129.1 (dd, J=10.1, 2.4Hz), 132.8, 139.6, 152.0 (d, J=7.1Hz), 154.6 (d, J=7.2Hz), 156.2 (d, J=5.8Hz), 158.7 (d, J=5.8Hz), 162.2. HRMS (ESI+) calc. for [M+Na]+ (C13H9F2NO4SNa): 336.0113, found: 336.0114. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 16h; | Step A: Methyl 3-amino-2,6-difluorobenzoate (652.8 mg, 3.488 mmol) was dissolved in 17.4 mL DCM (0.2 M) and treated sequentially with triethylamine (1.42 mL, 10.46 mmol) and furan-2-sulfonyl chloride (1.162 g, 6.976 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then diluted with additional DCM and washed with water (2x) and brine (Ix). The organic phase was dried over Na2SO4 and concentrated to provide methyl 2,6- difluoro-3-(N-(furan-2-ylsulfonyl)furan-2-sulfonamido)benzoate (1.561 g, 3.489 mmol). The crude material was then immediately dissolved in 17.5 mL 4:1 THF:MeOH (0.2 M) and treated with 2.0 M KOH (8.7 mL, 17.45 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The organic solvent was removed under reduced pressure and the aqueous residue acidified to pH 3 using 1.0 M HCl. Extraction with EtOAc (2x) was followed by washing the combined organic extracts with water (2x). The crude product was then extracted as its carboxylate salt with 1.0 M NaOH (2x). The combined aqueous NaOH extracts were acidified to pH 3 using 6.0 M HCl and extracted with EtOAc (2x). The combined organic extracts were washed with water (2x) and brine (Ix) and then dried over Na2SO4 and concentrated to afford 2,6-difluoro-3-(furan-2-sulfonamido)benzoic acid (475.0 mg, 1.566 mmol, 44.91% yield). LC/MS: m/z 302.0 [M-I]. | |
With triethylamine; In dichloromethane; at 20℃; for 16h; | Methyl 3-amino-2,6-difluorobenzoate (652.8 mg, 3.488 mmol) was dissolved in 17.4 mL dichloromethane (0.2 M) and treated sequentially with triethylamine (1.42 mL, 10.46 mmol) and furan-2-sulfonyl chloride (1.162 g, 6.976 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then diluted with additional dichloromethane and washed with water (2x) and brine (Ix). The organic phase was dried over Na2SO4 and concentrated to provide methyl 2,6-difluoro-3-(iV-(furan-2-ylsulfonyl)furan-2-sulfonamido)benzoate (1.561 g, 3.489 mmol). The crude material was then immediately dissolved in 17.5 mL 4:1 THF:MeOH (0.2 M) and treated with 2.0 M KOH (8.7 mL, 17.45 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The organic solvent was removed under reduced pressure and the aqueous residue acidified to pH 3 using 1.0 M HCl. Extraction with EtOAc (2x) was followed by washing the combined organic extracts with water (2x). The crude product was then extracted as its carboxylate salt with 1.0 M NaOH (2x). The combined aqueous NaOH extracts were acidified to pH 3 using 6.0 M HCl and extracted with EtOAc (2x). The combined organic extracts were washed with water (2x) and brine (Ix) and then dried over Na2SO4 and concentrated to afford 2,6-difluoro-3-(furan-2-sulfonamido)benzoic acid (475.0 mg, 1.566 mmol, 44.91% yield). LC/MS: m/z 302.0 [M-I]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine; In dichloromethane; at 8℃; | Step A: Into a 3000-mL 4-necked round-bottom flask was placed a solution of <strong>[84832-02-0]methyl 3-amino-2,6-difluorobenzoate</strong> (120 g, 609.63 mmol, 1.00 equiv, 95%) in dichloromethane (1800 mL) and pyridine (152 g, 1.92 mol, 3.16 equiv) followed by the addition of 3-fluoropropane-l-sulfonyl chloride (103 g, 643.75 mmol, 1.06 equiv) dropwise with stirring at 8 0C. After stirred overnight at 8 0C, the resulting mixture was washed with 2x400 mL of 5N HCl and 2x400 ml of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 150 g (75%) of methyl 2,6-difluoro-3-(3- fluoropropylsulfonamido)benzoate as a lavender colored solid. |
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