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CAS No. : | 13918-92-8 | MDL No. : | MFCD00042481 |
Formula : | C6H3ClF2O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FJSAJUXIHJIAMD-UHFFFAOYSA-N |
M.W : | 212.60 | Pubchem ID : | 2734273 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.44 |
TPSA : | 42.52 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.07 cm/s |
Log Po/w (iLOGP) : | 1.66 |
Log Po/w (XLOGP3) : | 2.15 |
Log Po/w (WLOGP) : | 3.81 |
Log Po/w (MLOGP) : | 2.38 |
Log Po/w (SILICOS-IT) : | 2.22 |
Consensus Log Po/w : | 2.45 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.82 |
Solubility : | 0.324 mg/ml ; 0.00153 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.68 |
Solubility : | 0.449 mg/ml ; 0.00211 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.5 |
Solubility : | 0.0666 mg/ml ; 0.000313 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.96 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; In dichloromethane; at 20℃; | A. (S)-2-Amino-3-naphthalen-2-yl-propionic acid methyl ester hydrochloride. ; (S)-2-(tert-Butoxycarbonylamino)-3-naphthalen-2-yl-propionic acid was treated as in EXAMPLE 2, Part A, to give a white solid. 1H NMR (400 MHz, CD3OD): 7.91-7.82 (m, 3H), 7.75 (br s, 1H), 7.54-7.47 (m, 2H), 7.38 (dd J=8.4, 1.7, 1H), 4.43 (dd, J=7.7, 6.0, 1H), 3.82 (s, 3H), 3.45 (dd, J=14.4, 5.9, 1H), 3.32 (dd, J=14.4, 7.7, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In dichloromethane; ethyl acetate; | Step 3: Preparation of 2,4-difluorobenzenesulfonamide 2,4-Difluorobenzenesulphonyl chloride (50.26 g, 237 mmol) was combined with concentrated ammonium hydroxide (100 mL) in methylene chloride (800 mL) and stirred at ambient temperature for 2 hours. Methylene chloride was removed in vacuo and solids were dissolved in ethyl acetate (800 mL). The solution was extracted with water (2*500 mL), saturated ammonium chloride (2*500 mL) and dried over sodium sulfate. The solvent was removed in vauo and 2,4-difluorobenzenesulfonamide was obtained by crystallization from ethyl acetate and hexanes (43.27 g, 225 mmol, 95% yield): mp 155-156 C. 1H NMR (CDCl3/300 MHz) 7.46-7.38 (m, 1H), 6.87 (brs, 2H), 6.59-6.51 (m, 2H). ESHRMS m/z 192.9990 (M+H+, Calcd 193.0009). Anal. Calcd for C6H5F2NO2S: C, 37.31; H, 2.61; N, 7.25; Found: C, 37.38; H, 2.51, N 7.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 15 1-[(2,4-Difluorophenyl)sulfonyl]-4-(1-piperazinyl)-1H-indole Hydrochloride (Scheme 1) The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 2,4-di-fluorophenylsulfonylchloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) delta 9.41 (br, 1H), 8.24 (m, 1H), 7.75 (m, 1H), 7.58 (m, 1H), 7.47-7.33 (m, 2H), 7.23 (t, J=8 Hz, 1H), 6.99 (d, J=5 Hz, 1H), 6.70 (d, J -8 Hz, 1H), 3.25 (m, 8H). MS (ESI+) for m/z 378 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; | Example 137 3-(2,4-Difluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 121 using 2,4-difluorobenzenesulfonyl chloride (2.19 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.532 g); m.p. 198-200 C. after trituration in hexanes/ethyl acetate (1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 20h; | Intermediate 36: 2,4-Difluoro-N-(2-hydroxyethyl)-N-methyl-benzenesulfonamide 2,4-Difluorobenzenesulfonyl chloride (CAS no. 13918-92-8) (4.0 g, 19 mmol) in DCM (10 mL) was added slowly to a solution of 2-(methylamino)ethanol (1.66 mL, 20.7 mmol) in DCM (200 mL) and 10% sodium hydroxide solution (200 mL) at 0 C. The reaction was allowed to warm to room temperature and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2*50 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4), filtered and evaporated under reduced pressure to afford the product (4.7 g, 98%). 1H NMR 6 (400 MHz, CDCl3): 1.98 (t, 1H), 2.94 (s, 3H), 3.32 (t, 2H), 3.79 (q, 2H), 6.94-7.03 (m, 2H), 7.89-7.95 (m, 1H). |
With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 20h; | 2,4-Difluorobenzenesulfonyl chloride (4 g, 18.81 mmol) in DCM (10 mL) was added slowly to a solution of 2-(methylamino)ethanol (1.66 mL, 20.70 mmol) in DCM (200 mL) and 10% sodium hydroxide solution (200 mL) at O0C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2 x 50 mL). The combined organics were washed with brine, dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a colourless oil (4.7 g). 1H NuMR delta (CDCl3): 1.98 (t, IH), 2.94 (s, 3H), 3.32 (t, 2H), 3.79 (q, 2H), 6.94 - 7.03 (m, 2H), 7.89 - 7.95 (m, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 20h; | 2,4-Difiuorobenzenesulfonyl chloride (1 g, 4.70 mmol) in DCM (2 mL) was added slowly to a solution of (2-[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (980 mg, 5.17 mmol) in DCM (65 mL) and 10% sodium hydroxide solution (65 mL) at O0C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2 x 50 mL). The combined organics were washed with brine (80 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a colourless oil (0.7 g). 1H NMR delta (CDCl3): 0.00 (s, 6H), 0.83 (s, 9H), 2.91 (s, 3H), 3.24 (t, 2H), 3.73 (t, 2H), 6.87 - 6.96 (m, 2H), 7.82 - 7.88 (m, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Reference Example 143; tert-butyl ({5- (2-cyanopyridin-3-yl) -l-[ (2,4- difluorophenyl) sulfonyl] -lH-pyrrol-3-yl}methyl)methylcarbamate; To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl [5- (2- cyanopyridin-3-yl) -lH-pyrrol-3-yl]methyl Jmethylcarbamate (156 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and 2,4- difluorobenzenesulfonyl chloride (159 mg) were added dropwise and the mixture was further stirred at room temperature for 1 <n="160"/>hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9: 1-*2: 1) to give the title compound as a colorless oil (yield 208 mg, 85%).1H-NMR (CDCl3) delta: 1.48(9H,s), 2.85 (3H,brs) , 4.29 (2H,brs) , 6.46(lH,brs) , 6.80-6.88 (IH,m) , 6.93 (lH,ddd, J=IO.2, 8.1, 2.4Hz) , 7.20(lH,ddd, J=8.8, 8.0, 5.8Hz) , 7.46 (IH, s) , 7.55(lH,dd, J=7.9,4.7Hz) , 7.93 (IH, dd, J=8.0, 1.6Hz) , 8.69(lH,dd, J=4.7,1.7Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a solution of 5-bromo-2-chloropyridin-3-amine (0.500 g, 2.89 mmol) in pyridine (1.45 ml) was dropwise added 2,4-difluorobenzene-1-sulfonyl chloride (0.614 ml, 2.89 mmol) at 0 C. The mixture was stirred for 40 min at room temperature and acidified with 1 N HCl. The residue was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70 g, 70% yield) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) delta 6.92-7.04 (2H, m), 7.76-7.84 (1H, m), 7.86-7.95 (1H, m), 8.27 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz); NH peak was not observed. | |
With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere; | General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added 2,4-difluorobenzenesulphonyl chloride (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%) | |
General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, 2,4-difluorobenzenesulphonyl chloride (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of 2,4-difluorobenzenesulphonyl chloride (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 545). |
With pyridine; at 0℃; for 1.05h; | Intermediate 4Preparation of lambda/-(5-bromo-3-pyridinyl)-2,4-difluorobenzenesulfonamide <n="78"/>To a cold (0 0C) stirred solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (18.6 g, 107.4 mMol) in dry pyridine (100 mL) was added 2,4-difluorobenzenesulfonyl chloride (25 g, 112.8 mMol) over 3 minutes. The reaction mixture was stirred at 0 0C for 1 h and evaporated to dryness under vacuum. The residue was diluted with H2O (400 mL) and EtOAc (400 mL). The organic layer was washed with H2O and brine, and the combined aqueous layers were extracted with EtOAc (100 mL). The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in boiling EtOAc (200 mL), and placed in a freezer for 2 days. Two crops were obtained through filtration, which were combined and triturated with boiling 35% EtOAc in hexanes. After cooling to room temperature, the precipitate was collected by filtration and dried to constant weight to provide 27.2 g of iV-(5-bromo-3-pyridinyl)-2,4- difluorobenzenesulfonamide as a light orange solid. MS (ES) m/e 351.0 (M + H)+. | |
With pyridine; at 0℃; for 1.05h; | To a cold (0 0C) stirred solution of <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (107.4 mmol) in dry pyridine (100 mL) was added 2,4-difluorobenzenesulfonyl chloride (112.8 mmol) over 3 min. The reaction mixture was stirred at 0 0C for 1 h and evaporated to dryness under vacuum. The residue was diluted with water (400 mL) and ethyl acetate (400 mL). The organic layer was washed with water and brine, and the combined aqueous layers were extracted with ethyl acetate (100 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in boiling ethyl acetate (200 mL) and then placed in a freezer for 2 days. Two crops of solid were obtained through filtration, which were combined and triturated with boiling 35% ethyl acetate/hexanes. After cooling to room temperature, the precipitate was collected by filtration and dried to constant weight to provide 27.2 g of N-(5-bromo-3-pyridinyl)- 2,4-difluorobenzenesulfonamide as a light orange solid. MS (ES) m/e 351.0 (M + H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | To a solution of 5-bromo-2-methoxypyridin-3-amine (10.15 g, 50 mmol) in pyridine (50 mL) was added <strong>[13918-92-8]2,4-difluorobenzene-1-sulfonyl chloride</strong> (11.68 g, 60 mol) slowly at 0 C. The mixture was stirred at rt for 19 hours and concentrated in vacuo. The residue was dissolved in MeOH (100 mL) and NaOH (2.50 g, 60 mmol). The resulted mixture was stirred at rt for 12 hours and concentrated in vacuo. The residue was dissolved in H2O (50 mL) and the resulted mixture was extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound as a brown solid (16.90 g, 89.1%). [0304] MS (ESI, pos. ion) m/z: 379.0 [M+H]+. | |
87% | With pyridine; dmap; In dichloromethane; at 20℃; | A mixture of <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (12.76 g, 60 mmol), pyridine (6 mL, 75 mmol), 5-bromo-2-methoxypyridin-3-amine 15a (10.15 g, 50 mmol), and DMAP (1.22 g, 10 mmol) in DCM (200 mL) was stirred at rt overnight. Water was added and the resulting mixture was extracted with DCM (200 mL×3). The combined organic layers were washed with water (200 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EtOAc = 5:1) to afford 16a as a yellow solid (16.48 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) delta 10.46 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.84 - 7.70 (m, 2H), 7.64 - 7.51 (m, 1H), 7.23 (td, J = 8.5, 2.0 Hz, 1H), 3.61 (s, 3H). MS (ESI+) m/z 379.1 [M + H]+ |
85.6% | With pyridine; at 0 - 20℃; for 24h; | General procedure: To a solution of 5-bromo-2-methoxypyridin-3-amine (1) (2.01 g,10 mmol) in pyridine (50 ml) at 0 C, 4-fluorophenylsulfonylchloride (2.14 g, 11 mmol) was added. Then the mixture was stirredat room temperature for 24 h. Pyridine was removed underreduced pressure and adding water (100 ml), extracted with ethylacetate (3 100 ml), the organic layer was washed with water(50 ml), dried with Na2SO4 and evaporated to give compound 2a asa white solid (3.22 g, 89.4% yield). |
85.6% | With pyridine; at 0 - 20℃; for 24h; | General procedure: To a solution of 5-bromo-2-methoxypyridin-3-amine (2.01 g,10 mmol) in pyridine (50 ml) at 0 C was added methanesulfonylchloride (1.72 g, 11 mmol). Then the mixture was stirred at roomtemperature 24 h. Pyridine was removed at reduced pressure andadd water (100 ml), extracted with ethyl acetate (3 100 ml), theorganic layer was washed with water (50 ml), dried with Na2SO4and evaporated to give compound 2a as a white solid. Yield 83.6% |
85.6% | With pyridine; at 0 - 20℃; for 24h; | General procedure: To a solution of 5-bromo-2-methoxypyridin-3-amine (1)(2.01 g, 10 mmol) in pyridine (50 ml) at 0 C was added methanesulfonylchloride (1.25 g, 11 mmol). Then the mixture was stirredat room temperature for 24 h. Pyridine was removed underreduced pressure before adding water (100 ml), then extractedwith ethyl acetate (3 100 ml), the organic layer was washed withwater (50 ml), dried with Na2SO4 and evaporated to give compound2a as a white solid (2.42 g, 86.5%). |
85.6% | With pyridine; at 25℃; for 24h; | General procedure: To a solution of 5-bromo-2-methoxypyridin-3-amine (2.01 g,10 mmol) in pyridine (50 mL) at 0 C was added methanesulfonylchloride (1.72 g, 11 mmol). Then the mixture was stirred at 25 C for24 h. Pyridine was removed at reduced pressure and add water (100 mL), extracted with ethyl acetate (3×100 mL), the organic layerwas washed with water (50 mL), dried with Na2SO4 and evaporated togive compound 6a as a white solid. Yield 78.4%, m.p. 150-151 C. 1HNMR (400 MHz, DMSO-d6) 9.51 (s, 1H, NH), 8.09 (d, J=2.4 Hz, 1H,Ar-H), 7.77 (d, J=2.4 Hz, 1H, Ar-H), 3.91 (s, 3H, OCH3), 3.16 (t,J=7.6 Hz, 2H, CH2), 1.73-1.65 (m, 2H, CH2), 1.42-1.33 (m, 2H, CH2),0.87 (t, J=7.2 Hz, 3H, CH3). ESI-MS: m/z 384.1 [M+H]+.Compounds 6b was synthesized according to the procedure describedin 6a. |
85.6% | With pyridine; at 0 - 20℃; for 24h; | General procedure: To a solution of 5-bromo-2-methoxypyridin-3-amine (3.02 g,15 mmol) in pyridine (60 ml) at 0 C was added methanesulfonyl chloride (2.60 g, 17 mmol). Then the mixture was stirred at room temperature for 24 h. Then the pyridine was removed at reduced pressure and added water (100 ml), extracted with ethyl acetate(200 ml) for two times, dried with anhydrous Na2SO4 and evaporated to give compound 5a as a white solid. |
83% | With pyridine; at 20℃; for 20h; | Step EN-(5-bromo-2-meth enzene- sulfonamide[00299] <strong>[13918-92-8]2,4-difluorobenzene-1-sulfonyl chloride</strong> (6.8 g, 32 mmol) was added into a solution of 5-bromo-2-methoxypyridin-3-amine (6.5 g, 32 mmol) in pyridine (10 mL) and the reaction mixture was stirred at r.t. for 20 hours before the reaction solution was concentrated to dry in vacuo to give a crude product which was purified with column chromatography (EtOAc : Petroleum ether = 1 :2 as eluent) to give the product as a brown solid (10 g, 83%). 1 H-NMR (300 MHz, DMSO-d6), delta 10.46 (s, 1 H), 8.52 (s, 1 H), 7.80-7.72 (m, 2H), 7.56 (m, 1 H), 7.20 (m, 1 H), 3.62 (s, 3H). LC/MS, ESI, m/z, 379, 381 (m+1 )+, Br pattern found. |
75% | With pyridine; at 20℃; for 36h; | 2-methoxy-3-amino-5-bromopyridine (7.00 g, 34.48 mmol) was dissolved in pyridine (50 mL), and <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (11.00 g, 51.71 mmol), and then naturally stirred to room temperature and stirred for 36 hours. Concentrate the reaction solution, Diluted with dichloromethane (200 mL), H2O (200 mL) twice, 10% citric acid (200 mL) washed three times. The organic phase was extracted and dried over anhydrous Na 2 SO 4 . Filter and concentrate the reaction to give a brown solid. Add ethyl acetate (20 mL) and petroleum ether (25 mL) to beat. After filtration and drying, finally 9.84 g of a white solid 1b was obtained in a yield of 75%. |
71.3% | With pyridine; at 0 - 20℃; | General procedure: To a stirred solution of 5-bromo-2-methoxypyridin-3-amine 1 (13.70 g, 67.5 mmol) in pyridine (140 mL) was added dropwise <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> 2 (14.35 g, 67.5 mmol) over 10 min at 0 C. The mixture, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h, at which time the reaction was diluted with water (400 mL) and the solids were filtered and washed with water. The precipitate was dried in a vacuum oven at 60 C to give N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide 3 (18.30 g, 71.3% yield) as a pale yellow powder, which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 7.96-7.86 (m, 2H), 7.83 (d, J = 2.2 Hz, 1H), 7.04-6.91 (m, 2H), 3.91 (s, 3H). MS (ESI, positive ion) m/z: 379.17 (M + H+, 79Br), 381.45 (M + H+, 81Br). |
70% | With pyridine; at 20℃; for 18h;Cooling with ice; | To a solution of 3 (10 g, 49.25 mmol) in pyridine (50 mL) wasadded benzenesulfonyl chloride 4 (64.03 mmol) slowly under icebath. After adding 4, the mixture was stirred for 18 h at room temperature.The resulting solution was quenched with iced water(500 mL), and stirred at room temperature for 1 h. The mixturewas filtered, and the precipitate was washed with water anddiethyl ether, and dried overnight to afford 5b |
69.9% | To a suspension of 5-bromo-2-methoxypyridin-3-amine (6.3 g, 31 mmol) in pyridine (25 mL) was added <strong>[13918-92-8]2,4-difluorobenzene-1-sulfonyl chloride</strong> (16.47 g, 77.5 mmol). The reactionwas stirred at 23C for 24 h. The solvent volume was then reduced to 50% under reduced pressure. The resulted solid was collected by filtration, and was washed with i-PrOH (5 mL x 2)followed by Et20 (5 mL). A suspension of the above solid and NaOH (2.48 g, 62 mmol) inMeOH (25 mL) was stirred at 23C for 1 h and then concentrated in vacuo. The residue wasdiluted with DCM (20 mL) and 2M HCl (20 mL), adjusted to pH 7 with 5% aq. NaHC03, andthen extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (20mL), dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as apale yellow solid (8.2 g, 69.9%). The title compound was characterized by LC-MS and 1HNMR as shown below:LC-MS (ESI, pos. ion) m/z: 379 [M+Ht;1HNMR (400 MHz, CDCh) 8 (ppm): 3.89 (s, 3H), 6.90-7.01 (m, 2H), 7.80-7.83 (d, J= 2.24 Hz,1H), 7.86-7.93(m, 2H). | |
69.9% | With pyridine; at 23℃; for 24h; | To 5-bromo-2-methoxy pyridine-3-amine (6.3g, 31mmol) pyridine (25 ml) is added to solution of 2,4-difluoro-1-sulfonyl chloride (16.47g, 77 . 5mmol). Reaction liquid in 23 C stirring 24 hours, concentrated under reduced pressure, the volume of the solution to the original 1/2. Filtering, collecting solid, solid with i-PrOH (5mLx2) and Et 2 O (5 ml) washing. The resulting solid and NaOH (2.48g, 62mmol) suspended in MeOH (25 ml) in, the reaction solution 23 C stirring 1 hour, concentrated under reduced pressure. For residual DCM (20 ml) and 2M hydrochloric acid (20 ml) is diluted, by 5% NaHCO 3 pH7 aqueous solution is adjusted to the rear, with DCM (20mLx3) extraction. Merger of the first organic phase and the salt water (20 ml) washing, anhydrous Na 2 SO 4 drying, and concentrating under reduced pressure, to obtain the title compound as a buff solid (8.2g, 69.9%). |
64% | With pyridine; at 20℃; for 24h; | General procedure: To a solution of 5-bromo-2-methoxypyridin-3-amine (3) (1.0 equiv) in anhydrous pyridine was added benzenesulfonyl chloride (1.0 equiv) at room temperature. The reaction was then stirred at room temperature for 24 h. The pyridine was removed under reduced pressure and the residue was purified by silica gel chromatography (10% ethyl acetate/petroleum ether to 100% ethyl acetate)to give the crude product. It was further washed with diethyl ether to give the title compound. 4.1.3.1 N-(5-Bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (4a) This compound was prepared from 5-bromo-2-methoxypyridin-3-amine (3) (3.0 g, 14.85 mmol) and <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (3.15 g, 14.85 mmol) according to the general synthesis procedure A to afford the title compound (3.58 g, 9.47 mmol, 64% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta 10.41 (s, 1H, NH), 8.10 (d, J = 2.5 Hz, 1H, Ar-H), 7.75 (m, 1H, Ar-H), 7.74 (d, J = 2.5 Hz, 1H, Ar-H), 7.54 (td, J = 8.5, 2.0 Hz, 1H, Ar-H), 7.21 (td, J = 8.5, 2.0 Hz, 1H, Ar-H), 3.60 (s, 3H, OCH3). ESI-MS: m/z = 379 [M+H]+. |
46% | With pyridine; at 0 - 20℃; | To a cooled solution of 17 (4.0 g, 19.8 mmol) in pyridine (40 mL) was added <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (18) (3.2 mL, 23.8 mmol) dropwise at 0 C. After the reaction mixture was allowed to warm to rt and stirred overnight, it was diluted with cold water. The precipitate was collected by filtration, washed with water, dried to afford 19 (3.42 g, 46%) as a pale pink solid, mp 154-156 C. 1H NMR (CDCl3) delta 7.91-7.88 (m+d, J = 2.0 Hz, 2H, Ar-H), 7.82 (d, J = 2.0 Hz, 1H, Ar-H), 7.22 (br s, 1H, NH), 7.00-6.92 (m, 2H, Ar-H), 3.90 (s, 3H, OCH3). |
45% | With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere; | General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%). |
32% | With pyridine; at 0 - 20℃; for 16.25h; | a) N-[5 -bromo-2-(methyloxy)-3-pyridinyl] -2,4-difluorobenzenesulfonamide. To a cooled (0 0C) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (100 mmol) in pyridine (200 rnL) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the mixture was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water (500 mL) and the solids filtered off and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 500C to give the title product as an ivory solid (32 % yield). MS(ES) m/e 380.9, 379.0 (M + H)+. |
31.7% | With pyridine; at 0 - 20℃; for 16.25h; | c) lambda/-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide; To a cooled (0 0C) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (20.3 g, 100 mmol) in pyridine (200 mL) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water (500 mL) and the solids filtered off and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 50 0C to give N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (12 g, 31.6 mmol, 31.7 % yield) MS(ES)+ m/e 379.0, 380.9 [M+H]+. |
31.7% | With pyridine; at 0 - 20℃; for 16.25h; | c) N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide To a cooled (0 C.) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (20.3 g, 100 mmol) in pyridine (200 mL) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water (500 mL) and the solids filtered off and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 50 C. to give N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (12 g, 31.6 mmol, 31.7% yield) MS(ES)+ m/e 379.0, 380.9 [M+H]+. |
31.7% | With pyridine; at 0 - 20℃; for 16.25h; | Intermediate 14Preparation of N- [5 -bromo-2-(methyloxy)- 3 -pyridinyll -2,4-difluorobenzenesulfonamideTo a cooled (0 0C) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (20.3 g, 100 mmol) in Pyridine (200 rnL) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water (500 mL) and the solids filtered off and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 50 0C to give N-[5-bromo-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (12 g, 31.6 mmol, 31.7 % yield). MS (ES) m/e 380.9, 379.0 (M + H)+. |
With pyridine; at 0 - 20℃; for 16.25h; | To a cooled (0 C) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (13.7 g, 67.5 mmol) in pyridine (200 ml) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (14.37 g, 67.6 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h. Most of the pyridine was removed in vacuo and the residue diluted with water (500 ml_). The solids were filtered off and washed with copious amounts of water to give 21 g of crude desired product. More solid appeared in the mother liquor and was filtered and washed with water to give an additional 1.5 g of desired material. The two batches were combined, triturated with 70 ml of methylene chloride, and dried in a vacuum oven at 50 0C to give the title compound (15 g)-LCMS (Method B) R1 = 1.11 min, MH+ = 378/380. | |
With pyridine; In dichloromethane; at 20℃; | A mixture of 1.80 g (8.8 mmol) C-5, 2.29 mL (17 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong>, 1.07 mL (13.3 mmol) pyridine and 20 mL DCM is stirred at RT over night.100 mL DCM is added and the reaction mixture is extracted three times with 50 mL aqueous 1M HCl. The organic layer is dried over MgS04 and the solvent is removed under reduced pressure. The solid is dissolved in water/MeCN and further purified by RP- chromatograpy. Yield: 2,9 g (86%). | |
With pyridine; In dichloromethane; at 20℃; | A mixture of 1.80 g (8.8 mmol) C-5, 2.29 mL (17 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong>, 1.07 mL (13.3 mmol) pyridine and 20 mL DCM is stirred at RT over night. 100 mL DCM is added and the reaction mixture is extracted three times with 50 mL aqueous 1M HCl. The organic layer is dried over MgS04 and the solvent is removed under reduced pressure. The solid is dissolved in water/MeCN and further purified by RP- chromatograpy. Yield: 2,9 g (86%). | |
2.9 g | With pyridine; In dichloromethane; at 20℃; | A mixture of 1.80 g (8.8 mmol) C-5, 2.29 mL (17 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong>, 1.07 mL (13.3 mmol) pyridine and 20 mL DCM is stirred at RT over night. 100 mL DCM is added and the reaction mixture is extracted three times with 50 mL aqueous 1M HCl. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The solid is dissolved in water/MeCN and further purified by RP-chromatograpy. Yield: 2.9 g (86%). |
2.9 g | With pyridine; In dichloromethane; at 20℃; | A mixture of 1.80 g (8.8 mmol) C-5, 2.29 mL (17 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong>, 1.07 mL (13.3 mmol) pyridine and 20 mL DCM is stirred at RT over night. 100 mL DCM is added and the reaction mixture is extracted three times with 50 mL aqueous 1M HCl. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The solid is dissolved in water/MeCN and further purified by RP-chromatograpy. Yield: 2.9 g (86%). |
With pyridine; at 0 - 20℃; for 16.25h; | N-[5-Bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide To a cooled (0 C.) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (13.7 g, 67.5 mmol) in pyridine (200 ml) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (14.37 g, 67.6 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h. Most of the pyridine was removed in vacuo and the residue diluted with water (500 mL). The solids were filtered off and washed with copious amounts of water to give 21 g of crude desired product. More solid appeared in the mother liquor and was filtered and washed with water to give an additional 1.5 g of desired material. The two batches were combined, triturated with 70 ml of methylene chloride, and dried in a vacuum oven at 50 C. to give the title compound (15 LCMS (Method B) R=1.1 1 mi MH=378/380. | |
With pyridine; at 0 - 20℃; for 16.25h; | Intermediate 36lambda/-[5-Bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide <n="120"/> To a cooled (0 0C) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (13.7 g, 67.5 mmol) in pyridine (200 ml) was added slowly <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (14.37 g, 67.6 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h. Most of the pyridine was removed in vacuo and the residue diluted with water (500 ml). The solids were filtered off and washed with copious amounts of water to give 21 g of crude desired product. More solid appeared in the mother liquor and was filtered and washed with water to give an additional 1.5 g of desired material. The two batches were combined, triturated with DCM (70 ml) and dried in a vacuum oven at 50 0C to give the title compound (15 g). LCMS (Method B) R1 = 1.11 min, MH+ = 378/380. | |
With pyridine; In dichloromethane; at 0 - 25℃; for 0.00833333h; | (1) 5-Bromo-3-amino-2-methoxypyridine (0.097 g, 0.48 mmol), pyridine (0.057 g, 0.72 mmol), and dissolved in dichloromethane (0.77 mL) to prepare a reaction solution 1, 2,4-difluorophenylsulfonyl chloride (0.12g, 0.58mmol) to prepare the reaction solution 2. The flow rate (0.5mL / min) set by the intelligent numerical control sampler is simultaneously introduced into a 500mum picker tube Mix in the first three-way mixer (ambient temperature 0 C), then flow out under its own pressure, and enter a 500 mum pick-up tube with a set temperature control (25 C).Complete the sulfonamidation reaction at the set residence time t1 (0.5min), and then pass the back pressure valve to obtain the first effluent | |
With pyridine; at 20℃; for 16h; | 2-4-Diflurobenzene-l-sulfonyl-chloride 2 (1 eq) was added slowly to a cool solution of 5-bromo- 2-methoxypyridine-3-amine 1 (1 eq) in pyridine. Reaction was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water and the solids were filtered off and washed with copious amounts of water. The precipitate was dried in high vacuum to give compound 3, and was used in the next step without further purification. LRMS-LC/MS (m/z): [M + H] + calcd for CiiHgBrFiNiOsS, 377.9; found 378.9) |
Yield | Reaction Conditions | Operation in experiment |
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59% | With pyridine; at 20℃; | To the solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyhdin-3-amine (400 mg, 1 .6 mmol) in pyridine (5 mL) was added 2,4- difluorobenzenesulfonyl chloride (407 mg, 1 .9 mmol) slowly, the reaction mixture was stirred at room temperature overnight, the solvent was evaporated in vacuo, and the residue was treated with brine (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was evaporated in vacuo, and the residue was purified by column chromatography using petroleum ether:EtOAc=5:1 as eluent to afford the desired product 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridin-3-yl)benzenesulfonamide as white solid in 59% yield (400 mg). m/z 427(M+H)+. |
59% | In pyridine; at 20℃; | To the solution of <strong>[893440-50-1]2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine</strong> (400 mg, 1.6 mmol) in pyridine (5 mL) was added 2,4-difluorobenzenesulfonyl chloride (407 mg, 1.9 mmol) slowly, the reaction mixture was stirred at room temperature overnight, the solvent was evaporated in vacuo, and the residue was treated with brine (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was evaporated in vacuo, and the residue was purified by column chromatography using petroleum ether:EtOAc=5:1 as eluent to afford the desired product 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide as white solid in 59% yield (400 mg). m/z 427 (M+H)+. |
With pyridine; at 20℃; for 2h; | To a stirred solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (3 g, 12.00 mmol) in pyridine (12 ml), 2,4-difluorobenzenesulfonyl chloride (1.774 ml, 13.19 mmol) was added and the reaction mixture stirred at room temperature for 2 hours. 2 N HCI (aq) solution (20 ml) and DCM (20 ml) were added and the layers separated. The aqueous layer was washed with additional DCM (2x15 ml). Then the organic layers were combined, dried (hydrophobic frit) and evaporated in vacuo to give a brown oil. There was still some pyridine in the reaction mixture so 2M HCI was added and 15ml DCM to extract one more time. The solvent was removed in vacuo to give the title compound as an orange solid (4.3g).LCMS (Method A) Rt = 1.20 min, MH+=426 [NB. also observe Rt = 0.73 min, MH+=344 consistent with boronic acid (hydrolysis product due to HPLC eluent)]. |
With pyridine; at 20℃;Inert atmosphere; | Intermediate B2,4-Difluoro-N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- pyridin-3-yl]-benzenesulfonamide; 2,4-difluorobenzenesulfonyl chloride (2.0 mL, 14.6 mmol) was added at RT (water bath) to a solution of 2-methoxy-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- pyridin-3-ylamine (3.6 g of crude) in pyridine (30 mL), and the mixture was stirred under argon overnight. The solvent was evaporated, and the residue was taken up in DCM and water. 1 N HCI was added until reaching pH 4, and the mixture was extracted with DCM, dried (MgS04) and concentrated. The crude material was purified by column chromatography (DCM/MeOH 1 to 3%) followed by precipitation from ether affording 1.48 g of the desired product. A second crop (1.71 g) was obtained by precipitation from the mother liquor using ether/cyclohexane. Total yield: 5.7 g (56 % over 2 steps).1H NMR (300 MHz, DMSO) delta 10.19 (s, 1 H), 8.20 (d, J = 1.6 Hz, 1 H), 7.70 (m, 2H), 7.57 (t, 1 H), 7.20 (t, 1 H), 3.61 (s, 3H), 1.29 (s, 12H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.3 g | 2,4-Difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide To a stirred solution of <strong>[893440-50-1]2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine</strong> (3 g, 12.00 mmol) in pyridine (12 ml), 2,4-difluorobenzenesulfonyl chloride (1.774 ml, 13.19 mmol) was added and the reaction mixture stirred at room temperature for 2 hours. 2 N HCl (aq) solution (20 ml) and DCM (20 ml) were added and the layers separated. The aqueous layer was washed with additional DCM (2*15 ml). Then the organic layers were combined, dried (hydrophobic frit) and evaporated in vacuo to give a brown oil. There was still some pyridine in the reaction mixture so 2M HCl was added and 15 ml DCM to extract one more time. The solvent was removed in vacuo to give the title compound as an orange solid (4.3 g).ECMS (Method A) Rt=i .20 mi MH+=426 | |
Intermediate 9 2,4-Difluoro-Lambda/-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- pyridinyljbenzenesulfonamideTo a stirred solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinamine (3 g, 12.00 mmol) in pyridine (12 ml), 2,4-difluorobenzenesulfonyl chloride (1.774 ml, 13.19 mmol) was added and the reaction mixture stirred at RT for 2 h. 2 N hydrogen chloride (aq) (20 ml) and dichloromethane (20 ml) were added and the layers separated. The aqueous layer was washed with additional dichloromethane (2x 15 ml) and the organic layers combined, dried (hydrophobic frit) and evaporated in vacuo to give a brown oil. There was still some pyridine in the reaction mixture so 2M hydrogen chloride (aq) and dichloromethane (15 ml) were added to extract one more time. The solvent was removed in vacuo to give the title compound as an orange solid (4.3g). LCMS (Method A): Rt 1.20 min, MH+ 427 [NB. also observe Rt 0.73 min, MH+ 345 consistent with boronic acid (hydrolysis product due to HPLC eluent)]. |
Yield | Reaction Conditions | Operation in experiment |
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86% | General procedure: A mixture of norfloxacin (a) or ciprofloxacin (b) (1 mmol) (refPreviewPlaceHolderScheme 1) and K2CO3 (152 mg, 1.1 mmol) was stirred in acetone (20 mL) at room temperature for 20 min. To the resulted mixture, the appropriate arenesulfonyl chloride (1.2 mmol) in acetone (5 mL) was added dropwise over a period of 20 min. The reaction mixture was further stirred at room temperature for 24 h. The separated solid was then filtered, washed with cold water, dried and crystallized from the appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
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90% | General procedure: A mixture of norfloxacin (a) or ciprofloxacin (b) (1 mmol) (refPreviewPlaceHolderScheme 1) and K2CO3 (152 mg, 1.1 mmol) was stirred in acetone (20 mL) at room temperature for 20 min. To the resulted mixture, the appropriate arenesulfonyl chloride (1.2 mmol) in acetone (5 mL) was added dropwise over a period of 20 min. The reaction mixture was further stirred at room temperature for 24 h. The separated solid was then filtered, washed with cold water, dried and crystallized from the appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
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49% | With pyridine; dmap at 20℃; Inert atmosphere; | 118.C 2,4-Difluorobenzenesulfonyl chloride (0.47 mL, 3.49 mmol) was added to solution of 5-bromo-4-methyl-2-(methyloxy)-3-pyridinamine (758 mg, 3.49 mmol) and 4- dimethylaminopyridine (43 mg, 0.35 mmol) in dry pyridine (1 1 .2 mL) and the mixture was allowed to stir at room temperture under nitrogen. After 1 h, additional 2,4- difluorobenzenesulfonyl chloride (0.47 mL, 3.49 mmol) was added. After another 30 minutes the reaction was concentrated, and the residue diluted with EtOAc, washed with water two times, then saturated NaHCC^ followed by brine, dried (Na2S0 ) and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexanes). Fractions containing only the product were combined and concentrated to yield N-[5-bromo-4-methyl-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (668 mg, 49%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.08 (s, 1 H) 8.21 (s, 1 H) 7.73 - 7.54 (m, 2 H) 7.24 - 7.14 (m, 1 H) 3.37 (s, 3 H) 2.40 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere; | General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added 2,4-difluorobenzenesulphonyl chloride (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%). |
With pyridine; In dichloromethane; at 0 - 20℃; | To a solution of 5-bromo-2-chloropyridin-3-amine (0.900 g, 4.34 mmol) in DCM (8.68 ml) was added pyridine (0.541 ml, 6.69 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (0.851 ml, 6.33 mmol) at 0 C. After stiffing overnight at room temperature, the reaction mixture was diluted with DCM and treated with saturated aq. NaHCO3. The resulting solid was collected by filtration and washed with water to give N-(5-bromo-2-chloropyridin-3-yl)-N-(2,4-difluorophenylsulfonyl)-2,4-difluorobenzenesulfonamide (0.65 g, 27%) as a white solid. The filtrate was extracted with DCM (2×50 mL), the combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.20 g, 12%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) delta 7.26 (1H, t, J=8.4 Hz), 7.59 (1H, t, J=10.0 Hz), 7.81 (1H, dd, J=16.0, 7.6 Hz), 8.04 (1H, d, J=2.4 Hz), 8.46 (1H, d, J=2.4 Hz), 11.1 (1H, brs). | |
With pyridine; at 0 - 20℃; for 24h; | General procedure: To a stirred solution of 5-bromo-2-methoxypyridin-3-amine 1 (13.70 g, 67.5 mmol) in pyridine (140 mL) was added dropwise 2,4-difluorobenzenesulfonyl chloride 2 (14.35 g, 67.5 mmol) over 10 min at 0 C. The mixture, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h, at which time the reaction was diluted with water (400 mL) and the solids were filtered and washed with water. The precipitate was dried in a vacuum oven at 60 C to give N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide 3 (18.30 g, 71.3% yield) as a pale yellow powder, which was used without further purification. |
With pyridine; In dichloromethane; at 0 - 25℃; for 0.00833333h; | (1) 5-Bromo-3-amino-2-chloropyridine (0.10 g, 0.48 mmol), pyridine (0.057 g, 0.72 mmol), and dissolved in dichloromethane (0.77 mL) to prepare reaction solution 1. 2,4-difluorophenylsulfonyl chloride (0.12 g, 0.58 mmol) was used to prepare reaction solution 2. The flow rate (0.5 mL / min) set by the intelligent numerical control sampler was simultaneously introduced into the first via a 500 mum picker tube. Mix in a three-way mixer (ambient temperature 0 C), then flow out under its own pressure, enter a 500 mum inside diameter tube with a set temperature control (25 C), and set the residence time t1 (0.5min). the sulfonamide complete reaction, followed by after-pressure valve to obtain a first effluent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine; at 80℃; for 2h; | [00203] A mixture of 5-bromo-2-methylpyridin-3 -amine (35 g, 187 mmol) and <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (47.7 g, 225 mmol) in pyridine (200 niL) was allowed to stir at 80C for 2 h. The reaction mixture was poured into water (1000 niL) and allowed to stir at ii for 30mm. The solid was collected by filtration, washed with water (3x100 mL) and then added into a mixture of EtOAc (150 mL) and MeOH (150 niL). The mixture was allowed to stir at ii for 30 mm. The suspension wasfiltered and the solid was dried to provide N-(5-bromo-2-methylpyridin-3-yl)-2,4-difluorobenzenesulfonamide (56 g, 82%). ?H NMR (400 MFIz, DMSO-d6) 6 10.66 (s, 1H), 8.45 (s, 1H), 7.81 (m, 1H), 7.69 (s, 1H), 7.60 (m, 1H), 7.27 (m, 1H), 2.23 (s, 3H). |
82% | With pyridine; at 80℃; for 2h; | Step 1: N-(5-bromo-2-methylpyridin-3-yl)-2,4-difluorobenzenesulfonamide A mixture of 5-bromo-2-methylpyridin-3-amine (35 g, 187 mmol) and <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (47.7 g, 225 mmol) in pyridine (200 mL) was allowed to stir at 80 C. for 2 h. The reaction mixture was poured into water (1000 mL) and allowed to stir at rt for 30 min. The solid was collected by filtration, washed with water (3*100 mL) and then added into a mixture of EtOAc (150 mL) and MeOH (150 mL). The mixture was allowed to stir at rt for 30 min. The suspension was filtered and the solid was dried to provide N-(5-bromo-2-methylpyridin-3-yl)-2,4-difluorobenzenesulfonamide (56 g, 82%). 1H NMR (400 MHz, DMSO-d6) delta 10.66 (s, 1H), 8.45 (s, 1H), 7.81 (m, 1H), 7.69 (s, 1H), 7.60 (m, 1H), 7.27 (m, 1H), 2.23 (s, 3H). |
48% | With pyridine; dmap; In dichloromethane; at 20℃; | General procedure: A mixture of <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (12.76 g, 60 mmol), pyridine (6 mL, 75 mmol), 5-bromo-2-methoxypyridin-3-amine 15a (10.15 g, 50 mmol), and DMAP (1.22 g, 10 mmol) in DCM (200 mL) was stirred at rt overnight. Water was added and the resulting mixture was extracted with DCM (200 mL×3). The combined organic layers were washed with water (200 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EtOAc = 5:1) to afford 16a as a yellow solid (16.48 g, 87% yield). |
With pyridine; In dichloromethane; at 20℃; for 5h; | A mixture of 4.0 g (21.4 mmol) C-3, 4.3 mL (32.1 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong>, 5.2 mL (64.2 mmol) pyridine and 50 mL DCM is stirred at RT for 5 h. After completion of the reaction, the solvent is removed under reduced pressure, the crude product is taken up in 50 mL water and extracted twice with 100 mL DCM. The combined organic layers are dried over MgS04 and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 7.88 g (91%). | |
With pyridine; In dichloromethane; at 20℃; for 5h; | A mixture of 4.00 g (21.4 mmol) C-3, 4.3 mL (32 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong>, 5.2 mL (64 mmol) pyridine and 50 mL DCM is stirred at RT for 5 h. After completion of the reaction, the solvent is removed under reduced pressure, the crude product is taken up in 50 mL water and extracted twice with 100 mL DCM. The combined organic layers are dried over MgS04 and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 7.88 g (91%). | |
With pyridine; In dichloromethane; at 20℃; for 5h; | A mixture of 4.00 g (21.4 mmol) C-3, 4.3 mL (32 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong>, 5.2 mL (64 mmol) pyridine and 50 mL DCM is stirred at RT for 5 h. After completion of the reaction, the solvent is removed under reduced pressure, the crude product is taken up in 50 mL water and extracted twice with 100 mL DCM. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 7.88 g (91%). | |
With pyridine; In dichloromethane; at 20℃; for 5h; | A mixture of 4.0 g (21.4 mmol) C-3, 4.3 mL (32.1 mmol) <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong>, 5.2 mL (64.2 mmol) pyridine and 50 mL DCM is stirred at RT for 5 h. After completion of the reaction, the solvent is removed under reduced pressure, the crude product is taken up in 50 mL water and extracted twice with 100 mL DCM. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 7.88 g (91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With pyridine; In dichloromethane; at 20℃; | A mixture of 1.50 g (5.8 mmol) E-3, 3.08 mL (23.2 mmol) 2,4-difluoro-benzenesulfonyl chloride, 1.9 mL (24.4 mmol) pyridine and 40 mL DCM is stirred at RT over night. The reaction mixture is concentrated under reduced pressure and the residue is purified with RP-chromatograpy. Yield: 0.71 g (28 %). |
28% | With pyridine; In dichloromethane; at 20℃; | A mixture of 1.50 g (5.8 mmol) E-3, 3.08 mL (23.2 mmol) 2,4-difluoro-benzenesulfonyl chloride, 1.9 mL (24.4 mmol) pyridine and 40 mL DCM is stirred at RT over night. The reaction mixture is concentrated under reduced pressure and the residue is purified with RP-chromatograpy. Yield: 0.71 g (28 %). |
28% | With pyridine; In dichloromethane; at 20℃; | A mixture of 1.50 g (5.8 mmol) E-3, 3.08 mL (23.2 mmol) 2,4-difluoro-benzenesulfonyl chloride, 1.9 mL (24.4 mmol) pyridine and 40 mL DCM is stirred at RT over night. The reaction mixture is concentrated under reduced pressure and the residue is purified with RP-chromatograpy. Yield: 0.71 g (28 %). |
28% | With pyridine; In dichloromethane; at 20℃; | A mixture of 1.50 g (5.8 mmol) E-3, 3.08 mL (23.2 mmol) 2,4-difluoro-benzenesulfonyl chloride, 1.9 mL (24.4 mmol) pyridine and 40 mL DCM is stirred at RT over night. The reaction mixture is concentrated under reduced pressure and the residue is purified with RP-chromatograpy. Yield: 0.71 g (28%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With pyridine; In dichloromethane; at 20℃; | A mixture of 75 mg (0.22 mmol) E-7, 59 mu. (0.44 mmol) 2,4-difluoro-benzenesulfonyl chloride and 56 mu. (0.71 mmol) pyridine in 3 mL DCM is stirred over night at RT. The reaction mixture is concentrated under reduced pressure and the residue is purified by RP chromatography (C18, 20-90% acetonitrile in water containing 0.1% formic acid). Yield: 52 mg (46%). HPLC-MS: M+H = 516; tR = 1, 17 min. |
46% | With pyridine; In dichloromethane; at 20℃; | A mixture of 75 mg (0.22 mmol) E-7, 59 muL (0.44 mmol) 2,4-difluoro-benzenesulfonyl chloride and 56 muL (0.71 mmol) pyridine in 3 mL DCM is stirred over night at RT. The reaction mixture is concentrated under reduced pressure and the residue is purified by RP chromatography (C18, 20-90% acetonitrile in water containing 0.1% formic acid). Yield: 52 mg (46%). HPLC-MS: M+H = 516; tR = 1,17 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With pyridine; In dichloromethane; at 20 - 45℃; for 20h;Inert atmosphere; | General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT, was added dropwise, <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (336 mg, 1.58 mmol) in CH2C12 (3 mL) over 5 mm. The suspension was heated to 45C under N2 for 4 h., at which point another portion of <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (169 mg,0.79 minol) in CH2C12 (2 mL) was added. The whole mixture was left to stir for at 45C under N2 for 16 h., then the solvent removed under reduced pressure. The resulting residue was suspended in acetone (10 mL), 1 M HCI (20 mL) added, and the entire mixture stirred for 10 minutes. The solid was then collected by filtration, washed well with 1 M HC1 and water, dried, and purified by chromatography as described below.In cases where the bis-sulphonarnide was also formed, a second step was introduced where the crude product above was treated with a 1:1 mixture of 1 ,4-dioxane and 2 M NaOH. The crude suiphomamide resulting from subsequent acidification of the reaction mixture was isolated by filtration, washed well with wafer, and dried. Purification was carried out by flash column chromatography (2% MeOHJCH2C12 as eluant), giving the title compound(1) as a pale yellow solid (211 mg, 54%), mp (MeOH/CH2C12) 266-269C. ?H NMR [400 MHz, (CD3)2S0] oe 11.15 (br s, 1 H), 8.69 (d, J= 2.0 Hz, I H), 8.25 (d, J= 2.4 Hz, 1 H), 8.01 (dt, J 8.7, 6.3 Hz, 1 H), 7.95 (s, I H), 7.83 (dd, J= 8.0, 1.5 Hz, 1 H), 7.68-7.75(m, 3 H), 7.65 (d, J 3.9 Hz, 1 H), 7.58 (dt, J 8.9, 2.4 Hz, I H), 7.30 (dt, J 8.2, 2.0 Hz,I H), 4.52 (s, 2 H), 3:09 (s, 3 H). Anal. (C24H17F2N303S2) C, H, N. |
54% | With pyridine; In dichloromethane; at 20 - 45℃; for 20h;Inert atmosphere; | To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 54%), mp (MeOH/CH2Cl2) 266-269 C. 1H NMR [400 MHz,(CD3)2SO] delta 11.15 (br s, 1 H), 8.69 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 2.4 Hz, 1 H), 8.01 (dt, J = 8.7, 6.3 Hz, 1 H), 7.95 (s, 1 H), 7.83 (dd, J = 8.0, 1.5 Hz, 1 H), 7.68-7.75 (m, 3 H), 7.65 (d,J = 3.9 Hz, 1 H), 7.58 (dt, J = 8.9, 2.4 Hz, 1 H), 7.30 (dt, J = 8.2, 2.0 Hz, 1 H), 4.52 (s, 2 H),3.09 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With pyridine at 25℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20h; | General procedure: To the solution of meridianin G (7) or meridianin C (3) indichloromethane (5 ml) was added DMAP (0.05 equiv.), aryl/heteroarylsulfonyl chloride (1.1 equiv.) and N,N-diisopropylethylamine(1.5 equiv.). The mixturewas stirred at room temperature for20 h. Reaction was then quenched by the addition of 10% HCl. Thisreaction mixture was extracted with dichloromethane (50 ml 3),and combined organic layer was evaporated on rotary evaporator.Purification by silica gel column chromatography (mesh 100e200)using dichloromethane-methanol (99:1 to 97:3) to get the titledproducts 14aead. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | A solution prepared by dissolving 2-methoxy-5-{7-(4-methoxy-3,5-dimethylphenyl)furo[3,2-c]pyridin-2-yl}pyridin-3-amine (0.04 mmol) obtained in Example 407 in dichloromethane (1 ml) was added with diisopropylethylamine (0.12 mmol) and <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (0.05 mmol), in sequence, and stirred overnight at room temperature. The reaction solution was added with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. After the filtrate was concentrated under reduced pressure, the residue thus obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1, v/v) to obtain the title compound as a light yellow solid (yield: 75%). 1H NMR (CDCl3, 400 MHz) delta 8.88(s, 1H), 8.77(s, 1H), 8.66(s, 1H), 8.25-8.05(m, 2H), 7.65-7.55(m, 2H), 7.10(t, 2H), 6.97(t, 2H), 3.83(s, 3H), 3.77(s, 3H), 2.43(s, 6H) |
75% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Example 408 2,4-Difluoro-N-[2-methoxy-5-{7-(4-methoxy-3,5-dimethylphenyl)furo[3,2-c]pyridin-2-yl}pyridin-3-yl]benzenesulfonamide A solution prepared by dissolving 2-methoxy-5-{7-(4-methoxy-3,5-dimethylphenyl)furo[3,2-c]pyridin-2-yl}pyridin-3-amine (0.04 mmol) obtained in Example 407 in dichloromethane (1 ml) was added with diisopropylethylamine (0.12 mmol) and <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (0.05 mmol), in sequence, and stirred overnight at room temperature. The reaction solution was added with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. After the filtrate was concentrated under reduced pressure, the residue thus obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1, v/v) to obtain the title compound as a light yellow solid (yield: 75%). 1H NMR (CDCl3, 400 MHz) delta 8.88 (s, 1H), 8.77 (s, 1H), 8.66 (s, 1H), 8.25-8.05 (m, 2H), 7.65-7.55 (m, 2H), 7.10 (t, 2H), 6.97 (t, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 2.43 (s, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | [00201] To a solution of 5-bromo-2-chloro-4-methylpyridin-3-amine (12 g, 54 mmol) in THF (360 niL) was added a 1.0 M solution of LiHMDS in THF (108 niL, 108 mmol) at -5C. The reaction mixture was allowed to stir at -5C for 10 mm. To the reaction mixture was then added 2,4- difluorobenzenesulfonyl chloride (17.3 g, 81 mmol). The reaction mixture was allowed to stir at ii for 12 h. The reaction mixture was diluted with saturated NFI4C1 solution (200 mL) and extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography to provide N-(5-bromo-2-chloro-4-methylpyridin-3-yl)-2,4- difluorobenzenesulfonamide (11.5 g, 53%). ?H NMR (400 MFIz, CDC13) 6 8.37 (s, in), 7.72 (m, in), 7.00 (m, 2H), 6.70 (s, in), 2.64 (s, 3H). | |
53% | Step 1: N-(5-bromo-2-chloro-4-methylpyridin-3-yl)-2,4-difluorobenzenesulfonamide To a solution of 5-bromo-2-chloro-4-methylpyridin-3-amine (12 g, 54 mmol) in THF (360 mL) was added a 1.0 M solution of LiHMDS in THF (108 mL, 108 mmol) at -5 C. The reaction mixture was allowed to stir at -5 C. for 10 min. To the reaction mixture was then added <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (17.3 g, 81 mmol). The reaction mixture was allowed to stir at rt for 12 h. The reaction mixture was diluted with saturated NH4Cl solution (200 mL) and extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography to provide N-(5-bromo-2-chloro-4-methylpyridin-3-yl)-2,4-difluorobenzenesulfonamide (11.5 g, 53%). 1H NMR (400 MHz, CDCl3) delta 8.37 (s, 1H), 7.72 (m, 1H), 7.00 (m, 2H), 6.70 (s, 1H), 2.64 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine; In dichloromethane; at 20℃; for 3h;Cooling with ice; | To an ice cooled solution of 5'-amino-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'- one (2.0 g, 8.58 mmol) in DCM (20 mL) were added pyridine (1.4 mL, 17.16 mmol) followed by <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> (1.7 mL, 12.87 mmol) dropwise. The mixture was at RT for 3 h. The mixture was diluted with DCM (100 mL), washed with water (100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as yellow solid (2.5 g, 89 %.).1H NMR (400 MHz, DMSO-d6): delta 11.0 (s, 1H), 10.86 (s, 1H), 7.95-7.83 (m, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.56 (t, J=8.8 Hz, 1H), 7.30-7.25 (m, 1H), 2.47-2.40 (m, 2H), 2.35-2.12 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With palladium diacetate; lithium carbonate In 1,4-dioxane at 140℃; for 4h; Schlenk technique; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere; | General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added 2,4-difluorobenzenesulphonyl chloride (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; triethylamine; In dichloromethane; for 3h;Inert atmosphere; Reflux; | 250ml 2,4 round bottom flask benzenesulfonyl chloride there was obtained: (2,4-difluorobenzenesulfonyl chloride) (2g, 10mmol) and 2,4-difluoro-benzenesulfonamide (<strong>[13656-60-5]2,4-difluorobenzenesulfonamide</strong>) (2.2g, 10mmol), 4-dimethylaminopyridine (DMAP: 4-dimethylaminopyridine) (0.02g, 0.2mmol) was injected by nitrogen. Dichloromethane (DCM) was dissolved into 30ml of the reaction, it was added dropwise triethylamine (triethylamine) (3.5ml, 25mmol) raised the temperature was allowed to react under reflux for 3 hours. Washed with water back down to room temperature after 3 hours, filtered and dried under reduced pressure to yield a white solid of compound 1 (Yield: 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine; In dichloromethane; at 20 - 45℃; for 20h;Inert atmosphere; | General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 545). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; In dichloromethane; at 20 - 45℃; for 20h;Inert atmosphere; | General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 545). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; In dichloromethane; at 20 - 45℃; for 20h;Inert atmosphere; | General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 545). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; In dichloromethane; at 20 - 45℃; for 20h;Inert atmosphere; | General procedure: To 5-(5-(5-Aminopyridin-3-yl)thiophen-2-yl)-2-methyl- isoindolin-1-one (49) (225 mg, 0.79 mmol) in dry pyridine (23 mL) under N2 at RT,was added dropwise, <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (336 mg, 1.58 mmol) in CH2Cl2(3 mL) over 5 min. The suspension was heated to 45 C under N2 for 4 h., at which pointanother portion of <strong>[13918-92-8]2,4-difluorobenzenesulphonyl chloride</strong> (169 mg, 0.79 mmol) in CH2Cl2 (2mL) was added. The whole mixture was left to stir for at 45 C under N2 for 16 h., then thesolvent removed under reduced pressure. The resulting residue was suspended in acetone (10mL), 1 M HCl (20 mL) added, and the entire mixture stirred for 10 minutes. The solid wasthen collected by filtration, washed well with 1 M HCl and water, dried, and purified bychromatography as described below. In cases where the bis-sulphonamide was also formed, a second step was introduced wherethe crude product above was treated with a 1:1 mixture of 1,4-dioxane and 2 M NaOH. Thecrude sulphonamide resulting from subsequent acidification of the reaction mixture wasisolated by filtration, washed well with water, and dried. Purification was carried out by flashcolumn chromatography (2% MeOH/CH2Cl2 as eluant), giving the title compound as a paleyellow solid (211 mg, 545). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: The target compound 10a was obtained by treating 9a (533 mg, 1 mmol) with BF3xEtO2 (2 mL, 1.5 mmol) in CH2Cl2 in first step, the crude deprotected compound was directly reacted with methyl sulfonyl chloride (1.2 ml, 1 mmol) in the presence of triethyl amine (3.3 mL, 3 mmol) in dry THF (50 ml). After stirring the reaction mixture for 6 h, the reaction mixture was poured on to crushed ice (1.4 g) and the reaction mixture extracted and purified by column chromatography affords final product 10a as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; In dichloromethane; at 20℃; for 4h;Cooling with ice; Alkaline conditions; | A flask containing 10 mmol of 3,4-methylenedioxyphenethylamine in 80 mL of dichloromethane was placed in an ice bath, then 13 mmol of pyridine was added to provide an alkaline environment. While stirring, 2 mmol of <strong>[13918-92-8]2,4-difluorobenzenesulfonyl chloride</strong> was slowly added dropwise. After lh, the ice bath was removed, and the reaction was continued at room temperature for 3 h to stop the reaction. The reaction solution was washed with water three times, washed once with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent is recovered by filtration and rotary distillation, and hexane is added to the remaining oily liquid to crystallize. After the crystals are completely crystallized, the product is recrystallized to give the product as a pale yellow solid, N-(2,4-difluorobenzenesulfonyl)-3,4-methyleneoxyphenylethylamine, yield 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With pyridine; In dichloromethane; at 20℃; for 12h; | General procedure: To a mixture of 3-amino-2-methyl-thieno[2,3-d]pyrimidin-4(6H)-one (1.0 mmol) (8 and 9) and benzenesulfonyl chloride (1.1 mmol) in DCM (10 mL) was added dropwise pyridine (1.2 mmol) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 12 hrs. The mixture was concentrated under reduced pressure, and theresidue was treated with water (30 mL). The aqueous mixture was neutralized by the addition of aqueous 10% HCl solution and extracted with DCM (230 mL). The organicphase was washed with aqueous saturated NH4Cl solution and brine. The organic layer was separated and dried over anhydrous MgSO4, filtered, and concentrated under reducedpressure to give the crude product, which was purified by silica gel chromatography to produce the pure corresponding compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine; In dichloromethane; at 20℃; for 12h; | General procedure: To a mixture of 3-amino-2-methyl-thieno[2,3-d]pyrimidin-4(6H)-one (1.0 mmol) (8 and 9) and benzenesulfonyl chloride (1.1 mmol) in DCM (10 mL) was added dropwise pyridine (1.2 mmol) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 12 hrs. The mixture was concentrated under reduced pressure, and theresidue was treated with water (30 mL). The aqueous mixture was neutralized by the addition of aqueous 10% HCl solution and extracted with DCM (230 mL). The organicphase was washed with aqueous saturated NH4Cl solution and brine. The organic layer was separated and dried over anhydrous MgSO4, filtered, and concentrated under reducedpressure to give the crude product, which was purified by silica gel chromatography to produce the pure corresponding compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | General procedure: Compound 11a (800 mg,2.0 mmol) was dissolved in 10 ml ethyl acetate and then 9 N HCl(5 ml) was added, the reaction mixture was stirred for 30 min at roomtemperature, the reaction solvent was neutralized by NaHCO3 topH=8, 50 ml ethyl acetate and 30 ml H2O was added, after stirredadequately, the organic layer was separated, and concentrated, andthen the crude product was purified by silica gel columnchromatography using a mixture solvent of dichloromethane:methanol (20:1), to give white powder (540 mg); Above whitepowder (150 mg, 0.5 mmol) was dissolved in THF (10 ml),iodomethane (107 mg, 0.75 mmol) and triethylamine (0.5 ml) wereadded in the solvent. After the reaction mixture was stirred for 1 h at room temperature, the solvent was concentrated, the residues was purified by silica gel column chromatography using a mixture solvent ofdichloromethane: methanol (40:1), to give (12aa) Yield 49%, White powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In dichloromethane; at 20℃; for 3h; | General procedure: To a mixture of7-(1,4-diazepan-1-yl)-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine 6 (1 mmol)in CH2Cl2 was added Et3N (2 mmol), followedby corresponding acid chloride or sulfonylchloride or alkyl halide (1.1 mmol)at room temperature and the mixture was allowed to stir for 3 h. The mixturewas diluted with water (50 mL), extracted with CH2Cl2(2 × 50 mL) and the combined organic layers were dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified bycolumn chromatography over silica gel [100-200 mesh; CH3OH:CH2Cl2 (1:9)]. Fractions containingthe product were concentrated under vacuum to obtain title compounds (10a-i,11a-g, 12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In tetrahydrofuran; at 20℃; for 3h; | General procedure: To a solution of 8 (0.2 mmol, 1 equiv) in THF (1 mL) was added the sulfonyl chloride, sulfamoyl chloride or acid chloride (0.24 mmol, 1.2equiv), followed by TEA (0.30 mmol, 1.5 equiv). The mixture was stirred at rt for 3 h. Water (0.4 mL), EtOAc (3 mL) and then saturated NaHCO3 solution (0.8 mL) were added. After 10 min, the aqueous layer was removed. Celite (600 mg) was added to the organic layer and the solvent was evaporated. Flash chromatography using silica gel with an EtOAc/hexanes gradient provided the purified sulfonamide, sulfamide or amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.4% | General procedure: The appropriate intermediate GTF-2 (10.0 mg, 0.275 mmoL) wasadded to anhydrous K2CO3 (18.9 mg, 0.14 mmoL) in dry acetone(8 mL). The mixture was stirred for 30 min at 60 C under nitrogenatmosphere, then sulfonyl chloride (0.14 mmoL) was added. Afterstirring overnight at reflux, the reaction mixture was filtered and theacetone was evaporated in vacuo. Then the residual was purified bysemi-preparative reversed-phase C18 HPLC with acetonitrile and waterto give B1-B5 as white powder.5,3?,4?,5?-tetramethoxyflavan-7-besilate (B1). Yield 72.0%, the residuewas purified by semi-preparative RP-HPLC (MeCN-H2O, 60:40,2.5 mL/min, tR = 32 min) to give B1 as white powder. 1H NMR(600 MHz, CDCl3): delta 7.90 (m, 2H, 2?', 6?'-H), 7.67 (t, J =7.5 Hz, 1H, 4?'-H), 7.54 (t, J = 7.8 Hz, 2H, 3?', 5?'-H), 6.59 (s, 2H, 2? 6?-H), 6.22 (d,J=2.2 Hz, 1H, 8-H), 6.11 (d, J=2.2 Hz, 1H, 6-H), 4.86 (dd, J =10.5,1.7 Hz, 1H, 2-H), 3.87 (s, 6H, 3?, 5?-OCH3), 3.84 (s, 3H, 4?-OCH3), 3.69(s, 3H, 5-OCH3), 2.77 (m, 1H, 4-H), 2.62 (m, 1H, 3-H), 2.18 (m, 1H, 3-H), 1.97 (m, 1H, 3-H). 13C NMR (150 MHz, CDCl3): delta 158.3, 156.0,153.5 (2C), 148.8, 137.8, 136.9, 135.9, 134.3, 129.3, 128.6, 110.1,103.8, 103.2 (2C), 97.5, 78.2, 61.0, 56.3 (2C), 55.8, 29.3, 19.8. HR-ESIMS:509.1242 [M+Na]+, (calcd for C25H26O8SNa, 509.1241). HPLCpurity: 95.19%. |
Tags: 13918-92-8 synthesis path| 13918-92-8 SDS| 13918-92-8 COA| 13918-92-8 purity| 13918-92-8 application| 13918-92-8 NMR| 13918-92-8 COA| 13918-92-8 structure
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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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