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Structure of 349-88-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With dihydrogen peroxide; titanium tetrachloride In water; acetonitrile at 25℃; for 0.0333333 h;
General procedure: A mixture of thiol (1 mmol), 30percent H2O2 (3 mmol, 0.3 mL), and TiCl4 (1 mmol, 0.11 mL) was stirred in CH3CN at 25 °C for the time indicated in refPreviewPlaceHolderTable 1. A white solid, (TiO2) immediately precipitated. After completion of the reaction as indicated by TLC, the mixture was quenched by adding H2O (10 mL), extracted with EtOAc (4 .x. 5 mL), and the extract was dried over anhydrous MgSO4. The filtrate was evaporated under vacuum to afford the analytically pure product or chromatographed by passing through a short column of silica gel, and the products were identified by comparison of their 1H and 13C NMR spectra, and melting point with authentic samples prepared by known methods.
89%
With N-chloro-succinimide; isopropyl alcohol In dichloromethane at 0 - 20℃; for 1 h;
General procedure: To a stirred solution of the corresponding thiol 1 (1 eq) [1]a and isopropanol (CAS: 67-63-0) (2 eq) in dichloromethane [2] (0.15 M), N-bromosuccinimide (CAS: 128-08-5) or N-chlorosuccinimide (CAS: 128-09-6) (4 or 3.5 equiv) was added portion wise1b at rt (in the case of NBS) or 0 °C (in the case of NCS). The reaction mixture is stirred at rt until starting material was not visible by TLC (approx. 1 h). Then, the mixture was diluted with cold, saturated NaHCO3, and extracted with EtOAc (x4).1c The combined organic extracts were dried over anh. Na2SO4 and concentrated in vacuo to afford the crude material. Filtration on a SiO2 column or radial chromatography using mixtures of hexanes/ethyl acetate/acetone as eluents, yielded the pure sulfonyl halides 2 or 3.
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 24, p. 9287 - 9291
[2] Synlett, 2009, # 17, p. 2773 - 2776
[3] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 10, p. 3692 - 3695
[4] Phosphorus, Sulfur and Silicon and the Related Elements, 2012, vol. 187, # 6, p. 769 - 775
[5] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5847 - 5850
[6] Tetrahedron Letters, 2012, vol. 53, # 3, p. 354 - 358
[7] Green Chemistry, 2014, vol. 16, # 6, p. 3125 - 3131
[8] Chemistry Letters, 1992, # 8, p. 1483 - 1486
[9] Tetrahedron Letters, 2010, vol. 51, # 2, p. 418 - 421
[10] Synthesis, 2012, vol. 2012, # 2, p. 316 - 322
[11] Tetrahedron Letters, 2017, vol. 58, # 23, p. 2244 - 2247
[12] Green Chemistry, 2017, vol. 19, # 9, p. 2286 - 2295
[13] Tetrahedron, 2012, vol. 68, # 25, p. 5095 - 5101
[14] Letters in Organic Chemistry, 2013, vol. 10, # 2, p. 111 - 117
[15] Journal of Sulfur Chemistry, 2013, vol. 34, # 4, p. 347 - 357
5
[ 405-31-2 ]
[ 349-88-2 ]
Reference：
[1] Synlett, 2009, # 17, p. 2773 - 2776
[2] Synthesis, 2012, vol. 2012, # 2, p. 316 - 322
[3] Journal of Sulfur Chemistry, 2013, vol. 34, # 4, p. 347 - 357
6
[ 462-06-6 ]
[ 349-88-2 ]
Reference：
[1] Angewandte Chemie, 1993, vol. 105, # 7, p. 1097 - 1099
[2] Journal of Organometallic Chemistry, 1994, vol. 475, # 1-2, p. 99 - 112
[3] Medicinal Chemistry Research, 2017, vol. 26, # 7, p. 1437 - 1458
[4] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 8, p. 1205 - 1214
[5] Journal of the American Chemical Society, 1940, vol. 62, p. 511,512
[6] Bulletin de la Societe Chimique de France, 1962, p. 1213 - 1218
[7] Collection of Czechoslovak Chemical Communications, 1984, vol. 49, # 5, p. 1182 - 1192
[8] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 777 - 782
[9] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 19 - 32
[10] New Journal of Chemistry, 2014, vol. 38, # 12, p. 6193 - 6197
[11] Molecules, 2018, vol. 23, # 7,
7
[ 1765-93-1 ]
[ 349-88-2 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 29, p. 10638 - 10641
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 3051 - 3057
11
[ 368-85-4 ]
[ 349-88-2 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1967, vol. 37, p. 149 - 155[2] Zhurnal Obshchei Khimii, 1967, vol. 37, # 1, p. 163 - 170
12
[ 349-89-3 ]
[ 349-88-2 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1967, vol. 37, p. 149 - 155[2] Zhurnal Obshchei Khimii, 1967, vol. 37, # 1, p. 163 - 170
13
[ 371-40-4 ]
[ 349-88-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1965, vol. 84, p. 24 - 30
14
[ 349-88-2 ]
[ 402-46-0 ]
Reference：
[1] Liebigs Annales, 1997, # 1, p. 141 - 154
[2] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 8, p. 1205 - 1214
[3] Journal of the American Chemical Society, 1940, vol. 62, p. 511,512
[4] J. Gen. Chem. USSR (Engl. Transl.), 1967, vol. 37, p. 149 - 155[5] Zhurnal Obshchei Khimii, 1967, vol. 37, # 1, p. 163 - 170
[6] Collection of Czechoslovak Chemical Communications, 1984, vol. 49, # 5, p. 1182 - 1192
[7] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 13, p. 1493 - 1498
[8] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 13, p. 1493 - 1498
[9] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 13, p. 1493 - 1498
[10] Patent: US5089499, 1992, A,
[11] Journal of Molecular Structure, 2014, vol. 1067, # 1, p. 43 - 51
[12] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4397 - 4406
[13] Molecules, 2018, vol. 23, # 7,
15
[ 349-88-2 ]
[ 124-40-3 ]
[ 383-31-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In tetrahydrofuran; water at 20℃; for 0.333333 h;
(1) 4-Fluoro-1-(N,N-dimethylaminosulfonyl)benzene To a solution of 4-fluorobenzenesulfonyl chloride (1.95 g, 10.0 mmol) in THF (40 mL) were added triethylamine (2.09 mL, 15.0 mmol) and 50percent aqueous dimethylamine solution (1.26 mL, 14.0 mmol) at room temperature, and the solution was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-fluoro-1-(N,N-dimethylaminosulfonyl)benzene (2.03 g, 10.0 mmol).yield: quantitative
100%
at 20℃; for 0.0833333 h;
[00728] A mixture of 4-fluorobenzene-1 -sulfonyl chloride (2.0 g, 10.3 mmol), HNMe2 (2.0M in MeOH; 1 1 .0 mL, 22.0 mmol) and DCM (1 1 .0 mL) was stirred at rt for 5 min. DCM (30 mL) was added. The organic phase was washed with 1 M HCI (30 mL) and brine (30 mL), dried over MgSCv and filtered. The solvent was removed under reduced pressure to afford 4-fluoro-/V,/V- dimethylbenzenesulfonamide as a white solid (2.12 g, quant.). A mixture of 4-fluoro-/V,/V- dimethylbenzenesulfonamide (1 .50 g, 7.39 mmol), NaSMe (2.08 g, 29.7 mmol) and DMF (9.0 mL) was stirred at 170 °C in a sealed tube for 16 h. After cooling to rt, 1 M NaOH (40 mL) was added. The aqueous phase was washed with Et20 (2 χ 40 mL), acidified to pH <2 with 2 M HCI and then extracted with Et20 (3 χ 40 mL). The combined organic phase was dried over MgSCv and filtered. The solvent was removed under reduced pressure to afford 4-mercapto-/V,/V- dimethylbenzenesulfonamide as an orange oil (503 mg, 31 percent). H NMR (500 MHz, CDCI3) δ 7.67 - 7.58 (m, 2H), 7.43 - 7.35 (m, 2H), 3.67 (s, 1 H), 2.71 (s, 6H).
86%
at 0℃; for 0.5 h;
A cooled (0 0C) solution of 4-fluorobenzenesulfonyl chloride (2.00 g; 10.3 mmol) in THF (40 ml) is treated with a 2 M solution of dimethylamine in THF (1 1.3 ml; 22.6 mmol) and stirred at 0 0C for 30 minutes. The solvents were removed under reduced pressure, the residue taken up in EtOAc, the organic phase was washed with a saturated solution of NH4CI twice and with water. The organic phase was dried on MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound (1.80 g, 86percent).
Preparation of 4-fluoro-N,N-dimethyl-benzenesulfonamide A solution of 4-fluorobenzenesulfonyl chloride (1.95 g, 10 mmol) and dimethylamine hydrochloric acid salt (978 mg, 12 mmol) in tetrahydrofuran (10 mL) was added to a solution of 4-dimethylaminopyridine (3.05 g, 25 mmol) in tetrahydrofuran (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by flash column (elution with 20percent ethyl acetate in petroleum ether) to afford 4-fluoro-N,N-dimethyl-benzenesulfonamide (1.02 g, 50percent) as a white solid. The following sulfonamides were prepared in an analogous manner as described for 4-fluoro-N,N-dimethyl-benzenesulfonamide by the reaction of 4-fluorobenzenesulfonyl chloride with commercially available amines.
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 18, p. 3502 - 3506
18
[ 349-88-2 ]
[ 383-31-3 ]
Reference：
[1] Patent: US4532240, 1985, A,
19
[ 349-88-2 ]
[ 74-89-5 ]
[ 433-14-7 ]
Reference：
[1] Nippon Kagaku Zasshi, 1955, vol. 76, p. 775,777[2] Chem.Abstr., 1957, p. 17793
[3] Patent: WO2007/31747, 2007, A1, . Location in patent: Page/Page column 42
[4] Patent: US2009/163534, 2009, A1, . Location in patent: Page/Page column 20-21
[5] Patent: US2003/208066, 2003, A1, . Location in patent: Page/Page column 26-27
[6] Organic Letters, 2016, vol. 18, # 9, p. 2280 - 2283
[7] Organic Letters, 2017, vol. 19, # 21, p. 5844 - 5847
[8] Chemical Communications, 2018, vol. 54, # 60, p. 8403 - 8406
20
[ 824-75-9 ]
[ 349-88-2 ]
[ 433-14-7 ]
Reference：
[1] Patent: US5877317, 1999, A,
21
[ 349-88-2 ]
[ 824-80-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium hydrogencarbonate; sodium sulfite In water at 80℃; for 4 h;
Take 250mL of mono vial,P-fluorobenzenesulfonyl chloride (48.5 mmol, 9.4 g, 1.0 equiv) was added,Sodium sulfite (97 mmol, 12.2 g, 2.0 equiv),Sodium bicarbonate (97 mmol, 8.1 g, 2.0 equiv)Add 60 mL of water,Equipped with reflux condenser,80 ° C for 4 h.The reaction ends,Dry water,Add methanol dissolved to filter,And then spin dry methanol to white solid 10.2g,Yield 99percent.
Reference：
[1] Patent: CN107033046, 2017, A, . Location in patent: Paragraph 0192; 0193; 0194
[2] Chemistry - An Asian Journal, 2016, vol. 11, # 15, p. 2121 - 2125
[3] Acta Chemica Scandinavica, Series A: Physical and Inorganic Chemistry, 1976, vol. A30, # 8, p. 579 - 585
[4] European Journal of Medicinal Chemistry, 2007, vol. 42, # 6, p. 880 - 884
[5] Journal of Organic Chemistry, 1992, vol. 57, # 9, p. 2594 - 2599
[6] Patent: WO2007/66844, 2007, A1, . Location in patent: Page/Page column 13-14
[7] Tetrahedron Letters, 2012, vol. 53, # 33, p. 4347 - 4350
[8] Molecules, 2013, vol. 18, # 1, p. 97 - 113
[9] European Journal of Organic Chemistry, 2014, vol. 2014, # 15, p. 3196 - 3202
[10] Journal of Organic Chemistry, 2014, vol. 79, # 24, p. 12018 - 12032
[11] Journal of Chemical Research, 2014, vol. 38, # 11, p. 639 - 642
[12] Tetrahedron, 2014, vol. 70, # 47, p. 9107 - 9112
[13] Green Chemistry, 2015, vol. 17, # 3, p. 1395 - 1399
[14] Chemical Communications, 2015, vol. 51, # 29, p. 6418 - 6421
[15] Advanced Synthesis and Catalysis, 2015, vol. 357, # 9, p. 2050 - 2054
[16] Organic Letters, 2016, vol. 18, # 16, p. 4144 - 4147
[17] Organic Letters, 2018, vol. 20, # 17, p. 5353 - 5356
[18] Tetrahedron Letters, 2017, vol. 58, # 7, p. 690 - 693
[19] Chemical Communications, 2017, vol. 53, # 12, p. 2056 - 2059
[20] Angewandte Chemie - International Edition, 2017, vol. 56, # 16, p. 4447 - 4451[21] Angew. Chem., 2017, vol. 56, # 16, p. 4447 - 4451,5
[22] European Journal of Medicinal Chemistry, 2018, vol. 160, p. 120 - 132
[23] Organic and Biomolecular Chemistry, 2018, vol. 16, # 42, p. 7959 - 7963
22
[ 349-88-2 ]
[ 116649-85-5 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 10, p. 4842 - 4848
(iv) The preparation of 4-fluorobenzenesulphonamide is described below: A solution of 4-fluorobenzenesulphonyl chloride (2.0 g) in dry tetrahydrofuran (5 ml) was added dropwise to a cold (ice-bath), stirred solution of aqueous ammonia (S.G. 0.88, 20 ml). After the addition, stirring was continued for 30 minutes and the precipitated solid was filtered off, washed with water and dried in air. There was thus obtained 4-fluorobenzenesulphonamide (0.70 g).
With ammonium hydroxide; at 100℃; for 1h;
General procedure: Substituted arylsulfonylchlorides was suspended in 3 mL ammonia water, and thenthe solution was refluxed at 100 C for 1 h. The mixture was cooleddown to room temperature. Substituted arylsulfamides wereobtained by filtration, washing with water and were then driedin vacuo (excepted for the commercially available 4-methylbenzenesulfonamide).
(±)-1-(4-fluorophenylsulfonyl)-3-methylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 20℃;Cooling with ice;
To an ice-cooled stirred suspension of (±)-2-methylpiperazine(0.32 g, 3.20 mmol) in DCM (10.00 mL) was added Et3N (0.41 mL,3.20 mmol) dropped with 4-fluorobenzene-1-sulfonyl chloride(0.58 g, 3.00 mmol) in DCM (5.00 mL), and the mixture was stirredat room temperature for 3 h. Then it was concentrated in vacuoand water (20.00 mL) was added to it. The residue was extractedby DCM (20 mL 3), the organic layer was combined, then washedwith brine (10.00 mL), dried (MgSO4), filtered and concentrated invacuo. The residue was purified by column chromatography on silicagel (EtOAc/PE 1:1) to afford the title compound 7h. 1H NMR (CDCl3,500 MHz) d: 7.75-7.74 (m, 2H, Ar-H), 7.20-7.17 (m, 2H, Ar-H), 3.57(s, 2H), 2.97-2.88 (m, 3H), 2.26-2.25 (m, 1H), 1.88-1.84 (m, 1H),1.46 (br s, 1H), 1.01-0.99 (m, 3H). ESI-MS m/z: 259 [M+H].
1-(3,5-dichloropyridin-4-yl)-4-(3-methylphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(4-methylphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(2-methylphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(3-methoxyphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(4-methoxyphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(2-methoxyphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(4-propan-2-ylphenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(3-chlorophenyl)sulfonyl-4-(3,5-dichloropyridin-4-yl)-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-(4-fluorophenyl)sulfonyl-1,4-diazepane[ No CAS ]
1-(2-chlorophenyl)sulfonyl-4-(3,5-dichloropyridin-4-yl)-1,4-diazepane[ No CAS ]
2-[[4-(3,5-dichloropyridin-4-yl)-1,4-diazepan-1-yl]sulfonyl]benzonitrile[ No CAS ]
1-[4-[[4-(3,5-dichloropyridin-4-yl)-1,4-diazepan-1-yl]sulfonyl]phenyl]ethanone[ No CAS ]
1-(2,4-dichlorophenyl)sulfonyl-4-(3,5-dichloropyridin-4-yl)-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-naphthalen-1-ylsulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-naphthalen-2-ylsulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-[2-(trifluoromethyl)phenyl]sulfonyl-1,4-diazepane[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-[4-(trifluoromethyl)phenyl]sulfonyl-1,4-diazepane[ No CAS ]
N-[4-[[4-(3,5-dichloropyridin-4-yl)-1,4-diazepan-1-yl]sulfonyl]phenyl]acetamide[ No CAS ]
1-(3,5-dichloropyridin-4-yl)-4-[3-(trifluoromethyl)phenyl]sulfonyl-1,4-diazepane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Combinatorial reaction / High throughput screening (HTS);
Examples 1-19; General Method:; A solution of l-(3,5-dichloropyridin-4-yl)-l,4-diazepane (100 mg, 0.41 mmol) in DCM (1 ml) was added to the appropriate sulfonyl chloride (0.41 mmol) under a nitrogen atomosphere. DIPEA (0.22 ml, 1.22 mmol) was then added and the mixture stirred overnight at ambient temperature. The reaction mixtures were washed with water and the products isolated by <n="24"/>flash column chromatography (Combi-Flash Optix 10 on a 12g silica cartridge, eluting with a 1:1 mixture of EtOAc and isohexane) to give colourless solids.; The following compounds were synthesised as a multiparallel array:
To a solution of 25.0g (0.102 mol) of <strong>[206548-14-3]2-amino-3-methyl-5-bromobenzoic acid methyl ester</strong> (U.S. Patent 5,776,961) in 300 mL of pyridine was added 21.93g (0.113 mol) of 4-fluorobenzenesulfonyl chloride. The reaction mixture was stirred for 18h at 80, cooled to room temperature and poured into water. The resulting mixture was extracted with ethyl acetate and the combined organics were then washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 14.53g (39%) of the desired product as a tan solid. Electrospray Mass Spec: 388.0 (M-H)-
36%
5-Bromo-2-(4-fluoro-benzenesulfonylamino)-3-methyl-benzoic acid By following the procedure of Example 134 the product of Example 133 and 4-flurobenzenesulfonyl chloride provides 5-bromo-2-(4-fluoro-benzenesulfonylamino)-3methyl-benzoic acid as a yellow solid in 36% yield. Electrospray Mass Spec: 386.0 (M-H)-
36%
5-Bromo-2-(4-fluoro-benzenesulfonylamino)-3-methyl-benzoic acid By following the procedure of Example 134 the product of Example 133 and 4-fluorobenzenesulfonyl chloride provides 5-bromo-2-(4-fluoro-benzenesulfonylamino)-3-methyl-benzoic acid as a yellow solid in 36% yield. Electrospray Mass Spec: 386.0 (M-H)-
14.53 g (39%)
In pyridine;
EXAMPLE 1 3-Methyl-5-bromo-2-(4-fluoro-benzenesulfonylamino)-benzoic acid To a solution of 25.0 g (0.102 mol) of <strong>[206548-14-3]2-amino-3-methyl-5-bromobenzoic acid methyl ester</strong> (U.S. Pat. No. 5,776,961) in 300 mL of pyridine was added 21.93 g (0.113 mol) of 4-fluorobenzenesulfonyl chloride. The reaction mixture was stirred for 18 h at 80, cooled to room temperature and poured into water. The resulting mixture was extracted with ethyl acetate and the combined organics were then washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluding with ethyl acetate/hexanes (1:3) to provide 14.53 g (39%) of the desired product as a tan solid. Electrospray Mass Spec: 388.0 (M-H)-
With triethylamine; In tetrahydrofuran; water; at 20℃; for 0.333333h;
(1) 4-Fluoro-1-(N,N-dimethylaminosulfonyl)benzene To a solution of 4-fluorobenzenesulfonyl chloride (1.95 g, 10.0 mmol) in THF (40 mL) were added triethylamine (2.09 mL, 15.0 mmol) and 50% aqueous dimethylamine solution (1.26 mL, 14.0 mmol) at room temperature, and the solution was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-fluoro-1-(N,N-dimethylaminosulfonyl)benzene (2.03 g, 10.0 mmol).yield: quantitative
100%
In methanol; dichloromethane; at 20℃; for 0.0833333h;
[00728] A mixture of 4-fluorobenzene-1 -sulfonyl chloride (2.0 g, 10.3 mmol), HNMe2 (2.0M in MeOH; 1 1 .0 mL, 22.0 mmol) and DCM (1 1 .0 mL) was stirred at rt for 5 min. DCM (30 mL) was added. The organic phase was washed with 1 M HCI (30 mL) and brine (30 mL), dried over MgSCv and filtered. The solvent was removed under reduced pressure to afford 4-fluoro-/V,/V- dimethylbenzenesulfonamide as a white solid (2.12 g, quant.). A mixture of 4-fluoro-/V,/V- dimethylbenzenesulfonamide (1 .50 g, 7.39 mmol), NaSMe (2.08 g, 29.7 mmol) and DMF (9.0 mL) was stirred at 170 C in a sealed tube for 16 h. After cooling to rt, 1 M NaOH (40 mL) was added. The aqueous phase was washed with Et20 (2 chi 40 mL), acidified to pH <2 with 2 M HCI and then extracted with Et20 (3 chi 40 mL). The combined organic phase was dried over MgSCv and filtered. The solvent was removed under reduced pressure to afford 4-mercapto-/V,/V- dimethylbenzenesulfonamide as an orange oil (503 mg, 31 %). H NMR (500 MHz, CDCI3) delta 7.67 - 7.58 (m, 2H), 7.43 - 7.35 (m, 2H), 3.67 (s, 1 H), 2.71 (s, 6H).
86%
In tetrahydrofuran; at 0℃; for 0.5h;
A cooled (0 0C) solution of 4-fluorobenzenesulfonyl chloride (2.00 g; 10.3 mmol) in THF (40 ml) is treated with a 2 M solution of dimethylamine in THF (1 1.3 ml; 22.6 mmol) and stirred at 0 0C for 30 minutes. The solvents were removed under reduced pressure, the residue taken up in EtOAc, the organic phase was washed with a saturated solution of NH4CI twice and with water. The organic phase was dried on MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound (1.80 g, 86%).
In tetrahydrofuran; water; at 0 - 20℃; for 24h;
(1) A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0C, and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and diisopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide
A 4-(4-Benzyl-piperazin-1-yl)-benzenesulfonamide 4-Fluorobenzenesulfonylchloride (25 g) were dissolved in dichloromethane (250 ml) and treated at 0 C. with an aqueous solution of ammonia (25%, 50 ml). The mixture was stirred for 2 hours with cooling and overnight at room temperature. The reaction mixture was acidified and the organic solvent evaporated. The residue was extracted with ethyl acetate to yield 20 g <strong>[402-46-0]4-fluorobenzenesulfonamide</strong>, which were dissolved in water (300 ml), treated with 1-benzyl-piperazine (102 g) and refluxed for 24 hours. The reaction mixture was filtered to yield 26 g of the title compound. (mass spec APCI [M+H]=332)
(S)-3-(4-Benzyloxy-phenyl)-2-(4-fluoro-benzene-sulfonylamino)-propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.22 g (5%)
With sodium carbonate; In water;
(a) (S)-3-(4-Benzyloxy-phenyl)-2-(4-fluoro-benzene-sulfonylamino)-propionic acid A mixture of (S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid (2.7 g, 0.010 mol), 4-fluoro-benzene-sulfonyl chloride (2.0 g, 0.010 mol), and sodium carbonate (2.2 g, 0.020 mol) in a mixture of tetra-hydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with saturated sodium chloride solution, dried (MgSO4), and rotary-evaporated under reduced pressure to give an oil. The oil was chromatographed on silica gel (445 g, 230-400 mesh) eluding with dichloromethane-methanol (20:1), and the fractions containing product were rotary-evaporated to give a solid. The solid was recrystallized from toluene to give the title compound as a light yellow solid; yield 0.22 g (5%), mp=138-139 C.
4-Fluoro-N,N-dimethylbenzenesulfonamide A solution of 38.9 g (0.20 mole) of 4-fluorobenzenesulfonylchloride in 20 ml of methylene chloride was added slowly to 300 ml of a 40% aqueous dimethylamine solution during 0.5 hour period. The reaction was exothermic. After the reaction mixture was cooled a yellow solid was precipitated. The solid was collected, dissolved in 300 ml of ethyl acetate, and dried over magnesium sulfate. The solution was concentrated to 100 ml and a light yellow crystal formed. The crystal was collected and air-dried to afford 39 g of the product, mp 40-43 C.
66-1) 1-[2-(4-Fluorobenzenesulfonylamino)ethyl]-4-(t-butoxycarbonyl)piperazine The 1-(2-aminoethyl)-4-(t-butoxycarbonyl)piperazine (2.01 g) obtained in Example 58 and 4-fluorobenzene sulfonylchloride (2.05 g) were dissolved in tetrahydrofuran (20 ml), and triethylamine (2.4 ml) was added thereto, and the mixture was stirred overnight at room temperature. Water (50 ml) was added to the reaction mixture which was then extracted with ethyl acetate, and the organic layer was washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (2.61g, 77percent) was obtained as a colorless oil.
Part A: 1-(4-Fluorophenylsulfonyl)-4-Oxopiperidine (30A). 4-Piperidone-HCl Hydrate (8.0 g, 52 mmol), 4-Fluorobenzenesulfonyl Chloride (10 g, 52 mmol), and 1.0 M NaOH (120 mL) were stirred in THF (200 mL) from 0 C to RT overnight. After phase separation, the aqueous layer was extracted further with EtOAc (1 L). The combined organic phases were extracted with 1 _HCl (180 mL), H20 (100 mL), and brine (50 mL). The solution was dried (Na2SO4), filtered, and concentrated in vacuo to yield sulfonamide 30A (12.1 g) as a pale yellow solid. MS(GC-MS, H20) m/e 258 (base, M+H+), 188 (13%). HRMS(CI, NH3) m/e Calc'd for (M+H+): 258.0600. Found: 258.0601.
N-t-butoxycarbonyl-DL-4-[(4-fluorophenyl)sulfonylamino]phenylalanine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example II-14 N-t-butoxycarbonyl-DL-4-[(4-fluorophenyl)sulfonylamino]-phenylalanine In the same manner as in Example II-(11-2) and Example II-(11-3) except for using N-t-butoxycarbonyl-DL-4-aminophenylalanine ethyl ester in place of N-t-butoxycarbonyl-L-4-aminophenylalanine ethyl ester and using 4-fluorobenzenesulfonyl chloride in place of benzenesulfonyl chloride, the reactions were carried out to obtain the title compound (overall yeield-quantitative) as white solid. 1H-NMR (CDCl3) delta; 7.78-7.71 (m, 2H), 7.21 (s, 1H), 7.13-6.91 (m, 6H), 5.03-4.88 (m, 1H), 4.67-4.49 (m, 1H), 3.19-2.89 (m, 2H), 1.42 (s, 9H). CI-MS (m/z); 383
3-(4-Fluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 125 3-(4-Fluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 121 using 4-fluorobenzenesulfonyl chloride (2.14 g 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p. 209-211 C. Calculated for C20H17FN2O4S: C, 59.99; H, 4.28; N, 7.00. Found: C, 59.96; H, 4.24; N, 6.87.
N-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
EXAMPLE 8 To a suspension of <strong>[214147-48-5]1-acetyl-4-aminopiperidine hydrochloride</strong> (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzenesulfonyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 20:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide (859 mg) was obtained. NMR (DMSO-d6, delta): 1.21 (2H, m), 1.54 (2H, m), 1.94 (3H, s), 2.66 (1H, br t, J=10.8 Hz), 3.02 (1H, dt, J=2.9, 12.0 Hz), 3.22 (1H, m), 3.64 (1H, br d, J=14.0 Hz), 4.05 (1H, br d, J=13.2 Hz), 7.44 (2H, t, J=8.9 Hz), 7.8-8.0 (3H, m)
Preparation of 4-fluoro-N,N-dimethyl-benzenesulfonamide A solution of 4-fluorobenzenesulfonyl chloride (1.95 g, 10 mmol) and dimethylamine hydrochloric acid salt (978 mg, 12 mmol) in tetrahydrofuran (10 mL) was added to a solution of 4-dimethylaminopyridine (3.05 g, 25 mmol) in tetrahydrofuran (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by flash column (elution with 20% ethyl acetate in petroleum ether) to afford 4-fluoro-N,N-dimethyl-benzenesulfonamide (1.02 g, 50%) as a white solid. The following sulfonamides were prepared in an analogous manner as described for 4-fluoro-N,N-dimethyl-benzenesulfonamide by the reaction of 4-fluorobenzenesulfonyl chloride with commercially available amines.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;
Dimethylamine hydrochloride (1.27g) was added to a solution OF 4-FLUORO- benzenesulphonyl chloride (3. 0G) and N, N-diisopropylethylamine (5. 37ML) in dichloromethane (30ML), the mixture was stirred at RT for lh, diluted with water, extracted with dichloromethane, dried and evaporated under reduced, yield 3.0g
Step 2. N-(3,6-dichloropyridazin-4-yl)-4-fluorobenzenesulfonamide To a 50 mL round-bottomed flask was added 3,6-dichloropyridazin-4-amine (148 mg, 902 mumol), sodium bis(trimethylsilyl)amide (365 mul, 1805 mumol) and THF (3 mL) at 0 C. The mixture was stirred at 0 C. for 30 min. 4-fluorobenzene-1-sulfonyl chloride (263 mg, 1354 mumol) was then added. The mixture was stirred at 0 C. for 1 hour. The reaction mixture was diluted with satd NH4Cl (10 mL) and extracted with EtOAc (3*30 mL). The combined organic extracts were washed with satd NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography (5% MeOH/EtOAc) to give N-(3,6-dichloropyridazin-4-yl)-4-fluorobenzenesulfonamide (252 mg, 86.7% yield). MS (ESI positive ion) m/z: 323 (M+1). 1H NMR (300 MHz, DMSO-d6) delta ppm 6.95 (s, 1H) 7.23-7.35 (m, 2H) 7.74-7.84 (m, 2H)
N-{6-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1H-indol-4-yl}-4-fluoro-benzenesulfonamide. Substituting N-(6-bromo-1H-indol-4-yl)-4-fluoro-benzenesulfonamide (prepared by treatment of <strong>[350800-81-6]6-bromo-1H-indol-4-ylamine</strong> with 4-fluoro-benzenesulfonyl chloride in pyridine) for 6-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MP=295-297 C, (M+H)+=492.
N-{6-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-1H-indol-4-yl}-4-fluoro-benzenesulfonamide. Substituting N-(6-bromo-1H-indol-4-yl)-4-fluoro-benzenesulfonamide (prepared by treatment of <strong>[350800-81-6]6-bromo-1H-indol-4-ylamine</strong> with 4-fluoro-benzenesulfonyl chloride in pyridine) for 6-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MP=295-297 C, (M+H)+=492.
With sodium hydride; In tetrahydrofuran; at 0℃; for 6h;
General procedure: The target compound 7a was obtained by reacting 4a (295 mg, 1.0 mmol) with benzenesulphonyl chloride (211 mg, 1.2 mmol), and NaH (50 mg, 2.0 mmol) in dry THF (50 mL). After stirring the reaction mixture for 6 h, the reaction mixture was poured on to crushed ice (5 g) and the reaction mixture extracted and purified by column chromatography affords final product as white solid.
With potassium carbonate; In tetrahydrofuran; water; at 0℃; for 16h;
With respect to the examples below, the general procedure for the synthesis of 3- sulfonylamino-2-oxopiperidines was: potassium carbonate (3 mmol) and (5)-3-amino- 2-oxopiperidine hydrochloride (1.5 mmol) were dissolved in water (5 ml) and the solution was cooled to 0 C, and a solution of substituted benzenesulfonyl chloride (1 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for 16 hours, and then the reaction was extracted with dichloromethane or chloroform. The combined organic layers were dried over sodium sulfate and reduced in vacuo to give a solid. This solid was redissolved in a minimum amount of dichloromethane and crystallised by addition of petroleum ether 40-60 C. The solid product was isolated by filtration and dried over potassium pentoxide.; Example 1: (S)-4-Fluoro-N-(2-oxopiperidin-3-yl)benzenesulfonamide; 0.196 g white fine powder (48 %). mp 153-156 C; [a]24D +30.35 (c 0.1 , MeOH); vmax/cm l 1656, 1650 (C=0, amide), 1493 (N-H, amide), 1329 (C-F), 1 158 (-S02-). Anal. (CuHi3FN203S) C, H, N: calcd C 48.52, H 4.81 , N 10.29; found C 48.13, H 4.74, N 10.18. 1H-NMR deltaEta 1H-NMR deltaEta. 7.90 (2H, dd, J 9 and 5, ArH2 and ArH6), 7.17 (2H, t, J 8.5, ArH3 and ArH5), 5.82 (2Eta, NHCH and NHCH2), 3.48 (IH, dd, J 1 1 and 6, CHNH), 3.31-3.25 (2H, m, GH2NH), 2.48-2.41 (I H, m, CH2CH), 1.99-1.88 (2H, m, CH2CH2NH), 1.87-1.66 ( H, m, CH2CH). 13C-NMR 6C 169.74 (CHCONH), 165.1 (d, J 255, ArC4), 135.2 (d, J 3, CS02), 130.1 (d, J 9, ArC2/6), 1 16.4 (d, J 23, ArC3/5), 53.3 (CHNH), 41.9 (CH2NH), 28.6 (CH2CHNH), 20.8 (CH2CH2NH). l9F- NMR 6F -105.1. HRMS (+ESI) CuH13FN203SNa: calcd 295.0523; found 295.0517.
With triethylamine; In chloroform; at 20℃;Inert atmosphere;
General procedure: To a solution of the suitable amine (30-60 mg), dissolved in CHCl3 (ethanol-free, 10-15 mL), Et3N (1.5 eq) and the suitable acyl or sulfonyl chloride (1.2 eq) were added, and the mixture was left stirring at RT for 2-24 hr. After completion of reaction (Tlc), the mixture was diluted with H2O (20 mL), made alkaline with Na2CO3 (saturated solution), and extracted with dichloromethane. After drying (Na2SO4) and removal of the solvent under vacuum, the residue was purified by flash chromatography (Eluent A: abs EtOH/ NH4OH/CH2Cl2/Et2O/Pet. ether 180: 9.9: 360: 360: 900. Eluent B: abs EtOH/ NH4OH/CH2Cl2/Et2O/Pet. ether 45: 2.5: 180: 180: 450. Eluent C: abs EtOH/ NH4OH/CH2Cl2/Pet. ether 65: 8: 340: 60).
N-(5-chloro-3-methylpyridin-2-yl)-4-fluorobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
502 mg
With pyridine; at 20.0℃; for 16.0h;
Intermediate 25: N-(5-chloro-3-methvlIvridin-2-vl-4-fluorobenzenesulfonamideTo a solution of <strong>[20712-16-7]5-chloro-3-methylpyridin-2-amine</strong> (500 mg, 3.51 mmol) in pyridine (7 mL) stirred in air at room temperature was added a solution of 4-fluorobenzene-1-sulfonyl chloride (819 mg, 4.21 mmol) in pyridine (7 mL). The reaction mixture was stirred at 20 C for 16 hours then the solventwas evaporated in vacuo. The crude was passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol followed by 2M ammonia/methanol, then a sulphonic acid (SCX) SPE cartridge eluting with methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by flash silica (Si) chromatography (O-100% ethyl acetate15 cyclohexane+0-20% methanol gradient). The appropriate fractions were combined and evaporatedin vacuoto give the title compound (502 mg) as an off-white solid. LCMS (2 mm, formic) Rt 1.02 mi m/z (ESj 301 (M+H).
502 mg
With pyridine; at 20.0℃; for 16.0h;
To a solution of <strong>[20712-16-7]5-chloro-3-methylpyridin-2-amine</strong> (500 mg, 3.51 mmol) in pyridine (7 mL) stirred in air at room temperature was added a solution of 4-fluorobenzene-1-sulfonyl chloride (819 mg, 4.21 mmol) in pyridine (7 mL). The reaction mixture was stirred at 20 C. for 16 hours then the solvent was evaporated in vacuo. The crude was passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol followed by 2M ammonia/methanol, then a sulphonic acid (SCX) SPE cartridge eluting with methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-20% methanol gradient). The appropriate fractions were combined and evaporated in vacuo to give the title compound (502 mg) as an off-white solid. LCMS (2 min, formic) Rt 1.02 min, m/z (ES+) 301 (M+H).
N-(3,5-dimethylpyridin-2-yl)-4-fluorobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.1 mg
With pyridine; at 20℃; for 20.5h;
Intermediate 12: N-(3,5-dimethylIDyridin-2-yl-4-fluorobenzenesulfonamideTo a stirred solution of <strong>[41995-30-6]3,5-dimethylpyridin-2-amine</strong> (129 mg, 1.056 mmol) in pyridine (5 mL) at room temperature, was added 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol). The reaction mixture was stirred at 20 C for 30 minutes, then left to stand for 16 hours. Additional 4- fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol) was then added and the reaction stirred for an additional 4 hours. The reaction mixture was concentrated in vacuo and purified by passingthrough an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol then 2M ammonia/methanol. Concentration of the product-containing fractions provided the title compound (84.1 mg) as a yellow oil. LCMS (2 mm, formic) Rt 0.89 mi m/z (ESj 281 (M+H).
84.1 mg
With pyridine; at 20℃; for 20.5h;
To a stirred solution of <strong>[41995-30-6]3,5-dimethylpyridin-2-amine</strong> (129 mg, 1.056 mmol) in pyridine (5 mL) at room temperature, was added 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol). The reaction mixture was stirred at 20 C. for 30 minutes, then left to stand for 16 hours. Additional 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol) was then added and the reaction stirred for an additional 4 hours. The reaction mixture was concentrated in vacuo and purified by passing through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol then 2M ammonia/methanol. Concentration of the product-containing fractions provided the title compound (84.1 mg) as a yellow oil. LCMS (2 min, formic) Rt 0.89 min, m/z (ES+) 281 (M+H).
4-fluoro-N-(6-methoxypyridin-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
164 mg
With pyridine;
Intermediate 16: 4-fluoro-N-(6-methoxvIvridin-2-vlbenzenesulfonamideA solution of 4-fluorobenzenesulfonyl chloride (188 mg, 0.967 mmol) and <strong>[17920-35-3]6-(methyloxy)-2-pyridinamine</strong> (100 mg, 0.806 mmol) was prepared in pyridine (5 mL). After standing, additional 4-fluorobenzenesulfonyl chloride (0.2 eq) was added and the reaction was left to stand over theweekend. The reaction mixture was then concentrated in vacuo and extracted to the organic phaseof an acidic work up between ethyl acetate and 5 percent citric acid. The organic phase was concentratedin vacuo, to provide the title compound (164 mg) as a thick red oil. The material was used directly in the next step without further purification. LCMS (2 mm, formic) Rt 0.96 mi m/z (ESj 283 (M+H).
164 mg
With pyridine;
A solution of 4-fluorobenzenesulfonyl chloride (188 mg, 0.967 mmol) and <strong>[17920-35-3]6-(methyloxy)-2-pyridinamine</strong> (100 mg, 0.806 mmol) was prepared in pyridine (5 mL). After standing, additional 4-fluorobenzenesulfonyl chloride (0.2 eq) was added and the reaction was left to stand over the weekend. The reaction mixture was then concentrated in vacuo and extracted to the organic phase of an acidic work up between ethyl acetate and 5percent citric acid. The organic phase was concentrated in vacuo, to provide the title compound (164 mg) as a thick red oil. The material was used directly in the next step without further purification. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 283 (M+H).
4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
430 mg
With pyridine;
Intermediate 27: 4-fluoro-N-(5-isopropvlpvridin-2-vlbenzenesulfonamide <strong>[603310-75-4]5-isopropylpyridin-2-amine</strong> (300 mg, 2.20 mmol) and 4-fluorobenzene-1-sulfonyl chloride (557 mg,2.86 mmol) were dissolved in pyridine (3 mL) and left to stand overnight. The reaction mixture was concentrated in vacuo and the crude product extracted to the organic phase of an acidic workup between ethyl acetate and 5 % citric acid. The organic phase was passed through a hydrophobic fritand concentrated in vacuoto give the title compound (430 mg). LCMS (2 mm, formic) Rt 0.90 mm, m/z (ESj 295 (M+H).1H NMR (400MHz, DMSO-d6) O ppm 8.00 - 7.76 (m, 3 H), 7.69 (dd, 1 H), 7.36 (t, 2 H), 7.12 (d, 1 H), 2.91 - 2.70 (m, 1 H), 1.13 (d, 6 H).
430 mg
With pyridine;
<strong>[603310-75-4]5-isopropylpyridin-2-amine</strong> (300 mg, 2.20 mmol) and 4-fluorobenzene-1-sulfonyl chloride (557 mg, 2.86 mmol) were dissolved in pyridine (3 mL) and left to stand overnight. The reaction mixture was concentrated in vacuo and the crude product extracted to the organic phase of an acidic workup between ethyl acetate and 5% citric acid. The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the title compound (430 mg). LCMS (2 min, formic) Rt 0.90 min, m/z (ES+) 295 (M+H). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.00-7.76 (m, 3H), 7.69 (dd, 1H), 7.36 (t, 2H), 7.12 (d, 1H), 2.91-2.70 (m, 1H), 1.13 (d, 6H).
Synthesis of methyl 1-[(4-fluorophenyl)sulfonylamino]cyclopropanecarboxylate 13A A suspension of <strong>[72784-42-0]methyl-1-aminocyclopropane carboxylate hydrochloride</strong> 12 (0.6 g, 3.96 mmol) in CH2Cl2 (60 mL) was added with TEA (1.1 mol eq, 0.6 mL) and the mixture was stirred at r.t. for 10 minutes. Then 4-fluorobenzensulfonyl chloride (1 mol eq, 0.77 g) and additional TEA (1.1 mol eq) were added and the solution was heated at 60°C overnight. The solvent was removed at reduced pressure, water was added to the residue (100 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The combined organic phases were dried over Na2SO4 and evaporated to reduced pressure to afford 13A as transparent oil (1.07 g, 99percent yield). 1HNMR (DMSO, 200 MHz) delta 1.17 (m, 2H), 1.27 (m, 2H), 3.32 (s, 3H), 7.46 (t, 2H, J=9), 7.80 (m, 2H), 8.78 (bs, 1H).
99%
With triethylamine; In dichloromethane; at 60℃;
Synthesis of methyl l-[(4- fluorophenyl)sulfonylamino] cyclopropanecarboxylate 13 A A suspension of methyl- 1-aminocyclopropane carboxylate hydrochloride 12 (0.6 g, 3.96 mmol) in CH2CI2 (60 mL) was added with TEA (1.1 mol eq, 0.6 mL) and the mixture was stirred at r.t. for 10 minutes. Then 4-fluorobenzensulfonyl chloride (1 mol eq, 0.77 g) and additional TEA (1.1 mol eq) were added and the solution was heated at 60°C overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase was extracted with EtOAc (3x40 mL). The combined organic phases were dried over Na2S04 and evaporated under reduced pressure to afford 13A as transparent oil (1.07 g, 99percent yield). FontWeight="Bold" FontSize="10" HNMR (DMSO, 200 MHz) delta 1.17 (m, 2H), 1.27 (m, 2H), 3.32 (s, 3H), 7.46 (t, 2H, J=9), 7.80 (m, 2H), 8.78 (bs, 1H).
With triethylamine; In dichloromethane; at 20℃; for 4h;
Methyl 1-(4-fluorophenylsulfonamido)cyclopropanecarboxylate. A mixture of methyl 1- aminocyclopropane-1-carboxylate hydrochloride (1.51 g, 9.96 mmol,1.00 equiv), triethylamine (2.52 g, 24.90 mmol, 2.50 equiv), dichloromethane (20 mL), 4-fluorobenzene-1 -sulfonyl chloride (1.95 g, 10.02 mmol, 1.00 equiv) was stirred for 4 h at room temperature. Water (50 mL) was added. The mixture was extracted with dichloromethane (3x50 mL). The combined extracts were washed with water (50 mL) and brine (50 mL) successively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude title compound (2.5 g) as yellow oil. MS-ESI: [M+H] 274.
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 4.0h;
First, 221 g of the resulting tetraphenyl compound and 227 g of aluminum chloride were dissolved in 570 mL of dichloromethane, and then a dichloromethane solution (100 mL) containing 224 g of 4-fluorobenzenesulfonyl chloride was dropped at 0 C., followed by gradual heating to room temperature and reaction for 4 hours. The solution was diluted with dichloromethane and washed with water, methanol, and hexane to obtain 268 g of a difluoro compound. Then, 268 g of the resulting difluoro compound was reacted in 740 g of fuming sulfuric acid (30% SO3) (reagent manufactured by Wako Pure Chemical Industries, Ltd.) at 115 C. for 20 hours. The solution was added little by little to a large amount of water and neutralized with NaOH, followed by precipitating sodium sulfate with ethanol three times to remove it, thereby obtaining an aromatic sulfonic acid derivative as represented by the formula (G6) given above. Its structure was confirmed by 1H-NMR.
(2S)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 18h;
4-Fluorobenzene-1 -sulfonyl chloride (2.14 g, 11.00 mmol, 1.00 equiv) was added into a solution of <strong>[2133-34-8](2S)-azetidine-2-carboxylic acid</strong> (1 g, 9.89 mmol, 1.10 equiv) in saturated aqueous sodium hydroxide (6 mL)/tetrahydrofuran (6 mL) at 0C. The resulting mixture was stirred for 18 h at room temperature. The mixture was extracted with ether. The pH value of the aqueous solution was adjusted to 3 with 2 M hydrogen chloride. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (1.7 g, 60%) as a white solid.
3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-2,5-bibenzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With tetrabutylammomium bromide; sodium hydroxide; In benzene; at 0 - 20℃;
General procedure: To a solution of 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazole 3 (2 mmol) and tetrabutylammonium bromide (0.2 mmol) in benzene (25 mL), a solution of 50% NaOH (25 mL) was added at 0 C followed by the addition of sulfonyl chloride 4 (2.2 mmol). The reaction mixture was stirred vigorously at room temperature for 5-6 h and the reaction was monitored by TLC. After the completion of the reaction, aqueous phase was separated and the organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate and concentrated to give crude products which were purified by column chromatography over silica gel using hexane-EtOAc (6:4) mixture as eluent.
N-[(2,4-dimethoxyphenyl)methyl]-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzene-1-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
N-[(2,4-Dimethoxyphenyl)methyl]-1 ,2,4-thiadiazol-5-amine (500 mg, 1 .99 mmol, 1 .00 equiv) was dissolved in tetrahydrofuran (10 m L) under an inert atmosphere of nitrogen. Then a solution of LiHMDS (3 m L, 1 .50 equiv) was added dropwise while stirring at -78 C before the reaction mixture was gradually warmed to room temperature and stirred for a further 30 minutes. The reaction was then cooled back to - 78 C and a solution of 4-fluorobenzene-1 -sulfonyl chloride (386 mg, 1 .98 mmol, 1 .00 equiv) in tetrahydrofuran (2 m L) was added dropwise. The temperature was once again gradually increased to room temperature and the reaction was stirred for a further 30 min. The reaction was then quenched by the addition of water, extracted with 3x20 m L of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 650 mg (80%) of N-[(2,4- dimethoxyphenyl)methyl]-4-fluoro-N-(1 ,2,4-thiadiazol-5-yl)benzene-1 -sulfonamide as a light yellow solid.
N-(2,3-dihydro-1H-inden-4-yl)-4-fluorobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With pyridine; at 0℃; for 2h;Inert atmosphere;
General procedure: To an ice-cooled solution of the amine (20mmol) in pyridine (8mL) was slowly added the corresponding sulfonyl chloride (30mmol) in pyridine (6mL). The mixture was stirred at 0°C for 2h and allowed to reach room temperature. Water was added (100mL) and the solid was collected and recrystallized from MeOH:CH2Cl2.
4-fluoro-N-(4-(5-((4-fluorophenyl)sulfonamido)benzo[d]oxazol-2-yl)phenyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With pyridine; In dichloromethane; at 20℃; for 18h;
General procedure: To a stirring mixture of 5-amino-2-(4-aminophenyl) benzoxazole (1 eq.) in anhydrous CH2Cl2 (5 mL) was added the respective sulfonyl chloride (2.1 eq.) followed by anhydrous pyridine (2.1 eq.). The reaction was allowed to stir at room temperature for 18 h and was then chromatographed over silica and concentrated. If necessary, the product was further purified by preparatory RP-HPLC (H2O:CH3CN gradient), concentrated, and lyophilized.
3'-N-p-fluorobenzenesulfonylstaurosporine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.3%
With triethylamine; In dichloromethane; at 20℃; for 4h;Inert atmosphere;
Under argon protection,In a 25 mL two-necked reaction flask,A solution of <strong>[62996-74-1]staurosporine</strong> (46.6 mg, 0.1 mmol),Dissolved in 3 mL of methylene chloride,An excess of triethylamine was added dropwise,Then p-fluorobenzenesulfonyl chloride was added,Stirring reaction at room temperature 4h,Water was added to terminate the reaction,Dichloromethane extraction,And dried over anhydrous Na2SO4,Vacuum evaporated,After separation by gel column chromatography,Methanol elution was3'-N-p-fluorobenzenesulfonyl<strong>[62996-74-1]Staurosporine</strong>(130)Yield 83.3%.
83.3%
With triethylamine; In dichloromethane; at 20℃; for 4h;Inert atmosphere;
Argon under the protection,In a 25 mL two-necked reaction flask, <strong>[62996-74-1]staurosporine</strong> (46.6 mg, 0.1 mmol) was added,Dissolved in 3 mL of dichloromethane, excess triethylamine was added dropwise,Then adding p-fluorobenzenesulfonyl chloride, stirring at room temperature for 4 h,The reaction was quenched with water, extracted with dichloromethane, dried over anhydrous Na2SO4, evaporated in vacuo,After gel column chromatography,Methanol was eluted with 52.0 mg of 3'-N-p-fluorobenzenesulfonic acid <strong>[62996-74-1]staurosporine</strong> (130) 52 mg, and the yield was 83.3%.
6-bromo-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With pyridine; In dichloromethane; at 20℃; for 4h;
To a solution of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (350 mg, 1.6 mmol) in dichloromethane (5 mL) was added pyridine (0.53 mL, 6.5 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.38 g, 2.0 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. Then, the reaction mixture was concentrated in vacuo to provide a residue, which was redissolved in ethyl acetate, washed with 1M hydrogen chloride, brine, dried with sodium sulfate, filtered and concentrated in vacuo to provide the crude product. The crude product was purified by column chromatography (eluting with a gradient of 0-30% ethyl acetate in hexanes) to provide the title compound (0.49 g, 81% yield).
tert-butyl 4-([(4-fluorophenyl)sulfonyl]amino}methyl)-4-hydroxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;
4-Fluorobenzenesulfonyl chloride (2.21 g, 1 1.4 mmol) was added portion-wise to a 0 C solution of te/ -butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (2.95 g, 12.8 mmol) and triethylamine (4.7 mL, 33.7 mmol) in dichloromethane (150 mL) and the reaction mixture was allowed to warm to room temperature and stir for 1 hour. It was then diluted with dichloromethane (100 mL) and washed sequentially with water (200 mL) and with saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL); addition of heptane (100 mL) caused a solid to precipitate. Solvents were evaporated off to afford the product as a white solid. Yield: 4.3 g, 1 1.1 mmol, 97%. LCMS m/z 387.4 [M-H+]. 1 H NMR (500 MHz, CDCI3) delta 7.91-7.86 (m, 2H), 7.22 (br dd, J=8.6, 8.5 Hz, 2H), 5.2-4.9 (v br s, 1 H), 3.87-3.67 (m, 2H), 3.24-3.09 (m, 2H), 2.92 (s, 2H), 2.12-1.94 (br s, 1 H), 1.63-1.55 (m, 2H), 1.53-1.45 (m, 2H), 1.45 (s, 9H).
With potassium carbonate; In acetonitrile; at 25℃; for 1.16667h;
Potassium carbonate (24.0 g, 174 mmol) was added to a solution of te/ -butyl 4- (aminomethyl)-4-hydroxypiperidine-1-carboxylate (5.00 g, 21.7 mmol) in acetonitrile (35 mL), and the reaction mixture was allowed to stir for 5 minutes. A solution of 4-fluorobenzenesulfonyl chloride (4.31 g, 22.1 mmol) in acetonitrile (15 mL) was slowly added over five minutes, and the resulting suspension was stirred at 25 C ; after 1 hour, 1 ,2-dibromoethane (7.50 mL, 87.0 mmol) was added, and the reaction mixture was heated at 80 C for 27 hours, whereupon it was cooled to 25 C and filtered. The reaction flask was rinsed with acetonitrile (2 x 18 mL), and the combined filtrates were concentrated under reduced pressure and diluted with ethyl acetate (72 mL). para-Toluenesulfonic acid monohydrate (8.38 g, 44.0 mmol) was added in one portion, and the reaction mixture was stirred at room temperature for 10 minutes, until a solution was obtained. It was then heated at 50 C for 1.5 hours, at which point it was cooled to 25 C and stirred for 2 hours to granulate the precipitate. This material was collected via filtration and rinsed with ethyl acetate, affording the product as a white solid. Yield: 7.26 g, 14.9 mmol, 69%.
tert-butyl 4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydrogencarbonate; In dichloromethane; at 20℃;
4-Fluorobenzenesulfonyl chloride (4.18 g, 21.5 mmol) was added portion-wise to a mixture of C23 (5.0 g, 20 mmol), saturated aqueous sodium bicarbonate solution (55 ml_), and dichloromethane (195 ml_). The reaction mixture was stirred at room temperature overnight, whereupon the aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) afforded the product as a white foam. Yield: 8.4 g, 20 mmol, quantitative. 1 H NMR (400 MHz, CDCI3) delta 7.79-7.73 (m, 2H), 7.28-7.22 (m, 2H, assumed; partially obscured by solvent peak), 3.8-3.66 (m, 2H), 3.79 (dd, J=5.0, 5.0 Hz, 2H), 3.19-3.08 (m, 2H), 3.08-2.89 (m, 2H), 2.89-2.67 (m, 2H), 1.96-1.82 (m, 2H), 1.54-1.48 (m, 2H), 1.47 (s, 9H).
100%
With sodium hydrogencarbonate; In dichloromethane; water; at 20℃;
4-Fluorobenzenesulfonyl chloride (4.18 g, 21.5mmol) was added portion-wise to a mixture ofPl (5.0 g, 20mmol), saturated aqueous sodium bicarbonate solution (55mL), and dichloromethane (195 mL). The reaction mixturewas stirred at room temperature overnight, whereupon theaqueous layer was extracted twice with dichloromethane,and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 10% methanol in dichloromethane)afforded the product as a white foam. Yield: 8.4g, 20 mmol, quantitative. 1 H NMR ( 400 MHz, CDC13 ) o7.79-7.73 (m, 2H), 7.28-7.22 (m, 2H, assumed; partiallyobscured by solvent peak), 3.8-3.66 (m, 2H), 3.79 (dd,1=5.0, 5.0 Hz, 2H), 3.19-3.08 (m, 2H), 3.08-2.89 (m, 2H),2.89-2.67 (m, 2H), 1.96-1.82 (m, 2H), 1.54-1.48 (m, 2H),1.47 (s, 9H).
(R)-[3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-5-oxazolidinyl]methyl p-fluorobenzenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.3%
With triethylamine; In dichloromethane; at 20℃; for 18h;
(R) - [3- (3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl] methyl alcohol (3.9 g, 13.16 mmol) was added to the three-CH2Cl2, triethylamine (3.67 mL, 26.13 mmol).A solution of p-fluorobenzenesulfonyl chloride (15.8 mmol) in CH2Cl2 was added dropwise and reacted at room temperature for 18 hours.TLC monitoring, the reaction is completed, the reaction solution water washing, saturated NaCl solution washing,Dried over anhydrous Na2SO4, filtered, dried to give the crude product,The product was recrystallized(R) -N- [3- (3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl] methylphenoxybenzenesulfonic acid4.8 g of ester, yield: 80.3%, chemical purity: 96.7%,
2-(diethylamino)ethyl 4-(4-fluorophenylsulfonamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine; In tetrahydrofuran;Heating;
General procedure: To a stirred solution of 4-chlorobenzenesulfonyl chloride (1) (0.001 mol) in dry THF, 2-(phenylthio)aniline (3a) (0.001mol) was added at 20C in the presence of triethylamine (0.001 mol) as a base in THF (20 mL). After the addition, the reaction mixture temperature was slowly raised to 40-50C and stirred for 4 h. The progress of the reaction was monitored by TLC using ethyl acetate: hexane (3:2). After completion of the reaction, the triethylamine hydrochloride salt was fltered off and the solvent was removed in a rotaevaporator. The residue was purifed by washing with hexane and recrystallization from ethanol. The resulting compound 4-chloro-N-(2-(phenylthio)phenyl)benzenesulfonamide (4a) was obtained in good yield (75%). The same procedure was adopted for the synthesis of the remaining title compounds (4b-f). The title compounds (5a-f) were synthesized by adopting the above procedure using 4-uorobenzenesulfonyl chloride (1) with the same amines (3a-f) (Scheme 1).
1-((4-fluorophenyl)sulfonyl)-5-methylindole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.87%
With dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 5℃; for 2h;
Add III-4 (0.80g, 5.03mmol), DMAP (123mg, 1.01mmol), DIEA (2.50mL, 15.09mmol) to 100mL three-necked flask, stir and dissolve with 10mL acetonitrile, slowly add at 05C 4-Fluorophenylsulfonyl chloride (IV-4, 1.18g, 6.04mmol) in 10mL acetonitrile solution, after the addition is completed, stirring is continued for 2 hours under low temperature conditions.TLC monitoring of raw material reactionsCompletely, concentrate the reaction solution, dissolve it with 30 mL of ethyl acetate, wash with 40 mL of water, and extract twice with ethyl acetate (20 mL×2)The organic phase is washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate; suction filtered, and the filtrate is dried and then subjected to column chromatography ( petroleum ether:Ethyl acetate = 10:1 rinse),After drying, 1.49 g of a brownish yellow solid V-9 was obtained with a yield of 74.87%.
With triethylamine; In acetonitrile; at 25℃; for 24h;
(1) 1 mmol of latinosyl N, N-dimethylamino-3-methylindole shown in Formula 1, 1.5 mmol of 4-fluorobenzenesulfonyl chloride as shown in Formula 2g was added to a 50 mL flask, Add 10mL of CH3CN to completely dissolve, slowly add 1.5mmol of Et3N, The reaction was stirred at 25 C for 24h to obtain a reaction solution; the reaction formula is as follows: (2) The reaction solution was concentrated under reduced pressure, CH2Cl2 and water were added, and the organic phases were combined. It was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated and evaporated to dryness, and then separated by silica gel column chromatography to obtain N, N-dimethylsulfonamide derivatives as shown in Formula 3g.
82%
With triethylamine; In acetonitrile; at 25℃; for 24h;
General procedure: To a solution of gramine (1, 1.0mmol) and arylsulfonyl chloride (2, 1.5mmol) in dryCH3CN (10ml) at 25 C, a solution of Et3N (1.5mmol) in dry CH3CN (5ml) was addeddrop wise for 10min [20-24]. After reaction for 24 h, the reaction solution was concentratedunder reduced pressure to give crude product. The crude product was dissolvedin CH2Cl2 (15ml) and diluted with water (15ml) and extracted with CH2Cl2 (30ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine(30ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gelcolumn chromatography to obtain the target compounds in 76%-98% yields. The datafor 3a-o are shown as follows.
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