* 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.
General procedure: Sodium carbonate (Na2CO3, 1.590g, 15mmol) was added to a solution of amino acids (2a-h, 12.5mmol) in water (15mL) with continuous stirring until all the solutes had dissolved. The solution was cooled to−5°C and the appropriate benzenesulphonyl chloride (1a-c, 15mmol) was added in four portions over a period of 1h. The slurry was further stirred at room temperature for about 4h. The progress of the reaction was monitored using TLC (MeOH/DCM, 1:9). Upon completion, the mixture was acidified using 20percent aqueous hydrochloric acid to pH 2. The crystals was filtered via suction and washed with pH 2.2 buffer. The pure products (3a-x) were dried over self-indicating fused silica gel in a desiccator. 2.2.1 2-(4-methylphenylsulphonamido) acetic acid (3a) The amino acid was glycine, yield (2.8410g, 99.34percent), mp, 88.4–88.6°C, FTIR (KBr, cm−1): 3448 (OH of COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C=O), 1598, 1440 (C=C), 1354, 1321 (2S=O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (DMSO-d6)δ: 7.90–7.88 (t, J=6.3Hz, 1H, NH), 7.65–7.63 (d, J=8.6Hz, 2H, ArH), 7.34–7.33 (d, J=8.05Hz, 2H, ArH), 3.52–3.51 (d, J=5.7Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6)δ: 170.7 (C=O), 143.1, 138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0412 (M-H)-, calculated, 228.0408.
99.34%
With sodium carbonate In water for 4 h;
General procedure: Sodium carbonate (Na2CO3, 1.590 g, 15 mmol) was added to a solution of amino acids (6a-h,12.5 mmol) in water (15 mL) with continuous stirring until all the solutes dissolved. The solutionwas cooled to -5°C and an appropriate benzenesulphonyl chloride (5a-c, 15 mmol) wasadded in four portions over a period of 1 h. The slurry was further stirred at room temperaturefor 4 h. The progress of the reaction was monitored by using TLC (MeOH/DCM, 1:9). Uponcompletion, the mixture was acidified using 20percent aqueous hydrochloric acid to pH 2. The crystalswas filtered via suction and washed with pH 2.2 buffer. The pure products (7a-x) weredried over self-indicating fused silica gel in a desiccator. 2-(4-methylphenylsulphonamido) acetic acid (7a). The amino acid was glycine, yield(2.8410 g, 99.34percent), appearance white needles, mp, 88.4-88.6°C, FTIR (KBr, cm-1): 3448 (OHof COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C = O), 1598, 1440 (C = C), 1354, 1321(2S = O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (500 MHz, DMSO-d6) δ: 7.89 (t,J = 6.3 Hz, 1H, NH), 7.64 (d, J = 8.6 Hz, 2H, ArH), 7.33 (d, J = 8.05 Hz, 2H, ArH), 3.51 (d,J = 5.7 Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (500 MHz, DMSO-d6) δ: 170.8 (C = O), 143.1, 138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0410(M-H)-, calculated, 228.0408.
86%
With sodium hydrogencarbonate In water; acetone at 25℃; for 0.25 h;
General procedure: Sulfonyl chloride (0.20 mmol) was dissolved in acetone (2 mL) and the resulting solution was injected in the reagent loop A. An aqueous NaHCO3 0.4 M (1 mL) was added to a solution of the amine (0.22 mmol) dissolved in PEG-400 (1 mL). The H2O/PEG400 solution (2 mL, 1:1,v/v) was then injected in the reagent loop B. A degassed solution of acetone and water were connected with pump A and B, respectively, and the flow rate was fixed at 0.5 mL min−1 (0.25 mL min−1 + 0.25 mL min−1). After switching the sample loops, the mixtures exited were joined in a T-piece, entered in a 10 mL PTFE coil reactor warmed at 25 °C, fitted with the back pressure regulator (100 psi), directed in UV detector and the output was recovered in a fraction collector. The reaction mixture was drooped in a tube containing Et2O/HCl 3 N (5 mL, 4:1, v/v). The two phases were separated, and the organic one was washed with H2O (2 × 1 mL), dried over Na2SO4, and concentrated under reduced pressure to give the desired pure compound.
81%
at 20 - 25℃;
General procedure: Syntheses of G1 and P1: To a stirred solution of glycine (0.75 g, 10.0 mmol) or l-phenylalanine (1.65 g, 10.0 mmol) in 20 mL of 1 M NaOH solution at 25 °C, p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added. After overnight stirring at room temperature, the solid residue was filtered off and the aqueous reaction portion was acidified with 1 M HCl. The obtained solid was filtered and purified by column chromatography on silica with hexane and EtOAc (1:2) to obtain compounds G1 and P1 as white solids. (Yields, 81percent and 76percent, respectively.) Compound G1: Yield 81percent as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (broad singlet, 1H, -COOH), 7.93 (t, J = 6.1 Hz, 1H, -NH-), 7.67 (d, J = 8.4 Hz, 2H, ArH), 7.37 (d, J = 8.3 Hz, 2H, ArH), 3.54 (d, J = 6.1 Hz, 2H, -CH2-), 2.37 (s, 3H, -CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 171.1, 143.8, 136.3, 129.9, 127.3, 40.3, 21.6 ppm. Anal. Calcd [C9H11NO4S]: C, 47.15; H, 4.84; N, 6.11; S, 13.99. Found: C, 48.36; H, 5.11; N, 5.93; S, 14.27.
72%
Stage #1: With sodium carbonate In water at 70 - 85℃; for 0.75 h; Stage #2: With hydrogenchloride In water at 20℃;
General procedure: The nitrogen tosylation was done using a reported procedure. In a round bottom flask, 2.4 equiv. of Na2CO3 was dissolved in 70 °C water (C = 0.66 mol/L). Then 1.0 equiv. of the desired anthranilic acid was added followed by 1.4 equiv. of tosyl chloride. The suspension was stirred at 70 °C for 40 min then at 85 °C for 5 min. The reaction mixture was then directly filtrated and the solid washed with 85 °C water. The filtrate was cooled to room temperature and then acidified to pH = 1 using an aqueous 6M HCl solution. The precipitated solid was collected by suction and dried over vacuum. The resulting tosyl anthranilic acids were used without further purification.
21%
Stage #1: With sodium hydroxide In diethyl ether; water at 20℃; for 3.16667 h; Stage #2: With hydrogenchloride In water
Glycine (1 g, 13.32 mmol) was dissolved in IN NaOH (aq.) and a solution of tosyl chloride (2.62 g, 13.72 mmol) in diethyl ether (15 ml) was added portion wise with stirring over 10 min. The resulting mixture was allowed to stir at room temperature for 3 h. The ethereal layer was separated and the aqueous layer treated with 2N HCl solution until acidified to pH 5. After cooling the resulting solution to 0 0C, the product began to precipitate from the solution. The solid was collected by filtration and the mother liquor placed in a fridge overnight causing more of the desired product to precipitate. The solid was again collected by filtration and the combined collected solid was dried under high vacuum affording 9 as a white powder (613 mg, 21percent). δH (400 MHz, MeOD) 2.41 (3H, s, CH3), 3.66 (2H, S5 CH2), 7.35 (2H, d, J=8 Hz5 ArH)5 7.73 (2H5 d, J=8 Hz, ArH); δc (100.6 MHz, MeOD) 20.3, 43.6, 127.0, 129.5, 137.6, 143.6, 171.0; MS (ES+) 246.8 (100percent, [M+H20]+); MS (ES') 227.9 (100percent, [M-H]-); HRMS [M-H]' requires 228.03360, found 228.03364.
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Reference：
[1] Acta Universitatis Lundensis, 1892, vol. 28, p. 2.Abt.,Abhandl.III,S.3
8
[ 98-59-9 ]
[ 56-40-6 ]
[ 95021-64-0 ]
[ 1080-44-0 ]
Reference：
[1] Acta Universitates Lundensis 28 <1892>, 2. Abt., Abhandl. III, S. 12,
9
[ 2232-08-8 ]
[ 56-40-6 ]
[ 288-32-4 ]
[ 1080-44-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1988, # 2, p. 356 - 360
10
[ 29981-92-8 ]
[ 56-40-6 ]
[ 1080-44-0 ]
[ 35487-17-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1988, # 2, p. 356 - 360
11
[ 51060-12-9 ]
[ 56-40-6 ]
[ 1080-44-0 ]
[ 34531-53-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1988, # 2, p. 356 - 360
12
[ 98953-60-7 ]
[ 7732-18-5 ]
[ 1080-44-0 ]
Reference：
[1] Acta Universitatis Lundensis, 1892, vol. 28, p. 2.Abt.,Abhandl.III,S.13
13
[ 115901-56-9 ]
[ 1080-44-0 ]
[ 104-15-4 ]
[ 22356-89-4 ]
[ 78-98-8 ]
Reference：
[1] Chemical Communications, 2003, # 22, p. 2838 - 2839
14
[ 67-56-1 ]
[ 1080-44-0 ]
[ 2645-02-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 3 h;
To a solution of (toluene-4-sulfonylamino)-acetic acid (2 g, 8.72 mmol) in methanol (60 mL), cone. H2SO4 (1.5 mL) was added. The mixture was stirred at room temperature for 3h then the solvent was removed under reduced pressure. The crude was dissolved in DCM (20 mL) and the organic phase was washed with H2O (1x20 mL), 5percent Na2CO3 (aq) (1x20 mL) and brine (1x20 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude (toluene-4-sulfonylamino)-acetic acid methyl ester was used in the next step without further purification. Yield: 98percent; LCMS (RT): 3.47 min (Method A); MS (ES+) gave m/z: 244.03 (MH+).
Reference：
[1] Patent: WO2006/123257, 2006, A2, . Location in patent: Page/Page column 77
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 7, p. 1671 - 1676
[3] Chemische Berichte, 1956, vol. 89, p. 1674,1679
[4] Journal of the American Chemical Society, 1956, vol. 78, p. 3841,3842
[5] Justus Liebigs Annalen der Chemie, 1961, vol. 640, p. 136 - 139
To a solution of (toluene-4-sulfonylamino)-acetic acid (2 g, 8.72 mmol) in methanol (60 mL), cone. H2SO4 (1.5 mL) was added. The mixture was stirred at room temperature for 3h then the solvent was removed under reduced pressure. The crude was dissolved in DCM (20 mL) and the organic phase was washed with H2O (1x20 mL), 5% Na2CO3 (aq) (1x20 mL) and brine (1x20 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude (toluene-4-sulfonylamino)-acetic acid methyl ester was used in the next step without further purification. Yield: 98%; LCMS (RT): 3.47 min (Method A); MS (ES+) gave m/z: 244.03 (MH+).
General procedure: Compounds 14-35, 60 and 61(1.53mmol, 1 equivalent) were treated with ethylene glycol (12.24mmol, 8 equivalent) and heated up to 100C to get the clear solution [17]. The reaction mixture was refluxed at 120-150C for 2-4h. the final mixture was cooled and poured on crushed ice to get the solid product. The product was purified by column chromatography using 30% ethyl acetate in hexane as solvent over silica gel (60-120 mesh).
A mixture of 2-(4- methylphenylsulfonamido)acetic acid (9, 200 mg, 0.873 mmol) and thionyl chloride (1 ml) was heated at reflux for 1.5 h. The excess thionyl chloride was removed in vacuo and the resulting white solid dried under high vacuum at 50 0C for 1.5 h. The product acid chloride 10 was used without further purification.
General procedure: Sodium carbonate (Na2CO3, 1.590g, 15mmol) was added to a solution of amino acids (2a-h, 12.5mmol) in water (15mL) with continuous stirring until all the solutes had dissolved. The solution was cooled to-5C and the appropriate benzenesulphonyl chloride (1a-c, 15mmol) was added in four portions over a period of 1h. The slurry was further stirred at room temperature for about 4h. The progress of the reaction was monitored using TLC (MeOH/DCM, 1:9). Upon completion, the mixture was acidified using 20% aqueous hydrochloric acid to pH 2. The crystals was filtered via suction and washed with pH 2.2 buffer. The pure products (3a-x) were dried over self-indicating fused silica gel in a desiccator. 2.2.1 2-(4-methylphenylsulphonamido) acetic acid (3a) The amino acid was glycine, yield (2.8410g, 99.34%), mp, 88.4-88.6C, FTIR (KBr, cm-1): 3448 (OH of COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C=O), 1598, 1440 (C=C), 1354, 1321 (2S=O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (DMSO-d6)delta: 7.90-7.88 (t, J=6.3Hz, 1H, NH), 7.65-7.63 (d, J=8.6Hz, 2H, ArH), 7.34-7.33 (d, J=8.05Hz, 2H, ArH), 3.52-3.51 (d, J=5.7Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6)delta: 170.7 (C=O), 143.1, 138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0412 (M-H)-, calculated, 228.0408.
99.34%
With sodium carbonate; In water; for 4h;
General procedure: Sodium carbonate (Na2CO3, 1.590 g, 15 mmol) was added to a solution of amino acids (6a-h,12.5 mmol) in water (15 mL) with continuous stirring until all the solutes dissolved. The solutionwas cooled to -5C and an appropriate benzenesulphonyl chloride (5a-c, 15 mmol) wasadded in four portions over a period of 1 h. The slurry was further stirred at room temperaturefor 4 h. The progress of the reaction was monitored by using TLC (MeOH/DCM, 1:9). Uponcompletion, the mixture was acidified using 20% aqueous hydrochloric acid to pH 2. The crystalswas filtered via suction and washed with pH 2.2 buffer. The pure products (7a-x) weredried over self-indicating fused silica gel in a desiccator. 2-(4-methylphenylsulphonamido) acetic acid (7a). The amino acid was glycine, yield(2.8410 g, 99.34%), appearance white needles, mp, 88.4-88.6C, FTIR (KBr, cm-1): 3448 (OHof COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C = O), 1598, 1440 (C = C), 1354, 1321(2S = O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (500 MHz, DMSO-d6) delta: 7.89 (t,J = 6.3 Hz, 1H, NH), 7.64 (d, J = 8.6 Hz, 2H, ArH), 7.33 (d, J = 8.05 Hz, 2H, ArH), 3.51 (d,J = 5.7 Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (500 MHz, DMSO-d6) delta: 170.8 (C = O), 143.1, 138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0410(M-H)-, calculated, 228.0408.
86%
With sodium hydrogencarbonate; In water; acetone; at 25℃; for 0.25h;
General procedure: Sulfonyl chloride (0.20 mmol) was dissolved in acetone (2 mL) and the resulting solution was injected in the reagent loop A. An aqueous NaHCO3 0.4 M (1 mL) was added to a solution of the amine (0.22 mmol) dissolved in PEG-400 (1 mL). The H2O/PEG400 solution (2 mL, 1:1,v/v) was then injected in the reagent loop B. A degassed solution of acetone and water were connected with pump A and B, respectively, and the flow rate was fixed at 0.5 mL min-1 (0.25 mL min-1 + 0.25 mL min-1). After switching the sample loops, the mixtures exited were joined in a T-piece, entered in a 10 mL PTFE coil reactor warmed at 25 C, fitted with the back pressure regulator (100 psi), directed in UV detector and the output was recovered in a fraction collector. The reaction mixture was drooped in a tube containing Et2O/HCl 3 N (5 mL, 4:1, v/v). The two phases were separated, and the organic one was washed with H2O (2 × 1 mL), dried over Na2SO4, and concentrated under reduced pressure to give the desired pure compound.
81%
With sodium hydroxide; at 20 - 25℃;
General procedure: Syntheses of G1 and P1: To a stirred solution of glycine (0.75 g, 10.0 mmol) or l-phenylalanine (1.65 g, 10.0 mmol) in 20 mL of 1 M NaOH solution at 25 C, p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added. After overnight stirring at room temperature, the solid residue was filtered off and the aqueous reaction portion was acidified with 1 M HCl. The obtained solid was filtered and purified by column chromatography on silica with hexane and EtOAc (1:2) to obtain compounds G1 and P1 as white solids. (Yields, 81% and 76%, respectively.) Compound G1: Yield 81% as white solid. 1H NMR (400 MHz, DMSO-d6): delta 12.66 (broad singlet, 1H, -COOH), 7.93 (t, J = 6.1 Hz, 1H, -NH-), 7.67 (d, J = 8.4 Hz, 2H, ArH), 7.37 (d, J = 8.3 Hz, 2H, ArH), 3.54 (d, J = 6.1 Hz, 2H, -CH2-), 2.37 (s, 3H, -CH3) ppm. 13C NMR (100 MHz, CDCl3): delta 171.1, 143.8, 136.3, 129.9, 127.3, 40.3, 21.6 ppm. Anal. Calcd [C9H11NO4S]: C, 47.15; H, 4.84; N, 6.11; S, 13.99. Found: C, 48.36; H, 5.11; N, 5.93; S, 14.27.
72%
General procedure: The nitrogen tosylation was done using a reported procedure. In a round bottom flask, 2.4 equiv. of Na2CO3 was dissolved in 70 C water (C = 0.66 mol/L). Then 1.0 equiv. of the desired anthranilic acid was added followed by 1.4 equiv. of tosyl chloride. The suspension was stirred at 70 C for 40 min then at 85 C for 5 min. The reaction mixture was then directly filtrated and the solid washed with 85 C water. The filtrate was cooled to room temperature and then acidified to pH = 1 using an aqueous 6M HCl solution. The precipitated solid was collected by suction and dried over vacuum. The resulting tosyl anthranilic acids were used without further purification.
21%
Glycine (1 g, 13.32 mmol) was dissolved in IN NaOH (aq.) and a solution of tosyl chloride (2.62 g, 13.72 mmol) in diethyl ether (15 ml) was added portion wise with stirring over 10 min. The resulting mixture was allowed to stir at room temperature for 3 h. The ethereal layer was separated and the aqueous layer treated with 2N HCl solution until acidified to pH 5. After cooling the resulting solution to 0 0C, the product began to precipitate from the solution. The solid was collected by filtration and the mother liquor placed in a fridge overnight causing more of the desired product to precipitate. The solid was again collected by filtration and the combined collected solid was dried under high vacuum affording 9 as a white powder (613 mg, 21%). deltaH (400 MHz, MeOD) 2.41 (3H, s, CH3), 3.66 (2H, S5 CH2), 7.35 (2H, d, J=8 Hz5 ArH)5 7.73 (2H5 d, J=8 Hz, ArH); deltac (100.6 MHz, MeOD) 20.3, 43.6, 127.0, 129.5, 137.6, 143.6, 171.0; MS (ES+) 246.8 (100%, [M+H20]+); MS (ES') 227.9 (100%, [M-H]-); HRMS [M-H]' requires 228.03360, found 228.03364.
Step A. Preparation of Nalpha-(4-methylbenzenesulfonyl)-glycine Glycine was reacted with 4-methylbenzenesulfonyl chloride under the conditions used in general procedure A giving the title compound which was recrystallized neat (60%). LC-MS: 228 (M-H)-, 99% pure.
With sodium hydrogencarbonate; In water; at 80℃;
General procedure: To approximately 2.5 equiv of sodium bicarbonate in water, wasadded 1 equiv of glycine. The solution was stirred at 80 C till complete dissolution. It was cooled to around 50 C and then 1 equiv ofsubstituted phenyl sulfonyl chloride was added. The solution wasstirred for 2-3 hours at 80 C. The reaction completion was monitoredby TLC. The solution was cooled to 10 C, neutralized with1 M HCl and kept for 30 min for precipitation. The solid compoundwas filtered out using vacuum and dried.20
With sodium hydroxide;
General procedure: Amino acid (100 mmol) was dissolved in 10% sodium hydroxide solution (100mL), and then arylsulfonyl chloride (100 mmol) was added in portions to this solution, stirred vigorously after each addition. Crushed ice (100 g) was added to the solution and then concentrated HCl was added dropwise until the mixture was acidified (pH 2-3). The resulting compounds 1a-1q were obtained as white crystalline solid.
With sodium carbonate; In water; at 20℃; for 5h;Cooling;
General procedure: Sodium carbonate (Na2CO3, 1.590 g, 15 mmol) was added to a solution of aminoacids (2a-h, 12.5 mmol) in water (15 mL) with continuous stirring until all the solutes had dissolved.The solution was cooled to -5C and the appropriate benzenesulphonyl chloride (1a-c,15 mmol) was added in four portions over a period of 1 h. The slurry was further stirred at room temperature for about 4 h. The progress of the reaction was monitored using TLC(MeOH/DCM, 1:9). Upon completion, the mixture was acidified using 20% aqueous hydrochloricacid to pH 2. The crystals was filtered via suction and washed with pH 2.2 buffer. Thepure products (3a-p) were dried over self-indicating fused silica gel in a desiccator.
In water; acetone; at 20℃; for 24h;Alkaline conditions;
General procedure: L-isomers of different amino acids were used for the synthesis and in 1H NMR spectra it was found that only one isomer was formed indicating that there is retention in configuration. The substituted aromatic or aliphatic sulfonylchlorides (1-13, 58, 59) (0.0143mol, 1 equivalent) were dissolved in the acetone (2ml). The mixture was added to water (2ml) containing glycine/phenylglycine/phenylalanine (0.0143mol, 1 equivalent) and sodiumbicarbonate (0.0429mol, 3 equivalent). The final reaction mixture was stirred at room temperature (rt) for 24h. The reaction was monitored by TLC using ethylacetate and methanol (8:2) as the mobile phase. The acetone was evaporated under reduced pressure and reaction mixture was neutralized with 1N HCl to get the product. The product was filtered and recrystallized with methanol to get the pure compound [34].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0℃;
General procedure: To 1 equiv of compound 1, was added 2.2 equiv of HOBt and2.2 equiv of EDCHCl. About 20 ml dichloromethane was addedand stirred. To this, was added triethylamine and 2.5 equiv of substitutedaniline derivative. The reaction was allowed to stir at 0 Covernight. The completion of the reaction was monitored by TLCand then worked up with DCM, dil. HCl and saturated sodiumbicarbonate solution. The compounds were finally purified by columnchromatography. Off-white solid, yield: 89%, mp 150-152 C IR (cm-1, KBr): 3363.86 (sec. N-H stretching), 3253.91 (sec. N-H stretching), 3100.5 (Aromatic C-H stretching), 2967 (Aliphatic C-H stretching), 1093.64 (S=O), 1H NMR (400 MHz, DMSO-d6, delta ppm): 2.34 (s, 3H, methyl), 3.62 (d, 2H, CH2), 6.90-7.75 (m, 9H, Ar-H), 7.80 (t, 1H, -NH), 9.78 (s, 1H, -NH); ESI-MS m/z: 305.16 [M+H]+, 327.10 [M+Na]+.
[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl}amine hydrochloride[ No CAS ]
[ 1080-44-0 ]
[ 558464-99-6 ]
Yield
Reaction Conditions
Operation in experiment
73%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;
Example 358: N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-(4-methylphenylsulfonylamino)acetamide triethylamine (45 1, 0.324 mmol), 4-dimethylaminopyridine (5 mg, 0.0449 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.108 mmol) and N-p-<strong>[1080-44-0]tosylglycine</strong> (25 mg, 0.108 mmol) were added to a solution of the 6-[(4-chlorophenylsulfonyl)(2,5-di fluorophenyl) methyl]pyridin-3-yl]methylamine hydrochloride (40 mg, 0.0898 mmol), which had been obtained in Example 354, in dichloromethane (6 ml).. The resulting mixture was stirred at room temperature for 16 hours.. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine.. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure.. The residue thus obtained was subjected to flash chromatography on a silica gel column.. A fraction obtained from the elution portion with hexane:ethyl acetate = 2.3 was concentrated under reduced pressure, whereby the title compound (41 mg, 0.0661 mmol, 73%) was obtained as a white powder.1H-NMR (400 MHz, CDCl3) delta: 2.44 (3H, s), 3.59 (2H, d, J = 6. 4 Hz), 4. 44 (2H, dd, J = 6.1, 2. 8 Hz), 5.42 (1H, t, J = 6.1 Hz), 5.95 (1H, s), 6.91 (1H, m), 6.96-7.03 (2H, m), 7.33 (2H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.66 (1H, dd, J = 8.1, 2.4 Hz), 7.74 (2H, d, J = 8.3 Hz), 8.01 (1H, m), 8.49 (1H, d, J = 2.4 Hz). mp: 217-218C. MS m/z: 620 (M++H).
73%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;
To a dichloromethane (6 ml) solution of the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine hydrochloride (40 mg, 0.0898 mmol) obtained in Example 66 were added triethylamine (45 mul, 0.324 mmol), 4-dimethylaminopyridine (5 mg, 0.0449 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.108 mmol) and N-p-<strong>[1080-44-0]tosylglycine</strong> (25 mg, 0.108 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloro-methane. The diluted mixture was then washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2.3 eluate was concentrated under reduced pressure to give the title compound (41 mg, 0.0661 mmol, 73%) as a white powder. 1H-NMR (400MHz, CDCl3) delta: 2.44(3H,s), 3.59(2H,d,J=6.4Hz), 4.44(2H,dd,J=6.1,2.8Hz), 5.42(1H,t, J=6.1Hz), 5.95 (1H, s), 6.91(1H,m), 6.96-7.03(2H,m), 7.33(2H,d,J=8.3Hz), 7.41(2H,d,J=8.6Hz), 7.57 (2H, d, J=8.6Hz), 7.58 (1H, d, J=8,1Hz), 7.66(1H,dd,J=8.1,2.4Hz), 7.74(2H,d,J=8.3Hz), 8.01(1H,m), 8.49(1H,d,J=2.4Hz). mp: 217 to 218C. MSm/z: 620(M++H).
General procedure: A mixture of methylamide 1b (2.3 g, 10 mmol)[30], hexamethyldisilazane (1.4 g, 9 mmol), chloro(chloromethyl)dimethylsilane (1.4 g, 10 mmol) and benzene (20 mL) was refluxed for 3 h, allowed to cool down, the precipitate formed filtered out, the volatiles removed in vacuo, and the residue dried in vacuo for 2 h at 100 C/20 mm Hg to afford 2.8 g (90%) of crude piperazinone 2b as a yellow oil. Found, %: C 49.23, H 6.61, N 9.91. C13H20N2O3SSi. Calculated, %: C 49.97, H 6.45, N 8.96. IR spectrum (KBr, nu, cm-1): 1648 s (NCO), 1596 w, 1496 m (Ar), 1336 s and 1164 s (SO2).
General procedure: General procedure: To a stirred solution of compound 1 (1.0 g, 6 mmol) in phosphorusoxychloride (15 mL), the desired 4-sulfonylaminoacetic acid derivative [(toluene-4-sulfonylamino)acetic acid (10a) or phenyl(toluene-4-sulfonylamino)acetic acid (10b)](6 mmol) was added in small portions. The reaction mixture was heated under reflux at85 C for 5 h (TLC). After cooling to room temperature, sodium hydroxide solution (1%,50 mL) was added and the resulting solid product was filtered, washed with water, dried,and finally recrystallized from MeOH to give 11a,b, respectively
2-chloro-5-(4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine[ No CAS ]
[ 1080-44-0 ]
2-(4-methylphenylsulfonylamino)-N-(2-chloro-5-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
General procedure: To a solution of arylsulfonylacetic acid, arylmethanesulfonylacetic acid, aroylmethanesulfonylacetic acid, arylaminosulfonylacetic acid (1 mmol) in dioxane (20 mL), compound 5 (1 mmol) and DMAP (0.1 mmol) in dioxane (2 mL) were added under nitrogen atmosphere and sonicated at RT. Then, DCC (1.4 mmol) in dioxane (10 mL) was added dropwise and the contents were again kept in sonication for another 3-5 hr. The separated precipitate, dicyclohexylurea was removed by filtration. The solution was evaporated to dryness and the residual solid was purified by column chromatography (silica gel, 60-120 mesh) using hexane-ethyl acetate (3:1) as eluent.
((3S,4R)-4-phenoxy-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol[ No CAS ]
[ 1080-44-0 ]
N-(2-((3S,4R)-4-(benzyloxy)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
General procedure: To a solution of compound 5 (1 eq) and acid (1.2 eq) in dichloromethane (3mL for 0.1g), were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI? HCl) (1.2 eq) and HOBT (1.2 eq) at 0C. The reaction mixture was stirred for 2h at the same temperature and progress of the reaction was monitored by TLC. After consumption of starting material 5, reaction mixture was diluted with dichloromethane (5mL) and washed with water (5mL) followed by brine (5mL). Organic layer was dried over anhydrous s sodium sulphate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography with gradient elution of ethyl acetate/petroleum ether to obtain the desired amode.
N-allyl-N-benzyl-2-(4-methylphenylsulfonylamino)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
General procedure: In a round bottom flask, 1.0 equiv. of the desired amino acid and 1.2 equiv. of allylbenzylamine were placed in DMF (C = 0,44 mol/L) under argon. Then 1.5 equiv. of HATU and 1.5 equiv. of HOAt were added. After 20 mn, 2.0 equiv. of DiPEA was added. The solution was stirred at room temperature until starting material was totally consumed(monitored by TLC). The reaction mixture was then quenched with water. The aqueous layer was extracted with DCM (3 times). The combined organic phases were then dried with MgSO4, filtrated and the solvent was removed under vacuum. The crude residue was purified by silica gel flash chromatography using cyclohexane/AcOEt as eluent (9:1 to 6:4).
N-(4-chlorophenyl)-2-((4-methylphenyl)sulfonamido)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0℃;
General procedure: To 1 equiv of compound 1, was added 2.2 equiv of HOBt and2.2 equiv of EDCHCl. About 20 ml dichloromethane was addedand stirred. To this, was added triethylamine and 2.5 equiv of substitutedaniline derivative. The reaction was allowed to stir at 0 Covernight. The completion of the reaction was monitored by TLCand then worked up with DCM, dil. HCl and saturated sodiumbicarbonate solution. The compounds were finally purified by columnchromatography.
N-(3-chlorophenyl)-2-(4-methylphenylsulfonamido)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0℃;
General procedure: To 1 equiv of compound 1, was added 2.2 equiv of HOBt and2.2 equiv of EDCHCl. About 20 ml dichloromethane was addedand stirred. To this, was added triethylamine and 2.5 equiv of substitutedaniline derivative. The reaction was allowed to stir at 0 Covernight. The completion of the reaction was monitored by TLCand then worked up with DCM, dil. HCl and saturated sodiumbicarbonate solution. The compounds were finally purified by columnchromatography.
N-(2,4-dimethylphenyl)-2-(4-methylphenylsulfonamido)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0℃;
General procedure: To 1 equiv of compound 1, was added 2.2 equiv of HOBt and2.2 equiv of EDCHCl. About 20 ml dichloromethane was addedand stirred. To this, was added triethylamine and 2.5 equiv of substitutedaniline derivative. The reaction was allowed to stir at 0 Covernight. The completion of the reaction was monitored by TLCand then worked up with DCM, dil. HCl and saturated sodiumbicarbonate solution. The compounds were finally purified by columnchromatography.
isopropyl 2-(1-bromoethyl)-4-phenoxybenzoate[ No CAS ]
[ 1080-44-0 ]
isopropyl 2-(1-(N-carboxylmethyl(toluene-4-sulfonyl)amino)ethyl)-4-phenoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
324 g
With sodium carbonate; potassium iodide; In 1-methyl-pyrrolidin-2-one; at 50℃; for 5h;
2L reaction flask,To a solution of isopropyl 2- (1-bromoethyl) -4-phenoxybenzoate (III, Example 8)P-toluenesulfonylglycine (190 g, 0.83 mol),Potassium iodide (13.8 g, 83 mmol),Sodium carbonate (131 g, 1.24 mol) and N-methylpyrrolidone (0.8 L)Heated to 50 C for 5 h.The reaction solution was cooled to room temperature,Water (1 L) / ethyl acetate (1.5 L) was added,The organic layer was washed with saturated brine (0.8 L)Dried over anhydrous sodium sulfate,filter,Concentrated in a pale yellow solid,The solid was recrystallized from ethanol (0.5 L)The target product V (324 g, 76% yield) was obtained.
{benzoyl[(4-methylphenyl)sulfonyl]amino}acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.49%
With sodium hydroxide; at 20℃;
General procedure: Appropriate benzenesulphonamides (3a-f, i-n and q-v, 1.0mmol) was dissolved in NaOH (10%, 10mL) in a 50mL round bottom flask. Benzoyl chloride (4, 1.1mmol, 0.2mL) was transferred into the solution of appropriate benzenesulphonamide and stirred at room temperature. The reaction progress was monitored by TLC (3% MeOH/DCM) to the disappearance of the benzenesulphonamide spot. Upon completion, the solution was transferred into a beaker containing crushed ice and then acidified to pH of 3 with concentrated hydrochloric acid. The solid was collected via suction filtration and transferred into a beaker containing CCl4 (10mL) and covered with watch glass boiled for 10min the mixture was allowed to cool slightly and then filtered. The products (5a-f, i-n and q-v) obtained were washed with 10-20mL of CCl4 and dried over fused self-indicating silica gel in a desiccator. 2.3.1 {Benzoyl[(4-methylphenyl)sulfonyl]amino}acetic acid (5a) Yield (0.3281g, 98.49%), mp, 104.60-104.90C, FTIR (KBr, cm-1): 3072 (C-H aromatic), 1729, 1687 (2C=O), 1601, 1583, 1453, 1423 (C=C), 1327, 1293 (2S=O), 1157, 1186 (SO2N), 1128, 1094, 1073, 1001 (C-N, C-O). 1H NMR (DMSO-d6) delta: 7.65-7.63 (d, J=8.6Hz, 2H, ArH), 7.57-7.43 (m, 5H, ArH), 7.34-7.33 (d, J=8.05Hz, 2H, ArH), 3.52-3.51 (d, J=5.7Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6) delta: 170.7, 167.8 (2C=O), 143.1, 138.4, 133.4, 131.3, 130.0, 129.8, 129.1, 127.1 (aromatic carbons), 44.3, 21.5 (aliphatic carbons). HRMS-ESI (m/z): 333.0679 (M+), calculated, 333.0671.
98.49%
With sodium hydroxide; at 20℃;
General procedure: Appropriate benzenesulphonamides (7a-f, i-n and q-v, 1.0 mmol) was dissolved in NaOH(10%, 10 mL) in a 50 mL round bottom flask and benzoyl chloride (8, 1.1 mmol, 0.2 mL) wasadded into the solution and stirred at room temperature. The reaction progress was monitoredby TLC (3% MeOH/DCM) to the disappearance of the benzenesulphonamide spot. Uponcompletion, the solution was transferred into a beaker containing crushed ice and then acidifiedto pH 3 with concentrated hydrochloric acid. The solid was collected via suction filtrationand transferred into a beaker containing CCl4 (10 mL) and covered with watch glass boiled for10 min. The mixture was allowed to cool slightly and then filtered. The products (9a-f, i-n andq-v) obtained were washed with 10±20 mL CCl4 and dried over fused self-indicating silica gelin a desiccator. {Benzoyl[(4-methylphenyl)sulfonyl]amino}acetic acid (9a). Yield (0.3281 g, 98.49%),appearance, white powder, mp, 104.60-104.80C, FTIR (KBr, cm-1): 3072 (C-H aromatic),1729, 1687 (2C = O), 1601, 1583, 1453, 1423 (C = C), 1327, 1293 (2S = O), 1157, 1186 (SO2N),1128, 1094, 1073, 1001 (C-N, C-O). 1H NMR (DMSO-d6, 500MHz) delta: 7.64 (d, J = 8.6 Hz, 2H,ArH), 7.50 (m, 5H, ArH), 7.33 (d, J = 8.05 Hz, 2H, ArH), 3.51 (d, J = 5.7 Hz, CH2), 2.34 (s, 3H,CH3). 13C NMR (DMSO-d6, 500MHz) delta: 170.8, 167.8 (2C = O), 143.1, 138.4, 133.4, 131.3,130.0, 129.8, 129.1, 127.1 (aromatic carbons), 44.3, 21.5 (aliphatic carbons). HRMS-ESI (m/z):333.0679 (M+), calculated, 333.0671.
With sodium hydroxide; at 20℃; for 2h;Inert atmosphere;
General procedure: Appropriate benzenesulphonamides (3a-f, and 3i-n, 1.0 mmol) was dissolvedin NaOH (10%, 10 mL) in a 50 mL round bottom flask. Benzoyl chloride (8, 1.1 mmol,0.2 mL) was transferred into the solution of appropriate benzenesulphonamide and stirred atroom temperature. The reaction progress was monitored by TLC (3% MeOH/CH2Cl2) to thedisappearance of the benzenesulphonamide spot. Upon completion, the solution was transferredinto a beaker containing crushed ice and then acidified to pH of 3 with concentratedhydrochloric acid. The solid was collected via suction filtration and transferred into a beakercontaining CCl4 (10 mL) and covered with watch glass boiled for 10 min. the mixture wasallowed to cool slightly and then filtered. The products (5a-f and 5i-n) obtained were washedwith 10±20 mL of CCl4 and dried over fused self-indicating silica gel in a dessicator.
N-(2-(4-bromophenyl)-2-(1H-indol-3-yl)ethyl)-2-((4-methylphenyl)sulfonylamino)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.9%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
Eggplant-shaped bottles,70.0 mg of compound B-2 (0.306 mmol)Compound A-11 (0.255 mmol) 80.0 mg,HOBT (0.51 mmol) of 68.9 mg,DMAP (0.051 mmol) of 6.2 mg,EDC (0.51 mmol) of 97.8 mg,Into argon, add anhydrous DMF, stirring at room temperature overnight.TLC (DCM: MeOH = 15: 1), extracted with ethyl acetate (30 mL x 3)Saturated brine and dried over anhydrous sodium sulfate.Concentrated, and column chromatographed (DCM: MeOH = 30: 1).To give product I-11 as 83.1 mg of a tan oil,Yield 73.9%.
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