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CAS No. : | 594-44-5 | MDL No. : | MFCD00007460 |
Formula : | C2H5ClO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FRYHCSODNHYDPU-UHFFFAOYSA-N |
M.W : | 128.58 | Pubchem ID : | 11667 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 25.49 |
TPSA : | 42.52 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.55 cm/s |
Log Po/w (iLOGP) : | 1.02 |
Log Po/w (XLOGP3) : | 0.75 |
Log Po/w (WLOGP) : | 1.66 |
Log Po/w (MLOGP) : | -0.08 |
Log Po/w (SILICOS-IT) : | 0.5 |
Consensus Log Po/w : | 0.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.04 |
Solubility : | 11.6 mg/ml ; 0.0904 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.22 |
Solubility : | 7.7 mg/ml ; 0.0599 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.17 |
Solubility : | 8.61 mg/ml ; 0.067 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.17 |
Signal Word: | Danger | Class: | 6.1,8 |
Precautionary Statements: | P260-P280-P284-P302+P350-P305+P351+P338-P310 | UN#: | 2927 |
Hazard Statements: | H302-H310-H314-H330 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.96 g | With sodium hydrogencarbonate; sodium sulfite In water for 4.2 h; Inert atmosphere | To a 4-neck flask, sodium sulfite (53.9 g), sodium hydrogen carbonate (65.34 g), and water (325 ml) were added at room temperature under nitrogen atmosphere. After the mixture was stirred at 80° C. for 1 .3 hours, ethanesulfonyl chloride (50.0 g) was add thereto, and the mixture was then stirred for an additional 4.2 hours. The reaction mixture was concentrated, and to the resulting residue was added ethanol, and the mixture was thrther concentrated. To the resulting residue was added toluene, and the mixture was concentrated and the resulting solid was dried, and then thereto was added ethanol (100 ml), and the mixture was heated under reflux. The resulting mixture was filtered and washed with ethanol. The filtrate and wash solution were combined and concentrated to give 38.96 g of sodium ethanesulfinate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.59% | Stage #1: With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 10℃; for 0.166667 h; Stage #2: at 0 - 25℃; for 16 h; |
N,N-Diisopropylethylamine (4.5 mL) was added into a reaction vessel containing acetonitrile (50 mL) and 3-(cyanomethylene)azetidine hydrochloride (1.5 g; Formula VII) at about 0°C to about 10°C. The reaction mixture was stirred for about 10 minutes. Ethanesulfonyl chloride (2.22 g) was added into the reaction mixture at about 0°C to about 5°C over about 5 minutes. The temperature of the reaction mixture was raised to about 20°C to about 25 °C, and then the reaction mixture was stirred for about 16 hours. On completion of the reaction, acetonitrile was recovered from the reaction mixture under reduced pressure at about 40°C to about 45°C to obtain an oily residue. Dichloromethane (50 mL) was added into the residue. The contents were washed with a saturated sodium chloride solution (30 mL), followed by complete recovery of dichloromethane under reduced pressure at about 40°C to obtain 2-(l-(ethylsulfonyl)azetidin-3- ylidene)acetonitrile . Yield: 98.59percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | at 0 - 25℃; for 16 h; Inert atmosphere | To a solution of 2-(azetine-3-yl) methyl cyanide(2.8 g, 21.4 mmol) and DIPEA(8.3 g, 64.3 mmol) in dichloromethane(30 mL) was added dropwise ethanesulfonyl chloride(4.1 g, 32.1 mmol) at 0°C under the protection of nitrogen, and the temperature was kept below 2°C when dropping. The reaction mixture was stirred at 25°C for reacting for 16 hours. TLC showed that the reaction was completed (petroleum ether/ethyl acetate =1:1). After the reaction mixture was quenched with water, extracted with dichloromethane (30 mL*2). The combined organic phase was washed with saturated salt water(20 mL*2), dried with anhydrous sodium sulfate, filtered, and spun dry. The residue was purified through column chromatography (dichloromethane/ethyl acetate =3/1) to give 2-(1-(ethylsulfonyl)azetine-3-yl)methyl cyanide(1.4 g, 33.0percent yield) as a pale yellow solid. 1H NMR (400MHz, CDCl3) δ = 5.50 - 5.41 (m, 1H), 4.79 (d, J=3.0 Hz, 2H), 4.71 (d, J=2.5 Hz, 2H), 3.06 (q, J=7.4 Hz, 2H), 1.40 (t, J=7.4 Hz, 3H). MS (ESI) Calcd. for C7H10N2O2S [M + H]+ 187, Found 187. |
192 mg | With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; | Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2) (250 mg, 1.29mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 5 h. Then the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product 3, was then suspended ina cetonitrile (20 mL) and cooled to 0 °C. N,N-Diisopropylethylamine (DIPEA) (1.12 mL, 6.44 mmol, 5 equiv.) was then slowly added while keeping the internal temperature below 5 °C. Then ethanesulfonyl chloride (EtSO2Cl) (0.184 mL, 1.94 mmol, 1.5 equiv.) was added over 1 h while keeping the internal temperature below 5 °C. The resulting reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The concentrated residue was then diluted with dichloromethane and was washed with aqueous sodium chloride solution. The aqueous phase was back-extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and the residue was purified using a silica gel column to afford compound 4: Yield 192 mg (81percent); off-white solid; m.p. 58–60 °C; IR: 3294, 3066, 2978, 2222, 1702, 1321, 1142 cm–1. Anal. calcd for C7H10N2O2S: C, 45.15; H, 5.41; N, 15.04; found: C, 45.32; H, 5.35; N, 15.21percent. MS (m/z): 209 [M + Na]+; 1H NMR (300 MHz, CDCl3): δ 1.37 (m, J = 6.7 Hz, 3H), 3.04 (m, J = 7.4 Hz, 2H), 4.69 (t, J = 2.5 Hz, 2H), 4.77 (t, J = 2.8 Hz, 2H), 5.43 (t, J = 2.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): δ 7.2, 42.6, 58.5, 58.9, 93.9, 114.9, 156.2, 168.6. |
0.192 g | With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 5℃; | Compound 2 (0.250g, 1.29mmol) dissolved in acetonitrile was slowly added dropwise trifluoroacetic acid (3ml).Stirred at room temperature for 4 hours gussets tracking.After completion of the reaction, the solvent spin dry, obtained was dissolved in acetonitrile and cooled to 0 deg.] C, was slowly added N, N- diisopropylethylamine (DIEA), maintaining the temperature not higher than 5 .Was slowly added compound 8 (0.184ml, 1.94mmol, 1.5equiv), at T Completion of the reaction followed by TLC, concentrated under reduced pressure, the crude product was diluted with dichloromethane, washed with brine, the aqueous phase was extracted with dichloromethane, the organic phase was concentrated, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.192g white solid with a yield of 81percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With hydrogenchloride; sodium chlorite; In acetonitrile; at 10 - 20℃; for 0.5h;Green chemistry; | General procedure: A 50 mL three-necked flask equipped with a thermometer and an addition funnel wasimmersed in an ice-bath. To the flask was sequentially added NaClO2 solid (1.61 g,15 mmol, 85% purity), MeCN (10 mL), and then conc. HCl (3 mL) at such a rate thatthe inner temperature was maintained less than 10 C. Then a solution of a thiol (5mmol) in 3 mL of MeCN was slowly added through the addition funnel to keep theinner temperature less than 20 C. For a disulfide, NaClO2 solid (3.22 g, 30 mmol,85% purity), MeCN (20 mL), and conc. HCl (6 mL) were used. The same workup asdescribed above afforded the sulfonyl chlorides in high purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; at 20℃; for 3h; | Compound VIII (160 g, 1.013 mol) was added to a three-necked flask, and then triethylamine (2.5 L) was added thereto, stirring was started, and ethylsulfonyl chloride (141.9, 1.1 mol) was added dropwise at room temperature, and the addition was continued, and stirring was continued at room temperature. After 3 hours, TLC dot plate (iodine color development) was used to monitor the disappearance of the spot of the raw material, and the mixture was diluted with hydrochloric acid and ethyl acetate, and the mixture was separated, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.The white solid compound VII 227.85 g was obtained in a yield of 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.4% | Triethylamine (1.946 mL, 13.959 mmol) was added to solution of aniline (0.980 mL, 10.738 mmol) in dichloromethane (12 mL) prepared at 0 C, and the mixture was stilTed for 20 mm at the same temperature. The reaction mixture was treated with ethanesulfonyl chloride (1.119 mL, 11.8 11 mmol and stilTed for additional 24 hr at the room temperature. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (5i02, 40 g cartridge; ethyl acetate / hexane = 0 % to 15 %) to give N-phenylethanesulfonamide as yellow oil(1.400 g, 70.4 %). | |
With sodium carbonate; In water; at 20℃; for 1.5h; | General procedure: To an aqueous solution (6 ml/mmol) of primary amine (1 eq) and Na2CO3 (2.0 eq), the sulfonyl chloride (1.5 eq) is added, and the resulting mixture is stirred at r.t. for over 1.5 h. The reaction is monitored by TLC, and after its completion, the mixture is filtered and the solid is dried under vacuum. The crude material is pure enough for its use in further syntheses. | |
With pyridine; In dichloromethane; at 20℃; | General procedure: 1.607g was added to a 100mL round bottom flask with a magnetic stir bar.15.0 mmol of toluidine, 50.0 mL of CH 2 Cl 2 and 4.170 mL, 30.0 mmol of Et 3 N,Finally, 1.273 mL, 18.0 mmol of acetyl chloride was added, and the reaction mixture was stirred at room temperature with a magnetic stirrer;TLC showed that after the consumption of p-toluidine was completed, the reaction was quenched with 100 mL of saturated NaHCO3 solution.It was then extracted 3 times with 100.0 mL of CH 2 Cl 2 and the combined organic phases were washed twice with 50 mL of brine.The solid obtained by distilling off the organic solvent was washed with a 5:1 mixture of petroleum ether/ethyl acetate to give a white solid p-methylacetanilide; |
In pyridine; at 0 - 20℃; | General procedure: To a stirred solution of the corresponding aniline (10 mmol, 1.0 equiv) in pyridine (20 mL) at 0 C, the corresponding sulfonyl chloride (11 mmol, 1.1 equiv) was added slowly. The reaction mixture was allowed to warm to ambient temperature, and was stirred overnight and monitored by TLC. When the aniline was completely consumed, the pyridine was evaporated under reduced pressure. The residue was quenched with EtOAc (10 mL) and 1 N HCl (10 mL), then the mixture was extracted with EtOAc (3 × 20 mL) and saturated NaHCO3 (3 × 10 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 10:1-4:1) to give the corresponding N-protected aniline. To a solution of the N-protected aniline (2 mmol, 1.0 equiv) in distilled MeOH (20 mL) was added phenyliodine diacetate (PIDA) (2.4 mmol, 1.2 equiv) under nitrogen atmosphere, and the mixture was stirred at room temperature and monitored by TLC. When the N-protected aniline was completely consumed, the reaction was quenched with saturated NaHCO3 (20 mL) and then the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried with anhydrous Na2SO4, then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 15:1-6:1) to give the corresponding quinone imine ketal 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Step 1: Ethylsulphonamide : The title compound was prepared using the same procedure as described in Example 12, Step 1, replacing isopropylsulphonyl chloride with ethylsulphonyl chloride. The compound was purified by trituration with hexane to give the product (6.17g, 73%) as a colourless solid. mp 53-56C. 1H NMR (360MHz, D6-DMSO) delta 1.22 (3H, t, J = 7.4Hz), 2.95 (2H, q, J = 7.4Hz), 6.69 (2H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium fluoride; In water; at 0 - 50℃; for 8h; | In a 500 ml volume glass reactor equipped with a stirring bar and a cooling condenser, 68 parts of potassium fluoride and 173 parts of water were placed, and potassium fluoride was dissolved by stirring. In the condenser, a cooling medium at 0 C. was circulated. Then, in the reactor, 128 parts of ethanesulfonyl chloride was added, and after the completion of the addition, the mixture was stirred at a temperature of 50 C. for 8 hours. The reactor was cooled to room temperature, then 100 g of water was added to the reaction solution, and thus the salt (potassium chloride) precipitated in the reaction was dissolved. The contents in the reactor were transferred into a separating funnel, and allowed to stand still; then the organic layer, the lower layer, was separated. To the obtained organic layer, anhydrous magnesium sulfate was added, and the organic layer was dried. After magnesium sulfate was separated by filtration, the filtrate was distilled under reduced pressure (5 kPa, 54 to 55 C.), and thus 105 parts (yield: 94%) of ethanesulfonyl fluoride, the target product, was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 100 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide Ethanesulfonyl chloride was reduced to sodium ethanesulfinate according to the procedure in J. Med. Chem. 1989, vol. 32, no. 11, p2436. Briefly, 2.5 ml of ethanesulfonyl chloride was added dropwise to a solution of 3.67 g of sodium carbonate and 5.51 g of sodium sulfate in 13 mL of water. After completion of the reaction the water was evaporated and the solids were suspended in ethanol and heated to 80 C for 1 h prior to filtering the solids. The filtrate was then evaporated to give 2.5 grams of the sodium ethanesulfinate. | ||
With sodium carbonate; sodium sulfate; In water; | Ethanesulfonyl chloride was reduced to sodium ethanesulfinate according to the procedure in J. Med. Chem. 1989, vol. 32, no. 11, p 2436. Briefly, 2.5 ml of ethanesulfonyl chloride was added dropwise to a solution of 3.67 g of sodium carbonate and 5.51 g of sodium sulfate in 13 mL of water. After completion of the reaction the water was evaporated and the solids were suspended in ethanol and heated to 80 C. for 1 h prior to filtering the solids. The filtrate was then evaporated to give 2.5 grams of the sodium ethanesulfinate. 293 mg of the sodium ethansulfinate was combined with 230 mg of methyl (4-bromoethyl)benzoate in 2 mL of DMF and heated to 120 C for 5 min in a microwave reactor. The reaction was then extracted with Ethyl Acetate and Brine to give 250 mg of methyl 4-(ethylsulfonylmethyl)benzoate after evaporation of the organic layer. 200 mg of methyl 4-(ethylsulfonylmethyl)benzoate was hydrolyzed via Procedure M to give 119 mg of 4-(ethylsulfonylmethyl)benzoic acid. | |
With sodium thiophenolate; In acetone; for 1h;Heating / reflux; | Sodium benzenethiolate (2.1 g, 15.6 mmol) was dissolved in acetone (50 ml) and ethanesulfonyl chloride (1.0 g, 7.8 mmol) added. The reaction mixture was refluxed for 1 h. Chloroform (200 ml) was added and the resultant mixture washed with water (100 ml). The aqueous layer was concentrated and dried in vacuuo for 8 h, producing a mixture (1.12 g) of sodium ethanesulfinate and sodium chloride. The product had 1H n.m.r. (270 MHz, D2O+DSS) delta1.08, t, 3H; 2.33, q, 2H. 13C n.m.r. delta7.90, 56.44. |
With sodium hydrogencarbonate; sodium sulfite; In water; at 70 - 80℃; for 4h; | General procedure: 4-Methoxybenzenesulfinic acid sodium salt (1j) was prepared by heating 2.5 g of sodium sulfite, 2.06 g of 4-methoxybenzenesulphonyl chloride, and 1.68 g of sodium bicarbonate in 9.6 mL of water at 70-80 C for 4 h. After cooling to room temperature, water was removed under vacuum and the residue was extracted by ethanol, recrystallization as a white solid, the yield was 67% (1.34 g). Similarly, other sodium arenesulfinates were prepared from their corresponding sulphonyl chlorides. | |
38.96 g | With sodium hydrogencarbonate; sodium sulfite; In water; for 4.2h;Inert atmosphere; | To a 4-neck flask, sodium sulfite (53.9 g), sodium hydrogen carbonate (65.34 g), and water (325 ml) were added at room temperature under nitrogen atmosphere. After the mixture was stirred at 80 C. for 1 .3 hours, ethanesulfonyl chloride (50.0 g) was add thereto, and the mixture was then stirred for an additional 4.2 hours. The reaction mixture was concentrated, and to the resulting residue was added ethanol, and the mixture was thrther concentrated. To the resulting residue was added toluene, and the mixture was concentrated and the resulting solid was dried, and then thereto was added ethanol (100 ml), and the mixture was heated under reflux. The resulting mixture was filtered and washed with ethanol. The filtrate and wash solution were combined and concentrated to give 38.96 g of sodium ethanesulfinate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.01% | With N-ethyl-N,N-diisopropylamine; In toluene; at 0 - 10℃; for 24h; | To a four-necked flask was added 2-hydroxypropanenitrile (71.08 g, 1 mol)Diisopropylethylamine (258.48 g, 2 mol) and 100 mL of toluene,Cooling to 0 ~ 10 C,<strong>[594-44-5]Ethylsulfonyl chloride</strong> (192.87 g, 1.5 mol) was slowly added dropwise and reacted at 0 to 10 C for 24 h.After filtration and desalting, the reaction solution was washed with 80 mL of saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed by vacuum to give 2 - cyanoethylsulfonate 15 6.6 8 g, melting point 3 8 ~ 40 C, yield 96.01%/ H NMR (300 MHz, CDCI3): 1.43 (t, / 7.5 Hz, 3H, CH3), 1.72 (d,Hz, 3 Hz, CH3), 3.25 (q, J = 7.5 Hz, 2 Hz, CH2), 5.24 (q, J = 6.5 Hz, 1 Hz, CH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 0.5h; | Preparation 1 (207.7mg ; 1. 14mmol) was suspended in DCM (5mL), and Et3N (0.34mL ; 2. [4MMOL)] was added while stirring. The mixture was cooled to [0C,] and [ETHANESULFONYL] chloride (255.0 mg; 1.98 [MMOL)] was added. The mixture was stirred for another 30 min. at [0C.] The reaction mixture was evaporated to dryness and the solid was dissolved in DCM (3mL) and flash chromatographed with the eluent hexan/EtOAc (1: 2) to give the title compound; mp: [72-73C.] [[A] D (C] = 9.89mg ; lOmL DCM) [=-25.] [28. 1H] NMR [(CI3)] 8 : 5.37, 5.29, 4.43, 4.36, 4.20, 3.22, 2.73, 2.29, 1.41. [13C] NMR 8 : 174.9, 65.6, 52.0, 48.7, 30.7, 8.1. IR [(KBR)] : 3302,1794, 1341,1132 [CM-1.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; for 0.25h; | 4-Bromo-alpha-methylbenzylamine (8.15 g, 40.73 mmol) and (4.15 g, 41.00 mmol) triethylamine dissolved in 150 ml dichloromethane was treated slowly with ethanesulfonyl chloride (5.27 g, 41.00 mmol) and stirred for 15 minutes. The reaction mixture was extracted with 50 ml 1N HCl/15 ml brine. The organic layer was separated, dried sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 7.52 (d,2H,J=12 Hz), 7.25 (d,2H,J=12 Hz), 4.77 (m,1H), 4.63 (m,1H), 2.77 (m,2H), 1.56 (d,3H,J=8 Hz), 1.27 (t,3H,J=8 Hz). MS calcd. 292.2; MS (M+-1) 291.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In dichloromethane; at 20℃; for 3h; | [00323] Ethanesulfonic acid {1-[2-(2-HYDROXYPHENYL)-7-METHYLQUINAZOLIN-4-YL]- PIPERIDIN-4-YL}-AMIDE. To a stirring solution of 2- [4- (4-Aminopiperidin-1-yl)-7- methylquinazolin-2-yl]-phenol (30 mg, 0.09 MMOL), ET3N (25 RL, 0.18 mmol), and CH2C12 (500 JJ, L) under N2, was added ethanesulfonyl chloride (10 USD, 0.09 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was purified via HPLC to obtain the desired sulfonamide as a TFA salt (33 mg, 0.06 mmol, 68% yield). LC/MS (10-99%) M/Z 427.3 retention time 2. 80 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; at 0℃; for 0.25h; | 3-(2-Hydroxy-5-methylphenyl)-3-phenylpropanol (4.84 g, 20 mmol) is suspended in 20 ml of dichloromethane. Triethylamine (7.0 ml, 50 mmol) is added and the resulting clear solution is cooled to 0 0C. After the slow addition of ethanesulfonyl chloride (4.2 ml, 44 mmol) the mixture is stirred for 15 minutes at 0 0C. tert-Butyl methyl ether (MTBE, 100 ml) is added. The mixture is washed with 1 mol/l solution of hydrochloric acid (2 x 50 ml), 5 percent solution of sodium hydrogen carbonate (50 EPO <DP n="21"/>ml) and brine (50 ml). The organic phase is dried over anhydrous magnesium sulfate, filtrated and evaporated in vacuo to give the product as a brown oil in quantitative yield (8.5 g).1H NMR (300 MHz, CDCI3): delta [ppm] = 1.37 (3H, t, J = 7.5 Hz, CH2CH3), 1.53 (3H, t, J = 7.5 Hz, CH2CH3), 2.32 (3H1 s, CH3), 2.43 - 2.53 (2H, m, CH2), 3.07 (2H, q, J = 7.5 Hz, CH2CH3), 3.28 (2H, dq, J = 7.5, 1.4 Hz, CH2CH3), 4.22 - 4.37 (2H, m, CH2), 4.60 (1 H, t, J = 7.9 Hz1 CH), 7.02 - 7.07 (1 H, m, 1 H-Ar), 7.09 - 7.13 (1 H, m, 1 H-Ar), 7.19 - 7.35 (6H, m, 1 H-Ar, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of <strong>[24673-56-1]3-Methyl-benzofuran-2-carboxylic acid</strong> [(S)-1-(1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide Following the general procedure of Examples 280h-j except substituting <strong>[24673-56-1]3-methyl-benzofuran-2-carboxylic acid</strong> for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 491.2 (M+H)+and diastereomer 2 MS(ES) 491.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of 5-Methoxy-benzofuran-2-carboxylic acid [(S)-1-(1-ethanesulfonyl-3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide Following the general procedure of Examples 280h-j except substituting <strong>[10242-08-7]5-methoxy-benzofuran-2-carboxylic acid</strong> for benzofuran-2-carboxylic acid and ethanesulfonyl chloride for 3-flurobenzenesulfonyl chloride provided the title compound as a mixture of diastereomers. Separation of the diastereomers by HPLC provided diastereomer 1: MS(ES) 507.4 (M+H)+and diastereomer 2 MS(ES) 507.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With pyridine; In methanol; hexane; dichloromethane; | Reference Example 6 N-[4-(1-t-Butoxycarbonylpiperidin-4-yloxy)phenyl]ethanesulfonamide To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)aniline (10.6 g) and pyridine (8 ml) in dichloromethane (75 ml) was added dropwise ethanesulfonyl chloride (4.1 ml) in an ice bath and the mixture was stirred at room temperature for 5 hours. After addition of methanol (1 ml), the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (11.7 g, yield 84%) as a pale pink solid. 1H NMR (400 MHz, CDCl3) delta ppm: 1.38 (3H, t, J=8.0), 1.47 (9H, s), 1.74 (2H, m), 1.90 (2H, m), 3.07 (2H, q, J=8.0), 3.34 (2H, m), 3.69 (2H, m), 4.42 (1H, m), 6.88 (2H, d, J=9.0), 7.17 (2H, d, J=9.0). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; | Example 134 3-Ethanesulfonylamino-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 121 using ethanesulfonyl chloride (1.5 mL, 15.8 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g. 10 mmol) and pyridine (25 mL) to afford the product (3.023 g); m.p. 175-177 C. after trituration in hexanes/ethyl acetate (1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -5℃; for 0.5h; | A) Ethanesulfonic acid butyl ester. n-Butanol (1.82 g, 2.24 mL, 24.5 mmol) was dissolved in 30 mL anhydrous methylene 15 chloride and diisopropylethylamine (5.28 g, 7.11 mL, 40.8 mmol) was added. The solution was cooled to -5 0C. Ethenesulfonyl chloride was added dropwise and the reaction was stirred for 0.5 hours. The mixture was washed with ice-cold water, cold 10 % hydrochloric acid, followed by cold water and then cold sodium bicarbonate solution and finally with cold brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent 20 was removed by evaporation. 4.05 g (99 %) slightly brownish liquid was extracted. The sub-title product was used for the next step without further purification.1H NMR (400 MHz, chloroform-d as solvent and internal reference) delta (ppm) 4.20 (t, 2H, J = 6.6), 3.09 (q, 2H, J= 7.5), 1.70 (m, 2H), 1.41 (m, 2H), 1.39 (t, 3H, J= 7.4), 0.95 (t, 3H, J = 7.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 5 - 20℃; for 4h; | Reference Example 20Preparation of 4-(4-ethanesulfonyl-piperazin-l-yl)-rhohenylamine.Reference Example 2OA: 4-(4-Nitrophenyl)-l-ethylsulfonylpiperazine. l-(4-Nitrophenyl) piperazine (100 g, 0.48 mol) was dissolved in dicfiloromethane (500 ml). Triethylamine (1.02 eq., 68 mL, 0.49 mol) was added and the reaction was cooled to 5 C.<strong>[594-44-5]Ethanesulfonyl chloride</strong> (1.02 eq, 46.5 mL, 0.49 mol) was added dropwise over 1 hour keeping the temperature under 20 C. Allow reaction to stir and warm to room temperature over 3 hours. The solution was poured into saturated sodium bicarbonate and then extracted (3X) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4- nitrophenyl)-l-ethanesulfonylpiperazine as a yellow solid (143 g, quantitative yield).GC/MS: (EI, M+) m/z = 300. |
100% | With triethylamine; In dichloromethane; at 5 - 20℃; for 4h; | Reference Example 20; Preparation of 4-(4-ethanesulfonyl~piperazin-l -yl)-phenylamine Reference Example 2OA: 4-(4-Nitrophenyl)- 1 -ethylsulfonylpiperazine. l-(4-Nitrophenyl) piperazine (100 g, 0.48 mol) was dissolved in dichloromethane (500 mL). Triethylamine (1.02 eq., 68 mL, 0.49 mol) was added and the reaction was cooled to 5 0C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (1.02 eq, 46.5 mL, 0.49 mol) was added dropwise over 1 hour keeping the temperature under 20 C. Allow reaction to stir and warm to room temperature over 3 hours. The solution was poured into saturated sodium bicarbonate and then extracted (3X) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4- nitrophenyl)-l-ethanesulfonylpiperazine as a yellow solid (143 g, quantitative yield). GCMS: (EI, M+) m/z = 300. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a dry round bottom flask was placed <strong>[240401-22-3]4-cyanopiperidinium chloride</strong> (13, 5g, 45.4 mmol) dichloromethane (150ml) and triethylamine (18.98ml, 136 mmol). To the reaction was added dropwise ethanesulfonyl chloride (4.56 ml, 45.4 mmol) and the solution stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3x 50 ml) and the combined organic <n="55"/>fractions dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1- (ethylsulfonyl)pirhoeridine-4-carbonitrile (14) as a white solid. MS 203 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 0 - 20℃; for 27h; | (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine(0.9OmM), prepared via General Procedure B-4, was dissolved in 20 mL of dichloromethane and cooled to 0 0C under N2 and 1.3 eq. triethylamine and 1.2 eq. of ethanesulfonyl chloride were added. The reaction mixture was allowed to warm up to room temperature and stirred27 hours at which time complete product formation was confirmed by LCMS. The reaction was diluted with 1 M HCl, extracted with dichloromethane, dried over MgSO4, and concentrated in vacuo. This crude product was very clean by LCMS and therefore not futher purified giving 0.35 g (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-(N- ethylsulfonyl,N-methyl)methanamine (100% yield). MS (Ql) 392 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 90% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | 4-Amino-1-butanol (commercially available, for example, from Aldrich) (0.5 ml, 5.4 mmol) was dissolved in dichloromethane (25 ml) together with triethylamine (4.5 ml, 32 mmol), and the stirred solution was cooled in an external ice-water bath under a nitrogen atmosphere. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (commercially available, for example, from Fluka) (1.5 ml, 16 mmol), dissolved in dichloromethane (15 ml), was added dropwise, using further dichloromethane (10 ml) to wash in. The reaction mixture was stirred under nitrogen and allowed to warm gradually to room temperature over three hours. The mixture was diluted with further dichloromethane (50 ml) and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with further dichloromethane (x 2). The combined organic solutions were dried (magnesium sulfate) and concentrated in vacuo to give the crude product (1.70 g). A portion of the crude material was purified by chromatography. The <n="56"/>brown oil (792 mg) was applied to a silica cartridge (50 g, Flashmaster 2), eluting with 0- 100% ethyl acetate-dichloromethane over 40 min to give the pure title compound as a colourless gum (621 mg, ca. 90%): LCMS RT = 2.15 min, ES+ve m/z 291 (M+NH4)+. |
With triethylamine; In dichloromethane; at 5 - 20℃; | 4-[(Ethylsulfonyl)amino]butyl ethanesulfonate 4-Amino-1-butanol (commercially available, for example, from Aldrich) (0.97 g, 11 mmol) was dissolved in DCM (50 ml) together with triethylamine (9.0 ml, 65 mmol), and the stirred solution was cooled to approximately 5 C. in an external ice-water bath under a nitrogen atmosphere. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (commercially available, for example, from Aldrich) (4.09 g, 31.8 mmol), dissolved in DCM (30 ml), was added dropwise, using further DCM (20 ml) to wash in. The reaction mixture was stirred under nitrogen and allowed to warm gradually to room temperature over 4 h. The mixture was diluted with further DCM (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (100 ml). The aqueous layer was extracted with further DCM (100 ml,*2). The combined organic solutions were dried (MgSO4) and concentrated in vacuo to give the crude product, which was used without further purification in the reaction below (3.11 g): LCMS RT=2.06 min, ES+ve m/z 274 (M+H)+, 291 (M+NH4)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.6 g | With pyridine; In dichloromethane; at 0 - 20℃; for 3.0h; | Methyl 4-aminobenzoate (2.0 g, 13.2 mmol, 1.0 eq) was dissolved in DCM (15 ml), stirred and pyridine (2.1 g, 26.4 mmol, 2.0 eq) was added to the reaction mixture. The reactionmixture was cooled to 0-5 C with ice bath. Then ethanesulfonyl chloride (2.0 eq, 15.8 mmol,1.2 eq) was added dropwise to the reaction mixture, and the temperature of the reaction was kept no more than 10 C. The reaction was warmed to room temperate and kept for 3 hours. The reaction mixture was poured into water, some solids appeared. The solids were collected by filtration and the collected solids were washed with water (20 mlx2) to give the product wet(4.6g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.59% | N,N-Diisopropylethylamine (4.5 mL) was added into a reaction vessel containing acetonitrile (50 mL) and <strong>[1314910-43-4]3-(cyanomethylene)azetidine hydrochloride</strong> (1.5 g; Formula VII) at about 0C to about 10C. The reaction mixture was stirred for about 10 minutes. Ethanesulfonyl chloride (2.22 g) was added into the reaction mixture at about 0C to about 5C over about 5 minutes. The temperature of the reaction mixture was raised to about 20C to about 25 C, and then the reaction mixture was stirred for about 16 hours. On completion of the reaction, acetonitrile was recovered from the reaction mixture under reduced pressure at about 40C to about 45C to obtain an oily residue. Dichloromethane (50 mL) was added into the residue. The contents were washed with a saturated sodium chloride solution (30 mL), followed by complete recovery of dichloromethane under reduced pressure at about 40C to obtain 2-(l-(ethylsulfonyl)azetidin-3- ylidene)acetonitrile . Yield: 98.59% | |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃;Product distribution / selectivity; | A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5 C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5 C. The resulting homogeneous solution was allowed to cool down to 0 C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5 C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45 C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45 C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60 % ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) delta 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H). | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; for 7h; | Intermediate No.33Step A-B. ll-(Ethylsulfonv0azetidin-3-ylidenelacetonitriletert-Butyl 3-(cyanomethylidene)azetidine-l-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HC1 in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to -10 C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrousNa2S04, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtO Ac/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C7H10N2O2S [M+H]+: 187, Found: 187. |
Dissolving raw material CF0726Y (0.4 g, 0.0021 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spinning solvent dry after raw material disappears, adding THF (10 mE) to dissolve it, then dropwise adding DIPEA (0.8 g, 6.18 mmol, 3 eq), stirring for 10 mi dropwise adding ethylsulfonyl chloride (0.32 g, 0.0025 mol, 1.2 eq), performing room-temperature stirring and ECMS tracking, spinning it dry after the reaction, using EAH20 for extraction, washing it once with NaHCO3 and washing with saturated saline solution, spuming it dry to obtain 0.3 g of yellow oily crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 82 g, 0.42 mol) was added to THF (850 mL) and the resulting solution was cooled to 0 C. before a 4 M HCl solution in 1,4-dioxane (850 mL, 3.38 mol, 8.0 equiv) was added over 1 h while keeping the temperature<5 C. The resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was placed under high vacuum for an additional 3 h before being treated with THF (900 mL) and diisopropylethyl amine (183 mL, 1.06 mol, 2.5 equiv) at room temperature. The resulting solution was then cooled to 0 C. and ethanesulfonyl chloride (56 mL, 0.59 mol, 1.4 equiv) was added while keeping the reaction temperature<5 C. The ice bath was removed and the reaction was stirred at room temperature for 18 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with ethyl acetate (1 L) and washed with saturated brine (1 L). The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was diluted with dichloromethane and absorbed onto silica gel (150 g). This mixture was purified by column chromatography (1.5 Kg silica gel) eluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8L), 30% EtOAc in heptane (12 L), and finally with 40% EtOAc in heptane (12 L) to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4) and 2-(3-chloro-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (4B) as a off-white solid (58.1 g, 68% yield), which was found to be an approximately one to one mixture of compound 4 and 4B. For 4: 1H NMR (300 MHz, CDCl3) delta 1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05; found: 187.1. For 4B: 1H NMR (300 MHz, CDCl3) delta 1.38 (t, 3H), 3.05 (q, 2H), 3.1 (s, 2H), 4.15 (d, 2H), 4.37 (d, 2H); MS: m/z calcd. 222.9; found: 222.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In toluene; at 5 - 25℃; for 2.16667h; | [Synthesis Example 7] Synthesis of 3,5-di-tert-butylphenyl Ethanesulfonate (Compound 7) 2.50 g (0.012 mol) of 3, 5-di-tert-butylphenol and 1.27 g (0.013 mol) of triethylamine were dissolved in 15 ml of toluene followed by dropping in 1.62 g (0.013 mol) of ethanesulfonyl chloride over the course of 10 minutes at 5C. Following completion of dropping, the mixture was stirred for 2 hours at 25C and the 3, 5-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in ice water and following separation of the organic layer, was washed twice with saturated brine followed by drying with MgSO4 and concentrating to obtain 3.27 g (yield: 91%) of 3,5-di-tert-butylphenyl ethanesulfonate. A purified product crystallized with n-hexane (white crystals, melting point: 52C) was used in a battery test. The resulting 3,5-di-tert-butylphenyl ethanesulfonate was analyzed by 1H-NMR, IR and mass spectrometry to confirm the structure thereof. The results are indicated below. (1) 1H-NMR (300 MHz, CDCl3): delta = 7.35 (t, J=1.7 Hz, 1H), 7.08 (d, J=1.7 Hz, 2H), 3.27 (q, J=7.6 Hz, 2H), 1.54 (t, J=7.6 Hz, 3H), 1.32 (s,18H) (2) IR (KBr method) : 2967, 1609, 1584, 1344, 1296, 1182, 1161, 946, 933, 872, 827, 793, 768, 708 cm-1 (3) Mass spectrometry: MS (EI) m/z (%) = 298 (14) [M+] : 283(100), 147(8), 57 (46) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; at -40 - 20℃; for 14h; | Commercial 1-Boc-piperazine (Compound 5) (3.0 g, 16.11 mmol) was dissolved in methylene chloride (30 mL), then to the reaction mixture, which was stirred at -40 C, were added triethylamine (5.61 mL, 40.28 mmol) and ethane sulfonyl chloride (1.83 mL, 19.33 mmol). The whole mixture was warmed up gradually and stirred for 14 hours. The whole mixture was poured into water and extracted with ethyl acetate. The organic layer of the extract was washed with dilute hydrochloric acid and saturated saline successively, then dried with sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica-gel column chromatography to give ethane sulfonyl derivative (Compound 6) (3.82 g, 85%). Compound 6 (3.82 g, 13.72 mmol) was dissolved in the mixed solvent made of dioxane (5 mL) and methylene chloride (5 mL), then to the redaction mixture, which was stirred at room temperature, was added 4N hydrochloric acid (dioxane solvent) (8.58 mL, 34.31 mmol). The whole mixture was stirred at room temperature for 15 hours, then the resulting crystallized solid was filtered to give Compound 7 (2.76 g, 94%). 1H-NMR (DMSO-d6) delta: 1.22 (t, 3H, J= 7.2 Hz), 3.06-3.22 (m, 6H), 3.414-3.3.52 (m,4H), 9.59 (brs, 1H). |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of tert-butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol) and triethylamine (2.18 g, 3 mL, 21.5 mmol) in DCM (10 mL) at 0 C was added ethanesulfonyl chloride (1.04 g, 8.05 mmol). After being warmed to rt and stirred for 2 hrs, the resulting reaction mixture was diluted with H20 (40 mL) and extracted with EA (50 mL) for three times. The combined organic layer was dried over anhydrous Na2S04and concentrated in vacuo to give crude tert-butyl 4-(ethylsulfonyl)piperazine-1-carboxylate (2.3 g) as a brown oil, which was used in the next step directly without any further purification | |
With triethylamine; In dichloromethane; at -40℃; for 14h; | [1284] tert-butyl 4-(ethylsulfonyl)piperazine-1-carboxylate : Commercial 1-Boc-piperazine (3.0 g, 16.11 mmol, 1 eq) was dissolved in methylene chloride (30 mL), then to the reaction mixture, which was stirred at -40C., were added triethylamine (5.61 mL, 40.26 mmol, 2.5 eq) and ethane sulfonyl chloride (1.83 mL, 19.33 mmol, 1.2 eq). The whole mixture was warmed up gradually and stirred for 14 hours. The whole mixture was poured into water and extracted with ethyl acetate. The organic layer of the extract was washed with dilute hydrochloric acid and saturated saline successively, then dried with sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica-gel column chromatography to provide tert-butyl 4-(ethylsulfonyl)piperazine-1-carboxylate. 1H NMR (400 MHz, CDCl3): 1.34-1.38 (m, 3H), 1.45 (s, 9H), 2.91-2.97 (m, 2H), 3.23-3.25 (m, 4H), 3.49-3.51 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 21℃;Cooling with ice; | A partial solution of (1,1-dimethylethyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (for a preparation see Example l(g)) (3.3905 g, 14.79 mmol) in dry dichloromethane (100ml) was stirred and cooled in ice and treated with triethylamine (2.081 ml, 14.93 mmol) followed by ethanesulphonyl chloride (1.415 ml, 14.93 mmol) added dropwise. The resulting cloudy solution was stirred thus for 0.5hrs then allowed to warm to 210C and stirred thus for 4 hrs then stood overnight. The reaction was washed with sat aq NaHCObeta solution and the aqueous phase extracted with DCM (x2). The combined organic fractions were washed with brine, dried (TN^SC^) and evaporated in vacuo to give a white solid (4.88g, 103%). This was used in subsequent reactions without further purification. MS (ES+) m/z 322 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (5.09 g) at 0 C. followed by the dropwise addition of ethane sulfonylchloride (which may be referred to as sso10; 3.2 mL; TCI) and the resulting mixture was stirred overnight slowly raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium hydroxide (20% by weight, Wet-type, 5 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (3.32 g).(Intermediate N-2 LCMS: 193.1 (MH+); retention time: 0.28 min; LCMS; condition A) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 78% | With triethylamine;N,N-dimethyl-formamide; In dichloromethane; at 20℃; | Synthesis of Compounds 5-11, 14, 18, 22-29, 32-34, 37, 40, 43, 53, 65-66, 69-70, 74, 77, and 78Syntheses of these compounds are shown in Scheme 7. To a solution of 1,5-bis-(3-hydroxy-phenyl)-penta-1,4-dien-3-one (synthesized by the method shown in Scheme 4) in CH2Cl2 (containing a small amount of DMF) was slowly added ethanesulfonyl chloride (10 eq.) and Et3N (10 eq.). The resulting mixture was stirred at room temperature for 4-5 hours. The reaction mixture was diluted with CH2Cl2, washed with water twice, and extracted with CH2Cl2. The organic extract was dried over Na2SO4, filtered, and concentrated to get crude as a yellow solid. The crude was purified by quick column filtration, then crystallization, and re-crystallization from EtOAc to get the desired product compound 6 as a light yellow crystalline solid. Yield >78%. ESI MS m/z: 451.2 [M+H]+; 1H NMR (300 MHz, CDCl3) delta: 7.71 (d, 2H, J=15.9 Hz, H-1, 5), 7.57-7.53 (m, 4H, aromatic ring H), 7.47 (t, 2H, J=7.8 Hz, aromatic ring H), 7.34-7.31 (m, 2H, aromatic ring H), 7.08 (d, 2H, J=15.9 Hz, H-2, 4), 3.34 (q, 4H, J=7.5 Hz, -OSO2CH2CH3), 1.58 (t, 6H, J=7.5 Hz, -OSO2CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrazine hydrate; In ethanol; at 10 - 20℃; for 1h; | General procedure: The nucleophilic substitution reactions of the hydrazine hydrate with various alkyl sulfonyl chloride (alkyl methane, ethane, propane, butane) were carried out as follows [14,22]: An ethanol solution of the alkyl sulfonyl chloride, R-SO2Cl (0.12 mol) was added dropwise to the ethanol solution of hydrazine hydrate (0.62 mol),maintaining the temperature between 10 and 12 C. Then, the reactionmixture was stirred for 1 h at room temperature. After thecompletion of the reaction, the solventwas removed under vacuumand the viscose residue was taken to ether phase using a continuousextraction method in 5 days. Then the ether was removedwith rotary evaporator. The resulting product recrystallized fromethyl acetate and then allowed to stand in the freeze and crystalswere obtained after a few weeks. |
With pyridine; hydrazine hydrate; In ethanol; at 70℃; for 2h; | General procedure: In a 50 mL round-bottomed flask, different substituted sulfonylchloride (1 mmol) were treated with hydrazine hydrate (5 mL) inethanol (10 mL) in the presence of few drops of pyridine at 70 C for 2 h.Reaction progress was checked by TLC periodically. The pure productswas obtained via collection of the precipitate by filtration, washing withhexane and water to remove impurities. Extra pure products were obtainedby crystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.4% | With pyridine; at 20.0℃; | Step 1:Ethanesulfonyl chloride was added dropwise to a stirred solution of 1-(4-aminophenyl)ethanone and 1 mL of pyridine. The reaction was stirred at room temperature overnight. When complete as determined by HPLC, using the H2O-Acetonitrile (ACN) gradient given below with a Gemini-NX C18, mum, 110 , 150×4.6 mm chromatography column, as well as by LCMS, the THF was evaporated. The evaporation residue was dissolved in 50 mL ethyl acetate, washed with 100 mL of 1M KHSO4, and then brine and dried on Na2SO4. The solvent was evaporated and the product used for the next step without further purification (3.57 g, yield 60.4%)HPLC Purification Protocol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine; at 0℃; for 1h; | Step 1: (4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in No.64 pyridine and No.266 ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N No.85 HCl and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave No.276 N-(4-bromo-2-fluorobenzyl)-ethanesulfonamide in pure form (1.06 g, 79percent).[0518]Step 2: To a solution of No.276 N-(4-bromo-2-fluorobenzyl)ethanesulfonamide (305 mg, 1.03 mmol) in No.56 dimethylformamide, No.82 Manganese (113 mg, 2.06 mmol), No.83 (2,2?-Bipyridine)nickel(II)-dibromide (27 mg, 0.07 mmol), No.81 ethyl 2-chloropropanoate (0.17 mL, 1.34 mmol) was added. It was followed by addition of No.84 trifluoroacetic acid (0.002 mL, 0.028 mmol). The mixture was stirred for 24 h at 65° C. The reaction mixture was quenched by concentrated HCl (7 drops). Then it was extracted with diethyl ether, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to obtain No.278 ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate in pure form (65 mg, 20percent).[0519]Step 3: To a solution of No.278 ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (60 mg, 0.189 mmol) in No.27 tetrahydrofuran and water co-solvent, No.88 sodium hydroxide (19 mg) was added at room temperature. The mixture was stirred for overnight and extracted with ethyl acetate, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to give No.280 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (55 mg).[0520]Step 4: No.280 2-(4-(Ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and No.36 (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (61 mg, 0.228 mmol) was dissolved and mixed in No.32 1,4-dioxane, followed by addition of No.34 N-hydroxybenzotriazole (42 mg, 0.311 mmol) and No.33 N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide (60 mg, 0.311 mmol) and No.35 triethylamine (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave No.282 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 83) in pure form (52 mg, 47percent).[0521]1H-NMR (400 MHz, CDCl3) delta 7.75 (d, 1H, J=6.40 Hz, Ar?H), 7.57 (d, 1H, J=6.36 Hz, Ar?H), 7.31 (m, 2H, Ar?H), 7.21 (m, 2H, Ar?H), 7.15 (d, 1H, J=5.92 Hz, Ar?H), 6.95 (m, 2H, Ar?H), 5.50 (m, 1H, amide-NH), 4.46 (m, 3H, amide-NH, Ar?CH2), 4.30 (d, 2H, J=5.04 Hz, Ar?CH2), 3.45 (q, 1H, J=5.68 Hz, amide-alpha-H), 2.97 (q, 2H, J=5.92 Hz, ethanesulfonly-2H), 2.37 (s, 1H, Ar?CH3), 1.43 (d, 3H, J=5.68 Hz, amide-3H), 1.30 (t, 3H, J=5.88 Hz ethanesulfonly-3H) |
79% | With pyridine; at 0℃; for 1h; | Step 1: No.72 (4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in No.73 pyridine and No.171 ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N No.56 HCl and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave No.172 N-(4-bromo-2-fluorobenzyl)ethane-sulfonamide in pure form (1.06 g, 79percent). |
79% | With pyridine; at 0℃; for 1h; | Step 1 : (4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0 °C. The mixture was stirred for 1 h at 0 °C. Then, the mixture was quenched with 1 N HCI and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave N-(4-bromo-2-fluorobenzyl)- ethanesulfonamide in pure form (1 .06 g, 79 percent). |
79% | In pyridine; at 0℃; for 1h; | Step 1 : (4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0 °C. The mixture was stirred for 1 h at 0 °C. Then, the mixture was quenched with 1 N HCI and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave N-(4-bromo-2-fluorobenzyl)ethane- sulfonamide in pure form (1 .06 g, 79 percent). |
79% | With pyridine; at 0℃; for 1h; | Step 1: (4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N HCl and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave N-(4-bromo-2-fluorobenzyl)-ethanesulfonamide in pure form (1.06 g, 79percent). |
79% | With pyridine; at 0℃; for 1h; | Step 1 : (4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0 °C. The mixture was stirred for 1 h at 0 °C. Then, the mixture was quenched with 1 N HCI and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave N-(4-bromo-2-fluorobenzyl)- ethanesulfonamide in pure form (1 .06 g, 79 percent). |
79% | With pyridine; at 0℃; for 1h; | Step 1 : 4-Bromo-2-fluorobenzylamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at O °C. The mixture was stirred for 1 h at O °C. Then, the mixture was quenched with 1 N HCl and extracted with ethyl acetate (EtOAc). Drying (MgSO4) and evaporation of the ethyl acetate followed and the residue was purified by CC (eluent EtOAc/n-hexane) to yield N-(4-bromo-2- fluorobenzyl)ethanesulfonamide in pure form (1 .06 g, 79 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonia; In dichloromethane; at 0 - 20℃; for 1h; | (rac)-Ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide[0418](rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ylamine (intermediate A-2 [D]) (227 mg, 1 mmol) and Et3N (152 mg, 1.5 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (193 mg, 1.5 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 hr before it was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and the organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (302 mg, 95% yield). MS: 319.0 (M+H)+. |
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | Intermediate B-4(rac)-Ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide To a solution of (rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ylamine (intermediate A-2 [D]) (227 mg, 1 mmol) and Et3N (152 mg, 1.5 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (193 mg, 1.5 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 hr before it was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and the organic layer was dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product (302 mg, 95% yield). MS: 319.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
158 mg | With triethylamine; In dichloromethane; at 20℃; for 1.5h; | Step 1 Preparation of N-((5-bromopyridin-2-yl)methyl)ethanesulfonamide [0209] [0210] To a solution of <strong>[173999-23-0](5-bromopyridin-2-yl)methanamine</strong> (250 mg, 1.34 mmol) in CH2Cl2 (3 mL) is added ethyl sulfonyl chloride (95 mg, 0.74 mmol) followed by triethylamine (0.3 mL, 2.0 mmol). The reaction is stirred at room temperature for 1.5 hours. The reaction is directly injected onto a 12 g silica gel column and chromatographed eluting from 100% hexanes to 50:50 ethylacetate:hexanes to afford the title compound (158 mg): m/z (Cl) M+H 279+281. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | 4-chlorodeacetyl colchicine (198 mg, 0.505 mmol) was dissolved in dichloromethane (4 mL) under argon atmosphere, and cooled at 0 degree C. Triethylamine (142 mul, 0.487 x 2mmol) and ethanesulfonyl chloride (72 mul, 0.487 x 1.5 mmol) were added, and stirred overnight, and a temperature is increased to room temperature. Water was added and the reaction mixture was quenched and extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by Silica gel chromatography (Biotage Isolera One and SNAP 25 g, methanol/chloroform) to obtain title compound (a yellow solid, 243 mg, 0.502 mmol, 99%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | Step 1: <strong>[594-44-5]Ethylsulfonyl chloride</strong> (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 3-bromo-4-(2,4-difluorophenoxy)aniline (328 mg, 1.1 mmol) and pyridine (178 muL, 2.2 mmol) in dichloromethane (2 ml) at 0 C. under nitrogen. After the mixture was allowed to warm to rt and stir overnight, it was treated with 1N HCl (10 ml) and extracted with dichloromethane (3*10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (430 mg, 99%) as a tan solid which was carried forward without purification. LCMS (M-H)-=391. |
84% | To a mixture of compound 13 (1.30 g, 4.33 mmol) and triethylamine(2.41 mL, 17.33 mmol) in DCM (5 mL) cooled to 0 C was added ethanesulfonyl chloride (1.23 mL, 13.00 mmol) in DCM dropwise andthen stirred at room temperature for 3 h. The reaction mixture wasevaporated in vacuo, diluted with water, and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na2SO4,and concentrated in vacuo. The resulting intermediate was used without further purification and suspended in 1,4-dioxane/10% NaOH(10 mL, 1/1), then the mixture was heated at 100 C for 2 h. The reactionmixture was evaporated in vacuo, diluted with water, and extractedwith EtOAc. The combined organic layers were washed withbrine, dried over Na2SO4 and concentrated. The residue was purified bycolumn chromatography on silica gel (EtOAc/petroleum ether, 1/10) toobtain the title compound 14 (1.45 g, 84%) as a light yellow solid. 1HNMR (300 MHz, CDCl3) delta (ppm): 7.52 (d, J = 2.6 Hz, 1H), 7.13 (dd,J = 8.8, 2.7 Hz, 1H), 7.06-6.93 (m, 2H), 6.91-6.82 (m, 1H), 6.75 (d,J = 8.8 Hz, 1H), 6.65 (s, 1H), 3.14 (q, J = 7.4 Hz, 2H), 1.40 (t,J = 7.4 Hz, 3H). | |
82% | With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 3-Bromo-4-phenoxyaniline (10 g, 33.44 mmol)Soluble in dichloromethane (80mL)Ethyl sulfonyl chloride (5.52 g, 43.48 mmol) was added under ice bath.Pyridine (5.28 g, 66.88 mmol),Stir at room temperature overnight, wash the organic phase with hydrochloric acid (2M, 100 mL*2).Washed with water (100 mL * 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and evaporated.N-(3-Bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (10.7 g, 27.42 mmol, molar yield 82%). |
82% | With pyridine; In dichloromethane; at 0 - 20℃; | 3-bromo-4-phenoxyaniline (10 g, 33.44 mmol)Soluble in dichloromethane (80mL) was added ethanesulfonyl chloride (5.52g, 43.48mmol) under ice-cooling,pyridine (5.28 g, 66.88 mmol),stir at room temperature overnight, wash the organic phase with hydrochloric acid (2M, 100 mL*2) and water (100 mL*2).Wash with saturated brine (100 mL) and dry over anhydrous sodium sulfate.After concentration, column chromatography (petroleum ether: ethyl acetate = 5:1) gave compoundN-(3-Bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (10.7 g, yield 82%). |
33.1% | 3-Bromo-4-(2,4-difluorophenoxy)aniline (3.24 g, 10.80 mmol) and triethylamine (4.37 g, 43.2 mmol) were stirred in dichloromethane (48.1 mL) at ambient temperature. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (4.16 g, 32.4 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (24 mL) and sodium hydroxide (10 % w/v, 12 mL, 0.427 mmol) were added, and the solution was heated to 70 C for 1 hour. The solution was neutralized to a pH of about 7 with saturated aqueous NH4C1 (200 mL). The aqueous phase was extracted with ethyl acetate (3x125 mL). The combined organics were washed with brine, dried (anhydrous MgS04), filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate/petroleum ether gradient,) to afford N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (1.4 g, 3.57 mmol, 33.1 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In tetrahydrofuran; dichloromethane; for 3h; | [Example 708] Compound p16 1-Ethylsulfonyl<strong>[4513-94-4]pyrrole-2-carbonitrile</strong> [1497] Ethanesulfonyl chloride (0.98 g, 7.60 mmol) was added to a mixed solution of <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> (500 mg, 5.43 mmol) and TEA (1.51 ml, 10.9 mmol) in THF (5 ml) and DCM (5 ml), followed by stirring for three hours. A saturated aqueous solution of sodium chloride was added to the reaction mixture, followed by extraction with DCM. The organic layer was then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to yield the title compound (694 mg, 69%) as a colorless oily substance. LCMS: m/z 185 [M+H]+ HPLC retention time: 0.55 min (analysis condition A) |
69% | With triethylamine; In tetrahydrofuran; dichloromethane; for 3h; | For <strong>[4513-94-4]1H-pyrrole-2-nitrile</strong> (500 mg, 5. 43mmol) and TEA (1.51 ml, 10. 9mmol) THF of (5 ml) with DCM (5 ml) is added to the mixed solution of ethane sulfonyl chloride ( 0.98g, 7. 60mmol), stirring 3 hours. Added to the reaction mixture with saturated sodium chloride aqueous solution, after extraction with DCM, the organic layer is dried with anhydrous sodium sulfate. After the desiccant filter, and will be concentrated under reduced pressure the residue by silica gel column chromatography (ethyl acetate / hexane) refining, to obtain the title compound (694 mg, 69%) of colorless oil. |
With triethylamine; In tetrahydrofuran; for 3h; | General procedure: Methanesulfonyl chloride (0.68 ml, 8.70 mmol) was added to a mixed solution of <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> (157 mg, 1.71 mmol) and TEA (2.14 ml, 15.4 mmol) in THF (2 ml) and DCM (2 ml), and this was stirred for three hours. A saturated aqueous sodium chloride solution was added to the reaction mixture, and extraction was performed with DCM. The organic layer was then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (245 mg, 84%) as a colorless oily substance. The title compound was synthesized from <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> under the same conditions as for Compound a39. However, the reaction was performed using ethanesulfonyl chloride in place of methanesulfonyl chloride and using only THF as a solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In dichloromethane; at 20℃; for 18h; | [0447] A flask with stir bar was charged with Example IG(1.02S g, 2.76 mmol), ethanesulfonyl chloride (0.55 mL, 5.SOmmol) and triethylamine (2.0 mL, 14.35 mmol) in dichloromethane(2S ml). The solution was stirred at ambient temperaturefor IS hours. The mixture was stripped down byrotary evaporator, suspended in THF (IS mL), then treatedwith I M sodium hydroxide (9 mL, 9.00 mmol). The mixturewas stirred at 60 C. for 20 hours. The mixture was cooled andshaken in a seperatory funnel with 100 mL each of ethylacetate and brine. The organics were dried over magnesiumsulfate. After filtration and solvent removal the crude productwas chromatographed on a 40g silica cartridge eluting with0-10% methanoldichloromethane to provide the title compound(1.13g, SS%). |
88% | With triethylamine; In dichloromethane; at 20℃; for 18h; | A flask with stir bar was charged with Example 1G (1.028 g, 2.76 mmol), ethanesulfonyl chloride (0.55 mL, 5.80 mmol) and triethylamine (2.0 mL, 14.35 mmol) in dichloromethane (28 ml). The solution was stirred at ambient temperature for 18 hours. The mixture was stripped down by rotory evaporator, suspended in THF (18 mL), then treated with 1 M sodium hydroxide (9 mL, 9.00 mmol). The mixture was stirred at 60 C for 20hours. The mixture was cooled and shaken in a seperatory funnel with 100 mL each of ethyl acetate and brine. The organics were dried over magnesium sulfate. After filtration andsolvent removal the crude product was chromatographed on a 40g silica cartridge elutingwith 0-10 % methanol/dichloromethane to provide the title compound (1.13g, 88 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.4% | With triethylamine; In dichloromethane; at 20℃; for 2h; | Step-i: Synthesis of methyl 2-(4-(ethylsulfonamido)phenyl)acetate (53a) A solution of methyl 2-(4-aminophenyl)acetate (2.0 g, 0.0121 mol) in DCM (25 mL) was treated with ethanesulfonyl chloride (1.8 g, 0.0145 mol) at RT for 2 h. The RM was diluted with DCM, washed with water, brine, dried over sodium sulphate, concentrated to get the titled compound (1.5 g, 48.4 %). LC-MS: 258.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: [00145] To a solution of <strong>[138500-88-6]4-aminomethylphenylboronic acid pinacol ester</strong> (1.1 eq.), DMAP (0.4 eq.), and DIPEA (1.0 eq.) in DCM (0.16 M), cooled to 0 C under a nitrogen atmosphere, was added dropwise the corresponding sulfonyl chloride (1.0 eq.). The reaction mixture was stirred at 0 C for 20 min, then allowed to return to room temperature and stirred overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with hydrochloric acid solution (0.5 M) and the organic washed with brine. The organic layer was dried over Na2S04, filtered and then concentrated under reduced pressure to afford the desired boronate ester. No further purification was attempted and the product was used directly in the next step. [00167] /V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll ethanesulfonamide [00168] Following general procedure A, 4-aminomethylphenylboronic acid, pinacol ester (299.1 mg, 1 .28 mmol) and ethanesulfonyl chloride (0.1 1 mL, 1 .17 mmol) afforded Lambda/-[[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]ethanesulfonamide (320.0 mg, 0.98 mmol, 84% yield) as an orange oil. [00169] UPLC-MS (ES+, Short acidic): 1.71 min, m/z 348.3 [M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 23B tert-butyl 4-[(3-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxylate and tert-butyl 4-[(5-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxy- late In analogy to intermediate 1 B, 381 mg (3.00 mmol) 3-methyl-4-nitro-1 H-pyrazole and 1.00 g (3.60 mmol) tert-butyl 4-(bromomethyl)piperidine-1 -carboxylate (CAS-No. 158407-04-6) were reacted to give after purification of the crude product by flash chromatography 940 mg (97 %) of the desired title compounds as a 60 : 40 mixture of regioisomers. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.05 / 1.11 (m, 2H), 1.38 (s, 9H), 1.46 (m, 2H), 2.01 (m, 1 H), 2.42 / 2.61 (s, 3H), 2.67 (m, 2H), 3.92 (m, 2H), 4.00 / 4.05 (d, 2H), 8.78 / 8.23 (s, 1 H). Intermediate 24B 4-[(3-methyl-4-nitro-1 H-pyrazol- 1-yl)methyl]piperidine and 4-[(5-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine A solution of 940 mg (2.90 mmol) tert-butyl 4- [(3-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate and tert-butyl 4- [(5-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate (intermediate 23B) in 5 mL dichloromethane was stirred with 2.2 mL (29.0 mmol) trifluoroacetic acid for three hours. The reaction mixture was filtered over NH2 derivatized silica gel, and the filtrate was evaporated yielding 557 mg of the desired title compounds as crude product which was used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.04 / 1.11 (m, 2H), 1.39 (m, 2H), 1.89 (m, 1 H), 2.38 (m, 2H), 2.42 / 2.60 (s, 3H), 2.90 (m, 2H), 3.95 / 4.01 (d, 2H), 8.80 / 8.23 (s, 1 H). Intermediate 25B 1-(ethylsulfonyl)-4-[(3-methyl-4-nitro-1 H-pyrazol-1-yl)methyl]piperidine and 1- iperidine A solution of 550 mg (2.45 mmol) 4-[(3-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine and 4-[(5-methyl-4-nitro-1 H-pyrazol-1 -yl)methyl]piperidine (intermediate 24B) in 5 mL DMF was stirred with 195 mu (2.06 mmol) ethanesulfonyl chloride and 1 .23 mL (8.83 mmol) triethylamine overnight. Saturated aqueous sodium bicarbonate was added to the reaction. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried, filtered, and evaporated. 628 mg of the desired title compounds as crude product were obtained which were used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.19 (t, 3H), 1.20 / 1.27 (m, 2H), 1.57 (m, 2H), 2.00 (m, 1 H), 2.42 / 2.62 (s, 3H), 2.76 (m, 2H), 3.01 (q, 2H), 3.58 (m, 2H), 4.03 / 4.09 (d, 2H), 8.80 / 8.24 (s, 1 H). | ||
A solution of 550 mg (2.45 mmol) 4-[(5-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine and 4-[(3-methyl-4-nitro-1 H-pyrazol-1 -yl)methyl]piperidine (intermediate 18B) in 5 mL DMF was stirred with 195 muL (2.06 mmol) ethanesulfonyl chloride and 1.23 mL (8.83 mmol) triethylamine overnight. Saturated aqueous sodium bicarbonate was added to the reaction. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried, filtered, and evaporated. 628 mg of the desired title compounds as crude product were obtained which were used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.19 (t, 3H), 1.20 / 1.27 (m, 2H), 1.57 (m, 2H), 2.00 (m, 1 H), 2.42 / 2.62 (s, 3H), 2.76 (m, 2H), 3.01 (q, 2H), 3.58 (m, 2H), 4.03 / 4.09 (d, 2H), 8.80 / 8.24 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 1.5h; | N,N-bis(4-methoxybenzyl)ethanesulfonamide, Example 12.0. To a solution of bis(4-methoxybenzyl)amine 12.01 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2 x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10- 80% EtOAc in hexanes) to provide the title compound 12.0 (1125 g, 3.22 mol, 92%) as white solid. ?H-NMR (400 MHz, CDC13) 7.23 (dd, J= 2.08, 6.62 Hz, 4H), 6.90 (dd, J= 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (s, 6H), 2.92 (q, J 7.40 Hz, 2H), 1.33 (t, J 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: 372.2 (M+Na). |
92% | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h;Large scale; | To a solution of bis(4-methoxybenzyl)amine 467.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C during the addition of the ethanesulfonyl chloride. Once addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 467.0 (1125 g, 3.22 mol, 92%) as a white solid.1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos.) m/z: = 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; at 5 - 10℃;Large scale; | To an ice-cooled solution of 100.1 (900 g, 3.49 mol) in DCM (9 L) was added TEA (634 mL, 4.55 mol) followed by ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq) dropwise (Note: The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched with water (4 L) and the layers were separated. The aqueous layer was then extracted with more DCM (2 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed onto a plug of silica gel purified by silica gel chromatography (eluent: 10-80% EtOAc in hexanes) to provide 100.0 (1.125 kg, 92% yield) as a white solid.1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J=2.1, 6.6 Hz, 4H), 6.90 (dd, J=2.1, 6.6 Hz, 4H), 4.29 (s, 4H), 3.83 (s, 6H), 2.92 (q, J=7.4 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H). (0809) LCMS-ESI (pos.) m/z: 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h;Inert atmosphere; | To an ice-cooled solution of 361.01 (900 g, 3.49 mol) in DCM (9 L) was added TEA (634 mL, 4.55 mol) followed by ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq) dropwise. (Note: The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. Alter 1.5 h, TLC showed complete loss of starting material. The reaction was quenched with water (4 L), and the layers were separated. The aqueous layer was then extracted with more DCM (2 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was absorbed onto a plug of silica gel purified by silica gel chromatography (eluent: 10-80% EtOAc in hexanes) to provide 361.0 (1125 g, 92% yield) as a white solid. 1H-NMR (400 MHz, CDC13) oe 7.23 (dd,J=2.1, 6.6 Hz, 4H), 6.90 (dd,J2.1, 6.6 Hz, 4H),4.29 (s, 4H), 3.83 (s, 3H) 3.83 (s, 3H), 2.92 (q, J=7.4 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H). LCMS-ESI (pos.) m/z: 372.2 (M+Na)t |
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 1.5h; | To a solution of bis(4-methoxybenzyl)amine 30.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10- 80% EtOAc in hexanes) to provide the title compound 30.0 (1125 g, 3.22 mol, 92%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos. ion) m/z: = 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; for 1.5h;Cooling with ice; | To a solution Example 4.11 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound Example 4.12 (1125 g, 3.22 mol, 92%) as a white solid. -NMR (400 MHz, CDC13) delta 7.23 (dd, J= 2.08, 6.62 Hz, 4H), 6.90 (dd, J= 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J= 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos. ion) m/z: = 372.2 (M+Na)+. |
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 1.5h; | V, V-Bis(4-methoxybenzyl)ethanesulfonamide, Intermediate 5.8. To a solution of bis(4-methoxybenzyl)amine Intermediate 5.8.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride. Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound Intermediate 5.8 (1125 g, 3.22 mol, 92%) as a white solid. -NMR (400 MHz, CDCL) d 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t , J= 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: = 372.2 (M+Na)+. |
53.4% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 200 g, 775.19 mmol) in DCM (2.5 L) was added Et3N (336.17 mL, 2325.5 mmol), and the reaction mixture was cooled to 0 C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> ( 95 mL, 1007.75 mmol) was added in drop-wise manner followed by DMAP (19.0 g, 155.03 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction was monitored by TLC and upon completion, the mixture was diluted with H 0 and the layers were separated and the aqueous phase was extracted with DCM (3 x 1.5 L). The combined organic layer was washed with H20, brine, and dried over Na2S04. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over Si02 gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in Hex affording the title compound (145 g, 53.4%) as a white fluffy solid. |
53.4% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | To a soiuiion of NN-his(4-methoxvbenzvi)amine (Intermediate EEl 1; 200 g, 77519 mrnoi) in DCM (2.5 L) was added triethylamine (336.17 ml, 2325.5 mnmol), and the reaction mixture was cooled to 0 ?C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (95 mE, 1007.75 mmoi. Aldrich) was then added in drop-wise manner followed by DMAI (19.0 g, 155.03 rnmoi). The resulting reaction mixture was stirred atambient temperature for 30 mm. The reaction was monitored by TLC and upon completion, the mixture was diluted with water and the layers were separated and the aqueous phase was extracted with DCM (.3 x 1.5 L). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over silica gel (1 00-200 mesh). eluting with agradient of 0-12% ethyl acetate in hexanes affording the title compound (145 g,53.4%) as white fluffy solid. Ri: 0.5 in 20% Ethyl acetate in hexane. |
53.4% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EEl 1; 200 g, 775.19 mmol) in DCM (2.5 L) was added Et3N (336.17 mL, 2325.5 mmol), andthe reaction mixture was cooled to 0 C. <strong>[594-44-5]Ethanesulfonyl chloride</strong> ( 95 mL,1007.75 mmol) was added in drop-wise manner followed by DMAP (19.0 g,155.03 mmol). The resulting reaction mixture was stirred at ambient temperaturefor 30 mm. The reaction was monitored by TLC and upon completion, themixture was diluted with H20 and the layers were separated and the aqueousphase was extracted with DCM (3 x 1.5 L). The combined organic layer waswashed with H20, brine, and dried over Na2504. The solvent was removed under reduced pressure to afford the cmde material which was purified by column chromatography over 5i02 gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexane affording the title compound (145 g, 5 3.4%) as a white fluffy solid. |
1125 g | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h; | N,N-Bis(4-methoxybenzyl)ethanesulfonamide, Example 12.0 To a solution of bis(4-methoxybenzyl)amine 12.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq), followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C. during the addition of the ethane sulfonyl chloride. Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2*2 L). The combined organic layers were washed with brine (2*1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 12.0 (1125 g, 3.22 mol, 92%) as white solid. 1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, J=2.08, 6.62 Hz, 4H), 6.90 (dd, J=2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q, J=7.40 Hz, 2H), 1.33 (t, J=7.40 Hz, 3H). GC-MS (ESI pos ion) m/z: =372.2 (M+Na)+. |
With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h; | To a solution of bis(4-methoxybenzyl)amine 30.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). (The internal temperature was kept between 5-10 C during the addition of the ethanesulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by the addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2SO4, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 30.0 (1125 g, 3.22 mol, 92%) as white solid. 1H- NMR (400 MHz, CDC13) oe 7.23 (dd,J= 2.08, 6.62 Hz, 4H), 6.90 (dd,J= 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (app s, 6H), 2.92 (q,J= 7.40 Hz, 2H), 1.33 (t,J= 7.40 Hz, 3H). GC-MS (ESI pos. ion) m/z: = 372.2 (M+Na). | |
1125 g | With triethylamine; In dichloromethane; at 5 - 10℃; for 1.5h;Large scale; | To a solution of bis(4-methoxybenzyl)amine 84.1 (900 g, 3.49 mol, 1 eq) in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed by dropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq). The internal temperature was kept between 5-10 C during the addition of the ethane sulfonyl chloride. Once addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched by addition of water (4 L) to the reaction mixture. The layers were separated and the aqueous layer was extracted with DCM (2x 2 L). The combined organic layers were washed with brine (2x 1 L), dried over Na2S04, and concentrated in vacuo. The material thus obtained was adsorbed onto a plug of silica gel and purified by chromatography (silica gel (60-120 mesh) eluting with a gradient of 10-80% EtOAc in hexanes) to provide the title compound 84.0 (1125 g, 3.22 mol, 92%) as a white solid. -NMR (400 MHz, CDC13) delta 7.23 (dd, J = 2.08, 6.62 Hz, 4H), 6.90 (dd, J = 2.12, 6.60 Hz, 4H), 4.29 (s, 4H), 3.83 (m, 6H), 2.92 (q, J = 7.40 Hz, 2H), 1.33 (t, J = 7.40 Hz, 3H). GC-LCMS (ESI pos.) m/z: = 372.2 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In dichloromethane; at 0 - 25℃; for 16h;Inert atmosphere; | To a solution of 2-(azetine-3-yl) methyl cyanide(2.8 g, 21.4 mmol) and DIPEA(8.3 g, 64.3 mmol) in dichloromethane(30 mL) was added dropwise ethanesulfonyl chloride(4.1 g, 32.1 mmol) at 0C under the protection of nitrogen, and the temperature was kept below 2C when dropping. The reaction mixture was stirred at 25C for reacting for 16 hours. TLC showed that the reaction was completed (petroleum ether/ethyl acetate =1:1). After the reaction mixture was quenched with water, extracted with dichloromethane (30 mL*2). The combined organic phase was washed with saturated salt water(20 mL*2), dried with anhydrous sodium sulfate, filtered, and spun dry. The residue was purified through column chromatography (dichloromethane/ethyl acetate =3/1) to give 2-(1-(ethylsulfonyl)azetine-3-yl)methyl cyanide(1.4 g, 33.0% yield) as a pale yellow solid. 1H NMR (400MHz, CDCl3) delta = 5.50 - 5.41 (m, 1H), 4.79 (d, J=3.0 Hz, 2H), 4.71 (d, J=2.5 Hz, 2H), 3.06 (q, J=7.4 Hz, 2H), 1.40 (t, J=7.4 Hz, 3H). MS (ESI) Calcd. for C7H10N2O2S [M + H]+ 187, Found 187. |
192 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; | Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2) (250 mg, 1.29mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 5 h. Then the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product 3, was then suspended ina cetonitrile (20 mL) and cooled to 0 C. N,N-Diisopropylethylamine (DIPEA) (1.12 mL, 6.44 mmol, 5 equiv.) was then slowly added while keeping the internal temperature below 5 C. Then ethanesulfonyl chloride (EtSO2Cl) (0.184 mL, 1.94 mmol, 1.5 equiv.) was added over 1 h while keeping the internal temperature below 5 C. The resulting reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The concentrated residue was then diluted with dichloromethane and was washed with aqueous sodium chloride solution. The aqueous phase was back-extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and the residue was purified using a silica gel column to afford compound 4: Yield 192 mg (81%); off-white solid; m.p. 58-60 C; IR: 3294, 3066, 2978, 2222, 1702, 1321, 1142 cm-1. Anal. calcd for C7H10N2O2S: C, 45.15; H, 5.41; N, 15.04; found: C, 45.32; H, 5.35; N, 15.21%. MS (m/z): 209 [M + Na]+; 1H NMR (300 MHz, CDCl3): delta 1.37 (m, J = 6.7 Hz, 3H), 3.04 (m, J = 7.4 Hz, 2H), 4.69 (t, J = 2.5 Hz, 2H), 4.77 (t, J = 2.8 Hz, 2H), 5.43 (t, J = 2.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): delta 7.2, 42.6, 58.5, 58.9, 93.9, 114.9, 156.2, 168.6. |
0.192 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 5℃; | Compound 2 (0.250g, 1.29mmol) dissolved in acetonitrile was slowly added dropwise trifluoroacetic acid (3ml).Stirred at room temperature for 4 hours gussets tracking.After completion of the reaction, the solvent spin dry, obtained was dissolved in acetonitrile and cooled to 0 deg.] C, was slowly added N, N- diisopropylethylamine (DIEA), maintaining the temperature not higher than 5 .Was slowly added compound 8 (0.184ml, 1.94mmol, 1.5equiv), at T Completion of the reaction followed by TLC, concentrated under reduced pressure, the crude product was diluted with dichloromethane, washed with brine, the aqueous phase was extracted with dichloromethane, the organic phase was concentrated, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.192g white solid with a yield of 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | General procedure: A solution of compound 4a,b (0.456 mmol) in dry THF (10 mL)was cooled to 0 C, and triethylamine (0.25 mL, 2.47 mmol) wasadded thereto. A solution of the appropriate sulfonyl chloride(0.90 mmol) in dry THF (3 mL) was added dropwise to the reactionmixture at the same temperature. The reaction mixture was stirredat room temperature for 2 h. After reaction completion, the mixturewas quenched with ethyl acetate (10 mL) and water (10 mL).The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3 5 mL). The combined organiclayer extract were washed with saline (3 10 mL), and dried overanhydrous sodium sulfate. The organic solvent was evaporatedunder reduced pressure, and the crude residue was purified by columnchromatography (silica gel, appropriate ratio of hexane/ethylacetate) to obtain the pure product. |
85% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | General procedure: was cooled to 0 C, and triethylamine (0.25 mL, 2.47 mmol) was addedthereto. The appropriate sulfonyl chloride (0.90 mmol) was dissolved indry THF (3 mL), and the solution was added dropwise to the reactionmixture at 0 C. The reaction mixture was stirred at ambient temperaturefor 2 h. The mixture was quenched with ethyl acetate (10 mL) andwater (10 mL). The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate (3 × 5 mL). The combined organicextracts were washed with saturated saline (3×10 mL), and dried overanhydrous sodium sulfate. The organic solvent was evaporated underreduced pressure, and the crude residue was purified by normal phasecolumn chromatography (silica gel, an appropriate ratio of hexane :ethyl acetate) to isolate pure product. The yield percentages and thespectral data are provided in the supplementary file. |
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | General procedure: The appropriate phenolic intermediate 4a-f (0.456 mmol) was dissolved in dry THF (10 mL), and the mixture was cooled to 0 C. Triethylamine (0.25 mL, 2.47 mmol) was added thereto. A solution of appropriate sulfonyl chloride (0.912 mmol) in dry THF (2 mL) was added dropwise to the reaction mixture at 0 C. The reaction mixture was stirred at room temperature for 2 h until reaction completion. The mixture was quenched with ethyl acetate (10 mL) and water (10 mL).The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extract was washed with saline (3×10 mL) and dried over anhydrous Na2SO4. The organic solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (silica gel, appropriateratio of hexane: ethyl acetate) to obtain the pure product. The spectral data of compounds 1b and 1f-m have been reported in our previous report48 and those for the other target compounds are reported herein in details |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: To the cooled solution (5-8) of appropriate sulfonyl chloride (20 mmol) and triethylamine (3.5 ml) in dichloromethane (100 ml) 4,4-diethoxybutane-1-amine (3.4 g, 20 mmol) was added. Reaction mixture was stirred at room temperature for 12 h, washed with saturated NaHCO3 solution in water (100 ml). Organic layer was separated, dried over MgSO4 and evaporated to give target compounds 1. | |
90% | General procedure: 4,4-Diethoxybutan-1-amine (3.4 g,20 mmol) was added to a cooled (5-8) solution of theappropriate sulfonyl chloride (20 mmol) and Et3N (3.5 ml) in CH2Cl2 (100 ml). The reaction mixture was stirred atroom temperature for 12 h, then washed with saturatedNaHCO3 solution (100 ml), the organic layer was separatedand the residual solvents were removed under reducedpressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In tetrahydrofuran; at 20℃; for 4h; | General procedure: Coumarin sulfonates 1-38 were synthesized by reactingdifferent hydroxylated coumarin derivatives (1 mmol) withcommercially available sulfonyl chlorides derivatives (1.2 mmol) inTHF (15 mL) and triethyl amine (1 mmol) was used as base. Reactionmixture was stirred for 4 h at room temperature to afford avariety of coumarin sulfonate esters 1e38. TLC monitoring wasused to determine the progress of the reaction. After the completionof reaction, THF was evaporated under reduced pressure andthe solid product obtained was washed with distilled water anddried under vacuum. The products were recrystallized in methanoland gave good yields. All the synthetic compounds 1-38 werecharacterized by different spectroscopic techniques such as EI-MS,HREI-MS, 1H-NMR, and 13C-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | With pyridine; In dichloromethane; at 20℃; for 12h; | solution of <strong>[304897-49-2]tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate</strong> (0.900 g, 3.089mmol), pyridine (0.299 mL, 3.706 mmol) and ethanesulfonyl chloride (0.477 g, 3.706 mmol) in dichloromethane (30 mL) was stirred at the room temperature for 12 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give tert-butyl 4-(4-(ethylsulfonamido)benzyl)piperazine-1-carboxylate as yellow solid (0.800 g, 67.5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.8% | With pyridine; In dichloromethane; at 20℃; for 18h; | A solution of <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (0.457 mL, 3.995 mmol), pyridine (0.483 mL, 5.993 mmol) and ethanesulfonyl chloride (0.453 mL, 4.794 mmol) in dichloromethane (10 mL) was stirred at the room temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous 1M-hydrochloric acid solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 80 %) to give N(3-fluoro-4-methylphenyl)ethanesulfonamide as yellow solid (0.623 g, 71.8 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.9% | With pyridine; In dichloromethane; at 20℃; for 18h; | A solution of 4-fluoro-3-methylaniline (0.500 g, 3.995 mmol), pyridine (0.483 mL,5.993 mmol) and ethanesulfonyl chloride (0.453 mL, 4.794 mmol) in dichloromethane(10 mL) was stirred at the room temperature for 18 hr. Then, water was added to thereaction mixture, followed by extraction with ethyl acetate. The organic layer waswashed with aqueous 1M-hydrochloric acid solution, dried with anhydrous Mg504,filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 gcartridge; ethyl acetate / hexane = 0 % to 80 %) to give N(4-fluoro-3-methylphenyl)ethanesulfonamide as yellow solid (0.633 g, 72.9 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.3% | With pyridine; In dichloromethane; at 20℃; for 12h; | A solution of <strong>[7149-75-9]4-chloro-3-methylaniline</strong> (0.500 g, 3.53 1 mmol) and pyridine (0.427 mL, 5.297 mmol) in dichloromethane (20 mL) was mixed at the room temperature with ethanesulfonyl chloride (0.400 mL, 4.237 mmol) and stuffed at the same temperature for 12 hr. Then, aqueous 1M-hydrochloric acid solution was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 5 percent to 50 percent) to give N(4-chloro-3-methylphenyl)ethanesulfonamide as beige solid (0.440 g, 53.3 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.0% | With pyridine; In dichloromethane; at 20℃; for 12h; | A solution of <strong>[29027-20-1]3-chloro-5-methylaniline</strong> (0.500 g, 3.531 mmol) and pyridine (0.427 mL, 5.297 mmol) in dichloromethane (20 mL) was mixed at the room temperature with ethanesulfonyl chloride (0.400 mL, 4.237 mmol), and stirred at the same temperature for 12 hr. Then, aqueous 1M-hydrochloric acid solution was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chroNHmatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 5 % to 50 %) to give N(3-chloro-5-methylphenyl)ethanesulfonamide as beige solid (0.380 g, 46.0 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.8% | With pyridine; In dichloromethane; at 20℃; for 5h; | A solution of i-methyl-1H-indazol-4-amine (0.300 g, 2.038 mmol), pyridine (0.197mL, 2.446 mmol) and ethanesulfonyl chloride (0.231 mL, 2.446 mmol) in dichloromethane (20 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous iN-hydrochloric acid solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The title compound was used without further purification (N-( 1-methyl-i H-indazol-4-yl)ethanesulfonamide, 0.350 g, 71.8 %, yellow oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.8% | With pyridine; In dichloromethane; at 20℃; for 5h; | A solution of i-methyl-1H-indazol-6-amine (0.300 g, 2.038 mmol), pyridine (0.197 mL, 2.446 mmol) and ethanesulfonyl chloride (0.231 mL, 2.446 mmol) in dichloromethane (20 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous iN-hydrochloric acid solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The title compound was used without further purification (N-( 1-methyl-i H-indazol-6-yl)ethanesulfonamide, 0.360 g, 73.8 %, yellow oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.7% | With pyridine; In dichloromethane; at 20℃; for 5.0h; | A solution of i-methyl-iH-indazol-7-amine (0.500 g, 3.397 mmol), pyridine (0.328 mL, 4.077 mmol) and ethanesulfonyl chloride (0.385 mL, 4.077 mmol) in dichloromethane (20 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous iN-hydrochloric acid solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The title compound was used without further purification (N-( i-methyl-i H-indazol-7-yl)ethanesulfonamide, 0.550 g,67.7 %, yellow solid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Under N2 protection and a condition free of water and oxygen, Intermediate 2 (627 mg, 3.0 mmol) was dissolved in tetrahydrofuran (20 ml), which was cooled to 0C, and sodium hydride (180 mg, 60 wt%, 4.5 mmol) was added, followed by stirring for 30 min. Ethylsulfonyl chloride (1.16 g, 9.0 mmol) was added dropwise, and the temperature was allowed to rise spontaneously to room temperature, followed by reaction for 1 hour. The reaction was quenched by addition of water (20 ml) to the reaction solution, which was then extracted with ethyl acetate (20 ml*2). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, re-dissolved in tetrahydrofuran (5 ml), and cooled to -10C to 0C. Potassium t-butoxide (35 mg, 0.31 mmol) was added, and the reaction was allowed to proceed for 24 hours at this temperature. After the reaction was completed, a saturated aqueous solution of ammonium chloride (10 ml) and water (10 ml) were added. The solution was extracted with ethyl acetate (20 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain a white solid 2a (730 mg, yield 81%). | |
81% | Anaerobic treatment, nitrogen protection, intermediate 2 (627 mg, 3.0 mmol) dissolved Solution in tetrahydrofuran (20 mL), cool to 0 C, add sodium hydride (180 mg, ) 60 Wt%, 4.5 mmol), stirred for 30 min, and ethyl sulfonyl chloride (1.16 g, 9.0 20 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. Water (20 mL) was added to the reaction solution, The reaction mixture was extracted with ethyl acetate (20 mL chi 2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, redissolved in tetrahydrofuran (5 mL), cooled to -10 C to 0 C, adding potassium t-butoxide (35 mg, 0.3 mmol), maintaining this temperature stirring at 24 hours. The reaction was completed by the addition of saturated aqueous ammonium chloride solution (10 mL), water (10 C) ML) and extracted with ethyl acetate (20 mL chi3). The combined organic layers were washed with anhydrous sodium sulfate 5 dry, concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (nu / nu) = 5: 1) to give white solid 2a (730 mg, yield 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dipotassium hydrogenphosphate; In tetrahydrofuran; water; at 0 - 20℃; | A three-necked flask was charged with <strong>[62037-46-1]1-amino-3-chloropropyl-2-ol hydrochloride</strong> (14.60 g, 100 mmol) and tetrahydrofuran(73 mL), water (73 mL), stirred and cooled to 0 to 5 C, added with dipotassium hydrogen phosphate (34.84 g, 200 mmol), stirred for 5 minAfter the clockwise drop of ethyl sulfonyl chloride (13.50g, 105mm0l), plus the temperature after warming to room temperature for 3-4 hours, the end of the reaction0.5mol / L dilute hydrochloric acid 73mL quenching reaction, stirring and dispensing, water and then extracted with ethyl acetate 35mL 2 times, combined organic saturatedAnd washed with salt (73 mL), dried over anhydrous sodium sulfate and concentrated to give N-(3-chloro-2-hydroxypropyl) ethane sulfonamide Followed by the next step (GC purity of about 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; at 20.0℃; for 4.0h; | Ethanesulfonyl chloride (1.28 mL; 13.5 mmol) was added into a solution of <strong>[1134328-09-8]tert-butyl (3-(methylamino)phenyl)carbamate</strong> (2 g, 9 mmol), triethymaine (3.79 mL, , 26.99 mmol) in ACN (100 mL) at room temperature. The solution was stirred at room temperature for 4h00. Water was added and the reaction mixture was extracted with DCM. The organic layer was separated and dried over MgSO4, filtered and the solventwas evaporated.The residue (3.2g) was purified by silica gel chromatography (Irregular SiOH, 40jim,80g, Mobile phase: gradient from 90%: DCM, 10% Heptane to 97% DCM, 3% MeOH,0.3% NH4OH. The fractions were combined and the solvent was evaporated to give2.55g of an impure fraction which was repurified by silica gel chromatography(Irregular SiOH, 40jim, 80g, Mobile phase: gradient from 70%: DCM, 30% Heptane to97% DCM, 3% MeOH, 0.3% NH4OH. The fractions were combined and the solventwas evaporated to give 1.24g (39%, 88% of purity based on LC/MS) of intermediate642 (39% pure at 88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: Methyl (1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate (0635) (0636) A solution of <strong>[61367-07-5]methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride</strong> (120 g, 0.62 mol) and Et3N (346 mL, 2.48 mol) in anhydrous DCM (2.5 L) was stirred at RT for 30 min. Ethanesulfonyl chloride (80.6 g, 0.63 mol) was added dropwise over 30 min to the reaction mixture at 0-5 C. After addition, the mixture was stirred at 0 C for 3 h. The mixture was quenched with water (250 mL) at 0 C. After partition, the organic layer was washed with H2O (600 mL, 5 volumes) and 1 N HCl (2 × 600 mL, 2 × 5 volumes), H2O (600 mL, 5 volumes) and brine (600 mL, 5 volumes), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude methyl (1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate (117.6 g, 76%) as a light yellow solid, which was used for the next step without further purification.1H NMR (CDCl3400 MHz): delta 4.36 (d, J = 8.0 Hz, 1 H), 3.67 (s, 3 H), 3.29-3.22 (m, 1 H), 3.04 (q, J = 7.6 Hz, 2 H), 2.25-2.21 (m, 1 H), 2.15-2.09 (m, 2 H), 2.08-2.01 (m, 2 H), 1.58-1.51 (m, 2 H), 1.39-1.25 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With pyridine; In dichloromethane; at 20℃; for 0.5h; | To a solution of <strong>[884495-22-1]5-bromo-2-fluoropyridin-3-amine</strong> (3 g, 20 mmol) in pyridine (10 mL) and DCM (20 mL) at room temperature was added ethanesulfonyl chloride (2.2 mL, 24 mmol). After stirring for 30 min, the solvent was evaporated. The resulting residue was diluted with MeOH (4 mL) and partitioned between EtOAc and brine. The organic layer was separated, and the aq. layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography afforded the title compound (2 g, 40%). LCMS for C7H9BrFN2O2S (M+H)+: calculated m/z=283.0, 285.0; found 283.0, 284.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.21% | To a solution of <strong>[612-28-2]N-methyl-2-nitroaniline</strong> (0.5g, 3.28mmol, 1.Oeq) in dimethylformamide (lOmL) at 0 C, sodium hydride (0.33g, 8.2mmol, 2.5eq) was added portionwise. Reaction mixture was stirred at 0 C for 30 mm. Then ethanesulfonyl chloride (0.84g, 6.57mmol, 2.Oeq) was added dropwise. Reaction mixture was allowed to stir at 110 C for 1 8h. After completion of the reaction, the reaction mixture was transferred into ice- cold water and extracted with ethyl acetate. Organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain crude product. This was purified by column chromatography using 15% ethyl acetate in hexane as eluant to obtain pure 190.1 (0.7g, 87.2 1%). MS(ES): m/z 245.16 [M+H]t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With water; sodium carbonate; eosin y; In acetonitrile; at 100℃; under 760.051 Torr; for 20h;Schlenk technique; Irradiation; Inert atmosphere; | General procedure: To a Schlenk tube were added 1 (0.2 mmol), 2 (1.5 eqiuv, 0.3 mmol), Eosin Y (2mol %, 0.004 mmol), Na2CO3 (2 eqiuv, 0.4 mmol), H2O (4.0 equiv, 0.8 mmol) CH3CN (2 mL). Then the mixture was stirred at 100 C (oil bath temperature) in argon atmosphere (1 atm) under 5 W blue LED light for 20 h until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the reaction mixture was washed with brine. The aqueous phase was re-extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 3 : 1 to 1 : 1) to afford the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.4% | 36.0 g of intermediate 7, 252 ml of acetonitrile and 252 ml of 3N hydrochloric acid solution were added to a 1000 ml four-necked flask, and stirred at 25 to 30 C for 16 hours. After the reaction was completed, the reaction solution was concentrated to a liquid-free flow, and 144 was added. Milli of acetonitrile was stirred at 30 C for 2 hours, then slowly cooled to 5-10 C, and stirred for 2 hours, filtered, the mother liquor was discarded, and the filter cake was retained for use.The above filter cake and 432 ml of acetonitrile were added to a 1000 ml four-necked flask, and 97.1 ml of N,N-diisopropylethylamine was slowly added dropwise under a nitrogen atmosphere; the temperature was controlled below 15 C, and 26.3 ml was slowly added dropwise. Ethylsulfonyl chloride was slowly warmed to 20 C after the completion of the dropwise addition, and stirred at this temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated to a liquid-free flow, and then, 360 ml of dichloromethane and 180 ml of a 12.5% aqueous sodium chloride solution were successively added, and the organic phase was concentrated to give the crude 2-[1-(ethylsulfonyl) 3-azetidine subunit] acetonitrile.The above crude product was dissolved in 36 ml of ethyl acetate, and the temperature was raised to 50 C. The temperature was controlled at 40 to 50 C. 48 ml of n-heptane was slowly added dropwise, and the temperature was slowly lowered to 30 C. 0.2 g of seed crystals were added and stirred for 10 to 10 20 minutes, add the remaining 48 ml of n-heptane, slowly reduce the temperature to 0 ~ 5 C, stir at 0 ~ 5 C for 30 ~ 50 minutes, filter, the filter cake was placed in a vacuum drying oven, dried at 40 C, 30.5 g of product, the yield was 88.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | General procedure: Sulfonamides 2g-2j were prepared from aryl-substituted 2-amino-5-nitrophenols 1c-1d. Dissolve arylsubstituted 2-amino-5-nitrophenol(15.0 mM) in 150 mL anhydrous DCM, TEA was added into solution(105.0 mM, 7 equiv). After TEA added corresponding sulfonyl chloride(45 mM, 3 equiv) added into solution, reacted at room temperatureovernight. After reaction completed DCM evaporated under vacuumadded 200 mL water added into the flask neutralized with 6 N HCl untilpH=1-2. Collect the solid intermediate by filtration. Wash the intermediatewith water, which was used to the next reaction without furtherpurification.The intermediate was dissolved in 100 mL methanol and 50 mL 4 NNaOH aq solution was added into the solution, stir at room temperaturefor 2 h. After reaction completed neutralized the solution with 6 N HCluntil pH=1-2. The precipitate was collected by filtration and was withwater and cold ether to provide desire product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 25h; | General procedure: <strong>[3366-95-8]Secnidazole</strong> (1 mmol) was dissolved in dioxane (6 mL) on icebath.After complete dissolution, we slowly added substitutedsulphonylchloride (1a-9a) (2 mmol). After 30 min, 33% aqueousNaOH (aq) solution (5 mL) was added to the reaction mixture withcontinuous stirring for 1 h. The ice bath was removed and stirringcontinued for 24 h at room temperature then reaction mixture waspoured onto ice-water, precipitates were obtained and recrystallizedwith minimum diethyl ether to obtain pure products (M1-M9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[Step 1] 4-[(Ethylsulfonyl)amino]-3-(trifluoromethoxy)benzoic acid Using <strong>[457097-93-7]methyl 4-amino-3-(trifluoromethoxy)benzoate</strong> (300 mg) and ethanesulfonyl chloride (0.724 ml), synthesis was carried out in the same manner as in Step 1 of Example 8 to obtain the title compound (408 mg) as a solid. 1H-NMR (DMSO-D6) delta: 1.25 (3H, t, J=7.3 Hz), 3.27 (2H, q, J=7.3 Hz), 7.69 (1H, d, J=9.2 Hz), 7.80-7.84 (1H, m), 7.91 (1H, dd, J=8.5, 1.8 Hz), 10.27 (1H, s), 13.31 (1H, br s). MS (ESI/APCI) m/z: 312 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium hydroxide; In acetone; at 20℃; | 1.29 g (10.0 mmol) of metformin, 1.28 g (10.0 mmol) of ethylsulfonyl chloride, 300 mL of anhydrous acetone, and 0.056 g (1 mmol) of potassium hydroxide were placed in a 500 mL flask, and stirred at room temperature overnight. The reaction progress was detected by TCL. When there was no significant change in the reaction product, the pH was adjusted to neutral with dilute hydrochloric acid to quench the reaction, and then the mixture was dried under reduced pressure to give a crude product, then petroleum ether: ethyl acetate = 2:1 (v/v) was passed through a silica gel column as an eluent to give 2.0 g of Compound 4 as a white powder. Rf was 0.7 (dichloromethane:methanol: glacial acetic acid = 9:1:0.025). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With triethylamine; In dichloromethane; at 20℃;Cooling with ice; | Weigh Example 2 The prepared 4- (tert-butyl) -N-((4-aminophenyl) thiocarbamoyl) benzamide V-17 (150 mg, 0.46 mmol) was placed in a 25 mL single-necked flask, and DCM was added to dissolve it. . Add triethylamine (0.07 mL, 0.55 mmol) and ethylsulfonyl chloride (0.05 mL, 0.55 mmol) under an ice bath, and react at room temperature overnight. After confirming the completion of the reaction by TLC, it was concentrated and purified through a silica gel column with petroleum ether and ethyl acetate (V / V = 6/1) as mobile phases to obtain V-26 as a white solid with a yield of 29%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In dichloromethane; at 20℃; for 0.5h;Cooling; | General procedure: A solution of the appropriate coumarin analogues (0.1 mmol) and triethylamine (0.2 mmol) in dry dichloromethane (5 mL) was cooled in an ice bath. A solution of an appropriate sulfonyl chloride derivative (0.12 mmol) in dry dichloromethane (2 mL) was subsequently added dropwise at the same temperature. The reaction mixture was allowed to warm to room temperature and stirred for additional 0.5 h until the disappearance of starting material, as monitored by TLC. The reaction mixture was extracted with ethyl acetate (3 × 20 mL), and the combined organic phase was washed with brine (3 × 25 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude residue was purified by flash column chromatography (silica gel, PE/EA = 10:3 to 10:4,v:v) to afford the desired compounds. 6-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl ethanesulfonate (5a). White powder. Yield: 86%; m.p. = 150-151 C;1H-NMR (400 MHz, DMSO-d6) delta 7.55 (d,J= 8.6 Hz, 1H, ArH), 7.34 (d,J= 8.7 Hz, 1H, ArH), 3.71 (q,J= 7.3 Hz, 2H, CH3CH2), 3.10 (t,J= 8.4 Hz,2H, CH2CH2CH2), 2.79 (t,J= 7.4 Hz, 2H, CH2CH2CH2), 2.35 (s, 3H, CH3), 2.18-2.09 (m, 2H, CH2CH2CH2), 1.43 (t,J= 7.3 Hz, 3H, CH3CH2);13C-NMR (100 MHz, CDCl3): delta 159.66, 155.75, 153.24, 148.50, 127.81, 122.56, 120.51, 118.16, 117.39, 46.37, 32.15, 30.62, 22.47, 9.89, 8.35; ESI-MSm/z: 309.4 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridine; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | General procedure: To a solution of 4-bromo-2-methoxyaniline (11a) (300 mg, 1.48 mmol) in anhydrous CH2Cl2(15 mL) was added pyridine (0.24 mL, 2.97 mmol) and 1-propanesulfonyl chloride (0.18 mL, 1.63 mmol) under an argon atmosphere.The mixture was stirred at room temperature for 16 h.After being quenched with 1 N HCl(aq) (1.0 mL), water and CH2Cl2were added and then the layers were separated. The combinedorganic phases were washed with brine, dried over anhydrousNa2SO4, filtered and concentrated. The residue was purified bycolumn chromatography on silica gel (EtOAc/hexane, 10:90 to15:85) to give 13a (490.1 mg, 99%) as a light yellow oil. |
Tags: 594-44-5 synthesis path| 594-44-5 SDS| 594-44-5 COA| 594-44-5 purity| 594-44-5 application| 594-44-5 NMR| 594-44-5 COA| 594-44-5 structure
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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