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CAS No. : | 2766-74-7 | MDL No. : | MFCD00051667 |
Formula : | C4H2Cl2O2S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SORSTNOXGOXWAO-UHFFFAOYSA-N |
M.W : | 217.09 | Pubchem ID : | 2733925 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.41 |
TPSA : | 70.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.55 cm/s |
Log Po/w (iLOGP) : | 1.83 |
Log Po/w (XLOGP3) : | 2.92 |
Log Po/w (WLOGP) : | 3.41 |
Log Po/w (MLOGP) : | 1.08 |
Log Po/w (SILICOS-IT) : | 2.87 |
Consensus Log Po/w : | 2.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.33 |
Solubility : | 0.102 mg/ml ; 0.000468 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.07 |
Solubility : | 0.0186 mg/ml ; 0.0000857 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -2.83 |
Solubility : | 0.32 mg/ml ; 0.00148 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.8 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 0 - 20℃; | The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R.B. flask, equipped with a mechanical stirrer, an air condenser, a dropping funnel, and a moisture-guard tube, was placed chlorosulfonic acid (240 mL, 3.594 mol). Under stirring, PCl5 (300 g, 1.44 mol, 0.40 equiv) was added in portions, over ca. 45 mins. During the addition, a large volume of HCl gas evolved vigorously,- but the temperature of the mixture did not rise significantly (<40 0C). By the time all the PCl5 had been added, an almost clear, pale yellow solution resulted, with only a few solid pieces of PCI5 floating in the suspension. It was stirred until gas evolution ceased (0.5 h).[0102] Then the reaction vessel was cooled in ice, and 2-chloro-thiophene (66.0 mL, 0.715 mol) was added via the dropping funnel, over 1.0 h. With the addition of the very first few drops of 2-Cl-thiophene, the mixture turned dark purple, and by the time all of the thiophene had been added, a dark purple solution resulted. During the addition, HCl gas evolved <n="35"/>continuously, at a slow rate. The reaction mixture was then stirred at room temperature overnight.[0103] Then the mixture, dark-purple clear solution, was added dropwise to crushed ice (3 L), over 0.5 h. On addition to ice, the purple color disappeared instantaneously; the colorless thin emulsion was stirred mechanically at room temperature for ca. 15 h. Then the mixture was extracted with CH2Cl2 (3 x 300 mL). The combined CH2Cl2-extract was washed with water (Ix 200 mL), saturated NaHCO3 (Ix 250 mL), brine (1 x 100 mL), dried (Na2SO4), and concentrated on a rotary evaporator to yield the crude product as a pale yellow glue, which showed a tendency to solidify, yielding a semi-solid mass. This was then purified by high- vacuum distillation (bp 110-112712mm) to yield 135.20 g (88percent) of the title compound as a colorless/pale-yellow semi solid. |
88% | at 0 - 40℃; | Example 1: Synthesis of the intermediate sulfonylurea carbamate (8)Step 1 - Preparation 5-chlorothiophene-2-sulfonyl chloride: <n="64"/>[0269] The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R.B. flask, equipped with a mechanical stirrer, an air condenser, a dropping funnel, and a moisture-guard tube, was placed chlorosulfonic acid (240 mL, 3.594 mol). Under stirring, PCI5 (300 g, 1.44 mol, 0.40 equiv) was added in portions, over ca. 45 mins. During the addition, a large volume of HCl gas evolved vigorously, but the temperature of the mixture did not rise significantly (<40 0C). By the time all the PCI5 had been added, an almost clear, pale yellow solution resulted, with only a few solid pieces of PCI5 floating in the suspension. It was stirred until gas evolution ceased (0.5 h). [0270] Then the reaction vessel was cooled in ice, and 2-chloro-thiophene (66.0 mL, 0.715 mol) was added via the dropping funnel, over 1.0 h. With the addition of the very first few drops of 2-Cl-thiophene, the mixture turned dark purple, and by the time all of the thiophene had been added, a dark purple solution resulted. During the addition, HCl gas evolved continuously, at a slow rate. The reaction mixture was then stirred at room temperature overnight.[0271] Then the mixture, dark-purple clear solution, was added drop wise to crushed ice (3 L), over 0.5 h. On addition to ice, the purple color disappeared instantaneously; the colorless thin emulsion was stirred mechanically at room temperature for ca. 15 h. Then the mixture was extracted with CH2Cl2 (3 x 300 mL). The combined CH2Cl2-extract was washed with water (Ix 200 mL), saturated NaHCO3 (Ix 250 mL), brine (1 x 100 mL), dried (Na2SO4), and concentrated on a rotary evaporator to yield the crude product as a pale yellow glue, which showed a tendency to solidify, yielding a semi-solid mass. This was then purified by high- vacuum distillation (bp 110-112°/12mm) to yield 135.20 g (88percent) of the title compound as a colorless/pale-yellow semi solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 0 - 23℃; | A. Synthesis of (tert-butyl)[(5-chloro(2-thienyl))sulfonyl]amine (0316) A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0°C was treated with a solution of 5.7 mL (75.5 mmol) oft-butylamine. After warming to 23°C, the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98percent) of the named compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With chlorosulfonic acid; phosphorus pentachloride; at 0 - 20℃; | The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R.B. flask, equipped with a mechanical stirrer, an air condenser, a dropping funnel, and a moisture-guard tube, was placed chlorosulfonic acid (240 mL, 3.594 mol). Under stirring, PCl5 (300 g, 1.44 mol, 0.40 equiv) was added in portions, over ca. 45 mins. During the addition, a large volume of HCl gas evolved vigorously,- but the temperature of the mixture did not rise significantly (<40 0C). By the time all the PCl5 had been added, an almost clear, pale yellow solution resulted, with only a few solid pieces of PCI5 floating in the suspension. It was stirred until gas evolution ceased (0.5 h).[0102] Then the reaction vessel was cooled in ice, and 2-chloro-thiophene (66.0 mL, 0.715 mol) was added via the dropping funnel, over 1.0 h. With the addition of the very first few drops of 2-Cl-thiophene, the mixture turned dark purple, and by the time all of the thiophene had been added, a dark purple solution resulted. During the addition, HCl gas evolved <n="35"/>continuously, at a slow rate. The reaction mixture was then stirred at room temperature overnight.[0103] Then the mixture, dark-purple clear solution, was added dropwise to crushed ice (3 L), over 0.5 h. On addition to ice, the purple color disappeared instantaneously; the colorless thin emulsion was stirred mechanically at room temperature for ca. 15 h. Then the mixture was extracted with CH2Cl2 (3 x 300 mL). The combined CH2Cl2-extract was washed with water (Ix 200 mL), saturated NaHCO3 (Ix 250 mL), brine (1 x 100 mL), dried (Na2SO4), and concentrated on a rotary evaporator to yield the crude product as a pale yellow glue, which showed a tendency to solidify, yielding a semi-solid mass. This was then purified by high- vacuum distillation (bp 110-112712mm) to yield 135.20 g (88%) of the title compound as a colorless/pale-yellow semi solid. |
88% | With chlorosulfonic acid; phosphorus pentachloride; at 0 - 40℃; | Example 1: Synthesis of the intermediate sulfonylurea carbamate (8)Step 1 - Preparation 5-chlorothiophene-2-sulfonyl chloride: <n="64"/>[0269] The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R.B. flask, equipped with a mechanical stirrer, an air condenser, a dropping funnel, and a moisture-guard tube, was placed chlorosulfonic acid (240 mL, 3.594 mol). Under stirring, PCI5 (300 g, 1.44 mol, 0.40 equiv) was added in portions, over ca. 45 mins. During the addition, a large volume of HCl gas evolved vigorously, but the temperature of the mixture did not rise significantly (<40 0C). By the time all the PCI5 had been added, an almost clear, pale yellow solution resulted, with only a few solid pieces of PCI5 floating in the suspension. It was stirred until gas evolution ceased (0.5 h). [0270] Then the reaction vessel was cooled in ice, and 2-chloro-thiophene (66.0 mL, 0.715 mol) was added via the dropping funnel, over 1.0 h. With the addition of the very first few drops of 2-Cl-thiophene, the mixture turned dark purple, and by the time all of the thiophene had been added, a dark purple solution resulted. During the addition, HCl gas evolved continuously, at a slow rate. The reaction mixture was then stirred at room temperature overnight.[0271] Then the mixture, dark-purple clear solution, was added drop wise to crushed ice (3 L), over 0.5 h. On addition to ice, the purple color disappeared instantaneously; the colorless thin emulsion was stirred mechanically at room temperature for ca. 15 h. Then the mixture was extracted with CH2Cl2 (3 x 300 mL). The combined CH2Cl2-extract was washed with water (Ix 200 mL), saturated NaHCO3 (Ix 250 mL), brine (1 x 100 mL), dried (Na2SO4), and concentrated on a rotary evaporator to yield the crude product as a pale yellow glue, which showed a tendency to solidify, yielding a semi-solid mass. This was then purified by high- vacuum distillation (bp 110-112/12mm) to yield 135.20 g (88%) of the title compound as a colorless/pale-yellow semi solid. |
With chlorosulfonic acid; | EXAMPLE 1 Preparation of 5-dimethylamino-4-nitro-2-(N-methyl-N-1,1,2,2-tetrachloroethylthiosulfonamido)thiophene An 80-g (0.68 mol) sample of 2-chlorothiophene was added dropwise to a cooled (dry ice/acetone bath, about -10 to -15 C.) and stirred solution of 160 g (1.38 mol) of chlorosulfonic acid. After the addition was completed, the reaction mixture was stirred at 50 C for 2 hours, cooled, and then poured into 250 g of ice. The aqueous reaction mixture was extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulfate, and evaporated to give 40 g of 5-chloro-2-thienylsulfonyl chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.4% | at 60℃; for 3h; | In a three-neck flask 6.16 mL (46.1 mmol) 5-chlorothiophene-2-sulfonylchlorid was added drowse to 55.6 mL fuming nitric acid. In the beginning the solution was cooled to provide a temperature beneath 60 C. After three hours of stirring, the reaction was completed and the solution was poured on iced-water. The product was collected by vacuum filtration yielding 11.161 g of yellow crystals (92.4 %). 1H NMR (200 MHz, chloroform-d) d 8.30 (s, 1 H). 13C NMR (0791) (50 MHz, chloroform-d) d 129.8. MS m/z : 263 M+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran; at 0 - 23℃; | A. Synthesis of (tert-butyl)[(5-chloro(2-thienyl))sulfonyl]amine (0316) A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0C was treated with a solution of 5.7 mL (75.5 mmol) oft-butylamine. After warming to 23C, the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98%) of the named compound as an oil. |
In tetrahydrofuran; diethyl ether; | A. Synthesis of (tert-butyl)[(5-chloro(2-thienyl))sulfonyl]amine A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0 C. was treated with a solution of 5.7 mL (75.5 mmol) of t-butylamine. After warning to 23 C., the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98%) of the named compound as an oil. | |
In tetrahydrofuran; diethyl ether; | A. Synthesis of (tert-butyl)[(5-chloro(2-thienyl))sulfonyl]amine A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0 C. was treated with a solution of 5.7 mL (75.5 mmol) of t-butylamine. After warning to 23 C., the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98%) of the named compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With ammonium hydroxide; In water; acetonitrile; at 0 - 20℃; | 3 g (1 mol equiv.) 5-Chloro-thiophene-2-sulfonyl chloride was dissolved in 30 mL acetonitrile and cooled to 0C. Dropwise, 6.5 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 2.49 g (91 %) 5-chloro-thiophene-2-sulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) delta 7.21 (d, J=4.0 Hz, 1 H), 7.43 (d, J=4.0 Hz, 1 H), 7.79 (br.s., 2H). |
78% | The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R. B. flask, equipped with a mechanical stirrer, cone. NH4OH (500 mL, 148.50 g NH3, 8.735 mol NH3, 13.07 equiv NH3) was placed. The flask was cooled in ice and <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (145.0 g, 0.668 mol) was added, in portions over 0.5 h (it is a low-melting solid, and it was melted by warming, which was then conveniently added via a wide-bored polyethylene pipette). The sulfonyl chloride immediately solidifies in the reaction flask. After all the sulfonyl chloride had been added, the flask containing it was rinsed with THF (25 mL), and this also was transferred to the reaction vessel. Then the heavy suspension was stirred at room temperature for ca. 20 h. At the end of this time the reaction mixture was still a suspension but of a different texture.[0105] Then the mixture was cooled in ice, diluted with H2O (1.5 1), and acidified with cone. HCl to pH ca. 3. The solid product was collected by filtration using a Buchner funnel, rinsed with cold water, and air-dried to afford the title compound as a colorless solid, 103.0 g (78%). MS (M-H): 196.0; 198.0 | |
78% | With ammonia; In tetrahydrofuran; water; at 0 - 20℃; for 20.5h; | Step 2 - 5-chlorothiophene-2-sulfonamide;Cone. NH4OH <n="65"/>[0272] The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R. B. flask, equipped with a mechanical stirrer, cone. NH4OH (500 mL, 148.50 g NH3, 8.735 mol NH3, 13.07 equiv NH3) was placed. The flask was cooled in ice and <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (145.0 g, 0.668 mol) was added, in portions over 0.5 h (it is a low-melting solid, and it was melted by warming, which was then conveniently added via a wide-bored polyethylene pipette). The sulfonyl chloride immediately solidifies in the reaction flask. After all the sulfonyl chloride had been added, the flask containing it was rinsed with THF (25 mL), and this also was transferred to the reaction vessel. Then the heavy suspension was stirred at room temperature for ca. 20 h. At the end of this time the reaction mixture was still a suspension but of a different texture.[0273] Then the mixture was cooled in ice, diluted with H2O (1.5 1), and acidified with cone. HCl to pH ca. 3. The solid product was collected by filtration using a Buchner funnel, rinsed with cold water, and air-dried to afford the title compound as a white solid, 103.O g (78%). MS (M-H): 196.0; 198.0 |
With ammonium hydroxide; | A. 5-Chloro-2-thiophenesulfonamide 5-Chloro-2-thiophenesulfonyl chloride (4 g, 18.4 mmole) was added to ammonium hydroxide (100 ml of conc. aqueous solution). This mixture was stirred at room temperature and concentrated under vacuum. The precipitate was filtered and washed with hexanes and water to produce 1.94 g of solid. PMR (CD3 SOCD3) 7.87 (s, 2H), 7.45 (d, J=4 Hz, 1H) and 7.23 (d, J=4 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine; at 0 - 20℃; for 2h; | Example 27 Ethyl 7-[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indole-2-carboxylate To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.70 g) and pyridine (10 mL) was added <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (0.89 g) at 0C, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The elude was treated with activated carbon and concentrated to give the title compound (1.09 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 180 - 181C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydroxide; In tetrahydrofuran; water; at 0 - 25℃; for 17.5h; | 5-(1-Ethyl-propyl)-imidazolidine-2,4-dione (12.3 g, 72.3 mmol) was dissolved in a 150 mL solution of aqueous NaOH (11.6 g, 289.2 mmol). The solution was heated by microwave in a sealed vessel for 1 h. (Microwave conditions: 15 min 100% power, 150 C., 50 psi, then 5 min 0% power, then 15 min 100% power, 150 C., 50 psi, then repeat sequence.) Water and ammonium hydroxide were removed from the reaction mixture in vacuo and the resulting crude amino acid and NaOH mixture was used in the next reaction without further purification. [00093] The crude amino acid and NaOH mixture was dissolved in 300 mL of water. The mixture was cooled to 0 C. in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (17.3 g, 79.5 mmol) was dissolved in 100 mL of THF and added dropwise to the reaction mixture over 0.5 h. After 1 h the reaction mixture was allowed to warm gradually to 25 C. and stirred for 16 h. THF was removed in vacuo and then the mixture was acidified to pH 1 with IN HCl. After about 15 min, a precipitate began to crash out of the milky white solution. After 1 h, the mixture was cooled in a refrigerator for 1 h and then filtered. The precipitate was washed with 1 N HCl to provide N-[(5-chloro-2-thienyl)sulfonyl]-3-ethylnorvaline as a white solid (18.5 g, 78%). Mass Spectrum (-ESI): 325 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; at 0 - 20℃; for 72h; | A mixture of 2(S)-amino-3-ethylpentanol (34.1 g, 0.26 mol) and methylene chloride (700 mL) was placed under Argon, and cooled to 0 C. Triethylamine (36.2 mL, 0.26 mol) was added, followed by the dropwise addition of <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (56.4 g, 0.26 mol) in methylene chloride (400 mL). The reaction mixture was allowed to warm slowly to room temperature as the ice bath melted. After 3 days at room temperature, the reaction mixture was divided into two-0.6 L portions. Each portion was diluted with ethyl acetate (1L), and washed three times with saturated potassium phosphate monohydrate (200 mL), once with brine (200 mL), and dried (Na2SO4). Concentration under reduced pressure gave a white solid (74.5 g, 92%). The product (87.98 g) from several runs were combined and recrystallized from hot heptane:ethyl acetate (4:1, 775 mL) to give the title compound as crystals (74.9 g, 85%): mp 115-117.6 C.; Opt. Rot. [alpha]D25=+10.81 (1% solution, MeOH); 1H NMR (DMSO-d6, 500 MHz): delta 7.71 (d, J=8.1 Hz, 1H), 7.44 (d, J=4.1 Hz, 1H), 7.22 (d, J=4.1 Hz, 1H), 4.56 (t, J=5.2 Hz, OH), 3.31-3.15 (m, 3H), 1.40-1.15 (m, 4H), 1.07 (m, 1H), 0.79 and 0.76 (two overlapping triplets, J=7.3 Hz, 6H); 13C NMR (DMSO-d6, 100 MHz): delta 141.75, 133.73, 130.95, 127.60, 60.41, 56.89, 41.57, 21.31, 20.80, 11.79, 11.51; MS(-ESI): [M-H]-1, 1 chlorine isotope pattern, 310(100%), 312 (30%); Anal. Calc. for C11H18CINO3S2: C, 42.37, H, 5.82, N, 4.49. Found: C, 42.34, H, 5.65, N, 4.43. Chiral HPLC (Chiralpak AD, 25×0.46 cm, eluant 8:2 hexane/isopropanol containing 0.1% TFA, flow rate 0.5 mL/min, UV detection at 254 nm, retention times for the S and R isomers are 10.95 min and 11.95 min, respectively) revealed an S/R ratio of 100.0:0.0. |
With triethylamine; In dichloromethane; | Example 7 5-Chloro-N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]-2-thiophenesulfonamide A mixture of 2(S)-amino-3-ethylpentanol (34.1 g, 0.26 mol) and methylene chloride (700 mL) was placed under Argon, and cooled to 0 C. Triethylamine (36.2 mL, 0.26 mol) was added, followed by the dropwise addition of <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (56.4 g, 0.26 mol) in methylene chloride (400 mL). The reaction mixture was allowed to warm slowly to room temperature as the ice bath melted. After 3 days at room temperature, the reaction mixture was divided into two-0.6 L portions. Each portion was diluted with ethyl acetate (1 L), and washed three times with saturated potassium phosphate monobasic (200 mL), once with brine (200 mL), and dried (Na2SO4). Concentration under reduced pressure gave a white solid (74.5 g, 92%). The product (87.98 g) from several runs were combined and recrystallized from hot heptane:ethyl acetate (4:1, 775 mL) to give the title compound as crystals (74.9 g, 85%): mp 115-117.6 C.; Opt. Rot. [alpha]D25=+10.81 (1% solution, MeOH); 1H NMR (DMSO-d6, 500 MHz): delta7.71 (d, J=8.1 Hz, 1H), 7.44 (d, J=4.1 Hz, 1H), 7.22 (d, J=4.1 Hz, 1H), 4.56 (t, J=5.2 Hz, OH), 3.31-3.15 (m, 3H), 1.40-1.15 (m, 4H), 1.07 (m, 1H), 0.79 and 0.76 (two overlapping triplets, J=7.3 Hz, 6H); 13C NMR (DMSO-d6, 100 MHz): delta141.75, 133.73, 130.95, 127.60, 60.41, 56.89, 41.57, 21.31, 20.80, 11.79, 11.51; MS(-ESI): [M-H]-, 1 chlorine isotope pattern, 310 (100%), 312 (30%); Anal. Calc. for C11H18ClNO3S2: C, 42.37; H, 5.82; N, 4.49. Found: C, 42.34; H, 5.65; N, 4.43. Chiral HPLC (Chiralpak AD, 25*0.46 cm, eluant 8:2 hexane/isopropanol containing 0.1% TFA, flow rate 0.5 mL/min, UV detection at 254 nm, retention times for the S and R isomers are 10.95 min and 11.95 min, respectively) revealed an S/R ratio of 100.0:0.0. | |
With triethylamine; In dichloromethane; at 0℃; for 0.5h;Inert atmosphere;Product distribution / selectivity; | A mixture of (S)-2-amino 3ethyl pentan-1-ol (9) (200 mg) and methylene chloride (20 mL) was placed under argon, and cooled to 0 C. Triethyl amine (484 mg) was added followed by the drop wise addition of <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (347.2) in methylene chloride (5 mL) for 30 min to obtain (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol (1A) (45.2% overall yield and 98% ee). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydroxide; In diethyl ether; water; at 20℃; for 1.08333h; | A solution of 5-chloro-2-thiophenesulfonyl chloride (2.17 g, 10 mmol) in ethyl ether (20 ml) was added to a stirred solution of N-(1-methylcyclopropyl)guanidine hydrochloride (1.48 g, 10 mmol) in 1 N sodium hydroxide (20 ml) during 5 min, and the mixture was stirred at room temperature for 1 h. The resulting precipitate was isolated by filtration, washed with ethyl ether and dried to give 2.44 g (83%) of the title compound as a white solid: 1H-NMR (DMSO-d6): delta 0.65 (br s, 4H), 1.25 (s, 3H), 7.12 (d, 1H), 7.34 (d, 1H), 6.5-8.0 (broad peaks, 3H); LC-MS: m/z 294/296 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydroxide; In diethyl ether; water; at 20℃; for 1.5h; | A solution of 5-chloro-2-thiophenesulfonyl chloride (4.9 g, 22.5 mmol) in ethyl ether (50 ml) was added to a stirred suspension of N-octylguanidine hemisulfate (5.0 g, 22.7 mmol) in 1N sodium hydroxide (50 ml), and the mixture was stirred at room temperature for 90 min. The organic phase was separated, dried over sodium sulfate, concentrated, and triturated with heptane (25 ml) to afford 4.0 g (51%) of the title compound as an off-white solid: 1H-NMR (DMSO-d6): delta 0.86 (distorted t, 3H), 1.1-1.5 (m, 12H), 3.05 (t, 2H), 6.6-7.4 (very broad peak, 3H), 7.11 (d, 1H), 7.34 (d, 1H); LC-MS: m/z 352/354 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium hydroxide; In diethyl ether; water; at 20℃; for 1h; | A solution of 5-chloro-2-thiophenesulfonyl chloride (10 g, 46 mmol) in ethyl ether (100 ml) was added to a stirred solution of N-ethylguanidine hydrochloride (5.7 g, 46 mmol) in 1N sodium hydroxide (100 ml), and the mixture was stirred at room temperature for 1 h. The resulting precipitate was isolated by filtration, washed with ethyl ether and dried to give 9.15 g (73%) of the title compound as a white solid: 1H-NMR (DMSO-d6): delta 1.02 (t, 3H), 3.09 (quint, 2H), 7.12 (d, 1H), 7.37 (d, 1H), 6.5-8.0 (broad peaks, 3H); LC-MS: m/z268/270 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With pyridine; at 20℃; for 16h; | Eine Loesung von 500 mg (3.87 mmol) 2, 5-DIFLUORANILIN in 5 ml Pyridin wird mit 925 mg (4.26 mmol) 5-CHLORTHIOPHEN-2-SULFONYLCHLORID versetzt und 16 h bei Raumtemperatur geruehrt. Nach Verduennen mit Ethylacetat wird die organische Phase einmal mit gesaettigter NATRIUMHYDROGEN- carbonat-Loesung, dreimal mit 1 N Salzsaeure und nochmals mit gesaettigter NATRIUMHYDROGEN- carbonat-Loesung gewaschen, ueber Natriumsulfat getrocknet und im Vakuum vom Loesungsmittel befreit. Das erhaltene Rohprodukt wird an Kieselgel chromatographiert (Laufmittel : Cyclo- HEXAN/ETHYLACETAT 10 : 1---> 7 : 1, v/v). Die PRODUKTHALTIGE Fraktion wird eingedampft und in einer Mischung aus Pentan und Diethylether (20 : 1, v/v) verruehrt. Der ausgefallene Feststoff wird abge- saugt und im Vakuum getrocknet. Ausbeute : 550 mg (46% d. Th.) HPLC (Methode 2) : Rt = 4.67 min. MS (DCI/NH3) : M/Z = 327 (M+NH4) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine In dichloromethane for 48h; | 1.D D. 5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)- 1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide To {2-ethyl-1-[1-(4-methoxybenzyl)- 1H-pyrazol-5-yl]butyl}amine (0.500 g, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.29 mL, 2.1 mmol) and 5-chlorothiophene-2-sulfonyl chloride (0.450 g, 2.09 mmol). After 2 days the reaction mixture was diluted with EtOAc (30 mL), washed with 1 N HCl (30 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexane, 3:7, then 1:1) provided 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (0.415 g, 51%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 0.62 (t, 3H, J=7.4 Hz), 0.70 (t, 3H, J=7.3 Hz), 0.93-1.04 (m, 2H), 1.16-1.40 (m, 3H), 3.71 (s, 3H), 4.46 (m, 1H), 5.20 (q, 2H, J=15.8 Hz), 6.12 (d, 1H, J=1.8 Hz), 6.84 (d, 1H, J=4.1 Hz), 6.88 (d, 2H, J=8.7 Hz), 6.95 (d, 1H, J=4.0 Hz), 7.05 (d, 2H, J=8.7 Hz), 7.24 (d, 1H, J=1.8 Hz), 8.46 (d, 1H, J=9.5 Hz); Mass Spectrum (-ESI): 466 (M-H)-. Anal: Calc'd for C21H26ClN3O3S2 C, 53.89; H, 5.60; N, 8.98. Found: C, 53.96; H, 5.72; N, 8.66. |
With dmap; triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine In dichloromethane | 10.E E. 5-Chloro-N-{2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide To a stirred solution of the {2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}amine (0.77 g, 2.8 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.59 mL, 4.2 mmol) and 5-chlorothiophene-2-sulfonylchloride (0.73 g, 3.4 mmol). The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed twice with 1N HCl, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to yield a tan solid in 54% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, 1H, J=9.5 Hz), 7.41 (m, 1H), 7.24 (m, 3H), 7.10 (m, 3H), 6.31 (m, 1H), 4.50 (m, 1H), 3.83 (s, 3H), 1.31 (m, 1H), 1.19 (m, 2H), 1.06 (m, 2H), 0.59 (t, 3H, J=7.3 Hz), 0.50 (t, 3H, J=7.3 Hz); IR (solid ATR, cm-1) 3270, 3090, 2880, 1515, 1410; MS (ESI+): 454 (M+H)+. Anal: Calc'd for C20H24N3O3S2Cl: C, 52.91; H, 5.33; N, 9.26. Found: C, 53.08; H, 5.33; N, 9.16. |
With dmap; triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In dichloromethane; for 18h; | F. 5-Chloro-N-{2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide To a stirred solution of the {2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}amine (0.133 g, 0.481 mmol) in CH2Cl2 (10 mL) was added Et3N (0.10 mL, 0.72 mmol) followed by <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (0.115 g, 0.529 mmol). The reaction mixture was stirred for 18 h, concentrated in vacuo, partitioned between 0.1N HCl and EtOAc. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 3:7) provided pure material as a yellow solid in 60% yield. 1H NMR (400 MHz, DMSO-d6) delta 8.83 (broad m, 1H), 7.79 (s, 1H), 7.22 (m, 2H), 7.11 (m, 3H), 7.01 (d, 1H, J=4.0 Hz), 5.30 (s, 2H), 4.47 (d, 1H, J=8.4 Hz), 1.56 (m, 1H), 1.39 (m, 1H), 1.29 (m, 1H), 0.79 (m, 1H), 0.61 (m, 1H), 0.59 (t, 3H, J=7.4 Hz), 0.52 (t, 3H, J=7.3 Hz); IR (solid ATR, cm-1) 3050,2870,1520, 1420; Mass Spectrum (+ESI): 457 (M+H)+. Anal: Calc'd for C19H22N4O2S2ClF: C, 49.94; H, 4.85; N, 12.26. Found: C, 50.24; H, 4.84; N, 12.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In dichloromethane; for 3.5h; | D. N-[1-(1-Benzyl-1H-imidazol-2-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide To a stirred solution of [1-(1-benzyl- 1H-imidazol-2-yl)-2-ethylbutyl]amine (448 mg, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.36 mL, 2.6 mmol) and 5-chlorothiophene-2-sulfonylchloride (453 mg, 2.09 mmol). The mixture was stirred for 3.5 h and then diluted with EtOAc, washed twice with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, CHCl3, then 1% MeOH/CHCl3 to 2% MeOH/CHCl3) to yield a white solid in 59% yield. 1H NMR (400 MHz, DMSO-d6): delta 8.51 (br s, 1H), 7.29 (m, 2H), 7.26 (m, 1H), 7.08 (m, 2H), 6.99 (m, 3H), 6.75 (s, 1H), 5.05 (m, 2H), 4.33 (d, 1H, J=8.05 Hz), 1.51 (m, 1H), 1.41 (m, 1H), 1.26 (m, 1H), 0.69 (m, 2H), 0.55 (t, 3H, J=7.44 Hz), 0.48 (t, 3H, J=7.38 Hz). IR (solid ATR, cm-1) 2970, 1480. Mass Spectrum (ES+): 438 (M+H)+. Anal: Calc'd for C20H24ClN3O2S2 C, 54.84; H, 5.52; N, 9.59 Found: C, 54.64; H, 5.58; N, 9.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With triethylamine; In dichloromethane; at 20℃; for 16h; | D. N-{1-[1-(Benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}-5-chlorothiophene-2-sulfonamide In a flask containing a mixture of triethylamine (0.045 mL, 0.325 mmol) and {1-[1-(benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}amine (0.081 g, 0.296 mmol) in CH2Cl2 (1 mL) at ambient temperature was added <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (0.064 g, 0.296 mmol). After 16 h the mixture was diluted with CH2Cl2 (10 mL) and poured into saturated aqueous NaHCO3 (10 mL). The organic phase was separated and washed sequentially with 1N HCl solution, distilled water, brine and then dried over MgSO4, filtered, and concentrated to an oil. Purification by flash chromatography (hexane/EtOAc, 4:1) afforded the product as a solid (0.084 g, 62%). Mass Spectrum (+ESI): 454 (M+H)+. Anal: Calc'd for C20H24ClN3O3S2 C, 52.91; H, 5.33; N, 9.26 Found: C, 53.00; H, 5.45; N, 9.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 1h; | Example 248; 5-Phenvl-3-ureido-thiophene-2-sulfonic acid (S)-piperidin-3-vlamide; tert-butyl (3S)-3-[(5-chloro-2-thienyl)sulfonyl]amino}piperidine-1-carboxylate. ; 5- Chlorothiophene-2-sulfonyl chloride (lg, 4. 6062mmol), tert-butyl (3S)-3-aminopiperidine-1- carboxylate (1.1070g, 5. 5274mmol), and 20mL dichloromethane were added to a 50mL round bottom flask. Diisopropylethylamine was then added with stirring. Let stir one hour. Wash reaction mixture with water, then dry over MgSO4. Filter, and concentrate filtrate to dryness; 1.75g, 99percent, 4. 60mmol.'H NMR (300 MHz, CDC13) 5 ppm 1.69 (m, 2 H), 1.80 (m, 2 H), 3.20 (m, 1 H), 3.31 (m, 1 H), 3.41 (m, 2 H), 3.56 (m, 1 H), 4.94 (d, 1 H), 6.94 (d, 1 H), 7.45 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In dichloromethane; at -78 - 20℃; | J 4- {2-(2,4-dichlorophenyl)-5-methyl-4-r(piperidin- 1 -ylamino)carbonyl"|- lH-imidazol- 1 - o yllphenyl 5-chlorothiophene-2-sulfonate2-(2,4-Dichlorophenyl)-l-(4-hydroxyphenyl)-5-methyl-N-piperidin-l-yl-lH-imidazole-4- carboxamide, prepared as described in B, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.16 ml, 1.12 mmol) in dichloromethane (2.5 ml) were cooled to -780C. 5- Chlorothiophen-2-sulfonyl chloride (244 mg, 1.12 mmol) in dichloromethane (2.5 ml) was s carefully added to the reaction mixture. The resulting mixture was stirred at -780C for Ih, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory etaPLC gave the title compound (84 mg, 60%) as a solid. o 1H nuMR (400 MHz) delta 7.90 (s, NH), 7.34-7.26 (m, 4H), 7.10 (d, 4H), 6.96 (d, IH), 2.88- 2.85 (m, 4H), 2.49 (s, 3H), 1.79-1.74 (m, 4H), 1.47-1.42 (m, 2H). MS m/z 625 (M+H)+. |
60% | With triethylamine; In dichloromethane; at -78 - 20℃; | 2-(2, 4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-lH-imidazole-4- carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.16 ml, 1.12 mmol) in dichloromethane (2.5 ml) were cooled to-78C. 5- Chlorothiophen-2-sulfonyl chloride (244 mg, 1.12 mmol) in dichloromethane (2.5 ml) was carefully added to the reaction mixture. The resulting mixture was stirred at-78C for lh, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (84 mg, 60%) as a solid. 'H NMR (400 MHz) 8 7.90 (s, NH), 7.34-7. 26 (m, 4H), 7.10 (d, 4H), 6.96 (d, 1H), 2.88- 2.85 (m, 4H), 2.49 (s, 3H), 1.79-1. 74 (m, 4H), 1.47-1. 42 (m, 2H). MS m/z 625 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydroxide; In tetrahydrofuran; hydrogenchloride; water; | 5-(1-Ethyl-propyl)-imidazolidine-2,4-dione (12.3 g, 72.3 mmol) was dissolved in a 150 mL solution of aqueous NaOH (11.6 g, 289.2 mmol). The solution was heated by microwave in a sealed vessel for 1 h. (Microwave conditions: 15 min a 100% power, 150 C., 50 psi, then 5 min 0% power, then 15 min a 100% power, 150 C., 50 psi, then repeat sequence.) Water and ammonium hydroxide were removed from the reaction mixture in vacuo and the resulting crude amino acid and NaOH mixture was used in the next reaction without further purification. The crude amino acid and NaOH mixture was dissolved in 300 mL of water. The mixture was cooled to 0 C. in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (17.3 g, 79.5 mmol) was dissolved in 100 mL of THF and added dropwise to the reaction mixture over 0.5 h. After 1 h the reaction mixture was allowed to warm gradually to 25 C. and stirred for 16 h. THF was removed in vacuo and then the mixture was acidified to pH 1 with IN HCl. After about 15 min, a precipitate began to crash out of the milky white solution. After 1 h, the mixture was cooled in a refrigerator for 1 h and then filtered. The precipitate was washed with 1 N HCl to provide N-[(5-chloro-2-thienyl)sulfonyl]-3-ethylnorvaline as a white solid (18.5 g, 78%). Mass Spectrum (-ESI): 325 (M-H)-. |
78% | With sodium hydroxide; In tetrahydrofuran; water; | 5-(1-Ethyl-propyl)-imidazolidine-2,4-dione (12.3 g, 72.3 mmol) was dissolved in a 150 mL solution of aqueous NaOH (11.6 g, 289.2 mmol). The solution was heated by microwave in a sealed vessel for 1 h. (Microwave conditions: 15 min a 100% power, 150 C., 50 psi, then 5 min 0% power, then 15 min a 100% 150 C., 50 psi, then repeat sequence.) Water and ammonium hydroxide were removed from the reaction mixture in vacuo and the resulting crude amino acid and NaOH mixture was used in the next reaction without further purification. The crude amino acid and NaOH mixture was dissolved in 300 mL of water. The mixture was cooled to 0 C. in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (17.3 g, 79.5 mmol) was dissolved in 100 mL of THF and added dropwise to the reaction mixture over 0.5 h. After 1 h the reaction mixture was allowed to warn gradually to 25 C. and stirred for 16 h. THF was removed in vacuo and then the mixture was acidified to pH 1 with 1N HCl. After about 15 min, a precipitate began to crash out of the milky white solution. After 1 h, the mixture was cooled in a refrigerator for 1 h and then filtered. The precipitate was washed with 1 N HCl to provide N-[(5-chloro-2-thienyl)sulfonyl]-3-ethylnorvaline as a white solid (18.5 g, 78%). Mass Spectrum (-ESI): 325 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; methanol; | Example 8 5-Chloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide To a solution of L-valinol (25.8 mg, 0.25 mmol) in THF (3 mL) was added triethylamine (58 muL, 0.3 mmol) and 5-chlorothiophene-2-sulfonyl chloride (54 mg, 0.25 mmol). The solution was stirred for 8 to 16 h, then concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC1 to give Example 8 (19.5 mg). The following compounds (Examples 8-10, Table 2) were prepared using 5-thiophene-2-sulfonyl chloride and 5-bromothiophenesulfonyl chloride with L-valinol and D-valinol and following the procedure outlined in Example 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.11 g (16%) | In N,N-dimethyl-formamide; | Example 16 Synthesis of 4',5-Dichloro-N-methyl-2'-nitro-2-thiophenesulfonanilide (Compound No. 370) To a suspension of sodium hydride (60%, 0.15 g (3.75 mmol)) in DMF (5.0 ml), <strong>[15950-17-1]4-chloro-N-methyl-2-nitroaniline</strong> (0.34 g (1.82 mmol)) was added with stirring at room temperature. To the resulting mixture, after 30 minutes' stirring at room temperature, 5-chloro-2-thiophenesulfonyl chloride (0.67 g (3.11 mmol)) was added. The reaction mixture was stirred at room temperature for 24 hours and then poured into water and extracted with chloroform. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with acetone-hexane (1:4) as eluent, to give 0.11 g (16%) of the title compound as pale yellow crystals. mp: 85.0-86.0 C.; NMR (CDCl3) delta: 3.31 (3H, s), 6.96 (1H, d, J=4.0 Hz), 7.17 (1H, d, J=8.5 Hz), 7.26 (1H, d, J=4.0 Hz), 7.56 (1H, dd, J=8.5 & 2.5 Hz), 7.90 (1H, d, J=2.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine; In pyridine; at 20℃; for 1h; | To a stirred solution of commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) in pyridine (10 mL) was added at room temperature commercially available 1-methylpiperazine (0.46 g, 4.61 mmol). The reaction mixture was stirred at room temperature for 1 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/methanol) to yield the title compound (0.92 g, 63%) as an off-white solid. MS (ISP) 280.9 [(M+H)+], mp 242 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 mL) was added at 0 C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.96 g, 77%) as an off-white solid. MS (ISP) 272.2 [(M+H)+], mp 101 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a stirred solution of 2-dimethylamino-ethylamine (1.61 g, 13.8 mmol) in THF (20 mL) was added at 0 C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/MeOH) to yield the title compound (1.23 g, 99%) as a light yellow oil. MS (ISP) 269.0 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a stirred solution of 4-(2-aminoethyl)-morpholine (1.80 g, 13.8 mmol) in THF (20 mL) was added at 0 C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.34 g, 93%) as a colorless oil. MS (ISN) 309.0 [(M-H)-]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 mL) was added at 0 C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.15 g, 88%) as a white solid. MS (ISN) 284.3 [(M-H)-], mp 69 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydrogencarbonate; In tetrahydrofuran; diethyl ether; water; at 40 - 60℃; | a) 3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenol A mixture of orcinol monohydrate (5.0 g, 35.2 mmol) and <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (7.64 g, 35.2 mmol) in 50 mL of saturated aqueous sodium bicarbonate, 50 mL of diethyl ether, and 15 mL of tetrahydrofuran was stirred at 60C for 2 h and then at 40C overnight. The reaction mixture was extracted into diethyl ether, dried (MgSO4), and passed through a thick pad of silica gel (ca. 500 mL) using elutions of dichloromethane and then 3% diethyl ether / dichloromethane to provide 5.49 g (51%) of the title compound as a pale orange oil. 1H-NMR (300 MHz, CDCl3) delta 7.40 (d, 1 H, J = 4 Hz), 6.94 (d, 1 H, J = 4 Hz), 6.59 (br s, 1 H), 6.49 (br s, 1 H), 6.40 (t, 1 H, J = 2 Hz), 5.38 (s, 1 H), 2.26 (3 H). Mass spectrum (MALDI-TOF gentisic acid matrix) calcd. for C11H9ClO4S2: 327.0 (M + Na). Found: 327.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium sulfate; triethylamine; In dichloromethane; | 8. 5-Chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide To (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (1.07 g, 6.25 mmol) and triethylamine (0.87 mL, 6.2 mmol) in CH2Cl2 (15 mL) at 0 C. was added dropwise a solution of 5-chlorothiophene-2-sulfonylchloride (1.34 g, 6.25 mmol) in CH2Cl2 (15 mL). The reaction mixture was warmed to 25 C. and stirred for 24 h. It was then diluted with EtOAc (100 mL) and washed with aqueous 0.1 N HCl (50 mL) and brine (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried using Na2SO4 and concentrated. Flash chromatography (eluent: 3:7 EtOAc-hexane) provided 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (1.66 g, 75%) as a white solid. Recrystallization (EtOAc-heptane, 1:4) provided white needles (1.39 g, 84% recovery), mp 136-137 C. Anal: Calc'd for C10H13ClF3NO3S2 C, 34.14; H, 3.72; N, 3.98. Found: C, 34.24; H, 3.97; N, 3.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.2% | With hydrogenchloride; In tetrahydrofuran; sodium hydroxide; | A. [(5-Chlorothien-2-yl)sulfonyl]amino}(4,4-difluorocyclohexyl)acetic acid The amino(4,4-difluorocyclohexyl)acetic acid (2.68g, 10.973 mmol) was dissolved in 2N NaOH (20 mL). The solution was cooled to 0 C., <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (3.25g, 12.42 mmol) was added (5 min) dropwise as a solution in THF (10 mL). The solution was allowed to warm up to 25 C. overnight. After 19 h, THF was removed in vacuo and the mixture was acidified to a pH of about 1 to about 2 with 2N HCl (20 mL). The aqueous layer was washed with EtOAc (4*50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to produce [(5-chlorothien-2-yl)sulfonyl]amino}(4,4-difluorocyclohexyl)acetic acid as a crude oil (3.8 g, 98.2%). Mass Spectrum (-ESI): 372 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Reference Example 118; tert-butyl { [l-[ (5-chloro-2-thienyl) sulfonyl] -4-fluoro-5- (2- fluoropyridin-3-yl) -lH-pyrrol-3-yl] methyl }methylcarbamate; To a suspension of sodium hydride (60% in oil, 24.0 mg) <n="144"/>in tetrahydrofuran (2 mL) was added tert-butyl [5- (2- fluoropyridin-3-yl) -4-fluoro-lH-pyrrol-3- yl]methyl}methylcarbamate (150 mg) under ice-cooling, and the mixture was stirred for 15 min. 15-Crown-5 (133 mg) and a solution of <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> in tetrahydrofuran (1 mL) were added dropwise and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9: 1-»2 : 1) to give the title compound as a colorless oil (yield 229 mg, 98%) .1H-NMR (CDCl3) delta: 1.48(9H,s), 2.89(3H,s), 4.28 (2H,brs) , 6.84(lH,d, J=4.1Hz) , 7.01 (IH, d, J=4. IHz) , 7.20 (lH,brs) , 7.30(lH,ddd, J=7.3, 5.2, 1.7Hz) , 7.83 (IH, ddd, J=9.1, 7.5, 2. OHz) , 8.31 (IH, d, J=4.7Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With pyridine; In dichloromethane; at 0 - 20℃; | To a cooled (0 C.) solution of 2-amino-4,4,4,-trifluoro-3-phenyl-butyric acid methyl ester (200 mg, 0.81 mmol) from Step 4 in dichloromethane (DCM; 5 mL) was added 5-chloro-2-thienylsulfonyl chloride (193 mg, 0.89 mmol). Pyridine (1.5 eq., 1.21 mmol, 96 mg, 109 muL) was then added to the reaction mixture. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. Flash chromatography on SiO2 (gradient EtOAc/hexanes) yielded the title compound (268 mg, 77%) as an 8.4:1 mixture of diastereomers. 1H NMR 500 MHz (DMSO-d6): delta 3.06 (s, 0.36 H), 3.50 (s, 2.64 H), 3.93-3.98 (m, 1 H), 4.40-4.45 (m, 1 H), 7.10 (d, J=4.03 Hz, 0.88 H), 7.17 (d, J=4.15 Hz, 0.12 H), 7.24-7.34 (m, 5.88 H), 7.38 (d, J=4.15 Hz, 0.12 H), 9.02 (d, J=9.15 Hz, 0.88 H), 9.36 (d, J=9.15 Hz, 0.12 H). MS (-ESI): m/z 426 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 4-methyl-morpholine; dmap In dichloromethane at 1 - 6℃; for 21.5h; Large scale reaction; | |
83% | With 4-methyl-morpholine; dmap In dichloromethane at 0 - 10℃; for 16h; | 9.2 (S)-2-Amino-(R)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-butan-1-ol hydrochloride (44.83 g) and 4-dimethylaminopyridine (1.02 g) were added to a 1-L reaction flask. Methylenechloride (400 mL) was added and the mixture was cooled to 0 to 5° C. N-methylmorpholine (32.7 g) was added and the mixture maintained at 0 to 10° C. 5-chlorothiophene-2-sulfonyl chloride (34.4 g) was added via an addition funnel dropwise at 0 to 10° C. The reaction mixture was held at 5° C. until complete by HPLC (about 16 hours). A solution of concentrated hydrochloric acid (15 g) and water (219 g) was added and the mixture was adjusted to 25 to 30° C. The mixture was stirred at 25 to 30° C. for 10 min., and the two layers separated. The organic layer was washed with a solution of concentrated hydrochloric acid (15 g) and water (219 g) at 25 to 30° C. for 10 min., and the two layers separated. The organic layer was washed with water (250 mL) at 25 to 30° C. for 10 minutes, and the two layers separated. The organic layer was concentrated at atmospheric pressure to approximately half its original volume, and heptane (400 mL) was added. The mixture was cooled to 0 to 5° C. and the solid filtered. The product was washed with a mixture of methylene chloride and heptane (1:4 v/v, 250 mL total volume) then dried on the filter to provide the product (55 g, 83% yield. 94% AN HPLC purity). |
73% | With dmap In dichloromethane at 20℃; for 2h; | 1.H H. To a solution of (2S,3R)-2-amino-3-(3,5-difluorophenyl)-4,4,4-trifluorobutan-1-ol hydrochloride (29.1 g, 0.1 mol) and 4-(dimethylamino)-pyridine (DMAP, 27 g, 0.22 mol) in dichloromethane (800 mL) a solution of 5-chlorothiopene-2-sulphonyl chloride (22.3 g, 0.103 mol) in dichloromethane (60 mL) was added dropwise (mild exotherm). The mixture was stirred at room temperature for 2 hours, washed with 2N HCl (3×300 mL), brine (300 mL), NaHCO3 solution (300 mL), dried over MgSO4, and concentrated. The residue was dissolved in MTBE, washed with 0.5N HCl, brine, dried over MgSO4, and concentrated to afford 42.4 g of crude product. The crude product was dissolved in Et2O (100 mL) and heptane (500 mL) was added dropwise. The precipitated solids were filtered, washed with heptane, and dried in vacuum at room temperature to afford 32 g of the title product as off-white solid (73% yield). |
70% | With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 45 - 50℃; for 1.5h; | 9.1 (S)-2-Amino-(R)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-butan-1-ol hydrochloride (222 g) was added to a 5-L reaction flask. Isopropyl acetate (1.3 L) was added and the mixture stirred at room temperature to dissolve the solids. Ethyldiisopropylamine (246 g) was added and the mixture heated to 45-50° C. 5-chlorothiophene-2-sulfonyl chloride (157 g) was added via an addition funnel dropwise at 50° C. The reaction mixture was heated at 50° C. until complete by HPLC (about 1.5 hours) and the reaction mixture cooled to room temperature. Water (1.5 L) was added, the mixture stirred for 10 minutes, and the two layers separated. The organic layer was concentration under vacuum and co-evaporated with heptane (1.5 L). Heptane (1 L) was added, adjusted to an ambient temperature and the solid filtered. The product was washed with heptane, dried in a vacuum oven for 16 hours, and the product (240 g, 72.4% yield. 90% AN HPLC purity) collected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With pyridine; dmap; In dichloromethane; at 20℃; for 40h; | A mixture of (S)-3-((2S,3R)-2-amino-3-(3,5-difluorophenyl)-4,4,4-trifluorobutanoyl)-4-benzyloxazolidin-2-one hydrochloride (10 g, 21.6 mmol), 5-chlorothiopene-2-sulphonyl chloride (9.4 g, 43.2 mmol), DMAP (5.6 g, 43.2 mmol), pyridine (3.4 g, 3.5 mL, 43.2 mmol), and dichloromethane (300 mL) was stirred at room temperature for 40 hours. A NaHCO3 solution (300 mL) was added. The phases were separated and the organic phase was washed with 2N HCl (2×300 mL), brine, and concentrated. Flash chromatography purification (silica gel, methylene chloride) afforded 9.3 g of the title product (71% yield). 1H NMR (CD3OD, delta, ppm): 7.42 (d, J=4 Hz, 1 H), 7.34-7.22 (m, 3 H), 7.20-7.15 (m, 2 H), 7.04 (d, J=4 Hz, 1 H), 7.03-6.96 (m, 3 H), 5.91 (d, J=7 Hz, 1 H), 4.38-4.30 (m, 1 H), 4.29-4.19 (m, 1 H), 4.13 (dd, J=9, 2 Hz, 1 H), 4.0 (dd, J=9, 8 Hz, 1 H), 2.93 (dd, J=13.5, 3 Hz, 1 H), 2.57 (dd, J=13.5, 9 Hz, 1 H). MS (m/z, positive ESI, for M+H): 609. MS (m/z, negative ESI, for M-H): 607. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 50℃; | Synthesis of methyl 1-[(5-chloro-2-thienyl)sulfonylamino]cyclopropanecarboxylate 16 A suspension of methyl-1-aminocyclopropen carboxylate hydrochloride 12 (1 g, 1.43 mmol) in CH2Cl2 (100 mL) was added with TEA (1.1 mol eq, 1.01 mL) and the mixture was stirred at r.t. for 10 minutes. Then 5-chloro-thiophene-2-sulfonyl chloride (1 mol eq, 1.43 g) and additional TEA (1.1 mol eq) were added and the solution was heated at 50°C overnight. The solvent was removed at reduced pressure, water was added to the residue (100 mL) and the aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phases were dried over Na2SO4 and evaporated to reduced pressure to afford 16 as pale orange oil (quantitative yield). 1HNMR (DMSO, 200 MHz) delta 1.23 (m, 2H), 1.35 (m, 2H), 1.98 (s, 3H), 7.23 (d, 1H, J= 4), 7.73 (d, 1H, J=3.9), 9.12 (bs, 1H). |
100% | With triethylamine; In dichloromethane; at 50℃; | Synthesis of methyl l-[(5-chloro-2- thienyl)sulfonylamino]cyclopropanecarboxylate 16 A suspension of methyl- 1-aminocyclopropen carboxylate hydrochloride 12 (1 g, 1.43 mmol) in CH2C12 (100 mL) was added with TEA (1.1 mol eq, 1.01 mL) and the mixture was stirred at r.t. for 10 minutes. Then 5-chloro-thiophene-2-sulfonyl chloride (1 mol eq, 1.43 g) and additional TEA (1.1 mol eq) were added and the solution was heated at 50°C overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phases were dried over Na2S04 and evaporated under reduced pressure to afford 16 as a pale orange oil (quantitative yield). FontWeight="Bold" FontSize="10" HNMR (DMSO, 200 MHz) delta 1.23 (m, 2H), 1.35 (m, 2H), 1.98 (s, 3H), 7.23 (d, 1H, J= 4), 7.73 (d, 1H, J=3.9), 9.12 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With pyridine; In dichloromethane; at 20 - 45℃; | Example 683-[3-[(5-Chloro-2-thienyl)sulfonyl]amino}-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide; To a solution of 3-[3-amino-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 14) (22 mg, 0.07 mmol) in anhydrous pyridine (1 mL) and anhydrous dichloromethane (3 mL) (gentle heating of the mixture for a few minutes with a heatgun was required in order for the starting material to go in solution) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (16.71 mg, 0.077 mmol) in anhydrous dichloromethane (0.5 mL). The reaction was stirred at room temperature for 45 min, then at 45 C. for 30 min. A solution of 5-chloro-2-thiophenesulfonyl chloride (16.7 mg) in anhydrous dichloromethane (0.2 mL) was added to the reaction mixture and stirred at 45 C. for 25 h. The reaction mixture was cooled and then partitioned between water and dichloromethane. The organic layer was passed through an hydrophobic frit and evaporated in-vacuo to yield a pale yellow solid. The solid was dissolved in MeOH-DMSO (1 mL) and purified by MDAP on Sunfire C18 column, eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile). Appropriate fraction was evaporated in-vacuo to yield the title compound as a white solid (15.7 mg, 45%). LCMS (5 min run) RT=2.62 min, ES+ve m/z 495/497 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With pyridine In chloroform at 20℃; | 58 Intermediate 583-[3-Amino-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile; To a solution of 3-[3-amino-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 57) (470 mg, 1.59 mmol) in dry DCM (3 mL) and pyridine (1 mL, 12 mmol) was added 5-chloro-2-thiophenesulfonyl chloride (517 mg, 2.38 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (15 mL) and 2 M hydrochloric acid (15 mL). The aqueous was extracted with ethyl acetate and the combined organic solutions washed with water and brine, passed through a hydrophic frit and then concentrated in vacuo to leave a dark red oil. This was loaded in dichloromethane on to a silica 100 g cartridge and purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (206 mg, 27%) as a pale brown powder. LCMS (System A) RT=1.17 min ES+ve m/z 477/479 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With pyridine; In dichloromethane; at 45℃; for 62h;Inert atmosphere; | Intermediate 641,1-Dimethylethyl 3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-cyano-1H-indazole-1-carboxylate; 1,1-Dimethylethyl 3-amino-4-cyano-1H-indazole-1-carboxylate (for a preparation see Intermediate 63) (4.3 g, 16.65 mmol) was dissolved in a mixture of dichloromethane (40 mL) and pyridine (40 mL). 5-Chloro-2-thiophenesulfonyl chloride (7.23 g, 33.3 mmol) was added to the solution and it was stirred at 45 C. under nitrogen for 60 h. LCMS showed approx 30% starting material remaining, so further quantity of 5-chloro-2-thiophenesulfonyl chloride (3.5 g, 16.12 mmol) was added to the reaction, and the mixture was stirred for 2 h. LCMS showed no change in product so the reaction was concentrated under vacuo. The residue was dissolved in DCM (200 mL) and washed 3 times with water (200 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue (10 g) was dissolved in DCM and loaded onto a 750 g silica column and purified by chromatography on the Companion system using a 0-25% ethyl acetate-DCM gradient. Appropriate fractions were evaporated in vacuo to give the title compound (5.8 g, 56%) as an orange solid. LCMS (System A) RT=1.45 min, ES+ve m/z 636/638 (M+NH4)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With pyridine In dichloromethane Inert atmosphere; | 60 Intermediate 601,1-Dimethylethyl[(3-[3-[(5-chloro-2-thienyl)sulfonyl]amino}-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate; 1,1-Dimethylethyl[(3-[3-amino-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 59) (3.4 g, 8.49 mmol) was dissolved in a mixture of dichloromethane (14 mL) and pyridine (21 mL) and the reaction was left to stir under nitrogen for 2 h. LCMS showed starting material remaining, so an extra portion of 5-chloro-2-thiophenesulfonyl chloride (0.461 g, 2.12 mmol) was added to the reaction mixture and stirred for 45 min. The reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (250 mL) and washed with water (3×250 mL). The organic layer was washed once with brine (200 mL) and dried over anhydrous magnesium sulfate before being evaporated in vacuo. The residue was dissolved in dichloromethane, loaded onto a 100 g silica cartridge and purified by chromatography on Flashmaster II using a 0-100% ethyl acetate-cyclohexane gradient over 80 min. Appropriate fractions were combined and the solvent was evaporated to give the title compound (2.7 g, 55%) as an orange solid. LCMS (System A) RT=1.27 min, ES+ve m/z 581/583 (M+H)+. |
55% | Stage #1: 1,1-dimethylethyl [(3-[3-amino-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate With pyridine In dichloromethane for 2h; Inert atmosphere; Stage #2: 5-chlorothien-2-ylsulfonyl chloride In dichloromethane for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With pyridine; In dichloromethane; at 0 - 20℃; | Intermediate 61,1-Dimethylethyl 3-[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate; To a solution of 1,1-dimethylethyl 3-amino-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 5) (6.03 g, 22.9 mmol) and 5-chloro-2-thiophenesulfonyl chloride (3.07 mL, 22.9 mmol) in DCM (30 mL) was added dropwise at 0 C. a solution of pyridine (3.7 mL, 46 mmol) in DCM. The reaction mixture was stirred allowing to warm from 0 C. to room temperature over 2 h, then stirred at room temperature over the weekend. Pyridine (50 mL) were added and resulting mixture was stirred at 50 C. for another 24 h. The reaction mixture was then quenched with 50 mL of a saturated NaHCO3 solution. The organic layer was partitioned and the aqueous layer was further extracted with 50 mL of DCM. The organic solutions were combined, washed with water (50 mL) then brine (50 mL), and dried with an hydrophobic frit. The crude product was purified by chromatography on two 100 g Si cartridges on Flashmaster, eluting with 0 to 25% gradient of EtOAc in DCM, over 60 min to give the desired product as a pale orange solid: (2.21 g, 22%). LCMS (System A) RT=1.35 min, ES+ve m/z 444 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With pyridine In dichloromethane at 45℃; for 72h; Inert atmosphere; | 9 Intermediate 91,1-Dimethylethyl 3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1 -carboxylate; To a solution of 1,1-dimethylethyl 3-amino-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 5) (3.24 g, 12.31 mmol) and 5-chloro-2-thiophenesulfonyl chloride (8.01 g, 36.9 mmol) in DCM (50 mL) was added pyridine (9.95 mL, 123 mmol). The reaction mixture was stirred at 45° C. under nitrogen for 3 days. The reaction mixture was quenched using saturated sodium bicarbonate solution (100 mL) and diluted with DCM (100 mL). The phases were separated and the aqueous phase was extracted using DCM (100 mL). The combined organic solutions were washed with brine and filtered through an hydrophobic frit. The solvent was removed in vacuo and the residue was dissolved in DCM (30 mL). This was applied to a 330 g silica cartridge and eluted with a gradient of 0-25% ethyl acetate in DCM over 10 CV. The required fractions were evaporated in vacuo to give the title compound (4.17 g, 54%) as a white solid LCMS (System B) RT=4.12 min, ES+ve m/z 624/626/628, and 1,1-dimethylethyl 3-[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate (1.45 g, 26%) as a pale yellow solid LCMS (System B) RT=3.72 min, ES+ve m/z 444/446 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; at 20℃;Inert atmosphere; | Intermediate 35-Chloro-N-[1-[(3-cyanophenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide; To 3-[3-amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 2) (7.89 g, 28.3 mmol) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (Aldrich)(6.15 g, 28.3 mmol) in pyridine (9.17 mL, 113 mmol) under nitrogen at room temperature. Reaction was exothermic and went deep red. After 40 minutes the reaction mixture was separated between ethyl acetate (500 mL) and 2N hydrochloric acid (500 mL). The aqueous phase was washed with ethyl acetate (400 mL). The combined organic solutions were dried over magnesium sulphate and evaporated in vacuo. The deep red residue was dissolved in DCM and applied to a 340 g silica cartridge. The cartridge was eluted with a gradient of 0-10% ethyl acetate in dichloromethane over 8 CV. Evaporation of the appropriate fractions gave the title compound (11.1 g, 85%) as an off-white solid. LCMS (System A) RT=1.15 min, ES+ve m/z 459/461 (M+H)+. |
85% | With pyridine; at 20℃; for 0.666667h;Inert atmosphere; | Intermediate 11 5-Chloro- V-[1-[(3-cyanophenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2- thiophenesulfonamideTo 3-[3-amino-4-(methyloxy)-1 /-/-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 10)(7.89 g, 28.3 mmol) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (Aldrich)(6.15 g, 28.3 mmol) in pyridine (9.17 mL, 1 13 mmol) under nitrogen at room temperature. Reaction was exothermic and went deep red. After 40 minutes the reaction mixture was separated between ethyl acetate (500 mL) and 2N hydrochloric acid (500 mL). The aqueous phase was washed with ethyl acetate (400 mL). The combined organic solutions were dried over magnesium sulphate and evaporated in vacuo. The deep red residue was dissolved in DCM and applied to a 340g silica cartridge. The cartridge was eluted with a gradient of 0-10% ethyl acetate in dichloromethane over 8CV. Evaporation of the appropriate fractions gave the title compound (1 1.1 g, 85%) as an off- white solid. LCMS (System A) RT=1.15 min, ES+ve m/z 459/461 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With pyridine In dichloromethane at 20℃; | 45 Intermediate 455-Chloro-N-[1-[(3-cyanophenyl)methyl]-7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide; To a solution of 3-[3-amino-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 44) (665 mg, 2.24 mmol) in dry DCM (10 mL) was added 5-chloro-2-thiophenesulfonyl chloride (0.300 mL, 2.24 mmol), followed with pyridine (2 mL). The resultant dark yellow solution was stirred at room temperature overnight. More 5-chloro-2-thiophenesulfonyl chloride was added (0.100 mL) and the reaction stirred for a further 1 h. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (×2). The combined organic solutions were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to leave a deep red oil. This residue was loaded in dichloromethane to a silica 100 g cartridge and purified by chromatography on Flashmaster eluting with a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (323 mg, 30%) as a pale yellow powder. LCMS (System A) RT=1.2 min, ES+ve m/z 476/478 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | Example 16 5-Chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (214 mg, 1.30 mmol) and triethylamine (0.538 mL, 3.9 mmol) in 5 mL dichloromethane at 0 C. was added a solution of <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (0.267 mL, 1.23 mmol) in 1 mL dichloromethane. The reaction was stirred at 0 C. for 30 min and at room temperature for 30 min. The crude reaction mixture was purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to give 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (330 mg, 84%). 1H NMR (400 MHz, CDCl3) delta ppm 7.40 (d, J=4.03 Hz, 1H), 6.91 (d, J=4.03 Hz, 1H), 5.24 (d, J=7.30 Hz, 1H), 3.86 (d, J=11.33 Hz, 1H), 3.32-3.48 (m, 1H), 3.05 (d, J=6.55 Hz, 1H), 2.32 (br. s., 1H), 1.72-1.83 (m, 1H), 1.58-1.73 (m, 3H), 1.11-1.36 (m, 5H). MS [M+H]+=310; [M+Na]+=332. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | To a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-1-ol (2 g, 8.1 mmol) in isopropyl acetate (10 mL), 4-methyl morpholine (2.7 mL, 24.6 mmol) was added. The mixture was stirred at 20 to 25 C. for 5 to 10 minutes and then <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20 to 25 C. for 6 to 18 hours. Water (10 mL) was added to the reaction mixture and the solid dissolved. The two layers were separated, the organic layer was washed with 10% NaHCO3 (10 mL) and 10% NaCl (10 mL), and heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was reduced in volume by about half by distillation under atmospheric conditions. While the solution remained at 80 to 90 C., heptane (10 mL) was added over 5 to 10 minutes. A solid began to form during heptane addition. After addition, the mixture was cooled to 20 to 25 C., the solution was stirred for 1 to 2 hours, and then further cooled to 5 to 10 C. for 1 hour. The solid was collected by filtration, washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of an off-white solid. 98% area HPLC purity and >99% chiral purity by HPLC. | |
67% | Example 2 Preparation of 5-Chloro-N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoro-methyl)propyl]thiophene-2-sulfonamide 4-methyl morpholine (2.7 mL, 24.6 mmol) was added to a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-1-ol (2 g, 8.1 mmol) in isopropyl acetate (10 mL). The mixture was stirred at about 20-25 C. for about 5-10 minutes and then <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20-25 C. for 6-18 hours. Water (10 mL) was then added to the reaction mixture, whereby the solids dissolved. The two layers were then separated and the organic layer was washed with a solution of 10% NaHCO3 (10 mL) and 10% NaCl (10 mL). Heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was then distilled down to about half of its original volume under atmospheric distillation. While the solution remained at about 80-90 C., heptane (10 mL) was added over 5-10 minutes, during which time solids formed. After the addition of heptane, the mixture was cooled to 20-25 C., stirred for about 1-2 hours, and then further cooled to about 5-10 C. for 1 hour. The solid was then collected by filtration, washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of the product as an off-white solid. 98 area% HPLC purity and >99% chiral purity by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Embodiment 21: Preparation of Compound 6k (5-Chloro-thiophene-2-sulfonic acid (5,8-dimethyl-9H-carbazol-1-yl)amide)); A mixture of 4 (0.5 g, 3.08 mmol) and 10% Pd/C (0.2 g) in methanol (30 mL) was stirred under hydrogen for 1 hour. Pd/C was removed by filtration and filtrate was evaporated in vacuo to yield oily product. To the product, ethyl acetate (30 mL) and 5-chloro-thiophene-2-sulfonyl chloride (0.7 g, 3.24 mmol) were added and stirred at room temperature for 1 hour. The reaction was roughly purified by passing through silica gel packed funnel and wash with ethyl acetate. The filtrate was evaporated in vacuo and the crude product was reacted with acetonylacetone (0.5 mL, 4.38 mmol) in the presence of p-toluenesulfonic acid (0.7 g, 4.06 mmol) in EtOH (20 mL) at reflux for 3 hours. Finally, the mixture was purified with column chromatography to afford white solids, compound 6k (0.87 g, 72.40 %; Hex/EA = 8/1, Rf = 0.33). mp = 232-234 C; ESI (M-H+) 389.0; 1H NMR (400 Hz, DMSO-d6) delta 2.71 (s, 3H, CH3), 6.86 (d, J= 7.2 Hz, 1H, ArH), 7.07-7.16 (m, 3H, ArH), 7.31 (d, J= 8.0 Hz, 1H, ArH), 7.37 (d, J= 4.0 Hz, 1H, ArH), 10.20 (s, 1H, NH), 10.57 (s, 1H, NH); 13C NMR (100 Hz, DMSO-d6) delta 16.49, 20.05, 117.51, 117.84, 119.14, 119.61, 120.37, 120.40, 120.64, 124.99, 126.24, 127.87, 129.83, 132.63, 132.71, 135.32, 138.08, 138.60. Anal. (C18H15CIN2O2S2): Calcd, C, 55.31; H, 3.87; N, 7.17; S, 16.41; Found, C, 55.37; H, 3.60; N, 7.45; S, 16.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.3% | With potassium carbonate; In tetrahydrofuran; at 20℃; for 6h; | To a solution of (2S,35)-2-aminobutane-l,3-diol (<strong>[44520-55-0]D-threoninol</strong>, 880 mg, 8.12 mmol) in THF (15 mL) and potassium carbonate, 5-chlorothiophene-2-sulfonyl chloride(1679 mg, 7.73 mmol) in THF (3 mL) was added. The reaction mixture was stirred at room temperature for 6 h and then quenched with water (20 mL). THF was removed in vacuo, the residue was extracted with ethyl acetate and the organic layer was washed with water, brine and dried. After standard work-up, 1.378 g of crude liquid was purified by flash chromatography (hexane:ethyl acetate, 0-90%) to provide 1.20 g (54.3%) of product.MS (m/z): 285.81 (M++l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.1% | With triethylamine; In acetonitrile; at 20℃; for 16h; | To a solution of <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (108.5 mg, 0.5 mmol) in 4 mL of CH3CN, N-(3,4-dichlorobenzyl)propan-2-amine (108.4 mg, 0.55 mmol, 1.1 eq) and triethylamine (0.68 mmol, 1.25 eq) were added. The reaction mixture was stirred at room temperature for 16 h and then quenched with water. CH3CN was concentrated in vacuo and the crude residue was extracted with ethyl acetate. The organic layers were separated and washed with IN HC1, aqueous Na2C03, water and brine, and then dried over Na2S04. Subsequent filtration and concentration in vacuo provided a crude product that was purified by flash chromatography using 10-25% ethyl acetate in hexane to yield the title compound (78 mg, 39.1%). Mp 66-67 C. Elemental Analysis (Ci4Hi4Ci3N02S2) Calcd: C 42.17, H, 3.54, N, 3.51; Found: C, 42.52, H, 3.44, N, 3.48, MS (m/z) 398.2 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine In dichloromethane at 25℃; for 2h; | 26.5 Step 5:A mixture of C-(4-Methanesulfonyl-[2,2']bipyridinyl-6-yl)-methylamine (40.0mg, 0.153 mmol), triethylamine (58.0 μΙ_, 0.459 mmol), 5-chlorothiophene-2-sulfonyl chloride (42.0 mg, 0,184 mmol) and DCM (2 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to afford 5- chloro-thiophene-2-sulfonic acid (4-methanesulfonyl-[2,2]' bipyridinyl-6-ylmethyl)-amide as a white solid (20.0 mg, 30 %). m/z: [ES+] 443, 445, 446 [M+1]1 H NMR: (400 MHz, CDCI3) 3.13 (3H, s, CH3), 4.54 (2H, m, CH2), 6.41 (1 H, br s, NH), 6,78 (1 H, s, ArH), 7.38 (1 H, d, ArH), 7.43 (1 H, m, ArH), 7.73 (1 H, d, ArH), 7.90 (1 H, m, ArH), 8.33 (1 H, d, ArH), 8.72-8.75 (2H, m, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine; In dichloromethane; at 20℃; | To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)- pyridin-3-ylamine (E-9) in 5 mL DCM is added 1 12 mg (0.61 mmol) 5-chloro-thiophen-2- sulfonyl chloride and 72 mu. (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgS04 and concentrated under reduced pressure. The crude product is purified by RP chromatography (CI 8, 20-80% ACN in water containing 1% formic acid). Yield: 101 mg (65%). HPLC-MS: M+H = 506/508; tR=0.91 min. |
65% | With pyridine; In dichloromethane; at 20℃; | To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 112 mg (0.61 mmol) 5-chloro-thiophen-2-sulfonyl chloride and 72 muL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 101 mg (65%). HPLC-MS: M+H = 506/508; tR=0.91 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; In acetone; for 4h;Inert atmosphere; | The compound 3 (lg, 2.7mM) was dissolved in dry acetone and stirred for 5 mins. The NN-DIPEA (0.7 mL) was then added drop-wise to the stirring mixture during 10 mins inert nitrogen gas environment and stirred for an additional 10 mins. The <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (0.72 g) was then added to the reaction mixture drop-wise under inert nitrogen gas environment. The reaction mixture was stirred under inert nitrogen gas environment for 4 hrs. The completion of the reaction was monitored using TLC method. After the completion of the reaction, the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with distilled water. The organic layer was dried over sodium sulfate and concentrated to obtain the crude product, which was finally purified by column chromatography using EtOAcHexane (1:5) as eluent. % yield = 70%, Mass: m/z 550.5 (M+l)+; IR: 3468, 2970, 2368, 1559, 1215, 766; 'H-NMR (300MHz, DMSO-d6): delta 1.01 (t, 6H, J = 7.05 Hz, 7.14 Hz), 2.52 (m, 7H), 3.50 (s, 2H), 6.89 (s, 1H), 7.02 (d, 1H, J = 4.05 Hz), 7.12 (s, 1H), 7.15 (d, 1H , J = 2.4 Hz), 7.37 (d, 1H, J = 1.95 Hz), 7.39 (d, 1H, J = 1.89 Hz), 7.50 (d, 1H, J = 4.05 Hz), 7.59 (d, 1H, J = 1.98 Hz),7.95 (d, 1H, J = 1.89 Hz). |
70% | With N-ethyl-N,N-diisopropylamine; In acetone; for 3h;Inert atmosphere; | General procedure: The compound8was dissolved in dry acetone and stirred for 5 min. The N,N-diisopropylethyl amine (DIPEA) (1.2 equivalent) was then added dropwise to the stirring mixture during 10 min under nitrogen condition, and stirred for an additional 10 min. The desired aromatic/aliphatic/alicyclic sulfonyl chloride (1.2 eq.) was added to the reaction mixture dropwise under nitrogen condition, and then stirred for about 3 hrs. The completion of the reaction was monitored using TLC method. After the completion of the reaction, the solvent was evaporated under vacuum, and the residue was dissolved in ethyl acetate and washed with distilled water. The organic layer was dried over sodium sulfate and concentrated to obtain thecrude product, which was finally purified by column chromatography using EtOAc:Hexane(1:5) to yield the corresponding final products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | To a mixture of diisopropylethylamine (0.53mL, 3. 0mmol) and (d)-leucinamide·HCl (4, 0.17g, 1.0mmol) in CH2Cl2 (10mL) was added slowly <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (6, 0.26g, 1.20mmol). The resulting mixture was stirred at room temperature overnight, and then diluted with CH2Cl2, washed with H2O, and dried over MgSO4. The crude residue was purified by silica gel chromatography to give 8 (267mg, 86%) as a white powder; tlc Rf=0.50 (EtOAc/n-hexane=1 : 1); UV lambdamax (MeOH) nm (logepsilon): 288 (1.583); mp 228-229C; [alpha]D+10.0 (c 0.002, MeOH); cLogP=2.34; 1H NMR (DMSO-d6) delta 0.70 (3H, d, J=6.6Hz, CH3), 0.80 (3H, d, J=6.6Hz, CH3), 1.27-1.38 (2H, m, CHCH2), 1.50-1.55 (1H, m, CH3CHCH3), 3.64 (1H, t, J=7.2Hz, COCH), 6.88 (1H, br, NH), 7.27 (1H, s, NH), 7.61 (2H, d J=8.7Hz, thiophene-H), 7.76 (2H, d, J=8.7Hz, thiophene-H), 7.95 (1H, br, NH); 13C NMR (DMSO-d6) delta 21.7, 23.2, 24.4, 42.1, 55.2, 128.0, 131.8, 134.6, 141.0, 173.2; FABMS: 311 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Example 262- [methyl-(thiophene-2-sulfonyl)-amino]-N- [6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyll-acetamideTo a solution of 2-(methylamino)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)acetamide (84 mg, 259 imol) (from example 25, step b) and N,N-diisopropylethylamine (136 tl, 777 imol) in CH2C12 (3 ml) were added thiophene-2-sulfonyl chloride (47.3 mg, 259 imol). It was stuffed at room temperature overnight. Ethyl acetate was added. The organic layer was washed with iN HC1, brine, saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 2-[methyl-(thiophene-2-sulfonyl)-amino] -N[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl] -acetamide (56 mg, 46%) as a white solid. MH+= 471.N N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane; for 4h;Reflux; | Synthesis of methyl (2S)-2-[(5-chloro-2-thienyl)sulfonylamino]-3-hydroxy-propanoate 5 To L-serine methyl ester hydrochloride (5 g, 32.13 mmol) dissolved in methylene chloride (200 ml) was added with TEA (2 equiv., 8.95 ml) and in one portion <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (1.0 equiv., 6.97 g). The reaction was refluxed for 4 hours. The solvent was evaporated and the crude was dissolved in AcOEt (100 ml) and washed with water (1 X 80 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from diethyl ether and petroleum ether afforded 10 g of the white product. Yield = 93% 1HNMR (DMSO, 200 MHz) delta 2.81 (2H, q, J = 7.2 Hz), 3.52 (3H, s), 3.92 (1H, t), 5.06 (1H, bs), 7.24 (1H, dd, J = 4.2 Hz), 7.45 (1H, dd, J = 4Hz), 8.92 (1H, bs) |
93% | With triethylamine; In dichloromethane; for 4h;Reflux; | Synthesis of methyl (2S)-2-[(5-chloro-2-thienyl)sulfonylamino]-3-hydroxy- propanoate 5 L-Serine methyl ester hydrochloride (5 g, 32.13 mmol) dissolved in methylene chloride (200 ml) was added with TEA (2 equiv., 8.95 ml) and in one portion 5- chlorothiophene-2-sulfonyl chloride (1.0 equiv., 6.97 g). The reaction was refluxed for 4 hours. The solvent was evaporated and the crude was dissolved in AcOEt (100 ml) and washed with water (1 X 80 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from diethyl ether and petroleum ether afforded 10 g of the white product. Yield = 93% FontWeight="Bold" FontSize="10" HNMR (DMSO, 200 MHz) delta 2.81 (2H, q, J = 7.2 Hz), 3.52 (3H, s), 3.92 (1H, t), 5.06 (1H, bs), 7.24 (1H, dd, J = 4.2 Hz), 7.45 (1H, dd, J = 4Hz), 8.92 (1H, bs) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In diethyl ether; at 20℃; for 48h;Schlenk technique; Inert atmosphere; | General procedure: A Schlenk flask (250 mL) was charged with the iron chalcogenides(l-Ex)[CpFe(CO)2]2 (2.83 mmol) in 100 mL of diethyl ether.The sulfonyl chloride (2.83 mmol) dissolved in 20 mL of diethylether was added dropwise to the iron chalcogenide solution. Theresulting mixture was stirred for 48 h at room temperature. Thesolvent was removed under vacuum and the remaining solid wasdissolved in ca. 2 mL of CH2Cl2 and was introduced to a silica gelcolumn made up in hexane. Elution with a mixture of diethyl etherand hexane (9:1 volume ratio) gave an orange band which was collectedand identified as CpFe(CO)2ESO2Ar followed by a red bandwhich was also collected and identified as CpFe(CO)2Cl. TheCpFe(CO)2ESO2Ar were recrystallized from CH2Cl2/hexane at 4 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In diethyl ether at 20℃; for 48h; Schlenk technique; Inert atmosphere; | 3.2. General procedure for the preparation of CpFe(CO)2ESO2Ar (E = S,Se) General procedure: A Schlenk flask (250 mL) was charged with the iron chalcogenides(l-Ex)[CpFe(CO)2]2 (2.83 mmol) in 100 mL of diethyl ether.The sulfonyl chloride (2.83 mmol) dissolved in 20 mL of diethylether was added dropwise to the iron chalcogenide solution. Theresulting mixture was stirred for 48 h at room temperature. Thesolvent was removed under vacuum and the remaining solid wasdissolved in ca. 2 mL of CH2Cl2 and was introduced to a silica gelcolumn made up in hexane. Elution with a mixture of diethyl etherand hexane (9:1 volume ratio) gave an orange band which was collectedand identified as CpFe(CO)2ESO2Ar followed by a red bandwhich was also collected and identified as CpFe(CO)2Cl. TheCpFe(CO)2ESO2Ar were recrystallized from CH2Cl2/hexane at 4 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃; | L-Proline (1.0 g, 8.7 mmol) was dissolved in 2 mol/L aqueous sodium hydroxide solution (10 ml) and tetrahydrofuran (10 ml), 5-chloro-thiophene-2-sulfonylchloride (1.4 mL, 10 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, and the aqueous layer was neutralized with 2 mol/L hydrochloric acid and extracted with dichloromethane. The obtained organic layer was dried over sodium sulfate. The desiccant was filtered off, and the solvent was evaporated to give the title compound as a pale-brown solid (2.5 g, 8.4 mmol, 97%). MS (ESI) m/z 296 (M+H)+ 1H NMR (400 MHz, DMSO) delta 7.64 (d, J=4.1 Hz, 1H), 7.34 (d, J=4.1 Hz, 1H), 4.11 (dd, J=8.7, 4.1 Hz, 1H), 3.47-3.38 (m, 1H), 3.28-3.19 (m, 1H), 2.08-1.94 (m, 1H), 1.94-1.78 (m, 2H), 1.74-1.62 (m, 1H). |
97% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃; | L-Proline (1.0 g, 8.7 mmol) was dissolved in 2 mol/L aqueous sodium hydroxide solution (10 mL) and tetrahydrofuran (10 mL), 5-chloro-thiophene-2-sulfonylchloride (1.4 mL, 10 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, and the aqueous layer was neutralized with 2 mol/L hydrochloric acid and extracted with dichloromethane. The obtained organic layer was dried over sodium sulfate. The desiccant was filtered off, and the solvent was evaporated to give the title compound as pale-brown-brown crystals (2.5 g, 8.4 mmol, 97%).MS (ESI) m/z 296 (M+H)+1H NMR (400 MHz, DMSO) delta 7.64 (d, J=4.1 Hz, 1H), 7.34 (d, J=4.1 Hz, 1H), 4.11 (dd, J=8.7, 4.1 Hz, 1H), 3.47-3.38 (m, 1H), 3.28-3.19 (m, 1H), 2.08-1.94 (m, 1H), 1.94-1.78 (m, 2H), 1.74-1.62 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dmap; In pyridine; at 20℃; for 22h; | Compound 8 N-[2-(benzylsulfanyl)-5-chloropyridin-3-yl]-5-chlorothiophene-2-sulfonamide [0158] pyridine (5 ml) was added <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (356 mg, 1.64 mmol) and catalytic amount of DMAP. The reaction was stirred at room temperature for 6 hours, and additional <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (356 mg, 1.64 mmol) was added. The reaction was continued for 16 hours and was concentrated. The crude mixture was diluted with MeOH, treated with 4M NaOH (1.6 ml) at 100 C. for 10 minutes, cooled to room temperature, acidified with 6M HCl, and extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-25% EtOAc in hexane) to yield Compound 8 (424 mg, 60%). [0160] 1H NMR (METHANOL-d4) delta 8.35 (d, J=2.3 Hz, 1H), 7.67 (d, J=2.3 Hz, 1H), 7.21-7.28 (m, 6H), 6.91 (d, J=3.8 Hz, 1H), 4.29 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.9% | With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: To a stirred solution of the appropriate indolamine (1.50 mmol),and Et3N (4.50 mmol) in dry CH2Cl2 (3 mL/mmol) at 0 C was addeddropwise a solution of benzylsulfonamide (2.25 mmol) under nitrogen.The mixture was reacted at 0 C for 2 h, and for 18e22 h atroom temperature. The residue was poured into water (20 mL) andextracted with CH2Cl2 (3 x 20 mL). The combined organic layerswere dried (Na2SO4), filtered and concentrated under reducedpressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH, 98:2) gave compounds 1e30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.5% | With TEA; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | To a solution of 17 (100 mg, 0.325 mmol) in 5 mL of DCM, TEA (181 muL, 1.302 mmol) added and reaction was cooled to 0 C, <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (106 mg, 0.488 mmol) was added and stirred for 2 h at RT. Then water was added and extracted with DCM which was dried over sodium sulfate. The DCM layer was concentrated and purified by flash chromatography in DCM and MeOH (95:5) to get pure product (85 mg). Yield: 53.5%; off-white solid; m.p. 98-100 C; 1H NMR (300 MHz, DMSO-d6) delta (ppm): 8.50 (s, 1H), 7.52 (d, J = 4.2 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.09-7.06 (m, 1H), 6.61 (t, J = 10.2 Hz, 1H), 4.70 (s, 5H), 4.02 (s, 5H), 3.71-3.66 (m, 1H), 3.22-3.19 (m, 2H); 13C NMR (100 MHz, DMSO-d6) delta: 153.91, 152.41, 139.48, 135.54, 134.54, 131.58, 130.04, 127.99, 114.74 (2C), 106.91, 79.70 (2C), 70.88, 62.25 (2C), 47.11, 45.36, 40.12; LC-MS (ESI +ve) m/z 488.1 [M+H]+; HRMS (ESI +ve) m/z [M+H]+calcd for: C19H19ClFN3O5S2; 488.0511, found 488.0501; HPLC Purity: 99.29%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; | The title compound was prepared from 36a (50 mg, 0.28 mmol),<strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (67 mg, 0.31 mmol) andsodium hydride (13 mg of a 60% w/w dispersion in mineral oil,0.34 mmol) according to the procedure described for the preparationof 27. The same work up and purification afforded 53 (47 mg,47%) as a white solid; 1H NMR (400 MHz, DMSO-d6) d = 12.26 (br.s,1H), 8.24 (s, 1H), 7.62 (d, J = 4.0 Hz, 1H), 7.20 (d, J = 4.0 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H); LCMS (Method A, UV, ES) RT = 0.91 min,[M+H]+ = 360, 362, 100% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; dmap; In dichloromethane; at 20℃; | General procedure: A mixture of 2,4-difluorobenzenesulfonyl chloride (12.76 g, 60 mmol), pyridine (6 mL, 75 mmol), 5-bromo-2-methoxypyridin-3-amine 15a (10.15 g, 50 mmol), and DMAP (1.22 g, 10 mmol) in DCM (200 mL) was stirred at rt overnight. Water was added and the resulting mixture was extracted with DCM (200 mL×3). The combined organic layers were washed with water (200 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EtOAc = 5:1) to afford 16a as a yellow solid (16.48 g, 87% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 20h; | To a solution of (2S,4R)-l-[(2S)-2-aminopropanoyl]-4-[(4-methoxyphenyl)methylsulfonyl]-N- [(2S,3S)- 1 , 1 , l-trifluoro-2-hydroxy-4-methylpentan-3-yl]pyrrolidine-2-carboxamide x HC1 (Intermediate A-5, 0.050 g, 0.085 mmol) in DCM (1 mL) cooled to 0C was added Huenig's base (0.044 mL, 0.254 mmol), followed by <strong>[2766-74-7]5-chlorothiophene-2-sulfonyl chloride</strong> (0.022 g, 0.102 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 20 hours. The mixture was diluted with DCM, poured into a sat. NH4C1 aq. solution and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over Na2S04, filtered, and evaporated to dryness. The residue was purified by silica gel flash chromatography, eluting with a 0 - 20% EtOAc-heptane gradient gradient to give the title compound (0.034 g, 55%) as a light brown solid. MS: 734.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere; | General procedure: To a stirred solution of 4 (1.0 mmol) in THF (5 mL) was added appropriate sulfonyl chloride (1.1 mmol) and NaHCO3 (38 mmol). The reaction mixture was stirred at room temperature for 4 h under nitrogen atmosphere. Then the solvent was evaporated in vacuum. The residue was diluted with water. The whole mixture was extracted with AcOEt for three times. The combined organic layer was washed with water, sat. brine, and dried over Na2SO4. The crude product was purified by column chromatography using petroleum ether/AcOEt (10/1-8/1, v/v) as eluent to afford F01-F35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; triethylamine In dichloromethane for 15h; | 3.1 General procedure: 4.1.1. General method for the preparation of 3′-aryl sulfonyl derivatives ofspiro[fluorene-9,5′-imidazolidine]-2′,4′-dione (IIIa and IIIb)Arylsulfonyl chloride (5.8 mmol) was added dropwise to a stirredmixture of compound II (4.8 mmol), triethylamine (4.8 mmol) andcatalytic amount of DMAP in DCM (10 mL), and stirred for 15 h. Thereaction mixture was neutralized with 1 N aqueous HCl and extractedwith dichloromethane (4×25 mL). After evaporation of the solvent,the crude product was recrystallized from ethanol-water mixture inorder to obtain yellowish white semi-solid. compounds IIIa and IIIb[26]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | With 1-butyl-3-methylimidazolium hydroxide In dichloromethane Reflux; | 4 Preparation of N-[(diethoxyphosphonyl)-4-fluorobenzyl]-5-chloro-2-thiophenesulfonamide (IId) Weigh 1.0 mmol of intermediate 1 (diethyl α-aminobenzylphosphonate) and 1.0 mmol 5-Chloro-thiophene-2-sulfonyl chloride in a 50 mL reaction flask, then add 10 mL of dichloromethane and 0.5 mmol of basic ionic liquid [Bmim] OH, heat to reflux, and the reaction was monitored by TLC. Purification by chromatography (eluent: ethyl acetate: petroleum ether = 1:2) to give a white solid.For the target compound (IId),The yield was 83.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | With triethylamine; In dichloromethane; at 25℃; for 4h; | General procedure: To a mechanically stirred suspension of suspension of 1 (0.21 g, 0.53 mmol) in 30 ml CH2Cl2 were added triethylamine (0.5 ml) and aromatic sulfonyl chloride (0.53 mmol) at 25 C for 4 h. The reaction process was detected by TLC method. Then, antagonized by dilute sodium hydroxide, extracted, and washed with ether and water, evaporated under vacuum. Finally, the mixture was recrys-tallizated from ethyl acetate , providing a total product yield of 65.4%-88.6 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | General procedure: To a stirred suspension of 2-(3,4-dimethoxyphenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine. Hydrochloride (IP-NH) (150 mg, 0.404 mmol) in dry dichloromethane (5.0 mL),Hunig?s base (0.18mL, 1.01 mmol) at 0C, corresponding sulfonyl chloride (0.606 under N2atmospherewas added. Later mmol) was added to the above solution and resultant mixture was heated to room temperature for 2 h. The reaction progress was monitored by TLC; after completion of reaction, as indicated by TLC, the reaction mixture was diluted with dichloromethane and organic layers were washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The resultant residue was purified by column chromatography (silica gel 100-200 mesh, ethyl acetate /pet ether60%) to yield compounds IPS 1-22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With pyridine In acetonitrile at 70℃; for 5h; | General procedure: 17a-f (0.77 mmol, 1 eq) and pyridine (0.19 mL, 2.32 mmol,3 eq) were dissolved in abs. MeCN (10 mL) and the desired aryl orheteroaryl sulfonyl chloride (0.10 mL, 0.77 mmol, 1 eq) was added. Theresulting reaction mixture was stirred at 70 °C for 5 h. After cooling toroom temperature CH2Cl2 (10 mL) was added. The organic layer was washed with HCl (10%, 10 mL), dried over Na2SO4 and concentratedunder reduced pressure. The residue was purified via column chromatography(heptane/EtOAc, gradient 10:0 to 1:1) to afford desired indolinylmethylsulfonamide 8e-z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With pyridine In acetonitrile at 70℃; for 5h; | General procedure: 17a-f (0.77 mmol, 1 eq) and pyridine (0.19 mL, 2.32 mmol,3 eq) were dissolved in abs. MeCN (10 mL) and the desired aryl orheteroaryl sulfonyl chloride (0.10 mL, 0.77 mmol, 1 eq) was added. Theresulting reaction mixture was stirred at 70 °C for 5 h. After cooling toroom temperature CH2Cl2 (10 mL) was added. The organic layer was washed with HCl (10%, 10 mL), dried over Na2SO4 and concentratedunder reduced pressure. The residue was purified via column chromatography(heptane/EtOAc, gradient 10:0 to 1:1) to afford desired indolinylmethylsulfonamide 8e-z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With pyridine; In acetonitrile; at 70℃; for 5h; | General procedure: 17a-f (0.77 mmol, 1 eq) and pyridine (0.19 mL, 2.32 mmol,3 eq) were dissolved in abs. MeCN (10 mL) and the desired aryl orheteroaryl sulfonyl chloride (0.10 mL, 0.77 mmol, 1 eq) was added. Theresulting reaction mixture was stirred at 70 C for 5 h. After cooling toroom temperature CH2Cl2 (10 mL) was added. The organic layer was washed with HCl (10%, 10 mL), dried over Na2SO4 and concentratedunder reduced pressure. The residue was purified via column chromatography(heptane/EtOAc, gradient 10:0 to 1:1) to afford desired indolinylmethylsulfonamide 8e-z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With pyridine In acetonitrile at 70℃; for 5h; | General procedure: 17a-f (0.77 mmol, 1 eq) and pyridine (0.19 mL, 2.32 mmol,3 eq) were dissolved in abs. MeCN (10 mL) and the desired aryl orheteroaryl sulfonyl chloride (0.10 mL, 0.77 mmol, 1 eq) was added. Theresulting reaction mixture was stirred at 70 °C for 5 h. After cooling toroom temperature CH2Cl2 (10 mL) was added. The organic layer was washed with HCl (10%, 10 mL), dried over Na2SO4 and concentratedunder reduced pressure. The residue was purified via column chromatography(heptane/EtOAc, gradient 10:0 to 1:1) to afford desired indolinylmethylsulfonamide 8e-z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.5% | With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: To a stirred solution of the appropriate indolamine (1.50 mmol),and Et3N (4.50 mmol) in dry CH2Cl2 (3 mL/mmol) at 0 C was addeddropwise a solution of benzylsulfonamide (2.25 mmol) under nitrogen.The mixture was reacted at 0 C for 2 h, and for 18e22 h atroom temperature. The residue was poured into water (20 mL) andextracted with CH2Cl2 (3 x 20 mL). The combined organic layerswere dried (Na2SO4), filtered and concentrated under reducedpressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH, 98:2) gave compounds 1e30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With triethylamine; In dichloromethane; at 20℃; for 18h; | General procedure: A solution of compound 8 (90 mg, 0.44 mmol), 4-chlorobenzenesulfonyl chloride (103 mg, 0.49 mmol) and triethylamine (68 muL, 0.49 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 h. The reaction was quenched through the addition of water (20 mL) and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The mixture was then diluted with dichloromethane (20 mL) and the separated aqueous layer further extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with aqueous phosphate buffer solution (0.5 M, pH 7) (20 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound 9a as a beige solid (96 mg, 0.25 mmol, 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In dichloromethane; at 0 - 5℃; for 1h; | General procedure: Berbamine hydrochloride 1 (500 mg, 0.73 mmol) was suspended in 5ml CH2Cl2. Themixture was cooled to 0-5 C. Triethylamine (180 mg, 1.78 mmol) and sulfonyl chloride(0.79 mmol) were added to the reaction solution. The solution was stirred for 1 hat 0 C and stirred another hour at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. Combined organic layers werewashed with saturated salt, dried over anhydrous Na2SO4, filtered, evaporated andpurified on silica gel column chromatography (Eluent: CH2Cl2/CH3OH 8:1) to givethe product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: diallylamine With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: 5-chlorothien-2-ylsulfonyl chloride In dichloromethane at 20℃; | General procedure for the synthesis of sulfonyl diallylamines (1a-t). General procedure: Triethylamine (116 mg, 1.15 mmol) was added dropwise to a stirred solution of diallylamine (100 mg, 1.03 mmol) in dry dichloromethane (3.0 mL) at 0 °C. After 0.5h, sulfonyl chloride (1.0 mmol) was slowly added to the mixture. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a seperatory funnel containing water (3.0 mL). The aqueous was removed and the organic phase was subsequently washed with 1 M HCl (3.0 mL), and brine(3.0 mL), dried over Na2SO4 and filtered. The volatiles were removed in vacuo and the residue was subjected to flash column chromatography to give the sulfonyl diallylamines. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With pyridine In N,N-dimethyl-formamide at 0 - 20℃; for 24h; | 4.1.1 General procedure for synthesis of compounds 3a-k General procedure: To a solution of (E)-4-(phenyldiazenyl)aniline (1) (0.507mmol, 0.1000g) in DMF (0.400mL/mmol) at 0°C was added slowly pyridine (0.400mL/mmol) and proper sulfonyl chloride (2a-k) (0.507mmol). The reaction was allowed to stir at room temperature for 24h. After completion of the reaction, the resulting mixture was poured into water (10mL) and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with water (30mL), brine (30mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2 100% or cicloexane:AcOEt 9:1) gave compounds 3a-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine In dichloromethane at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tri-n-propylamine; fluorosulfonyl fluoride In acetone at 20℃; for 2h; Inert atmosphere; | 3. General Procedure for Aryl Sulfonyl Fluorides Synthesis General procedure: An oven-dried reaction flask (30 mL) equipped with a stirring bar was charged with aryl sulfonyl chloride (1, 2 mmol), n-Pr3N (6.0 mmol, 860 mg, 3.0 equiv.) and THF (10 mL). Then the flask was covered with a plastic stopper before the sulfuryl fluoride gas (SO2F2) was introduced into the mixture by slowly bubbling from a SO2F2 balloon. The air in the flask was excluded by SO2F2 gas for about 10 seconds and the resulting mixture was subsequently allowed to stir at room temperature for 2 h. Once the reaction reached its completion, the mixture was diluted with water and the aqueous phrase was extracted with EtOAc (20 mL 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness under vacuum. The residue was purified through flash silica gel chromatography using a mixture of ethyl acetate and petroleum ether as eluent to afford the desired aryl sulfonyl fluoride 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triphenylphosphine; 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane; sodium hydroxide In 1,2-dimethoxyethane at 25℃; for 24h; Schlenk technique; Inert atmosphere; Glovebox; | General Procedure for the Borane-Promoted Reductive Deoxygenation CouplingReaction of Sulfonyl Chlorides with Alkyl Bromides (1-18, 36-39): General procedure: A 25 mL Schlenk tube was equipped with a magnetic stir bar, PPh3 (0.6 mmol,0.157 g), B2pin2 (0.4 mmol, 0.102 g), Sulfonyl Chlorides (0.3 mmol) and NaOH (1mmol, 40 mg) were added in glove box, then moved it out of the glove box. The tube was evacuated and backfilled nitrogen three times, followed by Alkyl Bromides (0.2mmol) and fresh distilled DME (1.0 mL) in sequence. The reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with saturated NH4Cl aqueous solution, then extracted with ethyl acetate (2 mL×3), and the organic layer was separated. The organic phase was dried over Na2SO4 and concentrated in vacuum. The concentrat was separated and purified by silica gel flash chromatography (PE) to obtain the corresponding product. |
Tags: 2766-74-7 synthesis path| 2766-74-7 SDS| 2766-74-7 COA| 2766-74-7 purity| 2766-74-7 application| 2766-74-7 NMR| 2766-74-7 COA| 2766-74-7 structure
[ 155731-14-9 ]
5-Chlorothiophene-2-sulfonic acid tert-butylamide
Similarity: 0.54
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