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CAS No. : | 6961-82-6 | MDL No. : | MFCD00051974 |
Formula : | C6H6ClNO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JCCBZCMSYUSCFM-UHFFFAOYSA-N |
M.W : | 191.64 | Pubchem ID : | 81410 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 42.45 |
TPSA : | 68.54 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.94 cm/s |
Log Po/w (iLOGP) : | 1.15 |
Log Po/w (XLOGP3) : | 0.74 |
Log Po/w (WLOGP) : | 2.07 |
Log Po/w (MLOGP) : | 0.9 |
Log Po/w (SILICOS-IT) : | 0.63 |
Consensus Log Po/w : | 1.1 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.83 |
Solubility : | 2.82 mg/ml ; 0.0147 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.76 |
Solubility : | 3.34 mg/ml ; 0.0174 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.58 |
Solubility : | 0.502 mg/ml ; 0.00262 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.75 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
With potassium carbonate In acetone | ||
With potassium carbonate In acetone for 8h; Reflux; | Synthetic procedure of intermediates 8a-8d General procedure: A mixture of 7a-7d (1.0 equiv), ethyl chloroformate (1.2 equiv) and fine powdered K2CO3 (1.5 equiv) in dry acetone was heated to reflux for 8 h. Then 1 M HCl was added to acidify the reaction to pH=1. The solvent was removed in vacuo and the aqueous phase was extracted by ethyl acetate for 3 times. The combined organic phase was washed twice with brine and dried over MgSO4. The solvent was removed under reduced pressure to give 8a-8d as white solid over 95 % yields. The crude product was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 2.16667h; | 5.1 Step 1 To a solution of 2-chlorobenzene-l-sulfonyl chloride (2.0 g, 9.5 mmol, 1.3 mL) in THF (20.0 mL) was added NH3.H20 (3.3 g, 28.4 mmol, 3.7 mL, 25% solution) at 0°C. The mixture was stirred at 0°C for 10 min and then warmed to 20°C for 2 h. The reaction mixture was concentrated to afford 2-chlorobenzenesulfonamide (1.8 g, 9.4 mmol, 99.1% yield). 1H NMR (400MHz, DMSO-d6) δ 7.96 (dd, J= 1.4, 7.8 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.54 - 7.34 (m, 7H). |
99.1% | With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 2.16667h; | 3.1 Step 1 To a solution of 2-chlorobenzene-1-sulfonyl chloride (2.0 g, 9.5 mmol, 1.3 mL) in THF (20.0 mL) was added NH3.H2O (3.3 g, 28.4 mmol, 3.7 mL, 25% solution) at 0°C. The mixture was stirred at 0°C for 10 min and then warmed to 20°C for 2 h. The reaction mixture was concentrated to afford 2-chlorobenzenesulfonamide (1.8 g, 9.4 mmol, 99.1% yield).1H NMR (400MHz, DMSO-d6) d 7.96 (dd, J = 1.4, 7.8 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.54 - 7.34 (m, 7H). |
99.1% | With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 2.16667h; | I.3.1 Example 3: Synthesis of N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6- yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide (96) To a solution of 2-chlorobenzene-1-sulfonyl chloride (2.0 g, 9.5 mmol, 1.3 mL) in THF (20.0 mL) was added NH3.H2O (3.3 g, 28.4 mmol, 3.7 mL, 25% solution) at 0°C. The mixture was stirred at 0°C for 10 min and then warmed to 20°C for 2 h. The reaction mixture was concentrated to afford 2-chlorobenzenesulfonamide (1.8 g, 9.4 mmol, 99.1% yield).1H NMR (400MHz, DMSO-d6) ^ 7.96 (dd, J = 1.4, 7.8 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.54 - 7.34 (m, 7H). |
97.5% | S.30 Synthesis of 2-Chlorobenzenesulfonamide [Compound (III-11)] Synthesis Example 30 Synthesis of 2-Chlorobenzenesulfonamide [Compound (III-11)] Using 2-chlorobenzenesulfonyl chloride [Compound (XXII-11)] (5 g, 0.0237 mol), the Compound (III-11) was synthesised according to the process of Synthesis Example 26. White solid, m.p.: 185-7° C., yield: 4.42 g, percent yield: 97.5%. IR KBr cm-1: 3268, 3106, 1563, 1344, 1161, 1044, 768, 672. 1H-NMR (60 MHz, d6-DMSO, δ): 7.3-7.7 (5H, m, aromatic ring H*3, NH2), 7.7-8.06 (1H, m, aromatic ring H). | |
86.5% | With hydroxylamine 1) = 30 deg C 2) 80 deg C, 0.5 - 1 h; | |
With ammonium hydroxide; ethyl acetate at 20℃; for 16h; | ||
With ammonium hydroxide In acetonitrile at 0 - 20℃; for 1h; Inert atmosphere; | Compound 11: General procedure for sulfonamide preparation General procedure: In a 50 ml RB flask, sulfonyl chloride (500 mg) was taken in acetonitrile (5 ml) and the solution was cooled to 0 deg. Cel. To this aqueous ammonia solution (1.5 ml) was added dropwise. RM was then stirred at RT for 1 hr. RM was evaporated to dryness and the residue was then trichirated with minimum water and suspension was filtered and solid was dried to get the sulfonamide as solid. | |
Multi-step reaction with 2 steps 1: sodium hydroxide 2: copper(II) oxide; oxygen / dimethyl sulfoxide / 8 h / 100 °C | ||
With ammonia In methanol at 20℃; for 0.5h; | 43.A.1 Step A: 2-Chloro-N-(2-chlorophenyl) sulfonyl-6-[3-j2-j1-(trifluoromethyl) cyclopropyljethoxy]pyrazol-1-yl] pyrithne-3-carboxamidc 2-Chlorobenzenesulfonyl chloride (50 iL, 0.3667 mmol) was dissolved in ammonia in methanol (150 pL of 7 M, 1.050 mmol) and stirred at room temperature for 30 minutes. The mixture was evaporated to dryness and re-evaporated from dichloromethane. The solids were dissolved in THF (1 niL) and DBU (60 1.tL, 0.4012 mmol) was added. The mixture was stirred at 70 °C for 30 minutes to liberate any remaining ammonia from the reaction. | |
With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 2.16667h; | 3.1 Step 1: To a solution of 2-chlorobenzene-l-sulfonyl chloride (2.0 g, 9.5 mmol, 1.3 mL) in THF (20.0 mL) was added N.H20 (3.3 g, 28.4 mmol, 3.7 mL, 25% solution) at 0°C. The mixture was stirred at 0°C for 10 min and then warmed to 20°C for 2 h. The reaction mixture was concentrated to afford 2-chlorobenzenesulfonamide (1.8 g, 9.4 mmol, 99.1% yield). 1H NMR (400MHz, DMSO-d6) δ 7.96 (dd, J= 1.4, 7.8 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.54 - 7.34 (m, 7H). | |
With hydroxylamine In acetonitrile at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 20℃; for 1h; | Typical Procedure General procedure: CH2Cl2 (3.06 ml) was added to the 20 mL Scint vial containing DMAP (5.61 mg, 0.046 mmol), 2-chloro-1-methylpyridin-1-ium iodide (0.282 g, 1.102 mmol), benzoic acid 1a (0.1122 g, 0.919 mmol), methanesulfonamide 2a (0.175 g, 1.837 mmol) at room temperature. After stirring for 5 min, TEA (0.38 ml, 2.76 mmol) was slowly added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. The reaction solvent was removed via vacuum and the crude was taken up in ethyl acetate, washed with 1N HCl. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The crude was purified by flash column eluted with ethyl acetate in hexane from 0 to 50% to 100% to give the desired product 3a as a white solid. (0.1409 g, 77%). |
With dmap; amberlyst-15; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide on Merrifield's resin 1.) ClCH2CH2Cl, t-BuOH, rt., 24 h; 2.) EtOAc, 2 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 2-chlorobenzenesulfonamide; dimethyl N-cyanodithioiminocarbonate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h; Stage #2: With hydrogenchloride In N,N-dimethyl-formamide at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; N'-methyl polystyrene HL; N-cyclohexylcarbodiimide In dichloromethane at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In acetonitrile at 0 - 20℃; | 4.1 EXAMPLE 4: SYNTHESES OF SPECIFIC COMPOUNDS; Route 1; (2-Chloro-benzenesulfonyl)-carbamic acid methyl ester; To 25.0 g 2-chloro-benzenesulfonamide was added 75 ml. acetonitrile and 45.2 ml. (2.5 eq) triethylamine. The mixture was cooled with an ice bath and 15.1 ml. methyl chloroformate was slowly added dropwise. The mixture was was stirred overnight at room temperature and concentrated in vacuo. Water was added and de aqueous layer was washed two times with ether. Acidification of the aqueous layer with 2 M HCI led to formation of a white precipitate. The suspension was filtered, the residue was washed with H2O and dried in vacuo to yield 19.1 g of a white solid. 1H NMR (400 MHz, DMSOd6) δ 3.58 (s, 3H), 7.52-7.61 (m, 1 H), 7.62-7.72 (m, 2H), 8.10 (dd, J = 8 and 1.5 Hz, 1 H), 12.42 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: (R)-(-)-2-(4-trifluoromethanesulfonyloxy)phenylpropionic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 2h; Stage #2: 2-chlorobenzenesulfonamide With 1,2-diazabicyclo[5.4.0]undec-7-ene In dichloromethane for 4h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With lithium hydroxide In N,N-dimethyl acetamide at 50℃; for 20h; | II-5 Example II-5 (using lithium hydroxide as a base): Preparation of 2-chloro-N-(3-In a 150 mL flask under N2 containing a solution of 2-chlorobenzenesulphonamide (4.81 g; 25.1 mmol; 1.0 eq.) in DMA (45 mL), lithium hydroxide (1.14 g; 47.7 mmol; 1.9 eq.) was added in one portion and after stirring for 10 minutes 2, 3-dichloroquinoxaline (5.0 g; 25.12 mmol; 1.0 eq.) was added in one portion. The reaction mixture was stirred at 50°C for 20h until completion as indicated by UPLC/MS.The reaction mixture (clear brown solution) was then cooled down to 5°C (ice-bath) and hydrochloric acid IN (25.1 mL) was added in one pot. The resulting suspension was aged in a ice bath for 20 minutes until complete precipitation. Then, the suspension was filtered and washed with water (3x50 mL), and the resulting solid was washed with MTBE (2x30 mL) to remove 2, 3 dichloroquinoxaline in excess. Additional crop was obtained upon precipitation in the MTBE phase (heptane was added to the filtrate to initiate precipitation and a second crop was obtained by filtration). The 2 crops were combined to give after drying title product as beige solid (6.25 g; crude yield: 70.2 %). HPLC Purity: 98.9% (max plot ), Rt: 3.86 min; UPLC/MS: purity : 100% (max plot ), Rt: 1.08 min |
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 3h; | 7 In the presence of potassium carbonate (625 mg), 2,3-dichloroquinoxaline (275 mg) and 2-chlorobenzenesulfonamide (264 mg) were allowed to react in the solution of dimethylformamide (4 mL) for 3 hours at 90 °C. To the reaction mixture, water and hydrochloric acid were added and extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated to obtain the title compound (493 mg) having the following physical data. TLC: Rf 0.58 (hexane: ethyl acetate = 1:1); NMR (d6-DMSO): δ 7.64, 8.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | Synthesis Example 14 Synthesis of N-[(2-Chlorophenyl)sulfonyl]-6-chloro-4-methoxypyridine-2-carboxamide [Compound (I-705)] Using 2-chlorobenzenesulfonamide [Compound (III-11)] (0.255 g, 1.33 mmol) and 6-chloro-4-methoxypicolinic acid [Compound (II-75)] (0.25 g, 1.33 mmol), the Compound (I-705) was synthesised according to the process of Synthesis Example 3. White solid, yield: 0.27 g, percent yield: 66.3%, m.p.: 175-177 C. IR KBr cm-1: 3472, 3292, 1728, 1605, 1434, 1392, 1170, 1035. 1H-NMR (60 MHz, CDCl3, delta): 3.8 (3H, s, OCH3), 6.9 (1H, d, J=2 Hz, pyridine ring H), 7.3-7.6 (4H, m, pyridine ring H*1, aromatic ring H*3), 8.0-8.4 (1H, m, aromatic ring H), NH indistinctness. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: 2,3-dichloropyrazine; 2-chlorobenzenesulfonamide With caesium carbonate In N-methyl pyrrolidinone at 130℃; for 20h; Stage #2: With citric acid In water; ethyl acetate at 20℃; | 2 Intermediate 2: 2-chloro-N-(3-chloropyrazin-2-yl)benzenesulfonamide (cf. Scheme 2, compound III) EPO 2,3-dichloropyrazine (Ig; 6.71 mmol; 1.00 eq.) and 2-dichlorobenzenesulfonamide (1.29g; 6.71mmol; 1.00 eq.) were stirred in NMP (9ml). To this reaction mixture was added cesium carbonate (2g; 6mmol; 0.90 eq.) and the reaction mixture was stirred and heated up to 1300C for 2Oh. The reaction was cooled down to room temperature, added to water 98ml and washed with AcOEt (2x30ml). The aqueous phase was acidified with citric acid and extraced with AcOEt (3x60ml). The organic extracts were combined, washed with brine (10ml), dried over MgSO4 and evaporated down. The residue was purified by Flash master using a gradient AcOEt/cHex 2:8 to AcOEt 100% in 45 min, the title compound was isolated, after filtration and evaporation. The solid was recrystallized in a mixture EtOAc:Chex (30:70) to give the pure 2-chloro-N-(3-chloropyrazin-2-yl)benzene sulfonamide as a yellowish solid (Ig, 49% yield, 100%HPLC purity).IH NMR (300MHz, CDCl3); 7.3-7.5 (m, 3H), 7.8-8.0 (m, 3H), 8.3 (m, IH). MS(ESI+): 304.1; MS(ESI ): 302.0. |
With potassium carbonate In N,N-dimethyl acetamide at 50℃; for 24h; | The synthesis of compounds of Formula (IF) is illustrated by the following example wherein A' is reacted with B'. The crude ratio of compounds A', B' C and D', in table 5, has been |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With carbon disulfide; potassium hydroxide In <i>N</i>-methyl-acetamide | 4 Dimethyl N-(2-chlorophenylsulfonyl)carbonimidodithioate EXAMPLE 4 Dimethyl N-(2-chlorophenylsulfonyl)carbonimidodithioate To a stirred solution of 28.75 g of 2-chlorobenzenesulfonamide in 75 ml of dimethylformamide at ambient temperature was added 8.45 g of potassium hydroxide and 4.55 ml of carbon disulfide. The mixture was stirred at ambient temperature for 2 hours. To this mixture was then added another 8.45 g of potassium hydroxide and 4.55 ml of carbon disulfide. The mixture was stirred at ambient temperature for another 2 hours and then cooled to about 5° C. To this mixture was added 23.0 g of methyl iodide. Another 23 g of methyl iodide was then added at ambient temperature. The mixture was stirred at ambient temperature for two hours and then added to 1 liter of chilled water. The precipitate was collected by filtration, and dried to yield 20.0 g of dimethyl N-(2-chlorophenylsulfonyl)carbonimidodithioate, m.p. 119°-123° C. NMR (DMSO-d6)δ: 2.6 (s, 6H); 7.5-8.4 (m, 4H) ppm. | |
Stage #1: carbon disulfide; 2-chlorobenzenesulfonamide With potassium hydroxide In water; N,N-dimethyl-formamide at 0 - 10℃; for 0.5h; Stage #2: methyl iodide In water; N,N-dimethyl-formamide at 10 - 20℃; for 0.5h; | 4.2 N-(Bis-methylsulfanyl-methylene)-2-chloro-benzenesulfonamide; To 41.6 g 2-chloro-benzenesulfonamide was added 300 ml. DMF and 22 ml. carbondisulfide. The mixture was cooled with an ice bath. A solution of 29 g KOH (15.0 mL) in 100 mL H2O was added dropwise at such a rate that the temperature was kept below 10°C. The mixture was stirred for 30 minutes at 5°C. Subsequently, 32 mL MeI was added dropwise at such a rate that the temperature was kept below 100C. Then, the mixture was allowed to warm to room temperature and stirred for another 30 minutes. H2O was added and a precipitate formed. This was filtered off and washed with H2O. The residue was triturated with EtOH, filtered off and dried in vacuo to yield 42.6 g white crystals. 1H NMR (200 MHz, CDCI3) δ 2.57 (s, 6H), 7.32-7.60 (m, 3H), 8.11-8.27 (br d, J = 7.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In 5,5-dimethyl-1,3-cyclohexadiene | 3 EXAMPLE 3 EXAMPLE 3 In a flask fitted with a water condenser and dry-ice condenser in series, a stirrer and a thermometer, a suspension of 191.6 g of o-chlorobenzenesulfonamide in 500 ml xylene was dried by azeotropically removing any moisture present. Next, 2.0 g of triethylamine and 20 g of butyl isocyanate were added, and the reaction mixture was refluxed for 15 minutes. Phosgene (105 g) was then introduced over 2.5 hours at such a rate that a temperature of 133°-135° C. was maintained. The dry-ice condenser was then removed and the reaction mass was refluxed until a temperature of 142° C. was obtained. After cooling to room temperature and filtration, the solvent and butyl isocyanate were removed under vacuum and the residue was distilled. Obtained were 196 g (90.0% yield) of o-chlorobenzenesulfonyl isocyanate (B.P. 96° C./0.5 mm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hydroxide In N,N-dimethyl-formamide at 90 - 160℃; | |
With potassium hydroxide In <i>N</i>-methyl-acetamide | 7 2-(1-Propylthio)benzenesulfonamide EXAMPLE 7 2-(1-Propylthio)benzenesulfonamide To a solution of potassium hydroxide (85%, 12 gm, 0.2 mole) and n-propylmercaptan (18.1 ml, 0.2 mole) in 100 ml dimethylformamide at 90° C. was added a solution of 2-chlorobenzenesulfonamide (19.1 gm, 0.1 mole) in 100 ml dimethylformamide. The reaction mixture was heated to reflux for five hours, cooled, and the solvent was removed in vacuo. The residue was diluted with water, made acidic with concentrated hydrochloric acid and extracted with ether. The ether extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield the crude product. Recrystallization from a suitable solvent such as toluene afforded 19 gm (82%) product: m.p. 58°-64°. NMR (CDCl3)δ: 1.0 (t, 3H, --CH3); 1.8 (m, 2H, --CH2 --); 3.1 (t, 2H, --SCH2); 5.2 (s, 2H, --NH2); and 7.2-8.0 (m, 4H, --ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; | 21 A dichloromethane solution of l-cyclohexyl-3 -oxo-2 -phenyl- 2, 3 -dihydro-IH-indazole-5-carboxylic acid (104) was treated at room temperature with HATU (1.2 eq) , DIPEA (3 eq) and then 2-chlorobenzenesulfonamide to yield the title compound (524) , which was isolated by silica chromatography . ESI-MS m/z calculated for [M+H]+: 510; found: 510.01H-NMR (300 MHz, DMSOd6) δ 0.93-1.20 (m, 3H), 1.31-1.55 (m, 3H), 1.69 (t, 4H, J 11.5 Hz,), 3.59 (t, IH, J 12.1Hz), 7.31-7.41 (m, IH), 7.52 (d, 4H, J 3.9Hz), 7.59 (d, IH, J 8.6Hz), 7.71 (t, IH, J 8.0Hz), 8.34-8.12 (m, 4H), 8.61 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Ru/Fe3O4; potassium carbonate at 150℃; for 12h; Inert atmosphere; | |
89% | With [(η5-C5Me5)Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)]OTf2; caesium carbonate In water at 120℃; for 15h; Inert atmosphere; Schlenk technique; | |
89% | With [(η5-C5Me5)Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)]OTf2; caesium carbonate In water at 120℃; for 15h; Schlenk technique; | 23 Example 23: N- benzyl-2-chlorophenyl sulfonamide The 2-chlorophenyl sulfonamide (192mg, 1mmol), catalyst A (8.3mg, 0.01mmol, 1mol%), cesium carbonate (33mg, 0.1mmol, 0.1equiv.), Benzyl alcohol (130mg, 1.2mmol) and water ( 1ml) were successively added to the reaction flask 25mlSchlenk.After the reaction mixture was reacted at 120 15 hours, cooled to room temperature.A large amount of precipitated, water was removed by filtration, the filter cake was washed with water three times to give the title compound, yield: 89% |
82% | With potassium carbonate; benzaldehyde at 135℃; for 18h; Schlenk technique; Green chemistry; | |
74 %Chromat. | With tris(triphenylphosphine)rhodium(l) chloride; potassium carbonate at 135℃; for 36h; | |
93 %Chromat. | With manganese(IV) oxide; potassium carbonate at 135℃; for 24h; | |
83 %Chromat. | With palladium diacetate; potassium carbonate In neat (no solvent) at 135℃; for 48h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In acetonitrile Reflux; | 3 2-Chloro-N-[ethylamino-(3-ethyl-4,5-dihvdro-pyrazol-1 -yl)-methylenel-benzenesulfonamide (compound 1 1 ).; 1 .42 g (1 mol equiv.) 3,N-Diethyl-4,5-dihydro-pyrazole-1 -carboximidothioic acid methyl ester and1 .43 g (1 .05 mol equiv.) 2-chlorobenzenesulfonamide were added to 20 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2S04, filtered and evaporated to dryness. The residue obtained after purification by flash chromatography on silica gel (Et20) was triturated with diisopropyl ether to afford 2.08 g (81 %) 2-chloro-N-[ethylamino-(3-ethyl-4,5-dihydro-pyrazol-1 -yl)-methylene]- benzenesulfonamide.1HNMR (400 MHz, CDCI3) δ 1 .15 (t, J=7.3 Hz, 3H), 1 .17 (t, J=7.3 Hz, 3H), 2.38 (q, J=7.3 Hz, 2H), 2.80 (t, J=9.8 Hz, 2H), 3.44-3.53 (m, 2H), 4.1 1 (t, J=9.8 Hz, 2H), 6.73 (br.s., 1 H), 7.33 (dt, J=7.6, 2.0 Hz, 1 H), 7.38 (dt, J=7.6, 2.0 Hz, 1 H), 7.46 (dd, J=7.6, 2.0 Hz, 1 H), 8.17 (dd, J=7.6, 2.0 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate In dimethyl sulfoxide at 150℃; for 2h; | 37 EXAMPLE 372-chloro-N-{3-[2,2,2-trifluoro-1-(4-cyanophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 42); 2-Chloro-3-[2,2,2-trifluoro-1-(4-cyanophenyl)ethoxy]-quinoxaline (Compound BO) (42.6 mg, 0.117 mmol) was dissolved in dimethyl sulfoxide (1.0 mL). To this, 2-chlorobenzenesulfonamide (22.4 mg, 0.117 mmol) and potassium carbonate (16.2 mg, 0.117 mmol) were added at room temperature and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (1.0 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1). Further, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-{3-[2,2,2-trifluoro-1-(4-cyanophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 42) (20.6 mg, yield: 34%).ESIMS m/z: 518 (M+H)+; 1H-NMR (270 MHz, DMSO-d6, δ): 7.22 (br s, 1H), 7.52-7.66 (m, 7H), 7.97-8.13 (m, 4H), 8.38 (br s, 1H), 12.52 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloro-3-[2,2,2-trifluoro-1-(4-fluorophenyl)ethoxy]-quinoxaline; 2-chlorobenzenesulfonamide With potassium carbonate In dimethyl sulfoxide at 150℃; for 0.5h; Stage #2: With acetic acid In water; dimethyl sulfoxide | 54 EXAMPLE 542-chloro-N-{3-[2,2,2-trifluoro-1-(4-fluorophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 59); Compound CS (478 mg, 2.51 mmol) and 2,3-dichloroquinoxaline (618 mg, 3.11 mmol) were dissolved in tetrahydrofuran (10 mL). To this, 60% sodium hydride (in oil) (124 mg, 3.11 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 1 hour. Then, saturated ammonium chloride was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give a mixture (702 mg) of 2-chloro-3-[2,2,2-trifluoro-1-(4-fluorophenyl)ethoxy]-quinoxaline and 2,3-dichloroquinoxaline. This mixture was dissolved in dimethyl sulfoxide (7.0 mL). To this, 2-chlorobenzenesulfonamide (455 mg, 2.37 mmol) and potassium carbonate (328 mg, 2.37 mmol) were added at room temperature and the mixture was stirred at 150° C. for 30 minutes. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (1.0 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was purified by preparative thin-layer chromatography (hexane/ethyl acetate=7/3). Further, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-{3-[2,2,2-trifluoro-1-(4-fluorophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 59) (541 mg, yield: 42%).ESIMS m/z: 511 (M+H)+; 1H-NMR (300 MHz, CDCl3, δ): 6.63-6.78 (m, 1H), 7.05-7.15 (m, 2H), 7.31-7.61 (m, 9H), 8.20-8.54 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloro-3-[2,2,2-trifluoro-1-(3-fluorophenyl)ethoxy]-quinoxaline; 2-chlorobenzenesulfonamide With potassium carbonate In dimethyl sulfoxide at 150℃; for 1h; Stage #2: With acetic acid In water; dimethyl sulfoxide | 78 EXAMPLE 782-chloro-N-{3-[2,2,2-trifluoro-1-(3-fluorophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 83); Compound DA (100 mg, 0.515 mmol) and 2,3-dichloroquinoxaline (103 mg, 0.515 mmol) were dissolved in tetrahydrofuran (2.0 mL). To this, 60% sodium hydride (in oil) (30.9 mg, 0.773 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 2 hours. Then, saturated ammonium chloride was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give a mixture (170 mg) of 2-chloro-3-[2,2,2-trifluoro-1-(3-fluorophenyl)ethoxy]-quinoxaline and 2,3-dichloroquinoxaline. This mixture was dissolved in dimethyl sulfoxide (3.0 mL). To this, 2-chlorobenzenesulfonamide (91.3 mg, 0.477 mmol) and potassium carbonate (65.9 mg, 0.477 mmol) were added at room temperature and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (1.0 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was purified by preparative thin-layer chromatography (hexane/ethyl acetate=7/3). Further, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-{3-[2,2,2-trifluoro-1-(3-fluorophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 83) (129 mg, yield: 49%).ESIMS m/z: 512 (M+H)+; 1H-NMR (300 MHz, DMSO-d6, δ): 7.15 (br s, 1H), 7.28-7.34 (m, 1H), 7.52-7.92 (m, 10H), 8.38 (br s, 1H), 12.48 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloro-3-[2,2,2-trifluoro-1-(3-chlorophenyl)ethoxy]-quinoxaline; 2-chlorobenzenesulfonamide With potassium carbonate In dimethyl sulfoxide at 150℃; for 1h; Stage #2: With acetic acid In water; dimethyl sulfoxide | 79 EXAMPLE 792-chloro-N-{3-[2,2,2-trifluoro-1-(3-chlorophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 84); Compound DB (100 mg, 0.475 mmol) and 2,3-dichloroquinoxaline (95.4 mg, 0.475 mmol) were dissolved in tetrahydrofuran (2.0 mL). To this, 60% sodium hydride (in oil) (28.5 mg, 0.713 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 2 hours. Then, saturated ammonium chloride was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give a mixture (153 mg) of 2-chloro-3-[2,2,2-trifluoro-1-(3-chlorophenyl)ethoxy]-quinoxaline and 2,3-dichloroquinoxaline. This mixture was dissolved in dimethyl sulfoxide (3.0 mL). To this, 2-chlorobenzenesulfonamide (78.6 mg, 0.410 mmol) and potassium carbonate (56.7 mg, 0.410 mmol) were added at room temperature and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (1.0 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was purified by preparative thin-layer chromatography (hexane/ethyl acetate=7/3). Further, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-{3-[2,2,2-trifluoro-1-(3-chlorophenyl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 84) (110 mg, yield: 44%).ESIMS m/z: 528 (M+H)+; 1H-NMR (300 MHz, DMSO-d6, δ): 7.16 (br s, 1H), 7.48-7.65 (m, 9H), 7.84 (br s, 1H), 8.15 (br s, 1H), 8.39 (br s, 1H), 12.53 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.5% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; | 35b b) 2-Chloro-N-{(6S,7aR)-3-oxo-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-6-yl}-benzenesulfonamideTo a solution of (6R,7aR)-6-Bromo-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (50 mg, 0.130 mmol) in DMF (3 mL) in a sealed tube, was added K2CO3 (27.3 mg, 0.197 mmol) and 2-Chloro-benzenesulfonamide (50.5 mg, 0.263 mmol) and heated to 80° C. for 12 h. All volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified through biotage column chromatography (elution with 40% ethyl acetate in hexane) to afford 17 mg (26.5%) of the title compound as a white solid. LC-MS: 489 [M+1]+. |
26.5% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; Sealed tube; | 35.b b) 2-Chloro-N-{ (6S,7aR)-3-oxo-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro- pyrrolo[l,2-c]imidazol-6-yl}-benzenesulfonamideTo a solution of (6R,7aR)-6-Bromo-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro- pyrrolo[l,2-c]imidazol-3-one (50 mg, 0.130 mmol) in DMF (3 mL) in a sealed tube, was added K2C03 (27.3 mg, 0.197 mmol) and 2-Chloro-benzenesulfonamide (50.5 mg, 0.263 mmol) and heated to 80 °C for 12 h. All volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na2S04 and concentrated. The residue was purified through biotage column chromatography (elution with 40% ethyl acetate in hexane) to afford 17 mg (26.5%) of the title compound as a white solid. LC-MS: 489 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; [bis(acetoxy)iodo]benzene In dichloromethane at 60℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 1,10-Phenanthroline; palladium(II) trifluoroacetate; oxygen In toluene at 140℃; for 40h; | 2 2.2. General procedure: 4-methyl-N-phenylbenzenesulfonamide (3a) General procedure: 2.2 General procedure: 4-methyl-N-phenylbenzenesulfonamide (3a) A 25 mL oven-dried reaction vessel was charged with Pd(TFA)2 (2.3 mg, 0.01 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol), p-toluene sulfonamide (1a, 34.2 mg, 0.2 mmol), cyclohexanone (2a, 32 μL, 0.3 mmol). The reaction vessel was flushed with oxygen three times and then sealed. Toluene (0.7 mL) was added by syringe and the resulting solution was stirred at 140 °C for 40 h. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give the corresponding product 3a (39.9 mg) as white solid in 81% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20.0℃; for 4.0h;Inert atmosphere; | General procedure: In 25ml RB flask to a solution of Compound 9 (200 mg) in dry DMF (5ml), EDCI (250 mg, 1.25eq) and DMAP (130 mg,1eq) were added followed by addition of Sulfonamide (1eq). RM was stirred at RT for 4hrs. Solvent from the reaction mixture was evaporated. To the residue water was added and acidified with 6N HCl, solid precipitated out. Solid was filtered and dried. Crude solid was purified by flash chromatography eluating with 4-8% MeOH/DCM as solvent system to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With nitromethane; copper dichloride for 2h; Milling; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 24h; | General procedure for title compound 6 and 7 General procedure: To a stirred solution of 3I-3III (10 mmol) and Et3N (12 mmol) in anhydrous acetonitrile was added sulfamide (4a-i and 5, 10 mmol) followed by addition EDCI (12 mmol) and DMAP (12 mmol). The mixture was stirred at r.t. for 24 h. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl and water for 3 times respectively, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was subjected to silica gel chromatography or crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With C6H9O(1-)*2CO*Rh(1+); 1,1'-Binaphthalin-2,2'-diylbis(methylen)bis(diphenylphosphan); hydrogen; silica gel In methanol; toluene at 120℃; for 20h; Inert atmosphere; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 2-chlorobenzenesulfonamide; diosgenin acetate With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 8h; Inert atmosphere; Stage #2: In toluene Reflux; Dean-Stark; | Gerneral procedure: General procedure: To a solution of steroidal sapogenin (1 equiv) and RSO2NH2 (4 equiv)in freshly distilled dichloromethane (DCM, 0.1 M) was added BF3•Et2O (4 equiv) underargon at ambient temperature. The resulting yellow mixture was allowed to stand for eight toten hours until thin layer chromatography (TLC) showed full consumption of the startingmaterial. The dark red mixture was quenched by adding a saturated aqueous solution ofNaHCO3 and extracted with DCM for three times. The combined organic layers were washedwith brine, dried over Na2SO4, and concentrated under reduced pressure. The residue wasdissolved in toluene and heated to reflux with a Dean-Stark trap for five to eight hours.Removal of the solvent under reduced pressure and flash column chromatography of the crudeon silica gel afforded the product with indicated yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In acetonitrile at 90℃; for 18h; | |
78% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine In acetonitrile at 90℃; for 18h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With oxygen; copper(II) oxide In dimethyl sulfoxide at 100℃; for 8h; | General procedure for primary aryl sulfonamides 2 General procedure: A mixture of aryl sulfonyl amino acid 1 (0.5 mmol), CuO (0.15 mmol), and DMSO (0.5 mL) was placed in a 25-mL, round-bottom flask. The mixture was stirred for 8 h at 100 °C under air. Then, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified by silica-gel column chromatography with ethyl acetate / petroleum ether to afford the desired product 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With cerium(III) chloride; [bis(acetoxy)iodo]benzene; 1-(1-ferroceneamidoethyl)-3-isopropylimidazole; copper(II) bis(trifluoromethanesulfonate); 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 60℃; for 6h; | 4 Embodiment 4 Under room temperature, in DMSO to the proper amount of organic solvent, by adding 100mmol compounds represented by the following general formula (I) compound, 130mmol aboving (II) compound, 18mmol catalyst (to 4.5mmol1 - (1-ferrocene amido ethyl) - 3-isopropyl-1-imidazole Iodized salt and 13.5mmolCu (OTf)2(triflic acid copper) mixture), 220mmol oxydizers PhI (OAc)2, 60mmol alkali DBU and 23mmol accelerator CeCl3, then heating up to 60 °C, and stirring reaction in the temperature under 6 hours;After the reaction, the reaction solution is filtered, filtrate under stirring the pH value adjusted to neutral, and then fully saturated salt water for washing, chloroform extraction 2-3 time, combined with the phase, is distilled under reduced pressure, the resulting residue over silica gel column chromatography, to volume ratio of 1:2 of the mixed solution of petroleum ether and ethyl acetate to elute, collect eluant and evaporating eliminates takes elution solvent, thereby obtaining the compound (III) variety, in order to yield 95.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With ruthenium trichloride; 2-(N,N-dimethylamino)ethanol; copper(I) triflate; bis-[(trifluoroacetoxy)iodo]benzene In N,N-dimethyl-formamide at 80℃; for 7h; | 4 Example 4 At room temperature,To a suitable amount of an organic solvent (a mixture of N, N-dimethylformamide and polyethylene glycol 200 in a volume ratio of 1: 2)100 mmol of the compound of formula (I)150 mmol of the compound of formula (II)150 mmol of the compound of formula (III)16 mmol of a composite catalyst (a mixture of 8 mmol of bis (tricyclohexylphosphine) nickel chloride and 8 mmol of dodecanoyl iron)200 mmol Oxidant bis (trifluoroacetic acid) iodobenzene (PhI (TFA) 2),11mmol Auxiliaries Trifluoromethanesulfonate (CuOTf),150 mmol of alkali N, N-dimethylethanolamine (DMEA) and 7 mmol of activator of ruthenium oxyhydroxide,And then stirred to 80 ° C,And the reaction was stirred at that temperature for 7 hours;After completion of the reaction, the compound of the above formula (IV) was obtained by post-treatment in a yield of 90.1%. |
74.6% | With 2-(N,N-dimethylamino)ethanol; copper(I) triflate; bis-[(trifluoroacetoxy)iodo]benzene In N,N-dimethyl-formamide at 80℃; for 7h; | 1 Comparative Example 1 At room temperature,To a suitable amount of an organic solvent (a mixture of N, N-dimethylformamide and polyethylene glycol 200 in a volume ratio of 1: 2)100 mmol of the compound of formula (I)150 mmol of the compound of formula (II)150 mmol of the compound of formula (III)16 mmol of a composite catalyst (a mixture of 8 mmol of bis (tricyclohexylphosphine) nickel chloride and 8 mmol of dodecanoyl iron)200 mmol Oxidant bis (trifluoroacetic acid) iodobenzene (PhI (TFA) 2),11mmol Auxiliaries of copper trifluoromethanesulfonate (CuOTf) and150 mmol of base N, N-dimethylethanolamine (DMEA),And then stirred to 80 ° C,And the reaction was stirred at that temperature for 7 hours;After the reaction,Post-processing,To give a compound of formula (IV)The yield was 74.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; [bis(acetoxy)iodo]benzene In 1,2-dichloro-ethane at 80℃; for 16h; regioselective reaction; | Rhodium-Catalyzed Amidation of Azoxybenzenes with Sulfonamides; (Z)-1-[2-(4-Methylphenylsulfonamido)phenyl]-2-phenyldiazeneOxide (3a); Typical Procedure General procedure: In air, a 10 mL of dried Schlenk tube was charged with azoxybenzene (1a; 79.2 mg, 0.40 mmol), TsNH2 (2a; 102.6 mg, 0.60 mmol), [Cp*Rh- Cl2]2 (3.1 mg, 0.005 mmol), AgSbF6 (13.7 mg, 0.04 mmol), and PhI(OAc)2 (193.2 mg, 0.60 mmol). Then the freshly distilled 1,2-dichloroethane (1.0 mL) was injected into the Schlenk tube. The reaction tube was placed in an oil bath and stirred at 80 °C for 16 h; then it was cooled to r.t. and the reaction completion was checked by TLC. H2O (10.0 mL) was subsequently added to the reaction mixture and extracted with CH2Cl2 (3 5.0 mL). The organic layers were combined, dried (MgSO4), and concentrated under reduced pressure to yield the crude product, which was further purified by flash chromatography (silica gel, PE/EtOAc 9:1 → 5:1, v/v), affording the product 3a as a pale yellow solid (120.4 mg, 0.33 mmol, 82%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With bis(η3-allyl-μ-chloropalladium(II)); potassium carbonate; tert-butyl XPhos In 2-methyltetrahydrofuran at 85℃; Sealed tube; Microwave irradiation; Inert atmosphere; | 2 4.1.2.2.2 (S)-2-Chloro-N-(1,3,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)benzenesulfonamide (11) To a solution of compound 63 (150 mg, 0.56 mmol), 2-chlorobenzenesulfonamide (129 mg, 0.67 mmol), K2CO3 (155 mg, 1.12 mmol) in 2-metyhtetrahydrofuran (5 mL) at room temperature were added allylpalladium chloride dimer (4 mg, 0.011 mmol) and tBuXPhos (5 mg, 0.011 mmol). The mixture was sealed in a microwave tube and heated to 85 °C overnight. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water, and extracted with EtOAc (3 * 10 mL). Combined organic layers were washed with brine, then dried with Na2SO4. The crude proudct was purified by flash column chromatography (gradient elution, gradient 0-40% EtOAc/60-90 °C petroleum ether) to give compound 11 (133 mg, 0.35 mmol, 63% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.65-7.55 (m, 2H), 7.49 (t, J = 6.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 4.01-3.85 (m, 1H), 3.15 (s, 3H), 2.66 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 166.80, 136.62, 136.17, 134.53, 132.84, 131.77, 131.73, 130.83, 127.60, 125.66, 114.64, 109.72, 104.40, 58.61, 34.51, 28.33, 11.41; HRMS (ESI) m/z [M+H]+ calcd for (C17H19ClN3O3S+) 380.083, found 380.0828; retention time 3.12 min, > 96% pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 2h; Stage #2: 2-chlorobenzenesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; | 43.A.1 2-Chloro-6-[3 -[2-[ 1 -(trifluoromethyl) cyclopropyl] ethoxy]pyra.zol- 1- yl]pyridine-3-carboxylic acid (100 mg, 0.2661 mmol) and carbonyl diimidazole (53 mg, 0.3269 mmol) were combined in TI-IF (1.000 mL) and stirred for 2 hours. At this point, this mixture was added to the sulfonamide mixture (from step-i) and the reaction was stirred for overnight at room temperature. The reaction was diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over magnesium sulfate, and evaporated to afford 2-chloro-N-(2- chlorophenyl) sulfonyl-6- [3 -[2-[1 -(trifluoromethyl) cyclopropyl] ethoxy]pyrazol- 1- yl]pyridine-3-carboxamide along with starting material and primary amide. The mixture was used as it is for the next reaction. EST-MS mlz calc. 548.02997, found 549.28 (M+1) -1-; Retention time: 0.76 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate; silver(I) triflimide In dichloromethane at 60℃; for 24h; | 18 Example 18 (1) 0.0040g iridium catalyst [Cp * IrCl2] 2,0.0076 g silver salt bis(trifluoromethanesulfonyl)imide silver,0.825g oxidant silver acetate,31.4 μL acetophenone-O-methyl oxime and0.0764 g of o-chlorobenzenesulfonamide in a reaction tube.Add 2mL of dichloromethane as a solvent,Heating and stirring reaction,The temperature of heating and stirring is 60°C.Reaction time 24h.(2) After the reaction is over,Separation by column chromatography (300-400 column chromatography silica gel column packing,Eluent: ethyl acetate: petroleum ether = 12:100 v/v),Can get the product N-[2-(1-methoxyimino)ethyl]phenyl-2-chlorobenzenesulfonamide.The yield is 89%.The structural characterization of the products are shown in Figures 23 and 24, respectively. |
82% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate; silver(I) triflimide In dichloromethane at 60℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With [bis(acetoxy)iodo]benzene; iodine at 50℃; for 24h; Inert atmosphere; | 4.2.1. General Procedure for the Preparation of N-Sulfonyl Imines (2) (1H-NMR Yields) General procedure: To an oven-dried reaction tube was added aldehyde (1.25 mmol, 5 equivalents), PhI(OAc)2(0.50 mmol, 2 equivalents), sulfonamide (0.25 mmol, 1 equivalent), I2 (0.25 mmol, 1 equivalents),and CDCl3 (3 mL). The mixture was stirred at 50 °C under argon for 24 h. After 24 h, the reaction wascooled to room temperature and an internal standard was added (1,4-dimethoxybenzene, 0.25 mmol,35 mg); the mixture then was stirred for an additional 5-10 min. The percent yield was calculatedagainst the internal standard via 1H-NMR integrations of the imine C-H signal and the aromatic (4H)signal of the internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 1.9% 2: 10.7% | With [2-(2-aminoethyl)phenyl]chloropalladium ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane; caesium carbonate; ruphos In tetrahydrofuran at 80℃; for 12h; Inert atmosphere; | 5.2 Step 2 A mixture of 3,6-dichloro-4-ethylpyridazine (500 mg, 2.8 mmol), 2- chlorobenzenesulfonamide (595 mg, 3.1 mmol), Cs2C03 (2.7g, 8.5 mmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (132 mg, 282.4 umol) and [2-(2-aminoethyl)phenyl]- chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (194 mg, 282.4 umol) in THF (30.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction was concentrated to give a residue. The residue was purified by column chromatography (Si02) to give a crude product (280 mg). The crude product was purified by prep-HPLC (TFA condition) to afford 2-chloro-N-(6-chloro- 5-ethylpyridazin-3-yl)benzenesulfonamide (20 mg, 54.2 umol, 1.9% yield). 1H NMR (400MHz, METHANOL-^) δ 8.20 (d, J= 7.7 Hz, 1H), 7.64 (br s, 1H), 7.57 - 7.53 (m, 2H), 7.52 - 7.46 (m, 1H), 2.71 (q, J= 7.5 Hz, 2H), 1.23 (t, J= 7.4 Hz, 3H); and 2-chloro-N-(6-chloro-4- ethylpyridazin-3-yl)benzenesulfonamide (100 mg, 270.9 umol, 10.7% yield). 1H NMR (400MHz, METHANOL-^) δ 8.21 (d, J= 7.6 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.56 - 7.48 (m, 2H), 2.61 (br d, J= 6.7 Hz, 2H), 1.18 (br t, J= 7.2 Hz, 3H). |
1: 1.9% 2: 10.7% | With chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; caesium carbonate; tert-butyl XPhos; ruphos In tetrahydrofuran at 80℃; for 12h; Inert atmosphere; | 3.2 Step 2: A mixture of 3,6-dichloro-4-ethylpyridazine (500 mg, 2.8 mmol), 2- chlorobenzenesulfonamide (595 mg, 3.1 mmol), CS2CO3 (2.7g, 8.5 mmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (132 mg, 282.4 umol) and [2-(2-aminoethyl)phenyl]- chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (194 mg, 282.4 umol) in THF (30.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction was concentrated to give a residue. The residue was purified by column chromatography (Si02) to give a crude product (280 mg). The crude product was purified by prep-HPLC (TFA condition) to afford 2-chloro-N-(6-chloro- 5-ethylpyridazin-3-yl)benzenesulfonamide (20 mg, 54.2 umol, 1.9% yield). 'H NMR (400MHz, METHANOL-^) δ 8.20 (d, J= 7.7 Hz, 1H), 7.64 (br s, 1H), 7.57 - 7.53 (m, 2H), 7.52 - 7.46 (m, 1H), 2.71 (q, J= 7.5 Hz, 2H), 1.23 (t, J= 7.4 Hz, 3H); and 2-chloro-N-(6-chloro-4- ethylpyridazin-3-yl)benzenesulfonamide (100 mg, 270.9 umol, 10.7% yield). LH NMR (400MHz, METHANOL-^) δ 8.21 (d, J= 7.6 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.56 - 7.48 (m, 2H), 2.61 (br d, J= 6.7 Hz, 2H), 1.18 (br t, J= 7.2 Hz, 3H). |
1: 10.7% 2: 10.7% | With chloro(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II); caesium carbonate; ruphos In tetrahydrofuran at 80℃; for 12h; Inert atmosphere; | 3.2 Step 2 A mixture of 3,6-dichloro-4-ethylpyridazine (500 mg, 2.8 mmol), 2- chlorobenzenesulfonamide (595 mg, 3.1 mmol), Cs2CO3 (2.7g, 8.5 mmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (132 mg, 282.4 umol) and [2-(2-aminoethyl)phenyl]- chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (194 mg, 282.4 umol) in THF (30.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction was concentrated to give a residue. The residue was purified by column chromatography (SiO2) to give a crude product (280 mg). The crude product was purified by prep-HPLC (TFA condition) to afford 2-chloro-N-(6-chloro- 5-ethylpyridazin-3-yl)benzenesulfonamide (20 mg, 54.2 umol, 1.9% yield).1H NMR (400MHz, METHANOL-d4) d 8.20 (d, J = 7.7 Hz, 1H), 7.64 (br s, 1H), 7.57 - 7.53 (m, 2H), 7.52 - 7.46 (m, 1H), 2.71 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H); and 2-chloro-N-(6-chloro-4- ethylpyridazin-3-yl)benzenesulfonamide (100 mg, 270.9 umol, 10.7% yield).1H NMR (400MHz, METHANOL-d4) d 8.21 (d, J = 7.6 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.56 - 7.48 (m, 2H), 2.61 (br d, J = 6.7 Hz, 2H), 1.18 (br t, J = 7.2 Hz, 3H). |
1: 1.9% 2: 1.9% | With [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-((2-aminoethyl)phenyl)]palladium(II) chloride; caesium carbonate; ruphos In tetrahydrofuran at 80℃; for 12h; Inert atmosphere; | I.3.2 Step 2: A mixture of 3,6-dichloro-4-ethylpyridazine (500 mg, 2.8 mmol), 2- chlorobenzenesulfonamide (595 mg, 3.1 mmol), Cs2CO3 (2.7g, 8.5 mmol), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (132 mg, 282.4 umol) and [2-(2-aminoethyl)phenyl]- chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (194 mg, 282.4 umol) in THF (30.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction was concentrated to give a residue. The residue was purified by column chromatography (SiO2) to give a crude product (280 mg). The crude product was purified by prep-HPLC (TFA condition) to afford 2-chloro-N-(6-chloro- 5-ethylpyridazin-3-yl)benzenesulfonamide (20 mg, 54.2 umol, 1.9% yield).1H NMR (400MHz, METHANOL-d4) d 8.20 (d, J = 7.7 Hz, 1H), 7.64 (br s, 1H), 7.57 - 7.53 (m, 2H), 7.52 - 7.46 (m, 1H), 2.71 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H); and 2-chloro-N-(6-chloro-4- ethylpyridazin-3-yl)benzenesulfonamide (100 mg, 270.9 umol, 10.7% yield).1H NMR (400MHz, METHANOL-d4) d 8.21 (d, J = 7.6 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.56 - 7.48 (m, 2H), 2.61 (br d, J = 6.7 Hz, 2H), 1.18 (br t, J = 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.9% | With [2-(2-aminoethyl)phenyl]chloropalladium ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane; caesium carbonate; ruphos In tetrahydrofuran at 80℃; for 12h; Inert atmosphere; | 12.3 Step 3 A mixture of tert-butyl ((lr,4r)-4-((6-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)- 8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate (90 mg, 159.0 umol), 2- chlorobenzenesulfonamide (34 mg, 174.9 umol), Cs2C03 (155 mg, 477.0 umol), dicyclohexyl-[2- (2,6-diisopropoxyphenyl)phenyl]phosphane (8 mg, 15.9 umol) and [2-(2-aminoethyl)phenyl]- chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl) phenyljphosphane (11 mg, 15.9 umol) in THF (5.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction was concentrated to give a residue. The residue was purified by prep-TLC (Si02) to give tert-butyl ((lr,4r)-4-((6-(6-(2- chlorophenylsulfonamido)-2-(trifluoromethoxy)pyridin-3-yl)-8-ethylquinazolin-2- yl)amino)cyclohexyl)carbamate (80 mg, 33.3 umol, 20.9% yield). M+H+ = 721.3(LCMS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium metabisulfite; sodium azide; tetrabutylammomium bromide; triphenylphosphine In water; acetonitrile at 80℃; for 12h; Inert atmosphere; | |
62% | With sodium metabisulfite; sodium azide; tetrabutylammomium bromide; triphenylphosphine In water; acetonitrile at 80℃; for 12h; Inert atmosphere; Schlenk technique; | 15 Synthesis of compound 2o: Under nitrogen protection,Diazo salt 1o (282.9mg, 1.25mmol), NaN3 (32.5mg, 0.5mmol), PPh3 (157.4mg, 0.6mmol), Na2S2O5 (190.1mg, 1.0mmol), TBAB (241.7mg, 0.75mmol) and MeCN /H2O = 2/1 (1 mL) was added to a Schlenk reaction tube.The reaction was stirred at 80 ° C for 12 h and then lowered to room temperature.The system was diluted with 10 mL of water and extracted with ethyl acetate (10 mL*3).Dry over anhydrous sodium sulfate, filter, concentrate,Column chromatography gave a white solid 2o (62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 6-bromobenzo[d]thiazole-2-carbonitrile With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos In 1,4-dioxane at 100℃; for 0.5h; Inert atmosphere; Stage #2: 2-chlorobenzenesulfonamide In 1,3-dioxane for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.1% | With caesium carbonate; tert-butyl XPhos; In tetrahydrofuran; at 80℃; for 12h; | To a solution of 2-chlorobenzenesulfonamide (1.0 g, 5.4 mmol) in THF (40.0 mL) was added <strong>[70952-62-4]3,6-dichloro-4-methoxypyridazine</strong> (0.6 g, 3.6 mmol), [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (288 mg, 363.1 umol), and Cs2C03 (2.3 g, 7.2 mmol). The reaction mixture was stirred at 80C for 12 h. The reaction mixture was concentrated to give a residue. The residue was diluted with H20 (20.0 mL) and extracted with EtOAc (20.0 mL chi 3). The combined organic layers were washed with brine (20.0 mL chi 3), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to give 2- chloro-N-(6-chloro-5-methoxypyridazin-3-yl)benzenesulfonamide (75 mg, 6.1% yield) as a red solid. 'H NMR (400MHZ, DMSO- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 1-(2-chlorophenyl)-2-methyl-1H-imidazole-4-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: 2-chlorobenzenesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran | Preparation of 1-(2-chlorophenyl)-N-[(2-chlorophenyl)sulfonyl]-2-methyl-1H-imidazole-4-carboxamide 0.2 g (0.845 mmol) of 1-(2-chlorophenyl)-2-methyl-1H-imidazole-4-carbxylic acid in THF was heated under reflux with 0.21 g (1.27 mmol) of carbonyldiimidazole for 1 h, and 0.243 g (1.27 mmol) of 2-chlorophenylsulfonamide and 0.193 g (1.27 mmol) of DBU were added after cooling. The mixture was stirred overnight and then concentrated and dissolved in dichloromethane and dilute hydrochloric acid. The organic phase was washed two more times with dilute hydrochloric acid, dried and concentrated. The residue was stirred with acetonitrile, filtered off with suction and dried. Yield 0.22 g (63% of theory) log P (neutral): 0.85; MH+: 410.0 1H-NMR (400 MHz, D6-DMSO) □ ppm: 2.4 (s, 3H), 7.5-7.8 (m, 7H), 8.1-8.2 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With [(Cp*IrCl)2(4,4′,6,6′-tetrahydroxy-2,2′-bipyrimidine)][Cl]2; potassium hydroxide In water at 130℃; for 12h; | 7 2-chloro-N-methylbenzenesulfonamide Combine o-chlorobenzenesulfonamide (95.8 mg, 0.5 mmol), iridium catalyst (5.1 mg, 0.005 mmol, 1 mol%), potassium hydroxide (28 mg, 0.5 mmol, 1 equiv), then, methanol (0.3 mL)and water (0.9 mL) were added to the reaction vessel in sequence.After the reaction mixture was reacted at 130 ° C for 12 hours in a reaction vessel, it was cooled to room temperature. The solvent was removed by rotary evaporation, and then the purified target compound was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate), yield: 88%. |
88% | With [(Cp*IrCl)2(4,4′,6,6′-tetrahydroxy-2,2′-bipyrimidine)][Cl]2; potassium hydroxide In water at 130℃; for 12h; Schlenk technique; | |
88% | With caesium carbonate at 125℃; for 12h; Schlenk technique; | 4.4. General procedure for the N-methylation of amines with methanol catalyzed by Cp*Ir(at)CTF General procedure: To an oven-dried, 25 mL Schlenk tube were added amines (0.5 mmol), methanol (1.5 mL), Cp*Ir(at)CTF (15.0 mg, 0.0025 mmol,0.5 mol %), Cs2CO3 (163 mg, 0.5 mmol). The mixture of reaction was heated at 125 °C in an oil bath for 12 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by flash column chromatography with hexanes/ethyl acetate to afford the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(II) choride dihydrate In N,N-dimethyl-formamide at 110℃; for 6h; | General procedure for the preparation of compounds (11a -11z) General procedure: Amine (1.5 mmol) was dissolved in DMF (8 mL), and potassium carbonate (4.5 mmol), CS2 (1.8 mmol) were added. The mixture was reacted at room temperature for 0.5 h. Then, 9a (1.0 mmol),CuCl2 2H2O (1.0 mmol) was added, the mixture was reacted at 110 °C for 6 h. After completion, the solvent was evaporated and then 10 mL of water was added. The mixture was extracted with dichloromethane and the combined organic phase was dried over anhydrous Na2SO4. After removal of solvents, the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (1:1) to afford the desired product (11a - 11z). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.2 mg | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 17h; | 8 Example 8: (5033) N-(2-Chlorophenyl)sulfonyl-6-(N-methylanilino)benzofuran-2-carboxamide To a room temperature stirred solution of INT-12 (30.0 mg, 0.11 mmol, 1.00 eq.), 2- chlorobenzene1-sulfonamide (21.5 mg, 0.11 mmol, 1.00 eq.) and PyBOP (70.0 mg, 0.14 mmol, 1.20 eq.) in anhydrous dichloromethane (561 mL, 0.20 M) was added DIPEA (78.1 µL, 0.45 mmol, 4.00 eq.). The resulting solution was stirred at RT for 17 h and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (30 g HP C18, 30-100% acetonitrile/water with 0.1% formic acid gradient) to give the title compound as a yellow solid (44.2 mg).1H NMR (400 MHz, DMSO-d6) d (5037) [ppm]: 8.17 (dd, 1 H), 7.89 (s, 1 H), 7.73- 7.64 (m, 2 H), 7.64- 7.58 (m, 1 H), 7.57 (d, 1 (5038) H), 7.41- 7.35 (m, 2 H), 7.21- 7.16 (m, 2 H), 7.13 (t, 1 H), 7.04 (d, 1 H), 6.85 (dd, 1 H), (5039) 3.33 (s, 3 H); LC-MS (method 4): Rt = 1.64 min, MS (ESIpos): m/z = 441 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.4 mg | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 23h; | 4 Example 4: (5001) N-(2-Chlorophenyl)sulfonyl-6-[ethyl(methyl)amino]benzofuran-2-carboxamide To a RT stirred solution of INT-8 (35.0 mg, 0.16 mmol, 1.00 eq.), 2-chlorobenzene-1- sulfonamide (30.5 mg, 0.16 mmol, 1.00 eq.) and PyBOP (99.6 mg, 0.19 mmol, 1.20 eq.) in anhydrous dichloromethane (798 mL, 0.20 M) was added DIPEA (111 µL, 0.64 mmol, (5005) 4.00 eq.). The resulting solution was stirred at room temperature for 23 h and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (30 g HP C18, 30-100% acetonitrile/water with 0.1% formic acid gradient) (5006) (5007) to give the title compound as a yellow solid (44.4 mg).1H NMR (400 MHz, DMSO-d6) d (5008) [ppm]: 12.92 (s, 1 H), 8.17 (dd1 H), 7.91 (s, 1 H), 7.75- 7.59 (m, 3 H), 7.55 (d, 1 H), 6.86 (5009) (dd, 1 H), 6.75 (s, 1 H), 3.47 (q, 2 H), 2.94 (s, 3 H), 1.06 (t, 3 H); LC-MS (method 4): Rt = (5010) 1.38 min, MS (ESIneg): m/z = 391 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosgene In 5,5-dimethyl-1,3-cyclohexadiene at 110℃; for 4h; | 3 A production process for improving the quality of sulfonyl isocyanate includes the following steps: Step S1, add p-chlorobenzene sulfonamide to the preparation kettle, add xylene and mix to form a sulfonamide solution, heat to azeotropically distill to remove water, and cool to room temperature for later use, wherein the amount of p-chlorobenzene sulfonamide and xylene is per 1 mole Add 1000mL xylene to p-chlorobenzenesulfonamide, and the heating temperature is 110;Step S2, add 10 parts of xylene to the synthesis kettle, and then perform a heating program, the temperature is controlled at 110°C,Combine the 4 parts sulfa solution prepared in step S1 and 1Part of n-butyl isocyanate is added to the synthesis kettle,'And pass 10 parts of phosgene,Control the feeding time for 2 hours,Keep it warm for another 2 hours,Produced product 1,Among them, the catalyst n-butyl isocyanate needs to be added dropwise 2 hours before the sulfa solution is added. After the sulfa solution is transferred, reduce the phosgene flow rate until it reaches the cumulative amount required by the process;Step S3: Transfer 4 parts of product 1 prepared in step S2 to the light-breaking kettle, and pass 2 parts of nitrogen to drive the unreacted phosgene and other tail gas to the condenser to obtain product 2, and the tail gas is refluxed after condensation Synthesis kettleIn step S4, the 8 parts of product 2 prepared in step S3 are rectified, filtered, and dried to obtain a finished product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With 1,2-dimethoxyethane; hydrogen; C51H53ClOP3Ru(1+)*ClO4(1-) at 120℃; for 36h; Autoclave; | 2.2. Catalytic study details General procedure: Under an atmosphere of nitrogen, a stainless steel 100 mL autoclave,equipped with a magnetic stir bar, was charged with Ru-Cat. (0.5 - 5.0mol) and the solvent to be used (5 mL). A solution of the substrates (0.5mmol) in the solvent (5 mL) was then added via a syringe. The autoclavewas purged by three cycles of pressurization/ venting with N2 (1 - 5 bar),and then pressurized with the desired pressure (40 ~ 80 bar). Theautoclave was heated to the desired temperature (100 ~ 160 C) and thecontents stirred. After the pre-determined reaction time, the autoclavewas cooled to room temperature and the pressure slowly released. Thereaction mixture was filtered through a plug of silica gel and thenanalyzed by GC and GC-MS. The mixture was concentrated underreduced pressure. The residue was purified by column chromatographyon silica gel (EtOAc in petroleum ether) to afford the correspondingreduced product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 25℃; | General procedure: L01, L05, L06, L10, L14, L15, L19, L23, L27, L31, L35 - L46, L55 and L56 were obtained using the following synthesis procedure [30-32] . Taking N -((4,6-dimethoxypyrimidin-2-yl)carbamoyl) -2- fluoro-5-vinylbenzenesulfonamide ( L19 ) as an example: At ambi- ent temperature, 2-fluoro-5-vinylbenzenesulfonamide ( 10b ) (0.2 g, 1.0 mmol), phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate ( 17a ) (0.3 g, 1.0 mmol), and DBU(0.22 mL, 1.5 mmol) were added to 5 mL acetonitrile under stirring conditions. The reaction mixture was monitored by TLC and the solvent was removed under reduced pressure until its completion. After that, additional 20 mL H 2 O was poured into the flask, the pH value of the transparent aqueous so- lution was slowly adjusted to 2 ∼3 using 1 mol/L HCl aqueous solu- tion, until the formation of a larger amount of white solid. The re- sulting precipitate was collected by suction filtration, washed with a small amount of water, and dried in vacuum to obtain the final product L19 (0.34 g, 89.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.2 mg | With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 20h; | 73 N-(2-chlorobenzenesulfonyl)-6-(propan-2-yl)-1-benzofuran-2-carboxamide To a room temperature stirred solution of 6-(propan-2-yl)-1-benzofuran-2-carboxylic acid (40.0 mg, 0.19 mmol, 1.00 eq.), 2-chlorobenzene-1-sulfonamide (37.5 mg, 0.20 mmol, 1.00 eq.) and PyBOP (122 mg, 0.24 mmol, 1.20 eq.) in anhydrous dichloromethane (979 μL, 0.20 M) was added N,N-diisopropylethylamine (136 µL, 0.78 mmol, 4.00 eq.). The resulting solution was stirred at room temperature for 20 h and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (30 g HP C18, 40-100% acetonitrile/water gradient buffered with 0.1% formic acid) to give the title compound as a white solid (68.2 mg).1H NMR (400 MHz, DMSO-d6) δ 8.18 (dd, 1H), 7.96 (s, 1H), 7.75 - 7.65 (m, 3H), 7.62 (td, 1H), 7.51 (s, 1H), 7.28 (dd, 1H), 3.04 (hept, 1H), 1.25 (d, 6H); LC-MS (Method 2): Rt= 1.58 min, MS (ESIpos): m/z = 378 [M+H]+ |
68.2 mg | With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 20h; | 73 N-(2-chlorobenzenesulfonyl)-6-(propan-2-yl)-1-benzofuran-2-carboxamide To a room temperature stirred solution of 6-(propan-2-yl)-1-benzofuran-2-carboxylic acid (40.0 mg, 0.19 mmol, 1.00 eq.), 2-chlorobenzene-1-sulfonamide (37.5 mg, 0.20 mmol, 1.00 eq.) and PyBOP (122 mg, 0.24 mmol, 1.20 eq.) in anhydrous dichloromethane (979 μL, 0.20 M) was added N,N-diisopropylethylamine (136 µL, 0.78 mmol, 4.00 eq.). The resulting solution was stirred at room temperature for 20 h and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (30 g HP C18, 40-100% acetonitrile/water gradient buffered with 0.1% formic acid) to give the title compound as a white solid (68.2 mg).1H NMR (400 MHz, DMSO-d6) δ 8.18 (dd, 1H), 7.96 (s, 1H), 7.75 - 7.65 (m, 3H), 7.62 (td, 1H), 7.51 (s, 1H), 7.28 (dd, 1H), 3.04 (hept, 1H), 1.25 (d, 6H); LC-MS (Method 2): Rt= 1.58 min, MS (ESIpos): m/z = 378 [M+H]+ |
Tags: 6961-82-6 synthesis path| 6961-82-6 SDS| 6961-82-6 COA| 6961-82-6 purity| 6961-82-6 application| 6961-82-6 NMR| 6961-82-6 COA| 6961-82-6 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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