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CAS No. : | 936-16-3 | MDL No. : | MFCD03426201 |
Formula : | C7H7NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GVYVHZKTSVDMNT-UHFFFAOYSA-N |
M.W : | 169.20 | Pubchem ID : | 13638 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.3 |
TPSA : | 54.55 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) : | -7.01 cm/s |
Log Po/w (iLOGP) : | 0.9 |
Log Po/w (XLOGP3) : | 0.46 |
Log Po/w (WLOGP) : | 1.03 |
Log Po/w (MLOGP) : | 0.24 |
Log Po/w (SILICOS-IT) : | 0.89 |
Consensus Log Po/w : | 0.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.58 |
Solubility : | 4.43 mg/ml ; 0.0262 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 11.3 mg/ml ; 0.067 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.64 |
Solubility : | 0.388 mg/ml ; 0.00229 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.34 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
97% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 15℃; for 3 h; Inert atmosphere | Step 1. Saccharin (10.0 g, 54.6 mmol) was slowly added to solution of LiAlH4 (2.24 g, 59.0 mmol) in 300 mL of THF at 0°C. The reaction mixture was stirred for 3h at 15°C under an inert atmosphere. Upon completion, EtOAc (100 mL) was slowly added followed by addition of 10percent H2S04 (lOOmL). The organic layer was separated and washed with 100 mL of 5percent sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 (4.4 g, 97percent). |
87% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 15℃; for 16.5 h; | tetrahydrofuran (2 mL) was added drop-wise to a 0 °C suspension of lithium aluminum hydride (45.6 mg, 1.20 mmol) in tetrahydrofuran (3 mL). After the reaction mixture had stirred for 30 minutes at 0 °C, it was gradually warmed to 15 °C and stirred at 15 °C for 16 hours. The white suspension was treated with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the product as a grey solid. Yield: 160 mg, 0.946 mmol, 87percent. 1H NMR (400 MHz, CDCI3) δ 7.81 (d, J=7.8 Hz, 1 H), 7.63 (dd, half of ABX pattern, J=7.5, 7.3 Hz, 1 H), 7.54 (dd, half of ABX pattern, J=7.5, 7.5 Hz, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 4.95-4.80 (br s, 1 H), 4.55 (s, 2H). |
81% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; | Preparation 16 2,3-Dihydrobenzo[d]isothiazole 1,1-dioxide To a cold solution of lithium aluminum hydride (0.414 g) in anhydrous tetrahydrofuran (30 mL), kept at 0° C. with an external ice bath, was added sulfobenzimide (1 g, 5.5 mmol). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with the addition of water and 2.5M aqueous sulfuric acid. The mixture was filtered through Celite and washed with ethyl acetate. The organic layer was washed with 1M aqueous sulfuric acid, dried (anhydrous magnesium sulfate), filtered, and concentrated to afford an off-white solid (0.75 g, 81percent). 1H NMR (CDCl3, 300 MHz) δ 7.81-7.78 (d, 1H, J=7.8 Hz), 7.64-7.59 (dt, 1H, J=1.2, 7.5 Hz), 7.52-7.49 (dt, 1H, J=0.75, 7.5 Hz), 7.41-7.37 (d, 1H, J=8.1 Hz), 4.8 (br s, 1H), 4.55-4.54 (d, 1H, J=3.6 Hz). |
35.6% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether for 48 h; | Example 82 1,2-Benzisothiazoline-1,1-dioxide To a solution of 1,2-benzisothiazoline-3-one-1,1-dioxide (25, 554 mg, 3.02 mmol) in THF (8.0 mL) was slowly added lithium aluminum hydride (1M in ether, 4.09 mL, 4.09 mmol). The solution was stirred for 48 hrs, followed by the slow addition of drops of Na2SO4 10H2O at 0° C. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness to afford the title compound (182 mg, 35.6percent). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.65 Hz, 1H), 7.67 (d, J=7.49, 1.17 Hz, 1H), 7.58 (t, J=7.44 Hz, 1H), 7.44 (d, J=7.59 Hz, 1H), 4.74 (brs, 1H), 4.59 (s, 2H) |
35.6% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether for 0.8 h; | Lithium aluminium hydride1 M in ether (4.09 mL) was addedslowly at 0 C to a solution of o-sulfobenzimide (7, 554 mg,3.02 mmol) in THF (8.0 mL), and stirred for 48 min. Subsequently,sodium sulfate hydrate was added to the solution and filteredthrough Celite. The organic layer was concentrated in reducedpressure to afford the title compound (182 mg, 35.6percent); 1H NMR(400 MHz, CDCl3) d 7.85 (d, J = 7.7, 1H), 7.67 (dt, J = 7.5, 1.2 Hz,1H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 4.74 (br, 1H),4.59 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 18 - 20℃; for 1.33333h; | Ethyl chloroformate (136ml) was added dropwise to a chilled solution of 2,3-dihydro- 1,2-benzisothiazol-1 ,1 -dioxide (68.Og) in pyridine (340ml) over 1h, maintaining the temperature below 180C. The slurry was stirred for 10min at 2O0C, diluted dropwise with water (1000ml) over 75min and stirred for a further 30min. The mixture was chilled to 0-50C, aged for 1 h and isolated by filtration. The cake was washed with cold water (2x250ml), and dried in vacuo to give the title compound as a white solid (72.35g).400 MHz NMR in dimethyl sulphoxide-d6. Dimethyl sulphoxide-d5 as reference at 2.50 ppm. delta (ppm): 1.30 (3) t J=7.1Hz, 4.32 (2H) q J=7.1Hz, 5.01 (2H) s, 7.64-7.70 (2H) m, 7.81 (1 H) td J=7.6Hz J=1.0Hz, 7.98 (1 H) d J=8.0Hz |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation; | Intermediate 30Ethyl 1 -[4-(1 ,1 -dioxido-1 ,2-benzisothiazol-2(3H)-yl)phenyl]-3-[[(frapis-4- methylcyclohexyl)carbonyl](1-methylethyl)amino]-1H-pyrazole-4-carboxylateA solution of Intermediate 5 (108 mg), 2,3-dihydro-1 ,2-benzisothiazole 1 ,1 -dioxide (35 mg), copper (I) iodide (4 mg), potassium carbonate (58 mg) and (IR^RJ-lambda/./V-dimethyl-i ^- cyclohexanediamine (12 mg) in DMF (4 mL) was heated in a microwave at 100° C, 300 W for 1 h and then evaporated to dryness. The residue was dissolved in ethyl acetate and washed sequentially with aqueous sodium bicarbonate solution, water and 2M HCI, dried using a EPO <DP n="48"/>hydrophobic frit and evaporated to dryness. The crude product was then purified by MDAP HPLC to give the title compound. MS calcd for (C30H36N4O5 + H)+: 565 MS found (electrospray): (M+H)+ = 565 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 90 - 110℃; for 21h; | 2-Chloro-4-(4-Boc-piperazin-l-yl)quinazoline (140 mg, 0.40 mmol), 253-dihydro-l,2- benzisothiazole l5l-dioxide (85 mg, 0.50 mmol) and potassium carbonate (110 mg, 0.80 mmol) in DMSO (2 ml) were heated at 90° for 16 h and then at 110° for 5 h. The reaction mixture was diluted with brine and extracted with dichloromethane (x3). The combined o organic phases were dried (MgSO4) and evaporated to dryness. The residue was dissolved in dichloromethane (2 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred at ambient temperature for 16 h. The solvent was evaporated and the crude was purified by preparative HPLC to give the acetate of the title compound (71 mg, 40percent). 1H NMR (400 MHz, DMSO-J6) d ppm 7.90 - 8.02 (2 H, m) 7.61 - 7.84 (5 H, m) 7.33 - 7.41 (1 H3 m) 5.19 (2 H, s) 3.79 - 3.88 (4 H, m) 2.87 - 2.95 (4 H, m); ESI-MS m/z M+H+ 382. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Example 27. 4-(1,1-Dioxido-1,2-benzisothiazol-2(3H)-yl)-2-piperazin-1-ylquinazoline. 2,4-Dichloroquinazoline (60 mg, 0.30 mmol), 2,3-dihydro-l,2-benzisothiazole 1,1-dioxide (50 mg, 0.30 mmol) and sodium hydride (11 mg, 0.45 mmol) were dissolved in anhydrous DMF (2 ml). The mixture was heated at 60° C under nitrogen atmosphere for 10 min. Piperazine (52 mg, 0.60 mmol) was added and the heating was continued for 10 minutes. 5 The reaction mixture was diluted with water (0.5 ml), filtered and purified by preparative HPLC to give the acetate of the title compound as a solid (36 mg, 27 percent). 1H NMR (400 MHz, MeOD-d4) delta ppm 8.49 (1 H3 d) 7.58 - 7.87 (6 H, m) 730 - 7.38 (1 H, m) 5.58 (2 H, s) 4.03 - 4.16 (4 H3 m) 3.15 - 3.26 (4 H3 m); ESI-MS m/z M+H+ 382. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.5% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; for 24h; | Example 83 2-((5-Isobutyl-1-phenyl-1H-pyrazol-3-yl)methyl)-<strong>[936-16-3]2,3-dihydrobenzo[d]isothiazole-1,1-dioxide</strong> (Compound 28) To a solution of 1,2-benzisothiazoline-1,1-dioxide (51.8 mg, 0.306 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (423 mg, 3.06 mmol), followed by stirring for 10 min. This solution was added with (5-isobutyl-1-phenyl-1H-pyrazol-3-yl)methyl bromide (108 mg, 0.367 mmol) in methylene chloride, and stirred for a day. Dilution was carried out in ethyl acetate before filtration. The filtrate was extracted with 1N HCl and an aqueous saturate sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=3:1?2:1) to afford the title compound (99.8 mg, 85.5percent). 1H NMR (400 MHz, CDCl3) delta 7.81-7.79 (m, 2H), 7.58-7.33 (m, 8H), 6.35 (s, 1H), 4.54 (s, 2H), 4.39 (s, 2H), 2.50 (d, J=7.06 Hz, 2H), 1.84-1.77 (m, 1H), 0.84 (d, J=6.56 Hz, 6H) 13C NMR (100 MHz, CDCl3) delta 147.2, 144.7, 139.7, 135.1, 134.0, 132.6, 129.2, 129.0, 128.1, 125.7, 124.6, 121.3, 106.0, 50.0, 41.3, 35.2, 28.3, 22.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; | Example 84 2-[{1-(tert-Butyl)-5-isobutyl-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 29) To a solution of 1,2-benzisothiazoline-1,1-dioxide (70.4 mg, 0.416 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (578 mg, 4.16 mmol) at room temperature, followed by stirring for 10 min. This solution was slowly added with drops of {1-(tert-butyl)-5-isobutyl-1H-pyrazol-3-yl}methyl bromide (126 mg, 0.462 mmol) in methylene chloride (4 mL), and then stirred at room temperature for a day. When the reaction was completed as measured by TLC (Hexane:EtOAc=6:1), the reaction mixture was filtered through celite in vacuo. The filtrate was neutralized with 1M HCl and an aqueous saturate sodium hydrogen carbonate solution. After extraction with ethyl acetate and water, the organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=6:1) to afford the title compound (124 mg, 79percent, white solid). M.P. 102.5-105.4° C.; 1H NMR (300 MHz, CDCl3) delta 7.81 (d, J=6.6 Hz, 1H), 7.60-7.48 (m, 2H), 7.36 (d, J=7.4 Hz, 1H), 6.18 (s, 1H), 4.45 (s, 2H), 4.34 (s, 2H), 2.64 (d, J=7.1 Hz, 2H), 2.06-1.09 (m, 1H), 1.64 (s, 9H), 0.98 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) delta 143.62, 143.10, 135.4, 134.3, 132.5, 128.9, 124.5, 121.3, 106.7, 59.9, 49.9, 41.5, 37.3, 30.5, 28.4, 22.7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; | Example 86 2-[{1-(2,6-Dichlorophenyl)-5-isobutyl-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 31) To a solution of N,N-dimethylformamide (1 mL) in 1,2-benzisothiazoline-1,1-dioxide (31.4 mg, 0.186 mmol) was added potassium carbonate (255 mg, 1.85 mmol) at room temperature, followed by stirring for 10 min. This solution was slowly added with drops of {1-(2,6-dichlorophenyl)-5-isobutyl-1H-pyrazol-3-yl}methyl bromide (73.3 mg, 0.202 mmol) in methylene chloride (2 mL), and stirred for a day at room temperature. When the reaction was completed as measured by TLC (Hexane:EtOAc=4:1), the reaction mixture was filtered through celite. The filtrate was neutralized with 1M HCl and an aqueous saturate sodium hydrogen carbonate solution. After extraction with ethyl acetate and water, the organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=2:1) to afford the title compound (61.9 mg, 74percent, white solid). M.P. 130.2-139.2° C.; 1H NMR (300 MHz, CDCl3) delta 7.84 (d, J=7.7 Hz, 1H), 7.62-7.30 (m, 6H), 6.40 (s, 2H), 4.57 (s, 2H), 4.38 (s, 2H), 2.24 (d, J=7.3 Hz, 2H), 1.92-1.79 (m, 1H), 0.89 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) delta 148.3, 146.4, 135.4, 135.2, 135.1, 134.2, 131.0, 129.0, 128.8, 124.6, 121.4, 105.4, 49.6, 41.3, 34.8, 27.5, 22.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; | Example 87 2-[{1-(tert-butyl)-5-phenyl-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 32) To a solution of N,N-dimethylformamide (0.9 mL) in 1,2-benzisothiazoline-1,1-dioxide (10.6 mg, 0.063 mmol) was added potassium carbonate (83.9 mg, 0.607 mmol) at room temperature, followed by stirring for 10 min. This solution was slowly added with drops of {1-(tert-butyl)-5-phenyl-1H-pyrazol-3-yl}methyl bromide (18.7 mg, 0.064 mmol) in methylene chloride (3 mL), and stirred for a day at room temperature. When the reaction was completed as measured by TLC (Hexane:EtOAc=4:1), the reaction mixture was filtered through celite. The filtrate was neutralized with 1M HCl and an aqueous saturate sodium hydrogen carbonate solution. After extraction with ethyl acetate and water, the organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=6:1?2:1) to afford compound 23 (9.50 mg, 40percent, white solid). |
40% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; | Example 88 2-[{1-(tert-Butyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 33) To a solution of 1,2-benzisothiazoline-1,1-dioxide (10.3 mg, 0.061 mmol) in N,N-dimethylformamide (0.9 mL) was added potassium carbonate (88.5 mg, 0.640 mmol) at room temperature, followed by stirring for 10 min. The solution was slowly added with drops of {1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl}methyl bromide (20.9 mg, 0.067 mmol) in methylene chloride (3 mL), and stirred at room temperature for a day. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), the reaction mixture was filtered through celite. The filtrate was neutralized with 1M HCl and an aqueous saturate sodium hydrogen carbonate solution. After extraction with ethyl acetate and water, the organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=6:1?1:1) to afford the title compound (10.2 mg, 42percent, white solid). M.P. 163.5-167.5° C.; 1H NMR (300 MHz, CDCl3) delta 7.86 (d, J=7.6 Hz, 1H), 7.65-7.53 (m, 2H), 7.41 (d, J=7.5 Hz, 1H), 7.35-7.29 (m, 2H), 7.13-7.06 (m, 2H), 6.27 (s, 1H), 4.53 (s, 2H), 4.46 (s, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) delta 164.4, 162.3, 161.1, 143.6, 142.9, 135.3, 134.2, 132.6, 132.2, 132.1, 129.9, 129.0, 124.5, 121.5, 115.0, 114.7, 109.3, 61.3, 50.0, 41.3, 31.2 |
42% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; | Example 89 2-[{1-(tert-Butyl)-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 34) To a solution of 1,2-benzisothiazoline-1,1-dioxide (24.3 mg, 0.144 mmol) in N,N-dimethylformamide (1 mL) was added dropwise potassium carbonate (180 mg, 1.30 mmol) at room temperature, followed by stirring for 15 min. This solution was slowly added with drops of {1-(tert-butyl)-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl}methyl bromide (51.6 mg, 0.143 mmol) in methylene chloride (4.5 mL), and stirred for a day at room temperature. When the reaction was completed as measured by TLC (Hexane:EtOAc=4:1), the reaction mixture was filtered through celite. The filtrate was neutralized with 1M HCl and an aqueous saturate sodium hydrogen carbonate solution. After extraction with ethyl acetate and water, the organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=4:1?2:1) to afford the title compound (25.4 mg, 39percent, white solid). M.P. 144.6-148.2° C.; 1H NMR (300 MHz, CDCl3) delta 7.85 (d, J=7.7 Hz, 1H), 7.68-7.48 (m, 6H), 7.41 (d, J=7.4 Hz, 1H), 6.29 (s, 1H), 4.54 (s, 2H), 4.47 (s, 2H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3) delta 143.9, 142.4, 137.9, 135.3, 134.2, 132.6, 130.9, 130.8, 130.5, 129.0, 125.7, 124.8, 124.7, 124.5, 122.1, 121.5, 109.4, 61.5, 50.1, 41.3, 31.3 |
39% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.2 mg | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; for 24h; | To a solution of {1-(tert-butyl)-5-(4-piperidin-1-yl-phenyl)-1H-pyrazol-3-yl}methanol (54.9 mg, 0.175 mmol) in methylene chloride (1.5 mL) were added PPh3 (93.1 mg, 0.355 mmol) and CBr4 (121 mg, 0.365 mmol) at 0° C., followed by stirring at the same temperature for one hour to give {1-(tert-butyl)-5-(4-piperidin-1-yl-phenyl)-1H-pyrazol-3-yl}methyl bromide. When the reaction was completed as measured by TLC(Hexane:EtOAc=2:1), 1,2-benzisothiazoline-1,1-dioxide (27.3 mg, 0.161 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. At the same temperature, potassium carbonate (228 mg, 1.65 mmol) was added, and the resulting solution was stirred for a day. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), water was added, after which extraction was carried out with ethyl acetate and brine. The organic layer thus formed was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=4:1?1:1) to afford the title compound (15.2 mg, 20percent, white solid). (0324) M.P. 150.4-165.2° C.; (0325) 1H NMR (300 MHz, CDCl3) delta 7.89 (d, J=7.9 Hz, 1H), 7.64-7.52 (m, 2H), 7.40 (d, J=7.1 Hz, 1H), 7.30-7.17 (m, 2H), 6.29 (d, J=8.7 Hz, 2H), 6.22 (s, 1H), 4.52 (s, 2H), 4.46 (s, 2H), 3.26-3.23 (brs, 4H), 1.79-1.74 (brs, 4H), 1.67-1.63 (brs, 2H), 1.49 (s, 9H); (0326) 13C NMR (75 MHz, CDCl3) delta 151.9, 144.4, 143.3, 135.4, 134.3, 132.5, 131.1, 128.9, 124.5, 123.7, 121.4, 114.9, 109.0, 61.0, 50.0, 41.4, 31.2, 25.7, 24.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
55.4 mg | With potassium carbonate; In N,N-dimethyl-formamide; for 24h; | 2-[{1-(tert-Butyl)-5-(4-cyclohexylphenyl)-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 36) (0327) To a solution of {1-(tert-butyl)-5-(4-cyclohexylphenyl)-1H-pyrazol-3-yl}methanol (101 mg, 0.323 mmol) in were added PPh3 (71.8 mg, 0.655 mmol), and CBr4 (217 mg, 0.655 mmol) at 0° C., followed by stirring at the same temperature for one hour to give {1-(tert-butyl)-5-(4-cyclohexylphenyl)-1H-pyrazol-3-yl}methyl bromide. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), drops of N,N-dimethylformamide (1.5 mL) in 1,2-benzisothiazoline-1,1-dioxide (57.1 mg, 0.388 mmol) were slowly added. (0328) At the same temperature, potassium carbonate (447 mg, 3.23 mmol) was added, and the resulting solution was stirred for a day. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), water was added dropwise, after which extraction was carried out with ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=4:1) to afford the title compound (55.4 mg, 31percent, white solid). (0329) M.P. 135.7-141.5° C.; (0330) 1H NMR (300 MHz, CDCl3) delta 7.83 (d, J=7.5 Hz, 1H), 7.63-7.50 (m, 2H), 7.40 (d, J=7.5 Hz, 1H), 7.30-7.20 (m, 4H), 6.24 (s, 1H), 4.53 (s, 2H), 4.45 (s, 2H), 2.56 (brs, 1H), 1.92-1.77 (m, 5H), 1.48-1.27 (m, 14H); (0331) 13C NMR (75 MHz, CDCl3) delta 148.5, 144.3, 143.4, 135.4, 134.3, 132.5, 131.3, 130.3, 128.9, 126.2, 124.5, 121.4, 109.0, 61.1, 50.0, 44.3, 41.4, 34.4, 31.2, 26.9, 26.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.8 mg | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; for 72h; | To a solution of (1-isobutyl-5-phenyl-1H-pyrazol-3-yl)methanol (52.1 mg, 0.226 mmol) in methylene chloride (1 mL) were added PPh3 (146 mg, 0.557 mmol), CBr4 (185 mg, 0.557 mmol) at 0° C., followed by stirring at the same temperature for 30 min to give (1-isobutyl-5-phenyl-1H-pyrazol-3-yl)methyl bromide. When the reaction was completed as measured by TLC (Hexane:EtOAc=4:1), a solution of 1,2-benzisothiazoline-1,1-dioxide (57.1 mg, 0.388 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. (0333) Then, drops of potassium carbonate (313 mg, 2.26 mmol) were added at the same temperature to the solution that was then stirred for 3 days. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), water was dropped to the reaction mixture. After extraction with ethyl acetate and brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=2:1) to afford the title compound (37.8 mg, 44percent percent, white solid). (0334) M.P 129.7-137.3° C.; (0335) 1H NMR (300 MHz, CDCl3) delta 7.86-7.63 (m, 1H), 7.63-7.51 (m, 2H), 7.49-7.37 (m, 6H), 6.42 (s, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 3.96 (d, J=7.5 Hz, 2H), 2.24-2.15 (m, 1H), 0.79 (d, J=6.7 Hz, 6H); (0336) 13C NMR (75 MHz, CDCl3) delta 145.9, 145.6, 136.8, 135.2, 134.0, 133.0, 132.6, 130.8, 129.0, 128.7, 124.6, 121.4, 106.1, 56.8, 49.9, 41.3, 29.6, 19.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2 mg | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; for 24h; | To a solution of {5-(4-fluorophenyl)-1-isobutyl-1H-pyrazol-3-yl}methanol (19.4 mg, 0.078 mmol) in methylene chloride (1 mL) were added PPh3 (42.8 mg, 0.163 mmol) and CBr4 (66.3 mg, 0.200 mmol) at 0° C., followed by stirring at the same temperature for 30 minute to give {5-(4-fluorophenyl)-1-isobutyl-1H-pyrazol-3-yl}methyl bromide. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), drops of 1,2-benzisothiazoline-1,1-dioxide (24.3 mg, 0.078 mmol) N,N-dimethylformamide (1.5 mL) were slowly added to the solution. (0338) Then, potassium carbonate (113 mg, 0.816 mmol) were added at the same temperature, and the resulting solution was stirred for a day. When the reaction was completed as measured by TLC (Hexane:EtOAc=2:1), water was added, after which extraction was carried out with ethyl acetate and brine. The organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=2:1) to afford the title compound (19.2 mg, 62percent percent, white solid). (0339) M.P. 110.8-118.2° C.; (0340) 1H NMR (300 MHz, CDCl3) delta 7.61-7.52 (m, 2H), 7.46-7.33 (m, 4H), 7.18-7.12 (m, 2H), 6.41 (s, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 3.91 (d, J=7.5 Hz, 2H), 2.26-2.08 (m, 1H), 0.80 (d, J=6.7 Hz, 6H); (0341) 13C NMR (75 MHz, CDCl3) delta 146.0, 144.5, 136.8, 135.2, 134.0, 133.0, 132.6, 131.0, 130.8, 129.2, 129.1, 124.8, 124.5, 121.4, 115.9, 115.6, 106.3, 56.7, 49.9, 45.7, 41.2, 29.6, 19.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; | Example 85 2-[{1-(4-Fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl}methyl]-2,3-dihydro[d]isothiazole 1,1-dioxide (Compound 30) To a solution of 1,2-benzisothiazoline-1,1-dioxide (97.1 mg, 0.574 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (793 mg, 5.74 mmol) at room temperature, followed by stirring for 10 min. The solution was slowly added with drops of methylene chloride (5 mL) in {1-(4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl}methyl bromide (199 mg, 0.638 mmol), and stirred for a day at room temperature. When the reaction was completed as measured by TLC (Hexane:EtOAc=3:1), the reaction mixture was filtered through celite. The filtrate was neutralized with 1M HCl and an aqueous saturate sodium hydrogen carbonate solution. After extraction with ethyl acetate and water, the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (Hexane:EtOAc=6:1) to afford the title compound (124 mg, 79percent, white solid). M.P. 119.3-122.7° C.; 1H NMR (300 MHz, CDCl3) delta 7.83-7.49 (m, 3H), 7.41-7.34 (m, 3H), 7.20-7.14 (m, 2H), 6.35 (s, 1H), 4.52 (s, 2H), 4.39 (s, 2H), 2.46 (d, J=7.2 Hz, 2H), 1.87-1.73 (m, 1H), 0.84 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) delta 163.7, 160.4, 147.4, 144.8, 135.9, 135.1, 134.0, 132.7, 129.1, 127.7, 127.6, 124.6, 121.3, 116.2, 115.9, 106.1, 53.5, 50.0, 41.3, 35.1, 28.3, 22.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16h; | A mixture of C105 (80 mg, 0.16 mmol), C113 (39.3 mg, 0.232 mmol), cesium carbonate (114 mg, 0.350 mmol), and potassium iodide (28.9 mg, 0.174 mmol) in /V,/V-dimethylformamide (2 mL) was stirred at 80 °C for 16 hours. The reaction mixture was then diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium chloride solution (3 x 30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Preparative thin layer chromatography on silica gel (Eluent: 1 :3 ethyl acetate / petroleum ether) provided the product as a light yellow oil. Yield: 55 mg, 94 muetaiotaomicronIota, 59percent. LCMS m/z 607.0 [M+Na+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | General procedure: [1-(tert-Butyl)-5-{4-(piperidin-1-yl)phenyl}-1H-pyrazol-3-yl]methanol (54.9 mg, 0.18 mmol) was reacted with tripheny phosphine(93.1 mg, 0.36 mmol) and carbontetrabromide (121 mg,0.37 mmol) for 1 h. at 0 C. Without purification, the reaction mixturewas added to compound 8 (27.3 mg, 0.16 mmol) in DMF, andstirred for overnight. Then the reaction mixture was extracted withethyl acetate. The organic layer was dried over magnesium sulfate,filtered, concentrated in reduced pressure, and purified by columnchromatography (Hex: EtOAc = 4: 1 then 1: 1) to give title compound(15.2 mg, 20percent). 1H NMR (300 MHz, CDCl3) d 7.89 (d, J = 7.9 Hz, 1H), 7.64?7.52(m, 2H), 7.40 (d, J = 7.1 Hz, 1H), 7.30?7.17 (m, 2H), 6.29 (d,J = 8.7 Hz, 2H), 6.22 (s, 1H), 4.52 (s, 2H), 4.46 (s, 2H), 3.26?3.23(m, 4H), 1.79?1.74 (m, 4H), 1.67?1.63 (m, 2H), 1.49 (s, 9H).; 13CNMR (75 MHz, CDCl3) d 151.9, 144.4, 143.3, 135.4, 134.3, 132.5, 131.1, 128.9, 124.5, 123.7, 121.4, 114.9, 109.0, 61.0, 50.0, 41.4,31.2, 25.7, 24.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.5% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; | General procedure: Potassium carbonate was dissolved in DMF, and 1,2-bezeneisothiazolin-1,1-dioxide (8) (1 equiv.) in dichloromethanewas added to the reaction solution, and stirred for overnight. Then,the reaction mixture was filtered through Celite, and washed with1 N HCl and saturated sodium hydrogen carbonate solution. Residualsolution was dried over magnesium sulfate, and concentratedin vacuo, and purified by column chromatography to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 80℃; for 3h; | Step 1. To a mixture of 6-methyl-2,4-dichloropyrimidine (162 mg, 0.994 mmol) and 1 (185 mg, 1.1 mmol) in anhydrous CH3CN (4 mL) was added K2CO3 (274 mg, 2 mmol), the mixture was stirred at 80°C for 3 hrs. Concentration under reduced pressure resulted in 11 (130 mg), which was submitted to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 2h; | Step 2. To a solution of 8 (150 mg, 0.54 mmol) and 1 (92 mg, 0.54 mmol) in anhydrous DMF (4 mL) was added cesium carbonate (353 mg, 1.08 mmol), and the resulting mixture was stirred at 40°C for 2 hours. Upon completion, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (60 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by prep-HPLC (0.04percentHCl/CH3CN/H2O system) resulted in Compound 77 (3.9 mg, 9.0percent) as a white solid. 1H NMR (DMSO-d6, 400MHz) delta 8.78 (d, 1H), 8.61 (d, 1H), 8.10-8.03 (m, 2H), 7.84 (d, 1H), 7.76-7.71 (m, 3H), 6.99 (s, 1H), 5.14 (s, 2H), 2.40 (s, 3H); LCMS (ESI): m/z 355.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | Step 2. Solution of 1 (97 mg, 0.053 mmol) in DMF (4 mL) was cooled to 0°C and NaH (13.9 mg, 0.058 mmol) was added. The mixture was stirred at 0°C for 30 minutes followed by addition of 10 (100 mg, 0.48 mmol). The solution was allowed to stir 15 hours at 0°C. The resulting mixture was poured into water (20 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. Purification with prep- HPLC (0.04percentNH3.H2O/ ACN/ H20 system) resulted in Compound 114 (20 mg) as a white solid. 1H NMR (DMSO-d6, 400MHz) delta 8.56 (d, 1H), 8.51-8.46 (m, 2H), 8.06 (d, 1H), 7.88- 7.82 (m, 1H), 7.81-7.67 (m, 3H), 7.50 (dd, 8.2 Hz, 1H), 7.09 (d, 1H), 5.17 (s, 2H); LCMS (ESI+): m/z 341 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Step 2. A mixture of 12 (100 mg, 0.40 mmol), 1 (67 mg, 0.40 mmol), potassium carbonate (55 mg, 0.40 mmol), Cul (3.8 mg, 0.019 mmol), and L-proline (2.3 mg, 0.019 mmol) in dioxane (4 mL) was stirred at 110°C for 16 hours under an inert atmosphere. Upon completion, water (40 mL) was added and the reaction mixture was extracted with EtOAc (90 mL). The organic phase was washed with brine (50 mL) and concentrated under reduced pressure. Purification with prep-HPLC (0.075percent TFA/CH3CN/H20 system) resulted in Compound 121 (40 mg, 29percent) as yellow solid and TFA salt. 1H NMR (DMSO-d6, 400MHz) delta 8.69-8.68 (d, 1H), 8.53-8.52 (d, 1H), 7.99-7.94 (m, 3H), 7.77 (m, 1H), 7.67-7.62 (m, 3H), 7.07-7.05 (d, 1H), 6.83-6.81 (d, 1H), 4.95 (s, 2H); LCMS (ESI): m/z 340.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
230 mg | With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; | Step 2. A mixture of 14 (200 mg, 0.70 mmol), 1 (143 mg, 0.84 mmol), Cs2CO3 (459 mg, 1.41 mmol), Cul (40 mg, 0.21 mmol) and 2-(dimethylamino)acetic acid hydrochloride (30 mg, 0.21 mmol) in dioxane (2 mL) was degassed and purged with N2 (3X). The mixture was stirred at 100°C for 12 h under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL), adjusted to pH=7 with 2N HC1, and separated. The aqueous layer was extracted with ethyl acetate (2 x 40 mL) and the combined organic layer was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 15 (230 mg) as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate; In 1,4-dioxane; at 100℃; for 12h; | Step2. A mixture of compound 17 (300 mg, 1.18 mmol), 1 (240 mg, 1.42 mmol), Cs2CO3 (769 mg, 2.36 mmol), Cul (67 mg, 0.35 mmol) and 2-(dimethylamino)acetic acid hydrochloride (49 mg, 0.354 mmol) in dioxane (20 mL) was degassed and purged with N2 for (3X). The mixture was stirred at 100°C for 12 hrs, filtered, and then diluted with ethyl acetate (50 mL). The solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 18 as a dark brown oil which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate; In 1,4-dioxane; at 100℃; for 12h; | Step 2. A mixture of 20 (160 mg, 0.58 mmol), 1 (99 mg, 0.58 mmol), Cs2CO3 (380 mg, 1.17 mmol), Cul (33 mg, 0.17 mmol) and 2-(dimethylamino)acetic acid hydrochloride (24 mg, 0.17 mmol) in dioxane (2 mL) was degassed and purged with N2 (3X). The mixture was stirred at 100°C for 12 h and then filtered and concentrated. The crude material was purified by prep- HPLC to give Compound 140 (27 mg, 10percent) as a white solid. 1H NMR (DMSO-d6, 400MHz) delta 8.98 (s, lH), 8.74 (d, 1H), 8.34 (d, 1H), 7.99 (d, 1H), 7.92 (dd, 1H), 7.85-7.79 (m, 1H), 7.71-7.66 (m, 2H), 7.34 (s, 1H), 7.21 (s, 1H), 5.10 (s, 2H); LCMS (ESI): m/z 408.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h; | To a mixture of 2,6-dichloropyrazine (193 mg, 1.30 mmol) and 1 (200 mg, 1.18 mmol) in DMF (5 mL), was added Cs2CO3 (770 mg, 2.36 mmol). The resulting mixture was stirred at 100°C for 5 hours. The mixture was cooled to 25°C and poured into ice water. The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried with anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by TLC (petroleum ether/ethyl acetate = 2: 1) to afford 21 (220 mg, 60percent) as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With caesium carbonate; cesium fluoride; In N,N-dimethyl-formamide; at 80℃; for 1h; | Step 2. A mixture of 23 (180 mg, 0.70 mmol), 1 (60 mg, 0.35 mmol), CsF (107 mg, 0.70 mmol), Cs2CO3 (458 mg, 1.41 mmol) in DMF (3 mL) was degassed and purged with N2 (3X). The mixture was stirred at 80°C for 1 h, filtered, and then purified by prep-HPLC to give Compound 143 (15 mg, 5percent) as a light yellow solid. 1H NMR (DMSO-d6, 400MHz) delta 7.97 (d, 1H), 7.81 (s, 1H), 7.72 (d, 1H), 7.43 (s, 1H), 7.31 (s, 2H), 7.18 (s, 2H), 5.09 (s, 2H), 2.33 (s, 3H); LCMS (ESI): m/z 356.0 (M+H). |
Tags: 936-16-3 synthesis path| 936-16-3 SDS| 936-16-3 COA| 936-16-3 purity| 936-16-3 application| 936-16-3 NMR| 936-16-3 COA| 936-16-3 structure
[ 603-72-5 ]
2H-Naphtho[1,8-cd]isothiazole 1,1-dioxide
Similarity: 0.85
[ 27148-03-4 ]
Benzo[d]isothiazole-3(2H)-thione 1,1-dioxide
Similarity: 0.85
[ 4703-15-5 ]
N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide
Similarity: 0.77
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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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