There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 6668-56-0 | MDL No. : | MFCD06342770 |
Formula : | C6H3ClFNO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RRONENSZKCGROA-UHFFFAOYSA-N |
M.W : | 239.61 | Pubchem ID : | 2782799 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.31 |
TPSA : | 88.34 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.5 cm/s |
Log Po/w (iLOGP) : | 0.97 |
Log Po/w (XLOGP3) : | 1.78 |
Log Po/w (WLOGP) : | 3.16 |
Log Po/w (MLOGP) : | 0.86 |
Log Po/w (SILICOS-IT) : | -0.28 |
Consensus Log Po/w : | 1.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.63 |
Solubility : | 0.559 mg/ml ; 0.00233 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.25 |
Solubility : | 0.134 mg/ml ; 0.000558 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.6 |
Solubility : | 0.595 mg/ml ; 0.00248 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.23 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P321-P363-P405-P501 | UN#: | 1759 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
140 g | With ammonium hydroxide In water; isopropyl alcohol at -40 - -20℃; for 0.5 h; | 1580 mL of aqueous ammonia was added to a 5 L reaction vessel, isopropanol 1 L and water 1.5 L, Stir, cool to -40 ° C, and then drop 3-nitro-4-fluorobenzenesulfonyl chloride, keeping the temperature below -20 ° C. After the dropwise addition, the pH value is 8, the temperature is stirred for half an hour, and then HCl 30ml is added dropwise to keep the temperature below -20 ° C and adjust pH = 1-2. remove isopropyl alcohol, add water 1L, beating filter, after drying 140 g of 3-nitro-4-fluorobenzenesulfonamide, total yield: 68percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 65% 2: 3% | Stage #1: ethyl 1H-pyrrole-2-carboxylate With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran for 0.25h; Stage #2: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride In tetrahydrofuran at 20℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.6% | With ammonium hydroxide In tetrahydrofuran; dichloromethane for 2h; Cooling with ice; | Synthesis of 4-fluoro-3-nitrobenzenesulfonamide (2) In the ice salt bath, compound 1 38.41 g was dissolved with 80 mL of mixed solution of THF:DCM with the ratio 1:1. The aqueous ammonia was added dropwise for 2 h. The reaction was monitored by TCL. After that, diluted hydrochloric acid (50 mL, 5 M) was added to the reaction mixture, which extracted with EA. The organic layer was washed with hydrochloric acid (50 mL, 4 M), then aqueous brine, dried over MgSO4, filtrated to get yellow solid and recrystallization to obtain 2 (27.39 g, 77.6% yield) as a slight yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (dd, J= 7.0, 2.3 Hz, 1H), 8.20 (ddd, J= 8.7, 4.0, 2.2 Hz, 1H), 7.82 (dd, J= 11.0, 8.8 Hz, 1H), 7.3(s, 2H). MS (ESI) m/z: 219.15 [M-H]-. |
40% | With ammonium hydroxide In tetrahydrofuran; methanol at -78 - -65℃; for 0.5h; | |
162.4 g | With ammonium hydroxide In isopropyl alcohol at -35℃; for 0.5h; |
140 g | With ammonium hydroxide In water; isopropyl alcohol at -40 - -20℃; for 0.5h; | 1.2 Preparation of 3-nitro-4-fluorobenzenesulfonamide 1580 mL of aqueous ammonia was added to a 5 L reaction vessel, isopropanol 1 L and water 1.5 L, Stir, cool to -40 ° C, and then drop 3-nitro-4-fluorobenzenesulfonyl chloride, keeping the temperature below -20 ° C. After the dropwise addition, the pH value is 8, the temperature is stirred for half an hour, and then HCl 30ml is added dropwise to keep the temperature below -20 ° C and adjust pH = 1-2. remove isopropyl alcohol, add water 1L, beating filter, after drying 140 g of 3-nitro-4-fluorobenzenesulfonamide, total yield: 68% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With chlorosulfonic acid at 80℃; for 10h; | Synthesis of 1-fluoro-3-nitrobenzene-1-sulfonyl chloride (1) Fluoro-2-nitrobenzene (17.9 mL, 0.17 mol) and chlorosulfuric acid (30 mL, 0.45 mol) were added into the round bottom flask. Subsequently, the solution was refluxed at 80 °C for 10 h until the reaction was completed (TLC control). The solution was cooled to 25 °C , and poured into ice bath. The organic layers were extracted with ether, dried with MgSO4 and concentrated and purified to afford 1 (38.41 g, 94.4% yield) as slight yellow solid. |
80% | With chlorosulfonic acid at 100℃; for 12h; | Synthesis of intermediate 37 To a round bottom flask were added chlorosulfonic acid (2.48 g, 21.26 mmol) and 2-fluoronitrobenzene (1.00 g, 7.09 mmol). The temperature was raised to 100 ° C and stirred for 12 hours. After detecting the reaction by TLC, the reaction system was cooled to room temperature, and the system solution was slowly added dropwise toThe excess chlorosulfonic acid was quenched with ice water, and the reaction system was extracted 3 times with ethyl acetate (30 mL × 3). The organic phases are combined and the organic phases are combined. Wash with saturated sodium bicarbonate solution (30 mL). After the liquid was separated, the organic phase was removed from the water and spin-dried to obtain the product. Yield 80%, pale yellow oily liquid. 1 hour |
69% | With chlorosulfonic acid In neat (no solvent) at 0 - 70℃; for 2h; |
65% | With chlorosulfonic acid at 100℃; for 18h; | 1.a PREPARATION 14-fluoro-/V-methyl-3-nitrobenzenesulfonamidea) 4-fluoro-3-nitrobenzenesulfonyl chloride1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to rt, poured over ice and extracted with CH2CI2. The combined organic layers were then washed with sat. aq. NaHC03, then brine, dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (55.3 g, 65%) as a brown oil. |
65% | With chlorosulfonic acid at 100℃; for 18h; | 1.1 Step 1. 4-fluoro-3-nitrobenzenesulfonyl chloride1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to room temperature, poured over ice and extracted with methylene chloride. The combined organic layers were then washed with NaHC03, then brine, dried over MgS04, filtered and concentrated in vacuo to afford 4-fluoro-3-nitrobenzenesulfonyl chloride (55.3 g, 65% yield) as a brown oil. |
65% | With chlorosulfonic acid at 65 - 100℃; for 18h; | 1.1 Step 1. 4-fluoro-3-nitrobenzenesulfonyl chloride1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to room temperature, poured over ice and extracted with methylene chloride. The combined organic layers were then washed with NaHC03, then brine, dried over MgS04, filtered and concentrated in vacuo to afford 4-fluoro-3-nitrobenzenesulfonyl chloride (55.3 g, 65% yield) as a brown oil. |
65% | With chlorosulfonic acid at 100℃; for 18h; | 4.1 PREPARATION 44-fluoro-/V-methyl-3-nitrobenzenesulfonamide Step 1. 4-fluoro-3-nitrobenzenesulfonyl chloride1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to room temperature, poured over ice and extracted with methylene chloride. The combined organic layers were then washed with NaHC03, then brine, dried over MgS04, filtered and concentrated in vacuo to afford 4-fluoro-3-nitrobenzenesulfonyl chloride (55.3 g, 65% yield) as a brown oil. |
65% | With chlorosulfonic acid at 65 - 100℃; for 18h; | 1 Step 1. 4-fluoro-3-nitrobenzenesulfonyl chloride1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to rt, poured over ice and extracted with CH2CI2. The combined organic layers were then washed with NaHC03, then brine, dried over MgS04, filtered and concentrated in vacuo to afford 4-fluoro-3-nitrobenzenesulfonyl chloride (55.3 g, 65%) as a brown oil. |
65% | With chlorosulfonic acid at 65 - 100℃; for 18h; | |
53% | With chlorosulfonic acid at 65 - 90℃; for 0.0833333h; Inert atmosphere; | 36.1 Step 1. Synthesis of 36-1 Into a 50-mL 3-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed sulfurochloridic acid (19.6 g, 168.21 mmol). This was followed by addition of 1-fluoro-2-nitrobenzene (10 g, 70.87 mmol) dropwise with stirring at 65°C in 5 min. The resulting solution was stirred at 90°C for overnight. The reaction was cooled to room temperature, and then poured into 50 mL of water/ice. The mixture was extracted with 3 x 50 mL of dichloromethane. The organic layer was washed with 100 mL of saturated sodium bicarbonate and then 2 x 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the desired product (9 g, 53% yield). |
With chlorosulfonic acid at 95℃; for 18h; | ||
With chlorosulfonic acid | A 4-Fluoro-3-nitrophenylsulfonyl Chloride. Example A 4-Fluoro-3-nitrophenylsulfonyl Chloride. 2-Fluoronitrobenzene (10.0 g, 70.9 mmol) was added to chlorosulfonic acid (10.0 ml, 150 mmol) at 65° C. After stirring at 85° C. for 18 h, the reaction mixture was cooled to room temperature and poured onto ice chips and extracted with CH2Cl2 (2*250 ml). The combined organic extracts were washed with saturated NaHCO3 solution and dried (MgSO4). Concentration at room temperature and then at 100° C. under high vacuum produced 2.40 g (14%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 8.76 (1H, dd, J=2.4, 6.5 Hz), 8.33 (1H, ddd, J=2.4, 3.8, 9.2 Hz), 7.61 (1H, t, J=9.2 Hz). MS (EI): 239 (15, M+), 204 (100). | |
With chlorosulfonic acid at 80℃; for 10h; | ||
With chlorosulfonic acid at 0 - 90℃; for 5h; | General procedure for the synthesis of 3-nitro-4-fluoro benzene sulfonamides (A21): General procedure: To a ice-cooled solution of chloro sulfonic acid (10 ml) at 0 °C was added l-fluoro-2-nitrobenzene 1 (1 g). The reaction mixture was brought to room temperature and heated to 90 °C for 5 h. After completion of the reaction, it was brought to room temperature and poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgS04, concentrated and purified by column chromatography to obtain the 4-fluoro-3- nitrobenzenesulfonyl chloride. | |
With chlorosulfonic acid at 65 - 100℃; for 14h; | 2 A 25 mL flask equipped with a reflux condenser was charged with chiorosulfonicacid (5.2 mL, 78.0 mmol, 2.2 eq) and heated to 65 °C. 1-Fluoro-2-nitrobenzene (3.7 mL, 35.0 mmol, 1 eq) was added dropwise. The resulting brown mixture was then heated to 100 °C. After 14 h, the cooled reaction mixture was poured onto ice (50 g) and the aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with saturated sodium bicarbonate (2 x 50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the sulfonyl chloride (5.06 g, 21.1 mmol, 60%) as a brown liquid that was used in the next step without further purification. | |
With chlorosulfonic acid | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 0.5 h / 60 °C 2: phosphorus pentachloride / trichlorophosphate / 6 h / Heating / reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 162.4 g / aq. NH3 / propan-2-ol / 0.5 h / -35 °C 2: 97 percent / DIPEA / dimethylsulfoxide / 16 h / 20 °C | ||
Multi-step reaction with 2 steps 1: ammonium hydroxide / tetrahydrofuran; methanol / 0.5 h / -78 - -65 °C 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 162.4 g / aq. NH3 / propan-2-ol / 0.5 h / -35 °C 2: 68 percent / DIPEA / dimethylformamide / 12 h / 20 °C 3: 99 percent / HCl / dioxane / 6 h / 20 °C 4: 56 percent / EDCI; DMAP / tetrahydrofuran; dimethylformamide / 16 h / 20 °C 5: 99 percent / BH3 / tetrahydrofuran / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 162.4 g / aq. NH3 / propan-2-ol / 0.5 h / -35 °C 2: DIPEA / dimethylformamide / 12 h / 20 °C 3: HCl / dioxane / 6 h / 20 °C 4: EDCI; DMAP / tetrahydrofuran; dimethylformamide / 16 h / 20 °C 5: BH3 / tetrahydrofuran / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 162.4 g / aq. NH3 / propan-2-ol / 0.5 h / -35 °C 2: 68 percent / DIPEA / dimethylformamide / 12 h / 20 °C 3: 99 percent / HCl / dioxane / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 162.4 g / aq. NH3 / propan-2-ol / 0.5 h / -35 °C 2: DIPEA / dimethylformamide / 12 h / 20 °C 3: HCl / dioxane / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 162.4 g / aq. NH3 / propan-2-ol / 0.5 h / -35 °C 2: DIPEA / dimethylformamide / 12 h / 20 °C 3: HCl / dioxane / 6 h / 20 °C 4: EDCI; DMAP / tetrahydrofuran; dimethylformamide / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane | 1.1I 4-(4-(2-fluorobenzyl)-4-methoxy-1-piperidinyl)-N-((4-fluoro-3-nitrophenyl)sulfonyl)benzenecarboximidamide EXAMPLE 1I 4-(4-(2-fluorobenzyl)-4-methoxy-1-piperidinyl)-N-((4-fluoro-3-nitrophenyl)sulfonyl)benzenecarboximidamide A solution of EXAMPLE 1H (0.200 g, 0.587 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.245 mL, 1.76 mmol) and 4-fluoro-3-nitrobenzenesulfonyl chloride (prepared according to the procedure described in U.S. patent applicaiton Ser. No. 09/957,256, 0.169 g, 0.704 mmol), stirred overnight, and concentrated. The residue was purified by silica gel chromatography eluding with 40% ethyl acetate in hexanes to provide the desired product. MS (ESI) m/e 543 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In methanol; ethyl acetate | 1 4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene. Example 1 4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene. p-Anisidine (760 mg, 6.18 mmol) was added to a solution of 4-fluoro-3-nitrophenylsulfonyl chloride (740 mg, 3.09 mmol; Example A) in MeOH (10 ml) at ambient temperature. After stirring at room temperature for 15 min, the reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provided 603 mg (60% yield) of the title compound. 1H-NMR (CDCl3): δ 8.42 (1H, dd, J=2.3, 6.8 Hz), 7.88 (1H, ddd, J=2.4, 4.0, 8.8 Hz), 7.33 (1H, dd, J=8.8, 9.9 Hz), 6.98 (2H, m), 6.81 (2H, m), 6.45 (1H, s), 3.77 (3H, s). MS (EI): 326 (11, M+), 122 (100). Anal. Calcd. for C13H11FN2O5S: C, 47.85; H, 3.40; N, 8.59; S, 9.83. Found: C, 47.68; H, 3.44; N, 8.54; S, 9.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With phosphorus pentachloride In trichlorophosphate for 6h; Heating / reflux; | The above acid (2 g, 7.7 mmol), PCl5 (1.8 g, 7.5 mmol), in POCl3 (60 mL), were refluxed for 6 hrs. The resulting mixture was cooled to r.t., and concentrated. To the oily residue was added crushed ice. The solid was filtered and washed with water (2x50 mL), dried to obtain 40 (99%). 1H-NMR (CDCl3,500 MHz): δ 8.8 (m, IH), 8.36 (m, IH), 7.6 (m, IH). |
With phosphorus pentachloride; trichlorophosphate Reflux; Cooling with ice; | 31 Reference Example 31 4-Fluoro-3-nitrobenzenesulfonyl chloride To 2-fluoronitrobenzene (2.33 g) was added fuming sulfuric acid (20 mL), and the mixture was stirred at 60°C for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice and potassium chloride (10 g), and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g). To phosphoryl chloride (85 mL) were added 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g) and phosphorus pentachloride (2.82 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane - n-hexane/ethyl acetate = 3/1) to give the title compound (2.65 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide In water; acetone at 0℃; for 3h; Inert atmosphere; | ||
With sodium azide In water; acetone at 0℃; for 3h; | 1.4 1.4 Sulfonylazide (SZ4) 6 7[ 0292 ] A saturated solution of sodium azide (280 mg, 4.30 mmol) in water was added slowly to a saturated solution of 6 (see Wendt et al, J. Med. Chem. 2006, 49, 1165-1181) (500 mg, 2.1 mmol) in acetone at 0°C. The mixture was stirred at 0°C for 3 hours. Ethyl acetate (20 mL) and saturated aqueous potassium carbonate solution (20 mL) were added to the mixture and after extraction with ethyl acetate (20 mL x3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated. Product 7 was used without further purification in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine In dichloromethane at 20℃; for 5h; | 86 Reference Example 86 2-Fluoro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)aniline To a solution of 2,3,4,5-tetrahydro-1H-benzo[B]azepine (0.37 g), triethylamine (0.35 mL) and 4-dimethylaminopyridine (26 mg) in methylene chloride (8 mL) was added 4-fluoro-3-nitrobenzenesulfonyl chloride (0.5 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7 mL). To the solution were added methanol (7 mL) and nickel(II) bromide (23 mg). To the mixture was added sodium borohydride (0.24 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane - n-hexane/ethyl acetate = 1/1) to give the title compound (0.26 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: morpholine; 4-fluoro-3-nitrobenzene-1-sulfonyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h; Stage #2: 2-methoxyethylamine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 150℃; Microwave irradiation; | 103.1 EXAMPLE 1035-{4-[1 -[2-(methyloxy)ethyl]-5-(4-morpholinylsulfonyl)-1 H-benzimidazol-2-yl]-1 H-imidazol2-yl}-1 ,3-benzothiazoleStep 1. N-[2-(methyloxy)ethyl]-4-(4-morpholinylsulfonyl)-2-nitroaniline [2- (methyloxy)ethyl][4-(4-morpholinylsulfonyl)-2-nitrophenyl]amine: Added morpholine (73.0 μΙ, 0.835 mmol) to 4-fluoro-3-nitrobenzenesulfonyl chloride (200 mg, 0.835 mmol) and 1 equiv. of DIEA in Tetrahydrofuran (THF) (2199 μΙ). Stirred at RT for two hours. LCMS showed product. Added [2-(methyloxy)ethyl]amine (72.6 μΙ, 0.835 mmol) and 2 equiv. of DIEA (874 μΙ, 5.008 mmol) (x2). Heated the reaction to 150 °C in the microwave. LCMS looked good; material was carried on without further purification to the next step. MS {m/z) 346.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In tetrahydrofuran at -35℃; for 1h; | 1.b b) 4-fluoro-/V-methyl-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL) was added Et3N (150 mL, 1.08 mol). The mixture was cooled to -35 °C and ΟΗ3ΝΗ2·ΗΟΙ (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to rt and diluted with 1 :1 water/EtOAc. The organic layer was separated and washed with sat. aq. NaHC03, then brine, dried over MgS04, filtered, and concentrated in vacuo. The crude residue was purified via flash column chromatography (20%EtOAc/petroleum ether) to afford the title compound (38 g, 90%) as a yellow solid. |
90% | With triethylamine In tetrahydrofuran at -35℃; for 1h; | 1.2 Step 2. 4-fluoro-/V-methyl-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL), was added triethylamine (150 mL, 1.08 mol). The mixture was cooled to - 35 °C and methylamine hydrochloride (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to room temperature and diluted with 1 :1 water/ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, then brine, dried over MgS04, filtered and concentrated in vacuo. The crude residue was purified via column chromatography (20% ethyl acetate/petroleum ether) to give 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (38 g, 90% yield) as a yellow solid. |
90% | With triethylamine In tetrahydrofuran at -35℃; for 1h; | 1.2 Step 2. 4-fluoro-N-methyl-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL), was added triethylamine (150 mL, 1.08 mol). The mixture was cooled to -35 °C and methylamine hydrochloride (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to room temperature and diluted with 1 :1 water/ethyl acetate. The organic layer was separated and washed with saturated aqueous sodiumbicarbonate, then brine, dried over MgS04, filtered and concentrated in vacuo. The crude residue was purified via column chromatography (20% ethyl acetate/petroleum ether) to give 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (38 g, 90% yield) as a yellow solid. |
90% | With triethylamine In tetrahydrofuran; water at -35 - 20℃; | 4.2 Step 2. 4-fluoro-/V-methyl-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL), was added triethylamine (150 mL, 1.08 mol). The mixture was cooled to - 35 °C and methylamine hydrochloride (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to room temperature and diluted with 1 :1 water/ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, then brine, dried over MgS04, filtered and concentrated in vacuo. The crude residue was purified via column chromatography (20% ethyl acetate/petroleum ether) to give 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (38 g, 90% yield) as a yellow solid. |
90% | With triethylamine In tetrahydrofuran; water at -35℃; | 2 Step 2. 4-fluoro-/V-methyl-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 ml_), was added Et3N (150 ml_, 1.08 mol). The mixture was cooled to -35 °C and < Η3ΝΗ2·Η< Ι (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to rt and diluted with 1 :1 water/EtOAc. The organic layer was separated and washed with satd. aq. NaHC03, then brine, dried over MgS04, filtered and concentrated in vacuo. The crude residue was purified via flash column chromatography (20% EtOAc/petroleum ether) to give 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (38 g, 90%) as a yellow solid. |
90% | With triethylamine In tetrahydrofuran; water at -35 - 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2: hydrogen / palladium / tetrahydrofuran / 50 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2: hydrogen / 10% palladium on charcoal / tetrahydrofuran / 50 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / water; tetrahydrofuran / -35 - 20 °C 2: hydrogen / palladium on activated charcoal / tetrahydrofuran / 50 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: triethylamine / water; tetrahydrofuran / -35 °C 2: hydrogen / palladium on activated charcoal / tetrahydrofuran / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2.1: sodium hydride / mineral oil / 0.5 h / 20 °C 2.2: 20 °C 3.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2.1: sodium hydride / 0.5 h / 20 °C 2.2: 20 °C 3.1: hydrogen / 10% palladium on charcoal / ethanol / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: triethylamine / water; tetrahydrofuran / -35 °C 2.1: sodium hydride / 0.5 h / 20 °C 2.2: 20 °C 3.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In 1,4-dioxane; at 100℃; for 20h;Microwave irradiation; | EXAMPLE 60A/-methyl-3-(1 /-/-purin-6-ylamino)-4-[4-(trifluoromethyl)-1 -piperidinyl]benzenesulfonamidea) A/-methyl-3-nitro-4-[4-(trifluoromethyl)-1-piperidinyl]benzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (320 mg, 1.37 mmol) in 1 ,4-dioxane (5 mL) in a microwave reaction tube was added <strong>[657-36-3]4-(trifluoromethyl)piperidine</strong> (209 mg, 1.37 mmol). The mixture was heated at 100 °C for 20 h and purified by flash column chromatography (10-70percent EtOAc/hexanes) to afford the title compound (330 mg, 68percent) as a yellow oil. LCMS (ES) m/z 368 (M+H)+; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.58 (td, J=12.19, 3.66 Hz, 2 H) 1 .90 (d, J=12.38 Hz, 2 H) 2.42 (br. s, 3 H) 2.60 (br. s, 2 H) 3.04 (t, J=12.51 Hz, 2 H) 7.46 (d, J=8.84 Hz, 1 H) 7.52 (br. s, 1 H) 7.83 (dd, J=8.84, 2.27 Hz, 1 H) 8.14 (d, J=2.27 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In 1,4-dioxane at 100℃; for 20h; Microwave irradiation; | 61.a EXAMPLE 61/V-methyl-3-(1 H-purin-6-ylamino)-4-[3-(trifluoromethyl)-1 -piperidinya) A/-methyl-3-nitro-4-[3-(trifluoromethyl)-1-piperidinyl]benzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (320 mg, 1.37 mmol) in 1 ,4-dioxane (5 mL) was added 3-(trifluoromethyl)piperidine (251 mg, 1 .64 mmol). The mixture was heated at 100 °C for 20 h. The mixture was concentrated and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (381 mg, 76%) as a brown oil. LCMS (ES) m/z 368 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (br. s, 1 H) 1 .65 (br. s, 1 H) 1.80 (br. s, 1 H) 1.98-2.02 (m, 2H), 2.43 (s, 3H) 2.71 br. s, 1 H) 2.92 - 3.05 (m, 2H) 3.32 (m, 1 H) 7.48 (s, 1 H) 7.56 (br. s, 1 H) 7.82 - 7.90 (m, 1 H) 8.16 (s, 1 H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In 1,4-dioxane at 80℃; for 20h; Sealed tube; Microwave irradiation; | 66.a EXAMPLE 66A/-methyl-4-{2-[2-(methyloxy)ethyl]-1-piperidinyl}-3-(1 H-purin-6- ylamino)benzenesulfonamidea) A/-methyl-4-{2-[2-(methyloxy)ethyl]- -piperidinyl}-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (320 mg, 1.37 mmol) in 1 ,4-dioxane (5 ml.) in a microwave reaction tube was added 2-[2- (methyloxy)ethyl]piperidine (215 mg, 1.50 mmol). The reaction vessel was sealed and heated at 80 °C for 20 h. The mixture was cooled to rt and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the title compound (288 mg, 59%) as a brown oil. LCMS (ES) m/z 358 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .57 (br. s, 2 H) 1 .65 (br. s, 3 H) 1.78 (br. s, 1 H) 1.98 (s, 1 H) 2.39 (s, 3 H) 2.92 (s, 4 H) 3.04 (br. s, 2 H) 3.17 (br. s, 3 H) 7.45 (s, 2 H) 7.74 (s, 1 H) 8.05 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride; 4-Ethynylaniline With pyridine Inert atmosphere; Stage #2: (R)-N<SUP>1</SUP>,N<SUP>1</SUP>-dimethyl-4-(phenylthio)butane-1,3-diamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine at 0℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine at 0℃; for 0.5h; Inert atmosphere; | |
53% | With pyridine at 0℃; for 0.5h; | |
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C 3: hydrogen / palladium on activated charcoal / tetrahydrofuran / 50 °C / 760.05 Torr / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2: N-ethyl-N,N-diisopropylamine / 50 °C 3: hydrogen / 10% palladium on charcoal / tetrahydrofuran / 50 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: triethylamine / water; tetrahydrofuran / -35 - 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C 3: hydrogen / palladium on activated charcoal / tetrahydrofuran / 50 °C / Inert atmosphere |
Multi-step reaction with 3 steps 1: triethylamine / water; tetrahydrofuran / -35 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C 3: hydrogen / palladium on activated charcoal / tetrahydrofuran / 50 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: triethylamine / water; tetrahydrofuran / -35 - 25 °C 2: triethylamine / tetrahydrofuran / 0.5 h / -40 - 20 °C 3: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 16 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2: N-ethyl-N,N-diisopropylamine / 50 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / water; tetrahydrofuran / -35 - 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C |
Multi-step reaction with 2 steps 1: triethylamine / water; tetrahydrofuran / -35 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / water; tetrahydrofuran / -35 - 25 °C 2: triethylamine / tetrahydrofuran / 0.5 h / -40 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine / tetrahydrofuran / 1 h / -35 °C 2.1: triethylamine / tetrahydrofuran / 5 h / 25 °C 3.1: tetrahydrofuran / 20 h / 25 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.03 h / 25 °C 4.2: 1 h / 25 °C 5.1: hydrogen / 10% palladium on charcoal / methanol / 25 °C | ||
Multi-step reaction with 5 steps 1: triethylamine / water; tetrahydrofuran / -35 °C 2: triethylamine / tetrahydrofuran / 5 h / 25 °C 3: tetrahydrofuran / 20 h / 25 °C 4: sodium hydride / N,N-dimethyl-formamide / 25 °C 5: hydrogen / palladium 10% on activated carbon / methanol / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.2% | A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-l ,2,4- thiadiazol-5-amine (851 mg, 3.39 mmol) and THF (10 mL) to give a clear, light yellow solution. The flask was cooled in a dry ice and acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3387 mu?, 3.39 mmol) was added dropwise over 1 minute to give a suspension. The flask was removed from the cooling bath for 10 min, then re-cooled for 5 min. A solution of 4-fluoro-3-nitrobenzene-l-sulfonyl chloride (737.72 mg, 3.08 mmol) in THF (3 mL with a 1 mL flask/syringe wash) was added dropwise over 2 min. The mixture was stirred for another 5 min, then the mixture was warmed to room temperature. The reaction mixture was diluted with water and extracted with EtO Ac (3x). The combined organic extract was dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (0 to 30% EtO Ac/heptane) to give N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(l,2,4- thiadiazol-5-yl)benzenesulfonamide (758 mg, 1.668 mmol, 54.2 % yield) as a yellow solid. .H NMR (400 MHz, CHLOROFORM-d) delta = 8.24 (s, 1 H), 8.18 (dd, J = 2.4, 6.7 Hz, 1 H), 7.99 (ddd, J = 2.4, 3.9, 8.8 Hz, 1 H), 7.33 - 7.28 (m, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.32 (dd, J = 2.3, 8.4 Hz, 1 H), 6.21 (d, J= 2.4 Hz, 1 H), 5.37 (s, 2 H), 3.76 (s, 3 H), 3.63 (s, 3 H). m z (ESI) 477.0 (M+H)+. | |
A 100-mL round-bottom flask was charged with <strong>[1063733-41-4]N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine</strong> (INTERMEDIATE A, 1.478 g, 5.88 mmol) and THF (10 mL) to give a clear, light-yellow solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (5.88 mL, 5.88 mmol) was added drowpise over 2 min. The cooling bath was removed for 5 minutes, then re-cooled for 5 min. A solution of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (1.281 g, 5.35 mmol) in THF (3 mL with a 1 mL flask/syringe wash) was added dropwise over 2 minutes. The cooling bath was removed and the reaction was warmed to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was concentrated from EtOAc (2x), then taken up in EtOAc, sonicated for 1 min, and filtered through a membrane filter. The resulting solid was transferred to a sonication vial, then put under high vacuum at 60 C for 10 min to give N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE S) as a yellow solid. 1H NMR (400MHz , CHLOROFORM-d) delta = 8.24 (s, 1 H), 8.18 (dd, J= 2.4, 6.7 Hz, 1 H), 7.99 (ddd, J= 2.4, 3.9, 8.8 Hz, 1 H), 7.33 - 7.28 (m, 1 H), 7.09 (d, J= 8.4 Hz, 1 H), 6.32 (dd, J= 2.3, 8.4 Hz, 1 H), 6.21 (d, J= 2.4 Hz, 1 H), 5.37 (s, 2 H), 3.76 (s, 3 H), 3.63 (s, 3 H). m/z (ESI) 477.0 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: tert-butyl (7-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)carbamate With sodium hydride In tetrahydrofuran; mineral oil at -78 - 0℃; for 0.25h; Inert atmosphere; Stage #2: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride In tetrahydrofuran; mineral oil at -78 - 0℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium hydroxide In water; acetone for 1.5h; Inert atmosphere; Sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 0 - 20℃; for 12h; | General procedure for the synthesis of 3-nitro-4-fluoro benzene sulfonamides (A21): General procedure: To a stirred solution of the respective amines (1 equiv.) in dichloromethane was added pyridine (3 equiv.) at 0 °C and stirred for 0.5 h, followed by the addition of the 4-fluoro-3- nitrobenzenesulfonyl chloride and stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with IN HC1, brine, dried, concentrated and purified by column chromatography to obtain 3-nitro-4-fluoro benzene sulfonamides A21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.7% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | 170 Intermediate S12 A 1 4-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-nitro-benzenesulfonamide To a magnetically stirred solution of 4-fluoro-3-nitrobenzenesulfonyl chloride(2.97 ml_, 20.87 mmol) and A/,A/-diisopropylethylamine (11.14 ml_, 62.6 mmol) in THF (60 ml.)at -7 8 °C under nitrogen was added 1 -(fluoromethyl)cyclopropan-l -amine hydrochloride (2.75 g, 21.91 mmol), and the resulting mixture was agitated at -7 8 °C for 15 min and then -1 0 °Cfor 30 min before being warmed to ambient temperature and stirred overnight. The mixturewas partitioned between EtOAc (60 ml.) and water (40 ml_). The organic phase was collectedand the water back-extracted with EtOAc (40 ml_). The combined organics were dried (NaS04)5 and distilled to dryness to give the crude, which was purified by automated columnchromatography (Si02; RediSep - 80 g; 0 to 20% EtOAc in hexane) to afford the desiredproduct as a yellow solid (1.2 g, 4.11 mmol, 19.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 0 - 20℃; for 18h; | 2 In a 100 mL flask, the sulfonyl chloride was dissolved in dichloromethane (21 mL)and cooled to 0 °C. 2-(Aminomethyl)-1-ethylpyrrolidine (2.9 mL, 21.0 mmol, 1 eq) was added dropwise over 5 mm and the reaction mixture was allowed to warm to room temperature overnight. After 18 h, the resulting yellow precipitate was filtered and washed with diethyl ether (100 mL) to afford the crude sulfonamide as a hygroscopic yellow powder that was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; nitric acid at 30 - 65℃; | 1.1 To 1 L of the reaction vessel was added 180 g (0.925 mol, 1 eq) of 4-fluorobenzenesulfonyl chloride and concentrated sulfuric acid 540 mL (3 V / g), stirred to rise 30 ° C, dropping fuming nitric acid 61g (0.925mol, 1eq), keep the temperature below 65 ° C. After addition, the mixture was stirred overnight at 56 ° C to give 3-nitro-4-fluorobenzenesulfonyl chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.06% | Stage #1: 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride In tetrahydrofuran at 25℃; for 14h; | 8 Synthesis of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-fluoro-3-nitrophenyl)sulfonyl)-2-(5-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin- l(5H)-yl)benzamide : To a solution of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2- e]pyridin-l(5H)-yl)benzamide (500.00 mg, 690.22 umol, 1.00 eq) in THE (10.00 mL), LiHMDS (1 M, 1.52 mL, 2.20 eq) in THE was added at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 4-fluoro-3-nitro-benzenesulfonyl chloride (181.92 mg, 759.24 umol, 1.10 eq) was added. The mixture was stirred at 25 °C for 14 h. The reacting solution was quenched with sat. aq. NH4Cl (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatogaphy (pure PE to DCM:MeOH = 10:1) to afford 4-(4-((4’-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-fluoro-3- nitrophenyl)sulfonyl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2- e]pyridin-l(5H)-yl)benzamide (90.00 mg, 97.03 //mol, 14.06% yield) as a yellow oil. The product was confirmed by LC-MS and used directly for the next step without further purification |
14.06% | Stage #1: 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride In tetrahydrofuran at 25℃; for 14h; | 1-8; 1-10; 1-11 Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-N-((4-fluoro-3-nitrophenyl)sulfonyl)-2-(5-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide : To a solution of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2- e]pyridin-1(5H)-yl)benzamide (500.00 mg, 690.22 umol, 1.00 eq) in THF (10.00 mL), LiHMDS (1 M, 1.52 mL, 2.20 eq) in THF was added at 0 oC. The mixture was stirred at 0 oC for 30 min, and then 4-fluoro-3-nitro-benzenesulfonyl chloride (181.92 mg, 759.24 umol, 1.10 eq) was added. The mixture was stirred at 25 oC for 14 h. The reacting solution was quenched with sat. aq. NH4Cl (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatogaphy (pure PE to DCM:MeOH = 10:1) to afford 4-(4-((4'-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-fluoro-3- nitrophenyl)sulfonyl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2- e]pyridin-1(5H)-yl)benzamide (90.00 mg, 97.03 µmol, 14.06% yield) as a yellow oil. The product was confirmed by LC-MS and used directly for the next step without further purification. |
Stage #1: 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride In tetrahydrofuran at 25℃; for 14h; | 12; 14; 15 Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-fluoro-3-nitrophenyl)sulfonyl)-2-(5-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-l(5H)-yl)benzamide : To a solution of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2- e]pyridin-l(5H)-yl)benzamide (500.00 mg, 690.22 umol, 1.00 eq) in THF (10.00 mL), LiHMDS (1 M, 1.52 mL, 2.20 eq) in THF was added at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 4-fluoro-3-nitro-benzenesulfonyl chloride (181.92 mg, 759.24 umol, 1.10 eq) was added. The mixture was stirred at 25 °C for 14 h. The reacting solution was quenched with sat. aq. NH4C1 (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatogaphy (pure PE to DCM:MeOH = 10: 1) to afford 4-(4-((4'-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-fluoro-3- nitrophenyl)sulfonyl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2- e]pyridin-l(5H)-yl)benzamide (90.00 mg, 97.03 μπιο, 14.06% yield) as a yellow oil. The product was confirmed by LC-MS and used directly for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triphenylphosphine In toluene for 2h; Inert atmosphere; | 36.2 Step 2. Synthesis of 36-2 Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-fluoro-3 -nitrobenzene-1-sulfonyl chloride (9 g, 37.56 mmol) in toluene (90 mL). This was followed by addition of PPh3 (29.5 g, 112.47 mmol) in several batches in 60 min (exothermic). The resulting solution was stirred for 1 h. To this, water (50 mL) was carefully added maintaining the reaction temperature less than 45°C. The resulting solution was stirred for 1 h at room temperature. The reaction mixture was extracted with 3x100 mL of dichloromethane. The combined organic layers were washed with 3 x 200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1: 10-1:3) to afford the desired product (4 g, 61% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; dmap In dichloromethane at 0 - 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethyl acetate at 15 - 50℃; for 12h; | 2.1 Step 1 Synthesis of benzyl 3-nitro-4-fluorobenzenesulfonate In a 1000 mL four-necked flask, 151.2 g (1.4 moles) of benzyl alcohol, 111.1 g (1.1 moles) of triethylamine and 400 mL of ethyl acetate were added, and the mixture was stirred and cooled to 15°C or lower.A solution of 239.5 g (1.0 mol) of 3-nitro-4-fluorobenzenesulfonyl chloride in 200 mL of ethyl acetate was added dropwise at 20° C. and the addition was continued for 2 hours. The mixture was heated to 50° C. for 10 hours.Cool to room temperature, add moisture layer, the aqueous layer was extracted twice with ethyl acetate, the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and the solvent was removed to obtain crude 3-nitro-4-fluorobenzenesulfonic acid. Benzyl ester 303.5g, yield 97.6%, content 97.81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine In tetrahydrofuran for 0.5h; Cooling with ice; | Synthesis of intermediate 38a Add intermediate 37 (100 mg, 0.417 mmol) to a round bottom flask, add 10 mL of anhydrous THF to dissolve, lower the temperature in an ice bath for 10 min, and add cyclopropylamine (23.83 mg, 0.417 mmol) and triethylamine (105.49 mg, 1.04 mmol ), Stir for 20min in an ice bath, spin-dry the solvent after the TLC reaction is complete, dilute the system with ethyl acetate (20mL) and saturated brine (20mL), adjust the pH to about 7, separate the liquid, discard the aqueous phase, and spin dry the organic The phase was purified by silica gel column chromatography (petroleum ether PE / ethyl acetate EA = 4: 1) to obtain the product in a yield of 60%.Light yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; | |
68.2% | Stage #1: 4-fluoro-3-nitrobenzene-1-sulfonyl chloride With triethylamine In tetrahydrofuran at -35℃; for 0.166667h; Inert atmosphere; Stage #2: methylamine In tetrahydrofuran at -35℃; for 1h; Inert atmosphere; | 1.1 Step 1: Synthesis of 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (Compound 3) To the mixture of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (2 g, 8.4 mmol) in THF (80 mL) was added Et3N (5.08 g, 50.4 mmol), the mixture was stirred at -35oC under N2for 10 min., and then the solution of methylamine in THF (1 M, 10 mL, 10 mmol) was added dropwise, the mixture was stirred at -35oC for 1 hour, diluted with EtOAc (100 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave the crude product (2 g) as a yellow oil, which was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v/v) to obtain the target compound 3 (1.33 g, yield 68.2%) as solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.47 (dd, J = 7.0, 2.3 Hz, 1H), 8.18 (ddd, J = 8.7, 4.0, 2.4 Hz, 1H), 7.93 - 7.80 (m, 2H), 2.48 (d, J = 4.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In tetrahydrofuran at -35 - 0℃; for 2.5h; | 1 Step 1: 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide To a cooled (-35 °C) solution of 4-Fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine (3.13 mL, 22.46 mmol), followed by addition of Bis-(4-methoxybenzyl)amine (4.97 mL, 20.7 mmol) in THF (50 mL) solution over 30 min. while the temperature was kept at -35 °C. After completion of the addition, the temperature was allowed slowly to warm to 0 °C over 1 h., and the mixture was stirred at 0 °C for an additional hour. The mixture was neutralized with 1 N HC1 to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with 1 N HC1 (10 mL), 7.5% NaHC03 aqueous solution (20 mL), and brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 min. and left at r.t. for 1 h. The mixture was filtered and washed with hexane to afford the desired title product (6.85 g) without further purification. The mother liquid was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexane was added as the procedures mentioned above to afford the additional 0.51 g of the title product. Total product 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained is 7.36 g (78%). NMR (400 MHz, DMSO-de): d 8.18-8.23 (m, 2 H), 7.75-7.79 (q, 1 H), 7.08 (d, 4 H), 6.81 (d, 4 H), 4.31 (s, 4 H), 3.71 (s, 6 H). 19F NMR (376 MHz, DMSO-d6): d -112.54 (s, 1 F). LCMS calculated for C22H22FN2O6S (M+H)+: m/z = 461.11; found: 461.1. |
78% | With triethylamine In tetrahydrofuran at -35 - 0℃; for 2.5h; | 7 Step 7: 4-fluoro-N,N-bis[ ( 4-methoxyphenyl)methyl ]-3-nitro-benzenesulfonamide To a cooled (-35 °C) solution of 4-Fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine (3.13 mL, 22.46 mmol), followed by addition of bis-(4-methoxybenzyl)amine (4.97 mL, 20.73 mmol) in THF (50 mL) solution over 30 min. while the temperature was kept at -35 °C. After completion of the addition, the temperature was allowed slowly to warm to 0 °C over 1 h., and the mixture was stirred at 0 °C for an additional hour, TLC (PE : EA = 5 : 1, Rf = 0.5)). The mixture was neutralized with 1 N HC1 to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with IN HC1 (10 mL), 7.5% NaHCCh aqueous solution (20 mL), and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 min. and left at r.t. for 1 h. The mixture was filtered and washed with hexane to afford the desired title product (6.85 g) without further purification. The mother liquid was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexane was added as the procedures mentioned above to afford the additional 0.51 g of the title product. Total product 4-fluoro-N,N-bis[(4- methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained is 7.36 g (78%). 'H NMR (400 MHz, DMSO-de): d 8.18-8.23 (m, 2 H), 7.75-7.79 (q, 1 H), 7.08 (d, 4 H), 6.81 (d, 4 H), 4.31 (s, 4 H), 3.71 (s, 6 H).19F NMR (376 MHz, DMSO-d6): d -112.54 (s, 1 F). LCMS calc for C22H22FN2O6S (M+H)+: m/z = 461.11 ; Found: 461.1. |
78% | With triethylamine In tetrahydrofuran at -35 - 0℃; for 2.5h; | 1 Step 1: 4-fluoro-N,N-bis[(4-methoxyphenyl)methyl ]-3-nitro-benzenesulfonamide To a cooled (-35 °C) solution of 4-Fluoro-3-nitrobenzenesulfonyl chloride (4.89 g, 20.42 mmol) in THF (50 mL) was added Triethylamine (3.13 mL, 22.46 mmol), followed by addition of Bis-(4-methoxybenzyl)amine (4.97 mL, 20.7 mmol) in THF (50 mL) solution over 30 min. while the temperature was kept at -35 °C. After completion of the addition, the temperature was allowed slowly to warm to 0 °C over 1 h., and the mixture was stirred at 0 °C for an additional hour. The mixture was neutralized with 1 N HC1 to pH about 4-5 and diluted with EtOAc (100 mL). The organic layer was separated, washed with 1 N HC1 (10 mL), 7.5% NaHC03 aqueous solution (20 mL), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (30 mL), and hexane was added to the suspension until it became cloudy. The resulting suspension was sonicated for 2 min. and left at r.t. for 1 h. The mixture was filtered, and washed with hexane to afford the desired title product (6.85 g) without further purification. The mother liquid was concentrated under reduced pressure. The residue was treated with DCM (5 mL) and hexane was added as the procedures mentioned above to afford the additional 0.51 g of the title product. Total product 4-fluoro-N,N- bis[(4-methoxyphenyl)methyl]-3-nitro-benzenesulfonamide obtained is 7.36 g (78%). 1H NMR(400 MHz, DMSO-d6): δ 8.18-8.23 (m, 2 H), 7.75-7.79 (q, 1 H), 7.08 (d, 4 H), 6.81 (d, 4 H),4.31 (s, 4 H), 3.71 (s, 6 H). 19F NMR (376 MHz, DMSO-d6): -11 δ2.54 (s, 1 F). LCMS calculated for C22H22FN2O6S (M+H)+: m/z = 461.11; found: 461.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.8% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Sealed tube; | 2 Synthesis of 6-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-fluoro-3-nitrobenzenesulfonyl)-4-(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-1-one: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-4-(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-2H-isoquinolin-1-one (10.00 mg, 0.014 mmol, 1.00 equiv), THF (0.50 mL). This was followed by the addition of NaH (1.01 mg, 0.042 mmol, 3.0 equiv) at 0 °C. To this was added 4-fluoro-3-nitrobenzenesulfonyl chloride (6.75 mg, 0.028 mmol, 2.00 equiv) at 0 °C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 3mL water. The resulting solution was extracted with 2x5 mL of ethyl acetate.The resulting mixture was washed with 2x5 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This reaction was repeated 20 times and obtained 110 mg (42.8%) of 6-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-fluoro-3-nitrobenzenesulfonyl)-4-(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-1-one [66] as a light yellow solid. LC-MS (ES, m/z): M+l=913. |
42.8% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h; Sealed tube; Inert atmosphere; | 2 Synthesis of 6-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-(4-fhioro-3-nitrobenzenesulfonyl)-4-(l-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-l-one: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-4- (l-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro-2H-isoquinolin- 1-one (10.00 mg, 0.014 mmol, 1.00 equiv), THE (0.50 mL). This was followed by the addition of NaH (1.01 mg, 0.042 mmol, 3.0 equiv) at 0 °C. To this was added 4-fluoro-3- nitrobenzenesulfonyl chloride (6.75 mg, 0.028 mmol, 2.00 equiv) at 0 °C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 3mL water. The resulting solution was extracted with 2x5 mL of ethyl acetate .The resulting mixture was washed with 2x5 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This reaction was repeated 20 times and obtained 110 mg (42.8%) of 6-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en- l-yl]methyl]piperazin-l-yl)-2-(4-fluoro-3-nitrobenzenesulfonyl)-4-(l-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinolin-l-one as a light yellow solid. LC-MS (ES, m/z ): M+l=913. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.47% | With ammonium hydroxide In acetonitrile at 10 - 30℃; for 8h; Large scale; | 1-2 Example 2 In a 100L reaction kettle, 40kg of acetonitrile and 9.6kg of 4-fluoro-3-nitrobenzenesulfonyl chloride were sequentially added, and the temperature was lowered to 10°C in an ice water bath. Take 20 kg of 28% ammonia water, slowly drop it into the reaction solution, and keep the temperature below 30°C. After dripping, the reaction is kept warm for 8h; 40kg of dichloromethane is added to the reaction solution and stirred for 1h; the liquid is separated and the organic layer is collected; the organic phase is concentrated under reduced pressure at 40-50 to obtain the crude product; the crude product is slurried with 6kg ethanol to obtain the product 7.96kg , The yield is 91.47%, and the purity is 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine In dichloromethane | General Method for Synthesizing 8a-f. General procedure: A solution of 4β-aminopodophyllotoxin (7, 0.15 mmol, 1.0 eq) and Et3N(0.195 mmol, 1.3 eq) in CH2Cl2 (5 mL) was treated with the appropriate sulfonyl chloride (0.195 mmol, 1.3 eq). The reactionmixture was stirred at 45°C overnight. The reaction was stopped with H2O. The organic layer was washed with EtOAc (3 × 5 mL)and brine (5 mL), dried over Na2SO4, and evaporated. The crude product was purified by column chromatography(petroleum ether-EtOAc, 3:1-1:1) to afford the target products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | Step-1: Synthesis of 4-fluoro-N-(4-methoxybenzyl)-3-nitrobenzenesulfonamide To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (5g, 21 mmol) in DMF (50 mL) were added (4-methoxyphenyl)metha i (345g, 5.04 mmol) to the reaction mixture at 0 oC. The reaction mixture was stirred at room temperature for 2h. After completion of reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated to get the pure title compound. (3.5g, 49.2%). LC-MS: 339.05 [M-H]+ |
49.2% | In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | Step-1: Synthesis of 4-fluoro-N-(4-methoxybenzyl)-3-nitrobenzenesulfonamide To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (5g, 21 mmol) in DMF (50 mL) were added (4-methoxyphenyl)metha i (345g, 5.04 mmol) to the reaction mixture at 0 oC. The reaction mixture was stirred at room temperature for 2h. After completion of reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated to get the pure title compound. (3.5g, 49.2%). LC-MS: 339.05 [M-H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With triethylamine In N,N-dimethyl-formamide at 0℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 82.1 Step 1: A solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (2.39 g, 10 mmol), dimethylamine hydrochloride (815 mg, 10 mmol) in dichloromethane (15 mL) was cooled to 0 °C and treated with triethylamine (3.06 mL, 22 mmol). Once the addition was complete, the cooling bath was removed and the reaction slowly warmed to room temperature. After stirring an additional 2 h at room temperature, the reection mixture was transferred to a separatory’ funnel, washed with water and cryastalized from ethyl acetate to give d-fluoro-AyV-dimethyl- 3 -nitrobenzenesulfonamide (1.2 g, 48%) as a pale yellow solid. |
48% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 82.1 Step 1: A solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (2.39 g, 10 mmol), dimethylamine hydrochloride (815 mg, 10 mmol) in dichloromethane (15 mL) was cooled to 0 °C and treated with triethylamine (3.06 mL, 22 mmol). Once the addition was complete, the cooling bath was removed and the reaction slowly warmed to room temperature. After stirring an additional 2 h at room temperature, the reection mixture was transferred to a separatory’ funnel, washed with water and cryastalized from ethyl acetate to give d-fluoro-AyV-dimethyl- 3 -nitrobenzenesulfonamide (1.2 g, 48%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In pyridine at 0 - 20℃; | 32 Example 32 Preparation of Compound 32 Under anhydrous conditions,4-(1H-pyrazol-3-yl)aniline (159.0 mg, 1.0 mmol) was dissolved in dry pyridine (5.0 mL),3-nitro-4-fluoro-benzenesulfonyl chloride (239.0 mg, 1.0 mmol) was added to the reaction solution under ice-water bath conditions (0 °C),React at room temperature for 6-8h and stop the reaction.The reaction solution was diluted with ethyl acetate, washed with water and saturated NaCl solution,It was dried over anhydrous Na 2 SO 4 , and separated and purified by column chromatography (PE/EA=1.5/1V/V) to obtain yellow floc 31 (322.0 mg, yield: 89.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.9% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; | 15 Example 15 Preparation of Compound 15 3-(1H-pyrazol-5-yl)aniline (100.2 mg, 0.63 mmol) was dissolved in dry DMF (5.0 mL) under anhydrous conditions,Anhydrous K2CO3 (130.2 mg, 0.94 mmol) was added,Under ice-water bath conditions (0°C),To this solution was added 3-nitro-4-fluorobenzenesulfonyl chloride(180.8 mg, 0.75 mmol),After 30min at 0-4°C, the reaction was changed to room temperature, and after 6-8h,TLC showed that 3-(1H-pyrazol-5-yl)aniline disappeared, stopping the reaction.The reaction solution was diluted with ethyl acetate, and the aqueous phase was tested with pH paper.Adjust pH between 9-11 with NaHCO 3 saturated solution, wash with water,Washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated,Separation and purification by column chromatography (PE/EA=1.5/1V/V) gave 15 as a yellow floc (95.6 mg, yield: 41.9%). |
Tags: 6668-56-0 synthesis path| 6668-56-0 SDS| 6668-56-0 COA| 6668-56-0 purity| 6668-56-0 application| 6668-56-0 NMR| 6668-56-0 COA| 6668-56-0 structure
[ 713-21-3 ]
2-Fluoro-5-nitrobenzenesulfonyl chloride
Similarity: 0.89
[ 1146290-36-9 ]
2-Fluoro-4-nitrobenzene-1-sulfonyl chloride
Similarity: 0.89
[ 349-88-2 ]
4-Fluorobenzene-1-sulfonyl chloride
Similarity: 0.65
[ 701-27-9 ]
3-Fluorobenzenesulfonyl chloride
Similarity: 0.64
[ 406233-31-6 ]
4-Fluoro-3-nitrobenzenesulfonamide
Similarity: 0.64
[ 713-21-3 ]
2-Fluoro-5-nitrobenzenesulfonyl chloride
Similarity: 0.89
[ 1146290-36-9 ]
2-Fluoro-4-nitrobenzene-1-sulfonyl chloride
Similarity: 0.89
[ 121-02-8 ]
2-Methyl-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.81
[ 4533-95-3 ]
2-Chloro-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.74
[ 97-08-5 ]
4-Chloro-3-nitrobenzenesulfonyl Chloride
Similarity: 0.73
[ 713-21-3 ]
2-Fluoro-5-nitrobenzenesulfonyl chloride
Similarity: 0.89
[ 1146290-36-9 ]
2-Fluoro-4-nitrobenzene-1-sulfonyl chloride
Similarity: 0.89
[ 121-02-8 ]
2-Methyl-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.81
[ 4533-95-3 ]
2-Chloro-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.74
[ 97-08-5 ]
4-Chloro-3-nitrobenzenesulfonyl Chloride
Similarity: 0.73
[ 713-21-3 ]
2-Fluoro-5-nitrobenzenesulfonyl chloride
Similarity: 0.89
[ 1146290-36-9 ]
2-Fluoro-4-nitrobenzene-1-sulfonyl chloride
Similarity: 0.89
[ 121-02-8 ]
2-Methyl-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.81
[ 4533-95-3 ]
2-Chloro-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.74
[ 97-08-5 ]
4-Chloro-3-nitrobenzenesulfonyl Chloride
Similarity: 0.73
[ 713-21-3 ]
2-Fluoro-5-nitrobenzenesulfonyl chloride
Similarity: 0.89
[ 1146290-36-9 ]
2-Fluoro-4-nitrobenzene-1-sulfonyl chloride
Similarity: 0.89
[ 121-02-8 ]
2-Methyl-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.81
[ 4533-95-3 ]
2-Chloro-5-nitrobenzene-1-sulfonyl chloride
Similarity: 0.74
[ 97-08-5 ]
4-Chloro-3-nitrobenzenesulfonyl Chloride
Similarity: 0.73
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :