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CAS No. : | 2905-25-1 | MDL No. : | MFCD00051971 |
Formula : | C6H4BrClO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VFPWGZNNRSQPBT-UHFFFAOYSA-N |
M.W : | 255.52 | Pubchem ID : | 520403 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.23 |
TPSA : | 42.52 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.98 cm/s |
Log Po/w (iLOGP) : | 1.85 |
Log Po/w (XLOGP3) : | 2.64 |
Log Po/w (WLOGP) : | 3.46 |
Log Po/w (MLOGP) : | 2.28 |
Log Po/w (SILICOS-IT) : | 2.02 |
Consensus Log Po/w : | 2.45 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.43 |
Solubility : | 0.096 mg/ml ; 0.000376 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.18 |
Solubility : | 0.167 mg/ml ; 0.000655 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.79 |
Solubility : | 0.041 mg/ml ; 0.00016 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
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 |
---|---|---|
90% | Stage #1: 2-bromoaniline With tris(bipyridine)ruthenium(II) dichloride hexahydrate; isopentyl nitrite In acetonitrile at 20℃; for 0.0833333h; Sealed tube; Stage #2: With thionyl chloride In water; acetonitrile at 20℃; for 20h; Irradiation; | |
79.4% | Stage #1: 2-bromoaniline With hydrogenchloride; sodium nitrite In water at -5 - 0℃; Stage #2: With thionyl chloride; copper(l) chloride In water at -5 - 0℃; | In a specific embodiment disclosed in the present invention, a sample of 2-bromobenzenesulfonyl chloride is prepared: Step S1: Add 172 grams (1mol) of 2-bromoaniline to 333ml (4mol) of hydrochloric acid and 333ml of water and then cool to -5°C,Add dropwise sodium nitrite aqueous solution (72.5g, 200ml), control the temperature below 0, then dropwise add sodium fluoroborate aqueous solution (131.8g, 300ml),Control the temperature below 0, filter, wash the filter cake once with dilute acid, wash once with a small amount of ice methanol, and dry. The fluoroboric acid diazonium salt solid is obtained.Step S2: Add 238 grams (2mol) of thionyl chloride dropwise to 500ml of water, and then lower the temperature to about 0°C,After dripping, add 1 gram of cuprous chloride, reduce the temperature to -5°C, add the diazonium fluoroborate prepared in the previous step to the above solution in batches,Control the temperature at -50, and then react at the same temperature overnight. After the reaction, extract with ethyl acetate (300ml*3 times),The organic layer was washed once with 10% sodium carbonate aqueous solution (300ml), and then washed with water (300ml) once,Finally, wash with saturated saline (300ml) once.Concentrate most of the ethyl acetate, stir and cool to -5°C to crystallize, filter with suction, and dry.Obtain 202.9 grams of pure 2-bromobenzenesulfonyl chloride, with a yield of 79.4%. |
76.5% | Stage #1: 2-bromoaniline With hydrogenchloride In water at 30 - 50℃; for 1h; Stage #2: With sodium nitrite In water at -5 - 0℃; for 0.916667h; Stage #3: With thionyl chloride; water; copper(l) chloride at -5 - 0℃; for 2.83333h; |
(i) NaNO2, aq. HCl, dioxane, (ii) SO2, CuCl2, KCl, benzene; Multistep reaction; | ||
Yield given. Multistep reaction; | ||
Stage #1: 2-bromoaniline With tetrafluoroboric acid; sulfuric acid; sodium nitrite In water at -5℃; Inert atmosphere; Stage #2: With thionyl chloride; copper(l) chloride In water at -5 - 0℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In tetrahydrofuran; at 5℃; for 0.333333h; | Ammonia (50ML) was added to a stirred solution of 2-bromo BENZENESULPHONYL chloride (5. 0g) in tetrahydrofuran (100MI) at 5C. The mixture was stirred for 20 min and then evaporated to dryness and then the residual solid was triturated with water. The solid was collected by filtration and suspended in DICHLOROMETHANE (100ml). 4- (Dimethylamino) pyridine (0.25 g) and triethylamine (3. 2MOI) were added, followed by di- tert-butyl dicarbonate (5.8 g) and the solution was stirred at ambient temperature for 1h. The solution was washed with 1 M hydrochloric acid, water and dried (NA2SO4). The solvent was evaporated to give the title compound (5.8g). LCMS RT = 3.08 min. | |
With ammonium hydroxide; In acetonitrile; at 0 - 20℃; for 1h;Inert atmosphere; | General procedure: In a 50 ml RB flask, sulfonyl chloride (500 mg) was taken in acetonitrile (5 ml) and the solution was cooled to 0 deg. Cel. To this aqueous ammonia solution (1.5 ml) was added dropwise. RM was then stirred at RT for 1 hr. RM was evaporated to dryness and the residue was then trichirated with minimum water and suspension was filtered and solid was dried to get the sulfonamide as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine; dmap at 55℃; for 16h; | |
90% | With pyridine Ambient temperature; | |
90% | With pyridine at 20℃; | 4.1.3. N-(3,4-Dimethyl-5-isoxazolyl)-2-bromobenzenesulfon-amide (9) 3,4-Dimethylisoxazol-5-amine (1.32 g, 11.74 mmol) was added to a solution of 2-bromobenzene-1-sulfonyl chloride (3.0 g, 11.74 mmol) in pyridine and the mixture was stirred at room temperature overnight. The resulting mixture was first mixed with ice water (150 mL) and filtrated by vacuum. The pH of the filtrate was then adjusted to 2 with 6 N hydrochloric acid and then filtrated again. The residue was purified by flash column chromatography with n-hexane/ethyl acetate/acetic acid (200:200:1, v/v/v) as eluent to afford 9 as a white crystal in yield of 90%, mp 125-126 °C. |
4.0 g (>100%) | With hydrogenchloride In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate | 1.B B. B. N-(3,4-Dimethyl-5-isoxazolyl)-2-bromobenzenesulfonamide To a solution of 3.0 g (11.74 mmol) of 2-bromobenzenesulfonyl chloride in 10 ml of pyridine was added 1.32 g (11.74 mmol) of 3,4-dimethyl-5-isoxazolamine. The mixture was stirred at room temperature under argon overnight, added to 150 ml of ice water and filtered. The filtrate was acidified to pH 2 using 6N aqueous hydrochloric acid and the grey solid was filtered and dried. The solid was crystallized from methanol/water to afford 4.0 g (>100%) of compound B as tan crystalline needles (m.p. 125-126° C.). |
With hydrogenchloride In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate | 2 N-(3,4-Dimethyl-5-isoxazolyl)-2-bromobenzenesulfonamide EXAMPLE 2 N-(3,4-Dimethyl-5-isoxazolyl)-2-bromobenzenesulfonamide To a solution of 3.0 g (11.74 mmol) of 2-bromobenzenesulfonyl chloride in 10 mL of pyridine was added 1.32 g (11.74 mmol) of 3,4-dimethyl-5-isoxazolamine. The mixture was stirred at room temperature under argon overnight, added to 150 mL of ice water and filtered. The filtrate was acidified to pH 2 using 6N aqueous hydrochloric acid and the grey solid was filtered and dried. The solid was crystallized from methanol/water to afford 4.0 g (greater than 100%) of Example 2 as tan crystalline needles. Melting point: 125°-126° C. Analysis for C11 H11 BrN2 O3 S Calc'd: C, 39.89; H, 3.35; N, 8.46; S, 9.68; Br, 24.13. Found: C, 39.32; H, 3.35; N, 8.21; S, 9.52; Br, 24.08. | |
4.0 g (>100%) | With hydrogenchloride In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate | 1.B B. B. N-(3,4-Dimethyl-5-isoxazolyl)-2-bromobenzenesulfonamide To a solution of 3.0 g (11.74 mmol) of 2-bromobenzenesulfonyl chloride in 10 ml of pyridine was added 1.32 g (11.74 mmol) of 3,4-dimethyl-5-isoxazolamine. The mixture was stirred at room temperature under argon overnight, added to 150 ml of ice water and filtered. The filtrate was acidified to pH 2 using 6N aqueous hydrochloric acid and the grey solid was filtered and dried. The solid was crystallized from methanol/water to afford 4.0 g (>100%) of compound B as tan crystalline needles (m.p. 125 - 126°C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | EXAMPLE 37 2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> and 2-bromobenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 84-86 C., yield 31%. | |
31% | EXAMPLE 77 2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> and 2-bromobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 84-86 C., yield 31%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine In dichloromethane at 0℃; | |
In chloroform for 17h; Ambient temperature; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 6 2-Bromo-N-t-butylbenzenesulfonamide (6a): t-Butylamine (10 mL, 98 mmol), followed by DIPEA (19 mL, 110 mmol) was added to a solution of 2-bromobenzenesulfonyl chloride (25 g, 98 mmol) in DCM (210 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then extracted with 1M aqueous HCl (2×80 mL), followed by saturated aqueous NaHCO3 (80 mL) and saturated aqueous NaCl (80 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Crystallization from EtOAc and hexane afforded intermediate (6a) (21.5 g). MS m/z: [M+H+] calcd 292.19. found 292.0. |
In dichloromethane at 0 - 20℃; for 6h; | 6 2-Bromobenzenesulfonyl chloride (2.30 g) was dissolved in methylene chloride (6 ml). At 0°C under an argon atmosphere, a solution of t-butylamine (1.89 ml) in methylene chloride (3 ml) was added to the resulting solution. After stirring at 0°C for 1 hour and at room temperature for 5 hours, the reaction mixture was diluted with methylene chloride (200 ml), followed by washing with a saturated aqueous solution (100 ml) of sodium bicarbonate. The solution was dried over anhydrous sodium sulfate, filtered and then distilled under reduced pressure to remove the solvent. The residue thus obtained was recrystallized from hexane/methylene chloride, whereby the title compound (2.38 g) was obtained as colorless prism crystal.1H-NMR(CDCl3) δ: 1.22(9H,s), 5.09(1H,br s), 7.38(1H,dt,J=7.8,1.7Hz), 7.46(1H,dt,J=7.8,1.3Hz), 7.72 (1H, dd, J=7.8, 1.3Hz), 8.17 (1H, dd, J=7.8, 1.7Hz). MS(FAB)m/z: 292(M+H)+. | |
With N-ethyl-N,N-diisopropylamine at 0 - 20℃; | 9 2-Bromobenzenesulfonyl chloride (100.9 g, 394.9 mmol) was dissolved in methylene chloride (500 mL, 8.0 mol) and cooled at 0° C. t-Butylamine (41.3 mL, 395 mmol) was added in 3 portions over approximately 1 minute. DIPEA (75.7 mL, 434 mmol) was immediately added in 3 portions over approximately 1 minute. The mixture was warmed to room temperature and stirred overnight. The product was washed with 1M H3PO4 (2×), with saturated. NaHCO3, and with saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to yield 2-bromo-N-t-butyl-benzenesulfonamide (112 g) as a light brown solid. | |
Stage #1: o-bromobenzenesulfonyl chloride; <i>tert</i>-butylamine In dichloromethane at 0℃; for 0.0166667h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 3 2-Bromobenzenesulfonyl chloride (100.9 g, 394.9 mmol) was dissolved in DCM (500 mL, 8.0 mol) and cooled at 0° C. t-Butylamine (41.3 mL, 395 mmol) was added in 3 portions over approximately 1 minute. DIPEA (75.7 mL, 434 mmol) was immediately added in 3 portions over approximately 1 minute. The mixture was warmed to room temperature and stirred overnight. The product was washed with 1M H3PO4 (2*), with saturated. NaHCO3, and with saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to yield 2-bromo-N-t-butyl-benzenesulfonamide (112 g) as a light brown solid. | |
In dichloromethane at 20℃; for 2h; | 1.A.A-2 Step A-2: T-butyl-2-bromophenylsulfonamide To a stirred solution of 25.4g of 2-bromophenylsulfonyl chloride [(0.] lmol) in 200mL of dichloromethane at rt was slowly added 31. [5ML] of t- butylamine (0. [3MOL).] After stirring for 2h at rt, the reaction mixture was filtered and the filtrate was concentrated to give the title [COMPOUND. 1H] NMR (500 MHz, [CDC13)] [8] 8.18 (dd, [1H,] [J=1] and 8 Hz), 7.73 (dd, [1H,] [J=1] and 8 Hz), 7.46 (dt, 1 H, [J=1.] 5 and 8 Hz), 7. [38] (dt, [1H, J =] 1.5 8 Hz). | |
In chloroform at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 0 - 20℃; | |
89% | With triethylamine In dichloromethane | |
78% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
70% | With pyridine at 20℃; Inert atmosphere; | |
65% | Stage #1: o-bromobenzenesulfonyl chloride With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 1-amino-2-propene In dichloromethane at 20℃; | 209 N-Allyl-2-bromobenzenesulfonamide N-Allyl-2-bromobenzenesulfonamideTo a solution of 2-bromobenzene-1-sulfonyl chloride (5 g, 19.6 mmol) in DCM (100 mL) was added TEA (5.5 mL, 39.2 mmol) at O °C. After 10 min, allylamine (1.3 g, 21.5 mmol) was added and stirred at RT overnight. The reaction mixture was diluted with water (70 mL) and extracted with DCM (2 x 75 mL). The combined organic layer washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give the title compound (3.5 g, 65 %) as solid. LC-MS m/z 274.01 (M)+, 1.888 min (ret. time) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol for 2h; Reflux; | 2-Bromo-N-methylbenzenesulfonamide (20a); Typical Procedure General procedure: To a solution of commercially available 2-bromobenzenesulfonyl chloride (18, 500 mg, 1.96 mmol) in EtOH (20 mL), MeNH2 (0.7 mL,7.83 mmol) was added and the mixture was refluxed for 2 h. The residual solvent was evaporated under reduced pressure and the crude product obtained was purified by column chromatography (10% EtOAc-PE) to afford 20a12 (484 mg, 99%) as a white solid; mp 99-101 °C; Rf = 0.20 (10% EtOAc-PE). |
92% | In methanol; chloroform; water at 0 - 20℃; | |
57% | In chloroform; water for 4h; Heating; |
56% | In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; | Intermediate AK (0248) 2-Bromo-N-ethylbenzenesulfonamide Intermediate AK (0248) 2-Bromo-N-ethylbenzenesulfonamide (0249) To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride (0.995 g, 3.89 mmol), and THF (5 mL). The vial was then charged with EtNH2 in THF (5 mL, 2.0 M). The mixture was stirred for 24 hours before adding it to a separatory funnel containing 1 N HCl and EtOAc. The layers were mixed thoroughly and then separated. The organic layer was then washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and concentrated to dryness to give the crude product. Subjecting the oil to FCC yielded the title compound (580 mg, 56%). 1H NMR (600 MHz, CDCl3) δ 8.17-8.10 (dd, J=7.8, 1.7, 1H), 7.75-7.69 (dd, J=7.8, 1.2, 1H), 7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.16-4.91 (t, J=6.7, 1H), 3.06-2.87 (m, 2H), 1.19-1.00 (t, J=7.3, 3H). |
With pyridine In N,N-dimethyl-formamide at 20℃; for 4h; | 125 Example 125; 2-Bromosulfonyl chloride (2.0 g, 7.83 mmol) was dissolved in anhydrous DMF (5 ml_) and anhydrous pyridine (5 ml_), followed by addition of ethylamine in THF (2 M solution, 7.83 mL, 15.66 mmol). The so formed solution was stirred at ambient temperature for 4 h. Ethyl acetate and 1 N HCI were added to the mixture. The organic layer was washed with brine and 2 M Na2CO3 and dried over MgSO4. After concentration of the organic layer, 2- bromo-Λ/-ethyl-benzenesulfonamide (0.51 g) was obtained as a brown solid; LRMS for C8H10BrSNO2 (M+H)+ at m/z = 265. | |
In dichloromethane at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine In dichloromethane at 0 - 20℃; for 12h; Schlenk technique; Inert atmosphere; | |
In dichloromethane at 5℃; | 12.i Example 12; 2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[2'-(morpholin-4-ylsulfonyl)[1,1'-biphenyl]-4- yl]butoxy}hexyl)amino]ethyl}phenol acetate; I) 4-R (2-BROMOPHENYL) sulfonyllmorpholine Morpholine (2ml) was added to a stirred solution of 2-bromo BENZENESULPHONYL chloride (1. 0G) in dichloromethane (200ml) at 5° under nitrogen. The solvent was evaporated and the residual solid was triturated with water to give the title compound (1.3g). TLC (SIO2, ether-hexane 1: 1) Rf 0.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine In dichloromethane at 0℃; | |
In tetrahydrofuran at 0℃; for 0.166667h; | 10.v tert-Butyl (2-bromophenyl)sulfonyl(isopropyl) carbamate A stirred solution of 2-BROMO-BENZENESULPHONYL CHLORIDE (2. 0g) in tetrahydrofuran (50MI) was treated with isopropylamine (5ml) at 0° for 10 min. The solvent was evaporated and the residual solid triturated under water. A portion of the compound (1. 0G) in acetonitrile (20ML) was treated with di-tert-butyl dicarbonate (1. 0G), 4- (DIMETHYLAMINO) pyridine (44mg) and triethylamine (0. 7MOI) at 0° UNDER nitrogen for 15 min. The solvent was evaporated and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic extract was washed with water, dried (NA2SO4) and evaporated to give the title compound as a pale yellow solid (1.2g). TLC (silica, petroleum ether-ether 4: 1) Rf = 0.44 | |
With triethylamine In dichloromethane at 20℃; for 30h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In dichloromethane for 15h; | 215.A Step A.; Preparation of 2-Bromo-N-(1,1-dimethylpropyl)Benzenesulfonamide To a solution of 2-methyl-2-butanamine (11.4 mL, 97.8 mmol) in dichloromethane (100 mL) was added, dropwise over a 10 min period, a solution of 2-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) in dichloromethane (ca. 50 mL). After stirring for 15 h the reaction was concentrated in vacuo. The residue was crystallized from methyl t-butyl ether to provide 10.5 g (87%) of 2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide in two crops: LCMS (neg. ion spectrum) m/z 304/306 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; for 8 - 16h; | To a solution of (S) isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was added triethylamine (46 P, L, 0.24 mmol) and 2-bromobenzenesulfonyl chloride (51 mg, 0.2 mmol). The solution was stirred for 8 TOL6 hours, then concentrated. The residue was dissolved in MEOH (1.5 mL) and purified by semi-preparative RP-HPLC using the following conditions: Column: Phenomenex C18 Luna 21.6 mm x 60 mm, 5 1 Solvent A: Water (0.02percent TFA buffer) Solvent B: Acetonitrile (0.02 percent TFA buffer) Solvent Gradient: Time 0: 10 percent B; 2.5 min: 10 percent B; 14 min: 90 percent B. Flow Rate: 22.5 mL/min The product peak was collected based on UV absorption and concentrated to give Example 1 (37.7 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In chloroform | 1.A Step A: Step A: 2-Bromo-N-(tert-butyl)benzenesulfonamide To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Flash chromatography (silica gel, 15% ethyl acetate-hexane) afforded the title compound (2.12 g, 84%) as a white solid; 1 H NMR (300 MHz, CDCl3) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H). |
84% | In chloroform | 12.A Step A Step A 2-Bromo-N-(tert-butyl)benzenesulfonamide To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Flash chromatography (silica gel, 15% ethyl acetate-hexane) afforded the title compound (2.12 g, 84%) as a white solid; 1 H NMR (300 MHz, CDCl3) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H). |
70% | With <i>tert</i>-butylamine In dichloromethane | 11 N-tert-butyl-2-bromobenzenesulfonamide EXAMPLE 11 N-tert-butyl-2-bromobenzenesulfonamide To a solution of 4.0 g (16 mmol) 2-bromobenzenesulfonyl chloride in 75 mL methylene chloride at 0° C. was added 3.7 mL (35 mmol) tert-butylamine. The mixture was allowed to warm to RT and stir for 1 hour. The mixture was poured into aqueous 5% HCl and extracted three times with ether. The combined organic material was dried over MgSO4, was stripped of solvent in vacuo, then was recrystallized from hexane/acetone to give 3.19 g (70% yield) of the title compound. Rf 0.17 in 10% EtOAc/hexane, visualized by UV; 1 H-NMR (300 MHz, CDCl3): δ8.17 (m, 1H), 7.72 (m, 1H), 7.50-7.33 (m, 2H), 5.12 (s, 1H), 1.22 (s, 9H). |
With <i>tert</i>-butylamine | Preparation of intermediates 2-bromo tert-butylbenzenesulfonamide IV Preparation of intermediates 2-bromo tert-butylbenzenesulfonamide IV Tert-butylamine (30 mL, 0.29 mol) was slowly added to a solution of 2-bromobenzenesulfonyl chloride (30 g, 0.11 mol) with mechanical stirring at room temperature. After four hours, the precipitate was filtered and the solvent was evaporated to afford the sulfonamide. 1H nmr (400 MHz, CDCl3) δppm 8.15 (1H, dd, J=10.5, 2.0 Hz), 7.68 (1H, dd, J=10.5, 2.0 Hz), 7.40 (1H, m), 7.31 (1H, m), 5.15 (1H, br. s), 1.18 (9H, s). | |
In chloroform | 1.B Step B Step B 2-Bromo-N-(tert-butyl)benzenesulfonamide To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Flash chromatography (silica gel, 15% ethyl acetate-hexane) afforded the title compound, (2.12 g, 84%) as a white solid; 1 H NMR (300 MHz, CDCl3) δ8.18 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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A. N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-bromobenzenesulfonamide <strong>[89464-87-9]2-amino-3-methoxy-5-methylpyrazine</strong> (1.50 g, 10.8 mmol; synthesised according to Bradbury, R. H., et. al. J. Med. Chem. 1997, 40, 996-1004) and 2-bromobenzenesulfonyl chloride (2.80 g, 11.0 mmol) were reacted according to the procedure of Example 25, Step A. 44A was a pink solid, 2.0 g (52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; dmap; In pyridine; methanol; | A. 2-Bromo-N-(4,5-dimethyl-3-isoxazolyl)benzenesulfonamide To <strong>[13999-39-8]4,5-dimethyl-3-isoxazolamine</strong> (1.62 g, 13.00 mmol, prepared as described in T. Konoike et al., Tetrahedron Letters, 37, 3339 (1996)) and 4-dimethylaminopyridine (159 mg, 1.3 mmol) in 6.5 ml pyridine at 0 C., 2-bromobenzenesulphonyl chloride (3.65 g, 14.3 mmol) was added in portions over 10 minutes. After stirring at room temperature overnight, the mixture was added dropwise to 40 ml 6N HCl at 0 C. The mixture was extracted with 3*50 ml EtOAc. The combined organic extracts were washed with 30 ml each of 1N HCl and brine and dried and concentrated. The residue was dissolved in 160 ml MeOH and 160 ml 3% aqueous NaHCO3 solution was added and the mixture was concentrated in vacuo to remove most of the MeOH. The solid was filtered off and the aqueous filtrate was acidified to pH 2 with solid NaHSO4, and extracted with 3*100 ml of EtOAc. The extracts were washed with brine, dried and concentrated to give the title compound of this step (3.0 g, 70%). Rf=0.57, silica gel, 1:1 hexane/EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran at 0 - 20℃; for 6h; | |
91% | With dmap; triethylamine In tetrahydrofuran; water at 20℃; for 16h; Inert atmosphere; | |
With pyridine In tetrahydrofuran at 20℃; for 2h; | 120 Example 120; Preparation of 2-bromo-N,N-dimethyl-benzenesulfonamide. 2-Bromo-benzenesulfonyl chloride (1 g, 3.91 mmol) was mixed with N,N-dimethylamine (7.8 mL) in THF and followed by addition of pyridine (5 mL) and DMF ( 3 mL). The mixture was stirred at EPO ambient temperature for 2 h. Water (5 ml_) was added to the mixture and the mixture was extracted with ethyl acetate (3 x 20 ml_). The combined organic layer was washed with diluted brine and brine. 2-Bromo-N,N-dimethyl-benzenesulfonamide was obtained as light yellow solid (0.893 g); LRMS for C8H10NO2Br (M+H)+ at m/z = 265 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol for 2h; Reflux; | 2-Bromo-N-methylbenzenesulfonamide (20a); Typical Procedure General procedure: To a solution of commercially available 2-bromobenzenesulfonyl chloride (18, 500 mg, 1.96 mmol) in EtOH (20 mL), MeNH2 (0.7 mL,7.83 mmol) was added and the mixture was refluxed for 2 h. The residual solvent was evaporated under reduced pressure and the crude product obtained was purified by column chromatography (10% EtOAc-PE) to afford 20a12 (484 mg, 99%) as a white solid; mp 99-101 °C; Rf = 0.20 (10% EtOAc-PE). |
98% | With 4‐dimethylaminopyridine; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; | |
97% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 19℃; for 0.0833333h; |
92% | In methanol; chloroform at 0 - 20℃; | |
91% | With triethylamine In dichloromethane; lithium hydroxide monohydrate at 20℃; for 0.416667h; | |
90% | In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 3h; | 1.2.10 2-Bromo-N-methylbenzenesulfonamide (15) To a stirred solution of 2 (1.96 mmol, 500 mg) in THF (1 mL) at 0 °C, 40% methylamine aqueous solution (5.87 mmol, 0.51 mL, 40% in H2O) was added dropwise over 10 min, and the resulting mixture was stirred at RT for 3 h Water (15 mL) was added and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with brine (30 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford 15 (440 mg, 90%) as a white solid; mp = 103-104 °C, lit. mp = 99-101 °C1H-NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 1.8, 7.7 Hz, 1 H), 7.75 (dd, J = 1.3, 7.7 Hz, 1 H), 7.49 (td, J =1.3, 7.6 Hz, 1 H), 7.43 (td, J = 1.8, 7.6 Hz, 1 H), 5.06 (br s, 1 H), 2.62 (d, J = 5.3 Hz, 3 H). 13C-NMR (100 MHz, CDCl3): δ = 137.6 (qC), 135.1 (CH), 133.9 (CH), 132.2 (CH), 128.0 (CH), 119.7 (qC), 29.4 (CH3). FT-IR (cm-1): = 3302, 3086, 2980, 2889, 1574, 1414, 1313, 1258, 1157, 1081, 1023, 952, 849, 752, 648, 579. |
89% | With triethylamine In dichloromethane at 0℃; | |
With pyridine In tetrahydrofuran at 20℃; for 4h; | 126 Example 126; 2-Bromosulfonyl chloride (2.0 g, 7.83 mmol) was dissolved in anhydrous DMF (5 mL) and anhydrous pyridine (5 mL), followed by addition of methylamine in THF (2 M solution, 7.83 mL, 15.66 mmol). The so formed solution was stirred at ambient temperature for 4 h. Ethyl acetate and 1 N HCI were added to the mixture. The organic layer was washed with brine and 2 M Na2CO3 and dried over MgSO4. After concentration of the organic layer, 2- EPO bromo-/V-methyl-benzenesulfonamide (1.70 g) was obtained as a yellow solid; 1H NMR (CDCI3, 300 MHz) δ 2.62 (d, J=5.4 Hz, 3H)1 5.25 (broad, 1 H), 7.47 (m, 2H), 7.75 (dd, Ji=7.6 Hz, J2=I .5 Hz, 1 H), 8.14 (dd, J1 =7.5 Hz, J2=2.0 Hz, 1 H). | |
In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; for 2.83333h; | 1-1.A (Step A) Synthesis of 2-bromo-N-methylbenzenesulfonamide 2-Bromobenzenesulfonyl chloride (manufactured by Fluorochem Co., 25 g) was dissolved in tetrahydrofuran (40 mL), and under stirring at 0° C., 40% methylamine aqueous solution (TCI, 25 mL) was added dropwise thereto over ten minutes. After stirring the mixture at room temperature for 2 hours and 40 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. To the residues, hexane and a small amount of ethyl acetate were added, followed by stirring. Solids were filtered to obtain the target compound (23.26 g). | |
In dichloromethane at 0℃; for 0.5h; | ||
With triethylamine In dichloromethane at 0℃; | ||
With triethylamine In ethanol; dichloromethane at 0 - 20℃; for 2h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In acetonitrile | 3 Preparation of 1(or 2 or 4)-(p-Bromophenylsulfonyl)-s-triazole-3-carboxamide EXAMPLE 3 Preparation of 1(or 2 or 4)-(p-Bromophenylsulfonyl)-s-triazole-3-carboxamide To a cooled, stirred mixture of 3.0 g. of 1,2,4-triazole-3-carboxamide and 6.9 g. of bromobenzenesulfonyl chloride in 125 ml. of anhydrous ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23 hours. The heterogeneous mixture is filtered and washed successively with ether, cold water and then ether and dried in vacuo at room temperature for 7 hours, to obtain a crude colorless solid. This material is heated in about 50 ml. of dry acetonitrile and the hot mixture is filtered. The pale yellow filtrate is concentrated to about 10 ml. by water pump evacuation. The colorless solid which separates is collected and washed with acetonitrile then dried in vacuo overnight. To remove final, very minute impurities, the product obtained is then thoroughly washed with water, filtered and dried in vacuo overnight, m.p. 130°-136° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: O-benzylhydoxylamine hydrochloride With potassium carbonate In methanol; water at 10℃; for 0.0833333h; Stage #2: o-bromobenzenesulfonyl chloride In tetrahydrofuran; methanol; water at 20℃; | 2 Example 2. Preparation of Compounds According to General Synthesis of Scheme B.[0121] The preparation of iV-benzyloxy-2-bromo-benzenesulfonamideis detailed below as a representative example of the synthetic method exemplified in Scheme B. [0122] To a suspension of O-benzylhydroxylamine hydrochloride (3.75g, 23.48mmol) in MeOH (3 ml) and water (3.6ml) was added a solution of potassium carbonate (3.24g, 23.48mmol) in water (3.6ml), maintaining an internal reaction temperature below 1O0C. The reaction mixture was stirred for 5 minutes, whereupon THF (12ml) and 2-bromobenzene sulfonyl chloride (3g, 11.74mmol) were added. The reaction mixture was stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by TLC. The resulting suspension was concentrated in vacuo to remove any volatiles, and the aqueous suspension was extracted with diethyl ether (3 x 100ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude target compound. Purification was achieved by trituration of the solid in heptane, followed by filtration and further washing of the solid with heptane, to give the expected compound as a white solid (3.62g, 90% yield). δH(400MHz, DMSO) 10.83 (IH, s), 8.04 (IH5 d, 1.7Hz), 8.02 (IH, d, 1.9Hz), 7.57-7.66 (2H, m), 7.30-7.36 (5H, m), 4.87 (IH, s); TR= 2.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 0℃; | Example 1: Ortho-bromo-Sulfonamides; [Show Image] 2-Bromobenzenesulfonyl chloride (1 eq) and pyridine (2 eq.) dissolved in dichloromethane (1 mL/ mmol of sulfonyl chloride) were introduced in a round bottomed flask. The reaction mixture was cooled to 0 C. The substituted-aniline (1 eq.) was slowly added. The resulting mixture was allowed to stir overnight. A 0.5 M solution of hydrochloric acid was added. The organic phase was separated and washed with water then brine. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was triturated in a minimal amount of methanol. The desired compound was obtained as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 92% 2: 5% | With sulfuric acid; nitric acid for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In dichloromethane at 20℃; for 2h; | |
98% | With pyridine In dichloromethane at 20℃; for 16h; | |
97% | With pyridine at 80℃; for 1h; |
96% | With pyridine at 80℃; for 1h; | 1.2.9 2-Bromo-N-phenylbenzenesulfonamide (14) A mixture of 2 (1 mmol, 255 mg) and aniline 30 (1 mmol, 91 µL) in pyridine (0.8 mL) was stirred for 1 h at 80 °C. AThe volatiles were removed and the crude was purified by flash chromatography (CH2Cl2/acetone, 100:4) to give 14 (300 mg, 96%) as a white solid; mp = 133-134 °C, lit. mp = 129-131 °C Rf = 0.6 (CH2Cl2/acetone, 100:4). 1H-NMR (400 MHz, CDCl3): δ = 8.08 - 7.98 (m, 1 H), 7.73 - 7.74 (m, 1 H), 7.40 - 7.32 (m, 1 H), 7.30 (br s, 1 H), 7.24 - 7.03 (m, 5 H). 13C-NMR (100 MHz, CDCl3): δ = 137.8 (qC), 135.7 (qC), 135.1 (CH), 134.1 (CH), 132.4 (CH), 129.4 (2 CH), 127.8 (CH), 125.8 (CH), 121.7 (2 CH), 119.8 (qC). FT-IR (cm-1): = 3276, 3085, 2980, 2888, 1596, 1572, 1491, 1401, 1339, 1156, 1123, 1024, 904, 753, 699, 580. |
92% | With pyridine In dichloromethane at 20℃; Sealed tube; | |
79% | In N,N-dimethyl-formamide at 0 - 20℃; | |
50% | In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Inert atmosphere; | |
With pyridine In dichloromethane at 20℃; for 2h; Inert atmosphere; | ||
With triethylamine In dichloromethane at 20℃; for 2h; | ||
With triethylamine In dichloromethane at 20℃; | ||
With dmap; triethylamine In dichloromethane at 20℃; | ||
With pyridine In dichloromethane at 20℃; | ||
With triethylamine In dichloromethane at 20℃; Inert atmosphere; | ||
With pyridine at 80℃; for 2h; | ||
With pyridine at 0 - 20℃; for 24h; | ||
With pyridine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In tetrahydrofuran at 15 - 20℃; | 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (2a) To a stirred mixture of finely ground KOH solid (0.93 g, 16.6 mmol) and 1(2.0 g, 7.7 mmol) in THF (8.0 mL), 2-bromobenzenesulphonyl chloride (2.6 g,10.0 mmol) in THF (5.0 mL) was added at 15 °C. After the reaction mixture was stirred at RT for 3 h, the mixture was poured into ice water and the pH was adjusted to 9.5-10 with aqueous 2 N KOH solution. The mixture was extractedwith EtOAc. The combined organic layer was washed with water, brine, driedover anhydrous Na2SO4 and filtered. The solvent was evaporated under vacuum. The crude product was purified by silica gel column chromatography with CH2Cl2/MeOH (200:1 to 20:1) as eluent to afford 2a as a white solid (3.3 g,90%), mp 127.7-128.8 °C. 1H NMR (600 MHz, CDCl3): d 8.04 (dd, J = 1.5, 8.0 Hz,1H), 7.64 (t, J = 5.7 Hz, 2H), 7.54 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.36(dd, J = 1.5, 7.6 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 2.4, 8.9 Hz, 1H), 3.62(s, 2H), 3.83 (s, 3H), 2.32-2.50 (br, 8H), 2.29 (s, 3H). LC-MS (ESI, m/z): Calcd forC21H25BrN3O3S ([M+H]+) 479.4, found: 479.9. Compounds 2b, 2c, and 2d wereprepared with the same procedure according to 2a, and the data were listed asbelow. |
82.3% | Stage #1: 5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole With potassium hydroxide In tetrahydrofuran at 10 - 35℃; for 1.16667h; Large scale; Stage #2: o-bromobenzenesulfonyl chloride In tetrahydrofuran at 10 - 35℃; for 5.41667h; Large scale; | 1.v Step (v): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l- piperazinyl)methyI]-lH-indoIe Step (v): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l- piperazinyl)methyI]-lH-indoIeTetrahydrofuran (85.78 Kg) was charged into a reactor at 20 °C - 35 °C. Then charged the crystallized 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole (21.5 Kg, 0.0829 Kg Mole) into the reactor at 20 - 35 °C and stirred the mass well. The mass was cooled to 10 °C - 20 °C with chilled water in the jacket. Charged powdered potassium hydroxide (16.1 1 Kg) to the above suspension at 10 °C - 20 °C in 10 minutes under stirring. Slight exotherm was observed. Mass temperature rose from 15.1 °C to 16.3 °C. The mass was further stirred for 60 minutes at 10 °C - 20 °C. A solution of 2- bromobenzenesulfonyl chloride (27.71 Kg, 0.1084 Kg Mole) in 41.72 Kg tetrahydrofuran was added through addition tank at a constant rate in 60 minutes at 10 °C - 30 °C. The reaction was exothermic and the mass temperature went up from 16 °C to 30 °C. Then removed the chilled water from the jacket and stirred the mass for 3 hours at 25 °C - 35 °C. As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by thin layer chromatography (Eiuent system: Chloroform and Methanol in 8:2 ratio and the product is relatively non-polar). Since thin layer chromatography shows the presence of starting material (5-methoxy-3-[(4- methyl-l-piperazinyl)methyl]-lH-indole), another lot of 2-bromo benzenesulfonyl chloride (4.5 Kg, 0.0176 Kg Mole) dissolved in 13.71 Kg tetrahydrofuran was added to the reaction mass at 30 °C in 25 minutes. No exotherm observed. The reaction mass was further stirred for 60 minutes at 30 °C - 35 °C. Since the starting material was absent as per thin layer chromatography, it was taken for further workup.In the mean while charged 360 L demineralised water into another reactor and cooled the contents to 10 °C - 15 °C. The above reaction mass was quenched into chilled water in 60 minutes (mass temperature was 12.1 °C). The pH of the reaction mass was adjusted to ~ 9.5 with an aqueous solution of potassium hydroxide. The product was extracted with (4 x 155 L) ethyl acetate maintaining the mass temperature at 10 °C - 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction. The combined organic layer was taken for extraction of the product into aqueous acetic acid..... jAcetic acid (8.69 Kg, 0.1448 Kg mole) was dissolved in 137 L of demineralised water and cooled the mass to 10 °C - 15 °C. Charged the above organic extracts into it and stirred for 30 minutes at 10 °C - 15 °C. The mass was allowed to settle for 20 minutes and separated the bottom aqueous acetic acid extract containing the product into a fresh clean reactor.Further, the extraction and separation process with fresh aqueous acetic acid solution was repeated thrice using 3 x 145 Kg of aqueous acetic acid solution (prepared by dissolving 25.74 Kg, 0.429 Kg Mole of acetic acid in 412 L of demineralised water) following the similar procedure mentioned above, maintaining mass temperature at 10 °C - 15 °C. The combined aqueous acetic acid extracts (containing the product) were taken into the reactor. It was washed with 44 L of ethyl acetate by stirring the mass at 10 °C - 15 °C for 15 minutes, followed by 15 minutes settling. The aqueous product layer was separated. The pH of the aqueous solution was found to be 4.5. The mass was cooled to 10 °C - 15 °C and the pH of the solution was adjusted to ~ 9.5 with chilled caustic lye solution (31 Kg). The product was extracted with (4 x 155 L) of ethyl acetate, maintaining the mass temperature at 10 °C - 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction.The organic layer was washed with (2 x 1 12 Kg) brine solution (prepared from 51.6 Kg vacuum salt and 175 L water) at 10 °C - 15 °C. The organic layer was dried over 32 Kg of anhydrous sodium sulfate at 20 °C - 35 °C and filtered into another clean reactor. Solvent was removed under 500 - 600 mm Hg by circulating 50 °C - 55 °C water in the jacket of the reactor.To the residual mass in the reactor after solvent removal, charged 36 L of methanol followed by 72 L of isopropanol. The reaction mass was heated to reflux temperature (65 °C - 75 °C). At mass temperature ~ 70 °C a clear solution was obtained. The mass was allowed to cool to 35 - 45 °C with room temperature water circulation in the reactor jacket. Further, it was cooled to 15 °C - 20 °C by circulating brine in the jacket and maintained under stirring for 2 hours at 15 °C - 20 °C. The solids were filtered through nutsche and sucked well under vacuum. The cake was washed with 36 L of isopropanol (15 °C - 20 °C) and sucked well. The wet solid material (37.76 Kg) was taken in tray drier and air dried at 25 °C - 35 °C for 60 minutes. Further, it was dried at 40 °C - 45 °C for 6 hours to obtain 32.64 Kg of the title product.Overall Yield: 82.3 % (based on Mannich base charged);HPLC purity: 99.36 %;Single major impurity: 0.29 %;Total impurities: 0.64 %;Assay: 100.5 %;Loss on drying at 105 °C: 0.21 %;Melting range (°C): 128.1 - 129.2; IR spectra (cm-1): 2931, 2786, 1607, 1474, 1369, 1222, 1 178, 1032, 737, 597; 1H- NMR (CDCl3, δ ppm): 2.29 (3H, s), 2.32 - 2.50 (8H, bs), 3.62 (2H, s), 3.83 (3H, s),6.83 - 6.86 (1H, dd, J = 8.98, 2.46 Hz), 7.19 - 7.20 (1H, d, J = 2.42 Hz), 7.36 - 7.40 (1 H, dt, J = 7.68, 1.56 Hz), 7.45 - 7.47 (1H, t, J = 7.50 Hz), 7.53 - 7.55 (1H, d, J = 9.00, Hz), 7.64 -7.66 (2H, m), 8.03 - 8.05 (1H, dd, J = 7.89, 1.54 Hz); 13C - NMR (CDCI3, δ ppm): 45.94, 53.07, 53.33, 55.17, 55.60, 103.28, 1 13.20, 1 13.69,117.83, 120.42, 127.05, 127.69, 129.57, 131.16, 131.57, 134.48, 135.90, 138.09, 156.12; Mass [M+H]+: 478.1, 480.1. |
82% | With potassium hydroxide In tetrahydrofuran at 10 - 20℃; |
32.64 kg | Stage #1: 5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole With potassium hydroxide In tetrahydrofuran at 10 - 20℃; for 1.16667h; Large scale; Stage #2: o-bromobenzenesulfonyl chloride In tetrahydrofuran at 10 - 35℃; for 5.41667h; Large scale; | 1.v Step (v): Preparation of 1 -[(2-bromophenyl)sulfo- nyl]-5-methoxy-3-[(4-methyl-i -piperazinyl)methyl] -1 H-indole 10038] Tetrahydrofuran (85.78 Kg) was charged into a reactor at 20° C.-35° C. Then charged the crystallized 5-methoxy-3-[(4-methyl-i -piperazinyl)methyl] -i H-indole (21.5 Kg, 0.0829 Kg Mole) into the reactor at 20-35° C. and stirred the mass well. The mass was cooled to 10° C.-20° C. with chilled water in the jacket. Charged powdered potassium hydroxide (16.11 Kg) to the above suspension at 10° C.-20° C. in 10 minutes under stirring. Slight exotherm was observed. Mass temperature rose from 15.1° C. to 16.3° C. The mass was further stirred for 60 minutes at 10° C.-20° C. A solution of 2-bromobenzenesulfonyl chloride (27.71 Kg, 0.1084 Kg Mole) in 41.72 Kg tetrahydrofuran was added through addition tank at a constant rate in 60 minutes at 10° C.-30° C. The reaction was exothermic and the mass temperature went up from 16° C. to 30° C. Then removed the chilled water from the jacket and stirred the mass for 3 hours at 25° C.-35° C. As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by thin layer chromatography (Eluent system: Chloroform and Methanol in 8:2 ratio and the product is relatively non-polar). Since thin layer chromatography shows the presence of starting material (5-methoxy-3-[(4-methyl- 1 -piperazinyl)methyl]- 1H-in- dole), another lot of 2-bromo benzenesulfonyl chloride (4.5 Kg, 0.0176 Kg Mole) dissolved in 13.71 Kg tetrahydrofuran was added to the reaction mass at 30° C. in 25 minutes. No exotherm observed. The reaction mass was further stirred for 60 minutes at 30° C.-35° C. Since the starting material was absent as per thin layer chromatography, it was taken for further workup.10039] In the mean while charged 360 L demineralised water into another reactor and cooled the contents to 10° C.- 15° C. The above reaction mass was quenched into chilled water in 60 minutes (mass temperature was 12.1° C.). The pH of the reaction mass was adjusted to .-9.5 with an aqueous solution of potassium hydroxide. The product was extracted with (4x 155 L) ethyl acetate maintaining the mass temperature at 10° C.-15° C. The pH of aqueous layer was adjusted to .-9.5 before each extraction. The combined organic layer was taken for extraction of the product into aqueous acetic acid.10040] Acetic acid (8.69 Kg, 0.1448 Kg mole) was dissolved in 137 L of demineralised water and cooled the mass to 10° C.-15° C. Charged the above organic extracts into it and stirred for 30 minutes at 10° C.-15° C. The mass was allowed to settle for 20 minutes and separated the bottom aqueous acetic acid extract containing the product into a fresh clean reactor.10041] Further, the extraction and separation process with fresh aqueous acetic acid solution was repeated thrice using 3x145 Kg of aqueous acetic acid solution (prepared by dissolving 25.74 Kg, 0.429 Kg Mole of acetic acid in 412 L of demineralised water) following the similar procedure mentioned above, maintaining mass temperature at 10° C.- 15° C. The combined aqueous acetic acid extracts (containing the product) were taken into the reactor. It was washed with 44 L of ethyl acetate by stirring the mass at 10° C.-15° C. for 15 minutes, followed by 15 minutes settling. The aqueous product layer was separated. The pH of the aqueous solution was found to be 4.5. The mass was cooled to 10° C.-15° C. and the pH of the solution was adjusted to .-9.5 with chilled caustic lye solution (31 Kg). The product was extracted with (4x1 55 L) of ethyl acetate, maintaining the mass temperature at 10° C.-15° C. The pH of aqueous layer was adjusted to .-9.5 before each extraction.10042] The organic layer was washed with (2x112 Kg) brine solution (prepared from 51.6 Kg vacuum salt and 175 L water) at 10° C.-15° C. The organic layer was dried over 32 Kg of anhydrous sodium sulfate at 20° C.-35° C. and filtered into another clean reactor. Solvent was removed under 500-600mm Hg by circulating 50-55° C. water in the jacket of the reactor.10043] To the residual mass in the reactor after solvent removal, charged 36 L of methanol followed by 72 L of isopropanol. The reaction mass was heated to reflux temperature (65° C.-75° C.). At mass temperature .-70° C. a clear solution was obtained. The mass was allowed to cool to 35-45° C. with room temperature water circulation in thereactor jacket. Further, it was cooled to 15-20° C. by circulating brine in the jacket and maintained under stirring for 2 hours at 15° C.-20° C. The solids were filtered through nutsche and sucked well under vacuum. The cake was washed with 36 L of isopropanol (15-20° C.) and sucked well. The wet solid material (37.76 Kg) was taken in tray drier and air dried at 25° C.-35° C. for 60 minutes. Further, it was dried at 40° C.-45° C. for 6 hours to obtain 32.64 Kg of the title product.10044] Overall Yield: 82.3% (based on Mannich base charged);10045] HPLC purity: 99.36%;10046]10047]10048]10049] Loss on drying at 105° C.: 0.21%;10050] Melting range (° C.): 128.1-129.2;10051] IR spectra (cm’): 2931, 2786, 1607, 1474,1369, 1222, 1178, 1032, 737, 597;10052] ‘H-NMR (CDC13, ö ppm): 2.29 (3H, s), 2.32-2.50 (8H, bs), 3.62 (2H, s), 3.83 (3H, s), 6.83-6.86 (1H,dd, J=8.98, 2.46 Hz), 7.19-7.20 (1H, d, J=2.42 Hz),7.36-7.40 (1H, dt, J=7.68, 1.56 Hz), 7.45-7.47 (1H, t,J=7.50 Hz), 7.53-7.55 (1H, d, J=9.00, Hz), 7.64-7.66(2H, m), 8.03-8.05 (1H, dd, J=7.89, 1.54 Hz); ‘3C-NMR (CDC13, ö ppm): 45.94, 53.07, 53.33, 55.17,55.60, 103.28, 113.20, 113.69, 117.83, 120.42, 127.05,127.69, 129.57, 131.16, 131.57, 134.48, 135.90, 138.09, 156.12;10053] Mass [M+H]: 478.1, 480.1.Single major impurity: 0.29%;Total impurities: 0.64%;Assay: 100.5%; |
Stage #1: 5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole With sodium hydride In DMF (N,N-dimethyl-formamide) at 10 - 25℃; for 1h; Stage #2: o-bromobenzenesulfonyl chloride at 10 - 25℃; for 1h; | Description 7: 1- (2-BROMOBENZENESULFONYL)-5-METHOXY-3- (4-METHYLPIPERAZIN-L- YLMETHYL)-1H-INDOLE (D7) 5-methoxy-3- (4-methylpiperazin-1-ylmethyl)-1 H-indole (2.59 g, 0.01 moles) in DMF (30 mL) was added slowly to a suspension of sodium hydride (0.26 g, 0.011 moles) in DMF (10 mL) maintaining the temperature below 10 C. The mixture was stirred for 1 hr at 25 C. Later reaction mixture was cooled to 10 C and 2- Bromobenzene sulfonyl chloride (2.54 g, 0.01 moles) was added drop-wise. The reaction mixture was further stirred for 1 hr at 25 C. After the completion of reaction (TLC), the reaction mixture was poured onto ice-water mixture and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Volatile impurities were distilled off under reduced pressure to obtain the crude residue. The residue obtained was purified by flash chromatography (silica gel, EtOAc/TEA, 9.9/0. 1) to afford the compound, which was identified by IR, NMR and mass spectral analyses as the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane at 0 - 20℃; Inert atmosphere; | |
50% | In chloroform at 20℃; for 2h; | |
In chloroform Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium hexamethylsilazane / tetrahydrofuran / 2.25 h / -78 - 20 °C / Inert atmosphere 1.2: 1 h / 0 °C / Inert atmosphere 1.3: 2 h / 0 - 20 °C / Inert atmosphere 2.1: potassium hydrogen bifluoride / methanol; water / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.8% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 2-Bromo-N-(2-methylallyl)benzenesulfonamide 2-Bromo-N-(2-methylallyl)benzenesulfonamide To a solution of 2-bromobenzene-1 -sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 mL) at 0 °C was added TEA (13.64 mL, 98 mmol) and 2-methylprop-2-en-1 - amine (6.96 g, 98 mmol) and stirred for 10 min. Then it was stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2 x 200 mL). The combined organic layer washed with ice cold water (2 x 100 mL), washed with brine solution(100 mL), dried over anhydrous Na2S04. It was filtered and concentrated to give the title compound (20 g, 68.3 mmol, 69.8 % yield). LC-MS m/z 289.81 (M+H)+, 2.20 min (ret. time). |
69.8% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 18 2-Bromo-N-(2-methylallyl)benzenesulfonamide To a solution of 2-bromobenzene-1-sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 mL) at 0 °C was added TEA (13.64 mL, 98 mmol) and 2-methylprop-2-en-1- amine (6.96 g, 98 mmol) and stirred for 10 mm. Then it was stirred at ambient temperaturefor 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM(2 x200 mL). The combined organic layer was washed with ice cold water (2 x 100 mL),washed with brine solution(1 00 mL), dried over anhydrous Na2SO4. It was filtered andconcentrated to give the title compound (20 g, 68.3 mmol, 69.8 % yield). LC/MS m/z =289.81 (M+H), 2.20 mm (ret. time). |
69.8% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 2-Bromo-N-(2-methylallyl)benzenesulfonamide To a solution of 2-bromobenzene-l-sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 mL) at 0 °C was added TEA (13.64 mL, 98 mmol) and 2-methylprop-2-en-l- amine (6.96 g, 98 mmol) and stirred for 10 min. Then it was stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2 x 200 mL). The combined organic layer washed with ice cold water (2 x 100 mL), washed with brine solution(100 mL), dried over anhydrous Na2S04. It was filtered and concentrated to give the title compound (20 g, 68.3 mmol, 69.8 % yield). LC-MS m/z 289.81 (M+H)+, 2.20 min (ret. time). |
69.8% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 2-Bromo-N-(2-methylallyl)benzenesulfonamide To a solution of 2-bromobenzene-1 -sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 ml.) at 0 °C was added TEA (13.64 ml_, 98 mmol) and 2-methylprop-2-en-1- amine (6.96 g, 98 mmol) and stirred for 10 min. The reaction was then stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2 x 200 ml_). The combined organic layer was washed with ice cold water (2 x 100 ml_), washed with brine solution (100 ml_), and dried over anhydrous Na2S04, filtered and concentrated to give the title compound (20 g, 68.3 mmol, 69.8% yield). LC-MS m/z 289.81 (M+H)+, 2.20 min (ret. time). |
69.8% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | Intermediate 15: 2-Bromo-N-(2-methylallyl)benzenesulfonamide To a solution of 2-bromobenzene-1-sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 mL) at 00C was added TEA (13.64 mL, 98 mmol) and 2-methylprop-2-en-1- amine (6.96 g, 98 mmol) and stirred for 10 min afterwhich time the reaction was stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2 x 200 mL). The combined organic layer was washed with ice cold water (2 x 100 mL), washed with brine solution(100 mL), dried over anhydrous Na2SO4. It was filtered and concentrated to give the title compound (20 g, 68.3 mmol, 69.8 % yield). LC-MS m/z = 289.81 (M+H)+, 2.20 min (ret. time). |
62% | Stage #1: o-bromobenzenesulfonyl chloride With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 2-methylallylamin In dichloromethane at 0℃; | 209 2-Bromo-N-(2-methylallyl)benzenesulfonamide 2-Bromo-N-(2-methylallyl)benzenesulfonamideTo a solution of 2-bromobenzene-1-sulfonyl chloride (5 g, 19.6 mmol) in DCM (100 mL) was added TEA (5.5 mL, 39.2 mmol) at 0 °C. After 10 min, 2-methyl allylamine (1.3 g, 21.5 mmol) was added at 0 °C, then stirred at RT overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer washed with brine, dried over anhydrous Na2S04, filtered and concentrated to give the title compound (3.5 g, 62 %) as solid. LC-MS m/z 287.99 (M)+, 1.993 min (ret. time) |
53% | With pyridine at 20℃; for 8 - 10h; Inert atmosphere; | 1.2 To a solution of 2-methylallylamine (500 mg, 7.03 mmol) in pyridine (5 mL) was added 2-bromobenzenesulfonyl chloride (1.63 g, 6.39 mmol) dissolved in pyridine (5 mL). The reaction was stirred at room temperature for 8-10 hours under nitrogen. TLC (Thin Layer Chromatography) was monitored to check the progress of the reaction. After the reaction was complete, the reaction mixture was neutralized with 30% HCl (100 mL) and then extracted with dichloromethane (DCM) (4x30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness to yield the crude compound. The crude compound was purified by column chromatography using 15% ethyl acetate in hexane to yield the pure compound 27 (1.08 g, 53%). |
53% | With pyridine at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In 1,4-dioxane at 10℃; | Intermediate 64. 1 -((2-Bromophenyl)su Ifonyl)pyrrol idi ne To a solution of 2-bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) in dry dioxane (10 mL) at approximately 10 00 was added dropwise pyrrolidine (0.65 mL, 7.81 mmol). The mixture was warmed to room temperature and stirred for 0.5 hrs. EtOAc (100 mL) was added and the organic layer was washed with H20 (3 x 30 mL) and brine (30 mL) passed through a phase separation cartridge and the solvent removed under reduced pressure to give the title compound as a yellow oil (1.24 g >95%).1H NMR (ppm)(400 MHz, CDCI3): 1.89-1.94 (4H, m), 3.39-3.44 (4H, m), 7.35-7.46 (2H, m),7.74 (IH, dd, J=1.3, 7.8 Hz), 8.12 (IH, dd, J1.8, 7.8 Hz) |
71% | With triethylamine In dichloromethane at 0 - 20℃; for 12h; Schlenk technique; Inert atmosphere; | |
70% | With triethylamine In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine In dichloromethane at 20℃; Inert atmosphere; | |
83% | With triethylamine In dichloromethane at 0 - 20℃; for 12h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; at 20℃; for 12h; | methyl-1-aminocyclopropanecarboxylate hydrochloride (300 mg, 1.979 mmol) was dissolved in CH2Cl2(7 ml), added with 2-bromobenzene-1-sulfonyl chloride (550 mg, 2.17 mmol) and triethylamine (1.1 ml, 7.92 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (X2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(2-bromophenylsulfonamido)cyclopropanecarboxylate (560 mg, 1.68 mmol, 85 percent).[640] 1H NMR (400 MHz, CDCl3) delta 8.09 (dd, J = 2, 7.6 Hz, 1H), 7.78 (dd, J = 1.2, 7.6 Hz, 1H), 7.45 (m, 2H), 5.99 (s, -NH-SO2), 1.49 (m, 2H), 1.44 (m. 2H). |
85% | With triethylamine; In dichloromethane; at 20℃; for 12h; | methyl-1-aminocyclopropanecarboxylate hydrochloride (300 mg, 1.979 mmol) was dissolved in CH2Cl2 (7 ml), added with 2-bromobenzene-1-sulfonyl chloride (550 mg, 2.17 mmol) and triethylamine (1.1 ml, 7.92 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (X2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(2-bromophenylsulfonamido)cyclopropanecarboxylate (560 mg, 1.68 mmol, 85percent). 1H NMR (400 MHz, CDCl3) delta 8.09 (dd, J=2, 7.6 Hz, 1H), 7.78 (dd, J=1.2, 7.6 Hz, 1H), 7.45 (m, 2H), 5.99 (s, -NH-SO2), 1.49 (m, 2H), 1.44 (m. 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine; In dichloromethane; at 20℃; for 12h; | In a 50-mL flask, 1-amino-cyclohexanecarboxylic acid methylester hydrochloride (350mg, 1.80mmol) and methylenechloride (20 mL) were charged, and then triethylamine (0.836mL, 5.99mmol) was charged, followed by stirring for 30 minutes at room temperature. 2-bromo-benzenesulfonylchloride (383mg, 1.49mmol) was added thereto, followed by stirring for 12 hours at room temperature. Then, purified water (10 ml) was added thereto to bring the reaction to an end. The organic layer was separated, and washed with saturated ammonium chloride solution (20 ml). Then, the washed organic layer was separated, and added with magnesium sulfate so as to remove remaining moisture. Then, through filtering and vacuum distillation, the solvent was removed so as to obtain the residue. The mixture was purified with column chromatography (EA/n-Hex=1:5) so as to obtain 1-(2-bromo-benzenesulfonylamino)-cyclohexanecarboxylic acid methylester (285mg, 51%). [886] 1H NMR (400 MHz, CDCl3) delta 8.08 (dd, 1H), 7.74 (dd, 1H), 7.39-7.49(m, 2H), 3.59 (s, CH3-CO2-, 3H), 1.25-2.19 (m, 10H). |
51% | In a 50-mL flask, 1-amino-cyclohexanecarboxylic acid methylester hydrochloride (350 mg, 1.80 mmol) and methylenechloride (20 mL) were charged, and then triethylamine (0.836 mL, 5.99 mmol) was charged, followed by stirring for 30 minutes at room temperature. 2-bromo-benzenesulfonylchloride (383 mg, 1.49 mmol) was added thereto, followed by stirring for 12 hours at room temperature. Then, purified water (10 ml) was added thereto to bring the reaction to an end. The organic layer was separated, and washed with saturated ammonium chloride solution (20 ml). Then, the washed organic layer was separated, and added with magnesium sulfate so as to remove remaining moisture. Then, through filtering and vacuum distillation, the solvent was removed so as to obtain the residue. The mixture was purified with column chromatography (EA/n-Hex=1:5) so as to obtain 1-(2-bromo-benzenesulfonylamino)-cyclohexanecarboxylic acid methylester (285 mg, 51%). 1H NMR (400 MHz, CDCl3) delta 8.08 (dd, 1H), 7.74 (dd, 1H), 7.39-7.49 (m, 2H), 3.59 (s, CH3-CO2-, 3H), 1.25-2.19 (m, 10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine In dichloromethane at 20℃; | General procedure: A: Sulfonyl chloride (1 eq.) was dissolved in a mixture of dry DCM (0.2 M) and TEA (1.5 eq.). Amine (1.2 eq.) was added and the reaction was stirred at 20 °C until completion (TLC). The solvent was removed under reduced pressure and the crude product was purified by column flash-chromatography on silica to give the sulfonamide. |
64% | With triethylamine In dichloromethane at 0 - 20℃; for 12h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine In dichloromethane at 0 - 20℃; for 12h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | General procedure: To a solution of 2-iodophenol (10a) (500 mg, 2.27 mmol) in anhydrous dichloromethane (20 mL), Et3N (2 mL) and DMAP (14 mg, 5 mol %) were added at 0 C and stirred for 15 min. Then 2-bromobenzene-1-sulfonyl chloride (11) (581 mg, 2.27 mmol) in anhydrous dichloromethane (10 mL) was added dropwise to the reaction mixture and stirred for 2 h. The reaction mixture was washed with H2O (3*10 mL) and brine (10 mL) and dried (Na2SO4). Then it is concentrated under reduced pressure to give the crude product, which was subjected to silica gel chromatography (5% EtOAc/pet ether). 5.2.2. Preparation of 2-iodopyridin-3-yl 2-bromobenzenesulfonate (12b). Prepared using <strong>[40263-57-8]2-iodopyridin-3-ol</strong> (10b) (500 mg, 2.26 mmol), 2-bromobenzene-1-sulfonyl chloride (11) (578 mg, 2.26 mmol), anhydrous dichloromethane (30 mL), Et3N (2 mL) and DMAP (14 mg, 5 mol %). The product was purified by column chromatography (20% EtOAc/pet ether) to yield compound 12b (975 mg, 98%) as a white solid; mp 140-143 C; Rf (30% EtOAc/pet. ether) 0.30; IR (KBr, cm-1) νmax: 3099, 2981, 1386, 1180; 1H NMR (CDCl3, 400 MHz): δ=8.28 (dt, J=4.6, 1.4 Hz, 1H), 8.06 (dt, J=7.5, 2.2 Hz, 1H), 7.85 (dt, J=7.7, 1.1 Hz, 1H), 7.57-7.46 (m, 3H), 7.27-7.24 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ=148.8, 148.3, 136.3, 135.7, 132.5, 130.1, 128.0, 123.6, 121.9, 114.4; HRMS (ES+): MH+, found 439.8451, 441.8425. C11H8BrINO3S requires 439.8453, 441.8432. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.89% | With triethylamine In dichloromethane at 20℃; for 10h; Cooling with ice; | Synthesis of 2-bromo-N-methyl(or N-2,3-dimethyl-phenyl,)-benzenesulfonamide (4,5) General procedure: Et3N (0.23 g, 2.29 mmol) was added to the solution of 2-bromobenzenesulfonyl chloride44 (0.25 g, 1 mmol) and methylamine hydrochloride (or N-2,3-dimethylphenyl) (1.35 mmol) in dichloromethane (DCM) under ice, drop wise. After the completion of addition the mixture was stirred at room temperature for 10 hrs and quenched with saturated NH4Cl solution. The organic layer was separated and aqueous layer was extracted with AcOEt. The combined organic layer was evaporated under vacuum after drying over anhydrous Na2SO4 to obtained yellow oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.4% | With triethylamine In dichloromethane at 20℃; for 10h; Cooling with ice; | Synthesis of 2-bromo-N-methyl(or N-2,3-dimethyl-phenyl,)benzenesulfonamide (4,5) General procedure: Et3N (0.23 g, 2.29 mmol) was added to the solution of 2-bromobenzenesulfonyl chloride44 (0.25 g, 1 mmol) and methylamine hydrochloride (or N-2,3-dimethylphenyl) (1.35 mmol) in dichloromethane (DCM) under ice, drop wise. After the completion of addition the mixture was stirred at room temperature for 10 hrs and quenched with saturated NH4Cl solution. The organic layer was separated and aqueous layer was extracted with AcOEt. The combined organic layer was evaporated under vacuum after drying over anhydrous Na2SO4 to obtained yellow oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetrabutylammomium bromide; sodium hydroxide; In benzene; at 0 - 20℃; | General procedure: To a solution of 1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazole 3 (2 mmol) and tetrabutylammonium bromide (0.2 mmol) in benzene (25 mL), a solution of 50% NaOH (25 mL) was added at 0 C followed by the addition of sulfonyl chloride 4 (2.2 mmol). The reaction mixture was stirred vigorously at room temperature for 5-6 h and the reaction was monitored by TLC. After the completion of the reaction, aqueous phase was separated and the organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate and concentrated to give crude products which were purified by column chromatography over silica gel using hexane-EtOAc (6:4) mixture as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.25h;Inert atmosphere; | Intermediate FI (0510) N-(1-((2-Bromophenyl)sulfonyl)piperidin-4-yl)acetamide (0511) A solution of 2-bromobenzene-1-sulfonyl chloride (0.500 g, 1.96 mmol), <strong>[5810-56-0]4-acetamidopiperidine</strong> (0.335 g, 2.45 mmol), and diisopropylethyl amine (1.0 mL, 5.8 mmol) in CH2Cl2 (5 mL) was stirred for 15 min at rt. The reaction mixture was then washed with 1 N HCl (2×5 mL) followed by brine (10 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (0.672 g, 95%). The product was used without further purification. 1H NMR (400 MHz, CDCl3) delta 8.09-8.05 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.38 (m, 2H), 6.08 (d, J=8.0, 1H), 3.87-3.79 (m, 2H), 2.93-2.85 (m, 2H), 2.00-1.93 (m, 5H), 1.59-1.51 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.25h;Inert atmosphere; | Intermediate GA (0546) Racemic-1-((2-Bromophenyl)sulfonyl)-<strong>[108-49-6]3,5-dimethylpiperazine</strong> (0547) A solution of 2-bromobenzene-1-sulfonyl chloride (100 mg, 0.39 mmol), <strong>[108-49-6]2,6-dimethylpiperazine</strong> (56 mg, 0.49 mmol), and diisopropylethyl amine (0.202 mL, 1.17 mmol) in CH2Cl2 (2.5 mL) was allowed to stir for 15 min at rt. The reaction mixture was then directly subjected to FCC purification to give the title compound (0.105 g, 81%). 1H NMR (600 MHz, CDCl3) delta 8.09-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 1H), 7.43-7.37 (m, 1H), 3.70-3.66 (m, 2H), 2.97-2.91 (m, 2H), 2.38-2.33 (m, 2H), 1.06-1.04 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 12.5h;Inert atmosphere; | Intermediate AU (0268) 2-Bromo-N-(3-hydroxy-1,1-dimethylpropyl)benzenesulfonamide (0269) To a 20 mL vial were added a stirbar, <strong>[42514-50-1]3-amino-3-methylbutan-1-ol</strong> (428 mg, 4.15 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (994 mg, 3.89 mmol) and stirred for 12.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound. (676 mg, 54%). MS (ESI): mass calcd. for C11H16BrNO3S 321.00, m/z found 344.0 [M+Na]+; 1H NMR (600 MHz, CDCl3) delta 8.15 (dd, J=7.9, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 1H), 6.15 (s, 1H), 3.93-3.81 (m, 2H), 1.76 (t, J=6.0, 2H), 1.20 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.77% | With pyridine; at 90℃; | A mixture of la (0.35 g, 1.76 mmol), 2-bromobenzenesulfonyl chloride (0.67 g, 2.64 mmol) and pyridine (3 ml) was refluxed overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layer was collected, dried over anhydrous MgS04, and concentrated in vacuo to yield a brown residue, which was purified by a flash column over silica gel (ethyl acetate: n-hexane = 1: 1, Rf = 0.83) to afford 2m (0.30 g, 40.77%) as a yellow solid. 'H-NMR (500MHZ, CDCI3): delta 3.18 (t, /= 8.5 Hz, 2H), 4.49 (t, /= 8.5 Hz, 2H), 7.38-7.42 (m, 1H), 7.48-7.52 (m, 2H), 7.67 (t, /= 8.0 Hz, 1H), 7.92 (s, 1H), 8.43 (d, /= 8.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dichloro bis(acetonitrile) palladium(II); lithium carbonate In 1,4-dioxane at 140℃; for 33h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrazine hydrate / tetrahydrofuran / 0.5 h / 0 - 20 °C 2: iodine; tert.-butylhydroperoxide / 1,2-dichloro-ethane; decane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | With potassium hydroxide In tetrahydrofuran at 15 - 20℃; | tert-Butyl 4-((1-((2-bromophenyl)sulfonyl)-5-methoxy-1H-indol-3-yl)methyl)piperazine-1-carboxylate (5a) To a stirred mixture of finely ground KOH solid (0.93 g, 16.6 mmol)and 4 (2.7 g, 7.7 mmol) in THF (8.0 mL), 2-bromobenzenesulphonyl chloride(2.6 g, 10.0 mmol) in THF (5.0 mL) was added at 15 °C. After the reaction mixture was stirred at RT for 3 h, the mixture was poured into ice water andthe PH was adjusted to 9.5-10 with aqueous 2 N KOH solution. The mixture was extracted with EtOAC. The combined organic layer was washed withwater, brine, dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under vacuum. The crude product was purified by silica gel column chromatography with CH2Cl2/MeOH (200:1 to 20:1) as eluent to afford 5a as awhite solid (3.9g, 89.7%), mp 136.9-138.7 °C. 1H NMR (600 MHz, CDCl3): d 8.09(d, J = 6.4 Hz, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 9.0 Hz, 1H), 7.46 (t, J = 7.7Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.20 (s, 1H), 6.85 (dd, J = 2.0, 9.0 Hz, 1H), 3.82 (s,3H), 3.66 (s, 2H), 3.44 (s, 4H), 2.45 (s, 4H), 1.45 (s, 9H). LC-MS (ESI, m/z): Calcdfor C25H30BrN3O5S ([M+Na]+) 526.2, found: 526.4. |
77.7% | Stage #1: tert-butyl 4-((5-methoxy-1H-indol-3-yl)methyl)piperazine-1-carboxylate With potassium hydroxide In tetrahydrofuran at 20 - 32℃; for 2h; Stage #2: o-bromobenzenesulfonyl chloride In tetrahydrofuran at 20 - 32℃; for 1.5h; | 1.iv & v preparation of 1-[(2-bromophenyI)sulfonyl]-5-methoxy-3-[(1-t- butyloxycarbonyl piperazin-4-yl)methyI]-1H-indole Tetrahydrofuran (THF) (4.6 Litres) was charged into a reactor at 25 °C, followed by the addition of powdered potassium hydroxide (860.6 grams, 85 %, 13.06 moles) at 25 °C under stirring. THF (3 Litres) was charged into a 5 Litres, three necked round bottom flask, provided with a mechanical stirrer and thermometer pocket. 3-[(l -t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-lH-indole (obtained in above step) (1287.7 grams, 3.7324 moles) was charged into the flask at 25 °C and stirred the mass well for complete dissolution. Then the clear 3-[(l-t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-l H-indole solution, prepared as above, was slowly transferred to the reactor containing potassium hydroxide under stirring, maintaining the mass temperature below 25 °C. After completion of the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2- bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 - 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 - 30 °C.As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar. The starting material was absent as per TLC. A second lot of 2-bromophenylsuIfonyl chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction, The reaction mass was unloaded into neat carboys.Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was found to be 1 1.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.Purity: 91.46 %; - NMR (CDC13, 5 ppm): 1.45 (9H, s), 2.42 - 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 - 6.86 (1H, m), 7.18 - 7.19 (1H, m), 7.38 - 7.45 (2H, m), 7.52 - 7.55 (1H, m), 7.64- 7.66 (2H, m), 8.06 - 8.08 (1H, d, J = 7.76 Hz);Mass [M+Hf : 564.3, 566.4. Step (v): Purification of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t- butyloxycarbonyl piperazin-4-yI)methyI]-lH-indole The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 - 45 °C to obtain solids. Isopropanol (14 Litres) and methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution. Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1.6 Litres + 0.8 Litres). It was sucked well and air dried at 40 - 45 °C for 4 hours in tray driers. Weight of compound: 1554.8 grams, Cream colored crystalline powder, Yield: 77.7 % Purity: 99.42 %; - NMR (CDCI3, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 - 6.86 (lH, dd, J = 8.34, 2.09 Hz), 7.19 (1 H, d, J = 2.0 Hz), 7.36 - 7.40 (1 H, t, J = 7.14 Hz), 7.43 - 7.47 (1H, t, J = 7.56 Hz), 7.52 - 7.55 (1 H, d, J = 8.95 Hz), 7.64 - 7.66 (2H, m), 8.06 - 8.08 ( 1H, d, J = 7.87 Hz); Mass: [M+H]+: 564.3, 566.3 |
With potassium hydroxide In tetrahydrofuran at 10 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dichloro bis(acetonitrile) palladium(II); lithium carbonate In 1,4-dioxane at 100℃; for 24h; Schlenk technique; Inert atmosphere; stereoselective reaction; | Desulfitative Reactions; General Procedure General procedure: In a typical experiment, the alkene derivative (1.5 mmol), halobenzenesulfonyl chloride derivative (1 mmol), Li2CO3 (0.222 g, 3 mmol), and PdCl2(CH3CN)2 (12.9 mg, 0.05 mmol) were dissolved in 1,4-dioxane (2 mL) under an argon atmosphere. The reaction mixture was stirred at 100 °C for 24 h. After evaporation of the solvent, the product was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With pyridine; In dichloromethane; at 20℃; for 18h; | General procedure: To a stirring mixture of 5-amino-2-(4-aminophenyl) benzoxazole (1 eq.) in anhydrous CH2Cl2 (5 mL) was added the respective sulfonyl chloride (2.1 eq.) followed by anhydrous pyridine (2.1 eq.). The reaction was allowed to stir at room temperature for 18 h and was then chromatographed over silica and concentrated. If necessary, the product was further purified by preparatory RP-HPLC (H2O:CH3CN gradient), concentrated, and lyophilized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine; In 1,4-dioxane; at 20℃; | To a solution of N-methylpyridin-3-amine (0.47 g, 4.35 mmol) in dry dioxane (5 mL) was added 2- bromobenzenesulfonyl chloride (1.1 g, 4.35 mmol) and pyridine (1.4 mL, 17.4 mmol) and the mixture was stirred at r.t. overnight. H20 (10 mL) was added and the mixture was extracted with EtOAc (60 mL). The organic layer was washed with H20 (2 x 20 mL) and brine (20 mL) passed through a phase separation cartridge and the solvent removed under reduced pressure to give the title compound as a golden yellow oil (1.35 g, 95%).1H NMR (ppm)(400 MHz, CDCI3): 3.44 (3H, s), 7.24-7.30 (IH, m), 7.36-7.40 (2H, m), 7.67 (1 H, ddd, J=1 .5, 2.5, 8.3 Hz), 7.72 - 7.76 (1 H, m), 7.93 - 7.96 (1 H, m), 8.46 (2H, dd, J=5.3 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium diacetate; lithium carbonate In 1,4-dioxane at 140℃; for 4h; Schlenk technique; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With palladium diacetate; lithium carbonate In 1,4-dioxane at 140℃; for 4h; Schlenk technique; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine In tetrahydrofuran at 20℃; for 12h; | 4.2 General procedure for the synthesis of compounds 2a, 3a-3m, 3q-3z, 3aa and 6 General procedure: To a solution of 4-aminoacetophenone (0.68g, 5mmol) and pyridine (1.6mL, 20mmol) in THF (10mL) was slowly added the substituted sulfonyl chloride (5mmol). The reaction mixture was stirred at room temperature for 12h. Water (50mL) was added and the mixture was extracted with ethyl acetate (10mL×3), the combined organic phase was washed with 1N hydrochloric acid (30mL×2) and water (30mL×2), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the product. |
88.2% | With pyridine In dichloromethane at 20℃; | |
82% | Stage #1: 1-(4-aminophenyl)ethan-1-one With pyridine In dichloromethane at 20℃; for 1h; Stage #2: 2-bromobenzenesulphonyl chloride In dichloromethane for 10h; | 19.1 (1) Preparation of N-(4-acetylphenyl)-2-bromo-benzenesulfonamide p-Aminoacetophenone (2.00 g, 14.80 mmol) was added to a 50 mL single-necked flask and 10 mL of dichloromethane was added.Further, pyridine (1.17 g, 14.80 mmol) was added to the system, and the mixture was stirred at room temperature for 1 hour.The reaction system was an orange-yellow liquid, and o-bromobenzenesulfonyl chloride (4.16 g, 16.28 mmol) was slowly added dropwise. The color of the system was deepened and finally turned into a red clear liquid.The reaction was followed by thin layer chromatography, and the reaction was substantially complete after 10 hours.After the reaction is completed, the reaction system is poured into a beaker and washed with water.Pour off the water layer and wash it 5 times.Finally, the organic layer containing a small amount of water was transferred to a single-mouth flask and steamed.A pink solid was precipitated, filtered under reduced pressure and washed with a small portion of dichloromethane.Get a yellow solid, dry,Mass 4.30g (theoretical mass 5.24g),The yield was 82.0%. |
With pyridine at 80℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium sulfate In water at 20℃; for 3.2h; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium sulfate In water at 20℃; for 3.2h; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrazine hydrate / tetrahydrofuran / 0.25 h / 10 °C 2: sodium sulfate / water; acetonitrile / 9 h / 20 °C / Electrochemical reaction | ||
Multi-step reaction with 2 steps 1: hydrazine hydrate / tetrahydrofuran / 0.25 h / 10 °C 2: sodium sulfate / water; acetonitrile / 9 h / 20 °C / Electrochemical reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With dmap; triethylamine; In dichloromethane; at 20℃; for 16h; | To an ice cold stirred solution of crude <strong>[912368-73-1](S)-tert-butyl 3-(methylamino)piperidine-1-carboxylate</strong> (3.0 g, 14 mmol) in CH2C12 (100 mL) was added Et3N (2.1 mL, 15.4 mmol),DMAP (342 mg, 2.8 mmol) and 2-bromobenzene-1-sulfonyl chloride (3.9 g, 15.4 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with CH2C12 (100 mL) and washed with water. The organic layer was dried over anhydrous Na2504 and concentrated under reduced pressure. Crude product was purified with silica gel chromatography using 10%EtOAc / petroleum ether to afford 1.2 g of(S)-tert-butyl 3-(2-bromo-N-methylphenyl- sulfonamido)piperidine- 1 -carboxylate as pale yellow thick mass.LC-MS (ES+) [M +1]: 433.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.4% | With sodium carbonate; sodium sulfite In water at 30℃; for 3h; Inert atmosphere; | 3 Example 3: Preparation of 2-bromobenzenesulfinic acid VII 24.90 g of sodium sulfite was dissolved in water at 30 ° C and configured into a 150 mL solution, 33.00 g of sodium carbonate was dissolved in water at 30 ° C and configured into a 150 mL solution, and the two solutions were mixed and stirred at 30 ° C for 10 minutes. Under nitrogen protection, 20 g of 2-bromobenzene sulfochloride VIII was slowly added dropwise at 30 ° C, and stirred at 30 ° C for 3 hours. Most of the solvent was removed by vacuum concentration (temperature 55 ° C ~ 75 ° C, pressure -0.085 MPa ~ -0.1 MPa), 160 mL of ethanol was added, and the mixture was stirred at 75 ° C for 0.5 hour and then cooled to 10-20 ° C and stirred for 0.5 hours. Filtered to give an off-white solid, 80 mL of acetonitrile was added, and the mixture was stirred at 10 to 20 ° C for 1 hour, filtered to give an off-white solid. 80 mL of water and 80 mL of toluene were added, and 2 mol of 1/L hydrochloric acid was added dropwise at 5 to 15 ° C to adjust the pH to 3 to 4 and stirred for 0.5 hour. The layers were allowed to stand, and the aqueous phase was extracted twice with 40 mL of toluene, the combined organic phases were washed twice with a mass concentration of 15% saline (the mass concentration means the mass of sodium chloride as a percentage of the total mass of the saline ) and dried over anhydrous sodium sulfate. Filtered, concentrated in vacuum (temperature 45 ° C ~ 55 ° C, pressure -0.085 MPa ~ -0.1 MPa) till dried to obtain 15.3 g of light yellow oil which was 2-bromobenzenesulfinic acid VII, the yield was 88.4%, and the HPLC purity was 98.49%. |
With sodium sulfite In water at 80℃; for 16h; | ||
Stage #1: o-bromobenzenesulfonyl chloride With sodium sulfite In water at 70 - 80℃; for 5h; Stage #2: With hydrogenchloride In water at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydrogen difluoride; tetra-n-butyl-ammonium chloride In dichloromethane; water monomer at 20℃; for 48h; | Sulfonyl Fluorides 1d, 1e, and 1f; General Procedure General procedure: A 50 mL round-bottomed flask was charged with an aq solution ofKHF2 (3.12 g in 8.04 g of H2O; ca. 28% w/w; 40.0 mmol), the respectivearenesulfonyl chloride (20.0 mmol), Bu4NCl (0.056 g, 0.20 mmol, 1mol%), and DCM (22 mL), and the reaction mixture was stirred vigorouslyat r.t. for 4 h (1d) and 48 h (1e and 1f). Then, the mixture wastransferred to a separatory funnel, extracted with DCM (3 × 50 mL),and the combined organic phases were dried (MgSO4). The mixturewas filtered through a pad of silica gel (d = 4 cm; ∅ 6 cm), rinsed withDCM (500 mL), and the combined filtrates were evaporated, and driedin vacuo to obtain the desired sulfonyl fluoride. The products 1d, 1e,and 1f were analytically pure. |
86% | With tri-n-propylamine; sulfur(VI) fluoride In propan-2-one at 20℃; for 2h; Inert atmosphere; | 3. General Procedure for Aryl Sulfonyl Fluorides Synthesis General procedure: An oven-dried reaction flask (30 mL) equipped with a stirring bar was charged with aryl sulfonyl chloride (1, 2 mmol), n-Pr3N (6.0 mmol, 860 mg, 3.0 equiv.) and THF (10 mL). Then the flask was covered with a plastic stopper before the sulfuryl fluoride gas (SO2F2) was introduced into the mixture by slowly bubbling from a SO2F2 balloon. The air in the flask was excluded by SO2F2 gas for about 10 seconds and the resulting mixture was subsequently allowed to stir at room temperature for 2 h. Once the reaction reached its completion, the mixture was diluted with water and the aqueous phrase was extracted with EtOAc (20 mL 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness under vacuum. The residue was purified through flash silica gel chromatography using a mixture of ethyl acetate and petroleum ether as eluent to afford the desired aryl sulfonyl fluoride 2. |
With potassium hydrogen difluoride In water monomer; acetonitrile at 20℃; | General Procedure I for the Preparation of Aryl Sulfonyl Fluorides (Fig. 2A). General procedure: Arylsulfonyl chloride (commercially available from Sigma-Aldrich or synthesizedaccording to known procedures) dissolved in acetonitrile (Fisher HPLC grade,0.5-1 M) was treated with saturated potassium bifluoride aqueous solution(Sigma-Aldrich, ∼5 M, 1.5-2.5 equiv). The emulsion was stirred vigorously for1-4 h before being partitioned between ethyl acetate and water. The organicsolution was collected, dried over anhydrous sodium sulfate (Na2SO4),concentrated, and purified by column chromatography, if necessary, to yieldthe desired aryl sulfonyl fluoride (33 examples, 90-100% isolated yield). |
With potassium hydrogen difluoride In water monomer; acetonitrile at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With palladium diacetate; lithium carbonate; In 1,4-dioxane; at 140℃; for 16h;Inert atmosphere; Schlenk technique; | General procedure: To a 25 mL oven dried Schlenk tube, benzenesulfonyl chloride (1.5 mmol), Methoxalen (0.216 g, 1 mmol), Li2CO3 (0.148 g, 2 mmol), 1,4-dioxane (2 mL) and Pd(OAc)2 (11.2 mg, 0.05 mmol) were successively added. The reaction mixture was evacuated by vacuum-argon cycles (5 times) and stirred at 140 C (oil bath temperature) for 16 hours. After cooling the reaction at room temperature and concentration, the crude mixture was purified by silica column chromatography to afford the C2-arylated Methoxalen. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | General procedure: The amine 6, as a TFA salt (100mg, 0.22mmol), was dissolved in anhydrous DCM (20mL), and stirred in an ice bath at 0°C. Triethylamine (0.19mL, 1.33mmol) was added and the reaction mixture was warmed to room temperature. Corresponding benzene sulfonyl chloride (0.33mmol) was added to the reaction mixture and the reaction mixture was stirred for 48h at room temperature under an argon atmosphere. Next, the mixture was transferred to a separatory funnel where the organic layer was washed with an aqueous solution of saturated NaHCO3 (30mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (1:4 ethyl acetate/hexane solvent system) and recrystallized from diethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: fangchinoline With triethylamine at 0℃; for 1h; Inert atmosphere; Stage #2: o-bromobenzenesulfonyl chloride Inert atmosphere; | 1 Example 1 The preparation method of fangchinoline derivatives with anticancer activity, first dissolve 100mg of fangchinoline dTet (about 0.18mmol) in 3 mL of dichloromethane, place in a two-necked flask, and repeatedly pour argon into the flask Air three times until the air is evacuated to fill the bottle with argon, and the temperature is controlled to 0°C. Under magnetic stirring, 66.5 mg (about 0.72 mmol) of triethylamine dissolved in 2 mL of dichloromethane was added. After reacting for 1 h, 50.7 mg (about 0.20 mmol) of 2-bromobenzenesulfonyl chloride was added, and the reaction was followed by TLC. After the reaction, the reaction solution was concentrated and purified by a neutral alumina column. The eluent was dichloromethane: methanol (120:1, 100:1, 80:1), separated and purified, and a white powdery product 123.6 was obtained. mg (about 0.149 mmol), the yield is 83%. After NMR and HRMS analysis, the product obtained is 7-O-(m-Br-benzenesulfonyl) fangchinoline. The NMR spectrum is shown in Figures 1 and 2 Shown. |
83.5% | With pyridine In dichloromethane at 0℃; | 4.1.5 Synthesis of sulfonyl fangchinoline derivatives General procedure: A mixture of fangchinoline (100mg, 0.16mM) and pyridine (55mg, 0.64mM) was dissolved in 2mL of CH2Cl2 at 0°C under argon protection, followed by the slow addition of R3SO2Cl (0.18mM). TLC analysis was performed until completion of the reaction, and the solution was concentrated by rotary evaporation. The residue was purified by column chromatography, and 4c-4j was obtained by using CH2Cl2/CH3OH as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(II) bis(trifluoromethanesulfonate); N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 24h; Inert atmosphere; Schlenk technique; regioselective reaction; | General Procedure for Sulfonylation General procedure: Sulfonyl chloride 2 (0.4 mmol, 2.0 equiv.), Cu(OTf)2 (10 mol% ) were weighed into a Schlenk tube. The reaction vessel was capped and subjected to three vacuum-purge/nitrogen-flush cycles. Then alkene 1 (0.2 mmol, 1.0 equiv.) and DIPEA (0.3 mmol, 1.5 equiv.) in MeCN (1.5 mL) was added through the side-arm by syringe. The reaction was stirred under nitrogen at 100 for 24 h. After reaction, the mixture was cooled to room temperature. Volatile solvent and reagents were removed by rotary evaporation and the residue was purified by silica gel flash chromatography using petroleum ether/EtOAc (50:1 to 15:1) to afford the desired product 3 or 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling with ice; | General procedure A for sulfonamide synthesis:3 General procedure: Aryl sulfonyl chloride S3 (1.0 equiv.) wasadded to an ice cold solution of DIPEA (2.0 equiv.) and the amine S2 (1.5 equiv.) in DCM (0.25 M).The reaction mixture was stirred at room temperature and monitored by TLC. Upon completion, thecrude was diluted in DCM (10 mL), washed with aqueous HCl (1M, 2 10 mL) and brine (1 10 mL).The organic phase was dried over MgSO4 and concentrated under reduced pressure.The crude material was solubilized in DCM (0.25 M). DIPEA (2.0 equiv.), DMAP (20 mol%) and Boc2O(1.3 equiv.) were added to the mixture, in this order. The reaction was stirred at room temperature andmonitored by TLC. Upon completion, the crude was diluted in DCM (10 mL), washed with brine (3 10mL), dried over MgSO4 and concentrated under reduced pressure. The crude material was purified byflash chromatography on silica gel to afford the pure compound. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling with ice; | General procedure A for sulfonamide synthesis:3 General procedure: Aryl sulfonyl chloride S3 (1.0 equiv.) wasadded to an ice cold solution of DIPEA (2.0 equiv.) and the amine S2 (1.5 equiv.) in DCM (0.25 M).The reaction mixture was stirred at room temperature and monitored by TLC. Upon completion, thecrude was diluted in DCM (10 mL), washed with aqueous HCl (1M, 2 10 mL) and brine (1 10 mL).The organic phase was dried over MgSO4 and concentrated under reduced pressure.The crude material was solubilized in DCM (0.25 M). DIPEA (2.0 equiv.), DMAP (20 mol%) and Boc2O(1.3 equiv.) were added to the mixture, in this order. The reaction was stirred at room temperature andmonitored by TLC. Upon completion, the crude was diluted in DCM (10 mL), washed with brine (3 10mL), dried over MgSO4 and concentrated under reduced pressure. The crude material was purified byflash chromatography on silica gel to afford the pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2,3-Dihydro-3-methylindole With triethylamine In dichloromethane at 20℃; for 0.0833333h; Sealed tube; Stage #2: 2-bromobenzenesulphonyl chloride In dichloromethane at 20℃; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | Synthetic procedure for 3-methoxyphenyl 2-bromobenzenesulfonate (24) Et3N (2 equiv.) and 2-bromobenzenesulfonyl chloride (23) (1 equiv.) were addedslowly to a solution of 3-methoxyphenol (0.5 g, 1.1 equiv.) in dry DCM at 0 °C undernitrogen atmosphere. The solution was stirred for 4 h at RT. Slush and HCl 2M wereadded to pH = 4 and the reaction mixture was extracted in DCM (3 × 15 mL). The collectedorganic phases were washed with K2CO3 s.s. (2 × 10 mL), dried with Na2SO4, filtered andevaporated under vacuum to give products 24 as white powder in high yield and purity.Yield 96%; m.p. 163-166 °C; silica gel TLC Rf 0.45 (EtOAc/Hexane 50% v/v); δH (400MHz, DMSO-d6): 8.08 (d, J = 8.4 Hz, 1H, Ar-H), 7.99 (d, J = 8.4 Hz, 1H, Ar-H), 7.75 (dd, J =7.4 Hz, 1H, Ar-H), 7.65 (dd, J = 7.4 Hz, 1H, Ar-H), 7.33 (dd, J = 7.1 Hz, 1H, Ar-H), 6.93 (d, J= 7.1 Hz, 1H, Ar-H), 6.70 (m, 2H, Ar-H), 3.73 (s, 3H, CH3); δC (400 MHz, DMSO-d6): 162.0,152.7, 146.8, 134.7, 131.7, 134.7, 131.1, 130.3, 129.0, 115.6, 106.9, 102.0, 55.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzyl-triethyl-ammonium chloride; potassium hydroxide In dichloromethane; lithium hydroxide monohydrate at 20℃; for 0.5h; | 4.1.1 General procedure for preparation of intermediate 4 General procedure: To a mixture of material 1 or 2 (1.0 equiv), corresponding benzenesulfonyl chloride derivate 3 (1.5 equiv), benzyltriethylammonium chloride (0.2 equiv) in DCM (10mL) was added a solution of potassium hydroxide (2.0 equiv) in water (2mL), then reacted at room temperature for 30min. DCM (10mL) was added and the organic phase was collected and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE/EA (v/v)=3/1) to afford the intermediate 4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With benzyl-triethyl-ammonium chloride; potassium hydroxide In dichloromethane; lithium hydroxide monohydrate at 20℃; for 0.5h; | 4.1.1 General procedure for preparation of intermediate 4 General procedure: To a mixture of material 1 or 2 (1.0 equiv), corresponding benzenesulfonyl chloride derivate 3 (1.5 equiv), benzyltriethylammonium chloride (0.2 equiv) in DCM (10mL) was added a solution of potassium hydroxide (2.0 equiv) in water (2mL), then reacted at room temperature for 30min. DCM (10mL) was added and the organic phase was collected and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE/EA (v/v)=3/1) to afford the intermediate 4 |
Tags: 2905-25-1 synthesis path| 2905-25-1 SDS| 2905-25-1 COA| 2905-25-1 purity| 2905-25-1 application| 2905-25-1 NMR| 2905-25-1 COA| 2905-25-1 structure
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. |
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P243 | Take precautionary measures against static discharge. |
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P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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