100% |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at -30 - 20℃; for 18h; |
27.1 4-Hydroxybenzenesulfonyl chloride
A solution of 7 g (30 mmol) of the sodium salt of 4-hydroxybenzenesulfonic acid dihydrate in 40 ml of dimethylformamide is added dropwise to a solution of 15.5 ml (181 mmol) of oxalyl chloride in 120 ml of dichloromethane cooled to -30° C. The reaction medium is slowly brought back to ambient temperature and then stirred at ambient temperature for 18 h. After the addition of 200 ml of ice, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated. 6.2 g (100%) of 4-hydroxybenzenesulfonyl chloride are obtained in the form of a colorless oil. |
97% |
With thionyl chloride In N,N-dimethyl-formamide at 60℃; for 3.5h; |
19
A solution of thionyl chloride (15 g, 9.2 mL) and DMF (150 mg, 0.16 ml_) was added to sodium 4-hydroxybenzenesulfonate (4.9 g, 25 mmol). The resulting mixture was stirred at 60 0C for 3.5 h. The solution was poured into ice and stirred for 5 min. The aqueous solution was extracted with dichloromethane, dried over sodium sulfate and evaporated to provide sulfonyl chloride (4.7 g, 97%) as an oil. The crude product (-1.9 mmol) and 4-hydroxybenzylamine (207 mg, 1.9 mmol) were stirred in pyridine (6 mL) for 2 h and evaporated. The residue was purified by two columns of silica gel (a. hexane-acetone 3:1 to 1 :1 , (b. MeOH in dichloromethane 2% to 7 %) to afford 4-hydroxy-N-(4-hydroxyphenyl)- benzenesulfonamide (140 mg, 28%) as a brownish solid. MS (ES) m/z: 265.12(M), 264.08 (M-I )I 13C-NMR (CD3OD): δ 161.0, 154.5, 129.5, 129.0, 128.8, 124.0, 115.5, 115.3. |
70% |
Stage #1: sodium p-hydroxybenzenesulfonate
Stage #2: With thionyl chloride |
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With thionyl chloride; N,N-dimethyl-formamide at 65℃; for 6h; |
69.1
Stage 69.1:A solution of 31.4 ml (430 mmol) of thionyl chloride and 0.2 ml (2.58 mmol) of DMF was quickly added to 10 g (43 mmol) of 4-hydroxybenzenesulfonic acid sodium salt under N2 atmosphere. The resulting mixture is stirred at 65° C. for 6 h. At the end of this time, the mobile, nearly homogenous reaction mixture is poured on ice with vigorous stirring. An oily lower layer is produced and which is dissolved in 100 ml of CH2Cl2. The aqueous layer is extracted with CH2Cl2 and the combined organic solution is dried over MgSO4 and concentrated under reduced pressure to give 8.19 g of 4-hydroxybenzenesulfonyl chloride; NMR (CDCl3): 5.3 (br s, 1H), 7.01 (d, 2H, J=9.08 Hz), 7.94 (d, 2H, J=9.08 Hz). |
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With thionyl chloride In N,N-dimethyl-formamide at 65℃; for 3h; |
62
Thionyl chloride (10 ml) was dropwise added to a DMF (5 ml) solution of sodium 4-hydroxybenzenesulfonate (1.00 g), followed by heating at 65°C for 3 hours. The reaction solution was cooled and Tol (10 ml) was added thereto. The solvent was evaporated under reduced pressure, water was added, followed by extraction with chloroform. The organic layer was washed with aqueous saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless solid (587 mg). |
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With thionyl chloride In N,N-dimethyl-formamide at 60℃; for 3.5h; |
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1.93 g |
With thionyl chloride; N,N-dimethyl-formamide at 60℃; for 3.5h; |
1.1 4.2.1.1. 4-Hydroxybenzene-1-sulfonyl chloride (5)
A mixture of sodium 4-hydroxybenzenesulfonate 4 (1.96 g, 10 mmol) in thionyl chloride (3.7 ml) and catalytic DMF (0.06 ml) was stirred at 60 °C for 3.5 h. After cooling to ambient temperature, the reaction mixture was poured into ice water (10 ml) and extracted by dichloromethane, washed with brine, dried over Na2SO4. The organic solvent was evaporated and compound 5 was obtained as 1.93 g colorless oil. ESI-MS m/z 192.9 (M+H)+. |
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With thionyl chloride In N,N-dimethyl-formamide at 60℃; for 3.5h; |
1.1 Synthesis of 4-hydroxy phenyl-1-sulfonyl chloride (compound 4)
The 1.96g (10mmol, 1 . 0eq) P-hydroxybenzene sulfonic acid sodium salt is dissolved in 3.7 ml thionyl chloride in, then adding 0.06mlDMF, is omitted, the 60 °C reaction 3.5h, after the reaction solution is poured into the ice water, stirring 5 min, dichloromethane is used for extraction, saturated salt water for washing the organic phase, anhydrous Na 2 SO 4 drying, concentrating, shall be 1.93g of colorless transparent oily crude product, can be directly used for the reaction of the next purification. |
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With thionyl chloride In N,N-dimethyl-formamide for 2h; Reflux; |
thionyl chloride (49 parts by weight), Hydroxybenzene sodium sulfonate (20 parts by weight) was added in portions, was added dropwise addition of dimethylformamide (1.4 parts by weight), was heated under reflux for 2 hours. The reaction solution was crystallized in ice water, and extracted with ethyl acetate, the organic layer separated and concentrated to give 19.7 parts by weight of a hydroxy-benzenesulfonyl chloride. Subsequently, 2-(ethylamino)ethanol (9 parts by weight) was dissolved in N- methylpyrrolidone (50 parts by weight) solution, after hydroxybenzene sulfonyl chloride (19.2 parts by weight) was added dropwise in an ice bath, and stirred for 2 hours at 50 °. After adding water to the reaction solution, ethyl acetate was carried out a liquid separation operation with a 1N aqueous hydrochloric acid solution. After concentrating the organic layer, a 30% aqueous solution of sodium hydroxide was added 200ml, for 5 hours heated and stirred at 80 . The reaction mixture ethyl acetate, was carried out a liquid separation operation with 1N aqueous hydrochloric acid solution. The organic layer was concentrated and purified by silica gel chromatography, 4-(N-ethyl-N-hydroxyethylsulfamoyl)phenol was obtained 15.1 parts by weight. |
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With thionyl chloride at 70℃; for 6h; Alkaline conditions; |
1(F)
4-Hydroxybenzene-1-sulfonyl fluoride (6-5). A 50 mL round-bottom flask was charged with 78 4-hydroxybenzenesulfonate (2.56 g). 79 Thionyl chloride (10 mL) was added and the mixture was heated to reflux under a nitrogen atmosphere for 6 hours. The bulk of the excess thionyl chloride was removed by distillation, and the last traces were removed by addition of 80 toluene (10 mL) and rotary evaporation. The resulting crude 75 sulfonyl chloride (a yellow oil) was dissolved in CH3CN (20 mL) and treated with saturated aqueous KHF2 (5 mL). The reaction mixture was stirred at room temperature overnight and monitored by GC-MS. Upon completion, the sulfonyl fluoride was extracted with EtOAc (3×20 mL), dried over anhydrous Na2SO4, and concentrated. The desired product was obtained as colorless crystals (1.84 g, 80% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=12.0 Hz, 2H), 7.04 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 162.7, 131.2, 123.2 (d, J=23 Hz), 116.7; 19F NMR (376 MHz, CDCl3) δ +66.8; ESI-MS (m/z): 177 [MH]+. |
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With thionyl chloride In N,N-dimethyl-formamide at 60 - 70℃; for 5h; Inert atmosphere; |
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With thionyl chloride In N,N-dimethyl-formamide for 2h; Reflux; |
Thionyl chloride (49 parts by weight)To the mixture, sodium hydroxybenzenesulfonate (20 parts by weight) was added in portions,Furthermore, after adding dimethylformamide (1.4 parts by weight) dropwise,Heated to reflux for 2 hours. The reaction solution was crystallized in ice water, extracted with ethyl acetate, and the organic layer was separated and concentrated.19.7 parts by weight of hydroxybenzenesulfonyl chloride was obtained. |
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With thionyl chloride In N,N-dimethyl-formamide at 45℃; for 1h; |
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With thionyl chloride In N,N-dimethyl-formamide at 60℃; for 3.5h; |
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4.4 g |
Stage #1: sodium p-hydroxybenzenesulfonate In toluene at 130℃; for 5h;
Stage #2: With thionyl chloride; N,N-dimethyl-formamide at 60℃; for 4h; |
2.2.6 2.6 Synthesis of 4-hydroxybenzenesulfonyl chloride
A 100 mL single-necked flask was charged with sodium 4-hydroxybenzenesulfonate (5 g) and 50 mL of toluene, which were subjected to reflux at 130°C in an oil bath for 5 h. Water was separated by a water separator. After water was separated, the resulting mixture was concentrated to remove toluene. 6 mL of SOCl2 was added to the flask, 0.2 mL of DMF was added dropwise, and the mixture was stirred for 4 h in an oil bath at 60°C. The oil bath was removed, and the resulting mixture was concentrated to remove SOCl2. The residue in the flask was added dropwise into 100 mL of ice water, the mixture was stirred for 15 min, and then 100 mL of DCM was added to perform extraction, followed by liquid-liquid separation. The aqueous phase was extracted with DCM (20 mL × 2). The organic phases were combined, washed with 30 mL of a saturated NaCl aqueous solution, and subjected to liquid-liquid separation. The organic phase was dried over 20 g of anhydrous sodium sulfate and filtered, and the filtrate was concentrated, so as to obtain 4.4 g of 4-hydroxybenzenesulfonyl chloride. |
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With thionyl chloride In N,N-dimethyl-formamide at 45℃; for 1h; |
3 Synthesis of compound 3b.
Sodium 4-hydroxybenzenesulfonate (200 mg, 1.0 mmol), thionyl chloride (800 mL, excess) and DMF (1 mL) were combined in a round bottom flask and stirred at 45°C for 1 hour. The reaction mixture was concentrated in vacuo and then ethyl ether was added and concentrated in vacuo again. The resultant residue was used without further purification. |