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Structure of 4025-75-6 * Storage: {[proInfo.prStorage]}
* 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.
With tert-butylhypochlorite In water; acetonitrile at 0 - 20℃;
General procedure: Alkyl halide (or sulfate) (5 mmol) and thiourea (0.381 g, 5 mmol) were heated at reflux in EtOH (5 mL) for 1 h. After removal of the solvent in vacuum and washing with Et2O (3 × 5 mL), the corresponding S-alkyl isothiourea salt was obtained as a white solid in almost quantitative yield. Without purification, the product was transferred into a three-necked round-bottom flask equipped with a thermometer and an addition funnel in an ice-bath, followed by addition of water (0.45mL) and MeCN (10 mL). To the resultant vigorously stirred mixture was added dropwise a solution of t-BuOCl (2.86 mL) in MeCN (5 mL), keeping the inner temperature at 0–20 °C. The mixture was then stirred for 30 min. Removal of the solvent under vacuum, addition of Et2O (15 mL), washing with H2O (2 × 10 mL), drying over Na2SO4, and concentration under vacuum gave the desired product in high purity. The product was further purified by recrystalization from petroleum ether–EtOAc.
0.636 g
With hydrogenchloride; sodium chlorite In acetonitrile at 10 - 20℃; for 0.5 h; Green chemistry
General procedure: Step 1. An alkyl halide or mesylate (5 mmol) and thiourea (0.381 g, 5 mmol) wererefluxed in 5 mL of ethanol for 1 h. After removal of the solvent in vacuum thecorresponding S-alkyl isothiourea salt was obtained as white solid or sticky oil.Step 2. A 50 mL three-necked flask equipped with a thermometer and asolid-addition funnel was immersed in an ice-bath. To the flask was sequentiallyadded NaClO2 solid (for isothiouronium chlorides or sulfonate, 1.61 g, 15 mmol; forisothiouronium bromides, 2.14 g, 20 mmol, 85percent purity), MeCN (10 mL), and thenconc. HCl (for isothiouronium chlorides or sulfonate, 3 mL; for isothiouroniumbromides, 4 mL) during 1 min at such a rate that the inner temperature was maintainedless than 10 °C. Then S-alkyl isothiourea salt was slowly added througth the solidaddition-funnel to keep the inner temperature less than 20 °C. After the addtion, theresulting mixture was stirred for another 30 min. Then 25 mL of water was added, and the resultant mixture was evaporated in vacuum at 15 °C to remove acetonitrile. Afteraddition of 100 mL of water, the solid products were obtained by filtration on aBuchner funnel and dried under an infrared lamp, while the liquid products wereobtained by extraction with 15 mL of ethyl acetate, drying with Na2SO4, andconcentration in vacuum.For 1,4-dibromobutane, the amounts of thiourea, NaClO2 solid, MeCN, and conc.HCl were doubled.
1.001 g
With sodium hypochlorite; sulfuric acid In diethyl ether; water at 0 - 20℃; for 0.5 h; Green chemistry
General procedure: The appropriate alkyl halide (or mesylate) (5 mmol) and thiourea (0.381 g, 5 mmol) were refluxed in EtOH (5 mL) for 1 h. After removal of the solvent in vacuum and washing with Et2O (3 × 5 mL), the corresponding S-alkyl isothiourea salt was obtained as a white solid or sticky oil in an almost quantitative yield. Without purification, the product was transferred into a three-necked round-bottomed flask equipped with a thermometer and an addition funnel in an ice-bath. Then, 6 M H2SO4 (2 mL), followed by Et2O (30 mL) were added. To the resultant vigorously stirred mixture was added dropwise 5percent bleach (for alkyl chlorides and mesylates, 30 mL; foralkyl bromides, 37.5 mL) by keeping the inner temperature 0–20 °C (for the preparation of alkanedisulfonyl dichlorides, 0.762 g, 10 mmol thiourea, 4 mL of 6 M H2SO4, 50 mL of Et2O, and 75 mL of 5percent bleach were used). After the addition, the mixture was stirred for another 30 min. The mixture was partitioned in a separatory funnel, and the ethereal phase was washed with brine (25 mL), dried (Na2SO4), and evaporated in vacuum to afford the desired product. The oily products were extracted with CHCl3 (3 × 2.5 mL) and evaporated to remove the by-product, bromine. If necessary, the products can be dissolved in minimal PE–EtOAc (5:1) and filtered through a column of silica gel (h = 5 cm) with PE–EtOAc (5:1) as eluent to remove the impurities (Table 2).
Reference：
[1] Journal of the Chemical Society, 1927, p. 818
[2] Patent: CN108440452, 2018, A, . Location in patent: Paragraph 0043-0044; 0050-0051; 0057-0058; 0064-0065; 0071
3
[ 36639-50-6 ]
[ 4025-75-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 6, p. 1701 - 1708
[2] Organic Letters, 2004, vol. 6, # 23, p. 4285 - 4288
[3] Patent: US2008/103189, 2008, A1, . Location in patent: Page/Page column 38
[4] European Journal of Organic Chemistry, 2018, vol. 2018, # 15, p. 1774 - 1784
4
[ 170640-75-2 ]
[ 4025-75-6 ]
Reference：
[1] Synthesis, 2006, # 24, p. 4131 - 4134
5
[ 10026-13-8 ]
[ 36639-50-6 ]
[ 4025-75-6 ]
Reference：
[1] Patent: US5300506, 1994, A,
[2] Patent: US2009/281114, 2009, A1,
[3] Patent: US5434154, 1995, A,
6
[ 4357-96-4 ]
[ 4025-75-6 ]
Reference：
[1] Journal of the American Chemical Society, 1937, vol. 59, p. 1837,1839
[2] Journal of the American Chemical Society, 1987, vol. 109, # 24, p. 7472 - 7477
With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide; In dichloromethane; at 60℃; for 2.0h;
Take 7.3g DMF (0.1mol) ice bath and cool down to below 0 C, magnetically stirred, 9.86g of tricolor BTC (0.033mol) dissolved in 10ml of anhydrous dichloromethane, Slowly drip into DMF, the reaction is controlled below 0 C, after the completion of the addition, the reaction is stirred for 30 min, and the white solid is produced as Vilsmeier reagent; 21.6 g of p-nitrobenzyl methanesulfonic acid (0.1 mol) was dissolved in 10 ml of anhydrous dichloromethane, slowly dropped into Vilsmeier reagent system, and reacted at 60 C. After TLC detection (expansion phase: ethyl acetate: petroleum ether = 2:1), the reaction was carried out for 2 hours, and after cooling the system, the system was concentrated to 10 ml for use;
With phosphorus pentachloride; In toluene; for 1.0h;Heating / reflux;
(4-nitrophenyl)methanesulfonyl chloride: A mixture containing sodium (4-nitrophenyl)-methanesulfonate (100 g, 0.42 mol), phosphorous pentachloride (100.5 g, 0.48 mol) and toluene (600 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to ambient temperature, filtered and concentrated to give the title compound.
With triethylamine; In dichloromethane; at 20℃; for 1.0h;
To a solution of (4-nitro-phenyl)-methanesulfonyl chloride (300 mg, 1.3 mmol) in DCM (5 mL) was added aniline (145 mg, 1.56 mmol) and TEA (263.1 mg, 2.6 mmol) , Then the mixture was stirred at rt for 1 hr. The reaction was monitored by TLC, The mixture was concentrated in vacuum to give residue, which was purified by a silica gel column (PE/EA=3:1) to give c-(4-nitro- phenyl)-n-phenyl-methanesulfonamide (151 mg, yield: 80%) as a yellow solid. ?H NIVIR (400 IVIHz, DMSO-d6): oe = 9.92 (s, 1H), 8.21 (d, J= 8.0 Hz, 2H), 7.55 (d, J= 8.0 Hz, 2H), 7.32 (t, J 8.0 Hz, 2H), 7.19 (d, J= 8.0 Hz, 2H), 7.09 (t, J= 8.0 Hz, 1H), 4.68 (s, 2H).
With ammonium carbonate; ammonia; In acetonitrile; for 1.0h;
Synthesis of (4-nitrophenyl)methanesulfonamide To a solution of <strong>[4025-75-6](4-nitrophenyl)methanesulfonyl chloride</strong> (4 g, 17 mmol) in acetonitrile (100 mL) was added a solution of ammonium carbonate (3 g, 31.3 mmol) in ammonia (50 mL). The reaction mixture was stirred for 1 h, and TLC indicated the starting material consumed completely. The organic solvent was removed under reduced pressure. Addition of water (10 mL) led to precipitate formation. The solid was collected, washed with water (2*5 mL), and dried to give (4-nitrophenyl)methanesulfonamide (3.4 g, 93%) as a white solid. MS (ES+) C7H8N2O4S requires: 216, found: 217 [M+H]+.
65%
With ammonia; ammonium carbonate; In water; acetonitrile; at 20℃; for 1.0h;Product distribution / selectivity;
(4-Nitrophenyl)methanesulfonyl chloride (1.0 g, 4.3 mmol) was dissolved in acetonitrile (10 mL), then to this solution was added concentrated aqueous ammonia (10 mL) saturated with ammonium carbonate and the reaction mixture was vigorously stirred for 1 h at room temperature. Then acetonitrile was removed under reduced pressure and the residue diluted with cold water (10 mL) leading to a precipitate formation. The precipitate was filtered off and washed with water (2*5 mL), ether and dried. Yield of (4-nitrophenyl)methanesulfonyl amide 0.6 g (65%) ; a. Synthesis of (4-nitrophenyl)methanesulfonyl amideThe same procedure as for compound 6.; a. Synthesis of (4-nitrophenyl)methanesulfonyl amideThe same procedure as for compound 6.
65%
With ammonia; In water; acetonitrile; at 20℃; for 1.0h;
a. Synthesis of (4-nitrophenyl)methanesulfonyl amide(4-Nitrophenyl)methanesulfonyl chloride (1.0 g, 4.3 mmol) was dissolved in acetonitrile (10 mL), then to this solution was added concentrated aqueous ammonia (10 mL) saturated with ammonium carbonate and the reaction mixture was vigorously stirred for 1 h at room temperature. Then acetonitrile was removed under reduced pressure and the residue diluted with cold water (10 mL) leading to a precipitate formation. The precipitate was filtered off and washed with water (2×5 mL), ether and dried. Yield of (4-nitrophenyl)methanesulfonyl amide 0.6 g (65%)
65%
With ammonia; ammonium carbonate; In acetonitrile; at 20℃; for 1.0h;
Example 6: Synthesis of {4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}- methanesulfonamide (Compound 6)a. Synthesis of (4-nitrophenyl)methanesulfonyl amide.(4-Nitrophenyl) methanesulfonyl chloride (1.0 g, 4.3 mmol) was dissolved in acetonitrile (10 ml_), then to this solution was added concentrated aqueous ammonia (10 ml_) saturated with ammonium carbonate and the reaction mixture was vigorously stirred for 1 h at room temperature. Then acetonitrile was removed under reduced pressure and the residue diluted with cold water (10 ml_) leading to a precipitate formation. The precipitate was filtered off and washed with water (2*5 ml_), ether and dried. Yield of (4- nitrophenyl) methanesulfonyl amide 0.6 g (65%)
With ammonia; In tetrahydrofuran; water; at 0℃; for 0.25h;
To a stirred solution of conc. NH4OH (17 mL) in THF (34 mL) cooled to 0 C. was added dropwise (4-nitro-phenyl)-methanesulfonyl chloride (2 g, 8.42 mmol). The reaction was stirred at 0 C. for 15 min then poured into ice-water and extracted 3 times with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford sulfonamide (4-nitro-phenyl)methanesulfonamide.
cis-3,5-dimethyl-1-(4-nitro-phenylmethanesulfonyl)-piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; In dichloromethane; at 20℃; for 0.333333h;
A solution of 250 mg (1.06 mmol) of 4-nitrophenylmethanesulfonyl chloride and 133 mg (1.17 mmol) of cis-2,6-dimethylpiperazine in CH2Cl2 (10 mL) was treated with 325 muL (2.33 mmol) of triethylamine at RT for 20 min. The mixture was diluted with CH2Cl2 (15 mL) and washed with water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 298 mg (90%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): delta 8.25 (d, 2H, J=8.8 Hz), 7.87 (d, 2H, J=8.8 Hz), 4.24 (s, 1H), 3.59-3.53 (m, 2H), 2.92-2.82 (m, 2H), 2.30-2.23 (m, 2H), 1.04 (d, 6H, J=6.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C13H19N3O4S, 314.1 (M+H), found 314.1.
piperidin-4-one O-(3-trifluoromethylbenzyl)oxime[ No CAS ]
[ 4025-75-6 ]
C20H20F3N3O5S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 1.0h;
A solution of piperidin-4-one O-(3-trifluoromethylben2;yl)oxime (408 mg, 1.50 mmol) and triethylamine (0.460 ml. 3.30 mmol) in dichloromethane (4 ml), (4- nitrophenyl)methanesulfonyl chloride (390 mg, 1.65 mmol) in dichloromethane (2 ml) was slowly added at 0 C and stirred at room temperature for 1 hour. Saturated <n="438"/>aqueous NaHCO3 solution (10 ml) was added, extracted with chloroform (30 ml x 2), dried (MgSO4) and evaporated under reduced pressure to give yellow solid. This crude material was taken up in toluene (13 ml). To the mixture, iron powder (420 mg, 7.50 mmol), NH4Cl (802 mg, 15.0 mmol) and H2O (1.5 ml) was added. The reaction mixture was heated at 105 C and stirred for 2 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, then filtrate through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (ethyl acetate/hexane, 30/70-60/40) to afford l-(4- aminobenzenesulfonyl)piperidin-4-one 0-(3-trifluoromethylbenzyl)oxime (471 mg, 95 %, pale yellow oil). To a solution of the free base in ethyl acetate, 47V-HC1 in ethyl acetate was added. The resulting precipitate was collected and dried in vacuo to give the title compound (417 mg, 63 %).
With hydrogenchloride; In dichloromethane; ethyl acetate;
EXAMPLE 67 N-(3-Hydroxy-2,2-dimethyl-propyl)-C-{4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-phenyl}-methanesulfonamide (Z-isomer) A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): delta0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI-MS: m/z 301 (M-H)-.
4-Nitrobenzyl sulfonyl chloride To a suspension of 28.3 g (118 mmol, 1.0 equiv.) of finely ground sodium 4-nitrobenzyl sulfonate in 250 mL of toluene was added 24.6 g (118 mmol, 1.0 equiv) of finely ground phosphorous pentachloride as the solid in portions. After addition the mixture was heated to reflux for one hour. The mixture was cooled, and volatile material was removed in vacuo. The residue was dissolved in 500 mL chloroform and 250 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 27.8 g (100%) of 4-nitrobenzyl sulfonyl chloride, pure by 1 H NMR.
27.8 g (100%)
In chloroform; water; toluene;
4-Nitrobenzyl sulfonyl chloride To a suspension of 28.3 g (118 mmol, 1.0 equiv.) of finely ground sodium 4-nitrobenzyl sulfonate in 250 mL of toluene was added 24.6 g (118 mmol, 1.0 equiv) of finely ground phosphorous pentachloride as the solid in portions. After addition the mixture was heated to reflux for one hour. The mixture was cooled, and volatile material was removed in vacuo. The residue was dissolved in 500 mL chloroform and 250 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 27.8 g (100%) of 4-nitrobenzyl sulfonyl chloride, pure by 1H NMR.
27.8 g (100%)
In chloroform; water; toluene;
4-Nitrobenzyl sulfonyl chloride. To a suspension of 28.3 g (118 mmol, 1.0 equiv.) of finely ground sodium 4-nitrobenzyl sulfonate in 250 mL of toluene was added 24.6 g (118 mmol, 1.0 equiv) of finely ground phosphorous pentachloride as the solid in portions. After addition the mixture was heated to reflux for one hour. The mixture was cooled, and volatile material was removed in vacuo. The residue was dissolved in 500 mL chloroform and 250 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 27.8 g (100%) of 4-nitrobenzyl sulfonyl chloride, pure by 1 H NMR.
4-Nitro-N,N-dimethylbenzenmethanesulfonamide Anhydrous dimethylamine was bubbled through 250 mL of cloroform at 0 C. for thirty minutes. A solution of 27.8 g (118 mmol, 1.0 equiv.) of 4-nitrobenzyl sulfonyl chloride was added dropwise at 0 C. An exothermic reaction ensued and the mixture was allowed to warm to room temperature. The mixture was concentrated in vacuo to yield 32.2 g of 4-nitro-N,N-dimethylbenzenemethanesulfonamide contaminated with dimethylamine hydrochloride. This mixture was taken on without purification.
With dimethyl amine; In chloroform;
4-Nitro-N,N-dimethylbenzenmethanesulfonamide Anhydrous dimethylamine was bubbled through 250 mL of chloroform at 0 C. for thirty minutes. A solution of 27.8 g (118 mmol, 1.0 equiv.) of 4-nitrobenzyl sulfonyl chloride was added dropwise at 0 C. An exothermic reaction ensued and the mixture was allowed to warm to room temperature. The mixture was concentrated in vacuo to yield 32.2 g of 4-nitro-N,N-dimethylbenzenemethanesulfonamide contaminated with dimethylamine hydrochloride. This mixture was taken on without purification.
With dimethyl amine;
4-Nitro-N,N-dimethylbenzenemethanesulfonamide. Anhydrous dimethylamine was bubbled through 250 mL of cloroform at 0 C. for thirty minutes. A solution of 27.8 g (118 mmol, 1.0 equiv.) of 4-nitrobenzyl sulfonyl chloride was added dropwise at 0 C. An exothermic reaction ensued and the mixture was allowed to warm to room temperature. The mixture was concentrated in vacuo to yield 32.2 g of 4-nitro-N,N-dimethylbenzenemethanesulfonamide contaminated with dimethylamine hydrochloride. This mixture was taken on without purification.
The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to give 4-nitrobenzyl sulphonyl chloride (48.9 g, 83%) which was pure by 1 H NMR. Methylamine gas was bubbled through a solution of 4-nitrobenzyl sulphonyl chloride (37.9 g, 0.16 mol), in dichloromethane (325 ml), until uptake had ceased (0.5 h). The resulting solid was filtered, washed with H2 and dried under vacuum to give the title-sulphonamide (32.5 g, 88%), delta(250MHz, D6 -DMSO) 2.61 (3H, s, Me), 4.55 (2H, s, CH2), 7.06 (1H, s, NH), 7.66 (2H, d, J=8.7Hz, Ar-H), 8.25 (2H, d, J=8.7Hz, Ar-H).
4-Nitro-N-(phenylmethyl)benzenemethanesulphonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane;
(a) 4-Nitro-N-(phenylmethyl)benzenemethanesulphonamide Benzylamine (0.8 ml) was added in one portion to a solution of <strong>[4025-75-6]4-nitrobenzenemethanesulphonyl chloride</strong> (0.6 g) in dichloromethane (50 ml) stirred at ambient temperature. A white solid precipitated at once. Stirring was continued for 1 h, solvent was evaporated and the residual solid washed with water (100 ml), ether (200 ml) and dried. The title compound was obtained as a white solid (0.64 g) m.p. 180-1. A sample (0.2 g) was recrystallized from hot ethanol (5 ml) to give analytically pure material as an off-white solid (0.15 g), m.p. 182-3.
4-Nitro-N-(2-propenyl)benzenemethanesulphonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane;
(a) 4-Nitro-N-(2-propenyl)benzenemethanesulphonamide 4-Nitrophenylmethanesulphonyl chloride (5.0 g) was added dropwise in dry dichloromethane (50 ml) to a stirred solution of allylamine (3.3 ml) in dry dichloromethane (50 ml) at room temperature under nitrogen over 15 min. Stirring was continued for 45 min. The mixture was washed with water (3*50 ml), dried (MgSO4) and the solvent evaporated to give a very pale yellow solid (5.22 g). A sample (0.26 g) was recrystallized from ethanol to give the title compound as very pale yellow needles (0.182 g), m.p. 118-120.5.
To a solution of 2-(3- nitrophenyl)acetyl chloride (1.0 mmol) in CHCI3 (5 mL), pyrrolidine (0.213 g, 3.0 mmol) was added. The resulting mixture was stirred for 4 h at rt. The mixture was concentrated onto silica and the residue was purified by column chromatography (Si02, EtOAc/Hexanes, 0-100%) to afford the title compound (0.20 g, 74%).
In dichloromethane; at 10℃;
4-nitrobenzylsulfonyl-pyrrolidine: Pyrrolidine (74.2 g, 1.05 mol) was added dropwise to a solution of (4-nitrophenyl)-methanesulfonyl chloride (98 g, 0.42 mol) in dichloromethane (150 mL) at 10 C. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, concentrated and recrystallized from ethanol and dichloromethane to give the title compound. 1H-NMR (300 MHz, CDCl3) delta 1.86(m, 4H), 3.22 (t, J=6.6 Hz, 4H), 4.32 (s, 2H), 7.59 (d, J=8.7 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H).
To a solution of (S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner to that described in Scheme 1, Step 1-2) (243 mg, 0.509 mmol) dissolved in pyridine (1 mL), cooled at 0 C., <strong>[4025-75-6](4-nitrophenyl)methanesulfonyl chloride</strong> (100 mg, 0.424 mmol) was added. The mixture was stirred at 0 C. for 2 hours. The mixture was then diluted with EtOAc and washed with HCl 0.1N, NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((4-nitrophenyl)methyl-sulfonamido)acetoxy)ethyl)pyridine 1-oxide was obtained (287 mg, 0.42 mmol, quantitative yield).
(S)-4-(2-(2-((4-aminophenyl)methylsulfonamido)-acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide[ No CAS ]
To a solution of (S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner to that described in Scheme 1, Step 1-2) (243 mg, 0.509 mmol) dissolved in pyridine (1 rnL), cooled at 0C, <strong>[4025-75-6](4-nitrophenyl)methanesulfonyl chloride</strong> (100 mg, 0.424 mmol) was added. The mixture was stirred at 0C for 2h. The mixture was then diluted with EtOAc and washed with HCl O. IN, NaHC03 sat. sol. and brine. The organic phase was dried over Na2S04 and the solvent was evaporated. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2- ((4-nitrophenyl)methylsulfonamido)acetoxy)ethyl)pyridine 1 -oxide was obtained (287 mg, 0.42 mmol, quantitative yield).
With tert-butylhypochlorite; In water; acetonitrile; at 0 - 20℃;
General procedure: Alkyl halide (or sulfate) (5 mmol) and thiourea (0.381 g, 5 mmol) were heated at reflux in EtOH (5 mL) for 1 h. After removal of the solvent in vacuum and washing with Et2O (3 × 5 mL), the corresponding S-alkyl isothiourea salt was obtained as a white solid in almost quantitative yield. Without purification, the product was transferred into a three-necked round-bottom flask equipped with a thermometer and an addition funnel in an ice-bath, followed by addition of water (0.45mL) and MeCN (10 mL). To the resultant vigorously stirred mixture was added dropwise a solution of t-BuOCl (2.86 mL) in MeCN (5 mL), keeping the inner temperature at 0-20 C. The mixture was then stirred for 30 min. Removal of the solvent under vacuum, addition of Et2O (15 mL), washing with H2O (2 × 10 mL), drying over Na2SO4, and concentration under vacuum gave the desired product in high purity. The product was further purified by recrystalization from petroleum ether-EtOAc.
0.636 g
With hydrogenchloride; sodium chlorite; In acetonitrile; at 10 - 20℃; for 0.5h;Green chemistry;
General procedure: Step 1. An alkyl halide or mesylate (5 mmol) and thiourea (0.381 g, 5 mmol) wererefluxed in 5 mL of ethanol for 1 h. After removal of the solvent in vacuum thecorresponding S-alkyl isothiourea salt was obtained as white solid or sticky oil.Step 2. A 50 mL three-necked flask equipped with a thermometer and asolid-addition funnel was immersed in an ice-bath. To the flask was sequentiallyadded NaClO2 solid (for isothiouronium chlorides or sulfonate, 1.61 g, 15 mmol; forisothiouronium bromides, 2.14 g, 20 mmol, 85% purity), MeCN (10 mL), and thenconc. HCl (for isothiouronium chlorides or sulfonate, 3 mL; for isothiouroniumbromides, 4 mL) during 1 min at such a rate that the inner temperature was maintainedless than 10 C. Then S-alkyl isothiourea salt was slowly added througth the solidaddition-funnel to keep the inner temperature less than 20 C. After the addtion, theresulting mixture was stirred for another 30 min. Then 25 mL of water was added, and the resultant mixture was evaporated in vacuum at 15 C to remove acetonitrile. Afteraddition of 100 mL of water, the solid products were obtained by filtration on aBuchner funnel and dried under an infrared lamp, while the liquid products wereobtained by extraction with 15 mL of ethyl acetate, drying with Na2SO4, andconcentration in vacuum.For 1,4-dibromobutane, the amounts of thiourea, NaClO2 solid, MeCN, and conc.HCl were doubled.
1.001 g
With sodium hypochlorite; sulfuric acid; In diethyl ether; water; at 0 - 20℃; for 0.5h;Green chemistry;
General procedure: The appropriate alkyl halide (or mesylate) (5 mmol) and thiourea (0.381 g, 5 mmol) were refluxed in EtOH (5 mL) for 1 h. After removal of the solvent in vacuum and washing with Et2O (3 × 5 mL), the corresponding S-alkyl isothiourea salt was obtained as a white solid or sticky oil in an almost quantitative yield. Without purification, the product was transferred into a three-necked round-bottomed flask equipped with a thermometer and an addition funnel in an ice-bath. Then, 6 M H2SO4 (2 mL), followed by Et2O (30 mL) were added. To the resultant vigorously stirred mixture was added dropwise 5% bleach (for alkyl chlorides and mesylates, 30 mL; foralkyl bromides, 37.5 mL) by keeping the inner temperature 0-20 C (for the preparation of alkanedisulfonyl dichlorides, 0.762 g, 10 mmol thiourea, 4 mL of 6 M H2SO4, 50 mL of Et2O, and 75 mL of 5% bleach were used). After the addition, the mixture was stirred for another 30 min. The mixture was partitioned in a separatory funnel, and the ethereal phase was washed with brine (25 mL), dried (Na2SO4), and evaporated in vacuum to afford the desired product. The oily products were extracted with CHCl3 (3 × 2.5 mL) and evaporated to remove the by-product, bromine. If necessary, the products can be dissolved in minimal PE-EtOAc (5:1) and filtered through a column of silica gel (h = 5 cm) with PE-EtOAc (5:1) as eluent to remove the impurities (Table 2).
ethyl 1-((4-nitrobenzyl)sulfonyl)piperidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With NMM or DIPEA; In dichloromethane; at 0℃;
General procedure: General procedure for the synthesis of compounds 3a, e-g Compound 2 (1 equiv) was dissolved in 40 mL of anhydrous CH2Cl2, and NMM or DIPEA (3 equiv) was added at 0 C followed by the corresponding carbonyl or sulfonyl chloride (1 equiv). The mixture was stirred until completion of the reaction (TLC control) and subsequently washed with 4 * 30 mL 2 M HCl and H2O. The organic layer was dried over anhydrous Na2SO4, and the solvent was removed in vacuo. If necessary, a subsequent purification by flash-chromatography was performed to obtain compounds 3a, e-g. The preparation of 1-(Benzylsulfonyl)piperidine-2-carboxylate (3a) and (S)-1-(Benzylsulfonyl)piperidine-2-carboxylate (S-3a) has already been described. 30
With triethylamine; In 1,2-dichloro-ethane; at 60℃; for 2.52h;
10 ml of the product <strong>[4025-75-6]p-nitrophenylmethanesulfonyl chloride</strong> system was added to step 1, 11.1 g (0.11 mol) of triethylamine was added, and 7.37 g (0.11 mol) of pyrrole was dissolved in 10 ml of dichloroethane. The p-nitrobenzenemethanesulfonyl chloride system was added dropwise, and after 30 minutes of dropwise addition, the reaction was kept at 60 C for 2.52 h. TLC detection, unfolding phase (ethyl acetate: petroleum ether = 4:1), after the reaction is completed, the system is allowed to cool, then extracted 2-3 times with water, and extracted 2-3 times with saturated sodium hydrogencarbonate. The extract was extracted 2-3 times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, and evaporated to give a pale yellow solid, which was dried to give 25.4 g, yield 94%;
4-(1-cyclopropyl-6-fluoro-3-(((7-(((4-nitrobenzyl)sulfonyl)oxy)-2-oxo-2H-chromen-3-yl)methoxy)carbonyl)-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-ium trifluoroacetate[ No CAS ]
N-(4-fluorobenzyl)-1-(4-nitrophenyl)methanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.4%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h;
4.1.49. 1-(4-((N-(4-filuorobenzyl)sulfiamoyl)methyl)phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (20aa)
Step 1. To a stirred solution of (4-fluorophenyl)methanamine (626mg, 5 mmol) in anhydrous THF (30 mL) was added triethylamine (1.01g, 10 mmol) and cooled to 0 °C in an ice bath. Then (4-nitrophenyl)methanesulfonyl chloride (21, 1.18 g, 5 mmol) in anhydrous THF (30mL) was added dropwise into the cold solution and the mixture wasallowed to warm to room temperature. After 2 h, the mixture was diluted with EA (100 mL) and washed with 1 M HCl (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give N-(4-fluorobenzyl)-1-(4-nitrophenyl)methanesulfonamide (22a, 1.27 g, 78.4%), which was used in the next step without further purification.
78.4%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h;
4.1.49. 1-(4-((N-(4-filuorobenzyl)sulfiamoyl)methyl)phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (20aa)
Step 1. To a stirred solution of (4-fluorophenyl)methanamine (626mg, 5 mmol) in anhydrous THF (30 mL) was added triethylamine (1.01g, 10 mmol) and cooled to 0 °C in an ice bath. Then (4-nitrophenyl)methanesulfonyl chloride (21, 1.18 g, 5 mmol) in anhydrous THF (30mL) was added dropwise into the cold solution and the mixture wasallowed to warm to room temperature. After 2 h, the mixture was diluted with EA (100 mL) and washed with 1 M HCl (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give N-(4-fluorobenzyl)-1-(4-nitrophenyl)methanesulfonamide (22a, 1.27 g, 78.4%), which was used in the next step without further purification.
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