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CAS No. : | 63624-28-2 | MDL No. : | MFCD00060683 |
Formula : | C8H9ClO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AYGZKRRIULCJKC-UHFFFAOYSA-N |
M.W : | 236.67 | Pubchem ID : | 2734626 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 52.51 |
TPSA : | 60.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.65 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 1.54 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 0.97 |
Log Po/w (SILICOS-IT) : | 1.34 |
Consensus Log Po/w : | 1.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.4 |
Solubility : | 0.949 mg/ml ; 0.00401 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.43 |
Solubility : | 0.88 mg/ml ; 0.00372 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.2 |
Solubility : | 0.149 mg/ml ; 0.00063 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.29 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P280-P303+P361+P353-P301+P330+P331-P304+P340+P310-P305+P351+P338+P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
66% | With triethylamine;dmap; In dichloromethane; at 20℃; for 24h; | Example 199; 1 -(2,4-Dimethoxybenzensulfonyl)-2-oxo-3-{2-oxo-1 -phenyl-2-[(S)-3-(4- propylpiperazin-1 -yl)pyrrolidin-1 -yl]ethyl}-2,3-dihydro-1 H-benzimidazole-5- carbonitrile; To a solution of 2-oxo-3-{2-oxo-1-phenyl-2-[(S)-3-(4-propyl-piperazin-1-yl)-pyrrolidin- 1-yl]-ethyl}-2,3-dihydro-1 H-benzoimidazole-5-carbonitrile (32 mg, 0.07 mmol), triethylamine (0.02 ml_, 0.13 mmol) and DMAP (catalytic amount) in CH2CI2 (2 ml.) 2,4-dimethoxybenzenesulfonyl chloride (17 mg, 0.077 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, diluted with water and extracted the aqueous phase with CH2CI2 (3 x). The combined organic phase was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 4% methanol in CH2CI2 as eluent to afford 1-(2,4-dimethoxy- benzenesulfonyl)-2-oxo-3-{2-oxo-1-phenyl-2-[(S)-3-(4-propyl-piperazin-1-yl)- pyrrolidin-1-yl]ethyl}-2,3-dihydro-1 H-benzoimidazole-5-carbonitrile (29 mg, 66%) as a white solid. 1H-NMR (400 MHz, CDCI3): delta 0.88-0.94 (m, 3H), 1.28 (m, 2H), 1.84 (m, 1 H), 2.14 (m, 1 H), 2.25-2.59 (m, 9H), 2.79-3.12 (m, 2H), 3.23-3.58 (m, 2H), 3.48 (s, 3H), 3.73- <n="156"/>3.99 (m, 2H), 3.89 (s, 3H), 6.36-6.44 (m, 2H), 6.65 (d, 8.9 Hz, 1 H), 7.00-7.10 (m, 1 H), 7.22-7.26 (m, 2H), 7.34-7.39 (m, 4H), 7.94 (d, 8.5 Hz, 1 H), 8.14 (d, 8.9 Hz, 1 H). MS (API-ES, pos) m/z = 673 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h; | A stirred solution of 1- (2', 4, 4'-trifluoro-1, 1'-BIPHENYL-2-YL) ethylamin (0.71 g, 2.84 MMOL) in DICHLOROMETHANE (5 mL) was treated with 2,4- DIMETHOXYBENZENESULFONYL chloride (0.71 g, 3.0 MMOL), and N, N-diisopropylethylamine (0. 77 g, 6.0 MMOL). The reaction was stirred at room temperature for twelve hours, and the solvent was evaporated in vacuo to a crude oil. The crude oil was purified by preparative liquid chromatography on a BIOTAGE 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 50% methyl TEFF-BUTYL ether in hexane at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from ethyl acetate-hexane yielded the title compound (0.93 g, 2.07 mmol, 73%) as a homogeneous, colorless, crystalline solid, m. p. 192- 194C ; MS [ (+ESI), M/Z] : 452 [M+H] + ; MS [(-ESI), M/Z] : 450 [M-H]- ; IR (Solid), A : 3281,1592, 1470,1421, 1319,1136, 1022,817, 681 CM~1 ; 1H NMR (400 MHz, DMSO-d6) 6 : 1.18 (d, J = 6.7 Hz, 3H), 3.79 (s, 6H), 4.05 (m, 1 H), 6.36-6. 56 (m, 2H), 6.98-7. 14 (m, 3H), 7.22 (broad t, 1 H), 7. 26-7.42 (m, 3H), 7.81 (broad d, J = 8.0 Hz, 1 H), exists as approximately 1: 1 mixture of rotamers; Anal. calcd for C22H2OF3NO4S : C, 58.53 ; H, 4.47 ; N, 3.10. Found: C, 58.52 ; H, 4.45 N, 3.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 2h; | Example 5 (-)-(2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide Sodium hydride (14.4 mg of 60% dispersion in mineral oil, 0.36 mmol) was added to an ice-cold solution of the more polar diastereomer product from step C (150 mg, 0.35 mmol) in DMF (3.2 ml). The reaction mixture was stirred at 0 C. for 1 h and then 2,4-dimethoxyphenylsulfonyl chloride (86.2 mg, 0.364 mmol) was added. After the reaction mixture had been stirred at room temperature for one hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) and trituration with diethyl ether (6 ml) and hexane (6 ml) resulted in 130 mg of the (-) diastereomer as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In DMF (N,N-dimethyl-formamide); at 0℃; for 1.5h; | Potassium tert-butoxide (1.21 g, 10.8 mmol) was added to an ice-cold solution of the product from step A (3.00 g, 10.8 mmol) in DMF (30 ml), and the mixture was stirred at 0 C. for 30 min. After addition of 2,4-dimethoxyphenylsulfonyl chloride (2.5 g, 10.8 mmol), the reaction mixture was left to stir at 0 C. for 1 hour. Further addition of 0.2 equivalent each of potassium tert-butoxide and sulfonyl chloride led to no further advance in the reaction according to thin-layer chromatography. The reaction mixture was stirred into dilute potassium carbonate solution, and the resulting precipitate was filtered off. The precipitate was taken up in ethyl acetate, and the extract was washed with saturated brine and dried over MgSO4. Purification by chromatography (silica gel, gradient 30% to 50% ethyl acetate in heptane) and recrystallization from diethyl ether resulted in 0.96 g of the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 2h; | Example 1 (+)-(2S, 4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide Sodium hydride (12 mg of 60% dispersion in mineral oil, 0.3 mmol) was added to an ice-cold solution of the less polar diastereomer product from step C (115 mg, 0.25 mmol) in DMF (1.5 ml). The reaction mixture was stirred at 0 C. for 1 h and then 2,4-dimethyoxyphenylsufonyl chloride (71 mg, 0.3 mmol) was added. After the reaction mixture had been stirred at room temperature for one hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 93 mg of Example 1 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1.5h; | D) (2S, 4R)-1-[5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2,4-dimethoxypyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-carboxylic acid dimethylamide Sodium hydride (12 mg of 60% dispersion in mineral oil, 0.3 mmol) was added to an ice-cold solution of the mixture of diastereomers from step C (139 mg, 0.30 mmol) in DMF (1.5 ml). The reaction mixture was stirred at 0 C. for 0.5 h and then 2,4-dimethoxyphenylsulfonyl chloride (71 mg, 0.3 mmol) was added. After the reaction mixture had been stirred at room temperature for one hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 63 mg of the less polar diastereomer ((-) isomer) and 25 mg of the more polar diastereomer ((+) isomer) as colorless waxes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.00 g of isomer B obtained in step 1-4 was added under ice cooling to a 20 mL dimethylformamide solution of 0.215 g of sodium hydride under a nitrogen atmosphere, and the reaction mixture was stirred for 40 minutes. 5 mL dimethylformamide solution of 1.27 g of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise to the reaction mixture. The reaction mixture was stirred for 35 minutes at the same temperature, after which 50 mL of chloroform and 50 mL of a 5% potassium carbonate aqueous solution were added, and the reaction mixture was stirred for another 1 hour at room temperature. After liquid separation, the aqueous layer was extracted with chloroform (15 mL × 2), and the combined organic layer was dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 3.74 g of residue (amorphous, pale yellow). The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane = 1/1; v/v) to obtain 2.30 g of the titled compound (amorphous, colorless amorphous). [alpha]D28 =-199 (c =0.590, chloroform) MS (ESI pos.) m/z : 654([M+Na]+) 1 H-NMR (300 MHz, CDCl3) delta (ppm); 1.87 - 3.94 (m, 4 H), 2.33 (s, 3 H), 2.76 (s, 3 H), 3.56 - 3.79 (m, 6 H), 3.86 (s, 3 H), 4.76 - 5.00 (m, 1 H), 5.15 - 5.43 (m, 1 H), 6.43 (d, J=2.2 Hz, 1 H), 6.58 - 6.64 (m, I H), 6.78 (d, J=8.4 Hz, I H), 6.92 - 7.00 (m, 1 H), 7.07 (brs, 1 H), 7.20 - 7.31 (m, 2 H), 7.72 - 7.81 (m, 1 H), 7.92 (d, J=8.7 Hz, 1 H), 8.16 (d, J=8.9 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg of the diastereoisomer mixture obtained in step 9-3 was added under ice cooling to a suspension of 18 mg of sodium hydride in 2 mL of N,N-dimethylformamide under a nitrogen atmosphere, and the reaction mixture was stirred for 1 hour at the same temperature. 107 mg of 2,4-dimethoxybenzenesulfonyl chloride was added and the reaction mixture was stirred for 30 minutes at the same temperature, after which 30 mL of ethyl acetate and 20 mL of a 5% potassium carbonate aqueous solution were added, and the reaction mixture was stirred for 15 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (20 mL × 2), the combined organic layer was dried with magnesium sulfate, the drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain 300 mg of residue (brown oily substance). The residue thus obtained was separated and purified by column chromatography (silica gel 60N, mobile phase: ethyl acetate/acetone = 3/1; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 30 mg (isomer A: reddish-brown, amorphous) and 27 mg (isomer B: reddish-brown, amorphous). Isomer A: [alpha]D28 = -169 (c = 0.111, chloroform) MS (ESI pos.) m/z : 710 ([M+Na]+) 1 H-NMR (300 MHz, CDCl3) delta (ppm) ; 1.85 - 5.44 (m, 9 H), 2.38 (s, 3 H), 2.78 (s, 3 H), 3.64 (s, 3 H), 3.75 (s, 3 H), 3.77 (s, 3 H), 3.86 (s, 3 H), 3.95 (s, 3 H), 6.34 (d, J=2.3 Hz, 1 H), 6.40 - 6.48 (m, 2 H), 6.55 - 6.63 (m, 2 H), 7.62 - 7.69 (m, 2 H), 8.16 (d, J=9.0 Hz, 1 H) Isomer B: [alpha]D28 = +177 (c = 0.104, chloroform) MS (ESI pos.) m/z : 710 ([M+Na]+) 1 H-NMR (300 MHz, CDCl3) delta (ppm); 1.76 - 2.03 (m, 1 H), 2.10 - 2.26 (m, 1 H), 2.53 - 2.56 (m, 3 H), 2.63 (s, 3 H), 3.22 (s, 3 H), 3.31 - 3.52 (m, 1 H), 3.62 - 4.01 (m, 1 H), 3.70 (s, 3 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 3.87 (s, 3 H), 3.95 (s, 3 H), 4.08 - 4.16 (m, 1 H), 4.97 - 5.20 (m, 1 H), 6.29 (d, J=2.3 Hz, 1 H), 6.41 (s, 1 H), 6.49 (d, J=2.3 Hz, 1 H), 6.56 - 6.65 (m, 2 H), 7.61 (s, 1 H), 8.04 (d, J=8.6 Hz, 1 H), 8.23 (d, J=9.0 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
620 mg of the compound obtained in step 15-1 (diastereoisomer mixture) was added under ice cooling and a nitrogen atmosphere to a 10 mL N,N-dimethylformamide solution of 67 mg of sodium hydride, and the reaction mixture was stirred for 40 minutes. After this, a 2 mL N,N-dimethylformamide solution of 400 mg of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise. The reaction mixture was stirred for 30 minutes at the same temperature, after which 5 mL of ethyl acetate and 10 mL of a 5% potassium carbonate aqueous solution were added, and the reaction mixture was stirred at room temperature overnight. The precipitated solids were filtered off and separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/acetone = 99/1; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 184 mg (isomer A: colorless, amorphous) and 256 mg (isomer B: colorless, amorphous). Isomer A: [alpha]D25 = -225 (c = 0.187, chloroform) MS (ESI pos.) m/z : 612([M+H]+), (ESI pos.) m/z : 634([M+Na]+) 1 H-NMR (499 MHz, CDCl3) delta (ppm) ; 1.53 - 1.62 (m, 1 H), 1.85-1.98 (m, 1 H), 2.18 - 2.32 (m, 7 H), 2.75 (s, 3 H), 3.10-3.25 (m, 1 H), 3.55-3.86 (m, 9 H), 4.89-5.01 (br, 1 H), 5.21 - 5.39 (m, 1 H), 6.40 (d, J=1.8 Hz, 1 H), 6.58 (dd, J=9.0, 2.3 Hz, 1 H), 6.76 (d, J=7.9 Hz, 1 H), 6.85 - 6.97 (m, 2 H), 7.07 (dd, J=8.5, 1.2 Hz, 1 H), 7.17 - 7.24 (m, 1 H), 7.74 - 7.84 (m, 2 H), 8.15 (d, J=8.8 Hz, 1 H) Isomer B: [alpha]D25 =+142 (c = 0.240, chloroform) MS (ESI pos.) m/z : 612([M+H]+), (ESI pos.) m/z : 634([M+Na]+) 1 H-NMR (499 MHz, CDCl3) delta (ppm) ; 1.81 - 1.96 (m, 1 H), 2.11 - 2.23 (m, 4 H), 2.46 (s, 3 H), 2.62 (s, 3 H), 3.24 (s, 3 H), 3.36 - 3.49 (m, 1 H), 3.73 - 3.87 (m, 7 H), 4.06-4.11 (m, 1 H), 5.00 - 5.15 (m, 1 H), 6.47 (d, J=2.4 Hz, 1 H), 6.60 (dd, J=9.0, 2.3 Hz, 1 H), 6.66 - 6.73 (m, 2 H), 7.03 - 7.10 (m, 2 H), 7.18 - 7.24 (m, 1 H), 7.81 (d, J=8.2 Hz, 1 H), 8.15-8.25 (m, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
301 mg of the compound obtained in step 16-2 (diastereoisomer mixture) was added under ice cooling and a nitrogen atmosphere to a 3 mL tetrahydrofuran solution of 26 mg of sodium hydride, and the reaction mixture was stirred for 20 minutes. After this, a 2 mL tetrahydrofuran solution of 170 mg of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise, and the reaction mixture was stirred for 2 hours at room temperature. Then 5mL of ethylacetate and 10mL of a 5% potassium carbonate aqueous solution were added and the reaction mixture was stirred for 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (10 mL × 3), and the combined organic layer was dried with sodium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/acetone = 99/1; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 115 mg (isomer A: colorless, amorphous) and 127 mg (isomer B: colorless, amorphous). Isomer A: [alpha]D25 = -248 (c = 0.183, chloroform) MS (ESI pos.) m/z : 680([M+H]+), (ESI pos.) m/z : 702([M+Na]+ 1H-NMR (499 MHz, CDCl3) delta (ppm) ; 1.89 (s, 1 H), 2.19 - 3.94 (m, 21 H), 4.65 - 5.06 (m, 1 H), 5.23 - 5.44 (m, 1 H), 6.43 (s, 1 H), 6.57 (dd, J =9.0, 2.3 Hz, 2 H), 6.97 - 7.05 (m, 1 H), 7.42 (d, J=8.8 Hz, 1 H), 7.75 (s, 1 H), 7.93 (d, J=8.5 Hz, 1 H), 8.09 - 8.20 (m, 1 H) Isomer B: [alpha]D25 = +211 (c = 0.200, chloroform) MS (ESI pos.) m/z : 680([M+H]+), (ESI pos.) m/z : 702([M+Na]+) 1 H-NMR (499 MHz, CDCl3) delta (ppm) ; 1.88 - 2.23 (m, 2 H), 2.33 (s, 3 H), 2.55 - 2.81 (m, 6 H), 3.36 (s, 3 H), 3.47 - 3.63 (m, 1 H), 3.79 - 3.88 (m, 7 H), 4.07 - 4.19 (m, 1 H), 4.95 - 5.19 (m, 1 H), 6.48 (d, J=2.1 Hz, 1 H), 6.57 (dd, J=8.8, 2.1 Hz, 1 H), 6.63 (d, J=8.2 Hz, 1 H), 6.99 - 7.07 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.67 (s, 1 H), 7.92 - 8.01 (m, 1 H), 8.13 (d, J=8.8 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
353 mg of the compound obtained in step 18-1 (mixture of diastereoisomers) was added under ice cooling and a nitrogen atmosphere to a suspension of 35 mg of sodium hydride in 3 mL of tetrahydrofuran, and the reaction mixture was stirred for 20 minutes. After this, a 2 mL tetrahydrofuran solution of 219 mg of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise. The reaction mixture was stirred for 2 hours at the same temperature, after which 5 mL of ethyl acetate and 10 mL of a 5% potassium carbonate aqueous solution were added, and the reaction mixture was stirred for 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (10 mL × 3), and the combined organic layer was dried with sodium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain two kinds of diastereoisomer of the titled compound in amounts of 191 mg (isomer A: colorless, amorphous) and 75 mg (isomer B: colorless, amorphous). Isomer A: [alpha]D25 = -222 (c = 0.176, chloroform) MS (ESI pos.) m/z : 646([M+H]+), (ESI pos.) m/z : 668([M+Na]+) 1 H-NMR (499 MHz, CDCl3) delta (ppm) ; 1.99 - 2.24 (m, 2 H), 2.43 (s, 3 H), 2.66 - 2.76 (m, 4 H), 3.52 - 3.63 (m, 4 H), 3.86 (s, 3 H), 4.77 - 4.82 (m, 1 H), 5.14 - 5.30 (m, 1 H), 5.51 - 5.63 (m, 2 H), 6.40 (d, J=2.1 Hz, 1 H), 6.60 (dd, J=8.8, 2.4 Hz, 1 H), 6.67 - 6.71 (m, 1 H), 6.73 - 6.79 (m, 1 H), 7.07 (dd, J=8.2, 1.2 Hz, 1 H), 7.28 (dd, J=8.8, 2.4 Hz, 1 H), 7.41 (d, J=2.4 Hz, 1 H), 7.91 (d, J=8.8 Hz, 1 H), 8.18 (d, J=9.1 Hz, 1 H) Isomer B: [alpha]D25 = +157 (c = 0.185, chloroform) MS (ESI pos.) m/z : 668([M+Na]+) 1 H-NMR (499 MHz, CDCl3) delta (ppm) ; 1.88 - 2.03 (m, 1 H), 2.22 - 2.33 (m, 1 H), 2.55 (s, 3 H), 2.70 (s, 3 H), 3.40 - 3.53 (m, 1 H), 3.57 (s, 3 H), 3.75 - 3.89 (m, 4 H), 4.04 (dd, J=9.5, 6.7 Hz, 1 H), 5.06-5.24 (m, 2 H), 5.41 (d, J=1.5 Hz, 1 H), 6.42 (d, J=2.1 Hz, I H), 6.59 (dd, J=9.0, 2.2 Hz, 1 H), 6.69 (dd, J=7.9, 1.2 Hz, 1 H), 6.83 - 6.91 (m, 1 H), 7.07 (d, J=2.4 Hz, 1 H), 7.28 (dd, J=8.8, 2.4 Hz, 1 H), 7.51 (d, J=7.0 Hz, 1 H), 7.93 (d, J=8:8 Hz, 1 H), 8.20 (d, J=8.8 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | To the suspension obtained were added drop by drop and at room temperature 69.5 g (0.583 mole) of thionyl chloride. After standing overnight, the mixture was poured onto crushed ice. The white precipitate obtained was drained, washed abundantly with water then dried under phosphoric vacuum. Yield 75% mp 72 C. (litt. 70.5 C.). | |
(I): R1=CH3; R2=6-CH3; R3=2-Cl; R4=H; R5=-N(CH3)2; R6=2-OCH3; R7=OCH3; n=2; W=O This compound is prepared according to the procedure described in Example 11, starting with the compound obtained in Preparation 3.61 (racemic isomer B). The product is chromatographed on silica gel, eluding with a DCM/MeOH mixture (98/2; v/v). The expected product is obtained after crystallization from a DCM/iso ether mixture; m.p.=268-270 C. Working according to the procedures described in the above examples, starting with the compounds of formula (II) described in Preparations 3 and 2,4-dimethoxybenzenesulphonyl chloride, the compounds according to the invention collated in Table I below are prepared. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 114 5-Chloro-3-(3-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-2H-benzimidazol-2-one A solution of 2 g of 5-chloro-3-(3-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one in 170 ml of THF is cooled to -40 C. and 0.97 g of potassium tert- butylate is added. The mixture is stirred for 30 minutes at -10 C. and then cooled to -50 C. and a solution of 1.7 g of 2,4-dimethoxybenzenesulfonyl chloride in 70 ml of THF is added. The reaction mixture is stirred for 2 hours, the temperature being allowed to rise to RT, and then concentrated under vacuum. The residue is taken up with water, extracted with DCM and dried over Na2 SO4 and the solvent is evaporated off under vacuum to give 2.3 g of the expected product after crystallization from a cyclohexane/DCM mixture (90/10; v/v). M.p.=173 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 3-Amino-5-chloro-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-phenylindol-2-one A solution of 0.3 g of 3-amino-5-chloro-1,3-dihydro-3-phenylindol-2-one in 7 ml of DMF is cooled to 0 C. under an argon atmosphere and 0.037 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 20 minutes, 0.275 g of 2,4-dimethoxybenzenesulfonyl chloride is added and the reaction mixture is stirred overnight, the temperature being allowed to rise to RT. It is poured into water, extracted with AcOEt, washed with water and with a saturated solution of NaCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether/hexane mixture. m=0.31 g. M.p.=108-110 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 33 5-Ethoxy-1,3-dihydro-3-[2-(N,N-diisopropylamino)ethyl]-1-(2,4-dimethoxybenzenesulfonyl)-2H-benzimidazol-2-one 0.05 g of sodium hydride as a 60% dispersion in oil is added in portions to a solution of 0.5 g of 5-ethoxy-1,3-dihydro-3-[2-(N,N-diisopropylamino)ethyl]-2H-benzimidazol-2-one in 7 ml of THF and the mixture is stirred for 30 minutes at RT. 0.42 g of 2,4-dimethoxybenzenesulfonyl chloride is then added and the mixture is stirred for 1 hour at RT. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with AcOEt, washed with water and dried over Na2 SO4 and the solvent is evaporated off under vacuum to give 0.7 g of the expected product after crystallization from iso ether. M.p.=132 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3 3-Amino-5-chloro-3-(2-chlorophenyl)-1,3-di-hydro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one This compound is prepared according to the procedure described in EXAMPLE 1 from 0.315 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 0.256 g of 2,4-dimethoxybenzenesulfonyl chloride. This gives the expected product after crystallization from a DCM/iso ether mixture. m=0.300 g. M.p.=179-180 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 86 5-Ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-phenylindol-2-one This compound is prepared according to the procedure described in EXAMPLE 1 from 0.500 g of 5-ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-3-phenylindol-2-one and 0.280 g of 2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=0.383 g. M.p.=228-229 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 88 3-Amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one This compound is prepared according to the procedure described in EXAMPLE 1 from 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/hexane/iso ether mixture. M.p.=196-198 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 205 5-Chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(methylamino)indol-2-one This compound is prepared according to the procedure described in EXAMPLE 1 from 0.25 g of 5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-3-(methylamino)indol-2-one and 0.165 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.075 g of the expected product is obtained after crystallization and recrystallization from a DCM/iso ether mixture. M.p.=183-185 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 50℃; for 16h; | 2,4-Dimethoxyphenylsulfonyl chloride CJ. Med. Chem.. 1977, 20, 1235; 376 mg) was added to a stirred solution of 7V-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-l,3-thiazol- 2-yl]acetamide (150 mg) in pyridine (1.5 niL) and the resultant solution was heated at 500C for16 hours. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by preparative HPLC on Kromasil Cl 8 reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent at a flow rate of about 10 mL/minute. The material so obtainedwas triturated under diethyl ether to give the title compound as a white solid (70 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H),2.29 (s, 3H), 3.76 (s, 3H), 3.83 (s, 3H), 6.60 (m, IH), 6.69 (d, IH), 9.64 (d, IH), 6.75 (d, IH),8.25 (br s, IH), 9.80 (s, IH); Mass Spectrum: M+H+ 483. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | 1e) 3-Amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2- oxoindoline-5-carbonitrile; 3.54 g (12.03 mmol) of 3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile were dissolved in 80 ml of anhydrous dimethylformamide (dried over molecular sieve). Under an atmosphere of nitrogen and with cooling using an ice-bath, 1.49 g (13.23 mmol) of potassium te/f-butoxide were added a little at a time. The colour of the reaction mixture changed, and the brown solution was stirred at 00C for another hour to ensure that the deprotonation proceeded to completion. At low temperature, 3.16 g (13.23 mmol) 2,4- dimethoxybenzenesulphonyl chloride were added, and the mixture was stirred at 00C for another two hours. The course of the reaction was monitored by TLC (silica gel, dichloromethane/methanol in a ratio of 9:1 ). The reaction mixture was poured into ice- water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was evaporated. The residue was suspended in diethyl ether and stirred until the product precipitated as a solid and could be removed by filtration. After removal of the solvent, the mother liquor was once more treated with diethyl ether (2 x) until finally, after drying, 4.67 g (9.44 mmol, 79%) of the desired 3-amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2- <n="18"/>ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile were obtained as a solid substance.ESI-MS [M+H+] = 495.15 Calculated for C24H22N4O6S = 494.53 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-Chloro-1-(2,4-dimethoxy-benzenesulphonyl)-3-(2-methoxyphenyl)-3-(4-pyridin-3-yl-piperazin-1-yl)-1,3-dihydro-indol-2-one; Sodium hydride (10.8 mg, 60% dispersion in mineral oil, 0.27 mmol) was added to a solution of 5-chloro-3-(2-methoxyphenyl)-3-(4-pyridin-3-yl-piperazin-1-yl)-1,3-dihydro-indol-2-one (1494-71) (90.0 mg, 0.21 mmol) in THF (7 mL) at 0 C. After 1 hour, 2,4-dimethoxybenzenesulphonic acid chloride (49.0 mg, 0.21 mmol) was added to the reaction solution, with ice cooling, and stirred for 12 h at room temperature. Water was carefully added to the preparation and it was then extracted twice with ethyl acetate. The combined organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated at reduced pressure. The residue was purified by silica-gel chromatography (solvent gradient 0-7% methanol in dichloromethane).Yield: 99.0 mg.ESI-MS: 638.15; 637.15; [M+H+]=636.15; 635.15; 472.10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 1.64 g of the compound obtained in the preceding step in 20 ml of DMF is cooled to 4 C., 0.25 g of 60% sodium hydride in oil is added and the mixture is stirred at 4 C. for 30 minutes. 1.34 g of 2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture is stirred at RT for 4 hours. 50 ml of water are added to the reaction mixture, the resulting mixture is extracted with EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture (97/3; v/v). 2 g of the expected product are obtained after crystallization from a DCM/iso ether mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B) 5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one. 0.08 g of 60% sodium hydride in oil is added, at 20 C., to a mixture of 0.7 g of the compound obtained in the preceding step in 15 ml of THF, and the mixture is stirred for 20 minutes. 0.44 g of 2,4-dimethoxy-benzenesulphonyl chloride is then added and the mixture is stirred for 1 hour 30 minutes.The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum.The residue is chromatographed on silica gel, eluding with DCM and then-with EtOAc and with acetone. 0.7 g of the expected product is obtained after crystallization from iso ether, m.p.=136-141 C. (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B) 5-Chloro-3-(2-ethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one 0.085 g of 60% sodium hydride in oil is added to a mixture of 0.9 g of the compound obtained in the preceding step in 20 ml of a THF/DMF mixture (90/10; v/v), and the mixture is stirred at RT for 15 minutes. 0.45 g of 2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture is stirred at RT for 30 minutes.The reaction mixture is poured into water and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum.The residue is chromatographed on silica gel, eluding with a DCM/MeOH mixture (96/4; v/v).0.42 g of the expected product is obtained after crystallization from iso ether, m.p.=225 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B) 3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5-methyl-3-[2-oxo-2-[4-(2-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one 0.0335 g of 60% sodium hydride in oil is added, at RT, to a mixture of 0.3 g of the compound obtained in the preceding step in 10 ml of THF, and the mixture is stirred for 30 minutes. 0.2 g of 2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture is stirred at RT for 1 hour. 50 ml of water are added to the reaction mixture and the resulting mixture is extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum.The residue is chromatographed on silica gel, eluding with a DCM/MeOH mixture (98/2; v/v).0.32 g of the expected product is obtained after crystallization from iso ether, m.p.=239 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B) 5-Chloro-3-(2-isopropoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-[2-oxo-2-[4-(4-pyridyl)-1-piperazinyl]ethyl]-1,3-dihydro-2H-indol-2-one, laevorotatory isomer. 0.025 g of 60% sodium hydride in oil is added to a mixture of 0.3 g of the compound obtained in the preceding step in 10 ml of THF, and the mixture is stirred at 20 C. for 15 minutes. 0.19 g of 2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture is stirred at 20 C. for 2 hours.The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum.The residue is chromatographed on silica gel, eluding with DCM and then with acetone. 0.1 g of the expected product is obtained. 1H NMR: DMSO-d6: delta (ppm): 0.6: d: 3H; 1.2: d: 3H; 3.0 to 4.0: m+2s: 16H; 4.6: mt: 1H; 6.4 to 7.2: mt: 9H; 7.4: bd: 1H; 7.7: dd: 2H; 8.1: d: 2H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.17 g of 60% sodium hydride in oil is added to a mixture of 2.4 g of the compound obtained in the preceding step in 30 ml of THF, and the mixture is stirred for 20 minutes at RT. 1.7 g of 2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture is stirred for 1 hour at RT. The resulting mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.65 g of the expected product are obtained after crystallization from iso ether, m.p.=157-158 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 1.178 g of the compound obtained in the preceding step in 10 ml of DMF is cooled to 0 C., 0.188 g of 60% sodium hydride in oil is added, under an argon atmosphere, and the mixture is stirred until the evolution-of gas has ceased. 1.02 g of 2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture is stirred at RT for 3 hours. The reaction mixture is poured into 5% K2CO3 solution and extracted with EtOAc, the organic phase is washed with water, with 5% K2CO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture (95/5; v/v). 1.254 g of the expected product are obtained after crystallization from a DCM/ether/iso ether mixture, m.p.=172-173 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.225 g of 60% sodium hydride in oil is added to a mixture of 2.1 g of the compound obtained in the preceding step in 10 ml of DMF, and the mixture is stirred at RT for 30 minutes. 1.2 g of 2,4-dimethoxy-benzenesulphonyl chloride are then added and the mixture is stirred at RT for 18 hours. The reaction mixture is poured into water and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with DCM. 2.5 g of the expected product are obtained after crystallization from iso ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
D) 5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-isopropoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-pyridyl)-1-piperazine-carboxylate, laevorotatory isomer 0.02 g of 60% sodium hydride in oil is added, under an argon atmosphere, to a mixture of 0.213 g of the compound obtained in the preceding step in 3 ml of DMF, and, after the evolution of gas has ceased, 0.119 g of 2,4-dimethoxybenzesulphonyl chloride is then added and the mixture is stirred at RT for 3 hours.The reaction mixture is poured into 5% K2CO3 solution and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum.The residue is chromatographed on silica gel, eluding with a DCM/MeOH mixture of from (95/5; v/v) to (93/7; v/v).0.161 g of the expected product is obtained after crystallization from a DCM/hexane/iso ether mixture, m.p.=160-164 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.5 g of 60% sodium hydride in oil is added to a mixture of 3.6 g of 5-chloro-1H-indole-2,3-dione in 20 ml of DMF, and the mixture is stirred for 30 minutes at 20 C. 4.8 g of 2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture is stirred at 20 C. for 1 hour. The resulting mixture is concentrated under vacuum (1.3 Pa), the residue is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is triturated in iso ether and the precipitate formed is filtered off by suction. 2.9 g of the expected product are obtained after crystallization from hot EtOAc, m.p.=194.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Add 0.123 g of potassium tert-butylate to a solution of 0.3 g of laevorotatory 3-(2-chloro-phenyl)-5-ethoxy-3-methyl-1,3-dihydro-indol-2-one (Preparation 1) in 7 ml of tetrahydrofuran cooled to -30 C. Allow the temperature to return to 0 C., cool to -60 C. and then add 0.259 g of 2,4-dimethoxy-benzenesulphonyl chloride. After stirring overnight at 20 C., hydrolyse with water and extract with ethyl acetate. Dry the organic phase over sodium sulphate, and evaporate to dryness. Take up the residue in isopropyl ether while stirring. The expected product, in the form of white powder, is filtered and dried under vacuum.m.p.=197 C.1H NMR 250 MHz (DMSO-d6): 1.25 (t, 3H); 1.68 (s, 3H); 3.61 (s, 3H); 3.8-3.99 (m, 5H); 6.33 (d. 1H); 6.69-6.78 (m, 2H); 6.9-6.98 (m, 1H); 7.28-7.5 (m, 3H); 7.7-7.81 (m, 2H); 7.89-7.92 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; at 20℃; | Example 37 3-Chloro-6-(2,4-dimethoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrole (37) 2,5-Dimethoxybenzenesulfonyl chloride (63 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 37 (69 mg, 70% yield) as a yellow solid. LC-MS (M+H = 408, obsd. = 408). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | 1.5 (±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 24.47 mg (0.22 mmol) of potassium tert-butoxide were added undiluted to a solution of 100 mg (0.20 mmol) of (±)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of absolute dimethylformamide while cooling at 0 C. The reaction mixture was stirred at 0 C. for one hour. A clear colorless solution formed. At 0 C., 51.6 mg (0.22 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were added. The reaction mixture was allowed to thaw to room temperature and was stirred at room temperature overnight. After conversion was complete, the reaction mixture was poured into 10 ml of ice-water and initially neutralized and then adjusted to pH 9 with 2 ml of 1 N sodium hydroxide solution. A precipitate separated out and was washed with water and dried in a vacuum drying oven to result in 68 mg of dry solid. In order to remove the slight impurities, the solid was stirred in 3 ml of diethyl ether. After leaving to stand overnight, the solid was again filtered off and washed with a little diethyl ether and dried. 40 mg (0.06 mmol, 29%) of (±)-5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate were obtained. ESI-MS [M+H+]=705.4 calculated for C35H40N6O8S=704.81 1H-NMR ([d6]-DMSO, 500 MHz) delta[ppm]=8.22-8.10 (m, 2H), 7.96 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=8.7 Hz), 7.65 (s, 1H), 7.13 (m, 1H), 6.67-6.63 (m, 2H), 4.08 (m, 2H), 3.84 (s, 3H), 3.67-3.45 (m, 3H), 3.51 (s, 3H), 3.04 (m, 2H), 2.74 (pd, 2H, J=9.4 Hz), 2.46 (m, 1H), 2.28 (m, 2H), 2.14 (m, 1H), 2.10 (s, 3H), 1.79 (pt, 2H, J=10.3 Hz), 1.61 (pd, 2H, J=10.2 Hz), 1.36 (m, 2H), 0.99 (t, 3H, J=6.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 0.28 g of the compound from Preparation 2.1 in 10 ml of THF is cooled to -30 C., 0.073 g of potassium tert-butoxide is added and the mixture is left stirring while allowing the temperature to rise to 0 C. The reaction mixture is cooled to -60 C., 0.147 g of the compound from Preparation 3.1 is added and the mixture is left stirring at 20 C. overnight. The reaction mixture is hydrolyzed by addition of water, extraction is carried out with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The expected compound is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Example 48; 1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-[4-(4-ethylpiperazin-1-yl)-phenylamino]-5-iodo-1,3-dihydroindol-2-one48.1 1-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydroindol-2-oneSodium hydride (145 mg of a 50% strength dispersion in mineral oil, 3.03 mmol) was added to an ice-cooled solution of 3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydroindol-2-one (1.0 g, 2.52 mmol) in DMF (20 ml). The reaction mixture was stirred at 0 C. for 15 minutes and then 2,4-dimethoxyphenylsulfonyl chloride (99 mg, 0.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, water was added, and the resulting precipitate was filtered off. The precipitate formed after stirring in ethyl ether (50 ml) overnight was filtered off with suction, resulting in 730 mg of the title compound (45% yield).ESI-MS: 597.05 [M+H]+ |
Tags: 63624-28-2 synthesis path| 63624-28-2 SDS| 63624-28-2 COA| 63624-28-2 purity| 63624-28-2 application| 63624-28-2 NMR| 63624-28-2 COA| 63624-28-2 structure
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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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