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CAS No. : | 22808-73-7 | MDL No. : | MFCD03768500 |
Formula : | C8H9NO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XLOVNJUCAFIANM-UHFFFAOYSA-N |
M.W : | 215.23 | Pubchem ID : | 89847 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.72 |
TPSA : | 94.84 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.16 cm/s |
Log Po/w (iLOGP) : | 1.31 |
Log Po/w (XLOGP3) : | 0.64 |
Log Po/w (WLOGP) : | 1.2 |
Log Po/w (MLOGP) : | 0.28 |
Log Po/w (SILICOS-IT) : | -0.14 |
Consensus Log Po/w : | 0.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.7 |
Solubility : | 4.33 mg/ml ; 0.0201 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.21 |
Solubility : | 1.34 mg/ml ; 0.00621 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.05 |
Solubility : | 1.93 mg/ml ; 0.00897 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.74 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
99% | With dmap; N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; | TO A] stirred solution of 4-sulfamoyl-benzoic acid methyl ester (6.01 g, 27.8 [MMOL),] 4- oxo-2-m-tolyl-pentanoic acid (6.35 g, 30.7 mmol), N, N-diisopropylethylamine (12.2 mL, 69.5 [MMOL),] and DMAP (5 mole %) in CH2Cl2 (275 mL) at rt under N2 was added [BROMO-TRIPYRROLIDINO-PHOSPHONIUM] hexafluorophosphate (PyBroP) (18.1 g, 38.9 [MMOL),] and the reaction mixture was allowed to stir overnight. The mixture was diluted with [1 M HCI] (100 mL) and [CH2CI2] (150 mL), and the layers were separated. The organic phase was washed with 1 M HCI (1 x 100 mL), 1N NaOH (1 x 100 mL) and brine [(1] x 100 mL). The organic layer was dried over [NA2SO4,] and then filtered, and the solvent was removed under reduced pressure. Purification on silica gel (0-15% EtOAc in hexane) gave 12.0 g (99%) of desired ester as a white [SOLID.'H] NMR (400 MHz, [CDCI3)] : 8.15 (d, [J=8. 6HZ,] 2H), 7.99 (d, [J=8. 6HZ,] 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1 H), 6.87 (m, 2H), 3.97 (s, 3H), 3.93 (dd. J = 4.3 and 9.5 Hz, 1 H), 3.29 (dd. J = 9.5 and 18.1 Hz, 1 H), 2.60 (dd. J = 4.3 and 18.1 Hz, [1H),] 2.28 (s, 3H), 2.07 (s, 3H). |
99% | With dmap; N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; | To astirred solution of 4-sulfamoyl-benzoic acid methyl ester (6.01 g, 27.8 mmol), 4-oxo-2-/r/-to.yi-pentanoic acid (6.35 g, 30.7 mmol), /V,A/-diisopropylethylamine(12.2 mL, 69.5 mmol), and DMAP (5 mole %) in CH2CI2 (275 ml) at rt under N2was added bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBroP)10 (18.1 g, 38.9 mmol), and the reaction mixture was allowed to stir overnight.The mixture was diluted with 1M HCI (100 ml) and CH2CI2 (150 ml), and thelayers were separated. The organic phase was washed with 1M HCI (1 x 100mL), 1N NaOH (1 x 100 ml) and brine (1 x 100 rnL). The organic layer wasdried over NajSCU, and then filtered, and the solvent was removed under15 reduced pressure. Purification on silica gel (0-15% EtOAc in hexane) gave12.0 g (99%) of desired ester as a white solid. 1H NMR (400 MHz, CDCI3):8.15 (d, J = 8.6 Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.10(d, J = 7.6 Hz, 1H), 6.87 (m, 2H), 3.97 (s, 3H), 3.93 (dd. J = 4.3 and 9.5 Hz,1H), 3.29 (dd. J = 9.5 and 18.1 Hz, 1H), 2.60 (dd. J = 4.3 and 18.1 Hz, 1H),20 2.28 (s, 3H), 2.07 (s, 3H). |
99% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate;dmap; In dichloromethane; at 20℃; | B. 4-(4-Oxo-2-m-tolyl-pentanoylsulfamoyl)-benzoic acid methyl ester. To a stirred solution of 4-sulfamoyl-benzoic acid methyl ester (6.01 g, 27.8 mmol), 4-oxo-2-m-tolyl-pentanoic acid (6.35 g, 30.7 mmol), N,N-diisopropylethylamine (12.2 mL, 69.5 mmol), and DMAP (5 mole %) in CH2Cl2 (275 mL) at rt under N2 was added bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBroP) (18.1 g, 38.9 mmol), and the reaction mixture was allowed to stir overnight. The mixture was diluted with 1 M HCl (100 mL) and CH2Cl2 (150 mL), and the layers were separated. The organic phase was washed with 1 M HCl (1*100 mL), 1N NaOH (1*100 mL) and brine (1*100 mL). The organic layer was dried over Na2SO4, and then filtered, and the solvent was removed under reduced pressure. Purification on silica gel (0-15% EtOAc in hexane) gave. 12.0 g (99%) of desired ester as a white solid. 1H NMR (400 MHz, CDCl3): 8.15 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.87 (m, 2H), 3.97 (s, 3H), 3.93 (dd. J=4.3 and 9.5 Hz, 1H), 3.29 (dd. J=9.5 and 18.1 Hz, 1H), 2.60 (dd. J=4.3 and 18.1 Hz, 1H), 2.28 (s, 3H), 2.07 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,2-dimethoxyethane; for 1.08333h;Heating / reflux; | A mixture of methyl 4- (aminosulfonyl) benzoate (5.10 g) and potassium carbonate (6.55 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes. After cooling the mixture, a solution of benzyl chloridocarbonate (5.25 g) in dimethoxyethane (30mL), and the resulting mixture was refluxed for 1 hour. The reaction was quenched by adding IN hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a pale yellow oil, which was solidified upon standing. The solid was triturated in diisopropyl ether (30 mL) to give methyl 4-(1 [ (benzyloxy) carbonyl] amino} sulfonyl) benzoate as a white powder (3.38 g). Methyl4- ( { [ (benzyloxy) carbonyl] amino} sulfonyl) benzoate NMR(CDCl3,delta) : 3.98 (3H, s), 5.10 (2H, s), 7.22 (2H, m), 7.34 (3H, m), 7.64(1H, s, br), 8.08 (2H, d, J=9Hz), 8.16 (2H, d, J=9Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 18h; | EXAMPLE 21Manufacture of the Compound (25) from the Compounds (23) and (24)The compound (23) (537 mg, 1 mmol) and carbonyl diimidazole (194 mg, 1.2 mmol) were dissolved in anhydrous THF (1 ml), then methyl sulfamoylbenzoate (the compound (24)) (258 mg, 1.2 mmol) and diisopropyl ethylamine (158 mg, 1.2 mmol) were added thereto as stirring at room temperature and the mixture was made to react at room temperature for 18 hours. After that, the solvent was evaporated therefrom under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with 0.5N HCl, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous saline solution successively, dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom under reduced pressure and the residue was purified by a silica gel column chromatography (eluting with ethyl acetate:ethanol=10:1) to give the compound (25) (734 mg, 74%) as a pale yellow oily substance.1H NMR (400 MHz, CDCl3, 25 C.): delta=1.40 (9H, s, -C(CH3)3), 3.69-3.90 (12H, m, O-CH2-), 3.94 (3H, s, CH3), 4.2 (2H, bs, O-CH2-CO-), 5.02 (2H, s, Ph-CH2-), 6.67 (1H, s, Ph-H), 6.80 (1H, d, J=7.8 Hz, Ph-H), 7.34 (1H, d, J=7.8 Hz, Ph-H), 7.69 (1H, s, NH), 8.14 (4H, s, Ph-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride; lithium borohydride; In tetrahydrofuran; methanol; | Step 3 Preparation of 4-(hydroxymethyl)benzenesulfonamide To a solution of methyl [4-(aminosulfonyl)]benzoate (5.8 g, 27 mmol) (Step 2) in THF (400 ml), methanol (1.6 ml, 40 mmol) and lithium borohydride (20 ml, 2M solution in THF, 42 mmol) were added over 10 minutes. After heating at reflux for 3.5 hours, the reaction mixture was cooled and poured over ice containing 1N HCl (80 ml). The reaction mixture was extracted with ethyl acetate, dried (Na2 SO4), filtered and concentrated. The crude mixture was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 4-(hydroxymethyl)benzenesulfonamide (3.8 g, 75%) as a white solid. |
17% | 4-Hvdroxymethyl-benzenesulfonamide; To a solution of 5.2 g 4-sulfamoyl-benzoic acid methyl ester in 100 ml. THF and 1.44 ml. MeOH, 0.77 g lithium borohydride was added portion-wise over a period of 10 minutes. The mixture was heated at reflux overnight, cooled to room temperature, and poured onto ice containig 100 ml. 1 N HCI. The mixture was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by automated flash chromatography (EtOAc/Hexane 1 :1 ) to give 0.75 gram (17%) of product. 1H NMR (400 MHz, DMSO-de) delta 4.57 (d, J=5.81 Hz, 1 H), 5.38 (t, J=5.81 Hz, 1 H), 7.48 (d, J=8.34 Hz, 2H), 7.78 (d, J=8.34 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | Step 2 Preparation of methyl [4-(aminosulfonyl)]benzoate To a solution of 4-(aminosulfonyl)benzoic acid (16 g, 79.6 mmol) (Step 1) in methanol (600 ml), conc. H2 SO4 (1.2 ml) was added and the mixture was heated at reflux for 4 days. The solvent was removed and washed with ether. The white solid (16.5 g, 96%) was used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; | EXAMPLE 74 4-(Aminosulfonyl)benzoic acid methyl ester A slurry of 30.2 g (0.15 mole) of p-carboxybenzenesulfonamide in 500 ml of methanol was treated with 30 g of anhydrous hydrogen chloride and the mixture was heated at reflux temperature for 3 hr. The solution was concentrated under vacuum to give 32.3 g of white, crystalline residue. A 5.0 g portion of this residue was recrystallized from 25 ml of methanol to give 3.3 g of title compound as a white powder, mp 174-178 C. Analysis: Calculated for C8 H9 NO4 S: C, 44.65; H, 4.22; N, 6.51. Found: C 44.80; H, 4.30; N, 6.47. | |
With potassium hydroxide; In diethyl ether; water; | 8(a) 4-Sulfamoyl-benzoic acid methyl ester. To a solution of KOH (108 mg, 2.0 mmol) in water (1 mL) was added Et2O and cooled to 0 C. MNNG (292 mg, 1.99 mmol) was added and the resulting yellow solution was added to a suspension of 4-Sulfamoyl-benzoic acid in Et2O at room temperature and stirred overnight. The reaction was quenched with acetic acid and the resulting mixture was diluted with water. The mixture was then extracted with ethyl acetate and the combined organic extracts was washed with bine and dried over Na2SO4. Removal of solvent gave the crude product which was used in the next reaction without further purification. 1H NMR (400 MHz, MeOD) delta 8.17 (d, 2H), 8.00 (d, 2H), 3.92 (s, 3H). |
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