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Structure of 2393-23-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Synthesis of N-Sulfenylimines from Disulfides and Primary Methanamines
Robert Kawȩcki ;
Abstract: N-Sulfenylimines (sulfenimines, thiooximes, N-alkylidenesulfenamides) were efficiently synthesized through the reaction of primary amines and disulfides with NBS or bromine. This reaction can be carried out in an open flask at room temperature without the need for any transition-metal-containing additives. The use of thiols instead of disulfides gave similar results. A wide range of amines were reacted with aryl and alkyldisulfides, resulting in the formation of sulfenimines in a yield of 44–99%.
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CAS No. : | 2393-23-9 |
Formula : | C8H11NO |
M.W : | 137.18 |
SMILES Code : | NCC1=CC=C(OC)C=C1 |
MDL No. : | MFCD00008122 |
InChI Key : | IDPURXSQCKYKIJ-UHFFFAOYSA-N |
Pubchem ID : | 75452 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338 |
Class: | 8 |
UN#: | 2735 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.61 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.7 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.84 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.0 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.43 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.24 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.53 |
Solubility | 4.03 mg/ml ; 0.0294 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.16 |
Solubility | 9.42 mg/ml ; 0.0687 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.54 |
Solubility | 0.396 mg/ml ; 0.00288 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.54 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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 |
---|---|---|
Preparation 3 : 3-bromo-1-[4-(methyloxy)phenyl]methyl}-1W-pyrrole-2,5-dione (P3) <n="53"/>A mixture of 3-bromo-2,5-furandione (6 g), 1-[4-(methyloxy)phenyl]methanamine (4.44 mL), and AcOH (80 mL) was heated at 100 0C overnight. The solution was then concentrated in vacuo. AcOH (70 mL) and AcONa (2 g) were added to the crude product and the mixture was reflux for 2 hours. Water was then added and the aqueous phase was extracted with DMC. The organic phase was dried and evaporated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate from 9/1 to 7/3 to give the title compound (8.2 g). NMR (1H, CDCI3) delta 7.32 (d, 2H), 6.86 (m, 3H), 4.66 (s, 2H), 3.80 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; for 1.5h; | Synthesis 1-1 -A N-(4-Methoxybenzyl)-2-bromo-5-nitropyridin-4-amine A solution of 4-methoxybenzylamine (0.756 g, 5.51 mmol) in acetonitrile (2 mL) was added to a mixture of <strong>[1137475-57-0]2-bromo-4-chloro-5-nitropyridine</strong> (1.19 g, 5.01 mmol) and triethylamine (0.768 mL, 5.51 mmol) in acetonitrile (8 mL). After stirring for 1.5 hours, the solution was diluted with ethyl acetate (100 mL) which was then washed successively with water and brine before being concentrated in vacuo to a light brown oil which solidified on standing to give the title compound (1.31 g, 3.87 mmol, 77%). 1H NMR (d6- DMSO, 400 MHz) delta 9.00 (br t, 1 H, J = 6.3 Hz), 8.80 (s, 1 H)1 7.35 (d, 2H, J = 8.7 Hz), 7.10 (s, 1 H), 6.95 (d, 2H, J = 8.8 Hz), 4.60 (d, 2H, J = 6.0 Hz), 3.70 (s, 3H). LCMS (1) Rt = 2.13 min; m/z (ESI-) 336, 338 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate - 166 -was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product which was purified by columnchromatography (11.69 g, 56.0%) as a soild |
56.0 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stilTed at room temperature for 16 hours. After vacuum filtration, the filtratewas concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound (11.69 g, 56.0%) as a solid. |
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reactionmixture was stilTed at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound as a solid (11.69 g, 56.0%). |
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stilTed at room temperature for 16 hours. After vacuum filtration, the filtratewas concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound (11.69 g, 56.0%) as a solid. |
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | GammaRho1 2-(4-Methoxy-benzyl)- l-oxo-2,3-dihvdro-lH-isoindole-5-carbonitrile To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (11.69 g, 56.0%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | A solution of 9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (1.00 g, 3.96 mmol) in DMF (15.0 mL) was treated at room temperature with (4- methoxyphenyl)methanamine (1.09 g, 7.93 mmol), HATU (2.26 g, 5.95 mmol) and DIPEA (2.08 mL, 11.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by Biotage with 0-20percent of MeOH in CH2CI2 to give 1.30 g (88percent) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.45 (t, J=5.3 Hz, 1 H), 8.67 (t, J=1.8 Hz, 1 H), 8.33 - 8.39 (m, 1 H), 8.18 - 8.31 (m, 3 H), 7.95 (ddd, J=5.6, 3.4, 2.2 Hz, 2 H), 7.20 - 7.32 (m, 2 H), 6.80 - 6.97 (m, 2 H), 4.45 (d, J=5.7 Hz, 2 H), 3.72 (s, 3 H); LCMS RT = 5.99 min, m/z 372.0 [M+H+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.2% | In ethanol;Reflux; Inert atmosphere; | General procedure: The mixture containing substituted 2-aminobenzoic acid (0.71 mmol), substituted benzylamine (0.71 mmol), triethyl orthoformate (0.3 ml, 1.70mmol) and anhydrous ethanol (15 ml) was refluxed under N2 atmosphere for 2-8 h, cooled to room temperature and stood overnight. The precipitate was filtered, washed with ethanol, dried and recrystallized from ethanol to give the white or light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
525 mg | at 150℃; for 6h; | To <strong>[871836-51-0]4-chloro-1H-pyrazolo[4,3-c]pyridine</strong> (1.3 g, 8.46 mmol) was added (4- methoxyphenyl) methanamine (5 mL) and the resultant reaction mixture was heated in a closed reaction vessel at 150 °C for 6 h. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with saturated NH4C1 solution (12x50 mL), water (2x200 mL), brine (150 mL), dried over Na2SO4 and concentrated. The crude compound was purified by silica-gel (100-200) column chromatography, compound eluting at 40percent EtOAc/hexane to afford N-(4- methoxybenzyl)- 1H-pyrazolo[4,3-c]pyridin-4-amine (525 mg) as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With montmorillonite K-10; In ethanol; at 80℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: To a solution of 1 (2.0 mmol) in absolute EtOH (8.0 mL)in a glass tube was added dropwise the appropriate amine(3.6 mmol) and K-10 (0.3 g mmol-1); the quartz tubewas sealed with reaction mixture and introduced intoa microwave oven. The flask was irradiated for 30 min(150 W) the temperature of 80 C. After completion of thereaction the mixture was filtered, the organic phase wasdried with Na2SO4, filtered and the solvent was evaporatedunder reduced pressure to give the crude products. All thecompounds were purified by column chromatographyon silica gel using 2-5% EtOH-CH2Cl2 as eluent to giveanalytically pure products 3a-m. The products werecharacterized by corresponding spectroscopic data (1H and13C NMR, and HRMS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.2% | at 160℃; for 2h;Microwave irradiation; | The 2-chloro-6-methyl-4 - (trifluoromethyl) pyridine (6.1g, 31 . 2mmol) adding microwave tube, add 4- methoxy animal pen amine (4.28g, 31 . 2mmol), 160 C microwave reaction 2 hours, the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) purified, to get the yellow solid title compound (1.5g, yield 16.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 160℃; for 2h;Microwave irradiation; | A mixture of <strong>[1206972-45-3]2-chloro-5-(trifluoromethoxy)pyridine</strong> (0.99 g, 5 mmol), 4-methoxybenzylamine (2.6 mL, 20 mmol), DIEA (1.3 mL, 7.5 mmol), K2003 (1.0 g, 7.5 mmol) and DMF (13 mL) was stirred at 160 oC (microwave) for 2 hrs. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and H20 (25 mL). The organic layer was separated (phase separating cartridge) and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (Biotage SNAP 50 g column, 0 to 15% EtOAc/isohexane). The product was triturated with Et20 to give the title compound as a yellow oil(0.33 g, 40%).1H NMR (ppm)(400 MHz, CDCI3): 3.80 (3H, s), 4.42 (2H, d, J=5.8 Hz), 4.91 (IH, s), 6.35 (IH, d, J8.8 Hz), 6.90 - 6.87 (2H, m), 7.25 - 7.28 (3H, m), 8.04 (1 H, d, J=2.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | The solution of 4-methoxybenzylamine (211 muIota_, 0.226 g, 1.65 mmol) in ethanol (4 mL) was added 37percent formaldehyde (62 muIota_, 0.049 g, 1.65 mmol). The mixture was stirred for 1 hour. Then the solution of <strong>[1198-14-7]5-bromoquinolin-8-ol</strong> (0.336 g, 1.5 mmol) in ethanol (5 mL) was added to the reaction mixture. After that the mixture was refluxed at 50°C for 72 hours. The reaction mixture was allowed to cool down and the obtained precipitate was filtered off, washed with ethanol and crystallized from ethanol to give the titled compound (0.150 g, 27percent) as yellow crystals. Mp. 129-132 °C. 1 H NMR (300 MHz, CDCI3): delta 3.81 (d, 5H), 4.12 (s, 2H), 6.87 (d, 2H), 7.28 (d, 2H), 7.46-7.51 (m, 1 H), 7.62 (s, 1 H), 8.40 (d, 1 H), 8.83 (d, 1 H). 13C NMR (75 MHz, CDCI3): delta 49.4, 52.3, 55.2, 109.4, 1 13.9, 120.9, 122.3, 127.0, 129.6, 131.2, 134.9, 135.3, 139.6, 149.0, 152.0, 158.9. LCMS RT= 4.19 min. ESI+ m/z: 375.6 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | To a stirred solution of 15-1 (2.0 g, 17.6 mmol) in DCE (50.0 mL) was added 15-2 (2.29mL, 17.6 mmol) and Acetic acid (1 mL, 17.6 mmol) and the reaction mixture was stirred for 1hour. Sodium cyanoborohydride (1.65 g, 26.4 mmol) was then added and the reaction mixture wasstirred at room temperature for 16 hours. It was diluted with 20percent IP A/DCM and organic layer was5 washed with saturated aqueous NaHC03 solution, water, dried over sodium sulfate andconcentrated. Crude material was purified by column chromatography (silica, gradient, 0percent-2.5percentMethnol in DCM) to afford 15-3 as Light yellow gummy solid. Yield-61 percent; LC MS: ES+ 23 5 .2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | General procedure: A solution of 24 (1.0 equiv.), HOBt (1.1 equiv.) and EDC (1.5 equiv.) in DMF (1.3 mmol/mL) was stirred at rt for 15 minutes. The appropriate amine (2.0 equiv.) was added and the resulting solution was stirred at rt for 5 hours. Reaction media was diluted with water and aqueous phase was extracted 3 times with EtOAc. Combined organic layers were washed successively with a solution of HCl 1N, a saturated solution of NaHCO3 and brine, dried over Na2SO4 and concentrated. The resulting solid was then purified by column chromatography on silica gel using the appropriate heptanes:EtOAc mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a solution of (4-methoxyphenyl)methanamine (19.9 g, 145 mmol) in acetonitrile (150 ml_) at room temperature was added potassium carbonate (20.0 g, 145 mmol) and <strong>[65202-50-8]methyl 6-chloropyridazine-3-carboxylate</strong> (12.5 g, 72.4 mmol). The reaction mixture was stirred at 80 C for 16 h before it was cooled to room temperature and diluted with water (300 ml_). The aqueous layer was extracted with ethyl acetate (200 ml_ c 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether =1/3) to afford methyl 6-(4-methoxybenzylamino)pyridazine-3-carboxylate (28.0 g, crude) as a light yellow oil. (LCMS (ESI) m/z: 274.1 [M+H]+. Used in the next step directly without additional purification. |