Structure of 15184-96-0
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CAS No. : | 15184-96-0 |
Formula : | C9H12N2O2 |
M.W : | 180.20 |
SMILES Code : | O=[N+](C1=CC=C(CN(C)C)C=C1)[O-] |
MDL No. : | MFCD00035956 |
InChI Key : | ZRLVPQKSXHTXMN-UHFFFAOYSA-N |
Pubchem ID : | 278498 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 52.74 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.06 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.94 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.5 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.81 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.43 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.35 |
Solubility | 0.808 mg/ml ; 0.00449 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.64 |
Solubility | 0.417 mg/ml ; 0.00231 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.29 |
Solubility | 0.918 mg/ml ; 0.00509 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 |
-5.99 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 |
2.0 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) |
1.48 |
* 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 |
---|---|---|
85% | With iron; In acetic acid; at 80℃; for 5h; | To a solution of dimethyl-(4-nitro-benzyl)-amine (Ig, 5.55mmol) in acetic acid (10ml) was added activated iron powder (3g) and the reaction mixture was stirred for 5 hr at 800C. The reaction mixture was filtered; the filtrate diluted with water and neutralized with 10% sodium hydroxide solution. The product was extracted with ethyl acetate, the organic layer was dried and evaporated to give a residue. Purification by column chromatography using chloroform/methanol (98:2) to give 4-dimethylaminomethyl- phenylamine (0.7g, 85%) |
78.2% | With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate; In ethanol; at 65 - 78℃; for 5h; | General procedure: A mixture of compounds 5a-e (0.05 mol) in ethanol was heated to 65 C, FeCl3·6H2O (2.8 g, 0.001 mol) and activated carbon (0.18 g, 0.015 mol) were added, and 80% hydrazine hydrate (25 g, 0.5 mol) was added drop wise at such a rate to keep the temperature below 70 C, the reaction was heated at reflux for 5 h and then cooled to room temperature and concentrated. Water (100 mL) was added, the reaction solution was extracted three times with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to obtain the compounds 6a-e. |
78.2% | With iron(III) chloride hexahydrate; hydrazine hydrate; In ethanol; for 5h; | General procedure: A mixture of compounds 5 or 7a-c (0.05 mol) in ethanolwas heated to 65 C, FeCl3·6H2O (2.8 g, 1 mmol) and activatedcarbon (0.18 g, 15 mmol) were added, and 80% hydrazinehydrate (25 g, 0.5 mol) was added dropwise at such arate to keep the temperature below 70 C, the reaction washeated at reflux for 5 h and then cooled to room temperatureand concentrated. Water (100 mL) was added, the reactionsolution was extracted three times with CH2Cl2 (60 mL). Theorganic extracts were combined, dried over sodium sulfate,filtered, and concentrated to obtain the compounds 8a-d. |
78.2% | With iron(III) chloride; hydrazine hydrate; In ethanol; at 60 - 70℃; for 5h; | General procedure: 1 (0.05 mol) was added to 90% ethanol (100 mL),The mixture was heated to 60 C with stirring, and ferric chloride (0.001 mol) and activated carbon (0.015 mol) were added. At 70 C, hydrazine hydrate (0.5 mol) was added dropwise, and the mixture was refluxed for 5 hours. After completion of the reaction, the mixture was filtered under suction, and the filtrate was concentrated. Water (200 mL), dichloromethane (100 mL×3)Concentrated to a colorless liquid orWhite solid 2a-c. |
75% | With hydrazine hydrate; iron(III) chloride hexahydrate; pyrographite; In ethanol; at 65 - 70℃; for 5h; | A mixture of 3.5 g (19.4 mmol) of compound (b) in ethanol was heated to 65C. 0.83 g (0.39 mmol) of FeCl36H2O and 0.07 g (5.85 mmol) of activated carbon were added and 9.8 g (194 mmol) of 80% hydrazine hydrate was added dropwise at a rate maintaining the temperature below 70C .The reaction was heated at reflux for 5 hours, cooled to room temperature and concentrated. 500 ml of water was added and the reaction solution was extracted three times with DCM.The organic extracts were mixed, dried over sodium sulfate, and concentrated to obtain 3.2 g (75%) of a colorless cucumber compound (c). |
palladium; In ethanol; | REFERENCE EXAMPLE 15 In ethanol (100 ml) was dissolved dimethyl-4-nitrobenzylamine (20.7 g), and to the mixture was added dried 10% palladium on carbon (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-aminobenzyl-dimethylamine (8.75 g) as pale yellow oil. 1 H NMR (200 MHz, CDCl3) delta: 2.21 (6H, s), 3.31 (2H, s), 3.53-3.70 (2H, br), 6.65 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4 Hz). | |
With hydrogen;palladium 10% on activated carbon; In methanol; under 3750.38 Torr; for 16h; | 6.9 g (38.1 mmol) 4-nitro-dimethylbenzylamine are dissolved in 100 mL MeOH, combined with 1 g of palladium on activated charcoal (10 % Pd) and stirred for 16 h under a hydrogen atmosphere (5 bar) in the autoclave. After this time, total conversion can be detected (monitoring of reaction by HPLC). The catalyst is filtered off and all the volatile constituents are eliminated in vacuo. 6.8 g crude C-I are obtained, which is used without further purification in the syntheses of Examples 1, 2 and 6. MS-ESI+: 151 (M+H)+ | |
Stannous chloride (28.1 g, 148 mmol) was added to a solution of Compound 4a2 (5.33 g, 29.6 mmol) in ethanol (200 mL) and heated to 60 C. Sodium borohydride (0.560 g, 14.8 mmol) in ethanol (80 mL) was added dropwise. Two hrs later the reaction mixture was added to ice water. The slurry was filtered through Celite 545 and the filtrate cake rinsed with ether. The collected liquors were brought to pH 11 with 1N NaOH and extracted with ether. The combined organic layers were washed with water, dried over MgSO4 and filtered. The dried organic solution was then reduced in vacuo to provide 4-dimethylaminomethyl-phenylamine Compound 4a which was used in the next step without further purification. MS 207 (MH+). | ||
With hydrogenchloride; iron; acetic acid; In ethanol; water; for 0.75h;Reflux; | PREPARATION 6: 4-((DIMETHYLAMINO)METHYL)ANILINE To a reaction flask was added N,N-dimethyl(4-nitrophenyl)methyamine (4.553 g). Anhydrous ethanol was added to dissolve N,N-dimethyl(4-nitrophenyl)methyamine. After adding acetic acid (5.2 mL), the mixture was mechanically stirred. To 1 N HCl (40 mL) was added iron powders (11.339g). The iron powders were immersed for 10 min and filtered by suction. The filter cake was washed with absolute ethanol and then added into the reaction flask. The mixture was warmed in an oil bath to reflux, and maintained under reflux until the reaction was completed (about 35 min). After the reaction was completed, the reaction solution was filtered by suction. The filter cake was washed with absolute ethanol. The filtrate was concentrated and then added into distilled water (100 mL). The pH of the mixture was adjusted with NaOH to 14. Lots of solids were precipitated. The solids were filtered by suction. The filtrate was extracted with dichloromethane (100 mL * 1), and the aqueous phase was discarded. To the organic phase was added distilled water (60 mL). The pH was adjusted with 2 N HCl to 2. The resultant product was mixed and stood to separate. The organic phase was discarded. The pH of the aqueous phase was adjusted with NaOH to 7. The mixture was extracted with dichloromethane (40 mL * 2) and the aqueous phase was discarded. The organic phase was washed with distilled water (40 mL * 1) once and the aqueous phase was discarded. The organic phase was directly concentrated to give the target compound. | |
With hydrogenchloride; iron; acetic acid; In ethanol; water; for 0.583333h;Reflux; | To a reaction flask was added N,N-dimethyl(4-nitrophenyl)methyamine (4.553 g). Anhydrous ethanol was added to dissolve N,N-dimethyl(4-nitrophenyl)methyamine. After adding acetic acid (5.2 mL), the mixture was mechanically stirred. To 1 N HCl (40 mL) was added iron powders (11.339 g). The iron powders were immersed for 10 min and filtered by suction. The filter cake was washed with absolute ethanol and then added into the reaction flask. The mixture was warmed in an oil bath to reflux, and maintained under reflux until the reaction was completed (about 35 min). After the reaction was completed, the reaction solution was filtered by suction. The filter cake was washed with absolute ethanol. The filtrate was concentrated and then added into distilled water (100 mL). The pH of the mixture was adjusted with NaOH to 14. Lots of solids were precipitated. The solids were filtered by suction. The filtrate was extracted with dichloromethane (100 mL*1), and the aqueous phase was discarded. To the organic phase was added distilled water (60 mL). The pH was adjusted with 2 N HCl to 2. The resultant product was mixed and stood to separate. The organic phase was discarded. The pH of the aqueous phase was adjusted with NaOH to 7. The mixture was extracted with dichloromethane (40 mL*2) and the aqueous phase was discarded. The organic phase was washed with distilled water (40 mL*1) once and the aqueous phase was discarded. The organic phase was directly concentrated to give the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | In acetonitrile; at 20℃; for 3h; | General procedure: To the solution of 4-nitrobenzylbromide (10.8 g, 0.05mol) or 4-chloronitrobenzene (7.9 g, 0.05 mol) in acetonitrile(50 mL), excessive secondary amine (50 mL) was added andstirred at room temperature for 3 h. Then water (100 mL)was added and extracted two times with dichloromethane(CH2Cl2). The organic extracts were combined, dried oversodium sulfate, filtered, and concentrated to obtain the compounds5 and 7a-c. |
85.5% | In acetonitrile; at 20℃; for 3h; | General procedure: 4-Nitrobenzyl bromide (10.8 g, 0.05 mol) or 4-chloronitrobenzene (7.9 g, 0.05 mol) was dissolved in acetonitrile (50 mL), excessive secondary amine (50 mL) was added, the reaction was stirred at room temperature for 3 h, water (100 mL) was added, and extracted two times with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to obtain the compounds 5a-e. |
85.5% | In acetonitrile; at 20℃; for 3h; | General procedure: Preparation of p-nitrobenzyl bromide (10.8 g, 0.05 mol) was added to acetonitrile (50 mL).Stir at room temperature. Add small molecule secondary amine (0.25mol), react at room temperature for 3h, after the reaction is completed, add water, extract with dichloromethane (100mL×3), dry Na2SO4Dry organic layer,Concentrate to a pale yellow liquid or a yellow solid 1a-c. |
84% | With potassium carbonate; In water; acetonitrile; at 0 - 50℃; for 1h; | To a mixture of 4-nitrobenzyl bromide (4g, 18.5mmol) and potassium carbonate (7.65g, 55.5mmoi) in acetonitrile (50ml) at 0-50C was added 40% aqueous dimethyl amine solution (1.5eq). After 1 hr at room temperature, the solvent was evaporated; the crude material was dissolved in water and extracted with ethyl acetate. The organic layer was dried and concentrated to give dimethyl-(4-nitro-beitauz;yl)-amine (2.8g, 84%) |
83% | In acetonitrile; at 20℃; for 3h; | 25 ml of excess compound dimethylamine was added to a solution of 5 g (23.1 mmol) of 1-(bromomethyl)-4-nitrobenzene (compound a) in 30 ml of acetonitrile. The mixture was stirred at room temperature for 3 hours, added with 5 ml of water and then extracted twice with DCM (dichloromethane, dichloromethane). The organic phase was dried over sodium sulfate, filtered and condensed to give 3.5 g (83%) of a yellow oil compound (b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The following compounds are prepared analogously to Example V: ... 4-(4-isopropyl-piperidino-methyl)-nitrobenzene 4-(4-phenyl-piperidino-methyl)-nitrobenzene 4-(4-benzyl -piperidino-methyl)-nitrobenzene 4-(4-ethoxycarbonyl-piperidino-methyl)-nitrobenzene 4-(dimethylamino-methyl)-nitrobenzene 4-(di-n-propylamino-methyl)-nitrobenzene 4-(4-tert.butoxycarbonyl-piperazino-methyl)-nitrobenzene 3-(dimethylamino-methyl)-nitrobenzene ... | ||
The following are prepared analogously: ... 4-(4-benzyl-piperidino-methyl)-nitrobenzene 4-(4-ethoxycarbonyl-piperidino-methyl)-nitrobenzene 4-(dimethylamino-methyl)-nitrobenzene 4-(dipropylamino-methyl)-nitrobenzene ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | C-I) 4-Amino-dimethylbenzylamine7 g (46.3 mmol, 1 eq) 4-nitrobenzaldehyde are dissolved in 1 ,2-dichloroethane, then27.7 mL of dimethylamine (55.6 mmol, 1.2 eq, 2 molar solution in THF) are added and the solution is stirred for 10 min at RT. To this are then added, successively, 3.2 mL (55.6 mmol, 1.2 eq) acetic acid and 14.7 g (69.5 mmol, 1.5 eq) sodium trisacetoxyboro hydride and the reaction mixture is stirred for 1 h at RT. The reaction mixture is slowly poured into saturated, aqueous sodium hydrogen carbonate solution. The aqueous phase is washed twice with 100 mL of DCM and the combined organic phases are dried on magnesium sulphate. 6.9 g (38.1 mmol, 82%) 4-nitro-dimethylbenzylamine are obtained, which is used in the following reduction without any further purification. MS-ESI+: 181 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In accordance with this invention, it has been discovered that this process is applicable to a variety of compounds. In theory, any aromatics that can be nitrated under conventional conditions and contain a basic nitrogen atom can be nitrated using this protocol. Some examples are listed in Table 1 through Table 4. For all the examples listed in tables 1 through 4, the nitration was carried out by adding a solution or suspension of the nitrate salt to approximately 10 equivalents of concentrated sulfuric acid. The substrates that can be covered in this invention are summarized in the following groups. |
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