Structure of 2359-60-6
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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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CAS No. : | 2359-60-6 |
Formula : | C11H16N2 |
M.W : | 176.26 |
SMILES Code : | NC1=CC=C(C=C1)N1CCCCC1 |
MDL No. : | MFCD00051688 |
InChI Key : | TVOSOIXYPHKEAR-UHFFFAOYSA-N |
Pubchem ID : | 413501 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.45 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 60.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.9 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.75 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.89 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.0 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.08 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.94 |
Solubility | 0.202 mg/ml ; 0.00115 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.02 |
Solubility | 0.169 mg/ml ; 0.000956 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.76 |
Solubility | 0.306 mg/ml ; 0.00174 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) |
No |
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 |
-5.42 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 |
2.0 alert |
Brenk? Structural Alert: implemented from |
1.0 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) |
1.07 |
* 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 |
---|---|---|
100% | With palladium on activated charcoal; hydrogen; In ethyl acetate; at 20℃; for 3h; | 4-Fluoronitrobenzene (323 mg, 2.3 mmol) was dissolved in DMSO (5 ml), potassium carbonate (475 mg, 3.5 mmol) and piperidine (460 mul, 4.6 mmol) were added, and the mixture was stirred at 90 C. for 9 hr. Then, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated aqueous NaCl. The organic layer was dried over Na2CO3, the solvent was evaporated to give compound Y197 (yield; 472 mg, 100%). Compound Y197 was dissolved in ethyl acetate (20 ml), Pd/C (186 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. Then, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (40:1)) to give compound Y222 (yield, quantitative, 394 mg). Compound Y491 (mentioned later) (80 mg, 0.18 mmol) was dissolved in dichloromethane (2 ml), compound Y222 (100 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 5 hr. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (35:1)) to give the title compound (yield; 68 mg, 64%). 1H NMR (500 MHz, CDCl3) delta8.40 (s, 1H), 8.0 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.52 (dd, 1H, J=8.0, 7.5 Hz), 6.92 (dd, 2H, J=9.0, 3.5 Hz), 6.77 (dd, 2H, J=9.0, 6.5 Hz), 5.33 (t, 1H, J=6.0 Hz), 4.07 (bs, 2H), 3.11-3.09 (m, 4H), 2.79-2.64 (m, 4H), 1.69-1.53 (m, 10H), 1.43 (s, 9H), 1.09-1.01 (m, 2H) 13C NMR (125 MHz, CDCl3) delta154.9, 141.6, 140.8, 131.4, 130.9, 129.8, 125.8, 125.7, 79.7, 77.4, 48.7, 36.6, 29.6, 28.6, 25.7, 24.2 HRMS (FAB-) m/z: [M-H]- calcd for C28H39N4O6S2, 591.2311. found, 591.2324 |
99% | With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; | A suspension of 1.01 g (5 mmol) 1-bromo-4-nitrobenzene, 1.5 g K2CO3, 0.59 mL (6 mmol) piperidine in 10 mL of DMF was heated to reflux overnight. Upon cooling, the reaction mixture was dilute with water, extracted with EA, and the organic layer was washed with water, followed by saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography (PE : EA = 50:1, 30:1) to afford 902 mg (87%) yellow solid. The solid was dissolved in methanol, 90 mg Pd-C (10%) was added and stirred under hydrogen overnight at room temperature and then filtered through Celite and concentratedin vacuo. The crude product was purified by flash chromatography (PEEA = 5:1) to afford 4l? 0.706 g 99%. |
96% | Synthesis of 4-Piperidin-1-yl-phenylamine Ammonium chloride (228 mg, 4.2 mmol) in water (4 mL) was added to a solution of 1-(4-nitro-phenyl)-piperidine (220 mg, 1.0 mmol) in THF (6 mL) and the resulting mixture was stirred at 75 C. for 30 minutes. Iron powder (238 mg, 4.2 mmol) was then added portion wise and the mixture stirred for 5 hours at 75 C. The reaction mixture was filtered over celite, the filtrate was basified with sodium bicarbonate solution and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 180 mg (96%) of 4-Piperidin-1-yl-phenylamine. LCMS: 177.13 (M+1)+, 80.6%, 1H NMR: (DMSO-d6): delta 6.67 (m, 2H), 6.47 (m, 2H), 4.51 (s, 2H), 2.57 (t, 4H), 1.6 (q, 4H), 1.49 (m, 2H) |
85% | With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 23h; | To a solution of <strong>[6574-15-8]1-(4-nitrophenyl)piperidine</strong> 15 (5.67 g, 0.028 mol) in EtOH (150 mL) was added 10%Pd/C (0.586 g, 10% w/w). The resulting mixture was stirred at roomtemperature under an atmosphere of hydrogen for 23 h. Aftercompletion, the mixture was filtered through Celite and washedwith EtOH. The solvent was removed in vacuo to afford a red oilwhich was extracted with DCM (3 x 10 mL) and washed with brine.The combined organic extracts were dried (MgSO4) and the solventwas removed in vacuo to give the title compound 18 (4.12 g, 85%) as ared oil which was used without further purification. deltaH (400 MHz;CDCl3) 1.51-1.57 (2H, m, H-40), 1.70-1.75 (4H, m, H-30), 3.00 (4H, t,J 5.5 Hz, H-20), 3.41 (2H, s, NH2), 6.63 (2H, d, J 8.8 Hz, H-2), 6.83(2H, d, J 8.8 Hz, H-3). deltaC (100 MHz; CDCl3) 24.2 (C-40), 26.2 (C-30),52.6 (C-20), 116.2 (C-2), 119.1 (C-3), 139.8 (C-1), 145.8 (C-4); IR numax(ATR)/cm-1: 3336, 2930, 2851, 1620, 1509, 1229, 819; m/z(ESI+): 259 (71%), 177 (100%); HRMS (ESI+) found (MH+): 177.1380,C11H17N2 requires 177.1386. The 1H NMR data were in agreementwith literature values [26]. |
80% | With palladium 10% on activated carbon; hydrazine hydrate; In ethanol; for 12h;Reflux; | The second step: to install a magnetic stir, thermometer, condenser 500mL three-necked flask is addedThe first step in the reaction of 15.0g of 4-nitrophenyl piperidine powder, 2.0g of 10% mass fraction of Pd / C,180mL of ethanol was added as a solvent, and stirred to obtain a uniform suspension. After heating to reflux, the suspensionWas slowly added dropwise 45.0g of mass fraction of 80% hydrazine hydrate solution, stirring continued at reflux for 12h. The reaction was completeCompleted, the reaction solution was filtered hot to remove Pd / C, the filtrate was concentrated under reduced pressure to 1/4 of its original volume, under a nitrogen atmosphereCooling and crystallization, to obtain a gray 4-aminophenyl-piperidine 10.2 g of crystals, 80% yield; |
75% | With palladium 10% on activated carbon; hydrazine hydrate; In ethanol; for 10h;Reflux; | In a 500mL round-bottom flask, 28.3g (0.14mol) of nitro compound 1, 0.2g of 10 wt% Pd/C, 20mL hydrazine monohydrate and 180mL of ethanol was stirred at a reflux temperature for 10h. The solution was filtered hot to remove Pd/C, and the filtrate was evaporated under reduced pressure to dryness. A deep purplish red liquid was obtained. The product (2) was used for the next step without further purification. The yield was 18.1g (75%). IR (KBr): 3429, 3346cm-1 (-NH2 str.). 1H NMR (500MHz, DMSO-d6, delta, ppm): 6.66 (d, J=8.8Hz, 2H, He), 6.48 (d, J=8.8Hz, 2H, Hd), 4.49 (s, 2H, -NH2), 2.84 (t, J=5.4Hz, 4H, Hc), 1.59 (m, 4H, Hb), 1.45 (m, 2H, Ha). 13C NMR (125MHz, DMSO-d6, delta, ppm): 143.5 (C4), 141.9 (C7), 118.6 (C6), 114.7 (C5), 52.1 (C3), 25.8 (C2), 23.8 (C1) |
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; | 10% Palladium on carbon (0.05 g) was added to a solution of the nitroaniline (0.001 mol) in ethanol (50 mL) under a H2 (g) atmosphere (via balloon). The reaction mixture stirred at r. t. overnight and was then filtered through celite. The filtrate was concentrated to afford a dark yellow oil. | |
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; | Step 2:; 10% Palladium on carbon (0.05 g) was added to a solution of the nitroaniline (0.001 mol) in ethanol (50 mL) under a H2 (g) atmosphere (via balloon). The reaction mixture stirred at r. t. overnight and was then filtered through celite. The filtrate was concentrated to afford a dark yellow oil. | |
384 mg | With iron; ammonium chloride; In methanol; water; at 100℃; | General procedure: The compound S1 (261 mg, 1.25 mmol), iron powder (210 mg, 4.76 mmol, 3 equiv.) and ammonium chloride (335 mg, 6.27 mmol, 5 equiv.) were dissolved in methanol : water (2 : 1, 15 mL). The reaction mixture was heated at 100 C overnight, cooled to RT, filtered through celite and the solvent was reduced under vacuum. The condensed mixture was extracted with DCM, washed with brine, dried with sodium sulfate and all solvent was evaporated to furnish the condensed residue, which was purified by flash chromatography (elution system - EA/Hexane = 1 : 1 ) to obtain the title compound (245 mg, 1.43 mmol). |
With 5%-palladium/activated carbon; hydrogen; In ethanol; water; at 20℃; | General procedure: The substituted nitro compound 11 (1 equiv in a mixture of EtOH-H2O, 95:5, 20mL) was treated with 10% Pd-carbon (5% w/w). The reaction was subjected to hydrogenation under hydrogen gas at room temperature and the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through a Celite bed and concentrated in a vacuum to afford product 12. | |
With FeO(OH)/C; hydrazine hydrate; In ethanol; at 0 - 80℃; for 4h; | General procedure: To a solution of 1a (5 g, 22.5 mmol) in 95% ethanol (100 mL) wasadded goethite (FeO(OH))/C (1.0 g) at room temperature. And a solution of 80% hydrazine hydrate (25 mL, 400 mmol) in 95% ethanol (50 mL) was added dropwise to the mixture at 0 C. The reaction mixture was stirred at 80 C for 4 h. The solvent was removed in vacuo to give 2a (3.8 g, yield 74.5%). MS m/z: 278.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Following the procedure outlined in Step 2 of Example 1, but substituting 4-piperidin-1-yl-1-nitrobenzene for 1-methyl-4-(4-nitrophenyl)piperazine, afforded 4-piperidin-1-ylaniline, which was reacted with 9-chloroacridine (according to Step 4 in the procedure of Example 1) to obtain the title compound with 6% overall yield. 1H NMR (CDCl3, 500 MHz): 8.05 (2H, m), 8.00 (2H, m), 7.48 (2H, m), 7.09 (4H, m), 6.86 (2H, m), 3.13 (4H, m), 1.71 (4H, m), 1.58 (2H, m); MS (ESI+TOF): 354 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.7% | With trifluoroacetic acid; In iso-butanol; at 100℃; | General procedure: To a solution of 3a-r (1.50 mmol, 1 eq) and 6a-b (1.50 mmol, 1eq) in 2-BuOH (8 mL) were added TFA (2 mL). The slurrywas heatedto 100 C for 2e3 h. The reaction mixture was allowed to cool toroom temperature and was neutralized with a saturated aqueoussodium bicarbonate solution. The mixture was then extracted withethyl acetate (50 mL) three times. The crude was purified by flashchromatography with 25:1 (v/v) dichloromethane - methanol. |
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