Structure of 144222-22-0
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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. : | 144222-22-0 |
Formula : | C11H22N2O2 |
M.W : | 214.30 |
SMILES Code : | NCC1CCN(C(OC(C)(C)C)=O)CC1 |
MDL No. : | MFCD01076207 |
InChI Key : | KLKBCNDBOVRQIJ-UHFFFAOYSA-N |
Pubchem ID : | 736817 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.91 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 64.11 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.56 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.65 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.92 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.21 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.15 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.69 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.33 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.48 |
Solubility | 7.03 mg/ml ; 0.0328 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.67 |
Solubility | 4.55 mg/ml ; 0.0212 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.33 |
Solubility | 10.1 mg/ml ; 0.0471 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 |
-6.95 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 |
0.0 |
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) |
2.17 |
* 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% | In methanol; for 2h;Heating / reflux; | [0538] A solution of 643 mg (3.00 mmol) tert. butyl-4-aminomethyl-piperidin-1-carboxylate and 471 mg (3.00 mmol) <strong>[31872-62-5]4-methoxy-3-nitro-pyridine</strong> in 5 mL MeOH was refluxed for 2 hours and then evaporated down i. vac. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 100:0-->19:1 v/v) (Yield: 1.010 g, quantitative). [0539] The intermediate product was added to a suspension of 500 mg Raney nickel in 30 mL MeOH and the mixture was hydrogenated for 6 hours at 50° C. and 50 psi H2-pressure. The catalyst was filtered off and the filtrate evaporated i. vac. The crude product was purified by column chromatography (Alox (neutral, activity II-III), Gradient dichloromethane/MeOH 99:1-->19:1 v/v) purified. [0540] Yield: 0.480 g (53percent of theory) [0541] Rf=0.15 (silica gel, dichloromethane/MeOH 19/1 v/v) [0542] ESI-MS: (M+H)+=307 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With 4-methyl-morpholine; In dichloromethane; | EXAMPLE 18 N-(N-tert.butoxycarbonyl-piperidin-4-yl-methyl)-3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid amide Prepared analogously to Example 7 from 3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid and N-tert.butoxy-carbonyl-piperidin-4-yl-methylamine in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield:38% of theory Rf value:0.68 (silica gel; dichloromethane/ethanol=9:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; water; | Reference Example 29 Preparation of 1-(tert-Butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine N-{3-(Trifluoromethyl)benzoyl}glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and Et3N (1.72 g) were added to a solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g) in dry CH2Cl2 (200 mL). The reaction mixture was stirred at 25 C. for 20 h. H2O (100 mL) was added to the reaction mixture and the mixture was extracted with CH2Cl2 (2*50 mL). The combined extracts were washed with H2O (2*50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed under reduced pressure to afford an yellow oil which was purified by column chromatography (SiO2, 70% EtOAc-hexane) to give 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (6.39 g, 85%): 1H-NMR (CDCl3, 300 MHz) delta1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J=7.2, 7,2 Hz), 7.79 (d, 1H, J=7,2 Hz), 8.0 (d, 1H, J=7.2 Hz), 8.11 (s, 1H); The purity was determined by RPLc/MS (97); ESI/MS m/e 444.3 (M++H, C21H28F3N3O4). |
85% | With triethylamine; In dichloromethane; water; | [Reference Example 29] Synthesis of 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine N-[3-(Trifluoromethyl)benzoyl]glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and triethylamine (1.72 g) were added to an anhydrous dichloromethane (200 mL) solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g). The resulting reaction mixture was stirred at 25 C for 20 hours, and H2O (100 mL) was then added to the mixture. The obtained mixture was extracted with dichloromethane (50 mL * 2). The extracts were combined, washed with H2O (50 mL * 2) and brine (50 mL), dried (over MgSO4) and concentrated to thereby afford a yellow oil. The obtained crude product was purified by column chromatography (SiO2,70% ethyl acetate-hexane) to provide 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine as a white solid (6.39 g, 85%). 1H NMR(CDCl3, 300MHz) delta 1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J = 7.2, 7.2 Hz), 7.79 (d, 1H, J = 7.2 Hz), 8.0 (d, 1H, J = 7.2 Hz), 8.11 (s, 1H). The purity was determined by RPLC/MS (97%). ESI/MS m/e 444.3 (M++H, C21H28N3O4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; at 100℃; for 48h; | 4-[(3-Pyhdin-4-yl-[2, 6]naphthyridin- 1 -ylamino) -methylj-piperidine- 1 -carboxylic acid tert-butyl ester.; To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (50.0 mg, 0.197 mmol) in 1 ,4- dioxane (5 ml_) is added 4-aminomethyl-piperidine-1 -carboxylic acid fert-butyl ester (128 mg, 0.590 mmol) and 40% aqueous NaOH (29.0 μl_, 0.290 mmol) at rt. The reaction mixture is heated to 1000C for 48 h, and then cooled to rt, diluted with EtOAc and filtered through a Florisil plug. The filtrate is evaporated to dryness to yield the title compound as a yellow oil, which is used without further purification for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In acetonitrile; for 0.516667h; | A solution of 4-(aminomethyl)-1-boc-pipeiotadine (370 mg, 1.73 mmol) in acetonitrile (1 ml_) was added over 1 minute to a solution of <strong>[1137475-57-0]2-bromo-4-chloro-5-nitropyridine</strong> (373 mg, 1.57 mmol) and triethylamine (0.24 mL, 1.73 mmol) in acetonitrile (5 mL). The solution was stirred for 30 minutes then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (x3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 4-((2-bromo-5-nitropyridin-4- ylamino)methyl)piperidine-1-carboxylate as a light brown foam (640 mg, 98%) which was used without further purification.1H NMR (MeOD, 400MHz) delta 8.82 (s, 1 H), 7.25 (s, 1 H), 4.14 (m, 3H), 3.35 (s, 1H), 1.97- 1.88 (m, 1H), 1.80 (m, 3H), 1.27-1.17 (m, 3H). LCMS (1) Rt = 2.35 min; m/z (ESI+) 415, 417 (MH+). |
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