Structure of 58859-46-4
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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. : | 58859-46-4 |
Formula : | C8H16N2O2 |
M.W : | 172.22 |
SMILES Code : | O=C(N1CCC(N)CC1)OCC |
MDL No. : | MFCD00006484 |
InChI Key : | GQQQULCEHJQUJT-UHFFFAOYSA-N |
Pubchem ID : | 100867 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H227-H315-H319-H335 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.88 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 49.65 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.56 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.1 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.11 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.19 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.24 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.07 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.78 |
Solubility | 28.6 mg/ml ; 0.166 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.83 |
Solubility | 25.4 mg/ml ; 0.147 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.49 |
Solubility | 55.5 mg/ml ; 0.322 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 |
No |
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 |
-7.27 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) |
1.92 |
* 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 |
---|---|---|
45% | In N,N-dimethyl acetamide; at 155℃; for 68h;Inert atmosphere; | Compound 3 (0.38 mmol, 100 mg) was dissolved in dimethylacetamide (3 mL), followed by addition of ethyl 4-aminopiperidinecarboxylate (3.8 mmol, 0.65 mL). The reaction mixture was stirred at 155 C in a silicone oil bath for 68 hours and then cooled to room temperature. The reaction mixture was then diluted with ethyl acetate and poured into a 50% saturated brine solution and then extracted with dichioromethane. The crude product was purified by column chromatography on silica gel (hexnne/ethyl acetate; 10:90) to afford Compound 4 (69.5 mg, 45%) as a yellow solid. [00124] 1H NMR (500 MHz, Methanol-d4 σ 7.35 - 7.26 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.06 - 6.98 (m, 4H), 6.93 (ddd, J = 8.1 , 7.3, 1 .1 Hz, 1 H), 5.22 (s, 2H), 4.10 (qd, J = 7.0, 4.0 Hz, 4H), 3.95 (it, J = 11.0, 4.0 Hz, 2H), 2.98 (s, 1 H), 2.10 - 1.98 (m, 2H), 1.45 (dd, J = 11.9, 4.2 Hz, 2H), 1.24 (td, J = 7.1 , 3.3 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) σ 163.56 (d, J = 244.6 Hz), 157.19, 155.18, 142.92, 135.30, 133.75, 129.56, 122.50, 120.86, 116.52, 116.35, 116.08, 109.13, 62.70, 51.43, 45.24, 44.10, 33.11 , 14.96. IR (neat): 3275, 1694, 1220 cm'1, m/z: [(M+H)+ ] calcd for (C22H26FNO2) 397.2040; Found 397.2070. mp 120-123 C. |
45% | In N,N-dimethyl acetamide; at 155℃; for 68h;Inert atmosphere; | Compound 3 (0.38 mmol, 100 mg) was dissolved in dimethylacetamide (3 mL), followed by addition of ethyl 4-aminopiperidinecarboxylate (3.8 mmol, 0.65 mL). The reaction mixture was stirred at 155 C in a silicone oil bath for 68 hours and then cooled to room temperature. The reaction mixture was then diluted with ethyl acetate and poured into a 50% saturated brine solution and then extracted with dichioromethane. The crude product was purified by column chromatography on silica gel (hexnne/ethyl acetate; 10:90) to afford Compound 4 (69.5 mg, 45%) as a yellow solid. [00124] 1H NMR (500 MHz, Methanol-d4 σ 7.35 - 7.26 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.06 - 6.98 (m, 4H), 6.93 (ddd, J = 8.1 , 7.3, 1 .1 Hz, 1 H), 5.22 (s, 2H), 4.10 (qd, J = 7.0, 4.0 Hz, 4H), 3.95 (it, J = 11.0, 4.0 Hz, 2H), 2.98 (s, 1 H), 2.10 - 1.98 (m, 2H), 1.45 (dd, J = 11.9, 4.2 Hz, 2H), 1.24 (td, J = 7.1 , 3.3 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) σ 163.56 (d, J = 244.6 Hz), 157.19, 155.18, 142.92, 135.30, 133.75, 129.56, 122.50, 120.86, 116.52, 116.35, 116.08, 109.13, 62.70, 51.43, 45.24, 44.10, 33.11 , 14.96. IR (neat): 3275, 1694, 1220 cm'1, m/z: [(M+H)+ ] calcd for (C22H26FNO2) 397.2040; Found 397.2070. mp 120-123 C. |
34% | at 180℃; for 0.0166667h;Microwave irradiation; | A mixture of intermediate 1(. 5 g, 1.9 mmol) and 4-amino-1-ethoxycarbonylpiperidine as a colorless oil (0.495 g, 2.8 mmol) was added to the microwave tube, stirred uniformly, microwave 180 C reaction 1min, cooled to room temperature, reddish brown solid, with methanol 15mL and dichloromethane 5mL dissolved after mixing, the column was purified to obtain a white solid, The yield was 34.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,3-Lutidine; 1-methyl-pyrrolidin-2-one; sodium hydroxide; In tetrahydrofuran; | EXAMPLE 8a To a 25 mL 3-neck flask equipped with a thermometer, reflux consenser and stir bar were added, under a nitrogen atmosphere, 822 mg (4.8 mmol) of Compound XII (Lancaster Synthesis, Inc., Windham, N.H.), and 0.93 mL of lutidine. The mixture was heated to 120 C., whereupon a solution of 1.04 g (4 mmol., 1 eq.) of Compound X (Aldrich Chemical Co., Milwaukee, Wis.), 8 mmol of tetrabutylammonium fluoride (obtained from its 1.0M THF solution by distillation under vacuum with anhydrous toluene) and 4 mL of N-methylpyrrolidinone was added slowly over 2 h. The reaction mixture was allowed to stir at 120 C. for 1 h. High-performance liquid chromatography revealed >95% coversion to Compound XIVa (in free base form). The reaction mixture was allowed to cool to ambient temperature, and slowly poured into a solution of 5% aqueous NaOH while stirring. The resulting suspension was allowed to stir at 0-10 C. for 30 minutes, and the resulting solid product was collected by vacuum filtration, washed with water (3*5 mL), and air dried for 30 minutes under vacuum to afford crude Compound XIVa (in free base form): 1 H NMR (300 MHz, CDCl3) δ7.53 (1H, d, J=7.8 Hz), 7.22-6.92 (7H, m, two groups), 5.12 (2H, s), 4.37 (1H, NH br. d), 4.12 (2H+1H, m overlapped), 4.07 (2H, q, J=7.0 Hz), 2.98 (2H, pseudo t), 2.09 (2H, pseudo d), 1.30 (2H, m overlapped), 1.24 (3H, t, J=7.0 Hz); 13 C NMR (75 MHz, CDCl3) δ164.2 and 161.0 (13 C-19 F coupling), 155.6, 153.3, 142.2, 134.5, 131.4, 128.3, 121.8, 120.0, 116.6, 116.3, 116.1, 107.5, 61.5, 50.1, 45.0, 42.8, 32.6, 14.8. It is to be noted that under the same reaction conditions as above, but without the use of tetrabutylammonium fluoride, only 5% conversion (high-performance liquid chromatography) to Compound XIVa (in free base form) was achieved after 3 h at 120 C. The crude Compound XIVa (in free base form) obtained above was placed in a 50 mL, 3-neck flask equipped with a thermometer, reflux condenser and stir bar. 5 mL of 48% hydrobromic acid was added, and the resulting mixture was heated to 110 C. and allowed to stir at that temperature for 2 h. After the reaction was complete (>98% conversion to norastemizole as shown by high-performance liquid chromatography), the reaction mixture was allowed to cool to room temperature, and 10 mL of toluene and 10 mL of water were added, with stirring. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.1 parts (40.5%) | With sodium hydroxide; In water; | Example 4 A mixture of 9.8 parts of ethyl 4-amino-1-piperidinecarboxylate and 15 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole was heated to 120 C. The mixture was stirred at 120 C. during 43 hours. After cooling, 100 parts of trichloromethane were added and the whole was thouroughly stirred. The mixture was washed with water. The aqueous layer was separated and the organic mixture was filtered and evaporated. The collected solid material was dissolved in 100 parts of water and subsequently 100 parts of 20% sodium hydroxide solution were added. The precipitate was filtered and dried in vacuo at 50 C., yielding 12.1 parts (40.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 181 C. (compound 21). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With phenol; at 82 - 100℃; for 92h;Sealed tube; | 4-Chloro-(8-trifluoromethyl)quinoline (1.50 g, 6.5 mmol), ethyl 4-amino-1-piperidinecarboxylate (1.02 g, 5.9 mmol), and phenol (3.04 g, 32 mol) were heated at 82C in asealed Carius vessel for 20 hours. Additional ethyl 4-amino-1-piperidine carboxylate(0.20 g, 1.2 mmol) was added. The vessel was again sealed and heated for a further 3days at 100C. whereupon TLC indicated that no unreacted quinoline remained. Thereaction mixture was diluted with chloroform (25 mL) and rinsed with 10% 8 soda (5 x10 mL), followed by further rinsing with brine (2 x 10 mL). The organic layer was driedover MgSO4 and concentrated under reduced pressure with warming to yield a thick,brown oil. This was diluted with dichloromethane and adsorbed onto silica, thenpurified by flash chromatography on silica, eluting with a gradient of 100% hexanes to100% ethyl acetate. The desired product was obtained as a beige solid (0.63 g, 27%, Rf =0.4 (silica, ethyl acetate)). The quinoline phenolate was also isolated fromchromatography (a sparkling, white, crystalline solid, 0.94 g, 50%, mp = 175.4-181.0C,Rf = 0.7 (silica, ethyl acetate)). |
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