Structure of 200283-08-5
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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. : | 200283-08-5 |
Formula : | C14H28N2O5 |
M.W : | 304.38 |
SMILES Code : | O=C(NCCN(CCO)C(OC(C)(C)C)=O)OC(C)(C)C |
MDL No. : | MFCD24466012 |
InChI Key : | AIUKWIFZPQMOBA-UHFFFAOYSA-N |
Pubchem ID : | 22741532 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 21 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.86 |
Num. rotatable bonds | 11 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 79.7 |
TPSA ? Topological Polar Surface Area: Calculated from |
88.1 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.02 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.13 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.62 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.71 |
Solubility | 5.89 mg/ml ; 0.0194 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.57 |
Solubility | 0.812 mg/ml ; 0.00267 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.1 |
Solubility | 2.42 mg/ml ; 0.00796 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 |
-7.35 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
1.0 |
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 |
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) |
2.97 |
* 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 |
---|---|---|
84% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 72h; | [00431] To a solution of fert-butyl (2-((fert-butoxycarbonyl)amino)ethyl)(2- hydroxyethyl)carbamate (2.3 g, 7.56 mmol), phthalimide (1.21 g, 8.24 mmol), and triphenyl phosphine (2.16 g, 8.24 mmol) in tetrahydrofuran (50 mL) at 0 C was added dropwise diisopropyl azodicarboxylate (DIAD) (1.62 mL, 8.24 mmol) and the reaction mixture stirred at room temperature for three days. The solvent was removed to get the crude product which was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give fert-butyl (2-((tert- butoxycarbonyl)amino)ethyl)(2-(l,3-dioxoisoindolin-2-yl)ethyl)carbamate (2.75 g, 84%) as a foamy white solid. NMR (300 MHz, CDCb): delta ppm 7.82 (m, 2H); 7.72-7.69 (m, 2H); 5.16 (bs, 1H); 3.83-3.79 (m, 2H); 3.50-3.49 (m, 2H); 3.33-3.28 (m, 4H); 1.40 (s, 9H); 1.21 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; ethanol; at 20℃; for 24h; | N-(2-Hydroxyethyl)ethylenediamine (2.06 g; commercial) and TEA (13.8 mL) weredissolved in EtOH (30 mL) and THF (30 mL), di-tert-butyl dicarbonate (10.8 g) was addedand the mixture was stirred at rt for 1 day. TBME and 2M aq. HC1 was added and the org. layer was washed with sat. aq. NaHCO3 and brine, dried over Mg504 and concentrated under reduced pressure. The title compound was obtained as an off-white oil (6.98 g; quant.).M53 (ESI, mlz): 305.01 [M+H]; tR = 0.73 mm. |
95% | With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; | General procedure: The corresponding amino alcohol was dissolved in a suspension of NaHCO3 in THF/H2O (1 : 1).tert-Butoxycarbonyl anhydride was added slowly at 0 C. The mixture was stirred overnightat room temperature. By slow addition of AcOH at 0 C the mixture was then acidified topH = 4 and extracted with CH2Cl2 (1 × 30 mL, 2 × 25 mL). The combined organic phases weredried over Na2SO4, filtered, and the solvent was removed by evaporation. The crude productstill contained acetic acid. The amount of residual acetic acid was determined by integralsarising from hydrogen atoms (CH3COOH) in the 1H NMR spectra. The compounds were usedfor further reactions without additional purification. Residual acetic acid: 18-33.0%.Boc-protected N-(2-hydroxyethyl)ethylenediamine (2a): For the synthesis of 2a, the followingwas used: 1a (1.00 g, 9.6 mmol), NaHCO3 (2.42 g, 28.8 mmol), THF/H2O (60 mL), Boc2O(5 g, 23.0 mmol). Residual AcOH: 17.8%. Yield: 2.94 g (95%). Colorless oily liquid. 1H NMR(400 MHz, CDCl3), delta (ppm): 1.40 (s, 9H, 3CH3), 1.43 (s, 9H, 3CH3), 3.27 (br, 4H, 2CH2), 3.33 (br, 2H,CH2), 3.70 (br, 2H, CH2). 13C NMR (400 MHz, CDCl3), delta (ppm): 28.39 (s, CH3), 28.40 (s, CH3), 39.8(s, CH2), 48.5 (s, CH2), 51.3 (s, CH2), 62.9 (s, CH2), 79.5, 80.4 (s, OC(CH3)3), 156.4 (br, N(CO)O). |
65% | In tetrahydrofuran; at 0 - 20℃; | [00430] To a solution of 2-((2-aminoethyl)amino)ethanol (2.0 g, 20 mmol) in tetrahydrofuran (40 mL) at 0 C was added a solution of di-fert-butyldicarbonate (9.2 g, 40 mmol) in tetrahydrofuran (10 mL) and the reaction mixture stirred overnight at room temperature. The solvent was removed and the residue dissolved in ethyl acetate. The solution was washed with brine, dried with anhydrous sodium sulfate and the solvent removed under vacuum to get the crude product, which was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give fert-butyl (2-((teri-butoxycarbonyl)amino)ethyl)(2-hydroxyethyl)carbamate (3.8 g, 65%). |
In dichloromethane; at 20℃; for 2h; | 2-((2-Aminoethyl)amino)ethan-1-ol (2.0 g, 19.2 mmol) (10.0 g, 84.62 mmol) and di-tert-butyl dicarbonate (9.26 g, 40.32 mmol) were dissolved in dichloromethane (57 ml) and the mixture was was stirred at room temperature for 2 hours. The solvent was removed under reducedpressure. The compound was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In acetonitrile; at 20℃; for 48h; | General procedure: The corresponding Boc-protected aminoalcohol was dissolved in dry acetonitrile.N-methylisatoic anhydride and K2CO3 were added to the solution. The mixture was stirredfor 48 h at room temperature. The solvent then was removed by evaporation and the crudeproduct was purified by centrifugally accelerated, radial, thin-layer chromatography. Theeluent was changed from n-hexane to n-hexane/acetone to acetone. The fractions whichcontained the product (TLC) were combined and the solvent was removed by evaporation. 3a: For the synthesis of 3a, the following was used: 2a (2.94 g, 9.7 mmol), CH3CN (100 mL),N-methylisatoic anhydride (2.60 g, 14.7 mmol), K2CO3 (6.9 g, 50 mmol). Yield: 1.26 g (31%).White powder. 1H NMR (200 MHz, CDCl3), delta (ppm): 1.40 (s, 18H, 6CH3), 2.88 (s, 3H, CH3), 3.27(br, 2H, CH2), 3.38 (br, 2H, CH2), 3.55 (br, 2H, CH2), 4.32 (t, 3J(H/H) = 5.43 Hz, 2H, CH2), 6.54 (ddd,J(H/H) = 8.1, 7.2, 1.0 Hz, 1H, CArH), 6.63 (d, 3J(H/H) = 8.5 Hz, 1H, CArH), 7.35 (ddd, J(H/H) = 8.6,7.1, 1.7 Hz, 1H, CArH), 7.85 (dd, J(H/H) = 8.0, 1.6 Hz, 1H, CArH). 13C NMR (200 MHz, CDCl3), delta(ppm): 28.51 (s, CH3), 28.57 (s, CH3), 29.7 (s, CH3), 39.7 (s, CH2), 46.7 (s, CH2), 62.4 (s, CH2), 80.5(s, OC(CH3)3), 109.8 (s, CipsoCOO), 111.0 (s, CAr), 114.6 (s, CAr), 131.8 (s, CAr), 135.0 (s, CAr), 152.3(s, CipsoN), 156.1 (s, N(CO)O), 168.5 (s, (CO)O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; | N-(O-(3-maleinimidobenzoyl)-2-hydroxyethyl)-N,N'-bis-tertiarybutyloxycarbonyl-1,2-diaminoethane To a solution of 8 g (26.3 mmol) <strong>[200283-08-5]N-(2-hydroxyethyl)-N,N'-bis-tertiarybutyloxycarbonyl-1,2-diaminoethane</strong> in 50 ml of tetrahydrofuran and 4 ml (28.9 mmol, 1.1 eq) of triethylamine, 6.82 g (29 mmol, 1.1 eq) of maleinimidobenzoic acid chloride, dissolved in 100 ml of tetrahydrofuran, are added drop-wise at room temperature while stirring within 1 h. After stirring for a further 8 h at room temperature, according to DC, the reaction is completed. The triethylammonium chloride formed in the reaction is filtered off. After removal of the tetrahydrofuran and the excess triethylamine under a vacuum, the oil formed is purified using column chromatography (silica gel: ethyl acetate/hexane (1:1), Rf-value (ethyl acetate/hexane 1:1)=0.2, yield: 9.6 g (19.1 mmol) of the product in the forM a yellow oil, corresponding to 72.6% of the theoretically possible yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 42h; | To a suspension of intermediate 4 (3.0 g, 11.14 mmol), the intermediate 1 (5.08 g, 16.71 mmol) and triphenylphosphine (4.38 g, 16.71 mmol) in a mixture of dry tetrahydrofuran (33ml) and dry N,N-dimethylformamide (6 ml) was added diisopropyl azodicarboxylate (3.31 ml,16.71 mmol). The suspension was stirred at room temperature for 15 hours. More diisopropyl azodicarboxylate (1 .05 eq) and triphenylphosphine (1 .8 eq) were added and the mixture was stirred at room temperature for 27 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organiclayer was dried, filtered and the solvent was removed under reduce pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.Yield: 3.25 g of intermediate 5 (52%)LCMS method 1: MH = 578 (MW+Na), RT = 1.281 mm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; In tetrahydrofuran; tert-butyl alcohol; at 90℃; for 4h; | To a solution of intermediate 1 (4.03 g, 16.66 mmol) in a mixture of tetrahydrofuran and tertbutanol (1:1, 100 ml) were added 4-(dimethylamino)pyridine (1.22 ml, 10.00 mmol) and di-tert-butyl dicarbonate (7.27 g, 33.32 mmol). The mixture was stirred at 9000 for 4 hours. The mixture was cooled to room temperature and water water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elutionfrom 0% to 30% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.Yield: 4.36 g of intermediate 32 (88%)LOMS method 1: MH = 242 (MW-tBu), RT = 0.858 mm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Diacid 6, 0.50 g (0.70 mmol), was dissolved in methylene chloride, 0.18 g (0.90 mmol) of DCC and 12 mg (0.10 mmol) of DMAP were added, and the mixture was stirred for 1 h at 0C. The precipitate was filtered off, 0.85 g (2.81 mmol) of 7 was added to the filtrate, and the mixture was stirred for 24 h at room temperature. The product was isolated by column chromatography and was deprotected by treatment with trifluoroacetic acid in methylene chloride for 3 h. The solvent was removed under reduced pressure. |
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