Structure of 101-06-4
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CAS No. : | 101-06-4 |
Formula : | C16H19NO |
M.W : | 241.33 |
SMILES Code : | OCCN(CC1=CC=CC=C1)CC1=CC=CC=C1 |
MDL No. : | MFCD00020574 |
InChI Key : | WTTWSMJHJFNCQB-UHFFFAOYSA-N |
Pubchem ID : | 22657 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 74.37 |
TPSA ? Topological Polar Surface Area: Calculated from |
23.47 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.76 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.57 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.38 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.92 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.75 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.05 |
Solubility | 0.214 mg/ml ; 0.000886 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.71 |
Solubility | 0.47 mg/ml ; 0.00195 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.3 |
Solubility | 0.00121 mg/ml ; 0.000005 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
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 |
-5.95 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) |
1.27 |
* 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 |
---|---|---|
In methanol; | A. Condensed ethylene oxide (7 ml, 125 mmol) was added to a mixture of dibenzylamine (19.2 ml, 100 mmol) in methanol (20 ml) cooled to 0C. After 2 hours at room temperature, the mixture was evaporated without heating above room temperature. The residue was distilled to afford the title compound, bp. 220-225C/25 mm, which solidified on standing, mp 48C. | |
at 130℃; under 3102.97 Torr; for 18h;Inert atmosphere; Autoclave; Large scale; | Dibenzylamine (7627 g) was charged to a 24-L N2-purged pressure vessel. The reactor was pressurized and vented several times with N2, then pressurized with N2 and heated to 130 C. Ethylene oxide (1880 g) was fed into the reactor at such a rate to keep the pressure below 60 psia (?4 h). Upon completing the ethylene oxide addition, the reaction mixture was stirred at 130 C for 14 h. After lowering the temperature to 60 C and releasing pressure, 45%potassium hydroxide (70 g) was added to the vessel and the reaction mixture stirred at 110 C to remove water. The temperature was increased to 130 C and butylene oxide (11,277 g) was fed into the reactor at such a rate to keep the pressure below 60 psia (~31 h). Upon completing the addition, the reaction mixture was stirred for 4 h at 130 C. The reaction mixture was cooled to room temperature and the reaction mixture neutralized with acetic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dibromo sulfoxide; In cyclohexane; N,N-dimethyl-formamide; for 15h; | To <strong>[101-06-4]N,N-dibenzyl-2-aminoethanol</strong> (80.68 g) were added cyclohexane (500 ml) and DMF (12.9 ml), and thereto was added dropwise thionyl bromide (83.4 g). The mixture was stirred for 15 hours, and to the reaction solution was added an saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (72.1 g). 1H NMR (400 MHz, CDCl3) delta 7.48-7.39 (m, 8H), 7.36-7.33 (m, 2H), 3.74 (s, 4H), 3.43 (m, 2H), 2.97 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In ethanol; for 16h;Heating / reflux; | Example 1; Dibenzylaminoethanol:; To a 250 mL round bottom flask equipped with stirbar, reflux condensor, nitrogen inlet, and septum was added potassium carbonate (56.5 g, 0.41 mol), ethanol (80 mL), and ethanolamine (9.9 mL, 0.16 mol). The stirred solution was heated to reflux and benzyl chloride (37.9 mL, 0.33 mol) was added via syringe. The resulting solution was stirred for 16 hours at reflux, allowed to cool, then poured into water (200 mL). The solution was extracted with chloroform (3x300 mL). The combined organic layers were dried with magnesium sulfate, filtered, then evaporated to dryness. Recrystallization from hexanes yielded the product as colorless crystals (32.8 g, 83 %). 1H NMR (300 MHz, CDCl3) delta 7.33 (10 H), 3.60 (4 H), 3.58 (2 H), 2.67 (2H). 13C NMR (75 MHz, CDCl3) delta 138.9, 129.2, 128.6, 127.4, 58.7, 58.4, 55.0. |
69% | With potassium carbonate; In ethanol; for 36h;Reflux; | Dibenzylamino Ethanol Benzyl chloride (278.5g, 2.2 mol), ethanol amine (60 mL, 1 mol), potassium carbonate (283.1g, 2.05mol) and ethanol (2 L) were mixed together in a 3L 3- neck flask, fitted with an overhead stirrer, a condenser and a glass plug. The apparatus was heated up to reflux for 36 hr, after which the insoluble solid was filtered through a medium frit. The filtrate was recovered and ethanol was removed by rotoary evaporation. The viscous liquid was redissolved in ether, the solid suspension removed by filtration and extracted twice against water. The ether solution was kept and the aqueous layer was extracted twice with dichloromethane (2 x 400 mL). The fraction were recombined, dried over MgSO4, stirred over carbon black for 15 min and filtered through a celite pad. Dichloromethane was removed and the solid was redissolved into a minimal amount of ether (combined volume of 300 mL with the first ether fraction, 300 mL). Hexanes ( 1700 mL) was added and the solution was heated up gently till complete dissolution of the product. The solution was then cooled down gently, placed in the fridge (+ 40C) overnight and white crystals were obtained. The recrystallization was done a second time. 166.63g, 69% yield. 1H NMR (d6-DMSO) delta 7.39-7.24 (10H), 4.42 (IH), 3.60 (4H), 3.52 (2H), 2.52 (2H). |
69% | With potassium carbonate; In ethanol; for 36h;Reflux; | Benzyl chloride (278.5 g, 2.2 mol), ethanol amine (60 mE, 1 mol), potassium carbonate (283.1 g, 2.05 mol) and ethanol (2 E) were mixed together in a 3 E 3-neck flask, fitted with an overhead stirrer, a condenser and a glass plug. The apparatus was heated up to reflux for 36 hr, after which the insoluble solid was filtered through a medium frit. The filtrate was recovered and ethanol was removed by rotary evaporation. The viscous liquid was redissolved in ether, the solid suspension removed by filtration and extracted twice against water. The ether solution was kept and the aqueous layer was extracted twice with dichioromethane (2x400 mE). The fraction were recombined, dried over MgSO4, stirred over carbon black for 15 mm and filtered through a celite pad. Dichloromethane was removed and the solid was redissolved into a minimal amount of ether (combined volume of 300 mE with the first ether fraction, 300 mE). Rexanes (1700 mE) was added and the solution was heated up gently till complete dissolution ofthe product. The solution was then cooled down gently, placed in the fridge (+4 C.) overnight and white crystals were obtained. The recrystallization was done a secondtime. 166.63 g, 69% yield. ?RNMR(d5-DMSO)oe 7.39- 7.24 (bR), 4.42 (1R), 3.60 (4R), 3.52 (2R), 2.52 (2R). |
54% | Preparation of aminoalcohol by dibenzylation: 2-Dibenzylamino-ethanol (Intermediate) [Show Image] To a vigorously stirred solution of 6.7 ml (1.12 mol, I equiv.) ethanolamine in 120 ml of (1/1) MeOH/H2O were added 7.2 g (1.8 mol, 1.6 equiv.) of sodium hydroxide and 24.6 g (1.8 mol., 1.6 eq). The suspension was refluxed for 30' before addition of 24.5 ml (2.3 mol., 2 equiv.) of benzyl chloride. The mixture was refluxed overnight before cooled to room temperature and extracted with 3x160 ml of diethyl ether. The organic solution was dried over sodium sulphate, and evaporated. The residue was distilled Kugel Rohr (100C, 1 mm Hg). Colorless oil (54%).1H NMR (400 MHz, CDCl3) delta 7.30 (m, 10H, Ph), 3.68 (s, 4H, NCH2Ph), 3.60 (t, J = 5.4 Hz, 2H, OCH2CH2N), 2.68 (t, J = 5.4 Hz, 2H, OCH2CH2N), 2.36 (Sb, 1 H, OH).LC/MS (ES+) m/z 242.1 (M+H)+ | |
54% | 31) Preparation of aminoalcohols; a. By dibenzylation:; Preparation of 2-Dibenzylamino-ethanol (Intermediate):; [Show Image] To a vigorously stirred solution of 6.7 ml (1.12 mol, 1 equiv.) ethanolamine in 120 ml of (1/1) MeOH/H2O was added 7.2 g (1.8 mol., 1.6 equiv.) of sodium hydroxide. The suspension was refluxed for 30 minutes before addition of 24.5 ml (2.3 mol., 2 equiv.) of benzyl chloride. The mixture was refluxed overnight before cooled to room temperature and extracted with 3x160 ml of diethyl ether. The organic solution was dried over sodium sulphate, and evapored. The residue was distilled by Kugel Rohr (100C, 1 mm Hg). Colorless oil (54%). 1H NMR (400 MHz, CDCl3) delta 7.30 (m, 10H, Ph), 3.68 (s, 4H, NCH2Ph), 3.60 (t, J = 5.4 Hz, 2H, OCH2CH2N), 2.68 (t, J = 5.4 Hz, 2H, OCH2CH2N), 2.36 (sb, 1 H, OH) LC/MS (ES+) m/z 242.1 (M+H)+ | |
50% | With triethylamine; In ethanol; for 12h;Reflux; | Step 1: Preparation of 2-(dibenzylamino)ethanol (Intermediate 31) To a solution of 2-aminoethanol (500 mg, 8.19 mmol) and TEA (2.74 mL,19.7 mmol) in EtOH (11 mL) was added benzyl chloride (1.90 mL, 16.4 nimol) in EtOH (2.0 mL) at room temperature. The reaction mixture was refluxed for 12 hours.After evaporation of volatiles, the residue was diluted with diethyl ether. The mixture was extracted with diluted with diethyl ether and extracted with 2 N aq. HCI. The separated aqueous layer was neutralized with Na2CO3 and extracted with diethyl ether. The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound (980 mg, 50%), which was used for the nextreaction without further purification.?H-NMR (400 MHz, CDCI3): 7.36-7.15 (m, 1OH), 3.63 (s, 4H), 3.58 (t, J= 5.2 Hz, 2H), 2.67 (t, J= 5.2 Hz, 2H) * OH peak was not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: DMSO (3.92 mmol, 2 equiv.) was added dropwise to a stirred solution of oxalyl chloride (2.35 mmol, 1.2 equiv.) in CH2Cl2 (15 mL) under argon at -78 C and the reaction mixture was stirred for 5 min. Then a solution of 2-(dibenzylamino)alcohols 2a-d (1.96 mmol, 1 equiv.) in CH2Cl2 (1 mL) were added. After 30 min of stirring at -78 C triethylamine (7.8 mmol, 4 equiv.) was added, and mixtures were allowed to warm to room temperature over 30 min. The reaction mixtures were then diluted with H2O (30 mL) and CH2Cl2 (30 mL) and the layers were separated. The organic layers were washed with 1% HCl (10 mL), H2O (10 mL), 5% NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtrated and concentrated under reduced pressure. The resulting crude 2-(dibenzylamino)aldehydes 3a-d were used without additional purification. | ||
To a solution of oxalyl chloride (6.95 g, 54.7 mmol) in dichloromethane (150 mL), a solution of dimethyl sulfoxide (9.26 g, 118.5 mmol) in dichloromethane (100 mL) was added dropwise at -70CC. After stirring for 30 mm at -70CC, a solution of 2-(dibenzylamino)ethanol (11 g, 45.58 mmol) in dichloromethane (150 mL) was added to thereaction mixture dropwise. After stirring for another 45 mi triethylamine (19.2 mL, 136.7mmol) was added dropwise and stirred at -70CC for 1.5h.Saturated sodium bicarbonate (200 mL) was added into the reaction mixture, which was extracted with dichloromethane (200 mL). Theorganic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated invacuoto afford the 2-(dibenzylamino)acetaldehyde, which was immediately used in the nextstep.1H NMR (400 MHz, CDC13) oe 9.54 (t, J=1.5 Hz, 1H), 7.42 - 7.24 (m, 1OH), 3.71 (s, 4H),3.20 (d, J=1.5 Hz, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 60℃; for 6h; | To a solution of 2-aminoethanol (10 g, 0.16 mol) in MeCN (150 mL) was added bromomethylbenzene (57.5 g, 0.34 mol) and K2CO3 (45.3 g, 0.33 mol). The mixture was stirred at 60 C. for 6 hours, then cooled to room temperature and filtered. The filtrate was concentrated to give crude 2-(dibenzylamino) ethanol. | |
With potassium carbonate; In acetonitrile; at 60℃; for 6h; | Step 1: Preparation of 2-(dibenzyIamino) ethanol To a solution of 2-aminoethanol (10 g, 0.16 mol) in MeCN ( 150 ml.) was added bromometliylbenzene (57.5 g, 0.34 mol) and K2CO3 (45.3 g, 0.33 mol). The mixture was stirred at 60 C for 6 hours, then cooled to room temperature and filtered. The filtrate was concentrated to give crude 2-(dibenzylamino) ethanol. | |
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetonitrile; at 10℃; for 20h; | To a solution of 2-aminoethanol (10 g, 163.71 mmol) in MeCN (200 mL) was added K2C03 (45.2 g, 327.42 mmol) and tetrabutylammonium iodide (6.05 g, 16.37 mmol) sequentially. (Bromomethyl)benzene (56.08 g, 327.42 mmol) was added dropwise at 10CC. The suspension was stirred for 20 h. After the addition of CHC13 (25 mL), the solid was filtered andwashed with CHC13 (2 x 20 mL). The resulting filtrate was carefully evaporated, and the crude product was purified by silica gel column chromatographyto give 2-(dibenzylamino)ethanol. 1HNMR (400 MHz, CDC13) = 7.38 - 7.21 (m, 1OH), 3.63 (s, 4H), 3.59 (t, J=5.1 Hz, 2H), 2.67 (t, J5.4 Hz, 2H), 2.58 (br. s., 1H) ppm. |
1920 g | With potassium carbonate; In acetonitrile; at -10 - 50℃; for 8h;Large scale; | 500 g of ethanolamine, 10 L of acetonitrile and 2200 g of potassium carbonate were successively added to a 20 liter glass reactor. The reaction solution was cooled to -10 C, and 2800 g of benzyl bromide was added dropwise to the reaction mixture, and the dropwise addition time was 5 h. After the addition was completed, the reaction solution was heated to 50 C, and the reaction was continued for 3.0 h. HPLC detection showed that the starting material had completely reacted. The reaction was filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated to give a pale yellow solid 1920g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; In diethyl ether; at 0℃;Inert atmosphere; | General procedure: Benzyl 2-(dibenzylamino) derivatives (3.92 mmol, 1 equiv.) were added to a stirred suspension of lithium aluminum hydride (11.75 mmol, 3 equiv.) in Et2O (15 ml) under argon atmosphere at 0 C. After 15 min cooling bath was removed and mixtures were stirred overnight and cooled again to 0 C. Mixtures has been worked-up by careful dropwise addition of 0.5 mL of H2O, 1 mL of 15% KOH and 1.5 mL of H2O. Aluminum salts were removed by filtration, and the filtrates were concentrated under reduced pressure. Crude products were purified by flash chromatography (hexane/ethyl acetate 70:30, v/v). |