Structure of 944470-56-8
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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. : | 944470-56-8 |
Formula : | C14H20FNO3 |
M.W : | 269.31 |
SMILES Code : | O=C(OC(C)(C)C)N[C@H](CO)CC1=CC=CC(F)=C1 |
MDL No. : | MFCD28359279 |
InChI Key : | HFOFNJNYQFXYDX-LBPRGKRZSA-N |
Pubchem ID : | 58282810 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H320-H335 |
Precautionary Statements: | P264-P270-P301+P312-P330 |
Num. heavy atoms | 19 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 70.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.56 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.87 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.37 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.67 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.47 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.51 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.58 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.77 |
Solubility | 0.453 mg/ml ; 0.00168 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.24 |
Solubility | 0.155 mg/ml ; 0.000575 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.91 |
Solubility | 0.033 mg/ml ; 0.000122 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 |
-6.26 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.87 |
* 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 |
---|---|---|
74% | To a solution of N-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (10 g, 35.3 mmol) in THF (200 ml.) at 0 0C stirred was added BH3-THF (88 ml_, 88 mmol-1 M in THF). After 12h, the reaction was quenched with AcOH:MeOH (8:50, 58 ml.) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were concentrated and the residue passed through a pad of silica gel (hexanes/EtOAc, 1 :1 ) to afford the product compound (7.0 g, 74%) as a white solid: LCMS (ES) m/e 270 (M+H)+. | |
74% | To a solution of N-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (10 g, 35.3 mmol) in THF (200 mL) at 0 0C stirred was added BH3-THF (88 ml_, 88 mmoM M in THF). After 12h, the reaction was quenched with AcOH:MeOH (8:50, 58 mL) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then <n="31"/>extracted several times with DCM. The combined organic fractions were concentrated and the residue passed through a pad of silica gel (hexanes/EtOAc, 1 : 1 ) to afford the product compound (7.0 g, 74%) as a white solid: LCMS (ES) m/e 270 (M+H)+. | |
74% | Preparation 1 Preparation of 2-r(2S)-2-amino-3-(3-fluorophenyl)propyll-1 /-/-isoindole-1 ,3(2/-/)-dione a) 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1-(hydroxymethyl)ethyl]carbamate To a solution of N-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (10 g, 35.3 mmol) in THF (200 ml.) at 0 0C stirred was added BH3-THF (88 ml_, 88 mmol-1 M in THF). After 12h, the reaction was quenched with AcOH:MeOH (8:50, 58 ml.) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were concentrated and the residue passed through a pad of silica gel (hexanes/EtOAc, 1 :1 ) to afford the product compound (7.0 g, 74%) as a white solid: LCMS (ES) m/e 270 (M+H)+. |
70% | With borane; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Boc-L-3-fluorophenylalanine (1.0g, 3.5 mmol)) was dissolved in dry THF (15ml) at 0 0C under N2. BH3 (1 M in THF, 9.6ml) was added dropwise. The reaction was stirred for 30 min before it was warmed up to rt. Methanol was added to quench the excess BH3. The mixture was washed with brine, dried over MgSO4. The solvent was removed under vacuum and the residue was purified on Biotage (30% EtOAc/hexane) to give 0.66g of white solid 1 b (70%). |
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3h; | Step A tert-butyl[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]carbamate To a solution of <strong>[114873-01-7](2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propanoic acid</strong> [Aldrich] (3.00 g, 10.6 mmol) in tetrahydrofuran (30 mL, 400 mmol) at 0 C. was added 1.0 M borane-THF complex in tetrahydrofuran (32 mL, 32 mmol). The reaction mixture was stirred at room temperature for 3 hrs, cooled with an ice bath, quenched with AcOH:MeOH (1:5, 10 mL and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure. The residue was used directly for the next reaction. LCMS (ES) m/e 270 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 1.0h; | To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1-(hydroxymethyl)ethyl]carbamate (7.0 g, 26.0 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and phthalimide (4.21 g, 28.6 mmol) in THF (150 ml.) at 25 C was added diisopropyl azodicarboxylate (7.58 ml_, 39.0 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue triturated with Et2O (100 ml.) and filtered to give the crude product (22 g) as a white solid which was used directly without further purification: LCMS (ES) m/z 399 (M+H)+. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 1.0h; | To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1- (hydroxymethyl)ethyl]carbamate (7.0 g, 26.0 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and phthalimide (4.21 g, 28.6 mmol) in THF (150 ml.) at 25 0C was added diisopropyl azodicarboxylate (7.58 ml_, 39.0 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue triturated with Et2O (100 ml.) and filtered to give the crude product (22 g) as a white solid which was used directly without further purification: LCMS (ES) m/z 399 (M+H)+. | |
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 2.0h; | Step B 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione [1.0]-hydrogen chloride To a solution of tert-butyl[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]carbamate (9.40 g, 34.9 mmol), triphenylphosphine (9.15 g, 34.9 mmol), and phthalimide (5.14 g, 34.9 mmol) in tetrahydrofuran (100 mL, 1000 mmol) at room temperature was added diethyl azodicarboxylate (17.9 mL, 45.4 mmol). The reaction was stirred at room temperature for 2 hr and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (0-40%) to give the desired intermediate. LCMS found: 399.0 (M+1). To the solution of the purified intermediate in methanol (20 mL, 400 mmol) was added 4.0 M hydrogen chloride in dioxane (30 mL, 100 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give 3.1 g (26% total yield for the two steps) of the final product, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione [1.0]-Hydrogen chloride, as white solid. LC/MS found: 299.0 (M+H)+. |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; | b) 1 , 1 -dimethylethyl {(1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)-1 -[(3- fluorophenyl)methyl]ethyl}carbamate <n="31"/> To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1-(hydroxymethyl)ethyl]carbamate (7.0 g, 26.0 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and phthalimide (4.21 g, 28.6 mmol) in THF (150 ml.) at 25 C was added diisopropyl azodicarboxylate (7.58 ml_, 39.0 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue triturated with Et2O (100 ml.) and filtered to give the crude product (22 g) as a white solid which was used directly without further purification: LCMS (ES) m/z 399 (M+H)+. |