Structure of 676133-24-7
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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. : | 676133-24-7 |
Formula : | C10H13BrClN |
M.W : | 262.57 |
SMILES Code : | N[C@H]1CCCC2=C1C=C(Br)C=C2.[H]Cl |
MDL No. : | MFCD22393203 |
InChI Key : | GOFDJFJHJKVZRC-PPHPATTJSA-N |
Pubchem ID : | 68538495 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 61.25 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.05 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.08 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.73 |
Solubility | 0.0488 mg/ml ; 0.000186 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.26 |
Solubility | 0.143 mg/ml ; 0.000546 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.78 |
Solubility | 0.044 mg/ml ; 0.000167 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) |
Yes |
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) |
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 |
-5.74 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.37 |
* 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 |
---|---|---|
66.3% | A solution of (R)-7-BROMOTETRALIN-L-OL (8.13 g, 35.8 mmol) in toluene (75 mL) was cooled in an ice bath and treated with diphenylphosphorylazide (DPPA, 11.8 g, 9.6 mL, 43 mmol). A solution of 1, 8-diazabicyclo [5.4. 0] undec-7-ene (DBU, 6.5 g, 6.4 mL, 43 mmol) in toluene (20 mL) was added over 35 min and the mixture was allowed to stir at 0 C for 2 h and ambient temp for 16 h. The mixture was filtered through a pad of silica gel (eluted 6: 1 hexanes/ethyl acetate) to remove precipitates and the volatiles were removed in vacuo to give an oily residue of the crude S-azide. This material was used directly in the next step without further characterization. The azide was dissolved in dry THF (60 mL) and added dropwise at RT to a slurry of lithium aluminum hydride (1. 63g, 43 mmol) in dry THF (50 mL). The mixture was stirred at RT for 1H and then heated to reflux for 1 h. The reaction was cooled to RT and quenched by successive addition of water (1.63 mL), 15% aq NaOH (1.63 mL) and water (4.9 mL). The resulting mixture was stirred for 1 h and then filtered through a pad of Celite (eluted diethyl ether). The volatiles were removed in vacuo and the residue taken up into ethyl acetate (120 mL) and treated with 4N HC1 in dioxane (10 mL). The resulting precipitate was filtered (wash ethyl acetate), collected and vacuum dried to give (S)-7-bromo-1, 2,3, 4-TETRAHYDRO-1-NAPTHYLAMINE hydrochloride as a white solid (6.23 g, 66. 3%, note 14). [Note 13. Procedure adapted from: Rover, S.; Adam, G. ; Cesura, A. M.; Galley, G.; Jenck, F.; Monsma Jr. , F. J.; Wichmann, J.; Dautzenberg, F. M. J. Med. Chem. 2000,43, 1329- 1338. Authors report a somewhat diminished yield due to partial formation of a dihydronapthalene via elimination of the hydroxyl moiety Note 14. Analytical chiral HPLC indicated a 96: 4 mixture of enantiomers (Daicel Crownpak (-) COLUMN, isocratic elution 10% methanol in water (0. 1% TFA), 0.8 mL/min, RT 39.4 min (minor enantiomer), 57.6 min (major enantiomer)]. | |
66.3% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2.0h;Heating / reflux; | A solution of (R)-7-BROMOTETRALIN-1-OL (8.13 g, 35.8 mmol) in toluene (75 mL) was cooled in an ice bath and treated with diphenylphosphorylazide (DPPA, 11.8 g, 9.6 mL, 43 mmol). A solution of 1, 8-diazabicyclo [5.4. 0] undec-7-ene (DBU, 6.5 g, 6.4 mL, 43 mmol) in toluene (20 mL) was added over 35 min and the mixture was allowed to stir at 0 C for 2 h and ambient temp for 16 h. The mixture was filtered through a pad of silica gel (eluted 6: 1 hexanes/ethyl acetate) to remove precipitates and the volatiles were removed in vacuo to give an oily residue of the crude S-azide. This material was used directly in the next step without further characterization. The azide was dissolved in dry THF (60 mL) and added dropwise at RT to a slurry of lithium aluminum hydride (1.63g, 43 mmol) in dry THF (50 mL). The mixture was stirred at RT for Ih and then heated to reflux for 1 h. The reaction was cooled to RT and quenched by successive addition of water (1.63 mL), 15% aq NaOH (1.63 mL) and water (4.9 mL). The resulting mixture was stirred for 1 h and then filtered through a pad of Celite (eluted diethyl ether). The volatiles were removed in vacuo and the residue taken up into ethyl acetate (120 mL) and treated with 4N HC1 in dioxane (10 mL). The resulting precipitate was filtered (wash ethyl acetate), collected and vacuum dried to give (S)-7-bromo-1, 2,3, 4-TETRAHYDRO-1-NAPTHYLAMINE hydrochloride as a white solid (6.23 g, 66. 3%, note 14). [Note 13. Procedure adapted from: Rover, S.; Adam, G.; Cesura, A. M.; Galley, G.; Jenck, F.; Monsma Jr. , F. J.; Wichmann, J.; Dautzenberg, F. M. J. Med. Chem. 2000,43, 1329- 1338. Authors report a somewhat diminished yield due to partial formation of a dihydronapthalene via elimination of the hydroxyl moiety Note 14. Analytical chiral HPLC indicated a 96: 4 mixture of enantiomers (Daicel Crownpak (-) column, isocratic elution 10% methanol in water (0. 1% TFA), 0.8 mL/min, RT 39. 4 min (minor enantiomer), 57.6 min (major enantiomer)]. The following compounds are prepared essentially according to the procedures described in the schemes, charts, examples and preparations set forth herein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | With triethylamine; In dichloromethane; at 0 - 23℃; for 12.0h; | To a stirred solution of above amine hydrochloride (0.94 g,3.6 mmol) in CH2Cl2 (30 mL) was consecutively added triethylamine(1.5 mL, 10.89 mmol) and di-tert-butyl-dicarbonate (1.17 g,5.44 mmol) at 0 C. The reaction mixture was stirred at 23 C for12 h. The reaction mixture was then diluted with CH2Cl2 andwashed with water and brine solution, dried over Na2SO4 andconcentrated. The crude product was purified by column chromatographyover silica gel (20% EtOAc/hexanes) to give 16 (1.0 g, 85%over two steps) as an amorphous solid. Rf 0.7 (20% EtOAc/hexanes);[a]D239.32 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)δ 7.54-7.39 (m, 1H), 7.33-7.09 (m, 1H), 6.94 (d, J 8.1 Hz, 1H), 4.78(q, J 10.6, 8.8 Hz, 2H), 2.88-2.50 (m, 2H), 2.02 (td, J 10.9, 9.9,4.9 Hz, 1H), 1.78 (ddp, J 23.3, 11.4, 4.2 Hz, 3H), 1.49 (s, 9H); 13CNMR (100 MHz, CDCl3) δ 155.55, 139.66, 136.43, 131.38, 130.84,130.31, 119.73, 79.77, 48.67, 30.45, 28.89, 28.57, 20.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.94 g | With hydrogenchloride; In methanol; water; for 2.5h; | A solution of 15 (1.2 g, 3.63 mmol) in MeOH (20 mL) was treatedwith 6 N HCl in isopropanol (5 mL). After 2.5 h, solvent wasremoved in vacuo, and the residue was co-evaporated with ethylacetate. The residue obtained was dried under high vacuum toprovide (S)-7-bromo-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride(0.94 g). |
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