Structure of 1127-74-8
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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. : | 1127-74-8 |
Formula : | C10H11NO |
M.W : | 161.20 |
SMILES Code : | C1=C2C(=CC=C1)NCCCC2=O |
MDL No. : | MFCD03426404 |
Boiling Point : | No data available |
InChI Key : | NKRKBYFBKLDCFB-UHFFFAOYSA-N |
Pubchem ID : | 294788 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 51.57 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.1 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.69 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.75 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.5 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.35 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.37 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.73 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.31 |
Solubility | 0.786 mg/ml ; 0.00488 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.98 |
Solubility | 1.69 mg/ml ; 0.0105 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.44 |
Solubility | 0.0592 mg/ml ; 0.000367 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 |
-6.04 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) |
1.79 |
* 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 |
---|---|---|
99% | With pyridine; In dichloromethane; at 20℃; | To a stirring solution of 1,2,3,4-tertahydrobenzo[bjazepine-5-one (50 g, 0.31 mol) in DCM (250 mL) was added pyridine (175 mL). The mixture was cooled with ice bath and TsC1 (84 g, 0.44 mol) was added. The mixture was warmed to room temperature and stirredovernight. Water (750 mL) was added and the mixture was extracted with DCM (300 mL3). The combined organic phase was washed with water, brine, dried over anhydrous Na2504 and concentrated under reduced pressure. The residue was washed with a mixed solvent (petroleum ether/EtOAc = 70:1) to give the title product as a light yellowish solid (97 g, 99%). ESI MS m/z = 316.05 [M+Hf |
97.8% | With pyridine; In dichloromethane; at 20℃; for 2h;Cooling with ice; | To a stirring solution of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (50 g, 310.17 mmol) in DCM (250 mL) was added pyridine (175 mL). The mixture was cooled with ice bath and TsCl (84.0 g, 440.76 mmol) was added. The mixture was warmed to room temperature and stirred 2 hrs. Water (750 mL) was added and the mixture was extracted with DCM (4×300 mL). The combined organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was washed with mixed solvent (PE:EA=50:1) to give the desired compound (95.7 g, 97.8%) as an off-white solid. ESI-MS m/z: 333.15 [M+NH4]+. |
In pyridine; at 50℃; for 1h;Product distribution / selectivity; | Step 1. Preparation of (+/-) 1- (Toluene-4-sulfonyl)-1, 2,3, 4-tetrahydro-benzo [b] azepin-5- one. To a solution of 1, 2,3, 4-Tetrahydro-benzo [b] azepin-5-one (500 mg, 3.1 mmol) in pyridine (2 ml) is added p-toluenesulfonyl chloride (650 mg, 3.4 mmol), and the mixture is heated at 50 C for 1 hour. The reaction mixture is poured into IN HCl (100 ml) and extracted with ethyl acetate (3x20 ml). The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated to a solid. The solid is purified by silica gel column chromatography (eluent, 30 % ethyl acetate in hexanes) to give the title compound as a solid. Mass spectrum (ES+): 316 (M+H). |
18.9 g | With pyridine; at 20℃; for 12h;Cooling with ice; | Reference Example 12 1-tosyl-3,4-dihydro-1H-benzo[b]azepine-5(2H)-one 3,4-dihydro-1H-benzo[b]azepine-5(2H)-one (10.0 g) was dissolved into pyridine (30 mL), thereto was added p-toluenesulfonyl chloride (13.6 g) under an ice bath and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was added with water (60 mL) and then stirred at room temperature for 40 minutes. The obtained crystal was collected by filtration and washed with water, and then dried to thus obtain the title compound (18.9 g) as a light yellow white solid. 1H-NMR (400 MHz, CDCl3) delta7.71 (ddd, J=7.8, 1.7, 0.4 Hz, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.55-7.46 (m, 2H), 7.41-7.35 (m, 1H), 7.23-7.30 (m, 2H), 3.86 (t, J=6.6 Hz, 2H), 2.45-2.39 (m, 5H), 2.00-1.91 (m, 2H). ESI/MS (m/z) 316 (M+H)+. |
18.9 g | With pyridine; at 20℃; for 12h;Cooling with ice; | 3,4-Dihydro-1H-benzo[b]azepine-5(2H)-one (10.0g)Dissolved in pyridine (30 mL),Toluenesulfonium chloride (13.6 g) was added under ice bath, and stirred at room temperature for 12 hours. Water (60 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 40 minutes. The obtained crystals were collected by filtration, washed with water, and dried to give the title compound (18.9 g) as pale yellow white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With PPA; at 100℃; for 1.5h; | Polyphosphoric acid (25g) was heated at 100C under nitrogen until it could be stirred. 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.4 (2.6g, 8.2 6mmol) was added portionwise and the reaction mixture was heated at 100C for 1.5h. It was poured into ice and basified with 2M NaOH(aq). The aqueous layer was extracted twice with dichloromethane. The organic extracts were combined, washed with brine, dried and reduced in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc: 60% hexane) to yield the title compound (1.05g, 79%). |
Step 5. Preparation of 1, 2,3, 4-Tetrahydro-benzo [b] azepin-5-one. To preheated polyphosphoric acid (PPA, 220 g) at 70-80 C was added 1- (Toluene-4-sulfonyl)-1, 2,3, 4-tetrahydro-benzo [b] azepin-5-one (50.0 g, 0.16 mol). The mixture was stirred for 3.0 h at the same temperature and then poured into ice water. After the pH was adjusted to about 8-9 by adding aq NaOH, the mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgS04, and concentrated. The residue was purified by silica gel column chromatography (eluent, 3: 1 n-hexanes: ethyl acetate) to give 1, 2,3, 4-Tetrahydro-benzo [b] azepin-5-one (22g). |
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