Structure of 1246765-38-7
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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. : | 1246765-38-7 |
Formula : | C8H7BrN2O |
M.W : | 227.06 |
SMILES Code : | O=C1NC2=C(C=C(Br)C=C2)CN1 |
MDL No. : | MFCD13180559 |
InChI Key : | LPMQSNAFKKEZAK-UHFFFAOYSA-N |
Pubchem ID : | 66683712 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 56.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
41.13 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.65 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.98 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.81 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.86 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.5 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.37 |
Solubility | 0.974 mg/ml ; 0.00429 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.65 |
Solubility | 5.09 mg/ml ; 0.0224 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.8 |
Solubility | 0.036 mg/ml ; 0.000158 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 |
-6.84 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) |
1.95 |
* 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 |
---|---|---|
57.5% | Step 2: 6-bromo-3.4-dihvdroquinazolin-2(1 H)-one; To a solution of triphosgene (0.445 g, 1.5 mmol) in tetrahydrofuran (20 mL) was added triethylamine (0.454 g, 4.5 mmol) dropwise at 0 0C under nitrogen. After stirring for 30 min, a solution of 2-(aminomethyl)-4-bromoaniline (0.201 g, 1 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was allowed to stir for 16 h at room temperature. The mixture was diluted with water (15 mL) and the pH of the resultant mixture was adjusted to 8 - 9 by the addition of 1 M aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate (30 mL). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by re- crystallization from a mixture o dichloromethane and diethyl ether to give the title compound (0.13 g, 57.5%) as a yellow solid. 1 H NMR (400MHz, DMSO-Cf6) delta ppm 9.12 (s, 1 H), 7.29 (S, 1 H), 7.27(d, J = 8.4 Hz, 1 H), 6.87 (s, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.28 (s, 2H). | |
55% | With triethylamine; at 0 - 20℃; for 16.0h; | 10048] To accomplish the synthesis of the desired compounds 6a-f, synthesis of the key intermediate (10) was required, which in turn was envision from the l3uchwald- Hartwig coupling reaction of 6-bromo-3,4-dihydroquinazo- lin-2(1H)-one (9) (H. Venkatesan, F. M. Hocutt, T. K. Jones, M. H. Rabinowitz, I Org. Chem., 75, 3488 (2010)-incor- porated herein by reference in its entirety) with tert-butyl piperazine-1 -carboxylate. Thus the synthesis of compound (9) was commenced with the reduction of bromobenzonitrile with borane to afford diamine (8), which was reacted with triphosgene to get the desired bromide (9) in 23% overall yield from (7). However, the l3uchwald-Hartwig coupling of bromides 9 with tert-butyl piperazine- 1 -carboxylate, under different reaction conditions (PdCl2dppf, KOAc, DMF, 80 C.; Pd(PPh3)4, toluene, ethanol, Na2CO3, reflux) were not successful; the desired 10 was not observed in any case (scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.9%; 6.7% | With dichlorobis(tri-O-tolylphosphine)palladium; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;Inert atmosphere; | General procedure: 10148] A mixture of bromo derivative 5 (1.6 mmol), potassium carbonate (4.9 mmol) and olefin intermediate 3 (1.6 mmol) in anhydrous DMF (50 mE) was degassed and filled with argon gas. Palladium catalyst (0.08 mmol) was added to the mixture and heated at 1000 C. for 16 h. The resulting pale brown mixture was cooled to room temperature, which was diluted with brine and ethyl acetate followed by filtration to eliminate the insoluble material. A second method to process the reaction mixture was to filter through a pad of celite, and later mix with ethyl acetate and brine for extraction of products. The extracted organic layer was washed with brine, dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash column chromatography on silica gel (230-400 mesh; 40 g) using a gradient solvent mixture of dichloromethane:methanol (100:0 to 95:5). In case of more polar compounds about 0.05% ammonia solution was used as another co-solvent to accelerate the elution. The less polar keto compound 6 was eluted first (Yield=5-20%) followed by olefin product 7 (Yield=5-60%). (rac-)(E)-6-(3-hydroxy-4-(4-(4-propylphenyl)piperazin-1-yl)but-1-en-1-yl)quinolin-2(1H)-one (10) Yield: 0.22 g (33.6%). 1H NMR (400 MHz, DMSO-d6): delta 11.76 (s, 1H), 7.86 (d, 1H), 7.66 (s, 1H), 7.64 (d, 1H), 7.26 (d, 1H), 7.02 (d, 2H), 6.84 (d, 2H), 6.62 (d, 1H), 6.49 (d, 1H), 6.32 (dd, 1H), 4.84 (s, 1H), 4.38 (br. s, 1H), 3.08 (br. s, 4H), 2.61 (br. s, 4H), 2.42 (t, 2H), 1.51 (m, 2H), 0.87 (t, 3H). ES-MS m/z 418.2 (C26H31N3O2+1)+. HPLC data: purity 99.9%, retention time 8.1 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 2.0h; | A solution of N-bromosuccinimide(2.26 g, 12.7 mmol) in 30 ml dry DMF was added drop wise to a solution of 10b (1.79 g,12.1 mmol) in 35 ml dry DMF at 0 C. The mixture was stirred at 0 C for 2 h. Waterwas added and the solution was extracted with ethyl acetate. The organic layer waswashed with brine, and then dried over anhydrous MgSO4. The resulting yellow solidwas purified by crystallization from acetone to afford 10a (1.37 g, 6.00 mmol, 50 %) aswhite solid. 1H-NMR (500 MHz, DMSO-d6): delta = 4.29 (s, 2H), 6.71 (d, 3J = 8.2 Hz, 1H),6.87 (s, 1H), 7.27 (dd, 3J = 8.4 Hz, 4J = 2.3 Hz, 1H), 7.29 (s, 1H), 9.13 (s, 1H). 13C-NMR(125 MHz, DMSO-d6): delta = 41.9, 112.0, 115.3, 120.7, 128.2, 130.1, 137.5, 154.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux; | General procedure: Heteroarylboronic acid (1.3 equivalents), aryl bromide (1 equivalent), and tetrakis(triphenylphosphine) palladium(0) (5mol %) were suspended in DME to give a 0.07-0.1M solution of boronic acid under nitrogen atmosphere. A 0.5M aqueous solution of sodium carbonate (6 equivalents) was added. The mixture was refluxed for 3.5-14h, cooled to room temperature, diluted with water and extracted several times with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, concentrated and purified by flash chromatography and were if necessary recrystallized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux; | General procedure: Heteroarylboronic acid (1.3 equivalents), aryl bromide (1 equivalent), and tetrakis(triphenylphosphine) palladium(0) (5mol %) were suspended in DME to give a 0.07-0.1M solution of boronic acid under nitrogen atmosphere. A 0.5M aqueous solution of sodium carbonate (6 equivalents) was added. The mixture was refluxed for 3.5-14h, cooled to room temperature, diluted with water and extracted several times with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, concentrated and purified by flash chromatography and were if necessary recrystallized. |
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