Structure of 14348-75-5
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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. : | 14348-75-5 |
Formula : | C13H6Br2O |
M.W : | 337.99 |
SMILES Code : | C3=C2C1=C(C=C(Br)C=C1)C(C2=CC(=C3)Br)=O |
MDL No. : | MFCD00010790 |
InChI Key : | CWGRCRZFJOXQFV-UHFFFAOYSA-N |
Pubchem ID : | 259922 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 70.71 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.72 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.56 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.42 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.91 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.95 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
4.11 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.36 |
Solubility | 0.00146 mg/ml ; 0.00000433 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.64 |
Solubility | 0.00771 mg/ml ; 0.0000228 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.75 |
Solubility | 0.0000605 mg/ml ; 0.000000179 mol/l |
Class? Solubility class: Log S scale |
Poorly 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) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
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 |
-5.12 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) |
2.2 |
* 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 |
---|---|---|
11 g (77%) | With ammonium chloride; magnesium; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; acetic acid; | c 2,7-Dibromo-9,9'-spirobifluorene A Grignard reagent prepared from 0.72 g (30 mmol) of magnesium turnings and 5.1 ml (30 mmol) of 2-bromobiphenyl in 15 ml of diethyl ether was added dropwise while stirring (in an ultrasonic bath) to a boiling suspension of 10.0 g (29.6 mmol) of 2,7-dibromo-9-fluorenone in 100 ml of dry diethyl ether over a period of 2 hours. After addition was complete, the mixture was boiled for a further 3 hours. After cooling overnight, the precipitate formed was filtered off with suction and washed with cold ether. The magnesium complex which had been filtered off with suction was hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dibromo-9-fluorenol formed was filtered off with suction, washed with water and sucked dry. For the ring closure reaction, the dried fluorenol was boiled in 100 ml of glacial acetic acid, after addition of 3 drops of 30 concentrated HCl, for 6 hours. The mixture was allowed to crystallize overnight, the product formed was filtered off with suction and washed with glacial acetic acid and water. Yield: 11 g (77percent) of 2,7-dibromo-9,9'-spirobifluorene. This was purified further by recrystallization from THF. 1H-NMR (CDCl3, ppm): 6.73 (d, J=7.63 Hz, 2 H, H-1',8'); 6.84 (d, J=1.83 Hz, 2 H, H-1,8); 7.15 (td, J=7.63, 1.22 Hz, 2 H, H-2',7'); 7.41 (td, J=7.63, 1.22 Hz, 2 H, H-3',6'); 7.48 (dd, J=8.24, 1.83 Hz, 2 H, H-3,6); 7.67 (d, J=8.24; 2 H; H-4,5); 7.85 (d, J=7.63, 2 H, H-4',5'). |
11 g (77%) | With hydrogenchloride; ammonium chloride; magnesium; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; acetic acid; | Example 1 Synthesis of 2,7-dibromo-9,9'-spirobifluorene A Grignard reagent prepared from 0.72 g (30 mmol) of magnesium turnings and 5.1 ml (30 mmol) of 2-bromobiphenyl in 15 ml of diethyl ether is added dropwise over the course of 2 hours while stirring (in an ultrasonic bath) to a boiling suspension of 10.0 g (29.6 mmol) of 2,7-dibromo-9-fluorenone in 1 00 ml of dry diethyl ether. After addition is complete, the mixture is boiled for a further 3 hours. After cooling overnight, the precipitate formed is filtered off with suction and washed with cold ether. The magnesium complex filtered off is hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dibromo-9-fluorenol formed is filtered off with suction, washed with water and sucked dry. For the ring closure reaction, the dried fluorenol is boiled in 100 ml of glacial acetic acid, after addition of 3 drops of concentrated hydrochloric acid, for 6 hours. The mixture is allowed to crystallize overnight, the product formed is filtered off with suction and washed with glacial acetic acid and water. Yield: 11 g (77percent) of 2,7-dibromo-9,9'-spirobifluorene. It can be further purified by recrystallization from THF. 1 H-NMR (CDCl3, ppm): 6.73 (d, J=7.63 Hz, 2H, H-1',8'); 6.84 (d, J=1.83 Hz, 2H, H-1,8); 7.15 (td, J=7.63, 1.22 Hz, 2H, H-2',7'); 7.41 (td, J=7.63, 1.22 Hz, 2H, H-3',6'); 7.48 (dd, J=8.24, 1.83 Hz, 2H, H-3,6); 7.67 (d, J=8.24; 2H; H-4,5); 7.85 (d, J=7.63, 2H, H-4',5'). |
11 g (77%) | With ammonium chloride; magnesium; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; acetic acid; | l) Synthesis of 2,7-dibromo-9,9'-spirobifluorene The Grignard reagent prepared from 0.72 g (30 mmol of magnesium turnings and 5.1 ml (30 mmol) of 2-bromobiphenyl in 15 ml of diethyl ether is added dropwise over a period of 2 hours, while stirring (in an ultrasonic bath), to a boiling suspension of 10.0 g (29.6 mmol) of 2,7 dibromo-9-fluorenone in 100 ml of dry diethyl ether. After the addition is complete, the mixture is boiled for a further 3 hours. After cooling overnight, the precipitated solid is filtered off with suction and washed with cold ether. The magnesium complex filtered off is hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dibromo-9-fluorenol formed is filtered off with suction, washed with water and sucked dry. For the ring-closure reaction, the dried fluorenol is boiled in 100 ml of glacial acetic acid for 6 hours, after addition of 3 drops of concentrated HCI. The mixture is allowed to crystallize overnight, the product formed is filtered off with suction and is washed with glacial acetic acid and water. Yield: 11 g (77 percent) of 2,7-dibromo-9,9'-spirobifluorene. It can be further purified by recrystallization from THF. 1H-NMR (CDCl3, ppm): 6.73 (sd, J = 7.63 Hz, 2 H, H-1',8'); 6.84 (d, J = 1.83 Hz, 2 H, H-1,8); 7.15 (td, J = 7.63, 1.22 Hz, 2 H, h-2',7'); 7.41 (td, J = 7.63, 1.22 Hz, 2H, H-3',6'); 7.48 (dd, J = 8.24, 1.83 Hz, 2H, H-3,6); 7.67 (d, J = 8.24 Hz; 2 H; H-4,5); 7.85 (d, J= 7.63, 2H, H-4',5'). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In a 250 mL two-necked flask, 9- (2-bromophenyl) -9H-carbazole (1.65 g, 5.12 mmol) was dissolved in 50 mL of THF. After cooling to -78 ° C, n-BuLi (2.5 M in hexane, 2.15 mL, 5.38 mmol) was slowly added dropwise. After 2 hours, 2,7-dibromo-9Hfluoren-9-one (1.73 g, 5.12 mmol) was added. After 3 hours, the reaction was terminated with an aqueous solution of NH4Cl, diethyl ether . The water was dried over MgSO4 and the solvent was removed. After precipitation with ethanol, the solid was filtered. The resulting solid was dissolved in acetic acid (50 mL), and a catalytic amount of HCl was added thereto. The mixture was refluxed for 6 hours, cooled to room temperature, filtered, washed with ethanol and dried to obtain 2.11 g (73percent) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.2% | A solution of 10 mL of o-dibromobenzene (0.1 mmol) in methyl tetrahydrofuran was added dropwise to a solution of 5 mL of phenylmagnesium bromide (0.11 mmol) in methyltetrahydrofuran under argon atmosphere at 80 ° C. Reaction 12 h. The reaction solution was then added dropwise to 10 mL of 2, 7-dibromofluorenone (0.1 mmol) in ether. The mixture was heated to reflux for 2 h, hydrolyzed and filtered. The solid was dissolved in 5 mL of mixed acid (glacial acetic acid and hydrochloric acid) (200-300 mesh silica gel) to give the product 2, 7-dibromo-9, 9 '-spirobifluorene , which was purified by column chromatography on silica gel eluted with a mixed solvent of methylene chloride and n-hexane.36 . 2 mg, yield 76.2percent. The resulting 2, 7-dibromo-9,9-spirobifluorene was reacted with lithium diphenylphosphine (0.15 mmol) in tetrahydrofuran solvent. After refluxing for 12 h, methanol was added to the reaction solution, (200-300 mesh silica gel) to obtain the desired product. 2-Bis (diphenylphosphino) -9, 9-spirobifluorene 35. 9 mg was obtained by the same procedure as that of Example 1, Mg, and the yield was 70.1percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium t-butanolate; In toluene; for 10h;Inert atmosphere; Reflux; | synthetic route:250mL three bottles,In the atmosphere of nitrogen gas,0.01 mol of 2,7-dibromo-9-fluorenone was added,0.025 mol of intermediate G1,0.04 mol of sodium tert-butoxide,1 x 10-4 mol Pd (dppf) Cl2,180 mL of toluene,Heated to reflux for 10 hours,Sampling point plate,Raw material reaction is complete;Natural cooling to room temperature (20 ~ 25 ),filter,The filtrate was collected and evaporated under reduced pressure (-0.09 MPa, 85 C)Column chromatography,Get the target product,HPLC purity 98.6%Yield 68.6%. |