Structure of 327-51-5
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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. : | 327-51-5 |
Formula : | C6H2Br2F2 |
M.W : | 271.88 |
SMILES Code : | C1=C(Br)C(=CC(=C1F)Br)F |
MDL No. : | MFCD00000346 |
InChI Key : | GLVMLJCMUBZVTJ-UHFFFAOYSA-N |
Pubchem ID : | 67596 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 41.76 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.37 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.63 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.05 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.78 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.17 |
Solubility | 0.0182 mg/ml ; 0.0000669 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.18 |
Solubility | 0.178 mg/ml ; 0.000656 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.66 |
Solubility | 0.00595 mg/ml ; 0.0000219 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
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) |
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 |
-5.47 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
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 |
1.0 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) |
1.68 |
* 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 |
---|---|---|
In diethyl ether; | a 4-Bromo-2,5-difluorobenzaldehyde n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise to a stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in diethyl ether (60 ml) at -70° C. After 1 h, the solution was warmed to 0° C. over 1 h, diluted with water, the layers separated and the ether layer dried over sodium sulphate and evaporated. Purification by column chromatography (Biotage), eluding with 5percent ethyl acetate/hexane, gave a yellow oil (1.82 g). 1H NMR 300 MHz (CDCl3) 10.28 (1H, s), 7.61 (1H, dd), 7.48 (1H, dd). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With ammonium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; | Method 6 4-Bromo-2,5-difluorobenzaldehyde To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at -40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise. After 1 h at -40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at -40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74percent) as a solid. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 10.28 (d, 1H) 7.61 (dd, 1H) 7.48 (dd, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Example 31 Preparation of 4-bromo-2,5-difluorobenzaldehyde [0289] 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at -78 C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at -78 C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86%): 1H NMR (400 MHz, CDCl3): delta 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H). | |
66.7% | To a stirred solution of XXXII-1 (12 g, 44.1 mmol) in THF (150 mL) was added dropwise of XXXII-1A (44.1 mmol, 34 mL, 1.3 M) at -40 C. After stirred 1 h at -40 C., DMF (64 g, 882 mmol) was added and the mixture was stirred overnight. NH4Cl (aq., 2M) was added and the mixture was extracted with EtOAc. The organic phase was dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (PE/EA=10/1) to afford XXXII-2 (6.5 g, yield: 66.7%). | |
55.8% | To a solution of l,4-dibromo-2,5-difluorobenzene (15 g, 55 mmol) in toluene (600 mL) cooled to -78 C was added butyllithium (22 mL, 55 mmol) and the reaction was kept at -78 C for 30 minutes. N,N-dimethylformamide (4.4 g, 61 mmol) was added and the reaction was stirred for 2 hours while warming to ambient temperature. To the reaction was added water (200 mL) and EtOAc (400 mL) and the organic layers were separated. The organic layer was washed with brine (200 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with 5% EtOAc/Hexane to yield 4-bromo-2,5-difluorobenzaldehyde (6.7 g, 55.8%). |
37% | n-Butyl lithium (3.6 ml,7.7 mmol) was added drop wise to a solution of 1,4- dibromo-2,5-difluoro-benzene (2g, 7.35mmol) in dry ether at -78C under nitrogen atmosphere and the resulting mixture was stirred at -78C for 30 minutes. This was followed by the addition of DMF (0.85ml, 11.03mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600mg of the product (37% yield).1H NM (CDC13, 300 MHZ): delta 10.27-10.26 (d, 1H), 7.61-7.57 (t, 1H), 7.49- 7.44 (q, 1H) | |
To a Et2O solution (200 mL) containing 1,4-dibromo-2,5-difluorobenzene (19.72 g, 72.5 mmol) cooled to -78 degrees C. was added 30.5 mL of a 2.5 M hexanes solution of n-BuLi (76.2 mmol). The resulting green solution was stirred for 20 min at -78 degrees C. when DMF (7.95 g, 10.8 mmol) was added. The reaction was stirred for 30 min and then quenched with H2O. The organics were taken up in EtOAc and washed with sat. NaHSO4 followed by drying over MgSO4. The solvent was removed in vacuo and the residual oil purified on the Biotage (2-5% EtOAc/hexanes) yielding 11.4 g (51.7 mmol) of 4-bromo-2,5-difluorobenzaldehyde. 1H NMR (400 MHz, CDCl3) delta 10.2 (s, 1H), 7.57 (m, 1H), 7.45 (m, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 4h;Inert atmosphere; | (1019) (1020) intermediate 31-1 (1021) [00354] Into a 100-mL round-bottom flask that purged and maintained under an inert atmosphere of nitrogen was added 4-bromo-2-chloro-l-iodobenzene (1.20 g, 3.78 mmol), benzyl piperazine-l -carboxylate (0.924 g, 4, 19 mmol), NaOtBu (1.10 g, 1 1.4 mmol), XantPhos (0.695 g, 1.20 mmol), Pd2(dba)3 (0.393 g, 0.430 mmol), and toluene (10 mL). The reaction mixture was stirred for 4 h at 60 C and then concentrated in vacuo to provide a crude product that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- chlorophenyl)piperazine-l -carboxylate as a colorless oil (713 mg, 46%). LCMS (ESI, m/z) 409, 41 1 [ M 1 [ j . |
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