Structure of 14401-72-0
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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. : | 14401-72-0 |
Formula : | C8H6Cl2O |
M.W : | 189.04 |
SMILES Code : | CC(C1=CC(Cl)=CC(Cl)=C1)=O |
MDL No. : | MFCD00045189 |
InChI Key : | JGMBBKVZFUHCJC-UHFFFAOYSA-N |
Pubchem ID : | 2758058 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 46.66 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.1 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.86 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.2 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.94 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.43 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.9 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.15 |
Solubility | 0.133 mg/ml ; 0.000706 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.88 |
Solubility | 0.251 mg/ml ; 0.00133 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.97 |
Solubility | 0.0204 mg/ml ; 0.000108 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) |
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 |
-5.42 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 |
2.0 |
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) |
1.18 |
* 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 |
---|---|---|
12.3 g | for 3h;Reflux; | 3?,S?-Dichloroacetophenone (9.7 g, 51 mmol) was heated at reflux in N,N-dimethylformamide dimethylacetal (50 mL) for 3 h. After cooling to ambient temperature, the reaction mixture was concentrated and dried under vacuum to give of anorange solid (12.3 g) that was used without further purification.1HNMRoe 7.82 (d, 1H), 7.74 (s, 2H), 7.42 (s, 1H), 5.58 (d, 1H), 3.18 (bs, 3H), 2.95 (bs, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Methylamine (2M solution in [MEOH-13] mL) was added to a solution of 3,5-di- [CHLOROACETOPHENONE] (500 mg) in MeOH (26 mL) under a Nitrogen atmosphere. The mixture was stirred at r. t. for 18 hours, then it was cooled to [0C] and sodium borohydride (98 mg) was added. The mixture was stirred at [0C] for 2 hours, then it was quenched with water and extracted with DCM. The organic layer was dried and concentrated in vacuo to give the title compound (340 mg) as an yellow oil. T. I. c. : CH/AcOEt 1: 1, Rf=0.15. NMR [(CDCI3)] : [5] (ppm) 7.3 (m, 3H); 3.6 (q, [1 H)] ; 2.3 (s, 3H); 1.35 (d, 3H). MS (ES/+): [M/Z=204] [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Methylamine (2M solution in [MEOH-13] mL) was added to a solution of intermediate 14 (500 mg) in MeOH (26 mL) under a Nitrogen atmosphere. The mixture was stirred at r. t. for 18 hours, then it was cooled to [0C] and sodium borohydride (98 mg) was added. The mixture was stirred at [0C] for 2 hours, then it was quenched with water and extracted with DCM. The organic layer was dried and concentrated in vacuo to give the title compound (340 mg) as yellow oil. T. [I.] c.: CH/AcOEt 1: [1,] Rf=0.15. NMR [(CDCI3)] : 8 (ppm) 7.3 (m, 3H); 3.6 (q, [1 H)] ; 2.3 (s, 3H); 1.35 (d, 3H). MS (ES/+): m/z=204 [[M+HL+.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0159] A reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 5.52 g, 1 38 mmol), DME (23 ml) and 2-chloro-5-trifluoromethylpyridine (7.06 g, 42 mmol). 3,5-Dichloroacetophenone (8.3 g, 44 mmol) in DME (23 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45 C. overnight. Upon completion of the reaction, the mixture was cooled to 5 C. and 10% aqueous sodium hydroxide solution (23 ml) was slowly added to the reaction mixture followed by methanol (46 ml) then hydroxylamine hydrochloride (14.5 g, 210 mmol). The mixture was heated to 72 C. for 4 hours then cooled and diluted with water (1500 ml) with stirring. The resulting solid was removed by filtration and dried under vacuum. It was then slurried in cyclohexane (100 ml) then filtered, washing with further cyclohexane. The crude solid 13.30 g (86%) was used in subsequent reactions without further purification. [0160] Mass Spectrum: Found: (M-H)-348 [0161] HPLC (?,=220-230 nm) RT 3.83 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With hydrogenchloride; sodium nitrite; In water; sodium acetate; | EXAMPLE 1 3',5'-dichloroacetophenone. 300 ml of water and 70 ml of concentrated hydrochloric acid are added to 48.6 g (0.30 mol) of 3,5-dichloroaniline. Then, after 30 minutes, 27.5 g (0.40 mol) of sodium nitrite in 32 ml of water are run in dropwise while maintaining the temperature between 0 C. and 5 C. 16.2 g (0.2 mol) of sodium acetate are added to the filtered reaction mixture. This solution is run in dropwise into a solution of 28.5 g (0.48 mol) of acetaldoxime, 25.0 g (0.10 mol) of copper sulphate pentahydrate, 20.5 g (0.018 mol) of anhydrous sodium sulphite and 121 g (1.50 mol) of sodium acetate in 250 ml of water maintained at 15 C. After stirring for 1 hour, the mixture is acidified by addition of concentrated hydrochloric acid. After steam distillation and chromatography of the crude product on a silica column (eluent 90/10 heptane/ethyl acetate), 16.6 g (yield 30 %) of 3', 5'-dicholoroacetophenone (compound 1) are recovered in the form of a colourless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium nitrite; In water; sodium acetate; | a) preparation of (3,5-dichlorophenyl)ethanone (compound 90) from 3,5-dichloroaniline (passing from IV to V): 300 ml of water and 70 ml of concentrated hydrochloric acid are added to 48.6 g (0.30 mol) of 3,5-dichloroaniline. 30 minutes after, 27.5 g (0.40 mol) of sodium nitrite in 32 ml of water are run in dropwise while maintaining the temperature between 0 and 5 C. 16.2 g (0.2 mol) of sodium acetate are added to the filtered reaction mixture. This solution is run in dropwise onto a solution of 28.5 g (0.48 mol) of acetaldoxime, 25.0 g (0.10 mol) of copper sulphate pentahydrate, 20.5 g (0.018 mol) of anhydrous sodium sulphite and 121 g (1.50 mol) of sodium acetate in 250 ml of water maintained at 15 C. After stirring for 1 h, the mixture is acidified by addition of concentrated hydrochloric acid. After steam distillation and chromatography of the crude product on a silica column (heptane 90, ethyl acetate 10), there are recovered 16.6 g (30%) of (3,5-dichlorophenyl)-ethanone in the form of a colourless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With bromine; In acetic acid; | i) 2-Bromo-1-(3,5-dichlorophenyl)-1-ethanone: 1.03 ml (0.02 mol) of bromine are added, at room temperature, to 3.77 g (0.019 mol) of (3,5-dichlorophenyl)ethanone in solution in 50 ml of acetic acid. After stirring for 12 hours, evaporation of the acetic acid leads to the production of a yellow precipitate: 2-bromo-1-(3,5-dichlorophenyl)-1-ethanone (yield 81%). |
With N-Bromosuccinimide; toluene-4-sulfonic acid; In ethyl acetate; at 20℃; for 12h; | 0.27g (1.5mmol) 3,5- dichloro-acetophenone, 0.27g (1.5mmol) N- bromosuccinimide and 0.03g (0.15mmol) of p-toluenesulfonic acid dissolved in 15mL ethyl acetate , the reaction was stirred for 12 hours at room temperature, TLC tracking, completion of the reaction, deionized water (3 × 10mL) and washed, the organic solvent was removed under reduced pressure to give the crude product alpha- bromo-4- (3,5-dichloro) acetophenone ketone, 95% yield, was used directly without purification in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; magnesium; In water; benzene; | 3',5'-Dichloroacetophenone To a suspension of magnesium turnings (2 g.) in dry ether (20 ml.), under nitrogen was added iodomethane (12 g.), in dry ether (50 ml.), at such a rate that the reaction refluxed. The addition took 1 hour. Dry benzene (150 ml.) was added and the ether blown off under a strong stream of nitrogen. 3,5-Dichlorobenzonitrile (5 g.) was dissolved in dry benzene (60 ml.) and then added dropwise over 10 minutes and the resulting mixture refluxed for 3 hrs. After cooling to 0 6N hydrochloric acid (100 ml.), was added slowly over 10 minutes. The resulting mixture was refluxed for 6 hours. After cooling water (50 ml.) and ether (50 ml.) were added and the mixture filtered. The aqueous phase was washed with ether (2*50 ml.), and the combined organic layers washed with sodium hydrogen carbonate solution (50 ml.), brine (50 ml.) and dried over magnesium sulphate. Evaporation yielded the title compound. Nuclear Magnetic Resonance spectrum (NMR) was as follows: 2.6, 3H, s; 7.4, 1H, m; 7.6, 2H, d. | |
A solution of methyl iodide (4 mL) in anhydrous Et20 (40 mL) was dropped into a suspension of magnesium (1.6 g) in anhydrous [ET20] (16 mL) under a Nitrogen atmosphere. At the end of the dropping, benzene (120 mL) was added and the [ET20] eliminated with a Nitrogen flux. Then, a solution of 3, 5-dichlorobenzonitrile (4 g) in benzene (48 mL) was added and the mixture was heated to reflux for 3 hours. The solution was cooled to [0C] and a 6N hydrochloric acid solution was added and the mixture was stirred overnight at r. t.. Water and [ET20] were added and the layers were separated. The organic phase was washed with a saturated sodium hydrogen carbonate solution and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 95: 5) to give the title compound (2.55 g) as an orange oil. T. [I.] c.: CH/AcOEt 8: 2, Rf=0.64. NMR [(CDCI3)] : 8 (ppm) 7.75 (s, 2H); 7.6 (s, [1 H)] ; 2.55 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To the product from step A (5.42 g, 23.2 mmol) in 100 mL of tetrahydrofuran was added methylmagnesium bromide (11.6 mL, 34.8 mmol) drop-wise. After stirring at ambient temperature for 25 min, IN hydrochloric acid was added and the mixture extracted with two portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to provide the title compound which was used without further purification. 1H NMR (500 MHz, CDCl3) delta: 7.84 (d, J = 1.9 Hz, 2H); 7.58 (d, J = 1.8 Hz, IH); 2.63 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With selenium(IV) oxide; In 1,4-dioxane; for 4h;Reflux; | Selenium dioxide (30.0 g 270 mmol) was dissolved in dioxane (450 mL) and warmed to 50C. 3,5-Dichloroacetophenone (30. Og, 158 mmol) was added at at this temperature and the resulting mixture was refluxed for 4 h. After completion of the reaction, the mixture was filtered through celite and concentrated in vacuo. (3,5- Dichlorophenyl)(oxo)acetic acid was isolated and purified by column chromatography, eluting with ethyl acetate/hexane mixtures(28 g, 80%).Mass spectroscopy: (ESI -ve) 217 [M-H]~ |
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