Structure of 61072-56-8
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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. : | 61072-56-8 |
Formula : | C7H4ClFO |
M.W : | 158.56 |
SMILES Code : | O=CC1=CC=C(Cl)C=C1F |
MDL No. : | MFCD00143282 |
Boiling Point : | No data available |
InChI Key : | UVGYSEIWAOOIJR-UHFFFAOYSA-N |
Pubchem ID : | 2724908 |
GHS Pictogram: |
![]() |
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 | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.8 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.72 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.11 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.71 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.48 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.04 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.41 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.53 |
Solubility | 0.468 mg/ml ; 0.00295 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.1 |
Solubility | 1.26 mg/ml ; 0.00796 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.23 |
Solubility | 0.0938 mg/ml ; 0.000592 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 |
-5.77 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 |
1.0 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) |
1.26 |
* 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 |
---|---|---|
78.7% | With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h; | Example 1 1-(5-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (1)1-(Bromomethyl)-4-chloro-2-fluorobenzene was prepared using the following two-step procedure. To a stirred solution of 4-chloro-2-fluorobenzaldehyde (1.0 g, 6.31 mmol) in methyl alcohol (CH3OH; 15 mL) was added sodium borohydride (NaBH4; 0.47 g, 12.6 mmol) at 0 C. The reaction mixture was stirred at RT for 1 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice pieces, and the volatiles were evaporated under reduced pressure. The residue was diluted with H2O (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (SiO2, 100-200 mesh) to afford the corresponding alcohol (0.8 g, 5.0 mmol, 78.7%) as a semi solid. 1H NMR (200 MHz, CDCl3): delta 7.41 (q, J=8.0, 15.6 Hz, 1H), 7.17-7.05 (m, 2H), 4.73 (d, J=6.2 Hz, 2H), 1.83 (t, J=6.2 Hz, 1H). |
With hydrogenchloride; sodium borohydrid; In 1,4-dioxane; methanol; | (1) First, 25 g of 4-chloro-2-fluorobenzaldehyde was dissolved in a mixed solvent consisting of 250 ml of 1,4-dioxane and 25 ml of methanol, to which 2.4 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, a small amount of diluted aqueous hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 25 g of 4-chloro-2-fluorobenzyl alcohol. 1 H--NMR (300 MHz, CDCl3): delta (ppm) 1.82 (1 H, t, J=6.1 Hz), 4.72 (2 H, d, J=6.1 Hz), 7.08 (1 H, dd, J=2.1, 9.8 Hz), 7.15 (1 H, dd, J=2.1, 8.2 Hz), 7.37 (1 H, dd, J=8.2, 8.2 Hz) | |
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1.5h; | 4.75 g of 4-chloro-2-fluorobanzaldehyde and 30 ml of methanol were mixed. It was cooled to 0 C, and 0.57 g of sodium borohydride was added to it, and stirred at 0 C for 30 minutes and at room temperature for 1 hour. Water was added to the reaction mixture, and concentrated under reduced pressure. The obtained residue was extracted with chloroform. The organic layer was washed successively with 5 % hydrochloric acid, saturated aqueous solution of sodium chloride, dried by magnesium salfate, and concentrated under reduced pressure to obtain 4.57 g of (4-chloro-2-fluorophenyl)methanol.1H-NMR (CDCl3, TMS) delta (ppm): 7.37 (1H, t, J=8.0 Hz), 7.12-7.17 (1H, m), 7.08 (1H, dd, J=9.7 Hz, 1.9 Hz), 4.73 (2H, s), 2.04 (1H, br.s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 4h; | A round bottom flask was charged with 8-oxa-3-azabicyclo[3.2.1]octane (495 mg,3.32 mmol), K2 C03 (436 mg, 3.16 mmol) and 4-chloro-2-fluorobenzaldehyde (500 mg, 3.15 mmol), and the contents were dissolved in DMSO (10 mL) and heated to 120 C. After 4 h, the reaction mixture was diluted in DCM (200 mL) and washed 3X with brine. The organics were dried over anhydrous Na2 S04 and concentrated. The resulting orange oil was chromatographed on a silica column with a gradient (100% hexanes to 80% Hexanes/20% EtOAc) to provide 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde as a yellow solid (336 mg, 43 %). 1H NMR(400 MHz, Chloroform-d) 810.32 (s, lH), 7.72 (s, lH), 7.46 (ddd,J= 8.7, 3.3, 1.7 Hz, 1H), 7.08 (dd, J= 8.7, 1.3 Hz, 1H), 4.47-4.41 (m, 2H), 3.21 (d, J= 11.5 Hz, 2H), 2.91 (d, J= 11.7 Hz, 2H),2.19-2.06 (m, 2H), 2.06-1.96 (m, 2H). LCMS (ESI, m/z): 252.1 [M+Ht. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide; In acetonitrile; for 24h; | To a solution of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (222mg) in MeCN (20m1) was addedMnO (480mg). The mixture was stirred for 24h. The mixture was filtered over celite, theorg. layer was dried over MgSO4 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): tR = 0.76 mm; [M+H]: not visible. | |
With manganese(IV) oxide; In acetonitrile; at 20℃; for 24h;Inert atmosphere; | To a solution of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (222 mg) in MeCN (20 mL) was added MnC>2 (480 mg). The mixture was stirred for 24h. The mixture was filtered over celite, the org. layer was dried over MgS04 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): tR = 0.76 min; [M+H]+: not visible. | |
With manganese(IV) oxide; In acetonitrile; for 24h; | To a solution of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (222mg) in MeCN (20ml) was added Mn02 (480mg). The mixture was stirred for 24h. The mixture was filtered over celite, the org. layer was dried over MgS04 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): tR = 0.76min; [M+H]+: not visible. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19 g | With 1,3-dimethyl-2-imidazolidinone; potassium carbonate; at 100℃; for 15h; | (1) A suspension of Compound 1 (10.0 g), Compound 2 (14.0 g), and potassium carbonate (13.1 g) in 1,3-dimethyl-2-imidazolidinone (80 mL) was stirred at 100°C for 15 hours. The reaction mixture was cooled to room temperature, then water was added thereto, and extracted with ethyl acetate. The resultant organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=99:1-90:10) to give Compound 3 (19.0 g) as a yellow viscous material. MS (APCI) : m/z 324/326 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | A vial was charged with <strong>[33689-29-1]methyl 1-hydroxycyclopropane-1-carboxylate</strong> (1.28 g, 11.0 mmol, 1.10 equiv) and THF (20 mL). Sodium hydride (60% in oil, 600 mg, 15.0 mmol, 1.50 equiv) was added dropwise at 0 C. The resulting solution was stirred for 0.5 h at room temperature. Then 4- chloro-2-fluorobenzaldehyde (1.59 g, 10.0 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (20 mL). The mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 500 mg (20% yield) of methyl 1-(5- chloro-2-formylphenoxy)cyclopropane-1-carboxylate as a white solid. LCMS (ESI, m/z): 255 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; | Example 234 Synthesis of ethyl 5-bromobenzo[b]thiophene-2-carboxylate. To a solution of 4-chloro-2-fluorobenzaldehyde (2 g, 12.6 mmol) and ethyl 2-mercaptoacetate (1.58 g, 12.6 mmol) in EtOH (40 mL) was added Na2CO3 (1.58 g, 15.1 mmol). The reaction mixture was stirred at reflux for 14 h. Then the mixture was concentrated in vacuo. Water (30 mL) was added and the mixture was extracted with DCM (50 mL*3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc=1/1) to give the ethyl 5-bromobenzo[b]thiophene-2-carboxylate as a yellow solid (2.36 g, yield: 78%). ESI-MS [M+H]+: 240.9. |
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