Structure of 6318-51-0
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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. : | 6318-51-0 |
Formula : | C12H8ClNO |
M.W : | 217.65 |
SMILES Code : | O=C(C1=CC=C(Cl)C=C1)C2=NC=CC=C2 |
MDL No. : | MFCD02930888 |
InChI Key : | KHXSJSBQIWAIEG-UHFFFAOYSA-N |
Pubchem ID : | 80594 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 59.12 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.96 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.36 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.51 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.97 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.95 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.49 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.65 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.23 |
Solubility | 0.128 mg/ml ; 0.000588 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.78 |
Solubility | 0.357 mg/ml ; 0.00164 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.11 |
Solubility | 0.00167 mg/ml ; 0.00000769 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
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 |
-5.85 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) |
1.63 |
* 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 |
---|---|---|
With Kluyveromyces polysporus alcohol dehydrogenase S237R mutant; isopropyl alcohol; NADPH; In aq. phosphate buffer; at 30℃;pH 7.0;Enzymatic reaction;Kinetics; Catalytic behavior; | General procedure: Bioconversion was conducted with 20 mM 1a-10a,20 U·mL-1KpADH variants, 40 mM isopropanol in PBS buffer (pH 7.0,100 mM) in total volume of 2 mL at 30 C and 180 rpm overnight. Then,1 mL of the reaction mixture was withdrawn and extracted with ethylacetate. The organic phase was isolated by centrifugation and driedover anhydrous MgSO4. The conversion rate and enantioselectivity ofthe products were analyzed as described in supporting information. | |
With Kluyveromyces polysporus alcohol dehydrogenase E214 G/S237C mutant variant; NADPH; In aq. phosphate buffer; at 30℃;pH 7.0;Enzymatic reaction;Kinetics; | General procedure: Six variants with significantly improved activity were selected to test their stereoselectivity and conversion rate. Bioconversion was conducted with 20mM 1a-9a, 20UmL-1 KpADH or variants in PBS buffer (pH 7.0, 100mM) in total volume of 2mL at 30C and 180rpm overnight. Then, 1mL of the reaction mixture was withdrawn and extracted with equal volume of ethyl acetate. The organic phase was isolated by centrifugation at 12000×g for 2min, and dried over anhydrous MgSO4. The conversion rate and stereoselectivity of the products were determined using the Agilent 1100 equipped with a Chiralcel OB-H column or a Chiralcel OD-H column (0.46mm×250mm×5μm, Diacel, Japan). Detailed conditions for stereoselectivity analysis and the retention times of (R)- and (S)-alcohols could be found in Table S3 [28]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In ethanol; | 10L glass reactor with mechanical stirring,thermometer,Under nitrogen protection,First with magnesium shavings,p-chlorobenzaldehyde and tetrahydrofuran heated to form a solution,And then dropping 2-cyanopyridine,The reaction to the remaining 2-cyanopyridine remaining,Cooling for post-processing,Add water quench,Adjust pH to about 5,The organic phase was separated and the reaction product was extracted with ethyl acetate,The solvent was concentrated by petroleum ether to obtain the crude product of the first step. The crude product was purified by petroleum ether and ethyl acetate. First add the first step product and 95percent ethanol,Add sodium borohydride cooling,The reaction to no raw material for post-treatment,The system is concentrated to dryness,Add water and stir,Suction filtered crude,After ethyl acetate and activated carbon decolorization,Purification with petroleum ether and ethyl acetate gave the pure product of alpha- (4-chlorophenyl) pyridine-2-methanol,The total molar yield was 75percent with a purity of 99.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With pyridinium chlorochromate; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | To a stirred solution of (4-chlorophenyl) (pyridin-2-yl) methanol (5 g, 22.83 mmol) in CH2C12 (85 mL) under argon atmosphere was added pyridinium chlorochromate (5.9 g, 27.37 mmol, 1.2 equiv) and celite (5 g) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was filtered through celite, washed with CH2C12 and the filtrate was concentrated under reducedpressure. Purification using silica gel column chromatography (20percent EtOAc Hexanes as eluent) afforded 3.5 g of (4-chlorophenyl) (pyridin-2-yl) methanone (Yield = 7 1percent). ESI + MS: m/z 218 ([M + Hj). |
With pyridinium chlorochromate; In dichloromethane; | The compounds of the present invention were synthesized according to the procedure, which is illustrated schematically in FIG. 1 for three MPH alkyl analogs. Referring to FIG. 1, para-bromochlorobenzene 1 was converted into a Grignard reagent with Mg/THF which was then reacted with the pyridine-2-carboxaldehyde 2 to produce the alcohol 3. The alcohol 3 was oxidized with pyridinium chlorochromate in CH2Cl2 to produce the ketone 4. The ketone 4 was then reacted with a Grignard reagent that contains the required R group to produce the alcohol 5. After dehydration with refluxing HCl, the resulting Z and E olefin mixture 6 was hydrogenated with 10percent Pt/C in HOAc containing 3percent CF3COOH to produce the final compounds 7 with a ratio of about 40:60 of the R,R/S,S and R,S/S,R racemates for the ethyl compound. The racemates were separated by column chromatography and their relative configurations were determined by x-ray crystallography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.7% | With (R,R)-DIOPRuCl2(R)-Me-BIMAH; potassium tert-butylate; hydrogen; In toluene; at 35℃; under 26601.8 Torr; for 4h;Autoclave; | In a 5L autoclave, under the condition of argon, 400 g of (4-chlorophenyl)(pyridin-2-yl)methanone was added from the feed inlet; 3 L of toluene was added; Bubble out of gas, continuous bubbling 30min; degassing is complete. Under an argon atmosphere, 100 mg of catalyst (R,R)-DIOPRuCl2(R)-Me-BIMAH was added from the feed port, and finally 6 g of potassium tert-butoxide was added; after the addition was completed, the feed port was quickly closed tightly. Replacing argon with hydrogen gas and slowly introducing hydrogen gas to 35 atm, and then closing the inflation valve and closing the hydrogen channel; finally stirring, maintaining the reaction at 35 C.; after the start of stirring, the pressure dropped. Observe the changes in pressure, after 4h, the pressure no longer changes, sampling for GC analysis,The conversion rate was 99.7% and the ee value was 98.2%. |
96% | With bis(1,5-cyclooctadiene)diiridium(I) dichloride; N-((1R,2R)-2-(((R)-1-(2-(diphenylphosphanyl)ferrocenyl)ethyl)amino)cyclohexyl)-2,4,6-trimethylbenzenesulfonamide; hydrogen; lithium tert-butoxide; In methanol; at 40℃; under 22502.3 Torr; for 12h;Autoclave;Catalytic behavior; | (1) The chiral ligand L2 (17.3 mg, 0.025 mmol), metal complex [Ir(COD)Cl] 2 (8.0 g,0.012 mmol) was added to the reaction flask, methanol (1.5 mL) was added under an argon atmosphere, and the reaction was stirred at 25 C for 0.5 h to obtain a catalyst.(2) (4-Chlorophenyl)(pyridin-2-yl)methanone (52.2 g, 0.24 mol) was added to the autoclave, and the catalyst prepared in the step (1) was directly added, lithium t-butoxide (0.96 g). , 12mmol), methanol (100mL), charged with H2 (3.0MPa), reacted at 40 C for 12h, after the reaction is completed, the reaction solution is concentrated under reduced pressure to recover the organic solvent, then add appropriate amount of water, extracted with ethyl acetate, the liquid is The organic phase and the aqueous phase are dried and de-solubilized to obtain (S)-(4-chlorophenyl)(pyridin-2-yl)methanol (50.5 g,0.23 mol), yield: 96%, HPLC purity 98%, ee value 99.9%.The 1H NMR spectrum and the 13C NMR spectrum of (S)-(4-chlorophenyl)(pyridin-2-yl)methanol prepared in this example are shown in Fig. 1 and Fig. 2, respectively, from Fig. 1 and Fig. 2 The resulting (S)-(4-chlorophenyl)(pyridin-2-yl)methanol product can be determined. Racemic compound (4-chlorophenyl)(pyridin-2-yl)methanol and (S)-(4-chlorophenyl) prepared in Example 10The HPLC analysis spectra of the (pyridin-2-yl)methanol product are shown in Figures 3 and 4, respectively.Comparing Fig. 3 and Fig. 4, it can be seen that the two racemates of (4-chlorophenyl)(pyridin-2-yl)methanol have different peak times in the HPLC analysis spectrum.It was confirmed that the final preparation of Example 10 was (S)-(4-chlorophenyl)(pyridin-2-yl)methanol, and the product was highly pure. |
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