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Chemical Structure| 6318-51-0

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Product Details of [ 6318-51-0 ]

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

Safety of [ 6318-51-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319
Precautionary Statements:P305+P351+P338

Computational Chemistry of [ 6318-51-0 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

29.96 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.36
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.51
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.97
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.95
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.49
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.65

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.23
Solubility 0.128 mg/ml ; 0.000588 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.78
Solubility 0.357 mg/ml ; 0.00164 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-5.11
Solubility 0.00167 mg/ml ; 0.00000769 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.85 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.63

Application In Synthesis of [ 6318-51-0 ]

* 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.

  • Downstream synthetic route of [ 6318-51-0 ]

[ 6318-51-0 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 6318-51-0 ]
  • [ 176022-47-2 ]
  • [ 112966-26-4 ]
YieldReaction ConditionsOperation 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].
  • 2
  • [ 6318-51-0 ]
  • [ 27652-89-7 ]
YieldReaction ConditionsOperation 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.
  • 3
  • [ 27652-89-7 ]
  • [ 6318-51-0 ]
YieldReaction ConditionsOperation 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.
  • 4
  • [ 6318-51-0 ]
  • [ 176022-47-2 ]
YieldReaction ConditionsOperation 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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