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Chemical Structure| 189028-95-3 Chemical Structure| 189028-95-3

Structure of 189028-95-3

Chemical Structure| 189028-95-3

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Product Details of [ 189028-95-3 ]

CAS No. :189028-95-3
Formula : C20H20FNO4
M.W : 357.38
SMILES Code : O[C@@H](CCCC(=O)N1[C@H](COC1=O)C1=CC=CC=C1)C1=CC=C(F)C=C1
MDL No. :MFCD13194798
InChI Key :AVAZNWOHQJYCEL-MSOLQXFVSA-N
Pubchem ID :10269700

Safety of [ 189028-95-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 189028-95-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 26
Num. arom. heavy atoms 12
Fraction Csp3 0.3
Num. rotatable bonds 7
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 97.23
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

66.84 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.49
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

2.8
Log Po/w (WLOGP)?

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

3.14
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.

2.75
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

3.53
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.94

Water Solubility

Log S (ESOL):?

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

-3.7
Solubility 0.0714 mg/ml ; 0.0002 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.

-3.86
Solubility 0.0493 mg/ml ; 0.000138 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

-5.35
Solubility 0.00159 mg/ml ; 0.00000446 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

Yes
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

No
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

Yes
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.

-6.49 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)

3.47

Application In Synthesis of [ 189028-95-3 ]

* 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 [ 189028-95-3 ]

[ 189028-95-3 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 149437-76-3 ]
  • [ 189028-95-3 ]
  • 2
  • [ 99395-88-7 ]
  • [ 149437-76-3 ]
  • [ 189028-95-3 ]
YieldReaction ConditionsOperation in experiment
This invention adopts the "one-pot synthesis" according to bookletmai Bu intermediates for the synthesis of (4S)-3-[ (5S)-5-(4-fluoro phenyl)-5-hydroxy- fifth heavenly stem acyl group ]-4-phenyl -1, 3-oxygen nitrogen heterocyclic pentane-2-one (II), has the advantage of short synthetic route. One-pot synthesis (one-potreaction) is a high-efficiency organic synthetic method. "One-pot synthesis" in the reaction step from the reaction can be a plurality of relatively simple proceeding easily available raw materials, without intermediate separation, direct access to the molecules of the complex structure, thus having the advantage of the cost of synthesizing, and friendly to the environment.Firstly the 42g compound (I) dissolved in 420 ml in the reaction solution. The reaction solution includes: tetrahydrofuran, chloroform, dioxane or dichloromethane, and most preferably dichloromethane. In this embodiment, the reaction solution is dichloromethane, then added into the 1L three-necked bottle , will three-necked bottle is placed over the magnetic stirring device to mix uniformly to perform mechanical stirring. Compound (I) shown in the chemical structural formula as follows:In three-necked bottle is placed in the ice bath, ice-bath temperature is kept at 0 C three-necked bottle in until the oven is not higher than 10 C. Successive adds by drops Fu Suanji 30 ml and pivalyl chloride 75 ml. In this embodiment, the fu Suanji in particular to triethylamine. three-necked bottle is maintained during the dropping of the oven is not higher than 15 C. fu Suanji can absorb the acid generated in the reaction, a weakly alkaline substance with an acid salt, avoid acid influence the reaction or reaction balance. fu Suanji including triethylamine, pyridine, sodium methoxide or potassium hydroxide, and most preferably triethylamine. pivalyl chloride is an acylation reagent, pivaloyl chloride in organic synthesis in organic molecules can be oxygen, nitrogen, carbon, sulfur atom is introduced to the acyl.Triethylamine and pivalylchlorine instillment to room temperature reaction after 4 hours. Adding ice-bath to the oven is not higher than 10 C, dropwise S-4-phenyl-2-oxazolidinone 20g and N, N-dimethyl formamide 200 ml of the mixed solution, keep three-necked bottle the oven is not higher than 20 C, dropping temperature to reflux temperature of the reaction 2 hours. S-4-phenyl-2-oxazolidinone is an important pharmaceutical intermediates, is mainly used for asymmetric chiral organic synthesis.Salt bath to the oven is not higher than 0 C, successive instillment borane dimethyl sulfide 15 ml and (R)-2-methyl-CBS-oxazole borane 7.5 ml, maintain the oven is not higher than in three-necked bottle 5 C, after dropping temperature to stirring the mixture at room temperature for 30 minutes, add 150 ml dichloromethane, the reaction continued at room temperature for 3 hours. Borane dimethyl sulfide with synthesizing chiral the positioning function.Dropwise 300 ml quenching reaction of methanol, is added to the system again 100ml5% hydrogen peroxide and 20ml2N sulfuric acid, stirring 30 minutes, the organic layer is separated. Using 200ml2N sulfuric acid and 500ml5% wash once all sodium bisulfite solution, concentrating the organic layer to dry. Wherein F is fluoro, Ph is phenyl.Then using 200 ml isopropanol to dissolve residue, dripping 40 ml deionized water. Solid precipitated gradually during the dropping, the stirring at room temperature dropwise 2-3h, filtered, the filter cake drying to obtain 45g white solid.Detection method: high performance liquid chromatography (China Pharmacopoeia 2015 year version of the two-section appendix VD).Octadecyl silane bonds and silica gel as a filler, with cheap acetonitrile mobile phase, column temperature is 40 C, detection wavelength of 245 nm, flow rate is 0.5 ml/min. Isomer and weighed amount of product, respectively, using the mobile phase containing the dissolved and diluted into 0.01 mg/ml, diastereoisomer 0.01 mg/ml, isomer 0.01 mg/ml solution, as the system application solution. Applicability of system solution precision measuring 20ul, into the liquid chromatograph, and record chroatogram, diastereoisomer, vigiv, isomer peak in turn, non-enantiomer of the retention time of about 20 min, the main peak of the retention time of about 15 min, isomer produces the peak about 25 min, the main peak and the degree of separation of the isomer should be more than 2.0.The product weighed for proper amount of mobile phase containing the dissolved and diluted to 1.0 mg/ml solution is used for the solution of the sample. Sample solution taking precise quantity 20ul, into the liquid chromatograph, calculated normalization according to the area, such as in the chromatogram of the sample corresponding to isomer chromatographic peaks, the peak area of the isomer should not be more than the main peak and the sum of the peak area of 0.1%.Chromatographic conditions and system suitability test: with octadecyl silane bo...
 

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