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Chemical Structure| 844648-22-2 Chemical Structure| 844648-22-2

Structure of 844648-22-2

Chemical Structure| 844648-22-2

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Product Details of [ 844648-22-2 ]

CAS No. :844648-22-2
Formula : C9H6F2O2
M.W : 184.14
SMILES Code : O=C1CCOC2=C1C(F)=CC(F)=C2
MDL No. :MFCD11518474
InChI Key :OJVRCPGUGZXUAP-UHFFFAOYSA-N
Pubchem ID :46835427

Safety of [ 844648-22-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 844648-22-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 0
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 40.93
TPSA ?

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

26.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.74
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

1.58
Log Po/w (WLOGP)?

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

2.77
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.

1.89
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

3.21
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.24

Water Solubility

Log S (ESOL):?

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

-2.32
Solubility 0.884 mg/ml ; 0.0048 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.

-1.74
Solubility 3.33 mg/ml ; 0.0181 mol/l
Class?

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

Very 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

-3.42
Solubility 0.0708 mg/ml ; 0.000385 mol/l
Class?

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

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

No
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.

-6.3 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

1.0
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)

2.09

Application In Synthesis of [ 844648-22-2 ]

* 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.

  • Upstream synthesis route of [ 844648-22-2 ]

[ 844648-22-2 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 844648-19-7 ]
  • [ 844648-22-2 ]
YieldReaction ConditionsOperation in experiment
86% at 50℃; for 1.5 h; At a temperature of 50 0C, 3-(3,5-difluorophenoxy)propanoic acid (20.0 g, 99 mol) was dissolved portion-wise into 60 ml of concentrated sulfuric acid. The resulting yellow-green solution was stirred for 1.5 hours at 50 0C, cooled to room temperature, and poured on ice water (800 ml). After a period of 1 hour, the colourless precipitate was isolated by filtration and washed with water. The title compound was dried over phosphorous pentaoxide: 15.69 g of a colourless solid, 86 percent yield
84% at 10 - 50℃; Large scale 345 kg of concentrated sulfuric acid was introduced into the reactor A,After cooling to 10 ° C, 142 kg of 3- (3,5-difluorophenoxy) propanoic acid was added dropwise.50 After stirring,After the reaction was completed, the reaction mixture was cooled to 20 ° C.1421 kg of purified water was charged into the reactor B,0 & gt; C.The reaction product of the reactor A was slowly dropped into the reactor B while maintaining the temperature at 10 ° C or lower, and 1890 kg of dichloromethane was added and stirred.After separating the organic layer,1421 kg of purified water was added and the pH was adjusted to 7.5 using a 5percent sodium carbonate aqueous solution (14 kg of sodium carbonate + 284 kg of purified water).The organic layer was separated, concentrated in vacuo at 40 & lt; 0 &483 kg of heptane was added and stirred.After filtration, it was vacuum-dried at 40 DEG C,5,7-difluorochroman-4-one (109 kg, 84percent).
73%
Stage #1: With thionyl chloride In toluene for 1.5 h; Heating / reflux
Stage #2: With trifluorormethanesulfonic acid In chloroform at -65 - 20℃; for 2 h;
Stage #3: With sodium hydroxide In chloroform; water
To a solution of 3-(3,5-difluorophenoxy)-propionic acid (1.11 g, 5.49 mol) in toluene (10 mL) was added thionyl chloride (2.0 mL, 27 mmol). The solution was heated at reflux for 1.5 h, then was concentrated in vacuo. The residue was dissolved in CHCl3 (10 mL), cooled to -65° C., and treated dropwise with trifluoromethanesulfonic acid (0.73 mL, 8.2 mmol). The mixture was allowed to warm to room temperature with stirring over 2 h. After the addition of H2O, the layers were separated. The organic layer was washed with 1 N NaOH, then dried over MgSO4, filtered, concentrated, and purified by flash chromatography (hexanes/EtOAc) to provide the title compound (0.73 g, 73percent). TLC (silica, 50percent EtOAc/hexanes): Rf=0.43. 1H NMR (400 MHz, CDCl3): 6.52-6.47 (m, 2H), 4.54 (t, J=6.4 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H).
References: [1] Patent: WO2008/151927, 2008, A2, . Location in patent: Page/Page column 61.
[2] Patent: KR2018/11830, 2018, A, . Location in patent: Paragraph 0061; 0076; 0077.
[3] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 31.
  • 2
  • [ 942195-90-6 ]
  • [ 844648-22-2 ]
YieldReaction ConditionsOperation in experiment
88% With trifluorormethanesulfonic acid In water at 80℃; for 2 h; STEP 7:
5,7-Difluoro-2,3-dihydro-4H-chromen-4-one
A mixture of methyl 3-(3,5-difluorophenoxy)propanoate (11.6 g, 53.7 mmol, STEP 6) and trifluoromethanesulfonic acid (23.2 mL, 2.0 mL/g of substrate) was stirred at 80° C. for 2 hours.
After cooling to room temperature, the reaction mixture was diluted with water (120 mL), and extracted with toluene (120 mL).
The organic layer was washed successively with aqueous solution of potassium carbonate (50 mL), water (50 mL), and dried over magnesium sulfate.
The organic mixture was concentrated in vacuum to afford the title compound (8.75 g, 88percent) as a white solid, which was used in the next step without further purification.
1H NMR (CDCl3, 270 MHz) δ: 6.51-6.40 (m, 2H), 4.55-4.50 (m, 2H), 2.86-2.75 (m, 2H) ppm.
References: [1] Patent: US2007/142448, 2007, A1, . Location in patent: Page/Page column 33.
  • 3
  • [ 844648-16-4 ]
  • [ 844648-22-2 ]
YieldReaction ConditionsOperation in experiment
80% at 10 - 50℃; Large scale 30 kg of concentrated sulfuric acid was added to reactor A.11 kg of 3- (3,5-difluorophenoxy) propanenitrile was added at 10 to 20 ° C,The mixture was heated to 50 DEG C and stirred. When the reaction was completed, it was cooled to room temperature.Reactor B was charged with 100 L of purified water and cooled to 0 .Reactant A was charged to Reactor B.110 L of dichloromethane was added, and 5percentThe pH was adjusted to 7 using an aqueous solution of sodium hydroxide.After stirring, the organic layer was separated.After concentrating under reduced pressure, 55 L of heptane was added, stirred, and filtered. Vacuum drying at 40 ° C yielded 5,7-difluorochroman-4-one (9 kg, 80percent).
References: [1] Patent: KR2018/11830, 2018, A, . Location in patent: Paragraph 0057; 0082; 0083.
[2] Patent: WO2008/151927, 2008, A2, .
  • 4
  • [ 2713-34-0 ]
  • [ 844648-22-2 ]
References: [1] Patent: KR2018/11830, 2018, A, .
[2] Patent: WO2008/151927, 2008, A2, .
 

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