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Chemical Structure| 352-24-9 Chemical Structure| 352-24-9

Structure of Ethyl 4,4-difluoroacetoacetate
CAS No.: 352-24-9

Chemical Structure| 352-24-9

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Product Details of [ 352-24-9 ]

CAS No. :352-24-9
Formula : C6H8F2O3
M.W : 166.12
SMILES Code : O=C(OCC)CC(C(F)F)=O
MDL No. :MFCD00039277
InChI Key :CBDPWKVOPADMJC-UHFFFAOYSA-N
Pubchem ID :67697

Safety of [ 352-24-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H227
Precautionary Statements:P501-P210-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P403+P235

Computational Chemistry of [ 352-24-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 0
Fraction Csp3 0.67
Num. rotatable bonds 5
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 32.54
TPSA ?

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

43.37 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.31
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

1.1
Log Po/w (WLOGP)?

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

1.61
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.

0.64
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

1.36
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.2

Water Solubility

Log S (ESOL):?

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

-1.23
Solubility 9.72 mg/ml ; 0.0585 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.6
Solubility 4.14 mg/ml ; 0.0249 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

-1.31
Solubility 8.06 mg/ml ; 0.0485 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

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

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.

-6.53 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

1.0 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)

1.77

Application In Synthesis of [ 352-24-9 ]

* 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 [ 352-24-9 ]

[ 352-24-9 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 352-24-9 ]
  • [ 81982-54-9 ]
YieldReaction ConditionsOperation in experiment
65% With ammonium acetate; In methanol; (A) Preparation of: Ethyl 4,4-difluoro 3-amino-2-butenoate STR44 Ammonium acetate (62 g, 805 mM) is added at room temperature to a solution of ethyl 4,4-difluoro acetoacetate (7.400 g, 44.5 mM) in anhydrous methanol (120 ml). Stirring is continued at room temperature for 40 hours; the mixture is then poured into 5% sodium bicarbonate solution (200 ml), and extracted with ether (2*150 ml). The organic layer is dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo, yielding the expected compound as a yellowish oil. 4.700 g (yield 65%). IR (CHCl3): 3500, 1680, 1640 cm-1. NMR (CDCl3) 1.27 (t,JHH =7 Hz, 3H); 4.14 (q, JHH =7 Hz, 2H); 4.83 (s, broad, 1H); 5.95 (t, JHF =55 Hz, 1H).
  • 2
  • [ 352-24-9 ]
  • [ 50-00-0 ]
  • [ 4089-07-0 ]
  • ethyl 1,3-bis(2-ethoxy-1-(4-hydroxybenzyl)-2-oxoethyl)hexahydropyrimidine-5-carboxylate [ No CAS ]
  • ethyl 1,3-bis(2-ethoxy-1-(4-hydroxybenzyl)-2-oxoethyl)-5-(difluoroacetyl)hexahydropyrimidine-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
12%; 57% In water; at 20℃; for 24h;pH 5.9; General procedure: To a solution of the appropriate amino ester hydrochloride 2a?g (3.0 mmol) in acetate buffer (pH 5.9) (0.9 mL) ethyl 4,4-difluoro-3-oxobutanoate 4a (1.5 mmol) and formaldehyde 33percent aqueous solution (22.5 mmol) were added. The resulting mixture was stirred for 24 h at room temperature, then it was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over Na2SO4 and evaporated in vacuo. The product was purified by column chromatography on Kieselgel 60 (dichloromethane ?ethyl acetate 10:0?7:3 or hexane?ethyl acetate 10:0?7:3). In the case of amino esters hydrochlorides 2a and L-2b only nonfluoratedhexahydropyrimidines 5a and 5b were isolated in yields 71 and 65percent respectively. Their physico-chemical properties coincided with the previously described.
  • 3
  • [ 352-24-9 ]
  • [ 141459-53-2 ]
  • 1-tert-butyl-4-(difluoromethyl)-3-methyl-7H-pyrazolo[3,4-b]pyridin-6-one [ No CAS ]
  • 4
  • [ 352-24-9 ]
  • [ 76593-36-7 ]
  • 7-chloro-2-(difluoromethyl)-8,9-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With polyphosphoric acid; at 120℃; for 6.0h; To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric add (10 mL) was added ethyl 4,4-difiuoroacetoacetate (2.74 ml). The mixture was heated to 120 “C for 6 hours. While hot, the reaction mixture was then slowly added into a stirred saturated NaHCCb solution (200 mL). Once the pH~7, the aqueous layer was extracted with chloroformdPA (4:1). The organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified using aTeledyne SCO Combi-Flash system (liquid loading with DCM, 120G column, 0 - 40% EtOAc/DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1H NMR (400 MHz, CDCb) 6 6.90 (s, 1H), 6.48 (t, J = 54.9 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). E5-MS [M+l]+: 260.
39% With polyphosphoric acid; at 120℃; for 6.0h; To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric add (10 mL) was added ethyl 4,4-difiuoroacetoacetate (2.74 ml). The mixture was heated to 120 “C for 6 hours. While hot, the reaction mixture was then slowly added into a stirred saturated NaHCCb solution (200 mL). Once the pH~7, the aqueous layer was extracted with chloroformdPA (4:1). The organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified using aTeledyne SCO Combi-Flash system (liquid loading with DCM, 120G column, 0 - 40% EtOAc/DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1H NMR (400 MHz, CDCb) 6 6.90 (s, 1H), 6.48 (t, J = 54.9 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). E5-MS [M+l]+: 260.
39% With polyphosphoric acid; at 120℃; for 6.0h; To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric add (10 mL) was added ethyl 4,4-difiuoroacetoacetate (2.74 ml). The mixture was heated to 120 “C for 6 hours. While hot, the reaction mixture was then slowly added into a stirred saturated NaHCCb solution (200 mL). Once the pH~7, the aqueous layer was extracted with chloroformdPA (4:1). The organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified using aTeledyne SCO Combi-Flash system (liquid loading with DCM, 120G column, 0 - 40% EtOAc/DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1H NMR (400 MHz, CDCb) 6 6.90 (s, 1H), 6.48 (t, J = 54.9 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). E5-MS [M+l]+: 260.
 

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