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Chemical Structure| 72235-52-0 Chemical Structure| 72235-52-0

Structure of 72235-52-0

Chemical Structure| 72235-52-0

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Product Details of [ 72235-52-0 ]

CAS No. :72235-52-0
Formula : C7H7F2N
M.W : 143.13
SMILES Code : NCC1=CC=C(F)C=C1F
MDL No. :MFCD00010142
InChI Key :QDZZDVQGBKTLHV-UHFFFAOYSA-N
Pubchem ID :2733244

Safety of [ 72235-52-0 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H227-H314
Precautionary Statements:P280-P305+P351+P338-P310
Class:8
UN#:2735
Packing Group:

Computational Chemistry of [ 72235-52-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 34.03
TPSA ?

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

26.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.75
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

0.98
Log Po/w (WLOGP)?

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

2.11
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.

2.41
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

2.28
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.91

Water Solubility

Log S (ESOL):?

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

-1.72
Solubility 2.71 mg/ml ; 0.0189 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.

-1.11
Solubility 11.0 mg/ml ; 0.0768 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

-2.98
Solubility 0.151 mg/ml ; 0.00105 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.

-6.48 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

2.0
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)

1.1

Application In Synthesis of [ 72235-52-0 ]

* 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 [ 72235-52-0 ]

[ 72235-52-0 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 1335210-24-6 ]
  • [ 72235-52-0 ]
  • [ 1335210-25-7 ]
YieldReaction ConditionsOperation in experiment
C. (3S,llaR)-N-[(2,4-Difluorophenyl)methyl]-3-methyI-6-(methyloxy)-5,7-dioxo- 2,3,5,7,11,1 la-hexahydro [1,3] oxazolo [3,2-a]pyrido [l,2-
With 4-methyl-morpholine; chloroformic acid ethyl ester; In dichloromethane; at 0℃;Flow reactor; A solution of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4- dihydropyridine-3 -carboxylic acid (V) in acetic acid / Dimethyl carbonate (25. Og, 0.079 moles) and methane sulfonic acid (3.79 g, 0.039 moles) were introduced in micro channel reactor. After residence time of 9 mins at l30C, the reaction mixture containing 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2- oxoethyl)-l,4-dihydropyridine-3 -carboxylic acid (IVa) was further introduced into a second Tube Flow reactor and cyclised with solution of (S)-2-amino-propan-l- ol in (8.35g,0. l 1 moles) in Dimethyl carbonate at l00C at a residence time of 6 mins followed by quenching with Aq HC1 solution. The organic layer containing (3 S, 1 laR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,l 1,1 la-hexahydrooxazolo-[3,2- a] pyrido[ 1 ,2-ri/pyrazine -8-carboxylic acid (III b) was separated and introduced into a third Tube Flow Reactor with a solution of N-Methyl Morpholine (12. Og, 0.119 moles) and a solution of 2,4-diflurobenzylamine (l5.8g,0. l2moles) in MDC solvent and reacted in presence of Ethyl chloroformate (l2.06g,0. l l moles) at 0C . After a residence time of 2 mins yields (3S, l laR)-N-(2,4-Difluorobenzyl)- 6-methoxy-3-methyl-5,7-dioxo-2,3,5,7, l 1,1 la-hexahydrooxazolo-[3,2- a]pyrido[l,2- (0306) HPLC purity : 98.0% (0307) Yield : 85.0%.
  • 2
  • [ 1335210-34-8 ]
  • [ 72235-52-0 ]
  • [ 1335210-35-9 ]
YieldReaction ConditionsOperation in experiment
78% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 80℃; for 5h; Compound 6 (0.6 g, 1.95 mmol),1-ethyl-(3-dimethylaminopropyl)carbonic acid diimine hydrochloride (EDCI, 0.51 g, 2.65 mmol),2,4-difluorobenzylamine (0.29 ml, 2.44 mmol) in acetonitrile (10 ml) was heated to 80 C for 5 h.The reaction was quenched by the addition of 6 ml of water, the lower layer was a viscous yellow oily liquid, and the upper layer was suspended.The solvent of acetonitrile was evaporated under reduced pressure and suction filtered to give a crude material (yel.The crude product was recrystallized from AcOEt/petroleum ether = 4/1 solvent 15 ml to give compound 7 0.66 g(Rf = 0.25, TLC developer: AcOEt),The yield was 78%.
85 g (3S,11aR)-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a- hexahydro[1,3]oxazolo [3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (100 gm) and carbonyldimidazole (78.89 gm) were suspended in acetonitrile (1000 mL). The mixture was heated to a temperature of 75C and stirred for 1 hour. The resulting solution was cooled to a temperature of 20C and treated with 2,4- difluorobenzyl amine solution (55.2 gm was dissolved in 200 mL of acetonitrile). The reaction mixture was maintained for 2 hours, concentrated and the compound was extracted with ethyl acetate (1000 mL). Isopropyl alcohol (500 mL) was added at a temperature of 40C, stirred the reaction mass for 30 minutes at a temperature of 50C and the cooled the reaction mass to 25C. The reaction mixture was maintained for 8 hours at the same temperature. The product was collected by filtration and dried under vacuum (85 gm).
With 4-methyl-morpholine; chloroformic acid ethyl ester; In dichloromethane; at 0℃;Flow reactor; Large scale; A solution of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4- dihydropyridine-3 -carboxylic acid (V) in acetic acid / Dimethyl carbonate ( 5.0Kg, 15.8 moles) and methane sulfonic acid (533.0 g, 5.6 moles) were introduced in micro channel reactor. After residence time of 9 mins at l30C gives 5-methoxy- 6-(methoxycarbonyl)-4-oxo- 1 -(2-oxoethyl)- 1 ,4-dihydropyridine-3 -carboxylic acid (IVa). The reaction mixture was further introduced in a Tube Flow reactor and cyclised with solution of R-3 amino butanol ( 1.97 kg, 22.2 moles) in Dimethyl carbonate at l00C at a residence time of 5.15 mins followed by quenching with Aq HC1 solution. The organic layer containing (4S,l2aR)-7-methoxy-4-methyl- 6,8-dioxo-3,4,6,8,l2,l2a-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l- b][l,3]oxazine-9-carboxylic acid (III) was separated and introduced in a Tube Flow Reactor with a solution of N-Methyl Morpholine (2.25 Kg, 22.22 moles) and a solution of 2,4-diflurobenzylamine(3.l8 kg, 22.2 moles) in MDC solvent and reacted in presence of Ethyl chloroformate (1.73 Kg, 20.63 moles) at 0C. After a residence time of l. l5mins yields (4S,l2aR)-N-(2,4-Difluorobenzyl)-7-methoxy- 4-methyl-6,8-dioxo-3,4,6,8,l2,l2a-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l- b][l,3]oxazine-9-carboxamide (Ila) which was isolated in IPA after acid base workup. (0250) HPLC purity: 99.0% (0251) Yield: 80.0%.
  • 3
  • [ 72235-52-0 ]
  • [ 1335210-35-9 ]
 

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