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Chemical Structure| 18063-02-0 Chemical Structure| 18063-02-0
Chemical Structure| 18063-02-0

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CAS No.: 18063-02-0

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Product Details of [ 18063-02-0 ]

CAS No. :18063-02-0
Formula : C7H3ClF2O
M.W : 176.55
SMILES Code : O=C(Cl)C1=C(F)C=CC=C1F
MDL No. :MFCD00000659
InChI Key :QRHUZEVERIHEPT-UHFFFAOYSA-N
Pubchem ID :87438

Safety of [ 18063-02-0 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H314
Precautionary Statements:P280-P305+P351+P338-P310
Class:8(3)
UN#:2920
Packing Group:

Computational Chemistry of [ 18063-02-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 36.54
TPSA ?

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

17.07 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.7
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

2.57
Log Po/w (WLOGP)?

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

3.18
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.

2.9
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

3.18
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.71

Water Solubility

Log S (ESOL):?

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

-2.89
Solubility 0.227 mg/ml ; 0.00128 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.

-2.58
Solubility 0.468 mg/ml ; 0.00265 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

-3.52
Solubility 0.0536 mg/ml ; 0.000303 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.

-5.55 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

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)

1.28

Application In Synthesis of [ 18063-02-0 ]

* 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 [ 18063-02-0 ]

[ 18063-02-0 ] Synthesis Path-Downstream   1~17

  • 2
  • [ 40963-14-2 ]
  • [ 18063-02-0 ]
  • N-(1-Carbamoyl-1,2-dimethyl-propyl)-2,6-difluoro-benzamide [ No CAS ]
  • 3
  • [ 7579-20-6 ]
  • [ 18063-02-0 ]
  • 2-(2,6-difluoro-phenyl)-pyrido[3,4-<i>d</i>][1,3]oxazin-4-one [ No CAS ]
  • 4
  • [ 16947-63-0 ]
  • [ 18063-02-0 ]
  • N-(2,6-dimethyl-4-nitrophenyl)-2,6-difluorobenzamide [ No CAS ]
  • 5
  • [ 777-12-8 ]
  • [ 18063-02-0 ]
  • N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In tetrahydrofuran; EXAMPLE 1 STR6 At 0 to 5 C., 2,6-difluorobenzoyl chloride (1.77 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), tetrahydrofuran (30 ml) and triethylamine (1.1 g). The reaction mixture was stirred at 30 to 40 C. for 5 hours, and then tetrahydrofuran was evaporated. The solid residue was washed with water and recrystallized from ethanol to give the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide (2.8 g). mp. 256-257 C.
  • 6
  • [ 3034-57-9 ]
  • [ 18063-02-0 ]
  • [ 945226-58-4 ]
YieldReaction ConditionsOperation in experiment
83% In tetrahydrofuran; pyridine; at 20.0℃; for 3.0h; 2-Amino-5-bromo-4-trifluoromethylthiazole (0.8 g) was dissolved in 3 ml_ of 1 :1 mixture of THF and pyridine. 2,6-difluorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on silica gel gave the title compound as a white solid. Yield 83percent.
  • 7
  • [ 369-26-6 ]
  • [ 18063-02-0 ]
  • [ 1160624-36-1 ]
YieldReaction ConditionsOperation in experiment
52% With triethylamine; at 20℃; for 1.5h; Step C: Methyl 3-[(2,6-difluorophenyl)carbonyl]amino}-4-fluorobenzoate; To a solution of <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (5.5 g, 33 mmol) in DCM (100 ml_) was added TEA (6.8 ml_, 49 mmol) and 2,6-difluorobenzoyl chloride (4.3 ml_, 34 mmol). After 90 min at rt, the reaction mixture was washed with H2O and concentrated to a brown oil. The product was purified by column chromatography (eluting with 30-60percent EtOAc /hexanes) to generate the desired product in 52percent yield (5.37 g, 17 mmol). MS (ESI) m/z = 310 [M+Hf .
  • 8
  • [ 1585-90-6 ]
  • [ 18063-02-0 ]
  • [ 1333082-91-9 ]
  • 9
  • [ 1585-90-6 ]
  • [ 18063-02-0 ]
  • (+/-)-2-((3aS,4S,7aR)-4-(2-acetoxyethyl)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl)ethyl 2,6-difluorobenzoate [ No CAS ]
  • 10
  • [ 28466-26-4 ]
  • [ 18063-02-0 ]
  • [ 1153946-38-3 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In acetonitrile; at 20℃;Cooling with ice; Inert atmosphere; 1/-/-Pyrazol-4-amine (for a preparation see intermediate 1 ; 0.54 g, 6.5 mmol) was dissolved in acetonitrile (25 ml) with triethylamine (1.81 ml, 13.0 mmol) to give a red- purple suspension which was cooled in an ice-water bath. To the suspension was added a solution of 2,6-difluorobenzoyl chloride (Aldrich; 0.817 ml, 6.5 mmol) in acetonitrile (25 ml) dropwise over 15 min. The mixture was stirred cold under nitrogen. The reaction was stirred and allowed to warm slowly towards room temperature over 2 h, then at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and water (-100 ml each). The aqueous phase was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue (1.41 g) was purified on silica (50 g) using 0-100% EtOAc-cyclohexane then 0-20% methanol- EtOAc. Relevant fractions were concentrated in vacuo to give some pure product (0.925 g) and some less pure material (0.50 g). The latter material was re-purified on silica (20 g) using EtOAc to give further pure product (0.366 g). The two batches of pure product were combined to give the title compound (1.28 g) as a pale cream solid; LCMS (System 1): MH+= 224, tRET = 2.08 min.
Intermediate 6: 2,6-Difluoro-N-1H-pyrazol-4-ylbenzamide.1H-Pyrazol-4-amine (for a preparation see intermediate 5; 0.54 g, 6.5 mmol) was dissolved in acetonitrile (25 ml) with triethylamine (1.81 ml, 13.0 mmol) to give a red- purple suspension which was cooled in an ice-water bath. To the suspension was added a solution of 2,6-difluorobenzoyl chloride (Aldrich; 0.817 ml, 6.5 mmol) in acetonitrile (25 ml) dropwise over 15 min. The mixture was stirred cold under nitrogen. The reaction was stirred and allowed to warm slowly towards room temperature over 2 h, then at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and water (-100 ml each). The aqueous phase was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue (1.41 g) was purified on silica (50 g) using 0-100% EtOAc-cyclohexane then 0-20% methanol- EtOAc. Relevant fractions were concentrated in vacuo to give some pure product (0.925 g) and some less pure material (0.50 g). The latter material was re-purified on silica (20 g) using EtOAc to give further pure product (0.366 g). The two batches of pure product were combined to give the title compound (1.28 g) as a pale cream solid; LCMS (System1): MH+= 224, tRET = 2.08 min.
  • 11
  • [ 67-56-1 ]
  • [ 18063-02-0 ]
  • [ 13671-00-6 ]
  • [ 385-00-2 ]
  • 12
  • [ 156118-16-0 ]
  • [ 18063-02-0 ]
  • N-(6-bromo-4-methylpyridin-3-yl)-2,6-difluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With pyridine; In dichloromethane; at 20℃; To a (0 C) cooled and stirred solution of 2,6-difluorobenzoyl chloride (357 2.83 mmol) in DCM (5 mL) was added <strong>[156118-16-0]6-bromo-4-methylpyridin-3-amine</strong> (583 mg, 3.12 mmol) followed by the addition of pyridine (344 mu, 4.25 mmol). The resulting mixture was then stirred at room temperature overnight. Water (5 mL) was added to the above mixture and then extracted with DCM (3x10 mL). The combined organic layers were washed with 10% aq.HCl (10 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum to afford 650mg (70%) of the title compound as a white solid. XHNMR (400 MHz, DMSO- d6) delta 10.56 (s, 1H, D20 exchangeable), 8.41 (s, 1H), 7.66 (s, 1H), 7.65-7.58 (m, 1H), 7.27 (t, = 7.0Hz, 2Eta), 2.27 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH)+, Br79' 81].
  • 13
  • [ 156118-16-0 ]
  • [ 18063-02-0 ]
  • N-(5-bromo-4-methylpyridin-2-yl)-2,6-difluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With pyridine; In dichloromethane; at 0 - 20℃; To a (0 C) cooled and stirred solution of 2,6-difluorobenzoyl chloride (500mg, 2.83 mmol) in DCM (10 mL) was added 4-bromo-3-methylaniline (632 mg, 3.40 mmol) followed by the addition of pyridine (275 mu, 3.40 mmol). The resulting mixture was warmed to room temperature and stirred overnight. Water (10 mL) was then added to the above mixture and extracted with DCM (3x20 mL). The combined organic layers were washed with 10% aq.HCl (lOmL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum to afford 250mg (28%) of the title compound as a white solid. XHNMR (400 MHz, DMSO-ife) delta 11.44 (s, 1H, D20 exchangeable), 8.53 (s, 1H), 7.63 (s, 1H), 7.61-7.54 (m, 1H), 7.21 (t, = 7.0Hz, 2Eta), 2.41 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH) + Br79' 81]
  • 14
  • [ 18063-02-0 ]
  • [ 15992-83-3 ]
  • 2,6-difluoro-N-[1,8]naphthyridin-2-ylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% With 3-dimethylaminoacrolein; In pyridine; dichloromethane; at 20℃; for 0.5h; Part II- Synthesis of 2,6-Difluoro-N-[1,8]naphthyridin-2-ylbenzamide; [1,8]-Naphthyridin-2-ylamine (85 mg, 0.59 mmol) was dissolved in dichloromethane(2 mL) and pyridine (0.10 mL, 1.2 mmol). 2,6-Difluorobenzoyl chloride (0.068 mL, 0.76mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture was diluted with ethyl acetate and washed with water followed bybrine. The resulting organic solution was purified by column chromatography (EtOAc/hexanes) to give 2,6-difluoro-N-[1,8]naphthyridin-2-ylbenzamide. Yield 35 mg (21 %).LCMS (ESI): calc. C1sH9FzN30 = 285; obs. M+H = 286.
  • 15
  • [ 1023595-19-8 ]
  • [ 18063-02-0 ]
  • [ 1448754-05-9 ]
  • 16
  • 2-amino-N-benzyloxyacetamide 2,2,2-trifluoroacetic acid [ No CAS ]
  • [ 118289-17-1 ]
  • [ 18063-02-0 ]
  • 3-benzyloxy-2-(2-bromo-4-pyridyl)-1-(2,6-difluorobenzoyl)imidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% To a suspension of 2-am ino-N-benzyloxy-acetam ide 2,2,2-trifluoroacetic acid(Intermediate Ab, 59 mg, 0.2 mmol) and <strong>[118289-17-1]2-bromopyridine-4-carboxaldehyde</strong> (37 mg, 0.2 mmol)in acetonitrile (1 mL) was added N,N-diisopropylethylamine (33.0 iL, 0.2 mmol). The whitesuspension was heated for 2 h at 50 °G. The mixture was cooled on an ice-water bath to < 5 00 and N,N-diisopropylethylamine (33.0 iL, 0.2 mmcl) was added. Subsequently a solution of 2,6- difluorobenzoyl chloride (30 iL, 0.24 mmol) in acetonitrile (0.1 mL) was added dropwise keeping the temperature below 5 00. The temperature of the reaction mixture was allowed to come to room temperature. The mixture was partially diluted with ethyl acetate (5 mL) and water (3 mL)was added slowly. The resulting phases were separated and the water layer was extracted with ethyl acetate (3 mL). The combined organic layers were washed with water (5 mL), 5percent NaHCO3- solution (5 mL), water (5 mL) and brine (5 mL), filtered over an PE filter filled with Na2504 and concentrated under reduced pressure. The crude residue was purified by column chromatography (heptane to ethyl acetate = 100/0 to 0/100 v/vpercent) to afford the title compound(63 mg, 64percent) as a white solid.
  • 17
  • [ 1593-60-8 ]
  • [ 18063-02-0 ]
  • N-((2,6-difluorobenzoyl)oxy)-4-methylbenzenesulfonamide [ No CAS ]
 

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