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Chemical Structure| 226260-01-1

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Product Details of [ 226260-01-1 ]

CAS No. :226260-01-1
Formula : C9H10FNO2
M.W : 183.18
SMILES Code : O=C(N(OC)C)C1=CC=CC(F)=C1
MDL No. :MFCD02684305
InChI Key :RQOXEMMAAVCMRU-UHFFFAOYSA-N
Pubchem ID :21265757

Safety of [ 226260-01-1 ]

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

Computational Chemistry of [ 226260-01-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 45.38
TPSA ?

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

29.54 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.25
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

1.53
Log Po/w (WLOGP)?

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

1.88
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.

2.2
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

1.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.82

Water Solubility

Log S (ESOL):?

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

-2.08
Solubility 1.51 mg/ml ; 0.00826 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.

-1.76
Solubility 3.19 mg/ml ; 0.0174 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

-2.48
Solubility 0.611 mg/ml ; 0.00333 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.

-6.33 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)

1.6

Application In Synthesis of [ 226260-01-1 ]

* 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 [ 226260-01-1 ]

[ 226260-01-1 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 6638-79-5 ]
  • [ 1711-07-5 ]
  • [ 226260-01-1 ]
YieldReaction ConditionsOperation in experiment
86.5% With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere To a solution of Ν,Ο-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in DCM (1.5 L) was added Et3N (383 g, 3.78 mol) at room temperature (RT). To the stirred mixture, 1-1 (150 g, 946 mmol) was added dropwise at 0 °C under N2 atmosphere. The solution was stirred at the same temperature for 1 h, and then slowly warmed to RT for 10 h. The mixture was added to water (~1L) and extracted with EtOAc (2 x 500 mL). The combined organic phases were dried with Na2S04, filtered and concentrated. The residue was purified by flash column chromatography (eluent: PE) to give 1-2 as a white solid (150 g, yield: 86.5percent). 1H NMR (400 MHz, CDC13): δ 7.49-7.43 (1 H, m), 7.41-7.32 (2 H, m), 7.18- 7.10 (1 H, m), 3.54 (3 H, s), 3.34 (3 H, s).
References: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1415 - 1419.
[2] Patent: WO2016/145103, 2016, A1, . Location in patent: Paragraph 0165.
[3] Patent: US6174874, 2001, B1, .
[4] Patent: US2008/249095, 2008, A1, . Location in patent: Page/Page column 44.
  • 2
  • [ 455-38-9 ]
  • [ 6638-79-5 ]
  • [ 226260-01-1 ]
YieldReaction ConditionsOperation in experiment
71% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 75 h; EXAMPLE 4 3-Fluoro-N-methoxy-N-methylbenzamide To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and N dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate- hexane (4: 6) to separate the pure product (130 mg, 71percent). H-n. m. r. (CDC13) 8 3.36 (s, 3H, N-Me), 3.55 (s, 3H, N-OMe), 7. 1. -7.2 (m, 1H, ArH), 7.3-7. 5 (m, 3H, Ar)
71% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 75 h; Example 4 3-Fluoro-N-methoxy-N-methylbenzamide To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and AC (7 dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETHYLCARBODIIMIDE hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate- hexane (4: 6) to separate the pure product (130 mg, 71percent). APOS;H-N. m. r. (CDCL3) 8 3.36 (s, 3H, N-Me), 3.55 (s, 3H, N-OMe), 7.1.-7. 2 (m, 1H, Ar), 7.3-7. 5 (m, 3H, Ar)
61% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere 3-fluoro-N-methoxy-N-methylbenzamide
To a solution of 3-fluorobenzoic acid (30 g, 214.1 mmol) in DCM (300 mL) were added EDC.HCl (45 g, 235 mmol) and N,O-dimethylhydroxylamine.HCl (23 g, 235 mmol) at 0° C. under N2.
The reaction mixture was stirred at rt for 3 h, then diluted with water (1000 mL) and extracted with DCM (3*200 mL).
The organics were washed with brine, dried over Na2SO4, and concentrated to obtain the 3-fluoro-N-methoxy-N-methylbenzamide (24 g, 61percent).
(183.91 [M+H]) 1H NMR: (400 MHz, CDCl3) δ: 3.38 (s, 3H), 3.57 (s, 3H), 7.14-7.19 (m, 1H), 7.37-7.43 (m, 2H), 7.48-7.50 (d, J=7.6, 1H).
References: [1] Patent: WO2005/54199, 2005, A1, . Location in patent: Page/Page column 39-40.
[2] Patent: WO2004/52868, 2004, A1, . Location in patent: Page 29.
[3] Patent: US2014/274933, 2014, A1, . Location in patent: Paragraph 0091; 0092.
  • 3
  • [ 1711-07-5 ]
  • [ 226260-01-1 ]
YieldReaction ConditionsOperation in experiment
86.5% With triethylamine In dichloromethane at 0 - 20℃; for 11 h; Inert atmosphere 10264] To a solution of N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in DCM (1.5 L) was addedEt3N (383 g, 3.78 mol) at RT. To the stirred mixture, G-1 (150 g, 946 mmol) was added dropwise at 00 C. under N2 atmosphere. The solution was stirred at the same temperature for 1h, and then slowly warmed to RT for 10 h. The mixture wasadded to water (.—1 L) and extracted with EtOAc (2x500 mE).The combined organic phases were dried with Na2504, filtered and concentrated. The residue was purified by flashcolunm chromatography (eluent: PE) to give G-2 as a white solid (150 g, yield: 86.5percent). ‘H NMR (400 MHz, CDC13): ö 7.49-7.43 (1H, m), 7.41-7.32 (2H, m), 7.18-7.10 (1H, m),3.54 (3H, s), 3.34 (3H, s).
References: [1] Patent: US2015/72982, 2015, A1, . Location in patent: Paragraph 0263; 0264.
 

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