2613-30-1|4-Chloro-2,5-difluoroaniline| Ambeed

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Quality Control of [ 2613-30-1 ] Purity: 98% SDS Specification

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Product Details of [ 2613-30-1 ]

CAS No. :	2613-30-1
Formula :	C₆H₄ClF₂N
M.W :	163.55
SMILES Code :	NC1=CC(F)=C(Cl)C=C1F
MDL No. :	MFCD06808807
InChI Key :	PYRVOUSDQGBZRG-UHFFFAOYSA-N
Pubchem ID :	14624525

Safety of [ 2613-30-1 ]

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

Computational Chemistry of [ 2613-30-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	35.77
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.62
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.07
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.05
Log P_o/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.	2.94
Log P_o/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	2.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.46

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.6
Solubility	0.409 mg/ml ; 0.0025 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.	-2.25
Solubility	0.929 mg/ml ; 0.00568 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	-3.2
Solubility	0.102 mg/ml ; 0.000627 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.	-5.83 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	2.0 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)	1.61

Application In Synthesis of [ 2613-30-1 ]

* 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.

Downstream synthetic route of [ 2613-30-1 ]

[ 2613-30-1 ] Synthesis Path-Downstream 1~21

1
[ 2613-30-1 ]
[ 2268-02-2 ]

References: [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97.

3
[ 106-47-8 ]
[ 57946-56-2 ]
[ 367-22-6 ]
[ 2613-33-4 ]
[ 2613-30-1 ]

References: [1]Journal of Fluorine Chemistry,2005,vol. 126,p. 661 - 667.

4
[ 2613-30-1 ]
[ 541-41-3 ]
[ 224168-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;	EXAMPLE 36 Preparation of ethyl 4-chloro-2,5-difluorophenylcarbamate (XL) 4-Chloro-2,5-difluoroaniline (XXXIX) (2.1 g, 12.8 mmol) was mixed with pyridine (20 ml) at 0 C., to it was dropwise added ethyl chloroformate (1.5 g, 13.8 mmol). After stirring for 2.5 hr while temperature slowly raised to room temperature, pyridine was evaporated and the residue crystallized in ice-water (100 ml). The crystals were filtered, washed with water and dried in fume hood overnight (2.7 g). 1H NMR (CDCl3, 300 MHz) 1.33 (3H, t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 6.89 (1H, br), 7.12 (1H, dd, J=6.5, 6.5 Hz), 8.05 (1H, dd, J=7.8, 9.6 Hz) ppm.

References: [1]Patent: US6355799,2002,B1 .

5
[ 2613-30-1 ]
[ 79-10-7 ]
2,5-difluoro-4-chlorocinnamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sulfuric acid; sodium nitrite;palladium diacetate; In water;	Example 8 2,5-Difluoro-4-chlorocinnamic Acid 98.2 g of <strong>[2613-30-1]2,5-difluoro-4-chloroaniline</strong> were added dropwise at 0 C. to a mixture of 124 ml of conc. sulfuric acid and 472 ml of water. A solution of 48.3 g of sodium nitrite in 90 ml of water was then added dropwise at 0 C. such that the temperature was maintained. The mixture was then stirred at 0 C. for 30 minutes. Excess nitrite was destroyed by the addition of amido-sulfonic acid. 0.34 g of palladium(II) acetate was added to 54.8 g of acrylic acid and the mixture was warmed to 47 C. The diazonium salt solution was added dropwise at this temperature in the course of 2 hours such that the temperature did not exceed 49 C., then the mixture was stirred for a further 2 hours. After it had been cooled to room temperature, the solid was isolated by filtration, washed with water and dried. This afforded 116.7 g of 2,5-difluoro-4-chlorocinnamic acid (89% of theory).

References: [1]Patent: US2002/115885,2002,A1 .

6
[ 578-28-9 ]
[ 7439-89-6 ]
[ 2613-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid; ethyl acetate;	EXAMPLE 35 Preparation of 4-chloro-2,5-difluoroaniline (XXXIX) 1-Chloro-2,5-difluoro-4-nitrobenzene (XXXVIII) (17.5 g) was dissolved in acetic acid (150 ml) in a 1L 3-neck round bottom flask equipped with cooling condenser. To it iron powder (35.0 g) was added slowly while the solution was stirred by an overhead stirrer. The reaction was exothermic which occurred in less than 30 min and generated much heat that was absorbed by a cooling bath. After that, ethyl acetate (300 ml) was added and the mixture filtered. The solution was washed with water and dried over sodium sulfate. The product was purified by column chromatography (silica gel, hexane:ethyl acetate, 4:1) (14.3 g). 1H NMR (CDCl3, 300 MHz) 3.89 (2H, br), 6.56 (1H, m), 7.02 (1H, m) ppm.

References: [1]Patent: US6355799,2002,B1 .

7
[ 2613-30-1 ]
[ 172921-33-4 ]

Yield	Reaction Conditions	Operation in experiment
48.4%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 65℃;	Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). The resulting mixture was heated to 65° C. and a solution of 4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) was added dropwise (vigorous gas evolution was noted). After the reaction mixture cooled to ambient temperature, it was added to 2N HCl and extracted twice with diethyl ether. The organic extracts were then combined, washed with 2N HCl, washed with saturated sodium bicarbonate, dried, concentrated and purified by flash chromatography on silica gel (hexanes) to give the title compound as a white solid (1.11 g, 48.4percent yield): 1H NMR (CDCl3) delta 7.38 (dd, 2H), 7.21 (dd, 2H).
48.4%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile;	2. Preparation of 1-Bromo-4-chloro-2,5-difluorobenzene Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). The resulting mixture was heated to 65° C. and a solution of 4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) was added dropwise (vigorous gas evolution was noted). After the reaction mixture cooled ambient temperature, it was added to 2N HCl and extracted with ether twice. The organic extracts were then combined, washed with 2N HCl, washed with saturated sodium bicarbonate, dried, concentrated and purified by flash chromatography on silica gel (hexanes) to give the title compound as a white solid (1.11 g, 48.4percent yield): 1H NMR (CDCl3): delta 7.38 (dd, 2H), 7.21 (dd, 2H).

References: [1]Patent: US2009/88322,2009,A1 .Location in patent: Page/Page column 8.
[2]Patent: US2009/62125,2009,A1 .Location in patent: Page/Page column 8.

8
[ 578-28-9 ]
[ 2613-30-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With iron; acetic acid; at 110℃; for 3.0h;	4-Chloro-2,5-difluoroaniline To a mixture of 1-chloro-2,5-difluoro-4-nitrobenzene (1 equiv.) in acetic acid (0.5 M) was added Fe (5 equiv.), which was heated to reflux at 110 C. for 3 h. The mixture was filtered, the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography to give 4-chloro-2,5-difluoroaniline (80%) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.08-6.99 (m, 1H), 6.65 (dd, J=7.8, 10.7 Hz, 1H).
73.9%		Tin (II) chloride dihydrate (15.5 g, 68.7 mmol) was dissolved in ethyl acetate (50 mL) and 1-chloro-2,5-difluoro-4-nitrobenzene (2.65 g, 13.7 mmol) was added dropwise. The reaction mixture was then stirred at 70 C. for 1 h. The reaction mixture was then carefully added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed several more times with water, dried, filtered, concentrated and purified by flash chromatography on silica gel (hexane/diethyl ether) to give the title compound as a white solid (1.65 g, 73.9% yield): 1H NMR (CDCl3) delta 7.02 (dd, 1H), 6.57 (dd, 1H), 3.81 (br s, 2H).
73.9%	With tin(II) chloride dihdyrate; In ethyl acetate; at 70℃; for 1.0h;	1. Preparation of 4-Chloro-2,5-difluorophenylamine Tin (II) chloride dihydrate (15.5 g, 68.7 mmol) was dissolved in ethyl acetate (50 mL) and 1-chloro-2,5-difluoro-4-nitrobenzene (2.65 g, 13.7 mmol) was added dropwise. The reaction mixture was then stirred at 70 C. for 1 h. The reaction mixture was then carefully added to saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic phase was washed several more times with water, dried, filtered, concentrated and purified by flash chromatography on silica gel (hexane/diethyl ether) to give the title compound as a white solid (1.65 g, 73.9% yield): 1H NMR (CDCl3): delta 7.02 (dd, 1H), 6.57 (dd, 1H), 3.81 (br s, 2H).

References: [1]Patent: US2016/96841,2016,A1 .Location in patent: Paragraph 0261.
[2]Patent: US2009/88322,2009,A1 .Location in patent: Page/Page column 7-8.
[3]Patent: US2009/62125,2009,A1 .Location in patent: Page/Page column 8.

9
[ 2613-30-1 ]
methyl 4-acetamido-3-chloro-6-(4-chloro-3,6-difluoro-2-methylphenyl)picolinate [ No CAS ]