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5-Bromo-3-chloro-2-fluorobenzonitrile

5-Bromo-3-chloro-2-fluorobenzonitrile

5-Bromo-3-chloro-2-fluorobenzonitrile

CAS No.: 1000577-76-3

Category Products

Cat.NO.:A497059 Purity:95%

Product Details of [ 1000577-76-3 ]

CAS No. :	1000577-76-3
Formula :	C₇H₂BrClFN
M.W :	234.45
SMILES Code :	N#CC1=CC(Br)=CC(Cl)=C1F
MDL No. :	MFCD09800811
InChI Key :	CFAJQDDAWJDDIX-UHFFFAOYSA-N
Pubchem ID :	26598341

Safety of [ 1000577-76-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H312-H332
Precautionary Statements:	P280

Computational Chemistry of [ 1000577-76-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	43.82
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	23.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.03
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	3.06
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.53
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.	3.2
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	3.54
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.07

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.63
Solubility	0.0556 mg/ml ; 0.000237 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.	-3.23
Solubility	0.139 mg/ml ; 0.000594 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	-4.24
Solubility	0.0136 mg/ml ; 0.0000578 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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.	-5.56 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)	2.04

Application In Synthesis of [ 1000577-76-3 ]

* 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 [ 1000577-76-3 ]

[ 1000577-76-3 ] Synthesis Path-Downstream 1~23

1
[ 1000577-76-3 ]
C₇H₅BrClN₃ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 279 – 282.

2
C₇H₄BrClFNO [ No CAS ]
[ 1000577-76-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 279 – 282.

3
[ 1000577-76-3 ]
[ 73183-34-3 ]
[ 1383985-27-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium acetate;(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 110℃; for 1h;Microwave irradiation; Inert atmosphere;	Intermediate 573-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile; is A suspension of <strong>[1000577-76-3]5-bromo-3-chloro-2-fluorobenzonitrile</strong> (0.959 g, 4.09 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.08 g, 8.18 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) chloride (0.234 g, 0.29 mmol), and potassium acetate (1.20 g, 12.3 mmol) in dioxane (15 mL), was placed in a microwave vial. The mixture was degassed with a stream of argon for a couple of min, and the reaction mixture was then heated to 110 C. for 1 h in a microwave reactor. The reaction mixture was cooled to r.t., filtered through diatomaceous earth, and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using heptane/EtOAc (70/30) as eluent to give the title compound (1.22 g, quantitative yield): GC MS (EI) m/z 282 M+.

References: [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 36.

4
[ 110-91-8 ]
[ 1000577-76-3 ]
[ 1386460-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In toluene; at 140℃; for 0.5h;microwave irradiation;	A suspension of 5-Bromo-3-chloro-2-fluoro-benzonitrile (200 mg, 0.85 mmol), morpholine (74 mg, 0.85 mmol), caesium carbonate (389 mg, 1.2 mmol), palladium(ll) acetate (10 mg, 0.04 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol) in toluene (5 mL) was sealed in a microwave vial and heated for 30 min at 140C (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHC03, extracted with EtOAc, dried (Na2S04) and the solvent was removed in vacuo to give the title compound which was used without further purification in the next step. TLC Rf (hexane/EtOAc 1 : 1) = 0.60 ; tR (HPLC conditions c): 5.28 min.

References: [1]Patent: WO2012/93101,2012,A1 .Location in patent: Page/Page column 251.

5
[ 1000577-76-3 ]
[ 1386459-84-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[1000577-76-3]5-bromo-3-chloro-2-fluorobenzonitrile</strong> (13.2 g, 56.3 mmol) in THF (200 ml_) was added under an argon atmosphere a 1 M solution of boran-tetrahydrofuran-complex (70.4 ml_, 70.4 mmol) dropwise over 30 min. The reaction mixture was then heated at 65C for 1.5 h. After cooling to RT, a 2N HCI solution (70.4 ml_, 141 mmol) was added dropwise over 30 min. The reaction mixture was then again heated at 65C for 1 h and subsequently cooled to RT. Volatiles were evaporated and the residue was taken up in 1 M aqueous HCI solution, followed by extraction with EtOAc (3×150 ml_). The combined organics were washed with 1 M aqueous HCI solution. The combined acid phases were basified to pH=12 by addition of 4M aqueous NaOH solution and then extracted with EtOAc (3×150 ml_). The organics were dried (Na2S04), filtered and evaporated in vacuo to afford the title compound as a yellowish oil. MS (LC/MS): 238.0 [M+H]+; tR (HPLC conditions c): 3.25 min. The material thus obtained was used directly in the next step without further purification

References: [1]Patent: WO2012/93101,2012,A1 .Location in patent: Page/Page column 245.

6
[ 1000577-76-3 ]
[ 1386459-85-3 ]

References: [1]Patent: WO2012/93101,2012,A1 .

7
[ 1000577-76-3 ]
[ 1386459-86-4 ]

References: [1]Patent: WO2012/93101,2012,A1 .

8
[ 1000577-76-3 ]
[ 1386459-87-5 ]

References: [1]Patent: WO2012/93101,2012,A1 .

9
[ 1000577-76-3 ]
[ 1386461-57-9 ]

References: [1]Patent: WO2012/93101,2012,A1 .

10
[ 1000577-76-3 ]
[ 1386459-88-6 ]

References: [1]Patent: WO2012/93101,2012,A1 .

11
[ 1000577-76-3 ]
[ 1386459-89-7 ]

References: [1]Patent: WO2012/93101,2012,A1 .

12
[ 1000577-76-3 ]
3-chloro-2-fluoro-5-(2H-tetrazol-5-yl)-benzylamine hydrochloride [ No CAS ]

References: [1]Patent: WO2012/93101,2012,A1 .

13
[ 1000577-76-3 ]
[ 1386459-91-1 ]

References: [1]Patent: WO2012/93101,2012,A1 .

14
[ 1000577-76-3 ]
[ 1386459-92-2 ]

References: [1]Patent: WO2012/93101,2012,A1 .

15
[ 1000577-76-3 ]
[ 1386459-93-3 ]

References: [1]Patent: WO2012/93101,2012,A1 .

16
[ 1000577-76-3 ]
[ 1386460-02-1 ]

References: [1]Patent: WO2012/93101,2012,A1 .

17
[ 1000577-76-3 ]
[ 1386460-03-2 ]

References: [1]Patent: WO2012/93101,2012,A1 .

18
[ 1000577-76-3 ]
[ 1386460-04-3 ]

References: [1]Patent: WO2012/93101,2012,A1 .

19
[ 1000577-76-3 ]
[ 1386460-05-4 ]

References: [1]Patent: WO2012/93101,2012,A1 .

20
[ 1000577-76-3 ]
[ 1386460-06-5 ]

References: [1]Patent: WO2012/93101,2012,A1 .

21
[ 1000577-76-3 ]

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