120315-65-3|4-Bromo-3-methoxybenzonitrile| Ambeed

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Quality Control of [ 120315-65-3 ] Purity: 98% SDS Specification

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Product Details of [ 120315-65-3 ]

CAS No. :	120315-65-3
Formula :	C₈H₆BrNO
M.W :	212.04
SMILES Code :	N#CC1=CC=C(Br)C(OC)=C1
MDL No. :	MFCD09753723
InChI Key :	TWBFZKKJFREYES-UHFFFAOYSA-N
Pubchem ID :	22591181

Safety of [ 120315-65-3 ]

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

Computational Chemistry of [ 120315-65-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	45.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.15
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	2.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.33
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.	1.86
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	2.47
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.94
Solubility	0.243 mg/ml ; 0.00114 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.	-2.63
Solubility	0.496 mg/ml ; 0.00234 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	-3.47
Solubility	0.0718 mg/ml ; 0.000339 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.	-5.96 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	0.0
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)	1.47

Application In Synthesis of [ 120315-65-3 ]

* 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 [ 120315-65-3 ]

[ 120315-65-3 ] Synthesis Path-Downstream 1~35

2
[ 120315-65-3 ]
[ 121-44-8 ]
[ 1231191-82-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; In ethanol; at 80℃; for 2.5h;	The mixture of <strong>[120315-65-3]4-bromo-3-methoxybenzonitrile</strong> (800 mg, 3.77 mmol), hydroxylamine hydrochloride (524 mg, 7.55 mmol) and Et3N (1.05 mL, 7.55 mmol) in EtOH (13 mL) was heated at 800C for 2.5h. The mixture was cooled to ambient temperature, poured into water and extracted with EtOAc. The organic layers were washed with water. The combined organics were dried, filtered and solvent reduced by rotovap. The residue from step 1 was dissolved in Ac2O (7.1 mL, 75 mmol) and heated to 1200C overnight. The reaction mixture was cooled and water was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with sat. aq. NaHCO3, dried, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-40 percent EtOAc in Hex) to afford 3 -(4-bromo-3-methoxyphenyI)-5 -methyl- 1,2,4-oxadiazole (600 mg). 1H NMR (600 MHZ, CDCl3) delta 7.62 (d, J= 8.4 Hz, 1H), 7.53 (m, 2H), 3.95 (s, 3H)5 2.64 (s, 3H). MS calculated 269.0 (MH4), exp 268.9 (MH+).

References: [1]Patent: WO2010/71741,2010,A1 .Location in patent: Page/Page column 27; 28.

3
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carboxaldehyde [ No CAS ]
[ 120315-65-3 ]
[ 1255870-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 100℃; for 1.5h;	A mixture of 4-bromo-3-methoxy~benzonitrile (400mg, 1.88mmol), 5-(4,4,5,5-tetramethyl- p ,3.2Jdioxaborotan-2-yl)"pypidine-3-carbaldehyde (440 mg, 1.88 mmol), PdCl2(PPh3)Z (108mg, 0.15mmol) and Na2CO3 (2M in water, 1.88mL, 3.77mmol) in 1,4-dioxanbeta (8 mL) was heated at 100°C for 1.5h. After concentration in vacuo, the resulting residue was purified by flash column to give the title compound (449 mg, 100percent) as white solid; ESI- MS mlr. 239 IM+1)*.

References: [1]Patent: WO2010/130796,2010,A1 .Location in patent: Page/Page column 80.

4
[ 120315-65-3 ]
[ 1301610-33-2 ]
[ 1301610-92-3 ]

Yield	Reaction Conditions	Operation in experiment
47%	With triethylamine;copper(l) iodide; bis(tri-t-butylphosphine)palladium(0); at 0 - 20℃; for 18h;Inert atmosphere;	Step 1: tert-Butyl (1-(4-((4-cyano-2-methoxyphenyl)ethynyl)phenyl)cyclobutyl)carbamate: To a solution of <strong>[120315-65-3]4-bromo-3-methoxybenzonitrile</strong> (1.92 g, 7.075 mmol) in anhydrous triethylamine (8 mL) and 1 ,4-dioxane (8 mL) was added bis(tert- butylphosphine)palladium(O) (0.144g, 0.283mmol) and copper(l) iodide (13 mg,0.094mmol). The reaction mixture was then degassed with N2 for 10 minutes before being cooled to 0°C. A solution of ferf-butyl 1 -(4-ethynylphenyl)cyclobutylcarbamate (1.00 g, 4.72 mmol) in TEA (8 mL) was added dropwise to the cooled reaction mixture. The reaction was allowed to warm to RT and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue diluted with DCM (20 mL) and filtered through Celite. The resulting filtrate was concentrated in vacuo to afford a brown oil that was purified by silica gel chromatography (ethyl acetate/hexane gradient, 0-->50percent) yielding the title compound as an off-white solid (890 mg, 47percent). 1H NMR (500 MHz, CDCI3): delta 7.55-7.53 (m, 3H), 7.43 (d, 2H), 7.23 (d, 1 H), 7.12 (s, 1 H), 5.25 (s, 1 H), 3.94 (s, 3H), 2.54-2.51 (m, 4H), 2.1 1-2.13 (m, 1 H), 1.90-1.86 (m, 1 H), 1.34-1.25 (br s, 9H).

References: [1]Patent: WO2011/55115,2011,A1 .Location in patent: Page/Page column 74.

5
[ 120315-65-3 ]
[ 1309682-18-5 ]
[ 1309680-46-3 ]

Yield	Reaction Conditions	Operation in experiment
17%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1-methyl-pyrrolidin-2-one; water; at 170℃; for 0.75h;Microwave irradiation; Sealed tube;	Example". .14-[6-(4-hydroxy-3,5-dimethylphenyl)[1 ,2,4]triazolo[1 ,5-a] pyridin-2- yl]amino}-3-methoxybenzonitrile0.18 mmol intermediate example 2.1 (0.45 ml_, 0.4M in NMP), 0.15 mmol 4- Bromo-3-methoxybenzonitrile (1 .44 mL, 0.5M in NMP, 4 eq), 0.018 mmol Pd2(dba)3 (0.180 mL, 0.1M in NMP, 0.1 eq), 0.036 mmol rac-BINAP (0.180 mL, 0.1M in NMP, 0.2 eq) and 0.3 mmol NaOtBu (0.188 mL, 1 .6M in water, 3 eq) were combined in a sealed vial and heated at 170 ° C under microwave irradiation for 45 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 12.0 mg (17 percent) 4-[6-(4-hydroxy-3,5- dimethylphenyl)[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl]amino}-3- methoxybenzonitrile: 1 H-NMR (300 MHz, d6-DMSO): delta = 9.00 (1 H, s), 9.02 (1 H, s), 8.61 (1 H, s), 8.42 (1 H, d), 8.41 (1 H, s), 7.88 (1 H, d) 7.62 (1 H, d), 7.43 (1 H, d), 7.40 (1 H, s), 7.33 (2H, s), 3.90 (3H, s), 2.20 (6H, s) ppm. UPLC-MS: RT = 1 .23 min; m/z (ES+) 386.4 [MH+]; required MW = 385.4.
17%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1-methyl-pyrrolidin-2-one; at 170℃;Microwave irradiation;	0.18 mmol intermediate example 2.1 (0.45 mL, 0.4M in NMP), 0.15 mmol 4-Bromo-3-methoxybenzonitrile (1.44 mL, 0.5M in NMP, 4 eq), 0.018 mmol Pd2(dba)3 (0.180 mL, 0.1M in NMP, 0.1 eq), 0.036 mmol rac-BINAP (0.180 mL, 0.1M in NMP, 0.2 eq) and 0.3 mmol NaOtBu (0.188 mL, 1.6M in water, 3 eq) were combined in a sealed vial and heated at 170 °C under microwave irradiation for 45 min.After cooling, the solution was filtered and subjected to preparative HPLC to give 12.0 mg (17 percent) 4-[6-(4-hydroxy-3,5-dimethylphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-methoxybenzonitrile: 1H-NMR (300 MHz, d6-DMSO): delta = 9.00 (1 H, s), 9.02 (1 H, s), 8.61 (1 H, s), 8.42 (1 H, d), 8.41 (1 H, s), 7.88 (1 H, d) 7.62 (1 H, d), 7.43 (1 H, d), 7.40 (1H, s), 7.33 (2H, s), 3.90 (3H, s), 2.20 (6H, s) ppm. UPLC-MS: RT = 1.23 min; m/z (ES+) 386.4 [MH+]; required MW = 385.4.

References: [1]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 106.
[2]Patent: EP2343295,2011,A1 .Location in patent: Page/Page column 27-28.

6
[ 120315-65-3 ]
[ 1309593-60-9 ]
[ 1309593-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1-methyl-pyrrolidin-2-one; at 170℃; for 2h;Sealed vial; Microwave irradiation;	A solution of 0.17 mmol lnt2.1 in 1.33 mL NMP was combined with 0.44 mmol 4-Bromo-3-methoxybenzonitrile (48.6 mg, 2.6 eq), 0.04 mmol Pd2(dba)3 (36.6 mg, 0.23 eq), 0.12 mmol rac-BINAP (74.7 mg, 0.7 eq) and 0.25 mmol NaOtBu (24.03 mg, 1.5 eq) in a sealed vial and heated at 170 °C under microwave irradiation for 2 h.After cooling, the solution was filtered and subjected to preparative HPLC to give 4.7 mg of the title compound.UPLC-MS: RT = 1.15 min; m/z (ES+) 400.5 [MH+]; required MW = 399.5.

References: [1]Patent: EP2343297,2011,A1 .Location in patent: Page/Page column 36-37.

7
[ 188290-36-0 ]
[ 120315-65-3 ]
[ 1360592-45-5 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 10665 - 10669.

8
[ 120315-65-3 ]
[ 1352042-54-6 ]