865139-18-0|(4-(Benzyloxy)-2,6-dimethylphenyl)boronic acid| Ambeed

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Quality Control of [ 865139-18-0 ] Purity: 95% SDS Specification

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Product Details of [ 865139-18-0 ]

CAS No. :	865139-18-0
Formula :	C₁₅H₁₇BO₃
M.W :	256.11
SMILES Code :	CC1=C(B(O)O)C(C)=CC(OCC2=CC=CC=C2)=C1
MDL No. :	MFCD13194673
InChI Key :	CMCVDHBBWOUHOU-UHFFFAOYSA-N
Pubchem ID :	23157199

Safety of [ 865139-18-0 ]

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

Computational Chemistry of [ 865139-18-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	12
Fraction Csp3	0.2
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	77.18
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.69 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	3.02
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.41
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.	2.06
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	1.77
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.65

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.53
Solubility	0.0749 mg/ml ; 0.000293 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.	-3.73
Solubility	0.0478 mg/ml ; 0.000187 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	-4.73
Solubility	0.00478 mg/ml ; 0.0000187 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	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	Yes
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.	-5.72 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	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<0.0
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)	2.26

Application In Synthesis of [ 865139-18-0 ]

* 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 [ 865139-18-0 ]

[ 865139-18-0 ] Synthesis Path-Downstream 1~35

1
[ 865139-18-0 ]
[ 104901-43-1 ]
[ 865139-19-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium carbonate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; toluene; for 24h;Heating / reflux;	[4-(Benzyloxy)-2,6-dimethylphenyl]boronic acid (354 mg, 1.38 mmol) and methyl 3-bromo-4-methylbenzoate (229 mg, 1.00 mmol) were dissolved in a mixture of 2 M aqueous sodium carbonate solution (1.38 mL), toluene (10 mL) and 1,2-dimethoxyethane (1 mL), the air was substituted with argon gas, and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (32.8 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18.3 mg, 0.02 mmol) were added. The reaction mixture was heated under reflux for one day. After cooling the reaction mixture, brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (255 mg, yield 71%) as a colorless oil. MS m/z 361 (MH+).

References: [1]Patent: EP1726580,2006,A1 .Location in patent: Page/Page column 118.

2
[ 95741-44-9 ]
[ 865139-18-0 ]

Yield	Reaction Conditions	Operation in experiment
60.2%		5-(Benzyloxy)-2-bromo-1,3-dimethylbenzene 12a (2.91 g, 10 mmol, prepared by a method disclosed in patent application ) was dissolved in 35 mL of tetrahydrofuran in an dry-ice bath, followed by addition of n-butyllithium (4.8 mL, 12 mmol). The reaction solution was stirred for 1.5 hours, added with tripropyl borate (5.64 g, 30 mmol), then heated to 30 C and stirred for 12 hours. The resulting solution was added dropwise with 10 mL of 2 M hydrochloric acid, then cooled down to the room temperature and stirred for another 2 hours. The resulting solution was concentrated under reduced pressure and filtere. The filter cake was washed with water (10 mL) and n-hexane (10 mL) successively to obtain the title compound (4-(benzyloxy)-2,6-dimethylphenyl)boronic acid 12b (1.54 g, yield 60.2%) as a white solid. MS m/z (ESI): 257.2 [M+1]
60%		To a solution (100 mL) of 5-(benzyloxy)-2-bromo-1,3-dimethylbenzene (8.78 g, 30.2 mmol) in tetrahydrofuran was added n-butyllithium hexane solution (1.6 M, 22.6 mL, 36.2 mmol) under stirring at -78C. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropyl borate (20.9 mL, 90.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added 2 M hydrochloric acid (150 mL) and the mixture was stirred for 2.5 hr. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Cold hexane was added to the residue to allow crystallization. The precipitated crystals were collected by filtration, washed with cold hexane and dried to give the title compound (4.65 g, yield 60%) as colorless crystals. 1H NMR (CDCl3) delta: 2. 36 (6H, s), 4. 57 (2H, s), 5.04 (2H, s), 6.63 (2H, s), 7.28-7.47(5H, m).
1.38 g		Under argon 5-(benzyloxy)-2-bromo-1 ,3-dimethylbenzene (2,38 g) is dissolved in tetrahydrofuran (30 mL) and cooled to -78C. n-Butyllithium (6.2 mL of a 1 .6 M solution in tetrahydrofuran) is added dropwise, the mixture is stirred for 4 hours followed by dropwise addition of triisopropyl borate (5.7 mL). The mixture is stirred for 12 hours while warming to room temperature. Then the mixture is poured on 2 N hydrochloric acid and stirred vigorously for 30 minutes. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated and he residue is crystallized from n-hexane. The precipitate is filtered off and dried ti give the title compound. Yield: 1 .38 g; LC (method 7): tR = 0.94 min; Mass spectrum (ESI"): m/z = 255 [M-H]

References: [1]Patent: EP2803664,2014,A1 .Location in patent: Paragraph 0158; 0159.
[2]Patent: EP1726580,2006,A1 .Location in patent: Page/Page column 117.
[3]Patent: WO2013/144098,2013,A1 .Location in patent: Page/Page column 140.

3
[ 865139-23-7 ]
[ 865139-18-0 ]
[ 865139-24-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; toluene; for 24h;Heating / reflux;	[4-(Benzyloxy)-2,6-dimethylphenyl]boronic acid (333 mg, 1.30 mmol) and ethyl 4-(acetylamino)-3-bromobenzoate (286 mg, 1.00 mmol) were dissolved in a mixture of 2 M aqueous sodium carbonate solution (1.30 mL), toluene (10 mL) and 1,2-dimethoxyethane (1 mL), the air was substituted with argon gas, and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (65.7 mg, 0.16 mmol) and tris(dibenzylideneacetone)dipalladium(0) (36.6 mg, 0.04 mmol) were added. The reaction mixture was heated under reflux under an argon atmosphere for one day. After cooling the reaction mixture, brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=13/7) to give the title compound (401 mg, yield 96%) as a colorless amorphous powder. MS m/z 418 (MH+).

References: [1]Patent: EP1726580,2006,A1 .Location in patent: Page/Page column 120.

4
[ 865139-18-0 ]
[ 14203-25-9 ]
[ 1237529-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In toluene; at 90℃; for 4h;Inert atmosphere;	Example 5; Preparation of 2-r4-(6-chloroquinolin-2-yloxy)-2,6-dimethylphenyl1-4-(tetrahvdropyran-4- ylmethyl)cvclopentane-1 ,3-dioneStep 1 : Preparation of 2-(4-benzyloxy-2,6-dimethylphenyl)-3-methoxycyclopent-2-enoneTo a suspension of 2-bromo-3-methoxycyclopent-2-enone (5.0Og, 26.0mmol), 4-benzyloxy-2,6- dimethylphenyl boronic acid (7.2Og, 28mmol) (described in EP1726580) and potassium phosphate (9.55g, 45mmol) in degassed toluene (125ml) is added palladium (II) acetate (0.135g, O.deltammol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.492g, 1.2mmol). The reaction mixture is then heated at 90 0C under a nitrogen atmosphere for 4 hours, then allowed to cool to room temperature. After partitioning between ethyl acetate (500 ml) and distilled water (500 ml), the organic phase is separated and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexane eluant) to afford 2-(4-benzyloxy-2,6- dimethylphenyl)-3-methoxycyclopent-2-enone as a white solid.

References: [1]Patent: WO2010/89210,2010,A1 .Location in patent: Page/Page column 63-64.

5
[ 865139-18-0 ]
[ 546-67-8 ]
[ 1236349-52-2 ]

Yield	Reaction Conditions	Operation in experiment
		Lead tetraacetate (5.7g, 0.013mol) and mercury (II) acetate (0.2g, 0.0006mol) are stirred together and thoroughly flushed with nitrogen. Chloroform (20ml) is added and the dark orange solution heated to 5O0C, followed by the addition of 4-benzyloxy-2,6-dimethylphenyl boronic acid (3g, 0.012mol) in one portion. After further heating at 5O0C for 3 hours the reaction mixture is cooled to O0C and potassium carbonate added (1.9g, 0.02mol). The suspension is stirred for just 5 minutes before filtering and evaporation of the crude solution under reduced pressure. The crude product is then azeotroped with diethyl ether to afford 4-benzyloxy-2,6-dimethylphenyl lead triacetate as a pale solid.

References: [1]Patent: WO2010/89211,2010,A1 .Location in patent: Page/Page column 49.

6
[ 865139-18-0 ]
[ 1471996-62-9 ]
methyl 2-((S)-6-((R)-4-(4-(benzyloxy)-2,6-dimethylphenyl)-5-cyano-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
125 mg	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In toluene; at 100℃; for 12h;Microwave irradiation; Inert atmosphere; Sealed tube;	In a microwave vial methyl 2-((S)-6-((R)-4-bromo-5-cyano-2,3-dihydro-1 H-inden-1 - yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (130 mg), 4-(benzyloxy)-2,6- dimethylphenylboronic acid (120 mg), dicyclohexyl(2',6'-dimethoxybiphenyl-2- yl)phosphine (S-Phos) (18 mg) and K3PO4 (200 mg) are suspended in toluene (2 ml_) and purged for 10 minutes with argon. Palladium-(ll)-acetate (5 mg) is added, the vial is sealed and the mixture is stirred at 1 00C for 12 hours. After cooling to room temperature the mixture is partitioned between diethylether and saturated aqueous NH CI solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10?40:60) to give the title compound. Yield: 125 mg; LC (method 10): tR = 1 .15 min; Mass spectrum (ESI+): m/z = 560 [M+H]+.

References: [1]Patent: WO2013/144098,2013,A1 .Location in patent: Page/Page column 140; 141.

7
[ 100-39-0 ]
[ 865139-18-0 ]

References: [1]Patent: WO2013/144098,2013,A1 .

8
[ 865139-18-0 ]
methyl {(S)-6-[(R)-5-cyano-4-(4-hydroxy-2,6-dimethyl-phenyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetate [ No CAS ]

References: [1]Patent: WO2013/144098,2013,A1 .

9
[ 865139-18-0 ]
methyl ((S)-6-{(R)-5-cyano-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetate [ No CAS ]

References: [1]Patent: WO2013/144098,2013,A1 .

10
[ 865139-18-0 ]
methyl 2-((S)-6-((R)-5-cyano-4-(2,6-dimethyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)-2,3-dihydro-1 H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate [ No CAS ]

References: [1]Patent: WO2013/144098,2013,A1 .

11
[ 865139-18-0 ]
((S)-6-{(R)-5-cyano-4-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid [ No CAS ]

References: [1]Patent: WO2013/144098,2013,A1 .

12
[ 7463-51-6 ]
[ 865139-18-0 ]