443776-76-9|(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol| Ambeed

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Quality Control of [ 443776-76-9 ] Purity: 97% SDS Specification

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Product Details of [ 443776-76-9 ]

CAS No. :	443776-76-9
Formula :	C₁₃H₁₉BO₃
M.W :	234.10
SMILES Code :	CC1(C)OB(OC1(C)C)C1=CC=CC(CO)=C1
MDL No. :	MFCD09266196
InChI Key :	ZEWWJJQAFTXUIS-UHFFFAOYSA-N
Pubchem ID :	44118236

Safety of [ 443776-76-9 ]

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

Computational Chemistry of [ 443776-76-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	6
Fraction Csp3	0.54
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	69.05
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.69 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	2.02
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.33
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.	1.14
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	1.71
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.69
Solubility	0.474 mg/ml ; 0.00203 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.	-2.46
Solubility	0.812 mg/ml ; 0.00347 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	-3.83
Solubility	0.0344 mg/ml ; 0.000147 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	Yes
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.	-6.29 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<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)	2.99

Application In Synthesis of [ 443776-76-9 ]

* 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 [ 443776-76-9 ]

[ 443776-76-9 ] Synthesis Path-Downstream 1~35

Yield	Reaction Conditions	Operation in experiment
43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step 34b: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)[0334]To a solution of compound 0601-107 (2.5 g, 11.6 mmol) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was added potassium acetate (3.4 g, 35 mmol) and PdCl2(dppf)2 (0.95 g, 1.1 mmol). The mixture was degassed with nitrogen and heated at 85 C. for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product, which purified by column chromatography (ethyl acetate in petroleum ether, 15% v/v) to give the compound 0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s, 1H).
43%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Compound in dioxane (100mL) 0601-107 (2.5g, 11.6mmol) and a solution of bis (pinacolato) diboron (4.4 g, 17.5 mmol), potassium acetate (3.4 g, 35 mmol) and and PdCl2 (dppf) 2 ( 0.95g, 1.1mmol) was added. The mixture was degassed with nitrogen and heated overnight at 85 C.. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether in ethyl acetate, 15% v / v) to give the compound 0602-107 as a pink solid obtained (1.55 g, 51%).
	With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos; In 1,4-dioxane; at 110℃;Inert atmosphere; Sealed tube;	General procedure: Step 1. General procedure for the preparation of pinacolbornane reagents: An oven-dried vial filled with argon was charged with Pd2dba3 (2 mol%), X-Phos (4 mol%), bis(pinacolato)diboron (3 equiv.) and KOAc (3 equiv.). I ,4-Dioxane was added, followed by the addition of the aryl chloride or bromide (0.5 M in 1 ,4-dioxane). The vial was sealed, and the reaction mixture was heated to 110C until aryl halide had been completely consumed, as determined by TLC analysis. At this point the reaction mixture was allowed to cool to room temperature. The reaction solution was then filtered through a thin pad of Celite (eluting with ethyl acetate) and the eluent was concentrated under reduced pressure. The crude material so obtained purified via flash chromatography on silica gel or utilized for Step 2m the Suzuki coupling reaction, directly and without purification.

2
[ 1021913-05-2 ]
[ 443776-76-9 ]
C₂₈H₃₂BrClN₂O₄ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2351 - 2358.

3
[ 480425-35-2 ]
[ 443776-76-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol Procedure:To a suspension of LiAlH4 (100 mg, 2.63 mmol) in THF (30 mL) was added portion-wise at room temperature methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 0.76 mmol). The reaction mixture was stirred at room temperature for additional 3 h. H2O (3 mL) was added dropwise at 0 C. then the mixture was filtered and concentrated under reduced pressure to give crude (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (190 mg) which was used for next step without characterization or purification.
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 3h;	To a suspension of LiAlH4 (100 mg, 2.63 mmol) in THF (30 mL) was added portion-wise at room temperature methyl 3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzoate (200 mg, 0.76 mmol).. The reaction mixture was stirred at room temperature for additional 3 h. H20 (3 mL) was added dropwise at 0C then the mixture was filtered and concentrated under reduced pressure to give crude (3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)phenyl)methanol (190 mg) which was used for next step without characterization or purification.

References: [1]Patent: US2012/309746,2012,A1 .Location in patent: Page/Page column 50.
[2]Patent: WO2012/163724,2012,A1 .Location in patent: Page/Page column 77.

4
[ 443776-76-9 ]
[ 1415695-25-8 ]
[ 76-05-1 ]
[ 1415694-92-6 ]

Yield	Reaction Conditions	Operation in experiment
21%		Step 2(S)-(3-(8-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methanol Procedure:A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (100 mg, 0.3 mmol), <strong>[443776-76-9](3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol</strong> (84 mg, 0.36 mmol), Pd2(dba)3 (30 mg, 0.05 mmol), X-Phos (30 mg, 0.06 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in dioxane/H2O (30 mL/5 mL) was stirred at reflux for 18 h under N2 atmosphere. The solvent was removed under reduced pressure and the residue purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 50% acetonitrile/50% water (0.1% TFA, v/v) initially, and proceed to 82% acetonitrile/18% water (0.1% TFA, v/v) in a linear fashion after 9 min.) to give (S)-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)methanol 222-trifluoroacetate (25 mg, 21%) as a yellow solid. 1H NMR (300 MHz, CD3OD): delta 9.18 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 1H), 7.49-7.35 (m, 3H), 6.23 (d, 1H, J=7.8 Hz), 5.98 (d, 1H, J=8.1 Hz), 4.70 (s, 2H), 4.24-4.20 (m, 1H), 3.59-3.55 (m, 1H), 3.41-3.38 (m, 1H), 2.13-1.98 (m, 3H), 1.72-1.70 (m, 1H), 1.13 (d, 3H, J=6.3 Hz). LC/MS: 401 [M+H]+. HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.54 min.
21%		A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin- l-yl)pyridin-2-yl)-[l,2,4]triazolo[l,5-a]pyridin-8-amine (100 mg, 0.3 mmol), (3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)methanol (84 mg, 0.36 mmol), Pd2(dba)3 (30 mg, 0.05 mmol), X-Phos (30 mg, 0.06 mmol) and Cs2C03 (196 mg, 0.6 mmol) in dioxane/H20 (30 mL/5 mL) was stirred at reflux for 18 h under N2 atmosphere. The solvent was removed under reduced pressure and the residue purified by preparative-HPLC (Gemini 5u C18 150x21.2 mm; inject volume: 3ml/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm;gradient conditions: 50% acetonitrile/50% water (0.1% TFA, v/v) initially, and proceed to 82% acetonitrile/18% water (0.1% TFA, v/v) in a linear fashion after 9 min.) to give (S)- (3-(8-(6-(2-methylpyrrolidin- l-yl)pyridin-2-ylamino)-[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl)methanol 222-trifluoroacetate (25 mg, 21 %) as a yellow solid. 1H NMR (300 MHz, CD3OD): delta 9.18 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.67 (s, 1H), 7.60 - 7.56 (m, 1H), 7.49 - 7.35 (m, 3H), 6.23 (d, 1H, J = 7.8 Hz), 5.98 (d, 1H, J = 8.1 Hz), 4.70 (s, 2H), 4.24 - 4.20 (m, 1H), 3.59 - 3.55 (m, 1H), 3.41 - 3.38 (m, 1H), 2.13 - 1.98 (m, 3H), 1.72 - 1.70 (m, 1H), 1.13 (d, 3H, J = 6.3 Hz). LC/MS: 401 [M + H]+. HPLC: 100 % at 214 nm, 100 % at 254 nm, tR = 5.54 min.

References: [1]Patent: US2012/309746,2012,A1 .Location in patent: Page/Page column 50-51.
[2]Patent: WO2012/163724,2012,A1 .Location in patent: Page/Page column 78.

5
[ 938443-23-3 ]
[ 443776-76-9 ]
Ku-0063794 [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1212 - 1216.

6
[ 443776-76-9 ]
[ 18162-48-6 ]
[ 495402-49-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; In tetrahydrofuran; at 0 - 20℃; for 24h;Inert atmosphere;	Under an argon atmosphere, DMAP (772 mg, 6.32 mmol) was slowly added over a solution of <strong>[443776-76-9]3-(hydroxymethyl)phenylboronic acid pinacol ester</strong> (1.0 g, 4.27 mmol) and TBDMSCl (900 mg, 5.98 mmol) in dry THF (20 mL) cooled at 0 C. The mixture was stirred for 24 h at 20 C. The white solid was filtered off, washed with cold THF and the organic filtrates were concentrated to dryness under vacuum. The residue was column chromatographed eluting with CH2Cl2, to obtain compound 4 as a white solid (1.06 g, yield: 71%). 1H NMR (400 MHz, CDCl3): delta 0.07 (s, 6H, Si(CH3)2), 0.92 (s, 9H, C(CH3)3), 1.32 (s, 12H, 2× OC(CH3)2), 4.73 (s, 2H, CH2O), 7.04-7.35 (m, 2H, ArH), 7.51-7.54 (m, 1H, ArH), 7.70-7.73 (m, 1H, ArH) ppm; 13C NMR (100 MHz, CDCl3): delta -5.2 (Si(CH3)2), 18.5 (C(CH3)3), 24.9 (4× CH3), 26.0 (C(CH3)3), 64.9 (CH2O), 83.6 (2× C-O), 127.6, 129.0, 132.2, 133.1, 140.4 ppm; MS m/z (%): 348 (1, M+), 291 (26), 191 (100); HRMS m/z Calcd for C19H33BO3SiNa: 371.2190, found: 371.2191.

References: [1]Tetrahedron,2013,vol. 69,p. 3465 - 3474.

7
[ 443776-76-9 ]
[ 104-94-9 ]
[ 1454653-66-7 ]