1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Cat.NO.:A228265 Purity:98%

Product Details of [ 1003846-21-6 ]

CAS No. :	1003846-21-6
Formula :	C₁₄H₂₃BN₂O₃
M.W :	278.16
SMILES Code :	CC1(C)C(C)(C)OB(C2=CN(C3CCCCO3)N=C2)O1
MDL No. :	MFCD16556148
InChI Key :	YYSLAWXDXHVRHU-UHFFFAOYSA-N
Pubchem ID :	51000384

Safety of [ 1003846-21-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1003846-21-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	20
Num. arom. heavy atoms	5
Fraction Csp3	0.79
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	78.16
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	45.51 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	1.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.56
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.	0.98
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	0.86
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.08

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.86
Solubility	0.38 mg/ml ; 0.00136 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.	-2.56
Solubility	0.763 mg/ml ; 0.00274 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	-2.9
Solubility	0.346 mg/ml ; 0.00124 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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.59 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)	3.98

Application In Synthesis of [ 1003846-21-6 ]

* 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 [ 1003846-21-6 ]

[ 1003846-21-6 ] Synthesis Path-Downstream 1~2

1
[ 1075-34-9 ]
[ 1003846-21-6 ]
2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1′-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	Synthesis of 2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.9 g, 36 mmol) was added to a solution of <strong>[1075-34-9]5-bromo-2-methyl-1H-indole</strong> (5.0 g, 23.8 mmol) in a mixture of DMF and water (9:1, 50 mL) at room temperature. Potassium carbonate (6.5 g, 48 mmol, 2.0 eq) was then added and the reaction mixture was purged with argon for 20 min. PdCl2(dppf)·dichloromethane (1.9 g, 2.38 mmol, 0.1 eq) was added, argon was passed through the solution for further 10 min and the mixture was heated at 80° C. for 16 h. After completion of the reaction (monitored by TLC, 50percent ethyl acetate-hexanes Rf=0.3), the reaction mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. washing with ethyl acetate. The combined filtrate was washed with water followed by brine, the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh, eluting with a 40-50percent gradient of ethyl acetate in hexanes to afford 2-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indole (2.0 g, 30percent) as a pale yellow sticky solid. LCMS purity: 93.89percent; (ES+): m/z 282.5 (M+H+); tr=1.99 min.

References: [1]Patent: US2015/252022,2015,A1 .Location in patent: Paragraph 0257; 0258.

2
[ 630125-49-4 ]
[ 1003846-21-6 ]
4-(3-nitro-5-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
730 mg	With dichloro(1,1′-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; johnphos; In 1,4-dioxane; water; at 45℃; for 4h;	General procedure: To a solution of di-tert-butyl (3-bromo-5-(trifluoromethyl)phenyl)imidodicarbonate (step 1 intermediate) (2.2 g, 4.89 mmol) in 1,4-dioxane (20 mL) were added N,N,N?25 trimethylethylenediamine (636 jiL, 4.89 mmol), sodium tert-butoxide (1.40 g, 14.7 mmol),tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (447 mg, 0.49 mmol) and (2- biphenyl)di-tert-butylphosphinetriethylamine (JohnPhos) (37 mg, 1 .47mmol) at RT and the reaction mixture was stirred at 45 C for 4 h. The mixture was cooled to RT and filteredthrough celite. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic solution was washed with 0.1 N HC1 followed by water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 2.01 g of the desired compound. The compound was as suchcarried forward to the next step without characterization.

References: [1]Patent: WO2018/215668,2018,A1 .Location in patent: Page/Page column 78; 79; 96.

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