210962-44-0|tert-Butyl 4-(4-(ethoxycarbonyl)phenoxy)piperidine-1-carboxylate| Ambeed

Structure of 210962-44-0

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Quality Control of [ 210962-44-0 ] Purity: 95% SDS Specification

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Product Details of [ 210962-44-0 ]

CAS No. :	210962-44-0
Formula :	C₁₉H₂₇NO₅
M.W :	349.42
SMILES Code :	O=C(N1CCC(OC2=CC=C(C(OCC)=O)C=C2)CC1)OC(C)(C)C
MDL No. :	MFCD13184258
InChI Key :	RQAFJRAGEIMIBQ-UHFFFAOYSA-N
Pubchem ID :	11783050

Safety of [ 210962-44-0 ]

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

Computational Chemistry of [ 210962-44-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	25
Num. arom. heavy atoms	6
Fraction Csp3	0.58
Num. rotatable bonds	8
Num. H-bond acceptors	5.0
Num. H-bond donors	0.0
Molar Refractivity	98.69
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	65.07 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	4.15
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	3.55
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.26
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.	2.51
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	2.72
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.89
Solubility	0.0448 mg/ml ; 0.000128 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.	-4.6
Solubility	0.00875 mg/ml ; 0.000025 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-3.97
Solubility	0.0372 mg/ml ; 0.000106 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	Yes
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	Yes
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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.91 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<2.0
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)	2.76

Application In Synthesis of [ 210962-44-0 ]

* 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 [ 210962-44-0 ]

[ 210962-44-0 ] Synthesis Path-Downstream 1~35

1
[ 120-47-8 ]
[ 109384-19-2 ]
[ 210962-44-0 ]

Yield	Reaction Conditions	Operation in experiment
85.6%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 24.0h;	Step 1 To a solution of DEAD (12.3 mL, 27.08 mmol)(40% in toluene)was added to a mixture of ethyl 4-hydroxybenzoate (XIII)(3.0 g, 18.05 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (XI)(4.72 g, 23.47 mmol)and triphenylphosphane (6.16 g, 23.47 mmol)in THF (40 mL)at 0 C. The mixture was stirred from 0 C. to room temperature over 1 day before concentrating in vacuo. The residue was diluted with EtOAc, washed with 1 N NaOH and brine, and then evaporated under vacuum. The crude product was purified by chromatography (0→30% EtOAc/hexanes)to give tert-butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate (XIV)(5.4 g, 15.45 mmol, 85.6% yield)as a colorless oil. ESIMS found for C19H27NO5 m/z 372.1 (M+Na).
85.6%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 24.0h;	To a solution of DEAD (12.3 mL, 27.08 mmol) (40% in toluene) was added to a mixture of ethyl 4-hydroxybenzoate (CXI) (3.0 g, 18.05 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (CIX) (4.72 g, 23.47 mmol) and triphenylphosphane (6.16 g, 23.47 mmol) in THF (40 mL) at 0 C. The mixture was stirred from 0 C. to room temperature over 1 day before concentrating in vacuo. The residue was diluted with EtOAc, washed with 1 N NaOH and brine, and then evaporated under vacuum. The crude product was purified by chromatography (0→30% EtOAc/hexanes) to give tert-butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate (CXII) (5.4 g, 15.45 mmol, 85.6% yield) as a colorless oil. ESIMS found for C19H27NO5 m/z 372.1 (M+Na).
85.6%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 24.0h;	To a solution of DEAD (12.3 mL, 27.08 mmol) (40% in toluene) was added to a mixture of ethyl 4-hydroxybenzoate (XXXV) (3.0 g, 18.05 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (XXXVI) (4.72 g, 23.47 mmol) and triphenylphosphane (6.16 g, 23.47 mmol) in THF (40 mL) at 0 C. The mixture was stirred from 0 C. to room temperature over 1 day before concentrating in vacuo. The residue was diluted with EtOAc, washed with 1 N NaOH and brine, and then evaporated under vacuum. The crude product was purified by chromatography (0→30% EtOAc/hexanes) to give tert-butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate (XXXVII) (5.4 g, 15.45 mmol, 85.6% yield) as a colorless oil. ESIMS found for C19H27NO5 m/z 372.1 (M+Na).

62%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; for 24.0h;	Reference Example 1:4-[(1-Cyclopentyl-4-piperidinyl)oxy]benzaldehyde (1) Production of tert-butyl 4-[4-(ethoxycarbonyl)phenoxy]tetrahydro-1(2H)-pyridinecarboxylate: Ethyl 4-hydroxybenzoate (4.15 g, 25.0 mmol), tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate (5.0 g, 25.0 mmol) and triphenyl phosphine (7.87 g, 30.0 mmol) were dissolved in tetrahydrofuran (50 mL), and with stirring at 0C, diisopropyl azodicarboxylate (6.06 g, 30.0 mmol) was added thereto and stirred for 24 hours. The reaction solution was concentrated, and the precipitated white solid was taken out through filtration and washed with ethyl acetate. The mother liquid was washed with aqueous 1 N sodium hydroxide solution and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 9/1) to obtain the intended compound (5.45 g, 62 %) as a colorless solid.
39%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16.0h;	Step A: tert-Butyl-4-(4-carboxyethylphenyloxy)- 1 -piperidinecarboxylateTo a pre-cooled (00C) suspension of ethyl 4-hydroxybenzoate (10.0 g, 60.2, mmol), 1- tert-butoxycarconyl 4-hydroxypiperidine (12.1 g, 60.1 mmol), and triphenylphosphine (15.8 g, 60.2 mmol) in THF is added diisopropyl azodocarboxylate (11.6 g, 60.1 mmol).The mixture is allowed to come to rt, stirred for 16 h, diluted with ethyl acetate, washed with water, sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, filtered and evaporated in vacuo. The crude product is purified on silica to give the desired product (8.27 g, 39 %).

References: [1]Patent: US2017/313682,2017,A1 .Location in patent: Paragraph 0702; 0703.
[2]Patent: US2019/127370,2019,A1 .Location in patent: Paragraph 0972-0973.
[3]Patent: US2019/125740,2019,A1 .Location in patent: Paragraph 0551; 0552.
[4]Patent: EP1757594,2007,A1 .Location in patent: Page/Page column 72-73.
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 1845 - 1857.
[6]Patent: WO2007/106705,2007,A1 .Location in patent: Page/Page column 115.

2
[ 210962-44-0 ]
[ 162046-56-2 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With methanol; lithium hydroxide; In tetrahydrofuran; at 60℃; for 2.0h;	Step 2 To a solution of tent-butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate (XIV)(5.4 g, 15.45 mmol)in MeOH (10 mL)and THF (10 mL)was added LiOH (15.5 mL, 61.82 mmol)and the mixture stirred at 60 C. for 2 h. The mixture was concentrated and the residue triturated with water. The resulting solution was acidified with 2 N HCl until a solid precipitated. The solid was filtered and washed with water to afford 4[(1-tert-butoxycarbonyl-4-piperidyl)oxy]benzoic acid (XV)(4.7 g, 14.63 mmol, 94.6% yield)as a white solid. 1H NMR (499 MHz, DMSO-d6)δ ppm 1.40 (9H, s), 1.47-1.57 (2H, m), 1.89-1.97 (2H, m), 3.12-3.23 (2H, m), 3.63-3.70 (2H, m), 4.63-4.71 (1H, m), 7.04 (2H, d, J=9.06 Hz), 7.87 (2H, d, J=9.06 Hz); ESIMS found for C17H23NO5 m/z 344.1 (M+Na).
94.6%	With methanol; lithium hydroxide; In tetrahydrofuran; at 60℃; for 2.0h;	To a solution of <strong>[210962-44-0]tert-butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate</strong> (CXII) (5.4 g, 15.45 mmol) in MeOH (10 mL) and THF (10 mL) was added LiOH (15.5 mL, 61.82 mmol) and the mixture stirred at 60 C. for 2 h. The mixture was concentrated, and the residue triturated with water. The resulting solution was acidified with 2 N HCl until a solid precipitated. The solid was filtered and washed with water to afford 4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]benzoic acid (CXIII) (4.7 g, 14.63 mmol, 94.6% yield) as a white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.40 (9H, s), 1.47-1.57 (2H, m), 1.89-1.97 (2H, m), 3.12-3.23 (2H, m), 3.63-3.70 (2H, m), 4.63-4.71 (1H, m), 7.04 (2H, d, J=9.06 Hz), 7.87 (2H, d, J=9.06 Hz); ESIMS found for C17H23NO5 m/z 344.1 (M+Na).
94.6%	With methanol; lithium hydroxide; In tetrahydrofuran; at 60℃; for 2.0h;	To a solution of <strong>[210962-44-0]tert-butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate</strong> (XXXVII) (5.4 g, 15.45 mmol) in MeOH (10 mL) and THF (10 mL) was added LiOH (15.5 mL, 61.82 mmol) and the mixture stirred at 60 C. for 2 h. The mixture was concentrated and the residue triturated with water. The resulting solution was acidified with 2 N HCl until a solid precipitated. The solid was filtered and washed with water to afford 4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]benzoic acid (XXXVIII) (4.7 g, 14.63 mmol, 94.6% yield) as a white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.40 (9H, s), 1.47-1.57 (2H, m), 1.89-1.97 (2H, m), 3.12-3.23 (2H, m), 3.63-3.70 (2H, m), 4.63-4.71 (1H, m), 7.04 (2H, d, J=9.06 Hz), 7.87 (2H, d, J=9.06 Hz); ESIMS found for C17H23NO5 m/z 344.1 (M+Na).

	With sodium hydroxide; In ethanol; ethyl acetate;	Step 2 Synthesis of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid: 847 mg (2.43 mmol) of ethyl 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoate was dissolved in 50 ml of ethanol. 5 ml of 1 N sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 3 days. The reaction solution was concentrated and then treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the title compound. Yield: 697 mg (2.2 mmol) (92%) H-NMR (CDCl3) d δ 1.50 (9H, s), 1.70-2.00 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d), 8.05 (2H, d)
	With sodium hydroxide; In ethanol; ethyl acetate;	Step 2 Synthesis of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid: 847 mg (2.43 mmol) of ethyl 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoate was dissolved in 50 ml of ethanol, and 5 ml of 1 N sodium hydroxide was added thereto, and they were stirred for 3 days. The reaction solution was concentrated and treated in an ordinary manner with ethyl acetate as the extractant to obtain the title compound. Yield: 697 mg (2.2 mmol) (92 %) 1 H-NMR (CDCl 3) δ: 1.50 (9H, s), 1.70-2.00 (4H, m), 3.30.3.40 (2H, m), 3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d), 8.05 (2H, d)

References: [1]Patent: US2017/313682,2017,A1 .Location in patent: Paragraph 0702; 0704.
[2]Patent: US2019/127370,2019,A1 .Location in patent: Paragraph 0972; 0974.
[3]Patent: US2019/125740,2019,A1 .Location in patent: Paragraph 0551; 0553.
[4]Journal of Medicinal Chemistry,2003,vol. 46,p. 1845 - 1857.
[5]Patent: US2001/56123,2001,A1 .
[6]Patent: EP976722,2000,A1 .

3
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[ 210962-44-0 ]
[ 1005402-56-1 ]