25519-82-8|4-(4-Methoxybenzoyl)piperidine hydrochloride| Ambeed

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Quality Control of [ 25519-82-8 ] Purity: 97% SDS Specification

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Product Details of [ 25519-82-8 ]

CAS No. :	25519-82-8
Formula :	C₁₃H₁₈ClNO₂
M.W :	255.74
SMILES Code :	O=C(C1CCNCC1)C2=CC=C(OC)C=C2.[H]Cl
MDL No. :	MFCD00114817
InChI Key :	BBDTWYQCXXFKDH-UHFFFAOYSA-N
Pubchem ID :	2740587

Safety of [ 25519-82-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 25519-82-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	6
Fraction Csp3	0.46
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	73.92
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.33 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	2.41
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.3
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.	1.58
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	2.58
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.77

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.01
Solubility	0.252 mg/ml ; 0.000984 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.	-2.86
Solubility	0.355 mg/ml ; 0.00139 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	-3.69
Solubility	0.0522 mg/ml ; 0.000204 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.	-6.15 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<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)	1.54

Application In Synthesis of [ 25519-82-8 ]

* 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 [ 25519-82-8 ]

[ 25519-82-8 ] Synthesis Path-Downstream 1~24

Yield	Reaction Conditions	Operation in experiment
		A. A sample of anisole is treated according to the manipulative procedures described above in Example 1(c) and (d) to produce 4-(4-methoxybenzoyl)piperidine hydrochloride which, when recrystallized from isopropanol, had a mp of 251-256 C.

2
[ 71785-92-7 ]
[ 25519-82-8 ]
(1'-benzoyl-4'-hydroxy-[1,3'-bipiperidin]-4-yl)(4-methoxy-phenyl)methanone [ No CAS ]
(1'-benzoyl-3'-hydroxy-[1,4'-bipiperidin]-4-yl)(4-methoxyphenyl)methanone [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5362 - 5372.

3
[ 71785-92-7 ]
[ 25519-82-8 ]
[ 108-24-7 ]
1'-benzoyl-4-(4-methoxybenzoyl)-1,3'-bipiperidin-4'-yl acetate [ No CAS ]
1'-benzoyl-4-(4-methoxybenzoyl)-[1,4'-bipiperidin]-3'-yl acetate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5362 - 5372.

4
[ 25519-82-8 ]
[ 1356633-46-9 ]

References: [1]Patent: US2012/28954,2012,A1 .
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2957 - 2960.

5
[ 25519-82-8 ]
[ 1356629-00-9 ]

References: [1]Patent: US2012/28954,2012,A1 .
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2957 - 2960.

6
[ 25519-82-8 ]
C₃₀H₃₇FN₄O₆ [ No CAS ]

References: [1]Patent: US2012/28954,2012,A1 .

7
[ 25519-82-8 ]
C₂₅H₂₉FN₄O₄*2ClH [ No CAS ]

References: [1]Patent: US2012/28954,2012,A1 .

8
[ 25519-82-8 ]
N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide [ No CAS ]

References: [1]Patent: US2012/28954,2012,A1 .

9
[ 25519-82-8 ]
N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide [ No CAS ]

References: [1]Patent: US2012/28954,2012,A1 .

10
[ 25519-82-8 ]
[ 17874-79-2 ]
[ 1356633-44-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of5-(methoxycarbonyl)picolinic acid (319 mg, 1.76 mmol) and 4-(4-methoxybenzoyl) piperidinehydrochloride (300 mg, 1.17 mmol) in dimethylformamide (5 mL) was added triethylamine(0.406 mL), followed by the addition of HATU (669 mg, 2.64 mmol). The reactionmixture was stirred at ambient temperature for 4 hours before 50% aqueous sodiumbicarbonate solution (20 mL) was added. Then the mixture was extracted with ethylacetate (3 5 mL). The organic phasewas washed with saturated aqueous sodium chloride solution (2 5 mL), dried over sodiumsulfate, filtered and concentrated. The residue was purified by columnchromatography (silica gel, petroleum ether/ethyl acetate 1:1) to give the titlecompound (425 mg, 95% yield) as white solid.
80%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a mixture of <strong>[25519-82-8]4-(4-methoxybenzoyl)piperidine hydrochloride</strong> (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH-CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) delta 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) delta 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+ (found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602).

References: [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2957 - 2960.
[2]Patent: US2012/28954,2012,A1 .Location in patent: Page/Page column 196.

11
2-(3-bromo-2-oxopyrrolidin-1-yl)acetonitrile [ No CAS ]
[ 25519-82-8 ]
[ 1417917-74-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; In acetonitrile; at 130℃; for 0.2h;Microwave irradiation;	To a solution of 2-(2-bromo-5-oxopyrrolidin-1-yl)acetonitrile (730 mg, 3.6 mmol) and <strong>[25519-82-8](4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride</strong> (920 mg, 3.6 mmol) in acetonitrile (4 ml) was added triethylamine (1.5 ml, 1 1 mmol). The mixture was microwave at 130C for 12 minutes. The solvent was removed in vacuo and the residue was taken up in methylene chloride and water. The organic layer was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide slightly yellow oil (950 mg, 74% yield). 1 H NMR (400 MHz, CDCl3) delta 7.94 (d, J = 8.5 Hz, 2 H), 6.96 (d, J = 8.5 Hz, 2 H), 4.22-4.39 (m, 2 H), 3.90 (s, 3 H), 3.57 (dt, J = 22.6, 9.0 Hz, 2 H), 3.40- 3.51 (m, J = 8.5 Hz, 1 H), 3.23-3.39 (br s, 1 H), 2.93-3.20 (m, 3 H), 2.33-2.61 (m, 2 H), 2.13-2.31 (m, 1 H), 1 .83-2.03 (m, 4 H). HRMS calculated for 342.1818, found (ESI, [M + H]+), 342.1830.

References: [1]Patent: WO2013/8217,2013,A1 .Location in patent: Page/Page column 48.

12
[ 25519-82-8 ]
[ 66134-97-2 ]
[ 1417917-80-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In acetonitrile; at 20 - 70℃;	(4-Methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (524 mg, 2.05 mmol) was stirred at room temperature with triethylamine (0.657 mL, 477 mg, 4.71 mmol) in acetonitrile (80 mL). A solution of ethyl 2-(3-bromo-2-oxopyrrolidin-1-yl)acetate (513 mg, 2.05 mmol) in acetonitrile (20 mL) was added to the mix. The reaction was stirred 3 hours at 40C and then overnight at 50C. After 24 hours the reaction was not complete and the reaction was stirred an additional 48 hours at 70C then allowed to cool to room temperature. The solvents were removed in vacuo. The crude orange solid was eluted through a silica gel column with a 0 to 10% methanol / dichloromethane gradient to afford the title racemic compound (730 mg, 87% yield, 95% purity) as a thick amber oil. MS (ESI) [m/e, (M+H)] = 389.5. 1H NMR (400 MHz, chloroform-d) delta ppm 7.90 - 7.95 (m, 2 H), 6.91 - 6.96 (m, 2 H), 4.17 - 4.24 (m, 2 H), 3.95 -4.17 (m, 2 H), 3.88 (s, 3 H), 3.56 - 3.64 (m, 1 H), 3.36-3.50 (m, 2 H), 3.18-3.29 (m, 1 H), 3.04-3.13 (m, 1 H), 2.93- 3.04 (m, 2 H), 2.4 1 - 2.56(m, 1 H), 2.20-2.35 (m, 1 H), 2.04-2.19 (m, 1 H), 1.80- 1.95(m, 4 H), 1.26 - 1.32 (m, 3 H).

References: [1]Patent: WO2013/8217,2013,A1 .Location in patent: Page/Page column 52; 53.

13
[ 25519-82-8 ]
[ 95494-51-2 ]
2-{4-[4-(4-methoxybenzoyl)piperidin-1-yl]-4-oxobutyl}-3H-quinazolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 1 Synthesis of 2-{4-[4-(4-methoxy-benzoyl)-piperidin-1 -yl]-4-oxo-butyl}-3H- quinazolin-4-one ("A1") EDCI NMM HOBt DMF To a solution of 4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid (51.0 mg, 0.22 mmol), <strong>[25519-82-8](4-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride</strong> (84.4 mg, 0.33 mmol) and benzotriazol-1-ol hydrate (50.5 mg, 0.33 mmol) in DMF (0.5 ml_) are added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (74.8 mg, 0.30 mmol) and 4-methylmorpholine (39.5 mg, 0.39 mmol). The mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 2-{4-[4-(4- methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one as colorless, amorphous solid; HPLC/MS 1.71 min (A), [M+H] 435; 1H NMR (400 MHz, DMSO-d6) delta 12.15 (s, 1 H), 8.08 (dd, J = 8.1 , 1.5 Hz, 1H), 8.04 - 7.95 (m, 2H), 7.76 (ddd, J = 8.5, 7.1 , 1.6 Hz, 1 H), 7.59 (dt, J = 8.1 , 0.8 Hz, 1H), 7.45 (ddd, J = 8.1 , 7.1 , 1.2 Hz, 1 H), 7.12 - 6.99 (m, 2H), 4.40 (d, J = 12.9 Hz, 1H), 3.93 (d, J = 13.7 Hz, 1 H), 3.85 (s, 3H), 3.65 (tt, J = 11.2, 3.6 Hz, 1 H), 3.25 - 3.11 (m, 1 H), 2.73 (td, J = 12.8, 2.8 Hz, 1 H), 2.65 (t, J = 7.4 Hz, 2H), 2.42 (td, J = 7.3, 2.9 Hz, 2H), 1.98 (p, J = 7.2 Hz, 2H), 1.77 (m, 2H), 1.51 (qd, J = 12.1 , 4.0 Hz, 1 H), 1.34 (qd, J = 12.1, 4.1 Hz, 1H).

References: [1]Patent: WO2015/14442,2015,A1 .Location in patent: Page/Page column 60; 61.

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[ 25519-81-7 ]
[ 25519-82-8 ]