361345-40-6|tert-Butyl 4-(3-aminobenzyl)piperazine-1-carboxylate| Ambeed

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Quality Control of [ 361345-40-6 ] Purity: 95% SDS Specification

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Product Details of [ 361345-40-6 ]

CAS No. :	361345-40-6
Formula :	C₁₆H₂₅N₃O₂
M.W :	291.39
SMILES Code :	O=C(N1CCN(CC2=CC=CC(N)=C2)CC1)OC(C)(C)C
MDL No. :	MFCD06658979
InChI Key :	VKSINZNBWVJILC-UHFFFAOYSA-N
Pubchem ID :	7127799

Safety of [ 361345-40-6 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H312-H314-H332
Precautionary Statements:	P280-P301+P312-P301+P330+P331-P302+P352-P304+P340-P305+P351+P338-P310
Class:	8
UN#:	3259
Packing Group:	Ⅲ

Computational Chemistry of [ 361345-40-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	21
Num. arom. heavy atoms	6
Fraction Csp3	0.56
Num. rotatable bonds	5
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	92.3
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	58.8 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.12
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	1.74
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.42
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.	1.62
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	1.33
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.85

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.62
Solubility	0.692 mg/ml ; 0.00238 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.	-2.59
Solubility	0.746 mg/ml ; 0.00256 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	-3.12
Solubility	0.223 mg/ml ; 0.000764 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	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.	-6.84 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)	2.3

Application In Synthesis of [ 361345-40-6 ]

* 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 [ 361345-40-6 ]

[ 361345-40-6 ] Synthesis Path-Downstream 1~31

Yield	Reaction Conditions	Operation in experiment
98%		11.2. tert-butyl 4-(3-aminobenzyl)-1-piperazinecarboxylate The experimental protocol used is the same as that described for compound 1.A.2, intermediate 11.1 replacing intermediate 1.A.1. A yellow oil is obtained which, after cold crystallization, produces a yellow solid (yield 98%). Melting point: 102.3 C.

2
[ 361345-40-6 ]
[ 936092-53-4 ]
N-tert-butyl-3-[5-methyl-2-(4-piperazin-1-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%		[0201] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-benzyl)-piperazine- 1-carboxylic acid tert-butyl ester (0.1 g, 0.34 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (6 mL) and TFA (3 mL) added. The mixture was stirred at room temperature for Ih, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid triturated in hexanes/EtOAc (10/1, 55 mL). After filtration, the title compound was obtained as a white solid (32 mg, 22%). <n="121"/>[0202] 1H NMR (500 MHz, DMSOd6): δ 1.12 (s, 9H), 2.13 (s, 3H), 2.30-2.40 (m, 4H)5 2.85 (t, J= 4.7 Hz, 4H), 3.38 (s, 2H), 7.09 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, IH), 7.59 (d, J= 8.5 Hz, 2H), 7.94 (s, IH), 8.10 (s, IH), 8.13-8.16 (m, IH), 8.59 (s, IH), 8.96 (s, IH). MS (ES+): m/z 510 (M+H)+.

References: [1]Patent: WO2007/53452,2007,A1 .Location in patent: Page/Page column 119-120.

3
[ 361345-40-6 ]
[ 936092-35-2 ]
[ 936092-44-3 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.25h;Microwave irradiation;	[0260] A mixture of intermediate 31 (0.092 g, 0.33 mmol), 4-(3-amino-benzyl)- piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol), Pd2(dba)3 (0.03 g, 0.033 mmol), Xantphos (0.038 g, 0.065 mmol) and cesium carbonate (0.32 g, 0.98 mmol) was suspended in dioxane (5 mL) and microwaved at 160 "C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.075 g, 43%) as a brown solid.

References: [1]Patent: WO2007/53452,2007,A1 .Location in patent: Page/Page column 142.

4
[ 361345-40-6 ]
[ 1117684-37-3 ]
[ 1117685-94-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;palladium diacetate; In ISOPROPYLAMIDE; for 0.25h;Microwave irradiation;	tert-Butyl 4-(3-aminobenzyl)piperazine-1-carboxylate (2.5 g, 8.58 mmol), 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (Method 13, 1.918 g, 8.17 mmol), Cs2CO3 (3.99 g, 12.26 mmol), Pd(OAc)2 (0.128 g, 0.57 mmol) and xantphos (0.473 g, 0.82 mmol) were suspended in DMA (35 mL). The mixture was then thoroughly degassed using nitrogen and heated in a microwave for 15 mins. Then the mixture was cooled and filtered. Purification by ion exchange chromatography, using an SCX column and eluting with 0.35M NH3/MeOH afforded the title compound; (1.63 g, 41%) as a white solid.

References: [1]Patent: US2009/48269,2009,A1 .Location in patent: Page/Page column 58.

5
[ 361345-40-6 ]
[ 32315-10-9 ]
(4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4] diazepine [ No CAS ]
C₃₃H₃₇F₃N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A vial was charged with triphosgene (75.0 mg, 0.253 mmol), and this was dissolved in acetonitrile (2.5 mL). A solution of (4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro- l,4-methanopyrido[2,3-b][l,4]diazepine (150 mg, 0.491 mmol) in acetonitrile (2.5 mL) was added, followed by triethylamine (0.50 mL, 3.59 mmol). The reaction was stirred at room temperature for 4 h, and tert-butyl 4-(3-aminobenzyl)piperazine-l-carboxylate (480 mg, 1.65 mmol) was added as a solid, followed by DMAP (360 mg, 2.95 mmol). The reaction was stirred at 80 C for 16 h, and all solvents were removed in vacuo. The remaining material was dissolved in trifluoroacetic acid (5.0 mL), and the solution stirred at 50 C for 20 min. Excess trifluoroacetic acid was removed in vacuo, the remaining material dissolved in DMSO, and the resulting solution purified by preparative HPLC to give (4S)-N-(3-(piperazin-l-ylmethyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro- l,4-methanopyrido[2,3-b][l,4]diazepine-5(2H)-carboxamide trifluoroacetate (89.1 mg, 0.140 mmol, 29% yield)

References: [1]Patent: WO2014/186313,2014,A1 .Location in patent: Page/Page column 126.

6
[ 361345-40-6 ]
(4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4] diazepine [ No CAS ]
[ 76-05-1 ]
(4S)-N-(3-(piperazin-1-ylmethyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide 2,2,2-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%		A vial was charged with triphosgene (75.0 mg, 0.253 mmol), and this was dissolved in acetonitrile (2.5 mL). A solution of (4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine (150 mg, 0.491 mmol) in acetonitrile (2.5 mL) was added, followed by triethylamine (0.50 mL, 3.59 mmol). The reaction was stirred at room temperature for 4 h, and <strong>[361345-40-6]tert-butyl 4-(3-aminobenzyl)piperazine-1-carboxylate</strong> (480 mg, 1.65 mmol) was added as a solid, followed by DMAP (360 mg, 2.95 mmol). The reaction was stirred at 80 C. for 16 h, and all solvents were removed in vacuo. The remaining material was dissolved in trifluoroacetic acid (5.0 mL), and the solution stirred at 50 C. for 20 min. Excess trifluoroacetic acid was removed in vacuo, the remaining material dissolved in DMSO, and the resulting solution purified by preparative HPLC to give (4S)-N-(3-(piperazin-1-ylmethyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide trifluoroacetate (89.1 mg, 0.140 mmol, 29% yield). MS (ESI) calcd for C28H29F3N6O: 522.2.

References: [1]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0702; 0703.

7
[ 361345-40-6 ]
[ 1092789-65-5 ]
tert-butyl 4-(3-(3-(benzyloxy)-4-chlorobenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

References: [1]ChemMedChem,2016,vol. 11,p. 283 - 288.

8
[ 361345-40-6 ]
[ 3438-16-2 ]
5-chloro-2-methoxy-N-(3-(piperazin-1-ylmethyl)phenyl)benzamide [ No CAS ]

References: [1]ChemMedChem,2016,vol. 11,p. 283 - 288.

9
[ 361345-40-6 ]
[ 3438-16-2 ]
tert-butyl 4-(3-(5-chloro-2-methoxybenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

References: [1]ChemMedChem,2016,vol. 11,p. 283 - 288.

10
[ 361345-40-6 ]
[ 6280-89-3 ]
tert-butyl 4-(3-(2-chloro-5-methoxybenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

References: [1]ChemMedChem,2016,vol. 11,p. 283 - 288.

11
[ 361345-40-6 ]
[ 594-44-5 ]
tert-butyl 4-(3-(ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.3%	With pyridine; In dichloromethane; at 20℃; for 12h;	A solution of <strong>[361345-40-6]tert-butyl 4-(3-aminobenzyl)piperazine-1-carboxylate</strong> (0.940 g, 3.226 mmol), pyridine (0.3 12 mL, 3.87 1 mmol) and ethanesulfonyl chloride (0.456 g, 3.548 mmol) in dichloromethane (30 mL) was stirred at the room temperature for 12 hr, Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated ammonium chloride solution, separated, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give tert-butyl 4-(3-(ethylsulfonamido)benzyl)piperazine- 1 -carboxylate as yellow solid (1.080 g, 87.3%).

References: [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1532; 1533; 1534.

12
[ 203047-33-0 ]
[ 361345-40-6 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With ammonium chloride; zinc; In tetrahydrofuran; water; at 20℃; for 12h;	A solution of tert-butyl 4-(3-nitrobenzyl)piperazine-1-carboxylate (1.050 g, 3.267 mmol), ammonium chloride (0.874 g, 16.336 mmol) and Zinc dust (1.068 g, 16.336 mmol) in tetrahydrofuran (20 mL) / water (20 mL) was stirred at the room temperature for 12 hr. The reaction mixture was filtered to remove solids. Then, water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The title compound was used without further purification (tert-butyl 4-(3-aminobenzyl)piperazine- 1 -carboxylate, 0.940 g, 98.7 %, yellow solid).

References: [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1529; 1530; 1531.

13
[ 361345-40-6 ]
tert-butyl 4-(3-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2017/18803,2017,A1 .

14
[ 57260-71-6 ]
[ 361345-40-6 ]

References: [1]Patent: WO2017/18803,2017,A1 .

15
[ 3958-57-4 ]
[ 361345-40-6 ]

References: [1]Patent: WO2017/18803,2017,A1 .

16
[ 361345-40-6 ]
tert-butyl (S)-4-(3-((4-chloro-6-((3-(4-cyanophenyl)-1-(dimethylamino)-1-oxopropan-2-yl)amino)-1,3,5-triazin-2-yl)amino)benzyl)piperazine-1-carboxylate [ No CAS ]