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Chemical Structure| 4097-88-5 Chemical Structure| 4097-88-5

Structure of 4097-88-5

Chemical Structure| 4097-88-5

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Product Citations

Product Citations      Show More

Xuexiang Han ; Mohamad-Gabriel Alameh ; Ningqiang Gong ; Lulu Xue ; Majed Ghattas ; Goutham Bojja , et al.

Abstract: Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly afecting biodistribution, cellular uptake, endosomal escape and transfection efciency. However, the laborious synthesis of cationic lipids limits the discovery of efcacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identifcation of a tail-like amine-ring-alkyl aniline that generally afords efcacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.

Purchased from AmBeed: ; ; ;

Li, Bowen ; Manan, Rajith Singh ; Liang, Shun-Qing ; Gordon, Akiva ; Jiang, Allen ; Varley, Andrew , et al.

Abstract: The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for mRNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.

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Product Details of [ 4097-88-5 ]

CAS No. :4097-88-5
Formula : C5H15N3
M.W : 117.19
SMILES Code : CN(CCN)CCN
MDL No. :MFCD00198039
InChI Key :HYSQEYLBJYFNMH-UHFFFAOYSA-N
Pubchem ID :430288

Safety of [ 4097-88-5 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H227-H314
Precautionary Statements:P210-P260-P264-P280-P301+P330+P331+P310-P303+P361+P353+P310+P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405-P501
Class:8
UN#:2735
Packing Group:

Computational Chemistry of [ 4097-88-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 34.46
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

55.28 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.41
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-1.43
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

-1.16
Log Po/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.

-0.65
Log Po/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

-1.21
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.61

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

0.6
Solubility 465.0 mg/ml ; 3.97 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Highly soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

0.77
Solubility 693.0 mg/ml ; 5.91 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

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

-0.45
Solubility 41.4 mg/ml ; 0.353 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

No
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

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.

-8.03 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

1.0
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<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)

1.04

Application In Synthesis of [ 4097-88-5 ]

* 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 [ 4097-88-5 ]

[ 4097-88-5 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 4097-88-5 ]
  • [ 24424-99-5 ]
  • [ 263162-13-6 ]
YieldReaction ConditionsOperation in experiment
46% In tetrahydrofuran; at 0 - 20℃; for 20.5h; A solution of (BOC) [20] (9.60 g, 44 mmol) in THF (50 mL) was added over a period of 2 h to a solution of bis (diethylamino) [METHYLAMINE] (89) (10.32 g, 88 mmol) in THF (50 mL) at 0 C. The reaction mixture stirred for 30 min then allowed to warm to [20 C] and stirred for 20 h. The reaction mixture was partitioned between DCM and saturated aqueous [NACL,] the organic layer separated and the aqueous layer further extracted with DCM (3 x 25 mL). The combined organic extract was dried and the solvent evaporated at 30 [C] to give carbamate 90 (8.79 g, 46%) as a colourless oil, which was used without further purification.
35% In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere; To a solution of BOC2O (9.6 g, 44.0 mmol) in THF (50 mL) at 0C was added 2,2'-Diamino- N-methyldiethylamine (10.3 g, 88.0 mmol) under N2 atmosphere. The mixture was stirred for 2 hours at room temperature. The mixture was quenched with H2O (100 mL) and DCM (150 mL X 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column to obtain compound Mal-3-1 (3.3 g, 35%).1H NMR (400 Hz, CDCl3) δ 5.04 (brs, 1H), 3.26-3.16 (m, 2H), 2.78 (t, J= 6.0 Hz, 2H), 2.47 (t, J= 6.0 Hz, 2H), 2.43 (t, J = 6.0 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H)
30% In dichloromethane; at 0 - 20℃; for 3h; To a solution of A1-(2-aminoethyl)-A1-methylethane-l, 2-diamine (1.1 g, 9.4 mmol) in DCM (24 mL) at 0C was slowly added (Boc)20 (614 mg, 2.8 mmol in 4 mL DCM). The mixture was stirred at 0C for lh then warmed to RT. After 2h, the mixture was diluted with DCM and washed with brine. The organic layer was dried over Na2S04, filtered and concentrated to give ter/-butyl (2-((2-aminoethyl)(methyl)amino)ethyl)carbamate (600 mg, 30% yield) as an oil.
In dichloromethane; at 0℃; N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0 C. A solution of Boc2O (0.93 g, 4.27 mmol) in CH2 (10 mL) was then added dropwise at 0 C. over a period of 15 min. The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (1.1 g).tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (400 mg, 1.84 mmol) was taken up in CH3CN (10 mL) along with nicotinic acid (227 mg, 1.84 mmol) and EDCI (353 mg, 2.02 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (5% MeOH-CH2Cl2) to afford tert-butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (180 mg, 30%). MS calculated for C16H26N4O3: 322.2; found: [M+H]+323.tert-Butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (90 mg, 0.279 mmol) was taken up in a 25% TFA in CH2Cl2 solution (5 mL) and allowed to stand at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford the TFA salt of N-(2-((2-aminoethyl)(methyl)amino)ethyl)nicotinamide. This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (90 mg, 0.279 mmol), HATU (117 mg, 0.31 mmol) and DIEA (0.15 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH-CH2Cl2) afforded N-(2-((2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)(methyl)amino)ethyl)nicotinamide (30 mg, 20%). MS calculated for C33H48N4O2: 532.38; found: [M+H]+533.
In dichloromethane; at 0 - 20℃; for 2.75h; Example 8 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0 C. A solution of Boc2O (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 min. The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3*25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (1.1 g).
In dichloromethane; at 0 - 20℃; Example 8 Preparation of 5-((2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)(methyl)amino)ethyl)carbamoyl)-2-methylpyrazine 1-oxide (I-5) N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0 C. A solution of Boc2O (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 min. The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3*25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (1.1 g).
In dichloromethane; at 0 - 20℃; for 2.75h; Example 17 Preparation of (E)-methyl 4-(2-((2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)(methyl)amino)ethylamino)-4-oxobut-2-enoate (Compound I-4) N1-(2-Aminoethyl)-N-1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 min. The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3*25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
In dichloromethane; at 0 - 20℃; for 2.75h; Example 7 Preparation of (S)-N-(2-((2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)(methyl)amino)ethyl)-2-hydroxybenzamide (I-4) N-1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 minutes. The resulting reaction mixture was stirred at 0 C. for 30 minutes and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3*25 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
In dichloromethane; at 0 - 20℃; for 2.75h; Nl-(2-Aminoethyl)-Nl-methylethane-l,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2C12 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2C12 (10 mL) was then added dropwise at 0 C over a period of 15 min. The resulting reaction mixture was stirred at 0 C for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2C12 (100 mL). The organic layer was washed with brine (3 x 25 mL), dried (Na2S04) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
In dichloromethane; at 0 - 20℃; Example 7; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-3); N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 min The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (200 mg, 0.922 mmol) was taken up in 5 mL of CH3CN along with mycophenolic acid (295 mg, 0.922 mmol) and EDC (194 mg, 1.01 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 400 mg of (E)-tert-butyl 2-((2-(6-(4-hydroxy-6-methoxy- 7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)(methyl)amino)ethylcarbamate (84% yield). This material was taken up in 10 mL of 4 M HCl in dioxane and allowed to stir at room temperature for 2 h. The mixture was diluted with EtOAc (30 mL) and concentrated under reduced pressure to afford the HC1 salt of (E)-N-(2-((2-aminoethyl)(methyl)amino)ethyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo- 1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide. This material was then taken up in 10 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 252 mg, 0.77 mmol), HATU (322 mg, 0.85 mmol) and DIEA (540 3.1 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (50 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 300 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-((E)-6-(4-hydroxy-6- methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (53% yield). MS (EI) calcd for C44H63N3O6: 729.47; found 730 (M+1).
In dichloromethane; at 0 - 20℃; for 2.91667h; N1-(2-Aminoethyl)-N-1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) is dissolved in CH2Cl2 (100 mL) and cooled to 0 C. A solution of Boc2O (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) is then added dropwise at 0 C. over a period of 15 min. The resulting reaction mixture is stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture is diluted with CH2Cl2 (100 mL). The organic layer is washed with brine (3*25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
In dichloromethane; at 0 - 20℃; for 2.75h; The same procedure outlined in example 8 was used, substituting tert-butyl2-((2-aminoethyl)(methyl)amino)ethylcarbamate for tert-butyl 2-aminoethylcarbamate. tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate, in turn, could be prepared as follows: N1-(2-aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 min. The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate. Compound I-31: MS (EI) calcd for C31H52N6O2 540.42; found 541 [M+H]+.
1.1 g In dichloromethane; at 0 - 20℃; for 2.75h; [0244j Ni -(2-Aminoethyl)-N1 -methylethane- 1 ,2-diamine (5.0 g, 42.7 mmol) was dissolved in CH2C12 (100 mL) and cooled to 0 C. A solution of Boc2O (0.93 g, 4.27 mmol) in CH2C12 (10 mL) was then added dropwise at 0 C over a period of 15 mm. The resulting reaction mixture was stirred at 0 C for 30 mm and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2C12 (100 mL). The organic layer was washed with brine (3 x 25 mL), dried over Na2SO4, filtered andconcentrated under reduced pressure to afford tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (1.1 g).
1.1 g In dichloromethane; at 0 - 20℃; for 0.0458333h; Example 10 Preparation of V-(2-((2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19- hexaenamidoethyl)(methyl)amino)ethyl)nicotinamide (1-2) [0332] M-(2-Aminoethyl)-M-methylethane-l,2-diamine (5.0 g, 42.7 mmol) was dissolved in CH2C12 (100 mL) and cooled to 0 C. A solution of Boc20 (0.93 g, 4.27 mmol) in CH2C12 (10 mL) was then added dropwise at 0 C over a period of 15 min. The resulting reaction mixture was stirred at 0 C for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2CI2 (100 mL). The organic layer was washed with brine (3 x 25 mL), dried over Na2S04, filtered and concentrated under reduced pressure to afford tert-butyl 2-((2- aminoethyl)(methyl)amino)ethylcarbamate (1.1 g).
1.1 g In dichloromethane; at 0 - 20℃; for 2.75h; Example 7 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-14) N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 mm. The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate. (0377) tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (150 mg, 0.69 mmol) was taken up in 10 mL of CH3CN along with indomethacin (247 mg, 0.69 mmol) and EDC (146 mg, 0.76 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then diluted with EtOAc (40 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 360. Mg of the Boc-protected intermediate (93% yield). This material was taken up in 10 mL of 4 M HCl in dioxane and allowed to stir at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure to afford the HCl salt of N-(2-((2-aminoethyl)(methyl)amino)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide. (0378) This HCl salt of N-(2-((2-aminoethyl)(methyl)amino)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide (0.38 mmol) was taken up in 5 mL of CH3CN along with DHA (210 mg, 0.64 mmol), HATU (267 mg, 0.67 mmol) and DMA (334 μL, 2.01 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (25 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 320 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (65% yield). MS (EI) calcd for C46H59ClN4O4: 766.42; found 767 (M+1).
8.2 g Procedure: 2,2′-Diamino N-methyldiethylamine 12 (10.51 g, 89.6 mmoles) was dissolved in methanol (100 ml). The solution was cooled to 0 C. and trifluoroacetic acid (10.21 g) in methanol (30 ml) was added dropwise in 1 hour, 50 ml of water was then added, and the mixture stirred for 1 hour. BOC2O (19.5 g, 89.6 mmoles) and iodine (2.25 g, 8.96 mmoles) in ethanol (75 ml) was added dropwise over 1 hour and then the mixture stirred for 5 hours. The reaction was neutralized with sodium hydroxide solution, concentrated, and the crude partitioned between dichloromethane and water (100 ml/25 ml). The organic layer was separated, the aqueous layer extracted 2× dichloromethane (50 ml), the organic extracts combined, washed with 10% sodium bisulfite solution, and dried over MgSO4. Filtration, and concentration gave crude product which was purified by flash chromatography using dichloromethane/methano/aq NH3 90:10:2 and gave 8.2 grams of white solid 13. 1H NMR (400 MHz, CDCl3): δ 5.04 (1H, hr s), 3.18 (2H, q), 2.70 (2H, t), 2.39 (4H, m), 2.18 (3H, s), 1.77 (2H, br s), 1.40 (9H, s).

  • 2
  • manganese(II) perchlorate hexahydrate [ No CAS ]
  • [ 4097-88-5 ]
  • [ 3328-69-6 ]
  • [ 127-09-3 ]
  • {Mn2(HC6H2O(CHNCH2CH2)2NCH3)2(CH3CO2)}(1+)*ClO4(1-) = Mn2(HC6H2O(CHNCH2CH2)2NCH3)2(CH3COO)ClO4 [ No CAS ]
  • 3
  • manganese(II) perchlorate hexahydrate [ No CAS ]
  • [ 4097-88-5 ]
  • [ 7310-95-4 ]
  • [ 2156-56-1 ]
  • {Mn2(CH3C6H2O(CHNCH2CH2)2NCH3)2(CHCl2CO2)}(1+)*ClO4(1-) = Mn2(CH3C6H2O(CHNCH2CH2)2NCH3)2(CHCl2COO)ClO4 [ No CAS ]
  • 4
  • [ 4097-88-5 ]
  • [ 34619-03-9 ]
  • [ 263162-13-6 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; at 0℃; for 0.75h; N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2C12 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2C12 (10 mL) was then added dropwise at 0 C over a period of 15 min. The resulting reaction mixture was stirred at 0 C for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2CI2 (100 mL). The organic layer was washed with brine (3 x 25 mL), dried (Na2S04) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
  • 5
  • [ 4097-88-5 ]
  • [ 99970-84-0 ]
  • [ 1544599-53-2 ]
  • 6
  • [ 4097-88-5 ]
  • [ 349-02-0 ]
  • 4,4'-(((methylazanediyl)bis(ethane-2,1-diyl))bis(azanediyl))bis(3-nitrobenzamide) [ No CAS ]
YieldReaction ConditionsOperation in experiment
59.6% With potassium carbonate; In dimethyl sulfoxide; at 20℃; A mixture of /^-^-aminoethyO-Z^-methylethane-l^-diamine (0.318 g, 2.72 mmol), K2CO3 (1.501 g, 10.86 mmol) and <strong>[349-02-0]4-fluoro-3-nitrobenzamide</strong> (1 g, 5.43 mmol) in DMSO (20 mL) was stirred at rt overnight. Water was added and the resulting precipitate was collected by filtration and was dried under reduced pressure to afford 4,4'- (1751) (((methylazanediyl)bis(ethane-2,l-diyl))bis(azanediyl))bis(3-nitrobenzamide) (800 mg, 1.62 mmol, 59.6% yield) as a yellow solid. LCMS (LCMS Method A): Rt = 1.01 min, [M+H]+ = 446.
59.6% With potassium carbonate; In dimethyl sulfoxide; at 20℃; A mixture of M-(2-aminoethyl)-M-methylethane-1,2-d iamine (0.318 g, 2.72 mmcl), K2C03 (1.501 g, 10.86 mmcl) and <strong>[349-02-0]4-fluoro-3-nitrobenzamide</strong> (1 g, 5.43 mmcl) in DMSO (20 mL) was stirred at it overnight. Water was added and the resulting precipitate was collected by filtration and was dried under reduced pressure to afford 4,4-(((methylazanediyl)bis(ethane-2,1-diyl))bis(azanediyl))bis(3-n itrobenzamide) (800 mg, 1.62mmol, 59.6% yield) as a yellow solid. LCMS (LCMS Method A): Rt = 1.01 mi [M+H] = 446.
  • 7
  • [ 4097-88-5 ]
  • [ 41840-28-2 ]
  • [ 263162-13-6 ]
YieldReaction ConditionsOperation in experiment
71% In 1,4-dioxane; at 20℃; for 2h; N,N′ -bis(3-aminoethyl)methylamine (8.9 mL, 69 mmol) was dissolvedin 1,4-dioxane (40 mL) and S-Boc-2-mercapto-4,6-dimethylpyrimidine(4.2 g, 17 mmol) in dioxane (80 mL) was added dropwise to thissolution. The precipitate that formed during the dropwise addition wastaken up in a small amount of water. After stirring for 2 h, the water wasevaporated under reduced pressure. A saturated saline solution (200mL) was added to the residue, followed by extraction with ethyl acetate(50 mL). The organic phase was dried over anhydrous MgSO4 andevaporated under reduced pressure to give 5 as a yellow viscous oil(yield 2.7 g, 12 mmol, 71% yield). MALDI-TOF-MS (positive mode,α-CHCA) m/z = 217.73 (calculated value of C10H23N3O2 + H+ =218.32) (Fig. S5); 1H NMR (500 MHz, CDCl3): δ = 1.44 (9H, s, t-Bu), 1.96(2H, s, NH2CH2), 2.22 (3H, s, CH2N(CH3)CH2), 2.43 (4H, m,NH2CH2CH2N(CH3)CH2CH2NHCO), 2.77 (2H, t, J = 6.0 Hz, NH2CH2),3.20 (2H, d, J = 5.4 Hz, CH2NHCO), and 5.12 (1H, br, CH2NHCO) ppm(Fig. S6). HRMS (EI+) m/z [M]+ Calcd for C10H24N3O2 218.18685,found 218.18729.
 

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