Boc-NH-PEG2-CH2COOH | Aliphatic Chain Hydrocarbons

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Quality Control of [ 108466-89-3 ] Purity: 97% SDS Specification

COA

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CNMR

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Product Citations

PROTACs Targeting MLKL Protect Cells from Necroptosis

Rathje, Oliver H. ; Perryman, Lara ; Payne, Richard J. ; Hamprecht, Dieter W. ;

DOI: 10.1021/acs.jmedchem.3c00665 PubMed ID: 37535857 JMC,2023,66(16):11216-11236.

Abstract: Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chem. means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC mol. that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quant. relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.

Purchased from AmBeed: 30100-16-4 ; 4530-20-5 ; 1703808-53-0 ; 2840-26-8 ; 234081-98-2 ; 108466-89-3 ; 1005342-46-0 ; 154775-43-6 ; 214360-73-3 ; 31108-57-3 ; 57294-38-9 ; 234081-98-2 ; 73183-34-3 ; 462100-06-7 ; 187389-52-2 ; 191732-72-6 ; 173405-78-2 ; 154590-35-9 ; 6404-29-1 ; 1807518-63-3 ; 62595-74-8 ; 77383-17-6 ; 1310949-97-3 ; 138563-69-6 ; 138563-68-5 ; 2704620-74-4 ; 2284453-73-0 ; 191732-72-6 ; 181073-79-0

Product Details of [ 108466-89-3 ]

CAS No. :	108466-89-3
Formula :	C₁₁H₂₁NO₆
M.W :	263.29
SMILES Code :	CC(C)(C)OC(NCCOCCOCC(O)=O)=O
MDL No. :	MFCD17019374
InChI Key :	OMBVJVWVXRNDSL-UHFFFAOYSA-N
Pubchem ID :	2755940

Safety of [ 108466-89-3 ]

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

Computational Chemistry of [ 108466-89-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	0
Fraction Csp3	0.82
Num. rotatable bonds	11
Num. H-bond acceptors	6.0
Num. H-bond donors	2.0
Molar Refractivity	63.45
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	94.09 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.4
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	0.23
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.63
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.	-0.19
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	0.46
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.71

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.89
Solubility	33.8 mg/ml ; 0.128 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.77
Solubility	4.52 mg/ml ; 0.0171 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-1.71
Solubility	5.1 mg/ml ; 0.0194 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.	-7.74 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	1.0
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.	0.56

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)	2.95

Application In Synthesis of [ 108466-89-3 ]

* 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 [ 108466-89-3 ]

[ 108466-89-3 ] Synthesis Path-Downstream 1~35

1
[ 6066-82-6 ]
[ 108466-89-3 ]
[ 911102-04-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;	To a round bottom flask were added acid 33 (640 mg, 2.43 mmol), N- hydroxysuccinimide (419 mg, 3.64 mmol), DMAP (30 mg, 0.25 mmol), and 10 mL CH2CI2 under N2. The mixture was cooled down to 0 C and then a solution of DCC (752 mg, 3.64 mmol) in 10 mL CH2CI2 was added dropwise. The mixture was allowed to warm up to room temperature slowly overnight (16 h). Lots of white precipitates formed during the reaction. The precipitates were filtered off and the filtrate was washed with 20 mL 0.05 N HCl(aq) twice. The organic layer was dried with Na2S04 and concentrated under vacuum. The residue was dispersed in 20 mL EtOAc, and the insoluble precipitates were filtered off. The filtrate was concentrated to give T2 as a colorless oil (840 mg, 96%). NMR (400 MHz, CDCL): d 4.99 (s, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 4H), 3.54 (t, J= 5.2 Hz, 2H), 3.32 (br q, J= 5.2 Hz, 2H), 2.86 (s, 4H), 1.44 (m, 9H).
91%	With diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 2h;	Boc-AEEA-OH (26.4 g, 100 mmol) and HOSu (12.6 g, 110 mmol) were dissolved in 200 ml tetrahydrofuran. DIC (13.9 g, 110 mmol) was added dropwise under a condition of ice bath, and the reaction was continued at room temperature for 2 h after the dropwise addition. TLC showed that the reaction of the raw materials was completed. A vacuum concentration was performed, and the residue was recrystallized with EA to obtain 33.0 g of Boc-AEEA-OSu with yield: 91%, purity: 96.7%, MS: 361.4 (M+1).

References: [1]Patent: WO2019/140270,2019,A1 .Location in patent: Paragraph 0098.
[2]Patent: US2018/370904,2018,A1 .Location in patent: Paragraph 0026.
[3]Angewandte Chemie - International Edition,2006,vol. 45,p. 4936 - 4940.

2
[ 305-53-3 ]
[ 139115-91-6 ]
[ 108466-89-3 ]

References: [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 4936 - 4940.

3
[ 24424-99-5 ]
[ 108466-89-3 ]

References: [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 4936 - 4940.
[2]Patent: CN107670050,2018,A .
[3]Patent: CN107670048,2018,A .
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1030 - 1034.
[5]Patent: CN110041219,2019,A .

4
[ 108466-89-3 ]
2-[2-(2-amino-ethoxy)-ethoxy]-<i>N</i>-{2-[2-(6-chloro-hexyloxy)-ethoxy]-ethyl}-acetamide [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 4936 - 4940.

5
[ 108466-89-3 ]
[ 920264-36-4 ]

References: [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 4936 - 4940.

6
[ 139115-91-6 ]
[ 108466-89-3 ]

References: [1]Organic Preparations and Procedures International,2002,vol. 34,p. 326 - 331.
[2]Patent: CN107670050,2018,A .
[3]Patent: CN107670048,2018,A .
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 1030 - 1034.
[5]Patent: CN110041219,2019,A .

7
[ 108466-89-3 ]
Acetic acid (2R,3S,4R,5R,6S)-3-acetoxy-2-acetoxymethyl-5-acetylamino-6-[4-({2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-acetylamino}-methyl)-phenoxy]-tetrahydro-pyran-4-yl ester [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,2001,vol. 343,p. 675 - 681.

8
[ 108466-89-3 ]
Acetic acid (2R,3S,4R,5R,6S)-3-acetoxy-2-acetoxymethyl-5-acetylamino-6-[4-({2-[2-(2-amino-ethoxy)-ethoxy]-acetylamino}-methyl)-phenoxy]-tetrahydro-pyran-4-yl ester; hydrochloride [ No CAS ]

References: [1]Advanced Synthesis and Catalysis,2001,vol. 343,p. 675 - 681.

Yield	Reaction Conditions	Operation in experiment
		Synthesis of 8-tert-butyloxycarbonylamino-3,6-dioxaoctanoic acid (7) This compound was prepared in 83percent overall yield (4.3 g) as a thick yellow oil from 8-chloro-3,6-dioxaoctan-1-ol (3.35 g, 20.0 mmol) using Boc-carbonate (4.36 g, 20 mmol) in place of Fmoc-Cl in the procedure described above. 1H NMR (CDCl3) delta 4.18 (s, 2H), 4.2 (s, 2H), 3.34-3.77 (m, 8H), 1.5 (s, 9H). ESI-MS 264.1 (M+H+) (Calcd. 263.1).

10
[ 24424-99-5 ]
[ 134978-97-5 ]
[ 108466-89-3 ]

Yield	Reaction Conditions	Operation in experiment
62.1%	With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 12h;	Step 3a: To a stirred solution of compound 1a (5.0 g, 30.6 mmol) in 1,4-Dioxane (50 mL), Sodium carbonate (8.12 g, 76.5 mmol, dissolved in 10 mL water) and (Boc)2O (9.98 mL, 45.7 mmol) were added and stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. The reaction mass was partitioned between diethyl ether and water. Then aqueous layer was made acidic (pH=3) by 3N HCl solution and was extracted with DCM (2×200 mL). Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to yield 50 g of pure 3a (Yield: 62.1%). LCMS: 263.0 (M+H)+
62.1%	With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 12h;	To a stirred solution of compound la (5.0 g, 30.6 mmol) in 1,4-Dioxane (50 mL), Sodium carbonate (8.12 g, 76.5 mmol, dissolved in 10 mL water) and (Boc)20 (9.98 mL, 45.7 mmol) were added and stirred at room temperature for 12 h. The progress ofreaction was monitored by TLC. The reaction mass was partitioned between diethyl ether and water. Then aqueous layer was made acidic (pH = 3) by 3N HC1 solution and was extracted with DCM (2 x 200 mL). Organic layer was washed with water, brine, dried over Na2504 and evaporated under reduced pressure to yield 50 g of pure 3a (Yield:62.1%). LCMS: 263.0 (M+H).

References: [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3065 - 3078.
[2]Patent: US2015/73042,2015,A1 .Location in patent: Paragraph 0150; 0151.
[3]Patent: WO2015/33303,2015,A1 .Location in patent: Page/Page column 26; 27.

11
(2-(2-aminoethoxy)ethoxy)acetic acid methyl ester [ No CAS ]
[ 108466-89-3 ]
[ 1100909-84-9 ]

References: [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3065 - 3078.

12
[ 707542-11-8 ]
[ 108466-89-3 ]
[ 1154625-12-3 ]

References: [1]Journal of the American Chemical Society,2009,vol. 131,p. 6686 - 6688.

13
boc-Gly-Merrifield resin [ No CAS ]
[ 15761-39-4 ]
[ 13734-41-3 ]
[ 13836-37-8 ]
[ 54613-99-9 ]
[ 81-88-9 ]
[ 108466-89-3 ]
[ 1229593-79-6 ]

References: [1]European Journal of Organic Chemistry,2010,p. 2441 - 2444.

14
C₁₁₇H₁₄₀Cl₄N₂₇O₂₃PolS [ No CAS ]
[ 108466-89-3 ]
C₁₂₈H₁₅₉Cl₄N₂₈O₂₈PolS [ No CAS ]

References: [1]European Journal of Organic Chemistry,2010,p. 2441 - 2444.

15
C₃₆H₄₅N₃O₁₀*H⁽¹⁺⁾ [ No CAS ]
[ 108466-89-3 ]
[ 1246261-24-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of Lys-Urea-Glu (0.103 g, 0.121 mmol, Banerjee et al J Med.Chem., vol. 51, pp. 4507-4517, 2008) in DMF (2 mL) was added Boc-NH-PEG-COOH (0.060 g, 0.135 mmol) and TBTU (0.04Og, 0.125 mmol), followed by W-diisopropylethylamine (0.042 mL, 0.241 mmol). After stirring overnight at room temperature, the solvent was evaporated on a rotary evaporator. The crude material was purified by a silica column using methanol/methylene chloride (5:95) to afford 0.101 g (0.109 mmol, 90percent) of YC-VI-53, which was dissolved in a solution of 3percent anisole in TFA (1 mL). The mixture was reacted at room temperature for 10 min, then concentrated on a rotary evaporator. The crude material was purified by HPLC (Econosphere Cl 8 1Ou, 250 x 10 mm, H2O/CH3CN/TFA (92/8/0.1), 4 mL/min, Compound YC-VI-54 eluting at 11 min) to afford 0.035 g (57percent) of compound YC-VI- 54. 1H NMR (400 MHz, D2O) 54.17-4.21 (m, IH), 4.10-4.13 (m, IH), 4.00 (s, 2H), 3.67-3.71 (m, 6H), 3.14-3.20 (m, 4H), 2.43-2.46 (m, 2H), 2.08-2.13 (m, IH), 1.87-1.93 (m, IH), 1.76-1.79 (m, IH), 1.63-1.67 (m, IH), 1.45-1.50 (m, 2H), 1.33-1.40 (m, 2H). ESI-Mass calcd for Ci8H33N4Oi0 [M]+ 465.2, found 465.2.

References: [1]Patent: WO2010/108125,2010,A2 .Location in patent: Page/Page column 75-76.

16
[ 501-53-1 ]
[ 108466-89-3 ]
[ 1254054-91-5 ]

References: [1]Organic and Biomolecular Chemistry,2010,vol. 8,p. 4329 - 4345.

17
[ 108466-89-3 ]
[ 1207457-31-5 ]

References: [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662.

18
[ 108466-89-3 ]
[ 1207457-32-6 ]

References: [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662.

19
[ 108466-89-3 ]
[ 1207457-33-7 ]

References: [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662.

20
[ 108466-89-3 ]
[ 543-27-1 ]
C₁₆H₂₉NO₈ [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662.

21
[ 1068148-44-6 ]
[ 108466-89-3 ]
C₄₇H₆₆N₆O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		N-Boc-8-amino-3,6-dioxaoctanoic acid .x. dicyclohexylamine (300 mg) was dissolved in dimethoxyethane (10 mL). The amine was precipitated by addition of 37percent hydrochloric acid (60 muL) and removed by filtration. Removal of the solvent in vacuo yielded a yellow oil (200 mg, 0.76 mmol) which was dissolved in anhydrous DCM (3 mL). CDI (148 mg, 0.91 mmol) was added and the mixture was allowed to stand at rt for 30 min. DCM (15 mL), 30 (478 mg, 0.76 mmol) and NEt3 (77 mg, 105 muL, 0.76 mmol) were added and the mixture was kept under stirring at rt for 20 h. TFA (10 mL) was added, the mixture was allowed to stand at rt for 4 h before it was concentrated under reduced pressure. MeOH (20 mL) was added twice each time followed by evaporation under reduced pressure. Purification by preparative HPLC (isocratic: MeCN/0.1percent aq TFA 32:68, tR = 14 min) afforded the product as a white fluffy, hygroscopic solid (300 mg, 47percent). inlMMLBox +6.2 cm3 g-1 dm-1 (c 0.010 in MeCN/H2O 9:1); IR (neat): 1670, 1635, 1515, 1495, 1200, 1130 cm-1; 1H NMR (300 MHz, DMSO-d6): delta (ppm) 1.32-1.61 (m, 3H), 1.68 (m, 1H), 2.98 (m, 2H), 3.25 (m, 2H), 3.61 (m, 4H), 3.71 (m, 2H), 4.1 (dd, 1H, 2J = 15.4 Hz, 3J = 6.1 Hz), 4.18 (dd, 1H, 2J = 15.4 Hz, 3J = 6.2 Hz), 4.23 (s, 2H), 4.33 (m, 1H), 5.13 (s, 1H), 6.67 (m, 2H), 7.0 (m, 2H), 7.18-7.33 (m, 10H), 7.8 (br s, 3H), 8.39 (t, 1H, 3J = 5.8 Hz), 8.51 (d, 1H, 3J = 8.1 Hz), 8.81 (s, 2H), 9.12 (m, 1H), 9.32 (s, 1H), 10.98 (s, 1H); 13C NMR (150 MHz, MeOH-d4): delta (ppm) 25.4, 30.2, 40.6, 42.0, 43.7, 54.3, 58.7, 67.9, 71.1, 71.3, 72.1, 116.3, 117.3 (TFA), 119.2 (TFA), 128.1, 128.2, 129.49, 129.52, 129.8, 129.9, 130.0, 130.3, 140.8, 140.9, 154.7, 157.8, 162.7 (TFA), 163.0 (TFA), 163.2 (TFA), 163.4 (TFA), 173.3, 174.0, 174.9; MS (ES, acetonitrile/TFA): m/z 310 [M+2H]2+, 619 [M+H]+; HRMS: (LSI-MS): m/z [M+H]+ calcd for inlMMLBox: 619.3244, found: 619.3257; C33H42N6O6 .x. C4H2F6O4 (846.8).

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2859 - 2878.

22
[ 560088-79-1 ]
[ 108466-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,2-dimethoxyethane; water;	N-Boc-8-amino-3,6-dioxaoctanoic acid × dicyclohexylamine (300 mg) was dissolved in dimethoxyethane (10 mL). The amine was precipitated by addition of 37% hydrochloric acid (?60 muL) and removed by filtration. Removal of the solvent in vacuo yielded a yellow oil (200 mg, 0.76 mmol) which was dissolved in anhydrous DCM (3 mL). CDI (148 mg, 0.91 mmol) was added and the mixture was allowed to stand at rt for 30 min. DCM (15 mL), 30 (478 mg, 0.76 mmol) and NEt3 (77 mg, 105 muL, 0.76 mmol) were added and the mixture was kept under stirring at rt for 20 h. TFA (10 mL) was added, the mixture was allowed to stand at rt for 4 h before it was concentrated under reduced pressure. MeOH (20 mL) was added twice each time followed by evaporation under reduced pressure. Purification by preparative HPLC (isocratic: MeCN/0.1% aq TFA 32:68, tR = 14 min) afforded the product as a white fluffy, hygroscopic solid (300 mg, 47%). inlMMLBox +6.2 cm3 g-1 dm-1 (c 0.010 in MeCN/H2O 9:1); IR (neat): 1670, 1635, 1515, 1495, 1200, 1130 cm-1; 1H NMR (300 MHz, DMSO-d6): delta (ppm) 1.32-1.61 (m, 3H), 1.68 (m, 1H), 2.98 (m, 2H), 3.25 (m, 2H), 3.61 (m, 4H), 3.71 (m, 2H), 4.1 (dd, 1H, 2J = 15.4 Hz, 3J = 6.1 Hz), 4.18 (dd, 1H, 2J = 15.4 Hz, 3J = 6.2 Hz), 4.23 (s, 2H), 4.33 (m, 1H), 5.13 (s, 1H), 6.67 (m, 2H), 7.0 (m, 2H), 7.18-7.33 (m, 10H), 7.8 (br s, 3H), 8.39 (t, 1H, 3J = 5.8 Hz), 8.51 (d, 1H, 3J = 8.1 Hz), 8.81 (s, 2H), 9.12 (m, 1H), 9.32 (s, 1H), 10.98 (s, 1H); 13C NMR (150 MHz, MeOH-d4): delta (ppm) 25.4, 30.2, 40.6, 42.0, 43.7, 54.3, 58.7, 67.9, 71.1, 71.3, 72.1, 116.3, 117.3 (TFA), 119.2 (TFA), 128.1, 128.2, 129.49, 129.52, 129.8, 129.9, 130.0, 130.3, 140.8, 140.9, 154.7, 157.8, 162.7 (TFA), 163.0 (TFA), 163.2 (TFA), 163.4 (TFA), 173.3, 174.0, 174.9; MS (ES, acetonitrile/TFA): m/z 310 [M+2H]2+, 619 [M+H]+; HRMS: (LSI-MS): m/z [M+H]+ calcd for inlMMLBox: 619.3244, found: 619.3257; C33H42N6O6 × C4H2F6O4 (846.8).

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2859 - 2878.
[2]Journal of the American Chemical Society,2017,vol. 139,p. 16822 - 16829.
[3]MedChemComm,2019,vol. 10,p. 974 - 984.

23
[ 108466-89-3 ]
(R)-Nω-(8-amino-3,6-dioxaoctanoyl)-Nα-(2,2-diphenylacetyl)-N-(4-hydroxybenzyl)argininamide bis(hydrotrifluoroacetate) [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2859 - 2878.

24
[ 108466-89-3 ]
[ 1310327-56-0 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2859 - 2878.

25
[ 108466-89-3 ]
[ 1310327-62-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2859 - 2878.

26
[ 108466-89-3 ]
[ 1351946-91-2 ]
[ 1351946-96-7 ]

Yield	Reaction Conditions	Operation in experiment
28%		Preparation 18tert-butyl [2-(2-{2-[(3-{5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}propyl)amino]-2-oxoethoxy}ethoxy)ethyl]carbamateThe title compound was prepared by the general method described above for preparation 13, using [2-(2-tert-Butoxycarbonylamino-ethoxy)-ethoxy]-acetic acid (prepared as described in Angew. Chemie Int. Ed. (2006), 45(30), 4936-4940) instead of trans-4-tert-butoxycarbonyl-cyclohexane carboxylic acid, to yield a colourless gum (60 mg, 28percent).1H NMR (400 MHz, CDCl3) delta=1.42 (s, 9H), 1.67-1.98 (m, 7H), 2.14-2.23 (m, 4H), 2.27-2.33 (q, H), 2.64-2.68 (m, 2H), 3.04-3.09 (t, H), 3.21-3.26 (m, H), 3.29-3.37 (m, 3H), 3.53-3.56 (t, 2H), 3.62-3.68 (m, 4H), 3.98 (s, 2H), 4.99 (brm, H), 6.88 (brm, H), 7.53 (t, H), 8.33 (d, H), 8.35 (d, H).MS, m/z=465 ES+ [M+H]+, 465 Cl [M+H]+

References: [1]Patent: US2011/300174,2011,A1 .

27
[ 108466-89-3 ]
[ 1351947-14-2 ]
[ 1351947-13-1 ]

Yield	Reaction Conditions	Operation in experiment
43%		Preparation 36tert-butyl {2-[2-(2-[2-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}oxy)ethyl]amino}-2-oxoethoxy)ethoxy]ethyl}carbamateThe title compound was prepared by the general method described above for preparation 35, using [2-(2-tert-Butoxycarbonylamino-ethoxy)-ethoxy]-acetic acid (prepared as described in Angew. Chemie Int. Ed. (2006), 45(30), 4936-4940) instead of trans-4-tert-butoxycarbonyl-cyclohexane carboxylic acid, to yield a pale yellow gum (50 mg, 43percent).1H NMR (400 MHz, CDCl3) delta=1.41 (s, 9H), 1.72-1.81 (m, 1H), 1.84-2.01 (m, 2H), 2.18 (s, 3H), 2.21-2.30 (m, 1H), 2.33-2.40 (q, 1H), 3.16-3.26 (m, 4H), 3.50-3.52 (t, 2H), 3.62-3.69 (m, 6H), 4.01 (s, 2H), 4.16-4.19 (t, 2H), 7.44-7.45 (m, 1H), 8.10 (d, 1H), 8.15-8.16 (d, 1H).MS m/z=467 ES+ [M+H]+, 467 Cl [M+H]+

References: [1]Patent: US2011/300174,2011,A1 .

28
2-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)ethanamine 2,2,2-trifluoroacetate [ No CAS ]
[ 108466-89-3 ]
[ 1365253-82-2 ]