28170-07-2|Benzyl phenyl carbonate| Ambeed

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Quality Control of [ 28170-07-2 ] Purity: 95% SDS Specification

COA

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NMR

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Product Details of [ 28170-07-2 ]

CAS No. :	28170-07-2
Formula :	C₁₄H₁₂O₃
M.W :	228.24
SMILES Code :	O=C(OCC1=CC=CC=C1)OC1=CC=CC=C1
MDL No. :	MFCD07784341
InChI Key :	SNGLYCMNDNOLOF-UHFFFAOYSA-N
Pubchem ID :	11183772

Safety of [ 28170-07-2 ]

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

Computational Chemistry of [ 28170-07-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	12
Fraction Csp3	0.07
Num. rotatable bonds	5
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	63.9
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.53 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.56
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	3.57
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.25
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.	2.94
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	2.81
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.02

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.7
Solubility	0.0459 mg/ml ; 0.000201 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.	-4.0
Solubility	0.0227 mg/ml ; 0.0000996 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	-4.76
Solubility	0.004 mg/ml ; 0.0000175 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	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.	-5.16 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)	2.08

Application In Synthesis of [ 28170-07-2 ]

* 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 [ 28170-07-2 ]

[ 28170-07-2 ] Synthesis Path-Downstream 1~35

1
[ 1885-14-9 ]
[ 100-51-6 ]
[ 28170-07-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With pyridine; In dichloromethane; for 4h;	This compound is a known compound, but it is not commercially available. It was prepared by following a published procedure. (Rich et al., J. Org. Chem., 1978, 43, 3624). To a mixture of benzyl alcohol (freshly distilled, 69.2 g, 0.64 mol), pyridine (64 mL) and CH2Cl2 (115 mL) in a 500 mL 3 -necked flask equipped with a condenser, mechanical stirring and an addition funnel was added phenyl chloroformate (100 g, 0.64 mol) over a period of 1 h. The reaction mixture was stirred for an additional 3 h, and H2O (160 mL) was added. The organic phase was washed with aqueous H2SO4 (2 M; 150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was distilled in vacuum 127-131 C/0.1 mm Hg to give the desired compound as colorless oil, Yield: 108 g (94%) (literature yield: 79%).[0215] 1H NMR (500 MHz, CDCl3, 25 0C): delta 5.37 (s, 2H, CH2), 7.18-7.48 (m, 10 H, ArH). MS (FAB): m/z = 372.1 (MH+).
91%	With pyridine; In dichloromethane; for 1h;	According to: Pittelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15, 2195- 2202.Phenyl chloroformate (54.1 g, 500 mmol) was added dropwise to a mixture of benzyl alcohol (78.3 g, 500 mmol), dichloromethane (90 ml) and pyridine (50 ml) in a 1 l-f lask with condenser and addition funnel. The mixture was stirred for 1 h. Water (125 ml) was added. The phases were separated. The organic phase was washed with dilute sulfuric acid (2 M, 2x125 ml). Brine had to be added in the final wash in order to obtain good separation. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was vacuum destilled to yield a colourless liquid. Yield:104.3 g, 91 % EPO <DP n="71"/>1H-NMR (CDCI3) delta: 7.46-7.17 (2 multiplthetats, 10H), 5.27 (s, 2H)13C- NMR (CDCI3) delta: 152.5, 149.9, 133.5, 128.3, 127.6, 127.5, 127.3, 124.8, 119.8, 69.1
91%	In pyridine; dichloromethane; for 1h;	Benzyl phenyl carbonateAccording to: Pittelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15, 2195- 2202.Phenyl chloroformate (54.1 g, 500 mmol) was added dropwise to a mixture of benzyl alcohol (78.3 g, 500 mmol), dichloromethane (90 ml) and pyridine (50 ml) in a 1 l-f lask with condenser and addition funnel. The mixture was stirred for 1 h. Water (125 ml) was added. EPO <DP n="95"/>The phases were separated. The organic phase was washed with dilute sulfuric acid (2 M, 2x125 ml). Brine had to be added in the final wash in order to obtain good separation. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was vacuum destilled to yield a colourless liquid. Yield:104.3 g, 91 %1H-NMR (CDCI3) delta: 7.46-7.17 (2 multiplets, 10H), 5.27 (s, 2H)13C- NMR (CDCI3) delta: 152.5, 149.9, 133.5, 128.3, 127.6, 127.5, 127.3, 124.8, 119.8, 69.1

82%	With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	In a single-necked flask, benzyl alcohol 38 and triethylamine (1.1 eq) were added and dissolved in dichloromethane with stirring.Phenyl chloroformate 39 (1.0 eq) was weighed and slowly dropped at 0 C. After the addition was complete, stir at room temperature for 18h. The reaction solution was washed with water and dilute hydrochloric acid, and the pH was adjusted to 8 with NaHCO3. The organic phase was dried by adding anhydrous sodium sulfate.Filter and concentrate the filtrate to dryness to obtain the crude product. The crude product was passed through a silica gel column to obtain a transparent oily substance 40 with a yield of about 82%
62%	With triethylamine; In dichloromethane; at 0 - 20℃;	General procedure: The alcohol, thiol, or amine starting material (1.0 equiv.) was combined with the phenyl chloroformate reagent (1.0 equiv.) in anhydrous CH2Cl2 (15mL) at 0C, followed by the addition of base (1.0 equiv.). The resultant solution was stirred at 0C for 20 min, after which the ice bath was removed, and the reaction mixture was stirred at r.t. until the completion of the reaction as indicated by TLC. The reaction was quenched by adding brine (30mL), and the aqueous solution was extracted with ethyl acetate (3×15 mL). The organic layers were combined, dried over MgSO4, and evaporated under vacuum. The crude products from each reaction were purified by column chromatography.

References: [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 2675 - 2685.
[2]Organic Letters,2008,vol. 10,p. 1979 - 1982.
[3]Patent: WO2008/63721,2008,A2 .Location in patent: Page/Page column 82.
[4]Organic Letters,2018,vol. 20,p. 5938 - 5941.
[5]Patent: WO2006/79641,2006,A2 .Location in patent: Page/Page column 68-69.
[6]Patent: WO2006/87354,2006,A2 .Location in patent: Page/Page column 93-94.
[7]Patent: CN110283223,2019,A .Location in patent: Paragraph 0162-0165.
[8]Synthesis,2002,p. 2195 - 2202.
[9]Biochemical Pharmacology,2018,vol. 149,p. 124 - 130.
[10]Bulletin de la Societe Chimique de France,1899,vol. <3> 21,p. 828.
[11]Journal of the American Chemical Society,2010,vol. 132,p. 15167 - 15169.

2
[ 56-87-1 ]
[ 28170-07-2 ]
[ 1155-64-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1960,vol. 636,p. 117 - 131.

3
[ 28170-07-2 ]
[ 2946-89-6 ]
[ 110-60-1 ]
[ 23441-10-3 ]

References: [1]Journal of the Chemical Society C: Organic,1971,p. 748 - 753.

5
[ 56-18-8 ]
[ 28170-07-2 ]
[ 183249-68-5 ]

References: [1]Synthesis,2002,p. 2195 - 2202.

6
[ 124-09-4 ]
[ 28170-07-2 ]
[ 66095-18-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	In ethanol; at 20℃; for 2h;Reflux;	A mixture of 1,6-diaminohexane 39 (39.15 g, 0.338 mol) and <strong>[28170-07-2]benzyl phenyl carbonate</strong> (35.7 g, 0.156 mol) inethanol (125 ml) was stirred for 2 hours at room temperature and subsequently heated for an additional hour atreflux to achieve full conversion. The reaction mixture was allowed to cool to room temperature, affording awhite precipitate. After removing the precipitate by filtration, the supernatant was evaporated to dryness anddissolved in 330 ml 2 M aqueous HCl. The resulting solution was extracted with dichloromethane (DCM)(2x150 ml). The aqueous phase was subsequently adjusted to pH = 10 with 6 M aqueous NaOH and extractedwith DCM (3x150 ml). All organic phases were combined, dried over Na2SO4, evaporated to dryness, anddissolved in 200 ml diethyl ether. The resulting solution was extracted with 1M aqueous NaOH (3x50 ml), driedover Na2SO4, and evaporated to dryness to afford crude 40. The product was recrystallized from diethyl ether at-18C to afford white crystals (12.0 g, 31 %). 1H NMR (400 MHz, CDCl3): delta 1.03 (br.s, 2H), 1.58-1.14 (m, 8H),2.66 (t, J = 6.9 Hz, 2H), 3.18 (q, J = 6.7 Hz, 2H), 4.83 (br.s, 1H), 5.08 (s, 2H), 7.45 - 7.19 (m, 5H) ppm. 13CNMR (400 MHz, CDCl3): delta 26.63, 26.68, 30.07, 33.83, 41.12, 42.25, 66.67, 128.17, 128.21, 128.61, 136.78,156.51 ppm. RP-LCMS: calc. Mw= 250.2 g/mol, found m/z: 251.3 [M+H]+.Synthesis of

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.
[3]Synlett,2015,vol. 26,p. 2707 - 2713.

7
[ 462-94-2 ]
[ 28170-07-2 ]
[ 69747-36-0 ]

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.

8
[ 124-20-9 ]
[ 28170-07-2 ]
[ 89965-56-0 ]

References: [1]Synthesis,2002,p. 2195 - 2202.

9
[ 71-44-3 ]
[ 28170-07-2 ]
[ 103493-12-5 ]

References: [1]Synthesis,2002,p. 2195 - 2202.

10
[ 28170-07-2 ]
[ 107-15-3 ]
[ 72080-83-2 ]

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.
[3]Organic and Biomolecular Chemistry,2014,vol. 12,p. 2675 - 2685.

11
[ 28170-07-2 ]
[ 78-90-0 ]
[ 84477-88-3 ]

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.

12
[ 28170-07-2 ]
[ 109-76-2 ]
[ 46460-73-5 ]

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.

13
[ 28170-07-2 ]
[ 110-60-1 ]
[ 62146-62-7 ]

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.
[3]Patent: WO2016/27262,2016,A1 .Location in patent: Page/Page column 61; 62.

14
[ 28170-07-2 ]
[ 111-40-0 ]
[ 160256-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 20h;	According to: Pittelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15, 2195-2202.Benzyl phenylcarbonate (25,1 g, 1 10 mmol) was added dropwise to a solution of diethyl- enetriamine (5,16 g, 50 mmol) in dichloromethane (100 ml). The mixture was stirred for at least 20 h. The organic phase was washed with phosphate buffer (0.025 M K2HPO4, 0.025 MNaH2PO4, 2000 ml, pH adjusted to 3 with 2 M sulfuric acid). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo.Yield: 25.2 g A portion (5 g) of the crude oil was mixed with hydrochloric acid (2 M, 15 ml). The mixture was stirred for 15 minutes. The mixture was filtered. The isolated solid was mixed with abs. ethanol (600 ml). The mixture was brought to reflux. The boiling mixture was decanted in order to remove insoluble impurities. The compound crystallized over night at 5 C.Yield: 2.84 g (white crystals) 1H-NMR (af-DMSO) delta: 8.96 (b, 2H), 7.51 (t, J = 5.56 Hz, 2H), 7.40-7.30 (b, 10H), 5,04 (s,4H), 3.33 (q, J = 6.06 Hz, 4H), 3.00 (b, 4H)13C- NMR (af-DMSO) delta: 156.6, 137.2, 128.7, 128.3, 128.2, 66.0, 46.8, 37.1LC-MS (ES-positive mode), m/z: 372.5 [M+H]+
	In dichloromethane; for 20h;	According to: Pittelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15, 2195-2202.Benzyl phenylcarbonate (25,1 g, 1 10 mmol) was added dropwise to a solution of diethylenetriamine (5,16 g, 50 mmol) in dichloromethane (100 ml). The mixture was stirred for at least 20 h. The organic phase was washed with phosphate buffer (0.025 M K2HPO4,0.025 M NaH2PO4, 2000 ml, pH adjusted to 3 with 2 M sulfuric acid). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo.Yield: 25.2 g A portion (5 g) of the crude oil was mixed with hydrochloric acid (2 M, 15 ml). The mixture was stirred for 15 minutes. The mixture was filtered. The isolated solid was mixed with abs. ethanol (600 ml). The mixture was brought to reflux. The boiling mixture was decanted in order to remove insoluble impurities. The compound crystallized over night at 5 C.Yield: 2.84 g (white crystals) 1H-NMR (af-DMSO) delta: 8.96 (b, 2H), 7.51 (t, J = 5.56 Hz, 2H), 7.40-7.30 (b, 10H), 5,04 (s,4H), 3.33 (q, J = 6.06 Hz, 4H), 3.00 (b, 4H)13C- NMR (Gf-DMSO) delta: 156.6, 137.2, 128.7, 128.3, 128.2, 66.0, 46.8, 37.1LC-MS (ES-positive mode), m/z: 372.5 [M+H]+

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Journal of the American Chemical Society,2010,vol. 132,p. 15167 - 15169.
[3]Patent: WO2006/79641,2006,A2 .Location in patent: Page/Page column 69.
[4]Patent: WO2006/87354,2006,A2 .Location in patent: Page/Page column 94.

15
[ 28170-07-2 ]
[ 811-93-8 ]
[ 156892-82-9 ]

Yield	Reaction Conditions	Operation in experiment
87%		Example 2: Synthesis of compound 22.28 g (10 mmol) benzyl phenylcarbonate was dissolved in 20 ml ethanol and 1.03 ml (10 mmol) 1,2-diamino-l-methylpropane was added dropwise and stirred at RT overnight. The mixture was diluted with 25 ml water and acidified with 1M HC1 until pH < 3 and extracted with DCM. The aqueous phase was basified with 4M NaOH and extracted with DCM. The extract was dried with MgS04 and concentrated in vacuo. This gave 1.93 g (87%) monoprotected diamine. This material was dissolved in 25 ml dioxane, 2.028 g (10.5 mmol) Boc20 and 0.12 g (1 mmol) DMAP were added and the reaction was stirred at RT overnight. The mixture was concentrated in vacuo and purified by column chromatography (Si02, ether/heptane, 1 :0 to 7:3) to give 1.13 g (40%) of diprotected diamine. The diprotected diamine was dissolved in 10 ml dry DMF, 1.1 ml (17.5 mmol) iodomethane was added and the reaction mixture cooled in ice. 0.50 g (10.5 mmol) sodium hydride (60% in oil) was added in portions and stirred in ice for 2 hrs. The mixture was warmed to RT, quenched with 10 ml saturated NH4C1 and 50 ml water, extracted with ethyl acetate, dried with MgS04 and concentrated in vacuo. The product was purified by column chromatography (Si02, DCM/ethyl acetate, 1 :0 to 50:1) to give 0.358 g (29%) of Cbz-protected compound 2. 1H-NMR (300 MHz, CDC13): delta = 1.29 (s, 3H, Me), 1.35 (s, 3H, Me), 1.46 (s, 9H, Boc), 2.82/2.86 (s, 3H, Me, Z/E), 2.93 (s, 3H, Me), 3.72 (s, 2H, CH2N), 5.12 (s, 2H, benzyl), 7.35 (m, 5H, Phe). This material was dissolved in 20 ml methanol, 0.04 g Pd/C was added, the mixture was stirred under hydrogen for 3 hrs, filtered, and the filtrate concentrated. This gave 0.21 g (100%) of compound 2. MS (ESI): m/z = 217.2 (M+H+).

References: [1]Synthesis,2002,p. 2195 - 2202.
[2]Organic Syntheses,2007,vol. 84,p. 209 - 214.
[3]Patent: WO2011/133039,2011,A2 .Location in patent: Page/Page column 205.

16
C₉H₁₀O₅S [ No CAS ]
[ 108-95-2 ]
[ 28170-07-2 ]

References: [1]Journal of Organic Chemistry,2003,vol. 68,p. 5439 - 5444.

17
[ 100-51-6 ]
BocNH-C(=NBoc)-SCH₂-terminated resin [ No CAS ]
[ 28170-07-2 ]

References: [1]Journal of Organic Chemistry,2003,vol. 68,p. 5439 - 5444.

18
[ 4097-89-6 ]
[ 28170-07-2 ]
[ 247170-99-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	In ethanol; at 0 - 20℃;	This is also a known compound, (Jap. Pat. No. 11302243, Takayanagi, Hisao, Mitsubishi Chemical Industries). The patent reported a multi-step synthesis using ethylenediamine as a starting material. We found that compound E-IO can be prepared in a one step reaction under mild conditions:[0212] Benzyl Phenyl Carbonate* (Pittelkow, et al, Synthesis, 2002, 2195) (4.56 g, 20 mmol) was added to a stirring solution of TREN (1.46 g, 10 mmol) in absolute EtOH (50 mL) while cooling with an ice bath. The reaction mixture was stirred over night at room temperature. The volatiles were removed in vacuo, dissolved in minimum amount Of CH2Cl2 and loaded onto a flash silica column; compound E-IO was separated by gradient chromatography with 3-10 % CH3OH + 1% TEA in CH2Cl2. The isolated appropriate fractions were combined and pass through a strong basic alumina plug, and concentrated to afford pure BisZ-TREN as a thick colorless oil at 75 % yield.[0213] 1H NMR (500 MHz, CDCl3, 25 0C): delta 2.48 (t, 2H, J = 5.5Hz, CH2), 2.56 (s,br, 4H, CH2), 2.67 (t, 2H, J = 5.5Hz, CH2), 3.23 (s,br, 4H, CH2), 5.06 (s, 2H, CH2), 5.72 (s, 2H, CbzNH), 7.04 (m, 1OH, ArH). 13C NMR (500 MHz, CDCl3): delta, 38.91,39.35, 53.82, 52.69, 66.28, 127.78, 127.82, 136.58, 156.70. MS (FAB, NBA) C22H30N4O4: [M+H]+ 415.
		Example 1: Synthesis of the Macrocyclic Ligand (4); [0243] A variety of synthetic routes were pursued to obtain derivatized versions of compound 3. Those efforts lead to a method for the synthesis of compound 4. The derivatized building block used in the synthesis of 4 is prepared from lysine and tris(2-aminoethyl)amine (TREN) as outlined in Scheme 1 below.Scheme 1hydrogenation 18 19[0244] Reductive amination of the protected lysine derivative 22 using Z-protected tris(2- aminoethyl)amine (TREN) led to the intermediate 17, which was further derivatized by reaction with a protected aziridine. Removal of the Z-protection groups by hydrogenation afforded the carbonate salt 18, which was transformed into the corresponding free base. The <n="74"/>Boc-protected molecule 19 was then used to prepare compound 4 as outlined in Scheme 2 below.

References: [1]Patent: WO2008/63721,2008,A2 .Location in patent: Page/Page column 81.
[2]Inorganic Chemistry,2010,vol. 49,p. 9928 - 9939.
[3]Journal of the American Chemical Society,2014,vol. 136,p. 9106 - 9115.
[4]Patent: WO2008/92120,2008,A1 .Location in patent: Page/Page column 72-73.

19
[ 28170-07-2 ]
[ 946-80-5 ]

References: [1]Organic Letters,2008,vol. 10,p. 1979 - 1982.

20
[ 1885-14-9 ]
[ 28170-07-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sulfuric acid; benzyl alcohol; In dichloromethane; water;	Synthesis of benzyl phenyl carbonate (Synthesis, 2002, 15, 2195-2202) Benzyl alcohol (10.8 g, 100.0 mol) was dissolved in 100 mL of CH2Cl2. The solution was cooled down to 0 C. and phenyl chloroformate (15.7 g, 100 mol) was slowly added dropwise. The solution was stirred at RT overnight. Addition of 100 mL of H2O was followed by 2* washes with 100 mL of 2M H2SO4 each time. The organic phase was separated off and dried over Na2SO4. The solvent was removed in vacuo to obtain a colorless liquid (22.5 g, 99%). 1H NMR (CDCl3, 300 MHz): delta=7.45-7.31 (m, 6H, CH, aromat.), 7.25-7.14 (m, 4H, CH, aromat.), 5.25 (s, 2H, CH2, benzyl).
	With pyridine; benzyl alcohol; In dichloromethane; water;	Example 30 Benzyl phenyl carbonate According to: Piftelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15, 2195-2202. Phenyl chloroformate (54.1 g, 500 mmol) was added dropwise to a mixture of benzyl alcohol (78.3 g, 500 mmol), dichloromethane (90 ml) and pyridine (50 ml) in a 1 l-flask with condenser and addition funnel. The mixture was stirred for 1 h. Water (125 ml) was added. The phases were separated. The organic phase was washed with dilute sulfuric acid (2 M, 2*125 ml). Brine had to be added in the final wash in order to obtain good separation. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was vacuum destilled to yield a colourless liquid. Yield: 104.3 g, 91% 1H-NMR (CDCl3) delta: 7.46-7.17 (2 multiplets, 10H), 5.27 (s, 2H) 13C-NMR (CDCl3) delta: 152.5, 149.9, 133.5, 128.3, 127.6, 127.5, 127.3, 124.8, 119.8, 69.1

References: [1]Patent: US2013/203960,2013,A1 .Location in patent: Page/Page column.
[2]Patent: US2009/36353,2009,A1 .

21
[ 28170-07-2 ]
[ 169954-67-0 ]

References: [1]Patent: WO2011/133039,2011,A2 .

22
[ 15967-72-3 ]
[ 28170-07-2 ]
[ 400652-46-2 ]
(2-amino-propyl)-carbamic acid benzyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7317 - 7320.

23
[ 15967-72-3 ]
[ 28170-07-2 ]
[ 96-32-2 ]
[ 1350821-72-5 ]
C₁₇H₂₄N₂O₆ [ No CAS ]
C₁₇H₂₄N₂O₆ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7317 - 7320.

24
[ 78-90-0 ]
[ 28170-07-2 ]
(R)-benzyl 1-aminopropan-2-ylcarbamate [ No CAS ]
(2-amino-propyl)-carbamic acid benzyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7317 - 7320.

25
[ 78-90-0 ]
[ 28170-07-2 ]
[ 96-32-2 ]
C₁₄H₂₀N₂O₄ [ No CAS ]
C₁₇H₂₄N₂O₆ [ No CAS ]
C₁₇H₂₄N₂O₆ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7317 - 7320.

26
[ 56-18-8 ]
[ 28170-07-2 ]
[ 122248-80-0 ]
[3-(3-benzyloxycarbonylaminopropylamino)propyl]carbamic acid benzyl ester hydrochloride [ No CAS ]

References: [1]Organic Preparations and Procedures International,2012,vol. 44,p. 397 - 400.

27
[ 28170-07-2 ]
[ 13531-52-7 ]
C₁₃H₂₁N₃O₂ [ No CAS ]
[ 142038-97-9 ]

References: [1]Organic Preparations and Procedures International,2012,vol. 44,p. 397 - 400.

28
[ 28170-07-2 ]
[ 111-40-0 ]
[ 135646-62-7 ]
[2-(2-benzyloxycarbonylaminoethylamino)ethyl]carbamic acid benzyl ester hydrochloride [ No CAS ]

References: [1]Organic Preparations and Procedures International,2012,vol. 44,p. 397 - 400.

29
[ 28170-07-2 ]
[ 20439-47-8 ]
[ 142350-85-4 ]