An Improved Route to the Regioselective Synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane

doi:10.21203/rs.3.rs-2202136/v1

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An Improved Route to the Regioselective Synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane

https://doi.org/10.21203/rs.3.rs-2202136/v1

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1,7-dibenzyl-1,4,7,10-tetraazacyclododecane is a crucial intermediate in the preparation of tetra-armed 1,4,7,10-tetraazacyclododecane (two benzyl groups at N1- and N7- positions and two other aromatic groups at N4- and N10- positions), 1,7-disubstituted-1,4,7,10-tetraazacyclododecane, and DO2A metal chelators, which find widespread use in medicine. Current frequently-used synthesis is costly and involves multi-steps under harsh reaction conditions, delivering low yields. We present a simpler, highly regioselective synthesis of the 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane that operates under mild reaction conditions.

Synthesis

10-tetraazacyclododecane

Catalyst

Ligand

Since it was first synthesized by Stetter and Mayer in the 1960s, 1,4,7,10-tetraazacyclododecane and its derivatives have stimulated continued interest from generations of investigators due to the strong coordination ability with respect to metal cations, including transition metal ions and lanthanide ions[1–3]. The associated metal complexes exhibit enhanced thermodynamic stability and kinetic inertness. 1,4,7,10-tetraazacyclododecane and its derivatives are widely used in medicine[4,5], enzyme modeling[6], as non-viral gene delivery vectors[7], and in metal cation extraction[8].

In the synthesis of symmetric di- or tetra- substituted 1,4,7,10-tetraazacyclododecane derivatives, 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane plays an important role as the benzyl group is readily removed by catalytic hydrogenolysis[9–11]. Catalytic hydrogenolysis of the benzyl group after reaction of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane with tert butyl bromoacetate produces the essential ligand, DO2A-t-Bu ester[12].

Currently, there are four main synthetic routes to 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane.

Synthetic route 1: The protective bridged macrocyclic 1,4,7,10-tetraazacyclododecane is first generated by reacting 1,4,7,10-tetraazacyclododecane with glyoxal (40% wt. %) in methanol at an equimolar ratio, then reacted with excess benzyl bromide in acetonitrile at room temperature for 96 h. A subsequent increase of temperature to 45℃ for 72 h generates 1,7-dibenzyl substituted bridged macrocyclic 1,4,7,10-tetraazacyclododecane, which is deprotected with hydrazine hydrate[13] or 3M solution NaOH[14] or an ethanol solution of hydroxylamine [15], to obtain 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane with high yields. However, the process is lengthy (> 240h) and hydrazine hydrate is highly toxic. Fatima Oukhatar has exploited the transamination of o-diamines in the deprotection process, rendering the deprotection step safer and more efficient[16].

Synthetic route 2: The reaction of 1,4,7,10-tetraazacyclododecane with benzyloxyformyl chloride (cbzcl) generates1,7-dibenzyloxycarbonyl protected 1,4,7,10-tetraazacyclododecane, which reacts with benzyl bromide in acetonitrile, and debenzyloxycarbonyl using 4M HBr in acetic acid to obtain tetrahydrobromide from 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane [17]. This method suffers from such disadvantages as lower yield, the requirement for separation by column chromatography, and the formation of hydrobromide.

Synthetic route 3: 1,4,7,10-tetraazacyclododecane reacts with benzaldehyde to generate imine, and then undergoes NaBH(OAC)₃ reduction to generate 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane. This method delivers low yields[18].

Synthetic route 4: The Cyclization of diethylenetriamine with diethyl 3,3'- iminodipropionate (reaction time 7 days, 32% yield) affords 1,4,7,10-tetraazacycle-2,6-dione (1,4,7,10-tetraazacyclodecane-2,6-dione), followed by reaction with benzaldehyde generates imines. Subsequent reduction using NaBH(OAC)₃ affords 1,7-dibenzyl-1,4,7,10-tetraazacycle-2,6-dione, and additional reduction using diisobutyl aluminum hydride affords 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane [19–21]. This reaction is time-consuming and tedious operation, delivers low yields, and requires hazardous reducing agents.

Taking an overview, the laboratory synthesis of 1,7-dibenzyl1,4,7,10-tetraazacyclododecane requires many, time-consuming, steps and delivers low yields, limiting practical applications.

In a series of experiments to catalyze the hydrogenolysis of 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane using the 10% Pd/C and ammonium formate system, we have observed the selective hydrogenolysis of two benzyl groups (in the para position), which afforded 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane in high yields, under mild experimental conditions in a more efficient (less time-consuming) process.

This method facilitates convenient and efficient synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane, and can serve as a general approach for the synthesis of 1,7-diaryl compounds.

1,7-dibenzyl-1,4,7,10-tetraazacyclododecane (CAS: 156970-79-5) is a crucial intermediate in organic synthesis, notably the production of symmetrical tetrasubstituted 1,4,7,10-tetraazacyclododecane s (two benzyl groups at N¹- and N⁷-positions and two other aromatic groups at N⁴- and N¹⁰-positions), and symmetrical disubstituted 1,4,7,10-tetraazacyclododecane s as the benzyl group is readily removed by catalytic hydrogenolysis. Although several synthetic procedures have been reported in the literature, they exhibit the disadvantages of low yield, use of costly reagents and time-consuming operation, which has limited practical application.

We have employed a 10% Pd/C and ammonium formate system to catalyze hydrogenolysis of 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane, and achieved selective deprotonation of two benzyl groups in the para position, affording 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane with high yield under mild experimental conditions at short operating times.

In order to establish the effect of solvent on deprotection regioselectivity and yield, the reaction was performed in different solvents (Table 1). Although 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane was insoluble in methanol and ethanol under reflux, 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane was obtained in high yield. Given the unsatisfactory results in isopropanol, 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane was dissolved in trifluoroethanol under reflux, and 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane was obtained without the removal of the four benzyl 1,4,7,10-tetraazacyclododecane. From a consideration of price and environmental factors, ethanol was judged the optimal solvent.

Table 1

Effect of solvent on the yield^a,b
Entry	Solvent	Solubility of 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane		Yield(%)
Entry	Solvent	R.T.	REFLUX	Yield(%)
1	CH₃OH	-	-	92
2	CH₃CH₂OH	-	-	98
3	CF₃CH₂OH	-	+	96
4	CH₃CH(OH)CH₃	-	-	N.R.
a.10%Pd/C, The amount of palladium used was 0.75% (wt.%) of the substrate 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane

b.The same results were still obtained when different commercial samples of catalyst (10% Pd/C) were tested.

3.1 Instruments and reagents

Melting points were determined on a Micro melting point instrument (SGWX-4). All reagents were commercially sourced, and used without further purification unless otherwise specified. ¹H and ¹³C NMR spectra were recorded on a Bruker AM-400 spectrometer operated at 400 and 100 MHz for ¹H and ¹³C, respectively. High resolution mass spectra (HR-ESI-MS) were obtained on an Agilent6110 (Agilent Technologies, USA), operated in positive electrospray ionization mode. 10% Pd/C(Shanghai Aladdin Reagent Co., Ltd. Bide Pharmatech Co., Ltd.)

3.2. Synthesis

3.2.1 Synthesis of 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane

1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane (1,4,7,10-tetrabenzylcyclen) was synthesized according to literature procedures[18]. Yield: 76%, mp 144.5-145.7℃. ¹H NMR (400MHz, CDCl₃) δ/ppm: 7.35 (d, 4H, J = 8Hz, Ar-H), 7.25–7.17 (m, 16H, Ar-H), 3.42 (s, 8H, Ph-CH₂-), 2.68 (s, 16H, -NCH₂N-); ¹³C NMR (100MHz, CDCl₃) δ/ppm: 140.05, 128.88, 127.98, 126.49, 60.06, 52.98. HR-ESI-MS (m/z): C₃₆H₄₄N₄ for [M + H]⁺, calculated: 533.3639; Found: 533.3643. Elemental Analysis [C₃₆H₄₄N₄]: C, 81.16; H, 8.32; N, 10.52; Found: C, 81.21; H, 8.25; N, 10.39.

3.2.2 Synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane

To a suspension of 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane (0.53g, 1mmol) in ethanol was added 10%Pd/C (0.1g) and ammonium formate (0.3g, 4.75mmol). After refluxing for 4 h, the reaction mixture was filtered and the filtrate concentrated under vacuum to give the crude product as a yellowish waxy substance. The crude product was dissolved in CH₂Cl₂ (50 mL), the solution washed with saturated sodium bicarbonate (10×2 mL) and saturated sodium chloride solution (10×2 mL), dried (Na₂SO₄), filtered, and the solvent removed under vacuum to get the product as a white fluffy solid, 0.34g, yield: 96.3%, mp 83.4–85.7℃. ¹H NMR (400MHz, CDCl₃) δ/ppm: 7.39–7.24 (m, 10H, Ar-H), 3.61 (s, 4H, Ph-CH₂-), 2.69–2.57 (s, 16H, -NCH₂N-); ¹³C NMR (100MHz, CDCl₃) δ/ppm: 139.19, 129.32, 129.06, 128.40, 127.24, 60.02, 59.33, 51.83, 51.23, 46.29, 45.31. ESI-MS (m/z): C₂₂H₃₂N₄ for [M + H]⁺, calculated: 353.27; found: 353.31. Elemental Analysis [C₂₂H₃₂N₄‧0.25CH₂Cl₂]: C, 71.50; H, 8.77; N, 14.99; Found: C, 71.80; H, 8.77; N, 14.80.

An effective route for the regioselective synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane was developed with a yield of up to 98%. This unique stereoselective reaction was confirmed by ¹H NMR, ¹³C NMR, ESI-MS, and Elemental Analysis. The advantages of this method include ease of operation, low operation times, high yield and low cost, which represent a significant advancement over current synthesis methodologies. Our approach can achieve the efficient synthesis of novel ligands based on 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane, thereby facilitating practical application of this class of compounds.

Acknowledgments

Financial support from the Department of Science & Technology of Shandong Province for Study and Innovation is gratefully acknowledge

Declaration of Competing Interest

The authors affirm that they have no known financial or interpersonal conflicts that would have appeared to have an impact on the research presented in this study.

Ethical Approval

This declaration is “not applicable”

Competing interests

This declaration is “not applicable”

Authors' contributions statement

Xiaoting Zhang: Data curation, Investigation, Writing-original draft. Huirui Li: Data curation, Writing-review and editing. Dehao Kong: Data curation, Writing-review and editing. Fuxian Wan: Conceptualization, Projiect adminstration, Supervision, Writing-review and editing.

Funding

Natural Science Foundation of Shandong Province, China (No. ZR2020MB011) and Shandong Province Technology Development Plan(No. 2013GZX20109).

Availability of data and materials

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Schemes 1 to 5 are available in the Supplementary Files section

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An Improved Route to the Regioselective Synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane

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Abstract

1. Introduction

2. Results And Discussion

3. Experimental

3.1 Instruments and reagents

3.2. Synthesis

3.2.1 Synthesis of 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane

3.2.2 Synthesis of 1,7-dibenzyl-1,4,7,10-tetraazacyclododecane

4. Conclusions

Declarations

References

Schemes

Additional Declarations

Supplementary Files

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