Improved Synthesis of 10-(2-Alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic Acid Derivatives Bearing Acid-Sensitive Linkers

Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the method is demonstrated by improved syntheses of two known 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamides bearing acid-sensitive ω-tritylthio alkyl chains in much greater yields based on cyclen as the starting material.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Facile synthesis of 1-(acetic acid)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane: a reactive precursor chelating agent

1-(Acetic acid)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DOTA-Tris-^tBu ester or 1) is a precursor chelating agent for lanthanide ions and can be efficiently labeled with various functional moieties or macromolecules to improve the targeting specificity, intracellular delivery, bio-compatibility, and pharmacokinetics of resulting contrast media used in molecular imaging. This compound is commercially available but the extremely high cost seriously limits its wide utilization. Thus, we sought a convenient and inexpensive synthesis of DOTA-Tris-^tBu ester that is readily adapted for use in any laboratory. The synthetic approach described here is straightforward and has an overall yield of 92%. Significantly, the product can be purified conveniently without using of a time- and labor-intensive column chromatography. Other advantages of this method, such as operational convenience, starting material availability, and atom efficiency make it very attractive to prepare DOTA-Tris-^tBu ester in large quantity with a reduced cost.     

4,7,10-三(叔丁氧碳酰甲基)-1,4,7,10-四氮杂环十二烷-1-乙酰肼的微波合成

以轮环藤宁为起始原料,依次与溴乙酸叔丁酯,溴乙酸乙酯和水合肼反应合成了一种核磁共振对比剂螯合前体--4,7,10-三(叔丁氧碳酰甲基)-1,4,7,10-四氮杂环十二烷-1-乙酰肼（4）,其结构经¹H NMR, ¹³C NMR, FT-IR和MS(ESI)表征。研究了溶剂、水合肼用量、微波功率和反应时间对4收率的影响。结果表明：乙醇为溶剂,水合肼10 eq.,于400 W微波反应10 min, 4（粉末固体）收率90%。     

1,4,7,10-N,N,N,N.四(2-(4-(2-乙酰硫基乙氧基)苯氧基)乙基)-1,4,7,10-四氮杂环十二烷的合成研究

以对苄氧基苯酚为原料,经3步反应合成不对称的对苯二酚烷氧基化合物,并以此为原料,合成乙酰硫基修饰的cyclen四取代氢醌醚链化合物.该路线不仅反应条件温和,操作易行,且收率高,克服了文献报道的合成路线重复性差、收率低的缺点.关键中间体及目标化合物经~1H NMR、~(13)C NMR、MS、IR和元素分析表征.     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis-（2-（2,3-difluorophenyl）-ethyl）-1,4,7,10-tetraazacyclododecane

The new compound 1,4,7,10-tetrakis-(2-(2,3-difluorophenyl) ethyl) -1,4,7,10-tetra-zacyclododecane 2 has been synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into diamond crystals grown from CH3CN by slow diffusion at room temperature. It crystallizes in the triclinic system,space group P1 with a = 9.543(2) ,b = 10.507(3) ,c = 10.734(3) ,α = 60.979(3) ,β = 81.870(4) ,γ = 84.279(4) o,V = 931.1(4) 3,Z = 1,Dc = 1.307 g/cm3,C40H44F8N4,Mr = 732.79,F(000) = 384,μ = 0.105 mm-1,T = 296(2) K,MoKa radiation(λ = 0.71073) ,R = 0.0494 and wR = 0.0989 for 1589 observed reflections with I > 2σ(I) . Hydrogen bonds and C-H···π stacking interactions in 2 contribute to a supramolecular structure. Moreover,compound 2 has been determined by 1H NMR,13C NMR,MS,IR spectra and elemental analysis.     

Synthesis and acid-base and complex-forming properties of 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane

Conclusions A new complexone, 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane, has been synthesized and its acid-base and complex-forming properties have been studied. It shows a very high complexing capability and marked selectivity for cations of large ionic radius (Cd²⁺, Hg²⁺, Pb²⁺, La³⁺).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 844–849, April, 1984.     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis （2-（（4-hydroxy）phenoxy）ethyl）-1,4,7,10- tetraazacyclododecane

A novel molecule tetra-N-alkylation of cyclen （1,4,7,10-tetraazacyclododecane）, 1,4,7,10-tetrakis（2-（（4-hydroxy）phenoxy）ethyl）-1,4,7,10-tetraazacyclododecane 2, was synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into chiral helical compound crystals grown from EtOH by slow diffusion at room temperature and three of the four hydroquinone groups of the benzene ring formed a g-electron-rich cavity by C-H…π stacking interaction. The crystal belongs to the monoclinic system, space group P21/C with a = 13.9192（9）, b = 13.2871（6）, c = 22.1894（15）A^°, β = 91.4600（10）°, V = 4102.5（4）A^°3, Z = 4, Dc = 1.219 g/cm^3, C40H52N4O8, Mr = 752.89, F（000） = 1616,μ = 0.088 mm^-1, MoKa radiation （λ = 0.71073）, R = 0.0578 and wR = 0.1389 for 5588 observed reflections with I 〉 2σ（I）. Moreover, compound 2 was characterized with ^1H NMR, ^13C NMR, IR spectra and MS.     

Chelators for radioimmunotherapy: I. NMR and ab initio calculation studies on 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr)

This work describes the modification of the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' "-tetraacetic acid (DOTA) to improve the rate of metal loading for radioimmunotherapy applications. Previous ab initio calculations predicted that the compounds 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr) have a ca. 2000-fold improvement in yttrium metal loading rates compared to those of DOTA (Jang, Y. H.; Blanco, M.; Dasgupta, S.; Keire, D. A.; Shively, J. E.; Goddard, W. A., III. J. Am. Chem. Soc. 1999, 121, 6142-6151). In this study, we report the synthesis, purification, (1)H-NMR chemical shift assignments, pK(a) values, metal loading rate measurements, and additional ab initio calculations of these two compounds. The yttrium loading rates of DO3A1Pr are approximately twice those of DOTA, at pH 4.6 and 37 degrees C. The NMR data indicates that the DO4Pr analogue forms a stable type I complex but does not form a type II complex. The new ab initio calculations performed on DO4Pr and DO3A1Pr indicate that the rate-determining step is the deprotonation of the first macrocycle amine proton, not the second proton as assumed in the previous calculations. The new calculations predict an improvement in the rate of metal loading that more closely matches the experimentally observed change in the rate.     

Rapid synthesis of 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester)

A three-step route was used to synthesize 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester) from 1,4,7,10-tetraazacyclododecane (cyclen). The overall time of reaction was reduced from a combined ∼56 h to 2.3 h with an overall yield comparable to previously reported methods.     

A straightforward and convenient pathway for the synthesis of functional bismacrocyclic ligands

The synthesis of a novel DO3A-based bismacrocyclic ligand is reported. The synthetic pathway involved a series of simple and convenient steps, which can easily provide the desired product in larger quantities than produced in current synthetic procedures. This method enables the facile preparation of binuclear macrocyclic complexes which can be used in MRI, as well as other molecular imaging modalities.     

Effects of Bis(aromatic) Pendants on Recognition of Nucleobase Thymine by Zn2+ -1,4,7,10-tetraazacyclododecane (Zn2+ -cyclen)

We have previously shown that the nucleobase thymine binding to Zn²⁺ -cyclen (cyclen=1,4,7,10-tetraazacyclododecane) complex became stronger by appending acridine, naphthalene, or quinoline rings to the cyclen. Amongst these, the pendant bis((1-naphthyl)methyl) or bis((4-quinolyl)methyl) groups yielded the most effective thymine-recognizing Zn²⁺ -cyclen complexes [J. Am. Chem. Soc., 121 (1999) 5426]. The present study was undertaken to find causes of the bis(aromatic) ring effect by X-ray crystal structure analysis and NMR studies. The crystal structure of the Zn²⁺ -bis((1-naphthyl)methyl)-cyclen complex with a deprotonated 1-methylthymine (1-MeT) failed to show the anticipated evidence for the double ~ - ~ stacking interactions between the two naphthalenes and the Zn 2+ -bound 1-MeT m (1-MeT m =N(3')-deprotonated 1-MeT). Crystal data: formula C₃₆ H₄₇ N₇ O₇ Zn, M r =755.19, monoclinic, space group P2₁/ c (No. 14), a =15.438(2) Å, b =14.093(3) Å, c =16.726(2) Å, g =90.53(1) V =3638.7(8) Å 3 Z =4, R =0.035, R _w =0.049. However, the ¹H NMR studies of Zn²⁼ -bis((4-quinolyl)methyl)-cyclen with 1-MeT in varying H₂O/CH₃ CN solution showed increasing upfield shifts of Me(5') and H(6') of the Zn²⁺ -bound 1-MeT in more aqueous media, indicating that the double intercalation with the two quinolines became more significant in more protic environments. We conclude that the double ~ - ~ stacking effect accounts for the enhanced recognition of thymine base by the appended bis((1-naphthyl)methyl) or bis((4-quinolinyl)methyl) groups.     

Synthesis and structural characterization of new polynuclear complexes of 1-hydroxymethyl-3,5-dimethylpyrazole with Ni(II) and Fe(II)

The complexation of the simple 1-hydroxymethyl-3,5-dimethylpyrazole (HL) ligand with Fe and Ni salts leads to interesting polynuclear complexes in good yield. X-ray diffraction reveals that the resulting complexes (μ₄-L)₄Ni₄Cl₄(H₂O)₄ and (μ₂-L)₄(μ₃-L)₂Fe₈Cl₁₆(μ₄-O)₆ adopt cubane-type and open-cubane-type structures in the solid state.     

Synthesis and crystal structure of a Ni(II)complex with 1,7-diaminoethyl-4,10-dimethyl-1,4,7,10-tetraazacyclododecane

The crystal structure of a. Ni(II) complex with 1,7-diaminoethyl-4,10-dimethyl-1,4,7,10-tetraazacyclododecane has been determined by X-ray diffraction method. Crystal data for NiC14H38Br2N6O: monoclinic, space group P21/n, a=0.8848(3), b=1.4656(3), c=1.5828(3) nm, β=90.47(3)°, V=2.0525 nm3, Z=4. The two pendant primary amino groups are located in cis positions in the complex, "their nitrogen atoms and the four nitrogen donors of the foled tetraaza-macrocycle coordinate Ni(II) ion, forming a distorted octahedral geometry.     

Synthesis,characterization, spectroscopic study,and catalytic behavior of ruthenium(II) o-phenanthroline complex with dipicolinate

A new dipicolinate complex of Ru(II), cis-[Ru(phen)₂dipic]?·?9.5H₂O (1), where dipic is dipicolinate or pyridine-2,6-dicarboxylate and phen is 1,10-phenanthroline, has been synthesized and characterized by elemental analysis, spectroscopic (IR, UV-Vis), cyclic voltammetry, and single-crystal X-ray diffraction. ORTEP drawing of cis-[Ru(phen)₂dipic]?·?9.5H₂O shows that the coordination geometry around Ru(II) is a distorted octahedron. It crystallizes in the triclinic system, with space group P 1, a?=?10.4633(2)?Å, b?=?13.6332(4)?Å, c?=?13.6637(4)?Å, α?=?67.516(3)°, β?=?69.757(2)°, γ?=?77.201(2)°, V?=?1680.74(8)?ų, Z?=?2, and R _int?=?0.0311. In 1, two phen are bidentate N,N′ ligands. The Ru(II) in 1 is bonded to dipicolinate through pyridine nitrogen and one oxygen of carboxylate groups, thus pyridine-2,6-dicarboxylate is a bidentate N,O ligand. Efficient and selective oxidation of alcohols with NaIO₄ as oxidant was conducted by this complex catalyst in CH₃OH/H₂O as solvents under air at room temperature.     

The synthesis and evaluation of trimeric X-ray contrast agents

Novel trimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the aim of improving the already good safety profile of such agents. While the aim of low osmolality was achieved, the viscosity of the trimeric agents was found to be generally higher than current dimeric agents in clinical use.     

Synthesis and Crystal Structure of 2,5—Bis（morpholino）—3,4—bis（p—chlorophenyl）thiophene

1 INTRODUCTION -Thiocarbonylthioformamide synthesized in 1980[1, 2] is a class of stable and almost unexplored compounds[3]. We have reported the reaction of - thiocarbonylthioformamides in our previous paper[4]. Here, we will report a novel synthesis of 2 by the reaction of 1 and trimethyl phosphite in refluxing xylene. In order to determine the structure of 2, X- ray crystallographic study was carried out. 2 EXPERIMENTAL 2. 1 Preparation of the title compound Trimethyl phosph…     

The synthesis and evaluation of unsymmetrical dimeric X-ray contrast agents

Novel dimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the aim of improving the already good safety profile of such agents. The aim of low osmolality was achieved, and the viscosity of these dimeric agents was also found to be beneficially lower than current dimeric agents in clinical use.     

Synthesis and Crystal Structure Determination of 6-(N-Isopropyl)Amidino-2-Methylbenzothiazole Hydrochloride Monohydrate and 2-Amino-6-(N-Isopropyl)Amidinobenzothiazole Hydrochloride

Two novel substituted amidino-benzothiazoles 6-(N-isopropyl)amidino-2-methylbenzothiazole 4 and 2-amino-6-(N-isopropyl)amidinobenzothiazole 6 were prepared in multistep synthesis in form of hydrochloride salts. They were characterized by means of IR, ¹H, and ¹³C-NMR spectroscopy and elemental analysis. The crystal structures have been also determined by X-ray analysis. Both compounds crystallize as colorless prisms in the triclinic crystal system, space group P . Crystal data: (4) a = 8.741(4) Å, b = 9.602(7) Å, c = 9.946(2) Å, = 63.94(3)°, = 79.18(2)°, = 79.68(3)°, V = 732.1(6) ų, Z = R = 0.0396; a = 8.106(1) Å, b = 9.148(2) Å, c = 9.291(2) Å, = 104.83(1)°, = 103.36(2)°, = 90.62(1)°, V = 646.2(2) ų , Z = 2, R = 0.0376. The bond distances and angles in both structures are almost similar. Between these two structures was found the difference in the orientation of the 6-(N-isopropyl)amidino moiety with respect to the benzothiazole ring. In the crystal structures of the both compounds the intermolecular hydrogen bonds form three-dimensional networks.