COMPOUNDS FOR CHROMATOGRAPHIC SEPARATION OF RARE EARTH ELEMENTS AND S-, P-, D-METALS, METHOD OF SEPARATION, AND USE THEREOF
20220259119 · 2022-08-18
Assignee
Inventors
Cpc classification
C07F9/6524
CHEMISTRY; METALLURGY
C07B59/00
CHEMISTRY; METALLURGY
C07B2200/05
CHEMISTRY; METALLURGY
C07F9/65583
CHEMISTRY; METALLURGY
C07D401/06
CHEMISTRY; METALLURGY
International classification
C07B59/00
CHEMISTRY; METALLURGY
B01D15/42
PERFORMING OPERATIONS; TRANSPORTING
C07D401/06
CHEMISTRY; METALLURGY
Abstract
##STR00001##
The present invention relates to compounds of general formula (I), wherein —X is selected from a group consisting of H; C.sub.1 to C.sub.6, alkyl; halogen (F, Cl, Br or I); Y is selected from a group consisting of nitrogen; N-oxide; Z.sup.1, Z.sup.2, Z.sup.m, wherein m is 1 or 2, are independently selected from the group consisting of —CH.sub.2—CH.sub.2— and —CH.sub.2—CH.sub.2—CH.sub.24 A, A.sup.m, wherein m is 1 or 2, are independently selected from H; —CH.sub.2COOH; —CH.sub.2C(O)NH.sub.2; —CH.sub.2P(O)(OH).sub.2, and n is 1 or 2; R.sup.1, R.sup.2, R.sup.3 are independently H; C.sub.1 to C.sub.6, alkyl; C.sub.1 to C.sub.6 alkyloxy; C.sub.6 to C.sub.10 aryloxy; benzyloxy; C.sub.1 to C.sub.6 alkylthio; C.sub.6, to C.sub.10 arylthio; F; Cl; Br; I; OH; SH; NH.sub.2; C.sub.1 to C.sub.6, alkylamino; di(C.sub.1 to C.sub.6, alkyl)amino; C.sub.1 to C.sub.6 acylamino; di(C.sub.1 to C.sub.6 acyl) amino; C.sub.6 to C.sub.10 arylamino; di(C.sub.6 to C.sub.10 aryl)amino; CN; OH; nitro; COOR.sub.n, C(O)NHR.sub.n, C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H or C.sub.1 to C.sub.10 alkyl or C.sub.6, to C.sub.10 aryl; and/or neighboring two of R.sup.1, R.sup.2, R.sup.3 together with neighboring two carbon atoms of the aromatic cycle form a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF.sub.3, F, Cl, Br, I, C.sub.1 to C.sub.6, alkyl, C.sub.1to C.sub.6, alkyloxy, C.sub.1 to C.sub.6 alkylthio, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, NO.sub.2, COOH, COOR.sub.n, C(O)NHR.sub.n, C(O)N(R.sub.n).sub.2, wherein R.sub.n is WO 2020/244686 A1 independently H or C.sub.1 to C.sub.10 alkyl or C.sub.6 to C.sub.10 aryl; with the proviso that when n is 2 and all of Z.sup.1, Z.sup.2, Z.sup.m are —CH.sub.2—CH.sub.2—, then A is not —CH.sub.2COOH; for chromatographic separation of rare earth elements and/or s-, p- and d-block metals, as well as to the method of the separation of rare earth elements.
Claims
1-9. (canceled)
10. A method of chromatographic separation comprising: providing a mixture of at least one metal ion selected from Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, Y, alkaline earth metals, Al, Ga, In, Tl, Sn, Pb, Bi and transitional metals, and at least one further metal ion, wherein said further metal ion is selected from rare earth metal ions, transition metal ions, non-transition metal ions, and actinide ions, contacting the mixture with at least one compound of general formula (I) to form a chelates; applying the chelates to a chromatographic column; and, eluting from the chromatographic column a chelate of the at least one metal ion and a chelate of the at least one further metal ion; wherein: formula (I) is: ##STR00019## X is H, C.sub.1 to C.sub.6 alkyl, F, Cl, Br or I; Y is N or N-oxide; Z.sup.1, Z.sup.2, and Z.sup.m, wherein m is 1 or 2, are —CH.sub.2—CH.sub.2— or —CH.sub.2—CH.sub.2—CH.sub.2—; A and A.sup.m, wherein m is 1 or 2, are independently H, —CH.sub.2COOH, —CH.sub.2C(O)NH.sub.2; —CH.sub.2P(O)(OH).sub.2, or ##STR00020## n is 1 or 2; R.sup.2, and R.sup.3 are independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.6 to C.sub.10 aryloxy, benzyloxy, C.sub.1 to C.sub.6 alkylthio, C.sub.6 to C.sub.10 arylthio, F, Cl, Br, I, OH, SH, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, C.sub.1 to C.sub.6 acylamino, di(C.sub.1 to C.sub.6 acyl)amino, C.sub.6 to C.sub.10 arylamino, di(C.sub.6 to C.sub.10 aryl)amino, CN, OH, nitro, COOR.sub.n, C(O)NHR.sub.n, or C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H, C.sub.1 to C.sub.10 alkyl, or C.sub.6 to C.sub.10 aryl; and/or wherein any neighboring two of R.sup.1, R.sup.2, and R.sup.3 together with any neighboring two carbon atoms of the aromatic cycle form a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF.sub.3, F, Cl, Br, I, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.1 to C.sub.6 alkylthio, NH, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, NO.sub.2, COOH, COOR.sub.n, C(O)NHR.sub.n, or C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H, C.sub.1 to C.sub.10 alkyl, C.sub.6 to C.sub.10 aryl; with the proviso that when n is 2 and all of Z.sup.1, Z.sup.2, Z.sup.m are —CH.sub.2—CH.sub.2—, then A is not —CH.sub.2COOH.
11. The method of claim 10, wherein the at least one metal ion comprises Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, and Y, and the at least one further metal ion is selected from rare earth metal ions, transition metal ions, non-transition metal ions and actinide ions.
12-15. (canceled)
16. The method of claim 10 further comprising, repeating the applying and eluting steps to further separate the at least one metal ion.
17. The method of claim 10 further comprising decomplexing with acid the chelate of the metal ion to obtain the metal ion.
18. The method of claim 10, wherein the at least one metal ion is Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, or Y.
19. The method of claim 18, wherein the at least one further metal ion is different from the at least one metal ion and is Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, or Y.
20. The method of claim 10, wherein the at least one metal ion and the at least one further metal ion are s-, p- and d-block metals, selected from groups II.A, III.A, IV.A, V.A, I.B, II.B, and VIII.B metal.
21. The method of claim 20, wherein the at least one metal ion and the at least one further metal ion are different and are Ca.sup.2+, Fe.sup.2+, Fe.sup.3+, Co.sup.2+, Ni.sup.2+, Cu.sup.2+, Zn.sup.2+, Al.sup.3+, Pb.sup.2+, or Bi.sup.3+.
22. The method of claim 10, wherein X is H, —CH.sub.3, or Cl.
23. The method of claim 10, wherein R.sup.1, R.sup.2, and R.sup.3 are independently H, C.sub.1 to C.sub.6 alkyl, and/or neighboring two of R.sup.2, R.sup.3 together with neighboring two carbon atoms of the aromatic cycle form a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF.sub.3, F, Cl, Br, I, to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.1 to C.sub.6 alkylthio, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, NO.sub.2, COOH, COOR.sub.n, C(O)NHR.sub.n, and C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H or C.sub.1 to C.sub.10 alkyl or C.sub.6 to C.sub.10 aryl.
24. The method of claim 10, wherein at most one of A and A.sup.m is H.
25. The method of claim 10, wherein X is —CH.sub.3 or Cl, Y is N, and all of R.sup.2, and R.sup.3 are H.
26. The method of claim 10, wherein X is H, Y is N-oxide, and two of R.sup.1, R.sup.2, and R.sup.3 together with neighboring two carbon atoms of the aromatic cycle form a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF.sub.3, F, Cl, Br, I, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.1 to C.sub.6 alkylthio, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, NO.sub.2, COOH, COOR.sub.n, C(O)NHR.sub.n, and C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H or C.sub.1 to C.sub.10 alkyl or C.sub.6 to C.sub.10 aryl.
27. The method of claim 10, wherein the compound represented by formula (I) is: 1-((4,7-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2 oxide; 1-((4-(2-amino-2-oxoethyl)-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; 1-((4,10-bis(2-amino-2-oxoethyl)-7-(phosphonomethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; 1,1′-((7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4 diyl)bis(methylene))bis(isoquinoline 2-oxide); 1-((1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-4-yl)methyl)isoquinoline 2-oxide; 1-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-1-yl)methyl)isoquinoline 2-oxide; 1-((4,8,11-tris(carboxymethyl)-1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)isoquinoline 2-oxide; 2,2′,2″-(11-((6-chloropyridin-2-yl)methyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-triyl)triacetic acid; 2,2′,2″-(11-((6-methylpyridin-2-yl)methyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-triyl)triacetic acid; 1-((4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)methyl)isoquinoline 2-oxide; 1-((5,9-bis(carboxymethyl)-1,5,9-triazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; or 1-((4,8,12-tris(carboxymethyl)-1,4,8,12-tetraazacyclopentadecan-1-yl)methyl)isoquinoline 2-oxide.
28. A compound represented by formula (Ia), ##STR00021## X is H, C.sub.1 to C.sub.6 alkyl, F, Cl, Br or I; Y is N or N-oxide; Z.sup.1, Z.sup.2, and Z.sup.m, wherein m is 1 or 2, are —CH.sub.2—CH.sub.2— or —CH.sub.2—CH.sub.2—CH.sub.2—; A and A.sup.m, wherein m is 1 or 2, are independently H, —CH.sub.2COOH, —CH.sub.2C(O)NH.sub.2; or —CH.sub.2P(O)(OH).sub.2, and wherein at most one of A and A.sup.m is H; n is 1 or 2; R.sup.1, R.sup.2, and R.sup.3 are independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.6 to C.sub.10 aryloxy, benzyloxy, C.sub.1 to C.sub.6 alkylthio, C.sub.6 to C.sub.10 arylthio, F, Cl, Br, I, OH, SH, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, C.sub.1 to C.sub.6 acylamino, di(C.sub.1 to C.sub.6 acyl)amino, C.sub.6 to C.sub.10 arylamino, di(C.sub.6 to C.sub.10 aryl)amino, CN, OH, nitro, COOR.sub.n, C(O)NHR.sub.n, or C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H, C.sub.1 to C.sub.10 alkyl, or C.sub.6 to C.sub.10 aryl; and/or wherein any neighboring two of R.sup.1, R.sup.2, and R.sup.3 together with any neighboring two carbon atoms of the aromatic cycle form a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF.sub.3, F, Cl, Br, I, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.1 to C.sub.6 alkylthio, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, NO.sub.2, COOH, COOR.sub.n, C(O)NHR.sub.n, or C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H, C.sub.1 to C.sub.10 alkyl, C.sub.6 to C.sub.10 aryl; with the proviso that: when n is 2, all of Z.sup.1, Z.sup.2, Z.sup.m are —CH.sub.2—CH.sub.2—, then A is not —CH.sub.2COOH; when Y is nitrogen, then X is not H; and when n is 1, all of Z.sup.1, Z.sup.2, Z.sup.m are —CH.sub.2—CH.sub.2—, and Y is nitrogen, then X is not halogen.
29. The compound of claim 28, wherein X is selected from a group consisting of H; —CH.sub.3 and Cl.
30. The compound of claim 28, wherein R.sup.1, R.sup.2, R.sup.3 are independently H; C.sub.1 to C.sub.6 alkyl; and/or neighboring two of R.sup.2, R.sup.3 together with neighboring two carbon atoms of the aromatic cycle form a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF.sub.3, F, Cl, Br, I, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkyloxy, C.sub.1 to C.sub.6 alkylthio, NH.sub.2, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, NO.sub.2, COOH, COOR.sub.n, C(O)NHR.sub.n, C(O)N(R.sub.n).sub.2, wherein R.sub.n is independently H or C.sub.1 to C.sub.10 alkyl or C.sub.6 to C.sub.10 aryl.
31. The compound of claim 28 which is: 1-((4,7-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; 1-((4-(2-amino-2-oxoethyl)-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; 1-((4,10-bis(2-amino-2-oxoethyl)-7-(phosphonomethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; 1-((1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-4-yl)methyl)isoquinoline 2-oxide; 1-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-1-yl)methyl)isoquinoline 2-oxide; 1-((4,8,11-tris(carboxymethyl)-1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)isoquinoline 2-oxide; 2,2′,2″-(11-((6-chloropyridin-2-yl)methyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-triyl)triacetic acid; 2,2′,2″-(11-((6-methylpyridin-2-yl)methyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-triyl)triacetic acid; 1-((4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)methyl)isoquinoline 2-oxide; 1-((5,9-bis(carboxymethyl)-1,5,9-triazacyclododecan-1-yl)methyl)isoquinoline 2-oxide; or 1-((4,8,12-tris(carboxymethyl)-1,4,8,12-tetraazacyclopentadecan-1-yl)methyl)isoquinohne 2-oxide.
Description
BRIEF DESCRIPTION OF FIGURES
[0116]
[0117]
EXAMPLES
[0118] The numerical values of chemical shift in NMR spectra are given in ppm. Notation used in the NMR spectra: s (singlet), d (dublet), t (triplet), m (multiplet), bs (broad singlet). The reference was set to the following values:
[0119] .sup.1H (25° C.): 7.26 ppm (CDCl.sub.3); 3.75 ppm (Dioxane); 4.70 ppm (HOD).
[0120] .sup.1H (90° C.): 3.75 ppm (Dioxane); 4.23 ppm (HOD).
[0121] .sup.13C (90° C.): 67.2 ppm (Dioxane).
[0122] .sup.13C (25° C.): 77.16 ppm (CDCl.sub.3); 66.6 ppm (Dioxane).
[0123] .sup.31P (25° C.): 0.0 ppm (H.sub.3PO.sub.4).
LIST OF ABBREVIATIONS
[0124] ESI (electrospray ionization); HPLC (high performance liquid chromatography); HRMS (high resolution mass spectrometry); LC-MS (liquid chromatography-mass spectrometry); MOPS (3-morpholinopropane-1-sulfonic acid); NCA (no-carrier-added); TFA (trifluoroacetic acid); TLC (thin layer chromatography); UV (ultraviolet).
[0125] I. Synthesis of Compounds
[0126] Structures of starting macrocyclic derivatives A, B, C, D, E and F
##STR00005##
Example 1: Preparation of 1-(bromomethyl)isoquinoline 2-oxide (1a)
[0127] 1-(bromomethyl)isoquinoline (150 mg, 0.675 mmol) was dissolved in chloroform (15 mL) and cooled in water-ice bath. m-chloroperoxobenzoic acid (77%, 0.230 g, 1.03 mmol) was added while stirring. The reaction mixture was let to gradually warm up to room temperature and stirred for 24 hours. The solvent was evaporated and the residue was purified by column chromatography on silica in methanol/ethyl acetate mixture. Fractions containing the product were evaporated to give 102 mg of product as pale yellow solid (0.430 mmol, 64% yield relative to 1-(bromomethyl)isoquinoline).
##STR00006##
[0128] .sup.1H NMR (CDCl.sub.3, 25° C., 500 MHz): δ.sub.H 5.17 (CH.sub.2-arom., s, 2H); 7.61 (arom., ddd, 1H, .sup.3J.sub.HH=8 Hz, .sup.3J.sub.HH=7 Hz, .sup.4J.sub.HH=1 Hz); 7.64 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 7.73 (arom., ddd, 1H, .sup.3J.sub.HH=9 Hz, .sup.3J.sub.HH=7 Hz, .sup.4J.sub.HH=1 Hz); 7.80-7.83 (arom., m, 1H); 7.95 (arom., ddd, 1H, J.sub.HH=9 Hz, .sup.4J.sub.HH=2 Hz, .sup.4J.sub.HH=1 Hz); 8.19 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); .sup.13C{.sup.1H} NMR (CDCl.sub.3, 25° C., 125 MHz): δ.sub.C 20.9 (CH.sub.2-arom., s); 122.9 (arom., s); 124.0 (arom., s); 127.6 (arom., s); 127.8 (arom., s); 128.6 (arom., s); 128.8 (arom., s); 129.9 (arom., s); 136.9 (arom., s); 143.1 (arom., s).
[0129] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.10H.sub.9BrNO) calculated: 237.9862, found: 237.9863.
[0130] Preparation of 14(4,7-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methypisoquinoline 2-oxide (1)
[0131] Starting compound A (145 mg, 0.362 mmol), 1-(bromomethyl)isoquinoline 2-oxide (86 mg, 0.362 mmol) and cesium carbonate (354 mg, 1.09 mmol) were dissolved in acetonitrile (10 mL) and stirred for 24 hours at room temperature. The solids were filtered off and the filtrate was concentrated on rotary evaporator. Resulting oil was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). At this point, the doubly alkylated byproduct was also collected and processed separately. Fractions containing pure product in the form of tert.butyl ester were pooled, evaporated and dried in high vacuum. The resulting oil was divided into two equal parts that were processed separately. One part was used for further synthesis as described in Example 2. The second part was dissolved in neat TFA (4 mL) and stirred for 24 h at room temperature. TFA was evaporated on rotary evaporator, the residue dissolved in distilled water (2 mL) and purified on preparative HPLC (same conditions as above). Fractions containing the product were pooled and evaporated. The residue was dissolved in distilled water (2 mL) and lyophilized, giving 41.0 mg of the product as a white fluffy solid (0.055 mmol, 30% yield relative to A).
##STR00007##
[0132] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): δ.sub.H 2.64-3.95 (8×cycle CH.sub.2+2×CH.sub.2—COOH, 20H); 4.13-4.39 (CH.sub.2-arom., m, 2H); 7.64-7.78 (2×arom., m, 2H); 7.82-7.93 (2×arom., m, 2H); 8.09 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.14 (arom., d, 1H, .sup.3J.sub.HH=8 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 42.5 (CH.sub.2—COOH, s); 42.6 (CH.sub.2—COOH, s); 45.3 (cycle, s); 47.1 (CH.sub.2-arom., s); 48.1 (cycle, s); 49.1 (cycle, s); 50.1 (cycle, s); 50.9 (cycle, s); 52.8 (cycle, s); 53.1 (cycle, s); 53.2 (cycle, s); 123.5 (arom., s); 125.4 (arom., s); 127.7 (arom., s); 128.1 (arom., s); 130.6 (arom., s); 130.9 (arom., s); 131.0 (arom., s); 135.8 (arom., s); 144.0 (arom., s); 166.7 (CO, s); 173.5 (CO, s).
[0133] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.22H.sub.32N.sub.5O.sub.5) calculated: 446.2398, found: 446.2397.
[0134] Elem. analysis: M.Math.2.3TFA.Math.2.2H.sub.2O, calculated: C (42.7), H (5.1), N (9.4), F (17.5), found: C (42.8), H (4.5), N (8.9), F (17.4).
Example 2: 1-((4-(2-amino-2-oxoethyl)-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methypisoquinoline 2-oxide (2)
[0135] The synthesis started from compounds A and 1-(bromomethyl)isoquinoline 2-oxide as described in Example 1 up to the stage where the intermediate bis(tert.butyl) ester of compound 1, (t-Bu.sub.21), was obtained by preparative HPLC. A solution of t-Bu.sub.21 (estimated 57 mg, 0.102 mmol, 1/2 of the total prepared in Example 1) as obtained from preparative HPLC was neutralized with cesium carbonate to pH=7, evaporated and dried in high vacuum. The resulting solid was dissolved in acetonitrile (10 mL), cesium carbonate was added (110 mg, 0.338 mmol), followed by addition of iodoacetamide (48.4 mg, 0.262 mmol). The suspension was stirred for 48 h at 80° C. The solids were filtered off and the filtrate was concentrated on rotary evaporator. Resulting oil was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Fractions containing pure product in the form of tert.butyl ester were pooled, evaporated and dried in high vacuum. The residue was dissolved in neat TFA (4 mL) and stirred for 24 h at room temperature. TFA was evaporated on rotary evaporator, the residue dissolved in distilled water (2 mL) and purified on preparative HPLC (same conditions as above). Fractions containing the product were pooled and evaporated. The residue was dissolved in distilled water (2 mL) and lyophilized, giving 33.4 mg of the product as a white fluffy solid (0.041 mmol, 33% yield relative to A).
##STR00008##
[0136] .sup.1H NMR (D.sub.2O with internal dioxane reference, 90° C., 500 MHz): Eu 3.40-4.05 (8×cycle CH.sub.2+CH.sub.2—COOH+CH.sub.2—CONH.sub.2, 20H); 4.40 (CH.sub.2—COOH, s, 2H); 5.42 (CH.sub.2—arom., s, 2H); 8.23-8.34 (2×arom., m, 2H); 8.45-8.50 (arom., m, 1H); 8.52 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.58-8.64 (arom., m, 1H); 8.64 (arom., d, 1H, .sup.3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 90° C., 125 MHz): 49.1 (cycle, s); 49.8 (cycle, s); 49.9 (cycle, s); 50.1 (cycle, s); 50.5 (CH.sub.2-arom., s); 51.6 (cycle, s); 51.6 (cycle, s); 51.8 (cycle, s); 51.8 (cycle, s); 53.3 (CH.sub.2—COOH, s); 54.4 (CH.sub.2—CONH.sub.2, s); 55.2 (CH.sub.2—COOH, s); 123.5 (arom., s); 127.4 (arom., s); 128.9 (arom., s); 129.0 (arom., s); 131.4 (arom., s); 131.6 (arom., s); 132.1 (arom., s); 135.8 (arom., s); 139.2 (arom., s); 170.2 (CO, s); 172.3 (CO, s); 172.4 (CO, s).
[0137] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.24H.sub.35N.sub.6O.sub.6) calculated: 503.2613, found: 503.2611.
[0138] Elem. analysis: M.Math.2.5TFA.Math.1.6H.sub.2O, calculated: C (42.7), H (4.9), N (10.3), F (17.5), found: C (42.9), H (4.5), N (9.6), F (17.1).
Example 3: 14(4,10-bis(2-amino-2-oxoethyl)-7-(phosphonomethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)isoquinoline 2-oxide (3)
[0139] Cyclen (300 mg, 1.74 mmol) and paraformaldehyde (78.4 mg, 2.61 mmol) were mixed under argon atmosphere and dissolved in dry tetrahydrofuran (12 mL). tri(tert.butyl)phosphite (654 mg, 2.61 mmol) was added and the mixture was stirred at room temperature under argon for 24 h. The solvent was evaporated on rotary evaporator, the residue purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Mass spectrometer was used for detection. The intermediate with single phosphonate arm, i.e. di-tert-butyl ((1,4,7,10-tetraazacyclododecan-1-yl)methyl)phosphonate, was collected based on mass (m/z for [M+H].sup.+=379).
[0140] Fraction containing this intermediate were pooled, neutralized with cesium carbonate to pH=7, evaporated on rotary evaporator and dried in high vacuum. The resulting solid was mixed with cesium carbonate (400 mg, 1.84 mmol), acetonitrile (10 mL) and stirred for 30 minutes at room temperature. Then, 1-(bromomethyl)isoquinoline 2-oxide (55.3 mg, 0.232 mmol) was added and the mixture was stirred 6 h at 80° C. The solids were filtered off, the solvent was evaporated on rotary evaporator and the residue was purified on preparative HPLC (same as above). Major peak corresponding to mono-alkylated intermediate (m/z for [M+H].sup.+=536) was collected. Fraction containing this intermediate were pooled, neutralized with cesium carbonate to pH=7, evaporated on rotary evaporator and dried in high vacuum. The resulting solid was mixed with cesium carbonate (73 mg, 0.224 mmol), acetonitrile (4 mL) and iodoacetamide (10.4 mg, 0.056 mmol) and stirred at room temperature for 3 h. The solids were filtered off, the solvent was evaporated on rotary evaporator and the residue was purified on preparative HPLC (same as above). Fractions containing the product in the form of tert.butyl ester were pooled and the solvent was evaporated on rotary evaporator. The residue was dissolved in 2 mL of TFA and stirred for 24 h. TFA was evaporated on rotary evaporator, the residue dissolved in distilled water (2 mL) and purified on preparative HPLC (same conditions as above). Fractions containing the product were pooled and evaporated. The residue was dissolved in distilled water (2 mL) and lyophilized, giving 10.3 mg of the product as a white fluffy solid (yield not determined).
##STR00009##
[0141] .sup.1H NMR (D.sub.2O with internal dioxane reference, 90° C., 500 MHz): δ.sub.H 3.03-4.08 (8×cycle CH.sub.2+2×CH.sub.2—CONH.sub.2, 20H); 4.26 (CH.sub.2—PO.sub.3H.sub.2, bs, 2H); 5.03 (CH.sub.2—arom., bs, 2H); 8.23-8.36 (2×arom., m, 2H); 8.45-8.52 (2×arom., m, 2H); 8.60-8.65 (arom., m, 1H); 8.70 (arom., d, 1H, .sup.3J.sub.HH=8 Hz). .sup.31P{.sup.1H} NMR (D.sub.2O with external H.sub.3PO.sub.4 reference, 25° C., 202 MHz): δ.sub.P 9.6 ppm (bs).
[0142] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.23H.sub.37N.sub.7O.sub.6P) calculated: 538.2537, found: 538.2531.
Example 4: 1,1′-((7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4-diyl)bis(methylene))bis(isoquinoline 2-oxide) (4)
[0143] The compound was synthesized according to the procedure in Example 1 as the doubly alkylated byproduct, giving analogously 56.7 mg of the product as a white fluffy solid (0.061 mmol, 17% yield relative to A).
##STR00010##
[0144] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): 6H 2.80-3.93 (8×cycle CH.sub.2+2×CH.sub.2—COOH, 20H); 4.71 (CH.sub.2-arom., s, 4H); 7.56-7.72 (2×arom., m, 4H); 7.78-7.84 (arom., m, 2H); 7.84-7.90 (arom., m, 2H); 7.98-8.04 (arom., m, 2H); 8.04-8.10 (arom., m, 2H). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 48.2 (CH.sub.2-arom., s); 49.8 (cycle, bs); 50.0 (cycle, bs); 50.2 (cycle, bs); 50.3 (cycle, bs); 53.2 (CH.sub.2—COOH, s); 123.1 (arom., s); 126.3 (arom., s); 128.0 (arom., s); 128.5 (arom., s); 130.6 (arom., s); 130.6 (arom., s); 130.9 (arom., s); 135.1 (arom., s); 141.1 (arom., s); 172.4 (CO, s).
[0145] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.32H.sub.39N.sub.6O.sub.6) calculated: 603.2926, found: 603.2924.
[0146] Elem. analysis: M.Math.2.6TFA.Math.1.4H.sub.2O, calculated: C (48.3), H (4.7), N (9.1), F (16.0), found: C (48.4), H (4.6), N (9.0), F (15.9).
Example 5: 1-((1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-4-yl)methyl)isoquinoline 2-oxide (5)
[0147] Starting compound C (42.7 mg, 0.229 mmol) was dissolved in a mixture of acetonitrile (3 mL) and dimethylformamide (0.5 mL). Then, 1-(bromomethyl)isoquinoline 2-oxide (40 mg, 0.168 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was concentrated on rotary evaporator and the residue was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Two isomers of mono-alkylated intermediate (m/z for [M+H].sup.30 =344) were successfully separated and processed separately. Fractions containing the earlier-eluting of the two were pooled, evaporated on rotary evaporator and dried in high vacuum. The residue was dissolved in acetonitrile (1 mL), cesium carbonate (84.7 mg, 0.260 mmol) was added and the mixture was stirred for 10 min at room temperature. Then, tert.butyl bromoacetate (29.6 mg, 0.152 mmol) was added and the mixture was stirred at room temperature for 24 h. The solids were filtered off and the filtrate was concentrated on rotary evaporator. Resulting oil was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Fractions containing the product in the form of tert.butyl ester were pooled, evaporated on rotary evaporator and dried in high vacuum. The residue was dissolved in neat TFA (2 mL) and the mixture was stirred for 24 h at room temperature. TFA was evaporated on rotary evaporator, the residue dissolved in distilled water (2 mL) and purified on preparative HPLC (same conditions as above). Fractions containing the product were pooled and evaporated. The residue was dissolved in distilled water (2 mL) and lyophilized, giving 8 mg of the product as a white fluffy solid (0.011 mmol, 7% yield relative to 1-(bromomethyl)isoquinoline 2-oxide).
##STR00011##
[0148] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): δ.sub.H 2.01 (CH.sub.2—CH.sub.2—CH.sub.2, m, 2H); 2.79-3.70 (8×cycle CH.sub.2+2×CH.sub.2—COOH, 20H); 3.97 (CH.sub.2—COOH, s, 2H); 5.03 (CH.sub.2—arom., s, 2H);
[0149] 7.80-7.92 (2×arom., m, 2H); 8.03-8.08 (arom., m, 1H); 8.14 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.20-8.26 (arom., m, 1H); 8.35 (arom., d, 1H, .sup.3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 21.9 (CH.sub.2—CH.sub.2—CH.sub.2, s); 49.6 (cycle, s); 49.9 (cycle, bs); 50.3 (cycle, s); 50.4 (CH.sub.2-arom., s); 50.6 (cycle, s); 50.9 (cycle, s); 51.6 (cycle, s); 52.8 (cycle, s); 53.7 (CH.sub.2—COOH, s); 53.9 (cycle, s); 54.8 (CH.sub.2—COOH, bs); 55.0 (CH.sub.2—COOH, s); 123.3 (arom., s); 127.2 (arom., s); 128.3 (arom., s); 128.5 (arom., s); 131.4 (arom., s); 131.5 (arom., s); 131.5 (arom., s); 135.1 (arom., s); 139.2 (arom., s); 169.8 (CO, s); 172.8 (CO, s); 172.9 (CO, s).
[0150] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.25H.sub.36N.sub.5O.sub.7) calculated: 518.2609, found: 518.2604.
[0151] Elem. analysis: M.Math.1.5TFA.Math.2.8H.sub.2O, calculated: C (45.5), H (5.7), N (9.5), F (11.6), found: C (45.7), H (5.1), N (9.2), F (11.1).
Example 6: 14(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-1-yl)methyl)isoquinoline 2-oxide (6)
[0152] The compound was prepared following the procedure in Example 5 as the second isomer. Analogously, using cesium carbonate (80.1 mg, 0.246 mmol) and tert.butyl bromoacetate (28 mg, 0.143 mmol) in the second step and following the same procedure, 7 mg of final product was obtained as a white fluffy solid (0.0094 mmol, 6% yield relative to 1-(bromomethyl)isoquinoline 2-oxide).
##STR00012##
[0153] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): δ.sub.H 2.06-2.18 (CH.sub.2—CH.sub.2—CH.sub.2, m, 2H); 2.87-3.35 (6×cycle CH.sub.2, 12H); 3.39-3.64 (2×cycle CH.sub.2+2×CH.sub.2—COOH, 8H); 3.93 (CH.sub.2—COOH, s, 2H); 5.02 (CH.sub.2—arom., s, 2H); 7.79-7.91 (2×arom., m, 2H); 8.02-8.07 (arom., m, 1H); 8.10 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.15-8.20 (arom., m, 1H); 8.23 (arom., d, 1H, .sup.3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 21.3 (CH.sub.2—CH.sub.2—CH.sub.2, s); 49.8 (CH.sub.2—arom., s); 49.8 (cycle, bs); 51.2 (cycle, s); 51.5 (cycle, s); 51.5 (cycle, s); 52.4 (cycle, s); 52.4 (CH.sub.2—COOH, bs); 52.5 (cycle, s); 53.6 (CH.sub.2—COOH, s); 53.6 (cycle, s); 54.1 (cycle, s); 55.1 (CH.sub.2—COOH, s); 123.3 (arom., s); 126.9 (arom., s); 128.2 (arom., s); 128.4 (arom., s); 131.2 (arom., s); 131.4 (arom., s); 131.4 (arom., s); 135.1 (arom., s); 138.9 (arom., s); 170.7 (CO, bs); 172.8 (CO, s); 173.3 (CO, s).
[0154] HRMS (ESI) m/z: [(M+Na).sup.+] (C.sub.25H.sub.35N.sub.5O.sub.7Na) calculated: 540.2429, found: 540.2429.
[0155] Elem. analysis: M.Math.1.5TFA.Math.2.9H.sub.2O, calculated: C (45.4), H (5.8), N (9.5), F (11.5), found: C (45.5), H (5.1), N (9.1), F (11.3).
Example 7: 1-((4,8,11-tris(carboxymethyl)-1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)isoquinoline 2-oxide (7)
[0156] Starting compound D (67.3 mg, 0.336 mmol) was suspended in acetonitrile (10 mL) and 1-(bromomethyl)isoquinoline 2-oxide (40 mg, 0.168 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was concentrated on rotary evaporator and the residue was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Fractions containing the mono-alkylated intermediate (m/z for [M+H].sup.+=358) were pooled, evaporated on rotary evaporator and dried in high vacuum. The residue was dissolved in acetonitrile (4 mL), cesium carbonate (204 mg, 0.625 mmol) was added and the mixture was stirred for 10 min at room temperature. Then, tert.butyl bromoacetate (71.1 mg, 0.365 mmol) was added and the mixture was stirred at room temperature for 72 h. The solids were filtered off and the filtrate was concentrated on rotary evaporator. Resulting oil was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Fractions containing the product in the form of tert.butyl ester were pooled, evaporated on rotary evaporator and dried in high vacuum. The residue was dissolved in neat TFA (2 mL) and the mixture was stirred for 24 h at room temperature. TFA was evaporated on rotary evaporator, the residue dissolved in distilled water (2 mL) and purified on preparative HPLC (same conditions as above). Fractions containing the product were pooled and evaporated. The residue was dissolved in distilled water (2 mL) and lyophilized, giving 30.2 mg of the product as a white fluffy solid (0.038 mmol, 23% yield relative to 1-(bromomethyl)isoquinoline 2-oxide).
##STR00013##
[0157] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): δ.sub.H 1.81-1.91 (CH.sub.2—CH.sub.2—CH.sub.2, m, 2H); 1.91-2.01 (CH.sub.2—CH.sub.2—CH.sub.2, m, 2H); 2.55-2.77 (cycle CH.sub.2, m, 2H); 2.97-3.08 (cycle CH.sub.2, m, 2H); 3.08-3.29 (5×cycle CH.sub.2, m, 10H); 3.29-3.42 (cycle CH.sub.2, m, 2H); 3.54 (CH.sub.2—COOH, s, 2H); 3.64 (CH.sub.2—COOH, s, 2H); 3.72 (CH.sub.2—COOH, s, 2H); 4.72 (CH.sub.2—arom., s, 2H); 7.75-7.85 (2×arom., m, 2H); 7.96-8.01 (arom., m, 1H); 8.03 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.15-8.20 (arom., m, 1H); 8.21 (arom., d, 1H, 3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 21.0 (CH.sub.2—CH.sub.2—CH.sub.2, s); 21.1 (CH.sub.2—CH.sub.2—CH.sub.2, s); 48.3 (CH.sub.2—arom., s); 48.3 (cycle, s); 49.9 (cycle, s); 50.6 (cycle, s); 50.7 (cycle, s); 51.0 (cycle, s); 51.1 (cycle, s); 52.7 (CH.sub.2—COOH, bs); 53.1 (cycle, s); 53.2 (cycle, s); 54.0 (CH.sub.2—COOH, s); 54.2 (CH.sub.2—COOH, s); 123.6 (arom., s); 126.5 (arom., s); 128.1 (arom., s); 128.6 (arom., s); 131.1 (arom., s); 131.1 (arom., s); 131.2 (arom., s); 134.6 (arom., s); 141.2 (arom., s); 171.5 (CO, s); 171.9 (CO, s); 172.1 (CO, s).
[0158] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.26H.sub.38N.sub.5O.sub.7) calculated: 532.2766, found: 532.2764.
[0159] Elem. analysis: M.Math.2.1TFA.Math.1.6H.sub.2O, calculated: C (45.3), H (5.3), N (8.8), F (15.0), found: C (45.5), H (4.6), N (8.3), F (14.6).
Example 8: 2,2′,2″-(11-((6-chloropyridin-2-yl)methyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-triyl)triacetic acid (8)
[0160] The compound was prepared by a procedure analogous to Example 7, using the following amounts: starting compound D (80 mg, 0.399 mmol), 2-(bromomethyl)-6-chloropyridine (41.2 mg, 0.199 mmol); in the second step: cesium carbonate (294 mg, 0.901 mmol) and tert.butyl bromoacetate (103 mg, 0.526 mmol). Following the procedure in Example 7, analogously 27.3 mg of the product as a white fluffy solid was prepared (0.036 mmol, 18% yield relative to 2-(bromomethyl)-6-chloropyridine).
##STR00014##
[0161] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): δ.sub.H 1.87-2.04 (2×CH.sub.2—CH.sub.2—CH.sub.2, m, 4H); 2.80-3.02 (2×cycle CH.sub.2, m, 4H); 3.05-3.16 (2×cycle CH.sub.2, m, 4H); 3.22-3.41 (4×cycle CH.sub.2, m, 8H); 3.54 (2×CH.sub.2—COOH, s, 4H); 3.78 (CH.sub.2—COOH, s, 2H); 4.30 (CH.sub.2—arom., s, 2H); 7.37 (arom., d, 1H, .sup.3J.sub.HH=8 Hz); 7.43 (arom., d, 1H, .sup.3J.sub.HH=8 Hz); 7.80 (arom., t, 1H, .sup.3J.sub.HH=8 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 21.9 (CH.sub.2—CH.sub.2—CH.sub.2, s); 22.0 (CH.sub.2—CH.sub.2—CH.sub.2, s); 50.4 (cycle, s); 50.7 (cycle, s); 51.4 (cycle, s); 51.8 (cycle, s); 51.9 (cycle, s); 52.3 (cycle, s); 53.0 (cycle, s); 53.2 (cycle, s); 54.2 (CH.sub.2—COOH, s); 54.4 (CH.sub.2—COOH, s); 54.7 (CH.sub.2—COOH, s); 56.9 (CH.sub.2—arom., s); 123.3 (arom., s); 124.9 (arom., s); 141.2 (arom., s); 150.6 (arom., s); 152.0 (arom., s); 170.9 (CO, s); 173.4 (CO, s); 173.5 (CO, s).
[0162] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.22H.sub.35N.sub.5O.sub.6C.sub.1) calculated: 500.2270, found: 500.2264.
[0163] Elem. analysis: M.Math.2.0TFA.Math.1.9H.sub.2O, calculated: C (41.0), H (5.3), N (9.2), F (15.0), Cl (4.7), found: C (41.1), H (4.6), N (8.9), F (14.6), Cl (4.8).
Example 9: 2,2′,2″-(11-((6-methylpyridin-2-yl)methyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-triyptriacetic acid (9)
[0164] The compound was prepared by a procedure analogous to Example 7, using the following amounts: starting compound D (80 mg, 0.399 mmol), 2-(chloromethyl)-6-methylpyridine hydrochloride (35.6 mg, 0.199 mmol); in the second step: cesium carbonate (232 mg, 0.711 mmol) and tert.butyl bromoacetate (80.9 mg, 0.415 mmol). Following the procedure in Example 7, analogously 21.4 mg of the product as a white fluffy solid was prepared (0.027 mmol, 14% yield relative to 2-(chloromethyl)-6-methylpyridine hydrochloride).
##STR00015##
[0165] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): δ.sub.H 1.87-2.07 (2×CH.sub.2—CH.sub.2—CH.sub.2, m, 4H); 2.53-2.62 (cycle CH.sub.2, m, 2H); 2.70 (CH.sub.3, s, 3H); 2.73-2.84 (cycle CH.sub.2, m, 2H); 2.89-3.08 (2×cycle CH.sub.2, m, 4H); 3.15-3.29 (cycle CH.sub.2, m, 2H); 3.31-3.59 (3×cycle CH.sub.2+CH.sub.2—COOH, 8H); 3.86 (2×CH.sub.2—COOH, s, 4H); 3.96 (CH.sub.2—arom., bs, 2H); 7.71 (arom., d, 1H, .sup.3J.sub.HH=8 Hz); 7.76 (arom., d, 1H, .sup.3J.sub.HH=8 Hz); 8.32 (arom., t, 1H, .sup.3J.sub.HH=8 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25 ° C., 125 MHz): 19.0 (CH.sub.3, s); 21.7 (CH.sub.2—CH.sub.2—CH.sub.2, s); 22.3 (CH.sub.2—CH.sub.2—CH.sub.2, s); 47.3 (cycle, s); 48.6 (cycle, s); 50.9 (cycle, s); 51.8 (cycle, s); 51.8 (cycle, s); 52.1 (cycle, s); 52.6 (cycle, s); 52.8 (cycle, s); 54.7 (CH.sub.2—COOH, s); 54.9 (CH.sub.2—arom., s); 55.2 (CH.sub.2—COOH, s); 55.4 (CH.sub.2—COOH, s); 124.9 (arom., s); 127.1 (arom., s); 146.5 (arom., s); 151.0 (arom., s); 154.8 (arom., s); 169.4 (CO, s); 169.5 (CO, s); 174.7 (CO, s).
[0166] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.23H.sub.38N.sub.5O.sub.6) calculated: 480.2817, found: 480.2810.
[0167] Elem. analysis: M.Math.2.7TFA.Math.0.8H.sub.2O, calculated: C (42.5), H (5.2), N (8.7), F (19.2), found: C (42.5), H (4.9), N (8.6), F (19.3).
Example 10: 14(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)methypisoquinoline 2-oxide (10)
[0168] Starting compound B (54.6 mg, 0.153 mmol) and 1-(bromomethyl)isoquinoline 2-oxide (40 mg, 0.168 mmol) were dissolved together in acetonitrile (4 mL) and stirred for 24 hours at room temperature. The solvent was evaporated on rotary evaporator and the resulting oil was purified on preparative HPLC (C.sub.18 column, acetonitrile/water gradient with 0.1% TFA in the mobile phase). Fractions containing the product in the form of tert.butyl ester were pooled, evaporated on rotary evaporator and dried in high vacuum. The residue was dissolved in neat TFA (2 mL) and the mixture was stirred for 24 h at room temperature. TFA was evaporated on rotary evaporator, the residue dissolved in distilled water (2 mL) and purified on preparative HPLC (same conditions as above). Fractions containing the product were pooled and evaporated. The residue was dissolved in distilled water (2 mL) and lyophilized, giving 54.6 mg of the product as a off-white fluffy solid (0.092 mmol, 60% yield relative to B).
##STR00016##
[0169] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): 6H 3.15-3.37 (6×cycle CH.sub.2, m, 12H); 3.67 (CH.sub.2—COOH, s, 4H); 4.89 (CH.sub.2—arom., s, 2H); 7.73-7.84 (2×arom., m, 2H); 7.94-7.99 (arom., m, 1H); 8.01 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.12-8.16 (arom., m, 1H); 8.17 (arom., d, 1H, .sup.3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 49.7 (cycle, s); 49.9 (cycle, s);
[0170] 50.3 (cycle, s); 50.5 (CH.sub.2—arom., s); 56.5 (CH.sub.2—COOH, s); 123.5 (arom., s); 126.5 (arom., s); 128.0 (arom., s); 128.3 (arom., s); 131.1 (arom., s); 131.1 (arom., s); 131.1 (arom., s); 134.8 (arom., s); 141.0 (arom., s); 172.1 (CO, s).
[0171] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.20H.sub.27N.sub.4O.sub.5) calculated: 403.1976, found: 403.1973.
[0172] Elem. analysis: M.Math.1.7TFA, calculated: C (47.1), H (4.7), N (9.4), F (16.3), found: C (47.6), H (4.6), N (9.4), F (16.1).
Example 11: 14(5,9-bis(carboxymethyl)-1,5,9-triazacyclododecan-1-yl)methypisoquinoline 2-oxide (11)
[0173] The compound was prepared by a procedure analogous to Example 7, using the following amounts: starting compound F (19.6 mg, 0.115 mmol), 1-(bromomethyl)isoquinoline 2-oxide (20 mg, 0.084 mmol) in acetonitrile (2 mL); in the second step: cesium carbonate (79 mg, 0.243 mmol) and tert.butyl bromoacetate (23.7 mg, 0.122 mmol). Following the procedure in Example 7, analogously 8.3 mg of the product as a white fluffy solid was prepared (0.013 mmol, 15% yield relative to 1-(bromomethyl)isoquinoline 2-oxide).
##STR00017##
[0174] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): 6H 1.86-2.09 (CH.sub.2—CH.sub.2—CH.sub.2, m, 2H); 2.09-2.31 (CH.sub.2—CH.sub.2—CH.sub.2, m, 4H); 2.89-3.51 (6×cycle CH.sub.2, m, 12H); 3.63 (CH.sub.2—COOH, s, 4H); 5.11 (CH.sub.2—arom., s, 2H); 7.79-7.91 (2×arom., m, 2H); 8.00-8.07 (arom., m, 1H); 8.12 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.14-8.18 (arom., m, 1H); 8.26 (arom., d, 1H, .sup.3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 19.7 (CH.sub.2—CH.sub.2—CH.sub.2, s); 20.1 (CH.sub.2—CH.sub.2—CH.sub.2, s); 48.8 (cycle, s); 50.8 (CH.sub.2—arom., s); 50.8 (cycle, bs); 53.2 (cycle, bs); 55.1 (CH.sub.2—COOH, s); 123.2 (arom., s); 127.1 (arom., s); 128.2 (arom., s); 128.3 (arom., s); 131.4 (arom., s); 131.6 (arom., s); 131.7 (arom., s); 134.6 (arom., s); 138.3 (arom., s); 172.0 (CO, s).
[0175] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.23H.sub.33N.sub.4O.sub.5) calculated: 445.2446, found: 445.2445.
[0176] Elem. analysis: M.Math.1.6TFA.Math.1.4H.sub.2O, calculated: C (48.2), H (5.6), N (8.6), F (14.0), found: C (48.5), H (5.3), N (8.5), F (13.7).
Example 12: 14(4,8,12-tris(carboxymethyl)-1,4,8,12-tetraazacyclopentadecan-1-yl)methyl)isoquinoline 2-oxide (12)
[0177] The compound was prepared by a procedure analogous to Example 5, using starting compound E (108 mg, 0.504 mmol) and 1-(bromomethyl)isoquinoline 2-oxide (60 mg, 0.252 mmol) in acetonitrile (10 mL). Following separation on preparative HPLC as in the Example 5, only the major isomer of mono-alkylated intermediate (m/z for [M+H].sup.+=372) was collected. Analogously to Example 5, the second reaction step was performed with the following amounts: cesium carbonate (309 mg, 0.948 mmol) and tert.butyl bromoacetate (108 mg, 0.553 mmol). Further following the procedure in Example 5, analogously 20.6 mg of the product as a white fluffy solid was prepared (0.023 mmol, 9% yield relative to 1-(bromomethyl)isoquinoline 2-oxide).
##STR00018##
[0178] .sup.1H NMR (D.sub.2O with internal dioxane reference, 25° C., 500 MHz): 6H 1.95-2.09 (CH.sub.2—CH.sub.2—CH.sub.2, m, 2H); 2.09-2.24 (2×CH.sub.2—CH.sub.2—CH.sub.2, m, 4H); 2.87-2.97 (cycle CH.sub.2, m, 2H); 3.11-3.28 (3×cycle CH.sub.2, m, 6H); 3.29-3.46 (4×cycle CH.sub.2+CH.sub.2—COOH, 10H); 3.88 (CH.sub.2—COOH, s, 2H); 3.99 (CH.sub.2—COOH, s, 2H); 4.96 (CH.sub.2—arom., s, 2H); 7.78-7.89 (2×arom., m, 2H); 8.01-8.06 (arom., m, 1H); 8.10 (arom., d, 1H, .sup.3J.sub.HH=7 Hz); 8.16-8.21 (arom., m, 1H); 8.27 (arom., d, 1H, .sup.3J.sub.HH=7 Hz). .sup.13C{.sup.1H} NMR (D.sub.2O with internal dioxane reference, 25° C., 125 MHz): 18.6 (CH.sub.2—CH.sub.2—CH.sub.2, s); 21.2 (CH.sub.2—CH.sub.2—CH.sub.2, s); 22.0 (CH.sub.2—CH.sub.2—CH.sub.2, s); 50.1 (cycle, s); 50.2 (cycle, s); 50.4 (CH.sub.2—arom., s); 50.4 (cycle, s); 50.4 (cycle, s); 51.1 (cycle, s); 51.4 (cycle, s); 51.6 (cycle, s); 52.1 (cycle, s); 54.2 (CH.sub.2—COOH, s); 56.2 (CH.sub.2—COOH, s); 56.3 (CH.sub.2—COOH, s); 123.4 (arom., s); 127.0 (arom., s); 128.2 (arom., s); 128.4 (arom., s); 131.2 (arom., s); 131.4 (arom., s); 131.4 (arom., s); 134.9 (arom., s); 139.7 (arom., s); 168.4 (CO, s); 168.5 (CO, s); 172.3 (CO, s).
[0179] HRMS (ESI) m/z: [(M+H).sup.+] (C.sub.27H.sub.40N.sub.5O.sub.7) calculated: 546.2922, found: 546.2920.
[0180] Elem. analysis: M.Math.2.8TFA.Math.2.2H.sub.2O, calculated: C (43.3), H (5.1), N (7.7), F (17.6), found: C (43.5), H (4.4), N (7.3), F (17.1).
[0181] II Separation of s-, p- and d-block Metals
[0182] The chelator molecules described in this invention were tested for their ability to separate s-, p- and d-block metals by first forming chelates with a chelator that provides chromatographic selectivity towards the metals and then subjecting the chelates to conventional chromatographic separation.
Example 13: Variability in retention of metal chelates on reversed-phase HPLC usable for separation
[0183] Complexation of selected s-, p- and d-block metals (Ca.sup.+, Fe.sup.+, Fe.sup.+, Co.sup.+, Ni.sup.2+, Zn.sup.2+, Al.sup.3+, Pb.sup.2+) were carried out in parallel in 96-well plates as follows. MOPS buffer pH=7.0 (85 μL), approximately 0.01 M aqueous solution of the chelator (5 μL), and approximately 0.005 M aqueous solution of a metal salt of a composition given in Table 1 (10 μL) were pipetted into a well. The well-plate was covered with a pierceable sealing mat, shaken well for complete mixing of the components and let stand for 16 hour at room temperature. After that it was shaken again and briefly centrifugated to bring all liquid to the well bottom. Samples for HPLC analysis were taken directly from the wells with an automated autosampler. The conditions for HPLC analysis were as follows: column Phenomenex Kinetex C.sub.18 (100×3 mm, 2 6 lam), injection volume 1 μL, isocratic elution with a mobile phase as specified in Table 1, flow rate of 0.6 mL/min and detection by UV absorbance at 280 nm. Retention times for respective metal chelates are summarized in Table 1. For a given chelator, differing retention times of different metals signify that such metals can be chromatographically separated in the form of chelates with that chelator. The results in Table 1 demonstrate that various combinations of metals from the s-, p- and d-block can be separated according to the present invention.
TABLE-US-00001 TABLE 1 Compound (chelator) 8 .sup.a 10 .sup.b 11 .sup.c Metal ion Metal compound Retention time (minutes) Co.sup.2+ Co(NO.sub.3).sub.2 4.58 2.60 2.74 Ni.sup.2+ Ni(NO.sub.3).sub.2 4.47 2.56 2.87 Cu.sup.2+ CuCl.sub.2 1.9 3.18 2.74 Zn.sup.2+ Zn(NO.sub.3).sub.2 3.18 3.48 2.29 Pb.sup.2+ Pb(NO.sub.3).sub.2 .sup. (1.15) * 3.41 1.30 * Metal chelate unstable under the conditions, only free chelator detected (value in parentheses). .sup.a Eluent: 8% acetonitrile in 10 mM α-HIBA (pH = 5.5). .sup.b Eluent: 4.6% acetonitrile in water. .sup.c Eluent: 11% acetonitrile in water.
[0184] III Separation of Rare Earth Elements
[0185] The chelator molecules described in this invention were tested for their ability to separate rare earth elements by first forming chelates with a chelator that provides chromatographic selectivity towards rare earth elements and then subjecting the chelates to conventional chromatographic separation.
Example 14: Variability in Retention of Metal Chelates on Reversed-phase HPLC Usable for Separation
[0186] Solutions of metal chelates were prepared according to the procedure in Example 13 with the following pipetted amounts: MOPS buffer pH=7.0 (90 μL), 0.01 M solution of chelator (5 pi) and 0.01 M solution of metal chloride or nitrate (5 μL). The conditions for HPLC analysis were identical to those in Example 13 except for the composition of the mobile phase as specified in Table 2. Retention times for respective metal chelates are summarized in Table 2. For a given chelator, differing retention times of different metals signify that such metals can be chromatographically separated in the form of chelates with that chelator. The results in Table 2 demonstrate that various combinations of metals from the rare earth element group can be separated according to the present invention.
TABLE-US-00002 TABLE 2 Compound (chelator) 5 .sup.a 6 .sup.b 10 .sup.c Metal ion Retention time (minutes) La.sup.3+ 3.69 3.82 3.65 Ce.sup.3+ 3.78 4.14 3.64 Pr.sup.3+ 3.83 4.35 3.60 Nd.sup.3+ 3.73 4.43 3.51 Sm.sup.3+ 3.37 4.62 3.67 Eu.sup.3+ 2.97 4.62 3.67 Gd.sup.3+ 2.58 4.43 3.48 Tb.sup.3+ 2.21 3.67 3.38 Dy.sup.3+ 2.12 3.06 3.25 Ho.sup.3+ 2.07 2.60 3.09 Er.sup.3+ 2.05 2.35 3.03 Tm.sup.3+ 2.10 2.29 3.03 Yb.sup.3+ 2.10 2.25 3.05 Lu.sup.3+ 2.07 2.20 2.98 Y.sup.3+ 2.08 2.67 3.15 Sc.sup.3+ 2.54 2.58 4.17 .sup.a Eluent: 6.2% acetonitrile in water. .sup.b Eluent: 7.4% acetonitrile in water. .sup.c Eluent: 4.6% acetonitrile in 10 mM α-HIBA (pH = 5.5).
Example 15: HPLC Separation of Gd, Tb and Dy from a Mixture
[0187] Solutions of Gd, Tb and Dy chelates were prepared according to the procedure in Example 14 with the chelator 14(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-1-yl)methyl)isoquinoline 2-oxide (prepared in Example 6). The chelates were subjected to HPLC analysis individually and as a mixture. The conditions for HPLC analysis were identical to those in Example 13 except for the composition of the mobile phase that consisted of 7.4% acetonitrile in water with no additives.
Example 16: Acidic Decomplexation and Removal of the Free Chelator
[0188] Solution of Tb chelate of the chelator 14(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclotridecan-1-yl)methyl)isoquinoline 2-oxide (prepared in Example 6) was prepared according to procedure in Example 14 and subjected to HPLC analysis using an acidic mobile phase. The conditions for HPLC analysis were identical to those in Example 13 except for the composition of the mobile phase that consisted of 7.4% acetonitrile and 0.02% of TFA in water.
INDUSTRIAL APPLICABILITY
[0189] The present invention is considered as susceptible of industrial application in separation and purification of metals, separation and purification of metal radionuclides, concentrating diluted solutions of metal radionuclides by means of solid phase extraction, recovery of isotopically enriched metal material used for production of metal radionuclides, purification of starting metal material prior to its use for production of metal radionuclides, decontamination of surfaces contaminated by metal radionuclides, selective recovery of metals from nuclear waste, selective recovery of metals from products of nuclear fission, hydrometallurgical processing of spent nuclear fuel and other radioactive waste.