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WO2025250655A1 - Préparation de composés radiohalogénés pour la médecine nucléaire par élimination réductrice d'halogénures de bismuth(v) - Google Patents

Préparation de composés radiohalogénés pour la médecine nucléaire par élimination réductrice d'halogénures de bismuth(v)

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WO2025250655A1
WO2025250655A1 PCT/US2025/031218 US2025031218W WO2025250655A1 WO 2025250655 A1 WO2025250655 A1 WO 2025250655A1 US 2025031218 W US2025031218 W US 2025031218W WO 2025250655 A1 WO2025250655 A1 WO 2025250655A1
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James Kelly
Shuvra DEBNATH
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Cornell University
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Cornell University
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  • halogens small molecules labeled with radioactive isotopes of halogens (e.g., 18 F, 76 Br, 77 Br, 124 I, 131 I, 211 At) are widely used for diagnostic imaging, molecular radiotherapy, biological research, and drug discovery because of their chemical properties and nuclear decay characteristics (Adam, M.J., “Radiohalogenated Carbohydrates for Use in PET and SPECT,” J. Label. Compd. Radiopharm.45:167-180 (2002); Glaser et al., “Applications of Positron-Emitting Halogens in PET Oncology (Review),” Int. J. Oncol.22:253-267 (2003); Adam and Wilbur, “Radiohalogens for Imaging and Therapy,” Chem.
  • One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I): where is a point of attachment of ring A to ring B or, if ring B is absent, to R 1 or R 2 group; is a single or a double bond; ring B is optional and, if present, is aryl or heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C, N, O, or S; R 1 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl, -OC 1-6 alkyl, CF 3 , -C(O)H, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, 313156387v3 R 2 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl, -
  • This process comprises: providing a compound of Formula (IIa) or (IIb): where R is halogen; R ⁇ is optional and, if present, is independently H, OCH 3 , or CF 3 ; and X 1 is OTf or BF 4 ; providing a compound of Formula (III): R 6 -Hal (III), where R 6 is Na, K, Cs, NH 4 , or (C 1-6 alkyl) 4 N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).
  • Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (I): 313156387v3 where is a point of attachment of ring A to ring B; is a single or a double bond; ring B is optional and, if present, is selected from the group consisting of C 5 aryl, C 6 aryl, C 4 heteroaryl, C 5 heteroaryl, and C 6 heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C or N; R 1 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl, -OC 1-6 alkyl, CF 3 , -C(O)H, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, R 2 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl,
  • (Radio)haloaromatic moieties are prevalent in drug molecules and radiopharmaceuticals, but, despite decades-long interest in these compounds, there are few methods available for the rapid, efficient, and reproducible (radio)halogenation of electron- deficient or sterically hindered aromatic rings when the halide is in significant stoichiometric deficiency.
  • Disclosed herein is a convenient method of regioselective bismuth-mediated radiohalogenation of arylboronates that tolerates a wide range of functional groups and is effective with electron-rich, deficient, neutral, and sterically crowded aryl and heteroaryl rings (FIG.1C).
  • FIGs.1A-1D show Bi(V)-mediated aryl halogenation reactions.
  • FIG.1A shows regioselective transfer of ortho-methyl substituted aryl rings to iodide by an open aryl ligand system (previous work) (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128- 1136 (2024), which is hereby incorporated by reference in its entirety).
  • FIG.1B shows bismuth- mediated fluorination of arenes reported by Cornella and coworkers (Zhou et al., “A Practical Protocol for Large-scale Copper-mediated Radioiodination of Organoboronic Precursors: Radiosynthesis of [123 I]KX-1 for Auger Radiotherapy,” J. Labelled Comp. Radiopharm. 66(13):435-439 (2023); Kondo et al., “Copper-mediated Radioiodination Reaction Through Aryl Boronic Acid or Ester Precursor and its Application to Direct Radiolabeling of a Cyclic Peptide,” J. Radioanal. Nucl. Chem.64(8):336 ⁇ 345 (2021), which are hereby incorporated by reference in their entirety).
  • FIG.1C shows regioselective aryl transfer to radionuclides ( 77 Br, 124/125 I, and 211 At) using a bridged aryl ligand system (present disclosure).
  • FIG.2 shows an overview of a convenient method of regioselective bismuth- mediated radiohalogenation of arylboronates, which can be used to prepare 77 Br-, 124 I-, and 211 At-labeled derivatives of radiopharmaceuticals, including the prostate-specific membrane antigen (PSMA) inhibitor MIP-1095, with excellent radiochemical conversion (80-99%), radiochemical yield (42-78%), and radiochemical purity (>99%) at molar activities exceeding 250 GBq/ ⁇ mol.
  • PSMA prostate-specific membrane antigen
  • FIG.3 shows identification of reagents to promote synthesis of bismacycle(V) at room temperature and optimization of the transmetalation step.
  • FIG.4 shows a representative chromatogram of compound (6a).
  • FIG.5 shows a representative chromatogram of compound (17b).
  • FIG.6 shows a representative chromatogram of compound (18b).
  • FIG.7 shows a representative chromatogram of the Boc and urea protected [ 125 I]MIBG intermediate.
  • FIG.8 shows a representative (radio)chromatogram of Boc protected [ 125 I]MIP- 1095.
  • FIG.9 shows a representative chromatogram of crude [ 124 I]MIP-1095.
  • FIG.10 shows a representative chromatogram of [ 124 I]MIP-1095.
  • FIG.11 shows a flow diagram showing the key radiosynthetic steps following addition of Na[ 124 I]I to the reaction mixture.
  • FIG.12 shows a representative chromatogram of compound (22).
  • FIG.13 shows a representative chromatogram of compound (23).
  • FIG.14 shows a representative chromatogram of compound (8a).
  • FIG.15 shows a representative chromatogram of compound (8b).
  • FIG.16 shows a representative chromatogram of compound (8c).
  • FIG.17 shows a representative chromatogram of compound (8d).
  • FIG.18 shows a representative chromatogram of compound (8e).
  • FIG.19 shows a representative chromatogram of compound (8f).
  • FIG.20 shows a representative chromatogram of compound (8g).
  • FIG.21 shows a representative chromatogram of compound (9a).
  • FIG.22 shows a representative chromatogram of compound (9b). 313156387v3
  • FIG.23 shows a representative chromatogram of compound (9c).
  • FIG.24 shows a representative chromatogram of compound (9d).
  • FIG.25 shows a representative chromatogram of compound (9e).
  • FIG.26 shows a representative chromatogram of compound (9f).
  • FIG.27 shows a representative chromatogram of compound (9g).
  • FIG.28 shows a representative chromatogram of compound (9h).
  • FIG.29 shows a representative chromatogram of compound (6c).
  • FIG.30 shows a representative chromatogram of compound (6d).
  • FIG.31 shows a representative chromatogram of compound (10).
  • FIG.32 shows a representative chromatogram of compound (11).
  • FIG.33 shows a representative chromatogram of compound (12).
  • FIG.34 shows a representative chromatogram of compound (8h).
  • FIG.35 shows a representative chromatogram of compound (6b).
  • FIG.36 shows a representative chromatogram of compound (13).
  • FIG.37 shows a representative chromatogram of compound (14).
  • FIG.38 shows a representative chromatogram of compound (15).
  • FIG.39 shows a representative chromatogram of compound (17a).
  • FIG.40 shows a representative chromatogram of compound (17b).
  • FIG.41 shows a representative chromatogram of compound (17c).
  • FIG.42 shows a representative chromatogram of compound (17d).
  • FIG.43 shows a representative chromatogram of compound (17e).
  • FIG.44 shows a representative chromatogram of compound (17g).
  • FIG.45 shows a representative chromatogram of compound (17h).
  • FIG.46 shows a representative chromatogram of compound (18a).
  • FIG.47 shows a representative chromatogram of compound (18b).
  • FIG.48 shows a representative chromatogram of compound (18c).
  • FIG.49 shows a representative chromatogram of compound (18d).
  • FIG.50 shows a representative chromatogram of the Boc and urea protected [ 125 I]MIBG intermediate.
  • FIG.51 shows a representative chromatogram of compound (22).
  • FIG.52 shows a representative chromatogram of compound (23).
  • FIGs.53A-53B show conditions for developing a one-pot radiosynthesis of iodoarenes via reductive elimination.
  • FIG.53A shows a two-step, one-pot synthesis incorporating oxidation and reductive elimination (RE).
  • the duration of the oxidation reaction 313156387v3 and the reductive elimination reaction was 10 min and 2 hours, respectively.
  • FIG.53B shows a three-step, one-pot synthesis incorporating transmetalation, oxidation, and reductive elimination. All reactions were performed at room temperature using 0.8 equivalents of the oxidizing agent.
  • FIGs.54A-54C show a rationale for regioselectivity of aryl group transfer.
  • FIG. 54A shows a postulated mechanism for the Bi-mediated radiohalogenation of aryl trifluoroborate.
  • FIG.54B shows an optimized ground state structure of Bi(V) compound (7a) with the iodide ligand in equatorial (left) or axial (right) positions.
  • FIG.54C shows an optimized ground state structure of Bi(V) compound (7b) with the iodide ligand in equatorial (left) or axial (right) positions. Ground state structure optimization was performed using the B3LYP/LanL2DZ basis set.
  • FIGs.55A-55D show a one-pot radiohalogenation of aryl rings. Reactions consisted of a transmetalation step lasting 1 hour, an oxidation step lasting 1 hour, and a reductive elimination step lasting 1-4 hours.
  • Radiochemical conversion was determined by radio-HPLC and is reported for each compound. Compounds were isolated by HPLC in ⁇ 99% radiochemical purity.
  • FIG.55A shows substrate scope of bismuth-mediated [ 125 I]iodination of potassium aryltrifluoroborates and aryl boronic acids.
  • FIG.55B shows [ 77 Br]bromination of aryl boron compounds. The reductive elimination step took place at 80 0C.
  • FIG.55C shows [ 211 At]astatination of aryl boron compounds. The reductive elimination step was fixed at 2 hours due to the short half-life of astatine-211.
  • FIG.55D shows [ 18 F]Fluorination of unsubstituted arenes from the transmetalated bismacycle Bi(III) precursor was not observed.
  • FIG.56A-56C show an application of the one-pot bismuth-mediated radiohalogenation to prepare radiopharmaceuticals.
  • FIG.56A shows radiosynthesis of meta- [ 125 I]iodobenzylguanidine.
  • FIG.56B shows radiosynthesis of [ 124/125 I]MIP-1095 and its t-butyl protected [ 77 Br]bromo- and [ 211 At]astatine analogs.
  • FIG.56C shows compounds were purified by HPLC, and [ 124 I]MIP-1095 was used to perform in vivo microPET/CT imaging of LNCaP tumors in a xenograft mouse model.
  • the mice were intravenously administered 4.44 MBq [ 124 I]MIP-1095 and imaged 1 hour post injection.
  • One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I): where is a point of attachment of ring A to ring B or, if ring B is absent, to R 1 or R 2 group; is a single or a double bond; ring B is optional and, if present, is aryl or heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C, N, O, or S; R 1 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl, -OC 1-6 alkyl, CF 3 , -C(O)H, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, R 2 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alky
  • This process comprises: providing a compound of Formula (IIa) or (IIb): where R is halogen; 313156387v3 R ⁇ is optional and, if present, is independently H, OCH 3 , or CF 3 ; and X 1 is OTf or BF 4 ; providing a compound of Formula (III): R 6 -Hal (III), where R 6 is Na, K, Cs, NH 4 , or (C 1-6 alkyl) 4 N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).
  • Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (I): where is a point of attachment of ring A to ring B; is a single or a double bond; ring B is optional and, if present, is selected from the group consisting of C 5 aryl, C 6 aryl, C 4 heteroaryl, C 5 heteroaryl, and C 6 heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C or N; 313156387v3 R 1 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl, -OC 1-6 alkyl, CF 3 , -C(O)H, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, R 2 is optional and, if present, is selected from the group consisting of H, halogen, CN, C 1- 6 alkyl,
  • transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed subject matter. In some embodiments or claims where the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of” or “consisting essentially of.” [0071] Terms of degree such as “substantially,” “about,” and “approximately” and the symbol as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed.
  • alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 23 carbon atoms in the chain. For example, straight or branched carbon chain could have 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl.
  • aryl means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms.
  • Representative aryl groups include phenyl and naphthyl.
  • arylene refers to a group obtained by removal of a hydrogen atom from an aryl group. Non-limiting examples of arylene include phenylene and naphthylene.
  • heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur.
  • element(s) other than carbon for example, nitrogen, oxygen, or sulfur.
  • heteroaryl only one of the rings needs to be aromatic for the ring system to be defined as “Heteroaryl”.
  • Preferred heteroaryls contain about 5 to 6 ring atoms.
  • aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide.
  • Representative heteroaryls include pyridyl, 2- oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2- oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzo
  • heteroarylene refers to a group obtained by removal of a hydrogen atom from a heteroaryl group.
  • exemplary heteroarylene groups include, but are not limited to, groups derived from the heteroaryl groups described above.
  • substituted or substitution of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded.
  • Up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.
  • Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • halogen or “Hal” means fluoro (F), chloro (Cl), bromo (Br), iodo (I), or astato (At).
  • becquerel or “Bq” is a unit of radioactivity. One becquerel (Bq) is equal to one radioactive decay per second.
  • MBq refers to mega becquerel.
  • Hal is a radioisotope of halogen (radiohalogen). 313156387v3 [0084] In some embodiments Hal is, without limitation I, Br, Cl, F, 18 F, 123 I, 76 Br, 77 Br, 124 I, 125 I, 131 I, 34m Cl, and 211 At. [0085] In some embodiments, A is defined is independently selected at each occurrence from C, N, NH, O, or S, but it is to be understood that when X is O, S, or NH, such X is not substituted with R 3 , R 4 , or R 5 or attached to ring B, and X can only be O or S in the five-membered ring.
  • ring A can be, without limitation, selected the group [0087] In some embodiments ring A can be, without limitation, selected from the group consisting 313156387v3 [0089] In some embodiments, R 1 , R 2 , R 3 , R 4 , or R 5 is [0090] In some embodiments, R is F. 313156387v3 [0091] In some embodiments, the compound of Formula (I) is [0092] In some embodiments, the compound of Formula (I) is [0093] In some embodiments, the compound of Formula (I) has Formula (I ⁇ ): 313156387v3 Hal R 5 X X 4 X X R X R 2 R 3 (I ⁇ ).
  • the compound of Formula (III) can be, without limitation, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium iodide, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, NaF, NaBr, NaI, Na[ 18 F], Na[ 123 I], Na[ 76 Br], Na[ 77 Br], Na[ 124 I], Na[ 125 I], Na[ 131 I], Na[ 34m Cl] and Na[ 211 At].
  • reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at room temperature. In some embodiments, reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at a temperature of from about 0°C to about 120°C.
  • the reacting is carried out at a temperature of from about 0°C to about 20°C, about 0°C to about 40°C, about 0°C to about 60°C, about 0°C to about 80°C, about 0°C to about 100°C, about 20°C to about 30°C, about 20°C to about 40°C, about 20°C to about 60°C, about 20°C to about 80°C, about 20°C to about 100°C, about 20°C to about 120°C, about 40°C to about 60°C, about 40°C to about 80°C, about 40°C to about 100°C, about 40°C to about 120°C, about 60°C to about 80°C, about 60°C to about 100°C, about 60°C to about 120°C, about 70°C to about 80°C, about 70°C to about 90°C, about 70°C to about 100°C, about 70°C to about 120°C, about 80°C to about 100°C,
  • reacting the intermediate compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out in a polar, aprotic solvent.
  • Suitable polar, aprotic solvents that can be used include, without limitation, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, or combinations thereof.
  • reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out for from about 30 min to about 24 hours.
  • the reacting is carried out for from about 30 min to about 1 hour, about 30 min to about 5 hours, about 30 min to about 10 hours, about 30 min to about 15 hours, about 30 min to about 20 hours, about 1 hour to about 5 hours, about 1 hour to about 10 hours, about 1 hour to about 15 hours, about 1 hour to about 20 hours, about 1 hour to about 24 hours, about 5 hours to about 10 hours, about 5 hours to about 15 hours, about 5 hours to about 20 hours, about 5 hours to about 24 hours, about 10 hours to about 15 hours, about 10 hours to about 20 hours, 313156387v3 about 10 hours to about 24 hours, about 15 hours to about 20 hours, about 15 hours to about 24 hours, or about 20 hours to about 24 hours.
  • providing a compound of Formula (IIa) or (IIb) comprises: providing a compound of Formula (A): providing an oxidizing agent; and reacting the compound of Formula (A) with the oxidizing agent under conditions effective to produce the compound of Formula (IIa) or (IIb).
  • providing a compound of Formula (A) comprises: providing a compound of Formula (IV): where LG is a leaving group; providing a compound of Formula (V): where Y is Cl, F, or OTf ; and reacting the compound of Formula (IV) with the compound of Formula (V) under conditions effective to produce the compound of Formula (A).
  • providing a compound of Formula (IIa) or (IIb) comprises: providing a compound of Formula (IV): 313156387v3 where LG is a leaving group; providing a compound of Formula (V): reacting the compound of Formula (IV) with the compound of Formula (V) under conditions effective to produce the compound of Formula (IIa) or (IIb).
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an oxidizing agent.
  • Suitable oxidizing agents include, without limitation, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor TM ), 2,6-dichloro-1-fluoropyridinium triflate, and 2,6-dichloro- 1-fluoropyridinium tetrafluoroborate.
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in acetonitrile or CD 3 CN.
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out at a temperature of from about 20°C to about 40°C.
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out at a temperature of from about 20°C to about 25°C, about 20°C to about 30°C, about 20°C to about 35°C, about 25°C to about 30°C, about 25°C to about 35°C, about 25°C to about 40°C, about 30°C to about 35°C, or about 35°C to about 40°C.
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 5 min to about 48 hours. In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 15 min to about 2 hours.
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 5 min to about 1 hour, about 5 min to about 5 hours, about 5 min to about 10 hours, about 5 min 313156387v3 to about 15 hours, about 5 min to about 20 hours, about 5 min to about 25 hours, about 5 min to about 30 hours, about 5 min to about 35 hours, about 5 min to about 40 hours, about 5 min to about 45 hours, about 30 min to about 1 hour, about 30 min to about 5 hours, about 30 min to about 10 hours, about 30 min to about 15 hours, about 30 min to about 20 hours, about 30 min to about 25 hours, about 30 min to about 30 hours, about 30 min to about 35 hours, about 30 min to about 40 hours, about 30 min to about 45 hours, about 1 hour to about 5 hours, about 1 hour to about 10 hours, about 1 hour to about 15 hours, about 1 hour to about 20 hours, about 1 hour to about 25 hours, about 1 hour to about 30 hours, about 1 hour to about 35 hours, about 1 hour to about 35 hours, about
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an additive.
  • the additive is K 2 CO 3 .
  • reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an activator.
  • the activator is KF.
  • the process can further comprise reacting the compound of Formula (I): 313156387v3 with a solution of HCl in dioxane to produce the compound of Formula (I) where [0109]
  • Example 1 Materials and Methods [0111] Full experimental methods, including the synthesis and characterization of radiolabeled compounds and non-radioactive standards, are described in Example 2. Representative synthetic procedures are described below.
  • General Procedure for One-Pot Radioiodination of Aryl Boron Compounds [0112] Arylboronic acid (5a) or potassium aryl trifluoroborate (5c) (2 ⁇ mol) and bismacycle Bi(III) compound 4 (1.0 mg, 1.8 ⁇ mol) were weighed and transferred into a clean 313156387v3 and dried glass reaction vial equipped with a stir bar and dissolved in 900 ⁇ L of anhydrous acetonitrile. The reaction mixture was stirred for 1-4 hours at room temperature.
  • the resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC at 30 min intervals from 30 min to 2 hours. If unreacted [ 125 I]iodide was observed after 2 hours, another 100 ⁇ L of the Bi(V) stock solution was added to the reaction mixture, and reaction progress was monitored by radio-HPLC.
  • the radiochemical conversion was calculated by comparing the peak area of aryl [ 125 I]iodide to the peak area of unreacted [ 125 I]iodide in the radiochromatogram. The identity of the radiolabeled compound was confirmed by co-injection with a non-radioactive standard.
  • the aryl [ 125 I]iodide was purified and isolated by semi-prep HPLC.
  • the resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC. After 1 hour, an additional 250 ⁇ L of the Bi(V) stock solution was added to the reaction mixture which was stirred for another 1 hour to achieve >90% radiochemical conversion.
  • the radiolabeled intermediate was purified by semi-prep HPLC. Chromatographic details are available in Example 2. The fraction containing the compound was collected and passed through a pre-conditioned Sep-Pak C18 plus short cartridge (Waters, USA). The radiolabeled compound was eluted with 1 mL acetonitrile into a glass reaction vial.
  • the acetonitrile was evaporated under nitrogen flow at room temperature, and the resulting residue was dissolved in 0.5 mL 4 N HCl in dioxane and stirred for 1 hour at room temperature.
  • the mixture was diluted with water (20 mL) and passed through a pre-conditioned C18 cartridge as described above. The retained material was eluted with 1 mL ethanol into a glass reaction vial. The ethanol was slowly evaporated to a volume of approximately 0.2 mL under nitrogen flow at room temperature.
  • the resulting solution was diluted with 1.8 mL saline and passed through a 0.2 ⁇ m Millex® nylon syringe filter (Millipore Sigma, USA), yielding [ 124 I]MIP-1095 in 64% ndcRCY and >99% radiochemical and chemical purity.
  • the identity of the radiolabeled compound was confirmed by co-injection with a non- radioactive standard.
  • the total synthesis time was 4 hours from mixing compounds 4 and 21. Chromatographic details and a flow diagram depicting the radiosynthesis are available in Example 2.
  • microPET/CT Siemens InveonTM
  • reaction vial was charged with a Teflon-coated magnetic stir bar.
  • Reagents e.g., 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor TM ), 1-fluoro-2,6- dichloropyridinium tetrafluoroborate, 1-fluoro-2,6-dichloropyridinium triflate, 1- fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, arylboronic acids, arylboronic acid pinacol esters, potassium aryltrifluoroborates, iodoarene, and bromoarene standards were obtained from Millipore Sigma, Fisher Scientific, Oakwood Chemicals, AmBeed, and A2B Chemicals and used without further purification.
  • Potassium aryl trifluoroborates were prepared from commercially available arylboronic acids by following a previously reported experimental procedure (Vedejs et al., “Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of Arylboron Difluoride Lewis Acids,” J. Org. Chem.60:3020–3027 (1995), which is hereby incorporated by reference in its entirety).
  • a solution of the oxidizing agent (F-TEDA or Cl 2 FPyOTf; 0.16 ⁇ mol) in 100 ⁇ L acetonitrile was added dropwise to the solution of 2a-2c with continuous stirring at room temperature. The mixture was stirred for 10 min at room temperature.
  • a solution of Na[ 125 I]I containing 7.4 MBq in 10 ⁇ L was prepared by diluting the solution of Na[ 125 I]I in 0.1 M NaOH with anhydrous acetonitrile. After 1 hour of stirring, the Na[ 125 I]I solution was added dropwise to the reaction vial containing the Bi(V) mixture with continuous stirring at room temperature.
  • the mobile phases used were 0.01% v/v trifluoroacetic acid (TFA)/H 2 O (solvent A) and 0.01% v/v TFA/acetonitrile (solvent B). Elution of the column was performed at a flow rate of 2 mL/min using the gradient reported in Table 1 below. 313156387v3 Table 1.
  • the resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC. After 1 hour of stirring, another 250 ⁇ L of the Bi(V) stock solution was added to the reaction mixture with stirring, and the completion of the reaction was 313156387v3 monitored by radio-HPLC.
  • the radiolabeled intermediate was purified by semi-prep HPLC using the method outlined in Table 6 below (Chromatogram provided in FIG.9). Table 6.
  • the acetonitrile was evaporated under nitrogen flow, and the resulting residue was dissolved in 0.5 mL 4 N HCl in dioxane and stirred for 1 hour at room temperature.
  • the crude reaction mixture was diluted with water (20 mL) and passed through a preconditioned C18 cartridge as described above. The cartridge was washed with 5 mL H 2 O and the retained material was eluted with 1 mL absolute ethanol into a glass reaction vial. The ethanol was slowly evaporated to a volume of approximately 0.2 mL under nitrogen flow at room temperature.
  • Compound 23 was purified by HPLC using the method described below and isolated in 42% non-decay corrected radiochemical yield and >99% radiochemical purity. The identity of the radiolabeled product was confirmed by co- injection with the non-radioactive iodinated standard (FIG.13). 313156387v3 Table 9.
  • pinacol borane 28 50 mg, 0.06 mmol was dissolved in 8 mL methanol in a 20 mL glass reaction vial.
  • An aqueous solution of potassium hydrogen fluoride 53 mg (60 mmol) in 1.2 ml H 2 O was added dropwise into the reaction vial and was stirred continuously at room temperature overnight.
  • the organic solvent was evaporated under reduced pressure, and the reaction mixture was dried azeotropically with acetonitrile. The resultant residue was extracted with 100 mL acetonitrile.
  • Aryl rings can be transferred to nucleophiles at room temperature via regioselective reductive elimination from Bi(V) compounds (FIG.1A) (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128-1136 (2024), which is hereby 313156387v3 incorporated by reference in its entirety).
  • radiochemical conversion was only 30-45% even after 16 hours. This finding highlights the challenge of translating this approach to radiochemistry, for which the nucleophile is present in significantly sub-stoichiometric quantities ( ⁇ 1,000 to 10,000-fold molar deficit). Nearly quantitative RCC was achieved in 4-6 hours at 80 °C, but regioselectivity was compromised in the absence of the two ortho-methyl substituents.
  • Electrophilic bismacycle Bi(III) triflate 4 was prepared by treating bismacycle(III) iodide with silver triflate at room temperature. Modest transmetalation of phenylboronic acid 5a (Fig.3, entries 1-4) and poor transmetalation of pinacol borane 5b (Fig.3, entries 5-7) to 4 was observed at 2 hours.
  • Bi(V) bismacycle 7a was selected as a model compound.
  • Compound 7a demonstrated a distorted trigonal bipyramidal geometry where the sulfone-bridged aryl rings occupied one axial and one equatorial position, and the unbridged aryl receptor ligand was positioned in an equatorial coordination site (Fig.56B).
  • the larger iodide and smaller fluoride ligands occupied the remaining equatorial and axial coordination sites, respectively (Fig.54B).
  • the unbridged equatorial aryl ligand can undergo free rotation to align orthogonally to the axial coordination plane, resulting in reactive confirmation for reductive elimination. Furthermore, the equatorial iodide ligand can undergo Berry pseudo-rotation (Ugi et al., “Berry Pseudorotation and Turnstile Rotation,” Acc. Chem. Res.4(8):288–296 (1971), which is hereby incorporated by reference in its entirety) to the axial position by overcoming a 5.70 kcal/mol energy barrier.
  • Bi(V) complexes were prepared in sealed containers using dried solvents, with no additional precautions taken to exclude air or moisture. The complexes were then reacted with Na[125I]iodide in a 0.1 N 313156387v3 NaOH(aq) solution. [ 125 I]Iodide incorporation into 2,6-dimethylaryl rings with para substituents occurred with quantitative RCC at room temperature within 4 hours, irrespective of the nature of the substituent (Fig.55A, 8a-8g).
  • radioisotopes decay by emission of an Auger electron and alpha particle, respectively, and are potential agents for targeted radionuclide therapy (Idrissou et al., “Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide,” Pharmaceutics 13:980 (2021); Guérard et al., “Production of [(211)At]-astatinated Radiopharmaceuticals and Applications in Targeted ⁇ -particle Therapy,” Cancer Biother. Radiopharm.28(1):1-20 (2013), which are hereby 313156387v3 incorporated by reference in their entirety).
  • Radiopharmaceuticals [0172] To demonstrate the suitability of the method for preparing radiopharmaceuticals, two model compounds were selected whose synthesis could be accomplished in low yields by conventional methods or required the use of toxic organometallic precursors.
  • MIBG meta-iodobenzylguanidine
  • Fig.56A was 80%, and the compound was isolated in 53% non-decay corrected radiochemical yield (ndcRCY) and ⁇ 99% radiochemical purity (RCP). Further work will establish whether radiohalogenation can be achieved in the absence of protecting groups.
  • [ 211 At]Astatinated compound 23 was isolated in 42% ndcRCY and ⁇ 99% RCP.
  • the purified products were also chemically pure because the non-radiolabeled precursors and by-products, including the boron trifluoride and boronic acid precursors, unreacted Bi(III) compound, oxidizing agent, and Bi(V) complex, have significantly shorter retention times on the C18 reverse-phase column than the radiolabeled compound.
  • Electron- deficient positions in aryl rings showed lower radiochemical incorporation, evidently attributed to poor transmetalation.
  • Theoretical evidence for regioselectivity which can be explained by the geometry at the Bi(V) center is provided.
  • the synthetic method exhibits broad substrate scope and functional group tolerance and can be used to prepare radiopharmaceuticals that are otherwise inaccessible under such mild conditions or without using toxic organometallic reagents. This method provides a new tool for the synthesis of radiohalogenated radiopharmaceuticals for nuclear imaging and radiotherapy in preclinical and clinical laboratories.

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Abstract

La présente invention concerne un procédé de préparation d'un composé de formule (I), dans laquelle le cycle A, le cycle B, Hal, R1, et R2 sont tels que décrits dans la description.
PCT/US2025/031218 2024-05-29 2025-05-28 Préparation de composés radiohalogénés pour la médecine nucléaire par élimination réductrice d'halogénures de bismuth(v) Pending WO2025250655A1 (fr)

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