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EP-4423056-B1 - SYNTHESIS OF RESTRAINED COMPLEXING AGENTS

EP4423056B1EP 4423056 B1EP4423056 B1EP 4423056B1EP-4423056-B1

Inventors

  • WONG, Nicholas
  • GOSSELIN, FRANCIS

Dates

Publication Date
20260506
Application Date
20221026

Claims (15)

  1. A method of preparing a compound of Formula (I): a diastereomer thereof, a salt thereof, a solvate thereof, or a combination of any of the foregoing, wherein the method comprises: (a) a step (1-1) comprising reacting a compound of Formula (Ia): or a diastereomer thereof with a compound of Formula (Ib): in a solvent and in the presence of a reducing agent to form a compound of Formula (Ic): or a diastereomer thereof; (b) a step (1-2) comprising reacting the compound of Formula (Ic), or a salt thereof, with a compound of Formula (Id): in the presence of a base and in a solvent, to form a compound of Formula (Ie): or a diastereomer thereof; (c) a step (1-3) comprising reacting the compound of Formula (Ie) with a base in a solvent to form a compound of Formula (If): or a diastereomer thereof; (d) a step (1-4) comprising reacting the compound of Formula (If) with a compound of Formula (1g): in a solvent and in the presence of a carboxyl activating reagent, to form a compound of Formula (Ih): or a diastereomer thereof; and (e) a step (1-5) comprising reacting the compound of Formula (Ih) with an acid to form a compound of Formula (I), a diastereomer thereof, a salt thereof, or a solvate thereof, or a combination of any of the foregoing, wherein R 1 and R 2 are each independently C 1 -C 6 alkyl; R 3 is halo; and R 4 , R 5 , R 6 and R 7 are each independently halo or hydrogen.
  2. The method of claim 1, wherein the compound of Formula (I) is Compound 1:
  3. A method of preparing a compound of Formula (I): a diastereomer thereof, a salt thereof, or a solvate thereof, or a combination of any of the foregoing, wherein the method comprises: (a) a step (2-1) comprising reacting a compound of Formula (Ia): with a compound of Formula (Ib): in a solvent and in the presence of a reducing agent to form a compound of Formula (Ic): (b) a step (2-2) comprising reacting a compound of Formula (Ic) with an acid to produce a salt of Formula (Ic); (c) a step (2-3) comprising reacting the salt of Formula (Ic) with a compound of Formula (Id): in the presence of a base and in a solvent, to form a compound of Formula (Ie): a diastereomer thereof, or a salt thereof; (d) a step (2-4) comprising reacting a compound of Formula (Ie) with a base in a solvent to form a compound of Formula (2f): a diastereomer thereof, or a salt thereof; and (e) a step (2-5) comprising reacting the compound of Formula (If) or salt thereof with a compound of Formula (Ig): in a solvent and in the presence of a carboxyl activating reagent, to form a compound of Formula (Ih): a diastereomer thereof, or a salt thereof; and (f) a step (2-6) comprising reacting the compound of Formula (Ih) with an acid to form a compound of Formula (I), a diastereomer thereof, a salt thereof, a solvate thereof, or a combination of any of the foregoing, wherein R 1 and R 2 are each independently C 1 -C 6 alkyl; R 3 is halo; and R 4 , R 5 , R 6 , and R 7 are each independently halo or hydrogen.
  4. The method of claim 3, wherein the acid in the step (2-2) is orotic acid.
  5. The method of any one of claims 3-4, wherein the step (2-2) provides a salt of Formula (Ic) having the following structure:
  6. The method of claim 5, wherein the step (2-2) comprises crystallizing the salt of Formula (Ic), or a diastereomer thereof, as an orotate salt.
  7. The method of any one of claims 3-6, wherein the step (2-6) provides a salt of Formula (I), or a solvate thereof, having the following structure:
  8. The method of claim 7, wherein the step (2-6) further comprises crystallizing the salt of Formula (I).
  9. The method of any one of claims 3-8, wherein R 1 is methyl, or wherein R 2 is tert-butyl, or wherein R 3 is Br, or wherein R 4 , R 5 , R 6 , and R 7 are F.
  10. The method of any one of claims 3-9, wherein the salt of the solvate of Formula (I) has the structure:
  11. A compound of Formula (Ie): a diastereomer thereof, or a salt thereof, wherein R 1 and R 2 are each independently C 1 -C 6 alkyl.
  12. A compound of Formula (Ic): a diastereomer thereof, or a salt thereof, wherein R 1 is C 1 -C 6 alkyl.
  13. A crystalline salt of the compound of claim 12 with the structure:
  14. The crystalline salt of claim 13, wherein the salt has at least one of: (a) an X-ray powder diffraction pattern with characteristic peaks at 7.5° 2-Theta, 13.9° 2-Theta, 16.6° 2-Theta, 23.4° 2-Theta, and 25.6° 2-Theta; (b) a thermo-gravimetric analysis thermogram showing a mass loss of 3.3% between 20 °C and 150 °C; (c) a differential scanning calorimetry thermogram showing an endothermic peak at 172.8 °C; (d) an 1 H nuclear magnetic resonance spectrum with a characteristic peak at 5.68 ppm; (e) an X-Ray powder diffraction pattern with characteristic peaks at 7.2° 2-Theta, 14.0° 2-Theta, 15.2° 2-Theta, 22.7° 2-Theta, and 25.0° 2-Theta; (f) a thermo-gravimetric analysis thermogram showing a mass loss of 2.6% between 20 °C and 150 °C; (g) a differential scanning calorimetry thermogram showing an exothermic peak at 161.7 °C and an endothermic peak at 182.9 °C; (h) an 1 H nuclear magnetic resonance spectrum with a characteristic peak at 5.69 ppm; (i) an X-Ray powder diffraction pattern with characteristic peaks at 7.3° 2-Theta, 7.8° 2-Theta, 9.7° 2-Theta, 13.9° 2-Theta, 16.7° 2-Theta, 21.4° 2-Theta, 23.4° 2-Theta; (j) a thermo-gravimetric analysis thermogram showing a mass loss of 4.8% between 20 °C and 150 °C; (k) a differential scanning calorimetry thermogram showing an exothermic peak at 178.1 °C and an endothermic peak at 185.6 °C; (l) an 1 H nuclear magnetic resonance spectrum with a characteristic peak at 5.68 ppm.
  15. A crystallized salt of the compound of claim 12 with the structure: wherein the salt has at least one of: (a) an X-Ray powder diffraction pattern with characteristic peaks at 7.9° 2-Theta, 15.8° 2-Theta, 18.6° 2-Theta, 19.3° 2-Theta, 20.1° 2-Theta, 21.0° 2-Theta, and 24.7° 2-Theta; (b) a thermo-gravimetric analysis thermogram showing a mass loss of 2.4% between 20 °C and 140 °C; (c) a differential scanning calorimetry thermogram showing an endothermic peak at 154.7 °C; (d) an 1 H nuclear magnetic resonance spectrum with a characteristic peak at 6.39 ppm.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Application No. 63/272,547 filed on October 27, 2021. FIELD The present application is related to methods of preparing restrained complexing agents (RESCA) and RESCA compounds and salts thereof. BACKGROUND Proteins that bind molecules that are important in diagnosis, disease monitoring, and visualization ("marker-binding proteins") can have associated or attached a detectable label (e.g., radioactive label or fluorescent label) that permits visualizing the molecule and thus its location and quantity (qualitative or quantitative). In some cases, a detectable label is directly associated or attached to the marker-binding protein, but in other cases, detectable labels are attached to marker proteins via linking molecules ("linkers"), which may be uncleavable or cleavable (thus allowing for controlled association of the marker-binding protein with its detectable label). Linkers may associate with the detectable label in a variety of ways, including direct conjugation to chelation, the latter suited for some metal-containing detectable labels. However, linkers can require conditions for conjugation to the marker protein that are incompatible with a particular marker protein, or are inefficient, or require multiple reagents. Restrained complexing agent (RESCA) is a class of chelator molecules that have been successfully used to label biomolecules with 18F (fluorine-18) and facilitate PET (positron emission tomography) imaging that could be useful as a diagnostic and/or therapeutic tool for a variety of diseases and conditions. The properties of 18F, particularly its modest half-life, make it an attractive option for imaging technologies compared to other radionuclides, such as 89Zr (zirconium-89) and 124I (iodine-124). The use of aluminum monofluoride ({Al18F}2+) as the source of 18F has emerged as a strategy that allows 18F labeling via RESCA in aqueous media and at lower temperatures compared to previously known methods of 18F labeling, for example as described in WO 2016/065435. Despite the potential applications for RESCA, the laborious, low-yield synthesis is a potential barrier to widespread development and use of the RESCA-Al18F labeling strategy. An improved process for synthesizing RESCA would be useful for the continued development of the RESCA-Al18F labeling method and its various applications. BRIEF SUMMARY The present application provides methods of preparing RESCA compounds, RESCA compounds and salts thereof as defined in the appended claims. Provided herein is a method of preparing a compound of Formula (I): a diastereomer thereof, a salt thereof, a solvate thereof, or a combination of any of the foregoing,wherein the method comprises: (a) a step (1-1) comprising reacting a compound of Formula (Ia): or a diastereomer thereof with a compound of Formula (Ib): in a solvent and in the presence of a reducing agent to form a compound of Formula (Ic): or a diastereomer thereof;(b) a step (1-2) comprising reacting the compound of Formula (Ic), or a salt thereof, with a compound of Formula (Id) in the presence of a base and in a solvent,to form a compound of Formula (Ie): or a diastereomer thereof;(c) a step (1-3) comprising reacting the compound of Formula (Ie) with a base in a solvent to form a compound of Formula (If): or a diastereomer thereof;(d) a step (1-4) comprising reacting the compound of Formula (If) with a compound of Formula (1g): in a solvent and in the presence of a carboxyl activating reagent, to form a compound of Formula (Ih): or a diastereomer thereof; and(e) a step (1-5) comprising reacting the compound of Formula (Ih) with an acid to form a compound of Formula (I), a diastereomer thereof, a salt thereof, or a solvate thereof, or a combination of any of the foregoing, wherein R1 and R2 are each independently C1-C6 alkyl;R3 is halo; andR4, R5, R6 and R7 are each independently halo or hydrogen. In some embodiments, the solvent in the step (1-1) comprises an alcohol. In some embodiments, the solvent is ethanol. In some embodiments, the reducing agent in the step (1-1) is a hydride. In some embodiments, the reducing agent is NaBH(OAc)3. In some embodiments, step (1-1) further comprises purifying the compound of Formula (Ic) by column chromatography. In some embodiments, the solvent in the step (1-2) is a polar organic solvent. In some embodiments, the solvent is CH3CN. In some embodiments, the base in the step (1-2) is an organic base. In some embodiments, the organic base is an amine base. In some embodiments, the amine base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the step (1-2) further comprises purifying the compound of Formula (1e) by column chromatography. In some embodiments, the solvent in the step (1-3) is an aqueous solvent. In some embodiments, the solvent further comprises tetrahydrofuran (THF). In some embodiments, the base in the step (1-3) is KOH. In som