Process for production of heterodimers of glutamic acid
View Patent ↗A manufacturing process for the preparation of radiolabeled compounds of formula (I) includes reacting compounds of formula (II) with a source of radionuclide of a halogen in the presence of an oxidant under acidic condition, wherein: *I is 123 I, 124 I, 125 I or 131 I; R is lower alkyl, optionally substituted with one or more fluorine atoms; Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 , (CH 2 ) p ; Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , (CH 2 ) p ; R′ is H, C(O), S(O) 2 , C(O) 2 ; Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6; and p is 0, 1, 2, 3, 4, 5 or 6.
1. A process for the preparation of a radiolabeled compound of formula (I)
the process comprising:
reacting a compound of formula (II) with a metal salt of *I in the presence of an oxidant under acidic conditions,
wherein
*I is 123 I, 124 I, 125 I or 131 I;
R is lower alkyl, optionally substituted with one or more fluorides;
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 , (CH 2 ) p ;
Y is O, NR′, S, S(O) 2 , C(O) 2 , (CH 2 ) p ;
R′ is H, C(O), S(O) 2 , C(O) 2 ;
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4, 5 or 6; and
p is 0, 1, 2, 3, 4, 5 or 6.
2. The process of claim 1 , wherein the acidic conditions comprise a pH of less than about 3.
3. The process of claim 1 , wherein R is methyl.
4. The process of claim 1 , wherein the metal salt of *I is a Group IA metal salt of *I wherein *I is 123 I, 124 I, 125 I or 131 I.
5. The process of claim 4 , wherein the metal salt is a sodium salt.
6. The process of claim 1 , wherein the oxidant comprises a peracid.
7. The process of claim 1 , wherein the reacting comprises adding an acid to the compound of formula (II) and metal salt of *I, prior to adding the oxidant.
8. The process of claim 7 , wherein the acid comprises a mineral acid or an organic acid.
9. The process of claim 8 , wherein the mineral acid is a non-halogen bearing or releasing acid.
10. The process of claim 8 , wherein the acid comprises phosphoric acid, sulfuric acid or acetic acid.
11. The process of claim 8 , wherein an amount of the acid is sufficient to maintain a pH of from 1 to 3.
12. The process of claim 1 further comprising reacting a low concentration of a cold metal iodide with the compound of formula (II), the metal salt of *I, and the oxidant.
13. The process of claim 12 , wherein the low concentration is from 0.1 to 10 μg of cold metal iodide per 50 mCi of the metal salt of *I.
14. The process of claim 13 , wherein the cold metal iodide is Na 127 I.
15. The process of claim 1 , wherein the compound of formula (I) is:
wherein:
*I is 123 I, 124 I, 125 I or 131 I; and
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl.
16. The process of claim 15 , wherein Z is tert-butyl.
17. The process of claim 1 , wherein the compound of formula (I) is
18. The process of claim 1 further comprising chromatographically purifying the radiolabeled compound of the formula (I).
19. The process of claim 18 further comprising adding 2-3% sodium gentisate and 5-6% ascorbate/asorbic acid at a pH of from 4.5 to 5.5 to stabilize the radiolabeled compound represented by formula (I).
20. A process for the preparation of a radiolabeled compound of formula:
the process comprising:
reacting a compound of formula
with a metal salt of *I in the presence of an oxidant under acidic conditions,
wherein:
*I is 123 I; 124 I; 125 I or 131 I;
R is lower alkyl, optionally substituted with one or more fluorides; and
Z is H, C 1 -C 4 alkyl, benzyl, substituted benzyl or trialkylsilyl.
21. The process of claim 20 , wherein the acidic conditions comprise a pH of less than about 3.
22. The process of claim 20 , wherein R is methyl.
23. The process of claim 20 , wherein the metal salt of *I is a Group IA metal salt of *I wherein *I is 123 I; 124 I, 125 I or 131 I.
24. The process of claim 23 , wherein the metal salt is a sodium salt.
25. The process of claim 20 , wherein Z is H or C 1 -C 4 alkyl.
26. The process of claim 20 , wherein Z is tert-butyl.
27. The process of claim 20 further comprising chromatographically purifying the radiolabeled compound.
28. The process of claim 20 further comprising adding 2-3% sodium gentisate and 5-6% ascorbate/asorbic acid at a pH of from 4.5 to 5.5 to stabilize the radiolabeled compound.