Synthesis of tritiated (S)‐10‐bromoacetamidomethylcamptothecin

Abstract

Tritiated (S)-1 0-bromoacetamidomethylcamptothecin was prepared starting from (S)-1 0-hydroxycamptothecin. The key step consisted of palladium catalyzed direct tritium exchange on the intermediate (S)-10-aminomethylcamptothecin. 3H NMR spectroscopy indicated the tritium label was located exclusively at the C-5 position. Key Words:1 0-Bromoacetamidomethylcarnptothecin, Camptothecin, Tritium exchange, 3H NMR. IntroductionCamptothecin (1 ), a naturally occurring antineoplastic agent,' binds reversibly to DNA-topoisomerase I covalent complex and stablizes the enzyme-mediated DNA cleavage, inhibiting religation.2 In order to investigate whether the presence of a peripheral electrophilic substituent, for instance the bromoacetyl appendage in derivative 2 (SK&F S-lO6470), would render such binding irreversible, a radio-labeled analog of 2 was required.2 Investigation of the nature of any covalent binding of [3H]2 could provide information relative to the position of camptothecin binding on the DNA-topoisomerase I complex. Based upon the precedent that a deuterated analog of carnptothecin was prepared by deuterium exchange on the parent compound in the presence of Pd/C,3 our synthetic strategy employed a similar approach in introducing the tritium label into the intermediate (S)-l O-aminomethylcarnptothecin (6). In this paper we report the synthesis of [3H]SK&F S-106470 (8) and the use of 3H NMR to elucidate the position of the tritium label.

Tritium labelling of pharmaceuticals by metal‐catalysed exchange methods

“…N-methyl labelling of N-methyl amides and amines has been previously observed with iridium (I) catalysts with tritium gas but is usually accompanied by a high degree of ortho exchange in these cases. [14][15][16] Clearly the near complete selectivity for N-methyl urea incorporation observed with this example is worthy of further investigation.…”

“…A 30 minute pre-reduction with deuterium gas as outlined by Heys was used in an attempt to minimize the formation of [ 3 H]cyclooctane. 15 As is typical with Crabtree reactions which are run with stoichiometric or greater amounts of catalyst, recovery of product from HPLC purification was poor, resulting in a total batch of 11 mCi @ 97.2% RCP. 3 H NMR analysis showed that in addition to the expected aromatic incorporation, additional label was present in the urea ethyl substituent, and about 25% present in a single site in the pyrrolidine ring.…”

Synthesis of isotopically labelled compounds at Schering‐Plough, an historical perspective

“…In particular, the use of tris-triphenylphosphine ruthenium (II) chloride with tritiated water to prepare 3 H-labelled piperidines and piperazines 9 has become one of the most commonly used labelling methods in the group, given that the piperidine and piperazine functionality are extensively found in pharmaceutical structures. Examples of compounds prepared using this route are [ 3 H]lonafarnib (11) and [ 3 H]Sch 211803 (12). 10,11 In each case, a piperidine intermediate with a free NH was tritiated and then converted to the target compound in one or more steps using the medicinal chemistry route.…”

Iridium‐Catalyzed H/D Exchange

“…With the assumption that 2 forms a five-membered metallacyclic intermediate when reacted with 1, [10,11] further investigation was made to see if the six-and seven-membered intermediates also show deuteration. 2-Methoxyphenylacetic acid (18) and 3,4-dimethoxyphenylacetic acid (19) were used to study the six-membered metallacyclic intermediate system, whereas 3-(2-methoxyphenyl)propionic acid (20) was used to study the seven-membered intermediate system.…”

“…The high risk related to the usage of tritiated water prohibits its employment in standard methods. [10,14] Consequently, the catalyst system was tested with deuterium gas and 2 as model compound. A deuteration grade of 45 % was observed, but surprisingly at the C-4 position, para to the acid and meta to the methoxy group ( Figure 5), thus indicating that a different mechanism from the one described above has taken place (Scheme 2).…”