The syntheses of radiolabelled org 5222 and its main metabolite org 30526

Abstract

SUMMARYThe syntheses of trans-5-chloro-2,3,3a-l2b-tetrahydro-2-methyl- pyrrole (Org 30526) labelled with 3H are described. 3H-labelled Org 5222 of low specific activity was prepared by a base catalyzed exchange with tritiated water of an amide precursor, 3H-labelled Org 5222 with a high specific activity by a catalytic reductive dehalogenation. 3H-labelled Org 30526 was prepared both by demethylation of 3H-Org 5222 and by catalytic reductive iodination of 11-iodo-Org 30526. l4C-1abelled Org 5222 was synthesized in 6 steps using 14C-sarcosine as starting material. 36C1-labelled Org 5222 was prepared by diazotation reaction in the presence of H3%l.

Synthesis of stable isotope‐labeled metabolites of asenapine

“…LC‐MS (EI + ) desmethylasenapine 4 : m/z 272.1 (M + H) + ; [ 13 C 6 ]‐ 24 m/z 278.1 (M + H) + . The spectroscopic data for 21 as well as all other intermediates was in complete agreement with that reported in the literature …”

“…The original synthesis of asenapine, the radiochemical syntheses (including both 3 H and 14 C) and an improved manufacturing process have been reported . Because asenapine is marketed as a racemate, each of these syntheses are racemic.…”

“…Because asenapine is marketed as a racemate, each of these syntheses are racemic. The synthesis of [ 13 CD 3 ]‐asenapine N ‐oxide 7 , perhaps the simplest of the required metabolites, is outlined in Scheme and began with desmethylasenapine 4 . Methylation of 4 was accomplished via an Eschweiler–Clark reductive amination using [ 13 C,D 2 ] formaldehyde and [D 2 ]‐formic acid to give [ 13 CD 3 ]‐asenapine 7 in 85% yield .…”

“…To circumvent to synthesis of a labeled version of sarcosine 17 and provide for a reasonably straight forward synthesis of a labeled version of N ‐desmethylasenapine 4 , our efforts focused on starting with readily available [ 13 C‐6]‐phenol 14 (Scheme ). Conversion of 14 to [ 13 C 6 ]‐asenapine 23 was straight forward and followed the published protocol . Finally, demethylation was accomplished by reaction of 23 with α ‐chloroethyl chloroformate followed by ethanol hydrolysis to provide [ 13 C 6 ]‐ N ‐desmethylasenapine 24 in 60% yield …”

Base‐Promoted Isomerization of cis‐Lactam to trans‐Lactam of Asenapine and Optimization of Crystallization Process of Asenapine Maleate Salt: An Antipsychotic Drug

“…Multiple synthetic approaches have been disclosed in the literature for the preparation of asenapine . The main steps of largest reported process routes are outlined in Schemes and .…”