Development of a multigram asymmetric synthesis of 2-(R)-2-(4, 7, 10-tris tert-Butylcarboxymethyl-1, 4, 7, 10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl …

SG Levy, V Jacques, KL Zhou… - … Process Research & …, 2009 - ACS Publications
SG Levy, V Jacques, KL Zhou, S Kalogeropoulos, K Schumacher, JC Amedio, JE Scherer…
Organic Process Research & Development, 2009ACS Publications
A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-(R)-2-
(4, 7, 10-tris tert-butylcarboxymethyl-1, 4, 7, 10-tetraazacyclododec-1-yl)-pentanedioic acid,
1-tert-butyl ester ((R)-tert-Bu4-DOTAGA, 4) has been devised and demonstrated. The nine-
step synthesis features an improved synthesis of 2-(S)-5-oxotetrahydrofuran-2-carboxylic
acid, tert-butyl ester 8, the precursor to the novel alkylating agent (S)-5-benzyl 1-tert-butyl 2-
(methylsulfonyloxy) pentanedioate 12, which was used to introduce an orthogonally …
A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester ((R)-tert-Bu4-DOTAGA, 4) has been devised and demonstrated. The nine-step synthesis features an improved synthesis of 2-(S)-5-oxotetrahydrofuran-2-carboxylic acid, tert-butyl ester 8, the precursor to the novel alkylating agent (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyloxy)pentanedioate 12, which was used to introduce an orthogonally protected chiral glutarate arm to the 1,4,7,10-tetraazacyclododecane (cyclen) nucleus in high optical purity. Cyclen derivative (R)-t-Bu4-DOTAGA, 4, a key intermediate for the manufacture of a magnetic resonance imaging (MRI) candidate, was produced with high chemical (≥95%) and optical (ee ≥ 97%) purity. The process developed was successfully applied to the kilogram-scale cGMP synthesis of (R)-t-Bu4-DOTAGA.
ACS Publications