Regioselective synthesis of DTPA derivatives
AssigneeIDEC Pharmaceuticals Corporation
InventorsPaul Chinn, Albert Gyorkos, Michael J. LaBarre, Steve Ruhl, Thomas Ryskamp
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Abstract
The present invention provides a process for high yield regioselective synthesis of DTPA derivatives that eliminates the need for ion exchange chromotographic separation of intermediates. Moreover, as this process yields a single regioisomer of the chelate, it provides for the regiospecific synthesis of desired chelates useful as radiolabeling agents.
Claims29
A process for regioselective synthesis of a DTPA derivative suitable for chelating radioactive metals and coupling to immunoglobulins, the process comprising regioselectively coupling:
- (a) a monoprotected diamine;
- and
- (b) a compound comprising an amine and a moiety capable of effectively coupling the DTPA derivative to immunoglobulins or a compound comprising an amine and a moiety capable of being converted for effectively coupling the DTPA derivative to immunoglobulins;
- thereby synthesizing a substantially isomerically pure DTPA derivative.
A process for preparing a DTPA derivative of formula (I)
- wherein R1 and R2 are selected to provide a desired DTPA derivative, the process comprising:
- (a) coupling N-tert-butoxycarbonyl-p-nitro-L-phenylalanine (A) and mono protected diamine (B) to form compound (C);
- (b) removing the amine protecting groups in (C) to form the TFA-salt (D);
- (c) reducing (D) to form (E);
- (d) penta-akylating (E) to form (F);
- (e) removing the amine protecting groups in (F) to form the trifluoroacetic acid salt (G);
- (f) reducing the nitro group in (G) to form the trifluoroacetic acid salt (H);
- and
- (g) converting the amino group in (H) to form the DTPA derivative of formula (I).
A process for preparing MX-DTPA comprising:
- (a) coupling N-tert-butoxycarbonyl-p-nitro-L-phenylalanine (A) and mono-N-tert-butoxycarbonyl protected diamine (B′) to form N-(2-N-Tert-butoxycarbonyl-aminopropyl)-N-tert-butoxycarbonyl-p-nitrophenylalaninamide (C′);
- (b) removing the boc groups in (C′) to form N-(2-Aminopropyl)-p-nitrophenylalaninamide TFA-salt (D′);
- (c) reducing (D′) to form 2-Methyl-6-(p-nitrobenzyl)diethylenetriamine trihydrochloride (E′);
- (d) penta-alkylating (E′) to form N,N,N′,N″,N″-Pentakis[(tert-butoxycarbonyl)methyl]-2-[(4-nitrophenyl)methyl]-6-methyldiethylenetriamine (F′);
- (e) removing the boc groups in (F′) to form N,N,N′,N″,N″-Pentakis(carboxymethyl)-2-[(4-nitrophenyl)methyl]-6-methyldiethylenetriamine trifluoroacetic acid salt (G′);
- (f) reducing the nitro group in (G′) to form N,N,N′,N″,N″-Pentakis(carboxymethyl)-2-[(4-aminophenyl)methyl]-6-methyldiethylenetriamine trifluoroacetic acid salt (H′);
- and
- (g) converting the amino group in (H′) to form 2-(p-Isothiocyanatobenzyl)-6-methyldiethylenetriamine-N,N,N′,N″,N″-pentaacetic acid (MX-DTPA).
A substantially isomerically pure MX-DTPA composition.
A process for preparing CHx-DTPA comprising:
- (a) coupling N-tert-butoxycarbonyl-p-nitro-L-phenylalanine (A) and mono protected diamine (B″) to form compound (C″);
- (b) removing the amine protecting groups in (C″) to form the TFA-salt (D″);
- (c) reducing (D″) to form (E″);
- (d) penta-alkylating (E″) to form (F″);
- (e) removing the amine protecting groups in (F″) to form the trifluoroacetic acid salt (G″);
- (f) reducing the nitro group in (G″) to form the trifluoroacetic acid salt (H″);
- and
- (g) converting the amino group in (H″) to form the CHx-DTPA.
Dependencies are inferred from the claim text.