Formulation and method of synthesis

Patent metadata

Field	Value
Publication number	US-11077216-B2
Application number	US-201515318599-A
Country	US
Kind code	B2
Filing date	Jun 30, 2015
Priority date	Jun 30, 2014
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

The present invention provides a composition comprising anti-1-amino-3- 18 F-fluorocyclobutyl-1-carboxylic acid ( 18 F-FACBC) having an improved impurity profile compared with previous such compositions. Also provided is a method to obtain said composition.

First claim

The invention claimed is:

1. A method of preparation of a PET tracer composition in a cassette system having an end of synthesis (EOS) radiochemical purity (RCP) of at least 95%, comprising
(a) reacting in a reaction vessel of the cassette system a source of 18 F-fluoride with a precursor compound of Formula I:

wherein:
LG is a leaving group;
PG 1 is a carboxy protecting group;
and, PG 2 is an amine protecting group;
wherein said reacting step is carried out in acetonitrile;
to obtain a reaction mixture comprising a compound of Formula II:

wherein PG 1 and PG 2 are as defined for Formula I;
(b) transferring said reaction mixture comprising said compound of Formula II out of said reaction vessel onto a reversed phase solid phase cartridge of the cassette system and carrying out removal of PG 1 to obtain a reaction mixture comprising a compound of Formula III:

wherein PG 1 is as defined for Formula I;
(c) applying heat to said reaction vessel to remove residual solvent from the reaction vessel at the same time as carrying out removal of PG 1 on the reversed phase solid phase cartridge;
(d) transferring said reaction mixture comprising said compound of Formula III from the reversed phase solid phase cartridge back into said reaction vessel and carrying out removal of PG 2 to obtain a reaction mixture comprising 18 F-FACBC;
(e) purifying said reaction mixture comprising 18 F-FACBC by passing it through a hydrophilic lipophilic balanced (HLB) solid phase, wherein said purifying does not comprise passing the reaction mixture comprising 18 F-FACBC through an alumina solid phase, wherein the purified reaction mixture is obtained in steps (c) or (e) with citrate buffer, wherein said composition comprises no more than 5.0 μg/mL dissolved aluminium (Al) and no more than 25 μg/mL acetonitrile (MeCN).

2. The method as defined in claim 1 wherein LG is a linear or branched C 1-10 haloalkyl sulfonic acid substituent, a linear or branched C 1-10 alkyl sulfonic acid substituent, a fluorosulfonic acid substituent, or an aromatic sulfonic acid substituent.

3. The method as defined in claim 2 wherein LG is methanesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, or perfluoroalkylsulfonic acid.

4. The method as defined in claim 1 wherein LG is trifluoromethanesulfonic acid.

5. The method as defined in claim 1 wherein PG 1 is a linear or branched C 1-10 alkyl chain or an aryl substituent.

6. The method as defined in claim 5 wherein PG 1 is methyl, ethyl, t-butyl or phenyl.

7. The method as defined in claim 6 wherein PG 1 is methyl or ethyl.

8. The method as defined in claim 7 wherein PG 1 is ethyl.

9. The method as defined in claim 1 wherein PG 2 is a carbamate substituent, an amide substituent, an imide substituent or an amine substituent.

10. The method as defined in claim 9 wherein PG 2 is t-butoxycarbonyl, allyloxycarbonyl, phthalimide, or N-benzylideneamine.

11. The method as defined in claim 10 wherein PG 2 is t-butoxycarbonyl.

12. The method as defined claim 1 which is automated.

13. The method as defined in claim 1 wherein step (c) of applying heat to said reaction vessel is carried out at a temperature of 80° C.-140° C.

14. The method as defined in claim 1 wherein step (c) of applying heat to said reaction vessel is carried out at a temperature of 85° C.-130° C.

15. The method as defined in claim 1 , said composition comprises no more than 20 μg/mL acetonitrile (MeCN).

16. The method as defined in claim 1 , wherein step (c) comprises cooling the heated reaction vessel using nitrogen purging followed by application of vacuum.

Assignees

• Ge Healthcare Ltd

Inventors

• Dyrstad Knut Richard
• Wickstrom Torild
• Rajanayagam Thanushan

Classifications

• C07B59/001 Primary

  Acyclic or carbocyclic compounds · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• A61K51/04 Primary

  Organic compounds · CPC title

• C07C271/24

  with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C269/06

  by reactions not involving the formation of carbamate groups · CPC title