Process simplification for precursor compound

Patent metadata

Field	Value
Publication number	US-9238596-B2
Application number	US-201113994781-A
Country	US
Kind code	B2
Filing date	Dec 19, 2011
Priority date	Dec 20, 2010
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

The invention relates to a process for preparation of radiopharmaceutical precursors, and in particular protected amino acid derivatives which are used as precursors for production of radiolabelled amino acids for use in in vivo imaging procedures such as positron emission tomography (PET). Particularly, the invention relates to a process for preparation of a precursor useful in the preparation of the [ 18 F]-1-amino-3-fluorocyclobutanecarboxylic acid ([ 18 F] FACBC) PET tracer.

First claim

What is claimed is:

1. A method to obtain a compound of Formula (II):

wherein x is an integer of 0 to 4; and wherein said method comprises:
(a) debenzylation of a compound of Formula Ia:

wherein:
R 11 represents a C 1-5 straight- or branched-chain alkyl group;
R 12 represents an amino protecting group; and,
v is an integer of 0 to 4;

to yield a large scale batch of at least 100 g of a compound of Formula Ib:

wherein R 21 , R 22 and w are as defined for R 11 , R 12 and v of Formula Ia, respectively and wherein said large scale batch is purified only by glass sinter filtration, followed by evaporation;
(b) conversion of the compound of Formula Ib obtained directly from step (a) into a compound of Formula I:

wherein R 1 , R 2 and n are as defined for R 11 , R 12 and v of Formula Ia, respectively; and,
X represents a leaving group selected from a halogen, or the group —O—SO 2 —R 3 wherein R 3 is a halogen, a straight-chain or branched-chain C 1-10 alkyl, a straight-chain or branched-chain C 1-10 haloalkyl, and a C 6-10 aryl;
wherein said conversion is carried out by reaction of said compound of Formula Ib with a suitable form of X as defined for Formula I;
(c) reaction of the compound of Formula I obtained in step (b) with a suitable source of 18 F-fluoride to obtain a compound of Formula IIa:

wherein R 31 , R 32 and y are as defined for R 11 , R 12 and v of Formula Ia, respectively; and,
(d) deprotection of the compound of Formula IIa obtained in step (c) to remove R 31 and R 32 ; and

wherein said method provides a compound of Formula II suitable for use in in vivo imaging procedures.

2. The method as defined in claim 1 wherein X is a group represented by the group —O—SO 2 —R 3 .

3. The method as defined in claim 2 wherein R 3 is selected from the group consisting of toluenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, perfluoroalkylsulfonic acid, trimethylstannyl and triethylstannyl.

4. The method as defined in claim 3 wherein R 3 is trifluoromethanesulfonic acid.

5. The method as defined in claim 1 wherein X is halogen.

6. The method as defined in claim 5 wherein said halogen is bromo or chloro.

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

8. The method as defined in claim 1 wherein R 2 is selected from the group consisting of a t-butoxycarbonyl group, an allyloxycarbonyl group, a phthalimide group and N-benzylideneamine substituent.

9. The method as defined in claim 1 wherein said compound of Formula I is:

said compound of Formula Ia is:

and said compound of Formula Ib is:

and
wherein Et is ethyl, OTf is trifluoromethanesulfonic acid and Boc is tert-Butyloxycarbonyl.

10. The method as defined in claim 1 wherein said deprotection comprises removal of R 31 followed by removal of R 32 .

11. The method as defined in claim 1 wherein R 31 is ethyl.

12. The method as defined in claim 1 wherein R 32 is a t-butoxycarbonyl group.

13. The method as defined in claim 1 wherein said compound of Formula II is:

and said compound of Formula IIa is:

and
wherein Et is ethyl and Boc is tert-Butyloxycarbonyl.

14. The method as defined in claim 13 wherein said deprotection step comprises removal of Et by basic hydrolysis and removal of Boc by acidic hydrolysis.

15. The method as defined in claim 1 wherein steps (c) and (d) are carried out on an automated synthesiser.

Assignees

• Berg Tom Christian
• Ge Healthcare Ltd

Inventors

• Berg Tom Christian

Classifications

• C07C309/65

  of a saturated carbon skeleton · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · 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

• C07C303/28

  by reaction of hydroxy compounds with sulfonic acids or derivatives thereof · CPC title

• C07B59/001 Primary

  Acyclic or carbocyclic compounds · CPC title