# US 11,077,216 B2 · Formulation and method of synthesis

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- Number: US 11,077,216 B2
- Document ID: US11077216B2
- Status: Granted
- Kind: B2
- Application number: 15/318,599
- Filed: 2015-06-30
- Published: 2017-05-11
- Granted: 2021-08-03
- Earliest claimed: 2014-06-30
- Assignees: Ge Healthcare Limited
- Applicants: GE Healthcare Limited
- Inventors: Knut Richard Dyrstad; Torild Wickstrom; Thanushan Rajanayagam
- Web page: https://patentgrep.com/patent/US11077216B2

## CPC

- A61K 51/0402: {carboxylic acid carriers, fatty acids (amino acids A61K51/0406)}
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07C 227/20: by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C 2601/04: with a four-membered ring
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

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

## Claims

### Claim 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 18F-fluoride with a precursor compound of Formula I:
wherein:
LG is a leaving group;
PG1 is a carboxy protecting group;
and, PG2 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 PG1 and PG2 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 PG1 to obtain a reaction mixture comprising a compound of Formula III:
wherein PG1 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 PG1 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 PG2 to obtain a reaction mixture comprising 18F-FACBC;
(e) purifying said reaction mixture comprising 18F-FACBC by passing it through a hydrophilic lipophilic balanced (HLB) solid phase, wherein said purifying does not comprise passing the reaction mixture comprising 18F-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).

### Claim 2 (depends on 1)

The method as defined in claim 1 wherein LG is a linear or branched C1-10 haloalkyl sulfonic acid substituent, a linear or branched C1-10 alkyl sulfonic acid substituent, a fluorosulfonic acid substituent, or an aromatic sulfonic acid substituent.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The method as defined in claim 1 wherein PG1 is a linear or branched C1-10 alkyl chain or an aryl substituent.

### Claim 6 (depends on 5)

The method as defined in claim 5 wherein PG1 is methyl, ethyl, t-butyl or phenyl.

### Claim 7 (depends on 6)

The method as defined in claim 6 wherein PG1 is methyl or ethyl.

### Claim 8 (depends on 7)

The method as defined in claim 7 wherein PG1 is ethyl.

### Claim 9 (depends on 1)

The method as defined in claim 1 wherein PG2 is a carbamate substituent, an amide substituent, an imide substituent or an amine substituent.

### Claim 10 (depends on 9)

The method as defined in claim 9 wherein PG2 is t-butoxycarbonyl, allyloxycarbonyl, phthalimide, or N-benzylideneamine.

### Claim 11 (depends on 10)

The method as defined in claim 10 wherein PG2 is t-butoxycarbonyl.

### Claim 12 (depends on 1)

The method as defined claim 1 which is automated.

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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