Fluorination process

Patent metadata

Field	Value
Publication number	US-9468694-B2
Application number	US-201514809497-A
Country	US
Kind code	B2
Filing date	Jul 27, 2015
Priority date	Aug 12, 2005
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

The invention relates to a process for preparation of a compound of formula (I):

R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

which comprises:

(i) reaction with fluoride, suitably [ 18 F]fluoride, of a corresponding compound of formula (II):

wherein R 2 is selected from hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 6-14 aryl, C 6-14 arylalkyl, —(CH 2 CH 2 O) q —CH 3 wherein q is an integer of from 1 to 10;

R 1 is as defined for the compound of formula (I); and

R 3 is a leaving group. Certain novel precursors of formula (II) and radiopharmaceutical kits containing such precursors are also claimed.

First claim

The invention claimed is:

1. A compound of formula (IIa),

wherein
R 1 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
phenyl ring A is substituted by 1 to 3 substituents being chosen from any of the non-phenyl substituents defined for R 7 to R 10 ;
R 2 is hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 6-14 aryl, C 6-14 arylalkyl, or —(CH 2 CH 2 O) q —CH 3 where q is an integer of from 1 to 10;
R 3 is nitro, —N 2 + , chloro, bromo, iodo, —NR 4 (C 1-6 alkyl) 2 + where R 4 is C 1-6 alkyl, —OSO 2 R 5

where R 5 is C 1-6 alkyl, C 1-6 haloalkyl, or aryl, or where R 6 is hydrogen, C 1-6 alkyl, halo, aor nitro;
R 7 , R 8 , R 9 , and R 10 are each independently, fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) m OR 11 (where m is 1, 2, or 3), CF 3 , CH 2 —CH 2 Y, O—CH 2 —CH 2 Y, CH 2 —CH 2 —CH 2 Y, O—CH 2 —CH 2 —CH 2 Y (where Y is fluoro, chloro, bromo, or iodo), CN, (C═O)—R 11 , N(R 11 ) 2 , NO 2 , (C═O)N(R 11 ) 2 , O(CO) R 11 , OR 11 , SR 11 , COOR 11 , R ph , CR 11 ═CR 11 —R ph , CR 11 2 —CR 11 2 —R ph (where R ph is an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R 7 to R 10 and where R 11 is H or C 1-6 alkyl) or a protected derivative of any thereof.

2. A compound of formula (IIb):

wherein
R 1 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R 2 is hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 6-14 aryl, C 6-14 arylalkyl, or —(CH 2 CH 2 O) q —CH 3 where q is an integer of from 1 to 10;
R 3 is nitro, —N 2 + , chloro, bromo, iodo, —NR(C 1-6 alkyl) 2 + where R 4 is C 1-6 alkyl, —OSO 2 R 5

where R 5 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, or where R 6 is hydrogen, C 1-6 alkyl, halo, or nitro;
R 9 is hydroxy, —NO 2 , —CN, —COOR 11 or —OCH 2 OR 11 (where R 11 is hydrogen or C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or halo, or a protected derivative of any thereof.

3. A compound of formula (IIb) according to claim 2 where R 2 is hydrogen and R 3 is nitro.

4. A compound 2-[3-nitro-4-(methylformylamino)phenyl]-6-ethoxymethoxy-benzothiazole.

5. A radiopharmaceutical kit for the preparation of an 18 F-labelled tracer for use in PET, which comprises:
(i) a vessel containing a compound of formula (IIa), as defined in claim 1 ;
(ii) means for eluting the vessel with a source of 18 F − ;
(iii) an ion-exchange cartridge for removal of excess 18 F; and optionally
(iv) a cartridge for deprotection of the resultant product of formula (Ia):

wherein
R 1 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R 7 , R 8 , R 9 , and R 10 are each independently, fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) m OR 11 (where m is 1, 2, or 3), CF 3 , CH 2 —CH 2 Y, O—CH 2 —CH 2 Y, CH 2 —CH 2 —CH 2 Y, O—CH 2 —CH 2 —CH 2 Y (where Y is fluoro, chloro, bromo, or iodo), CN, (C═O)—R 11 , N(R 11 ) 2 , NO 2 , (C═O)N(R 11 ) 2 , O(CO) R 11 , OR 11 , SR 11 , COOR 11 , R ph , CR 11 ═CR 11 —R ph , CR 11 2 —CR 11 2 —R ph (where R ph is an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R 7 to R 10 and where R 11 is H or C 1-6 alkyl) or a protected derivative of any thereof; and
phenyl ring A is substituted by 1 to 3 substituents being chosen from any of the non-phenyl substituents defined for R 7 to R 10 .

6. A cartridge for a radiopharmaceutical kit for the preparation of an 18 F − labelled tracer for use in PET which comprises:
(i) a vessel containing a compound of formula (IIa) as defined in claim 1 ; and
(ii) means for eluting the vessel with a source of 18 F − .

7. A radiopharmaceutical kit for the preparation of an 18 F − labelled tracer for use in PET, which comprises:
(i) a vessel containing a compound of formula (IIb) as defined in claim 2 ;
(ii) means for eluting the vessel with a source of 18 F − ;
(iii) an ion-exchange cartridge for removal of excess 18 F − ; and optionally
(iv) a cartridge for deprotection of the resultant product of formula (Ib)

wherein
R 1 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R 9 is hydroxy, —NO 2 , —CN, —COOR 11 or —OCH 2 OR 11 (where R 11 is hydrogen or C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or halo, or a protected derivative of any thereof.

8. A cartridge for a radiopharmaceutical kit for the preparation of an 18 F − labelled tracer for use in PET which comprises:
(i) a vessel containing a compound of formula (IIb) as defined in claim 2 ; and
(ii) means for eluting the vessel with a source of 18 F − .

Assignees

• Ge Healthcare Ltd
• Ge Healthcare As

Inventors

• Storey Anthony Eamon
• Jones Clare Louise
• Bouvet Denis Raymond Christophe
• Lasbistes Nicolas
• Fairway Steven Michael
• Williams Lorenzo
• Gibson Alexander Mark
• Nairne Robert James
• Karimi Farhad
• Langstrom Bengt

Classifications

• B01J19/24

  Stationary reactors without moving elements inside (B01J19/08, B01J19/26 take precedence; with stationary particles B01J8/02) · CPC title

• A61K51/0453 Primary

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• B01J2219/24

  Stationary reactors without moving elements inside · CPC title

• C07C17/093 Primary

  by replacement by halogens · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title