A process for the synthesis of carbon labeled organic compounds

Patent metadata

Field	Value
Publication number	US-2021107859-A1
Application number	US-201917044774-A
Country	US
Kind code	A1
Filing date	Apr 3, 2019
Priority date	Apr 6, 2018
Publication date	Apr 15, 2021
Grant date	—

Abstract

A process for the synthesis of a carbon labeled organic compound containing a carbon labeled carboxyl group is described. A method of using carbon labeled organic compounds containing a carbon labeled carboxyl group according to the present disclosure; a process for manufacturing labeled pharmaceuticals and agrochemicals comprising synthesis of carbon labeled organic compounds containing a carbon labeled carboxyl group according to the present disclosure; and a process for producing tracers comprising synthesis of carbon labeled organic compounds containing a carbon labeled carboxyl group according to the present disclosure are also described.

First claim

1 . A process for the synthesis of a carbon labeled organic compound containing a carbon labeled carboxyl group according to formula (I)

wherein
*C is a 11 C, 13 C or 14 C isotope;
R 1 , R 2 and R 3 are, independently, a hydrogen atom, an aryl, a heteroaryl, a heterocycle, an alkyl, an alkyl halide, an alkene or an alkyne, said aryl, heteroaryl, heterocycle, alkene, alkyne and alkyl groups being optionally substituted, or
R 1 and R 2 form together with the carbon atom to which they are linked a carbonyl (—(C═O)— and R 3 is as defined above, or
R 1 and R 2 form together with the carbon atom to which they are linked an alkene with at least one double bond being alpha to the carboxyl group, said alkene being optionally substituted, and R 3 is as defined above, or
R 1 , R 2 and R 3 form together with the carbon atom to which they are linked an aryl, a heteroaryl, or a heterocycle, said aryl, heteroaryl and heterocycle being optionally substituted;
M 1 is a hydrogen atom, a silver cation (Ag + ), an alkaline cation selected from lithium (Li + ), sodium (Na + ), potassium (K + ), rubidium (Rb + ), or cesium (Cs + );

characterized in that
an organic compound containing a carboxyl group according to formula (II)

wherein R 1 , R 2 , R 3 and M 1 are as defined above,
is reacted with a labeled *CO 2 wherein *C is an isotope as defined above,
in the presence of a catalyst system comprising an inorganic salt of formula (III)
M 2 (L) m    (III)

wherein
M 2 is a transition metal selected from Cu, Pd, Ni, Ru, Ag, Rh, Fe, Co, Zn, Ir, Au, Pt,
m is 1 or 2;
L is a halogen atom selected from fluorine, chlorine, bromine, and iodide, a triflate or trifluoromethylsulfonate, a tosylate or p-toluenesulfonate, a mesylate or methanesulfonate, —CN, (CH 3 )COO—,

and a ligand of formula (IV), formula (V) or formula (VI)

wherein
n is 0 or 1;
n′ is 0 or 1;
n″ is 0 or 1;
n′″ is 0 or 1;
p is 0 or 1;
o is 0 or 1;
q is 0 or 1;
r is 0 or 1;
t is 0, 1, 2 or 3;
E is a single bond,

 —C(R 13 R 14 )— with R 13 and R 14 , independently being a hydrogen atom, an alkyl, an aryl, —CN, —NO 2 , a halogen atom selected from F, Cl, Br, I;
X is N(R 15 ) n′ , O, P, S(R 15 ) n′ , or P(R 15 ) n′ with R 15 being a hydrogen atom or an alkyl and with the proviso that when X is N(R 15 ) n′ , S(R 15 ) n′ , or P(R 15 ) n′ , and n′=n=0, is a double bond;
Z is N(R 15 ) n″ , O, P, S(R 15 ) n″ , or P(R 15 ) n″ , with R 15 being a hydrogen atom or an alkyl and with the proviso that when Z is N(R 15 ) n″ , S(R 15 ) n″ , or P(R 15 ) n″ , and n″=p=0, is a double bond;
A is N or P;
Y is a single bond,

 with R x being a hydrogen atom or an alkyl;
D is N(R 15 ) n′″ , O, P, S(R 15 ) n′″ , or P(R 15 ) n′″ with R 15 being a hydrogen atom or an alkyl and with the proviso that when D is N(R 15 ) n′″ , S(R 15 ) n′″ , or P(R 15 ) n′″ and n′″=n=0, is a double bond;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are, independently, a hydrogen atom, an alkyl, an alkoxy, an aryl, or —CN, said alkyl and aryl being optionally substituted, or
R 4 , R 5 , R 8 , R 9 , and R 12 are, independently, a hydrogen atom, an alkyl, an alkoxy, an aryl, or —CN, R 6 and R 7 and/or R 10 and R 11 form together with the carbon atoms to which they are linked a heterocycle, said alkyl, aryl and heterocycle being optionally substituted;
R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 and R 33 are, independently, a hydrogen atom, an alkyl, an alkoxy, an aryl, or a —CN, said alkyl and aryl being optionally substituted, or
when Y is a single bond, n=0, is a double bond, R 18 , R 21 , R 22 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 and R 33 are, independently, a hydrogen atom, an alkyl, an alkoxy, an aryl, or —CN, and R 19 and Rao and/or R 23 and R 24 form together with the carbon atoms to which they are linked an aryl, said alkyl and aryl being optionally substituted;
R 16 , R 17 and R 34 are, independently, a hydrogen atom, an alkyl, an alkoxy, an aryl, a heteroaryl, a heterocycle, said alkyl, aryl, heteroaryl and heterocycle being optionally substituted, —(C═S)—NR 35 R 36 , —(C═O)—NR 35 R 36 , —(CH 2 ) t —NR 35 R 36 , —(CH 2 ) t —PR 35 R 36 with
R 35 and R 36 being independently, a hydrogen atom, an alkyl, an alkene, an alkyne, an aryl, a heteroaryl, a heterocycle, said alkyl, alkene, alkyne, aryl, heteroaryl and heterocycle being optionally substituted,
R 35 and R 36 form together with the nitrogen atom to which they are linked an optionally substituted heteroaryl or heterocycle.

2 . The process according to claim 1 , wherein the ligand is of formula (IV)

wherein
p is 0 or 1;
E is a single bond,

 —C(R 13 R 14 )— with R 13 and R 14 , independently being a hydrogen atom, a C 1 -C 8 alkyl, or —CN;
X is N(R 15 ) n′ , n′=n=0, and is a double bond;
Z is O;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are, independently, a hydrogen atom, a C 1 -C 8 alkyl, an aryl having 6 to 14 carbon atoms, or a —CN, said alkyl and aryl being optionally substituted, or
R 5 , R 8 , R 9 , and R 12 are, independently, a hydrogen atom, a C 1 -C 8 alkyl, an aryl having 6 to 14 carbon atoms, or —CN, R 6 and R 7 and/or R 10 and R 11 form together with the carbon atoms to which they are linked a 5 to 10 membered heterocycle, said alkyl, aryl and heterocycle being optionally substituted.

3 . The process according to claim 1 , wherein the ligand of formula (IV) is

4 . The process according to claim 1 , wherein the ligand is of formula (V)

wherein
o is 0 or 1;
q is 0 or 1;
r is 0 or 1;
t is 0, 1, 2 or 3;
A is N or P;
R 16 , R 17 and R 34 are, independently, a hydrogen atom, a C 1 -C 8 alkyl, an aryl having 6 to 14 carbon atoms, a 5 to 10 membered heteroaryl, a 5 to 10 membered heterocycle, said alkyl, aryl, heteroaryl and heterocycle being optionally substituted, —(C═S)—NR 35 R 36 , —(C═O)—NR 35 R 36 , —(CH 2 ) t —NR 35 R 36 , —(CH 2 ) t —PR 35 R 36 with
R 35 and R 36 being independently, a hydrogen atom, a C 1 -C 8 alkyl, an aryl having 6 to 14 carbon atoms, a 5 to 10 membered heteroaryl, said alkyl, aryl, and heteroaryl being optionally substituted.

5 . The process according to claim 1 , wherein the ligand of formula (V) is

6 . The process accordi

Assignees

• Commissariat Energie Atomique

Inventors

• Audisio Davide
• Cantat Thibault
• Destro Gianluca

Classifications

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D209/42

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D207/416

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms · CPC title

• C07C253/30

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

• C07C303/40

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