Synthesis of prostate specific membrane antigen (PSMA) ligands

1 . A method for synthesizing a compound of formula (I), or a pharmaceutically acceptable salt thereof, using solid phase synthesis:

wherein

m is an integer selected from the group consisting of 1, 2, 3, 4, and 5;

q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6;

n is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6;

R is selected from the group consisting of C 6 -C 10 aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted 1 or more times with X;

X is —V—Y;

V is a bond or a C 1 -C 6 alkylene;

Y is a halogen; and

Ch is a chelating agent,

wherein said method comprises all of the following steps:

a) contacting a supported compound of formula (II)

with a compound of formula (III)

to provide a supported compound of formula (IV)

b) contacting the supported compound of formula (IV) with a deprotecting agent to provide a supported compound of formula (V)

c) contacting the supported compound of formula (V) with a compound of formula (VI)

to provide a supported compound of formula (VII)

d) contacting the supported compound of formula (VII) with a compound of formula (VIII)

to provide a supported compound of formula (IX)

e) contacting the supported compound of formula (IX) with a deprotecting agent to provide a supported compound of formula (X)

f) contacting the supported compound of formula (X) with a compound of formula (XI)

to provide a supported compound of formula (XII)

g) contacting the supported compound of formula (XII) with a cleavage reagent, and optionally with a deprotecting agent, to provide the compound of formula (I)

wherein

PG, and PG1 are each independently a carboxyl protecting group a carboxyl protecting group;

L is a linker;

PG2 and PG3 are each independently an amino protecting group;

R1 and R2 are each independently H, an activating ester group;

LG is a leaving group selected from the group consisting of imidazole, halogens and activating ester groups, and

p=q−1.

2 . The method according to claim 1 , wherein R is selected from

3 . The method according to claim 1 , wherein Ch is selected from the group consisting of:

4 . The method according to claim 1 , wherein said compound of formula (I) is a compound of formula (XIII)

5 . The method according to claim 1 , wherein said compound of formula (I) is a compound of formula (XIV)

6 . The method according to claim 1 , wherein PG, and PG1 are independently selected from the group consisting of benzyl, p-methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr).

7 . The method according to claim 1 , wherein PG2, and PG3, are independently selected from the group consisting of t-butyloxycarbonyl (Boc), 9-fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (alloc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl) (Dde), monomethoxytrityl (MMt), 1-(1-Adamantyl)-1-Methylethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) (ivDde) and 4-methyltrityl (Mtt).

8 . The method according to claim 1 , wherein at least one of the step a), d) or f) is performed using a coupling agent and/or a base.

9 . A method for synthesizing a compound of formula (I), or a pharmaceutically acceptable salt thereof, using solid phase synthesis:

wherein

m is an integer selected from the group consisting of 1, 2, 3, 4, and 5;

q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6;

n is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6;

R is selected from the group consisting of C 6 -C 10 aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted 1 or more times with X;

X is —V—Y;

V is a bond or a C 1 -C 6 alkylene;

Y is a halogen; and

Ch is a chelating agent,

wherein said method comprises all of the following steps:

a′) contacting a supported compound of formula (II′)

with a compound of formula (III′)

to provide a supported compound of formula (IV′)

b′) contacting the supported compound of formula (IV′) with a deprotecting agent to provide a supported compound of formula (V′)

c′) contacting the supported compound of formula (V′) with a compound of formula (VI′)

to provide a supported compound of formula (VII′)

d′) contacting the supported compound of formula (VII′) with a compound of formula (VIII′)

to provide a supported compound of formula (IX′)

e′) contacting the supported compound of formula (IX′) with a deprotecting agent to provide a resin-based compound of formula (X′)

f) contacting the supported compound of formula (X′) with a compound of formula (XI′)

to provide a supported compound of formula (XII′)

g′) contacting the supported compound of formula (XII′) with a cleavage reagent, and optionally with a deprotecting agent, to provide the compound of formula (I),

wherein

PG′, and PG1′ are each independently a carboxyl protecting group a carboxyl protecting group;

L′ is a linker;

PG2′ and PG3′ are each independently an amino protecting group;

R1′ and R2′ are each independently H, an activating ester group;

LG′ is a leaving group selected from the group consisting of imidazole, halogens and activating ester groups;

p=q−1.

10 . The method according to claim 9 , wherein PG′, and PG1′ are independently selected from the group consisting of benzyl, p-methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr).

11 . The method according to claim 9 , wherein PG2′, and PG3′, are independently selected from the group consisting of t-butyloxycarbonyl (Boc), 9-fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (alloc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl) (Dde), monomethoxytrityl (MMt), 1-(1-Adamantyl)-1-Methylethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) (ivDde) and 4-methyltrityl (Mtt).

12 . The method according to claim 9 , wherein at least one of the step a′), d′) or f′) is performed using a coupling agent and/or a base.

13 . The method according to claim 9 , wherein R is selected from

14 . The method according to claim 9 , wherein Ch is selected from the group consisting of:

15 . The method according to claim 9 , wherein said compound of formula (I) is a compound of formula (XIII)

16 . The method according to claim 9 , wherein said compound of formula (I) is a compound of formula (XIV)