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 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 deprotecting agent to provide a supported compound of formula (VIII)

e) contacting the supported compound of formula (VIII) with a compound (IX)

to provide a supported compound of formula (X)

f) contacting the supported compound of formula (X) with a cleavage reagent, and optionally with a deprotecting agent, to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof;

wherein

PG, PG1, PG4, PG5 and PG6 are each independently 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, and

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

2 . The method according to claim 1 , wherein PG, PG1, PG4, PG5, and PG6, 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).

3 . 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).

4 . The method according to claim 1 wherein at least one of the steps a)-f) is performed using a polar aprotic solvent.

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

6 . The method according claim 4 , wherein the polar aprotic solvent is selected from the group consisting of dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), a dichloromethane/dimethylformamide mixture, acetonitrile (ACN), an acetonitrile/dimethylformamide mixture, and dimethylsulfoxide (DMSO).

7 . The method according to claim 5 , wherein the base is selected from the group consisting of N,N-Diisopropylethylamine (DIPEA), N,N-Diisopropylethylamine ( i Pr2NEt), triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridine, and collidine.

8 . The method according to claim 5 , wherein the coupling agent is selected from the group consisting of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate (HDMC), 1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium; tetrafluoroborate (TATU), N,N,N′,N′-tetramethyl-S-(1-oxido-2-pyridyl)thiouronium tetrafluoroborate (TOTT), N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-Propanephosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM).

9 . The method according to claim 1 , wherein R1 and R2 are H.

10 . The method according to claim 1 , wherein the deprotecting agent used in step d) is piperidine.

11 . The method according to claim 1 , wherein step f) is performed using trifluoroacetic acid (TFA) or a trifluoroacetic acid (TFA)/water/triisopropylsilane mixture.

12 . The method according to claim 1 , wherein the resin comprising a linker group L is selected from the group consisting of p-alkoxybenzyl alcohol resin (Wang resin), 4-(1′,1′-dimethyl-1′-hydroxypropyl) phenoxyacetyl-alanyl-aminomethyl resin (DHPP resin), diphenyldiazomethane resin, (PDDM resin), Trityl-chloride resin and 2-chlorotrityl chloride resin.