Synthesis of fluorosilyl compounds

Abstract

The present disclosure relates to a compound of formula (1): The present invention relates to a method of synthesizing JPEG2025517444000056.jpg6140, wherein PG, R2 and R3 are as defined herein, and the use of said method in the preparation of a conjugate that binds to PSMA.

Description

[Technical field]

[0001] The present invention relates to methods for the synthesis of fluorosilyl compounds, more specifically compounds containing silicon fluoride acceptor (SiFA) moieties and derivatives thereof. [Background technology]

[0002] 4-(Dialkylfluorosilyl)benzoic acid is an example of a silicon fluoride acceptor (SiFA), a fluorine-containing molecule used in the synthesis of fluorine-labeled molecules, particularly 18 It is used when fortification with F radioisotope is desired. 18 F radioisotopes are widely used in positron emission tomography (PET).

[0003] SiFAs bind to the prostate-specific membrane antigen (PSMA) target molecule to form PSMA-SiFA conjugates. 18 When used in combination with F PET imaging, it allows visualization of prostate cancer. The addition of radiotherapeutic moieties to these PSMA-SiFA conjugates, specifically by adding chelating groups capable of chelating radioisotopes, allows visualization of relevant areas in conjunction with targeted radiotherapy. This dual function reduces the possibility of off-target radiation damage. WO2019 / 020831, WO2020 / 157177, and WO2020 / 157184 disclose PSMA-SiFA conjugates.

[0004] Known procedures for the synthesis of the SiFA 4-(di-tert-butylfluorosilyl)benzoic acid are disclosed, for example, in Chem. Eur. J. 2009, 15, 2140-2147 and WO2020 / 157128.

[0005] However, there remains a need for improved methods for the synthesis of SiFAs, including 4-(dialkylfluorosilyl)benzoic acids and their precursors. In particular, synthetic procedures that allow the preparation of such compounds in high yield and purity are desirable. Summary of the Invention

[0006] The present invention provides a method for producing a compound of formula (1), comprising reacting a compound of formula (2) with an alkyllithium reagent of formula (3) and a compound of formula (4):

[0007] [ka]

[0008] A method for preparing where PG is a protecting group; X is Br, Cl or I; R 2 and R 3 are independently linear or branched C 1-10 is alkyl; R 1 is a linear C 1-6 is alkyl; and Here, an alkyllithium reagent of formula (3) is added to a mixture containing compounds of formulas (2) and (4).

[0009] In the process of the present invention, a linear alkyllithium reagent of formula (3) is added to a mixture containing compounds of formulas (2) and (4). This one-pot procedure is in contrast to known procedures which typically require the stepwise addition of tert-butyllithium to a compound of formula (2) at cryogenic temperatures, followed by the addition of a compound of formula (4).

[0010] The method of the present invention has been found to significantly improve the yield of the compound of formula (1) compared to similar known procedures. Furthermore, the method of the present invention does not require the use of tert-butyllithium and does not require cryogenic reaction conditions. Linear alkyllithium reagents such as n-butyllithium can be used at milder reaction temperatures. Thus, the method of the present invention is inherently safer and more amenable to scale-up. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention relates to a method for producing a compound of formula (1), comprising reacting a compound of formula (2), an alkyllithium reagent of formula (3), and a compound of formula (4):

[0012] [ka]

[0013] and providing a method for preparing where PG is a protecting group; X is Br, Cl or I; R 2 and R 3 are independently linear or branched C 1-10 is alkyl; R 1 is a linear C 1-6 is alkyl; and Here, an alkyllithium reagent of formula (3) is added to a mixture containing compounds of formulas (2) and (4).

[0014] In the methods and compounds herein, PG is a protecting group. PG can be an acid labile protecting group. PG can be a silyl ether protecting group. PG can be selected from trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS) and di-tert-butylmethylsilyl (DTBMS). PG can be tert-butyldimethylsilyl (TBDMS).

[0015] In the methods and compounds herein, X is Br, Cl or I. X can be Br. X can be Cl. X can be I. The compound of formula (2) may be represented by formula (2a), (2b) or (2c):

[0016] [ka]

[0017] The compound may be: The compound of formula (2) has the formula (2a):

[0018] [ka]

[0019] The compound may be: The compound of formula (2) may be represented by formula (2d), (2e) or (2f):

[0020] [ka]

[0021] The compound may be: The compound of formula (2) has the formula (2d):

[0022] [ka]

[0023] The compound may be: In the methods and compounds herein, R 1 is a linear C 1-6 Therefore, the alkyl lithium reagent of formula (3) is a linear C 1-6 It is an alkyl lithium reagent. 1 is a linear C 1-5 R can be alkyl. 1 is a linear C 1-4R can be alkyl. 1 R may be selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. The alkyllithium reagent of formula (3) may be selected from methyllithium, ethyllithium, n-propyllithium, n-butyllithium, n-pentyllithium and n-hexyllithium. 1 The alkyllithium reagent of formula (3) may be n-butyllithium.

[0024] In the methods and compounds herein, R 2 and R 3 are independently linear or branched C 1-10 It is an alkyl group. 2 and R 3 are independently linear or branched C 1-6 R can be alkyl. 2 and R 3 are independently linear or branched C 1-4 R can be alkyl. 2 and R 3 are independently linear or branched C 3-10 R can be alkyl. 2 and R 3 are independently linear or branched C 3-6 R can be alkyl. 2 and R 3 are independently linear or branched C 3-4 R can be alkyl. 2 and R 3 are independently linear C 1-10 R can be alkyl. 2 and R 3 are independently linear C 1-6 R can be alkyl. 2 and R 3 are independently linear C 1-4 R can be alkyl. 2 and R 3 is an independent branch C 3-10 R can be alkyl. 2 and R 3 is an independent branch C 3-6 R can be alkyl. 2 and R3 is an independent branch C 3-4 R can be alkyl. 2 and R 3 R may be independently selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl and tert-butyl. 2 and R 3 may both be tert-butyl.

[0025] In the methods and compounds herein, R 2 is linear or branched C 1-10 R can be alkyl. 2 is linear or branched C 1-6 R can be alkyl. 2 is linear or branched C 1-4 R can be alkyl. 2 is linear or branched C 3-10 R can be alkyl. 2 is linear or branched C 3-6 R can be alkyl. 2 is linear or branched C 3-4 R can be alkyl. 2 is a linear C 1-10 R can be alkyl. 2 is a linear C 1-6 R can be alkyl. 2 is a linear C 1-4 R can be alkyl. 2 is branch C 3-10 R can be alkyl. 2 is branch C 3-6 R can be alkyl. 2 is branch C 3-4 R can be alkyl. 2 R may be selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl and tert-butyl. 2 can be tert-butyl.

[0026] In the methods and compounds herein, R 3 is linear or branched C 1-10 R can be alkyl. 3 is linear or branched C 1-6R can be alkyl. 3 is linear or branched C 1-4 R can be alkyl. 3 is linear or branched C 3-10 R can be alkyl. 3 is linear or branched C 3-6 R can be alkyl. 3 is linear or branched C 3-4 R can be alkyl. 3 is a linear C 1-10 R can be alkyl. 3 is a linear C 1-6 R can be alkyl. 3 is a linear C 1-4 R can be alkyl. 3 is branch C 3-10 R can be alkyl. 3 is branch C 3-6 R can be alkyl. 3 is branch C 3-4 R can be alkyl. 3 R may be selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl and tert-butyl. 3 can be tert-butyl.

[0027] The compound of formula (4) has the formula (4a):

[0028] [ka]

[0029] The compound may be: The compound of formula (1) has the formula (1a):

[0030] [ka]

[0031] The compound may be: The compound of formula (1) has the formula (1b):

[0032] [ka]

[0033] The compound may be: The method of the present invention comprises reacting a compound of formula (2d) with n-butyl lithium (n-BuLi) and a compound of formula (4a) to produce a compound of formula (1b):

[0034] [ka]

[0035] where n-BuLi is added to a mixture containing compounds of formula (2d) and (4a). In the method herein, the mixture containing the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of -10°C to 30°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of -10°C to 20°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of -5°C to 25°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of -5°C to 20°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of from -5°C to 15°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of from -5°C to 10°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of from -5°C to 5°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of from 0°C to 25°C during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature between 0° C. and 20° C. during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature between 0° C. and 15° C. during the addition of the alkyllithium reagent. The mixture containing the compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature between 0° C. and 10° C. during the addition of the alkyllithium reagent.The mixture containing compounds of formulae (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of from 0° C. to 5° C. during the addition of the alkyllithium reagent.

[0036] In the method of the present invention, 1.0 to 1.5 molar equivalents of an alkyllithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f). 1.0 to 1.3 molar equivalents of an alkyllithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f). 1.1 to 1.2 molar equivalents of an alkyllithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f). 1.15 molar equivalents of an alkyllithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f).

[0037] In the method of the present invention, 1.0 to 1.5 molar equivalents of the compound of formula (4) or (4a) may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f). 1.0 to 1.3 molar equivalents of the compound of formula (4) or (4a) may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f). 1.1 to 1.2 molar equivalents of the compound of formula (4) or (4a) may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f). Relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e) or (2f), 1.15 molar equivalents of the compound of formula (4) or (4a) may be used.

[0038] In the method used to prepare the compound of formula (1), (1a) or (1b) herein, an aprotic solvent may be used. A polar aprotic solvent may be used. The solvent used may be tetrahydrofuran (THF).

[0039] In the processes herein, the alkyllithium reagent is preferably added to the reaction mixture as a solution in an aprotic solvent, for example a solution in hexane, for example a 2.5M solution in hexane.

[0040] The method herein comprises deprotecting a compound of formula (1), (1a) or (1b) with an acid to give a compound of formula (5) or (5a):

[0041] [ka]

[0042] The method may include the further step of obtaining a compound of formula (I). The acid used in the deprotection step may be any acid suitable for deprotection. The acid used may be hydrochloric acid.

[0043] The method herein provides for the oxidation of a compound of formula (5) or (5a) to form a compound of formula (6) or (6a):

[0044] [ka]

[0045] The method may include the further step of obtaining a compound of formula (I). The oxidizing agent used in the oxidation step may be any suitable oxidizing agent. The oxidizing agent may be potassium permanganate (KMnO 4 The oxidation reaction may be carried out with NaH 2 PO 4 The oxidation reaction may further include the use of NaH 2 PO 4 The oxidation reaction may further include the use of HCl. The oxidation reaction may be followed by a grinding purification step, which may be, for example, a grinding purification step comprising the reaction of formula (7), (7a), (7b), or (7c):

[0046] [ka]

[0047] may be used to remove undesirable oxidation by-products such as compounds of the formula: In the grinding purification step, heptane:Et 2 A solvent system of 25:1 heptane:EtO in the trituration purification step may also be used. 2 O Solvent systems may also be utilized.

[0048] The grinding and refining step may include the following steps: The crude material containing the compound of formula (6) or (6a) is dissolved in 25:1 heptane:Et at an elevated temperature, for example at about 65° C. 2 Stir in O until dissolved, e.g., for up to 30 min. The resulting mixture is cooled to room temperature with stirring and then cooled to 0°C, for example with ice, over approximately 20 minutes. The crystallized product was filtered and the filter cake was washed with ice-cold 25:1 heptane:Et 2 O, followed by one or more washes with n-pentane. The product is dried under vacuum at room temperature until it reaches a constant weight.

[0049] Also provided is a method of synthesizing a compound of formula (I), comprising the step of oxidizing a compound of formula (II) with potassium permanganate;

[0050] [ka]

[0051] where each R is independently C 1 ~C 6 It is an alkyl group. The compound of formula (I) can be used to prepare radiopharmaceuticals. In some embodiments, the compound of formula (I) can be used to prepare radiopharmaceuticals in which the fluorine atom of the compound of formula (I), or its derivative, or subsequent product, is enriched with fluorine-18 isotope. It should be understood that the molecules disclosed herein that have fluorine atoms include embodiments in which the fluorine atom is enriched (i.e., above natural abundance) with fluorine-18 isotope.

[0052] The oxidation step described herein uses a single step oxidation and avoids the use of pyridinium chlorochromate, a well-known toxic and carcinogenic compound. Prior art methods utilizing pyridinium chlorochromate require extensive purification to ensure that all chromium compounds and their by-products are removed before the oxidation product can be safely used in subsequent synthetic steps, thus ensuring that the final product can be safely administered in a pharmaceutical composition.

[0053] The method of synthesizing a compound of formula (I) further comprises reacting a compound of formula (III) with an acid

[0054] [ka]

[0055] by deprotecting a compound of formula (II). The acid used to deprotect the compound of formula (III) may be hydrochloric acid.

[0056] The compound of formula (II), (5) or (5a) may be substantially purified prior to oxidation with potassium permanganate.The compound of formula (II), (5) or (5a) may be substantially purified by column chromatography prior to oxidation with potassium permanganate.

[0057] It has been found that purification of the compound of formula (II), (5) or (5a) prior to oxidation to the compound of formula (I), (6) or (6a) effectively reduces the presence of undesired by-products. Without wishing to be bound by theory, purification of the compound of formula (II), (5) or (5a) prior to the oxidation step results in fewer oxidation by-products being produced, which ultimately results in improved purification of the compound of formula (I), (6) or (6a).

[0058] The method further includes reacting a compound of formula (V), e.g., 4-bromophenyl)methoxy-tert-butyldimethylsilane (a compound having a TBDMS protecting group), with an alkyl lithium reagent and a compound of formula (IV)

[0059] [ka]

[0060] where R is defined above; The compound of formula (III) can include a step of synthesizing the compound of formula (III) by reacting with

[0061] It should be understood that other alcohol protecting groups besides the TBDMS protecting group are also contemplated within the scope of the present invention, particularly where the protecting group is removable under acidic conditions (e.g., removable with HCl in alcohol).

[0062] The synthesis of the compound of formula (III) can be carried out at a temperature between -10°C and 30°C, optionally between -5°C and 25°C, further optionally between 0°C and 20°C. The alkyllithium reagent may be n-butyllithium. Advantageously, unlike prior art methods, the use of n-butyllithium avoids the use of tert-butyllithium. tert-butyllithium is a highly reactive compound (pyrophoric, flammable, toxic, and corrosive) and must be handled with extreme care. For safety reasons, prior art methods stipulate that the tert-butyllithium reaction be carried out alone using a two-fold excess of tert-butyllithium, adding the reagent dropwise, and cooling the reaction with dry ice.

[0063] Advantageously, as disclosed herein, n-butyllithium can be used in the lithium-halogen exchange reaction. Because n-butyllithium is very unreactive and not highly pyrophoric, the lithium-halogen exchange reaction can be cooled with ice water. It has also been found that a nearly equimolar ratio of organolithium to aryl bromide can be used. Moreover, advantageously, all three reagents (compound of formula (IV), compound of formula (V) and n-butyllithium) can be present simultaneously in a "one-pot" reaction. Thus, the use of n-butyllithium offers the advantages of being safer (i.e., it is a milder organolithium reagent) and provides improved scalability with improved efficiency (i.e., fewer equivalents of organolithium reagent are required in a simple "one-pot" reaction that can be cooled with ice water instead of dry ice).

[0064] The method may further include the step of synthesizing a compound of formula (V), 4-bromophenyl)methoxy-tert-butyldimethylsilane, by protecting 4-bromobenzyl alcohol using tert-butyldimethylsilyl chloride and a Lewis base catalyst. The Lewis base catalyst may be imidazole.

[0065] As stated above, it should be understood that other alcohol protecting groups besides the TBDMS protecting group are also contemplated within the scope of the present invention, particularly where the protecting group is removable under acidic conditions (e.g., removable with HCl in alcohol).

[0066] The compounds of formula (6) or (6a) may be substantially free of metal ions, optionally substantially free of heavy metal ions or transition metal ions, or even optionally substantially free of manganese and / or chromium compounds.

[0067] After oxidation, the compound of formula (6) or (6a) can be used to introduce SiFA moieties into other molecules, e.g., to form ligand-SiFA conjugates, e.g., to form ligand-SIFA-chelator conjugates.

[0068] The compound of formula (6) or (6a) may be purified after oxidation. The trituration purification step described herein produces a compound of formula (7), (7a), (7b) or (7c):

[0069] [ka]

[0070] Undesirable by-products such as The presence of a compound of formula (7) or (7a) in a subsequent reaction step may be, for example, a compound of the formula:

[0071] [ka]

[0072] This can lead to by-products containing the group: The compounds of formula (6) or (6a) can be used to prepare radiopharmaceuticals. (a) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA); (b) a silicon fluoride acceptor (SIFA) moiety that contains a covalent bond between a silicon and a fluorine atom; and (c) one or more chelating groups, optionally containing a chelated non-radioactive or radioactive cation; The ligand-SIFA-chelator conjugate may be a ligand-SIFA-chelator conjugate comprising:

[0073] The radiopharmaceutical may be in the form of a composition, said composition comprising a compound of the formula:

[0074] [ka]

[0075] group at 0.1% (w / w) or less, 0.09% (w / w) or less, 0.08% (w / w) or less, 0.07% (w / w) or less, 0.06% (w / w) or less, 0.05% (w / w) or less, 0.04% (w / w) or less, 0.03% (w / w) or less, 0.02% (w / w) or less, or 0.01% (w / w) or less.

[0076] Fluorosilyl compounds with silyl t-butyl groups have fluorine atoms 18 F isotope enhanced PET imaging. Therefore, the method herein provides an additional 18 A F fluorine exchange step may also be included.

[0077] The method herein comprises the steps of reacting a compound of formula (l)a or (6a) with a compound of formula (X) to form a compound of formula (XI)

[0078] [ka]

[0079] wherein: SUPP stands for solid support or a link to a solid support; PROT represents a protecting group; X represents a protecting group; is either an optionally protected amine or azide group; and m and n are independently either 0 or 1.

[0080] The compound of formula (XI) can be considered as a PSMA-SiFA conjugate precursor. The method includes the steps of preparing a compound of formula (XII) from a compound of formula (XI)

[0081] [ka]

[0082] may further include where m and n are independently either 0 or 1; R CH is a chelating group; X is an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond,

[0083] [ka]

[0084] Linking group

[0085] [ka]

[0086] Or, the expression

[0087] [ka]

[0088] Linking group

[0089] [ka]

[0090] is selected from. The compound of formula (XII) contains a metal ion chelating group R CHThe PSMA-SiFA conjugate or PSMA-SiFA conjugate precursor can be considered to have the following structure:

[0091] Ligand-SIFA-chelator conjugate or R CH The chelating group of Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] Hexadecane (DO2A), 1,4,7,10-tetracyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''1,4,7,10-tetra(methylene)phosphonic acid (DOTMP), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphoric acid) (DPDP), diene Tetylenetriamine-N,N',N''-penta(methylene)phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethyleneglycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraacetic acid Azacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), tetra 3-hydroxy-N-methyl-2-pyridinone chelator (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino) )ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), abbreviated as Me-3,2-HOPO, 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridine-bis(methyleneaminetetraacetic acid (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazonan-1-yl]methyl-hydroxy-phosphoryl]propanoic acid, and triethylenetetraaminehexaacetic acid (TTHA).

[0092] Ligand-SIFA-chelator conjugate or R CH The chelating group of 1,4,7,10-tetracyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), or 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP).

[0093] Ligand-SIFA-chelator conjugate or R CH The chelating group of

[0094] [ka]

[0095] may be selected from: The chelating groups may be tailored as necessary to advantageously retain ions such as radioisotope metals.

[0096] The chelating group may include a chelated cation, which may be radioactive or non-radioactive. The chelating group may include a chelated metal cation, which may be radioactive or non-radioactive. Examples of cations that may be chelated by the chelating group include: 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 90 Y, 89 Y, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 Pm, 151 Pm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 177 Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb,203 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th cation, 18 a cationic molecule containing F, or 18 F-[AIF] 2+ The cation may be a radioactive cation selected from the cations Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Er and Th. The cation may be a non-radioactive cation selected from the cations Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th and Er. The cation may be Ga. The cation may be Lu. The cation may be a non-radioactive Ga 3+ It may be a cation.

[0097] The compound of formula (XII) is

[0098] [ka]

[0099] [ka]

[0100] may be selected from: The compound of formula (XII) may be a compound of formula (XIII).

[0101] [ka]

[0102] The compound of formula (XIII) may be a compound of formula (XIV).

[0103] [ka]

[0104] The method may further comprise enriching the fluorine atom of any of the compounds of formulae (I)-(IV) and (X)-(XIII) or compound (XIV) with the fluorine-18 isotope. For example, the radioactive isotope of fluorine may be introduced as a result of an isotope exchange reaction, in which, for example, the compound of formula (I) or compound (XIV) is enriched with the fluorine-18 isotope using [18F-] / Kryptofix2.2.2 / K+ as described in Angew Chem Int Ed Engl. 2006 Sep 11; 45(36): 6047-50, or enriched by methods known to those skilled in the art. The reaction may be carried out in a dipolar aprotic solvent.

[0105] The method may further include enriching the fluorine atoms of the compound of any of formulas (XI)-(XIII) or compound (XIV) with fluorine-18 isotope. The method may include enriching the fluorine atoms of the compound of formulas (XI)-(XIII) or compound (XIV) with fluorine-18 isotope to greater than 50%, 60%, 70%, 80%, 85%, 90%, 95% or 98%. The fluorine-18 isotope is beneficial and useful for PET imaging.

[0106] The method may include chelating a radioactive metal cation in a chelating group, or the method may include chelating a non-radioactive metal cation in a chelating group. The chelating group may chelate a radioactive cation, the chelated radioactive cation being: 68 Ga, 177 Lu, or 225 Advantageously, the radioactive metal ion is useful for imaging and / or radiotherapy. The chelating group may be chelated to a non-radioactive cation, and the chelated non-radioactive cation may be selected from nat It may be Ga.

[0107] In the methods herein, the ligand-SIFA-chelator conjugate comprises:

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] may be selected from: Also,

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka]

[0117] Also provided is a composition comprising a ligand-SIFA-chelator conjugate selected from the group consisting of:

[0118] [ka]

[0119] group at 0.1% (w / w) or less, 0.09% (w / w) or less, 0.08% (w / w) or less, 0.07% (w / w) or less, 0.06% (w / w) or less, 0.05% (w / w) or less, 0.04% (w / w) or less, 0.03% (w / w) or less, 0.02% (w / w) or less, or 0.01% (w / w) or less.

[0120] The method may further comprise using the ligand-SIFA-chelator conjugate or the compound of formula (XII or XIII), compound (XIV), or a compound further derived therefrom, in the diagnosis and / or treatment of disease. The method may further comprise using the ligand-SIFA-chelator conjugate or the compound of formula (XII) or (XIII), compound (XIV), or a compound further derived therefrom, in the diagnosis of disease, where any fluorine atom is enriched with fluorine-18 isotope. When administered, for example, to the human or animal body, the ligand-SIFA-chelator conjugate or the compound of formula (XII or XIII) can preferentially bind to the region of interest, and it can then be appreciated that, for example, the isotope present in the ligand-SIFA-chelator conjugate or the compound of formula (XII or XIII) can be useful for imaging the region to which the compound is bound. This may aid in determining diagnostic and / or treatment methods.

[0121] The method may further comprise the step of using the ligand-SIFA-chelator conjugate or the compound of formula (XII) or (XIII), compound (XIV), or a compound further derived therefrom, in the diagnosis and / or treatment of disease, wherein the chelating group chelates a radioactive cation, and wherein, optionally, the radioactive cation is 68 Ga, 177 Lu, or 225The method may further comprise using the ligand-SIFA-chelator conjugate or the compound of formula (XII) or (XIII), compound (XIV), or a compound further derived therefrom, in the diagnosis and / or treatment of disease, wherein the chelating group chelates a non-radioactive cation, and optionally the non-radioactive cation is selected from nat Ga. For example, it can be understood that when administered to the human or animal body, the ligand-SIFA-chelator conjugate or the compound of formula (XII) or (XIII), or compound (XIV), can preferentially bind to the target area. And, for example, the isotope present in the ligand-SIFA-chelator conjugate or the compound of formula (XII) or (XIII), or compound (XIV), can be useful for treating the area to which the compound is bound. For example, this can be useful for carrying the radioisotope close to the diseased cell / tissue.

[0122] Disclosed herein is the use of any one of the methods disclosed herein to make the corresponding compounds disclosed herein, and / or any derivative moieties made therefrom. As a non-limiting example, disclosed herein is the use of the methods disclosed in the first aspect of the invention to make compounds of formula (I), (I)a or (6a).

[0123] Disclosed herein are compounds disclosed herein when made by the corresponding methods disclosed herein, and / or any derivative moieties made therefrom. As a non-limiting example, disclosed herein are compounds of formula (I), (I)a, or (6a) when made using the methods disclosed in the first aspect of the present invention.

[0124] Compounds of formula (I)a / (6a) can in particular be prepared according to the following scheme:

[0125] [ka]

[0126] It can be prepared according to Step a - The alcohol group of 4-bromobenzyl alcohol is protected with a TBDMS group to give 4-bromophenyl)methoxy-tert-butyldimethylsilane (corresponding to a compound of formula (2d) or an embodiment of a compound of formula (V) in which TBDMS is used to protect the alcohol, referred to herein as compound (V)a).

[0127] Step b - The bromine group of (4-bromophenyl)methoxy-tert-butyldimethylsilane (compound (V)a) is exchanged for a dialkylfluorosilyl group by reaction with tert-butyl-difluorosilane (corresponding to a compound of formula (4a) or an embodiment of a compound of formula (IV) in which the R group is a tert-butyl group, referred to herein as compound (IV)a) and n-butyllithium to give di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane (corresponding to a compound of formula (1b) or an embodiment of a compound of formula (III) in which the R group is a tert-butyl group, referred to herein as compound (III)a)).

[0128] Step c - The TBDMS protecting group of compound (III)a was removed using acid and the resulting compound, 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol (corresponding to a compound of formula (5a) or an embodiment of a compound of formula (II) in which the R group is a tert-butyl group, referred to herein as compound (II)a) was purified by column chromatography.

[0129] Step d - The alcohol group of 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol (compound (II)a) was oxidized to the corresponding benzoic acid to give 4-(di-tert-butyl(fluoro)silyl)benzoic acid (corresponding to the compound of formula (6a) or an embodiment of the compound of formula (I); compound (I)a).

[0130] The following experiment is provided for the synthesis of a compound of formula (6a) or 4-(di-tert-butyl(fluoro)silyl)benzoic acid (compound (I)a), which corresponds to an embodiment of a compound of formula (I). EXAMPLES

[0131] Example A Preparation of 4-(di-tert-butyl(fluoro)silyl)benzoic acid Step a - Synthesis of (4-bromophenyl)methoxy-tert-butyldimethylsilane (V)a To a solution of 4-bromobenzyl alcohol (113.5 g, 606.8 mmol, 1.0 equiv) in DMF (1100 mL) was added imidazole (49.57 g, 728 mmol, 1 equiv) and TBDMS-Cl (98.78 g, 655.38 mmol, 1.08 equiv). The mixture was stirred at room temperature overnight.

[0132] The reaction mixture was diluted with water (1100 mL) and extracted with MTBE (2×500 mL, then 2×300 mL). The combined organics were washed with MgSO 4 The material was purified in two portions on silica eluting with 2% MTBE / isohexane to give the desired material as a colourless oil (184.0 g, 100%).

[0133] Step b - Synthesis of di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane (III) a To a solution of (4-bromophenyl)methoxy-tert-butyldimethylsilane ((V)a; 17.85 g, 59.23 mmol) and tert-butyl-difluorosilane (12.28 g, 68.11 mmol) in THF (170 mL) cooled to +1° C. (internal) was added n-butyllithium solution (2.5 M, 27.24 mL, 68.11 mmol) dropwise over 1 h. The solution was stirred at +1° C. (internal) for 2 h and then warmed to +15° C. (internal) over 30 min. The solution was diluted with MTBE (200 mL) and washed with saturated brine (200 mL). The aqueous solution was diluted with water (50 mL) and extracted into MTBE (3×200 mL). The combined organics were washed with MgSO 4 The mixture was dried at 40° C., filtered and evaporated to give a yellow oil (21.89 g, 97%) which was used without purification.

[0134] Step c- Synthesis of 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol (II)a To a solution of di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane ((III)a; 21.89 g, 57.20 mmol) in methanol (700 mL) was added concentrated HCl (11 mL) dropwise over 10 min with stirring, and the solution was then stirred at room temperature overnight.

[0135] The reaction mixture was evaporated to remove volatile organics and the residue was treated with saturated aqueous sodium bicarbonate (120 mL) until pH 8. The mixture was extracted into MTBE (3×200 mL). The combined organics were washed with MgSO 4 It was dried at 40° C., filtered and evaporated to give a pale yellow oil.

[0136] The oil was diluted with toluene (10 mL) and loaded onto a 330 g pre-wet (toluene) silica column. The column was eluted with a gradient of 0-10% ethyl acetate in toluene over 10 column volumes. Fractions were analyzed by TLC (5% ethyl acetate / toluene, KMnO 4 Staining with 5% CO and only the purest fractions were kept and combined to give the desired material as a white solid (8.078 g, 53%). Some mixed fractions were kept and combined with other batches for repurification.

[0137] Step d- Synthesis of 4-(di-tert-butyl(fluoro)silyl)benzoic acid (I)a A solution of 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol ((II)a; 33.17 g, 123.58 mmol) in tert-butanol (370 mL) and DCM (75 mL) was added to the reaction mixture with KMnO 4 (29.3 g in 185 mL) was added in a thin stream over 5 min., followed by NaH 2 PO 4A solution of HCl (56.27 g in 200 mL) was injected in a thin stream over 10 min, causing the internal temperature to rise from +20° C. to +35° C. The mixture was stirred for 2 h and then an aliquot was removed, treated according to the work-up procedure, separated and analysed by NMR which confirmed the reaction was complete.

[0138] Saturated NaSO 3 The reaction was quenched by the addition of aqueous (700 mL) and stirred for 30 min. Concentrated HCl (110 mL) was added dropwise over 10 min and then stirred for 30 min. The now cloudy white mixture was extracted into MTBE (1000 mL, then 2 x 500 mL). The combined extracts were washed with MgSO 4 It was dried at 40° C., filtered and evaporated to give a white solid (34.7 g, 99%).

[0139] This material was mixed with two other batches (total weight 111.06 g), dissolved in MTBE (1 L) at 50° C., and then evaporated to give a white solid (114.06 g) containing some residual MTBE. The solid was diluted with 25:1 heptane:Et 2 20° C. in ice (720 mL) and stirred at 65° C. for 30 min. The mixture was cooled to room temperature with stirring and then cooled to 0° C. in ice for 20 min. The mixture was filtered and the filter cake was diluted with ice-cold 25:1 heptane:Et 2 The mixture was washed with 2×O (3×100 mL) followed by n-pentane (500 mL). The resulting white solid was dried under vacuum at room temperature to constant weight. Yield: 102.28 g (90% of theoretical yield).

[0140] Example B - Reaction conditions for step b of the invention and comparison Comparative reaction conditions for step b (synthesis of di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane) are outlined in Table 1.

[0141] Table 1, entry 1 shows the reaction conditions from the literature (i.e., stepwise addition of alkyllithium reagents to 4-(TBS-oxymethyl)bromobenzene using tert-BuLi at cryogenic temperatures, followed by t-Bu 2SiF 2 These conditions are considered unsuitable for scale-up due to the large amount of by-products produced, the need for cryogenic temperatures, and the need to use tert-BuLi.

[0142] Entry 2 represents the procedure of entry 1 in which n-BuLi was used instead of tert-BuLi, but the reaction conditions were not significantly altered (i.e., stepwise addition and cryogenic temperatures were still used), resulting in a mixture of products that gave the desired product in lower yield.

[0143] Entry 3 represents a procedure according to the invention, in which n-BuLi is reacted with 4-(TBS-oxymethyl)bromobenzene and t-Bu 2 SiF 2 (i.e., one-pot). This resulted in improved yields of the desired product compared to the procedures in Entries 1 and 2, without the need for tert-BuLi or cryogenic temperatures.

[0144] Entry 4 represents the use of tert-BuLi instead of n-BuLi in the procedure of entry 3 without significant modification of the reaction conditions (i.e., one-pot and non-cryogenic), resulting in a mixture of products with low yields of the desired product.

[0145] Entries 5 and 6 represent the procedure according to the invention. Feasibility on a larger scale is demonstrated.

[0146] [Table 1-1]

[0147] [Table 1-2]

Claims

1. A method for preparing the compound of formula (1), comprising the step of reacting the compound of formula (2) with the alkyllithium reagent of formula (3) and the compound of formula (4): 【Chemistry 1】 In the formula, PG is a protecting group; X is Br, Cl, or I; R ２ and R ３ These are independently linear or branched C １－１０ It is alkyl; R １ is a straight chain C １－６ It is alkyl, The alkyllithium reagent of formula (3) is added to a mixture containing the compounds of formulas (2) and (4). method.

2. The method according to claim 1, wherein the alkyllithium reagent is n-butyllithium.

3. The method according to claim 1, wherein PG is an acid-unstable protecting group.

4. The method according to claim 3, wherein PG is tert-butyldimethylsilyl (TBDMS).

5. The method according to claim 1, wherein X is Br.

6. R ２ and R ３ The method according to claim 1, wherein both are tert-butyl.

7. The method according to claim 1, wherein a mixture containing compounds of formulas (2) and (4) is maintained at a temperature of -5°C to 10°C during the addition of an alkyllithium reagent.

8. Deprotect the compound of formula (1) using an acid to obtain the compound of formula (5). 【Chemistry 2】 The method according to claim 1, further comprising the step of obtaining

9. The method according to claim 8, wherein the acid is hydrochloric acid.

10. The compound of formula (5) is oxidized to the compound of formula (6). 【Transformation 3】 The method according to claim 8, further comprising the step of obtaining

11. The method according to claim 10, wherein the oxidizing agent is potassium permanganate.

12. The method according to claim 10, further comprising a grinding and purifying step.

13. The method according to claim 12, wherein the compound of formula (6) is used in the manufacture of a radiopharmaceutical.

14. Radiopharmaceuticals (a) One or more ligands capable of binding to prostate-specific membrane antigen (PSMA); (b) A silicon fluoride acceptor (SIFA) moiety containing a covalent bond between a silicon atom and a fluorine atom; and (c) One or more chelate groups optionally containing chelated non-radioactive or radioactive cations, The method according to claim 13, wherein the ligand-SIFA-chelating agent conjugate contains the ligand-SIFA-chelating agent conjugate.

15. １８ The method according to claim 14, further comprising the step of fluorine exchange.

16. Non-radioactive Ga chelated with a chelating agent ３＋ The method according to claim 14, comprising a cation.

17. The ligand-SIFA-chelating agent conjugate is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 The method according to any one of claims 14 to 16, selected from the following. 【Request Item 18】 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 A composition comprising a ligand-SIFA-chelating agent conjugate selected from, wherein the compound is prepared using the method of claim 12, and the composition comprises a ligand-SIFA-chelating agent conjugate selected from, the compound being prepared using the method of claim 12, and the composition comprising, 【Transformation 6】 Contains a compound containing the group at a concentration of 0.1% (w / w) or less. composition.

19. The composition according to claim 18, for use as a diagnostic agent or imaging agent for cancer, or for use in the treatment of cancer.

20. The composition according to claim 18 for the diagnosis, imaging, or prevention of angiogenesis / angiogenesis.

21. The composition according to claim 18, for use as a diagnostic agent or imaging agent for cancer, or for use in the treatment of cancer, which is prostate cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma.

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