Synthesis of fluorosilyl compounds

Abstract

The present disclosure relates to a method of synthesizing a compound of formula (1) wherein PG, R2 and R3 are as defined herein, and to the use of the method in the manufacture of conjugates that bind to PSMA. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to methods for synthesizing fluorosilyl compounds, and more particularly to compounds containing a fluorinated silicon acceptor (SiFA) moiety and derivatives thereof. Background Art

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

[0003] SiFA is linked to the prostate-specific membrane antigen (PSMA) targeting molecule to form PSMA-SiFA conjugates. 18 F PET imaging combined with prostate cancer visualization can be achieved. Adding a radiotherapy moiety to these PSMA-SiFA conjugates, especially a chelating group that can chelate radioisotopes, can achieve visualization of the relevant area while performing targeted radiotherapy. This dual function reduces the chance of off-target radiation damage. WO2019 / 020831, WO2020 / 157177 and WO2020 / 157184 disclose PSMA-SiFA conjugates.

[0004] For example, known procedures for the synthesis of SiFA 4-(di-tert-butylfluorosilyl)benzoic acid are disclosed in Chem. Eur. J. 2009, 15, 2140-2147 and WO 2020 / 157128.

[0005] However, there remains a need for improved methods of synthesizing SiFAs, including 4-(dialkylfluorosilyl)benzoic acid and its precursors. In particular, there is a need for synthetic procedures that can prepare such compounds in high yield and high purity. SUMMARY OF THE INVENTION

[0007] The present invention provides a method for preparing a compound of formula (1), comprising reacting a compound of formula (2) with an alkyl lithium reagent of formula (3) and a compound of formula (4):

[0008]

[0009] Where PG is a protecting group;

[0010] X is Br, Cl or I;

[0011] R 2 and R 3 are independently linear or branched C 1-10 alkyl;

[0012] R 1 It is linear C 1-6 alkyl; and

[0013] wherein an alkyl lithium reagent of formula (3) is added to a mixture comprising compounds of formula (2) and (4).

[0014] In the process of the present invention, a linear alkyl lithium reagent of formula (3) is added to a mixture containing compounds of formula (2) and (4). This one-pot procedure is in contrast to known procedures, which generally require stepwise addition of tert-butyl lithium to the compound of formula (2) at low temperatures, followed by addition of the compound of formula (4).

[0015] Compared with similar known procedures, the method of the present invention significantly improves the yield of the compound of formula (1). In addition, the method of the present invention does not require the use of tert-butyl lithium, nor does it require low temperature reaction conditions. Linear alkyl lithium reagents, such as n-butyl lithium, can be used at milder reaction temperatures. Therefore, the method of the present invention is inherently safer and more suitable for scale-up.

[0016] Description of the invention

[0017] The present invention provides a method for preparing a compound of formula (1), comprising reacting a compound of formula (2) with an alkyl lithium reagent of formula (3) and a compound of formula (4):

[0018]

[0019] Where PG is a protecting group;

[0020] X is Br, Cl or I;

[0021] R 2 and R 3 are independently linear or branched C 1-10 alkyl;

[0022] R 1 It is linear C 1-6 alkyl; and

[0023] wherein an alkyl lithium reagent of formula (3) is added to a mixture comprising compounds of formula (2) and (4).

[0024] 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.

[0025] In the methods and compounds herein, X is Br, Cl or I. X may be Br. X may be Cl. X may be I.

[0026] The compound of formula (2) may be a compound of formula (2a), (2b) or (2c):

[0027]

[0028] The compound of formula (2) may be a compound of formula (2a):

[0029]

[0030] The compound of formula (2) may be a compound of formula (2d), (2e) or (2f):

[0031]

[0032] The compound of formula (2) may be a compound of formula (2d):

[0033]

[0034] In the methods and compounds herein, R 1 It is linear C 1-6 Therefore, the alkyl lithium reagent of formula (3) is a linear C 1-6 Alkyl lithium reagents. 1 Can be linear C 1-5 Alkyl. 1 Can be linear C 1-4 Alkyl. 1 The alkyl lithium reagent of formula (3) may be selected from methyl lithium, ethyl lithium, n-propyl lithium, n-butyl lithium, n-pentyl lithium and n-hexyl lithium. 1 The alkyl lithium reagent of formula (3) may be n-butyl lithium.

[0035] In the methods and compounds herein, R 2 and R 3 are independently linear or branched C 1-10 Alkyl.2 and R 3 Can be independently linear or branched C 1-6 Alkyl. 2 and R 3 Can be independently linear or branched C 1-4 Alkyl. 2 and R 3 Can be independently linear or branched C 3-10 Alkyl. 2 and R 3 Can be independently linear or branched C 3-6 Alkyl. 2 and R 3 Can be independently linear or branched C 3-4 Alkyl. 2 and R 3 can be independently linear C 1-10 Alkyl. 2 and R 3 can be independently linear C 1-6 Alkyl. 2 and R 3 can be independently linear C 1-4 Alkyl. 2 and R 3 Can be independently branched C 3-10 Alkyl. 2 and R 3 Can be independently branched C 3-6 Alkyl. 2 and R 3 Can be independently branched C 3-4 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 2 They may all be tert-butyl.

[0036] In the methods and compounds herein, R 2 Can be linear or branched C 1-10 Alkyl. 2 Can be linear or branched C 1-6 Alkyl. 2 Can be linear or branched C 1-4 Alkyl. 2 Can be linear or branched C 3-10 Alkyl. 2 Can be linear or branched C 3-6 Alkyl. 2 Can be linear or branched C 3-4 Alkyl. 2 Can be linear C1-10 Alkyl. 2 Can be linear C 1-6 Alkyl. 2 Can be linear C 1-4 Alkyl. 2 It can be branched C 3-10 Alkyl. 2 It can be branched C 3-6 Alkyl. 2 It can be branched C 3-4 Alkyl. 2 R may be selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl and tert-butyl. 2 It may be tert-butyl.

[0037] In the methods and compounds herein, R 3 Can be linear or branched C 1-10 Alkyl. 3 Can be linear or branched C 1-6 Alkyl. 3 Can be linear or branched C 1-4 Alkyl. 3 Can be linear or branched C 3-10 Alkyl. 3 Can be linear or branched C 3-6 Alkyl. 3 Can be linear or branched C 3-4 Alkyl. 3 Can be linear C 1-10 Alkyl. 3 Can be linear C 1-6 Alkyl. 3 Can be linear C 1-4 Alkyl. 3 It can be branched C 3-10 Alkyl. 3 It can be branched C 3-6 Alkyl. 3 It can be branched C 3-4 Alkyl. 3 R may be selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl and tert-butyl. 3 It may be tert-butyl.

[0038] The compound of formula (4) may be a compound of formula (4a):

[0039]

[0040] The compound of formula (1) may be a compound of formula (1a):

[0041]

[0042] The compound of formula (1) may be a compound of formula (1b):

[0043]

[0044] The method of the present invention may comprise reacting a compound of formula (2d) with n-butyllithium (n-BuLi) and a compound of formula (4a) to form a compound of formula (1b):

[0045]

[0046] wherein n-BuLi is added to a mixture comprising compounds of formula (2d) and (4a).

[0047] In the methods herein, during the addition of the alkyl lithium reagent, the mixture comprising 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 alkyl lithium reagent, the mixture comprising 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 alkyl lithium reagent, the mixture comprising 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 alkyl lithium reagent, the mixture comprising 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 alkyl lithium reagent, the mixture comprising 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 15°C. During the addition of the alkyl lithium reagent, the mixture comprising 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 10°C. During the addition of the alkyl lithium reagent, the mixture comprising 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 5°C. During the addition of the alkyl lithium reagent, the mixture comprising the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of 0°C to 25°C. During the addition of the alkyl lithium reagent, the mixture comprising the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of 0°C to 20°C. During the addition of the alkyl lithium reagent, the mixture comprising the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of 0°C to 15°C. During the addition of the alkyl lithium reagent, the mixture comprising the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of 0°C to 10°C. During the addition of the alkyl lithium reagent, the mixture comprising the compounds of formula (2) and (4) or (2a) and (4a) or (2d) and (4a) may be maintained at a temperature of 0°C to 5°C.

[0048] In the methods herein, 1.0-1.5 molar equivalents of the alkyl lithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e), or (2f). 1.0-1.3 molar equivalents of the alkyl lithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e), or (2f). 1.1-1.2 molar equivalents of the alkyl lithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e), or (2f). 1.15 molar equivalents of the alkyl lithium reagent may be used relative to the compound of formula (2), (2a), (2b), (2c), (2d), (2e), or (2f).

[0049] In the methods herein, 1.0-1.5 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). 1.0-1.3 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). 1.1-1.2 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). 1.15 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).

[0050] In the methods herein for preparing compounds of formula (1), (1a) or (1b), an aprotic solvent may be used. A polar aprotic solvent may be used. The solvent used may be tetrahydrofuran (THF).

[0051] In the methods herein, it will be appreciated that the alkyl lithium reagent is added to the reaction mixture as a solution in an aprotic solvent, for example as a solution in hexane, for example a 2.5 M solution in hexane.

[0052] The method herein may further comprise the step of deprotecting the compound of formula (1), (1a) or (1b) using an acid to obtain a compound of formula (5) or (5a):

[0053]

[0054] The acid used in the deprotection step can be any acid suitable for deprotection. The acid used can be hydrochloric acid.

[0055] The method of the present invention may further comprise the step of oxidizing the compound of formula (5) or (5a) to obtain the compound of formula (6) or (6a):

[0056]

[0057] The oxidant used in the oxidation step may be any suitable oxidant. The oxidant may be potassium permanganate (KMnO4). The oxidation reaction may also include the use of NaH2PO4. The oxidation reaction may also include the use of NaH2PO4.HCl. The oxidation reaction may be followed by a grinding purification step. The grinding purification step may be used to remove unwanted oxidation byproducts, such as compounds of formula (7), (7a), (7b) or (7c):

[0058]

[0059] The trituration purification step can use a heptane:Et2O solvent system. The trituration purification step can use a 25:1 heptane:Et2O solvent system.

[0060] The grinding purification step may include the following steps:

[0061] • Stir the starting material comprising the compound of formula (6) or (6a) in 25:1 heptane:Et2O at elevated temperature, for example about 65°C, until dissolved, for example for up to 30 minutes.

[0062] • The resulting mixture is allowed to cool to room temperature, for example, within about 20 min, and then cooled to 0°C with ice, with stirring.

[0063] • Filter the crystalline product and wash the filter cake one or more times with ice-cold 25:1 heptane:Et2O and then with n-pentane.

[0064] • The resulting product was dried under vacuum at room temperature to constant weight.

[0065] Also provided is a method for synthesizing a compound of formula (I), comprising the step of oxidizing a compound of formula (II) with potassium permanganate,

[0066]

[0067] wherein each R is independently a C1 to C6 alkyl group.

[0068] The compounds of formula (I) can be used to make radiopharmaceuticals. In some embodiments, the compounds of formula (I) can be used to make radiopharmaceuticals, wherein the fluorine atoms of the compounds of formula (I) or derivatives thereof or subsequently prepared products are enriched with the fluorine-18 isotope. As disclosed herein, the molecules depicted herein with fluorine atoms are understood to include embodiments in which the fluorine atoms are enriched with the fluorine-18 isotope (i.e., above natural abundance).

[0069] The oxidation step described herein utilizes a single-step oxidation process that avoids the use of pyridinium chlorochromate, a well-known toxic carcinogenic compound. In prior art processes using pyridinium chlorochromate, extensive purification must be performed to ensure that all chromium compounds and any byproducts thereof are removed before the oxidation product can be safely used in subsequent synthetic steps, thereby ensuring that the final product can be safely administered in a pharmaceutical composition.

[0070] The method for synthesizing the compound of formula (I) may further comprise the step of synthesizing the compound of formula (II) by deprotecting the compound of formula (III) using an acid.

[0071]

[0072] The acid used for deprotecting the compound of formula (III) may be hydrochloric acid.

[0073] Prior to oxidation with potassium permanganate, 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.

[0074] It has been found that purifying the compound of formula (II), (5) or (5a) prior to oxidation to the compound of formula (I), (6) or (6a) advantageously reduces the presence of undesirable by-products. Without being bound by theory, if the compound of formula (II), (5) or (5a) is purified prior to the oxidation step, fewer oxidation by-products will be produced, thereby ultimately increasing the purity of the compound of formula (I), (6) or (6a).

[0075] The method may also include the following steps: synthesizing a compound of formula (III) by reacting a compound of formula (V) (e.g., (4-bromophenyl)methoxy-tert-butyl-dimethylsilane (a compound having a TBDMS protecting group)) with an alkyl lithium reagent and a compound of formula (IV).

[0076]

[0077] wherein R is as defined above.

[0078] It should be understood that in addition to the TBDMS protecting group, other alcohol protecting groups are contemplated within the scope of the present invention, particularly when the protecting group is removable under acidic conditions (e.g., removable with HCl in an alcohol).

[0079] The synthesis of the compound of formula (III) can be carried out at a temperature of -10°C to 30°C, optionally -5°C to 25°C, further optionally 0°C to 20°C.

[0080] The alkyl lithium reagent may be n-butyl lithium. Unlike the prior art methods, the use of n-butyl lithium advantageously avoids the use of tert-butyl lithium. Tert-butyl lithium is a very reactive compound (pyrophoric, flammable, toxic, corrosive) and must therefore be handled very carefully. For safety reasons, the prior art methods provide that the tert-butyl lithium reaction using a two-fold excess of tert-butyl lithium is carried out under isolated conditions, the reagent is added dropwise, and the reaction is cooled with dry ice.

[0081] Advantageously, as disclosed herein, n-butyl lithium can be used for lithium-halogen exchange reactions. Because the reactivity of n-butyl lithium is much lower and the pyrophoricity is not high, the lithium-halogen exchange reaction can be cooled with ice water. It is also found that organolithium and aryl bromide in roughly equimolar ratios can be used. In addition, advantageously, all three reagents (compound of formula (IV), compound of formula (V) and n-butyl lithium) can exist simultaneously in a "one-pot" reaction. Therefore, the use of n-butyl lithium provides a safer benefit (i.e., n-butyl lithium is a milder organolithium reagent), provides improved scalability and improved efficiency (i.e., less equivalent organolithium reagent is required in a simple "one-pot" reaction that can be cooled with ice water instead of dry ice).

[0082] The method may further include the following steps: synthesizing the compound of formula (V) (ie, (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane) by protecting 4-bromobenzyl alcohol using tert-butyldimethylsilyl chloride and a Lewis base catalyst. The Lewis base catalyst may be imidazole.

[0083] As mentioned above, it should be understood that in addition to the TBDMS protecting group, other alcohol protecting groups are also considered within the scope of the present invention. In particular, when the protecting group is removable under acidic conditions (e.g., removable with HCl in alcohol).

[0084] The compound of formula (6) or (6a) may be substantially free of metal ions, optionally substantially free of heavy metal or transition metal ions, or further optionally substantially free of manganese and / or chromium compounds.

[0085] After oxidation, the compound of formula (6) or (6a) is used to introduce a SiFA moiety into another molecule, for example to form a ligand-SiFA conjugate, for example to form a ligand-SIFA-chelator conjugate.

[0086] The compound of formula (6) or (6a) can be purified after oxidation. The grinding purification step described herein allows the removal of undesirable by-products, such as compounds of formula (7), (7a), (7b) or (7c):

[0087]

[0088] For example, in the subsequent reaction steps, the presence of the compound of formula (7) or (7a) may produce a by-product containing a group of the formula:

[0089]

[0090] The compound of formula (6) or (6a) can be used to prepare a radiopharmaceutical. The radiopharmaceutical can be a ligand-SIFA-chelator conjugate comprising:

[0091] (a) one or more ligands that bind to prostate-specific membrane antigen (PSMA);

[0092] (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between silicon and fluorine atoms; and

[0093] (c) one or more chelating groups, optionally containing chelated non-radioactive or radioactive cations.

[0094] The radiopharmaceutical may be in the form of a composition wherein the composition comprises no more than 0.1% (w / w), no more than 0.09% (w / w), no more than 0.08% (w / w), no more than 0.07% (w / w), no more than 0.06% (w / w), no more than 0.05% (w / w), no more than 0.04% (w / w), no more than 0.03% (w / w), no more than 0.02% (w / w), or no more than 0.01% (w / w) of a compound comprising a group of the formula:

[0095]

[0096] Fluorosilyl compounds with tert-butyl silyl groups have been used for PET imaging, where the fluorine atom is used as 18 Therefore, the method herein may include additional 18 F Fluorine exchange step.

[0097] The method herein may further comprise the step of reacting a compound of formula (I)a or (6a) with a compound of formula (X) to form a compound of formula (XI):

[0098]

[0099]

[0100] in:

[0101] SUPP stands for solid support or attachment to a solid support;

[0102] PROT stands for protecting group;

[0103] X represents a protecting group; optionally represents a protected amine group or an azide group; and m and n are independently 0 or 1.

[0104] The compound of formula (XI) can be considered as a PSMA-SiFA conjugation precursor.

[0105] The method may also include the step of preparing a compound of formula (XII) from a compound of formula (XI):

[0106]

[0107] in:

[0108] m and n are independently 0 or 1;

[0109] R CH is a chelating group;

[0110] X is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, a linking group of the following formula:

[0111]

[0112] Among them The amide bond of the label is formed by a chelating group or a linking group of the formula:

[0113]

[0114] The carbonyl terminal The bond to the label is formed by the chelating group.

[0115] The compound of formula (XII) can be regarded as having a metal ion chelating group R CH PSMA-SiFA conjugate or PSMA-SiFA conjugate precursor.

[0116] The chelating group or R of the ligand-SIFA-chelator conjugate CHIt can be selected from: 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-hydroxysuccinamide (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)phosphoric acid (DOTMP), N,N'-dipyridyloxyethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) (DPDP), diethylenetriamine N,N',N"penta(methylene)phosphoric acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (E DTA), ethylene glycol-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-tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), tetrakis 3-hydroxy-N-methyl-2-pyridone chelating agent (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate amino)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)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-triazacyclononane triacetic 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(hydroxypyridone) (THP), terpyridine-bis(methyleneaminotetraacetic 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-triazacyclononane-1-yl]methyl-hydroxy-phosphoryl]propionic acid and triethylenetetraaminehexaacetic acid (TTHA).

[0117] The chelating group or R of the ligand-SIFA-chelator conjugate CH It may be selected from: 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)phosphoric acid] (TRAP).

[0118] The chelating group or R of the ligand-SIFA-chelator conjugate CH Can be selected from:

[0119]

[0120] Chelating groups can be tailored to advantageously immobilize ions, such as radioisotope metals.

[0121] 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 are the following cations: 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co. 52 Fe, 56 You, 57 You, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 90 Y. 89Y. 99m Tc, 97 Such as 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 2. 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, including 18 F cationic molecules or 18 F-[AlF] 2+ The chelated cation may be a radioactive cation selected from the group consisting of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Er, and Th. The chelated cation may be a non-radioactive cation selected from the group consisting of 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 chelated cation may be a non-radioactive Ga 3+ cation.

[0122] The compound of formula (XII) may be selected from:

[0123]

[0124]

[0125] The compound of formula (XII) may be a compound of formula (XIII)

[0126]

[0127] The compound of formula (XIII) may be a compound of formula (XIV)

[0128]

[0129] The method may further comprise enriching the fluorine atoms of the compound of any one of formulae (I) to (IV) and (X) to (XIII) or compound (XIV) with fluorine-18 isotopes. For example, the radioactive isotopes of fluorine may be introduced by an isotope exchange reaction, wherein for example, the compound of formula (I) or compound (XIV) is enriched with fluorine-18 isotopes, for example, substantially as described in Angew Chem Int Ed Engl. 2006 Sep 11; 45(36): 6047-50, using [18F-] / Kryptofix 2.2.2 / K+, or in a manner known to those skilled in the art. The reaction may be carried out in a bipolar aprotic solvent.

[0130] The method may also include enriching the fluorine atoms of any of the compounds of formula (XI) to (XIII) or compound (XIV) with fluorine-18 isotopes. The method may include enriching the fluorine atoms of the compounds of formula (XI) to (XIII) or compound (XIV) with fluorine-18 isotopes to more than 50%, 60%, 70%, 80%, 85%, 90%, 95% or 98%. The fluorine-18 isotope is advantageously used for PET imaging.

[0131] The method may include chelating a radioactive metal cation in a chelating group; alternatively, the method may include chelating a non-radioactive metal cation in a chelating group. The chelating group may chelate a radioactive cation, and the chelated radioactive cation may be selected from 68 Ga, 177 Lu or 225 Ac. Advantageously, the radioactive metal ions can be used for imaging and / or radiotherapy. The chelating group can chelate a non-radioactive cation, and the chelated non-radioactive cation can be nat Ga.

[0132] In the methods herein, the ligand-SIFA-chelator conjugate may be selected from:

[0133]

[0134]

[0135]

[0136]

[0137] Also provided are compositions comprising a ligand-SIFA-chelator conjugate selected from:

[0138]

[0139]

[0140]

[0141]

[0142] wherein the compound is prepared using the methods described herein, and the composition comprises no more than 0.1% (w / w), no more than 0.09% (w / w), no more than 0.08% (w / w), no more than 0.07% (w / w), no more than 0.06% (w / w), no more than 0.05% (w / w), no more than 0.04% (w / w), no more than 0.03% (w / w), no more than 0.02% (w / w), or no more than 0.01% (w / w) of a compound comprising a group of the formula:

[0143]

[0144] The method may further comprise the steps 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 the disease. The method may further comprise the steps 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 of the disease, wherein any fluorine atoms are enriched with the fluorine-18 isotope. It will be appreciated that when administered to, for example, a human or animal body, the ligand-SIFA-chelator conjugate or the compound of formula (XII or XIII) may preferentially bind to an area of ​​interest, and then, for example, the isotope present in the ligand-SIFA-chelator conjugate or the compound of formula (XII or XIII) may be used to image the area to which the compound is bound. This may be used for diagnosis and / or determining a treatment method.

[0145] The method may further comprise the following steps: 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 a disease, wherein the chelating group chelates a radioactive cation, wherein, optionally, the radioactive cation may be selected from 68 Ga, 177 Lu or 225 Ac. The method may further comprise the following steps: 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 a disease, wherein the chelating group chelates a non-radioactive cation, wherein, optionally, the non-radioactive cation may be nat Ga. It will be appreciated 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) may preferentially bind to the area of ​​interest. Then, for example, the isotope present in the ligand-SIFA-chelator conjugate or the compound of formula (XII) or (XIII) or compound (XIV) may be used to treat the area to which the compound has been bound. This may be used, for example, to bring the radioisotope into proximity with diseased cells / tissues.

[0146] Disclosed herein is the use of any of the methods disclosed herein for preparing the corresponding compounds disclosed herein and / or any derivative moieties prepared therefrom. As a non-limiting example, disclosed herein is the use of the method disclosed in the first aspect of the present invention for preparing a compound of formula (I), (I)a or (6a).

[0147] Disclosed herein are compounds disclosed herein prepared by the corresponding methods disclosed herein, and / or any derivative moieties prepared therefrom. As non-limiting examples, disclosed herein are compounds of formula (I), (I)a or (6a) prepared using the methods disclosed in the first aspect of the present invention.

[0148] In particular, compounds of formula (I)a / (6a) can be prepared according to the following scheme:

[0149]

[0150] Step a: Protect the alcohol group of 4-bromobenzyl alcohol with a TBDMS group to obtain (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane (corresponding to the compound of formula (2d) or an embodiment of the compound of formula (V) wherein TBDMS is used to protect the alcohol, referred to herein as compound (V)a).

[0151] Step b: By reacting (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane (compound (V)a) with tert-butyldifluorosilane (corresponding to the compound of formula (4a) or the embodiment of the compound of formula (IV), wherein the R group is tert-butyl, referred to herein as compound (IV)a) and n-butyllithium, the bromine group of (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane (compound (V)a) is exchanged with a dialkylfluorosilyl group to obtain di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane (corresponding to the compound of formula (1b) or the embodiment of the compound of formula (III), wherein the R group is tert-butyl, referred to herein as compound (III)a).

[0152] Step c: Use acid to remove the TBDMS protecting group of compound (III)a, and purify the resulting compound, i.e., 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol (corresponding to the compound of formula (5a) or an embodiment of the compound of formula (II), wherein the R group is tert-butyl, referred to herein as compound (II)a) by column chromatography.

[0153] Step d: Oxidation of the alcohol group of 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol (compound (II) a) to the corresponding benzoic acid to obtain 4-(di-tert-butyl(fluoro)silyl)benzoic acid (corresponding to a compound of formula (6a) or an embodiment of a compound of formula (I); compound (I) a).

[0154] Provided below is an experiment for synthesizing 4-(di-tert-butyl(fluoro)silyl)benzoic acid (Compound (I)a), which is equivalent to synthesizing the compound of Formula (6a) or the compound of Formula (I).

[0155] Example A-Preparation of 4-(di-tert-butyl(fluoro)silyl)benzoic acid

[0156] Step a - Synthesis of (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane (V) a

[0157] To a solution of 4-bromobenzyl alcohol (113.5 g, 606.8 mmol, 1.0 eq) in DMF (1100 mL) was added imidazole (49.57 g, 728 mmol, 1 eq) and TBDMS-Cl (98.78 g, 655.38 mmol, 1.08 eq) The mixture was stirred at room temperature overnight.

[0158] The reaction mixture was diluted with water (1100 mL) and then extracted with MTBE (2 x 500 mL, then 2 x 300 mL). The combined organics were dried over MgSO4, filtered and evaporated to a crude oil. The material was purified in two batches on silica gel eluting with 2% MTBE / isohexane to give the desired material as a colorless oil (184.0 g, 100%).

[0159] Step b-Synthesis of di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane (III) a

[0160] To a solution of (4-bromophenyl)methoxy-tert-butyl-dimethyl-silane ((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), n-butyllithium solution (2.5 M, 27.24 mL, 68.11 mmol) was added 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 dried over MgSO4, filtered and evaporated to a yellow oil (21.89 g, 97%). The material was used without purification.

[0161] Step c-Synthesis of 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol (II) a

[0162] 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. The solution was then stirred at room temperature overnight.

[0163] The reaction mixture was evaporated to remove volatile organics and the residue was treated with saturated sodium bicarbonate (120 mL) to pH 8. The mixture was extracted into MTBE (3 x 200 mL). The combined organics were dried over MgSO4, filtered and evaporated to a pale yellow oil.

[0164] The oil was diluted with toluene (10 mL) and then loaded onto a 330 g pre-wet (toluene) silica gel column. The silica gel column was eluted with 10 column volumes of ethyl acetate in toluene in a gradient of 0-10%. The fractions were analyzed by TLC (5% ethyl acetate / toluene, stained with KMnO4) and only the purest fractions were retained and combined to give the desired material as a white solid (8.078 g, 53%). Some mixed fractions were retained and combined with fractions from other batches for repurification.

[0165] Step d-Synthesis of 4-(di-tert-butyl(fluoro)silyl)benzoic acid (I)a

[0166] To a solution of 4-(di-tert-butyl(fluoro)silyl)benzyl alcohol ((II)a, 33.17 g, 123.58 mmol) in tert-butyl alcohol (370 mL) and DCM (75 mL) was added aqueous KMnO4 (29.3 g, 185 mL) in a thin stream over 5 min. Then NaH2PO4 was added in a thin stream over 10 min. 4 . Aqueous HCl (56.27 g, 200 mL) was added to raise the internal temperature from +20° C. to +35° C. The mixture was stirred for 2 h, then an aliquot was removed, processed according to the workup procedure, separated and analyzed by NMR to indicate that the reaction was complete.

[0167] By adding NaSO saturated aqueous solution (700mL), the reaction was quenched and then stirred for 30min. Concentrated HCl (110mL) was added dropwise over 10min and then stirred for 30min. The white turbid mixture was extracted into MTBE (1000ml, then 2×500mL). The combined extracts were dried over MgSO , filtered and evaporated to a white solid (34.7g, 99%).

[0168] This material was combined with two other batches (combined weight 111.06 g), dissolved in MTBE (1 L) at 50° C., and then evaporated to a white solid (114.06 g) with some MTBE remaining. The solid was suspended in 25:1 heptane:Et2O (720 mL) and stirred at 65° C. for 30 min. The mixture was cooled to room temperature with stirring, then cooled to 0° C. with ice over 20 min, the mixture was filtered, and the filter cake was washed with ice-cold 25:1 heptane:Et2O (3×100 mL), then with n-pentane (500 mL). The resulting white solid was dried under vacuum at room temperature to constant weight. The yield was 102.28 g (90% theoretical yield).

[0169] Example B - Inventive and Comparative Reaction Conditions for Step b

[0170] A summary of the comparative reaction conditions for step b (synthesis of di-tert-butyl-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-fluoro-silane) is shown in Table 1.

[0171] Table 1, entry 1 represents the literature conditions (i.e., stepwise addition of alkyl lithium reagents to 4-(TBS-oxymethyl)bromobenzene using tert-BuLi (tert-butyl lithium) at low temperature, followed by addition of t-Bu2SiF2). These conditions resulted in the formation of large amounts of by-products and were considered unsuitable for scale-up due to the need for low temperatures and the use of tert-BuLi.

[0172] Entry 2 represents the use of n-BuLi (n-butyllithium) instead of tert-BuLi in the procedure of entry 1, but without substantial modification of the reaction conditions (i.e., stepwise addition and low temperature are still used). This results in a mixture of products, with lower yields of the desired product obtained.

[0173] Item 3 represents a procedure according to the present invention, wherein n-BuLi is added to a mixture comprising 4-(TBS-oxymethyl)bromobenzene and t-Bu2SiF2 (i.e., a one-pot process). This increases the yield of the desired product compared to the procedures of items 1 and 2, and does not require tert-BuLi or low temperatures.

[0174] Entry 4 represents the use of tert-BuLi instead of n-BuLi in the procedure of entry 3, but without substantial modification of the reaction conditions (i.e., one-pot and non-cryogenic). This resulted in a mixture of products, with poor yields of the desired product obtained.

[0175] Entries 5 and 6 represent the procedure according to the invention. Feasibility on a larger scale is demonstrated.

[0176]

Claims

1. A method for preparing a compound of formula (1), comprising reacting a compound of formula (2) with an alkyl lithium reagent of formula (3) and a compound of formula (4): 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 alkyl; R 1 It is linear C 1-6 alkyl; and The alkyl lithium reagent of formula (3) is added to a mixture containing the compound of formula (2) and the compound of formula (4).

2. The method of claim 1, wherein the alkyl lithium reagent is n-butyl lithium.

3. The method of claim 1 or claim 2, wherein PG is an acid-labile protecting group.

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

5. The process according to any one of claims 1 to 4, wherein X is Br.

6. The method according to any one of claims 1 to 5, wherein R 2 and R 2 All are tert-butyl.

7. The method according to any one of claims 1 to 6, wherein the mixture comprising the compound of formula (2) and the compound of formula (4) is maintained at a temperature of -5°C to 10°C during the addition of the alkyl lithium reagent.

8. The method according to any one of claims 1 to 7, further comprising: The step of deprotecting the compound of formula (1) using an acid to obtain a compound of formula (5):

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

10. The method according to claim 8 or 9, further comprising the step of oxidizing the compound of formula (5) to obtain a compound of formula (6):

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

12. The method according to claim 10 or 11, further comprising a grinding purification step.

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

14. The method of claim 13, wherein the radiopharmaceutical is a ligand-SIFA-chelator conjugate comprising: (a) one or more ligands that bind to prostate-specific membrane antigen (PSMA); (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon atom and a fluorine atom; and (c) optionally containing one or more chelating groups for chelating non-radioactive or radioactive cations.

15. The method according to claim 14, further comprising 18 F Fluorine exchange step.

16. The method of claim 14 or 15, wherein the chelating agent comprises chelated non-radioactive Ga 3+ cation.

17. The method according to any one of claims 14 to 16, wherein the ligand-SIFA-chelator conjugate is selected from:

18. A composition comprising a ligand-SIFA-chelator conjugate selected from: Wherein the compound is prepared by the method of claim 12, and the composition contains no more than 0.1% (w / w) of a compound containing a group of the formula:

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

20. The composition of claim 18, for use in the diagnosis, imaging or prevention of neovascularization / angiogenesis.

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

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