Synthesis of an intermediate of a gadolinium-based contrast agent

Abstract

The invention relates to the synthesis of the compound of formula (I), which is an intermediate of the gadolinium-based contrast agent (GBCA) gadopiclenol, the latter being marketed as a contrast medium for magnetic resonance imaging (MRI), through the synthesis of di-ethylene triamine tri-alkylated with glutarate esters or glutaric acid.

Description

[0001] SYNTHESIS OF AN INTERMEDIATE OF A GADOLINIUM-BASED CONTRAST AGENT

[0002] Technical field

[0003] The invention relates to the synthesis of intermediates of a gadolinium-based contrast agent (GBCA). Background of the invention

[0004] Gadolinium-based contrast agents (GBCAs) are commonly used in clinical practice to improve the contrast of images obtained during magnetic resonance imaging (MRI).

[0005] Gadopiclenol (rac-[(2R,2'E,2"E)-2,2',2"-(3,6,9-triaza-K3N3,N6,N9-l(2,6)- pyridina-KN1- cyclodecaphane-3,6,9-triyl)tris(5-{[(2E)-2, 3-d i hydroxy propyl] am ino}-5- oxopentanoatOK3O1,O1',O1")(3-)]gadolinium) is a GBCA recently marketed for MRI as

[0006] Gadopiclenol

[0007] Accordingly, improved methods for its manufacturing, as well as for manufacturing its intermediates, are sought after.

[0008] Gadopiclenol synthesis is disclosed in WO 2020 / 030618, and is set out in Scheme 1 :

[0009]

[0010] The first step for manufacturing gadopiclenol is the alkylation of pyclen (3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene) with diethyl 2-bromopentanedioate (that is, the bromo-derivative of diethyl glutarate ester), thereby providing the hexaester ( / .e. protected form) of 3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-l(15),ll,13-triene-tri(a- glutaric acid) (PCTGA). PCTGA hexaester is then hydrolysed providing PCTGA, which is in turn complexed with gadolinium ions to form the gadolinium complex of PCTGA (Gd-PCTGA).

[0011] The derivative of pyclen alkylated with three glutaric acid moieties, PCTGA, as well as its hexaester and gadolinated derivatives (PCTGA hexaester and Gd-PCTGA, respectively), are thus key intermediates for the synthesis of gadopiclenol.

[0012] Pyclen, the starting material of the synthesis, is commercially available and is commonly synthetized according to the Richman-Atkins methodology, as disclosed in Enel M. et al., Eur.

[0013] J. Org. Chem. 2018, 1765-1773 and set out in Scheme 2:

[0014] Scheme 2 As reported in this document, the synthesis has quite a low yield (27% or 36%) and the hydrolysis of the arylsulfonamide (tosyl or nosyl) groups requires harsh conditions or conditions generally not favourable for industrial application (e.g. highly acidic solutions, high temperature, and long reaction times). Both these aspects are not ideal for the industrial manufacturing process and, as a consequence, pyclen obtained through this synthetic route is very expensive.

[0015] Accordingly, manufacturing methods overcoming the issues related to the synthesis or use of pyclen would be preferable. Enel M. et al. further discloses the following synthesis of an alkylated pyclen derivative, i.e. the triacetylate ester derivative of pyclen (Scheme 3):

[0016] Scheme 3 The synthesis of Scheme 3 allows obtaining the pyclen derivative tri-alkylated with acetate esters with an overall yield of 60-65% and by-passing pyclen manufacturing, thereby overcoming the problems mentioned above. Namely, starting from diethylentriamine (DETA), the corresponding benzylated derivative is obtained by reaction with benzaldehyde and subsequent reductive amination; this derivative is then alkylated with bromoacetate t-butyl ester and hydrogenated to remove the benzyl protecting group; the obtained trialkylated diethylentriamine derivative is finally reacted with 2,6-dibromomethylpyridine to achieve the desired product. However, the synthesis proposed in Scheme 3 is not optimal for an industrial application, as it requires several steps to provide the final product (considering also the multiple steps for providing the first intermediate, i.e. the dibenzylated DETA), and also because at least two steps thereof (the reduction to provide dibenzylated DETA and the hydrogenolysis of the benzyl protective groups) involve using reducing agents and catalysts (respectively, NaBH4 and Pd / C), which are expensive and would be better to avoid for safety and environmental reasons; indeed, NaBH4 generates cancerogenic boron salts, and most countries have provisions whereby metal catalysts such as Pd / C cannot be freely disposed of.

[0017] Leygue N. etal., Eur. J. Org. Chem. 2019, 2899-2913, discloses the synthesis of another alkylated derivative of pyclen, i.e. the di-acetylate mono-glutarate ester derivative of pyclen, as set out in Scheme 4:

[0018]

[0019] D-glutamic acid

[0020] Scheme 4

[0021] Similar to the synthetic route of Scheme 3, the synthesis of Scheme 4 provides for obtaining first a dibenzylated trialkylated DETA derivative through a multistep route, then carrying out hydrogenolysis of the same, and finally reacting the alkylated DETA derivative with 2,6-dibromomethylpyridine to obtain the diacetylate monoglutarate ester derivative of pyclen. Considering that this synthesis is similar to the one of Enel M. et al. (Scheme 3), it presents similar disadvantages. Moreover, this synthetic route employs / V-bromosuccinimide and triphenylphosphine to brominate the alcohol, which further increase the environmental impact of the synthesis. Furthermore, the overall yield to obtain the final product, i.e. the diacetylate monoglutarate ester derivative of pyclen, is 21%, which is not ideal for an industrial application. Finally, by comparing the synthesis of Enel M. et al. (Scheme 3) with the one of Leygue N. el al. (Scheme 4), a drop of yield of almost three times is observed by introducing a single glutarate ester residue instead of an acetate one.

[0022] According to the prior art documents, it is of paramount importance to protect the starting diethylentriamine (DETA) (Scheme 3) and ethanolamine (Scheme 4) with the benzyl moieties before the alkylation with bromoacetate t-butyl ester; indeed, the alkylation in absence of such moieties could lead to an overalkylation, generating a mixture of tri-, tetra-, and pentaalkylated DETA, instead of the desired trialkylated derivative that can be later cyclized.

[0023] In view of the above, methods for manufacturing the key intermediates of gadopiclenol, i.e. PCTGA, as well as its precursor hexaester and gadolinated derivatives, overcoming the drawbacks of the prior art processes, are sought after.

[0024] It has now been found that it is possible to obtain the hexaester of PCTGA with few reaction steps, acceptable yields, and with a method suitable for industrial-scale manufacturing.

[0025] Summary of the invention

[0026] The present invention relates to a process for obtaining the compound of formula (I): or a salt thereof, as set out in independent claim 1.

[0027] The compound of formula (I) is PCTGA or a hexaester thereof, whereby it can be converted into Gd-PCTGA; the latter can be finally converted into gadopiclenol.

[0028] Accordingly, the present invention further relates to processes for obtaining PCTGA, Gd- PCTGA, and gadopiclenol, as set out in the claims.

[0029] The present invention relates as well to a compound of formula (III): Formula (III) or a stereoisomer, or an isomeric mixture of the same, or a salt thereof, as set out in the claims. The compound of formula (III) is a novel intermediate essential for the process of the invention. Embodiments of the invention are set out in dependent claims.

[0030] Detailed description of the invention

[0031] According to a first aspect, the present invention relates to a process for obtaining the compound of formula (I): or a salt thereof, wherein R1and R2represent, independently from each other, hydrogen or

[0032] Ci-Ce-alkyl, said process comprising the following steps: a) reacting / V1-(2-aminoethyl)ethane-l,2-diamine (also known as diethylenetriamine, with the compound of formula (II): Formula (II) or a salt thereof, wherein : R1and R2are as defined above for formula (I), and LG is a leaving group; Formula (III) or a salt thereof, wherein R1and R2are as defined above for formula (I); and b) reacting the compound of formula (III) with the compound of formula (IV): Formula (IV) wherein LG' is a leaving group; to obtain the compound of formula (I), or a salt thereof.

[0033] The process of the invention is summarized in Scheme 5.

[0034]

[0035] Scheme 5

[0036] The process of the invention provides for obtaining the compound of formula (I), which is PCTGA or a hexaester thereof, and thus a key intermediate of gadopiclenol, in just two steps: first, by a) alkylating the diethylenetriamine (DETA) with the compound of formula (II), which is a glutarate ester or glutaric acid derivative, thereby obtaining the compound of formula (III) ( / .e. alkylated DETA, in particular DETA tri-alkylated with glutarate esters or glutaric acid); and then by b) carrying out a cyclization step by reacting the compound of formula (III) with the compound of formula (IV), the latter being a derivative of 2,6-dimethyl pyridine. Thus, the process of the invention provides for obtaining a key intermediate of gadopiclenol, such as the compound of formula (I), advantageously by-passing pyclen manufacturing (thereby, overcoming the drawbacks mentioned above), and at the same time providing acceptable yields and carrying out few reaction steps; overall, the process of the invention is suitable for industrial-scale manufacturing. Step a) is particularly advantageous: by directly alkylating DETA with the compound of formula (II), the process of the invention dispenses of the step of manufacturing di-benzylated DETA and the subsequent step of hydrogenolysis. It has been surprisingly found that this direct alkylation does not provide a mixture of tri-, tetra-, and penta-alkylated DETA; in particular, no detectable amounts of tetra- or penta-alkylated DETA were observed following the alkylation. This offers several advantages: first, it reduces the overall steps and complexity of the preparation of tri-alkylated DETA, e.g. by dispensing with the di-benzylation and the hydrogenolysis steps. Moreover, it allows carrying out the subsequent cyclization step b) in the same reaction mixture of the alkylation step a); in other words, steps a) and b) can be carried out one-pot, without isolating the tri-alkylated DETA (the compound of formula (III)) before step b). This cannot be achieved according to the prior art processes, in that they provide for the hydrogenolysis of di-benzylated DETA, whereby the tri-alkylated DETA obtained from such hydrogenolysis must be isolated from its reaction mixture before carrying out the following cyclization steps. Accordingly, as the process of the invention allows carrying out the one-pot synthesis, it is particularly suitable for industrial-scale manufacturing. Moreover, dispensing with the isolation of tri-alkylated DETA allows using several esters of the compound of formula (II) ( / .e. any Ci-Ce-alkyl, preferably any C1-C4- alkyl) or the free acid derivative, whereby the process of the invention can be carried out using a wide range of reactants. On the contrary, the prior art processes, which require isolating the tri-alkylated DETA, can be performed exclusively with tert-butyl esters DETA derivatives; this is because it has been found that exclusively tert-butyl esters DETA derivatives are stable upon being isolated, while other esters undergo unwanted lactamization reactions. A further advantage of the process of the invention is the improvement of atom economy compared to the prior art processes, in that the process of the invention does not require di-benzylating DETA and subsequently removing the di-benzyl groups; this atom economy improvement makes the process of the invention greener and more sustainable.

[0037] In the present description, the term "alkyl" refers to any linear or branched, saturated or unsaturated (preferably saturated) hydrocarbon chain. The term "Cx-Cy-alkyl", wherein x and y denote two integers, refers to an alkyl as above defined with a number of carbon atoms comprised between x and y. For example, "Ci-Ce-alkyl" comprises within its meaning a linear or branched, saturated or unsaturated (preferably saturated) chain comprising from 1 to 6 carbon atoms such as: methyl, ethyl, propyl, / so-propyl, butyl (also known as n-butyl), iso- butyl, tert-butyl, and the like, as well as n-pentyl and isomers thereof (such as / so-pentyl and the like), and n-hexyl and isomers thereof (such as 2-methylpentyl, 3-methylpentyl, 2,3- dimethylbutyl, and the like). Similarly, the term "Ci-C4-alkyl" refers to a linear or branched, saturated or unsaturated (preferably saturated) chain comprising from 1 to 4 carbon atoms such as: methyl, ethyl, n-propyl, / -propyl, butyl (also known as n-butyl), / -butyl, sec-butyl, and t-butyl.

[0038] In the present description, the term "leaving group" refers to an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction, and particularly an atom or group of atoms departing with a pair of electrons in the heterolytic bond cleavage of step a) or of step b). Leaving groups are commonly known and widely used in organic chemistry, and can be, for example, halogen, such as bromo, chloro, and iodo, or leaving groups containing sulphur, e.g. containing sulfonyl or sulfonate ester groups, such as tosyl, tosylate, mesylate, triflate and nosyl groups.

[0039] The compounds of the above formulae (I), (II), and (III), as well as PCTGA, Gd-PCTGA, and gadopiclenol, may have one or more asymmetric carbon atom, also known as chiral carbon atom(s), and may thus give rise to stereoisomers (also called optical isomers). According to the present invention, any substantially pure resolved stereoisomer of the compound of formula (I), or of compound of formula (II), or of compound of formula (III), or of PCTGA, or of Gd-PCTGA, or of gadopiclenol, as well as any isomeric mixture of the same, can be obtained by carrying out the process of the invention together with conventional means to obtain substantially pure resolved stereoisomers of a given compound, or isomeric mixtures of the same. Such conventional means can be e.g. isolating via chromatography, possibly chiral chromatography, the desired stereoisomer(s) or enantiomeric couple(s) (e.g. as disclosed in WO 2020 / 030618), enriching isomeric mixtures (e.g. as disclosed in WO 2020 / 148431 and WO 2020 / 148436), and / or using suitable substantially pure resolved stereoisomer(s) of reactants, or isomeric mixtures of reactants, during the process of the invention, such as substantially pure resolved stereoisomer of the compound of formula (II) or an isomeric mixture of the same. In the present description, the term "isomeric mixture" refers to a mixture containing at least two stereoisomers of the compound of formula (I), or of the compound of (II), or of the compound of (III), or of PCTGA, or of Gd-PCTGA, or of gadopiclenol; accordingly, an isomeric mixture can be a racemic mixture, a mixture wherein one or more of the stereoisomer(s) (e.g. an enantiomer couple) is / are present in a higher amount with respect to the others (also called an enriched isomeric mixture), etc. preferred substantially pure resolved stereoisomer of the compound of formula (I), of formula (II), of formula (III), of PCTGA, or of Gd-PCTGA, is the R.R.R. or SSS stereoisomer. A preferred isomeric mixture of the compound of formula (I), of formula (II), of formula (III), of PCTGA, or of Gd-PCTGA, is the isomeric mixture comprising at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, and most preferably 90%, of the R.R.R. and / or SSS stereoisomer. A preferred stereoisomer of gadopiclenol is the one wherein the inner chiral carbon atoms of gadopiclenol (that is, the chiral carbon atoms of the glutarate moieties of gadopiclenol) have a R.R.R. or SSS configuration, and is herein defined as R.R.R. or SSS stereoisomer of gadopiclenol (respectively); a preferred isomeric mixture of gadopiclenol is the isomeric mixture comprising at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90%, of the R.R.R. and / or SSS stereoisomer of gadopiclenol.

[0040] In the present description, the term "salt" when referencing the compounds of formulae (I) to (IV), or PCTGA, or Gd-PCTGA, or gadopiclenol, refers to derivatives of such compounds wherein the parent compound is suitably modified by converting any of the free acid or basic groups, if present, into the corresponding addition salt with any base or acid; preferably, said salt is a pharmaceutically acceptable salt, namely a salt that is conventionally intended as being pharmaceutically acceptable, for example as disclosed in S. M. Berge, et al., J. Pharm. Sci. 1977, 66, 1-19.

[0041] As mentioned above, and according to a preferred embodiment, steps a) and b) are carried out in one-pot; in other words, according to an embodiment, step b) is carried out without isolating the compound of formula (III). As mentioned above, this embodiment provides several advantages that could not have been achieved with the prior art processes for obtaining tri-alkylated DETA. Accordingly, the process of the invention is particularly suitable for industrial-scale manufacturing.

[0042] According to an embodiment, R1and R2represent, independently from each other, a Ci- C4-alkyl; preferably, R1and R2represent, independently from each other, a Ci-C4-alkyl selected from the group consisting of: methyl, ethyl, n-propyl, / -propyl, n-butyl, / -butyl, secbutyl, and t-butyl. According to a preferred embodiment, R1and R2represent the same Ci- C4-alkyl. As showed in the experimental section below, the process of the invention is flexible, allowing to use a wide range of reactants, because it provides the possibility of selecting any Ci-Ce-alkyl, preferably any Ci-C4-alkyl, of the compound of formula (II), i.e. of the glutarate ester derivative, to effectively carry out the alkylation of step a). On the contrary, as mentioned above, the processes of the prior art necessarily use t-butyl to alkylate DETA.

[0043] According to an embodiment, LG is a halogen; preferably, LG is a halogen selected from the group consisting of chloro, bromo, and iodo.

[0044] The compound of formula (II) is a derivative of a glutarate ester when R1and R2represent a Ci-Ce-alkyl, or of glutaric acid when R1and R2represent hydrogen. It can be commercially available, or it can be prepared according to known means. For example, it can be prepared starting from glutamic acid (either L-, R-, or an isomeric mixture thereof), which can be converted to the corresponding LG-glutaric acid derivative by reacting glutamic acid with a suitable source of LG (e.g. a halide salt when LG is a halogen), possibly via diazotisation of the amine, and finally to the compound of formula (II) by esterifying the so-obtained LG- glutaric acid derivative with a suitable ester.

[0045] According to an embodiment, step a) is carried out by reacting the compound of formula (II) in stoichiometric excess with respect to DETA. According to a preferred embodiment, the equivalents of DETA vs. the compound of formula (II) reacted in step a) are 0.10 to 0.33; preferably 0.10 to 0.30; and more preferably are 0.25.

[0046] According to an embodiment, step a) is carried out in the presence of a base; preferably, the base is a tertiary amine, or is a salt comprising the carbonate ion; more preferably, the base is selected from the group consisting of: / V, / V-diisopropylethylamine (DIPEA), triethylamine (TEA), sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, and mixtures thereof. According to a preferred embodiment, the base used to carry out step a) is removed, e.g. filtered out, from the reaction mixture before carrying out step b); this preferred embodiment allows to change the base that can be used in the subsequent step b).

[0047] According to an embodiment, the equivalents of the base used to carry out step a) vs. the compound of formula (II) are 1 or higher; for example, the equivalents are 1 to 10; preferably, the equivalents are 1 to 6. If step a) is carried out with a solvent, e.g. the one mentioned below, the equivalents are more preferably 1.5 to 4; and even more preferably 1.5 to 2. If step a) is carried out without a solvent, the equivalents are more preferably 4 to 6.

[0048] Step a) can be carried out either without a solvent, or with a solvent; if step a) is carried out with a solvent and if R1and R2represent a Ci-Ce-alkyl, the solvent is preferably a nonaqueous solvent; more preferably, an aprotic non-aqueous solvent; and even more preferably, an aprotic non-aqueous solvent selected from the group consisting of: acetonitrile, n-butanol, toluene, / V, / V-dimethylformamide (DMF), / V, / V-dimethylacetamide (DMA), and mixtures thereof. When step a) is carried out without a solvent, DETA, the compound of formula (II), and optionally the base mentioned above are admixed together to carry out step a).

[0049] According to an embodiment, in step a), the concentration of the compound of formula (II) within the non-aqueous solvent, e.g. the one mentioned above, is 0.01 to 1.10 M, preferably 0.04 to 1.00 M, more preferably is 0.06 to 0.09 M, and even more preferably is 0.08 M.

[0050] According to an embodiment, step a) is carried out at a temperature of at least 40° C; preferably of at least 50 °C; more preferably of at least 60 °C; and even more preferably of at least 70 °C. For example, step a) can be carried out at a temperature from 50 °C to the boiling point of the solvent (if present), preferably by keeping the solvent (if present) at reflux.

[0051] Step a) can be carried out for an amount of time suitable for DETA and the compound of formula (II) to react, which can be verified by conventional means, e.g. by HPLC or qNMR; this amount of time may be dependent on other process parameters, such as e.g. the reaction temperature, which R1and R2groups are used, and / or the presence of a solvent. For example, when step a) is carried out with a solvent, step a) can be carried out for an amount of time of at least 15 hours; preferably, of at least 20 hours; more preferably, of at least 30 hours; even more preferably, of at least 40 hours; when step is carried out without a solvent, step a) can be carried out for an amount of time of at least 1 hour; preferably, higher than 2 hours; more preferably, of at least 4 hours; and even more preferably, of at least 6 hours. In any case, small amounts e.g. traces of DETA mono- or di-alkylated with the compound of formula (II) can be found in the reaction mixture after step a), and possibly after step b) (e.g. if step b) is carried out without isolating the compound of formula (III)).

[0052] According to an embodiment, LG' is a halogen or a leaving group containing sulphur; preferably, LG' is selected from the group consisting of chloro, bromo, iodo, tosyl group, tosylate group, mesylate group, triflate group and nosyl group; more preferably, LG' is a halide selected from the group consisting of chloro, bromo, and iodo.

[0053] The compound of formula (IV) is a 2,6-dimethyl pyridine derivative, and can be commercially available, or it can be prepared according to known means.

[0054] Step b) can be carried out reacting in stoichiometric amounts the compound of formula (IV) with the compound of formula (III). In case the amount of compound of formula (III) is not assessed before step b), the compound of formula (IV) can be reacted in step b) considering the starting amount of DETA. According to an embodiment, step b) is carried out using an amount of equivalents of the compound of formula (IV) vs. DETA higher than 0.5; such as of 0.5 to 3; preferably of 0.5 to 2; more preferably of 0.5 to 1.5; even more preferably of 0.8 to 1.2; and most preferably of about 1.

[0055] According to an embodiment, step b) is carried out in the presence of a base; preferably, the base is a tertiary amine or a salt comprising the carbonate ion; more preferably, the base is selected from the group consisting of: / V, / V-Diisopropylethylamine (DIPEA), triethylamine (TEA), sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, and mixtures thereof. The base used to carry out step b) can be different than the base used to carry out step a).

[0056] According to an embodiment, the equivalents of the base used to carry out step b) vs. the compound of formula (III) are 2 or higher; for example, the equivalents are 2 to 20; preferably, the equivalents are 2 to 15; more preferably, the equivalents are 2 to 10; even more preferably; the equivalents are 6 to 10.

[0057] Step b) can be carried out with a solvent; preferably, when R1and R2represent a Ci- Ce-alkyl, with a non-aqueous solvent; more preferably, such non-aqueous solvent is an aprotic non-aqueous solvent; and even more preferably, such aprotic non-aqueous solvent is selected from the group consisting of: acetonitrile, n-butanol, toluene, / V, / V-dimethylformamide (DMF), / V, / V-dimethylacetamide (DMA), and mixtures thereof. Alternatively, step b) can be carried out without a solvent (e.g. when step a) is carried out without a solvent), whereby the compound of formula (III) and of formula (IV), and optionally the base mentioned above, are admixed together to carry out step b). Preferably, step b) is carried out with a solvent, e.g. the one mentioned above.

[0058] As mentioned above, steps a) and b) are preferably carried out in one-pot; in other words, step b) is preferably carried out without isolating the compound of formula (III). Accordingly, the solvent to carry out steps a) and b) can be the same, e.g. the solvents mentioned above; when step a) is carried out without a solvent, step b) can either be carried out without a solvent, or it can be carried out with a solvent, e.g. the ones mentioned above.

[0059] According to an embodiment, step b) is carried out at a temperature of at least 40° C; preferably of at least 50 °C; more preferably of at least 60 °C; and even more preferably of at least 70 °C. For example, step b) can be carried out at a temperature from 50 °C to the boiling point of the solvent (if present), preferably by keeping the solvent (if present) at reflux.

[0060] Step b) can be carried out for an amount of time suitable for the compound of formula (III) and of formula (IV) to react, which can be verified by conventional means, e.g. by HPLC or qNMR; this amount of time may be dependent on other process parameters, such as e.g. the reaction temperature, which R1, R2, and / or LG' groups are used, and / or the presence of the solvent. For example, when step b) is carried out with a solvent, step b) can be carried out for an amount of time of at least 15 hours; preferably, of at least 20 hours; more preferably, of at least 30 hours; even more preferably, of at least 40 hours; when step is carried out without a solvent, step a) can be carried out for an amount of time of at least 1 hour; preferably, higher than 2 hours; more preferably, of at least 4 hours; and even more preferably, of at least 6 hours.

[0061] According to an embodiment, R1and R2in formulae (I), (II), and (III) represent hydrogen. This embodiment provides for a) reacting DETA with the following compound of formula (II)': Formula (II)' wherein LG is a leaving group (preferably, the leaving group LG as above defined), thus obtaining the hexaacid compound of formula (III)': and then provides for b) reacting the compound of formula (III)' with the compound of formula (IV) as above defined, thus obtaining the compound of formula (I) wherein R1and R2represent hydrogen, i.e. PCTGA. According to this embodiment wherein R1and R2represent hydrogen, step a) and / or b) can be carried out with an aqueous solvent, such solvent preferably comprising a base as mentioned above (that is, a base selected from the group consisting of: / V, / V-diisopropylethylamine (DIPEA), triethylamine (TEA), sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, and mixtures thereof).

[0062] A further aspect of the invention is the process for obtaining 3,6,9, 15-tetraazabicyclo- [9.3.1] pentadeca- 1(15), 11, 13-triene-tri(a-glutaric acid) (PCTGA) or a salt thereof, comprising (i) carrying out the process as above defined for obtaining the compound of formula (I) or a salt thereof; and (ii) converting the compound of formula (I) to PCTGA or a salt thereof. According to this aspect, the compound of formula (I), which is an ester of PCTGA when R1and R2represent Ci-Ce-alkyl, is converted to PCTGA by hydrolysing the ester groups of the compound of formula (I). This can be carried out by means known in the art (e.g. as disclosed in WO 2020 / 030618, WO 2020 / 148431, or WO 2020 / 148436), for example by acid or basic hydrolysis of esters, preferably by base-catalysed hydrolysis of esters.

[0063] Another aspect of the present invention is a process for obtaining the gadolinium complex of 3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-l(15),ll,13-triene-tri(a-glutaric acid) (Gd-PCTGA): or a salt thereof, comprising (ii) carrying out the process for obtaining PCTGA mentioned above or a salt thereof; and (iii) converting PCTGA to Gd-PCTGA, or to a salt thereof. According to this aspect, PCTGA is converted to Gd-PCTGA by coordinating the former with gadolinium(III) ions. This can be carried out by means known in the art (e.g. as disclosed in WO 2020 / 030618, WO 2020 / 148431, or WO 2020 / 148436), for example by adding to the reaction mixture a suitable source of gadolinium(III) ions, such as a salt of or an oxide of gadolinium(III), e.g. GdCh or Gd2Os.

[0064] Also, an aspect of the present invention is a process for obtaining gadopiclenol:

[0065] Gadopiclenol or a salt thereof, comprising (iii) carrying out the process for obtaining Gd-PCTGA mentioned above; and (iv) converting Gd-PCTGA to gadopiclenol, or to a salt thereof. According to this aspect, Gd- PCTGA is converted to gadopiclenol by reacting the former with isoserinol; this can be carried out by means known in the art, e.g. as disclosed in WO 2020 / 030618, WO 2020 / 148431, or WO 2020 / 148436.

[0066] According to a preferred embodiment, before the step of (iv) converting Gd-PCTGA to gadopiclenol, a step (iii)' of treating Gd-PCTGA to obtain an isomeric mixture thereof comprising at least 50%; preferably at least 60%; more preferably at least 70%; even more preferably at least 80%; and most preferably 90%, of the RRR and / or SSS stereoisomer is carried out. This can be done by means known in the art, e.g. by separating the RRR and / or SSS stereoisomers of Gd-PCTGA via chromatography (e.g. as disclosed in WO 2020 / 030618), and / or by enriching the isomeric mixture of Gd-PCTGA by acidifying and heating an aqueous solution of Gd-PCTGA, e.g. as disclosed in WO 2020 / 148431 or WO 2020 / 148436. According to this preferred embodiment, the isomeric mixture of Gd-PCTGA enriched in the RRR and / or SSS stereoisomer is then converted to an isomeric mixture of gadopiclenol comprising at least 50%; preferably at least 60%; more preferably at least 70%; even more preferably at least 80%; and most preferably 90%, of the RRR and / or SSS stereoisomer of gadopiclenol e.g. by means known in the art, for example by reacting the isomeric mixture of Gd-PCTGA mentioned above with isoserinol. According to this preferred embodiment, the process of the invention allows obtaining an isomeric mixture of gadopiclenol comprising a high amount of the RRR and / or SSS stereoisomers, which are the most favourable stereoisomers from a pharmaceutical point of view (as mentioned e.g. in WO 2020 / 030618).

[0067] A further aspect of the invention is a compound of formula (III): or a stereoisomer, or an isomeric mixture of the same, or a salt thereof, wherein R1and R2represent, independently from each other, hydrogen or Ci-Ce-alkyl.

[0068] The compound of formula (III) is an essential intermediate for the process of the invention, which is indeed obtained in step a) and reacted in step b) to provide the compound of formula (I) or PCTGA (when R1and R2represent hydrogen). According to a preferred aspect of the process of the invention, this compound of formula (III) is not isolated before step b), whereby it can be found in the reaction mixture before carrying out step b). Few amounts, e.g. traces, of the compound of formula (III) may be found also in the reaction mixture after step b) has been carried out.

[0069] According to a preferred embodiment, for the compound of formula (III), R1and R2represent, independently from each other, a Ci-C4-alkyl, preferably a Ci-C4-alkyl selected from the group consisting of: methyl, ethyl, n-propyl, / -propyl, n-butyl, / -butyl, sec-butyl, and t-butyl.

[0070] Another aspect of the present invention is the use of the compound of formula (III), or of a stereoisomer, or of an isomeric mixture of the same, or of a salt thereof, for obtaining:

[0071] • the compound of formula (I): Formula (I) or a salt thereof, wherein R1and R2are as above defined; or

[0072] • PCTGA: PCTGA or a salt thereof; or

[0073] • Gd-PCTGA: or a salt thereof; or

[0074] • gadopiclenol:

[0075]

[0076] Gadopiclenol or a salt thereof.

[0077] As mentioned above, the compound of formula (III), or stereoisomers or isomeric mixtures of the same, can be used to obtain any stereoisomers or any isomeric mixtures of the compound of formula (I), of PCTGA, of Gd-PCTGA, or of gadopiclenol, by conventional means. For example, a specific stereoisomer or isomeric mixture of the compound of formula (III) can be used to obtain the respective specific stereoisomer or isomeric mixture of the compound of formula (I). Further conventional means can be used to obtain stereoisomers or isomeric mixtures of the above mentioned compounds, e.g. any conventional means to separate specific stereoisomers, such as chromatography (possibly chiral chromatography) (as disclosed in WO 2020 / 030618), and / or any means to enrich isomeric mixtures, e.g. acidifying and heating a solution of Gd-PCTGA to obtain an isomeric mixture comprising a higher amount of RRR and SSS stereoisomers, as mentioned in WO 2020 / 148431 and WO 2020 / 148436.

[0078] Non-limiting examples of the processes of the invention are reported in the following section, aimed to illustrate the invention in greater detail without limiting its scope.

[0079] Experimental Section

[0080] Material and methods

[0081] Reactants and / or solvents employed in the following examples and not specifically synthesized therein are known and readily available. If they are not commercially available per se, they may be prepared according to known methods in literature.

[0082] 1H and13C NMR spectra were recorded on a Bruker Avance III spectrometer (Bruker, Milano, Italy) operating at 11.74 T and 298 K, corresponding to a protonic resonance frequency of 499.8 MHz.XH and13C NMR chemical shifts are reported relative to TMS and are referenced using the residual proton solvent resonances. Samples were prepared in 5 mm NMR tubes by dissolving the compounds in appropriate deuterated solvents. Analytical HPLC-MS runs were carried out on a Waters modular system equipped with Waters 1525 binary pump, Waters 2487 UV / Vis and Waters SQD 3100 (ESCI ionization mode) detectors (Waters Corporation, Milford, MA, USA). UPLC-MS analyses were performed using a UPLC Acquity H-Class coupled with QDa and TUV detectors (Waters Corporation, Milford, MA, USA). The ESI-MS were recorded on a Waters SQD 3100 (Waters Corporation, Milford, MA, USA).

[0083] Example 1 - Synthesis of the compound of formula (II)

[0084] Compounds of formula (II), 1,5-di-tert-butyl (R)-2-bromopentanedioate and diethyl (S)-2-chloropentanedioate, have been prepared as set out below. Further compounds of formula (II) can be prepared by analogy.

[0085] L-glutamic acid (4 g, 28.0 mmol) and NaBr (10 g, 97.0 mmol) were suspended in 2 M HBr (14 mL). The reaction mixture was cooled under -5 °C using a cold bath (acetonitrile cooled with liquid nitrogen). A total of 3.48 g of NaNO? (50.2 mmol) was then added in small aliquots over the course of 2.5 h. Once the additions were completed, the mixture was left for another 20 min in the cold bath before returning to room temperature; 3.52 mL of concentrated H2SO4 were then added and the reaction continued at RT overnight. The aqueous phase was then extracted with Et?O (20 mL x 4). The combined organic phases were dried with MgSO4, filtered and evaporated under reduced pressure. The product obtained was used for the subsequent reaction without further purification. Final weight: 5.50 g.

[0086] (R)-2-bromopentanedioic acid obtained according to the Example 1 I. (5.50 g, 26.1 mmol) was dissolved in CHsCOOtBu (70 mL). 70% HCIO4 (1.78 mL, 20.8 mmol) was added, and the mixture was stirred at room temperature for one night. A saturated solution of NaHCOs (15 mL) was then gradually added and then small portions of solid NaHCOs were added until gas evolution ceased. The mixture was extracted with Et?O (3x20 mL) and the combined organic phases were washed with NaHCOs sat. (100 mL), dried over anhydrous MgSCk, filtered and evaporated. The product was purified via a chromatographic column (SiO?, petroleum ether I AcOEt 98:2) obtaining a yellow oil (0.774 g, 2.4 mmol, 9.2%).

[0087] ESI-MS (m / z) : found 324.1 (M + H+), (calc for CishhsBrCk: 323.23).

[0088] HPLC-MS (Waters Atlantis 5 pm (4.6x100 mm)) : (A) : H2O + 0.1% TFA, (B) : ACN, flow = 1 mL / min; 0-2 min = 50% A and B; 2-16 min from 50% to 100% B; 16-19 min 100% B. Rt: 17.8 min

[0089] 1H-NMR (500 MHz, CDCI3) : 1.44, 1.48 (s, C-CH3, 18H), 2.15-2.63 (m, -CH2-CH2, 4H), 4.26 (q, -CH-COO, 1H).

[0090] 13C-NMR{1H} (125 MHz, CDCI3) : 28.7, 28.9 (-C-CH3), 29.8 (-CH2-COO), 30.3 (-CH- CH2), 44.3 ( -CH-COO), 82.1, 82.4 (-O-C-CH3), 169.1, 172.9 (-COOR).

[0091] (S)-2-Chloropentanedioic acid (0.2 g, 1.2 mmol, BLD Pharmatech GmbH) was dissolved in EtOH (5 mL) and the solution obtained was cooled in an ice bath. SOCI2 (263 uL, 3.6 mmol) was added dropwise to the reaction solution. After 46h, the reaction solution was evaporated and the product purified via chromatographic column (SiO2, petroleum ether / AcOEt 8 / 2, RF = 0.71) obtaining a colorless oil (167 mg, 62%). ESI-MS (m / z) : found 223.5 (M + H+), (calc for C9H15CIO4: 222.67).

[0092] XH-NMR (500 MHz, CDCI3) : 1.25, 1.32 (tt, O-CH2-CH3, 6H), 2.22, 2.37 (2 sext, -CH-CH2, 2H), 2.52 (t, -CH2-COO, 2H), 4.14, 4.24 (qq, -O-CH2-CH3, 4H), 4.40 (q, -CH-COO, 1H). 13C-NMR{1H} (125 MHz, CDCI3) : 13.9, 14.1 (-O-CH2-CH3), 29.7 (-CH2-COO), 30.2 (-CH- CH2), 56.3 ( -CH-COO), 60.6, 62.0 (-O-CH2-CH3), 169.0, 172.0 (-COOR).

[0093] Example 2 - Synthesis of the compound of formula (III) (Step a) of the process of the

[0094] I. Trial 1

[0095] To a solution of commercially acquired 1,5-dibutyl 2-bromopentanedioate (15 g, 46.5 mmol) in ACN (600 mL), K2CO3 (92.8 mmol, 12.82 g, 2 eq.) was added and the suspension was refluxed for 15 minutes. DETA (1.25 mL, 11.6 mmol, 0.25 eq .) was added dropwise and the reaction mixture was refluxed for 44 h, then it was cooled to room temperature. Then, the inorganic salts were filtered off.

[0096] II. Trials 2 to 19

[0097] The compound of formula (III) for trials 2 to 19 was prepared by analogy to Example 2 I. (Trial 1) using the parameters, reactants, and conditions set out in Table 1. Parameters, reactants, and conditions of Example 2 I. (Trial 1) are reported in Table 1 for completeness.

[0098]

[0099] Table 1 The presence of the compound of formula (III) was detected via HPLC-MS after all trials, confirming that the reaction of step a) successfully provided the desired product.

[0100] An aliquot of the solution obtained in trial 9 was collected. The analytical data of the DETA tri-alkylated with glutarate t-Bu-ester (trial 9) isolated from the aliquot by column chromatography on silica gel is reported below; the product, being the t-Bu- ester derivative, is stable at -20°C.

[0101] ESI-MS (m / z) : found 831.2 (M + H+), (calc for C43H79N3O12: 830.11).

[0102] HPLC-MS (Waters Atlantis 5 pm (4.6x100 mm)) : (A) : H2O + 0.1% TFA, (B) : ACN, flow = 1 mL / min; 0-2 min = 50% A and B; 2-16 min from 50% to 100% B; 16-19 min 100% B. Rt: 16.36 min

[0103] XH-NMR (500 MHz, CDCI3) : 1.44-1.47 (m, -C-CH3, 56H), 1.75-1.95 (m, -CH-CH2, 6H), 2.32 (m, -CH2-COOR, 6H), 2.40-2.80 (m, N-CH.2-CH.2-N, 8H), 3.10 (m, -CH-CH2-, 3H).

[0104] 13C-NMR{1H} (125 MHz, CDCI3) : 28.0, 28.1 (-C-CH3), 31.9 (-CH-CH2), 32.1 (-CH2-COO- ), 47.0, 51.2 (-N-CH2-), 61.3, 61.4 (-CH-CH2), 80.1, 81.0 (-O-C-CH3), 172.1, 172.7 (- COO-tBu).

[0105] Example 3 - Synthesis of the compound of formula (I) (Step b) of the process of the invention)

[0106] I. Trial 1

[0107] Without isolating the product of Example 2 I., Na2COs was added (12.29 g, 10 eq.), and the suspension was refluxed for 15 minutes. 2,6-bis(bromomethyl)pyridine (3.06 g, 11.6 mmol, 1 eq., Tokyo Chemical Industry Co., Ltd) was added in one portion and the reaction mixture was refluxed for 90 h. After cooling to room temperature, the solvent was removed under reduced pressure. The reaction mixture was dissolved in AcOEt (900 mL) and washed with H2O (2 x 300 mL) and Brine (1 x 300 mL), dried (Na?SO4) and evaporated under reduced pressure. The crude product (13.15 g) was obtained as brown oil and an aliquot (370 mg) was purified by flash chromatography (Phenyl 25 pm, PUREZZA (SepaChrom), size 12) to provide the final product (168 mg, 55% yield starting from diethylenetriamine).

[0108] The product was purified using the following flash chromatographic protocol: (A): H2O (B): MeOH, flow = 12 mL / min; 0-1 min = 40% B; 1-6 min = from 40% to 90% B; 6-11 min = 90% B; 11-22 min = from 90% to 100% B; from 22 to 28 min = 100% B. Rt: 20 min

[0109] ESI-MS (m / z): found 934.1 (M + H+), (calc for C50H84N4O12: 933.24).

[0110] UPLC-MS (Waters UPLC BEH C18 1.7 pm: (A): H2O + 0.1% TFA, (B): ACN + 0.1% TFA, flow = 0.4 mL / min; 0-14 min = from 40% to 100% B. Rt: 10.71 min

[0111] 1H-NMR (500 MHz, CDCI3): 0.85-1.00 (m, -CH2-CH3, 18H), 1.25-1.45 (m, -O-CH2-CH2- CH2-, 12H), 1.5-1.7 (m, -O-CH2-CH2, 12H), 1.8-2.2 (m, -CH-CH2, 6H), 2.25-2.52 (m, -CH2-COOR, 6H), 2.20-2.25 and 2.75-2.95 (m, -CH2- ring, 8H), 3.04, 3.38 (m, -CH- CH2-, 3H), 3.76, 3.90 (m, Py-CFh-N-, 4H), 4.00-4.20 (m, -O-CH2-, 12H), 7.17 (t, Py- CH-, 2H), 7.64 (t, Py-CH, 1H).

[0112] 13C-NMR{1H} (125 MHz, CDCI3): 13.6, 13.7 (-CH2-CH3,), 19.1, 19.2 (-O-CH2-CH2-CH2), 25.5 (-CH-CH2), 30.6, 30.7 (-O-CH2-CH2,), 30.8 (-CH2-CO), 50.5, 53.2 (CH2 ring), 57.7 (NCH2Py), 64.3 (-O-CH2-CH2), 65.3, 65.8 (-CH-CH2), 122.8, 137.4, 158.4 (C-Py), 172.7, 173.3 (-COOR).

[0113] II. Trials 5, 6, 8-10, 12, 14, and 16-19

[0114] Without isolating the products obtained in Trials 5, 6, 8-10, 12, 14, and 16-19 of Example 2 IL, compounds of formula (I) were prepared by analogy to Example 3 I. (Trial 1) using the parameters, reactants, and conditions set out in Table 2. Parameters, reactants, and conditions of Example 3 I. (Trial 1) are reported in Table 2 for completeness.

[0115] The Overall yield (%) reported in Table 2 is the yield of the process of the invention, that is step a) + step b), starting from reagent diethylenetriamine (DETA).

[0116]

[0117] Table 2

[0118] Table 2 demonstrates that the process of the invention provides the compound of formula (I), and that it can be effectively carried out using a one-pot procedure (that is, without isolating the compound of formula (III) obtained in step a)), whereby the process of the invention is particularly suitable for industrial manufacturing.

[0119] The analytical data of the Et-hexaester derivative of trial 17, purified via the flash chromatography protocol of Example 3, trial I., is reported below:

[0120] ESI-MS (m / z): found 765.7 (M + H+), (calc for C38H60N4O12: 764.91).

[0121] UPLC-MS (Waters UPLC BEH C18 1.7 pm : (A): H2O + 0.1% TFA, (B): ACN + 0.1% TFA, flow = 0.4 mL / min; 0-14 min = from 40% to 100% B. Rt: 10.42 min

[0122] 1H-NMR (500 MHz, CDCI3): 1.15-1.30 (m, -O-CH2-CH3, 18H), 1.65-2.05 (m, -CH-CH2, 6H), 2.25-2.47 (m, -CH2-COOR, 6H), 2.20-2.25 and 2.70-2.90 (m, -CH2- ring, 8H), 3.00, 3.33 (m, -CH-CH2-, 3H), 3.70, 3.92 (m, Py-CHz-N-, 4H), 4.00-4.20 (m, -O-CH2-CH3, 12H), 7.12 (t, Py- CH-, 2H), 7.59 (t, Py-CH, 1H).

[0123] 13C-NMR{1H} (125 MHz, CDCI3): 14.2, 14.4 (-O-CH2-CH3), 25.3 (-CH-CH2), 30.7 (-CH2-CO), 50.3, 52.3 (CH2ring), 57.7 (NCH2Py), 60.3 (-O-CH2-CH3), 65.0, 65.9 (-CH-CH2), 122.7, 137.4, 158.4 (C-Py), 172.7, 173.2 (-COOR).

[0124] The compound of formula (I) was synthesized as described in the procedure of Example 3 I. (Trial 1), but without carrying out the purification step via flash chromatography. The crude product (1.24 g) obtained was added to an aqueous solution of 5 M NaOH (7.68 mL), and the solution was stirred at room temperature for one night. 12 M HCI was dropped into the reaction solution until the pH is 2. The product was purified by liquid chromatography (XAD, starting the elution with H2O to remove NaCI salt and then passing to a H2O / ACN 50 / 50 mixture to elute the desired product), obtaining a white powder (375 mg, 55% over three steps).

[0125] The obtained white powder was characterized via UPLC-MS to confirm that 3,6,9,15- tetraazabicyclo-[9.3.1]pentadeca-l(15),ll,13-triene-tri(a-glutaric acid) (PCTGA) was obtained.

[0126] UPLC-MS (Waters UPLC BEH C18 1.7 pm : (A): H2O + 0.1% TFA, (B): ACN + 0.1% TFA, flow = 0.4 mL / min; 0-14 min = from 2% to 100% B. Rt: 2.22 min

[0127] Starting from PCTGA obtained according to this Example 4, Gd-PCTGA and then gadopiclenol can be obtained according to known processes e.g. as disclosed in WO 2020 / 030618, WO 2020 / 148431, and / or WO 2020 / 148436.

Claims

CLAIMS1. A process for obtaining the compound of formula (I) :Formula (I) or a salt thereof, wherein R1and R2represent, independently from each other, hydrogen or Ci-Ce-alkyl, said process comprising the following steps: a) reacting / V1-(2-aminoethyl)ethane-l,2-diamine (DETA):with the compound of formula (II):Formula (II) or a salt thereof, wherein : R1and R2are as defined above for formula (I), and LG is a leaving group;or a salt thereof, wherein R1and R2are as defined above for formula (I); andb) reacting the compound of formula (III) with the compound of formula (IV):Formula (IV) wherein LG' is a leaving group; to obtain the compound of formula (I), or a salt thereof.

2. The process according to claim 1, step b) is carried out without isolating the compound of formula (III).

3. The process according to claim 1 or 2, wherein R1and R2represent, independently from each other, Ci-C4-alkyl.

4. The process according to claim 3, wherein R1and R2represent, independently from each other, Ci-C4-alkyl selected from the group consisting of: methyl, ethyl, n-propyl, / -propyl, n-butyl, / -butyl, sec-butyl, and t-butyl.

5. The process according to any one of claims 1 to 4, wherein LG is a halogen.

6. The process according to claim 5, wherein LG is a halogen selected from the group consisting of chloro, bromo, and iodo.

7. The process according to any one of claims 1 to 6, wherein step a) is carried out in the presence of a base.

8. The process according to claim 7, wherein the base is a tertiary amine, or is a salt comprising the carbonate ion.

9. The process according to claim 8, wherein the base is selected from the group consisting of: / V, / V-diisopropylethylamine (DIPEA), triethylamine (TEA), sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, and mixtures thereof.

10. The process according to any one of claims 1 to 9, wherein step a) is carried out without a solvent; or wherein step a) is carried out with a solvent.

11. The process according to claim 10 wherein, when R1and R2represent a Ci-Ce-alkyl, step a) is carried out with a non-aqueous solvent.

12. The process according to claim 11 wherein, when R1and R2represent a Ci-Ce-alkyl, step a) is carried out with an aprotic non-aqueous solvent.

13. The process according to claim 12 wherein, when R1and R2represent a Ci-Ce-alkyl, step a) is carried out with an aprotic non-aqueous solvent selected from the group consisting of: acetonitrile, n-butanol, toluene, / V, / V-dimethylformamide (DMF), / V, / V-dimethylacetamide (DMA), and mixtures thereof.

14. The process according to any one of claims 1 to 13, wherein LG' is a halogen or a leaving group containing sulphur.

15. The process according to claim 14, wherein LG' is selected from the group consisting of chloro, bromo, iodo, tosyl group, tosylate group, mesylate group, triflate group and nosyl group.

16. The process according to claim 15, LG' is selected from the group consisting of chloro, bromo, and iodo.

17. The process according to any one of claims 1 to 16, wherein step b) is carried out in the presence of a base.

18. The process according to step 17, wherein the base is a tertiary amine or a salt comprising the carbonate ion.

19. The process according to step 18, wherein the base is selected from the group consisting of: / V, / V-Diisopropylethylamine (DIPEA), triethylamine (TEA), sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, and mixtures thereof.

20. The process according to any one of claims 1 to 19, wherein step b) is carried out without a solvent; or wherein step b) is carried out with a solvent.

21. The process according to claim 20 wherein, when R1and R2represent a Ci-Ce-alkyl, step b) is carried out with a non-aqueous solvent.

22. The process according to claim 21 wherein, when R1and R2represent a Ci-Ce-alkyl, step b) is carried out with an aprotic non-aqueous solvent.

23. The process according to claim 22 wherein, when R1and R2represent a Ci-Ce-alkyl, step b) is carried out with an aprotic non-aqueous solvent selected from the group consisting of: acetonitrile, n-butanol, toluene, / V, / V-dimethylformamide (DMF), / V, / V-dimethylacetamide (DMA), and mixtures thereof.

24. A process for obtaining 3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca- l(15),ll,13-triene-tri(a-glutaric acid) (PCTGA)or a salt thereof, comprising (i) carrying out the process for obtaining the compound of formula (I) according to any one of claims 1 to 23; and (ii) converting the compound of formula (I) to PCTGA, or to a salt thereof.

25. A process for obtaining the gadolinium complex of 3,6,9,15- tetraaza bicyclo- [9.3.1] pentadeca- 1( 15), ll,13-triene-tri(a-glutaric acid) (Gd-PCTGA):Gd-PCTGA or a salt thereof, comprising (ii) carrying out the process for obtaining PCTGA according to claim 24; and (iii) converting PCTGA to Gd-PCTGA, or to a salt thereof.

26. A process for obtaining gadopiclenol:Gadopiclenol or a salt thereof, comprising (iii) carrying out the process for obtaining Gd-PCTGA according to claim 25; and (iv) converting Gd-PCTGA to gadopiclenol, or to a salt thereof.Formula (III) or a stereoisomer, or an isomeric mixture of the same, or a salt thereof, wherein R1and R2represent, independently from each other, hydrogen or Ci-Ce-alkyl.

28. The compound according to claim 27, wherein R1and R2represent, independently from each other, Ci-C4-alkyl; preferably, a Ci-C4-alkyl selected from the group consisting of: methyl, ethyl, n-propyl, / -propyl, n-butyl, / -butyl, sec-butyl, and t-butyl.

29. Use of the compound as defined in claim 27 or 28 for obtaining: the compound of formula (I):Formula (I) or a salt thereof, wherein R1and R2are as above defined; or• 3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-l(15),ll,13-triene-tri(a-glutaric acid) (PCTGA)PCTGA or a salt thereof; or• the gadolinium complex of 3, 6,9,15-tetraaza bicyclo- [9.3.1] pentadeca- l(15),ll,13-triene-tri(a-glutaric acid) (Gd-PCTGA):or a salt thereof; oror a salt thereof.

Images