Method for preparing mixtures containing dimeric macrocyclic intermediates of gadolinium complexes

Abstract

The present invention relates to a process for the preparation of the intermediate 1-[bis[2-hydroxy-3-[4,7,10-tris[2-(1,1-dimethylethoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]propyl]amino]-1-deoxy-D-glucitol. Such intermediate is a dimeric gadolinium complex [μ-[1-[bis[2-(hydroxy-κO)-3-[4,7,10-tris[(carboxy-κO)methyl]-1,4,7,10-tetraazacyclododecan-1-yl-κN], which can be used as a contrast agent in the field of diagnostic imaging, in particular magnetic resonance imaging (MRI). 1 ,κN 4 ,κN 7 ,κN 10 ]propyl]amino]-1-deoxy-D-glucitrate(6-)]]di-gadolinium complex is useful for the synthesis of

Description

[Technical field]

[0001] The present invention relates to what is characterized in the claims, namely the chemical synthesis of a mixture containing an intermediate dimeric macrocycle, which is useful in the field of diagnostic imaging, in particular magnetic resonance imaging (MRI), and is a dimeric gadolinium complex [μ-[1-[bis[2-(hydroxy-κO)-3-[4,7,10-tris[(carboxy-κO)methyl]-1,4,7,10-tetraazacyclododecan-1-yl-κN]. 1 ,κN 4 ,κN 7 ,κN 10 ]propyl]amino]-1-deoxy-D-glucitrate(6-)]]di-gadolinium complexes. [Background technology]

[0002] Magnetic resonance imaging (MRI) is a well-known diagnostic imaging technique that is being used for an increasing number of indications in clinical diagnosis. Gadolinium (Gd(III)) complexes are commonly used as MRI contrast agents.

[0003] WO2017 / 098044 describes dimeric Gd(III) complexes useful as contrast agents in MRI, such as the dimeric Gd(III) complex [μ-[1-[bis[2-(hydroxy-κO)-3-[4,7,10-tris[(carboxy-κO)methyl]-1,4,7,10-tetraazacyclododecan-1-yl-κN 1 ,κN 4 ,κN 7 ,κN 10 ]propyl]amino]-1-deoxy-D-glucitrate(6-)]]di-gadolinium complex (herein referred to as compound 5). [ka]

[0004] As disclosed in WO2017 / 098044, compound 5 exhibits high relaxivity, in particular more than two-fold higher relaxivity than that exhibited by Dotarem® and ProHance® (non-specific contrast agents currently used in diagnostic practice). Therefore, compound 5 is a promising contrast agent for in vivo MRI diagnostic imaging.

[0005] WO2017 / 098044 further discloses the preparation of compound 5, as shown in the following reaction scheme (Scheme 1): [ka]

[0006] Specifically, referring to Scheme 1 above, WO2017 / 098044 discloses preparing compound 2 by adding a large excess of epichlorohydrin (52 mmol) to a solution of commercially available D-glucamine (10.5 mmol) in methanol and reacting for 26 hours at 50° C. Compound 2 is then reacted with a stoichiometric amount of compound 1A in acetonitrile in the presence of base Et3N at 70° C. for 72 hours to obtain intermediate compound 3 in 15% yield.

[0007] The process disclosed in WO2017 / 098044 for preparing intermediate compound 3 (see Scheme 1 above) has drawbacks such as long reaction times and low overall yields, especially in the step to obtain compound 3.

[0008] Furthermore, in the process disclosed in WO2017 / 098044, all intermediates such as intermediate compounds 2 and 3 are isolated, which is not optimal for carrying out the production on an industrial scale. Summary of the Invention [Problem to be solved by the invention]

[0009] In view of the above, there is a need to find improved processes for preparing compound 5 and / or its intermediates. [Means for solving the problem]

[0010] The present invention relates to a process for the preparation of a mixture comprising an intermediate compound 3 according to claim 1. [ka]

[0011] Compound 3 is a useful intermediate for the synthesis of compound 5, as shown in Scheme 1 above.

[0012] In particular, the present process for producing a mixture comprising compound 3 can avoid the isolation of the intermediate compound 2, making such a process convenient and suitable for industrial scale.

[0013] Furthermore, the production method of the present invention includes a step of removing at least a portion of the remaining epichlorohydrin and its derivatives. Since the production method of the present invention does not involve isolation, the removal of epichlorohydrin and its derivatives (step b)) can improve the efficiency of step c), i.e., the coupling between compound 1A and compound 2. In fact, epichlorohydrin and its derivatives react with compound 1A in step c), thereby producing, for example, the following formula: [ka] As a result, unnecessary by-products such as the above are produced, and the amount of the obtained compound 3 is reduced. Therefore, by removing a part of epichlorohydrin and its derivatives through step b), the amount of epichlorohydrin and its derivatives is reduced, and the amount of epichlorohydrin and its derivatives that can react with compound 1A is reduced, and the reaction efficiency of step c) is improved.

[0014] Furthermore, epichlorohydrin is classified as a probable or likely human carcinogen, and therefore its removal is crucial for the potential clinical application of the final product, compound 5.

[0015] The present invention further provides, as claimed in independent claim 14, a dimeric complex compound 5 [ka] The present process for producing compound 5 is advantageously carried out without isolation of intermediates. Since no isolation of intermediates is performed, the removal of epichlorohydrin and its derivatives is even more important in order to (i) provide an efficient process (i.e., reducing undesired reactions involving epichlorohydrin and its derivatives) and (ii) provide a final product, i.e., compound 5, with reduced amounts of harmful compounds (i.e., epichlorohydrin and its derivatives).

[0016] Specific embodiments of the above manufacturing method are set out in the dependent claims and below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description of the Invention According to a first aspect, the present invention provides compound 3 (i.e., 1-[bis[2-hydroxy-3-[4,7,10-tris[2-(1,1-dimethylethoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]propyl]amino]-1-deoxy-D-glucitol). [ka] A method for producing a mixture comprising the steps of: a) glucamine, preferably D-glucamine, in a solvent, preferably an aqueous solution containing at least a C1-C3 alcohol, such as methanol; [ka] Epichlorohydrin [ka] to give compound 2 (i.e., 1-[bis(3-chloro-2-hydroxypropyl)amino]-1-deoxy-D-glucitol). [ka] obtaining a first solution comprising: b) removing at least a portion of residual epichlorohydrin and its derivatives from a first solution containing compound 2 without isolating compound 2 from the first solution to obtain a second solution containing compound 2; c) Without isolating compound 2 from the second solution, compound 1A (i.e., 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid 1,4,7-tris(1,1-dimethylethyl) ester) [ka] to a second solution comprising compound 2, and reacting compound 2 with compound 1A to obtain a mixture comprising compound 3. The present invention relates to a manufacturing method comprising the steps of:

[0018] As used herein, the term "mixture comprising compound 3" refers to a mixture of compound 3 and a solvent (specifically, a solvent disclosed in detail below), which may further include other components, such as by-products (e.g., DO3A tBu-HCl) and unreacted reaction reagents, in solution and / or suspension.

[0019] The term "C1-C3 hydroxyalkyl" as used herein means a straight or branched hydrocarbon chain containing 1 to 3 carbon atoms and having one hydroxyl (-OH) group. Suitable examples include methanol, ethanol, propanol, and isopropanol.

[0020] The present process advantageously produces a mixture containing compound 3 in high yield and in short reaction times. Indeed, the reaction of step a) can be carried out for 8 to 24 hours, preferably in the range of 14 to 18 hours, more preferably 16 hours, and / or at a temperature of 20 to 35°C, preferably in the range of 23 to 28°C, more preferably 25°C, while the reaction of step c) can be carried out for a time of less than 72 hours, preferably less than 48 hours; the time can more preferably be in the range of 14 to 24 hours, even more preferably 16 to 18 hours. The reaction of step c) is preferably carried out at a temperature of 55 to 75°C, more preferably 63 to 67°C. Not isolating compound 2 allows further time saving and contributes to making the process more suitable for industrial scale.

[0021] Furthermore, it has been found that the reaction of step a) can be effectively carried out by using a small amount of epichlorohydrin, compared to the large excess of epichlorohydrin used in the prior art. This advantageously saves costs and also reduces the use of harmful compounds (as mentioned above, epichlorohydrin is classified as highly or likely to be carcinogenic in humans) and competing reactants (as mentioned above, epichlorohydrin may react with compound 1A during step c) and thus form by-products) that must be removed in the following step b). Indeed, according to a preferred embodiment, the reaction of step a) is carried out by reacting an amount of epichlorohydrin of 2.2 to 3.8 moles per mole of glucamine, more preferably 2.5 to 3.5 moles per mole of glucamine, even more preferably 2.9 to 3.1 moles per mole of glucamine, and most preferably 3 moles per mole of glucamine.

[0022] The present process has also been found to improve the overall yield for obtaining compound 3 compared to the process disclosed in WO2017 / 098044.

[0023] In step a), a solution comprising compound 2 is obtained by reacting glucamine, preferably D-glucamine, with epichlorohydrin, both of which are commercially available, for example according to the molar ratios provided above. Specifically, according to a preferred embodiment, glucamine (preferably D-glucamine) is first dissolved in water, and such an aqueous solution comprising glucamine is mixed (e.g., added over a period of, for example, 1-4 hours, preferably 2 hours) with a mixture comprising epichlorohydrin diluted with a C1-C3 alcohol, preferably methanol, preferably by maintaining the temperature at about room temperature (25° C.). Thus, the solvent for the reaction in step a) is preferably an aqueous solvent comprising a C1-C3 alcohol, preferably methanol.

[0024] Step b) allows the removal of residual epichlorohydrin (i.e. epichlorohydrin that has not reacted with glucamine in step a) and is present in the first solution comprising compound 2) and its derivatives (i.e. derivatives of epichlorohydrin that may be formed during the reaction, namely 3-chloro-1,2-propanediol and 1,3-dichloro-2-propanol). Indeed, thanks to this purification step b), which has been found to effectively remove at least a portion of epichlorohydrin and its derivatives, the second solution comprising compound 2 obtained by step b) has a lower content of epichlorohydrin and its derivatives than the first solution comprising compound 2 obtained by step a). In view of the above, step b) offers the advantage of removing harmful components from the solution, thus making it possible to improve the long-term safety of the final product (compound 5) that can be used in clinical practice. Moreover, step b) advantageously removes harmful components without the need to isolate intermediates (e.g. compound 2). In step b), the amount of epichlorohydrin and its derivatives competing with compound 2 in the reaction with compound 1A can be reduced, and the efficiency of the subsequent step c) can also be improved. This, together with avoiding the isolation of compound 2 during the preparation method of the present invention, can further improve the yield.

[0025] According to a preferred embodiment, the removal of residual epichlorohydrin and its derivatives, i.e. step b), is carried out according to the following steps: b1) removing C1-C3 alcohol, if present, from a first solution comprising compound 2, preferably by distilling the C1-C3 alcohol; b2) performing at least one liquid-liquid extraction, where the first liquid is the first solution containing compound 2 or the solution obtained by step b1) (if such step b1) is performed), and the second liquid is any organic solvent immiscible with the first liquid, such as methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl tetrahydrofuran (MeTHF), and methyl tert-butyl ether (MTBE). Preferably, the second liquid is MTBE.

[0026] It has been found that liquid-liquid extraction efficiently and effectively removes at least a portion of epichlorohydrin and its derivatives from the first solution, thereby reducing the amount of harmful components. For example, as described in more detail in the experimental section, the first solution (i.e., before liquid-liquid extraction) contains epichlorohydrin, 3-chloro-1,2-propanediol, and 1,3-dichloro-2-propanol in amounts up to 0.60% w / w, 0.20% w / w, and 1.00% w / w, respectively, while the second solution (i.e., after liquid-liquid extraction) can contain as low as 0.10% w / w, 0.06% w / w, and 0.05% w / w, respectively, of the solution. According to step b2), at least a portion of the remaining epichlorohydrin and its derivatives is removed from the solution by liquid-liquid extraction. Specifically, the first liquid (i.e., the first solution containing compound 2, or the solution obtained by step b1) (if such step b1) is carried out) is preferably an aqueous solution, and the second liquid is preferably any of the above-mentioned solvents that are immiscible with the aqueous solution. According to such an embodiment, the residual epichlorohydrin and its derivatives are extracted from the solution by virtue of an organic solvent that is immiscible with the aqueous solution (i.e., the second liquid of step b2), such as MTBE, and can then be discarded.

[0027] In step b2), the first liquid is preferably an aqueous solution, and the solution (second liquid) obtained by step b2) (i.e., recovered from step b2) is also preferably an aqueous solution. Thus, the liquid-liquid extraction in step b2) preferably uses an aqueous solution as the first liquid, which is recovered after extraction, and discards the second liquid after extraction.

[0028] Preferably, the liquid-liquid extraction in step b2) above is carried out one or more times, for example two to four times, preferably three times.

[0029] According to a preferred embodiment, the amount of the second liquid immiscible with the first liquid is in the range of 0.5 to 3 w / w, preferably 1 to 2 w / w, more preferably 1.2 to 1.8 w / w, and even more preferably 1.5 w / w relative to the amount of glucamine in step a).

[0030] The solution containing compound 2 obtained in step b) can be directly used in the next reaction step without isolating the intermediate (compound 2).

[0031] According to a preferred embodiment, the method comprises a step of changing the solvent after step b) and before step c), the step of changing the solvent comprises adding dimethylsulfoxide (DMSO) to the second solution containing compound 2 and removing solvents other than DMSO (such as water) from the solution, so that the second solution containing compound 2 after the step of changing the solvent comprises DMSO as a solvent. The amount of DMSO added according to this step is in the range of 2.0-4.0 w / w, preferably 2.5-3.5 w / w, more preferably 3 w / w, relative to the amount of glucamine in step a). Preferably, after the step of changing the solvent, the remaining water content (KF) is less than 15% w / w, more preferably less than 6% w / w. Removal of solvents other than DMSO, such as removal of water, from the second solution containing compound 2 to which DMSO has been added can be carried out by conventional means known to those skilled in the art, such as distilling such a solution under reduced pressure. According to this solvent exchange step, the second solution comprising compound 2 has DMSO as solvent, so that the subsequent reaction of step c) can advantageously be carried out in a reaction mixture comprising DMSO. This solvent exchange step advantageously does not include the isolation of compound 2. This solvent exchange step, in particular the distillation of solvents other than DMSO (such as water), has been found to further reduce the amount of epichlorohydrin and its derivatives, as disclosed in more detail in the experimental section.

[0032] In step c) of the process of the invention, compound 2 obtained in the upstream step is reacted with, preferably in molar excess, compound 1A, to obtain a mixture comprising compound 3. This reaction is preferably carried out without isolating compound 2 from the solution, for example after the solvent exchange step disclosed above, by combining a second solution comprising compound 2 with a molar excess of compound 1A. Compound 1A can be prepared according to known methods, for example as disclosed in Moore DA, Org. Synth. 2008, 85, 10.

[0033] According to a preferred embodiment, the solvent for the reaction in step c) comprises DMSO and at least a C2-C4 alcohol, preferably DMSO and isopropanol. For example, step c) can be carried out by combining a second solution (from the above solvent change step), preferably having DMSO as a solvent, with compound 1A dissolved in a C2-C4 alcohol, preferably isopropanol.

[0034] Step c) preferably uses a molar excess of compound 1A, so that compound 1A conveniently acts as both a reagent and a base for the reaction of step c). In fact, it has been found that a base is necessary to neutralize the hydrogen chloride produced in the present preparation method. If not neutralized, hydrogen chloride will react with the free amine of compound 1A to form the hydrochloride salt of compound 1A (compound 1A-HCl) and will not react with compound 2 to produce compound 3. However, it has also been found that not all bases are as effective at neutralizing hydrogen chloride as compound 1A: for example, according to the preparation method of the prior art WO2017 / 098044, even if Et3N is used as a base, part of compound 1A that should react with compound 2 will react with hydrogen chloride and, as a result, be converted to compound 1A-HCl. Surprisingly, it was found that adding a molar excess of compound 1A overcomes this problem, thereby resulting in a high yield in this reaction step: indeed, by adding a molar excess of compound 1A, compound 1A can stoichiometrically react with compound 2 to form compound 3, and at the same time, a portion of the excess compound 1A can effectively neutralize hydrogen chloride (forming compound 1A-HCl).

[0035] Addition of a molar excess of compound 1A also advantageously avoids the addition of additional components that act as bases, such as Et3N, to the reaction mixture, which avoids having to perform specific purification steps to remove such additional components that act as bases.

[0036] Thus, according to a preferred embodiment, step c) is carried out by mixing more than 2.0 moles of compound 1A per mole of compound 2, preferably up to 4.0 moles of compound 1A per mole of compound 2. For example, step c) is carried out by mixing 2.2 to 3.0 moles, preferably 2.4 to 2.8 moles, more preferably 2.5 moles of compound 1A per mole of compound 2.

[0037] As described above, a portion of the excess compound 1A reacts with hydrogen chloride to produce compound 1A-HCl. Compound 1A-HCl can be efficiently and effectively removed from the solution obtained from step c), i.e., the mixture containing compound 3. Thus, according to one embodiment, the preparation method further comprises step d): d) removing at least a portion of compound 1A hydrochloride (compound 1A-HCl) (e.g., formed during step c)) from the mixture containing compound 3, for example by precipitating compound 1A-HCl, without isolating compound 3 from the mixture. Includes.

[0038] Step d) preferably comprises: d1) adding MTBE to a mixture containing compound 3 to precipitate at least a portion of compound 1A-HCl; and d2) filtering the mixture obtained in step d1) to remove the precipitated compound 1A-HCl. This is carried out by:

[0039] The amount of MTBE added in step d1) is preferably in the range of 2-10 w / w, more preferably 3-4 w / w, and even more preferably 3.6 w / w, relative to the amount of glucamine in step a). The precipitation in step d1) is preferably promoted by cooling the mixture to a temperature of 5-15°C, more preferably 8-10°C.

[0040] Step d), particularly steps d1) and d2), can advantageously remove and possibly recover part of the excess compound 1A as a solid form of compound 1A-HCl (precipitated compound 1A-HCl), thereby further improving the purity of the mixture containing compound 3 (and thus compound 5) obtained according to the preparation method disclosed below. The precipitated and filtered compound 1A-HCl can be reused in step c) by converting it to compound 1A, which can improve the cost-effectiveness of the preparation method of the present invention.

[0041] According to a preferred embodiment, the method of the present invention further comprises the steps of: d3) concentrating the mixture containing compound 3 or preferably the mixture obtained by step d) or d2) without isolating compound 3 from the mixture; and d4) Add isopropanol and t-bromobutyl acetate to the mixture obtained by step d3) to obtain compound 1B (DOTA 4tBu). [ka] Preferably, compound 1B is obtained by stirring at room temperature for 2 to 3 hours. include.

[0042] Step d4) gives compound 1B (DOTA 4tBu). The derivative of compound 1B (i.e. Gd-DOTA or gadolinated complex of 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) can be easily removed when carrying out the preparation method for the preparation of dimeric complex compound 5 (disclosed in more detail below): in fact, compound 1B can be converted into the deprotected and gadolinated derivative (i.e. Gd-DOTA) by simply carrying out the steps for the preparation of compound 5 according to the invention (disclosed below), and Gd-DOTA can be easily removed by chromatography, for example with an ion exchange resin. Specifically, compound 1A and / or compound 1A-HCl (e.g., not precipitated in step d1)) are converted to DOTA 4tBu (compound 1B) according to step d4), which is first deprotected by carrying out step f) (below) to obtain DOTA(2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid, and finally complexed with gadolinium by carrying out step g) (below) according to the method for preparing compound 5 of the present invention to obtain Gd-DOTA. Gd-DOTA can then be effectively removed by standard purification methods, such as chromatography on ion exchange resins. This removal is highly advantageous since it has been found that Gd-DOTA is more easily removed (e.g. by chromatography on an ion exchange resin) than the gadolinium-deprotected derivative of compound 1A, and therefore (for more efficient purification) it is preferable to remove compound 1B after deprotection and conjugation rather than unreacted compound 1A and / or residual compound 1A-HCl that was not precipitated in step d1).Furthermore, since Gd-DOTA is a commercially available contrast agent, the Gd-DOTA removed as described above can advantageously be recovered (not discarded) and used in other process streams and / or for other purposes.

[0043] Steps d1) to d4) advantageously make it possible to remove most of the excess compound 1A, thereby further improving the purity of the mixture containing compound 3 (and thus compound 5) obtained according to the preparation method disclosed below. Indeed, it is clear from the HPLC analysis that by carrying out steps d1) to d4), the percentage of the area under the curve (AUC%) of the peak related to compound 1A can be reduced from about 3.3% to about 0.2%.

[0044] Furthermore, this purification method is highly advantageous in that it does not require isolation of intermediates (eg, compounds 3 or 4), which is advantageous for industrial-scale production.

[0045] Preferably, the solution obtained after step d4) is purified, for example by chromatography using an adsorption resin as stationary phase, to remove common impurities other than those specifically mentioned above (i.e. other than epichlorohydrin and its derivatives, as well as compound 1A-HCl).

[0046] According to a preferred embodiment, the present invention relates to a dimeric complex compound 5 [ka] A method for producing a process comprising the steps of: e) preparing a mixture comprising compound 3 according to any of the embodiments for preparing a mixture comprising compound 3 described above; f) Without isolating said compounds from the mixture of step e), the tert-butyl protecting group is removed from compound 3 to obtain free ligand compound 4, respectively. [ka] to obtain a solution of; g) adding gadolinium metal ions to the solution of step f) without isolating compound 4 to obtain a solution of compound 5; and h) recovering compound 5; wherein the reaction solvent in all steps after step e) is an aqueous solvent. It relates to a manufacturing method.

[0047] As used herein, the term "aqueous solvent" includes within its meaning water and aqueous solutions, such as saline, which may optionally contain small amounts (e.g., 10% or less by volume, preferably 8% or less, more preferably 5% or less) of organic solvents that act as solvents in the solution or mixture and are miscible with water. Preferably, the aqueous solvent is water.

[0048] Similarly, the expression "aqueous solution" includes within its meaning a solution that contains water. Suitable examples include aqueous solutions of one or more compounds (e.g., a reagent, an acid, a base, or a reaction product in water).

[0049] This method for producing compound 5 includes all the advantages of the method for producing a mixture containing compound 3 disclosed above.

[0050] Moreover, the process of the present invention for producing compound 5 comprises a preparation step carried out in one pot without intermediate isolation, which allows both time saving and improving the overall yield and efficiency. In fact, the prior art processes require the synthesis and isolation of individual intermediates. Such isolation steps are not particularly suitable for large-scale production.

[0051] The prior art processes use toxic substances such as TFA, TIPS, and DCM that are difficult to handle and therefore are not suitable for large-scale production, e.g., industrial production. These substances are corrosive and may adversely affect the synthesis equipment and the production of compound 5, or may be unsafe for the health of the workers. In contrast, the present process for producing compound 5 avoids or significantly reduces the use of toxic substances such as trifluoroacetic acid (TFA) and harmful solvents such as dichloromethane. In fact, it is preferred that the reaction solvent in all steps following step e) is aqueous and does not contain toxic substances such as TFA, TIPS, and / or DCM. It has also been surprisingly found that the use of aqueous solvents in all steps following step e) does not reduce the overall process yield; rather, the overall yield of the present process for producing compound 5 is improved compared to the prior art process.

[0052] In particular, the use of aqueous solvents as reaction solvents in all steps following the preparation of the coupling is highly advantageous, especially in terms of cost, environmental impact, and ease of implementation on an industrial scale. Indeed, in the process disclosed in WO2017098044, solvents such as DCM and substances such as TFA and TIPS are used, which are not only expensive but also difficult to handle, especially when scaling up the process to an industrial scale, and may not be safe from the viewpoint of worker health. The problems of the prior art processes are solved by the present invention, since the use of aqueous solvents in all steps following the preparation of compound 3 avoids or significantly reduces the use of organic solvents, making the process suitable for larger scale implementation, for example in industrial production, and easy to implement.

[0053] According to a preferred embodiment, before step f), a solvent exchange step is carried out on the mixture containing compound 3, and the solvent of the mixture containing compound 3 after the solvent exchange step is an aqueous solution or water. In particular, when the mixture containing compound 3 contains an organic solvent, the organic solvent can be replaced with an aqueous solvent by methods known to those skilled in the art, for example, by first diluting the mixture containing compound 3 with water or an aqueous solution, and then removing the organic solvent to obtain an aqueous solution containing compound 3.

[0054] Step f) involves the removal of the carboxyl protecting group from compound 3 to obtain an aqueous solution of the respective free ligand compound 4. Deprotection by hydrolysis of the tert-butyl protecting group can be carried out both under acidic and basic conditions using reaction reagents and conditions known to the skilled person. In one embodiment, deprotection is carried out by acidifying an aqueous solution of the protected ligand directly recovered from the upstream step to obtain an acidic solution of compound 4. Acidification is preferably carried out by addition of an acid selected, for example, from HCl, H2SO4, and H3PO4. In a preferred embodiment, deprotection is carried out with HCl. The acidic solution is then neutralized, followed by purification and partial concentration of the resulting mixture to recover an aqueous solution of compound 4, which is used directly in the complexation step g) without isolation.

[0055] Step g) involves complexing the ligand with gadolinium metal ions to obtain the desired dimeric complex compound 5. The complexation reaction can be conveniently carried out according to known procedures, for example by stoichiometrically adding a suitable Gd(III) derivative, specifically an oxide such as Gd2O3 or a gadolinium salt, to a solution of the ligand. In one embodiment, the complexation reaction is carried out by adding GdCl3 to the solution of the ligand directly recovered from step f) of the present process. The resulting mixture is adjusted to a pH of about 5 to about 7 and maintained under stirring to obtain an aqueous solution of gadolinium complex compound 5, which is then purified and concentrated to obtain a solution of the desired dimeric complex compound 5 with the desired purity.

[0056] Step h) involves the final isolation of the desired gadolinium complex compound 5. This step can be conveniently carried out according to known procedures. In one embodiment, the solution of purified complex recovered from step g) is spray dried to obtain the desired product as a white solid meeting the required purity specifications.

[0057] According to a more preferred embodiment, the method for preparing compound 5 comprises the following steps: e) obtaining a mixture comprising compound 3 according to any embodiment of the method for producing a mixture comprising compound 3 disclosed herein; f) acidifying the solution obtained in step e) to obtain an acidic aqueous solution of compound 4, neutralizing the acidic solution, and purifying the resulting neutral solution to obtain an aqueous solution containing compound 4, without isolating compound 4; g) adding gadolinium metal ions to a solution of compound 4 to obtain a solution of the corresponding complex compound 5; and h) isolating compound 5 Includes.

[0058] Step f) involves the deprotection of the protected ligand compound 3 by removing the carboxyl protecting group to obtain an aqueous solution of the respective free ligand compound 4. This reaction is preferably carried out by acidifying an aqueous solution of the protected ligand of compound 3 directly recovered from step e) of the present process.

[0059] In one embodiment, step f) comprises the steps of: i) adding an acid to the aqueous solution of compound 3 obtained after the solvent exchange step disclosed above to obtain an acidic solution of compound 4; ii) adding a base to the acidic solution to obtain a substantially neutralized solution of compound 4; iii) The neutralized solution is purified and optionally concentrated to obtain an aqueous solution of compound 4 suitable for direct use in the next complexation reaction without the need for ligand isolation. Includes.

[0060] In one embodiment, a solution of protected compound 3 is acidified by adding an acid, such as 34% aqueous HCl, using a large excess of HCl (e.g., 30-100 times, preferably 30-80 times, more preferably 40-50 times the molar amount of compound 3).

[0061] The acid is added at a temperature of 20 to 35° C., preferably 30 to 35° C. Then, the resulting solution is maintained with stirring at 30 to 40° C. for 10 to 36 hours, preferably 25 to 30 hours, and the ligand is deprotected, for example, by chromatography.

[0062] The acidic solution is then cooled, for example to 25° C., and neutralized by adding a base, preferably NaOH, to obtain a raw solution with a final pH of 6.5 to 7.5, which is then purified.

[0063] The purification steps preferably include i) distillation of the neutralized solution (to remove the produced t-butanol), ii) desalting of the distillation residue, and iii) chromatographic purification of the desalted solution.

[0064] In particular, in one embodiment, the solution obtained by addition of the base is first distilled, preferably at a temperature between 40 and 60° C., to remove the tert-butanol formed. The distillation residue is then desalted, preferably by nanofiltration, to purify the recovered solution.

[0065] In one embodiment, the solution obtained by nanofiltration is first concentrated, for example under reduced pressure, at a temperature of, for example, 40-60° C., preferably about 50° C., to a concentration preferably of 23-27% (w / w), and then purified by elution on a resin, more preferably Amberlite XAD® 1600. The eluate is optionally treated with activated charcoal, such as Carboprone 4N®, and concentrated under reduced pressure at about 50° C., to obtain an aqueous solution of compound 4, preferably with a final concentration in the range of 8-25%, which is used directly in the subsequent complexation reaction without isolation of the ligand.

[0066] Advantageously, the above procedure avoids or reduces the use of organic solvents, particularly hazardous solvents such as DCM and hazardous reactants such as TFA and TIPS, required in the above prior art processes by using water as the only or one of the main reaction solvents. These hazardous substances are difficult to handle and are not suitable for use in large-scale production. Furthermore, this process allows the desired ligand to be obtained in aqueous solution, which can be used in the complexation reaction without the need for isolation.

[0067] Step g) involves complexing compound 4 with gadolinium ions to obtain an aqueous solution of the desired chelate complex compound 5. More specifically, this step preferably comprises the steps of: i) adding a gadolinium salt, such as GdCl3, to a solution of compound 4 to obtain a mixture containing compound 5; ii) adding a base to obtain a mixture with a pH of about 5 to about 7; iii) purifying the mixture to obtain a solution of compound 5; and iv) Concentrating the recovered solution. Includes.

[0068] The reaction is preferably carried out by adding GdCl3 directly to a solution of the ligand recovered from the previous step of the process. The addition is preferably carried out at a temperature between 25 and 45° C. The amount of GdCl3 required to completely complex the ligand is determined by titrating the ligand solution according to known procedures, for example using copper sulfate as a titrant.

[0069] In one embodiment, the ratio of the ligand of compound 4 to the added GdCl3 is 1:1.98-1:2.02 (mol / mol), preferably 1:2.00, to ensure complete consumption of the added lanthanide ion.

[0070] After the addition, the pH of the resulting mixture is adjusted to a range of about 5 to about 7.5 by adding a base, preferably NaOH.

[0071] For example, in one embodiment, GdCl3 is added to the ligand solution at a temperature of, for example, 20-25° C. The resulting mixture is adjusted to a pH of 7-7.5, for example about 7, by adding NaOH, and then stirred at 20-25° C. for about 25 hours to allow complete complexation of the ligand.

[0072] In another embodiment, GdCl3 and an amount of NaOH required to maintain the pH at the desired neutral value may be added simultaneously, and the resulting mixture may be stirred as above for about 25 hours.

[0073] In a preferred embodiment, the pH of the mixture obtained by adding GdCl3 is adjusted to about 5 to about 6, preferably about 5 to 5.6, more preferably about 5.3, and then the mixture is stirred at about 40°C for 1 to 4 hours, for example, about 2 hours. Then, the liberated Gd3 + The remaining free species, such as ligand or partially complexed ligand, are assessed, for example, by titration and / or HPLC methods and compensated by adding a calculated amount of ligand or GdCl3 to obtain an aqueous solution of the dimeric complex of formula 5, which is then purified.

[0074] Purification is preferably carried out by chromatography, preferably on a resin. In one embodiment, purification involves eluting the mixture obtained from the complexation reaction with a polymeric resin, preferably Amberlite XAD® 1600 resin.

[0075] In another embodiment, purification comprises first eluting the mixture obtained from the complexation reaction to minimize the free gadolinium content on a chelating resin, for example selected from Hi Trap IMAC FF, Lewatit MonoPlus TP 260, Lewatit TP 208, IRC748I, DIAION CR11, SiliaMets AMPA and SiliaMets DOTA, preferably selected from Diaion CR11 and Amberlite IRC748, and further purifying the collected eluate on a polymeric resin, such as Amberlite XAD® 1600 resin.

[0076] In practical implementation, the mixture, adjusted to an approximately neutral pH value, is suitably purified by elution on Amberlite XAD® 1600 resin.

[0077] Alternatively, the mixture, the pH of which is adjusted to a low value (e.g., 5-5.6), is preferably first eluted on a chelating resin, such as Amberlite IRC748 or Diaion CR11 resin. The collected eluate is then readjusted to a pH value, preferably of about 5.5-6, and concentrated, preferably at 50° C. under reduced pressure, to obtain an aqueous solution of the dimeric complex, preferably at a concentration of about 25% (w / w), which is purified on Amberlite XAD® 1600 resin.

[0078] The collected fraction is then treated with charcoal, if necessary, and filtered, and the resulting filtrate is then concentrated, preferably by distillation, for example, under reduced pressure at 45-55° C., to obtain a solution of dimeric complex 5 with a final concentration of about 25% (w / w).

[0079] According to a preferred embodiment, a purification step is carried out after step g) and before step h), which comprises purifying the solution obtained in step g) by ion exchange resin to remove the Gd-DOTA (i.e., DOTA complexed with gadolinium) formed in step g). As described above, the remaining compound 1A and / or compound 1A-HCl is converted to DOTA tBu (compound 1B) according to step d4), deprotected to DOTA in step f), and then finally converted to Gd-DOTA in step g) by complexing with gadolinium, so that Gd-DOTA may be present in the solution obtained after complex formation (step g). The Gd-DOTA thus obtained can be easily and effectively removed from the solution containing compound 5 according to this purification step.

[0080] Step h) involves recovering the dimeric complex compound 5, i.e. removing the solvent from the aqueous solution obtained in step g). The complex can be recovered from the aqueous solution obtained in step g) for example by freeze-drying or spray-drying. In a preferred embodiment, the desired dimeric complex is obtained as a white solid by directly spray-drying the solution obtained in step g) of the present preparation process.

[0081] The overall process yield, determined from the limiting reactant (glucamine), is at least 35%, preferably 40%, and more preferably about 45%.

[0082] Some compounds disclosed herein (e.g., Compounds 2-5) have one or more asymmetric carbon atoms, also referred to as chiral carbon atoms, and thus give rise to stereoisomers (e.g., enantiomers and / or diastereomers). Thus, to provide a method for producing all possible stereoisomers of Compounds 3, 4, and 5, as well as their racemic mixtures, their substantially pure resolved stereoisomers, all possible geometric isomers, and their pharma- ceutically acceptable salts (mixtures), the present invention can be adapted, for example, by using suitable chiral reactants as starting materials and / or separating the desired stereoisomers by chromatography, optionally chiral chromatography.

[0083] Experimental Section Materials and Methods The reaction reagents and / or solvents used in the present preparation methods are known and readily available unless otherwise specified, and if not commercially available, can be prepared according to literature methods known to those skilled in the art.

[0084] Non-limiting examples of preferred embodiments of the manufacturing method of the present invention are described in this section. Such examples are intended to explain the present invention in more detail, but are not intended to limit the scope of the present invention.

[0085] Example 1 - Synthesis of Compound 2 Solution and Removal of Epichlorohydrin and Its Derivatives [ka] The reaction of scheme 2 is carried out as follows: D-glucamine (20.00 g, 0.11 mol) is placed in a reactor (R1) and dissolved in water (40.00 g). The solution is transferred through a filter into a drum to remove suspended particulates. In another reactor (R2), epichlorohydrin (30.64 g, 0.33 mol), previously diluted with methanol (40.00 g), is charged with the D-glucamine solution over 2 hours, while maintaining the temperature at about 25° C. At the end of the addition, the first reactor (R1), the filter and the drum are rinsed with 10 g of water, and this washing is collected in the second reactor (R2). The mixture is kept under stirring for 16 hours. After the reaction is complete, methanol is distilled under a slight reduced pressure (temperature: about 42° C., reduced pressure: about 200 mbar). MTBE (30 g) is added to the aqueous solution and the mixture is subjected to liquid-liquid extraction while stirring well for 20 minutes. After this, the stirring is stopped in order to separate the two phases. The phases are separated and the extraction is repeated in the same way two more times (each time with 30 g of fresh MTBE). DMSO (60.0 g) is added to the aqueous phase obtained after the last separation. The mixture is concentrated by distilling water under reduced pressure (temperature kept below 55° C., reduced pressure=40 mbar) until the residual water content is less than 6% w / w. The solution of compound 2 obtained is used directly in the next step (i.e., Example 2).

[0086] Example 2 - Synthesis of a mixture containing compound 3 and removal of residual compound 1A·HCl [ka] The reaction of scheme 3 is carried out as follows: To the solution of compound 2 obtained in example 1, compound 1A (2.5 molar equivalents per mole of compound 2) in isopropanol obtained according to the disclosure of Moore DA, Org. Synth. 2008, 85, 10 is added. The resulting mixture is stirred at 65°C for 17 hours. After the reaction is complete, the mixture is cooled to 10°C and MTBE (72.0 g) is added. The precipitate of compound 1A·HCl formed during the reaction is removed by filtration. The cake is washed three times with MTBE (60 g each). The AUC% of the peak for compound 1A is about 3.3%. The solution of compound 3 is concentrated by distilling isopropanol and MTBE under reduced pressure (100 mbar) at 50°C to obtain a concentrated solution of compound 3 in DMSO. To this mixture, isopropanol (120 ml) and t-butyl bromoacetate are added to obtain compound 1B (DOTA4tBu), and the mixture is stirred at room temperature for 2.5 hours. The AUC% of the peak for compound 1A is about 0.2%. After conversion, water (120 ml) and 25% w / w ammonia solution (60 ml) are added to the mixture. The solution is loaded onto a column packed with pre-activated Amberlite XAD1600N (total amount of resin: theoretically 12 v / w of compound 3) at a flow rate (0.5 BV / h). Purification is performed using a mixture of isopropanol and water according to the following elution gradient: 1. 4 bed volumes of a 40:60 mixture of isopropanol and water 2. 4 bed volumes of a 90:10 mixture of isopropanol and water The fractions to be collected are selected based on evaluation of the HPLC-UV analysis detailed below (Procedure 1). The pure fractions are placed in a reactor and the mixture is concentrated by distillation under reduced pressure at a maximum of 50°C. Overall yield (Examples 1 and 2): 70%

[0087] Example 3 - Preparation of Compound 5 Deprotection of Compound 3 to Obtain Compound 4 Aqueous 34% hydrochloric acid (532.92 g; 4.97 mol) is added to the mixture obtained in Example 2 while maintaining the temperature at 30-35 ° C. After the end of the addition, the mixture is heated to 37 ° C and stirred for 36 h. The solution is then cooled to 25 ° C, neutralized by adding aqueous 30% sodium hydroxide solution, tert-butanol formed as a by-product is removed by distillation and the mixture is desalted by nanofiltration. The mixture is then partially concentrated under reduced pressure at 50 ° C to a concentration of 24% w / w and chromatographically purified on an Amberlite XAD® 1600 (1 L; eluent: water). The fractions selected by evaluation with HPLC-UV are treated with charcoal and concentrated under reduced pressure at 50 ° C to obtain a 10% w / w aqueous solution (0.0038 mol) of the desired ligand compound 4, which is quantified by potentiometric titration using a copper sulfate solution as the titrant.

[0088] Complexation of Compound 4 to Obtain Compound 5 and Isolation Thereof The solution of compound 4 obtained according to the method described above is heated to 37 ° C., and then an aqueous solution of gadolinium chloride (40.76 g gadolinium chloride in solution; 0.154 mol gadolinium) is added while maintaining the temperature in the range of 37-43 ° C. After the addition is complete, the pH is adjusted to 5.3 by adding 10% aqueous sodium hydroxide. The mixture is kept at 40 ° C. for 2 hours to form the paramagnetic complex compound 5. The presence of free species is evaluated, for example by titration. The solution is then purified with Diaion CR11 chelating resin (0.16 L) to reduce the content of free gadolinium. After loading, the resin is washed with water, the pH is adjusted to 5.5 and the solution is concentrated under reduced pressure at 50 ° C. to obtain a 25% w / w aqueous solution. This solution is loaded onto an Amberlite XAD® 1600 at pH 6 (3.3 L; eluent: water / MeCN gradient). Selected fractions, as assessed by HPLC-FLD and UV, are treated with charcoal and the resulting solution is distilled at 50° C. under reduced pressure. The final solution (25% w / w) is spray dried and the gadolinium complex is isolated as a white powder (70.8, equivalent to 64.4 g of anhydrous product; titration assay: 99% w / w%, anhydrous base). Overall yield from glucamine: 45%

[0089] Example 4 - Removal of epichlorohydrin and its derivatives by liquid-liquid extraction step b) On various solutions of compound 2 obtained according to step a) and containing different starting amounts of epichlorohydrin and its derivatives, several tests were carried out for the removal of epichlorohydrin and its derivatives according to liquid-liquid extraction step b). Table 1 shows the minimum and maximum amounts of epichlorohydrin and its derivatives in various solutions (i) before extraction (i.e., starting amount), (ii) after extraction, and (iii) after the solvent exchange step (which includes the distillation step, i.e., "Post-Distillation" in Table 1). The amounts in Table 1 are expressed as % w / w of the solution and were determined according to the method described in Section 4 below. [Table 1] Table 1 clearly shows that the liquid-liquid extraction step b) allows at least a partial removal of epichlorohydrin and its derivatives, which is further improved after distillation by a solvent exchange step.

[0090] Step 1 HPLC method: GEMINI DO3A Column: Phenomenex Gemini 250 x 4.6 mm 5 μm Mobile phase: A=CH3COONH40, 2%+MeOH 2:1 B=CH3CN Gradient: t (min) AB flow rate (mL / min) 0 60 40 0,7 5 60 40 0,7 30 10 90 0,7 35 10 90 0,7 36 60 40 0,7 45 60 40 0,7 Injection volume: 10μL Temperature: 40℃ DAD detection: 212-240nm Diluent: H2O / ACN 60 / 40

[0091] Step 2: HPLC characterization and analysis of DO3A-tri-tert-butyl ester Chromatography conditions HPLC system: liquid chromatograph (e.g. Agilent 1100) equipped with a solvent delivery system, autosampler, column thermostat, degasser, diode array detector or variable wavelength detector (or equivalent). Stationary phase: Zorbax Eclipse XDB-C8, 5μm, 150×4.6mm Column temperature: 45℃ Mobile phase: A: 0.01M K2HPO4, 0.017M H3PO4 B: Acetonitrile Elution: Gradient Time (min) %B 0 5 30 80 35 80 38 5 45 5 Flow rate 1mL / min Temperature 45℃ Detection UV 210 nm, Bw=8 nm; Reference 360 ​​nm, Bw=100 nm Injection volume 10μL Downtime 35 minutes Reference peak DO3A 3tBu Retention time DO3A 3tBu approximately 14~15 minutes

[0092] Procedure 3: HPLC method to monitor the formation and purification of compound 4 The formation and purification of the dimeric ligand compound 4 was monitored by reverse-phase HPLC with UV detection at 210 nm. Analysis conditions HPLC system: Liquid chromatograph Agilent 1260 Infinity Stationary phase: Synergi Polar-RP, 4μm, 150×4.6mm (Phenomenex, part number 00F-4336-EO) Column temperature: 40℃ Mobile phase: A: 10mM KH2PO4 B: Methanol Elution: Gradient Time (min) %B 0 0 5 0 35 60 40 60 41 80 46 80 47 0 60 0 Flow rate 0.8mL / min Detection UV / 210nm Injection volume 10μL Downtime 60 minutes Compound 4 R t 2.4 minutes

[0093] Procedure 4: GC method for determining the amount of epichlorohydrin and its derivatives Instrumentation: GC system equipped with automatic sample injector and flame ionization detector (e.g. Agilent 6890 or equivalent) Column 1: Front inlet, outlet, front detector Injector: Front Channel: Channel 1 Pressure Unit: PSI Auxiliary: Thermal Capillary column: DB-624, 75 m, inner diameter 530 μm, film thickness 3 μm (Agilent J&W, PN 125-1374) Liner: GC liner, helix open-end deactivated (Agilent Technologies, PN 5188-5396) Oven: Set at 40°C for 0 min; heat from 40°C to 200°C at 5°C / min; Hold at 200°C for 0 minutes; 200°C to 250°C at 100°C / min Heating; holding time 10 minutes Equilibrium time: 1.00 minutes Maximum oven temperature: 260℃ Front Inlet: Automatic Liquid Sampler Inlet Type: Split / Splitless EPC Injection temperature: 250℃ Mode: Split Split flow rate: 20mL / min Split ratio:5. Front injector: Injection volume: 1μL Sol.A Pre-Wash:6 Sol.B Pre-Wash: 0 Sample Wash: 2 Injector pump: 3 Viscosity Delay: 3 Sol.A Post Wash: 0 Sol.B Post Wash: 10 Washing solvent (pre- and post-): DMSO Column 1: Carrier gas: He Outlet Pressure Mode: Ambient Column pressure mode: constant flow rate Initial flow rate: 4.00mL / min Front detector: FID, 290℃ Supply gas: He Flow mode: constant flow rate Replenishment flow rate: 30mL / min Fire: Active Fuel flow rate (hydrogen): 40mL / min Oxidant flow rate (air): 400mL / min Ignition offset: 0.5pA Channel 1: Source: Front detector output Sampling rate: 20.0 Run time: 42.50 min (chromatograms evaluated up to 30 min) Reference peak: epichlorohydrin

Claims

1. A method for producing a mixture containing Compound 3, comprising the following steps: 【Chemical 1】 a) In a solvent, reacting glucamine with epichlorohydrin 【Chemical 2】 to obtain a first solution containing Compound 2; 【Chemical Formula 3】 b) Without isolating Compound 2 from the first solution, removing at least a part of the remaining epichlorohydrin and its derivatives from the first solution containing Compound 2 to obtain a second solution containing Compound 2; 【Chemical Formula 4】 c) Without isolating Compound 2 from the second solution, adding Compound 1A to the second solution containing Compound 2 and reacting Compound 2 with Compound 1A to obtain a mixture containing Compound 3. The production method comprising the above steps. 【Chemical Formula 5】

2.

3.

4. The solvent in step a) is an aqueous solution containing at least C １ -C ３ The production method according to claim 1, which is an alcohol-containing aqueous solution. The production method according to any one of Claims 1 to 3, wherein step a) is carried out by reacting epichlorohydrin in an amount of 2.2 to 3.8 moles per mole of glucamine. C １ -C ３ The production method according to claim 2, wherein the alcohol is methanol.

5. The production method according to Claim 4, wherein step a) is carried out by reacting epichlorohydrin in an amount of 2.5 to 3.5 moles per mole of glucamine.

6. The production method according to Claim 5, wherein step a) is carried out by reacting epichlorohydrin in an amount of 3 moles per mole of glucamine.

7. Step b) comprises the following steps: b2) A step of performing at least one liquid-liquid extraction, where the first liquid is the first solution containing Compound 2 or, when step b1) is carried out, the solution obtained by step b1), and the second liquid is any organic solvent immiscible with the first liquid. The production method according to any one of Claims 1 to 3, which is carried out according to the above step. b1) From the first solution comprising compound 2, preferably C １ -C ３ By distilling the alcohol, C １ -C ３ Removing it if the alcohol is present;

8. The production method according to Claim 7, wherein the second liquid is selected from the group consisting of methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl tetrahydrofuran (MeTHF), and methyl tert-butyl ether (MTBE).

9. Including a step of changing the solvent after step b) and before step c), wherein the step of changing the solvent comprises adding dimethyl sulfoxide (DMSO) to the second solution containing Compound 2 and removing solvents other than DMSO from the second solution containing Compound 2 to which DMSO has been added, whereby the second solution containing Compound 2 contains DMSO as the solvent. The production method according to any one of Claims 1 to 3.

10. ​ ​ The production method according to claim 9, wherein the water content (KF) remaining in the second solution comprising compound 2 and DMSO as the solvent is less than 15% w / w.

11. The production method according to claim 10, wherein the water content (KF) remaining in the second solution comprising compound 2 and DMSO as the solvent is less than 6% w / w.

12. The production method according to any one of claims 1 to 3, wherein step c) is carried out by admixing a molar excess of compound 1A to compound 2.

13. The production method according to claim 12, wherein step c) is carried out by admixing more than 2.0 moles of compound 1A to 1 mole of compound 2.

14. The production method according to claim 13, wherein step c) is carried out by admixing up to 4.0 moles of compound 1A to 1 mole of compound 2.

15. The production method according to claim 14, wherein step c) is carried out by admixing 2.2 - 3.0 of compound 1A to 1 mole of compound 2.

16. The production method according to any one of claims 1 to 3, wherein the reaction in step c) is carried out for a time of less than 48 hours.

17. The production method according to claim 16, wherein the reaction in step c) is carried out for 16 - 18 hours.

18. The production method according to any one of claims 1 to 3, wherein the reaction in step c) is carried out at a temperature of 55 - 75 °C.

19. The production method according to claim 18, wherein the reaction in step c) is carried out at a temperature of 63 - 67 °C.

20. The solvent for the reaction of step c) is DMSO and at least C ２ -C ４ The production method according to any one of claims 1 to 3, comprising an alcohol, preferably comprising DMSO and isopropanol.

21. Furthermore, step d): d) A step of removing at least a part of the hydrochloride salt of compound 1A (compound 1A - HCl) from the mixture containing compound 3 by precipitating compound 1A - HCl without isolating compound 3 from the mixture. The production method according to any one of claims 1 to 3, comprising this.

22. Step d) is d1) Adding MTBE to the mixture containing compound 3 to precipitate at least a part of compound 1A - HCl; and d2) Filtering the mixture obtained in step d1) to remove the precipitated compound 1A - HCl The production method according to claim 21, which is carried out by this.

23. Furthermore, the following steps: d3) A step of concentrating the mixture containing compound 3, or preferably the mixture obtained by step d) or d2), without isolating compound 3 from the mixture; and Step d4): Adding isopropanol and butyl t-bromoacetate to the mixture obtained in step d3) to obtain Compound 1B ​ The step of obtaining The production method according to any one of claims 1 to 3, comprising

24. A method for producing a dimeric complex compound 5 【Chemical Formula 7】 comprising the following steps: e) Producing a mixture containing Compound 3 according to any one of claims 1 to 3; f) Removing the tert-butyl protecting group from Compound 3 without isolating the compound from the mixture of step e) to obtain a solution of the free ligand compound 4 [Chemical Formula 8] respectively; g) Adding gadolinium metal ions to the solution of step f) without isolating Compound 4 to obtain a solution of Compound 5; and h) Recovering Compound 5 The production method, wherein the reaction solvent in all steps after step e) is an aqueous solvent

25. The method for producing a dimeric complex compound 5 according to claim 24, further comprising a purification step after step g) and before step h), the purification step comprising purifying the solution obtained in step g) with an ion exchange resin to remove the gadolinium complex of 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (Gd-DOTA) formed during and / or after step g). ​

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