Process for the preparation of gadoterate

Abstract

This invention relates to a method for preparing gadolinium alcohol of formula (I). In particular, the method includes the use of propylene oxide in an alkylation step of a compound of formula (II), wherein the propylene oxide reacts directly with the compound of formula (II) without separation, and wherein the propylene oxide is obtained as needed by decomposing propylene carbonate in the presence of a base or alkaline earth metal halide as a catalyst.

Description

[0001] This invention relates to a method for preparing gadoterol. Background of the Invention

[0003] This invention belongs to the field of magnetic resonance imaging (MRI) contrast agents, and particularly relates to a novel synthetic method for preparing gadoterol, a macrocyclic gadolinium chelate, which is the active pharmaceutical ingredient (API) of Prohance (M. Bottrill, L. Kwok, NJ Long, Chem. Soc. Rev. 2006, 35, 557-571).

[0004] Gadolinol is the first nonionic macrocyclic gadolinium chelate developed for clinical use and has been on the market for about 30 years (VMRunge, T.Ai, D.Hao, X.Hu, Invest. Radiol. 2011, 46, 807-816).

[0005] A method for preparing gadolinium alcohol is disclosed in EP 0 988 294. The disclosed method is summarized in Scheme 1 below:

[0006]

[0007] Option 1

[0008] As shown in Scheme 1, 1,4,7,10-tetraazacyclododecane is reacted with triethyl orthoformate in the presence of acid to obtain 5H,9bH-2a,4a,7,9a-octahydro-tetraazacyclooctameno[cd]cyclopentadiene (step a).

[0009] The obtained 5H,9bH-2a,4a,7,9a-octahydro-tetraazacyclooctameno[cd]cyclopentadiene was reacted with bromoacetic acid and NaOH to provide a sodium salt of 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (step b), which was then hydrolyzed in step c) without separation to provide a sodium salt of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A).

[0010] In step d), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt (DO3A) is alkylated with propylene oxide to provide 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) as the sodium salt. In step e), it is complexed with gadolinium chloride without separation to provide gadoterol, which is then purified and crystallized to obtain the final API.

[0011] Alkylation steps using commercial propylene oxide (PO) are described in step d), which is a low-boiling-point (34°C), extremely flammable liquid classified as a toxic agent under current GHS regulations (H350 and H340). As clearly stated in any Material Safety Data Sheet (MSDS) (see, for example, Merck's MSDS; also see D. Kahlich, U. Wiechern, J. Lindner, "Propylene oxide" in Ullmann's Encyclopedia of Industrial Chemistry, Viley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2005), propylene oxide can cause cancer, genetic defects, skin and eye irritation, and respiratory irritation.

[0012] For all these reasons, propylene oxide must be handled and stored with extreme care and caution. To overcome these problems, an in-depth investigation is needed to evaluate potential low-toxicity alternatives to this compound.

[0013] Propylene carbonate (PC) has been found to be a precursor for PO in the preparation of gadoterols, involving the conversion of PC to PO, which can be used immediately in subsequent alkylation steps without separation and collection, while maintaining the impurity characteristics and high yield of gadoterols obtained by known industrial methods.

[0014] From a toxicological perspective, PC is a safe reagent, and its application in the production process for gadolinium alcohol makes it possible to avoid problems associated with the transportation, storage, and handling of toxic reactants such as PO; in addition, its cost is comparable to that of PO.

[0015] Numerous publications describe the use of cyclic carbonates in the preparation of various functionalized alcohols and epoxides. In particular, US 4,371,704 discloses the conversion of substituted ethylene carbonates to substituted epoxides by heating cyclic carbonates with different alkali metal halides as catalysts. Specifically, US 4,371,704 discloses the conversion of PC to PO by heating PC in the presence of a catalyst selected from lithium fluoride, sodium fluoride, potassium fluoride, sodium chloride, and potassium chloride. This document reports the production of PO with very low selectivity and yield when using LiI as a catalyst. Conversely, KI provides good selectivity and yield but requires a relatively long time of 4.8 hours. NaI is not mentioned as a catalyst for providing propylene oxide. Therefore, this document concludes that LiI is a low-selectivity iodide for the production of propylene oxide from propylene carbonate. Invention Summary

[0016] This invention relates to the synthesis of gadoterol, wherein propylene oxide is produced when needed by thermal degradation of propylene carbonate catalyzed by alkali metal halide (Scheme 2).

[0017]

[0018] Option 2

[0019] The resulting propylene oxide is not stored but is immediately used in the synthesis of gadolinium alcohol. This process is called "on-site" or "as needed".

[0020] In this way, all the consequences and problems involved in the transportation, storage and disposal of propylene oxide are avoided.

[0021] On the other hand, propylene carbonate is considered a significant benefit because it is regarded as a safe and environmentally friendly compound due to its high boiling point (240°C), low vapor pressure, biodegradability, and low toxicity (J. Bayardon, J. Holz, B. Schaffner, V. Andrushko, S. Verevkin, A. Preetz, A. Borner, Angew. Chem. Int. Ed. 2007, 46, 5971-5974; J. Am. College Toxicol. 1987, 6, 23-51). Furthermore, propylene carbonate is widely used as a solvent because it is available on an industrial scale at relatively low cost and can be safely stored in large quantities (B. Schaffner, F. Schaffner, S. P. Verevkin, A. Borner, Chem. Rev. 2010, 110, 4554-4581). Attached Figure Description

[0022] Figure I shows a schematic representation of an apparatus that can be used in the method of the present invention, which is used to generate PO and use it directly in alkylation step i).

[0023] Figure 2 The diagram shows a representative of an alternative device in which PC is added continuously or in batches to refill the flask, in which PO is generated. Invention Overview

[0025] The object of this invention is a method for preparing gadolinium triol of formula (I):

[0026]

[0027] (I)

[0028] Includes the following steps:

[0029] i) Oxidize propylene according to the following formula:

[0030]

[0031] Reaction with compound of formula (II):

[0032]

[0033] (II)

[0034] Where M is an alkali metal or an alkaline earth metal, preferably an alkali metal, most preferably Na, and n is 1 or 2;

[0035] To obtain compound (III):

[0036]

[0037] (III)

[0038] Where M and n are as defined above;

[0039] ii) The obtained compound of formula (III) is reacted with Gd 3+ Metal ion coordination yields gadolinium (I)

[0040] Its features are:

[0041] Propylene oxide is prepared by decomposing propylene carbonate of the following formula in the presence of a metal halide as a catalyst:

[0042]

[0043] It reacts directly with the compound of formula (II) without separation.

[0044] More specifically, propylene carbonate is decomposed by heating it in the presence of a catalyst that is an alkali metal or alkaline earth metal halide.

[0045] Once obtained by PC decomposition, PO is immediately reacted with the compound of formula (II) without separation and / or collection.

[0046] PO is obtained by heating PC according to the thermal decomposition reaction reported in Scheme 2 above. PC is a liquid at the reaction temperature. The decomposition product, PO, is a low-boiling product that is gaseous at the reaction temperature and can be directly transferred and bubbled into the solution of compound (II) once obtained by the decomposition reaction without separation and / or collection.

[0047] In addition to the gaseous oxidation of propylene, the decomposition of PC also produces carbon dioxide, which, along with PO, is transferred into the solution of compound (II).

[0048] Preferably, the alkali metal or alkaline earth metal halide used as a catalyst in the preparation of propylene oxide is selected from sodium iodide, potassium iodide, lithium iodide, magnesium iodide, or calcium iodide; sodium bromide, potassium bromide, lithium bromide, magnesium bromide, or calcium bromide; sodium chloride, potassium chloride, lithium chloride, magnesium chloride, or calcium chloride; or sodium fluoride, potassium fluoride, lithium fluoride, magnesium fluoride, or calcium fluoride. More preferably, the metal halide is selected from sodium bromide, potassium bromide, or lithium bromide, or sodium iodide, potassium iodide, or lithium iodide, with iodides being the most preferred.

[0049] The preferred catalysts are sodium iodide and lithium iodide, with sodium iodide being the most preferred.

[0050] The amount of catalyst used in the decomposition of propylene carbonate can be from 0.1% w / w to 100% w / w, more preferably from 0.1% w / w to 5.0% w / w, and most preferably from 0.1% w / w to 2.0% w / w, for example, in the range of 0.5% w / w.

[0051] PC decomposition is preferably carried out by heating in a temperature range of 160°C to 250°C, most preferably 180°C to 220°C, for example 200°C.

[0052] In alkylation step i), the compound of formula (II) is preferably water-soluble.

[0053] Alkylation is carried out according to the conditions disclosed in EP0988294 and the cited references. In particular, the alkylation reaction is conveniently carried out in a temperature range of 20°C to 50°C. During alkylation, the pH is maintained at an alkaline value, preferably above 11.0, by adding a base such as KOH or NaOH, more preferably NaOH.

[0054] The coordination step ii) is carried out according to a known procedure, for example, by adding a suitable Gd(III) derivative, particularly an oxide such as Gd₂O₃, or preferably a gadolinium salt such as GdCl₃, to the solution obtained in step i) in a stoichiometric manner. In one embodiment, the coordination reaction in step ii) is carried out by adding a gadolinium salt, such as GdCl₃ / water, to the ligand solution obtained in step i) and adjusting the pH to a range of 6.5 to 7.5. The solution is maintained at a temperature in the range of 25°C to 60°C for a duration in the range of 0.5 to 1.5 hours until the coordination is complete.

[0055] Before proceeding with step ii), acid, preferably HCl, can be added to the solution obtained in step i) to neutralize Na2CO3, thereby removing it as CO2.

[0056] In one embodiment, the HPDO3A solution obtained in step i) is cooled to about 25°C, and then HCl is added until the final pH is about 4.5, resulting in CO2 formation and bubbling. Gadolinium salts are then loaded, formulated according to a known procedure (see, for example, EP 0 988 294).

[0057] In an alternative embodiment, gadolinium salt is loaded into the HPDO3A solution obtained in step i), and then HCl is added to adjust the pH to 4.0-5.0 to neutralize Na2CO3, and the process is carried out according to a known procedure (see, for example, the references cited above).

[0058] This alternative implementation involves changing the order in which the gadolinium salt and HCl are added, which allows for a favorable reduction in the amount of HCl required to achieve the desired pH conditions, making it possible to neutralize Na2CO3.

[0059] Compound (II) can be obtained as summarized in Scheme 1 above or as reported in EP 0 988 294, which describes the preparation of gadoterol from 1,4,7,10-tetraazacyclododecane without separating any intermediate products.

[0060] In a preferred embodiment, the alkylation reaction in step i) is carried out using a compound of formula (II) obtained from a previous preparation step without separation.

[0061] Propylene oxide is prepared in a first reactor (a decomposition reactor, usually a flask when carried out on a small scale): propylene carbonate is heated in the presence of an alkali metal or alkaline earth metal halide and the resulting propylene oxide is fed directly into another reactor (an alkylation reactor, usually a jacketed reactor) containing compound (II).

[0062] The required amount of propylene carbonate is added to the decomposition reactor and heated in the presence of alkali metal or alkaline earth metal halides.

[0063] The conversion of propylene carbonate to propylene oxide can be carried out in a batch mode (e.g., by adding propylene carbonate in batches to a decomposition reactor) or alternatively in a semi-batch or continuous mode (i.e., by continuously or batch feeding propylene carbonate into a decomposition reactor).

[0064] Figure 1 or Figure 2 Two different exemplary devices are described, which, according to the present invention, can be used to prepare propylene oxide and alkylation steps (i).

[0065] exist Figure 1 and Figure 2Among them, (1) is a nitrogen cylinder, (2) is a flask, (3) is a heating system, (4) and (5) are valves, (6) is a NaOH container, (7) is a pump system (e.g., Dosimat), (8) is a pH meter, (9) is a mechanical stirrer, (10) is a thermometer, (11) is a NaOH dropper, (12) is a pH meter probe, (13) is a porous glass tip, (14) is a jacketed reactor, (15) is a trap filled with 50% sulfuric acid, (16) is a trap filled with 30% sodium hydroxide, (17) is the inlet of the heating / cooling liquid, (18) is the outlet of the heating / cooling liquid, (19) is a vent, and (20) is a dropping funnel.

[0066] Although Figure 1 and 2 The equipment described is typically presented on a laboratory scale, but it can be easily scaled up to an industrial scale by technicians.

[0067] use Figure 1 The apparatus loads the required amount of propylene carbonate and catalyst into a flask (2). The temperature is increased to 160°C to 250°C and maintained for a time ranging from 0.5 to 2 hours, depending on the temperature, amount of catalyst, and type of catalyst. For example, at 200°C, 1 hour is sufficient to achieve complete decomposition of propylene carbonate, or even shorter, such as about 0.5 hours, when using NaI or LiI as a catalyst. During this time, the generated propylene oxide and CO2 are transported by a nitrogen stream and directly bubbled through a tube connected to a porous glass tip (13) at the end (this allows for easily soluble small bubbles, ensuring complete solubilization of propylene oxide and CO2 in the reaction mixture) into a jacketed reactor (14). In this way, in reactor (14), propylene oxide is able to react with compound (II) to produce compound (III) by continuously adding 30% NaOH to maintain the pH of the alkylation reaction at an alkaline value, for example using a metering system such as the Dosimat apparatus.

[0068] Alternatively, it can be used Figure 2The equipment is as follows: A certain amount of propylene carbonate (e.g., about 1 / 3 of the total) and a suitable amount of catalyst, depending on the initial partial weight of PC, are loaded into flask (2). The temperature is increased to 160°C to 250°C, for example 200°C, and maintained for 0.5 to 9 hours, preferably 0.5 to 3 hours, depending on the equipment used, the temperature, and the amount of catalyst, to achieve the decomposition of propylene carbonate. The resulting propylene oxide and CO2 are conveyed by a nitrogen stream and bubbled directly into the jacketed reactor (14) through a tube connected to the end porous glass tip (13). During the reaction time, additional propylene carbonate is continuously added to flask (2) through a dropping funnel to replenish the conversion of PC and maintain a stable level in flask (2). Interestingly, no other catalyst is added.

[0069] In this manner, by continuously adding 30% NaOH as described above to maintain the reaction constant pH at an alkaline value, the propylene oxide stream in reactor (14) can immediately react with the compound of formula (II) to produce the intermediate of formula (III), the addition being carried out, for example, using a Dosimat device.

[0070] Use the proposed method (e.g., using) Figure 2 The advantage of the semi-batch or continuous mode of the equipment illustrated in the diagram is the reduction in the amount of catalyst used, which is actually calculated based only on the initial PC portion loaded into the reactor, and no further addition is required during refilling with propylene carbonate. Furthermore, this setup is particularly advantageous for large-scale operation: in fact, the continuous feeding of PC into the system allows for the use of smaller, more easily heated decomposition reactors, thereby reducing the energy consumption required to reach the high temperatures demanded by the conversion reaction.

[0071] Since the PO produced by decomposition reacts immediately in the alkylation reaction, the method of the present invention allows for the avoidance not only of the storage of toxic and flammable substances such as PO, but also of their accumulation in the production workshop.

[0072] Experimental Section

[0073] program

[0074] The concentration of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt (compound (II), DO3A) in the initial solution was determined by complexometric titration, while the alkylation to 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt (compound (III), HPDO3A) was monitored by HPLC analysis.

[0075] Impurity characteristics of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (compound (III)) and gadolinium alcohol solution were evaluated by HPLC analysis.

[0076] Catalyst screening

[0077] The screening of PC decomposition catalysts was conducted as follows: a fixed decomposition temperature of 200°C and a PC amount of 2.0 equivalents (calculated against DO3A) were maintained, and the type and amount of catalyst were varied, determined as a percentage (w / w) relative to the initial PC. Alkylation reactions were then carried out for 5 h under identical operating conditions (e.g., including identical pH and temperature). The CO2 produced by PC decomposition was neutralized with NaOH.

[0078] Details are provided in the following representative examples using NaI as a conversion catalyst.

[0079] Example 1

[0080] 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (compound (III)) was prepared by the conversion of propylene carbonate to propylene oxide in the presence of NaI and the direct alkylation of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (DO3A sodium salt, compound (II)).

[0081] The reaction is described in Figure 1 The equipment is used.

[0082] A solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (400 g; 0.24 mmol / g) was loaded into a 1 L reactor (reactor 14) at 25 °C, and the pH was adjusted to 11.5 to 12.5 with 37% HCl (24.4 g). The temperature was increased to 40–45 °C and maintained during subsequent propylene oxidation and CO2 addition.

[0083] A portion of propylene carbonate (19.1 g) and NaI (0.096 g) were loaded into a 50 mL flask (2). The temperature was increased to 200 °C to promote the decomposition of PC to produce PO and CO2, which were then bubbled directly into reactor 14 through a tube connected to a porous glass tip at the end.

[0084] Maintaining the flask temperature at 200°C for 1 hour is sufficient to achieve complete degradation of PC.

[0085] In reactor 14, 30% NaOH (49.9 g) is automatically metered and fed to maintain the pH at the value described above during PO and CO2 bubbling.

[0086] The alkylation reaction was maintained at 40-45°C for a total of 5 hours, and the reaction endpoint was checked by HPLC analysis. Then the temperature of the alkylation medium was lowered to 25°C.

[0087] Repeat experiments: The alkali metal iodide (used as a catalyst for PC decomposition) and its amount were varied, while the decomposition temperature and the PC:compound (II) ratio used in the previous examples were kept constant. The results are summarized in Table 1.

[0088] Table 1

[0089]

[0090] 1 % Calculated relative to the initial PC.

[0091] 2 The reaction cessation time was determined by CO2 bubbling endpoint and / or pH stabilization.

[0092] In the table above, the % conversion of PC (w / w relative to the initial PC) was determined by weighing the reactor.

[0093] Unexpectedly, the results showed that using the selected iodide catalysts, especially NaI and LiI, allowed for a significant reduction in the amount of catalyst and time required to achieve complete conversion of PC to PO.

[0094] Example 2

[0095] 10-(2-hydroxypropyl)-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt (DO3A sodium salt, compound (II)) was prepared by conversion of PC to PO and alkylation of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt (HPDO3A sodium salt, compound (II)).

[0096] The reaction is described in Figure 2 The equipment is used.

[0097] A solution of sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (7.519 kg; 0.266 mol / kg corresponds to 2.00 mol) was loaded into an 8 L reactor (reactor 14) at 25 °C, and the pH was adjusted to 11.5 to 12.5 with 37% HCl (497 g). The temperature was increased to 40–45 °C and maintained during subsequent additions of PO and CO2.

[0098] The first portion of PC (100 g) and NaI (1.0 g) was loaded into a 100 mL flask (2). The temperature was increased to 200 °C and PC decomposed to produce PO and CO2, which were then directly bubbled into reactor 14 through a PVC tube connected to a porous glass tip at the end (this allowed for the production of small bubbles, ensuring that the PO and CO2 were completely solvated in the reaction mixture).

[0099] The flask temperature was maintained at 200°C for 9 hours, and during this time, an additional amount of PC (252 g) sufficient to achieve complete reaction was added through a dropping funnel (20). This replenished the converted amount and maintained a stable level of PC in the flask (2). No additional NaI was added during the PC refilling.

[0100] In reactor 14, 30% NaOH (919.2 g) is automatically metered and fed to maintain the pH in the range of 11.5 to 12.5 during PO and CO2 bubbling.

[0101] Alkylation was monitored hourly by HPLC analysis and completed after the decomposition of 1.72 equivalents of PC.

[0102] Example 3

[0103] Gadolinol (compound (I)) was prepared by combining 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (compound (III), HPDO3A sodium salt) with GdCl3.

[0104] Preparation of GdCl3

[0105] Add water (500 g) and Gd₂O₃ (362.5 g) to a 2 L flask; add 37% HCl (656.3 g) dropwise over 1 hour at 25 to 30 °C. Heat the suspension to 90-95 °C while stirring until completely dissolved, then cool to 25 °C.

[0106] The complexation of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (compound (III), HPDO3A)

[0107] A solution of HPDO3A (compound (III), containing theoretically 2.00 mol of HPDO3A) was transferred to a 10 L reactor, and then 37% HCl (400 g) from the first part was slowly added over 5 hours while maintaining the temperature below 30 °C to completely neutralize Na2CO3, resulting in CO2 formation and bubbling (final pH = 4.5).

[0108] Slowly add the GdCl3 solution over 1 hour; add the second portion of 37% HCl (291 g) and keep the solution under stirring for 2 hours (pH approximately 1.7).

[0109] Increase the temperature to 50°C, adjust the pH to 7.0 to 7.5 with 30% NaOH (1.17 kg; 8.78 mol), and complete the preparation within 2 hours.

[0110] The results of alkylation performed according to the method of the present invention described above are reported in Table 2 and compared with alkylation using commercial PO standard (disclosed in EP 0 988 294). The impurity characteristics of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate sodium salt (compound (III)) obtained by the method of the present invention are comparable to those obtained using commercial PO, and no new impurities were observed.

[0111] Table 2

[0112]

Claims

1. A method for preparing gadolinium triol of formula (I): (I) Includes the following steps: i) Oxidize propylene according to the following formula: Reaction with compound of formula (II): (II) Where M is an alkali metal or an alkaline earth metal, and n is 1 or 2; To obtain compound (III): (III) Where M and n are as defined above; ii) The obtained compound of formula (III) is reacted with Gd 3+ Metal ion coordination yields gadolinium (I) Its features are: Propylene oxide is prepared by decomposing propylene carbonate of the following formula in the presence of a metal halide catalyst, by heating at a temperature ranging from 160°C to 250°C: Furthermore, it reacts directly with compounds of formula (II) without separation. The metal halide is selected from sodium iodide, potassium iodide or lithium iodide, or sodium bromide, potassium bromide or lithium bromide.

2. The method of claim 1, wherein the metal halide is selected from sodium iodide, potassium iodide, and lithium iodide.

3. The method of claim 2, wherein the metal halide is sodium iodide or lithium iodide.

4. The method according to any one of claims 1 to 3, wherein the amount of catalyst ranges from 0.1% to 100% w / w of the amount of propylene carbonate.

5. The method of claim 4, wherein the amount of catalyst ranges from 0.1% to 5% w / w of the amount of propylene carbonate.

6. The method according to any one of claims 1-3 and 5, wherein the compound of formula (II) is soluble in water.

7. The method according to claim 4, wherein the compound of formula (II) is soluble in water.

8. The method of claim 1, wherein propylene carbonate is added in batch or in a semi-batch or continuous mode in a first reactor, wherein it is heated in the presence of a metal halide as a catalyst and the propylene oxide being formed is fed directly into the reactor containing compound (II).

9. The method of claim 1, wherein M is an alkali metal.

10. The method of claim 9, wherein M is Na.

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