Process for producing gadoteridol

Abstract

The present invention relates to a process for preparing gadoteridol of formula (I). In particular, the process comprises the use of propylene oxide in the alkylation step of a compound of formula (II), wherein propylene oxide is reacted directly with the compound of formula (II) without isolation, and propylene oxide is obtained on demand by decomposition of propylene carbonate in the presence of an alkali metal halide or alkaline earth metal halide as a catalyst. TIFF2023551567000016.tif54154

Description

Technical Field

[0001] The present invention relates to a method for producing gadoteridol.

[0002] The present invention pertains to the field of magnetic resonance imaging (MRI) contrast agents, and more particularly, to a novel synthesis method for producing gadoteridol (a macrocyclic gadolinium chelate, which is the active ingredient (API) of Prohance) (M. Bottrill, L. Kwok, N. J. Long, Chem. Soc. Rev. 2006, 35, 557 - 571).

Background Art

[0003] Gadoteridol is the first non - ionic macrocyclic gadolinium chelate developed for clinical use and has been on the market for approximately 30 years (V. M. Runge, T. Ai, D. Hao, X. Hu, Invest. Radiol. 2011, 46, 807 - 816).

[0004] The production method of gadoteridol is disclosed in EP0988294. The disclosed production process is summarized in Scheme 1 below.

Chemical formula

[0005] As shown in Scheme 1, 1,4,7,10 - tetraazacyclododecane is reacted with triethyl orthoformate in the presence of an acid to obtain 5H,9bH - 2a,4a,7,9a - octahydro - tetraazacyclooct[cd]pentalene (step a); The obtained 5H,9bH-2a,4a,7,9a-octahydro-tetraazacyclooct[cd]pentalene was reacted with bromoacetic acid and NaOH to obtain sodium 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (step b), which was hydrolyzed in step c) without isolation to obtain sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A); Sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A) was alkylated with propylene oxide in step d) to obtain 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid as the sodium salt (HPDO3A), which was complexed with gadolinium chloride in step e) to obtain gadoteridol without isolation, which was then purified and crystallized to obtain the final drug substance.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The alkylation step d) is carried out using commercially available propylene oxide (PO), which is a liquid with a low boiling point (34 °C) and high flammability and is classified as a toxic reagent according to current GHS rules (H350 and H340). As stated in the Material Safety Data Sheet (MSDS) (for example, see the MSDS of Merck; 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 abnormalities, irritation to the skin and eyes, and irritation to the respiratory tract.

[0007] For these reasons, propylene oxide must be handled and stored with great care. To overcome these problems, a detailed investigation was conducted to evaluate the possibility of less toxic alternatives to this compound.

[0008] In a method for producing gadoteridol comprising converting propylene carbonate (PC) to PO, PC can be used as a precursor of PO, and by using it directly in the next alkylation step without isolation and recovery of the PC, it has been found that the high yield and impurity profile of gadoteridol obtained by known industrial production methods can be maintained.

[0009] PC is a toxicologically safe reagent, and by using it in the method for producing gadoteridol, problems related to the transportation, storage, and handling of toxic reactants such as PO can be avoided.

[0010] The preparation of various functionalized alcohols and epoxides using cyclic carbonates has been described in many literatures. In particular, U.S. Patent No. 4,371,704 discloses the conversion of substituted ethylene carbonate to substituted epoxide by heating a cyclic carbonate using different alkali metal halides as catalysts. In particular, U.S. Patent No. 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. According to this literature, when LiI is used as a catalyst, PO is produced with very low selectivity and yield. Instead, when KI is used, good selectivity and yield are obtained, but it takes a relatively long time of 4.8 hours. Therefore, it is concluded that LiI has low selectivity as an iodide for producing propylene oxide from propylene carbonate.

Means for Solving the Problems

[0011] Abstract The present invention relates to the synthesis of gadoteridol (Scheme 2), which involves generating propylene oxide as needed by thermal decomposition of propylene carbonate using an alkali metal halide as a catalyst.

Chemical formula

[0012] The generated propylene oxide is used immediately for the synthesis of gadoteridol without storage. This approach is called "on-site" or "on-demand".

[0013] By doing so, all problems and issues related to the transportation, storage, and handling of propylene oxide are avoided.

[0014] On the other hand, propylene carbonate has a 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), making it a safe and environmentally friendly compound with significant advantages. Furthermore, propylene carbonate can be obtained relatively inexpensively on an industrial scale and can be safely stored in large quantities, so it is mainly used as a solvent (B. Schaffner, F. Schaffner, S. P. Verevkin, A. Borner, Chem. Rev. 2010, 110, 4554 - 4581).

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Embodiments for Carrying Out the Invention

[0016] Description of the Present Invention The object of the present invention is a method for producing gadoteridol represented by the formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0017] More specifically, the decomposition of propylene carbonate is carried out by heating propylene carbonate in the presence of a catalyst which is an alkali metal halide or an alkaline earth metal halide.

[0018] As soon as PO is obtained by the decomposition of PC, it is immediately reacted with the compound of formula (II) without isolation and recovery.

[0019] PO is obtained by heating PC according to the thermal decomposition reaction shown in Scheme 2 above. PC is liquid at the reaction temperature. The decomposition product, i.e., PO, is a low-boiling product and is a gas at the reaction temperature, and can be directly delivered and bubbled into the solution of the compound of formula (II) immediately after being produced by the decomposition reaction without isolation and / or recovery.

[0020] In addition to gaseous propylene oxide, carbon dioxide generated by the decomposition of PC transfers to the solution of the compound of formula (II) together with PO.

[0021] Preferably, the alkali metal halide or alkaline earth metal halide used as a catalyst in the preparation of propylene oxide is selected from iodides, bromides, chlorides or fluorides of sodium, potassium, lithium, magnesium or calcium. More preferably, the metal halide is selected from bromides or iodides of sodium, potassium or lithium, and iodide is most preferred.

[0022] Particularly preferred catalysts are sodium iodide and lithium iodide, and most preferred is sodium iodide.

[0023] The amount of the catalyst used for the decomposition of propylene carbonate can range from 0.1% w / w to 100% w / w, more preferably from 0.1% w / w to 5.0% w / w, most preferably from 0.1% w / w to 2.0% w / w, for example 0.5% w / w, based on the amount of propylene carbonate.

[0024] The decomposition of the PC is preferably carried out by heating at a temperature in the range of 160°C to 250°C, most preferably in the range of 180°C to 220°C, for example 200°C.

[0025] In the alkylation step i), the compound of formula (II) is preferably dissolved in water.

[0026] The alkylation is carried out according to the conditions disclosed in EP0988294 and the cited references. In particular, the alkylation reaction is preferably carried out at a temperature in the range of 20°C to 50°C. During the alkylation, the pH is maintained at a basic value, preferably 11.0 or higher, by the addition of a base such as KOH or NaOH, more preferably NaOH.

[0027] The complex formation step ii) is carried out according to known procedures, for example, by stoichiometrically adding an appropriate Gd(III) derivative, in particular an oxide such as Gd2O3, or preferably a gadolinium salt such as GdCl3, to the solution obtained in step i). In one embodiment, the complex formation reaction of step ii) is carried out by adding a gadolinium salt in water, such as GdCl3, to the solution of the ligand obtained in step i) and adjusting the pH to the range of 6.5 to 7.5. This solution is maintained at a temperature in the range of 25°C to 60°C for a time in the range of 0.5 hour to 1.5 hours until the complex formation is complete.

[0028] Before the complex formation step ii), an acid, preferably HCl, can be added to the solution obtained in step i) to neutralize Na2CO3 and remove it as CO2.

[0029] In one embodiment, the solution of HPDO3A obtained in step i) is cooled to a temperature of about 25°C, HCl is added until the final pH is about 4.5, causing the formation and bubbling of CO2. Then, the gadolinium salt is added and complex formation is carried out according to known procedures (see, for example, EP0988294).

[0030] In an alternative embodiment, a gadolinium salt is added to the solution of HPDO3A obtained in step i), and then HCl is added to adjust the pH to 4.0 - 5.0 by neutralizing Na2CO3, and complex formation is carried out according to a known procedure (for example, see the above-cited reference).

[0031] This alternative embodiment, which consists of changing the order of addition of the gadolinium salt and HCl, advantageously reduces the amount of HCl required to achieve the desired pH conditions that enable the neutralization of Na2CO3.

[0032] The compound of formula (II) can be obtained without isolating the intermediate product as summarized in Scheme 1 above or as reported in EP0988294 which describes the preparation of gadoteridol starting from 1,4,7,10-tetraazacyclododecane.

[0033] In a preferred embodiment, the alkylation reaction of step i) is carried out using the compound of formula (II) obtained in the previous preparation step without isolation.

[0034] Propylene oxide is prepared by heating propylene carbonate in the presence of an alkali metal halide or an alkaline earth metal halide in a first reactor (a decomposition reactor, usually a flask for small-scale cases), and the formed propylene oxide is directly fed to another reactor (an alkylation reactor, usually a jacketed reactor) containing compound (II).

[0035] Add the required amount of propylene carbonate to the decomposition reactor and heat it in the presence of an alkali metal halide or an alkaline earth metal halide.

[0036] The conversion of propylene carbonate to propylene oxide can be carried out in batch mode (for example, by adding propylene carbonate to the decomposition reactor all at once), or in semi-batch or continuous mode, that is, propylene carbonate can be fed continuously or in portions into the decomposition reactor.

[0037] Figures 1 or 2 show two different exemplary apparatuses that can be used in the preparation of propylene oxide and the alkylation step (i) of the present invention.

[0038] In Figures 1 and 2, (1) is a nitrogen cylinder, (2) is a flask, (3) is a heating device, (4) and (5) are valves, (6) is a container for NaOH, (7) is a pump device (such as Dosimat, etc.), (8) is a pH meter, (9) is a mechanical stirrer, (10) is a thermometer, (11) is a dropper for NaOH, (12) is a pH meter probe, (13) is a porous glass chip, (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 an inlet for heating / cooling fluid, (18) is an outlet for heating / cooling fluid, (19) is a vent, and (20) is a dropping funnel.

[0039] The apparatuses shown in Figures 1 and 2 are generally shown on a laboratory scale, but those skilled in the art can easily scale them up to an industrial scale.

[0040] Using the apparatus of FIG. 1, charge all of the required amount of propylene carbonate and the catalyst into the flask (2). Heat the temperature to 160° C. to 250° C., and hold for 0.5 hour to 2 hours according to the temperature, the amount of catalyst, and the type of catalyst. For example, when operating at 200° C., 1 hour is sufficient to obtain complete decomposition of propylene carbonate, and when using NaI or LiI as the catalyst, it is even shorter, for example, about 0.5 hour is sufficient. During this time, the generated propylene oxide and CO2 are transported by a nitrogen stream and directly bubbled into the jacketed reactor (14) through a pipe with a porous glass chip (13) connected to the end (this allows small gas bubbles that dissolve easily to be obtained, ensuring complete solubilization of propylene oxide and CO2 in the reaction mixture). In this way, in the reactor (14), while continuously adding 30% NaOH using a feeding device such as a Dosimat device to maintain the pH of the alkylation reaction at a basic value, propylene oxide can be reacted with the compound of formula (II) to obtain the compound of formula (III).

[0041] Alternatively, the apparatus of FIG. 2 can also be used. Charge a certain amount of propylene carbonate (for example, about 1 / 3 of the total amount) and an appropriate amount of catalyst determined based on the initial amount (by weight) of PC into the flask (2). Heat the temperature to 160° C. to 250° C., for example, 200° C., and hold for 0.5 to 9 hours, preferably 0.5 to 3 hours, according to the apparatus used, the temperature, and the amount of catalyst, to decompose the propylene carbonate. The generated propylene oxide and CO2 are transported by a nitrogen stream and directly bubbled into the jacketed reactor (14) through a pipe with a porous glass chip (13) connected to the end. During the reaction, additional propylene carbonate is continuously added to the flask 2 through the dropping funnel to replenish the converted amount of PC and keep the level in the flask (2) constant. Interestingly, no more catalyst is added.

[0042] In this way, as described above, for example, while continuously adding 30% NaOH using a Dosimat apparatus to keep the pH of the reaction constant at a basic value, the flow of propylene oxide reaching the reactor (14) can be immediately reacted with the compound of formula (II) to produce the intermediate of formula (III).

[0043] The advantage of the proposed method, for example using a semi-batch or continuous mode using the apparatus schematically shown in Figure 2, is that the amount of catalyst used can be reduced. The amount of catalyst is actually calculated only by the amount of PC initially loaded into the reactor and does not need to be further added during the refill of propylene carbonate. In fact, by continuously supplying PC to the system, a small decomposer reactor that is easy to heat can be used, and the energy consumption required to achieve the high temperature necessary for the conversion reaction can be reduced.

[0044] In this manufacturing method, not only can the storage of toxic and flammable substances such as PO be avoided, but also the accumulation in the manufacturing plant can be avoided because the PO generated by decomposition reacts immediately in the alkylation reaction.

[0045] Experimental part Procedure The concentration of sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (compound (II), DO3A) in the initial solution was measured by complexometric titration, and the alkylation to sodium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate) (compound (III), HPDO3A) was monitored by HPLC analysis. The impurity profiles of sodium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate) (compound (III)) and gadoteridol solution were evaluated by HPLC analysis.

[0046] Catalyst screening The screening of the PC decomposition catalyst was carried out by fixing the decomposition temperature at 200 °C and the amount of PC at 2.0 equivalents (calculated value relative to the amount of DO3A), and varying the type and amount of the catalyst (determined as %(w / w) relative to the starting PC). Subsequently, the alkylation reaction was carried out for 5 hours under the same operating conditions (e.g., at the same pH and temperature). NaOH was used to neutralize the CO2 generated by the decomposition of PC.

[0047] Details are described in the following representative examples using NaI as the conversion catalyst.

Example

[0048] Example 1 Preparation of sodium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (Compound (III)) by converting propylene carbonate to propylene oxide in the presence of NaI and directly alkylating sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A sodium salt, Compound (II)) The reaction was carried out using the apparatus of Figure 1. A solution of sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (400 g; 0.24 mmol / g) was charged into a 1 L reactor (Reactor 14), and the pH was adjusted to between 11.5 and 12.5 at 25 °C using 37% hydrochloric acid (24.4 g). The temperature was raised to 40 - 45 °C and maintained during the addition of propylene oxide and CO2. Propylene carbonate (19.1 g) and NaI (0.096 g) were charged into a 50 mL flask (2). The temperature was raised to 200 °C to promote the decomposition of PC, generating PO and CO2, and a porous glass tip was connected to the end and bubbled directly into Reactor 14 through a pipe. The temperature of the flask was maintained at 200 °C for 1 hour, which was sufficient to achieve complete decomposition of PC. During the bubbling of PO and CO2, the pH inside Reactor 14 was maintained at the above value by automatically dosing 30% NaOH (49.9 g). The alkylation reaction was maintained at 40 - 45 °C for a total of 5 hours, and the completion of the reaction was confirmed by HPLC analysis. Subsequently, the temperature of the alkylation medium was lowered to 25 °C. The alkali metal iodide (used as the PC decomposition catalyst) and its amount were changed, and the test was repeated while maintaining the decomposition temperature and the PC:Compound (II) ratio used in the previous test. The results obtained were summarized in Table 1.

Table 1

[0049] Example 2 Preparation of sodium 10-(2-hydroxypropyl)-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (HPDO3A, Compound (III)) by conversion of PC to PO and alkylation of sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A sodium salt, Compound (II)) The reaction was carried out using the apparatus shown in Figure 2. A solution of sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (7.519 kg; 0.266 mol / kg, corresponding to 2.00 mol) was charged into an 8 L reactor (Reactor 14), and the pH was adjusted to between 11.5 and 12.5 at 25 °C using 37% hydrochloric acid (497 g). The temperature was raised to 40 - 45 °C and maintained during the addition of PO and CO2. First, PC (100 g) and NaI (1.0 g) were charged into a 100 mL flask (2). The temperature was raised to 200 °C, PO and CO2 were generated by the decomposition of PC, and they were directly bubbled into Reactor 14 through a PVC pipe connected to a porous glass chip at the end (this can obtain small gas bubbles to ensure complete solubilization of PO and CO2 in the reaction mixture). The temperature of the flask was maintained at 200 °C for 9 hours. During this time, an amount of PC (252 g) sufficient to achieve the completion of the reaction was supplied through a dropping funnel (20) to replenish the converted amount and keep the level of PC in the flask (2) constant. No additional amount of NaI was added while replenishing PC. During the bubbling of PO and CO2, the pH in Reactor 14 was maintained in the range of 11.5 - 12.5 by automatically injecting 30% NaOH (919.2 g). The alkylation was monitored every hour by HPLC analysis and was completed after 1.72 equivalents of PC were decomposed.

[0050] Example 3 Complex formation of sodium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (Compound (III), HPDO3A sodium salt) with GdCl 3 Preparation of gadoteridol (Compound of formula (I)) by complex formation Preparation of GdCl 3 Preparation Water (500 g) and Gd2O3 (362.5 g) were placed in a 2 L flask, and 37% hydrochloric acid (656.3 g) was added dropwise at 25 - 30 °C over 1 hour. The suspension was heated from 90 °C to 95 °C, stirred until completely dissolved, and then cooled to 25 °C. Complex formation of sodium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (Compound (III), HPDO3A) A solution of HPDO3A (a compound of formula (III) containing 2.00 mol of HPDO3A in theory) was transferred to a 10 L reactor, and while maintaining the temperature below 30 °C, 37% HCl (400 g) was slowly added over 5 hours to completely neutralize Na2CO3, resulting in the generation and bubbling of CO2 (final pH = 4.5). The GdCl3 solution was slowly added over 1 hour, the second 37% hydrochloric acid (291 g) was added, and the solution was stirred for 2 hours (pH was about 1.7). The temperature was raised to 50 °C, and the pH was adjusted to 7.0 - 7.5 using 30% NaOH (1.17 kg; 8.78 mol), and complex formation was completed in 2 hours. The results of the alkylation carried out according to the method of the present invention are shown in Table 2 and compared with a standard alkylation using commercially available PO (disclosed in EP0988294). The impurity profile of sodium 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (Compound (III)) obtained by the method of the present invention was equivalent to that obtained using commercially available PO, and no new impurities were observed.

Table 2

Claims

1. Formula (I): 【Chemical 1】 A method for producing gadoteridol represented by the following steps: i) The following formula: [Chemical 2] Propylene oxide represented by the formula is reacted with a compound represented by formula (II): 【Chemical Formula 3】 [wherein M is an alkali metal or an alkaline earth metal, and n is 1 or 2] to obtain a compound represented by formula (III): 【Chemical Formula 4】 [wherein M and n are as defined above] ; ii) Complexing the obtained compound of formula (III) with a Gd ３＋ metal ion to obtain gadoteridol of formula (I) comprising Propylene oxide is prepared by the decomposition of propylene carbonate represented by the following formula in the presence of an alkali metal halide or an alkaline earth metal halide as a catalyst, and is directly reacted with the compound of formula (II) without isolation. The manufacturing method is characterized by this. [Chemical Formula 5]

2. The production method according to claim 1, wherein M is an alkali metal.

3. The production method according to claim 1, wherein M is Na.

4. The production method according to claim 1, wherein the metal halide is selected from iodides or bromides of sodium, potassium or lithium.

5. The production method according to claim 4, wherein the metal halide is selected from iodides of sodium, potassium and lithium.

6. The production method according to claim 5, wherein the alkali metal halide is sodium iodide or lithium iodide.

7. The production method according to any one of claims 1 to 6, wherein the amount of the catalyst is in the range of 0.1 to 100% w / w of the amount of propylene carbonate.

8. The production method according to claim 7, wherein the amount of the catalyst is in the range of 0.1 to 5% w / w of the amount of propylene carbonate.

9. The production method according to any one of claims 1 to 8, wherein propylene carbonate is heated at a temperature in the range of 160 ° C to 250 ° C.

10. The production method according to any one of claims 1 to 9, wherein the compound of formula (II) is dissolved in water.

11. Propylene carbonate is added all at once, or in semi-batch or continuous mode, into a first reactor heated in the presence of an alkali metal halide or an alkaline earth metal halide as a catalyst, and the formed propylene oxide is directly supplied to a reactor containing compound (II). The manufacturing method according to claim 1. ​

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