JP2022515893A - Manufacturing method of calcobutrol - Google Patents

Abstract

The present invention relates to a production method for synthesizing high-purity calcobutrol by producing high-purity butrol through a step of purifying butrol, which is an intermediate for gadobutrol synthesis, without using high-purity gadobutrol.

Description

The present invention relates to a method for producing a high-purity butrol having a purity of more than 99% by an efficient method for purifying a low-purity butrol, and producing a high-purity carcobutrol using the high-purity butrol.

Gadobutrol is a gadolinium-containing contrast agent for nuclear spin tomography, and in the field of gadolinium-containing MRI contrast agents (contrust agent), Gadobutrol is used worldwide as Gadovist or Gadavist (Gadobutrol). It is commercially available under the trade name of Gadavist).

For most gadolinium-containing contrast agents, including gadobutrol, it has been found to be advantageous to apply an excessive amount of complex-forming ligand in the form of a calcium complex in the formulation. The role of the calcium complex is to prevent the release of free gadolinium in the formulation (eg, by storage for several years using recomplexation with foreign ions derived from glass).

That is, in Gadobutrol, calcobutrol is an additive in the Galen preparation of Gadobutrol, and is used as an important agent for preventing the release of free gadolinium in the preparation (solution).

A method for synthesizing chalcobtrol is described in detail in the literature (Inorgan. Chem. 1997, 36, 6086-6093), but is known to result in a substance with a purity of 94%.

Korean Registered Patent No. 10-1057939 states that butrol (ligand) cannot be purified by crystallization at any pH due to the difference in polarity or the ability to form hydrogen bonds. He also stated that he tried to crystallize butrol through various comparative examples, but could not produce crystals. In addition, chalcobtrol can be used in ion exchange columns and Prep. It explains that it cannot be purified via HPLC.

Thereby, in the above patent, in order to obtain pure calcobutrol, as shown in FIG. 1, pure gadobutrol is synthesized, a decomplexing reaction is carried out, and carcobutrol is crystallized. It states that high-purity chalcobtrol must be synthesized.

However, the manufacturing method shown in FIG. 1 is uneconomical because it is a very long step process because it produces pure gadobutrol from butrol and synthesizes butrol again. Further, the production method is not preferable in that highly toxic gadolinium impurities generated during the decomplexing reaction may be present in gadobutrol.

In Korean Registered Patent No. 10-1693400, butrol with a purity of 98% is synthesized, and carcobutrol with a purity of 99.5% is synthesized using a relatively pure butrol. The core of this patent is that, as shown in FIG. 2, the butrol purity can be ensured by purifying the butrol-ester by crystallization to synthesize an intermediate having a purity of 99.7%.

However, the above method also has the disadvantage that in order to synthesize high-purity butrol, it is necessary to further carry out a step of synthesizing and hydrolyzing high-purity butrol-ester. Therefore, a method for purifying low-purity butrol to obtain high-purity butrol by a simpler manufacturing method is required, and a method for producing high-purity carcobutrol using high-purity butrol is required.

Korean Registered Patent No. 10-1057939 Korean Registered Patent No. 10-1693400

Inorg. Chem. 1997, 36, 6086-6093

An object of the present invention is to provide a method for producing a butrol by a simple production method, then producing a high-purity butrol through a purification step, and then producing a high-purity carcobutrol using the high-purity butrol. That is.

The present invention provides a method for purifying a butrol having a purity of about 65% to obtain a high-purity butrol having a purity of 99% or more, and using such a high-purity butrol to produce a high-purity carcobutrol. Provide a method.

It is known that butrols having a purity of 94% or less cannot be purified by crystallization by a general method. Further, it is very difficult to obtain high-purity petroleum by purifying crude petroleum having a purity of about 65%. Surprisingly, the present inventors have found that when a butrol with a purity of 65% is purified by an ion exchange resin and a crystallization method, a butrol with a purity of 99% or more can be efficiently synthesized, and the present invention has been reached. rice field.

Since the present invention does not include a step of decomplexing gadobutrol, there is no step of treating toxic gadolinium and it does not produce gadolinium that may be generated as an impurity. Further, according to the present invention, high-purity butrol can be obtained by a relatively simple purification step using an ion exchange resin and a crystallization method. The present invention has the advantage that high-purity carcobutrol can be produced using the high-purity butrol thus purified without an additional purification step.

It is a figure which shows the manufacturing method of the carcobutrol by the prior art. It is a figure which shows the manufacturing method of the carcobutrol by the prior art. It is a figure which shows the method of producing butrol from a cyclen by this invention. It is a figure which shows the HPLC analysis data for the crude butrol. It is a figure which shows the HPLC analysis data after the primary purification of the crude butrol. It is a figure which shows the HPLC analysis data after the additional purification of the crude butrol. It is a figure which shows the HPLC analysis data after the additional crystallization of the crude butrol. It is a table which shows the mobile phase condition of HPLC. It is a table which shows the result of elemental analysis by proton NMR.

The starting material cyclone (1,4,7,10-tetraazacyclododecane) is reacted with 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octane to form a reactant. Hydrochloric acid is added, then refluxed to concentrate in vacuum, and ethanol is added to the concentrate to add triol-4 hydrochloride (3- (1,4,7,10-tetraazacyclododecane-1-yl). ) Butane-1,2,4-triol-4 hydrochloride) is obtained. Triol-4 hydrochloride is reacted under basic conditions with haloacetic acid selected from the group consisting of chloroacetic acid, bromoacetic acid, and iodoacetic acid to synthesize butrol, and the pH of the reactants is adjusted and concentrated. Then, make a slurry with methanol to remove excess salt. The filtered methanol is concentrated and the concentrate is passed through a reverse osmosis (RO) device to further remove the salt, or it is adsorbed on a cationic resin and eluted with aqueous ammonia, and then concentrated to a crew of about 65% purity. You can get dobutrol. (Scheme 1 (FIG. 3) and HPLC data 1 (FIG. 4))

Crude butrol is subjected to a primary purification step using an anion exchange resin and a cation exchange resin to obtain butrol with a purity of 85%. Then, by crystallization using an aqueous methanol solution as a crystallization solvent, high-purity butrol can be obtained (HPLC data 2 (FIG. 5) and data 3 (FIG. 6)).

Further crystallization of the obtained high-purity butrol gives a higher-purity butrol (see FIG. 7).

As described above, crystallization is possible in the above-mentioned crystallization step, and purification is easy. Seed crystals can be used to increase the crystallization rate.

The preferred crystallization solvent is methanol having a water content of 20% or more (v / v), and the most preferable crystallization solvent is methanol having a water content of 20% to 50%. Within a water content of 10% or less, certain impurities are not easily removed.

The butrol produced by the above method is characterized by very high quality, and high-purity carcobutrol can be efficiently produced by using high-purity butrol. Therefore, the manufacturing method of the present invention is an economical manufacturing method by simplifying the manufacturing process, and is an environment-friendly manufacturing method. The above-mentioned purification step is a step in which a high-purity butrol can be synthesized by purifying an extremely low-purity butrol.

Hereinafter, examples will be described, but the scope of the present invention is not limited to the examples.

HPLC analysis conditions HPLC column-ODS hypercil, 3 μm, 125 × 4.6 mm
Mobile phase A: Obtained by dissolving 2.0 g of octane sulfonic acid sodium salt monohydrate in purified water and adjusting the pH to 2 using sulfuric acid.
Mobile phase B: acetonitrile Flow rate: 1.0 ml / min UV detection wavelength: 197 nm
Sample concentration: Measure after dissolving 7 mg / 1 ml in mobile phase A.
Injection buffer: 10 μl
Mobile phase conditions: Figure 8

Example 1. Crude Butane (2,2', 2 "-(10-((2R, 3S) -1,3,4-trihydroxybutane-2-yl) -1,4,7,10-tetraazacyclo Production of dodecane-1,4,7-triyl) triacetic acid) 100 g of cyclene (1,4,7,10-tetraazacyclododecane) was dissolved in 500 ml of purified water, heated to 40 to 45 ° C, and there. 84 g of 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octane was slowly added dropwise. After reacting for 24 hours, 408 ml of hydrochloric acid was added dropwise to the reaction solution, followed by 75 ° C. The reaction mixture was concentrated in vacuum for 2 hours, and 500 ml of ethanol was added thereto. The obtained solution was stirred under reflux, cooled, and the produced crystals were filtered.

The produced crystals were dissolved in 500 ml of purified water, and 170 g of chloroacetic acid was added thereto. The resulting solution was adjusted to pH 9-10 with 45% NaOH, heated to 70 ° C. and stirred for 12 hours while maintaining pH 9-10.

After cooling, the reaction was adjusted to pH 5 using HCl and concentrated. After adding 800 ml of methanol to the concentrate, the mixture was stirred at 60 ° C. for 1 hour and then filtered at 40 to 50 ° C.

The filtrate was concentrated, dissolved in 500 ml of purified water, and adsorbed on 1000 ml of cationic resin IR-120.

The resin was washed with 4 L of aqueous ammonia, eluted and concentrated.

Example 2. Butrol (2,2', 2 "-(10-((2R, 3S) -1,3,4-trihydroxybutane-2-yl) -1,4,7,10-tetraazacyclododecane-1," Purification of 4,7-triyl) triacetic acid) Concentrated butrol was dissolved in 500 ml of purified water and passed through a column containing a mixture of 100 ml of anion IRA-67 and 100 ml of cation IR-120. The butrol eluent that came out of the liquid was recirculated to a column containing the mixture, and this operation was repeated several times. The resin was washed, the eluent and the washing liquid were combined, and the pH was 3.5 with cations. It was adjusted to ~ 4.5, filtered and then concentrated. 100 ml of purified water was added to the concentrate, the temperature was raised to 80 ° C. to completely dissolve the mixture, and then 500 ml of methanol was added thereto. The obtained solution was gradually cooled to room temperature and seeded with a small amount. After stirring for 2 days, the produced crystals were filtered. The crystals were vacuum dried at 50 ° C. to obtain 90 g of butrol. (Total yield from cyclone 34.4%, purity 94%).

The crystals produced were dissolved in 360 ml of purified water, 900 ml of methanol was added thereto, and the mixture was then stirred for 2 days. The produced crystals were filtered and vacuum dried at 50 ° C. to obtain 68 g of butrol (crystallization yield 80%, purity 99.5% or more).

If the purity of the butrol crystals is 99.5% or less or impurities are not removed, further crystallization is performed.

^{1 1} H _- NMR (D2 O, 400 MHz): 3.1 to 3.9 (m, 28H)
[Elemental analysis]
Figure 9

Example 3. Production of Calcobtrol 10 g of high-purity butrol (purity 99.5% or higher) produced in Example 2 was dissolved in 100 ml of purified water, and 2.22 g of CaCO ₃ was added thereto. The mixture was stirred at room temperature for 1 hour, filtered and concentrated with a 0.2 μm filter, and then freeze-dried to obtain 10.7 g of calcobutrol (yield 99%, purity 99.5% or more).

The method for producing calcobtrol according to the present invention can produce high-purity calcobtrol in a relatively simple process, and thus can be used in the pharmaceutical industry for producing pharmaceutical products.

Claims (8)

Cyclen (1,4,7,10-tetraazacyclododecane) is reacted with 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octane to react with 3- (1,1). In the first step, 4,7,10-tetraazacyclododecane-1-yl) butane-1,2,4-triol is obtained, which is then reacted with haloacetic acid to produce crude butane.
The second step of primary purification of the crude butrol using an ion exchange resin and
The third step of secondary purification of the primary purified crude butrol by crystallization and
Butane with a purity of 99% or more (2,2', 2 "-(10-((2R, 3S) -1,3,4-trihydroxybutane-2-yl) -1,4,7,10" -A production method for obtaining tetraazacyclododecane-1,4,7-triyl) triacetic acid). The production method according to claim 1, wherein the second step is performed in combination with an anion exchange resin and a cation exchange resin. The anion exchange resin is selected from the group consisting of quaternary ammonium, tertiary ammonium, tertiary amine, secondary amine, and primary amine, and the cation exchange resin is a sulfonic acid group and a sulfonic acid group. The production method according to claim 2, which is selected from the group consisting of carboxyl groups. The production method according to claim 1, wherein the haloacetic acid is selected from the group consisting of chloroacetic acid, bromoacetic acid, and iodoacetic acid. The production method according to claim 1, wherein the third step is performed using an aqueous methanol solution as a crystallization solvent. The production method according to claim 5, wherein the crystallization solvent is an aqueous methanol solution having a water content of 20% or more. The production method according to claim 1, wherein the pH before crystallization is 3.5 to 4.5. A method for producing calcobutrol by reacting the butrol produced according to claim 1 with calcium carbonate.

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