KR101979836B1 - Process for the preparation of calcobutrol - Google Patents

Abstract

The present invention relates to a method for preparing high-purity calcobutrol, which comprises: a first step of preparing crude butrol; a second step of primarily purifying the crude butrol; and a third step of secondarily purifying the firstly purified crude butrol.

Description

PROCESS FOR THE PREPARATION OF CALCOBUTROL [0002]

The present invention relates to a process for preparing high purity butyrthol by more than 99% through efficient purification of low purity butrol and thereby producing high purity calchobutrol.

 Gadobutrol is a gadolinium-containing contrast agent for nuclear spins tomography, and in the field of Gadolinium-containing MRI contrast agents, Gadobutrol is a Gadovist or Gadavist, Lt; / RTI >

For most gadolinium-containing contrast agents, including gadobutrol, it has been found advantageous to apply an excess of complex-forming ligand in the form of a calcium complex. The role of the calcium complex is to prevent the release of free gadolinium in the formulation (e.g., by multi-year storage through re-complexation with foreign ions in the glass).

That is to say, in the gadobest, chalcobutrol is an additive in the herbal preparation of Gadobutrol and is used as an important additive to prevent the release of free gadolinium in the preparation (solution).

The synthesis of chalcobutrol is described in Inorg. Chem. 1997, 36, 6086-6093, but it is known to have a purity of 94%.

Korean Patent No. 10-1057939 states that butrol (ligand) can not be purified by crystallization at any pH due to the difference in polarity or the ability to form hydrogen bonds. It has been attempted to crystallize butrol through various comparative examples, but it has not been possible to generate crystals. Calcovitrol may also be used in ion exchange columns or Prep. It can not be purified by HPLC.

Accordingly, in this patent, it is described that, in order to obtain pure chalcobutrol, pure chalcobutrol is synthesized and the desorption reaction proceeds to crystallize chalcobutrol to synthesize high-purity chalcobutrol.

However, the above preparation method is not economical because a pure gadobutrol is produced in butrol and then butrol is synthesized again. Therefore, gadolinium impurities having high toxicity may be present in the butyrate during desorption reaction Which is undesirable.

In Korean Patent No. 10-1693400, butrol having a purity of 98% is synthesized and calbutobutrol having a purity of 99.5% is synthesized using relatively pure butrol. The key to this patent is that by purifying the butrol-ester through crystallization, the purity of the butrol can be secured by synthesizing an intermediate of 99.7% purity.

However, the above method also has a disadvantage in that a high-purity butrol-ester must be synthesized and an additional hydrolysis process must be carried out in order to synthesize high-purity butrol. Therefore, there is a need for a method for purifying butrol of low purity with a high purity through a simpler production method, and a method for producing the chalcobutrol in high purity is needed.

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

Inorg. Chem. 1997, 36, 6086-6093

 It is an object of the present invention to provide a method for preparing high purity buttrol through a simple process and then purifying it through a simple production process, and thereby producing high purity chalcobutrol.

 The present invention provides a method for purifying butrol having a purity of about 99% or more by purifying butrol having a purity of about 65%, and a method for producing high purity calckobutrol through such high purity butyrate .

It is known that butrols having a purity of 94% or less can not be purified by crystallization by a general method. In addition, it is very difficult to purify from high purity bootrol from Crude butrol with a purity of about 65%. The present inventors surprisingly found that, when purifying butrol with a purity of 65% by an ion exchange resin and a crystallization method, butrol having a purity of 99% or more can be efficiently synthesized, the present inventors have arrived at the present invention.

The present invention does not include a desorption step of gadobutrol so that there is no process for treating toxic gadolinium and does not produce gadolinium which can be generated as an impurity. In addition, it is possible to purify butrol of high purity through a relatively simple process by an ion exchange resin and a crystallization method. This purified purity of high purity has the advantage of producing high purity of calcobutrol without further purification process.

The starting material, cyclane (1,4,7,10-tetraazacyclododecane) is reacted with 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octane, (3 - (1,4,7,10-tetraazacyclodecan-1-yl) butane-1,2,4-triol hydrochloride) was added to the reaction mixture, . Triol-4-hydrochloride is reacted with haloacetic acid selected from the group consisting of chloroacetic acid, bromoacetic acid and iodoacetic acid under basic conditions to synthesize butrol, and the pH of the reaction mixture is adjusted to pH, and the mixture is concentrated and slurried with methanol to give an excessive amount of a salt Remove. The filtered methanol is concentrated and the concentrate is further removed through RO equipment or adsorbed on cation resin, eluted with ammonia water and concentrated to obtain crude dextrol of about 65% purity. (Scheme 1. HPLC Data 1)

Crude dextrose is first purified using anion exchange resin and cation exchange resin to produce butrol with 85% purity. Subsequently, when crystallization is performed using a crystallization solvent with an aqueous methanol solution, highly pure butrol can be obtained. (HPLC Data 2, Data 3)

When crystallization is further performed on the obtained highly pure butrol, a higher purity buttrol can be obtained.

As described above, crystallization is possible in the above-described crystallization process and purification is easy. When a seed is used, the crystallization rate can be promoted.

A preferable crystallization solvent is methanol having a water content of 20% or more (v / v), and the most preferable crystallization solvent is methanol having 20% to 50%. Specific impurities can not be removed well within 10% moisture.

The butrols prepared in this manner are characterized by very high quality and high purity calcobutrol can be efficiently produced through high purity butrol. Therefore, it is an economical manufacturing method and an environment-friendly manufacturing method by simplifying the manufacturing process steps. In the purification process, it is possible to purify butrol at a very low purity and to synthesize it with high purity.

EXAMPLES Hereinafter, examples will be described, but the contents of the present invention are not limited by the examples.

HPLC  Analysis condition

HPLC Column - ODS HyperSilm, 3 um, 125 X 4.6 mm

Mobile phase A: 2.0 g of sodium hydrogencarbonate monohydrate is dissolved in purified water and the pH is adjusted to 2 using sulfuric acid.

Mobile phase B: acetonitrile

Flow rate: 1.0 ml / min

UV detection wavelength: 197 nm

Sample concentration: 7 mg / 1 ml dissolved in mobile phase A

Injection volume: 10 ul

Example 1 . Crud (Crude) Butrol's Produce   (2 , 2 ', 2 "- (10 - ((2R, 3S) -1,3,4-trihydroxybutan-2-yl) -1,4,7,10-tetraazacyclodecane- , 7-triyl) triacetic acid)

100 g of cyclohexane (1,4,7,10-tetraazacyclododecane) was dissolved in 500 ml of purified water and the temperature was raised to 40 to 45 ° C to obtain 4,4-dimethyl-3,5,8-trioxabicyclo [ 1,0] octane are slowly added dropwise. The reaction is carried out for 24 hours, 408 ml of hydrochloric acid is added dropwise and the mixture is stirred at 75 ° C for 2 hours. The reaction solution was concentrated in vacuo, and 500 ml of ethanol was added thereto. The mixture was refluxed with stirring, cooled, and the produced crystals were filtered.

The resulting crystals are dissolved in 500 ml of purified water, and 170 g of chloroacetic acid is added. The pH is adjusted to 9-10 with 45% NaOH and the temperature is raised to 70 ° C. The mixture is stirred for 12 hours while maintaining the pH at 9-10.

After cooling, the pH is adjusted to 5 with HCl and the reaction solution is concentrated. 800 ml of methanol is added to the concentrate, stirred at 60 ° C for 1 hour and then filtered at 40-50 ° C.

Concentrate the filtrate, dissolve in 500 ml of purified water, and adsorb it on 1000 ml of cation resin IR-120.

The resin is washed with 4 L of ammonia water and eluted and concentrated.

Example 2 . Butrol's  refine  (2, 2 ', 2 "- (10 - ((2R, 3S) -1,3,4- Trihydroxybutane 2-yl) -1,4,7,10-tetraazacyclodecane-1,4,7-triyl) triacetic acid)

The concentrated butyrol is dissolved in 500 ml of purified water, and the solution is passed through a column in which 100 ml of the anion IRA-67 and 100 ml of the cation IR-120 are mixed. Repeat the operation to recycle the liquid effluent of the butyrol to the mixed column again several times. The resin is washed and the eluate and washing solution are combined. The pH is adjusted to 3.5 to 4.5 with a cation, filtered and concentrated. 100 ml of purified water is added to the concentrate, the temperature is raised to 80 ° C and completely dissolved, and 500 ml of methanol is added. Slowly cool to room temperature and seed a small amount. Stir 2 days and filter the resulting crystals. And vacuum dried at 50 ° C to obtain 90 g of butrol. (Total yield 34.4%, purity 94% from cyclane)

The resulting crystals were dissolved in 360 ml of purified water and 900 ml of methanol was added thereto. Slight seeding and stirring for 2 days. The resulting 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 crystal is 99.5% or less, or if impurities are not removed, crystallization proceeds further.

¹ H-NMR (D ₂ O, 400 MHz): 3.1-3.9 (m, 28H)

[Element analysis]

Example 3 . Calcobutrol  Produce

10 g of the high purity buthtrrol (purity: 99.5% or more) prepared in Example 2 was dissolved in 100 ml of purified water, and CaCO ₃ 2.22 g. The mixture was stirred at room temperature for 1 hour, filtered through a 0.2 μm filter, concentrated, and lyophilized to obtain 10.7 g. (Yield: 99%, purity: 99.5% or more)

The process for preparing chalcobutrol according to the present invention can be used for the production of pharmaceuticals in the pharmaceutical industry since it can produce high purity of chalcobutrol through a relatively simple process.

Claims (8)

(1, 4, 10-tetraazacyclododecane) with 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] 4,7,10-tetraazacyclodecan-1-yl) butane-1,2,4-triol and reacting it with haloacetic acid to prepare crude de butrol;
A second step of first purifying the crude dextrose by using an anion exchange resin and a cation exchange resin; And
And a third step of secondly purifying the first purified crodobutrol in an aqueous methanol solution having a water content of 20% or more.
(2, 2 ', 2 "- (10 - ((2R, 3S) -1,3,4-trihydroxybutan-2-yl) -1,4,7,10- Tetraacacyclodecane-1,4,7-triyl) triacetic acid) delete  The cation exchange resin according to claim 2, wherein 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 selected from the group consisting of a sulfonic acid group and a carboxyl group The method comprising:  The process according to claim 1, wherein the haloacetic acid is selected from the group consisting of chloroacetic acid, bromoacetic acid, and iodoacetic acid delete delete The method according to claim 1, wherein the pH before crystallization is 3.5 to 4.5 A process for producing calcobutrol by reacting buthrole prepared according to claim 1 with calcium carbonate