GADOBUTROL INTERMEDIATE AND GADOBUTROL PRODUCTION METHOD USING SAME

Abstract

Disclosed are: an intermediate capable of high-purity synthesis of gadobutrol which can be used as an MRI contrast agent; and a gadobutrol production method using same. The gadobutrol intermediate is represented by Chemical Formula 2 in the specification.

Claims

1. A gadobutrol intermediate represented by the following Chemical Formula 2: ##STR00009##

2. A gadobutrol intermediate production method comprising: reacting 1,4,7,10-tetraazacyclododecane with a lithium-halogen salt to produce a cyclen-lithium halogen complex, followed by reaction with 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane to obtain N-(6-hydroxy-2,2-dimethyl-1,3-dioxyphen-5-yl)-1,4,7,10-tetraazacyclododecane-lithium halogen complex represented by the following Chemical Formula 1; and reacting the lithium halogen complex represented by Chemical Formula 1 with hydrochloric acid to obtain a compound represented by the following Chemical Formula 2: ##STR00010##

3. The gadobutrol intermediate production method of claim 2, wherein an amount of hydrochloric acid used is 4.0 to 4.2 equivalents based on the lithium halogen complex represented by Chemical Formula 1.

4. The gadobutrol intermediate production method of claim 2, further comprising: filtering a reactant of the lithium halogen complex represented by Chemical Formula 1 and the hydrochloric acid to obtain the gadobutrol intermediate represented by Chemical Formula 2 in a crystalline form.

5. A gadobutrol production method comprising: alkylating a gadobutrol intermediate represented by the following Chemical Formula 2 with chloroacetic acid to obtain a butrol represented by the following Chemical Formula 3; and reacting the butrol represented by Chemical Formula 3 with gadolinium oxide: ##STR00011##

6. The gadobutrol production method of claim 5, further comprising: purifying a reactant of the gadobutrol intermediate and chloroacetic acid by filtering a salt and a water-soluble low-molecular material corresponding to 100 to 300 daltons using a nanofiltration system.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0031] Hereinafter, the present disclosure is described in more detail with reference to the following Examples, but the present disclosure is not limited by the Examples.

[0032]

Example 1

Production of Gadobutrol Intermediate Represented by Chemical Formula 2

[0033] 1,4,7,10-tetraazacyclododecane (59.7 Kg, 1 e.q.), lithium chloride (17.64 Kg, 1.14 e.q.), 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (50.0 Kg, 1 e.q.) and isopropyl alcohol (131.1 kg, 2.2 vol.) were added to a reactor and reacted by raising a temperature to 85 to 95 C. After the reaction, 495.8 Kg of methyl tert-butyl ether was added thereto, and the mixture was stirred at 20 to 25 C. for 1 hour, filtered, and washed with 47.5 kg of methyl tert-butyl ether. The filtrate was concentrated under reduced pressure, 176.8 Kg of methanol was added thereto, 163.4 Kg of hydrochloric acid was added thereto, and the mixture was stirred under reflux for 3 hours, and then concentrated under reduced pressure.

[0034] The obtained product was concentrated under reduced pressure by adding 266.3 kg of methanol (MeOH) thereto, and then was concentrated under reduced pressure by adding 266.3 kg of methanol thereto. 319.5 kg of methanol was added thereto, and the mixture was stirred under reflux for 3 hours, cooled to 0 to 5 C., stirred for 1 hour, then washed with 53.3 kg of methanol for filtration, and dried to obtain 107.5 Kg of 3-(1,4,7,10-tetraazacyclododecane-1-yl)butane-1,2,4-triol tetrahydrochloride (yield 73.4%, purity 98% (HPLC)).

[0035]

Example 2

Production of Gadobutrol Represented by Chemical Formula 4

[0036] Step A: Production of Butrol

[0037] 3-(1,4,7,10-tetraazacyclododecane-1-yl)butane-1,2,4-triol tetrahydrochloride (107.5 Kg, 1 e.q.), 2-chloroacetic acid (91.33 Kg, 4.3 e.q.), and purified water (429.6 Kg, 4 vol.) were added to the reactor. Then, the mixture was heated and stirred to 75 to 85 C. while maintaining pH 9 to 10 by adding dropwise 40% NaOH, thereby terminating the reaction. 133.9 Kg of hydrochloric acid was added to the mixture, and the mixture was concentrated under reduced pressure. 169.7 Kg of methanol was added to filter the salt, followed by nano-filtering to obtain 2,2,2-(10-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid to proceed with the next reaction.

[0038]

[0039] Step B: Production of Gadobutrol

[0040] After the nano-filtering, the filtrate was added to the reactor, and gadolinium oxide (46.1 Kg, 1.5 e.q.) was added thereto. The temperature was raised to 80 to 90 C., and then the mixture was heated and stirred to terminate the reaction. Then, the obtained product was purified by sequentially passing anionic and cationic resins therethrough, and then concentrated under reduced pressure. 90 kg of purified water was added thereto, the temperature was raised to 60 to 70 C., 853.2 Kg of methanol was added thereto, and the mixture was cooled to 0 to 5 C., filtered, washed with 71.1 Kg of methanol, and crystallized. 90 kg of purified water was added to dissolve the crystallized gadolinium complex, the temperature was raised to 60 to 70 C., then 853.2 Kg of methanol was added thereto, and the mixture was cooled to 0 to 5 C., filtered, washed with 71.1 Kg of methanol, and purified. The obtained product was dissolved by adding 90 kg of purified water, filtered, and the temperature was raised to 75 to 85 C., then 2559.6 kg of anhydrous ethanol was added thereto. The obtained product was cooled to 0 to 5 C., stirred for 1 hour, filtered, washed with 169.7 kg of anhydrous ethanol, and dried to obtain 93.8 Kg (yield 60.9%) of gadolinium complex of 2,2,2-(10-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, with purity of 99.8% (HPLC).