A METHOD FOR PREPARING GADOBUTROL

Abstract

The present disclosure relates to a novel method for preparing high-purity gadobutrol. The present disclosure can be easily applied to a large scale production because purity of intermediate can be managed via simple and mild process and accordingly, high-purity or ultra high-purity gadobutrol that has higher purity than previous gadobutrol can be prepared in high yield therethrough.

Claims

1. A method for preparing gadobutrol comprising: (S1) preparing a compound of Formula 3 below by using a compound of Formula 2 below or its salt; (S2) preparing a compound of Formula 4 below by using the compound of Formula 3; and (S3) preparing a compound of Formula 1 below by using the compound of Formula 4 where Formula 1: ##STR00008## Formula 2: ##STR00009## Formula 3: ##STR00010## Formula 4: ##STR00011## where R is linear or branched-chain alkyl of C.sub.1-C.sub.4.

2. The method according to claim 1, the (S1) step comprises reacting the compound of Formula 2 with a compound of Formula 5 below under existence of a mixed solvent of water and C.sub.4-C.sub.11 ether and an inorganic base where Formula 5: ##STR00012## And where R is identical with claim 1 and X is halogen, TsO.sup.− or MsO.sup.−.

3. The method according to claim 2, the ether is tetrahydrofuran (THF).

4. The method according to claim 2, the inorganic base is potassium carbonate (K.sub.2CO.sub.3), sodium bicarbonate (NaHCO.sub.3), potassium bicarbonate (KHCO.sub.3) or mixtures thereof.

5. The method according to claim 2, the (S1) step further comprises a crystallization process.

6. The method according to claim 5, a crystallization solvent used in the crystallization process is methylene chloride, C.sub.4-C.sub.11 ether, C.sub.4-C.sub.8 alkane or mixtures thereof.

7. The method according to claim 6, the crystallization solvent is a mixture of methylene chloride and n-Hexane.

8. The method according to claim 1, the salt of the compound of Formula 2 in the (S1) step is 4 hydrochloride of Formula 2-1 below where Formula 2-1: ##STR00013##

9. The method according to claim 1, the compound of Formula 3 in the (S1) step is a compound of Formula 3-1 below where Formula 3-1: ##STR00014##

10. The method according to claim 1, the (S2) step is performed by an acid hydrolysis.

11. The method according to claim 10, the (S2) step comprises a purification process of the compound of Formula 4 by using resin.

12. The method according to claim 11, the (S2) step further comprises the crystallization process.

13. The method according to claim 12, wherein a solvent used in the crystallization process is methanol, acetone or mixture thereof.

14. The method according to claim 1, the gadolinium ion source is gadolinium oxide, gadolinium acetate or gadolinium chloride.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0041] The present disclosure will be described more fully hereinafter with reference to the accompanying examples. However, the present disclosure may be embodied in many different forms, and should not be construed as being limited to the examples set forth herein.

[0042] In addition, reagents and solvents disclosed hereinafter were purchased from Sigma-Aldrich Korea unless otherwise said, IR was measured by using Jasco's FT-IR 4100 series; HPLC was measured by using Agilent Technoliges 1200 Series; and 1H NMR was measured by using Varian Mercury Instrument's oxford NMR 300 MHz Spectrometer. Purity was calculated as area % of HPLC.

EXAMPLE 1

Step 1: Preparation of tertbutyl-2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetate

[0043] 3-(1,4,7,10-tetraazacyclododecan-1-yl)butan-1,2,4-triol 4 hydrochloride (100 g, 0.2368 mol) was dissolved under stiffing in 500 ml of purified water and 1500 ml of tetrahydrofuran. Potassium carbonate (327 g, 2.3684 mol) was added thereto at room temperature and tert-butylbromoacetate (143.2 g, 0.434 mmol) was slowly added thereto. Upon completion of the addition, a reaction was performed at 63 to 68° C. When the reaction was terminated, 1000 ml of purified water was added thereto and stirred, and then an aqueous layer was separated. The solvent of separated organic layer was removed by concentrating under reduced pressure and then an organic layer was separated by using 1500 ml of purified water and 1000 ml of toluene. An aqueous layer was separated by adding 550 ml of hydrochloric acid to the organic layer. 500 ml of methylene chloride was added to the separated aqueous layer and pH was adjusted to 9.3 to 9.8 by using 100 g of sodium carbonate, and then an organic layer was separated therefrom. The separated organic layer was washed with 10% salt water to separate the organic layer and dehydration was performed, and then the solvent was concentrated under reduced pressure. 400 ml of methylene chloride and 1600 ml of n-hexane were added to the concentrated residue and the resulting solid therefrom was filtered and dried to prepare 117.3 g of tertbutyl-2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetate.

[0044] Yield: 80%, Purity: 99.7%

[0045] .sup.1H-NMR (CDCl.sub.3, 300 MHz): δ (ppm) 1.46 (s, 9H), 1.90-3.10 (m, 11H), 3.20-3.80 (m, 17H)

[0046] Infrared spectrum (KBr, cm.sup.1): 3350, 2980, 2960, 2860, 2820, 1730, 1455

Step 2: Preparation of 2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetic acid (butrol)

[0047] Internal temperature was raised to 57˜63° C. while tertbutyl-2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetate (30 g, 0.048 mol) prepared in Step 1 was dissolved under stiffing in 60 ml of purified water. After elevating the temperature, a mixed solution of 60 ml of purified water and 6 ml of sulfuric acid prepared in advance was added drop-wise. A reaction was performed for 4 hours at the same temperature and cooled to room temperature (20 to 25° C.) upon confirming termination of the reaction. When the cooling was completed, the same was treated with resin (5 v/w) and concentrated. 90 ml of methanol and 300 ml of acetone were added to the concentrated residue and resulting crystal was washed with acetone. The filtered crystal was dried in vacuo at internal temperature of 50° C. to prepare 20.1 g of 2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetic acid.

[0048] Yield: 92%, Purity: 98%

[0049] .sup.1H-NMR (CDCl.sub.3, 300 MHz): δ (ppm) 1.92-3.15 (m, 11H), 3.23-3.88 (m, 17H)

[0050] Infrared spectrum (KBr, cm.sup.1): 3350, 2980, 2960, 2860, 2820, 1730, 1455

Step 3: Preparation of gadolinium complex (gadobutrol) of 10-(2,3-dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid

[0051] 2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)tri acetic acid (15.4 g, 0.0342 mol) prepared in Step 2 was dissolved under stirring in 77 ml of purified water, and gadolinium oxide (8.67 g, 0.0240 mol) was added thereto. Internal temperature was raised to 87˜93° C. and the same was stirred for 1 hour at the same temperature. After confirming termination of the reaction, the reaction solution was filtered by using diatomite. Resin was added to the filtrate and stirred, then filtered. The same was decolorated and concentrated under reduced pressure. 7.7 ml of purified water was added to the concentrated residue and the same was stirred for 2 hours at internal temperature of 70 to 75° C. After termination of the dissolution, 121.5 ml of ethanol was added thereto and refluxed under stirring for 3 hours. The same was cooled to room temperature (20 to 25° C.), stirred for 1 hour at the same temperature and filtered under nitrogen atmosphere. The filtered crystal was dried in vacuo at internal temperature of 50° C. or less to prepare 16.2 g of gadolinium of 10-(2,3-dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid.

[0052] Yield: 78.3%, Purity: 99.99%

[0053] Infrared spectrum (KBr, cm.sup.−1): 3560, 3280, 2980, 2975, 2940, 2920, 2880, 2870, 1650, 1600, 1380

Comparative Example 1

[0054] Gadobutrol was prepared according to Scheme 1 disclosed in the conventional art (Inorg. Chem. 1997, 36, 6086-6093).

[0055] Yield: 65%, Purity: 95.98%

[0056] Infrared spectrum (KBr, cm.sup.−1): identical to Example 1.

Comparative Example 2

[0057] Gadobutrol was prepared according to Scheme 2 disclosed in the conventional art (Inorg. Chem. 1997, 36, 6086-6093).

[0058] Yield: 63%, Purity: 93.57%

[0059] Infrared spectrum (KBr, cm.sup.1): identical to Example 1.

[0060] Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present disclosure. Those skilled in the art will also appreciate that such equivalent embodiments do not depart from the spirit and scope of the disclosure as set forth in the appended Claims.

INDUSTRIAL APPLICABILITY

[0061] The preparation process of the present disclosure is very adequate for a large scale production because the process is very mild and high-purity gadobutrol can be prepared in high yield by simple process.