METHOD FOR PREPARING CALCOBUTROL

Abstract

Disclosed is a novel method of preparing highly pure calcobutrol using an intermediate (butrol) of gadobutrol without using highly pure gadobutrol. This method is capable of obtaining calcobutrol at high purity and high yield through a simple and environmentally friendly process, and thus can be easily applied to mass production.

Claims

1. A method for preparing calcobutrol 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. ##STR00008## wherein, 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. ##STR00009## wherein, R is identical with claim 1 and X is halog en, 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 claim 1, the salt of the compound of Formula 2 in the (S1) step is 4 hydrochloride of Formula 6 below. ##STR00010##

9. The method according claim 1, the compound of Formula 3 in the (S1) step is a compound of Formula 7 below. ##STR00011##

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 of claim 1, wherein the step (S3) comprises reacting the compound of Chemical Formula 4 with a calcium ion source.

15. The method of claim 14, wherein the calcium ion source is calcium carbonate, calcium chloride, calcium oxalate, calcium phosphate, or calcium hydroxide.

Description

EXAMPLE 1

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

[0047] 3-(1,4,7,10-tetraazacyclododecan-1-yl)butan-1,2,4-triol 4 hydrochloride (100 g, 0.2368 mol) was dissolved under stirring 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 Cert-butyl bromoacetate (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 separated 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 tert-butyl-2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetate.

[0048] Yield: 80%, Purity: 99.7%

[0049] .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)

[0050] 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)

[0051] Internal temperature was raised to 57˜63° C. while tert-butyl-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 stirring 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.

[0052] Yield: 92%, Purity: 98%

[0053] .sup.1H-NMR(CDCl.sub.3, 300 MHz): δ (ppm) 1.92˜3.15 (m, 11H), 3.23˜3.88(m, 17H)

[0054] Infrared spectrum(KBr, cm.sup.−1): 3350, 2980, 2960, 2860, 2820, 1730, 1455

Step 3: Preparation of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-calcium complex (calcobutrol)

[0055] 2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (15.4 g, 0.0342 mol), prepared in step 2, was dissolved in 154 ml of purified water with stirring and then added with calcium carbonate (3.42 g, 0.0335 mol). The internal temperature was increased to 87˜93° C. and the mixture was stirred at the same temperature for 1 hr. After the termination of the reaction, the reaction solution was filtered using diatomaceous earth, and the filtrate was concentrated under reduced pressure. The concentrated residue was added with 231 ml of ethanol and refluxed with stirring. The resulting product was cooled to room temperature (20˜25° C.), stirred at the same temperature for 1 hr, and filtered in a nitrogen atmosphere. The filtered crystal was dried in a vacuum at an internal temperature of 50° C. or less, thus obtaining 13.0 g of a 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-calcium complex.

[0056] Yield 74.3%, Purity 99.5%

[0057] .sup.1H-NMR (DMSO, d.sub.6): δ (ppm) 1.90˜2.30(m), 2.40˜2.90(m), 3.0˜3.80(m), 3.91(d)

[0058] Infrared spectrum (KBr, cm.sup.−1): 3400, 2960, 2840, 1600, 1410, 1290, 1275

EXAMPLE 2

[0059] 2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (18.0 g, 0.0399 mol), prepared in step 2 of Example 1, was dissolved in 144 ml of purified water with stirring, and then added with calcium carbonate (4.00 g, 0.0399 mol). The internal temperature was increased to 87˜93° C. and the mixture was stirred at the same temperature for 1 hr. After the termination of the reaction, the reaction solution was filtered using diatomaceous earth, and the filtrate was concentrated under reduced pressure. The concentrated residue was added with 180 ml of ethanol and 180 ml of acetone and refluxed with stirring. The resulting product was cooled to 0˜5° C., stirred at the same temperature for 1 hr, and filtered in a nitrogen atmosphere. The filtered crystal was dried in a vacuum at an internal temperature of 50° C. or less, thus obtaining 13.0 g of a 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-calcium complex.

[0060] Yield 62.9%, Purity 99.4%

[0061] .sup.1H-NMR (DMSO, d.sub.6): δ (ppm) 1.90˜2.30(m), 2.40˜2.90(m), 3.0˜3.80(m), 3.91(d)

[0062] Infrared spectrum (KBr, cm.sup.−1): 3400, 2960, 2840, 1600, 1410, 1290, 1275

INDUSTRIAL APPLICABILITY

[0063] The preparation process of the present disclosure is very adequate for a large scale production because the process is very mild and high-purity calcobutrol can be prepared by simple process.