METHOD FOR PREPARING GADOBUTROL

Abstract

The present invention provides a novel method for preparing high-purity gadobutrol or hydrates thereof. The preparation method of the present invention can have an advantage of simplifying a process by forming a gadolinium complex in-situ without purification of a butrol intermediate and omitting a resin purification process unlike a conventional method for synthesizing gadobutrol. In addition, the preparation method of the present invention can be used to produce high-purity gadobutrol or hydrates thereof at a high yield only through the simple process as above, and thus can be useful in mass production.

Claims

1. A method for preparing gadobutrol or hydrates thereof, the method comprising: (S-1) subjecting a compound of formula 3 below or a salt thereof to a carboxymethylation reaction to prepare a compound of formula 2 below; and (S-2) subjecting the compound of said formula 2 to a basic hydrolysis and forming a gadolinium complex in-situ to prepare a compound of formula 1 below: ##STR00010## wherein, in above formula 2, R is C.sub.1-C.sub.4 linear or branched-chain alkyl.

2. The method according to claim 1, wherein, in said (S-1), the compound of said formula 3 or the salt thereof and a compound of formula 4 below are reacted in the presence of a base: ##STR00011## wherein, R is C.sub.1-C.sub.4 straight or branched-chain alkyl, and X is halogen, TsO.sup.− or MsO.sup.−.

3. The method according to claim 1, wherein the salt of the compound of said formula 3 in said (S-1) is 4 hydrochloride salt of formula 3-1 below: ##STR00012##

4. The method according to claim 1, wherein the compound of said formula 2 in said (S-1) is a compound of formula 2-1 below: ##STR00013##

5. The method according to claim 1, wherein said (S-1) is performed in water, C.sub.1-C.sub.4 alcohol, or a mixed solvent thereof.

6. The method according to claim 5, wherein the mixed solvent is a mixture of water and isopropyl alcohol.

7. The method according to claim 2, wherein the base is an inorganic base.

8. The method according to claim 7, wherein the inorganic base is potassium carbonate (K.sub.2CO.sub.3), sodium hydrogen carbonate (NaHCO.sub.3), potassium hydrogen carbonate (KHCO.sub.3), or a mixture thereof.

9. The method according to claim 1, wherein said (S-1) further comprises a crystallization process.

10. The method according to claim 9, wherein a solvent used in the crystallization is methylene chloride, C.sub.3-C.sub.12 ester, or a mixture thereof.

11. The method according to claim 10, wherein the mixture is a mixture of methylene chloride and ethyl acetate.

12. The method according to claim 1, wherein said (S-2) does not use a resin.

13. The method according to claim 1, wherein said (S-2) comprises a process of adjusting pH to acid after completion of a basic hydrolysis reaction.

14. The method according to claim 13, wherein the pH is 2 to 5.

15. The method according to claim 1, wherein said (S-2) is to add a gadolinium ion source.

16. The method according to claim 15, wherein the gadolinium ion source is gadolinium oxide, gadolinium acetate, or gadolinium chloride.

17. The method according to claim 1, wherein said (S-2) comprises a salt removal process.

18. The method according to claim 17, wherein the salt removal process is performed through a nano filter.

19. The method according to claim 17, wherein an electrical conductivity of filtrate is 500 μS/cm or less in the salt removal process.

20. The method according to claim 17, wherein the salt removal process is performed by using 200 to 300 mL of water per 1 g of crude gadobutrol prepared by a reaction for forming the gadolinium complex.

21. The method according to claim 1, wherein said (S-2) further comprises a crystallization process.

22. The method according to claim 21, wherein a solvent used in the crystallization is water, C.sub.1-C.sub.4 alcohol, or a mixed solvent thereof.

23. The method according to claim 22, wherein the solvent used in the crystallization is methanol or anhydrous ethanol.

24. The method according to claim 1, wherein said method further comprises (S-3) purifying crude gadobutrol with resin.

25. The method according to claim 24, wherein the resin comprises a cation exchange resin and an anion exchange resin.

26. The method according to claim 25, wherein a volume ratio of the cation exchange resin and the anion exchange resin is 1:1 to 1:3.

27. The method according to claim 1, wherein said (S-3) further comprises a crystallization process.

28. The method according to claim 27, wherein a solvent used in the crystallization is water, C.sub.1-C.sub.4 alcohol, or a mixed solvent thereof.

29. The method according to claim 28, wherein a solvent used in the crystallization is ethanol.

Description

BEST MODE FOR INVENTION

[0067] Hereinafter, the present invention will be described in detail through preferred embodiments for better understanding of the present invention. However, the following embodiments are provided only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.

[0068] In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea and Daejung Chemicals & Metals Co., Ltd., unless otherwise specified. IR was measured by using Cary 630 FTIR of Agilent Technologies, and HPLC was measured by using 1200 Series of Agilent Technologies, and Dionex Ultimate 3000 series and Dionex Corona Veo RS detector from Thermo scientific. .sup.13C NMR was measured at 100 MHz by using Brucker's Biospin AG, Magnet system 400′54 Ascend, and MS was measured by using 6120 Quadrupoe LC/MS of Agilent Technologies. Purity was measured by using an area % of HPLC and an analysis method of related substances of “Gadobutrol monohydrate” in the European Pharmacopoeia. With regard to elementary analysis, C, H and N were measured by using Flash EA-2000 Organic Elemental Analyzer of Thermo Scientific, and O was measured by using Flash EA-1112 Series Elemental Analyzer of Thermo Finnigan.

Example 1: Preparation of Gadolinium Complex (Gadobutrol) of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

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

[0069] A 3-(1,4,7,10-tetraazacyclododecan-1-yl)butane-1,2,4-triol 4 hydrochloride (100 g, 0.2368 mol) was dissolved in 500 ml of purified water and 1000 ml of isopropyl alcohol while being stirred. Potassium carbonate (327 g, 2.3684 mol) was added at room temperature, and tert-butylbromoacetate (143.2 g, 0.7434 mmol) was slowly added. At the end of the addition, a reaction was performed at 77 to 83° C., and at the end of the reaction, 200 ml of purified water was added and dissolved while being stirred. After dissolution, an organic layer was removed through concentration under reduced pressure, and the organic layer was separated by using 1000 ml of purified water and 1000 ml of toluene, and 500 ml of hydrochloric acid was added to the separated organic layer so as to separate a water layer. 500 ml of methylene chloride was added to the separated water layer, and pH was adjusted to 9.3 to 9.8 with sodium carbonate (100 g), and the organic layer was separated. The separated organic layer was dehydrated and then concentrated under reduced pressure. The concentrated residue was subjected to crystallization by using methylene chloride (200 ml) and ethyl acetate (1400 ml), and the resulting solid was filtered and dried to obtain 139.2 g (yield: 95%, purity: 97.7%) of the title compound.

[0070] Mass spectrum: m/e 619 [(M+H)+]

[0071] .sup.13C-NMR (CDCl.sub.3, 100 MHz): δ (ppm) 27.86, 28.16, 45.01, 45.20, 55.43, 55.82, 56.26, 59.62, 64.70, 70.66, 81.88, 82.12, 172.09,

[0072] Infrared spectrum (KBr, cm.sup.−1): 3820, 2817, 1729, 1365, 1221, 1108, 1159.

Step 2: Preparation of Gadolinium Complex (Gadobutrol) of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

[0073] Tert-butyl-2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (139.2 g, 0.225 mol) prepared in step 1 was dissolved in 557 ml of purified water while being stirred, and sodium hydroxide (31.5 g, 0.7875 mol) was added, after which an internal temperature was raised to 75 to 80° C. At the end of raising the temperature, a reaction was performed at the same temperature for three hours. After confirming the completion of the reaction, the resulting mixture was cooled to 15° C. or less.

[0074] After the end of cooling, pH was adjusted to 3.3 to 3.7 by using bromic acid, and gadolinium oxide (57.09 g, 0.1575 mol) was added after decolorization treatment. An internal temperature was raised to 87 to 93° C. and the resulting mixture was stirred at the same temperature for one hour. After confirming the completion of the reaction, the reaction solution was filtered by using diatomaceous earth. The filtrate was concentrated under reduced pressure. 139.2 ml of purified water was added to the concentrated residue, and the internal temperature was raised to 70° C. or higher, and dissolved while being stirred. After the end of the dissolution, 2785 ml of methanol was added and stirred under reflux for three hours. After cooling to room temperature, the resulting mixture was stirred at the same temperature for two hours or more, and filtered under a nitrogen atmosphere. The filtered crystals were dried under vacuum at the internal temperature of 50° C. or less so as to obtain 126.2 g of the title compound (yield: 90%, content: 83.0%).

[0075] Mass spectrum: m/e 606 [(M+H)+]

[0076] Infrared spectrum (KBr, cm.sup.−1): 3295, 1639, 1592, 1384, 1327, 1269, 1079, 1016, 936, 721.

Example 2: Preparation of Gadolinium Complex (Gadobutrol) of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

[0077] Tert-butyl-2,2′,2″-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (139.2 g, 0.225 mol) prepared in step 1 of Example 1 was dissolved in 557 ml of purified water while being stirred, and sodium hydroxide (31.5 g, 0.7875 mol) was added, and an internal temperature was raised to 75 to 80° C. If heating was completed, a reaction was performed at the same temperature for three hours. After confirming the completion of the reaction, the reaction mixture was cooled to 15° C. or less.

[0078] After cooling was completed, pH was adjusted to 3.3 to 3.7 by using bromic acid, and gadolinium oxide (57.09 g, 0.1575 mol) was added after decolorization treatment. An internal temperature was raised to 87 to 93° C., and stirred at the same temperature for one hour. After confirming the completion of the reaction, the reaction mixture was cooled to room temperature and filtered by using diatomaceous earth. The filtrate was diluted, and salt was removed with a nano filter (DK1812 G/E (manufactured by Pure Tech P&T)) by using 34800 ml of water. The remaining mixed solution was concentrated under reduced pressure. The 139.2 ml of purified water was added to the concentrated residue, and the internal temperature was raised to 70° C. or higher, and the resulting mixture was dissolved while being stirred. After completion of the dissolution, 1392 ml of methanol was added and stirred under reflux for three hours. The resulting mixture was cooled to room temperature, stirred at the same temperature for two hours or more, and filtered under a nitrogen atmosphere. The filtered crystals were dried under vacuum at the internal temperature of 50° C. or less so as to obtain 82.7 g of the title compound (yield: 59%, purity: 99.97%).

[0079] Mass spectrum: m/e 606 [(M+H)+]

[0080] Infrared spectrum (KBr, cm.sup.−1): 3403, 3269, 2856, 1595, 1375, 1318, 1273, 1087, 1005, 992, 932

Example 3: Preparation of Gadolinium Complex (Gadobutrol Monohydrate) of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

[0081] A gadolinium complex of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (126.2 g, 0.2025 mol) prepared in step 2 of Example 1 was dissolved in 1262 ml of purified water while being stirred. Resin containing 126 ml of cation exchange resin and 252 ml of anion exchange resin was added to the filtrate of gadolinium oxide, stirred, filtered, and concentrated under reduced pressure. The 126.2 ml of purified water was added to the concentrated residue, and the resulting mixture was stirred at an internal temperature of 70° C. or higher. After completion of the dissolution, 1262 ml of ethanol was added, and stirred under reflux for three hours. The resulting mixture was cooled to room temperature, stirred at the same temperature for two hours, and filtered under a nitrogen atmosphere. The filtered crystals were dried under vacuum at the internal temperature of 50° C. or lower so as to obtain 94.6 g of the title compound (yield: 75.0%, purity: 99.99%).

[0082] Mass spectrum: m/e 606 [(M+H)+]

[0083] Elemental Analysis for C.sub.8H.sub.31N.sub.4O.sub.9Gd, H.sub.2O: C, 34.6 (34.7), H, 5.3 (5.3), N, 8.8 (9.0), O, 21.1 (25.7)

[0084] Infrared spectrum (KBr, cm.sup.−1): 3403, 3269, 2856, 1595, 1318, 1273, 1087, 1005, 992, 932

Example 4: Preparation of Gadolinium Complex (Gadobutrol) of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

[0085] After completion of the dissolution, 79.9 g of the title compound (yield: 57%, purity: 99.97%) was obtained in the same manner as in Example 2, except that 2785 ml of methanol was added.

[0086] Mass spectrum: m/e 606 [(M+H)+]

[0087] Infrared spectrum (KBr, cm.sup.−1): 3403, 3269, 3141, 2857, 1597, 1375 1320, 1273, 1066, 992, 932

Example 5: Preparation of Gadolinium Complex (Gadobutrol Monohydrate) of 10-(2,3-dihydroxy-1(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

[0088] After completion of the dissolution, 88.3 g of the title compound (yield: 63%, purity: 99.97%) was obtained in the same manner as in Example 2, except that 2785 ml of anhydrous ethanol was added instead of methanol.

[0089] Mass spectrum: m/e 606 [(M+H)+]

[0090] Elemental Analysis for C.sub.18H.sub.31N.sub.4O.sub.9Gd, H.sub.2O: C, 34.6 (34.7), H, 5.3 (5.3), N, 8.8 (9.0), O, 21.1 (25.7)

[0091] Infrared spectrum (KBr, cm.sup.−1): 3403, 3269, 3141, 2857, 1597, 1375, 1320, 1273, 1066, 992, 932

Comparative Example 1

[0092] Gadobutrol was prepared according to Scheme 1 disclosed to related art (Inorg. Chem. 1997, 36, 6086-6093).

[0093] Yield 65%, purity 95.98%

[0094] Infrared spectrum (KBr, cm.sup.−1): Same as Example 1.

Comparative Example 2

[0095] Gadobutrol was prepared according to Scheme 2 disclosed to related art (Inorg. Chem. 1997, 36, 6086-6093).

[0096] Yield 63%, purity 93.57%

[0097] Infrared spectrum (KBr, cm.sup.−1): Same as Example 1.

INDUSTRIAL APPLICABILITY

[0098] The preparation method of the present invention can have an advantage of simplifying a process by forming a gadolinium complex in-situ without purification of a butrol intermediate and omitting a resin purification process unlike a conventional method for synthesizing gadobutrol. In addition, the preparation method of the present invention can be used to produce high-purity gadobutrol or hydrates thereof at a high yield only through the simple process as above, and thus can be useful in mass production as well as related industry field.