HK1064098B - Lithium complexes of n-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, production and use thereof - Google Patents

Description

Lithium complex of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-tricarboxymethyl-1, 4, 7, 10-tetraazacyclododecane, preparation method and application thereof

Technical Field

The invention relates to a lithium complex of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-tricarboxymethyl-1, 4, 7, 10-tetraazacyclododecane, a preparation method and application thereof.

Background

Since they are useful as diagnostic agents for image formation, in particular MRI diagnostic agents, the preparation of metal complexes, in particular gadolinium complexes of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-tricarboxymethyl-1, 4, 7, 10-tetraazacyclododecane (GADOBUTROL), has been investigated by different methods (DE 4009119). Despite the advances made over the original methods, there is still a need for synthetic methods which are practical, environmentally friendly and low cost, especially on an industrial scale.

This object is achieved by the invention.

Disclosure of Invention

It has surprisingly been found that the crystalline complex formers of the formula I according to the invention (Complexbildner) are very suitable for the preparation of the gadolinium complex GADOBUTROL, the process of which is markedly superior to the simplest prior art (Inorg. chem.1997, 36, 6086-6093 and DE 19724186.7):

wherein:

3X together represent N lithium ions and m hydrogen atoms, and N and m are each a number from 0 to 3, preferably from 0.8 to 2.2, and the sum of N and m is 3, Y represents chlorine or bromine, i.e. the lithium complex of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-tricarboxymethyl-1, 4, 7, 10-tetraazacyclododecane.

It is particularly preferred that Y is chlorine, one X represents a lithium ion and the remaining two represent hydrogen atoms.

The compounds according to the invention can be prepared from N- (6-hydroxy-2, 2-dimethyl-1, 3-dioxepan-5-yl) -1, 4, 7, 10-tetraazacyclododecane-lithium chloride or lithium bromide complex (DE19724186.7) using chloroacetic acid or bromoacetic acid, lithium hydroxide and hydrochloric acid or hydrobromic acid in water and then crystallized from an ethanol-water mixture. The crystalline complex former is complexed with gadolinium in water, and the complex is then isolated salt-free by crystallization in ethanol/water, without the use of ion exchangers.

The invention has the advantages that: the complex former is isolated in crystalline form and is thus obtained in very pure form.

The process for preparing crystalline complex formers by replacing sodium hydroxide with lithium hydroxide (DE19724186.7) avoids the expensive separation of the equipment-corrosive sodium chloride from strongly acidic methanol-water solutions. In the process of the invention, lithium chloride or lithium bromide is formed instead of sodium chloride, which remains in the weakly acidic ethanol-water mother liquor when the complex former is crystallized. Lithium can be recovered from the mother liquor as lithium hydroxide by treatment with an anion exchanger. The cost reduction of the preparation method is very economical.

Detailed Description

For the preparation of GADOBUTROL, gadolinium is metered in precisely during the complexation. This reduces the amount of precipitation of the product comprising gadolinium.

In order to remove salts and other by-products from the gadolinium complex, in contrast to the prior art methods, no ion exchanger is required. The operation of the corresponding process unit and the associated precipitation products is therefore dispensed with.

This also eliminates the evaporation energy of the aqueous eluate of the ion exchanger.

The method according to the invention is implemented as follows: the lithium chloride or lithium bromide complex of N- (6-hydroxy-2, 2-dimethyl-1, 3-dioxepan-5-yl) -1, 4, 7, 10-tetraazacyclododecane is reacted in a polar solvent such as water, primary and secondary alcohols (e.g. ethanol or isopropanol), DMF, dimethoxyethane, diglyme or a mixture of these solvents, preferably in water, with chloroacetic acid or bromoacetic acid (preferably chloroacetic acid), and lithium hydroxide at a temperature of 40 to 150 deg.C (preferably 40 to 90 deg.C) and a pH of 8 to 14 (preferably 9 to 13) for 0.5 to 24 hours, preferably 1 to 6 hours.

To isolate the product, the pH is adjusted to 3.5 to 4.5, preferably 3.8 to 4.2, with hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid, preferably with hydrochloric acid, and then crystallized from a mixture of water and ethanol.

To convert the complex former of formula I to the gadolinium complex of formula II, the complex former is dissolved in water, the pH is adjusted to about 3.6 by the addition of hydrochloric acid, gadolinium oxide is added in a calculated amount, the complexation is carried out at 50-100 ℃, preferably 70-100 ℃, and then the gadolinium complex is crystallized by the addition of ethanol.

The present invention will be described in more detail below by way of examples.

Example 1

Preparation of lithium Complex of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-Tricarboxymethyl-1, 4, 7, 10-Tetraazacyclododecane

38.5g of chloroacetic acid were prepared in advance, dissolved in 40g of water, and the solution was cooled to 0-10 ℃. To this solution was added 17.1g of lithium hydroxide monohydrate. This solution is added to a solution of 41.25g (114.95mmol) of the lithium chloride complex of N- (6-hydroxy-2, 2-dimethyl-1, 3-dioxepan-5-yl) -1, 4, 7, 10-tetraazacyclododecane in about 45ml of water. The mixture was warmed to 65 ℃ and a total of 14.6g of lithium hydroxide monohydrate was then added in portions over a period of 2 hours at this temperature. After which it was stirred at 65 ℃ for 1 hour. The solution was then acidified with hydrochloric acid to pH 4. 500ml of ethanol were added to this solution over a period of 75 minutes at a temperature of 65-75 ℃. Upon completion of the addition of ethanol, crystals of the lithium complex spontaneously formed. After the addition of ethanol was completed, it was refluxed for 2 hours, then cooled to room temperature, crystals were filtered off, washed with 2X 20ml of 80% and 2X 20ml of 90% ethanol, and finally dried at 50 ℃.

Yield: 51.6g 93.67mmol (including water content) 81.5% of theory

H-NMR(D₂O): multiple peaks between 3.0 and 3.9ppm, N-CH₂-CH₂-N(4×)，N-CH₂-COOH (3 ×), N-CH (1 ×), CH-OH (1 ×), and CH₂-OH(2×)

IR(KBr，cm^-1)：3440，3360，3300，1675，1650，1590，1400

FAB-MS (matrix NBA-glycerol-DMSO): 451(M + H), 45(M + Li), 473(M + Na)

FAB-MS (matrix Magic pellet): 451(M + H), 457(M +7)

Water content: 9.45%, ethanol content: 0.0 percent

Elemental analysis of the mixture: lithium complex + 9.45% ═ 2.89mol of water

％	C	H	Cl	Li	N	Water (W)	EtOH
								Theoretical value	39.25	7.1	6.44	2.52	10.17	9.45	0
Measured value	38.82	6.86	6.83	2.64	10.17	9.45	0
								Difference in	-0.43	-0.24	0.39	0.12	0	0	0

Example 2

Preparation of gadolinium complex of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-tricarboxymethyl-1, 4, 7, 10-tetraazacyclododecane (GADOBUTROL)

51.6g (93.67mmol, containing 9.45% of water) of crystalline lithium complex of N- (1-hydroxymethyl-2, 3-dihydroxypropyl) -1, 4, 7-tricarboxymethyl-1, 4, 7, 10-tetraazacyclododecane (example 1) are dissolved in 51g of water completely freed of salt and the pH of the solution is then adjusted to 3.5 with concentrated hydrochloric acid. 16.9g of Gd was added to this solution₂O₃And the suspension was stirred at 90 ℃ for 1 hour. The suspension turned into a solution. The pH value of the solutionOptionally adjusted to 7 with solid lithium hydroxide monohydrate. The solution was slowly mixed with 960ml of ethanol at a temperature of about 78 c over a period of 2 hours to form a suspension. After the completion of the ethanol addition, the suspension was heated to reflux for 5 hours. The suspension is subsequently cooled to room temperature, the crystals are filtered off, washed with 100ml of ethanol and then dried at 50 ℃.

Yield: theoretical value of 85.73% in 51.02g 80.3mmol (including water content)

Drying loss: 1.06%, water content: 4.74 percent

Elemental analysis of GADOBUTROL (containing 1.7mol water 4.82% and 0.53mol LiCl):

％	C	H	N	Cl	Li	Gd	water (W)	EtOH
									Theoretical value	32.87	5.27	8.52	2.86	0.56	23.91	4.82	0
Measured value	32.96	5.25	8.49	2.91	0.53	23.85	4.74	0
									Difference in	0.09	-0.02	-0.03	0.05	-0.03	-0.06	-0.08	0

Recrystallization for complete desalination

51.02g GADOBUTROL (crude) 80.3mmol (including water) was dissolved in 47ml of water at about 75 ℃ and then 470ml of ethanol was slowly added to the solution over a period of 1 hour to form a suspension. After the addition of ethanol was complete, the suspension was heated under reflux for 2 hours, then cooled to 20 ℃ and stirred at this temperature for 1 hour, crystallized by suction filtration, washed with 66ml of ethanol and finally dried at 50 ℃.

Yield: 47.08 g-74.84 mmol (including water content) 93.2% of theory

Water content: 3.92 percent and the ethanol content is 0.16 percent

Elemental analysis of GADOBUTROL (containing 3.86% water 1.35mol, 0.15% ethanol 0.02mol and LiCl 0 mol):

％	C	H	N	Cl	Li	Gd	water (W)	EtOH
									Theoretical value	34.4	5.4	8.89	0	0	24.96	3.86	0.15
Measured value	34.48	5.01	8.76	0	＜0.01	24.96	3.92	0.16
									Difference in	0.08	-0.39	-0.13	0	＜0.01	0.09	0.06	0.01

Claims (5)

1. A compound of the general formula I:

wherein:

3X together represent n lithium ions and m hydrogen atoms, and n and m are each a number from 0 to 3,

and the sum of n and m is 3,

y represents chlorine or bromine.

2. Compounds of the general formula I according to claim 1, wherein n and m are each a number from 0.8 to 2.2.

3. Process for the preparation of compounds of the general formula I according to claim 1, characterized in that N- (6-hydroxy-2, 2-dimethyl-1, 3-dioxepan-5-yl) -1, 4, 7, 10-tetraazacyclododecane or its complexes with lithium chloride or bromide are reacted in a polar solvent with chloroacetic acid or bromoacetic acid and lithium hydroxide at a temperature of 40 to 150 ℃ and a pH of 8 to 14.

4. Use of a compound of formula I according to claim 1 for the preparation of gadobutrol of formula II:

5. a compound of formula I according to claim 1, wherein Y is chlorine, one X represents a lithium ion and the remaining two X represent a hydrogen atom.