SK281285B6 - Process for producing metal complexes of n-beta- -hydroxyalkyltri-n-carboxyalkyl-1,4,7,10- -tetraazacyclododecanenic and n-beta-hydroxyalkyltri-n- -carboxyalkyl-1,4,8,11-tetraazacyclotetradodecanenic derivatives - Google Patents

Abstract

A novel process is described for the preparation of metal complexes of N- beta -hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclo-dodecane and N- beta -hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraaza-cyclotetradecane derivatives.

Description

Technical field

The invention relates to a process for the preparation of the metal complexes of the N-B-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-B-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives described in the claims.

BACKGROUND OF THE INVENTION

Production of metal complexes of NB-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and NB-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives, which are important as diagnostic imaging agents (DE OS 36 25 417), in particular NMR diagnostic agents, has been tested in various ways, without yet finding a satisfactory route for their synthesis, particularly in the production of these compounds in the operational range.

DE 36 25 417 A1 describes a process for the preparation of metal complexes of N-substituted tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane derivatives to which three N-ethoxycarbonylmethyl-1,4,7 are converted, 10-tetraazacyclododecane derivatives which carry a substituent on the fourth nitrogen atom after cleavage of the carboxy protecting groups still present in the metal complex. The cyclic starting material required for this process is obtained by targeted ring synthesis. Two reactants are used which are cyclized by methods known in the literature (e.g. B. Richman, Org. Synthesis 58, 86 (1978) or J. Atkins, Amer. Chem. Soc. 96, 2268 (1974)). One of the two reactants contains a protected nitrogen atom and carries two cleavable groups at the end of the chain (e.g., bromine, mesyloxy, tosyloxy, triftal or alkoxycarbonyl) which are nucleophilically displaced by the terminal nitrogen atoms of the other reactant, which is protected triazazine compound. than the first reactant.

The chemical reactions of the protecting groups used in the process described in DE 36 25 417 A1 still lead to additional reaction steps in which the protecting groups must be removed again. In addition, large amounts of salts are eliminated during the cleavage, which need to be discarded. Therefore, it is desirable to avoid protecting groups directly in the process to be used within the operating range.

Tweedle et al. discloses in European patent application no. 292 689 A1, as in Verôffentlichung Inorg. Chem. 30, 1265-1269 (1991) that starting from an unsubstituted 1,4,7,10-tetraazacyclododecane macrocyclic compound, the N-formyl compound can be obtained via the tricyclic intermediate. The compound carrying three more unprotected nitrogen atoms can at this time be trialkylated with a haloacetic acid ester derivative, deformylated and converted to a tetrasubstituted tetraazamacrocycle. After cleavage of the carboxy-protecting groups, a tetrasubstituted complexing agent is obtained which can be reacted to the complex. Tweedlom et al. The described process for the synthesis of metal complexes of N-substituted tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane derivatives not only has the disadvantage of an unsatisfactorily high number of steps, but also for high cost of purification of intermediates as well as high expense for large the amount of ion exchanger required to operate within the operating range. Furthermore, the reaction of tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane (DO3A, compound (2) in

Inorg. Chem. 30, no. 6, 1267 (1991) with primary epoxides, but the yields in the reaction with the secondary epoxides are clearly poor and difficult to use in the operating range.

Therefore, there remains a need for a process for the preparation of metal complexes of NB-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and NB-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives which as far as possible, they do not limit the choice of electrophilic substances required in the reaction method and which are primarily intended to react with larger quantities of substances.

This object is solved by the present invention.

SUMMARY OF THE INVENTION

It has been found that the production of metal complexes of N-B-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-B-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives of general formula (I)

in which

R ¹ is -CH ₂ -COOY,

Y represents a hydrogen atom, the metal ion equivalent of the element having the order number 21 to 32, 37 to 39, 42 to 51 or 57 to 83, provided that at least two Y substituents are metal equivalents, n is 2 or 3,

R ² is a group of formula

OH

I CH-CH-R ⁵

I

R ⁴ where

R ⁴ and R ⁵ are each independently hydrogen, optionally 1 to 10 oxygen atoms, phenylene, phenyleneoxy or phenylenedioxy interrupted C 1 -C 20 alkyl radical optionally substituted by 1 to 3 C 1 -C 6 alkyl groups , 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 alkoxy of 1 to 7 carbon atoms or aralkoxy, 1 or 2 of the formula CO ₂ R ⁶ , wherein:

R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms or an aralkyl group having 1 to 4 carbon atoms in the alkyl moiety and having 6 to 10 carbon atoms in the aryl moiety, and / or 1 or 2 optionally chlorine or bromine, nitro or alkoxy of 1 to 6 carbon atoms substituted by phenoxy or phenyl groups, and salts thereof with inorganic and / or organic bases, amino acids or amino acid amides,

Consists of the preparation of a compound of the formula (II) obtained from 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane

of n (Π), in which n is 2 or 3, is reacted with an epoxide of formula (III)

Αν kde

R ⁴ and R ⁵ have the meanings indicated, wherein optionally present hydroxy or carboxy groups are optionally protected to the intermediate of formula (IV)

in which

R ² is as defined, the optionally present hydroxy or carboxy groups are optionally protected, the compound is hydrolyzed by addition of an inorganic base or acid to the intermediate of formula (V)

in which

R ² and n are as defined above and this compound is reacted in the presence of a base with a compound of formula (VI)

X-CH ₂ -COOZ (VI) wherein

X is a leaving group and

Z represents a hydrogen atom, a carboxy-protecting group or a metal cation, optionally after protecting the hydroxy or carboxy groups optionally present in the compound of formula (V) in a polar solvent at a temperature of -10 to 170 ° C for 1 to 100 hours, optionally protecting groups of the carboxyl and hydroxy groups are cleaved off and the complexing compound of formula (VII) thus obtained

in which

R ^{2 and} n are as defined, is reacted with the metal oxide or metal salt of an element of atomic numbers 21-32, 37-39, 42-51 or 57-83, and optionally, present are hydrogen substituted in a cations of inorganic and / or organic bases, amino acids or amino acid amides.

The process of the present invention exhibits these surprising effects;

1. The desired metal complex of formula (I) is obtained by a "single vessel reaction" under conditions favorable to operation in a higher yield than in the prior art method.

2. Intermediates may be obtained in such a surprisingly high purity that their isolation and purification may be omitted.

3. In contrast to the method disclosed by Tweedle et al., The reaction proceeds even with secondary epoxides in good yield.

4. Compared with the prior art, the method of the invention comprises a smaller number of steps.

5. The use of protecting groups is possible for the process according to the invention, but is not necessary.

Preferred is a process which comprises reacting a compound of formula (I)

<0, in which

R ¹ is -CH ₂ -COOY,

Y is the metal ion equivalent of element number 21 to 32, 37 to 39, 42 to 51 or 57 to 83, with the proviso that at least two Y substituents are metal equivalents, n is 2,

R ² is a group of formula

OH

I

CH-CH-R ⁵

IH ⁴ where ^!

R ⁴ and R ³ are each independently hydrogen, optionally 1 to 5 oxygen atoms, phenylene, phenyleneoxy or phenylenedioxy interrupted C 1 -C 20 alkyl radical optionally substituted by 1 to 3 C 1 -C 6 alkyl groups , 1 to 3 trifluoromethyl groups, 1 to 5 hydroxy groups, 1 to 3 alkoxy groups having 1 to 7 carbon atoms or 1 or 2 residues of the formula CO ₂ R ⁶ and / or optionally substituted by 1 or 2 nitro or alkoxy groups having 1 to 6 carbon atoms substituted phenoxy or phenyl groups, wherein

R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a benzyl group.

The process is particularly advantageous for the production of 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecane metal complexes and 10- (2-hydroxypropyl) metal complexes 1 -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane.

The process is particularly advantageous for the production of gadolinium and dysprozite complexes of 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane and gadolinium and dysprozite complexes 10- (2-hydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tatraazacyklododekánu.

Preferred radicals R ⁴ and R ⁵ are hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1- (hydroxymethyl) ethyl, propyl, isopropyl, isopropenyl, 2-hydroxypropyl, 3- hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutyl, isobutenyl, 2-hydroxybutyl, 3-hydroxybutyl, 4I ii

I

-hydroxybutyl, 2-hydroxy-2-methylbutyl, 3-hydroxy-2-methylbutyl, 4-hydroxy-2-methylbutyl, 2-hydroxyisobutyl, 3-hydroxy isobutyl, 2,3,4-trihydroxybutyl, 1,2,4- trihydroxybutyl, pentyl, cyclopentyl, 2-methoxyethyl, hexyl, decyl, tetradecyl, trietylénglykolmetyléterová, tetraetylénglykolmetyléterová a methoxybenzyl group and the -CH-O-CuHjj-OH, -CH ₂ OC ₆ H ₄ -O- (CH ₂ CH ₂ O) ₂ -CH ₃ -, -CH ₂ -O-C ₆ H ₄ -O- (CH ₂ CH ₂ O) ₃ -C ₅ H, _r , -CH ₂ -OC ₆ H ₄ -OC ₄ H ₈ -OH-, - (CH ₂ CH ₂ O) ₅ -CH ₃ -, -C ₅ H ₈ -COOH-,

-CgHu-OH,

-CH ₂ -OC ₆ H ₄ -OC ₆ H ₁₂ -COOH-, -CH ₂ -OC ₆ H ₄ -OC ₄ H ₈ -O-CH ₂ -CHOH-CH ₂ OH-, - (CH ₃ CH ₃ O 3) -CH ₃ , -.

-CH ₂ -OC ₁₀ H ₂₀ -COOH-, -CH ₂ -OC ₆ H ₄ -C 1 -,

-ch ₂ -oc ₆ h ₄ -no ₂ -, -ch ₂ -oc ₆ h ₃ -ci ₂ -, -CH ₂ -OC ₆ H ₄ -O-CH ₂ -COOH- and -CH ₃ -OC 2 -QH ,,.

Alkoxy substituents in R ⁴ and R ⁵ are straight or branched chain radicals having 1 to 6 carbon atoms or 1 to 7 carbon atoms, such as, for example, methoxy, ethoxy, propoxy and isopropoxy.

Suitable alkyl groups R ⁶ having 1 to 6 carbon atoms are straight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. Methyl, ethyl and tert-butyl are particularly preferred.

Preferred aryl groups and aralkyl groups R ⁶ are phenyl, naphthyl and benzyl.

Particularly preferred radicals R ⁶ are hydrogen, methyl and benzyl.

Tetraazatricyclotridecanes or tetraazatricyclopentadecanes of formula (II) used as starting materials are compounds available by methods known in the literature when 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane is reacted with dimethylformamide dimethyl acetal (U.S. Pat. Nos. 4,085,106 and 4,130,715). In the process of the invention, the advantages relate to the reaction steps described below.

Reaction conditions for process steps

1. (II) + (III) - (IV) - (V)

The reaction of the tricyclic intermediates of formula (II) with the epoxide of formula (III) is carried out with or without a solvent at a temperature of from 0 to 220 ° C, preferably at a temperature between room temperature and 210 ° C, for 1 to 48 hours. at a time of from 5 to 12 hours, optionally under a pressure of up to 10 MPa.

After cooling to -20 ° C to 80 ° C, preferably 0 to 30 ° C, the reaction mixture containing the compound of formula (IV) is contacted with a mixture of water and an organic solvent and stirred for 30 minutes to 12 hours, preferably 30 minutes to 3 hours, at a temperature from -20 ° C to room temperature, preferably from 0 ° C to room temperature.

By adding an inorganic base or acid at a temperature of from 0 to 150 ° C, preferably from room temperature to 120 ° C, over a period of from 1 to 72 hours, preferably from 6 to 24 hours, the reaction is carried out to obtain the intermediate of formula (V). optionally accompanied by deprotection in a manner known per se. This intermediate can also be isolated, if desired, as a salt, preferably as a hydrochloride.

Particularly suitable solvents for the reaction of compounds of formula (II) with compounds of formula (III) are aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexane or diethyl ether. Solvents used in admixture with water may be, for example, methanol, ethanol, isopropanol, tetrahydrofuran or dioxane.

Suitable bases or acids are, for example, alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates or mineral acids such as hydrochloric acid, sulfuric acid or methanesulfonic acid.

2. (A) + (VI) -> (VII)

The bases to be added as an acid acceptor in the further reaction of the intermediate of formula (V) with a compound of formula (VI) may be tertiary amines (e.g. triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] ] non-5-ene (DBN), 1,5-diazabicyclo [5.4.0] -undec-5-ene (DBU), alkali metal or alkaline earth carbonates, alkali metal or alkaline earth bicarbonates or alkali metal or alkaline earth hydroxides (for example, lithium, sodium, magnesium, calcium, barium or potassium carbonate, hydroxide or bicarbonate).

The reaction is carried out in a polar solvent such as water, acetonitrile, dimethylformamide, dimethylsulfoxide, phosphoric acid hexamethylamide or tetrahydrofuran, as well as in alcohols with a chain length of up to 8 carbon atoms such as methanol, ethanol, propanol, isopropanol, n-butanol , isobutanol or tert-butanol. The reaction is carried out at temperatures of from -10 to 170 ° C, preferably from 0 to 120 ° C, and particularly preferably from 40 to 100 ° C, for 30 minutes to 48 hours, preferably for 3 to 24 hours.

Optionally, the introduction or cleavage of the carboxy or hydroxy protecting groups is carried out by methods known in the literature.

Suitable acid-protecting groups are alkyl, aryl and aralkyl groups, for example methyl, ethyl, propyl, n-butyl, tert-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl or bis- (p-nitrophenyl) methyl, as well as trialkylsilyl groups.

The cleavage of the protecting groups is carried out in a manner known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the ester with an alkali compound in an aqueous-alcoholic solution at 0 to 50 ° C, acidic saponification with mineral acids or, for example, tert-butyl esters with trifluoroacetic acid. As metal cations Z, metal cations of elements selected from alkali and alkaline earth metals are possible.

Suitable hydroxyl protecting groups are, for example, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-tert-butylsilyl and diphenyl-tert-butylsilyl.

Hydroxy groups may also be presented, for example, as

THP-ether, α-alkoxyethyl ether, MEM-ether or as esters with aromatic or aliphatic carboxylic acids, for example with acetic acid or benzoic acid. In the case of polyols, the hydroxy groups can also be protected in the form of ketals, for example with acetone, acetylaldehyde, cyclohexanone or benzylaldehyde.

SK 281285 Β6

Hydroxy protecting groups can be released according to methods known to those skilled in the literature, for example, by hydrogenolysis, reductive cleavage with lithium and ammonia, treatment of ethers and ketals with acid, or treatment of esters with an alkaline substance (see, for example, TW Greene, "Protective Groups in Organic Synthesis", John) Wiley and Sons (1981)).

The intermediate complexes of the formula (VII) obtained can be advantageously purified by ion exchange treatment. Particularly suitable for this purpose are cation exchangers (VH ⁴ form) which are first washed with water and then eluted with an aqueous ammonia solution to give the desired compound. IR 120 (H ⁴ ) as well as AMB 252c (H ⁴ ) and Reillex ® have been found to be particularly preferred ion exchangers. When Reillex ^R is used, the complexing agent elutes with water or aqueous alcohols.

3. (VII) - (I)

The production of metal complexes of formula (I) is carried out in a manner known per se by reacting the complexing compound of formula (VII) with a metal oxide or metal salt of the element number 21 to 32, 37 to 39, 42 to 51 or 57 to 83, preferably in water or an aqueous solution of a lower alcohol (e.g. methanol, ethanol or isopropanol) at temperatures from 20 to 110 ° C, preferably from 80 to 100 ° C. The addition of 0.1 to 4 equivalents, preferably 0.5 to 2 equivalents, of an inorganic or organic acid, preferably acetic acid, is found to be particularly favorable.

The metal complex solution thus obtained can advantageously be purified by ion exchange cascade or batch treatment consisting of an acid cation exchanger (H ⁴ form) and a basic anion exchanger (OH 'form), preferably IR 120 (H ⁴ ) or AMB 252C / IRA 67.

The final purification is preferably performed by crystallization from a lower alcohol or an alcohol-water mixture. The alcohols used are methanol and isopropanol, preferably ethanol.

The metal salts used may be, for example, nitrate, acetate, carbonate, chloride or sulfate. The metal contained in the metal oxide or metal salt used may be an element having the order numbers 21 to 32, 37 to 39, 42 to 51 or 57 to 83.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Process for preparing gadolinium complex of 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

a) To 20 kg (116.10 mol) of cyclene (= 1,4,7,10-tetraazacyclododecane) in 140 liters of toluene was added 20 liters (150.55 mol) of dimethylformamide dimethyl acetal under nitrogen. The reaction mixture is slowly heated to high temperature and an azeotrope consisting of methanol, dimethylamine and toluene is distilled off. Finally, the solvent is distilled off completely by applying a vacuum. The remaining oil was allowed to cool to 50 ° C and then 18.7 kg (about 95%) (123.22 mol) 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] was added dropwise under a nitrogen atmosphere. octane. The whole is then stirred at 120 ° C for 24 hours. The reaction mixture was cooled to room temperature and a mixture of 100 liters of water and 150 liters of methanol was added dropwise. Stir for 1 hour at 50 ° C and then add 13.93 kg (348.3 mol) of sodium hydroxide dropwise. Finally, the reaction mixture is refluxed for 8 hours.

The solution is then evaporated to dryness as soon as possible, 200 liters of water are added once more and approximately 100 liters of water are distilled off again. Once again, 100 liters of water are added and this solution is extracted once with 200 liters of n-butanol and finally with 50 liters of n-butanol. The combined butanol phases are evaporated to dryness under reduced pressure and the residue is taken up in 300 l of water. Extraction is then carried out twice with 50 liters of ethyl acetate each time. The aqueous phase is separated and evaporated to a volume of approximately 200 liters.

b) Dissolve 43.84 kg (464.4 mol) of chloroacetic acid in 150 liters of water and adjust the pH to 7 with 50% aqueous sodium hydroxide solution. To this solution is added an aqueous phase evaporated to a volume of 200 liters and heated to 80 ° C. The pH is adjusted to 9.5-10 by the addition of 50% aqueous sodium hydroxide solution. After 10 hours an additional 10.96 kg (116.1 mol) of chloroacetic acid (previously neutralized in 35 liters of water by addition of 50% aqueous sodium hydroxide solution) is added. The reaction mixture was stirred at 80 ° C for 12 hours and then the pH was adjusted to 9.5-10. Cool to room temperature and adjust the pH to 0.8 by adding concentrated hydrochloric acid. The reaction mixture was then stirred at 60 ° C for 2 hours. Evaporate the solution to dryness as much as possible. The residue is contacted twice with a mixture of 200 liters of methanol and 200 liters of ethanol and then evaporated to dryness. The residue was then stirred at 50 ° C for 1 hour with 400 L of methanol. The precipitated sodium chloride is filtered off from the reaction mixture, then washed twice with 100 liters of methanol each time and the combined filtrates are evaporated to dryness under reduced pressure. The residue is dissolved in 200 liters of water and applied to an ion exchange column filled with AMB 252c. The column was washed with plenty of water and the compound was eluted with a 10% aqueous ammonia solution. The fractions containing the product were evaporated under reduced pressure as much as possible to dryness.

c) Dissolve the residue in 200 liters of water and add 16.31 kg (45 mol) of gadolinium oxide. The reaction mixture was refluxed for 3 hours. Finally, two liters of acetic acid are added and the whole is further refluxed for 2 hours. Then 5 kg of activated carbon are added and the reaction mixture is stirred at 90 ° C for 1 hour. The solution is filtered and the filtrate is passed several times through a cascade of ion exchange columns (containing IRA 67 (OH form), AMB 252c (H ⁴ form)), as checked by high performance liquid chromatography. The eluate is evaporated to a volume of 300 liters and slowly stirred with 2 liters of IR 120 acid ion exchange resin (H ⁴ form) as well as IRA 67 basic ion exchange resin (OH form) for 3 hours. The ion exchanger is filtered off and washed twice with 10 liters of water each. To the filtrate was added 5 kg of activated carbon and stirred at 80 ° C for 2 hours. The solution was filtered and the filtrate was evaporated under reduced pressure. The residue is recrystallized from approximately 400 liters of 95% aqueous ethanol. The precipitate is filtered off with suction, washed twice with 80 liters of pure ethanol each time and dried in an oven at 70 DEG C. for 48 hours. The yield of colorless crystalline powder is 47.6 kg (65.0% of theory) (corrected for water, based on cyclene).

Water content: 4.1%.

Elemental analysis (based on the anhydrous substance):

calculated: 35.75% C, 5.17% H, 9.27% N, 26.00% Gd, found: 35.92% C, 5.24% H, 9.20% N, 25.83% Gd.

Example 2

Process for the preparation of a dysproxy complex of 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

The corresponding dysprozite complex can be produced in an analogous manner if 16.78 kg (45 mol) of dysprozic oxide is reacted appropriately instead of gadolinium oxide.

Yield: 46.36 kg (62.7% of theory) (corrected for water based on cyclene).

Water content: 3.9%.

Elemental analysis (based on anhydrous material): calculated: 35.44% C, 5.12% H, 9.19% N, 26.64% Dy, found: 35.35% C, 5.21% H, 9 % N, 26.57% Dy.

Example 3

Process for preparing gadolinium complex of 10- (2-hydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

a) To 20 kg (116.10 mol) of cyclene (= 1,4,7,10-tetraazacyclododecane) in 140 liters of toluene was added 20 liters (150.55 mol) of dimethylformamide dimethyl acetal under nitrogen. The reaction mixture is slowly warmed to high temperature and the azeotrope consisting of methanol, dimethylamine and toluene is distilled off. Finally, the solvent is distilled off completely by applying a vacuum. The remaining oil was allowed to cool to 50 ° C and then 10.11 kg (174.15 mol) of propylene oxide were added dropwise under a nitrogen atmosphere. Then the reaction mixture is refluxed for 24 hours and finally propylene oxide is distilled off under reduced pressure. The reaction mixture was cooled to room temperature and a mixture of 100 liters of water and 150 liters of methanol was added dropwise. Stir for 1 hour at 50 ° C and then add 13.93 kg (348.3 mol) of sodium hydroxide dropwise. Finally, the reaction mixture is refluxed for 8 hours. The solution is then evaporated to dryness as soon as possible, 200 liters of water are added once more and approximately 100 liters of water are distilled off again. 100 L of water are added again and this solution is extracted once with 200 L of n-butanol and finally with 50 L of n-butanol. The combined butanol phases are evaporated to dryness under reduced pressure and the residue is taken up in 300 liters of water and then extracted twice with 50 liters of ethyl acetate each time. The aqueous phase is separated and evaporated to a volume of approximately 200 liters.

(b) 43.84 kg (464.4 mol) of chloroacetic acid are dissolved in 150 liters of water and the pH is adjusted to 7 by addition of 50% aqueous sodium hydroxide solution. To the resulting solution was added the aqueous phase evaporated to a volume of 200 liters and heated to 80 ° C. The pH is adjusted to 9.5-10 by the addition of 50% aqueous sodium hydroxide solution. After 10 hours an additional 10.96 kg (116.1 mol) of chloroacetic acid (previously neutralized in 35 liters of water by addition of 50% aqueous sodium hydroxide solution) is added. The reaction mixture was stirred at 80 ° C for 12 hours and then the pH was adjusted to 9.5-10. Cool to room temperature and adjust the pH to 0.8 by adding concentrated hydrochloric acid. Evaporate the solution to dryness as much as possible. The residue is contacted twice with a mixture of 200 liters of methanol and 200 liters of ethanol and then evaporated to dryness. The residue was then stirred at 50 ° C for 1 hour with 400 L of methanol. The precipitated sodium chloride is filtered off from the reaction mixture, then washed twice with 100 liters of methanol each time and the combined filtrates are evaporated to dryness under reduced pressure. The residue is dissolved in 200 liters of water and applied to an ion exchange column filled with AMB 252c. This was washed with enough water and the compound was eluted with a 10% aqueous ammonia solution. Product containing fractions are evaporated to dryness under reduced pressure as much as possible.

c) Dissolve the residue in 200 liters of water and add 17.62 kg (48.6 mol) of gadolinium oxide. The reaction mixture was refluxed for 3 hours. Finally, 2 liters of acetic acid are added and the whole is further refluxed for 2 hours. Then 5 kg of activated carbon are added and the reaction mixture is stirred at 90 ° C for 1 hour. The solution is filtered and the filtrate is passed several times through a cascade of ion exchange columns (containing IRA 67 (OH 'form), AMB 252c (H ⁺ form)) under high performance liquid chromatography control. The eluate was evaporated to a volume of 300 liters and slowly stirred with 2 liters of IR 120 acid ion exchange resin (H ⁺ form) as well as IRA 67 basic ion exchange resin (OH 'form) for 3 hours. The ion exchanger is filtered off and washed twice with 10 liters of water each. To the filtrate was added 5 kg of charcoal and stirred at 80 ° C for 2 hours. The solution was filtered and the filtrate was evaporated under reduced pressure. The residue is recrystallized from approximately 300 liters of ethanol. The precipitate is filtered off with suction, washed once with 50 liters of pure ethanol and dried in an oven at 70 DEG C. for 48 hours. The yield of colorless crystalline powder was 45.22 kg (i.e., 67.2% of theory) (corrected for water, based on cyclene).

Water content: 3.5%.

Elemental analysis (based on anhydrous material): Calculated: C 36.55, H 5.23, N 10.03, Gd 28.15, Found: C 36.68, H 5.31, 9 % N, 28.03% Gd.

Example 4

Process for the preparation of dysprozic complex of 10- (2-hydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In an analogous manner to Example 3 (c), the corresponding dysprozite complex can be prepared by reacting 18.13 kg (48.6 mol) of dysprozic oxide instead of gadolinium oxide.

The yield corresponds to 47.14 kg (i.e. 65.3% of theory) (corrected for water, based on cyclene).

Water content: 4.1%.

Elemental analysis (based on anhydrous material): Calculated: C, 36.20; H, 5.18; N, 9.94; Dy, 28.82. Found: C, 36.32; H, 5.27; N, 87.69% Dy.

Example 5

Process for preparing gadolinium complex of 10- (2-hydroxy-3-methoxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, 2,3-epoxypropyl methyl ether can be reacted in place of propylene oxide as described in Example 3. Thus, for example, from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane, 216.7 g of the title compound are obtained. title as a colorless powder. (Crystallization from aqueous acetone).

Yield: 61%.

Water content: 3.8%.

Elemental analysis (based on the anhydrous substance):

calculated: 36.72% C, 5.72% H, 9.52% N, 26.71% Gd, found: 36.51% C, 5.83% H, 9.39% N, 21.57% Gd.

SK 281285 Β6

Example 6

Process for preparing gadolinium complex of 10- (2-hydroxy-3-benzyloxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, 2,3-epoxypropylbenzyl ether was reacted in place of propylene oxide as described in Example 3. Use 1.1 equivalents of epoxide based on 1,4,7,10-tetraazacyclododecane and heat the reaction mixture at 110 ° C for 110 ° C. 16 hours (instead of 24 hours as described in Example 3).

This gave 249.2 g of the title compound as a colorless powder from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane. (The compound is crystallized from isopropanol).

Yield: 62%. Water content: 4.2%.

Elemental analysis (based on anhydrous substance): calculated: 43.36% C, 5.31% H, 8.43% N, 23.65% Gd, found: 43.21% C, 5.40% H, 8 N, 23.48% Gd.

Example 7

Process for preparing gadolinium complex of 10- (2,3,4-trihydroxybutyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, instead of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1] octane, 2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethylene oxide was reacted as described in Example 1 1.1 equivalents of epoxide, based on 1,4,7,10-tetraazacyclododecane, are used and the reaction mixture is heated at 110 ° C for 16 hours (instead of 24 hours as described in Example 1). Thus, from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane, 232.8 g of the title compound is obtained as a colorless powder. (The compound was crystallized from 90% aqueous ethanol). Yield: 64%.

Water content: 3.5%.

Elemental analysis (based on anhydrous material): Calculated: C 35.75, H 5.17, N 9.26, G 26%, Found: C 35.55, H 5.23 % N, 25.87% Gd.

Example 8

Process for preparing gadolinium complex of 10- (2-hydroxy-3-tert-butoxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, 2,3-epoxypropyl tert-butyl ester was reacted in place of propylene oxide as described in Example 3. 1.1 equivalents of epoxide, based on 1,4,7,10-tetraazacyclododecane, were used and the reaction mixture was heated to 110 ° C for 16 hours (instead of 24 hours as described in Example 3). This gave 225 g of the title compound as a colorless powder from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane. (The compound was crystallized from acetone / ethanol).

Yield: 59%. Water content: 4.0%.

Elemental analysis (based on anhydrous material): calculated: 39.99% C, 5.91% H, 8.88% N, 24.93% Gd, found: 39.81% C, 6.05% H, 8 % N, 24.82% Gd.

Example 9

Process for preparing gadolinium complex of 10- (2,6,7-trihydroxy-4-oxaheptyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, 2,2-dimethyl-4- (2 ', 3'-epoxy) propoxymethyl-1,3-dioxolane is reacted in place of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1] octane, such as as described in Example 1. 1.1 equivalents of epoxide, based on 1,4,7,10-tetraazacyclododecane, were used and the reaction mixture was heated at 110 ° C for 16 hours (instead of 24 hours as described in Example 1). This gave 242.2 g of the title compound as a colorless crystalline powder from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane. (The compound is crystallized from ethanol).

Yield: 62%.

Water content: 3.6%.

Elemental analysis (based on the anhydrous substance): calculated: 37.03% C, 5.44% H, 8.64% N, 24.24% Gd, found: 36.91% C, 5.58% H, 8 N, 49.13% Gd.

Example 10

Process for preparing gadolinium complex of 10- (2-hydroxy-3-isopropoxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododane

In a similar manner, 2,3-epoxypropyl isopropyl ether is reacted in place of propylene oxide as described in Example 3. Use 1.1 equivalents of epoxide based on 1,4,7,10-tetraazacyclododecane and heat the reaction mixture at 110 ° C for 110 ° C. 16 hours (instead of 24 hours as described in Example 3). There was thus obtained 232.5 g of the title compound as a colorless crystalline powder from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane. (The compound was crystallized from isopropanol). Yield: 63%. Water content: 3.1%.

Elemental analysis (based on anhydrous material): calculated: 38.95% C, 5.72% H, 9.08% N, 25.50% Gd, found: 38.85% C, 5.81% H, 8 N, 25.35% Gd.

Example 11

Process for preparing gadolinium complex of 10- (2-hydroxy-2-methylpropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, isobutylene oxide can be reacted in place of propylene oxide as described in Example 3. For example, from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane, 209.4 g of the title compound is obtained as a colorless powder. . (The compound was crystallized from aqueous acetone).

Yield: 60%. Water content: 4.0%.

Elemental analysis (based on anhydrous material): calculated: 37.75% C, 5.46% H, 9.78% N, 27.46% Gd, found: 37.61% C, 5.53% H, 9 % N, 27.38% Gd.

Example 12

Process for preparing gadolinium complex of 10- (2-hydroxy-3-phenoxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

In a similar manner, 2,3-epoxypropylphenylether is reacted in place of propylene oxide as described in Example 3. Use 1.1 equivalents of epoxide based on

1.4.7.10-tetraazacyclododecane and the reaction mixture is heated at 110 ° C for 16 hours (instead of 24 hours as described in Example 3). So from 100 g (0.58 mol)

1.4.7.10-tetraazacyclododecane gives 252.4 g of the title compound as a colorless crystalline powder. (The compound is crystallized from aqueous acetone.)

Yield: 64%.

Water content: 3.7%.

Elemental analysis (based on the anhydrous substance):

calculated: 43.49% C, 5.02% H, 8.45% N, 23.73% Gd, found: 43.31% C, 5.11% H, 8.38% N, 23.65 % Gd.

Claims (10)

PATENT CLAIMS A process for the preparation of metal complexes of N-B-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-B-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives of the general formula (I) in which: R ¹ is -CH ₂ -COOY, Y represents a hydrogen atom, the metal ion equivalent of the element having the order number 21 to 32, 37 to 39, 42 to 51 or 57 to 83, provided that at least two Y substituents are metal equivalents, n is 2 or 3, R ² is a group of formula OH CH-CH-R ⁵ I R ⁴ where R ⁴ and R ³ are each independently hydrogen, optionally 1 to 10 oxygen atoms, phenylene, phenyleneoxy or phenylenedioxy interrupted C 1 -C 20 alkyl radical, optionally substituted with 1 to 3 C 1 -C 6 alkyl groups , 1 to 3 trifluoromethyl groups, 1 to 7 hydroxy groups, 1 to 3 alkoxy groups having 1 to 7 carbon atoms or aralkoxy groups having 1 to 4 carbon atoms in the alkoxy moiety and 6 to 10 carbon atoms in the aryl moiety, 1 or 2 CO ₂ radicals R ⁶ and / or 1 or 2 optionally chlorine or bromine, nitro or C 1 -C 6 alkoxy substituted by phenoxy or phenyl, wherein: R ⁶ is H, alkyl of 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms or aralkyl group having 1 to 4 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in the aryl moiety, and the salts thereof with inorganic and / or organic bases, amino acids or amino acid amides, characterized in that a compound of formula (II) is obtained from 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane in which n represents No. 2 or 3, is reacted with an epoxide of formula (III) o / —X (III), R ⁴ R ⁵ in which R ⁴ and R ⁵ have the meanings indicated, wherein optionally present hydroxy or carboxy groups are optionally protected, to an intermediate of formula (IV) in which: R ² is as defined, the optionally present hydroxy groups and / or carboxy groups are optionally protected, the compound is hydrolyzed by addition of an inorganic base or acid to the intermediate of formula (V) wherein R ^{2 and} n are as defined, and this compound is reacted in the presence of an acid scavenger with a compound of formula (VI) X-CH-COOZ (VI), wherein X is a leaving group and Z represents a hydrogen atom, a carboxy protecting group or a metal cation, optionally after protecting the hydroxy or carboxy groups optionally present in the compound of formula (V), in a polar solvent at a temperature of -10 to 170 ° C for 1 to 100 hours, optionally protecting groups the carboxyl or hydroxy groups are cleaved off and the complexing compound of formula (VII) thus obtained is hooc- ^{COOH- N-} η (VI), UN N - ' _HOO c - / - _(CH ); in 2 n in which R ^{2 and} n are as defined, is reacted with the metal oxide or metal salt of an element of atomic numbers 21-32, 37-39, 42-51 or 57-83, and optionally, present are hydrogen by forming salts substituted in a cations of inorganic and / or organic bases, amino acids or amino acid amides. Process according to claim 1, characterized in that the reaction leading to the compound of the general formula (IV) is carried out at a temperature of from 20 to 210 ° C without a solvent or in an aprotic solvent. Process according to claim 1, characterized in that the reaction leading to the compound of the formula (V) is carried out at a temperature of from 20 to 120 ° C in aqueous alcohol with the addition of sodium or potassium hydroxide or hydrochloric acid. Process according to Claim 1, characterized in that chloroacetic acid is used as the compound of the general formula (VI) for the production of metal complexes of the formula (I). Process according to claim 1, characterized in that the reaction leading to the compound of the general formula (VII) is carried out without protection of hydroxy groups or Carboxy groups at a temperature of 40 to 100 ° C in water for 3 to 24 hours. Process according to Claim 1, characterized in that the corresponding starting materials are used for the production of metal complexes of the general formula (I) in which: R ¹ is -CH ₂ -COOY, Y is the metal ion equivalent of element number 21 to 32, 37 to 39, 42 to 51 or 57 to 83, provided that at least two Y substituents are metal equivalents, n is 2, R ² is a group of formula OH CH-CH-R ⁵ , IR ⁴ wherein R ⁴ and R ⁵ are each independently hydrogen, optionally 1 to 5 oxygen atoms, phenylene, phenyleneoxy or phenylenedioxy interrupted C 1 -C 20 alkyl radical optionally substituted by 1 to 3 C 1 -C 6 alkyl groups , 1 to 3 trifluoromethyl groups, 1 to 5 hydroxy groups, 1 to 3 alkoxy groups having 1 to 7 carbon atoms or 1 or 2 radicals of CO ₂ R ⁶ and / or optionally substituted by 1 or 2 nitro or alkoxy groups having 1 to 6 carbon atoms substituted phenoxy or phenyl groups, wherein R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a benzyl group. Process according to Claim 1, characterized in that the corresponding starting materials are used for the production of metal complexes of 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) -1, 4,7,10-tetraazacyclododecane. Process according to claim 1, characterized in that the corresponding starting materials are used for the production of metal complexes of 10- (2-hydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,1O tetraazacyclododecane. Process according to claim 1, characterized in that the corresponding starting materials are used for the preparation of gadolinium or dysprozite 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecane. Process according to claim 1, characterized in that the corresponding starting materials are used for the preparation of gadolinium or dysprozite 10- (2-hydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane.