SK124193A3 - Method of producing of metal complex n-beta-hydroxyalkyl- -tri-n-carboxyalkyl-1,4,7,10-tetra-azacyclododecanes and n-beta-hydroxyalkyldecanes derivatives - Google Patents

Abstract

Disclosed is a 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 of the general formula (I), which process can be characterised by preparing a compound of the general formula (II) out of said 1,4,7,10-tetraazacyclododecanene or 1,4,8,11- -tetraazacyclotetradodecanene, which compound is thereafter subjected to reaction with a corresponfing epoxide. Thus prepared compound is saponated and is subjected to reaction with oxide or salt of a corresponding metal.

Description

Technical field

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

BACKGROUND OF THE INVENTION

Production of metal complexes of Ν-β-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and Ν-β-hydroxyalkyltriN-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 finding a satisfactory route for their synthesis to date, 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 nitrogen substituent on the fourth 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 (for example, bromine, mesyloxy, tosyloxy, triftal or alkoxycarbonyl) which are nucleophilically displaced by the terminal nitrogen atoms of the other reactant, the protected triazazoline 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-1,4,7,10tetraazacyclododecane derivatives not only has the disadvantage of an unsatisfactorily high number of steps, but also of high cost of purification of intermediates as well as high expense for large amounts of an ion exchanger for operation within the operating range. Furthermore, although the reaction of tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane (DO3A, compound (2) in Inorg. Chem. 30, No. 6, 1267 (1991)) is possible with primary epoxides, the yields of the reaction are possible. with secondary epoxides are clearly poor and difficult to use in the operating range.

Therefore, there remains a task to develop a process for the production of komplex-β-hydroxyalkyltri-N-carboxyalkyl metal complexes3

1,4,7,10-tetraazacyclododecane and Ν-β-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives, which, as far as possible, do not limit the choice of electrophilic substances required in the reaction method and are primarily intended for reactions larger amounts 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 Ν-β-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and Ν-βhydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives of the general formula I

²ⁿ G) wherein

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, with the proviso that at least two Y substituents are metal equivalents, n is 2 or 3

OH

I

CH-CH-R ⁵

⁴ where

R ⁴ and R ⁵ are each independently hydrogen, optionally up 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, 1 or 2 radicals of the formula

CO ₂ R ⁶ , wherein

R® 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 C 1 -C 6 alkoxy substituted by phenoxy or phenyl, the optionally present hydroxy groups being optionally in protected form consisting of 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane compound of formula II obtained

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

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

in which

R ² is as defined above, (IV), wherein the optionally present hydroxy or carboxy groups are optionally protected, the compound is hydrolysed to an intermediate of the formula V

(V) in which

R ² and n have the meanings given above and this compound is reacted in the presence of a base with a compound of formula VI x-ch ₂ -cooz (vi) in which

X represents a leaving group and

Z represents a hydrogen atom, a carboxy-protecting group or a metal cation, optionally after protection of the hydroxy or carboxy group, in a polar solvent at a temperature of -10 to 170 ° C for 1 to 100 hours, optionally protecting groups and the thus-formed complexing agent VII

Ί

(VII) in which _n have the meanings given above, are reacted with a metal oxide or metal salt of the element numbering 21 to 32, 37 and optionally the inorganic and / or organic amino acid atoms present, or are present partially converted to esters or from 39 , 42 to 51 or 57 to 83 of hydrogen substitute the total acid groups or amides with base, amino acid or amide cations.

The process of the present invention exhibits the following surprising effects:

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

2) Intermediates can be obtained in such a surprisingly high purity that their isolation and purification can be dispensed with.

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 it is not necessary.

Preferred is a process characterized in that a compound of formula I is reacted

n

CO in which

R ¹ is -C 1 -COOY,

Y is the metal ion equivalent of an element having a sequence number of up 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

I

CH-CH-R ⁵

I

R ⁴ where

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 the formula CO ₂ R 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 metal complexes of 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecane and metal complexes of 10- (2-hydroxypropyl) - 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-tatraazacyclododecane.

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, 4-hydroxybutyl, 2-hydroxy-2-methylbutyl,

3-hydroxy-2-methylbutyl, 4-hydroxy-2-methylbutyl, 2-hydroxyisobutyl, 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl,

1,2,4-trihydroxybutyl, pentyl, cyclopentyl, 2-methoxy10 ethyl, hexyl, decyl, tetradecyl, triethylene glycol methyl ether, tetraethylene glycol methyl ether and methoxybenzyl groups as well as

-ch ₂ -oc ₁₁ h ₂₂ -oh-,

-ch ₂ -oc ₆ h ₄ -o- (ch ₂ ch ₂ o) ₂ ^-ch 3-

-ch ₂ -oc ₆ h ₄ -o- (ch ₂ ch ₂ o) ₃ -c ₅ h _1;

-CH ₂ -OC ₆ H ₄ OC ₄ H ₈ -OH,

- (ch ₂ ch ₂ o) ₅ -ch ₃ -, ^-C 9 ^H 18 ~ ^COOH- '

-CgHg-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 ₂ -oc ₁₀ h ₂₀ -cooh-,

-CH ₂ -OC ₆ H ₄ -ci-,

-h ₂ -oc ₆ h ₄ -no ₂ -,

-ch ₂ -oc ₆ h ₃ -ci ₂ -,

-CH ₂ -OC ₆ H _{4 -O-CH2} -COOH- and

-ch ₂ -oc ₆ h ₄ -c ₅ h ₁₁ .

Alkoxy substituents in R ⁴ and R ⁵ are straight or branched chain radicals containing 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 radical and a benzyl radical.

The 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. (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, preferably 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, with preferably 30 minutes to 3 hours, at a temperature from -20 ° C to room temperature, preferably at a temperature 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, for a period of from

Within 72 hours, preferably from 6 to 24 hours, the reaction to obtain the intermediate of formula V is carried out, 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.

As the solvents for the reaction of the compounds of the general formula

In particular, aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexane or diethyl ether are suitable with compounds of the formula III. The 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) (V) + (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, ety, Ν-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5). -en (DBN), 1,5-diazabicyclo [5.4.0] -undec-5-ene (DBU), alkali metal or alkaline earth carbonates, alkali metal hydrogencarbonates or alkali metal hydroxides or (for example, lithium carbonate, hydroxide or bicarbonate) , sodium, magnesium, calcium, barium or potassium).

alkaline earth alkaline earth

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 acetic acid or benzoic acid. In the case of polyols, the hydroxy groups may also be protected in the form of ketals, for example with acetone, acetylaldehyde, cyclohexanone or benzylaldehyde.

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, T. W. Greene,

Protective Groups in Organic Synthesis, John Wiley & Sons (1981)).

The intermediate compounds forming the complex of formula VII can be advantageously purified by treatment with an ion exchanger. Particularly suitable for this purpose are cation exchangers (VH ⁺ form) which are first washed with water and then eluted with an aqueous ammonia solution to give the desired compound. IR 120 (H ⁺ ) as well as AM3 252c (H ⁺ ) and Reillex ^R have been shown to be particularly preferred ion exchangers. When Reillex ^R is used, the complexing agent is eluted 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 agent of formula (VII) with a metal oxide or metal salt of an element of serial numbers 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 of 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 may advantageously be purified by treatment on an ion exchange cascade or in a batch consisting of an acid cation exchanger (H ⁺ form) and a basic anion exchanger (OH ^- form), preferably IR 120 (H ⁺ ) or AMB 252C / IRA 67th

The final purification is preferably performed by crystallization from a lower alcohol or a mixture of alcohol and water. 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 (carboxymethylene) -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 dimethylformamide under a nitrogen atmosphere. Reaction temperature and distilling off of dimethylamine and toluene, distilling off the solvent, temperature of 50 ° C and then liters (150.55 mol) of dimethylacetal are slowly heated to a high azeotrope consisting of methanol,

Finally, the total oil remaining is allowed to cool to 18 g (about 95%) (123.22 mol) 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane dropwise under a nitrogen atmosphere. 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) was added. The reaction mixture is stirred at 80 ° C for 12 hours and then the pH is adjusted to 9.5-5. Everything is cooled to room temperature and the pH is adjusted to 0.8 by addition of 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. Then the residue is stirred at 50 ° C for 1 hour with 400 liters 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 was 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 to dryness under reduced pressure as much as possible.

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 ⁺ form)), as checked by high performance liquid chromatography. The eluate was concentrated to a volume of 300 and slowly mixed with 2 l of acid ion exchanger IR 120 (H ⁺ form), as well as basic exchanger IRA 67 (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, instead of gadolinium oxide, 16.78 kg (45 mol) of dysprozic oxide is reacted accordingly.

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

Water content: 3.9%.

Elemental analysis (based on the anhydrous substance):

calculated: 35.44% C, 5.12% H, 9.19% N, 26.64% Dy, found: 35.35% C, 5.21% H, 9.11% N, 26.57% Dy.

Example 3

Process for preparing gadolinium complex 10- (2-hydroxypropyl) -1,4,7tris (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 dimethylamine and toluene are distilled off, the solvent is distilled off at 50 ° C and then 10.11 kg (174.15 mol) of azeotrope consisting of methanol,

Finally, by completely applying vacuum, the remaining oil is allowed to cool to dropwise under nitrogen atmosphere propylene oxide. 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. The aqueous phase was 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) was added. The reaction mixture is stirred at 80 ° C for 12 hours and then the pH is adjusted to 9.5-10. All is cooled to room temperature and the pH is adjusted to 0.8 by the addition of concentrated hydrochloric acid. The solution is

concentrated to dry such as it as much as possible. The residue sa twice shall to contact with a mixture 200 liters of methanol and 200 liters ethanol and then is evaporated to dryness. Then residue stir at at 50 'C during 1 hours with 400 liters 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 then filtered.

Evaporate to dryness under reduced pressure. The residue was dissolved in 200 liters of water and applied to an ion exchange column filled with AMB 252c. This was washed with enough water and then the compound was eluted with a 10% aqueous ammonia solution. The fractions containing the product were 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 with acetic acid and stirred for 2 hours. Then add hours. Finally, 2 liters of refluxing 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)), as checked by high performance liquid chromatography. The eluate was concentrated to a volume of 300 and slowly mixed with 2 l of acid ion exchanger IR 120 (H ⁺ form), as well as basic exchanger IRA 67 (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 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 the colorless crystalline powder is 45.22 kg (i.e. 67.2% of theory) (corrected for water, based on cyclene).

Water content: 3.5%.

Elemental analysis (based on the anhydrous substance):

calculated: 36.55% C, 5.23% H, 10.03% N, 28.15% Gd, found: 36.68% C, 5.31% H, 9.91% N, 28.03% Gd.

Example 4

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

In analogy to Example 3c), the corresponding dysprozite complex can be produced 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 the anhydrous substance):

calculated: 36.20% C, 5.18% H, 9.94% N, 28.82% Dy, found: 36.32% C, 5.27% H, 9.87% N, 28.69% 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 may 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 is obtained as a colorless powder. (Crystallization from aqueous acetone). Yield: 61%.

Water content: 3.8%.

Elemental analysis (based on anhydrous substance): calculated: 36.72% C, 5.72% H, 9.52% N, 26.71% Gd, found: 36.51% C, 5.83% H, 9 % N, 21.57% Gd.

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). There was thus obtained 1,4,7,10-tetraazacyclododecane from 100 g (0.58 mol)

249.2 g of the title compound as a colorless powder. (The compound is crystallized from isopropanol).

Yield: 62%.

Water content: 4.2%.

Elemental analysis (based on the anhydrous substance):

calculated: 43.36% C, 5.31% H, 8.43% N, 23.65% Gd, found: 43.21% C, 5.40% H, 8.32% 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, react with 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane 2- (2,2-dimethyl-1,3-dioxolane-422-yl) ethylene oxide as described in Example 1. 1 equivalent of epoxide based on 1,4,7,10-tetraazacyclododecane and the reaction mixture was 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 the anhydrous substance):

calculated: 35.75% C, 5.17% H, 9.26% N, 26.00% Gd, found: 35.55% C, 5.23% H, 9.14% 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

Similarly, 2,3-epoxypropyl t-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 a temperature of 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 the anhydrous substance):

calculated: 39.99% C, 5.91% H, 8.88% N, 24.93% Gd, found: 39.81% C, 6.05% H, 8.73% 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 [5.1.0] octane as described above. 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). There was thus obtained 1,4,7,10-tetraazacyclododecane from 100 g (0.58 mol)

242.2 g of the title compound as a colorless crystalline powder. (The compound is crystallized from ethanol). Yield: 62%.

Water content: 3.6%.

Elemental analysis (based on anhydrous substance):

calculated: 37.03% C, 5.44% H, 8.64% N, 24.24% Gd, found: 36.91% C, 5.58% H, 8.49% N, 24.13% Gd.

Example 10

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

In a similar manner, 2,3-epoxypropyl isopropyl 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 a period of time. 16 hours (instead of 24 hours as described in Example 3). There was thus obtained 1,4,7,10-tetraazacyclododecane from 100 g (0.58 mol)

232.5 g of the title compound as a colorless crystalline powder. (The compound is crystallized from isopropanol). Yield: 63%.

Water content: 3.1%.

Elemental analysis (based on anhydrous substance):

calculated: 38.95% C, 5.72% H, 9.08% N, 25.50% Gd, found: 38.85% C, 5.81% H, 8.93% 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 solid. powder. (The compound was crystallized from aqueous acetone).

Yield: 60%.

Water content: 4.0%.

Elemental analysis (based on the anhydrous substance):

calculated: 37.75% C, 5.46% H, 9.78% N, 27.46% Gd, found: 37.61% C, 5.53% H, 9.70% 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-epoxypropylphenyl 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 16 hours (instead of 24 hours as described in Example 3). Thus, from 100 g (0.58 mol) of 1,4,7,10-tetraazacyclododecane, 252.4 g of the title compound is obtained as a colorless crystalline powder. (The compound is crystallized from acetone.)

Yield: 64%.

Water content: 3.7%.

Elemental analysis (based on anhydrous material): calculated: 43.49% C, 5.02% H, 8.45% N, 23.73% Gd, found: 43.31% C, 5.11% H, 8 % N, 23.65% Gd.

water

W 12Μ - <13

Claims (10)

PATENT CLAIMS A process for the preparation of metal complexes of Ν-β-hydroxyalkyltri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and Ν-β-hydroxyalkyltri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives of the general formula I Ktoromν 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 or oxygen, or C 1 -C 10 phenyleneoxy interrupted alkyl radical, optionally with 1 phenylene, C 1 -C 20 phenylenedioxy substituted with 1 to 3 C 1-6 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 alkoxy C 1 to C 7 or aralkoxy having 1 to alkoxy and 6 to 10 or 2 C ₂ R radicals or chlorine or C 1 to C 6 alkoxy substituted by phenoxy or phenyl, in the aryl moiety, 1 and / or 1 or 2 of bromine, nitro 4 carbon atoms 6 carbon atoms 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; optionally in protected form, as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides, characterized in that the compound obtained from 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane is the compound obtained of formula II wherein n is 2 or 3, is reacted with an epoxide of formula IIIe (m), R ^R in which R ⁴ and R ⁵ have the meanings given above, wherein optionally present hydroxy or carboxy groups are optionally protected, to an intermediate of formula IV (IV), wherein: ABOUT R is as defined above, wherein optionally present hydroxy and / or carboxy groups are optionally protected, the compound is saponified to an intermediate of formula V (V) wherein: R ² and n have the meanings given above and this compound is reacted in the presence of an acid acceptor with a compound of formula VI x-ch ₂ -cooz (vi) in which. X is a leaving group and Z represents a hydrogen atom, a carboxy-protecting group or a metal cation, optionally after protection of 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; and the complexing compound of formula VII thus obtained HOOC 2 n y-COOH HOOC -R (VH) wherein R ² and n have the meanings given above, the metal or metal salt of the element up to 39, 42 to 51 or 57 to 83 hydrogen is substituted by acidic cations or amides by base, amino acid or amide cations. is reacted with an oxide of the order number 21 to 32, 37 and optionally the inorganic and / or organic amino acid atoms present or partially present are converted to esters, or Process according to claim 1, characterized in that the reaction leading to the compound of the 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 hydroxide or potassium hydroxide or hydrochloric acid. 4. The process of claim 1 wherein the compound of formula (VI) is chloroacetic acid. The process according to claim 1, wherein the reaction leading to the compound of formula VII is carried out without protection of the hydroxy or carboxy groups at a temperature of from 40 ° C to 100 ° C in water for 3 to 24 hours. A process according to claim 1, characterized in that the compound of formula I is reacted by (I). in which R ¹ is -CH ₂ -COOY, Y means the metal ion equivalent of a serial number element 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 I R ⁴ where 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 with 1 to 3 C 1 -C 6 alkyl groups carbon, 1 to 3 trifluoromethyl, 1 to 5 hydroxy, 1 to 3 alkoxy of 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 of 1 to 6 atoms carbon substituted by 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 10- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10 are used for the production of metal complexes -tetraazacyklododekán. Process according to claim 1, characterized in that 10- (2-hydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane is used for the production of metal complexes. The process according to claim 1, characterized in that it is used for the production of gadolinium or dysprozite 10- (1-hydroxymethyl-2,3 dihydroxypropyl) -1,4,7-tris (carboxymethyl) -1,4,7,10 -tetraazacyclo dodecane. Process according to claim 1, characterized in that 10- (2-hydroxymethyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane is used for the preparation of gadolinium or dysprozite complexes.