SK357392A3 - Process for preparing mono-n-substituted derivatives of tetraazacyclododecane and tetraazacyclotetradecane - Google Patents

Abstract

In this method, according to the invention, it is possible to produce by selective monofunctionalization mono-N-substituted tetraazamacrocycles of general formula (I). According to the invention tetraazatricyclotridecane, eventually tetraazatricyclopentanedecane of general formula (II) reacts with alpha, beta-unsaturated ester, amide or nitrile, or with epoxide, isothiocyanate, aziridine or bisepoxide, with or without solvent, under the temperature from 0 to 220 C, during 1 to 48 hours, eventually under the pressure up to 10 Mpa. Then the obtained reaction mixture after the cooling to the temperature -20 to 80 C is mixed with a mixture of water and organic solvent and is mixed during 0.5 to 12 hours, under the temperature from -20 C to the temperature of the room, followed by that obtained, eventually isolated, intermediates react to the final product of formula (I) and are separated.

Description

METHOD OF MANUFACTURING THE MONO-N-SUBSTITUTED IN THE 'TETRAAZACÍČETÍOUTKÁul Λ JfftM.ZAClU /) TETEAbSCÁAjvj

Technical field

The invention relates to a process for the production of mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives useful for the production of metal complexes for diagnostics and therapy.

BACKGROUND OF THE INVENTION

Mono-N-substituted tetraazamacrocycles of formula (I)

dl.

wherein n is 2 or 3 and

R represents a β-carboxyl or β-carboxylatealkyl group, a β-cyanoalkyl group, a β-carboxamidoalkyl group, a β-hydroxyalkyl group, an aminocarbonyl group, an aminothiocarbonyl group, a βsulfamoylalkyl group, or a second tetraazacyclododecanethane (tetraazacyclododecanethane) a chain wherein the carboxyl and hydroxyl groups are optionally present in protected form,

V183 / 93H-22.05.2001 are valuable precursors of tri-N-carboxyalkyl-substituted, preferably tri-N-carboxymethyl-substituted tetraazamacrocycles, which are present in the form of their complexes with metal ions with atomic numbers 21 to 29, 31, 32, 38, 39 , 42 to 44, 49 or 57 to 83 use as diagnostics and therapeutics (see EP application 255 471).

Because of their importance as key compounds for these complexes, especially as advantageous NMR diagnostics (Macrocyclic Chemistry Congress, Hamburg 1988), their production has been tested by all possible species and routes, without yet finding a satisfactory possibility of their synthesis.

Thus, for example, the statistical monoalkylation or monoacylation of unsubstituted tetraazamacrocycles has been described but is not too high due to the excessively large excesses of the relatively expensive starting amine used, in part due to the very expensive chromatographic separation of the product from the starting material. suitable at least for the production of larger amounts of substance (see Kaden, Helv. Chim. Acta, 69, 2081 (1986); Kimura, J. Chem. Soc. Chem. Commun. 1158 (1986); Kaden, Top. Curr. Chem. 121 157 (1984); EP Application Nos. 296,522 and 355,450).

If, in contrast to the statistical monosubstitution described above, a targeted monosubstitution is desired, then two variants are possible:

(a) the reaction of a tetraazamacrocycle containing three nitrogen protecting groups obtained by statistical trisubstitution; and

(b) reaction of a tetraazamacrocycle containing three nitrogen protecting groups obtained by targeted synthesis.

In the first variant, the protecting groups (e.g., tosylate or benzoate) at the three nitrogen atoms carried by the precursor are realized by statistical trisubstitution of the unsubstituted tetraazamacrocycle, so that the above-mentioned disadvantages of the statistical reaction, such as low yields and

V183 / 93H separation problems, especially in the production of larger amounts of substance (see, for example, Macrocyclic Chemistry Congress, Hamburg 1988). Following targeted monosubstitution to introduce the R substituent [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984); Kaden, Helv. Chim. Acta 66, 861 (1983); Basefield, Inorg. Chem. 25, 4663 (1986)], the protecting groups on the three nitrogen atoms must be removed, for example by using alkali metals in ammonia [Helv. Chim. Acta, 56, 2216 (1973); Helv. Chim. Acta 59: 1566 (1976); J. Org. Chem. 53, 3521 (1988)], lithium aluminum hydride [F. Wow, Liebigs Ann. Chem. (1977), 1344], Red-AI ® [E. H. Gold, J. Org. Chem. (1972), 37, 2208], Na-Hg [M. Kellog, J. Org. Chem. 1984, 49, 110], by electrolysis [M. Hesse, Helv. Chim. Acta 71 (1988), 7, 1708] or with hydrobromic acid / phenol / glacial acetic acid [N. G. Lukyanenko, Synthesis, 1988, 355]. These deprotection methods are generally associated with poor yields, limiting batch size with respect to the amount of reagents used (e.g., the Na-Hg method), and are particularly unsuitable for substituents carrying sensitive groups (e.g., hydroxyalkyl).

If variant b) is followed, that is to say, to prepare a precursor of a tetraazamacrocycle bearing protective groups on three nitrogen atoms by targeted synthesis, then starting from two reactants which are cyclized by methods known in the literature [e.g. Richman, Org. Synthesis 58: 86 (1978); Atkins J. Amer. Chem. Soc. 96, 2268 (1974)].

one of the two reactants contains a protected nitrogen atom and carries at the end of the chain two leaving groups (for example bromine, mesyloxy, tosyloxy, triflate or alkoxycarbonyl), which nucieophilically displace the triazazed other reactant protected from the terminal nitrogen atoms of the second reactant.

If a reactant with two terminal ester groups is used, then the two cyclic amide groups must be reduced, preferably with diborane in tetrahydrofuran. Especially this variant of cyclization is unsuitable for the production of larger amounts of the substance, because this reaction

V183 / 93H may be of high dilution to avoid, for example, polymerization reactions (see, for example, Tabushi, Tetrahed. Lett. 12, 1049 (1977); Kaden, Inorg. Chem. 25, 321 (1986)]. Also, the treatment with the subsequent reduction with diborane is not without problems, again especially at larger batches.

After cleavage of one of the protecting groups, the thus-released amino group can be alkylated or acylated. An example is the reaction of the disodium salt of N, N ', N' '- tris- (p-tolylsulfonyl) diethylenetriamine [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984)] with N-bis- (2-methanesulfonyloxy-ethyl) triphenylmethylamine in dimethylformamide at a temperature ranging from 80 to 150 ° C followed by cleavage of the triethyl group under acidic conditions. The yields of both reaction steps are generally poor. Also this variant b) is burdened by the disadvantages of the aforementioned a) for the removal of those protecting groups originating from the two reactants.

In addition to the previously described methods of statistical and targeted monosubstitution, targeted ring synthesis is also possible in which the desired substituent R is already present in one of the two reactants fed to the cyclization reaction.

In addition to the abovementioned cleavage of protecting groups, it has been shown that the cyclizations thus carried out generally proceed with low yields as compared to reactions of reaction partners equipped only with protecting groups [see Atkins, J. Amer. Chem. Soc. 96, 2268 (1974); Richman, Org. Synthesis 58: 86 (1978); 86 (1978); Fabrizzi, Inorg. Chem. 25,4131 (1986); Gazetta Chimica Italiana 115,399 (1985)]. In addition, the reactants carrying the R substituents must be especially substituted frequently by means of multi-step reactions [see Bulkowski, J. Org. Chem. 47, 412 (19821)].

Despite considerable effort, a satisfactory synthesis pathway has not yet been found for the mono-N-substituted tetraazamacrocycles of Formula I, which are key compounds for tri-N-carboxyalkyl-metal complexes, serving as valuable NMR and X-ray contrast agents.

V183 / 93H

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a process which is particularly suitable for producing larger quantities of a substance.

This object has been solved by providing a method according to the present invention.

Surprisingly, it has been found that selective monofunctionalization to the mono-N-substituted tetraazamacrocycles of formula I is achieved

(D in which n is the number 2 or 3 and

R represents a β-carboxyl or β-carboxylatealkyl group, a β-cyanoalkyl group, a β-carboxamidoalkyl group, a β-hydroxyalkyl group, an aminocarbonyl group, an aminothiocarbonyl group, a βsulfamoylalkyl group, or a second tetraazacyclododecanethane (tetraazacyclododecanethane) wherein the carboxyl and hydroxyl groups are optionally present in protected form when the tetraazatricyclotridecane or the tetraazatricyclopentanedecane of formula II is reacted

V183 / 93H - 22.05.2001

Λ Vis

with α, β- unsaturated ester, amide or nitrile, or sepoxide, isothiocyanate, aziridine or bisepoxide with or without solvent, at a temperature ranging from 0 ° C to 220 ° C, preferably ranging from room temperature to 210 ° C, at during 1 to 48 hours, preferably 5 to 12 hours, optionally at a pressure of up to 10 MPa, after cooling to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C mixed with a mixture of water and an organic solvent and stirred for 0.5-12 hours, preferably 0.5-3 hours at a temperature in the range of -20 ° C to room temperature, preferably in the range of 0 ° C to room temperature, thereafter, the thus formed, optionally isolated, intermediates bearing a formyl group on the nitrogen atom are added by adding an inorganic base or acid at a temperature ranging from 0 ° C to 150 ° C, preferably ranging from room temperature to 120 ° C, for 1 to 72 hours, preferably 6 to 24 hours n, with stirring, optionally in the next downstream deprotection by conventional methods, are reacted to the end product of formula I, and then isolated by known methods, preferably as hydrochloride.

The tetraazatricyclotridecanes or tetraazatricyclopentadecanes of formula II used as intermediates are available by methods known in the literature, for example by reacting 1,4,7,10tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane

VI83 (93H) with dimethylformamide dimethyl acetal (see, for example, U.S. Patents 4,085,106 and 4,130,715; J. Am. Chem. Soc. 102, 6364 (1980); EP 292 689).

Preferably, this reaction step is included in the process of the invention without the intermediates of formula (II) having to be isolated (one-pot reaction).

A special embodiment of the process according to the invention is the production of the compounds of the general formula I in which it represents

R ² R ¹ II

R is --C - CH - A

I

R ³ in which

R ¹ represents hydrogen, straight-chain or cyclic alkyl group having 1 to 6 carbon atoms, phenyl or benzyl, where phenyl may be substituted with one to two chloro, bromo, nitro, alkoxy having 1 to 7 carbon atoms, R @ aralkoxy radicals or CO ₂ R ⁴ radicals, wherein

R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group,

R ² and R ³ are independently R ¹ or CO ₂ R ⁴ a

R ⁵

I

A is CN-, CO ₂ R ⁴ or CON

I

R ⁶

V183 / 93H where

R ⁵ and R ⁶ independently of one another represent a hydrogen atom, saturated or unsaturated, straight, branched or cyclic, optionally 1 to 8 oxygen atoms or 1 to 3 phenylene or phenyleneoxy interrupted hydrocarbon radicals having up to 16 carbon atoms, optionally substituted with 1 to 5 hydroxyl groups or 1 to 2 CO ₂ R ⁴ radicals or a phenyl or benzyl radical optionally substituted by 1 to 3 hydroxyl groups or alkoxy groups having 1 to 6 carbon atoms, or

R ⁵ and R ⁶ together with the nitrogen atom denote a saturated or unsaturated five- or six-membered ring, optionally containing an additional nitrogen, oxygen, sulfur or carbonyl group, optionally substituted with 1 to 3 alkyl groups of 1 to 6 carbon atoms, which are optionally substituted with 1 to 3 hydroxy groups, the optionally present hydroxyl and / or carboxyl groups being optionally protected, which comprises reacting tetraazatricyclotridecane or tetraazatricyclopentadecane with the starting material of formula III

wherein R ¹ , R ² , R ³ and A are as defined above, wherein optionally present hydroxyl and / or carboxyl groups are optionally protected, in the presence or without a solvent, preferably aprotic solvents such as e.g. benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or diethyl ether, at a temperature of 0 ° C to 210 ° C, preferably 50 ° C to 180 ° C (where at higher reaction temperatures the solvent optionally used for dissolution added

V183 / 93H of the starting material (III), distilling in advance in vacuo) over a period of 12 to 48 hours, preferably 5 to 12 hours, after which the reaction mixture is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methanol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran or dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at a temperature in the range of -20 ° C to room temperature, preferably in the range of 0 ° C to room temperature, then the thus formed, optionally isolated intermediate, bearing a formyl group on the nitrogen atom, by adding an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or mineral acids such as hydrochloric acid, sulfuric acid or hydrobromic acid preferably at a temperature in the range of 0 ° C to 150 ° C, preferably in the range of room temperature to 120 ° C, for 1 to 72 hours, preferably 6 to 24 hours, with stirring, optionally with a subsequent following removal of the protecting groups by conventional means, reacted to give the final product of formula I, and then isolated by known methods, preferably in the form of the hydrochloride.

When R ^{@ 1} represents an alkyl group having 1 to 6 carbon atoms, methyl and ethyl are preferred. Other preferred R ¹ radicals are a hydrogen atom and an optionally substituted phenyl radical; Preferred substituents on the phenyl ring include nitro, C 1 -C 7 alkoxy, especially methoxy and ethoxy, and the CO ₂ R ⁴ radical, wherein R ⁴ is preferably a hydrogen atom, a methyl group, an ethyl group, a tert-butyl group or a benzyl group.

Preferred substituents R ⁵ and R ⁶ include hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group, 2-hydroxy-1- (hydroxymethyl) V183 / 93H - 22.05.2001 ethyl group, 1- (hydroxymethyl) - ethyl, propyl, isopropenyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutyl, isobutenyl, 2-hydroxybutyl, 3-hydroxybutyl, 4hydroxybutyl, 2- hydroxy-2-methylbutyl, -hydroxy-2-methylbutyl, 4-hydroxy-2-methylbutyl, 2-hydroxyisobutyl, 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl, 1,2,4trihydroxybutyl, pentyl , cyclopentyl, 2-methoxyethyl, hexyl, decyl, tetradecyl, triethylene glycol methyl ether, tetraethylene glycol methyl ether and methoxybenzyl. The amide moiety may also form a 5- or 6-membered heterocyclic ring in the presence of an amide nitrogen. For example, pyrrolidinyl ring, piperidyl ring, pyrazolidinyl ring, pyrrolidinyl ring, pyrazolinyl ring, piperazinyl ring, morpholinyl ring, imidazolidinyl ring, oxazolidinyl ring and thiazolidinyl ring may be mentioned.

The carboxyl and / or hydroxyl groups optionally present in the substrate of formula III are preferably present in protected form.

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

The cleavage of the protecting groups is carried out by methods known to those skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in an aqueous-alcoholic solution at temperatures between 0 ° C and 50 ° C, acidic saponification with mineral acids, or tert-butyl esters. with trifluoroacetic acid.

V183 / 93H - 22.05.2001

Examples of hydroxyl protecting groups include benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-tert-butylsilyl, or diphenyl-tert-butylsilyl.

Hydroxyl groups may also exist, for example, as THP ethers, alkoxy ethers, MEM ethers or as esters with aromatic or aliphatic carboxylic acids, such as acetic acid or benzoic acid. In the case of polyols, the hydroxyl groups may also be protected in the form of ketals with, for example, acetone, acetaldehyde, cyclohexanone or benzaldehyde.

Hydroxy protecting groups can be cleaved by methods known in the literature, for example by hydrogenolysis, reductive cleavage with lithium / ammonia, acidic treatment of ethers and ketals, or alkaline treatment of esters (see, for example, "Protective Groups in Organic Synthesis", TW Greene, John Wiley and Sons 1981).

Another special embodiment of the process of the present invention is the production of compounds of formula I wherein:

R is a group

OH

I - CH - CH - R ⁸ I

R ⁷ where

R ⁷ and R ⁸ independently of one another represent a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, optionally interrupted by 1 to 10 acid atoms, a phenyl group, a phenyleneoxy group or a phenylenedioxy group optionally substituted by 1 to 3 alkyl groups having 1 to 6 carbon atoms atoms, 1 to 3

V183 / 93H-22.05.2001 trifluoromethyl groups, 1 to 7 hydroxy groups, 1 to 3 alkoxy groups having 1 to 7 carbon atoms or aralkoxy groups, 1 to 2 CO ₂ R ⁴ groups and / or 1 to 2 phenoxy or phenyl groups which are optionally substituted with 1 to 2 chlorine, bromine, nitro or (1-6C) alkoxy groups, the optionally present hydroxy groups being present in protected form by reacting the tetraazatricyclotridecane or the tetraazatricyclopentadecane IV with the educt (iv) in which:

R ⁷ and R ⁸ are as defined above, wherein optionally present hydroxyl and / or carboxyl groups are optionally protected, in the presence or absence of a solvent, preferably aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran are used as solvents , dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide hexane or diethyl ether, at a temperature of 0 ° C to 210 ° C, preferably 50 ° C to 180 ° C (where at higher reaction temperatures the solvent optionally used to dissolve the added starting material of the formula IV, distilled off in advance) or in an autoclave under a pressure of 0.098 to 9.8 MPa, over a period of 1 to 48 hours, preferably 5 to 12 hours, after which the reaction mixture thus obtained is cooled to a temperature of -20 ° C. up to 80 ° C, preferably 0 ° C to 30 ° C, is mixed with a mixture of water and an organic solvent such as methanol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran or

V183 / 93H dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at a temperature in the range of -20 ° C to room temperature, preferably in the range of 0 ° C to room temperature, then an formed, optionally isolated, intermediate bearing a formyl group on the nitrogen atom by adding an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or mineral acids such as for example hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at temperatures from 0 DEG C. to 150 ^e C, preferably from room temperature to 120 ° C, for 1 to 72 hours, preferably 6 to 24 hours, with stirring, optionally followed by subsequent deprotection by conventional means, reacted to the final product of formula I, and then reacted in a manner known per se. both, preferably in the form of the hydrochloride.

Preferred substituents R ² and R ⁸ include hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1- (hydroxymethyl) ethyl, propyl, isopropenyl a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a butyl group, an isobutyl group, an isobutenyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group, a 4-hydroxybutyl group, a 2-hydroxy-2-methylbutyl group, 3-hydroxy-2-methylbutyl, 4-hydroxy-2-methylbutyl, 2-hydroxyisobutyl, 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, pentyl, cyclopentyl, 2methoxyethyl , hexyl, decyl, tetradecyl, triethylene glycol methyl ether, tetraethylene glycol methyl ether and methoxybenzyl, as well as

-CH2-O-C1-1H22-OH,

-CH 2 -OC ₆ H 4 -O- (CH ₂ CH ₂ O) 2 -CH 3,

V183 / 93H

-CH ₂ -O-C ₆ H 4 -O- (CH ₂ CH ₂ O) 3 -C ₅ H ₁ ,,

-CH-O ^ CeHR-Ile-OH,

- (CH ₂ CH ₂ O) ₅ -CH _3>

-c ₉ h ₁₈ -oh.

-c ₉ h ₁₈ -cooh

-CH ₂ -OC ₆ H ₄ -OC ₆ H ₁₂ -COOH,

-CH ₂ -OC ₆ H ₄ -O-C 4 H ₈ -O-CH ₂ -CHOH-CH ₂ OH

- (CH ₂ CH ₂ O) 3 -C ₅ Hii,

-CH ₂ -OC ₁₀ H 2 O-COOH,

-CH ₂ -OC ₆ H 4 -Cl,

-CH ₂ -OC _{2 R 6} H4NO

-CH ₂ -O-C 6 H ₃ Cl _2i

-CH ₂ -OC ₆ H ₄ -COOH,

-CH 2 -OC _e H ₄ -O-CH ₂ -COOH a

-Chris-čehu-CSHN.

When using volatile epoxides such as ethylene oxide or propylene oxide, the reaction is carried out in an autoclave.

The carboxyl and / or hydroxyl groups, if any, are present in the substrate IV, preferably in a protected form, as described above for the substrate 1 * 1.

Another special embodiment of the process of the present invention is the production of compounds of formula I,

V183 / 93H wherein R is -C --NHR ⁹ µ

X where

X is an oxygen or sulfur atom; and

R ⁹ represents a phenyl group, a 1-naphthyl group, a 2-naphthyl group or a straight or cyclic alkyl group having 1 to 6 carbon atoms, characterized in that tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with an educt of formula V ⁹ - N = C = X (V), in which X and R ^{9 are} as defined above, in the presence or absence of a solvent, preferably aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide hexane or diethyl ether, at 0 ° C to 180 ° C, preferably at room temperature to 150 ° C (where at higher reaction temperatures the solvent optionally used to dissolve the added starting material of formula V, before distilling off under vacuum), within 1 to 48 hours, preferably 5 to 12 hours, who is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methanol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran or dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at a temperature in the range of -20 ° C to room temperature, preferably in the range of 0 ° C to room temperature, then the thus formed, optionally isolated, intermediate thus formed bearing a formyl group on the nitrogen atom by addition of an inorganic base such as hydroxide

V183 / 93H lithium, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or mineral acids such as hydrochloric acid, sulfuric acid or hydrobromic acid, preferably hydrochloric acid, at a temperature in the range of 0 ° C to 150 ^e C, preferably in the temperature range miestnoti DEG to 120 DEG C., for 1 to 72 hours, preferably 6-24 hours, with stirring, reacted to the end product of formula I, and is isolated in known manner, the preferably in the form of the hydrochloride.

Another special embodiment of the process of the present invention is the preparation of compounds of formula I wherein R is

- (CH ₂ ) -NH-SO ₂ -R ¹⁰ wherein

R ¹⁰ represents an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group or a phenyl group which is optionally substituted by an alkyl group having 1 to 6 carbon atoms, a chlorine atom, a bromine atom or a nitro group, which comprises reacting tetraazatricyclotridecane, optionally tetraazatricyclopentanedecane, with the starting material of formula VI ch,

I ² \ o

^{N-SO-R, U} CH, / ² (VI), wherein R ¹⁰ is as hereinbefore defined, in the presence of a solvent, the solvents are preferably used aprotic solvents, such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, , acetonitrile, dimethylformamide, hexane or diethyl ether, at a temperature of 0 ° C to 180 ° C, preferably at a room temperature of up to 150 ° C (wherein in the case of

In higher reaction temperatures, the solvent is distilled off in vacuo for 1 to 48 hours, preferably 5 to 12 hours, then the reaction mixture is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran or dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at room temperature. from -20 ° C to room temperature, preferably from 0 ° C to room temperature, then the thus formed, optionally isolated, intermediate, bearing a formyl group on the nitrogen atom, by adding an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide or mineral acids such as hydrochloric acid, sulfuric acid hydrobromic seline, preferably hydrochloric acid, at a temperature ranging from 0 ° C to 150 ° C, preferably ranging from room temperature to 120 ° C, for 1 to 72 hours, preferably 6 to 24 hours, and allowed to react with stirring the final product of formula (I) and then isolated by known methods, preferably in the form of the hydrochloride.

Preferred R ¹⁰ substituents are phenyl and 4-methylphenyl.

Another particular embodiment of the process of the present invention is the preparation of compounds of formula I wherein R is the second molecule of 1,4,7,10-tetraazacyclododecane or 1,4,7,10-tetraazacyclotetradecane bonded via bis- (p-hydroxy) - alkylene chain —CH2 —CH — K — CH — CH 2 I

OH OH in which

V183 / 93H

K represents a bond or an alkylene chain of 1 to 16 carbon atoms, optionally interrupted by 1 to 6 oxygen atoms, or 1 to 2 benzyloxy, phenylene, phenyleneoxy or phenylenedioxy groups and optionally substituted by 1 to 6 hydroxyl or hydroxyalkyl groups or 1 to 8 alkoxy groups C 1-7 carbon atoms or aralkoxy groups, the optionally present hydroxy groups being optionally in protected form, which comprises reacting tetraazatricyclotridecane or tetraazatricyclopentadecane with an educt of formula ₍ VIIc) _; of ⁰ (VII), in which the C as described above, the optionally present hydroxy groups are optionally protected, in the presence of a solvent or not, wherein the solvents used are preferably aprotic solvents, such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or diethyl ether, at a temperature of 0 ° C to 220 ° C, preferably 50 ° C to 180 ° C (wherein at higher reaction temperatures the solvent optionally used to dissolve the added starting material of formula VII in advance distillation under vacuum), or in an autoclave under a pressure of 0.098 to 9.8 MPa, for 1 to 48 hours, preferably 5 to 12 hours, then the reaction mixture so obtained is cooled to a temperature in the range of -20 ° C to 80 ° C , preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methanol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran n or dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at a temperature in the range -20 ° C to room temperature, preferably in the range 0 ° C to room temperature,

V183 / 93H - 22.05.2001, the thus formed, optionally isolated, intermediate, bearing a formyl group on the nitrogen atom is then added by adding an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid, preferably hydrochloric acid, at a temperature in the range of 0 ° C to 150 ° C, preferably in the range of room temperature to 120 ° C, during 1 to 72 hours, preferably 6 to 24 hours, with stirring or subsequent subsequent deprotection by conventional means, reacted to the final product of formula I and then isolated by known methods, preferably in the form of the hydrochloride.

Preferred bridge members K include, for example:

-C2H4-.

-CH ₂ -,

-CH2-O-CH2-,

-CH 2 -O-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O- (CH ₂ -CH ₂ O) 2 -CH ₂ -,

-CHOH-

CHOH -CHOH-,

CHOH-CHOH--CHOH-,

-CH 2 -O-CH _r CH 2 -CHOH-CH 2 -O-,

-CH ₂ -OC ₆ H ₄ -O-CH 2 -,

-CH ₂ -OC ₄ H ₈ -O-CH 2 -,

-C (CH ₂ OH) ₂ V183 / 93H

-CH (CH ₂ OH) -CH 2 -O-C 6 H 4 -O-C 6 H 4 -O-CH 2 -.

CHOH-CHOH-CHOH--CHOH-,

-CH ₂ -O-CH 2 -C (CH ₂ OH) 2 -CH ₂ -O-CH ₂ -,

-CH ₂ -CH (CH ₂ OCH 3) -CH 2 -,

-CH _(OCH3) -,

-CH2-0-CH2-CH2-0-C6H4-CH2-,

In contrast to substrates II to VI, which, relative to the starting material of formula II, react equimolar to any excess, preferably with 1.05 to 2.0 equivalents, substrate VII is used in a lower amount of 0.5 to 0.3 equivalents .

The hydroxyl groups present optionally in the substrate VII are preferably present in a protected form, as mentioned above for substrate III.

The above-described processes according to the invention are characterized by high yields, a low number of reaction steps, a large number of variations of the desired substituent R, a problem-free up-scalling, in part a solvent discharge as well as a problem-free purification of the final product.

DETAILED DESCRIPTION OF THE INVENTION

The following examples serve to illustrate the invention in more detail.

Reactions with compounds of formula III ^R 1 - ( ^{R 1} ) - (III)

R ³ A

V183 / 93H-22.05.2001

Example 1

a) A mixture of 1- and 4-formamido-10 - [(2-ethoxycarbonyl) ethyl]] - 1,4,7,10-tetraazacyclodecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene was added, under a nitrogen atmosphere, 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal. The reaction mixture is slowly heated to reflux and the solvent is partially distilled off. Then 13.94 g (139.2 mmol) of ethyl acrylate were added dropwise under a nitrogen atmosphere and slowly warmed (over 30 minutes) to 80 ° C. The reaction mixture was stirred at this temperature for 12 hours. It is then cooled in an ice bath to 0 [deg.] C. and a mixture of 150 ml of ethanol and 20 ml of water is added, followed by stirring at room temperature for 30 minutes. It is then evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase = ethyl alcohol / concentrated aqueous ammonia = 10: 1). After evaporation of the main fractions, 31.71 g (91% of theory) of the product are obtained in the form of a yellowish oil.

Analysis (based on anhydrous substance);

calculated: C 55.98 H 9.39 N 18.65 found: C 55.91 H 9.43 N 18.59

b) 10- (2-carboxyethyl) -1,4,7,10-tetraazacyclododecane

To 31.0 g (103.2 mmol) of the title compound of Example 1a in 150 ml of ethyl alcohol and 150 ml of water was added 46.32 g (825.6 mmol) of potassium hydroxide and the reaction mixture was heated under reflux for 12 h. condenser. It is then cooled in an ice bath to 0 [deg.] C. and the pH is adjusted to 6 with 6N hydrochloric acid and evaporated in vacuo. The residue is extracted with a mixture of 300 ml of methanol and 50 ml of methylene chloride and filtered from potassium chloride. The filtrate was evaporated in vacuo and purified on a Reversed-Phase column (RP 18 / mobile phase: tetrahydrofuran / water gradient).

V183 / 93H

Yield: 23.02 g (87% of theory) of a yellowish viscous oily liquid which solidifies after a short time.

Analysis (based on anhydrous substance):

calculated: C 56.23 H 9.44 N 21.86 found: C 56.17 H 9.51 N 21.83

Example 2

10- (2-cyanoethyl) -1,4,7,10 tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 mL of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under a nitrogen atmosphere and the reaction mixture was slowly warmed to the reflux temperature while evaporating the solvent. It is then concentrated under reduced pressure and the residue is cooled to room temperature. Under nitrogen atmosphere, 9.24 g (174.15 mmol) of acrylic acid nitrile was added dropwise and slowly warmed to 75 ° C, whereupon it was stirred at this temperature for 9 hours. It is then cooled to room temperature and a mixture of 120 ml of methanol and 30 ml of water is added and stirred for 10 minutes at room temperature. Sodium hydroxide (13.93 g, 348.3 mmol) was added and the reaction mixture was stirred at 40 ° C for 24 h. The mixture was evaporated to dryness in vacuo and the residue was extracted three times with hot toluene (80 ° C). The organic phase is dried over potassium hydroxide and evaporated in vacuo.

Yield: 23.28 g (89% of theory) of a fine yellow oil which crystallizes on standing.

Analysis (based on anhydrous substance):

calculated: C 58.63 H 10.29 N 31.08 found: C 58.57 H 10.34 N 30.96

V183 / 93H

Example 3

10 - [(2-phenyl-2-carboxy) ethyl] -1,4,7,1,10-tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 mL of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under a nitrogen atmosphere, whereupon the mixture was slowly heated. to the reflux temperature while the solvent is distilled off. The mixture was then concentrated under reduced pressure. The residue is cooled to room temperature and 24.55 g (139.32 mmol) of ethyl 2-phenylvinyl ester are added dropwise under a nitrogen atmosphere and the reaction mixture is slowly warmed to 130 ° C and stirred at this temperature for 12 hours. It was then cooled to room temperature and a mixture of 150 ml of methanol and 150 ml of water was added and stirred at room temperature for 30 minutes. 52.11 g (928.8 mmol) of potassium hydroxide are then added and the mixture is refluxed for 12 hours. The reaction mixture is cooled to 0 ° C in an ice bath, the pH is adjusted to 7 with concentrated hydrochloric acid and evaporated to dryness. The residue is taken up in a mixture of 250 ml of methanol and 50 ml of methylene chloride, the precipitated potassium chloride is filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (mobile phase = methyl tert-butyl ether / methanol / concentrated aqueous ammonia = 6: 2.1).

Yield: 28.27 g (76% of theory) of a glassy solid.

Analysis (based on anhydrous substance):

calculated: C 83.72 H 8.81 N 17.48 found: C 83.64 H 8.93 N 17.37

Example

11- (2-cyanoethyl) -1,4,8,11-tetraazacyclotetradecane

To 20.0 g (99.83 mmol) of 1,4,8,11-tetraazacyclotetradecane in 200 ml of absolute toluene was added 13.68 g (114.8 mmol) under nitrogen.

V183 / 93H dimethylformamide dimethylacetal and heat slowly to reflux while distilling off the solvent. The mixture was then concentrated under reduced pressure and the residue was cooled to room temperature. Under nitrogen, 6.63 g (119.8 mmol) of acrylic nitrile is then added dropwise, the reaction mixture is slowly warmed to 75 ° C and stirred at this temperature for 9 hours. It is then cooled to room temperature and a mixture of 120 ml of tetramethyl alcohol and 30 ml of water is added, followed by stirring at room temperature for 10 minutes. Next, 11.98 g (299.5 mmol) of sodium hydroxide is added and stirred for 24 hours at 40 ° C. The reaction mixture was evaporated to dryness in vacuo and the residue was extracted three times with hot toluene (80 ° C). The organic phase is dried over potassium hydroxide and evaporated in vacuo.

Yield: 21.75 g (86% of theory) of a slightly yellow oily liquid which crystallizes on standing.

Analysis (based on anhydrous substance):

calculated: C 61.62 H 10.74 N 27.64 found: C 61.53 H 10.84 N 27.52

The compounds shown in Tables 1a and 1b are prepared in an analogous manner.

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V183 / 93H

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Example 5

a) A mixture of 1- and 4-formamido-10- (6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl) -1,4,7,10-tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 mL of absolute toluene was added 15.9 g (133.5 mmol) of dimethyl formamide dimethyl acetal under a nitrogen atmosphere and slowly warmed to room temperature. the solvent, while partially distilling off the solvent. 20.1 g (139.32 mmol) of 4,4-dimethyl-3,5-8-trioxabicyclo- (5.1.0) -octane are then added dropwise under a nitrogen atmosphere and the reaction mixture is heated slowly to 130 [deg.] C. for one hour. And stirred for 12 hours at 120 ° C. It is then cooled to room temperature and a mixture of 120 ml of methanol and 30 ml of water is added and stirred for one hour at room temperature. The reaction mixture is evaporated in vacuo and the residue is chromatographed on silica gel (mobile phase = methyl tert-butyl ether / methanol / concentrated aqueous ammonia = 15: 5: 1). Evaporation of the main fractions gave 36.39 g (91% of theory) of a slightly yellow, viscous oil which crystallized on standing,

Analysis (based on anhydrous substance):

H, 9.39; N, 16.27. Found: C, 55.82; H, 9.29; N, 16.20.

b) 10- (6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl) -1,4,7,10-tetraazacyclododecane

V183 / S3H

To 35.0 g (101.6 mmol) of the title compound of Example 5a in 200 mL of methanol and 50 mL of water was added 57.0 g (1.02 mol) of potassium hydroxide, and the mixture was refluxed for 5 hours. condenser. It is then evaporated to dryness in vacuo and the residue is extracted three times with 200 ml of hot (80 ° C) toluene. The organic phase is dried over potassium hydroxide and evaporated in vacuo.

Yield: 31.5 g (98% of theory) of a slightly yellow, viscous oil which solidifies on standing.

Analysis (based on anhydrous substance):

calculated: C 59.63 H 10.19 N 17.71 found: C 56.87 H 10.25 N 17.63.

Example 6

a) Mixture of 1- and 4-formamido-10- (2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under nitrogen and heated slowly to reflux, the solvent being distilled off. It is then concentrated under reduced pressure and the residue is cooled to 0 ° C. The residue is dissolved in 50 ml of toluene, the solution is placed in an autoclave, 20.23 g (348.3 mmol) of propylene oxide are added and the autoclave is closed. The cartridge is heated to 100 ° C for 24 hours. It is evaporated to dryness in vacuo and the residue is taken up in a mixture of 120 ml of methanol and 30 ml of water and stirred for one hour at room temperature. The solution is concentrated in vacuo and the residue is chromatographed on silica gel (mobile phase = methanol / isopropyl alcohol / concentrated ammonia = 10: 5: 1). Evaporation of the main fractions in vacuo gave 26.7 g (89% of theory) of a slightly yellow, colored oil.

Analysis (based on anhydrous substance):

V183 / 93H - 22.05.2001 calculated: C 59.79 H 10.14 N 21.69 found: C 55.72 H 10.19 N 21.61.

b) 10- (2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane

To 26.0 g (100.63 mmol) of the title compound of Example 6a in 250 mL of water was added 45.2 g (805.1 mmol) of potassium hydroxide and the reaction mixture was heated under reflux for 5 hours. It is then evaporated to dryness in vacuo and the residue is extracted three times with 200 ml of hot (80 ° C) toluene. The organic phase is dried over potassium hydroxide and evaporated in vacuo.

Yield: 22.02 g (95% of theory) of a slightly yellowish oily liquid which solidifies after a short time.

Analysis (based on anhydrous substance):

calculated: C 57.36 H 11.38 N 24.32 found: C 57.30 H 11.43 N24.28.

Example 7

10- [2-hydroxy-5- (2,2-dimethyl-1,3-dioxolan-4-yl) -4-oxapentyl] -1,4,7,10 tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under a nitrogen atmosphere and heated slowly to reflux. and the solvent is evaporated. It is concentrated by evaporation under reduced pressure, the residue is cooled to 40 ° C, and 24.04 g (127.7 mmol) of 2,2-dimethyl-4- (2 ', 3'-epoxy) - are added dropwise under nitrogen. of propoxymethyl-1,3-dioxolane and slowly (over one hour) heat to 110 ° C. The reaction mixture was stirred at this temperature for 12 hours, then cooled to room temperature and treated with a mixture of 120 mL of methanol and 30 mL of water. Stir for 30 minutes at room temperature, then add 85.1 g (1.16 mol) of potassium hydroxide and boil.

V183 / 93H was refluxed for 5 hours. The reaction mixture is concentrated in vacuo and the residue is extracted three times with 200 ml of hot (80 ° C) toluene. The combined organic extracts were dried over potassium hydroxide and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent = methanol / water / concentrated aqueous ammonia = 8: 2: 1). The main fractions are evaporated to dryness, the residue is dissolved in 500 ml of hot toluene, the insolubles are filtered off (silica gel), and the filtrate is evaporated to dryness.

Yield: 36.41 g (87% of theory) of a slightly yellow, viscous oil.

Analysis (based on anhydrous substance):

calculated: C 56.64 H 10.07 N 15.54 found: C 56.53 H 10.13 N 15.49.

Example 8

10- [3- (4-nitrophenoxy) -2-hydroxypropyl] -1,4,7,10-tetraazacyclododecane (as tetrahydrochloride)

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under a nitrogen atmosphere and slowly heated to reflux. The mixture is concentrated under reduced pressure, the residue is cooled to room temperature and a solution of 29.46 g (150.93 mmol) of 4-nitrophenyl-2,3-epoxypropyl ether in 100 ml is added dropwise under a nitrogen atmosphere. methylene chloride. The reaction mixture is then slowly warmed to 120 ° C while methylene chloride is distilled off (to the end under reduced pressure) and stirred for 12 hours at 120 ° C. It is then cooled to room temperature and a mixture of 160 ml of methanol and 20 ml of water is added and the mixture is stirred for 30 minutes at room temperature. Finally, 50 ml of concentrated hydrochloric acid are added and evaporated to dryness in vacuo. The residue is crystallized from a mixture of methanol and diethyl ether.

V183 / 93H

Yield: 48.27 g (81% of theory) of a yellow crystalline powder.

Analysis (based on anhydrous substance):

calculated: C 55.57 H 7.95 N 19.06 Found: C 55.49 H 8.03 N 19.01.

Example 9

a) 11- [3- (4-Nitroxyphenoxy) -2-hydroxypropyl] -1,4,8,11-tetrahydro-acyclotetradecane (as tetra-hydrochloride)

To 20.0 g (99.83 mmol) of tetaazacyclotetradecane in 200 ml of absolute toluene was added under nitrogen atmosphere 13.86 g (114.8 mmol) of dimethylformamide dimethyl acetal and heated slowly to reflux while distilling off the solvent to which is concentrated under reduced pressure. The resulting residue was cooled to room temperature and a solution of 23.38 g (119.8 mmol) of 4-nitrophenyl-2,3-epoxypropyl ether in 100 ml of methylene chloride was added dropwise under a nitrogen atmosphere. Thereafter, the reaction mixture was slowly heated to 120 ° C, while methylene chloride was distilled off (to the end under reduced pressure). It is further stirred at 120 ° C for 12 hours, cooled to room temperature and a mixture of 150 ml of methanol and 20 ml of water is added. The mixture is stirred for 30 minutes at room temperature, then 100 ml of concentrated hydrochloric acid are added and the mixture is heated under reflux for 12 hours. Finally, the reaction mixture is evaporated to dryness in vacuo and the residue is crystallized from a mixture of methanol and diethyl ether.

Yield: 41.61 g (77% of theory) of a yellowish crystalline powder.

Analysis (based on anhydrous substance):

calculated: C 42.16 H 6.89 N 12.94 Cl 26.20 found: C 42.10 H 6.93 N12.90 Cl 26.08.

V183? 93H

Example 10

a) 1- and 4- and 8-formamido-11- [2-hydroxy-2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethyl] 1,4,8,11- tetraazacyclotetradecane

To 20.0 g (99.83 mmol) of 1,4,8,11-tetraazacyclotetradecane in 200 ml of absolute toluene was added, under a nitrogen atmosphere, 13.68 g (114.8 mmol) of dimethylformamide dimethyl acetal and heated slowly to reflux. flow, the solvent being distilled off. The mixture was concentrated under reduced pressure, the residue was cooled to room temperature, and 17.27 g (119.8 mmol) of 2- (2,2-dimethyl-1,3-dioxolan-4-yl) was added dropwise under a nitrogen atmosphere. ethylene oxide adduct. The reaction mixture is slowly warmed to 130 ° C and stirred at this temperature for 12 hours, then cooled to 130 ° C and a mixture of 160 ml of methanol and 40 ml of water is added and stirred for one hour at room temperature. room temperature. It is then evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase = methyl tert-butyl ether / methanol / concentrated aqueous ammonia = 15: 5: 1).

Yield: 33.1 g (89% of theory) of a slightly yellow viscous liquid.

Analysis (based on anhydrous substance):

calculated: C 58.04 H 9.74 N 15.04 found: C 58.13 H 9.61 N 14.92.

b) 11- [2-Hydroxy-2- (2,2-dimethyl-1,3-dioxolan-4-yl) -ethyl] -1,4,8,11-tetra-azacyclotetradecane

To 32.0 g (87.22 mmol) of the title compound of Example 10 and 200 mL of methanol and 100 mL of water was added 39.15 g (698 mmol) of potassium hydroxide and the mixture was boiled for 5 hours. under reflux. It is then evaporated to dryness in vacuo and the residue is extracted three times with hot toluene (80 ° C). The organic phase is dried over potassium hydroxide and evaporated in vacuo.

V183 / 93H

Yield: 28.85 g (96% of theory) of a slightly yellow, viscous oil which solidifies after a short time.

Analysis (based on anhydrous substance):

calculated: C 59.27 H 10.53 N 16.26 found: C 59.18 H 10.61 N16.17.

The compounds shown in the following table are prepared in an analogous manner.

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Reactions of Compounds of Formula V R ⁹ _N = C = X (V)

Example 11

10- (N-phenylcarbamoyl) -1,4,7,10 tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 mL of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under a nitrogen atmosphere and heated slowly to reflux. flow, the solvent being distilled off and then concentrated under reduced pressure. The residue thus obtained was cooled to 0 ° C and added dropwise under a nitrogen atmosphere

16.6 g (139 mmol) of phenyl isothiocyanate and slowly warmed to 100 ° C, whereupon it was stirred at this temperature for 12 hours. The reaction mixture was then cooled to room temperature and a mixture of 160 ml of ethanol and 40 ml of water was added and stirred for 10 minutes at room temperature. Sodium hydroxide (18.58 g, 464.4 mmol) was added and the reaction mixture was stirred at 40 ° C for 24 h. It is then concentrated to dryness under vacuum and the residue is taken up in 400 ml of water. The aqueous phase is extracted five times with 200 ml of methylene chloride, the organic phase is dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel (mobile phase = methyl tert-butyl ether / methanol / concentrated aqueous ammonia = 6: 3: 1).

Yield: 29.1 g (86% of theory) of a slightly yellow solid.

Analysis (based on anhydrous substance):

calculated: C 61.83 H 8.65 N 24.03 found: C 61.71 H 8.72 N 23.94.

For example, the compounds listed in the following table are prepared in an analogous manner.

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Article

V183 / 93H

Reactions with a compound of formula VI ch ₂ | ' ^X ' n-so2-r ¹⁰ ch2

Example 12

a) A mixture of 1- and 4-formamido-10- [2- (p-tolylsulfonylamino) ethyl] -1,4,7,10-tetraazacyclododecane

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetal under nitrogen and heated slowly to reflux, the solvent is evaporated. The mixture was concentrated under reduced pressure and the residue was cooled to 0 ° C, after which a solution of 15.19 g (127.71 mmol) of p-tolylsulfonylaziridine in 100 ml of toluene was added dropwise under a nitrogen atmosphere, and the reaction mixture was stirred for 8 hours. hours at 80 ° C. The reaction mixture is evaporated to dryness in vacuo and the residue is taken up in a mixture of 180 ml of ethanol and 30 ml of water and stirred for 30 minutes at room temperature. It is then evaporated to dryness and the residue is chromatographed on silica gel (mobile phase = methyl tert-butyl ether / methanol / concentrated aqueous ammonia = 6: 2: 1).

Yield: 40.61 g (88% of theory) of a glassy solid.

Analysis (based on anhydrous substance):

calculated: C 54.38 H 7.86 N 17.62 S 8.06 found: C 54.31 H 7.93 N 17.58 S 7.99

b) 10- [2- (p-tolylsulfonylamino) ethyl] -1,4,7,10-tetraazacyclododecane

V183 / 93H

To 40.0 g (100.62 mmol) of the title compound of Example 9a in 180 mL of ethyl alcohol and 30 mL of water was added 20.12 g (503 mmol) of sodium hydroxide and the reaction mixture was refluxed for 12 hours. It is then evaporated to dryness and the residue is taken up in 100 ml of water. The pH of the solution was adjusted to 10 by the addition of 6 N hydrochloric acid and extracted twice with 250 ml of hot toluene (80 ° C). The organic phase is dried over anhydrous magnesium sulphate and evaporated in vacuo.

Yield: 36.07 g (97% of theory) of a yellowish solid.

Analysis (based on anhydrous substance):

calculated: C 55.26 H 8.46 N 18.95 S 8.68 found: C 55.21 H 8.52 N 18.90 S 8.59.

c) A mixture of 1- and 4-formamido-10- [2- (methylsulfonylamino) ethyl] -1,4,7,10-tetraazacyclododecane

Analogously to Example 12 (a), methylsulfonylaziridine can be used instead of ptolylsulfonylaziridine.

Yield: 89%.

Analysis (based on anhydrous substance):

calculated: C 44.84 H 8.47 N 21.79 S 9.97 found: C 44.76 H 8.53 N 21.73 S9.90.

d) 10- [2- (methylsulfonylamino) ethyl] -1,4,7,10-tetraazacyclododecane

Analogously to Example 12b), the title compound of Example 12c) can be prepared instead of the title compound of Example 12 a).

Yield: 96% of theory.

V183 / 93H - 22.05.2001

Analysis (based on anhydrous substance):

calculated: C 45.03 H 9.27 N 23.87 S 10.93 found: C 44.96 H 9.34 N 23.98 S10.85.

Reactions of Compounds of Formula VII ch ₂ -ch-k-ch-ch ₂ / (VII)

Example 13

a) Mixture of 1,1'- (2,6-dihydroxy-4-oxa-1,7-heptyl) -bis- [1,4,7,10tetraazacyclododecane] bis-formamide

To 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene was added 15.9 g (133.5 mmol) of dimethylformamide dimethyl acetate under a nitrogen atmosphere and heated slowly to reflux. The solvent was evaporated. The mixture is concentrated under reduced pressure, the residue is cooled to 40 ° C and 7.25 g (55.7 mmol) of bis- (2,3-epoxypropyl) ether are added dropwise under a nitrogen atmosphere and slowly warmed to room temperature. 120 [deg.] C. The reaction mixture was stirred for 24 hours at this temperature and then cooled to room temperature. A mixture of 200 ml of methanol and 100 ml of water is added and stirred for one hour at room temperature. Then the mixture is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase = methanol / isopropyl alcohol / concentrated aqueous ammonia = 8: 2: 1).

Yield: 18.63 g (63% of theory) of a glassy solid.

Analysis (based on anhydrous substance):

H, 9.50; N, 21.11

H, 9.57; N, 21.18.

b) 1,1 '- (2,6-dihydroxy-4-oxa-1,7-heptyl) -bis- [1,4,7,10-tetraazacyclododecane]

To 18.0 g (33.92) mmol of the title compound 13a) in 200 mL of methanol and 100 mL of water was added 28.55 g (508 mmol) of potassium hydroxide, and the reaction mixture was refluxed for 2 hours. . The mixture is evaporated to dryness in vacuo and the residue is extracted three times with 200 ml of hot toluene (80 ° C). The organic phase is dried over potassium hydroxide and evaporated in vacuo.

Yield: 15.62 g (97% of theory) of a sweet yellow viscous oil which solidifies on standing.

Analysis (based on anhydrous substance):

calculated: C 55.67 H 10.62 N 23.61 found: C 55.61 H 10.68 N23.56.

The compounds shown in the following table are obtained in an analogous manner.

Claims (7)

PATENT CLAIMS A process for the preparation of mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives of the general formula I / ch ^2. I N (I) wherein n is 2 or 3 a R is β-carboxyl or β-carboxylatealkyl, β-cyanolyl, β-carboxamidoalkyl, β-hydroxyalkyl, aminocarbonyl, aminothiocarbonyl, β-sulfamoylalkyl, or the second tetraazacyclododecane decane, tetraazacyclododecane decane, tetraazacyclododecane decane ) -alkylene chain, wherein the carboxyl and hydroxyl groups are optionally present in protected form, characterized in that the tetraazatricyclotridecane or the tetraazatricyclopentadecane of the general formula II is reacted V183 / 93H-22.05.2001 .N _R> / (II). N H with α, β- unsaturated ester, amide or nitrile, or sepoxide, isothiocyanate, aziridine or bisepoxide with or without solvent, at a temperature between 0 ° C and 220 ° C, preferably between room temperature and 210 ° C, within 1 to 48 hours, preferably 5 to 12 hours, optionally at a pressure of up to 10 MPa, after which the reaction mixture obtained after cooling to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 " C is mixed with a mixture of water and an organic solvent and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at a temperature in the range -20 ° C to room temperature, preferably in the range 0 ° C to room temperature thereafter, the thus formed, optionally isolated, intermediates bearing a formyl group on the nitrogen atom are added by adding an inorganic base or acid at a temperature ranging from 0 ° C to 150 ° C, preferably ranging from room temperature to 120 ° C, over 1 to 72 hours, preferably 6 to 24 hours The compound of formula (I) is reacted to the final product of formula (I) with stirring, optionally with subsequent subsequent deprotection, by conventional means, and then isolated, preferably in the form of the hydrochloride. A process according to claim 1 for the preparation of compounds of the formula I in which it represents V183 / 93H R ² R ¹ II R is —C - CH - A I R ³ in which R ¹ represents hydrogen, straight-chain or cyclic alkyl group having 1 to 6 carbon atoms, phenyl or benzyl, where phenyl may be substituted with one to two chloro, bromo, nitro, alkoxy of 1-7 carbon atoms, aralkoxy radicals or CO2R ⁴ residues, where: R ⁴ represents hydrogen, alkyl having 1 to 6 carbon atoms, phenyl or benzyl, R ² and R ³ independently of one another a group R ¹ or a group CO 2 R ^4, and R ⁵ I A is a radical CN-, CO 2 R ⁴ or CON I R ⁶ where R ⁵ and R ⁶ independently of one another represent a hydrogen atom, saturated or unsaturated, straight, branched or cyclic, optionally with 1 to 8 oxygen atoms or 1 to 3 phenylene or phenyleneoxy interrupted hydrocarbon radicals of up to 16 carbon atoms, optionally substituted with 1 to 5 hydroxyl groups or 1 to 2 CO 2 R ⁴ radicals or a phenyl or benzyl radical, optionally substituted by 1 to 3 hydroxyl or alkoxy groups having 1 to 6 carbon atoms, or V183 / 93H R ⁵ and R ⁶ together with the nitrogen atom denote a saturated or unsaturated five- or six-membered ring, optionally containing an additional nitrogen, oxygen, sulfur or carbonyl group, optionally substituted with 1 to 3 alkyl groups of 1 to 6 carbon atoms, which are optionally substituted with 1 to 3 hydroxy groups, the optionally present hydroxyl and / or carboxyl groups being optionally protected, characterized in that the tetraazatricyclotridecane or the tetraazatricyclopentadecane of the formula II is reacted with an educt of the formula R i Wherein R ¹ , R ² , R ³ and A are as defined above, wherein optionally present hydroxyl and / or carboxyl groups are optionally protected, in the presence or absence of a solvent, preferably aprotic solvents, such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or diethyl ether, at a temperature of 0 ° C to 210 ° C, preferably 50 ° C to 180 ° C ₍ wherein at higher reaction temperatures used to dissolve the added starting material of formula (III) in advance distilled off in vacuo ₍ within 12 to 48 hours, preferably 5 to 12 hours, after which the reaction mixture obtained is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methyl alcohol, ethyl alcohol, isopropanol, tetrahydrofuran or dioxane and stirred for 0.5-12 h, preferably 0.5 to 3 hours at from -20 DEG C. to room temperature, preferably between 0 ^DEG C to room temperature. The intermediate thus formed, optionally isolated, bearing a formyl group on the nitrogen atom, is then added by addition of an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or mineral acids, such as hydrochloric acid, sulfuric acid or hydrobromic acid, preferably hydrochloric acid, at a temperature in the range of 0 ° C to 150 ° C, preferably in the range of room temperature to 120 ° C, for 1 to 72 hours, preferably 6-24 hours, with stirring, optionally with subsequent removal of the _R protecting group is reacted to the final product of formula I and then isolated, preferably as hydrochloride. A process according to claim 1 for the preparation of compounds of formula I in which R is a group OH I - CH - CH - R ⁸ i and R ⁷ where R ⁷ and R ⁸ independently of one another represent a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, optionally interrupted by 1 to 10 oxygen atoms, a phenylene group, a phenyleneoxy group or a phenylenedioxy group optionally substituted by 1 to 3 alkyl groups having 1 to 6 carbon atoms atoms, 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 to 2 CO ₂ R ⁴ groups and / or 1 to 2 phenoxy or phenyl groups which are optionally substituted with 1 to 2 chlorine, bromine, nitro or V183 / 93H alkoxy groups having 1 to 6 carbon atoms, the optionally present hydroxy groups being present in protected form, characterized in that the tetraazatricyclotridecane or tetraazatricyclopentadecane of the formula II is reacted with the starting material of the formula IV o in which R ⁷ and R ⁸ are as defined above, wherein optionally present hydroxyl and / or carboxyl groups are optionally protected, in the presence or absence of a solvent, preferably aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide hexane or diethyl ether, at a temperature of 0 ° C to 210 ° C, preferably 50 ° C to 180 ° C ₍ wherein at higher reaction temperatures the solvent optionally used to dissolve the added starting material of formula (IV) is distilled off beforehand ₍ or in an autoclave at a pressure of from 1 to 10 MPa) over a period of from 1 to 48 hours, preferably from 5 to 12 hours, and then cooled to -20 ° C to -20 ° C. 80 ° C, preferably 0 ° C to 30 ° C, is mixed with a mixture of water and an organic solvent such as methanol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran or dioxane and stirred for 0.5-12 hours, preferably 0.5-3 hours at -20 ° C to room temperature, preferably 0 ° C to room temperature, then formed , optionally isolated, an intermediate bearing a formyl group on the nitrogen atom by addition of an inorganic base such as hydroxide ✓; lithium, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, V183 / 93H preferably sodium hydroxide and potassium hydroxide, or a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid, preferably hydrochloric acid, at a temperature in the range of 0 ° C to 150 ° C, preferably in the room temperature range to 120 ° C, within 1 to 72 hours, ⁵ preferably 6 to 24 hours, with stirring, optionally at a subsequent% deprotection _f is reacted to the final product of formula I and then isolated, preferably in the form of the hydrochloride. A process according to claim 1 for the preparation of compounds of formula I in which it is R group - C - NH ⁹ I. il x while X is an oxygen or sulfur atom; and R ⁹ represents a phenyl group, a 1-naphthyl group, a 2-naphthyl group or a straight or cyclic alkyl group having 1 to 6 carbon atoms, characterized in that a tetraazatricyclotridecane or a tetraazatricyclopentadecane of formula II is reacted with an educt of formula V; R ⁹ -N = C = X (V), * wherein X and R ^{9 are} as defined above, in the presence or absence of a solvent, preferably aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, V183 / 93H dimethylsulfoxide, hexane or diethyl ether, at 0 ° C to 180 ° C, preferably at room temperature to 150 ° C, wherein at higher reaction temperatures the solvent (s) optionally used to dissolve the added starting material (V) in advance vacuum distills off, over a period of 1 to 48 hours, preferably 5 to 12 hours, then the reaction mixture so obtained is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran or dioxane and stirred for 0.5-12 hours, preferably 0.5-3 hours, at a temperature ranging from -20 ° C to room temperature, preferably in the range of 0 ° C to room temperature, then the thus formed, optionally isolated intermediate, bearing a formyl group on the nitrogen atom, is added by the addition of an inorganic base such as hydroxide hydrox. lithium, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid, preferably hydrochloric acid, at a temperature ranging from 0 ° C to 150 ° C ° C, preferably in the range of room temperature to 120 ° C, for 1 to 72 hours, preferably 6 to 24 hours and with stirring, to react to the final product of formula I, and then isolated, preferably in the form of the hydrochloride. A process according to claim 1 for the preparation of compounds of formula I wherein R is a group - (CH ₂ ) _n NH-SO 2 -R ¹⁰ ° wherein R ¹⁰ represents an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group or a phenyl group which is optionally substituted by an alkyl group having 1 to 6 carbon atoms, a chlorine atom, a bromine atom or a nitro group, V183 / 93H, characterized in that a tetraazatricyclotridecane or a tetraazatricyclopentanedecane of the formula II is reacted with a seduct of the formula VI ^CH2 \ 10 N-SO-R (VI), b ₂ / wherein R ¹⁰ is as hereinbefore defined, in the presence of a solvent, the solvents are preferably used aprotic solvents, such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, , acetonitrile, dimethylformamide, hexane or diethyl ether, at 0 ° C to 180 ° C, preferably room temperature to 150 ° C, wherein at higher reaction temperatures the solvent is distilled off in vacuo for 1 to 48 hours in vacuo. preferably 5 to 12 hours, then the reaction mixture so obtained is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methanol, ethyl alcohol , isopropanol, tetrahydrofuran, dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours at from -20 DEG C. to room temperature, preferably between 0 ^and C to room temperature, then do as follows a formed, optionally isolated intermediate bearing a formyl group on the nitrogen atom by the addition of an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide or a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid, preferably hydrochloric acid, at a temperature between 0 ° C and 150 ° C, preferably between room temperature and 120 ° C, for 1 to 72 hours, V183 / S3H, preferably for 6 to 24 hours and with stirring, is reacted to give the final product of formula I and then isolated, preferably in the form of the hydrochloride. A process according to claim 1 for the preparation of compounds of formula I, in which it is R molecule of 1,4,7,10-tetraazacyclododecane or 1,4,7,10tetraazacyclotetradecane bonded via a bis- (β-hydroxy) -alkylene chain —CH2 -CH — K — CH-CH2— I I OH OH in which K represents a bond or an alkylene chain of 1 to 16 carbon atoms, optionally interrupted by 1 to 6 oxygen atoms, or 1 to 2 benzyloxy, phenylene, phenyleneoxy or phenylenedioxy groups and optionally substituted by 1 to 6 hydroxyl or hydroxyalkyl groups or 1 to 8 alkoxy groups C 1 to C 7 or aralkoxy, the optionally present hydroxy groups being optionally in protected form, characterized in that tetraazatricyclotridecane or tetraazatricyclopentadecane (II) can be reacted with an educt of formula (VI) CH-C-CH-CH. (VII), in which K is as defined above, Wherein the optionally present hydroxyl groups are optionally protected, in the presence or absence of a solvent, preferably aprotic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or diethyl ether, at a temperature of 0 ° C to 220 ° C, preferably 50 ° C to 180 ° C ₍ wherein at higher reaction temperatures the solvent, optionally used to dissolve the added starting material of formula VII) is distilled off in advance, or in an autoclave overpressure of 0.1 to 10 MPa, over 1 to 48 hours, preferably 5 to 12 hours, then the reaction mixture so obtained is cooled to a temperature in the range of -20 ° C to 80 ° C, preferably 0 ° C to 30 ° C, mixed with a mixture of water and an organic solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran or dioxane and stirred for 0.5 to 12 hours, s preferably from 0.5 to 3 hours at a temperature in the range of -20 ° C to room temperature, preferably in the range of 0 ° C to room temperature, then the thus formed or isolated intermediate, which bears a formyl group on the nitrogen atom, is added. such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid, preferably hydrochloric acid, at a temperature in the range of 0 DEG C. to 150 DEG C., preferably from room temperature to 120 ° C, for 1 to 72 hours, preferably 6-24 hours, with stirring, optionally with subsequent removal of the protecting group _t is reacted to a final * product I _in then it isolated, preferably as hydrochloride. Process according to claim 1, characterized in that reactions starting from 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane of the formula II are carried out without isolation of the intermediates to the compounds of the formula I.