SK117298A3 - Process for preparing 1,4,7,10-tetraazacyclododecane and its derivatives - Google Patents

Abstract

Preparation of eventually alkylsubstituted cyclene derivatives by cyclotetramerization eventually alkylsubstituted benzylaziridine derivatives in which the benzilaziridine derivative is prepared in situ from eventually alkylsubstituted benzylethanolamine derivative by reaction with vitriol acid and following reaction of relative vitriol acid ester with aqueous lye, without benzylaziridine derivative isolation is tetramerized to tetrabenzylcyclene by adding 0.25 to 0,35 mole of strong acid to mole of benzylaridine derivative and then by catalyst hydrogenation benzyl groups are separated.

Description

Technical field

The present invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane (cyclene) and derivatives thereof.

BACKGROUND OF THE INVENTION

1,4,7,10-tetraazacyclododecane (cyclene) is widely used not only as a macrocyclic ligand, but also as a starting material in the preparation of various metal-containing, pharmaceutically used complexes such as gadobutrol (INN), gadobenate (INN) or gadoteridol (INN) ).

1,4,7,10-tetraazacyclododecane is generally prepared by a multi-step synthesis by cyclic condensation of two linear starting products (J. Chem. Rev. 1989, 929, The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, Cambridge, U.K. 1989).

The disadvantage of this method is the high number of synthesis steps, the low overall yield, and the high amount of the inorganic salts formed therefrom, which are formed during the synthesis.

The cyclotetramerization of N-substituted aziridines is a substantially simpler method of preparing 1,4,7,10-tetraazacyclododecane. Various variants of this reaction are described in the literature. The corresponding N-substituted aziridine is first prepared from benzylethanolamine and then isolated. Aziridine is then in low yield in the presence of Bronsted acids such as p-TsOH (J. Heterocyclic Chem. 1968, 305) or Lewis acids such as trialkyl aluminum (US patent 3,828,023) or BF ₃ -etherate (Tetrahedron Letters, 1970, 1367). cyklotetramerizovaný. Although this method is feasible only for the preparation of small quantities (less than 5 g), it still constitutes, prior to 16 years after the first publication, a prior art (WO 95/31444).

31047 / H

All of the hitherto described cyclotetramerization reactions require the use of pure aziridines which, as is known, have potent mutagenic and carcinogenic effects (Roth, Giftliste, VCH Weinheim). For this reason, the cyclomerization of aziridines, which seems to be the easiest way to prepare 1,4,7,10-tetraazacyclododecane, is practically non-commercial. This implies great interest in a technically feasible, environmentally less polluting and substantially safer process for preparing 1,4,7,10-tetraazacyclododecane.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a practicable process for the preparation of 1,4,7,10-tetraazacyclododecane on an industrial scale that overcomes the above-mentioned disadvantages and, in particular, avoids the human threat to mutagenic and cancer-causing aziridine intermediate steps.

This object is achieved by the method according to the invention. It is a process for the preparation of cyclic derivatives by cyclotetramerization of benzylaziridine derivatives, which is characterized in that the benzylaziridine derivative is prepared in situ and, without isolation, is tetramerized by adding a strong acid to the tetrabenzylcyclene derivative and finally the benzyl groups are separated by hydrogenation.

In the present invention, the term cyclene derivative includes not only

1,4,7,10-tetraazacyclododecane, but also those derivatives in which the ethylene bridges have alkyl substituents. Thus, the term cyclene derivative includes, for example, [2S- (2a, 5α, 8a, 11a)] - 2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane and [2S (2α, 5α, 8a, 11a)] - 2,5,8,11-Tetraethyl-1,4,7,10-tetraazacyclododecane.

By analogy, the term tetrabenzylcyclene derivative within the scope of the present invention includes both 1,4,7,10-tetrabenzyl-1,4,7,10tetraazacyclododecane and derivatives wherein ethylene bridges have alkyl substituents. The term benzylaziridine derivative within the scope of the present invention includes benzylaziridine as well as those derivatives in which the aziridine ring has alkyl substituents. Thus, the term benzylaziridine derivative includes, for example, the compound (S) -1-benzyl-2-methyl-aziridine and (S) -1-benzyl-2-ethyl-aziridine.

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Thus, the invention includes a process for preparing optionally substituted derivatives

1,4,7,10-tetraazacyclododecane by tetramerization of the corresponding starting materials. Preferably, the invention includes the preparation of 1,4,7,10-tetraazacyclododecane.

A preferred embodiment starts from readily available benzylethanolamine, which is heated (80-150 ° C, preferably 90-110 ° C) with 1 to 1.4 equivalents of concentrated sulfuric acid in an organic solvent (e.g. toluene, cyclohexane, heptane, etc., concentration: 10-20%) and converted into the corresponding sulfuric acid ester by azeotropic distillation. The reaction takes 2 to 10 hours. The ester is then heated with 2 to 5 equivalents of aqueous lyes (e.g. NaOH, KOH) and the benzylaziridine formed therefrom is continuously azeotroped with water in a second reaction vessel, which first forms a closed system. The resulting aqueous benzylaziridine emulsion can, after dilution with an organic solvent (e.g., ethanol, methanol, THF), by continuously adding at least 0.25 to 0.4 mol (preferably 0.25 to 0.35 mol) of strong acid per mole of benzylaziridine (i.e. surprisingly, the equivalent amount of acid relative to the product) is completely converted to tetrabenzylcyclene.

As the organic solvent, for example, ethanol, methanol or tetrahydrofuran (THF) can be used. As a strong acid, para-toluenesulfonic acid (p-TsOH), methanesulfonic acid (MsOH), sulfuric acid or BF 3 etherate can be used.

The product is obtained after alkalization (0.2 to 0.5 equivalents of base, e.g. NaOH, KOH) of the reaction mixture by crystallization in polar solvents (e.g. THF, ethanol, acetone, isopropanol, diethyl ether, ethyl acetate, furan, dioxane, water or mixtures thereof) and then hydrogenated with the aid of a catalyst (Pd / C, 5 to 20% based on the tetrabenzylcyclene derivative, at a pressure of 0.1 to 2.0 MPa). After filtering the catalyst and distilling off the solvent, 1,4,7,10-tetraazacyclododecane is obtained in a yield of 45 to 60% of the total theoretical yield.

By analogy to this synthesis, an alkyl-substituted benzylethanolamine, for example L-2-benzylaminopropanol or L-2-benzylaminobutanol, can also be used to obtain cyclene derivatives having branching on ethylene bridges. In a preferred embodiment of this synthesis, (S) -1-benzyl-2-methyl-aziridine from L-2-benzylaminopropcinol is obtained analogously to the process described above.

3.1047 / H and without isolation, transforms to [2S- (2a, 5a, 8a, 11a)] - 2,5,8,11-tetramethyl-1,4,7,10-tetraaza (benzyl) -1,4,7 by tetramerization 10-tetraazacyclododecane, from which [2S- (2a, 5a, 8a, 11a)] - 2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane is obtained by hydrogenation.

The cyclotetramerization of the benzylaziridine derivatives of the invention differs from the prior art methods in that no isolation of the aziridine in pure form is necessary. The method thus described allows the process to be carried out in a closed system and thus avoids the risk to humans and the environment from cancer-causing aziridines.

In contrast to the known prior art cyclotetramerization of benzylaziridines, a stoichiometric amount (0.25 to 0.35 mol, relative to one acid) is used instead of a catalytic amount of acid (p-TsOH, MsOH, sulfuric acid, BF ₃ -etherate or trialkyl aluminum). mole of benzylaziridine).

When attempting to carry out the known process on a larger scale and thereby obtaining a larger amount of 1,4,7,10-tetraazacyclododecane, using only catalytic amounts of p-TsOH in converting the in situ benzylaziridine emulsion produced, only 12-25% of the theoretical yield was achieved. It has now surprisingly been found that by continuously adding from 0.25 to 0.35 equivalents of p-TsOH (relative to benzylaziridine) at 60-78 ° C for 6 to 9 hours of caseotropically distilled benzylaziridine emulsion, the yield was 1,4,7,7 10-tetrabenzyl-1,4,7,10-tetraazacyclododecane improved to 60-65% of the theoretical yield.

Further advantages of this process are in high overall yield and in small amounts of waste (sodium sulfate in the preparation of aziridine and toluene in hydrogenation) as compared to the known methods.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to illustrate the invention without limiting it.

Example 1

To a solution of 95 ml of benzylethanolamine in 690 ml of toluene is added 53 ml of concentrated sulfuric acid. The resulting suspension was heated to boiling for two hours. Water (14 ml),

The J47 / H formed is separated by means of a water separator. After cooling to 20 ° C, the reaction mixture is treated with 1300 ml of water, stirred for 10 minutes and the organic phase is separated. Immediately thereafter, the aqueous phase is added continuously to a solution of 92.2 g of NaOH in 95 ml of water prepared in the second reaction vessel. The reaction mixture is brought to reflux by heating. By distillation, 880 g of an aqueous N-benzylaziridine emulsion was distilled off into a third reaction vessel. The emulsion is mixed with 880 ml of ethanol and heated to 60 ° C. A solution of 38.0 g of p-TsOH in 19 ml of water was added via metering pump over 8 hours. After the addition was complete, the mixture was heated to reflux for two hours. Immediately thereafter, the reaction mixture was treated with a solution of 12.0 g of NaOH in 20 ml of water. The product thus formed is filtered and recrystallized from 600 ml of a 2: 1 mixture of ethanol - THF. The tetrabenzylcyclene (53 g) thus obtained was dissolved in 500 ml of isopropanol and hydrogenated with 10 g of Pd / C (10%) at 80 ° C and a H ₂ pressure of ₂₀ bar. After filtering off the catalyst, the reaction solution is concentrated and the product is recrystallized from toluene. 15.9 g (yield 55%) of cyclene are thus obtained in the form of colorless crystals. Mp 110-112 ° C.

Example 2 ml of benzylethanolamine was prepared as described in Example 1 with sulfuric acid and then with NaOH. The resulting aqueous N-benzylaziridine emulsion was mixed with 2.6 L of ethanol and heated to 50 ° C. To this was added a solution of 29.3 g of p-TsOH in 15 ml of water over 8 hours via a metering pump. After the addition was complete, the mixture was heated at reflux for two hours. Immediately thereafter, the reaction mixture was mixed with a solution of 9.5 g NaOH in 20 ml water. The product thus formed is filtered and recrystallized from 600 ml of a 2: 1 mixture of ethanol-THF. The tetrabenzylcyclene (55.7 g) thus obtained was dissolved in 500 ml of isopropanol and hydrogenated with 10 g of Pd / C (10%) at 80 ° C and a H ₂ pressure of ₂₀ bar. After filtering off the catalyst, the reaction mixture is concentrated and the product is recrystallized from toluene. 15.9 g (58% yield) of cyclene are thus obtained as colorless crystals. Mp 111-113 ° C.

Example 3

As in Example 1, only tetramerization was performed with 0.33 equivalents of methanesulfonic acid. Yield 52% cyclene. Mp 110-112 ° C.

Table 1 Comparative overview of reaction conditions and synthesis yields

31047 / H cyclone by cyclotetramerization of benzylaziridine

Conditions yield 0.03 eq. p-TsOH, 95% EtOH, sp. flow (analogue to lit. 1 *) 12-25% 0.33 eq. p-TsOH, 50% EtOH, 60-80 ° C (Ex. 1) 55% 0.25 eq. p-TsOH, 75% EtOH, 50-80 ° C (Ex. 2) 58% 0.33 eq. MsOH, 50% EtOH, 70 ° C (Ex. 3) 52%

* Lit. 1: J. Heterocyclic Chem. 1968, 305

Claims (5)

PATENT CLAIMS A process for the preparation of optionally alkyl-substituted cyclone derivatives by cyclotetramerization of optionally alkyl-substituted benzylaziridine derivatives, characterized in that the benzylaziridine derivative is prepared in situ from an optionally alkyl-substituted benzylethanolamine derivative by reaction with sulfuric acid and subsequent reaction of the corresponding benzyl sulfirate ester with isolation of the corresponding sulfuric acid ester. 0.25 to 0.35 mol of strong acid per mole of benzylaziridine derivative, this is tetramerized to a tetrabenzylcyclene derivative and then the benzyl groups are separated by catalytic hydrogenation. The method of claim 1, wherein the optionally alkyl-substituted cyclone derivative is 1,4,7,10-tetraazacyclododecane. 3. A process for the preparation of optionally alkyl-substituted tetrabenzylcyclene derivatives by cyclotetramerization of optionally alkyl-substituted benzylaziridine derivatives, characterized in that the benzylaziridine derivative is prepared in situ from the benzylethanolamine derivative by reaction with sulfuric acid followed by reaction of the corresponding sulfuric acid ester with sulfuric acid isolate 0.25 to 0.35 mol of strong acid per mole of benzylaziridine derivative, this tetramerizes to the cyclone derivative. A process according to claim 1 or 3, wherein the cyclone derivative is [2S- (2a, 5a, 8a, 11a)] - 2,5,8,11-tetramethyl-1,4,7,10-tetraazacycllo -Dodecane. Process according to claim 1 or 3, characterized in that the acid used is para-toluenesulfonic acid, methanesulfonic acid or sulfuric acid.