Preparation of N-arylmethyl aziridine derivatives, 1,4,7,10-tetr

Details Preparation of N-arylmethyl aziridine derivatives, 1,4,7,10-tetr Preparation of N-arylmethyl aziridine derivatives, 1,4,7,10-tetr

1997-12-02

2000-04-11

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

548968, 548969, 548955, C07D25502, C07D20306, C07D20314

Patent

active

060489790

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a novel process for the preparation of N-arylmethyl-aziridines, in particular N-benzyl-aziridine and N-benzhydryl-aziridine, and to the use of such aziridines.
In the field of magnetic resonance imaging, various lanthanide chelates of cyclen-derivative macrocyclic chelating agents have been proposed. Two, GdHP-DO3A (ProHance from Squibb) and GdDOTA (Dotarem from Guerbet), are available commercially. These macrocyclic chelating agents form particularly stable chelate complexes with the contrast-generating paramagnetic metal ions and thus are suitable carriers for the metal ions to ensure appropriate biodistribution and elimination.
Cyclen itself (1,4,7,10-tetraazacyclododecane) is a key and somewhat expensive intermediate in the preparation of these macrocyclic chelants.
Cyclen's tetraaza macrocycle can be prepared by a variety of synthetic routes, for example via diamine:diamine or triamine:monoamine cyclic condensations such as are described by Tweedle in EP-A-232751 and EP-A-292689. However in 1968 Hansen et al reported that tetrabenzylcyclen could be produced in good yield by cyclo-tetramerization of N-benzylaziridine.
The reaction described by Hansen et al in J. Heterocycl. Chem 5:305 (1968) involved refluxing a mixture of 10 g of N-benzyl-aziridine and 0.05 g of p-toluenesulphonic acid (PTSA) in 75 ml of 95% alcohol for six hours.
Cornier et al (in U.S. Pat. No. 3,828,023) and Ham (in a chapter entitled "Polymerization of Aziridines" in "Polymeric Amines and Ammonium Salts", Ed. Goethels, Pergamon, 1980) confirmed that cyclo-tetramerization of arylmethyl-aziridines occurs. Tsukube in J. Chem. Soc. Perkin Trans I 1983, 29-35 reported high yields for tetra-N-benzyl-cyclen using acid-catalysed cyclotetramerization of N-benzyl-aziridine using the reaction conditions of Hansen (supra).
Arylmethyl groups, such as benzyl groups, are frequently used as protecting groups in organic syntheses and selective removal of such groups represents straightforward chemistry. Since in this fashion the ring nitrogens of a tetra-(N-arylmethyl)-cyclen can be "deprotected" to yield cyclen, N-arylmethyl-aziridine tetramerization offers a simple and attractive route in the preparation of macrocyclic chelating agents for use in diagnostic contrast agents.
Several methods for the production of the N-arylmethyl-aziridine starting materials are known in the literature. Thus Appel et al in Chem Ber 107:5-12 (1974) describe the reaction of N-benzylethanolamine with triethylamine, carbon tetrachloride and triphenylphosphine: ##STR2##
Appel et al reported a yield of 66% for this reaction. However repeating the process using N-benzylethanolamine supplied by Aldrich, yields of only 39 to 45% were obtained. The best results were obtained when extra extraction steps were employed and the crude extract solution was combined with solid KOH before and during the rotary evaporation. The Appel process moreover has a number of severe disadvantages, including (1) the generation of large quantities of (C.sub.6 H.sub.5).sub.3 PO and HN(C.sub.2 H.sub.5).sub.3 Cl as by-products, (2) the use of carbon tetrachloride a material becoming increasingly expensive and difficult to use as a result of environment protection regulations, and (3) the lengthy reaction time of 14 hours, the necessity for temperature control at 12.degree. C. during cyclization and the overall synthesis and work up time of about three days.
Pfister, in Synthesis 969-970 (1984), described a one-pot synthesis involving reaction of N-benzylethanolamine, triphenylphosphine and diethylazodicarboxylate: ##STR3##
This reaction however gave only a very poor yield of 18%.
In 1969, Langlois et al in Tetrahedron Letters 25:2085-2088 (1969) reported a two-step synthesis from benzylamine: ##STR4##
Again however the yield at 45% was poor.
In U.S. Pat. No. 3,855,217 Thill proposed the production of N-benzyl-aziridine by the reaction of aziridine itself with a benzyl halide. The same process was reported by Tsukube (supra). While the reported yields were good, the use of

REFERENCES:
patent: 3828023 (1974-08-01), Cornier et al.
patent: 4093615 (1978-06-01), Ham et al.
Hansen et al., The Unique Synthesis of . . . , J. Heterocyclic Chem., 5: 305, Dec. 1968.
518. Cyclic imines from aminoalcohols, in: "Synthetic Methods of Organic Chemistry,", vol. 6 (Theilheimer W., Ed.), 1952, pp. 186-187.
Aliev et al., European Polymer Journal, vol. 16, No. 8, Jan. 1, 1980, pp. 679-688.
Goethals et al., Polymer Bulletin, vol. 6, No. 11/12, 1981, pp. 121-126.
Deyrup, Aziridines, chapter I, in: Small ring heterocycles, part 1, aziridines, azirines, thiiranes, thiirenes (Hassner, A., Ed.), 1983, Interscience, pp. 11-13.
Backes, Aziridine, in: "Methoden der organischen Chemie (Houben-Weyl) Band E16c Organische Stickstoff-Verbindungen III" (Klamann, D., Ed.), 1992, Georg Thieme Verlag, pp. 394-397.
Hansen et al., Journal of Heterocyclic Chemistry, vol. 5, No. 2, Apr. 1968, p. 305.
Brunner et al., Supramolecular Chemistry, vol. 2, No. 2-3, 1993, pp. 103-110.
Kuschmiers et al., Chemical Abstracts, vol. 101, No. 8, Aug. 20, 1984, abstract No. 63594w.

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