Preparation of n-arylmethyl aziridine derivatives,...

Details Preparation of n-arylmethyl aziridine derivatives,... Preparation of n-arylmethyl aziridine derivatives,...

2000-04-10

2001-09-11

Stockton, Laura L. (Department: 1626)

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

Organic compounds

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

Reexamination Certificate

active

06288224

ABSTRACT:

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-benzyl-aziridine.
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. 3,82,8,023) 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).
Aryimethyl 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-azirdne tetramerizarion 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:
(C
6
H
5
)
3
P+CCl
4
+N(C
2
H
5
)
3
+C
6
H
5
CH
2
NHCH
2
CH
2
OH→(C
6
H
5
)
3
PO+CHCl
3
+HN(C
2
H
5
)
3
Cl+C
6
H
5
CH
2
—N
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
6
H
5
)
3
PO and HN(C
2
H
5
)
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° 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:
This reaction however gave only a very poor yield of 18%.
In 1969, Lanclois et al in Tetrahedron Letters 25: 2085-2088 (1969) reported a two-step synthesis from benzylamine:
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 aziridine as a starting material is highly undesirable. Thus the entry for aziridine in The Merck Index, 11th Edition, page 600, 1989 carries the caution “Strongly irritating to eyes, skin, mucous membranes. Can be a skin sensitizer. This substance has been listed as a carcinogen by OHSA. Fed. Reg. 39, 3757 (1974).”
Thus there is a need for a simpie, environmentally acceptable and yet good yield process for N-arylmethylaziridine production which will yield a product suitable for use in a cyclo-tetramerization reactions to yield tetra(arylmethyl)cyclen.
We have now found that such a process is provided by the treatment of a purified N-(arylmethyl)ethanolamine-sulphonate ester with a base. The sulphonate ester itself can be prepared by treatment of an N-arylmethylethanolamine with sulphuric acid and this optionally is an initial step in the process of the invention.
Thus, viewed room one aspect, the invention provides a process for the preparation of an N-aryimethyl-aziridine of formula I
Ar—C(R
1
)
2
—N
  (I)
(where each R
1
independently is hydrogen or a group Ar and Ar is an optionally substituted phenyl group), said process comprising reacting a purified N-arylmethylethanolamine-sulphonate ester with a base.
In the N-arylmethyl-aziridines prepared according to the invention, preferably one R
1
group is hydrogen, and especially preferably both are hydrogen. Particularly preferably, the product of the process of the invention will be N-benzyl-aziridine or N-benzhydryl-aziridine, the compounds of formula I where Ar is an unsubstituted phenyl group.
As mentioned above, the process of the invention optionally includes the precursor step of generation of the sulphonate ester by reaction of an N-arylmethylethanolamine with sulphuric acid. The N-arylmethyethanolamine starting compound if not available commercially can readily be prepared by reaction of the corresponding arylmethylamine with 2-chloroethan-1-ol.
The N-(bisarylmethyl)-ethanolamine sulphonate esters and the N-(triarylmethyl)-ethanolamine sulphonate esters are themselves novel compounds and form a further aspect of the present invention.
Generation of the sulphonate ester is preferably carried out in a solvent, for example water at a temperature in the range 80 to 150° C., for example 50 to 100° C. The acid concentration used is preferably 7.25 to 8 molar, especially about 7.7 molar and the acid and N-(arylmethyl)ethanolamine reagents are conveniently used in a molar ratio of about 1:1. The reaction is relatively rapid, and may take only a matter of seconds to yield the sulphonate ester.
Where the ester is to be isolated (i.e. purified) before reaction with the base, this may be done by softening the solid mass with ethanol, grinding with ethanol, filtering and drying. In this way yields of 74% of a very pure product have been obtained.
Isolation of the sulphonate ester is straightforward since the ester precipitates out of aqueous solution.
The base used in the process of the present invention may be an organic or inorganic base, preferably an alkali metal hydroxide such as sodium hydroxide.
Reaction with the base is preferably effected in a solvent or solvent mixture, e.g. water. Solutions of the base and the sulphonate ester may be rapidly mixed to produce a reaction mixture. The reaction is conveniently effected at elevated temperature, e.g. 50 to 150° C., especially about 80° C., and for a period of 1 to 5 hours, particularly 2 to 3 hours.
The N-arylmethyl-aziridine product can be taken up in an organic solvent such as ether and subsequently isolated by solvent distillation, preferably in the presence of an acid neutralizing agent, e.g. KOH pellets.
Since the stability of the N-arylmethyl-aziridine seems to be reduced by the presence of N-arylmethylethanolamine, it is important that the product should be distilled carefully and stored over an acid neutralizing agent (preferably KOH) if it is not

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