Process for the production of C-substituted diethylenetriamines

Details Process for the production of C-substituted diethylenetriamines Process for the production of C-substituted diethylenetriamines

1995-10-12

1997-08-05

Raymond, Richard L.

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

Organic compounds

Carboxylic acid esters

560 32, 560115, 560159, 561368, 561369, 561447, 561468, 561478, 561512, C07C26906, C07C27120

Patent

active

056544677

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/00034, filed Jan. 8, 1994.
The invention relates to the object characterized in the claims, i.e., a process for the production of C-substituted diethylenetriamines.
In the literature, various processes to synthesize C-substituted diethylenetriamines are described, which all proceed according to the same basic system [see, e.g., Inorganic Chem. 25 (1986) 2772; DE 37 10 730; U.S. Pat. No. 4,622,420; Nucl. Med. Biol. (1991) 313; WO 91/14459]. In this connection, an amino acid ester with a free or protected amino group is reacted with ethylenediamine to the corresponding amide. Then, the amide is reduced with diborane to amine, and optionally present protective groups can be cleaved beforehand.
This method is subject to the following drawbacks:
a) A large borane excess (5-10 molar equivalents) is necessary, since the amide to be reduced is secondary and still contains two free amino groups.
b) The intermediate stages are poorly crystallizable and difficult to purify.
c) Because of the toxicity and the high price of the borane, this process is not suitable for use on an industrial scale or is at least economically unprofitable because of the high safety expense to be borne.
d) Very long reaction times as well as high reaction temperatures are necessary (18-30 hours in the boiling heat).
Attempts to replace the diborane by other, more easily manageable reducing agents, such as, e.g., lithium aluminum hydride (LAH) or diisobutylaluminum hydride (DIBAH), came to nothing. Complex reaction mixtures thus result in the case of LAH. But DIBAH cannot be used universally either, thus, e.g., phenolether groups optionally contained in the molecule (as C-substituent) are cleaved.
Therefore, there still exists a great interest in a technically feasible, universally applicable process for the production of C-substituted diethylenetriamines, all the more so as said substances are important feedstocks for the production of derivatized diethylenetriaminepentaacetic acids, which just as the diethylenetriamines themselves are an important family of substances in the pharmaceutical industry [see, e.g., U.S. Pat. No. 4,622,420; Inorg. Chem. 25 (1986) 2772; EP 0 405 704; Nucl. Mol. Biol. (1991) 31 ].
Thus, especially metal complexes of the pentaacetic acid derivatives are important compounds for the production of contrast media in the field of diagnosis (EP 0 405 704).
The object of the invention is therefore to provide a generally applicable process for the production of C-substituted diethylenetriamines that surmounts the drawbacks of the prior art and especially manages without the use of the expensive and toxic diborane.
This object is achieved by the process, according to the invention, for the production of carbon-substituted diethylenetriamines of general formula I ##STR2## in which R.sup.1 stands for a group --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n--(C.sub.6 H.sub.4).sub.l --(O).sub.r --R or for a group --(CH.sub.2).sub.m --(C.sub.6 H.sub.10).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.10).sub.l --(O).sub.r --R, -substituted C.sub.1 -C.sub.6 alkyl radical or a CH.sub.2 -COOR.sup.5 group, benzyl group, --(CH.sub.2).sub.p -alkylene bridge, benzyloxycarbonyl group, which is characterized in that an aminoethylalcohol, protected on the nitrogen, of general formula II ##STR3## in which R.sup.1 and R.sup.4 have the indicated meanings, is reacted with methanesulfonic acid chloride, tosyl chloride or trifluoroacetic anhydride in an organic solvent, by adding a base, to the corresponding mesylate, tosylate or triflate, is then filtered and the filtrate is reacted with an ethylenediamine of general formula III ##STR4## in which R.sup.2 and R.sup.3 have the indicated meanings to the desired nitrogen-protected, carbon-substituted triamine of general formula I.
The process according to the invention thus starts from easily accessible nitrogen-protected aminoethyl alcohols, which are first reacted with methanesulfonic acid chloride, toluenesulfonic acid chlor

REFERENCES:
patent: 2364178 (1944-12-01), Wilson
patent: 3236895 (1966-02-01), Lee et al.

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